[Federal Register Volume 62, Number 7 (Friday, January 10, 1997)]
[Rules and Regulations]
[Pages 1494-1619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-198]
[[Page 1493]]
_______________________________________________________________________
Part II
Department of Labor
_______________________________________________________________________
Occupational Safety and Health Administration
_______________________________________________________________________
29 CFR Parts 1910, 1915 and 1926
Occupational Exposure to Methylene Chloride; Final Rule
Federal Register / Vol. 62, No. 7 / Friday, January 10, 1997 / Rules
and Regulations
[[Page 1494]]
DEPARTMENT OF LABOR
Occupational Safety and Health Administration
29 CFR Parts 1910, 1915 and 1926
RIN 1218-AA98
Occupational Exposure to Methylene Chloride
AGENCY: Occupational Safety and Health Administration (OSHA),
Department of Labor.
ACTION: Final rule.
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SUMMARY: The Occupational Safety and Health Administration (OSHA)
hereby amends its existing regulations for employee exposure to
methylene chloride (MC), (also known as methylene dichloride,
dichloromethane or DCM). OSHA has determined, based on animal and human
data, that the current permissible exposure limits (PELs) allow
employee exposure to a significant risk of material impairment of
health. OSHA is reducing the existing 8-hour time-weighted average
(TWA) exposure from 500 parts MC per million parts (ppm) of air to 25
ppm. Also, OSHA is deleting the existing ceiling limit concentration of
1,000 ppm and is reducing the existing short-term exposure limit from
2,000 ppm (measured over five minutes in any 2 hour period) to 125 ppm,
measured as a 15-minute TWA. In addition, the Agency is setting an
``action level'' of 12.5 ppm, measured as an 8-hour TWA. The final rule
also contains provisions for exposure control, personal protective
equipment, employee exposure monitoring, training, medical
surveillance, hazard communication, regulated areas, and recordkeeping.
Together, these provisions will substantially reduce significant risk
to the extent feasible. This standard applies to all employment in
general industry, shipyards and construction. Small employers, for
purposes of the Regulatory Flexibility Act, 5 U.S.C. 601, are defined
as firms with fewer than twenty employees. The final standard will
prevent an estimated 31 cancer deaths per year and an estimated three
deaths per year from acute central nervous system and
carboxyhemoglobinemic effects, and will also reduce cardiovascular
disease and material impairment of the central nervous system. The
estimated cost, on an annualized basis, is $101 million per year.
DATES: This final rule becomes effective April 10, 1997.
Compliance: Start-up dates for specific provisions are set in
Sec. 1910.1052(n) of the regulatory text. However, affected parties do
not have to comply with the information collection requirements in
Sec. 1910.1052(d) exposure monitoring, Sec. 1910.1052(e) regulated
areas, Sec. 1910.1052(j) medical surveillance, Sec. 1910.1052(l)
employee information and training; and Sec. 1910.1052(m) recordkeeping,
until the Department of Labor publishes in the Federal Register the
control numbers assigned by the Office of Management and Budget (OMB).
Publication of the control numbers notifies the public that OMB has
approved these information collection requirements under the Paperwork
Reduction Act of 1995.
Comments: Interested parties may submit comments on the information
collection requirements for this standard until March 11, 1997.
ADDRESSES: In compliance with 28 U.S.C. 2112(a), the Agency designates
the Associate Solicitor for Occupational Safety and Health, Office of
the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution
Avenue, NW., Washington, D.C. 20210, as the recipient of petitions for
review of the standard.
Comments on the paperwork requirements of this final rule are to be
submitted to the Docket Office, Docket No. ICR96-15, U.S. Department of
Labor, Room N-2625, 200 Constitution Ave., NW., Washington D.C. 20210,
telephone (202) 219-7894. Written comments limited to 10 pages or less
in length may also be transmitted by facsimile to (202) 219-5046.
Copies of the referenced information collection request are
available for inspection and copying in the Docket Office and will be
mailed immediately to persons who request copies by telephoning Vivian
Allen at (202) 219-8076. For electronic copies of the Methylene
Chloride Final Standard and the Information Collection Request, contact
OSHA's WebPage on Internet at http://www.osha.gov/.
FOR FURTHER INFORMATION CONTACT: Bonnie Friedman, Director, OSHA Office
of Public Affairs, Room N-3647, U.S. Department of Labor, 200
Constitution Avenue, NW, Washington, D.C. 20210; Telephone (202) 219-
8148.
SUPPLEMENTARY INFORMATION:
Collections of Information: Comment Request
The Department of Labor, as part of its continuing effort to reduce
paperwork and respondent burden, conducts a preclearance consultation
program to provide the general public and Federal agencies with an
opportunity to comment on proposed and/or continuing collections of
information in accordance with the Paperwork Reduction Act of 1995
(PRA95) (44 U.S.C. 3506(c)(2)(A)). This program helps to ensure that
requested data can be provided in the desired format, reporting burden
(time and financial resources) is minimized, collection instruments are
clearly understood, and the impact of collection requirements on
respondents can be properly assessed. Currently, OSHA is soliciting
comments concerning the proposed approval for the paperwork
requirements of the Methylene Chloride Final Standard. Written comments
should:
Evaluate whether the proposed collection of information is
necessary for the proper performance of the functions of the agency,
including whether the information will have practical utility;
Evaluate the accuracy of the agency's estimate of the
burden of the proposed collection of information, including the
validity of the methodology and assumptions used;
Enhance the quality, utility, and clarity of the
information to be collected; and
Minimize the burden of the collection of information on
those who are to respond, including through the use of appropriate
automated, electronic, mechanical, or other technological collection
techniques or other forms of information technology, e.g., permitting
electronic submissions of responses.
Background: The Methylene Chloride Standard and its information
collection requirements are designed to provide protection for
employees from adverse health effects associated with occupational
exposure to MC. The standard requires employers to monitor employee
exposure to MC and inform employees of monitoring results. If
monitoring results are above the 8-hour TWA PEL or the STEL, then
employers must also inform employees of the corrective action that will
be taken to reduce employee exposure to or below the 8-hour PEL or
STEL. Employers may also be required to provide medical surveillance to
employees who are or may be exposed to MC. Employers are also required
to provide information and training to employees on the following:
health effects of MC, specifics regarding use of MC in the workplace,
the contents of the standard, and means the employee can take to
protect themselves from overexposure to MC.
Current Actions: This notice requests public comment on the
paperwork requirements in the Methylene Chloride Final Standard. The
Agency previously sought clearance on three Methylene
[[Page 1495]]
Chloride Notice of Proposed Rulemaking Information Collection Requests:
Shipyards, 1218-0177; Construction, 1218-0178; and General Industry,
1218-0179. Since the information requirements are identical for each
industry, the Agency has combined these three packages into one
entitled Methylene Chloride Sec. 1910.1052, OMB number 1218-0179.
Type of Review: Revision of a currently approved collection.
Agency: Occupational Safety and Health Administration.
Title: Methylene Chloride Sec. 1910.1052.
OMB Number: 1218-0179.
Agency Number: Methylene Chloride Docket Number H-71.
Recordkeeping: Employers must maintain employee medical records for
at least the duration of employment plus thirty years. Employee
exposure monitoring records must be maintained for at least 30 years.
Objective data, data showing that any materials in the workplace
containing MC will not release MC at levels which exceed the action
level or the STEL under foreseeable condition of exposures, must be
maintained as long as the employer is relying on the data in support of
the initial monitoring exemption.
Affected Public: Business or other for-profit, Federal government,
State and Local governments.
Total Respondents: 92,000.
Frequency: On Occasion.
Total Responses: Initial 719,948; Recurring 299,620.
Average Time per Response: 0.26 hour.
Estimated Total Burden Hours: Initial 188,728; Recurring 74,299.
Estimated Total Burden Cost: Initial $32,496,380; Recurring
$12,282,420.
Comments submitted in response to this notice will be summarized
and/or included in the request for the Office of Management and Budget
approval of the information collection request; they will also become a
matter of public record.
Federalism
This standard has been reviewed in accordance with Executive Order
12612, 52 FR 41685 (October 30, 1987), regarding Federalism. This Order
requires that agencies, to the extent possible, refrain from limiting
State policy options, consult with States prior to taking any actions
that would restrict State policy options, and take such actions only
when there is a clear constitutional authority and the presence of a
problem of national scope. The Order provides for preemption of State
law only if there is a clear Congressional intent for the Agency to do
so. Any such preemption is to be limited to the extent possible.
Section 18 of the Occupational Safety and Health Act (OSH Act),
expresses Congress' clear intent to preempt State laws with respect to
which Federal OSHA has promulgated occupational safety or health
standards. Under the OSH Act, a State can avoid preemption only if it
submits, and obtains Federal approval of, a plan for the development of
such standards and their enforcement. Occupational safety and health
standards developed by such State Plan-States must, among other things,
be at least as effective in providing safe and healthful employment and
places of employment as the Federal standards. Where such standards are
applicable to products distributed or used in interstate commerce, they
may not unduly burden commerce and must be justified by compelling
local conditions (See section 18(c)(2)).
The final MC standard is drafted so that employees in every State
will be protected by general, performance-oriented standards. States
with occupational safety and health plans approved under section 18 of
the OSH Act will be able to develop their own State standards to deal
with any special problems which might be encountered in a particular
state. Moreover, the performance nature of this standard, of and by
itself, allows for flexibility by States and employers to provide as
much leeway as possible using alternative means of compliance.
This final MC rule addresses a health problem related to
occupational exposure to MC which is national in scope.
Those States which have elected to participate under section 18 of
the OSH Act would not be preempted by this regulation and will be able
to deal with special, local conditions within the framework provided by
this performance-oriented standard while ensuring that their standards
are at least as effective as the Federal Standard.
State Plans
The 23 States and two territories with their own OSHA-approved
occupational safety and health plans must adopt a comparable standard
within six months of the publication of this final standard for
occupational exposure to methylene chloride or amend their existing
standards if it is not ``at least as effective'' as the final Federal
standard. The states and territories with occupational safety and
health state plans are: Alaska, Arizona, California, Connecticut (for
State and local government employees only), Hawaii, Indiana, Iowa,
Kentucky, Maryland, Michigan, Nevada, New Mexico, New York (for State
and local government employees only), North Carolina, Oregon, Puerto
Rico, South Carolina, Tennessee, Utah, Vermont, Virginia, the Virgin
Islands, Washington, and Wyoming. Until such time as a State standard
is promulgated, Federal OSHA will provide interim enforcement
assistance, as appropriate, in these states and territories.
Unfunded Mandates
The MC final rule has been reviewed in accordance with the Unfunded
Mandates Reform Act of 1995 (UMRA) (2 U.S.C. 1501 et seq.) and
Executive Order 12875. As discussed below in the Summary of the Final
Economic Analysis (FEA) (Section VIII of this document), OSHA estimates
that compliance with the revised MC standard will require the
expenditure of slightly more than $100 million each year by employers
in the private sector. Therefore, the MC final rule establishes a
federal private sector mandate and is a significant regulatory action,
within the meaning of Section 202 of UMRA (2 U.S.C. 1532). OSHA has
included this statement to address the anticipated effects of the MC
final rule pursuant to Section 202.
OSHA standards do not apply to state and local governments, except
in states that have voluntarily elected to adopt an OSHA State Plan.
Consequently, the MC standard does not meet the definition of a
``Federal intergovernmental mandate'' (Section 421(5) of UMRA (2 U.S.C.
658(5)). In addition, the Agency has concluded, based on review of the
rulemaking record, that few, if any, of the affected employers are
state, local and tribal governments. Further, OSHA has found that any
impact on such entities would be insignificant. In sum, the MC standard
does not impose unfunded mandates on state, local and tribal
governments.
The anticipated benefits and costs of this final standard are
addressed in the Summary of the FEA (Section VIII of this document),
below, and in the FEA [Ex. 129]. In addition, pursuant to Section 205
of the UMRA (2 U.S.C. 1535), having considered a reasonable number of
alternatives as outlined in this Preamble and in the FEA [Ex. 129], the
Agency has concluded that the final rule is the most cost-effective
alternative for implementation of OSHA's statutory objective of
reducing significant risk to the extent feasible. This is discussed at
length in the FEA [Ex. 129] and in the Summary and Explanation (Section
X of
[[Page 1496]]
this document) for the various provisions of the MC standard.
I. General
The preamble to the final rule on occupational exposure to
Methylene Chloride (MC) discusses the events leading to the final rule,
the physical and chemical properties of MC, the health effects of
exposure, the degree and significance of the risk presented by MC
exposure, the Final Economic Analysis and Regulatory Flexibility
Analysis, and the rationale behind the specific provisions set forth in
the final standard. The discussion follows this outline:
I. General
II. Pertinent Legal Authority
III. Events Leading to the Final Standard
IV. Chemical Identification
V. Health Effects
VI. Quantitative Risk Assessment
VII. Significance of Risk
VIII. Summary of the Final Economic Analysis
IX. Environmental Impact
X. Summary and Explanation of the Final Standard
A. Scope and Application
B. Definitions
C. Permissible Exposure Limits
D. Exposure Monitoring
E. Regulated Areas
F. Methods of Compliance
G. Respiratory Protection
H. Protective Clothing and Equipment
I. Hygiene Facilities
J. Medical Surveillance
K. Hazard Communication
L. Employee Information and Training
M. Recordkeeping
N. Dates
O. Appendices
XI. Authority and Signature
XII. Final Rule and Appendices
Appendix A: Substance Safety Data Sheet and Technical Guidelines for
Methylene Chloride
Appendix B: Medical Surveillance for Methylene Chloride
Appendix C: Questions and Answers--Methylene Chloride Control in
Furniture Stripping
II. Pertinent Legal Authority
The purpose of the Occupational Safety and Health Act, 29 U.S.C.
651 et seq. (``the Act'') is to ``assure so far as possible every
working man and woman in the nation safe and healthful working
conditions and to preserve our human resources.'' 29 U.S.C.
Sec. 651(b). To achieve this goal, Congress authorized the Secretary of
Labor to promulgate and enforce occupational safety and health
standards. U.S.C. Secs. 655(a) (authorizing summary adoption of
existing consensus and federal standards within two years of the Act's
enactment), 655(b) (authorizing promulgation of standards pursuant to
notice and comment), 654(b) (requiring employers to comply with OSHA
standards.)
A safety or health standard is a standard ``which requires
conditions, or the adoption or use of one or more practices, means,
methods, operations, or processes, reasonably necessary or appropriate
to provide safe or healthful employment or places of employment.'' 29
U.S.C. Sec. 652(8).
A standard is reasonably necessary or appropriate within the
meaning of Section 652(8) if it substantially reduces or eliminates
significant risk, and is economically feasible, technologically
feasible, cost effective, consistent with prior Agency action or
supported by a reasoned justification for departing from prior Agency
actions, supported by substantial evidence, and is better able to
effectuate the Act's purposes than any national consensus standard it
supersedes. See 58 FR 16612-16616 (March 30, 1993).
The Supreme Court has noted that a reasonable person would consider
a fatality risk of 1/1000 to be a significant risk, and would consider
a risk of one in one billion to be insignificant. Industrial Union
Department v. American Petroleum Institute, 448 U.S. 607, 646 (1980)
(the ``Benzene decision''). So a risk of 1/1000 (10-3) represents
the uppermost end of a million-fold range suggested by the Supreme
Court, somewhere below which the boundary of acceptable versus
unacceptable risk must fall. The Court further stated that ``while the
Agency must support its findings that a certain level of risk exists
with substantial evidence, we recognize that its determination that a
particular level of risk is significant will be based largely on policy
considerations.'' See, e.g., International Union, UAW v. Pendergrass,
878 F.2d 389 (D.C. Cir. 1989) (formaldehyde standard); Building and
Constr. Trades Department, AFL-CIO v. Brock, 838 F.2d 1258, 1265 (D.C.
Cir. 1988) (asbestos standard).
A standard is technologically feasible if the protective measures
it requires already exist, can be brought into existence with available
technology, or can be created with technology that can reasonably be
expected to be developed. American Textile Mfrs. Institute v. OSHA 452
U.S. 490, 513 (1981) (``ATMI ''), American Iron and Steel Institute v.
OSHA, 939 F.2d 975, 980 (D.C. Cir 1991) (``AISI '').
A standard is economically feasible if industry can absorb or pass
on the cost of compliance without threatening its long term
profitability or competitive structure. See ATMI, 452 U.S. at 530 n.
55; AISI, 939 F. 2d at 980.
A standard is cost effective if the protective measures it requires
are the least costly of the available alternatives that achieve the
same level of protection. ATMI, 453 U.S. at 514 n. 32; International
Union, UAW v. OSHA, 37 F. 3d 665, 668 (D.C. Cir. 1994) (``LOTO III '').
All standards must be highly protective. See 58 FR 16614-16615;
LOTO III, 37 F. 3d at 668. However, health standards must also meet the
``feasibility mandate'' of Section 6(b)(5) of the Act, 29 U.S.C.
655(b)(5). Section 6(b)(5) requires OSHA to select ``the most
protective standard consistent with feasibility'' that is needed to
reduce significant risk when regulating health hazards. ATMI, 452 U.S.
at 509.
Section 6(b)(5) also directs OSHA to base health standards on ``the
best available evidence,'' including research, demonstrations, and
experiments. 29 U.S.C. Sec. 655(b)(5). OSHA shall consider ``in
addition to the attainment of the highest degree of health and safety
protection * * * the latest scientific data * * * feasibility and
experience gained under this and other health and safety laws.'' Id.
Section 6(b)(7) of the Act authorizes OSHA to include among a
standard's requirements labeling, monitoring, medical testing and other
information gathering and transmittal provisions. 29 U.S.C.
Sec. 655(b)(7).
III. Events Leading to the Final Standard
The present OSHA standard for MC requires employers to ensure that
employee exposure does not exceed 500 ppm as an 8-hour TWA, 1000 ppm as
a ceiling concentration, and 2000 ppm as a maximum peak for a period
not to exceed five minutes in any two hours (29 CFR 1910.1000, Table Z-
2). This standard was adopted by OSHA in 1971 pursuant to section 6(a)
of the OSH Act, 29 U.S.C. 655, from an existing Walsh-Healey Federal
Standard. The source of this Walsh-Healey Standard [Ex. 7-1] was the
American National Standards Institute (ANSI) standard for acceptable
concentrations of MC (ANSI-Z37.23-1969), which was intended to protect
workers from injury to the neurological system including loss of
awareness and functional deficits linked to anesthetic and irritating
properties of MC which had been observed from excessive, acute or large
chronic exposures to MC in humans and experimental animals.
In 1946, the American Conference of Governmental Industrial
Hygienists (ACGIH) recommended a Threshold Limit Value (TLV) of 500 ppm
for MC [Ex. 2]. In 1975, the ACGIH lowered the
[[Page 1497]]
recommended TLV to 100 ppm [Ex. 7-11].
In March 1976, the National Institute for Occupational Safety and
Health (NIOSH) published ``Criteria for a recommended standard for
Methylene Chloride'' [Ex. 2], which recommended a reduction of
occupational exposures to MC to 75 ppm as an 8-hour TWA, and a lower
peak exposure not to exceed 500 ppm. Further exposure reduction based
on the ambient level of carbon monoxide was also recommended.
In February 1985, the National Toxicology Program (NTP) reported
the final results of animal studies indicating that MC is a potential
cancer causing agent [Ex. 7-8]. Subsequently, the U.S. Environmental
Protection Agency (EPA), upon receipt of the NTP studies, initiated a
risk assessment evaluation to determine whether or not MC presents an
unreasonable risk to human health or the environment and to determine
if regulatory actions are needed to eliminate or reduce exposures.
On May 14, 1985, EPA announced its determination that MC was a
probable human carcinogen. EPA classified MC as Group B2, in accordance
with its interim guidelines for cancer risk (49 FR 46294), and hence
announced the initiation of a 180-day priority review (50 FR 20126)
under section 4(f) of the Toxic Substances Control Act (TSCA). In
meeting its mandate under section 4(f) of TSCA to initiate a regulatory
action, on October 17, 1985, EPA published an Advance Notice of
Proposed Rulemaking (ANPR) (50 FR 42037) for the purpose of collecting
the necessary information required for initiating a rulemaking. In this
notice, EPA established December 16, 1985, as its deadline for
receiving comments.
On April 11, 1985, the U.S. Consumer Product Safety Commission
(CPSC) released its risk assessment findings for MC and began to
consider a regulatory action to ban MC containing products and to
develop a voluntary hazard communication program for consumers.
On December 18, 1985, the U.S. Food and Drug Administration (FDA)
published a proposal to ban the use of MC as an ingredient in aerosol
cosmetic products (50 FR 51551). This proposal was based on a risk
assessment that used the NTP animal data.
On July 19, 1985, Owen Bieber, President of International Union,
United Automobile, Aerospace and Agricultural Implement Workers of
America (UAW), petitioned OSHA to act expeditiously on reducing
workers' exposure to MC. Specifically, Mr. Bieber requested that OSHA:
(1) Publish a hazard alert; (2) issue an emergency temporary standard
(ETS); and (3) begin work on a new permanent standard for controlling
MC exposure. Subsequently, the following unions joined UAW in
petitioning OSHA to act on revising the current standard:
A. International Union, Allied Industrial Workers of America;
B. Glass, Pottery, Plastics and Allied Workers International Union;
C. United Furniture Workers of America;
D. The Newspaper Guild;
E. Communication Workers of America; and
F. United Steelworkers of America.
In March 1986, as a preliminary response to this petition, OSHA
issued ``Guidelines for Controlling Exposure to Methylene Chloride.''
That document, which was canceled by OSHA Notice ADM 8 (July 12, 1994),
provided information to employers and workers on risks of MC exposure
and methods for controlling such exposure [Ex. 8-11].
In April 1986, NIOSH published a Current Intelligence Bulletin #46
(CIB) on MC reflecting the findings of the NTP study [Ex. 8-26]. The
CIB concluded that MC should be regarded as a potential occupational
carcinogen and that exposure should be controlled to the lowest
feasible level.
On August 20, 1986, the CPSC issued a proposed rule [51 FR 29778]
``that would declare household products containing other than
contaminant levels of MC to be hazardous substances.'' The CPSC noted
the proposal was prompted by evidence that inhalation of MC vapor
increased the incidence of various malignant and benign tumors in rats
and mice. Accordingly, the Commission proposed to require that
household products which can expose consumers to MC vapor be treated as
hazardous substances and be labeled as provided by section 2(p)(1) of
the Federal Hazardous Substances Act (FHSA) (15 U.S.C. 1261(p)(1)). The
FHSA requires the use of labels which (1) indicate that exposure to a
product may present a cancer risk; (2) explain the factors (such as
level and duration of exposure) that control the degree of risk; and
(3) explain the precautions to be taken.
On November 17, 1986, OSHA denied the petition for an Emergency
Temporary Standard, but agreed that work on a permanent standard should
commence [Ex. 3A]. On November 24, 1986, OSHA announced, in an Advance
Notice of Proposed Rulemaking (ANPR) [51 FR 42257], that it was
considering revision of the occupational health standard for MC. The
Agency based this action on animal studies which indicated that the PEL
of 500 ppm did not provide adequate protection against potential cancer
risks and other adverse health effects. The ANPR summarized OSHA's
information regarding the production and use of MC, occupational
exposure to MC, and the potential adverse health effects associated
with MC exposure. In addition, the notice invited interested parties to
submit comments, recommendations, data, and information on a variety of
issues related to the regulation of MC. OSHA received 43 comments in
response to the ANPR. Those comments are discussed, as appropriate,
below.
On December 5, 1986, the FDA reopened the comment period for 30
days on the above-cited proposal to ban the use of MC in cosmetic
products [51 FR 43935]. The reopening enabled interested parties to
submit comments on studies received after the close of the initial
comment period regarding MC comparative pharmacokinetics, metabolism,
and genotoxicity.
On September 14, 1987, the CPSC issued a statement of
interpretation and enforcement policy, in lieu of continuing with
rulemaking, which expressed the Commission's determination that
consumer products containing MC and capable of exposing consumers to
significant amounts of MC may pose cancer risk to humans and,
therefore, are subject to the above- described hazardous substance
labeling requirements. The CPSC explicitly retained the option of
resuming the rulemaking if voluntary compliance with and enforcement of
the Commission's interpretation did not adequately induce firms to
label their products appropriately.
In 1988, based on the response to the ANPR, OSHA began contacting
small businesses and conducting a number of site visits, to develop a
clear understanding of how revisions to OSHA's MC standard would affect
small entities. For example, on April 27, 1989, OSHA participated in a
NIOSH conference on MC controls for the furniture stripping industry
(54 FR 11811, March 22, 1989) to learn how that industry, which is
dominated by small businesses, was dealing with MC exposure. That
conference focused on the progress of a NIOSH pilot program aimed at
developing affordable engineering controls for the furniture stripping
industry. OSHA continued to seek input from small businesses throughout
the MC rulemaking, as discussed below in the Preamble and in the Final
Economic Analysis [Ex. 129].
Also, in 1988, ACGIH officially lowered the TLV for MC to 50 ppm as
an 8-hour TWA. OSHA considered whether the TLV recommended by the
[[Page 1498]]
ACGIH would be an appropriate OSHA standard. The ACGIH is a
professional society devoted to administrative and technical aspects of
occupational and environmental health. Voting members of ACGIH are
scientists who work for government agencies or educational
institutions. Every year the ACGIH adopts new or revised TLVs for
several substances by a majority vote, not by consensus. OSHA has not
adopted the MC TLV (50 ppm) as the 8-hour TWA PEL because the Agency's
criteria for setting standards differ from those used by the ACGIH.
OSHA standards must eliminate significant risks to the extent feasible,
whereas the ACGIH sets limits under which it is believed that nearly
all workers may be repeatedly exposed day after day without adverse
health effects. Also, as evidenced by their ``Documentation of the
TLVs,'' the ACGIH does not perform quantitative risk assessments. This
difference between OSHA and ACGIH practice is critical because the
Supreme Court has required OSHA to perform quantitative risk
assessments when data permit, and to use these assessments to set
exposure limits.
On June 29, 1989, the FDA issued a final rule that banned the use
of MC in cosmetic products [54 FR 27328]. The Agency based its final
rule on scientific studies that showed inhalation of MC caused cancer
in laboratory animals. The FDA concluded, accordingly, ``that continued
use of MC in cosmetic products may pose a significant risk to human
health * * * '' The Agency considered comments and information
regarding the application of a physiologically-based pharmacokinetic
model to the prediction of human cancer risk. The FDA determined that
the risk assessment developed using animal studies should not be
changed to reflect the ``pharmacokinetic and metabolic data and
hypothesized GST metabolic mechanism of carcinogenicity.''
On August 8, 1990, the Consumer Product Safety Commission (CPSC)
issued a General Order (55 FR 32282) that required manufacturers,
importers, packagers and private labelers of consumer products
containing 1% or more of MC to report to the CPSC information on the
labeling and marketing of those products. The CPSC indicated that the
information obtained would aid the Commission in evaluating the CPSC's
policy concerning the labeling of MC-containing products as hazardous
substances, pursuant to the Federal Hazardous Substances Act.
On November 11, 1990, then-President Bush signed the Clean Air Act
Amendments (CAAA) of 1990. Title VI of the CAAA requires the phaseout
of ozone-depleting chemicals by the year 2000 (section 604) and
requires the EPA to determine which alternatives to ozone-depleting
chemicals are safe for use (section 612). MC was among the potential
substitutes studied by the EPA. In addition, section 112 of the CAAA
requires the EPA to address the residual risks of MC and other
specified Hazardous Air Pollutants (HAPs) by establishing Maximum
Achievable Control Technology (MACT) standards. In particular, section
112(d) requires EPA to promulgate National Emission Standards for
Hazardous Air Pollutants (NESHAP) (40 CFR part 63) over a 10-year
period. In addition, EPA regulates MC as a priority pollutant under the
Clean Water Act as amended (33 U.S.C. 1251, et seq.)
On February 12-13, 1991, EPA convened an international conference
on ``Reducing Risk in Paint Stripping'' that was well attended by
representatives of small businesses which use MC or its substitutes in
a wide range of operations. OSHA actively participated in the workgroup
and panel discussions to elicit information regarding the anticipated
impacts of a revised MC standard on paint stripping operations.
OSHA determined, based on animal and human data, that the existing
PELs for MC did not adequately protect employee health. Accordingly, on
November 7, 1991, OSHA issued a notice of proposed rulemaking (NPRM)
(56 FR 57036) to address the significant risks of MC-induced health
effects. The proposed rule required employers to reduce occupational
exposure to MC and to institute ancillary measures, such as employee
training and medical surveillance, for further protection of MC-exposed
workers. The provisions of the proposed rule are discussed in detail in
the Summary and Explanation, Section X, below. The Agency published a
correction notice on January 6, 1992 (57 FR 387). The NPRM solicited
comments on the proposed rule and raised 48 specific issues to elicit
information about MC health effects, use, and exposure controls, as
well as input regarding the appropriateness and impacts of particular
provisions. The written comment period, which ended on April 6, 1992,
produced 58 comments, including several hearing requests.
On February 11, 1992, then-President Bush announced an accelerated
phaseout schedule for ozone depleting substances and ordered the EPA to
accelerate its review of substitutes (such as MC) whose use would
reduce damage to the ozone layer.
On May 19, 1992, OSHA presented the MC proposal to the newly
reconstituted Advisory Committee on Construction Safety and Health
(ACCSH) for consultation. The Advisory Committee established a MC work
group to generate information and recommendations regarding MC use and
exposure in the construction industry.
In response to the hearing requests and to concerns raised by
commenters, the Agency issued a notice of informal public hearing (57
FR 24438, June 9, 1992), which scheduled hearings to start in
Washington, D.C. on September 16, 1992 and in San Francisco, California
on October 14, 1992. That notice also reopened the written comment
period until August 24, 1992. The hearing notice raised 16 issues,
based on the NPRM comments, which solicited input regarding the human
health risks of MC exposure and the impact of the proposed rule on MC
users. San Francisco was selected as a hearing site to facilitate
participation by small businesses, particularly foam blowers and
furniture refinishers, for whom attendance at the Washington, D.C.
hearing would have been economically burdensome.
On July 28, 1992, the MC work group's report was presented to the
ACCSH and was adopted as the Advisory Committee's recommendation to
OSHA. Based on the input from the ACCSH, OSHA issued a supplemental
hearing notice (57 FR 36964, August 17, 1992) which raised MC use,
exposure and control issues specific to the construction industry. The
supplemental notice extended the deadline for submission of comments
regarding the construction issues until September 22, 1992.
OSHA convened public hearings in Washington, D.C. on September 16-
24, 1992 and in San Francisco on October 14-16, 1992, with
Administrative Law Judge James Guill presiding. At the conclusion of
the hearings, Judge Guill set a post hearing period for the submission
of additional data, which ended on January 14, 1993, and for the
submission of additional briefs, arguments and summations, which ended
on March 15, 1993. The posthearing comment period elicited 35 comments.
On March 31, 1993, pursuant to section 112 of the CAAA, the EPA
issued a notice (58 FR 16808) requesting information on the anticipated
impacts of a National Emission Standard for Hazardous Air Pollutants
(NESHAP) for the halogenated solvent cleaning-vapor degreasing source
category. This notice characterized MC as the third most commonly used
halogenated solvent,
[[Page 1499]]
based on 1991 data. On November 29, 1993, the EPA issued a notice of
proposed rulemaking (58 FR 62566) describing MACT rules for the use of
MC and other HAPs in halogenated solvent cleaning-vapor degreasing
operations.
On March 11, 1994, OSHA reopened the rulemaking record for 45 days
(59 FR 11567) to receive public comment on reports related to
engineering controls for MC exposure in the furniture refinishing
industry, MC carcinogenicity, and the availability of water-based
substitutes for MC-based adhesives in the manufacture of flexible foam
products. In particular, OSHA solicited input regarding the extent to
which it was feasible for small businesses with furniture stripping
operations to comply with the proposed PELs using engineering controls
addressed in an OSHA contractor's report [Ex. 114]. The limited
reopening, which ended on April 25, 1994, elicited 29 comments.
OSHA has evaluated the impact of the final rule on the identified
application groups (except for farm equipment [Ex. 115-23], insofar as
this rulemaking does not address agricultural employment). The Agency's
analysis and conclusions are presented in the Final Economic Assessment
for this rulemaking [Ex.129], summarized in Section VIII, below.
On March 18, 1994, the EPA issued a final rule (59 FR 13044) which
addressed the use of MC as a substitute for ozone-depleting chemicals
being phased out under section 612 of the CAAA of 1990. The EPA has
found the use of MC to be acceptable in the production of flexible
polyurethane foam; polyurethane integral skin foams; metal cleaning;
electronics cleaning; precision cleaning; and adhesives, coatings and
inks. That Agency expressed concern regarding MC toxicity, stating
``methylene chloride use will be subject to future controls for
hazardous air pollutants under Title III section 112 of the CAA. In
addition, use of the compound must conform to all relevant workplace
safety standards * * * Use is also subject to waste disposal
requirements under RCRA (59 FR at 13088).'' The EPA also noted that it
is encouraging companies to decrease emissions of MC through the ``30/
50'' pollution prevention program, under which companies voluntarily
commit to reduce emissions 33 percent by the end of 1992 and 50 percent
by the end of 1995 (59 FR at 13093).
On April 21, 1994, the Department of Housing and Urban Development
(HUD) issued a notice (59 FR 19084) announcing that funds were
available for the removal of lead-based paint. That notice explicitly
provided that paint removal activities funded by HUD could not use
products containing MC.
On May 31, 1994, Judge Guill closed and certified the hearing
record for OSHA's MC rulemaking.
Pursuant to section 112(d) of the CAAA, the EPA has already
finalized NESHAP rulemakings that cover halogenated solvent cleaning
(59 FR 61801, December 4, 1994, 40 CFR part 63, subpart T), aerospace
manufacture and rework facilities (September 1, 1995, 40 CFR part 63,
subpart ) and wood furniture manufacturing (60 FR 62930, December 7,
1995, 40 CFR part 63, subpart JJ). MC-related NESHAP proceedings for
several industries (e.g., pharmaceuticals, flexible polyurethane foam,
polycarbonates and nylon 6 are currently underway.
Pursuant to its CAAA, CWA, RCRA and PPA mandates, EPA has proposed
effluent limitation guidelines for the pharmaceutical industry (60 FR
21592, May 2, 1995) which characterize MC as one of the most
significant priority pollutants to be addressed under the CWA. In
particular, EPA has addressed the use of stream stripping and
distillation technology to recover MC from wastewater for reuse or sale
for use in other industries. That Agency has also proposed requirements
for compliance monitoring of MC that, due to dilution with wastewater,
would be found at levels below current analytical limits of detection.
OSHA has attempted to consider the foreseeable impact of EPA action
on the use of MC because EPA-driven changes in such use would affect
the data on which OSHA relies to estimate the impact of this final
rule. In brief, while EPA action to reduce HAP exposure may encourage
employers to reduce or eliminate MC use, simultaneous EPA efforts to
reduce the emission of ozone-depleting chemicals may encourage
employers to maintain or increase MC use. Given the time frame for EPA
action and that Agency's need to coordinate proceedings that arise from
several statutory mandates, it is inappropriate to draw conclusions
regarding the impact of EPA regulatory action on the need for OSHA
action.
OSHA has also consulted with EPA to determine whether any potential
overlapping or conflicting requirements exist in OSHA's MC standard and
various EPA NESHAPs, and has committed to continue working with EPA on
future NESHAP compliance issues. OSHA discussed the MC regulation with
project officers for all recent, current and planned NESHAPs projects
and has determined that there are no overlapping or conflicting
requirements in the NESHAPs and OSHA's MC standard. Indeed, employers
can choose among a variety of means to comply which would not entail
any conflict in OSHA and EPA regulations.
In particular, OSHA conducted a thorough analysis of the EPA
Solvent Degreasing NESHAP. OSHA determined, and EPA agreed, that there
are no conflicting requirements in the two regulations. OSHA does not
require or recommend specific compliance strategies. One common method
of reducing worker exposure is local exhaust ventilation. In addition,
some of the alternative compliance strategies suggested in the EPA
solvent degreasing NESHAP include reducing room draft. OSHA has
determined that even if an employer chooses reducing room draft as its
compliance strategy for the EPA NESHAP, employers may use some local
exhaust ventilation to reduce worker MC exposures and still be in
compliance with both the OSHA MC standard and the EPA NESHAP. There are
also other combinations of compliance strategies that can be utilized
to comply with both regulations. OSHA plans further discussion of this
issue in its compliance assistance documents. The purpose of these
documents is to assist employers in selecting among the many
appropriate control strategies which satisfy requirements under both
OSHA and EPA regulations.
On October 25, 1995, OSHA reopened the rulemaking record (60 FR
54462) to obtain input regarding studies submitted by the Halogenated
Solvents Industry Alliance (HSIA) [Ex. 118-125] which address the use
of animal data to estimate human cancer risk from MC exposure. The
comments received on those studies [Exs. 126-1 through 126-37] are
discussed in relation to the Quantitative Risk Assessment (Section VI),
below.
The rulemaking record contains 129 exhibits, and 2717 pages of
hearing transcript. A wide range of employees, employers, union
representatives, trade associations, government agencies and other
interested parties contributed to the development of the rulemaking
record. The Agency appreciates these efforts to help OSHA develop a
record that provides a sound basis for the promulgation of this final
rule.
Throughout the ten years since OSHA initiated MC proceedings, the
Agency has sought and evaluated input regarding the anticipated impact
of a MC health standard on small entities. For example, Issue K of
OSHA's Advance Notice of Proposed
[[Page 1500]]
Rulemaking for MC (ANPRM) (51 FR 42257, November 24, 1986) solicited
comments, recommendations, data and information regarding the
anticipated impacts of a MC standard on small entities. Responses from
manufacturers of flexible polyurethane foam [Exs. 10-4 and 10-17] and
industrial paint removers [Ex. 10-7] indicated that rulemaking
regarding MC would affect small entities. Based on the response to the
ANPRM, OSHA initiated contacts with small businesses and conducted a
number of site visits, to develop a clear understanding of how
revisions to OSHA's MC standard would affect small entities.
Based on OSHA's contacts with small business and the response to
the ANPRM, the Preliminary Regulatory Impact Analysis (PRIA) for the MC
NPRM (56 FR 57036, November 7, 1991) considered small firms to be those
with fewer than 20 total employees. In addition, the PRIA estimated
that 45 percent of establishments using MC were ``small businesses.''
Issue 25 of the NPRM for MC stated that OSHA had analyzed the
impacts of the proposed rule on small businesses and had adapted the
standard to take into account the circumstances of small businesses,
where appropriate. The performance-oriented language covering the
demarcation of regulated areas (proposed paragraph (e)(4)) and the 30/
10 days of exposure thresholds for medical surveillance (proposed
paragraph (i)(1)(i)) reflected the Agency's determination to avoid
imposing unnecessary burdens on small entities. In addition, Issue 25
solicited information regarding anticipated small business impacts so
that OSHA could update the initial regulatory flexibility analysis
performed pursuant to 5 U.S.C. 604 of the Regulatory Flexibility Act.
Small businesses, particularly in the furniture refinishing [Exs.
19-1, 19-4, 19-6, 19-8, 19-10 and 19-11] and polyurethane foam blowing
industries [Ex. 19-3], expressed concern that the proposed rule would
impose excessive compliance burdens on their operations. Based in part
on these concerns, the Agency convened informal public hearings (57 FR
24438, June 9, 1992) in Washington, D.C. and San Francisco, CA. San
Francisco was selected as a hearing site to facilitate participation by
small businesses, particularly foam blowers and furniture refinishers,
for whom attendance at the Washington, D.C. hearing would have been
economically burdensome.
Hearing Notice Issue 8 solicited comments and testimony, with
supporting documentation, regarding the impact of the proposed rule on
small businesses, particularly in the furniture refinishing sector. A
significant number of small businesses participated in the Washington,
D.C. and San Francisco hearings, providing OSHA with useful testimony
and posthearing submissions. For example, Harold Markey of the Markey
Restoration Company proposed [Tr. 2660, 2672, 10/16/92] that
``furniture refinishing businesses be exempt from [25 ppm PEL] due to
the financial hardship that enforcement would cause.'' In addition, Mr.
Markey expressed appreciation for OSHA's efforts to facilitate his
participation in the hearing. As discussed above, OSHA subsequently
solicited (59 FR 11567, March 11, 1994) additional input regarding the
extent to which it was feasible for small businesses with furniture
stripping operations to comply with the proposed PELs using the
engineering controls addressed in an OSHA contractor's report [Ex.
114].
OSHA has had numerous contacts with furniture refinishers,
particularly with members of the National Association of Furniture
Refinishers and Refurbishers (NAFRR), the trade association for the
industry. In 1994, OSHA was represented at the NAFRR's annual
conference in Williamsburg, VA. The Agency has continued to provide
assistance to NAFRR members and other furniture refinishers regarding
appropriate industrial hygiene measures for workplaces where MC is
used. For example, OSHA has disseminated information about the
engineering controls developed by NIOSH for the furniture stripping
industry. OSHA will continue to strive for a cooperative relationship
with the small businesses affected by the MC final rule through careful
compliance with the Small Business Regulatory Enforcement Fairness Act
(SBREFA) (5 U.S.C. Chapter 8) and the Regulatory Flexibility Act (5
U.S.C. 601, et seq.), as amended. In addition, the Agency's ``Outreach
Program'' for the MC final rule will involve a commitment of
significant consultation and other resources by OSHA and other
concerned parties, building on the relationships established during the
rulemaking.
OSHA has developed a multifaceted outreach plan to provide
information and compliance assistance to the regulated community. In
particular, OSHA:
--Has developed a booklet which summarizes the provisions of the MC
standard;
--Has developed a compliance directive for the MC standard which
answers compliance-related questions about the MC standard;
--Is developing compliance guides directed at assisting small
businesses in complying with the MC standard, consistent with section
212 of the Small Business Regulatory Enforcement Fairness Act of 1996;
--Has recruited interested trade associations to assist in the
distribution of MC standard-related information, and the convening of
workshops to help small businesses understand available compliance
strategies;
--Has spoken to trade association meetings and distributed MC standard-
related materials;
--Has contacted manufacturers of MC to develop a strategy for inclusion
of OSHA MC-standard information in existing product stewardship
programs; and
--Is working with individuals interested in conducting workshops for
impacted industries, such as polyurethane foam manufacturers and
furniture refinishers, to train small businesses on compliance with
OSHA and EPA regulations.
All 50 states and the territories covered by the OSH Act provide
free consultation services for small businesses to assist them in
achieving compliance with OSHA standards. Those services are funded by
federal OSHA but supplied by the states in state plan states and by
private contractors in other areas. Those consultation services will
provide free assistance for small business so it will be easier to come
into compliance with the MC standard.
OSHA will also set up Cooperative Assessment Programs (CAP's) for
individual employers to assist them in achieving compliance in a
reasonable manner. In a CAP, an OSHA industrial hygienist works with
the employer and employee representatives, to determine a reasonable
number of cost-effective engineering controls and work practices to
bring the employer into compliance. A reasonable schedule is determined
for the implementation of those controls. Good faith efforts to
implement a CAP are generally considered to be in compliance with the
provisions of the standard. OSHA has had success in implementing CAP's
for the arsenic, lead and other standards. Employers have found that
working with OSHA or CAP's has led to cost effective compliance with
OSHA standards.
IV. Chemical Identification
Methylene chloride (MC), also called dichloromethane (DCM)
[Chemical Abstracts Service Registry Number 75-09-2] is a halogenated
aliphatic hydrocarbon with a chemical formula of CH2Cl2, a
molecular weight of 84.9, a
[[Page 1501]]
boiling point of 39.8 deg.C (104 deg.F) at 760 mm Hg, a specific
gravity of 1.3, a vapor density of 2.9 and a vapor pressure of 350 mm
Hg at 20 deg.C (68 deg.F). Concentration of MC in saturated air at
25 deg.C reaches 550,000 ppm. MC has low water solubility (1.3 gm per
100 gm of water at 20 deg.C), an extensive oil and fat solubility, and
a low flammability potential. It is used as a flame suppressant in
solvent mixtures (lower explosive limit of 12% and upper explosive
limit of 19%). It is a colorless volatile liquid with a chloroform-like
odor and its odor threshold varies between 100 and 300 ppm. Contact
with strong oxidizers, caustics and active metal powder may cause
explosions and fires. Decomposition products during combustion or fire
include phosgene, hydrogen chloride and carbon monoxide.
V. Health Effects
A. Introduction
The toxicology of MC is summarized below. A more detailed review of
MC toxicology can be found in the NPRM [56 FR 57036].
B. Absorption and Disposition of Methylene Chloride
Inhalation is the most significant route of entry for MC in
occupational settings. The quantity of MC taken into the body depends
on the concentration of MC in inspired air, the breathing rate, the
duration of exposure to MC, and the solubility of MC in blood and
tissues. Because MC is volatile, inhalation exposures to MC can be
quite high, especially in poorly ventilated spaces.
Dermal absorption of MC is a slow process relative to inhalation.
In the NPRM, OSHA described the rate of skin absorption of pure MC as
insignificant relative to inhalation. In contrast, Mr. Harvey Clewell,
in comments prepared for the U.S. Navy [Ex. 19-59], stated that
substantial occupational exposure could occur through the dermal route
when the employee is exposed to high concentrations of MC vapor and
protective clothing is not worn [Ex. 19-59]. Mr. Clewell provided a
physiologically-based pharmacokinetic (PBPK) model to describe the
potential absorption through skin exposed to high vapor concentrations
of MC. Where the employee is protected from inhalation exposure by use
of an air-supplied respirator and the skin (exposed surface area = two
hands) is unprotected in high MC-vapor concentrations, the primary
route of exposure in this case will be dermal exposure. Mr. Clewell has
determined that sufficient MC may be absorbed by the dermal route over
an 8-hour shift to give an internal concentration which would exceed
that experienced by workers exposed to MC through inhalation of 25 ppm
for 8 hours.
In the NPRM, OSHA also indicated that the burning sensation
associated with dermal exposure to liquid MC would likely lead
employers and employees to limit skin absorption. However, exposure to
high concentrations of vapor may not be associated with a burning
sensation, and there is evidence in the record [Tr. 2468-70, 10/15/92]
to suggest that employees are exposed to liquid MC without protective
clothing. OSHA believes that dermal exposure to liquid and high vapor
concentrations of MC should be limited to the extent feasible to
protect the employee from overexposure. For this reason, in this
standard OSHA has required that employers provide personal protective
clothing and equipment appropriate to the hazard. For example, if an
employee will be at risk of hand contact with liquid MC, impermeable
gloves must be provided.
C. Metabolism of MC
Once MC is absorbed into the body, it is widely distributed in the
body fluids and in various tissues. The uptake and elimination of MC
has been well described in human and animal studies [Exs. 7-156, 7-157,
7-174].
The carcinogenic mechanism of action for MC has not been clearly
established. Although it has not been proven whether MC is carcinogenic
through a genotoxic or non-genotoxic mechanism, current evidence
supports the hypothesis that MC is a genotoxic carcinogen. Genotoxic
carcinogens typically are reactive compounds or metabolized to reactive
compounds. MC is unreactive in the body until it is metabolized.
Therefore, many investigators believe that one or more of the
metabolites of MC, and not MC itself, is the ultimate carcinogen.
It has been established by Kubic and Anders [Ex. 7-167] and Ahmed
and Anders [Ex. 7-25] that MC is metabolized by rat liver enzymes in
vitro by two distinct pathways. The first pathway is the mixed function
oxidase system (MFO pathway) associated with the microsomal cell
fraction and the second is the glutathione dependent pathway localized
primarily in the cytoplasm and mediated by glutathione-S-transferase
(GST pathway). The metabolism of MC is illustrated in Figure 1.
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The MFO pathway metabolizes MC via a cytochrome-P450 dependent
oxidative dehalogenation [Ex. 7-167] which produces formyl chloride.
The formyl chloride decomposes to give chloride ion and carbon
monoxide. It has been postulated that if the MFO pathway contributes to
the carcinogenicity of MC, it is through the production of the reactive
compound, formyl chloride. The end product of the MFO pathway, carbon
monoxide, can be detected in the blood and breath of humans and animals
exposed to MC, and has been used as a surrogate measure of MC exposure
in humans.
The GST pathway metabolizes MC to formaldehyde and chloride ions
via a postulated S-chloromethylglutathione conjugate [Ex. 7-25].
Formaldehyde is further metabolized to carbon dioxide in mammalian
systems. Potential reactive metabolites in this pathway are the S-
chloromethylglutathione conjugate and formaldehyde (known to react with
protein, RNA and DNA).
Animal data indicate that the MFO pathway is saturated at ambient
concentrations less than 500 ppm, while the GST pathway remains linear
throughout the exposure levels examined [Exs. 7-161, 7-171]. Saturation
of the MFO pathway in humans has been estimated to occur at a level
which is within the range of the animal data (estimates range from 200
to 1000 ppm MC) [Exs. 7-114, 7-115, 8-32]. The GST pathway is not
thought to be saturated for any of the species investigated at doses up
to 4000 ppm.
D. Carcinogenicity
The evidence for the carcinogenicity of MC has been derived from
mutagenicity studies, animal bioassays and human epidemiological
studies. OSHA analyzed data from each of these sources in determining
that MC is carcinogenic to test animals and a potential occupational
carcinogen. The evidence that OSHA evaluated in making this
determination is summarized below. Additional evidence pertaining to
the hazard identification of MC is discussed in the Quantitative Risk
Assessment, Section VI, below.
1. Mutagenicity Studies
Mutagenicity and genotoxicity studies are useful in describing the
possible carcinogenic mechanism of action of MC. Evidence for the
interaction of MC or MC metabolites with DNA (producing mutations or
toxicity) is consistent with a genotoxic mechanism for the carcinogenic
action of MC, rather than a non-genotoxic action (i.e., by acting as a
promoter, increasing cell turnover). The EPA reviewed the literature on
the mutagenic potential of MC in their ``Health Assessment Document for
Dichloromethane (Methylene Chloride)'' (HAD) [Ex. 4-5] and studies
conducted by ECETOC in the ``Technical Analysis of New Methods and Data
Regarding Dichloromethane Hazard Assessments'' [Ex. 7-129].
As described in the MC Notice of Proposed Rulemaking (56 FR 57036),
the documentation of positive responses in the production of mutations
in bacteria, yeast and Drosophila, chromosomal aberrations in CHO cells
and sister chromatid exchanges (SCE) in CHO and V79 cells and equivocal
responses in other systems indicated the potential genotoxicity of MC.
A paper submitted to the record by Dr. Trevor Green [Ex. L-107],
for the Halogenated Solvents Industry Alliance (HSIA), investigated the
role of metabolites of the GST pathway in the bacterial mutagenicity of
MC. The authors of this study found that in glutathione-deficient
strains of Salmonella typhimurium there was approximately a two-fold
decrease in mutations. Mutation rates returned to normal when bacteria
were supplemented with exogenous glutathione. They also investigated
whether individual metabolites in the GST pathway were likely to be
responsible for mutagenesis. Experiments in S. typhimurium strains were
consistent with the S-chloromethylglutathione conjugate as the
mutagenic moiety. Experiments in Escherichia coli strains implicated
formaldehyde as the active mutagen. Overall, these results support the
hypothesis that MC may act as a genotoxic carcinogen, but the ultimate
reactive species still remains to be identified.
Dillon et al. [Ex. 21-89] also conducted experiments on the
mechanism of MC mutagenicity in bacterial cells, using wild type and
glutathione-deficient Salmonella typhimurium TA100. Dose-related
increases in mutagenicity were observed with and without metabolic
(cytosolic or microsomal) activation. The authors characterized the
mutagenicity as marginally highest in the presence of cytosol at the
highest MC concentrations. The glutathione-deficient strain was
slightly less responsive to MC-induced mutation than the wild type. In
contrast to the study by Green, Dillon et al. found that MC
mutagenicity was not appreciably enhance by the addition of microsomal
or cytosolic liver fractions or exogenous glutathione. They concluded
that it was not clear to what extent, if any, glutathione was involved
in MC mutagenicity, and noted that ``* * * the residual glutathione
present in the glutathione-deficient strain may have been sufficient to
facilitate the mutagenic responses observed.''
The differing results in these studies suggest that the exact
mechanism of MC mutagenicity, even in bacterial cells, has not been
determined with certainty. However, OSHA has concluded that the
evidence that MC is genotoxic is compelling. Additional studies
supporting classification of MC as a genotoxin were submitted to the
Agency in late 1995 and are discussed in the Quantitative Risk
Assessment, Section VI, below.
2. Animal Studies
The evidence for the carcinogenicity of MC has been derived
primarily from data obtained in chronic toxicity studies in rodents.
Table V-1 contains a summary of the major bioassays. These bioassays
have been conducted in three rodent species (rat, mouse and hamster)
using two routes of administration (oral and inhalation) and a wide
range of doses (from 5 mg/kg/d, oral to 4000 ppm inhaled for 6 hr/d, 5
d/wk).
The National Toxicology Program conducted two 2-year inhalation
bioassays [Ex. 7-8] using B6C3F1 mice and Fischer 344 rats. In the NTP
mouse study [Ex. 7-8], groups of 50 male and 50 female B6C3F1 mice were
exposed to 0, 2000 or 4000 ppm MC, 6 hr/day, 5 d/wk for 102 weeks. All
animals were necropsied and examined histopathologically.
Treated male and female mice had increased incidences of alveolar
or bronchiolar adenomas and carcinomas as compared with control
animals. In addition, there was an increased number of lung tumors per
tumor-bearing animal (multiplicity of tumors) with increasing dose of
MC.
In the liver, the toxic effects of MC were expressed as cytologic
degeneration in male and female mice which was not present in the
controls. An increased incidence of hepatocellular adenomas and
carcinomas (combined) was observed in male mice. The incidence of
hepatocellular carcinomas in male mice was statistically significantly
increased at 4000 ppm. Female mice also experienced dose-related
increases in the incidences of hepatocellular adenomas and carcinomas.
An increased multiplicity of liver tumors was also found in both male
and female mice.
[[Page 1504]]
Table V-1.--Methylene Chloride Lifetime Bioassays
----------------------------------------------------------------------------------------------------------------
Route and dosing Dosage (No. of
Reference Species/strain schedule animals) Comments
----------------------------------------------------------------------------------------------------------------
NTP (1985).................... B6C3F1 mouse.... Inhalation 6 hr/ 0, 2000, 4000 ppm (50 Lung and liver tumors
day, 5 days/ mice/ sex/dose). both sexes, both
week. doses.
Serota (NCA) (1986)........... B6C3F1 mouse.... Daily in water.. 0 (125M, 100F), 60 No tumors observed.
(200M, 100F), 125
(100M, 50F), 185
(100M, 50F), and 250
(125M, 50F) mg/kg/d.
NTP (1985).................... Fischer 344 rat. Inhalation 6 hr/ 0, 1000, 2000 and Mammary and
day, 5 days/ 4000 ppm (50 rats/ integumentary
week. sex/dose). fibromas and
fibrosarcomas in
both sexes.
Burek (DOW) (1980)............ Sprague-Dawley Inhalation 6 hr/ 0, 500, 1500 and 3500 Malignant salivary
rat. day, 5 days/ ppm (95 rats/sex/ gland tumors at 3500
week. dose). ppm, dose-related
increase in mammary
tumors.
Nitschke (DOW) (1982)......... Sprague-Dawley Inhalation 6 hr/ 0, 50, 200 and 500 No tumors observed.
rat. day, 5 days/ ppm (70 rats/ sex/
week. dose.
Serota (NCA) (1986)........... Fischer 344 rat. Daily in water.. 0, 5, 50, 125 and 250 No tumors observed.
mg/kg/d (135/sex at
0, 85/sex/dose).
Burek (DOW) (1980)............ Syrian Golden Inhalation 6 hr/ 0, 500, 1500, 3500 No tumors observed.
hamster. day, 5 days/ ppm (90 hamsters/sex/
week. dose).
----------------------------------------------------------------------------------------------------------------
The dose-related increase in the incidence of lung and liver tumors
in mice, and the increased multiplicity of these tumors, present the
strongest evidence for the carcinogenicity of MC. NTP concluded that,
based on the evidence from these lung and liver tumors, there was clear
evidence of the carcinogenicity of MC in both male and female mice.
In a second two-year bioassay, the NTP examined the effects of
inhalation of MC at 0, 1000, 2000 and 4000 ppm in F344 rats [Ex. 7-8].
Body weights of all exposure groups were comparable. The highest dose
female rats experienced reduced survival after 100 weeks of exposure.
The incidence of mammary tumors in the high dose group in both
sexes was statistically significantly higher than in control animals
(concurrent and historical). The incidence of mammary fibroadenomas
alone and the combined incidence of fibroadenomas and adenomas in male
and female rats occurred with statistically significant positive
trends. When subcutaneous fibromas or sarcomas in the male rat, which
were believed to have originated in the mammary chain, were included in
comparisons, differences between control and exposed animals were even
greater.
MC-exposed male and female rats also showed increased incidence of
liver effects, characterized by hemosiderosis, hepatocytomegaly,
cytoplasmic vacuolization and necrosis. Neoplastic nodules alone and
combined incidence of neoplastic nodules and hepatocellular carcinomas
in female rats occurred with significant positive trends by the life
table test. Pair-wise comparisons did not indicate statistically
significant effects at any one dose. Although this is suggestive of a
carcinogenic response in the female rat liver, NTP did not use this
response in their determination of the carcinogenicity of MC.
NTP based its determination of the carcinogenicity of MC in the rat
on the mammary tumor incidence data. NTP has concluded that the
increased incidences of mammary gland tumors in the female rats
provided clear evidence of carcinogenicity and, in the male rats, some
evidence of carcinogenicity.
The Dow Chemical Company [Ex. 7-151] conducted experiments in which
Sprague-Dawley rats and Syrian Golden hamsters were exposed to 0, 50,
1500 or 3500 ppm MC, 6 hr/d, 5 d/wk for 2 years. A dose-related
statistically-significant increase in the number of mammary tumors per
tumor-bearing female rat was observed. These results support the NTP
findings of increased mammary tumors in F344 rats. The background
mammary tumor response in the Sprague-Dawley rat is higher than in F344
rats, so a quantitative analysis of risk is easier to perform on the
data from the NTP study.
A statistically significant increase in male rat salivary tumors
was also observed in this study, although the authors believed that
this response should be discounted because of the presence of
sialodacryoadenitis virus in the rats. OSHA believes that the presence
of this virus in the rats would complicate the interpretation of the
data, and so has relied on the NTP studies for its quantitative risk
assessments.
No statistically significant excess incidence of tumors was
observed in either sex of hamsters at any exposure level. This suggests
that hamsters are less sensitive to the carcinogenic effects of MC than
either mice or rats. Metabolism data gathered in hamsters indicate that
hamsters have less capability to metabolize MC by the GST pathway than
rats or hamsters (or humans). This correlation between lack of GST
metabolism capacity and lack of tumor response supports the hypothesis
that GST metabolism is important in MC carcinogenesis and also
indicates that it would not be protective to use the hamster response
to MC as the basis for a carcinogenic risk assessment.
A second inhalation study in Sprague-Dawley rats conducted by
investigators at Dow Chemical [Ex. 7-173], with exposures up to 500
ppm, showed an increase in the number of mammary tumors per tumor-
bearing animal in female rats at the highest dose level only. This
study extended the finding of excess mammary tumors in rats to the 500
ppm level. However, because of the high background rates of mammary
tumors in Sprague-Dawley rats, the NTP study showed a clearer dose-
response relationship between MC exposure and incidence of mammary
tumors.
In a study conducted for the National Coffee Association [Ex. 7-
180], no statistically significant increased incidence of tumors was
observed in B6C3F1 mice or F344 rats exposed to up to 250 mg/kg/d MC in
drinking water. These studies used the drinking water route of exposure
instead of inhalation and exposed animals to lower doses (on an mg/kg/d
basis) than the NTP and high-dose Dow studies. These factors most
likely accounted for the lack of a positive tumor response. The NCA
studies were used by Reitz et al. in the development of the
physiologically-
[[Page 1505]]
based pharmacokinetic models for MC. Specifically, these studies helped
to determine that the lack of tumor development was consistent with
model predictions of the amount of GST metabolites in lung and liver of
mice and that the MFO pathway was most likely not primarily responsible
for the mouse tumor response.
The Agency believes that the NTP studies show the clearest evidence
of a carcinogenic effect of MC and has used these studies as the basis
of its risk assessment for the following reasons: (1) The studies were
well conducted and underwent extensive peer review. (2) The inhalation
route of exposure was used, which is the most appropriate route for
extrapolation to occupational exposures. (3) Dose-related,
statistically significant increases in tumor incidence were observed in
both sexes in mice and in female rats. OSHA believes that because of
the clear tumor response, and quality of the studies, the NTP studies
provide the best data for quantitative cancer risk assessment. OSHA
concludes from these studies that MC causes cancer in two species of
test animals by the inhalation route, and that a clear dose-response
has been demonstrated.
3. Epidemiological Studies
Epidemiological studies of occupational exposure to MC have been
conducted in the manufacturing of triacetate fibers, photographic film
production, and the manufacturing of paint and varnish. Those studies
were reviewed by OSHA in the preamble to the proposed rule [56 FR
57075] and are summarized and updated in this document. In addition, an
epidemiological study of MC exposure and astrocytic brain cancer is
reviewed in this text.
a. Studies of triacetate fiber production workers. Ott et al. [Ex.
7-76] performed a retrospective cohort study using a cellulose
diacetate and triacetate plant in Rock Hill, South Carolina to examine
the effects of MC on a working population. In particular, Ott et al.
evaluated the effects that were possibly mediated through the
metabolism of MC to carboxyhemoglobin. Employees at this plant had MC
exposures close to OSHA's time weighted average (TWA) permissible
exposure limit (PEL) of 500 ppm. Ott et al. used workers in a plant in
Narrows, Virginia as a comparison population because it had operations
similar to those at the Rock Hill plant, but did not use MC. In this
study, Ott et al. compared the number of deaths within the exposed
cohort with the United States population and the Narrows, Virginia
referent group. Ott et al. observed that the overall mortality of the
cohort was comparable to that of the age, sex, and race-matched U.S.
population. Comparing exposed and referent cohorts, statistical
differences in risk were observed in white men for ``all causes'' (risk
ratio=2.2, p<0.01), ``diseases of the circulatory system'' (risk
ratio=2.2, p<0.5), and ``ischemic heart disease'' (risk ratio=3.1,
p<0.05).
In interpreting the results of this study, Ott noted that there may
have been differences in hiring practices in the two plants which could
have contributed to the observed differences in mortality. In their
conclusion, Ott et al. stated that a healthy worker effect (HWE) and
the low power of their study did not permit them to dismiss the
possibility of increased health risks within the working population
exposed to MC.
Dr. Mirer of UAW testified [Tr. 1896-6, 9/24/92] that there is some
evidence that there is excess work-related heart disease mortality in
epidemiological studies that have observed SMRs greater than 80% for
ischemic heart disease or any other cardiovascular disease.
Furthermore, when the MC epidemiological studies are looked at
together, there is evidence, although limited, that MC exposure has an
effect on cardiovascular mortality.
On the other hand, Kodak [Ex. 91D] questioned the appropriateness
of the referent population in the Rock Hill study, alleging that the
SMR for ischemic heart disease in the referent population was unusually
low, and that this fact, rather than an effect of MC exposure, caused
the observed differences in ischemic heart disease rates.
In contrast, NIOSH considered the Rock Hill study to be suggestive
of an effect of MC on risk of cardiac disease. According to NIOSH [Tr.
879, 9/21/92] the Ott study did not use appropriate analytic techniques
that would allow the acute effects of MC on cardiac disease risk to be
examined. Furthermore, NIOSH suggested [Tr. 969, 9/21/92] that future
epidemiological studies should examine risks from MC exposure during
the period when employees are actively working.
In an update to the Rock Hill study, Lanes et al. followed the Ott
et al. cohort through September 1986 [Ex. 7-260] and December 1990 [Ex.
106]. Lanes et al. used the population of York County, South Carolina
as the comparison group. Statistically significant excess mortality was
observed for cancer of the liver and biliary passages (SMR=5.75,
CI:1.82-13.78) in the study group. Excess mortality was also observed
for buccal cavity and pharynx cancer (SMR=2.31, 95% CI:0.39-7.60) and
melanoma (SMR=2.28, CI:0.38-7.51), although mortality from these causes
did not reach statistical significance. No excess mortality was
observed for ischemic heart disease (SMR=0.90, CI:0.62-1.27).
Examination of the liver and biliary cancers indicated that the
workers had ten or more years of employment and at least 20 years since
first employment (4 observed v. 0.35 expected). Three of the four
employees who died from liver/biliary cancer had tumor sites in the
intrahepatic and common bile duct, common bile duct, and ampulla of
Vater. Approximate durations of employment for these three cases were
28 years, 20 years, and less than one year. No medical record for the
third case could be obtained. However, an autopsy report indicated
adenocarcinoma of the liver for this case. To estimate the expected
number of biliary cancer deaths, Lanes et al. used Surveillance,
Epidemiology, and End Results (SEER) mortality rates of the continental
United States. The computed risk estimate, based on 0.15 cases
expected, was SMR=20 (95% CI:5.2-56.0).
The authors hypothesized that the biliary duct cancer cases may
have been due to factors such as oral contraceptive use, gallstones, or
ulcerative colitis. However, it appeared that medical records showed no
indication of gallstones or ulcerative colitis in workers who died of
biliary cancer. Moreover, although these factors were not specifically
controlled for, there is no reason to believe the rates of these
factors would be different in the exposed cohort compared to the
general U.S. population.
Lanes et al. updated their study through December 31, 1990 [Ex.
106] using the National Death Index and focused on mortality from
pancreatic cancer, biliary and liver cancer, and ischemic heart
disease. Lanes et al. ascertained fifty more death certificates from
the end of the last follow-up period on September 1, 1986. As before,
York County, South Carolina was used as the comparison population.
The overall SMR from all causes of death was 0.90, and for
malignant neoplasms, the SMR was 0.82. In this follow-up, the SMR for
liver and biliary cancer dropped from 5.75 to 2.98 (95% CI:0.81-7.63).
No additional deaths from biliary or liver cancer were observed. In the
original and updated studies combined, four deaths from biliary/liver
cancer were observed and 0.64 were expected. Using a Poisson
distribution, Lanes et al. calculated the probability of failing to
observe any liver/biliary
[[Page 1506]]
cancer deaths in this update if the ``true'' value of the SMR for
liver/biliary cancer was 5.75 (from the previous study) and then
expecting 3.68 deaths in this follow-up (0.64 x 5.75). They estimated
the probability that this update would have no observed biliary/liver
cancer deaths if the true SMR were 5.75, as e-3.68=0.025. On the
other hand, if MC had no effect on liver and biliary cancer mortality,
Lanes et al. estimated that the probability of observing zero deaths
would have been 0.527 (e-0.64). Lanes et al. used the likelihood
ratio (0.527/0.025=21.08) to compare these two hypotheses. The authors
concluded that the null hypothesis that the SMR=1.0 was 21 times more
probable than the hypothesis that the SMR=5.75.
Because of the small number of cases involved and the instability
of the numbers generated in this type of statistical analysis, OSHA
believes that this study, overall, is suggestive (but not definitive)
of an association between occupational exposure to MC and elevation of
human cancer risk. Furthermore, the Agency has determined that the
study results are not inconsistent with the results of the NTP cancer
bioassay.
Hoechst-Celanese [Ex. 19-65, pp. 6-8; Ex. 19-19] was concerned that
OSHA considered the incidence of biliary cancer as evidence of a
positive effect. They argued that the reported excess in biliary tract
cancer did not support the conclusion that MC exposure is associated
with an increased risk of cancer. Specifically, they noted that,
(1) Biliary cancers have not been reported in any of the animal
cancer studies of MC; (2) no statistically significant increase in
biliary cancers was seen in the Cumberland study (described below);
(3) no statistically significant excess in biliary cancers was
reported in the Kodak studies (described below); (4) It was unlikely
that MC could have been responsible for the biliary tract cancer
observed in one employee who had been exposed to MC for less than
one year; and (5) the Rock Hill study did not control for other
chemical exposures.
Comments by the Halogenated Solvents Industry Alliance (HSIA) [Ex. 19-
45, p. 47] were in accord with those of Hoechst-Celanese.
Dr. Shy, on behalf of Kodak, asserted [Tr. 1303, 9/22/92; Ex. 91F]
that MC exposure failed to meet Bradford Hill's criteria for causality
(e.g., biological plausibility, dose-response, and consistency) for
producing biliary tract cancer. Dr. Shy acknowledged that animal
bioassays have demonstrated liver tumors from MC exposure, but he noted
that there is no evidence in humans that liver and biliary tract
cancers have the same etiology. Furthermore, Dr. Shy argued that,
(1) the results from the Lanes study is not supported by in vitro
or pharmacokinetic studies.
(2) a dose-response relationship could not be determined from the
Lanes study because there were no direct measurements of worker
exposure to MC.
(3) the observed association between MC exposure and liver/biliary
cancer was an isolated finding and the existence of a causal
relationship could not be concluded.
(4) the excess biliary tract cancer in the Lanes study was not
consistent with the other three epidemiological studies (Hearne, 1987,
1990, 1992; Hearne, 1992; Gibbs, 1992).
Dr. Shy did recognize that there was a strong association between
MC exposure and biliary tract cancer in the Lanes study (SMR=20).
Moreover, the 20 year time interval between first exposure and death
from biliary tract cancer provided evidence that ``exposure preceded
cancer with an appropriate interval for induction of the tumor [Ex.
91F].''
OSHA disagrees with the conclusions reached by Dr. Shy. The Agency
believes that the risks of biliary cancer observed in these studies is
consistent with risks derived from its pharmacokinetic analysis (see
the Quantitative Risk Assessment, Section VI). Since the occupational
exposures in these studies are likely to have been among the highest in
any of the epidemiologic cohorts, there is no evidence that the
increased biliary/liver cancer result is inconsistent with other
reported epidemiological findings. Regarding the biological
plausibility, the Agency notes that human biliary cells appear to
contain high concentrations of the mRNA for GST (the enzyme many
investigators believe to be responsible for MC-induced carcinogenesis)
[Exs. 124 and 124A]. Although this requires more investigation to
determine if there is a direct relationship, OSHA believes there is a
plausible mechanistic argument for MC causality in human biliary tract
cancers. The Agency agrees with Dr. Shy, however, that the lack of
dose-response data and the small number of cases in this cohort limit
the strength of conclusions that can be drawn from this study. After
weighing these considerations, the Agency has determined that there is
suggestive evidence of a causal role for MC in these cases of biliary
cancer.
Gibbs et al. conducted a study of another cellulose acetate and
triacetate fibers plant in Cumberland, Maryland [Ex. 54] to evaluate
the possible relationship between MC exposure and biliary/liver cancer.
This plant, which ceased to operate in 1982, had operations similar to
the plant in Rock Hill, and it was assumed to have had similar MC
exposure levels as well. However, exposure measurements were not
submitted for the Cumberland plant and it is unknown whether the
Cumberland employees experienced the same exposures as their Rock Hill
counterparts.
The Gibbs study investigated the mortality of 3,211 workers who
were employed at this plant on or after January 1970. There were 2,187
men and 1,024 women in the cohort. Most of the workers in the cohort
were hired prior to 1979 (2,566 total). The study population was
divided into three subcohorts based on their estimated exposure to MC:
1) 834 men and 146 women in the ``high exposure'' group (estimated to
be 350-700 ppm), 2) 1095 men and 832 women in the ``low but never high
exposure'' group (estimated to be 50-100 ppm), and 3) 256 men and 46
women in the ``no exposure'' group. This cohort was followed through
December 1989. The observed mortality was compared to expected death
rates for Allegany County, Maryland (where the plant was located and
where most of the cohort deaths occurred), the State of Maryland, and
the United States.
The author of this study believed that the county rates were the
most appropriate to use because the city of Cumberland is located in a
rural area of Maryland and the state rates may have been influenced by
rates in large urban areas such as Baltimore. In addition, local rates
tend to adjust for social, economic, ethnic, and cultural factors which
may be related to disease risk, access to medical care, etc. However,
if the fiber plant was the major employer in this rural area, then
county rates may reflect the cohort's mortality rather than the
background risk, in which case, state rates or U.S. population rates
would be more appropriate. The overall mortality rate for the high MC-
exposed group was below the expected rates for Allegany County,
Maryland, and the U.S. population.
As in the Rock Hill study, mortality from biliary tract cancer was
observed in the Cumberland study, although no statistically significant
elevated incidence of biliary cancer was found (two cases of biliary
tract cancer were observed). In the high exposure group, there was one
death (1.24 expected with Allegany rates (SMR=80.5) and 1.42 expected
with Maryland rates (SMR=70.4)). In the low MC-exposed group, there was
also one death from biliary/liver cancer. For the high MC-
[[Page 1507]]
exposed subcohort, Gibbs et al. estimated SMRs of 80.4, 70.3, and 75.1
when comparisons were made with Allegany County, Maryland, and U.S.
rates, respectively. In the low MC-exposed subcohort, the SMRs using
Allegany and Maryland rates were 75.4 and 76.4, respectively. This
cohort should be followed for a longer period of time to help clarify
the suggested association between MC exposure and biliary cancer
observed in the Rock Hill cohort.
Statistically significant excess mortality was also observed from
prostate, uterine, and cervical cancers, although these also
represented small numbers of cases: 13, 2, and 1, respectively.
The excess of prostate cancer in the Gibbs et al. study suggested
an exposure-response relationship (3 deaths in no MC-exposure group, 9
in low MC-exposure group, and 13 in high MC-exposure group). According
to Gibbs et al. and Shy [Tr. 1303, 9/22/92; Exs. 19-64, 91F], this
response may have been related to other chemical exposures
(occupational or non- occupational). In support of this hypothesis, no
other epidemiological or animal studies of MC exposure have suggested a
relationship between prostate cancer and MC. Hoechst-Celanese [Ex. 19-
65, pp. 10-12; Ex. 91D, p. 12] cautioned OSHA not to overinterpret the
excess of prostate cancer in the Cumberland study for the following
reasons:
(1) of all the epidemiological studies, only the Cumberland
study has shown an excess of prostate cancer; (2) of the thirteen
high subcohort men who died of prostate cancer, twelve worked in the
extrusion area of the Cumberland plant before methylene chloride was
used as a solvent in cellulose triacetate fiber production. Thus,
these men may have had longer exposure to other chemicals; (3) the
study did not control for other personal risk factors; (4) Gibbs
reported an increased incidence of prostate cancer elsewhere in the
textile industry; and (5) the large number of statistical tests may
have increased the probability of finding the death rate of a
specific cause to be elevated or depressed.
OSHA believes that the increased risk of prostate cancer should be
noted as a possible positive effect of MC exposure on cancer risk,
particularly considering the exposure-response relationship. However,
because of potential confounding factors and lack of corroborating
findings in other studies, OSHA believes this is suggestive rather than
conclusive evidence of a human carcinogenic effect.
b. Studies of film production workers.
In their original study of film production workers, Friedlander et al.
[Ex. 4-27] conducted both a proportionate mortality study and a
retrospective mortality cohort study to determine if workers exposed to
MC experienced an increased risk for specific causes of mortality. The
cohort in these studies consisted of workers who worked in any
department in film production that used MC as its primary solvent for
approximately thirty years. The cohort was followed through 1976.
Proportionate mortality analysis for those workers ever employed in
the study area versus a comparison group of workers in other Kodak Park
departments produced a proportionate mortality ratio (PMR) of 143.88
for liver (intrahepatic ducts-primary) cancer. For ischemic heart
disease, Friedlander et al. calculated a PMR of 94.74. No statistically
significant differences were observed at p 0.05.
For the cohort mortality study, Friedlander et al. used rates from
the 1964-70 hourly males age group exposed to MC in the film department
and the other Kodak Park departments for internal comparison. Mortality
rates for New York State, excluding New York City, males age group were
used for external comparisons.
Forty-five deaths from circulatory diseases were observed in the
MC-exposed cohort versus 38.5 expected in the Kodak Park referent
group. Also, 6 deaths from respiratory diseases were reported in the
MC-exposed group versus 3.2 expected for the Kodak Park comparison
group. No liver deaths were observed in this cohort. Thirty-three
deaths from ischemic heart disease were observed in this cohort
compared with 28.7 expected in the Kodak Park population. None of these
observed differences in mortality reached statistical significance.
Hearne et al. conducted several updates to the cohort study
involving MC exposure and mortality among workers in film production
areas at the Kodak plant in Rochester, New York [Exs. 7-122, 7-163, 49
A-1]. In the first update, the study cohort was followed through 1983.
Two referent groups were utilized in this study: the general population
of upstate New York men, excluding New York City, and Kodak Park
employees.
No statistically significant findings were observed for any cause
of death. However, Hearne et al. did find a relatively large number (8
observed) of pancreatic cancer deaths compared with the New York State
(3.2 expected) and Kodak (3.1 expected) populations. This observation
did not achieve statistical significance and a dose-response
relationship was not observed when Hearne et al. considered latency and
dose.
Hearne et al. then updated this study through 1988 [Ex. 7-163] and
1990 [Ex. 49 A-2]. In the 1988 update, nonsignificant deficits in
observed-expected ratios for lung and liver cancer were found. Also,
overall mortality from 1964 to 1988 was significantly less than in both
referent groups. Since 1986, the number of pancreatic cancer deaths
remained the same. As before, dose-response analysis showed no
statistically significant pattern when latency or dose were considered.
The 1990 update showed that deaths due to liver cancer, lung
cancer, and ischemic heart disease were below the expected numbers in
both referent groups. Also, no additional pancreatic cancer deaths were
observed in this second update. Since the start of the follow-up,
Hearne et al. observed 8 deaths from pancreatic cancer compared with
4.5 expected (SMR = 1.78, p = 0.17).
Hearne et al. [Ex. 49 A-1] conducted a second Kodak cohort study
involving workers in cellulose triacetate preparation and film base
manufacturing between 1946 and 1970. Hearne et al. addressed the
potential selection bias in the 1964-70 Kodak cohort by including only
workers exposed primarily to MC after it was introduced in these areas
and making the study more complete by adding workers in the Dope
Department, which prepares the viscous cellulose triacetate mixture
used in the film base coating, and the Distilling Department, which
redistills and reblends solvents recovered from the coating operations.
The 1,311 men in the cohort were followed through 1990. An
occupational control group could not be formed because death rates for
Kodak employees before 1964 were unavailable. Instead, male residents
of upstate New York living outside of the five New York City counties
were used.
Hearne et al. combined exposures by job and time period with
occupational history information to produce a career exposure estimate
for each individual in the study for dose-response analyses. The mean
career individual exposure was approximately 40 ppm for 17 years and
the average interval between first exposure and end of follow-up was
about 32 years.
Total mortality for this cohort was 22% below the expected
mortality (statistically significant). Circulatory diseases and
ischemic heart disease mortality were also statistically significantly
below expectation. For lung cancer there were 22 deaths (28.7 expected)
and for liver/biliary cancer
[[Page 1508]]
there was one death (1.5 expected). Hearne et al. found that the number
of pancreatic cancer deaths observed (4) was similar to the expected
number (4.4). In this cohort, the number of observed deaths was greater
than expected for diseases of the colon/rectum (13 observed v. 10.8
expected), brain (5 v. 2.3), and for leukemia (7 v. 3.4), but were not
statistically significant.
Hearne et al. concluded that the findings in the 1964-70 cohort
were consistent with the 1946-70 cohort: mortality from all causes,
cancer (including lung and liver malignancies), and ischemic heart
disease was lower than expected. Also, since the number of observed
pancreatic cancer deaths in this cohort was similar to the expected
number, Hearne et al. believed that this provided further evidence that
the earlier finding of an excess of pancreatic cancer in the 1964-70
cohort was due to chance or to factors other than MC exposure.
Kodak [Tr. 1287-88, 9/22/92] also investigated the risk of adverse
health effects during active occupational exposure to MC, as suggested
by NIOSH [Tr. 970, 9/21/92]. Using person-years of active employment
only in their analysis, Hearne observed 27 deaths (36 were expected in
the internal Kodak reference group) from ischemic heart disease in the
1964-70 Kodak cohort; in the 1946-70 cohort, Kodak recorded 33 deaths
compared with 43 expected in the New York State comparison population.
NIOSH testified [Tr. 877-83, 9/21/92] that the healthy worker
effect (HWE) could have obscured any excess mortality from ischemic
heart disease caused by MC exposure. NIOSH has stated that the HWE may
be particularly strong for cardiovascular diseases.
The HWE is likely to be less of a factor when occupational
comparison groups are used. Kodak's use of the Kodak Park employees as
a comparison group should reduce the HWE in its studies. However, there
are two potential problems with using occupational comparison groups in
this instance:
(1) Cancer rates are more stable in larger populations, so
comparison with state and national rates may be more appropriate.
(2) Due to the volume of MC used in the Kodak plant, the
occupational comparison group may be exposed to air- or water-borne
environmental concentrations of MC which could obscure the impact of
occupational exposure to MC on cancer incidence.
c. Study of workers in paint and varnish manufacturing. The NPCA
submitted to the record an epidemiological study of employees who
worked for at least one year in the manufacture of paint or varnish
[Ex. 10-29B]. OSHA's review of this study was published in the proposed
rule [56 FR 57077]. Although no statistically significant excess of
mortality was reported, OSHA noted that there were 4 pancreatic cancers
(1.93 expected) and 15 cancers of digestive organs and peritoneum
(10.66 expected) among MC-exposed workers.
d. Astrocytic brain cancer among workers in electronic equipment
production and repair. In its March 11, 1994 Notice of Limited
Reopening of the Rulemaking Record, OSHA solicited comments on a case-
control study submitted to the Agency by the National Cancer Institute
(NCI) [Exs. 112 and 113].
Heineman et al. conducted a case-control study to examine the
potential association between brain cancer and exposure to organic
solvents as a group and six chlorinated aliphatic hydrocarbons (CAHs)
including MC. Cases were defined as white males who died from brain or
other central nervous system tumors in southern Louisiana, northern New
Jersey, and Philadelphia, Pennsylvania. Controls were randomly selected
from death certificates and included white males who died of causes
other than brain tumors, cerebrovascular diseases, epilepsy, suicide,
and homicide. Controls were frequency-matched to cases by age, year of
death, and geographic area.
Four-digit Standard Industrial Classification (SIC) and 4-digit
Standard Occupational Classification (SOC) codes were employed to code
occupational histories of study subjects. These codes linked work
histories to job-exposure matrices which ``characterized likely
exposure to the six CAHs and to organic solvents'' [Ex. 112]. Gomez et
al. [Ex. 112] used an algorithm to assign estimates of probability and
intensity of exposure to each industry/occupation combination in
subjects' work histories. As noted by Gomez et al., these estimates
were based on ``occupation alone, industry alone, or both occupation
and industry, depending on the specificity of the exposure environment
that could be inferred from the occupational (SOC) code.''
The following surrogate measures of dose, for each substance, were
used to summarize ``likely'' exposure histories for each study subject:
duration of employment in occupation/industry combinations considered
exposed, a cumulative exposure score, and ``average'' intensity of
exposure. Odds ratios were calculated for exposure intensity categories
to refrain from using weights. These categories did not include
duration in jobs with lower intensity for subjects with high or medium
intensity jobs. In their statistical analyses, Heineman et al.
controlled for age, geographic area, and employment in electronics-
related occupations/industries.
Astrocytic brain cancer was not found to be associated with
``ever'' being exposed to organic solvents as a group or to any of the
six CAHs examined in this study. However, as probability of exposure to
organic solvents as a group, and MC in particular, increased, the risk
of brain cancer increased (chi-squared statistics for trend for organic
solvents and MC were 1.93 and 2.29 (p<0.05), respectively). For MC
there was a 2.4-fold increase in risk for subjects with a high
probability of exposure (confidence interval=1.0-5.9).
Risk of brain cancer significantly increased with duration of
exposure for subjects with high probabilities of MC exposure (OR=6.1;
CI=1.1-43.8). Heineman et al. found that, in the high probability of MC
exposure category, risk significantly increased with duration (chi for
trend=2.58, p<0.01). Similar results were seen for organic solvents and
methyl chloroform for all probabilities combined (chi-squared
statistics for trend were 2.35 (p<0.01) and 1.87 (p<0.05),
respectively).
Lagging exposure by 10 years produced findings analogous to those
noted above. Higher risks and a sharper increase with duration was
observed for organic solvents when exposure was lagged by 20 years (all
probabilities: 2-20 years, OR=1.3 (95% CI=0.9-2.0); 21+ years, OR=2.8
(1.1-3.7); p for trend=0.006; high probability: 2-20 years, OR=1.2 (95%
CI=0.7-1.9); 21+ years, OR=3.1 (1.3-7.4), p=0.009).
Subjects with a high probability of MC exposure experienced a
statistically significant increased risk as the cumulative exposure
score increased (chi-squared statistics for trend=2.18, p<0.05).
However, risk did not increase monotonically with cumulative exposure.
Lagging exposure 20 years supported the odds ratios and the trends
for organic solvents, particularly in men with a high probability of
exposure (low cumulative score: OR=1.1 (95% CI=0.5-2.3); medium: OR=1.4
(0.8-2.5); high: OR=2.2 (1.0-4.5); p for trend=0.02). Few individuals
had high cumulative scores when exposure was lagged 20 years for the
individual CAHs.
Compared with jobs with medium or low intensity exposures to
organic solvents and all six CAHs, risk of brain cancer was higher for
subjects who
[[Page 1509]]
worked in jobs with high intensity exposures. Brain cancer was
associated most strongly, and increased with probability of exposure,
among subjects who worked 20 or more years with high intensity exposure
to MC (all probabilities: OR=6.7, CI=1.3-47.4; high probability:
OR=8.8, CI=1.0-200.0).
Since many subjects were determined to have been exposed to more
than one of the CAHs, sometimes even in the same job, Heineman et al.
used logistic regression to examine, simultaneously, the effects of MC,
carbon tetrachloride, tetrachloroethylene, and trichloroethylene,
controlling for age, geographic area, and employment in electronics-
related occupations/industries. MC was the only substance to show a
statistically significant increase in risk as the probability of
exposure increased (low: OR=0.9, CI=0.5-1.6); medium: OR=1.4, CI=0.6-
3.1; high: OR=2.4, CI=0.9-6.4; chi-squared statistics for trend=2.08,
p<0.05). Risks associated with MC increased when adjustments for
exposure to the other agents were made. In addition, subjects employed
for 20 years or more in jobs with high average intensity MC exposure
showed an eight-fold excess of brain cancer (OR=8.5, CI=1.3-55.5),
taking all probabilities into consideration.
Among the six CAHs examined in this study Heineman et al. found the
strongest association between brain cancer and MC-exposure, for which
relative risks rose with probability, duration, and average intensity
of exposure, though not with the cumulative exposure index.
According to Heineman et al., the major weakness of this study was
not having direct information on exposure to solvents. Next-of-kin
data, poor specificity of some work histories for specific solvents,
and the interchangeability of solvents may have resulted in
misclassification of individuals with respect to any of the exposure
measurements used in this study. However, Heineman et al. pointed out
that the potential sources of error probably did not significantly bias
risk estimates away from the null or generate the observed trends.
Another limitation of this study, pointed out by Heineman et al.,
was that over one-third of the next-of-kin of eligible cases and
controls were not interviewed. According to Heineman et al., this could
have artificially created the associations seen in this study ``only by
underrepresenting cases who were unexposed, and/or controls who were
exposed, to solvents in general, and MC in particular'' [Ex. 113].
Heineman further remarked that differential misclassification was
probably not a problem in this study because occupational histories
came from next-of-kin of both cases and controls.
In light of the limitations of this study, however, Heineman et al.
commented that the consistency of exposure-response trends for MC was
surprising and suggestive. Moreover, Heineman et al. believed that the
trends and consistency of the associations between brain cancer and MC
could not be explained by chance alone.
Several commenters [Exs. 115-1, 115-31, 115-32, 115-36] indicated
that Heineman et al. relied too heavily on next-of-kin information.
Information provided by next-of-kin concerning jobs held, job
descriptions, dates of employment, and hours worked per week may be
flawed with recall bias. Next-of-kin may not be able to accurately
recall job-related information, especially for jobs held early in life.
If next-of-kin for cases or controls had better recall than the other
group, differential misclassification could occur. HSIA [Ex. 115-36]
stated that even small differences in error rates between cases and
controls could produce false associations. Both HSIA and NIOSH [Ex.115-
31] agreed that this indirect source of exposure information was likely
to produce some degree of misclassification. However, NIOSH noted that
misclassification ``is a typical problem in population based case-
control studies of this type [Ex. 115-31]'' and that this
misclassification could also explain the fact that no associations were
found between brain cancer and the cumulative exposure score.
Organization Resources Counselors (ORC) [Ex. 115-2] and Abbott
Laboratories [Ex. 115-30] were concerned that the lack of exposure
verification made this NCI study unreliable for setting MC exposure
limits. ORC stated that exposure values were assigned to all SIC and
SOC codes, and not developed based on job history information, which
would have given the study more validity. Kodak also expressed some
concern regarding this study due to lack of accurate records of past
exposures, reliance on expert judgement to a large degree, use of next-
of-kin to determine potential exposure, and undocumented qualifications
of those making judgements concerning the different occupations and
industries involved. In addition, Kodak felt that the exposure data
were ``at best, unsubstantiated semi-qualitative judgements of
likelihood and intensity of exposure [Ex. 115-1].'' Organization
Resources Counselors [Ex. 115-2] and Abbott Laboratories [Ex. 115-30]
asserted that it was impossible to tell if those who died of cancer had
been exposed to MC because there was no exposure verification. Vulcan
Chemicals [Ex. 115-32] criticized the investigators for not going to
work sites and determining the actual magnitude of exposure to the
CAHs. HSIA [Ex. 115-36] argued that ``concordance of proxy reports with
actual work histories may range from 0-50% for decedents' first jobs
and from 50-70% for last jobs.'' OSHA believes that exposure
verification would have increased the validity of the findings of this
study. However, lack of exposure verification does not nullify the
results of the study. The Agency believes that the associations
observed are suggestive of a human carcinogenic effect of MC.
Another issue that Kodak [Ex. 115-1] and Vulcan [Ex. 115-32]
emphasized was the possible exposure to other chemicals or sources of
potential human carcinogens, such as ionizing radiation,
electromagnetic fields, smoking history, and place of residence. Vulcan
[Ex. 115-32] noted that there may have been selection bias in this
study because of the large ratio of astrocytic brain cancer tumors to
the total number of brain tumors. Although they offered no explanation
of how this selection bias would operate, Vulcan did suggest that this
issue should be investigated further.
Vulcan was also concerned that the matching of controls and cases
with respect to occupations and socioeconomic status may be inadequate.
In particular, Vulcan criticized the Heineman study for not presenting
the occupations of the control group and for not matching the
socioeconomic status of the two groups. Similarly, Kodak [Ex. 115-1]
stated that some adjustment should have been made in order to match
across educational levels.
Kodak [Ex. 115-1] also believed that the estimates of trends
observed in this study could have been affected, if workers in the
longest duration or the higher probability of exposure categories had
longer dates of employment, worked in more stable industries, and had
better health benefits, better access to medical care, and more
sophisticated diagnostic procedures. OSHA believes that there is no
evidence that this is the case in this study.
HSIA [Ex. 115-36] criticized the methodology for assessing the
number of industries with exposures to CAHs. HSIA argued that Gomez et
al. did not fully explain how they determined that workplaces in the
specific SICs would have CAH exposures. According to HSIA, Gomez et al.
reported inaccurate
[[Page 1510]]
information regarding industry use of MC. HSIA cited EPA's ``Toxic Air
Pollutant/Source Crosswalk, A Screening Tool for Locating Possible
Sources Emitting Toxic Air Pollutants (EPA-450/4-87-023A, Dec. 1987)''
which revealed a higher number of SIC codes using MC. In conclusion,
HSIA asserted that Gomez et al.'s ``exposure scenario'' was incorrect.
Several commenters [Exs. 115-1, 115-31, 115-36] argued that the
Heineman et al. study should only be considered a hypothesis-generating
study and should not be used to adjust the PEL.
OSHA agrees with NIOSH that the Heineman et al. study was well-
conducted because there was a systematic attempt to estimate exposure
by work experience. Furthermore, there was a remarkably high
correlation between exposure to MC and brain tumors. OSHA concludes
that the results from this study strongly suggest a possible
association between MC and brain cancer. However, in the absence of
quantified exposure data for these workers, it remains relatively
speculative to attempt to estimate a quantitative dose-response
relationship. Therefore, OSHA concludes that the risk estimate based on
the animal data is the best available and accordingly it retains that
estimate for its significant risk analysis.
e. Summary of epidemiological studies. Considered as a whole, the
available epidemiologic evidence did not demonstrate a strong,
statistically significant cancer risk associated with occupational
exposures to MC. However, the positive trend for biliary tract/liver
cancer deaths, the association between occupational MC exposure and
astrocytic brain cancer and the statistically significant excess
prostate cancer results are suggestive of an association between MC
exposure and cancer risk. In addition, the non-positive epidemiological
studies summarized here are not of sufficient power to rule out the
positive results from the animal studies. This issue is addressed
further in the Quantitative Risk Assessment section of this document.
In summary, the epidemiological results are suggestive of an
association between occupational exposure to MC and elevated cancer
risk which offers supporting evidence to the positive animal bioassay
results.
4. Conclusion
OSHA concludes from the mutagenicity, animal bioassay and human
epidemiology data that MC causes cancer in test animals and that it is
a potential occupational carcinogen. The Agency has determined that,
because of the quality of the studies, the clear dose-response
relationship and the appropriateness of the route of administration,
the NTP rodent bioassay data are the best available for quantitative
cancer risk assessment.
OSHA also concludes that the epidemiology data, in some cases,
suggest a positive association between human MC exposure and cancer
incidence, but the dose-response relationships are not clear. The
Agency has determined that the remaining epidemiology data (the non-
positive studies) are not of sufficient power to rule out the results
obtained in the animal bioassay data and that the animal data provide
the best available data for quantitative risk assessment.
E. Other Toxic Responses
1. Central Nervous System Toxicity
MC acts on the central nervous system (CNS) as a CNS depressant.
CNS depression has been described in humans exposed to MC
concentrations as low as 175 ppm (8-hour TWA). This depression in CNS
activity was manifested as increased tiredness, decreased alertness and
decreased vigilance. These effects could compromise worker safety by
leading to an increased likelihood of accidents following MC exposure.
a. Animal studies. In the NPRM, OSHA reviewed two animal studies of
MC CNS toxicity (briefly summarized below) and concluded that the CNS
was potentially susceptible to reversible and irreversible effects due
to MC exposure.
Savolainen et al. [Ex. 7-178] studied biochemical changes in the
brains of rats exposed to MC. Rats were exposed to 500 ppm MC for 6 hr/
d. On the fifth day, after 3 and 4 hours of exposure to MC, levels of
acid proteinase in rat brains were significantly increased, but no
change in brain RNA levels was reported. The authors suggested that the
increase in acid proteinase may have been the result of increased
levels of CO from metabolism of MC. OSHA believes that this study shows
that MC can cause specific changes in the neurological system at a
biochemical level. The Agency intends to monitor the scientific
literature for additional developments on these effects, but has not
used this information in setting the MC exposure limits because it is
presently unclear how changes in acid proteinase are related to the
observed CNS depressive effects of MC in humans.
Rosengren et al. [Ex. 7-56] looked at the effects of MC on glial
cell marker proteins and DNA concentrations in gerbil brains after
continuous exposure to 210, 350 or 700 ppm MC. Because of high
mortality in the 2 higher doses, no data were collected at 700 ppm and
exposure was terminated after 10 weeks at 350 ppm. Exposure to 210 ppm
was continued for three months. Exposure to MC was followed by four
months of no exposure before animals were examined for irreversible CNS
effects. The authors found increased levels of glial cell marker
proteins in the frontal cerebral cortex and sensory motor cortex after
exposure to 350 ppm MC. These findings are consistent with glial cell
hypertrophy or glial cell proliferation. Levels of DNA were decreased
in the hippocampus of gerbils exposed to both 210 and 350 ppm and in
the cerebellar hemispheres after 350 ppm MC. Decreased DNA
concentrations indicate decreased cell density resulting from cell
death or inhibition of DNA synthesis.
The neurotoxic mechanism of action of MC in gerbil brains is not
understood. However, since the metabolism of MC to CO was determined to
be saturated at both 210 and 350 ppm (COHb levels were equivalent at
both exposure concentrations), the changes in glial cell proteins and
DNA concentrations was attributed to either a direct effect of MC or an
effect of a metabolite of the GST pathway. Although this study
describes biochemical changes in the CNS subsequent to MC exposure, the
high mortality of the experimental animals and the lack of MC toxicity
data in the gerbil make it difficult to determine the significance of
this study for extrapolation to other species. It is also unclear how
these effects would relate to CNS depression observed in humans after
MC exposure. In addition, continuous exposure to MC has been shown in
other experimental situations [Exs. 7-14 and 7-130] to elicit more
severe health effects than exposure to similar or higher concentrations
when the animals are allowed a recovery period (for example, 6 hours'
exposure per day). Exposure on a 6 or 8-hour per day schedule is also
more like occupational exposure scenarios and therefore those
experiments are generally easier to interpret when assessing risk to
workers.
In summary, OSHA believes that the rat and gerbil data described
above shows that MC can cause specific changes in the neurological
system at a biochemical level. The Agency intends to monitor the
scientific literature for additional developments on these effects to
determine if these types of effects have implications for human CNS
risks.
[[Page 1511]]
b. Human studies. The CNS depressant effects of MC have been well
described in the literature [Exs. 7-4, 7-153, 7-154, 7-160, 7-175, 7-
182, 7-183, 7-184]. MC causes CNS depression which is characterized by
tiredness, difficulty in maintaining concentration, decreased task
vigilance, dizziness, headaches, and, at high concentrations, loss of
consciousness and death. Accidental human overexposures to MC [Exs. 7-
18, 7-19] (for example, at concentrations greater than 10,000 ppm) have
resulted in narcosis and death. CNS depression has been described after
humans were exposed to experimental MC concentrations as low as 200 ppm
[Ex. 7-175] and occupational concentrations as low as 175 ppm [Ex. 7-
153].
i. Experimental studies. CNS depression was detected in human
subjects exposed to MC at concentrations as low as 200 ppm for 4 hours
or 300 ppm for 1.5 hours [Exs. 7-4, 7-160, 7-175, 7-182 and 7-184]. In
these experiments, which measured subtle CNS depression (such as dual
task performance and visual evoked response), it was not possible to
determine a no observed effect level (NOEL), because the lowest
experimental concentration used (200 ppm) elicited CNS effects. Since a
NOEL was not determined for the CNS effects of MC, those effects may
occur at lower exposures or after exposure for shorter durations.
The HSIA questioned whether bias was introduced into the results of
these studies by inadequate procedures to establish a ``double blind.''
This criticism raises a legitimate concern about the validity of the
study. However, since Putz et al. did not describe the blinding
procedures used in their experiments, the Agency concludes that there
is not enough evidence publicly available to make the conclusion that
the study is biased. OSHA believes that these studies were well
conducted and is relying on the quality of the studies overall as
evidence of the validity of the results. Absent evidence demonstrating
the inadequacy of the blinding procedures, OSHA has determined that
these studies show that MC can cause mild CNS depression in humans
exposed at concentrations as low as 200 ppm.
NIOSH expressed concern regarding the potential for neurobehavioral
impairment (expressed as CNS depression) at lower exposures and shorter
durations, particularly in relation to the setting of a STEL for MC
[Exs. 23-18 and 94]. In order to assess the potential impact of the CNS
effects of MC, NIOSH looked at data gathered from several studies and
compared breath concentrations of MC (as a surrogate for brain tissue
MC concentrations) at different ambient exposure levels with the CNS
depression described by Putz et al. [Ex. 7-175]. NIOSH concluded that:
At the proposed STEL of 125 ppm, increased uptake of MC in
active workers may place them in the breath concentration range
associated with mild neurobehavioral impairment. Although there are
insufficient data to draw firm conclusions, extrapolation from
existing studies suggests that the proposed STEL of 125 ppm may not
fully protect physically active workers from CNS impairment.
Therefore, a lower STEL should be considered, if feasible.
In response to concerns raised by NIOSH, the HSIA [Ex. 105] noted that
NIOSH's analysis of breath MC concentration versus neurobehavioral
impairment ``seemed highly speculative.'' HSIA emphasized that the
exposures which produced the reported neurobehavioral effects were
observed only after 2 to 4 hours of exposure and that the effects were
observed only when difficult tasks were measured.
To support their position, the HSIA asked Mr. Richard Reitz to use
a PBPK model to estimate the concentration of MC in brain tissue. This
analysis [Ex. 105] indicated that at exposures of 200 ppm for 15
minutes with persons exercising at 50 watts, the brain concentration of
MC would be predicted to be similar to that observed in the Putz et al.
study for subjects engaged in ``light activity'' for 2 hours at 200 ppm
MC, which did not produce measurable CNS depression. (Putz et al. did
not detect CNS depression in subjects exposed to 200 ppm for 2 hours).
The model also predicted that 15-minute exposures to 125 ppm while the
subject was exercising at 50 watts would produce brain MC
concentrations substantially less than that predicted for the 4 hour
exposure to 200 ppm MC.
OSHA considered the PBPK analysis presented by the HSIA, but was
concerned that there has been no experimental validation of the
predicted brain MC concentrations or any evidence as to what MC
concentration would produce detectable CNS depression. OSHA believes
the primary value of both the NIOSH and HSIA analyses is in
demonstrating the relative effect that exercise and duration of
exposure is likely to have on brain (or breath) concentrations of MC.
The PBPK analysis clearly demonstrates that increasing exercise level
increases brain concentration of MC, which is consistent with the
detected CNS depression. Workers engaged in strenuous activity while
exposed to MC should take special precautions, such as frequent breaks
in fresh air, especially if dizziness or lightheadedness occurs.
Although OSHA found the PBPK model to be useful for demonstrating
the interaction between exercise and brain concentration of MC, the
Agency did not use the model quantitatively (for example, in
determining the STEL). OSHA believes that the data suggest that there
may be CNS effects at levels below those tested. There are no studies
which directly address whether there are CNS effects after exposure to
STEL concentrations of MC. To the extent that these effects occur, the
STEL would not be protective. Mild and reversible CNS depression was
detected at 200 ppm for 4 hours and 300 ppm for 1.5 hours. The Agency
shares NIOSH's concern, based on extrapolation of breath MC
concentrations, that the proposed STEL may not be adequately protective
for physically-active workers.
OSHA concludes that there are clearly sufficient data to determine
that a 125 ppm 15-minute STEL is needed to prevent a significant risk
of material impairment to the CNS. Impairment of the CNS would also
increase the risk from accidents. Measured data show risks at 200 ppm
for four hours of exposure. A lower level at shorter duration is needed
to avoid that risk. NIOSH's calculations show that for active workers a
level lower than 125 ppm may be needed. However, because of feasibility
concerns, which would be greater at lower levels and the suggestion
that short duration of exposure (i.e., 15-minutes) may mitigate the
effects, OSHA is retaining the proposed level, but will carefully
monitor and follow up data to determine if this level eliminates
significant risk.
ii. Occupational exposure studies. In the NPRM, OSHA summarized
studies which it believed described a neuropathy associated with
chronic occupational exposure to solvents. Weiss [Ex. 7-196] described
the case of a 39-year old chemist who worked for 5 years with airborne
concentrations of MC as high as 660 ppm to 3600 ppm in a room with poor
ventilation. After 3 years of exposure, the worker developed
neurological symptoms, characterized by restlessness, palpitations,
forgetfulness, poor concentration, sleep disorders, and finally,
acoustical delusions and optical hallucinations. No hepatic damage or
cardiac toxicity was found. At the first appearance of symptoms,
cessation of exposure produced an immediate cessation of symptoms.
Later, longer and longer periods were required after termination of
exposure in order to alleviate the
[[Page 1512]]
symptoms. The increasing persistence of symptoms is consistent with a
diagnosis of toxic encephalosis.
Hanke et al. [Ex. 7-195] examined 32 floor tile setters who were
exposed primarily to MC at concentrations from 400 to 5300 ppm for an
average tenure of 7.7 years. Clinical examination of 14 of the workers
who had neurological symptoms (headache, vertigo, sleep disturbance,
digestive complaints and lapses in concentration and memory) revealed
changes in the EEG patterns of the exposed workers which persisted over
a weekend pause in exposure. These EEG changes were characteristic of a
toxic encephalosis produced by chronic intoxication with a halogenated
solvent (MC). The persistence of the EEG changes over the weekend break
indicated a prolonged effect of MC exposure on EEG patterns.
(Additional changes in the EEG found during exposure could be
attributed to an acute effect of MC). Although these studies represent
a small number of cases with very high chronic exposures, the evidence
is suggestive of a relationship between chronic MC exposure and toxic
encephalosis.
In a case study report, Barrowcliff et al. [Ex. 7-123] attributed
cerebral damage in a case study to CO poisoning caused by exposure to
MC. Axelson [Ex. 7-150] has described an increased number of
neuropsychiatric disorders among occupations with high solvent
exposures.
In the NPRM, OSHA expressed the opinion that these studies, taken
together, ``provide suggestive evidence of a permanent toxicity
[different from the observed reversible CNS depression] which may be
the result of chronic exposure to MC.'' NIOSH stated that this
assessment was too speculative and stated,
in the Hanke study, MC was apparently only one component of a
solvent mixture and may not have been the only neurotoxic agent* * *
In addition, the observation interval of 2.5 days was not long
enough to provide convincing evidence of irreversible effect,
regardless of the active agent.
Upon reexamination of these studies, OSHA agrees with NIOSH [Ex. 19-46]
that although a prolonged effect (over a weekend break in exposure) of
MC on EEG patterns has been demonstrated, these studies do not support
a determination that MC exposure is associated with irreversible brain
damage in humans.
OSHA reviewed several other studies of occupational exposure to MC
for evidence of CNS effects of MC. The first study was provided as an
English translation of a Czechoslovakian paper by Kuzelova et al. [Ex.
7-26]. These investigators examined workers in a film production plant
who were exposed to MC concentrations from 29 to 4899 ppm. Several
workers suffered frank MC intoxication and many workers showed signs of
MC-induced CNS depression. Toxicity associated with chronic MC exposure
was observed in workers exposed to MC for up to two years, but the
authors recommended continuing studies of the long-term health effects.
OSHA believes that this study shows CNS depression in workers
exposed to MC. The Agency agrees with the authors that this study was
not sufficient to adequately characterize the long-term CNS health
effects that may be induced by MC exposure.
Cherry et al. [Ex. 7-154] studied the effects of occupational
exposure to MC at 28 to 175 ppm in two exposed populations. In a 1981
study, the authors found a marginal increase in self-reported
neurological symptoms among exposed workers. This increase disappeared
when an appropriate reference group was used for comparison. However,
in a 1983 investigation, Cherry [Ex. 7-153] showed statistically
significant increases in tiredness and deficits in reaction time and
digit symbol substitution which correlated with MC in blood. Ambient MC
exposures for this population ranged from 28 to 175 ppm for the full
shift. This study demonstrated CNS effects due to occupational MC
exposures below 200 ppm (the lowest dose which was administered in the
experimental studies).
The HSIA [Ex. 105, p. 34] commented as follows:
Decades of experience with worker populations exposed even at
levels up to the current 500 ppm TWA have provided no evidence that
such workers have higher rates of accidents or other signs of
significant neurobehavioral impairment.
To the contrary, OSHA believes that the occupational studies
discussed above demonstrate that MC has an effect on the CNS at
occupational exposure levels as low as 175 ppm.
The Agency believes that the 1983 study by Cherry shows that
occupational exposure to MC concentrations below the former 8-hour TWA
PEL of 500 ppm can produce detectable CNS effects. Although the 1981
study, which relied on self-report of neurological symptoms, did not
demonstrate a CNS effect, the 1983 study examined more objective
measures of CNS depression and correlated the observed effects with a
direct measure of MC exposure. OSHA believes that this study
demonstrates that, although the CNS depression may be mild, it is
demonstrable in occupational settings and at concentrations in the
range of the STEL (although the exposures in this study were over an 8-
hour work day). As described above, OSHA is sufficiently concerned
about the potential for health effects at concentrations below the STEL
of 125 ppm that it will continue to gather information and revisit this
issue, if warranted.
2. Cardiac Toxicity
As described in the section on the metabolism of MC, MC is
metabolized in vivo (in animals and humans) to CO and CO2.
Cardiovascular stress has been observed after exposure to CO, so it is
reasonable to suspect that similar health effects would be observed
after exposure to MC (and metabolism to CO) [Ex. 7-73, 4-33].
Carbon monoxide successfully competes with oxygen and blocks the oxygen
binding site on hemoglobin, producing carboxyhemoglobin (COHb) and
reducing delivery of oxygen to the tissues. This reduces the oxygen
supply to the heart itself, which can result in myocardial infarction
(heart attack) [Ex. 4-33].
Generally, humans have a baseline level of COHb of less than 1%
COHb due to the endogenous production of CO from normal metabolic
processes. The measured level of COHb in the general non-smoking
population is from 1% to 3% because of direct exposure to CO from
combustion sources such as automobiles, etc. In smokers, COHb generally
ranges from 2% to 10% because of the additional CO exposure during
smoking. CO generated from exposure to MC would be additive to the COHb
burden already experienced by an individual from direct exposure to CO.
The cardiac health effects anticipated from exposure to MC itself or CO
as the result of metabolism of MC are described below.
a. Animal studies. There is no evidence from animal studies in the
MC rulemaking record that MC has a direct toxic effect on cardiac
tissue. After lethal doses of MC, death has been primarily attributed
to CNS and respiratory depression [Exs. 7-27, 7-28]. Also, chronic
studies (in which COHb levels have been maintained at 10% and higher)
[Exs. 7-3, 7-8, 7-14, 7-130, 7-151] have not shown direct
cardiotoxicity.
Chlorinated solvents have been shown to sensitize the cardiac
tissue to epinephrine- induced fatal cardiac arrhythmias [Ex. 7-226].
However, MC is less effective in sensitizing cardiac
[[Page 1513]]
tissue than other chlorinated analogues. MC caused sensitization of
cardiac tissues only at doses well above doses which produce a narcotic
effect. This finding indicates that compliance with an 8-hour TWA of 25
ppm MC would likely be sufficient to protect against such
sensitization.
b. Human studies. The metabolism of MC to CO and measurement of
COHb in human subjects exposed to MC were described in detail in the
NPRM. In summary, it was found that exercising increased MC uptake and,
subsequently, increased blood COHb levels compared to that of sedentary
individuals [Ex. 7-222]. In addition, COHb levels due to smoking were
found to be additive to the COHb produced by MC metabolism. Taken
together, these results suggested that smokers or individuals engaged
in physical exertion (as in a workplace) may be at increased risk from
CO- induced toxicity from MC exposure. This risk may be especially
elevated in individuals with silent or symptomatic cardiac disease who
may be susceptible to very small increases in COHb because of an
already impaired blood supply to the heart. Many American workers have
silent or symptomatic heart disease. This increased OSHA's concern for
the potential cardiac effects of MC and its metabolites.
Elevated COHb has been measured in humans experimentally and
occupationally exposed to MC [Exs. 7-4, 7-5-R0327, 7-102, 7-115, 7-157,
7-159, 7-169, 7-174, 7-176]. The effects of elevated COHb are primarily
increased risk of myocardial infarction, especially in susceptible
individuals. Atkins and Baker [Ex. 7-198] described two cases of
myocardial infarction in workers subsequent to CO exposure. COHb was
measured at 30% and 24% in these individuals, which is much higher than
normal general population levels of COHb. Humans exposed to MC would
not be expected to experience COHb at those levels unless the exposure
to MC was extremely high (greater than 500 ppm).
In a laboratory study of humans with coronary artery disease,
subjects were exposed to CO and observed for cardiac health effects
during exercise. In subjects with 3 to 10% COHb, decreased exercise
tolerance and increased anginal pain were observed [Ex. 7-198]. In an
epidemiological study submitted to OSHA by NIOSH during the MC public
hearings, the investigators observed a statistically significant excess
of ischemic heart disease mortality among tunnel workers when compared
with rates for the New York City population [Ex. 23-18]. This increase
in mortality is supported by clinical findings. Allred et al. [Ex. 23-
18] observed that elevation of COHb from 0.6% to as low as 2% decreased
time to myocardial ischemia and anginal pain during laboratory tests.
OSHA believes that these studies, taken together, suggest that small
increases in COHb can adversely affect persons with compromised cardiac
health. The results observed in the tunnel workers are particularly
relevant because they show an increased risk in a working population.
NIOSH used these studies to support its recommendation that the COHb
effects of MC be carefully considered in the MC rulemaking [Tr. 881-2,
9/21/92]. OSHA agreed with NIOSH that the effects observed at low
levels of COHb are cause for concern about the risks of MC metabolism
to CO.
In the NPRM, OSHA also reviewed case reports in which individuals
exposed to MC experienced myocardial infarctions [Exs. 7-102, 7-73].
These case reports suggested that exposure to MC increased cardiac
stress, although it was not determined whether this was a direct effect
of MC or as the result of metabolism of MC to CO. OSHA believes that
these case studies support the hypothesis that CO generated through
metabolism of MC would have the same adverse health effects as direct
CO exposure.
Two epidemiological studies (in film coating and fiber production
workers) [Exs. 7-75, 7-76, 7-122, 7-163] examined cardiac mortality due
to occupational exposure to MC. Ott [Ex. 7-76] compared mortality from
a plant in South Carolina that used MC to a reference plant in
Virginia. An increased risk ratio for ischemic heart disease (risk
ratio = 3.1) was observed in the MC-exposed workers compared to the
reference population.
This approach controls for the healthy worker effect by comparing
two working populations, and excess risk was demonstrated. The authors
believed that the apparent excess risk was due to geographical
variability in the incidence of ischemic heart disease. The population
from the reference plant was found to have an unusually low death rate
due to ischemic heart disease in comparison to the general population
rate.
In an update of the study [Ex. 7-75], the ischemic heart disease
rate in the exposed population was compared to that in the surrounding
York County, S.C. population instead of a reference plant. No
difference in ischemic heart disease rates was detected between exposed
workers and controls, although this approach would not control for the
healthy worker effect. The SMR was 0.94 (32 observed, 34.2 expected).
NIOSH disagreed with the conclusion of the authors of this study,
and indicated that the studies summarized above would be cause for
concern regarding the cardiac effects of MC. NIOSH suggested that the
raw data from the epidemiological studies of cellulose acetate film
production workers and the studies of workers in cellulose acetate
fiber manufacture be reviewed for cardiac mortality occurring during
the period of occupational exposure for the workers. OSHA is concerned
about the potential CO effects from metabolism of MC and will continue
to monitor the scientific literature on this topic. However, the Agency
is setting the exposure limits based on cancer and CNS effects and has
not reached final conclusions on this issue.
3. Hepatic Toxicity
Chlorinated hydrocarbons as a class, such as carbon tetrachloride
and chloroform, are toxic to the liver. In general, chlorinated
hydrocarbons cause cytotoxicity (cell death) in rodent livers.
Therefore, there was suspicion that the liver would also be a target
organ for MC (a chlorinated hydrocarbon) toxicity. OSHA evaluated the
available literature on the hepatic effects of MC in animal and human
studies.
a. Animal studies. Studies of the effects of MC exposure on the
rodent liver have not demonstrated significant acute liver toxicity,
even at lethal or near-lethal doses. As summarized in the NPRM, Kutob
et al. [Ex. 7-27] and Klaassen et al. [Ex. 7-28] conducted experiments
on halogenated methanes and hepatotoxicity. MC was determined to be the
least hepatotoxic of the halogenated methanes examined. The only injury
described was a mild inflammatory response associated with lethal MC
concentrations. These studies demonstrated that liver was not the
primary target organ for the acute toxicity of MC.
Weinstein et al. [Ex. 7-181] examined the hepatic effects of MC on
female mice who were continuously exposed for up to 7 days to MC
concentrations of up to 5000 ppm. Mild, nonlethal injury to the livers
was noted, characterized by balloon degeneration of the rough
endoplasmic reticulum (RER), transient severe triglyceride accumulation
(fatty liver), partial inhibition of protein synthesis and breakdown of
polysomes into individual ribosomes. The injury is similar to a mild
form of carbon tetrachloride toxicity (a structural analog of MC) and
suggests that although the toxicity due to MC is not as severe as that
produced by carbon tetrachloride, the mechanism of toxicity may be
similar.
[[Page 1514]]
In subchronic experiments more severe effects were observed in the
liver after continuous exposure. MacEwen et al. [Ex. 7-14] studied the
effects of continuous exposure of mice, rats, dogs and rhesus monkeys
to 1000 and 5000 ppm MC for up to 14 weeks. Fatty liver, icterus,
elevated SGPT and ICDH were reported in dogs at both concentrations.
These effects appeared at 6-7 weeks of exposure to 1000 ppm MC and at 3
weeks of exposure to 5000 ppm. Monkeys were less sensitive to hepatic
injury, and showed no changes in liver enzymes and only mild to
moderate liver changes at 5000 ppm MC. No liver alterations were
detectable in monkeys exposed to 1000 ppm MC. Mice and rats developed
liver toxicity at both exposure levels, characterized by increased
hemosiderin pigment, cytoplasmic vacuolization, nuclear degeneration
and changes in cellular organization.
Hepatic effects associated with chronic MC exposure were observed
in lifetime cancer bioassays in three rodent species: rats, mice and
hamsters. In studies conducted by the NTP and Dow Chemical Co., rats
were exposed to inhalation concentrations of MC from 50 ppm to 4000 ppm
6 hours per day, 5 days per week [Exs. 7-8, 7-151, 7-173]. Hepatic
effects were observed after exposure to MC concentrations as low as 500
ppm. These effects were characterized by increased fatty liver,
cytoplasmic vacuolization and an increased number of multinucleated
hepatocytes. At higher doses (greater than 1500 ppm), increased numbers
of altered foci and hepatocellular necrosis became apparent.
Serota et al. [Ex. 7-180] administered 5 to 250 mg MC/kg body
weight to rats in drinking water. Hepatic toxicity similar to that
observed in the inhalation studies was reported at doses from 50 to 250
mg/kg.
In mice, the chronic hepatic effects of MC were investigated in two
bioassays: NTP [Ex. 7-8] and Serota et al. [Ex. 7-179]. In the NTP
study, mice were exposed by inhalation to 2000 or 4000 ppm MC.
Cytologic degeneration was observed in both male and female mice and
increased incidences of hepatocellular adenomas and carcinomas were
found at both concentrations. The carcinogenic effects of MC are
described in greater detail above, in the discussion of MC
carcinogenicity.
In a drinking water study, Serota et al. found that mice exposed to
50 to 250 mg/kg/d MC had dose-related increases in the fat content of
the liver (a sign of liver toxicity). Although some proliferative
hepatocellular lesions were identified in this study, they were
distributed across all exposure groups. Hepatocellular tumor incidences
were not elevated above historical control incidences.
In the hamster, Burek et al. [Ex. 7-151] found minimal treatment-
related changes in the livers of the MC-exposed animals after exposure
to 500, 1500 or 3500 ppm MC. A dose-related increase in hemosiderin was
found in male hamsters at 6 months and at 3500 ppm at 12 months. No
other changes in liver physiology were reported.
OSHA believes that these studies demonstrate that the rodent liver
is not sensitive to acute affects of MC, but that chronic exposure to
MC caused toxic effects in rat and mouse liver and cancer in mouse
liver. These studies appear to have been well conducted and the
differences in toxicity observed across studies were likely due to
differences in dose or route of exposure. The hamsters appeared to be
insensitive to liver toxicity. OSHA believes that this is most likely
due to inherent species differences in response to toxicants.
b. Human studies. OSHA evaluated epidemiological studies and case
reports to determine the extent of hepatic effects detected after
exposure of humans to MC. Liver toxicity was measured as alterations in
the blood levels of any of several normal liver enzymes in these
studies.
i. Epidemiological studies. In a cross-sectional analysis of the
health of workers in an acetate fiber production plant in which workers
were exposed to 140 to 475 ppm MC, Ott et al. [Ex. 4-33c] reported
statistically significant increases in serum bilirubin and alanine
aminotransferase (ALT) (also known as serum glutamic pyruvic
transaminase (SGPT)) when compared with a reference group of industrial
workers. The elevation in bilirubin levels showed a dose-response
relationship, but the ALT levels were not associated with MC exposure.
The authors felt that the increase in ALT in MC-exposed workers could
not be attributed to MC because a dose-response relationship was not
demonstrated and, therefore, the increase in ALT between the exposed
and reference populations could be disregarded as a sign of liver
toxicity. The authors concluded that although bilirubin elevation may
be interpreted as a sign of liver toxicity, this interpretation was not
supported by alterations in other liver parameters. OSHA feels that ALT
cannot be disregarded as unrelated to MC exposure based on the lack of
dose response within the exposure group. The high variability of this
parameter and the low numbers of individuals within certain exposure
subgroups (e.g., 10 men exposed at 280 ppm), make a dose-response
relationship more difficult to demonstrate. Any mistake made in the
characterization in an exposure group would result in obscuring the
dose-response relationship. Although the evidence is not unequivocal,
OSHA believes that the elevated bilirubin coupled with the elevated ALT
values indicate suggestive evidence of a hepatotoxic response to MC
exposure in this worker population.
In an update to the study described above, Cohen et al. [Ex. 7-75]
found 4 cases of liver/biliary duct cancer in workers with more than 10
years of exposure to MC and after 20 years from first hire. Further
description of this study can be found in the discussion of MC
carcinogenicity, above.
In an English translation of a 1968 Czechoslovakian study, Kuzelova
et al. [Ex. 7-26] found no liver enzyme abnormalities in workers
exposed to MC concentrations from 29 ppm to 4899 ppm for up to two
years. In contrast, in an English translation of a German study which
focussed on neurological changes due to MC exposure, Hanke et al. [Ex.
7-195] observed pathological liver function tests and hepatomegaly
(enlarged liver) in 4 of 14 floor tile setters examined. These workers
were chronically exposed to MC at concentrations as high as 400 to 5300
ppm. The average tenure of employment of these workers was 7.7 years.
The authors of the Hanke study noted that although MC with its
impurities could be responsible for the liver damage, the evidence was
not conclusive. OSHA has determined that there is insufficient evidence
from the Kuzelova and Hanke studies to conclude that MC causes chronic
human hepatotoxic effects.
ii. Case reports. In addition to the cross-sectional analyses of
worker morbidity described above [Exs. 4-33c and 7-26], the
relationship of MC exposure and hepatotoxicity has been studied by
analysis of case reports. Welch [Ex. 7-73] collected 144 case reports
of clinical disease reported subsequent to occupational MC exposure.
Quantitative exposure estimates for individuals were unreliable, but
the presence of MC in the work environment was ascertained for each
employee. The most prevalent findings in these case reports were CNS
symptoms, upper respiratory syndrome and alterations in liver enzymes.
The patterns of alteration in liver enzymes were not consistent among
individuals, but may be suggestive of a MC-associated hepatotoxic
effect. One case of hepatitis of unknown etiology was identified. The
case physician believed
[[Page 1515]]
that the hepatitis was secondary to solvent exposure. The solvents to
which this employee was exposed included xylene and methylethyl ketone
as well as MC. OSHA believes that the confounding solvent exposures in
the hepatitis case and the unknown exposure histories of the
individuals with altered liver enzymes limit the interpretation of
these studies. OSHA has determined that these case reports provide
insufficient evidence to conclude that MC was the causative agent in
these cases.
Analysis of cases of fatal and near-fatal human exposures [Exs. 7-
18, 7-19] indicated no apparent acute alterations of liver function.
Acute concentrations of MC which caused narcosis and even death were
not associated with changes in liver enzymes.
OSHA concludes that limited evidence supports the hypothesis that
MC causes human hepatotoxicity, based on the data in the Ott study. The
remaining studies and case reports do not provide clear evidence of a
causative role of MC in hepatotoxicity. The Agency has set the exposure
limits based on cancer and CNS effects and has not reached final
conclusions on this issue.
4. Reproductive Toxicity
There are only limited data available regarding the potential
adverse teratogenic or reproductive effects due to MC exposure.
Teratogenicity studies have been conducted in rats and mice and limited
epidemiology and case reports have been described for humans.
a. Animal studies. A study [Ex. 4-5] using chicken embryos
indicated that MC disrupts embryogenesis in a dose-related manner.
Since the application of MC to the air space of chicken embryos is not
comparable to MC administration to animals with a placenta, the
exposure effect seen in the chick embryos can only be considered as
suggestive evidence that an effect may also occur in mammalian systems.
The teratogenicity of inhaled MC has also been studied in rats and
mice [Exs. 7-20, 7-21, 7-22]. In 1975, Schwetz et al. [Ex. 7-21]
conducted a study on Swiss Webster mice. Mice were exposed to 1250 ppm
MC for 7 hours/day, on days 6-15 of gestation. On day 18 of gestation,
Caesarian sectioning of dams was performed. A statistically significant
increase in mean maternal body weight (11-15%) was observed in dams
exposed to 1250 ppm MC; however, food consumption was not measured. The
only effect on fetal development associated with MC exposure was a
statistically significant increase in the number of fetuses which
contained a single extra center of ossification in the sternum. The
incidence of gross anomalies observed in the MC-exposed fetuses was not
significantly different from that in the control litters. Maternal COHb
level during exposure reached 12.6%; however, 24 hours after the last
exposure, COHb had returned to control levels.
In the same study by Schwetz et al. [Ex. 7-21], Sprague-Dawley rats
were exposed to 1250 ppm MC via inhalation for 7 hours daily on days 6-
15 of gestation. No MC-associated effects were observed in food
consumption or maternal body weight. Among litters from MC-exposed
dams, the incidence of lumbar ribs or spurs was significantly decreased
when compared to controls, while the incidence of delayed ossification
of sternebrae was significantly increased compared to controls. No
increased incidence of gross anomalies were observed in the fetuses
from exposed rats compared to fetuses from control litters. No MC-
associated effects were observed on the average number of implantation
sites per litter, litter size, the incidence of fetal resorptions,
fetal sex ratios or fetal body measurements, in the 19 litters that
were evaluated. As observed in the MC-exposed mice, there was
significant elevation of the COHb level in the dams, but the level
returned to control values within 24 hours of cessation of exposure.
In 1980, Hardin and Manson [Ex. 7-22] evaluated the effect of MC
exposure in Long-Evans rats after inhalation of 4500 ppm for 6 hours/
day, 7 days/week prior to and during gestation. Four exposure groups
were described. The first group was exposed to MC for 12 to 14 days
prior to gestation and during the first 17 days of pregnancy. The
second group was exposed to MC only during the 12 to 14 days prior to
gestation. The third group was exposed to MC only during the first 17
days of pregnancy. The fourth group (control group) was exposed only to
filtered air. The purpose of this study was to test whether MC exposure
prior to and/or during gestation was more detrimental to reproductive
outcome in female rats than exposure during gestation alone.
In rats exposed to MC during gestation, there were signs of
maternal toxicity, characterized by a statistically significant
increase in maternal liver weights. The only fetal MC effects observed
were statistically significant decreases in mean fetal body weights. No
significantly increased incidence of skeletal or soft tissue anomalies
was observed in the offspring.
In 1980, Bornschein et al. [Ex. 7-224] tested some of the offspring
of the Long-Evans rats from Hardin and Manson's study described above.
All four treatment groups were used to assess the postnatal toxicity of
MC exposure at 4500 ppm. The general activity measurements of groups of
5-day old pups showed no exposure-related effects. At 10-days of age,
however, significant MC-associated effects were observed in both sexes
in the general activity test. These effects were still apparent in male
rats at 150-days of age. This study showed that maternal exposure to MC
prior to and/or during pregnancy altered the manner in which the
offspring react and adapt to novel test environments at up to 150-days
of age. These effects suggest that MC exposure prior to, or during
pregnancy may influence the processes of orientation, reactivity, and/
or behavioral habituation. No changes in growth rate, long-term food
and water consumption, wheel running activity or avoidance learning
were reported.
OSHA concluded from the animal studies that maternal exposure to
high concentrations of MC during pregnancy may have some adverse
effects on the offspring, in particular with regard to behavioral
effects. The Agency has set the exposure limits based on cancer and CNS
effects and has not reached final conclusions on this issue.
b. Human studies. Limited data have been collected on the
reproductive effects of MC in male workers. In a study reported in the
Occupational Safety and Health Reporter [Ex. 7-43], a greater risk of
male sterility was found in male workers exposed to MC. In 1988, Kelly
[Ex. 7-165] reported 4 cases of oligospermia in MC-exposed workers.
This study was described in detail in the NPRM. Although the study
provided some evidence of an effect of MC on male fertility, the
observations were based on a small number of cases and OSHA believes
that more research is necessary before causative conclusions can be
drawn about the human male reproductive toxicity of MC.
The reproductive and developmental effects due to MC exposure in
female workers have also been studied. According to information
reported in an English translation of an abstract of a Russian article
by Vozovaya et al. [Ex. 7-16], detectable levels of MC were found in
the blood, milk, embryonal, fetal and placental tissues of nursing
women exposed to MC in a rubber product plant. No other information was
provided in the abstract. In a study by Taskinen et al. [Ex. 7-199],
increased rates of spontaneous abortions were observed in female
pharmaceutical
[[Page 1516]]
workers exposed to MC. Exposure data were not reported in this study
and it is unclear what confounding factors or other chemical exposures
were present. OSHA believes that more research is necessary in order to
evaluate the potential effect of MC on pregnancy outcomes, and so has
not reached a conclusion on this issue.
Carbon monoxide has well known adverse reproductive effects in
humans. Since MC is metabolized to CO, OSHA was concerned about the
adverse reproductive effects of CO as a metabolite of MC. The EPA has
reviewed the literature on the effects of maternal CO exposure on the
development of the fetus in the Air Quality Criteria for Carbon
Monoxide [Ex. 7-201]. Very high maternal CO exposures have resulted in
fetal or infant death or severe neurological impairment of the
offspring. CO reduces the amount of oxygen available to the tissues.
The developing fetus is very sensitive to these effects. According to
Fechter et al. [Ex. 7-200], low levels of CO exposure in animals have
been shown to adversely affect the fetus, producing CNS damage or
reduced fetal growth. These effects suggest that the fetus may be
especially sensitive to the toxic effects of MC through its metabolism
to CO.
As described above, OSHA is sufficiently concerned about the
potential for reproductive health effects of carbon monoxide as a
result of MC metabolism that it has decided to continue to gather
information and revisit this issue, if warranted.
F. Conclusion
OSHA's determination that MC is a potential occupational carcinogen
was based primarily on the positive findings of chronic inhalation
bioassays in rodents. MC is carcinogenic to mice of both sexes,
producing lung and liver neoplasms. In rats, MC produced dose-related
increases in mammary tumors and increases in the number of tumors per
tumor-bearing rat. The evidence in rodents is supported by
epidemiologic findings from cellulose triacetate fiber production
workers and a case-control study of individuals with astrocytic brain
cancer. The study of fiber production workers suggests an association
between liver and biliary cancer and long term (greater than 10 years)
exposure to MC. The case-control study indicates an association between
risk of astrocytic brain cancer and occupational exposure to MC. This
evidence is further supported by the findings of genotoxic activity of
MC in bacterial and mammalian cell systems. OSHA has set the 8-hour TWA
PEL of 25 ppm primarily to protect employees from the risk of cancer
due to MC exposure in the workplace.
CNS depression has been demonstrated in humans and animals at
relatively low inhalation concentrations of MC. The CNS depression
observed in those studies was relatively mild, although the effects
occurred at concentrations in the range of the STEL of 125 ppm. OSHA
believes that the STEL will be protective against CNS depression for
most employees exposed to MC most of the time, but the Agency is
sufficiently concerned about the potential for CNS health effects at
concentrations below the STEL and have decided to continue to gather
information and revisit this issue, if warranted.
VI. Quantitative Risk Assessment
Summary
After examining all the available data, both animal and human, and
both quantitative and qualitative, OSHA has concluded that MC is a
multi-species, multi-site carcinogen in various rodent species, and is
likely to be so in humans, and that it most probably acts via one or
more genotoxic metabolite(s). The evidence for this conclusion is quite
strong: there exist several positive bioassays with low background
incidence and dose-related increases; there is an unusually large
amount of mechanistic information; and there are several positive
epidemiological studies and no negative epidemiological studies of
sufficient power to rule out the animal-based potency estimates.
Furthermore, OSHA has conducted a quantitative risk assessment
based on the highest-quality animal tumor data, constructing a state-
of-the-art physiologically-based pharmacokinetic (PBPK) model
incorporating rodent and human metabolic information. That analysis
shows a final estimate of risk of 3.62 deaths per 1000 workers
occupationally exposed to 25 ppm MC for a working lifetime. [An
alternative analysis, which incorporated all of the data used in the
main analysis plus the assumption that human enzymes are even less
active to MC (as compared to mice) than that predicted by the main
analysis, gave a risk estimate of 1.23 deaths per 1000]. Both estimates
are clearly well above any plausible upper boundary of the
``significant risk'' range defined by the Supreme Court, used by OSHA
in its prior rulemakings, and reported in the scientific/economic
literature on risk. The estimated risk at the current PEL of 500 ppm is
126 excess cancers per 1000 workers; clearly, the 25 ppm standard will
effect a substantial reduction in a very high risk. The Final Economic
Analysis shows that the average risk at current exposure levels is
approximately 7.6 deaths per 1000 and ranges up to 126 per 1000; at
post-regulatory exposure levels (which account for the fact that the
action level will encourage some employers, where feasible, to lower
exposures below 25 ppm), average risk is estimated to be 1.7 deaths per
1000 (and nowhere higher than 3.62 per 1000 risk at the new PEL of 25
ppm)--also a substantial reduction of a highly significant risk.
Prior to the October 1995 record reopening, there was strong
evidence to support the determination that MC is a human carcinogen,
using well-established risk assessment models based on substantial
biologically-based evidence and theories: there were two multi-site
positive bioassays with dose-response trends and low background, and
suggestive epidemiology with no clearly conflicting epidemiology. The
only question was whether to use an administered-dose scaling or a PBPK
model.
Data submitted in the reopening of the record in late 1995 shed
light both on the hazard identification and the quantitative risk
assessment. Studies of isoenzyme activity and intracellular
distribution across species were interpreted by the Halogenated
Solvents Industry Alliance (HSIA) to suggest that MC is not a human
carcinogen. OSHA has concluded that the HSIA interpretation of the
studies is not supported by the evidence. There are numerous
methodological problems with the studies: for example, in the
experiment in which Graves et al. examined MC-induced mutations [Ex.
123], OSHA agrees with Dr. Douglas Bell [Ex. 126-26] that insufficient
numbers of doses and mutants were examined to reach any conclusions
whatsoever regarding differences in mutation spectra between chemicals.
More importantly, OSHA and most commenters agreed that the data
showed a quantitative--and quantifiable--difference between mice and
humans, not an infinite, qualitative one. In other words, there is
substantial evidence that humans and mice metabolize MC similarly, only
at different rates. HSIA's qualitative argument rests on two
questionable assumptions, both of which are contradicted by other data:
first, that the DNA single strand break assay is infinitely sensitive--
but the investigators do not even know if it is sensitive enough to
show the 7-fold difference in enzyme activity between mice and humans
that OSHA's main
[[Page 1517]]
PBPK analysis uses; and second, that the human isoenzyme most active
against MC, although clearly present in human cells, is located in a
different part of the cell. This interpretation: 1) contradicts some
basic beliefs of comparative physiology (Why would the cell structures
of humans and mice be so fundamentally different?); 2) would require
OSHA to do a ``subcellular PBPK analysis'' to predict risk--no one has
ever developed, let alone parameterized and validated, such a model;
and 3) contradicts other data on activation by mouse cytosolic
preparations--MC has been shown to have enhanced mutagenicity in
bacterial and mammalian cell preparations when mouse cytosolic
preparations were used to metabolize the MC. This requires metabolism
by cytoplasmic (not nuclear) GST and for the metabolites to be stable
enough to cross membranes and interact with DNA.
Therefore, the new studies do not cast doubt on the MC hazard
identification--in fact, they should probably increase the level of
concern because it is now more clear that MC is likely to act by a
genotoxic mechanism [animal tests are most relevant to humans when
clear genotoxic agents are involved] and that that pathway exists in
humans, and may be concentrated in cells of concern in human cancers,
such as the bile duct epithelium. OSHA notes that an epidemiologic
study of cellulose triacetate fiber workers has shown a statistically
significant increase in biliary duct tumors [Ex. 7-260].
On the other hand, the new data did reinforce OSHA's decision to
proceed with a PBPK-based risk assessment and helped OSHA to
incorporate the best available scientific data into a PBPK model. Here
OSHA presents two PBPK-based risk analyses, both of which represent
substantial refinements over the applied-dose risk assessment and over
previous PBPK analyses. OSHA's final risk assessment incorporates all
reliable data--OSHA's alternative analysis, in addition to the data in
the final risk assessment, also incorporates some suggestive/sparse
data found in new studies. As stated above, both analyses estimate
risks at 25 ppm well in excess of any possible boundary line between
significant and insignificant risk.
Both of OSHA's PBPK analyses made two major advances: 1) the use of
non-independent Monte Carlo simulation--Monte Carlo simulation is a
well-developed computational technique that allows the modeler to take
estimates of uncertainty in each of the many variables in a complex
model and generate a quantitative estimate of the total uncertainty in
the result. Others have used Monte Carlo simulation in PBPK modeling,
but OSHA added information on the covariance structure of all the
parameters, so that the uncertainty estimate would not be biased
(exaggerated, probably) by incorrectly assuming that all the variables
could simultaneously be at their lowest or highest values; and 2) the
use of Bayesian analysis--this allows uncertainty distributions to be
better estimated (narrowed) by cross-checking them against other
independently-collected data from laboratory experiments, rather than
simply guessing how big the uncertainties are and not refining the
estimates as the model runs.
Both these advances enabled OSHA to strike a balance between two
unsatisfactory extremes--a) the extreme overconfidence of using
estimates for each variable that did not allow for any uncertainty--or
b) the extreme ``underconfidence'' of assuming that all uncertainties
are independent of each other and of other laboratory data. The result
is an analysis that tells what science knows and does not know about
the relationship between ambient concentrations and the putative
relevant dose measure (concentration of GST metabolites in the target
organ) in mice and humans.
Again, OSHA's final risk assessment regards the very limited human
data base on GST-0 activity [a total of 39 liver samples and 5 lung
samples] as useful, but insufficient to discard the traditional
``allometric'' assumption (the well-validated assumption that, as a
general rule, metabolic parameters scale proportional to a function of
the animal's body weight). OSHA's alternative analysis accepts the
limited human data at face value to extrapolate without using
allometry. OSHA has concluded that the main analysis is better
supported by available evidence than is the alternative analysis, but
both yield significant risks. An important caveat is that both models
are strictly applicable to humans who are physiologically similar to
the six subjects analyzed by Dow (see the discussion later in this
document for a fuller explanation). Since the population of 200,000
workers will be much more heterogeneous than those six subjects, we
regard these estimates as ``overconfident''--some workers exposed at 25
ppm will have higher risks than 3.6 per 1000 (although some may have
lower risks as well).
Introduction
OSHA performs quantitative risk assessment, when information
permits, to help determine the Permissible Exposure Limit (PEL) for
toxic substances (contingent on the feasibility determination). The
first step of assessing risks to human health is hazard identification.
This step results in the determination that an exposure to a toxic
substance causes, is likely to cause, or is unlikely or unable to
cause, one or more specific adverse health effect(s) in workers. This
identification also shows which studies have data that would allow a
quantitative estimation of risk.
If studies are available that contain information regarding the
amount of exposure and disease, mathematical modeling allows
extrapolation of the information in the study to conditions of concern
in the workplace. OSHA uses these risk estimates to determine whether
exposure results in significant risk, and whether the standards
considered by OSHA substantially reduce the risk.
This section describes the record evidence received during the
public rulemaking concerning OSHA's quantitative risk assessment and
the reasons OSHA has maintained or modified its opinion from the
proposal. In the following sections, the evidence supporting and
casting doubt on the hypothesis that MC is a probable carcinogen (the
``Hazard Identification'' issues) is discussed first. Then the results
of OSHA's quantitative risk assessments, conducted to estimate the
carcinogenic potency of MC, are discussed.
A. Methylene Chloride Hazard Identification
Animal and human evidence, summarized in the health effects
section, indicates that MC can cause cancer, cardiac effects, central
nervous system damage and other health effects. As described in the
NPRM, OSHA's preliminary quantitative risk assessment was based on
cancer and relied on rodent bioassay data for quantitation of risks. In
1986, the National Toxicology Program (NTP) concluded that the mouse
bioassay data provided ``clear evidence'' of carcinogenesis in male and
female mice, based on the liver and lung tumors. The NTP also
determined that the rat mammary tumors observed in the bioassay
provided clear evidence of carcinogenesis in female rats and some
evidence of carcinogenesis in male rats. This evidence of cancer in
multiple species and in both sexes underlies the concern for MC as a
potential human carcinogen. On the basis of these studies, IARC has
classified MC as a 2B carcinogen, the EPA has classified MC as a B2
carcinogen and NIOSH has
[[Page 1518]]
classified MC as a potential occupational carcinogen. OSHA concurred
with these assessments.
Animal bioassays are a critical tool in determining the potential
hazard of a substance for humans. Virtually all of the toxic substances
that have been demonstrated to be carcinogenic in humans are also
carcinogenic in laboratory animals. Although it is possible that a
substance may be carcinogenic in a laboratory species, but not in
humans, it is reasonable to suspect that substances that cause cancer
in multiple animal species and at multiple target organ sites would be
carcinogenic in humans. Therefore, in the absence of sufficiently
powerful negative epidemiological studies or mechanistic studies
demonstrating that the purported carcinogenic mechanism of action of
the substance is irrelevant to humans, OSHA and other federal agencies
rely on well-conducted, high-quality bioassays as the primary basis for
their hazard identification and risk assessment. This is the case with
MC.
During this rulemaking, some commenters have supported and others
have questioned the hazard identification of MC as a potential human
carcinogen. Most recently, some commenters contested the relevance of
the mouse bioassay data for extrapolating to human cancer risks.
Although these issues were raised by some rulemaking participants
earlier in the rulemaking process, they were most thoroughly explored
in connection with the information received by the Agency in late 1995.
On October 24, 1995, OSHA reopened the MC record to receive comments on
several studies submitted to the Agency by the Halogenated Solvents
Industry Alliance (HSIA) pertaining to the mechanism of action of MC
carcinogenesis in mice, and the implications of these studies for
estimating human risks. The record closed on November 29, 1995, but was
reopened in order to give the public additional opportunity to comment
on the submitted studies. The record then closed on December 29, 1995.
Thirty-seven comments were received on this topic and reviewed as part
of this rulemaking.
The papers submitted by the HSIA consisted of a cover letter [Ex.
117], an overview of the sponsored research [Ex. 118] and seven
research papers on the mechanism of MC carcinogenesis [Ex. 119-124A].
The hypothesis under investigation in these seven studies was that the
pathways of MC metabolism and the mechanism of carcinogenesis in the
mouse represented a unique situation that would not take place in
humans, making the mouse unsuitable as the basis for extrapolating
risks of cancer to humans. The specific studies are described briefly
here and the comments received during the reopening of the rulemaking
record are discussed in detail below.
1. Summary of Studies Submitted by HSIA
Exhibit 119 ``Methylene Chloride: an inhalation study to
investigate toxicity in the mouse lung using morphological, biochemical
and Clara cell culture techniques,'' J.R. Foster, T. Green, L.L. Smith,
S. Tittensor, and I. Wyatt, Toxicology 91 (1994) 221-234.
This study investigated the potential role of MC as a mouse lung
carcinogen via non-genotoxic mechanisms and the Clara cell as the cell
of origin in mouse lung cancer. The hypothesis was that MC acts
specifically to produce toxicity (vacuolation) in Clara cells which
leads to cell proliferation and production of mouse lung tumors. The
authors investigated the toxicity of MC in bronchiolar Clara cells by
measuring the production of vacuoles after exposure to MC. The
investigators also measured DNA synthesis in Clara cells isolated from
mice exposed to MC as a measure of cell proliferation.
The authors observed a transient vacuolation of bronchiolar Clara
cells in mice exposed to 2000 and 4000 ppm MC, but not in mice exposed
to 0, 125, 250, 500 or 1000 ppm MC. When the mixed function oxidase
(MFO) pathway was inhibited, the bronchiolar cell vacuolation observed
after exposure to 2000 and 4000 ppm MC was reduced. Inhibition of the
glutathione S-transferase pathway (GST) had no effect on Clara cell
vacuolation. The researchers also found that exposure of mice to 1000
ppm MC or greater for 6 hours induced an increase in DNA synthesis in
Clara cells cultured in vitro from exposed animals.
Clara cells are present in mice, rats and humans, but appear to be
more abundant in mice than other species. Clara cells contain enzymes
for both the MFO and glutathione S-transferase (GST) pathways of MC
metabolism. According to the authors, the results of this study suggest
that metabolism of MC via the MFO pathway induces a transient toxicity
in Clara cells and a transient increase in DNA synthesis.
Exhibit 120 ``Methylene chloride-induced DNA damage: an
interspecies comparison,'' R.J. Graves, C. Coutts and T. Green,
Carcinogenesis, vol. 16 no. 8 pp. 1919-1926, 1995.
This study investigated the role of MC as a mouse carcinogen via a
genotoxic mechanism of action. The hypothesis under investigation was
that MC is metabolized to a genotoxic carcinogen via the GST pathway to
different extents in different species and that expression of this
genotoxicity correlates with risk of developing cancer across species.
The authors used production of single strand (ss) DNA breaks as a
measure of genotoxicity. The researchers measured DNA ss breaks in lung
and liver cells from mouse, rat, hamster and humans. They observed
increased DNA ss breaks in mouse liver cells, after in vivo exposure to
4000-8000 ppm MC for 6 hr and in mouse lung cells after exposure to
2000-6000 ppm MC. Depletion of glutathione in the liver (after
administration of buthionine sulfoximine) reduced the amount of ss
breaks observed. No increase in ss breaks was observed in Clara cells
isolated from mice exposed to MC in vivo. However, in experiments on
isolated mouse Clara cells, the authors observed increased DNA ss
breaks in cells exposed to concentrations of MC of 5 mM and above.
No increases in ss breaks above control levels were detected in rat
livers after exposure to 4000 ppm for 6 hr or in rat lungs after
exposure to 4000 ppm for 3 hr. Increases in ss breaks were also not
detected in hamster and human liver cells after exposure to MC in vitro
at concentrations up to 90 and 120 mM.
In Chinese hamster ovary (CHO) cells, MC plus mouse liver cytosol
(which contains the GST enzymes) also induced ss breaks, while
incubation of CHO cells with MC in the presence of mouse liver
microsomes (which contain the MFO enzymes) did not increase ss breaks.
The results suggest that mouse liver and lung cells are more
susceptible to MC-induced ss breaks than cells from rats, hamsters or
humans. Assuming that ss breaks are a relevant surrogate for
carcinogenicity, the authors infer from this study that humans, rats
and hamsters are insensitive to MC-induced liver cancer, because those
species lack the high level of GST metabolic activity to MC found in
the mouse liver cell and lung Clara cell.
Exhibit 121 ``Isolation of two mouse theta glutathione S-
transferases active with methylene chloride,'' G.W. Mainwaring, J. Nash
and T. Green, Zeneca Central Toxicology Laboratory, 1995.
This study was conducted in order to characterize the mouse GST
isozyme(s) responsible for MC metabolism. The results of this work
could be used to explore the hypothesis that a particular GST isozyme
was responsible for metabolizing MC to the carcinogenic metabolite and
that there may be different concentrations of this enzyme across
species.
[[Page 1519]]
The researchers used a variety of chromatography methods to isolate
two mouse glutathione S-transferases (MT-1 and MT-2, also known as T1-
1* and T2-2*, respectively) which metabolize MC, comparing the observed
enzyme activity with that described in rats. Rats were found previously
to have two GST isomers in the theta class (GST 5-5 and GST 12-12)
which metabolized MC. The mouse MT-1 and MT-2 enzymes were found to be
closely related to rat GST 5-5 and 12-12, respectively, and the
specific activity of mouse MT-1 was found to be similar to rat GST 5-5.
GST 12-12 and MT-2 were found to be extremely labile during
purification, and so the specific activities of those isozymes have not
been measured.
The results of this study suggest that the mouse and rat contain
GST theta enzymes similar in amino acid sequence and in specific
activity (GST 5-5 and MT-1). The authors postulate that the greater
conjugating activity seen in mice in other studies is ``probably due to
a difference in expression of the enzyme or to a significant
contribution from MT-2'' [Ex. 121].
Exhibit 122 ``Mouse Liver glutathione S-Transferase Mediated
Metabolism of Methylene Chloride to a Mutagen in the CHO/HPRT Assay,''
R.J. Graves and T. Green, Zeneca Central Toxicology Laboratory, 1995.
This study investigated the mutagenicity of MC as a potential
carcinogenic mechanism of action. The purposes of this study were to
clarify the ability of MC to act as a mutagen, because studies in
mammalian systems have yielded mixed results regarding the mutagenicity
of MC, and to more fully characterize the metabolite purportedly
responsible for MC mutagenicity by comparing the results to
formaldehyde (one metabolite of MC by the GST pathway). Mutagenicity
was measured by assaying CHO cells in vitro for mutations at the HPRT
locus of DNA. Ss DNA breaks were also monitored. Cells were exposed in
culture to MC mouse liver cytosol metabolites (which include metabolic
enzymes for the GST but not the MFO pathway), formaldehyde (one of the
MC GST metabolites) or 1,2-dibromoethane (1,2-DBE) (a reference
genotoxin).
Using standard techniques, MC GST metabolites were shown to be
weakly mutagenic using the CHO/HPRT assay. Formaldehyde was also
determined to be weakly mutagenic in this assay, but the effect was not
as great as with MC GST metabolites. 1,2-DBE, as expected, showed a
potent mutagenic response. The mutagenicity of MC GST metabolites and
formaldehyde was increased when cell density was increased, cells were
exposed in suspension rather than as attached cultures and cytosol
concentration was optimized.
MC mouse liver cytosol metabolites were observed to increase ss DNA
breaks in CHO cells exposed in suspension, but caused only marginal
increases in DNA-protein cross-links. In contrast, the researchers
found that formaldehyde induced both DNA ss breaks and DNA-protein
cross-links. Slight increases in ss DNA breaks were also seen with
exposure to either MC alone or the cytosol fraction alone.
Based on a comparison of the mutagenic effects of the three
compounds, particularly on the lack of MC-induced DNA-protein cross-
linking in this experimental system, the authors concluded that
formaldehyde does not play a major role in MC mutagenicity.
Accordingly, the researchers viewed the results of this study as
supporting the hypothesis that the DNA ss breaks induced by MC, and the
resultant DNA mutations, are caused by interaction of S-chloromethyl-
glutathione (formed by the GST pathway) with DNA.
Exhibit 123 ``DNA Sequence Analysis of Methylene Chloride-Induced
HPRT Mutations in CHO Cells: Comparison with the Mutation Spectrum
Obtained for 1,2-Dibromethane and Formaldehyde,'' R.J. Graves, P.
Trueman, S. Jones and T. Green, Zeneca Central Toxicology Laboratory,
1995.
The purpose of this study was to describe the types of mutations
induced by MC in order to further characterize the GST metabolite
likely to cause MC mutations and therefore perhaps be responsible for
the carcinogenicity of MC in the mouse. The spectrum of mutations in
the HPRT locus of CHO DNA induced by MC plus mouse liver cytosol was
compared to mutations induced by formaldehyde (a GST metabolite of MC)
or 1,2-dibromoethane (1,2-DBE, a reference genotoxin).
The results were expressed as a sequence analysis of 11 MC-induced
mutations, 6 formaldehyde-induced mutations and 13 1,2-DBE-induced
mutations. In comparing the distribution of types of mutations, the
results suggested to the researchers that formaldehyde-induced DNA
damage can contribute to MC mutagenicity, but that the majority of the
mutations were derived from other types of DNA damage, probably via an
interaction of S-chloromethylglutathione with DNA. The researchers
noted that a glutathione conjugate also plays a role in the
mutagenicity of 1,2-DBE. The increases above background mutation
frequency detected through this study were 24.7-fold for 1,2-DBE, 4.7-
fold for formaldehyde, and 8-fold for MC.
Exhibit 124 ``The distribution of glutathione S-transferase 5-5 in
the lungs and livers of mice, rats and humans'' [Preliminary
communication, T. Green, 1995].
Exhibit 124A ``The distribution of theta class glutathione S-
transferases in the liver and lung of mouse, rat and human.'' G.W.
Mainwaring, S.M. Williams, J.R. Foster and T. Green,1995.
The preliminary communication [Ex. 124] and the unpublished report
which followed [Ex. 124A] summarized the results of a study comparing
the inter- and intra-cellular distribution of the messenger RNA (mRNA)
for a glutathione S-transferase (GST) isoenzyme which metabolizes MC in
the lungs and livers of mice, rats and humans. The purpose of the
experiments summarized in these reports was to describe the
distribution of the mRNA for the GST theta isozyme believed to be
responsible for metabolism of MC to a carcinogenic metabolite in
different species. The researchers believed that differences in
distribution of the mRNA for this isozyme would correlate with
differences in distribution (and activity) of the isozyme itself, and
might explain differences in sensitivities of the species to the
carcinogenicity of MC.
The distribution of GST theta mRNA was visualized using DNA
oligonucleotide anti-sense probes complementary to the nucleotide
sequences for the GST theta isozymes. This technique is used to
visualize the mRNA coding for a specific protein (such as the GST theta
isozymes) within cells in tissues. The mRNA is a nucleotide sequence
transcribed from the DNA containing the gene for the specific protein.
After transcription, mRNA is transported to the cytoplasm, where it is
translated into the amino acid sequence which becomes the specific
protein (in this case, the GST theta isozyme). The finished protein
then migrates to its final site of activity within the cell.
Localization of the mRNA does not necessarily correspond to
localization of the specific protein.
The results of the study showed that the GST-specific mRNA could be
found in lungs and livers of all three species. Mouse liver cells
(particularly the nuclei) and mouse lung cells appeared (from the
photomicrographs shown in the article) to stain more heavily for the
GST mRNA than the lung or liver cells from rats or humans. Although the
amount of GST-specific mRNA was not quantified in this study, the
authors interpreted the photographs to suggest that, ``* * * mouse
tissues are stained
[[Page 1520]]
much more heavily than sections from either rat or human.'' Based on
the intracellular and intercellular distribution of the GST mRNA, the
authors stated,
The most significant findings are the presence of very high
concentrations of GST 5-5 mRNA in specific cells and nuclei of mouse
liver and lung. Metabolism of methylene chloride at high rates and
within nuclei to a reactive but highly unstable glutathione
conjugate is believed to facilitate alkylation of DNA by this
metabolite. The lack of high or nuclear GST 5-5 concentrations in
rat and human tissue, provides an explanation for the lack of
genotoxicity in these species. [Ex. 124]
In the letter submitting the studies summarized above to OSHA, HSIA
characterized the studies as follows:
This research, which is now complete, shows that B6C3F1 mice * *
* are uniquely sensitive at high exposure levels to methylene
chloride-induced lung and liver cancer, and that other species,
including humans, are not at similar risk. [Ex. 117]
They went on to conclude:
As a result of this research program, it appears that there are
no foreseeable conditions of human exposure in which the
carcinogenic effects seen in mice would be expected to occur in man.
* * * The risk assessment that is the basis for the methylene
chloride standard, which is in turn based on the increased liver and
lung tumor incidence observed in the mouse bioassay, must be
discarded in favor of scientific data that are relevant to human
risk.
In response to the request by HSIA, OSHA has reviewed the cancer hazard
identification of MC based on all of the evidence in the MC record,
with particular emphasis on the validity of the conclusion stated
immediately above. This review is presented below.
2. Carcinogenesis of Methylene Chloride
a. Animal evidence. Several long-term MC bioassays have been
conducted and are summarized in the Health Effects section. These
included studies in which the route of exposure was inhalation [Burek
et al., Ex. 4-25, Nitschke et al., Ex. 7-29, and NTP, Ex. 4-35] and two
studies in which the route of exposure was drinking water [National
Coffee Association, Exs. 7-30, 7-31]. In order to ensure full
consideration of the data, OSHA analyzed in its preliminary assessment
all data sets which showed an elevated incidence of tumors in a MC-
exposed group, compared to controls, whether or not the elevation of
tumor response was statistically significant. This analysis and the
individual datasets used were described in detail in the NPRM.
In the NTP bioassay [Ex. 4-35], groups of 50 nine-week old
B6C3F1 mice of each sex were exposed by inhalation to 0, 2000 or
4000 ppm MC. Groups of 50 eight-week old F344/N rats of each sex were
exposed to MC at concentrations of 0, 1000, 2000, or 4000 ppm. The
inhalation exposures were administered 6 hours a day, 5 days a week for
102 weeks. Food was provided to the animals ad libitum except during
the exposure periods, while water was available at all times via an
automatic watering system. All animals were observed twice a day for
mortality and moribund animals were sacrificed. Clinical examinations
were performed once a week for 3.5 months, then twice a month for 4.5
months, and once a month thereafter. Each animal was also weighed
weekly for 12 weeks, then monthly until the conclusion of the study at
102 weeks. All animals were necropsied and histologically examined.
Three different neoplastic lesions were observed to have significantly
increased incidence over the controls: adenomas and carcinomas of the
lung in male and female mice, adenomas and carcinomas of the liver in
male and female mice, and mammary gland fibroadenomas and fibromas in
male and female rats.
HSIA and others argued that benign tumors, especially the mammary
tumors in the rats, should not be counted as a carcinogenic response.
The NTP has addressed that issue in its Technical Report [Ex. 4-35] and
has concluded that the benign mammary tumors observed in the F344
female rats are ``clear evidence'' of carcinogenicity and noted that
such tumors may proceed to malignancy. OSHA agrees with this
determination and has considered the rat mammary tumors as part of its
cancer hazard identification for MC. However, OSHA's quantitative risk
assessment does not consider rat mammary tumor responses.
OSHA believes that the NTP studies provide the strongest evidence
of carcinogenicity of MC in animals. Many commenters and hearing
participants [Exs. 19-46, 7-128, 7-126, 25-E, 126-11,126-12, 126-16 and
others] supported the use of the NTP mouse study as the basis for
quantitative risk assessment. There are several reasons for this
described in the proposal and earlier in this document. In brief, the
NTP study used well established standard operating procedures that are
generally considered a predictor of a potential carcinogenic response
in humans. This study was also replicated by a second partial bioassay,
conducted by NTP, in which groups of female mice were exposed to 2000
ppm MC for 2 years. Statistically significant increases in alveolar/
bronchiolar and hepatocellular tumors were observed [Ex. 27].
Before the 1995 record reopening, some commenters had raised
specific arguments why a mouse study might not predict human
carcinogenic response to MC. Mr. Krenson of Besway Systems [Tr. 397, 9/
17/92] objected to OSHA using the NTP mouse study as the basis for
setting the PELs for MC. He believed that the mouse was irrelevant to
human risk because the doses used were ``extremely high'' and that he
believed that tests conducted on rats, hamsters and human
epidemiological investigations showed ``no conclusive proof of cancer
in human beings.'' OSHA disagrees with Mr. Krenson's conclusion. In
general, high doses in rodent bioassay studies are appropriate to
elicit a response due to the practical limitations on the number of
animals that can be used in a study. In MC, there was no observed acute
toxicity at the levels used in the study, which is an indication that
the doses were not too high. Use of high doses in bioassay studies is
common and its practical necessity has been affirmed by numerous expert
bodies, including several committees of the National Academy of
Sciences. In addition, for every known human carcinogen, positive
results were obtained at high rodent doses. Also, quantitative
comparisons, as conducted by Allen and Crump in 1988, demonstrate that,
in general, observations of cancer potency from epidemiology studies
agree with estimates of potency derived from rodent bioassay data. In
the case of MC, statistically significant excess tumors were observed
in mice after exposure to only 2000 ppm, or only four times the former
PEL of 500 ppm (8-hour TWA), and excess tumors were seen in rats at
4000 ppm. This level is within the range of human exposures experienced
in occupational settings. Certainly the lower exposure showing
substantial effect was not ``extremely high'' in relation to the
exposure limit, as Mr. Krenson claimed.
The HSIA and several others [Exs. 117, 126-1, 126-3, 126-5,126-
6,126-8,126-10, 126-13,126-20, 126-21, 126-29] also objected to using
the mouse data as the basis of human risk assessment, based on the
mechanism of action studies submitted to the Agency by HSIA on December
6, 1995. OSHA's analysis of the individual studies follows, but
overall, the Agency has determined that the mouse cancer data are
appropriate for assessment of the cancer risks to humans (although, as
discussed later in this section, OSHA has made extensive use of the
submitted data to modify the quantitative
[[Page 1521]]
estimates of risk derived from the mouse model).
b. Evidence pertaining to the mechanism of action of methylene
chloride. Several lines of evidence relate to the mechanism of
carcinogenesis of MC. The issues discussed in the papers submitted by
the HSIA and subsequent comments can be divided into those pertaining
to genotoxicity, those discussing potential non-genotoxic modes of
action, and those related to the enzymatic metabolism of MC. Although
some comments overlap these divisions, this organization is used in
this discussion to simplify consideration of the issues.
(1) Genotoxicity. It has not been conclusively demonstrated that MC
or its metabolites act by a genotoxic mechanism in mice and rats.
Substance-specific DNA adducts, which are among the strongest evidence
of direct genotoxicity, have not been identified from MC exposure.
However, evidence has been accumulating that MC is likely to be
carcinogenic through a genotoxic mechanism of action. For example, DNA-
protein cross-links have been demonstrated in mouse liver [Ex. 21-16],
increases in unscheduled DNA synthesis have been demonstrated in mouse
lung [Ex. 126-25] and other evidence of MC metabolite interaction with
mammalian DNA (such as increases in ss DNA breaks) has been observed.
It is not necessary for a substance to bind covalently with DNA in
order to act via a genotoxic mechanism, although evidence of covalent
binding is a strong indication of genotoxicity. In the case of MC,
although the reactive metabolites are presumed to exert a genotoxic
effect by binding to DNA, no MC metabolite-DNA adducts have yet been
identified. However, RNA adducts have been identified after MC
exposure, which supports the hypothesis that MC acts by a genotoxic
mechanism. Substance-specific DNA adducts have also not been identified
for some other carcinogens which are presumed to act via a genotoxic
mechanism.
In addition, as discussed in the Health Effects section, MC has
been found to be mutagenic in bacterial, yeast, Drosophila and
mammalian systems; associated with chromosomal aberrations in CHO
cells; and associated with sister chromatid exchanges in mammalian cell
culture systems, such as CHO and V79 cells.
Investigations of the role of metabolites of the GST pathway in the
bacterial mutagenicity of MC found that in glutathione-deficient
strains of Salmonella typhimurium MC-induced mutations were reduced
[Ex. L107]. Mutation rates returned to normal when bacteria were
supplemented with exogenous glutathione. This study supports the
hypothesis that MC may act as a genotoxic carcinogen via its GST
metabolites, although a study of similar design by Dillon et al. [Ex.
21-89] did not replicate these results.
(i) MC induced mutuations. Studies on the MC mechanism of
carcinogenesis included two studies on the mutations induced by MC in
the CHO/hypoxanthine phosphoribosyl transferase (HPRT) assay. In the
1995 study by Graves et al. [Ex. 122], the investigators compared
mutations induced by MC with those induced by formaldehyde and 1,2-
dibromoethane. The authors characterized the results of the studies as
follows:
Using the CHO/HPRT assay we have shown that MC is metabolized to
a mutagen by mouse liver cytosol in a reaction which is dependent
upon GST and GSH. Mutagenicity was enhanced by exposing the cells at
high density in suspension rather than as attached cultures, which
is consistent with the critical metabolites being extremely short-
lived.
The authors also observed that the MC-induced mutations were associated
with an increase in DNA ss breaks. They remarked, ``The results suggest
that MC-induced DNA ss breaks seen in other cell types are associated
with DNA damage which can lead to mutation.''
In a follow-on to the CHO/HPRT study, Graves et al. [Ex. 123]
conducted a sequence analysis of HPRT mutations in CHO cells, comparing
the spectrum of MC-induced mutations with those induced by 1,2-
dibromoethane or formaldehyde. The investigators analyzed 28 HPRT
mutations: 13 from 1,2-dibromoethane experiments, 6 from formaldehyde
experiments, and 11 from MC experiments. The authors characterized
their results as follows,
All three compounds induced primarily point mutations, with a
small number of insertions and deletions. * * * The mutation
sequence results for MC suggest that formaldehyde may also play a
role in MC mutagenesis, although the majority of mutations arise
from other types of DNA damage, probably DNA adducts formed by
reaction of S-chloromethyl glutathione with DNA.
Dr. Douglas A. Bell of NIEHS [Ex. 126-26] had specific comments
regarding the study on the mutation spectra [Ex. 123]. He stated,
This experiment is extremely weak scientifically and not of
publication quality. It is unlikely that such a naive experiment
could detect differences in spectra between the different chemicals
tested. To test the hypothesis that there are chemical specific
mutation spectra requires analysis of hundreds of mutants at several
different doses. This exhibit contains no useful information for
risk assessment.
OSHA agrees with Dr. Bell that there are serious methodological
problems with the paper. The Agency also agrees with Dr. Bell that the
important information in these two studies is that MC increases the
mutation frequency, showing a clear genotoxic effect.
(ii) Single strand DNA breaks. In a 1995 study, Graves et al. [Ex.
120] investigated the role of MC exposure in development of single
strand (ss) DNA breaks in the lung and liver of mice and rats and in
hamsters and human cell cultures. The authors observed a transient,
dose-related increase in DNA ss breaks in mouse hepatocytes after
inhalation exposure to MC. No increased amount of ss breaks was
observed in rat liver cells exposed to MC as compared to control cells.
The authors also reported a decrease in the amount of ss DNA breaks in
liver and lung when a glutathione depletor was administered to mice
immediately before MC exposure.
In mouse and rat hepatocytes incubated with MC, the authors found
increases in ss breaks, but no increases in ss breaks in hamster or
human hepatocytes exposed in vitro were observed. No increase in DNA
damage was observed in CHO cells exposed to MC plus mouse liver
microsomes, while MC plus mouse liver cytosol induced detectable ss DNA
breaks.
The authors characterized their findings in the lung as follows:
Here we show that Clara cells are also sensitive to MC-induced
DNA ss breaks and that the DNA-damaging metabolites are derived from
the GST pathway. * * * Overall, these findings support the proposal
that Clara cells are the cell of origin of MC-induced mouse lung
tumors.
For liver cancer, the investigators concluded:
These studies suggest that humans (and rats and hamsters) are
insensitive to MC-induced liver cancer.
Commenters raised issues about the relevance and utility of ss DNA
breaks in assessing the genotoxicity of MC. Dr. Karl T. Kelsey [Ex.
126-34] and Dr. Miriam Poirier [Ex. 126-37] raised concerns about the
sensitivity of the DNA ss break assay for detecting genotoxic effects.
Specifically, Dr. Kelsey stated,
Reviewing the literature, considerable weight seems to fall upon
the measure of DNA single strand breaks. I have serious concerns
about this assay. It is well known that the assay is extraordinarily
difficult to standardize and is sensitive only to very high doses of
genotoxic compounds. This data,
[[Page 1522]]
therefore, is certainly not compelling; persuading any competent
independent scientist of its relevance to humans would be difficult.
Dr. Poirier was concerned with the sensitivity of the DNA single strand
break assay and the relevance of DNA ss breaks to carcinogenesis. She
remarked that ss DNA breaks and mutagenicity are secondary indicators
of DNA damage. She indicated that a better measure of genotoxicity
would be formation of DNA adducts. Dr. Errol Zeiger [Ex. 126-28] of
NIEHS agreed, stating,
If the mechanism of carcinogenicity is through an alkylating S-
chloromethyl GSH complex, there should be evidence of DNA adducts in
vitro and in vivo.
OSHA agrees that DNA adducts are strong evidence of genotoxicity
and that ss DNA breaks and mutagenicity are not as specific or relevant
as indications of a genotoxic mechanism of action. However, the Agency
has determined that, even in the absence of identified MC-specific DNA
adducts, the accumulated evidence suggests that MC interacts with DNA
via a genotoxic mechanism of action and that the GST pathway is a
plausible carcinogenic pathway.
Dr. Melnick [Ex. 126-33] stated, ``* * * it has not been
demonstrated that the carcinogenicity of MC in mice is dependent solely
on the induction of DNA single strand breaks.'' Dr. Andrew G. Salmon
concurred with this analysis and also raised a serious concern about
the ability of the assay even to detect increases in ss breaks,
regardless of their relevance:
Green's account states that ``mouse hepatocytes were * * * 20-
fold * * * more sensitive to the effects of methylene chloride
[i.e., DNA strand breaks] than rat hepatocytes * * * '' and no
breaks were detected in hamster or human liver cells. This is
translated in the discussion to an assertion that not only humans
and hamsters but also rats are completely immune to the carcinogenic
effect of methylene chloride. However, the data simply do not
support the assertion of a categorical difference as proposed by the
HSIA. This particular work also raises a number of other issues,
such as whether the liver is an appropriate model tissue, and
whether single-strand breaks are an appropriate indicator of the
type of genetic damage produced by the putative genotoxic
metabolites of methylene chloride.
OSHA agrees that the ss DNA break assay is not as sensitive as
other methodologies for assessing the genotoxic potential of MC in
different systems and therefore data from the ss DNA break study must
be interpreted in a quantitative, not qualitative context, with
allowance for uncertainty in assay sensitivity. It is also unclear
whether ss DNA breaks are the appropriate surrogate measure for
carcinogenic potential. In light of the issues raised by commenters,
the Agency believes that the ss DNA break data should be interpreted
with caution.
(iii) DNA-protein cross-linking. Casanova and Heck [Ex. 21-16]
observed DNA-protein crosslinks in mouse liver, but not mouse lung,
after exposure to 500, 1500 and 4000 ppm. This study indicated that
metabolites of MC have the ability to interact with DNA. However, the
quantity of DNA-protein crosslinks did not show a strong correlation
with tumor incidence, and so the DNA-protein crosslinks were not used
as a dose-surrogate for MC exposure in OSHA's risk assessment.
The Chemical Industry Institute of Toxicology (CIIT) [Ex. 126-25]
submitted further evidence that MC exposure causes DNA-protein cross-
links in mouse liver but not mouse lung, hamster liver or hamster lung.
These investigators also observed RNA adducts in mouse, rat and human
cells after incubation with MC, but DNA-protein cross links were only
observed in the mice. In addition, they submitted a pharmacokinetic
model which modeled the DNA-protein cross-links as the dose surrogate
for MC exposure. Finally, they made extensive comparisons of their
model with the PBPK model submitted by Clewell [Ex. 96] and EPA's risk
assessment for MC. Dr. Roger McClellan summarized the conclusions they
reached as follows,
The pharmacokinetic results suggest that at very low
concentrations of DCM [methylene chloride], the yield of DPX [DNA-
protein cross-links] is almost linearly proportional to DCM
concentration * * *
DPX cannot be used directly as a surrogate for the internal dose
in humans, however, because human hepatocytes, unlike mouse
hepatocytes, do not appear to form DPX in measurable amounts in
vitro. * * * These results suggest that the mouse may not be an
appropriate animal model for human risk assessment due to its
unusual susceptibility to DPX formation and to the fact that cell
proliferation is a uniquely high-dose phenomenon that may occur only
in this species.
OSHA believes that this work provides more evidence for the
formation of genotoxic metabolites in mouse liver after MC exposure.
However, OSHA is not convinced that the DNA-protein cross-linking is
the appropriate dose-surrogate for pharmacokinetic modeling. One of the
strengths of Reitz's and subsequent PBPK models was that the dose
surrogate used in the modeling was linearly related to tumor incidence.
That is one reason that many investigators have focused on the GST
pathway, instead of the MFO pathway of metabolism as the carcinogenic
pathway. As explained by Dr. Lorenz Rhomberg [Ex. 126-16],
* * * if this proportionality in the case of GST is broken by a
deeper analysis, the rationale for focusing only on GST must be
reevaluated.
Dr. Rhomberg was referring to results presented by HSIA on the
distribution of GST theta isozymes within and among cells, but the same
sentiment applies here; if OSHA were to abandon PBPK modeling using GST
metabolites, all of the HSIA and other studies would have to be re-
evaluated and considerable more research might need to be done.
Finally, in the CIIT study, RNA adducts, a more direct measure of
genotoxicity than DNA ss breaks, were observed in human hepatocytes
after incubation with MC. The amount of RNA adducts in human cells was
only about 3-fold lower than the amount in mouse hepatocytes. It is
therefore clear that human hepatocytes in this system are forming
genotoxic metabolites after exposure to MC.
OSHA notes that, in mouse lung, the DNA-protein cross-links were
not observed, even though a clear dose-response relationship for tumors
has been established at this site. OSHA is not convinced that the
explanation for carcinogenesis in mice is DNA-protein cross-links in
liver. Overall, it is unclear whether the interspecies difference in
DNA-protein cross-linking is related in any way to the carcinogenic
mechanism of action.
OSHA concludes that there continue to be strong reasons for using
the mouse data as the basis for its quantitative risk assessment
because there is a clear dose-response relationship in the mouse liver
and lung tumor incidence data; the mouse metabolizes MC by the same
pathways as humans; PBPK models have been developed which account for
inter-species differences in MC metabolism; statistical techniques have
been developed to quantify the uncertainty and variability in the
parameters used in the PBPK models; and there are no data that
demonstrate that the mouse is an inappropriate model for assessing
human cancer risks. In fact, OSHA finds further evidence in the studies
described above which suggest that MC acts via a genotoxic mechanism in
human cells as well as in mice and rats, which further supports OSHA's
use of the mouse tumor incidence as the basis for quantitative risk.
(iv) Interpreting the genotoxicity studies. Several other issues
were raised regarding interpretation of the results of
[[Page 1523]]
these studies on the genotoxic mechanism of action of MC. NIOSH and
others [Exs. 126-30, 126-11, 126-32] commented that, in general, the
data presented by HSIA supported the hypothesis that the carcinogenic
metabolite(s) of MC were derived from the GST pathway. They agreed with
HSIA's interpretation of the data that the studies presented here
helped to confirm that the mechanism of MC carcinogenesis is through
one or more genotoxic metabolites of the GST pathway.
Interpretation of short-term effects in explaining chronic
mechanisms of action.
Concerns were raised about the generalizability of the results of
short-term genotoxicity assays to tumor incidence, especially when the
observed effect is transient, as in the vacuolation of Clara cells, the
appearance of ss DNA breaks in mouse liver and lung cells, etc. Dr.
Mirer of the UAW [Ex. 126-31] commented,
1. The evidence cited concerns acute effects which appear after
a few hours of high level exposure of the animal to methylene
chloride vapor, or the glassware (in vitro) mixing of homogenized
animal or human tissue with the solvent. In a number of studies the
effect in the whole animal is transient.
2. There is no evidence to connect the acute toxic effect, or
single strand breaks of DNA after acute exposure, to the chronic
effect of lung or liver injury, or cancer. * * *
Dr. Maronpot [Ex. 126-22] was concerned that the vacuolation observed
in Clara cells was not reproduced in the NIEHS mechanistic studies.
HSIA responded to this concern by remarking that the vacuolation could
only be found after single exposures to MC, and that the vacuolation of
Clara cells was also associated with increased DNA synthesis in these
cells. The fact that this response was only observed after single
exposures to MC again raises the issue of the transience of this
response and its relevance to MC carcinogenesis.
Increased cell turnover.
In these studies on genotoxicity, the authors remarked that
increased cell turnover was observed in the lung (transient increase in
DNA synthesis after single exposures to MC). Dr. Daniel Byrd [Ex. 126-
32] also commented on the DNA synthesis issue. Citing an HSIA study, he
contended that there appeared to be a common mechanism of action
between the lung and the liver since increased DNA synthesis was
observed in both tissues. Dr. Maronpot of the NIEHS [Ex. 126-22]
disagreed, stating,
The purported ``liver growth'' in methylene chloride-exposed mice
is actually an increase in liver weight attributable to accumulation of
glycogen within hepatocytes. There is no evidence of replicative DNA
synthesis (cell proliferation) in the liver of methylene chloride-
treated mice, and, hence, actual increases in the numbers of
hepatocytes did not occur. * * * It is noteworthy that recovery to
normal liver weight occurs within two weeks after cessation of exposure
to methylene chloride.
OSHA agrees with Dr. Maronpot that no data in the rulemaking record
show increases in liver cell proliferation as the result of MC
exposure, although increased DNA synthesis was actively searched for in
the NIEHS mechanistic and other studies. The increased DNA synthesis
observed in mouse Clara cells is a transient phenomenon that has not
been clearly linked to carcinogenesis in the mouse. In any event, cell
proliferation is not necessarily related in any way to carcinogenesis
and is often uncorrelated with the doses used in bioassays and the
tumor rates themselves. Many substances that cause prolonged cell
proliferation do not cause tumor formation and vice versa [Ex. 126-22],
and many experts believe that transient increases in cell
proliferation, such as seen with MC, cannot account for the
carcinogenic effect. Further discussion of cell turnover as a mechanism
of carcinogenicity is discussed below under ``Non-genotoxic
mechanisms.''
Clara cell as the mouse lung tumor cell of origin.
Another issue raised by commenters concerned the cell of origin of
the mouse lung tumors. The mouse lung has a higher proportion of Clara
cells than the human lung. The investigators hypothesized that if the
Clara cell were the mouse lung tumor cell of origin, the risk estimated
from the mouse lung tumor data may overstate human risk because humans
have fewer Clara cells, and therefore fewer potential target cells.
Green et al. have focused much of their research efforts into
determining the mechanism of action of MC in mouse lung and liver. In
lung tissue, as described above, they concentrated on experiments
addressing the hypothesis that the mouse Clara cell is the cell of
origin of the mouse lung tumors observed in the NTP bioassay. Dr.
Daniel Byrd [Ex. 126-32] indicated that he believed that the data
presented supported this conclusion. He stated, ``Mouse lung tumors
most likely arise from damaged Clara cells, although a few pathologists
continue to speculate that mouse lung tumors arise from other lung
cells, such as Type II pneumocytes.''
In contrast, Dr. Maronpot of the NIEHS [Ex. 126-22] disagreed with
that statement, indicating that ``* * * current belief among
researchers is that mouse lung tumors arise from Type II pneumocytes
rather than Clara cells.'' Dr. Melnick [Ex. 126-33] suggested that the
HSIA data are not consistent with the hypothesis that the Clara cell is
the tumor cell of origin. He stated,
DNA damage was detected in lungs of mice exposed to 2000 ppm
methylene chloride; however, no significant increase in DNA single
strand breaks was observed in Clara cells isolated from mice exposed
to 4000 ppm methylene chloride. This observation does not support
the conclusion that Clara cells were the cells of origin of
methylene chloride-induced mouse lung tumors.
In their paper, Graves et al. [Ex. 120] explain their results as
follows,
Attempts to measure DNA damage in Clara cells isolated from mice
which had been exposed to MC in vivo were unsuccessful. * * * [I]t
is possible that cells extensively damaged by MC do not survive the
isolation procedure. The observation that the in vivo vacuolation of
Clara cells observed after MC treatment is not seen in vitro when
the cells are isolated from the damaged lungs supports this
proposal.
This means that the authors could induce ss breaks in the DNA of
Clara cells in vitro, but in mice exposed to MC in vivo, it is not
clear that the DNA ss breaks observed in lung tissue were concentrated
in the Clara cells. In fact, the authors state,
Since Clara cells represent only 5% of the total lung cell
population, the DNA ss breaks observed in vivo may not exclusively
result from damage to this cell population.
OSHA believes that these issues raise serious doubts as to whether
current evidence supports the determination that the Clara cell is the
cell of origin of the mouse lung tumors. Although the absence of
increased ss breaks is not necessarily an indication of lack of
genotoxicity, the presence of ss breaks in lung tissue (and apparently
not concentrated in Clara cells) reveals an inconsistency in HSIA's
argument: either the ss breaks are irrelevant or Clara cells are not
the cells of origin, or both. Further discussion of the issues
surrounding identification of the Clara cell as cell of origin for
mouse lung tumors is contained below under ``Non-genotoxic mechanisms
of carcinogenesis.''
Ability of MC reactive metabolites to cross membranes.
Although no data were presented by the HSIA to address this issue
directly, several of the HSIA papers and the accompanying letters
postulate that the
[[Page 1524]]
reactive metabolites of the GST pathway are too short-lived to cross
membranes. This argument is used in combination with the claim of high
concentrations of the mRNA for the GST T1-1* in the nuclei of mouse
cells (but not those of rats and humans) to support the contention that
humans are not at risk of developing cancer after exposure to MC. The
reasoning is as follows: (1) Mice are the only species to have high
concentrations of GST T1-1* in the nucleus of lung and liver cells. (2)
The reactive metabolites of the GST pathway are too short-lived to
cross the nuclear membrane. (3) In order to produce a carcinogenic
effect, reactive metabolites must be produced inside the nucleus in
proximity to the DNA. (4) Because the mouse has high concentrations of
these enzymes in the nucleus (and rats and humans do not), the mouse is
uniquely susceptible to lung and liver cancer after exposure to MC. (5)
Therefore, there is no risk of humans developing cancer after exposure
to MC.
Some commenters [Exs. 126-12, 126-30, 126-33] maintained that
HSIA's submitted studies do not support this argument. As discussed
subsequently, the probe used in these experiments measured GST T1-1*
mRNA, not the isozyme itself. There is not necessarily a correlation
between the intracellular concentration of mRNA and the concentration
of enzyme at a specific locus. In addition, one would expect there to
be higher mRNA outside the nucleus (since that is where the enzyme is
transcribed from the mRNA), even if the enzyme were subsequently
concentrated inside the nucleus. Additionally, as discussed previously,
some of the evidence presented by HSIA suggests that the metabolites
can be generated outside the cell (not simply outside the nuclear
membrane) and interact with the DNA. Specifically, Dr. Dale Hattis [Ex.
126-12] has remarked that,
* * * as long as these reaction and detoxification processes are
not infinitely fast (and in principle they cannot be infinitely
fast), a finite fraction of the activated metabolite molecules must
reach the DNA and react. Even though this chain of events is
required by our basic understanding of the relevant kinetic
processes, in this case we also have direct empirical evidence that
active metabolites need not be generated in a cell's nucleus in
order to reach DNA and do damage. The DNA sequence mutations of
Graves and Green [Ex. 122] and Graves et al. [Ex. 123], and the DNA
single strand breaks reported by Graves et al. [Ex. 120] for CHO
cells were all produced by exposing mammalian cells to a tissue
culture medium that had been supplemented with mouse metabolizing
enzymes and methylene chloride. The active metabolites in those
cases were necessarily generated from outside of the cells, not just
in the cytoplasm of the cells that manifested the DNA damage.
Therefore, the claim that the active glutathione transferase
metabolite(s) must be generated in the nucleus and would be
ineffective if generated in the cytoplasm is flatly contradicted by
HSIA's own evidence.
HSIA [Ex. 126-29] strongly disagreed that their results should be
interpreted in this way and countered as follows:
The investigators had to use a suspension assay to maximize the
concentration ratio of methylene chloride to cells to about 10\14\,
and to optimize the GST activity from mouse liver preparation. Only
under these extreme nonphysiological conditions with a transformed
cell line could any increase in mutation frequency be observed.
There is absolutely no justification for assuming similar conditions
in humans, where GST activity is absent or at very low levels in the
cytoplasm and absent in the nucleus.
OSHA disagrees with HSIA, however, and finds Dr. Hattis' and the
other commenters' reasoning more sound. The results of these
experiments indicate that the metabolites of MC are stable enough to
cross the cellular and the nuclear membrane to interact with DNA. The
Agency recognizes that these are not physiological conditions, but the
conditions of the experiment do support the common-sense assumption
that enzymatic metabolism takes place in the cytoplasm of mouse cells
and show that some fraction of the GST metabolite(s) is stable enough
to cross membranes in the cell. Thus, the Agency believes that the
observed tumorigenesis in the mouse is not the exclusive result of
nuclear MC metabolism.
Other issues pertaining to genotoxicity.
The remaining comments on these studies focused on more general
issues such as the genotoxicity of MC and other factors related to the
GST metabolic pathway and MC-induced carcinogenesis. Dr. Melnick [Ex.
126-33] remarked:
Some fundamental questions related to this mechanism and its
uniqueness to mouse liver and mouse lung carcinogenesis are also not
addressed by the present research. For example, why do tumors not
develop in other organs in mice that also have high levels of GST
theta (e.g., kidney)?
OSHA believes this is an important question that reduces the strength
of HSIA's contention that the mouse responds in a unique way to MC. The
investigators have attempted to explain differences in potency of MC
with respect to liver and lung carcinogenesis by invoking differences
in DNA repair rates and GST metabolism within the nuclei of critical
cells. However, there are other tissues which, based on the HSIA
hypothesis, ought to be prime candidates for carcinogenesis. The
kidney, besides having high levels of GST theta, also has a slower rate
of DNA repair than the liver. It would appear to be a logical site of
carcinogenesis if HSIA's hypothesis is correct. OSHA believes that the
lack of tumor response in this organ (and perhaps other logical sites)
indicates that the hypothesis proposed by HSIA fails to account for all
relevant observations.
(2) Non-genotoxic mechanisms of carcinogenesis. Non-genotoxic
mechanisms of action have also been hypothesized for MC. Increased cell
turnover, due to cell death caused by MC toxicity, could theoretically
increase the available number of sites for mutation and subsequent
tumor formation. However, there is only limited evidence of increased
cell turnover after MC exposure. Casanova and Heck [Ex. 21-16] observed
increased DNA synthesis in lung tissue of mice exposed to MC. Green et
al. [Ex. 105] observed Clara cell vacuolation, and both studies
measured increased DNA synthesis on the first day of exposure to MC,
but not on subsequent days of exposure. Clara cells may be targets of
MC-induced toxicity because they contain higher levels of MC-
metabolizing enzymes and are therefore more likely to generate toxic MC
metabolites (for example, carbon monoxide is known to poison MFO
enzymes). Green et al. suggested that the Clara cell was the cell of
origin of the lung tumors observed in the NTP mouse study, because of
the metabolic properties of these cells and the increased cell turnover
observed within a day of MC exposure (in addition to the DNA damage
described above under the section entitled, ``Genotoxic mechanisms of
carcinogenesis'').
Green et al. further suggested that if the cell of origin of the
mouse lung tumors was the Clara cell, humans would be at substantially
less risk of lung cancer, because humans have proportionally fewer
Clara cells than mice do. However, OSHA believes that there is no clear
evidence confirming that Clara cells were the cell of origin of the
mouse lung tumors (see discussion above). Other cell types in the lung,
such as the Type II lung cell, also have relatively high metabolic
activity and could be the site of origin of lung tumors. These cells
have not been studied separately. Further studies are needed to clarify
the role of the Clara cell and other lung cell types and cells in other
tissues in MC carcinogenesis.
(i) Increased cell division. In 1994, Foster et al. [Ex. 119]
investigated increased cell division as the
[[Page 1525]]
mechanism of action of MC in mouse lung cells. Specifically, they
examined the mechanism of MC action on the transient vacuolation of
bronchiolar cells observed following single exposures to MC. In mice
exposed to 2000 and 4000 ppm MC, they observed increased numbers of
vacuolated cells in the bronchiolar epithelium. Pretreatment of mice
with a cytochrome P450 inhibitor decreased the number of vacuolated
cells, while pretreatment with a glutathione depletor did not. In a
replication of the observation made by Green et al. and described
above, the authors found increased cell division (measured as
incorporation of [3H]-thymidine) in Clara cells isolated from mice
exposed to 4000 ppm MC. They concluded:
We believe that these results strongly support the supposition
that the vacuolation of the Clara cells is due to a toxic metabolite
produced by the CYP [cytochrome P-450] pathway of metabolism.
Furthermore the most likely candidate for inducing the change is
thought to be formyl chloride.
OSHA agrees that these observations indicate that increased cell
turnover occurs in Clara cells of mice. This may possibly be a partial
explanation of the mechanism, but only a partial one. In cases where
cytotoxicity has been considered to be an explanation for risk
occurring only at ``high'' doses, this argument is confined to
chemicals believed to act non-genotoxically. MC is likely to be a
genotoxic carcinogen, so even if cell proliferation is a factor, the
genotoxic mechanism would be the primary mechanism of concern.
Genotoxic carcinogens are not generally believed to have a threshold
and the dose-response function is believed to be approximately linear
at low doses. In addition, the study focused on one type of cell, which
may not be the cell of origin for lung tumors. Carcinogenicity in
humans (as well as in mice and rats) seems to originate from various
cell types in various tissues.
(3) Metabolism of MC. As described above, the mechanism of
carcinogenesis for MC is not known. Numerous studies over many years
have explored numerous possible mechanisms and have provided
substantial information regarding the metabolism and the probable
metabolite responsible for the carcinogenic effect. As discussed in the
Health Effects section, MC is metabolized by two pathways: the mixed
function oxidase pathway (MFO) and the glutathione S-transferase (GST)
pathway. Both pathways produce reactive intermediates which potentially
could contribute to a genotoxic mechanism of carcinogenicity. During
development of the PBPK model for MC, Reitz et al. found that tumor
incidence correlated with the estimated amount of GST metabolite, as
well as with the amount of parent compound administered, but not with
the amount of MFO metabolite [Ex. 7-225]. The parent MC is not likely
to act as a genotoxic carcinogen because it is a fairly non-reactive
compound. In addition, MC blood levels in mice were lower than in rats,
so if MC was the carcinogenic moiety, one would expect the risk of
cancer in rats to be higher than mice, whereas the opposite was
observed. Consideration of these factors has led many investigators to
conclude that the GST pathway is responsible for carcinogenesis and
that it is likely to produce a genotoxic carcinogenic moiety. OSHA has
reviewed the data available on mechanism of action and has concluded
that the most plausible assumption is that the GST pathway is
responsible for the carcinogenic action of MC and that this should be
taken into account in the quantitative risk assessment. This represents
a case-specific departure from the default assumption that the
administered dose of the parent compound is the relevant metric for
exposure.
(i) Specific GST isozyme(s) responsible for MC metabolism to the
carcinogenic metabolite. Recent work sponsored by the HSIA was directed
at further characterization of the metabolism of MC by the GST pathway
[Exs. 121, 124, 124A]. Specifically, the HSIA work on MC metabolism has
focused on the isolation and description of isozymes in the GST theta
class of enzymes, which HSIA believes are responsible for the
metabolism of MC to the carcinogenic metabolite in mice. Mainwaring et
al. have shown that the GST isomer with the greatest specific activity
for MC is a member of the theta class of GST. [Ex. 121] In rats, three
members of the theta class have been identified, GST 5-5, GST 12-12 and
GST 13-13. In humans, two theta class enzymes have been identified, GST
T1-1 and GST T2-2 and in mice, two theta enzymes have been described,
GST T1-1* and GST T2-2* (also known as GST MT-1 and GST MT-2).
According to Mainwaring et al. [Ex. 121], rat GST 5-5 and mouse GST T1-
1* have similar specific activity toward MC and sequencing studies have
shown ``* * *that rat 5-5, mouse T1-1* and human T1-1 are orthologous
proteins as are rat 12-12 and mouse T2-2* and human T2-2'' [Ex. 124A].
The hypothesis under investigation in this work was that the enzyme
similar to rat GST 5-5 (mouse T1-1* and human T1-1) was the critical
enzyme responsible for metabolism of MC to the carcinogenic metabolite,
and that differences in the interspecies intra- and inter-cellular
distributions of this isozyme and differences in genotoxicity would be
important for characterizing the risk of carcinogenesis after exposure
to MC.
In order to examine the distribution of the GST isozymes of
interest, the investigators used DNA oligonucleotide anti-sense probes
complementary to three regions of the protein nucleotide sequences of
rat GST 5-5, mouse GST T1-1* and human GST T1-1 to localize specific
mRNA sequences in mouse, rat and human liver and lung tissue. They also
used an antibody raised against rat GST 12-12 to localize the protein
itself [Exs. 124, 124A]. In the full paper describing these experiments
[Ex. 124A], Mainwaring characterized the results of this study, as
follows:
The mouse enzymes [T1-1* and T2-2*] were present in
significantly higher concentrations in both liver and lung than the
equivalent enzymes in rat and human tissues. In mouse liver, both
enzymes were localized in limiting plate hepatocytes surrounding the
central vein, in bile duct epithelial cells and in the nuclei of
hepatocytes. In rat liver the distribution of GST 12-12 was
comparable to that seen for T2-2* in the mouse. GST 5-5 was not
localized in limiting plate hepatocytes or in nuclei of rat liver.
The levels of human transferase T1-1 in the liver were very low,
with an even distribution throughout the lobule. The GST 12-12
antibody did reveal high concentrations of this enzyme in human bile
ducts. The relative amounts of the theta enzymes in the lungs of the
three species followed the pattern seen in the liver, with very high
concentrations in Clara cells and ciliated cells of the mouse lung
and much lower levels in the Clara cells only of rat lung. Low
levels of human transferase T1-1 were detected in Clara cells and
ciliated cells found at the alveolar/bronchiolar junction of one
human lung sample. The enzyme was entirely absent from the large
bronchioles.
Mainwaring et al. concluded that:
This study has demonstrated a highly specific distribution of
the theta class GSTs 5-5 and 12-12 in liver and lung tissue from
mice, rats and humans. * * *it was apparent from these studies that
both the distribution and concentration of theses enzymes differed
markedly between the three species. Whilst neither mRNA levels nor
protein concentrations necessarily correspond to active enzyme, the
distribution shown by the mRNA for GST 12-12 was quantitatively
reflected by the antibody to the protein of this enzyme, suggesting
that these techniques do, in this case, reflect the distribution of
active enzyme. Although an antibody to GST 5-5 is not available, it
is reasonable to assume that mRNA levels for this enzyme are
similarly representative of the distribution of active enzyme.
An understanding of the cellular and sub-cellular distribution
of GST 5-5 has provided
[[Page 1526]]
an explanation for the species specificity of the mouse lung and
liver carcinogen methylene chloride, and has provided reassurance
that humans are not at risk from exposure to this chemical.
(ii) Issues raised pertaining to metabolic studies. Many commenters
commended the HSIA for providing new information on the mechanism of
action of MC and for confirming previous quantitative studies of the
interspecies differences in MC metabolism. However, commenters also
raised several specific issues regarding the conduct and interpretation
of these experiments.
Correlation of mRNA concentrations with enzyme concentrations.
Mainwaring et al. [Ex. 124A] correlated the inter- and intra-
cellular distribution of the mRNA for GST 12-12 in the rat with the
distribution of the antibody for GST 12-12. They stated that it is
reasonable to assume that since the protein and mRNA for the 12-12
isomer have similar distributions, the protein for the 5-5 isomer would
distribute in the same manner as the mRNA for the 5-5 isomer. In
support of their assumption, they noted that there is 80% homology
between the 5-5 and 12-12 isomer. Some commenters believed that this
was not a reasonable assumption and that there was no reason to believe
that the distribution of the GST 5-5 isomer protein would correlate
with the distribution of the GST 5-5 mRNA simply because there seemed
to be a correlation in the 12-12 isomer protein and mRNA distributions
[Exs. 126-7, 126-16]. OSHA concurs with these commenters, and until
there is actual measurement of the GST 5-5 protein, OSHA does not
believe that the question of the actual distribution of GST 5-5 isozyme
will have been settled.
More importantly, several commenters stressed that it was mRNA that
was actually observed in these studies, and mRNA levels do not
necessarily correspond to either protein levels or protein activity
within a cell [Exs. 126-7, 126-16, 126-28, 126-30, 126-32]. Although
Mainwaring et al. acknowledge this fact [Ex. 124A], the conclusions
reached by the authors still suggest that measurement of mRNA is
equivalent to measurement of enzyme activity. Referring to the
conclusions drawn by Mainwaring et al., Dr. Lorenz Rhomberg [Ex. 126-
16] commented:
This interpretation of mRNA distribution is profoundly in error
and contradicts some of the most well established and fundamental
principles of molecular biology.* * * Finding mRNA in the nucleus is
unsurprising and uninformative about the eventual location of the
protein products. Detecting mRNA only reveals that the cell may be
presumed to be manufacturing the corresponding protein.
Dr. Rhomberg was also concerned that the concentration of GST T1-1* in
the nucleus of mice may be an artifact of the experimental conditions,
resulting, perhaps, from a burst of mRNA synthesis. The concern that
the apparent nuclear concentration of GST may be an artifact was echoed
by Dr. Douglas A. Bell of the National Institute for Environmental
Health Sciences [Ex. 126-26]. He stated:
Why the [intracellular] distribution should be different among
species is unclear and unusual. Differences in processing of the
nuclear RNA transcript from full length pre- mRNA may be the
underlying cause of this phenomenon (or perhaps there is a
transcribed pseudogene that is complicating the process).
Because of the specific cellular mechanisms that would be required
to concentrate a protein in the nucleus, Dr. Rhomberg [Ex. 126-16]
indicated that translocation of the GST 5-5 protein to the nucleus only
in mice seemed unlikely. He stated:
It seems implausible * * * that for a series of orthologous
proteins, such localization would be found in a particular species
and not in other species.
OSHA agrees with the comments made by Dr. Rhomberg and Dr. Bell on this
issue, and concludes that the concentration of mRNA at a particular
cellular site does not necessarily correlate with concentration of the
enzyme itself. OSHA believes that caution should be used when
interpreting the results of these experiments.
Attribution of GST metabolizing activity to a single GST isozyme.
Concern was also raised about the validity of attributing all of
the glutathione S-transferase metabolism of MC to one isomer of the
theta class [Exs. 126-7, 126-12]. In particular, Dr. Dale Hattis noted
that there was less enzyme activity eluting coincident with the peak
identified as the 5-5 form than that eluting at pH 8, which was not
believed to correspond to the 5-5 form. Dr. Ronald Brown described
results from a paper by Blocki (1994) [Ex. 127-22] which showed that
``expression of the [5-5] isozyme contributes 50% of the total GST
activity toward this substrate.'' This leaves the question open as to
whether isozymes which may have lower specific activity for MC but
which may be expressed in much greater abundance (particularly
4-4), could contribute as much as the remaining 50% of the
total GST metabolism (see Table VI-1, reproduced below from Dr. Brown's
comment [Ex. 126-7], original source Blocki et al. (1994) [Ex. 127-
22]).
Table VI-1.--Relative Contribution of Different Rat Liver Glutathione S-Transferases in Dichloromethane Metabolism to Formaldehyde
--------------------------------------------------------------------------------------------------------------------------------------------------------
Glutathione S-transferases
-----------------------------------------
Class Class Class
--------------------------------------------------------------------------------------------------------------------------------------------------------
Comparative parameter (units)............... 1-1+1-2+2-2 3-3 3-4 4-4 b 5-5 b 13k
Specific activity (nmol/min/mg of protein).. <0.1 7 11 23 11,000 9
% Cytosolic protein (% of total in liver)... 6.4 0.7 0.3 0.6 0.002 0.005
Total activity (nmol/min/g of liver protein) <10 49 33 138 22 0.45
% Total activityc........................... <1.5 11 7 32 50 0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
a Data from Meyers et al., 1991.
b Data for 13,000 molecular weight glutathione transferase from Blocki et al., 1992.
c Assuming Vmax conditions for each.
In addition, Mainwaring et al. [Ex. 124A] noted that the
``substrate specificity of GST 12-12 is currently poorly
characterized,'' although the purified enzyme has no activity toward
MC. As described above, these enzymes appear to be very labile upon
purification. Therefore, it is unclear how much the 12-12 isomer itself
may contribute to MC metabolism. As Dr. Kenneth T. Bogen stated, ``* *
* while the substrate specificity of GST 12-12 may currently be poorly
characterized, current data do not appear to rule out GST 12-12
specificity toward MC.''
[[Page 1527]]
Limited human samples and human polymorphism in the GST theta
genes.
Several commenters expressed concern for the limited number of
human samples (one pooled lung sample and less than 40 human liver
samples have been assayed) and the potential effect of a known human
polymorphism for the glutathione S-transferase theta class genes on
risk estimations [Exs. 126-7, 126-16, 126-26, 126-35]. Specifically,
commenters raised concerns that there may be a large subpopulation of
GST conjugators who may be at increased risk from MC exposure that has
not been adequately characterized in the limited number of human
samples (especially lung samples) that have been tested. HSIA objected
to these comments, stating,
The human tissue data base for the metabolism of methylene
chloride by the GST pathway is one of the largest, if not the
largest, available for this type of risk assessment. To discount it
based on arguments concerning hypothetical polymorphisms, as these
commenters urge OSHA to do, would be contrary to the message
consistently put forward by the National Academy of Sciences and
regulatory authorities for the past decade. * * *''
In fact, the National Academy of Sciences report cited by HSIA,
``Science and Judgement in Risk Assessment'' does encourage agencies to
make use of biologically-based models, but cautions that using them
without adequately considering human variability would be a step
backwards:
EPA has not sufficiently accounted for interindividual
variability in biologic characteristics when it has used various
physiologic or biologically based risk-assessment models. The
validity of many of these models and assumptions depends crucially
on the accuracy and precision of the human biological
characteristics that drive them. In a wide variety of cases,
interindividual variation can swamp the simple measurement
uncertainty or the uncertainty in modeling that is inherent in
deriving estimates for the ``average'' person.
The Academy goes on to recommend specifically that making ``reasonable
inferences'' about interindividual variation is required, rather than
assuming that no such variation exists:
Even when the alternative to the default model hinges on a
qualitative, rather than a quantitative, distinction, such as the
possible irrelevance to humans of the alpha-2u- globulin mechanism
involved in the initiation of some male rat kidney tumors, the new
model must be checked against the possibility that some humans are
qualitatively different from the norm. Any alternative assumption
might be flawed, if it turns out to be biologically inappropriate
for some fraction of the human population.
When EPA proposes to adopt an alternative risk-assessment
assumption * * * it should consider human interindividual
variability in estimating the model parameters or verifying the
assumption of ``irrelevance.'' If the data are not available that
would enable EPA to take account of human variability, EPA should be
free to make any reasonable inferences about its extent and impact
(rather than having to collect or await such data), but should
encourage interested parties to collect and provide the necessary
data.
OSHA believes HSIA has misinterpreted the NAS recommendations, and
further disagrees with HSIA that the polymorphism is ``hypothetical.''
Investigators have demonstrated this polymorphism in human GST and have
shown how the polymorphism varies across races [Exs. 127-7, 127-9, 127-
17, 127-21, 127-23, 127-24, 127-25]. OSHA agrees with the commenters
that a human polymorphism in the GST theta genes may increase concern
for individuals that may be at higher risk from exposure to MC due to
their genetic make-up. The Agency has considered sensitive
subpopulations in the development of health standards, including this
rulemaking. For example, the subpopulation of workers with silent or
symptomatic heart disease was considered in assessing the cardiac risks
of MC (due to its metabolism to carbon monoxide). The variation in
enzyme activity raises additional uncertainty in the use of human data
to support the hypothesis that mice are uniquely sensitive to MC
carcinogenicity. However, for purposes of quantitative analysis, the
Agency has not attempted to systematically adjust the risk estimates
based on a ``high GST metabolizing'' individual because the frequency
and impact of such polymorphisms have not been clearly worked out.
Target site of MC carcinogenesis in mice versus humans.
Drs. Brown and Melnick [Exs. 126-7, 126-33] also raised the
possibility that the target site for MC carcinogenesis may be different
in humans than in mice or rats. Specifically, research on the
occurrence of theta isomers of GST in human blood was described. The
characterization of GST metabolism in human erythrocytes [Exs. 127-11,
127-12] suggests the possibility of the bone marrow as a potential
target of MC carcinogenesis and also the potential for metabolism in
the blood and translocation of the metabolites to a variety of
potential targets. The HSIA discounted human blood metabolism of MC,
stating,
The `very high capacity to conjugate methylene chloride'
mentioned by Brown is in fact very low, approximately 40-fold lower
than the highest activity detected in human liver.
OSHA believes that although the specific activity in the blood may be
lower than the human liver activity, the total activity of the GST
enzymes in blood and marrow may be significant when one also considers
the volume of these compartments. OSHA also notes that interspecies
tumor site concordance is not necessarily expected, and it is prudent
to consider any human tissues which have the potential to metabolize MC
to the putative carcinogen.
Concentration of protein complementary to rat GST 12-12 in human
bile ducts.
Dr. Bogen [Ex. 126-15] commented specifically on the human liver
protein complementary to the antibody to rat GST 12-12 protein. In
particular he was concerned that high concentrations of this enzyme
were reported in bile ducts of the human liver. He noted,
With regard to potential human carcinogenicity of MC relative to
its known carcinogenic potential in mice, it seems to me that these
particular data ought not to reduce regulatory concern, but rather
ought to increase regulatory concern, in view of the fact that bile
duct epithelium cells are the most likely stem cells for
hepatocytes. * * * Thus hepatocellular bile-duct epithelial cells
are likely to play an important role in liver carcinogenesis in both
mice and humans.
OSHA agrees with Dr. Bogen's concerns and also notes that in the
cohort study of textile workers conducted by Hoescht-Celanese [Ex. 7-
260], an excess of biliary cancers was observed in those workers
exposed to the highest concentrations of MC and those with the longest
latency period between exposure and disease. If the HSIA theory is
correct (i.e., a single isozyme is the culprit), then finding high
levels of this isozyme in human bile duct is strong evidence
implicating MC in human carcinogenesis.
Interpretation of data as qualitative versus quantitative
differences.
Perhaps most importantly for the purposes of MC risk assessment,
several commenters remarked that OSHA should use caution when
interpreting the data from the HSIA submissions, because any
interspecies differences are rightly considered first as quantitative
rather than qualitative ones. In part, the commenters cautioned that
one should pay special attention to the threshold of detection in all
assays. As Dr. Andrew Salmon stated,
Green and co-workers have consistently confused their inability
to measure a result or parameter value due to its magnitude or
frequency of occurrence being below their threshold for practical
detection, with a true
[[Page 1528]]
zero value for the parameter or zero risk of an occurrence [Ex. 126-
36].
OSHA agrees that caution should be used when attempting to characterize
a difference between species as an absolute qualitative difference. A
much higher burden of proof is required to support a claim of zero risk
than of diminished risk. (This higher burden is due to the need to
consider assay sensitivity and other factors; the fact that the
consequences of incorrectly concluding that humans are at zero risk are
particularly dire only adds to the already high threshold of scientific
evidence needed to successfully make such a claim). In the case of MC,
humans clearly have the ability to metabolize MC via the GST pathway
[Exs. 21-53, 127-16]. Even if the enzyme concentration of GST T1-1*
itself actually occurs only in the nuclei of mouse lung or liver (as
opposed to the concentration of mRNA, which may or may not be localized
differently within mouse cells), it is still unclear what impact (if
any) this fact would have on the characterization of human cancer risks
for MC. OSHA believes that the statement that there are absolute
species differences in the activity and intracellular distribution of
GST 5-5 is highly speculative and is not supported by the data
presented to date, because the data presented refers to the
distribution of mRNA for GST 5-5, not the enzyme concentrations or
activity levels of the enzyme; there is no quantification of the
intracellular levels of the mRNA or enzyme levels, only photographic
representations; and there is no evidence that any potential difference
in enzyme activity (when those experiments are completed) would be
greater than the difference already predicted from allometric scaling
considerations.
Conclusions reached by the HSIA.
HSIA concluded from these studies that because of a qualitative
inter-species difference in the distribution of the GST theta enzyme
responsible for MC carcinogenesis, humans would not be at risk of
developing cancer under ``foreseeable conditions of exposure.''
Although some commenters agreed with the conclusions reached by the
HSIA [e.g., Exs. 126-10, 126-13, 126-20], many commenters strongly
disagreed with this interpretation of these data pertaining to the risk
assessment for MC. These commenters [e.g., Exs. 126-7, 126-11, 126-12,
126-15, 126-16, 126-22, 126-26, 126-30, 126-36] were concerned that the
question was in reality an issue of quantitation of enzyme, not a
qualitative difference in metabolism. Dr. Lorenz Rhomberg commented:
The question is, is there any basis for believing that the
species difference in activity suggested by the mRNA data is greater
than has been previously supposed?
It should be emphasized that some degree of species difference
in metabolic activity is expected even under the default cross-
species extrapolation methods. That is, in keeping with the general
pattern of scaling of physiological processes across species,
general metabolic rates are presumed to be lower on a per unit of
tissue basis in larger animals. As a default, this pattern can be
presumed to apply to individual metabolic pathways as well, although
data on species-species activities can be used in place of such
defaults if available.
If species-species activities are discovered by experiment to be
less in humans than in mice to the degree already anticipated by
allometry, then the experiments are simply confirming the default
and no change in the human risk estimates is warranted. If humans
have a metabolic activity different than the allometric prediction,
the incorporation of such estimates into PBPK models can show
different human risks from those predicted under the default. The
allometric prediction is that, on a per unit of tissue basis, humans
should have about 7-fold lower activity than mice and about 4-fold
lower activity than rats.
Given the limit of detection of the assay methods, human
metabolic activity (or mRNA levels) only a bit less than the
allometric expectation of 7-fold less than mice are often difficult
to distinguish from zero. That is, claims that humans have no
activity (or no mRNA production) in certain tissues must be judged
in the light of the fact that only a small change from the already
acknowledged allometric difference can often make the human activity
undetectable. A 20-fold mouse-human difference, for example, really
only represents a 3-fold exaggeration of the 7-fold allometric
pattern, yet many assays may fail to reliably characterize a 20-fold
difference as a quantitative difference rather than a qualitative
difference.
For the above reasons, claims that human metabolic activity in
activating methylene chloride are so low as to be essentially
qualitatively different than mice should be interpreted with great
caution. In fact, existing assays have great difficulty in detecting
species differences in metabolic activity great enough to markedly
challenge existing risk assessments.
Another commenter discussed the fact that cellular levels of the GST 5-
5 isoenzyme would be expected to be distributed unevenly across cells,
putting some cells at greater or lesser risk. This would tend to
average out over a tissue and would be best described by tissue
metabolism data. Other commenters remarked that there was no need to
adjust the risk estimates based on these studies because current
pharmacokinetic models already account for interspecies differences in
metabolism. Although OSHA has incorporated data from these studies,
especially in its ``alternative analysis,'' OSHA agrees with Dr.
Rhomberg and the other commenters who have taken exception to the HSIA
conclusions.
The Agency does not accept the HSIA characterization of the results
of the summarized studies. OSHA has determined that no evidence has yet
been presented that demonstrates that humans are not at risk of
developing cancer after exposure to MC. At most, the presented studies
suggest a quantitative inter-species difference in MC metabolism, which
was established in previous scientific reports and is already accounted
for by PBPK modeling. As discussed extensively in this document, OSHA
has concluded that HSIA has undervalued certain strong evidence and has
overemphasized some more speculative hypotheses. However, as is clear
from this discussion OSHA has carefully considered all of the evidence.
Substantial evidence in the record clearly supports OSHA's conclusions.
Consequently, OSHA's approach of relying on the NTP mouse tumor data as
the basis of its quantitative risk assessment continues to be the best
approach to risk estimation.
c. Conclusions regarding the carcinogenesis of MC. The HSIA
submitted these documents to OSHA with a request that the Agency
consider the mouse tumor data in light of these additional studies and
reject use of the mouse tumor response data as the basis of the
Agency's quantitative risk assessment. OSHA believes it has given
proper weight to all the evidence, giving greater weight to that which
is of the highest scientific quality. However, in light of HSIA's
request, the Agency reopened the rulemaking record and reviewed all the
new data. After submitting these documents for review, the HSIA [Ex.
126-29] remarked on comments submitted to the docket by other
scientists,
In general, the comments submitted by R. Maronpot, R. Brown, L.
Rhomberg, K. Bogen and D. Hattis exhibit a reluctance to use the
large body of mechanistic data now available in assessing the
potential carcinogenic risk posed by methylene chloride, even though
most other commenters agree that the pathway responsible for its
observed carcinogenicity in mouse liver and lung, as well as species
variations in activity of this critical pathway, have now been
identified. Much of the comment addressed here appears to be
motivated by a desire to maintain the ``status quo'' for assessing
carcinogenic risk based on default principles that were developed
twenty years ago.
The HSIA goes on to say,
[[Page 1529]]
Many of the conclusions reached by the commenters * * * are
based, often erroneously, on single aspects of one or the other of
these publications, rather than on the entire data base, as a
``weight of evidence'' approach would demand and as is necessary to
understand the results.
OSHA finds it difficult to understand why HSIA believes that the
scientists they listed are primarily interested in preserving the
``status quo.'' Dr. Maronpot conducted the mechanistic studies on MC at
NIEHS, which have generated mechanistic information useful to the risk
assessment process. Dr. Rhomberg was instrumental in developing the
pharmacokinetic approach used by the Environmental Protection Agency in
its risk assessment of MC (an approach never used by the Agency
previously). Dr. Hattis, Dr. Bogen and Dr. Brown are all experts in the
application of pharmacokinetic modeling to risk assessment and have
repeatedly called for incorporating more mechanistic and physiological
data into pharmacokinetic models. These highly respected scientists,
among others, reviewed the HSIA submissions critically and
independently and reached conclusions different from those of the HSIA,
conclusions which themselves depart significantly from the ``status
quo.'' This does not suggest to OSHA that they are trying to preserve
some status quo in risk assessment, and OSHA finds nothing in the
comments of these experts to suggest that this is the case.
In order to respond to HSIA's desire to have OSHA further review
all of the data, the Agency has reviewed each submitted study carefully
and critically on its own merits to determine how each piece of data
fits into the overall picture of the mechanism of action for MC. OSHA
believes that in this process the critical issues raised by the HSIA
have received a full airing and the hazard identification and the risk
assessment for MC have been improved because of it. OSHA believes,
however, that looking only at the new studies submitted by HSIA, and
examining them uncritically, would contradict every principle of
scientific analysis.
In summary, in order to accept the HSIA's supposition that MC is
not carcinogenic in humans, one must believe the following:
1. GST 5-5 is the only isozyme which can metabolize MC to the
carcinogenic metabolite.
2. DNA single strand breaks are relevant and a sufficient measure
of the tumorigenicity of a compound.
3. The absence of detectable increases in DNA ss breaks in a single
experiment means that there are in fact no additional ss breaks.
4. The limited number of human samples (one sample of pooled lung
tissues being the absolute extreme of ``limited'' data) used to
determine metabolic parameters are truly representative of the range of
human variability.
5. An apparent correlation in the distribution of the GST 12-12
protein and GST 12-12 mRNA means that the distribution of GST 5-5
protein will correlate similarly with the distribution of GST 5-5 mRNA.
6. Visual interpretation of photomicrographs staining for GST mRNA
gives a true and accurate measure of GST activity in the cell.
And one must also ignore the following contradictory observations
and conclusions about the mechanism of action (in addition to ignoring
the suggestive epidemiologic evidence):
1. Metabolites of GST can cross cell and nuclear membranes and
interact with DNA to induce DNA ss breaks and mutations.
2. GST mRNA and protein stain heavily in human bile duct cells
(believed to be precursors of hepatocytes).
3. Human lung tissue has been shown to stain for GST mRNA.
4. Only 50% of the GST metabolism of MC can be accounted for by the
GST 5-5 isozyme.
5. The metabolic capacity of GST 12-12 for MC has not been
characterized.
OSHA concludes that these studies, even putting aside all technical
objections to the methodology and interpretation of individual studies,
do not change the conclusion that substantial evidence supports the
carcinogenicity of MC. The bioassay results in mice are still
qualitatively and quantitatively relevant to humans. Once the HSIA
studies have been replicated and key components quantified (like the
intracellular enzyme activity (instead of mRNA levels) of GST towards
MC), the HSIA data may be useful in characterizing quantitative
interspecies differences in MC GST metabolism. In particular, it would
be useful to determine whether all of the evidence that HSIA submitted
is consistent with an allometric difference (a difference expected
based on the size of the animal) in sensitivity to MC or with a greater
interspecies difference in sensitivity. (The specific activity of GST
toward MC in mice is estimated to be about 7-fold that of humans, based
on allometric considerations.) OSHA believes that its final risk
assessment, which relies on an analysis of all available PBPK data,
addresses both possible interpretations.
B. Selection of Database for Quantitative Risk Assessment
1. Animal Bioassays
The first step in performing a quantitative assessment of
carcinogenic risk based on animal data is to choose a data set or sets
from which to define the dose-response relationship. In its NPRM, OSHA
had chosen the NTP female mouse lung and liver tumors to determine its
estimates of risk. OSHA chose these responses because they provided
clear dose-response relationships, had low background tumor rates and
were more sensitive measures of dose-response than corresponding male
mouse tumor sites.
The EPA, the CPSC and the FDA chose to use the combined incidence
of adenomas and carcinomas of the lung and liver as the basis for their
risk assessments. Specifically, the EPA [Exs. 25-D, 28] placed emphasis
on the experimental species and sex group showing the highest risk: the
number of female mice showing either adenoma or carcinoma in either
lung or liver (or both). The CPSC [Ex. 25-I] pooled benign and
malignant tumors of either the mammary gland, lung or liver and
averaged male and female estimates to derive an overall risk estimate.
The FDA [Ex. 6-1] used benign and malignant responses of female mice.
The Crump report [Ex. 12] noted that it may be reasonable to combine
lung and liver responses to give an indication of the potency of MC,
due to the fact that metabolism of MC occurs by the same pathway in
both lung and liver and thus results in the same ultimate metabolites.
However, the report added that since both tissues have different
background responses, combining responses may tend to complicate the
interpretation of risk estimates.
In OSHA's final rule, the NTP study (rat and mouse, inhalation) was
chosen for quantitative risk assessment because it provided the best
toxicological and statistical information on the carcinogenicity of MC
[Exs. 12, 7-127] and because the study was of the highest data quality.
In the NTP study, MC induced significant increases both in the
incidence and multiplicity of alveolar/bronchiolar and hepatocellular
neoplasms in male and female mice. In rats, dose-related, statistically
significant increases in mammary tumors were also observed. OSHA chose
the female mouse tumor response as the basis of its quantitative risk
assessment, because of the high quality of data, the clear dose
response of liver and lung
[[Page 1530]]
tumors and the low background tumor incidence. Although the female rat
mammary tumor response was also dose-related, the data of high quality
and amenable to quantitative risk assessment, the mouse data set had a
clearer dose-response in both liver and lung tumors than the rat
mammary tumor response and the mouse background tumor incidence was
lower than in the rat. Therefore the mouse data set was chosen for
quantitative analysis.
OSHA included the lung adenomas in the quantitative analysis. The
evidence suggests that the presence of benign tumors with the potential
to progress to malignancies should be interpreted as representing a
potentially carcinogenic response. This belief is supported by the
OSTP's views on chemical carcinogenesis (50 FR 10371). OSTP stated that
at certain tissue sites, such as the lung, most tumors diagnosed as
benign really represent a stage in the progression to malignancy.
Additionally, NIOSH, the EPA, the CPSC and the FDA have also included
benign responses in their assessments. Therefore, it is appropriate and
sometimes necessary to combine certain benign tumors with malignant
ones occurring in the same tissue and the same organ site. In
particular, OSTP also stated that ``the judgement of the pathologist as
to whether the lesion is an adenoma or an adenocarcinoma is so
subjective that it is essential they be combined for statistical
purposes.'' (50 FR 10371).
OSHA chose female mouse lung tumors as the specific tumor site for
its final quantitative risk assessment. There is no a priori reason to
prefer the mouse lung tumor response over the liver tumor response,
because both data sets were of high quality, showed a clear dose-
response relationship and had low background tumor incidence. In fact,
in the NPRM, the Agency reported estimates of risk generated using both
sites. However, to reduce the complexity of the final PBPK analysis,
which required highly intensive computations, OSHA chose one site (the
female mouse lung tumor response) for its final risk estimates. The
risks calculated using the female mouse liver response would likely be
slightly lower than those calculated using the lung tumor response. On
the other hand, pooling the total number of tumor-bearing animals
having either a lung or liver tumor (or both) (which is the procedure
EPA advocates [see its 1986 Guidelines for Cancer Risk Assessment])
would have yielded risk estimates higher than OSHA's final values.
The NTP study has been described in the Health Effects section and,
above, in the discussion regarding hazard identification.
2. Epidemiologic Data
The epidemiology data are not as useful for quantitative risk
assessment as the animal data because the animal data provide a clear
dose-response, with fairly precise indices of exposure, which cannot be
derived from the epidemiology data. All other things being equal, risk
assessors would prefer to use epidemiologic data to assess cancer risk
in humans over data from animal studies whenever good data on human
risk exist. However, the uncertainty inherent in epidemiologic studies
must be accounted for; in particular, ``positive'' studies often have
lower confidence limits that do not rule out the no-effect hypothesis,
while ostensibly ``negative'' studies often have UCLs that would
support a substantial positive effect. OSHA believes (see discussion
below) that the latter circumstance applies to some of the MC studies.
Other factors, such as duration and intensity of a chemical exposure
(which can rarely be controlled and accurately measured in an
epidemiological study), difficulty in accurately defining the exposed
population, and other confounding factors diffuse a study's predictive
power of true risks.
Frequently, animal studies indicate a positive response to a
particular chemical when epidemiologic studies of exposures to the same
chemical fail to exhibit a statistically significant increase in risk.
When animal studies show a substance to be a carcinogen but
epidemiologic studies are non-positive, the minimum risk which could be
detected by the human study should be estimated to assess the strength
of the epidemiologic study and justify its importance in the risk
assessment process. Similarly, the animal-based potency estimate can be
used to predict the number of human deaths investigators would likely
have seen in an epidemiologic study if the animal-based estimate was
correct; if the observed number of human deaths is markedly
inconsistent with this predicted number, the relevance of the animal-
based estimate might well be called into question. If the human data
are equivocal, or the epidemiologic study is not sufficiently sensitive
to identify an increased risk predicted by a well-conducted animal
bioassay, it is necessary to consider the animal data to protect
workers from significant risk. OSHA concludes that the MC epidemiology
studies do not have adequate information upon which to base a
quantitative risk assessment. OSHA has, however, used the analyzed
epidemiological data to determine whether the results are consistent
with those estimated using the rodent models. This is discussed later
in the document.
3. Conclusions
After reviewing the animal data and the quantifiable epidemiology
data, OSHA has determined that the NTP female mouse lung tumor response
is the appropriate data set on which to base its quantitative risk
assessment, and has determined that the most scientifically-appropriate
way to use these data involves constructing a PBPK model to extrapolate
from animals to humans. OSHA believes that the non-positive
epidemiology data, in particular those from Kodak, are of in sufficient
power to rule out the risk estimates derived from the animal data.
C. Choice of Dose-Response Model
Several approaches have been used to estimate cancer risk from
exposure to toxic agents. A standard approach uses mathematical models
to describe the relationship between dose (airborne concentration or
target tissue dose surrogate) and response (cancer). Generally,
mathematical functions are fit to the data points observed at different
exposure levels and these functions are used to estimate the risk that
would occur at exposure levels below those observed. The shapes of
these curves vary, ranging from linear extrapolations from the observed
points through the origin (zero exposure and zero risk) to curves which
may deviate far from linearity at the very highest or lowest doses. The
use of a particular model or curve can be justified in part by
statistical measures of ``goodness-of-fit'' to observed data points.
That is, there are various statistical tests which measure how closely
a predicted dose-response curve fits the observed data.
The most commonly used model for low-dose extrapolation is the
multistage model of carcinogenesis. This model, derived from a theory
proposed by Armitage and Doll in 1961, is based on the biological
assumption that cancer is induced by carcinogens through a series of
independent stages. The Agency believes that this model conforms most
closely to what we know about the etiology of cancer. There is no
evidence that the multistage model is biologically inappropriate,
especially for genotoxic carcinogens, which MC most likely is. The most
recent data submitted by the HSIA [Exs. 117-124A] clearly add
substantial support to the previous body
[[Page 1531]]
of evidence indicating that one or more metabolites of MC is a
genotoxic carcinogen. The low-dose linearity feature of this model is
scientifically required for any exposure that confers additional risk
upon a pre-existing background level of risk produced by a similar or
equivalent mechanism. Given the underlying connection between DNA
mutations and cancer and the obvious background incidence of cancer in
the human population, the overwhelming scientific consensus is that
genotoxins follow low-dose linear functions.
The multistage model is generally considered to be a conservative
model because it is approximately linear at low doses and because it
assumes no threshold for carcinogenesis, although there are other
plausible models of carcinogenesis which are more conservative at low
doses. ``No threshold'' means that any incremental amount of exposure
to a carcinogen is associated with some amount of increased risk.
``Approximately linear at low doses'' means that one unit of change in
dose will result in one unit of change in risk at low doses.
The most common approach for setting the parameters in the
multistage model is to assume that the dose-response curve is described
by a polynomial of k-1 degrees, where k is the number of dose groups
tested. The multistage model thus takes the form
P(Cancer) = 1--exp(-f(dose)),
with f(dose) given by:
f(dose) = a + b1(dose) + b2(dose)2 + ...+ bk-
1(dose)k-1.
The number of stages is specified by k-1, and the parameters a (the
background risk) and bi are estimated from the observed data.
Alternatives to the multistage model include the tolerance
distribution models such as the probit model, the logit model and the
Weibull model. The tolerance distribution models generally predict
dose-response relationships which are sigmoid in shape. Thus, these
models will approach zero more rapidly than a linear multistage model.
This means that at low doses, these models will predict lower risks
than will a linear multistage model.
In the MC rulemaking, most of the risk assessments submitted to the
Agency used the linearized multistage model to predict risk. The
differences in risk estimates were not generally due to the dose-
response model used, but to whether the risk assessor used
pharmacokinetic modeling to estimate target tissue doses, and what
assumptions were used in the pharmacokinetic modeling.
D. Selection of Dose Measure
1. Estimation of Occupational Dose
The purpose of low dose extrapolation is to estimate risk of cancer
at a variety of occupational exposures. This requires that the doses be
converted into units comparable to those in which the experimental dose
is measured.
In its NPRM, OSHA first converted the experimental dose, measured
in ppm, to an inhaled dose, measured in mg/kg/day. The female mouse
body weight used in these calculations was 0.0308 kg. The breathing
rate for mice was 0.05 m3/day. The Agency then assumed that
equivalent doses in mg/kg/day would lead to equivalent risk. Once the
experimental dose (in mice) had been converted to mg/kg/day, it was
then converted to ppm using the human breathing rate of 9.6 m3/
workday and human body weight of 70 kg in order to estimate risks at
various potential exposure levels. To determine the dose to humans
corresponding to the risk estimated from the mouse data, OSHA used the
following equations:
[GRAPHIC] [TIFF OMITTED] TR10JA97.001
OSHA assumed that risk estimates derived for mice at a given mg/kg/d
would be equivalent to risks experienced by humans at that mg/kg/d.
Doses in mg/kg/d in humans were converted to ppm to determine risk at
various potential workplace exposures using the following equations:
[GRAPHIC] [TIFF OMITTED] TR10JA97.002
This process was used by K.S. Crump et al. in their risk assessment
submitted to OSHA [Ex. 12]. Use of mg/kg/d as a measure of dose has
been criticized by Mr. Harvey Clewell, representing the U.S. Navy [Ex.
19-59]. He stated,
Strictly speaking, the concept of a mg/kg/day dose applies only
to exposures for which the term ``administered dose'' is well
defined, which does not include inhalation exposure to a volatile,
lipophilic chemical such as MC....If a non-pharmacokinetic dose
surrogate is desired, the choice should be time-weighted average
concentration (ppm) as used by the FDA.
Mr. Clewell preferred use of dose surrogates calculated in the PBPK
models to estimate human risk. OSHA has given careful consideration to
the issues raised by Mr. Clewell and, in the risk assessment presented
here, considered dose surrogates estimated in PBPK models and time-
weighted average concentration in addition to the mg/kg/d dose
presented in the NPRM.
For all dose measures used to estimate human risk, the assumptions
used by OSHA for body weights and exposure times and rates were those
described above. In OSHA's final risk assessment, a Bayesian analysis
was used and the prior distribution for breathing rate was centered on
OSHA's preferred value of 9.6 m3/d.
[[Page 1532]]
2. mg/kg/d Versus Other Measures of Exposure
Quantitative risk assessments based on animal data are conducted
under the assumption that animals and humans have equal risks from
lifetime exposures to a chemical when exposure is measured in the same
unit for both species. Opinions vary, however, on what is the correct
measure of exposure. For site-of-contact tumors, a ppm-to-ppm
conversion is a generally accepted measure of dose. For systemic
tumors, commonly used dose conversions include mg/kg/day (as used by
OSHA in its MC NPRM), mg/surface area/day (with surface area
approximated by BW2/3), mg/BW3/4/day, and mg/kg/lifetime.
When adequate and appropriate pharmacokinetic or metabolic data are
available, these data are sometimes used to estimate internal dose. In
the case of MC, metabolic data have been gathered and pharmacokinetic
models have been used by various investigators to estimate target
tissue doses for MC.
Some commenters [Exs. 19-28, 19-57] had expressed concern that OSHA
used a surface area correction factor in its risk assessment in the
NPRM. In fact, in the NPRM, OSHA extrapolated from mice to humans based
on body weight rather than surface area. However, the Agency requested
comment on which species conversion factor would be appropriate to use
in OSHA's final risk assessment and whether incorporation of
pharmacokinetic information should influence the choice of the
conversion factor. Two commenters [Exs. 19-83, 23-21] referred to the
interagency document on interspecies scaling which ultimately
recommends BW3/4 as the appropriate extrapolation factor in the
absence of appropriate pharmacokinetic information, although the
document also indicates that extrapolation factors based on BW or
BW2/3 would also be consistent with the available data (EPA Draft
Report: ``A cross-species scaling factor for carcinogen risk assessment
based on equivalence of mg/kg3/4/day.'' 57 FR 24152, June 5,
1992).
There was also considerable discussion as to whether it was
appropriate to apply an extrapolation factor such as BW3/4 or
BW2/3 in addition to PBPK modeling of dose, to account for
pharmacodynamic differences between species (such as differences in DNA
repair rates and other non-metabolic differences in interspecies
susceptibility to an agent). The EPA applied the BW2/3
extrapolation factor after incorporation of the PBPK data for MC in
their 1987 draft update of the MC risk assessment. In their previous
risk assessment, which did not incorporate PBPK data, EPA also used
BW2/3 as the extrapolation factor. Since OSHA has preferred the BW
extrapolation in other chemical-specific risk assessments and has used
BW as the extrapolation factor in its best estimate of risk in the NPRM
for MC, OSHA agrees with Dr. Lorenz Rhomberg's assessment [Ex. 28] that
OSHA should continue to use body weight as its extrapolation factor in
its final MC risk assessment. Thus, OSHA's risk estimate does not make
any allowance for possible pharmacodynamic differences between rodents
and humans, or within the diverse human population.
3. Pharmacokinetic Modeling of Dose
OSHA discussed issues relating to the use of pharmacokinetic data
in its NPRM. These issues were further explored during the hearings and
in pre-hearing and post-hearing comments. In response to the ANPR [51
FR 42257], Dow Chemical submitted documentation of a physiologically-
based pharmacokinetic model (PBPK) [Exs. 8-14d and 10-6a], developed
for MC by Reitz and Anderson, which described the rates of metabolism
of the MFO and GST pathways and the levels of MC and its metabolites in
various tissues of rats, mice, hamsters and humans. This model was
presented as a basis for converting an applied (external) dose of MC to
an internal dose of active metabolite in the lung and liver in various
species under various MC exposure scenarios. Since publication of the
NPRM, several parties have submitted pharmacokinetic models or comments
on modeling to the rulemaking record. These are discussed in detail
below.
a. General issues in PBPK modeling. Physiologically-based
pharmacokinetic modeling can be a useful tool for describing the
distribution, metabolism and elimination of a compound of interest
under conditions of actual exposure and, if data are adequate, can
allow extrapolation across dose levels, across routes of exposure and
across species. One limitation of using PBPK modeling is a widespread
lack of adequate and appropriate physiological and metabolic data to
define the model. In particular, difficulties arise in attempting to
define a model for which the mechanism of carcinogenesis has not been
established, when it is unclear whether there would be tumor site
concordance across species, and when the metabolic pathway(s)
responsible for carcinogenesis has not been determined.
The concentration of a chemical in air or the total inhaled dose
(mg/kg/d) may not be the most biologically relevant dose to use in
comparing toxicity across doses or across species. The dose measure
that would be most useful in risk assessment is the dose to the target
tissue of the chemical or metabolite that is known to directly cause
the toxic effect. Generally, this quantity is unknown in almost every
case because the proximate carcinogenic moiety is usually highly
reactive, and therefore very difficult to measure in biological
systems. Since the proximate toxic agent is unlikely to be a quantity
readily measured in the laboratory, it is sometimes desirable to use
dose surrogate concentrations, calculated by methods such as PBPK
modeling, to obtain a more direct estimate of a dose-response
relationship. Examples of dose surrogates that may be relevant to the
toxic mechanism of action of a chemical are peak concentrations of a
particular metabolite at a target tissue site, area under the
concentration-time curve of a metabolite at a target site, and blood
concentration of the parent chemical or a relevant metabolite.
If the dose surrogate chosen is directly relevant to the mechanism
of action of a chemical, there is greater confidence in the risk
estimates generated using the dose surrogate than those generated using
total inhaled concentration. If the mechanism of action of a chemical
is uncertain, and therefore the relevance of the dose surrogate to
carcinogenicity is in question, there is proportionally less confidence
in the predicted risks estimated using that dose surrogate. Risk
estimates from PBPK modeling can also be limited by the quality and
quantity of available metabolic data. Since risk estimates are directly
dependent upon the dose or dose surrogate chosen, reliable measures of
all relevant physiological parameters and all relevant metabolic
pathways in all target tissues from all species under investigation are
critical. In addition, measures of the uncertainty and inter-individual
variability of these parameters must be generated.
In its NPRM, OSHA solicited information on the appropriateness of
physiologically- based pharmacokinetic modeling for the MC risk
assessment. Specifically, OSHA asked the following questions:
(a) How can pharmacokinetics be best applied to the risk assessment
of MC and what are the current limitations of this approach in the
quantitation of health risks? What weight should OSHA give to
pharmacokinetic data in its risk assessments and why?
(b) Given that five separate risk assessments have utilized the
pharmacokinetic models for MC in five
[[Page 1533]]
different ways (resulting in from 0 to 170 fold reduction in the final
risk when compared with assessments not utilizing pharmacokinetic
data), how can OSHA best utilize the existing pharmacokinetic data and
still be certain of protecting worker health?
(c) Which parameters in the pharmacokinetic models are most
sensitive to errors in measurement or estimation? Can an increased
database reduce the uncertainties in these parameters?
(d) How much confidence can be placed in the human in vitro MC
metabolism data, especially that for lung tissue? How will human
variability in these parameters affect the extrapolation of risk from
rodent species?
(e) Are there any studies in progress which attempt to verify the
predictive ability of the model in vivo, (e.g., by giving doses in a
lifetime bioassay which will produce cancer in a species other than the
B6C3F1 mouse and the F344 and Sprague-Dawley rats)?
(f) OSHA recognizes the large areas of uncertainty which exist in
applied dose risk assessment procedures. If pharmacokinetic modeling
reduces these uncertainties, can the reduction in uncertainty be
quantified? Are additional uncertainties introduced into the risk
assessment process by the use of pharmacokinetic models?
(g) By using the pharmacokinetic models in the risk assessment
process, one is making an assumption about the carcinogenic mechanism
of action of methylene chloride. Are there any new studies on the
carcinogenic mechanism of action of MC which would support or refute
this assumption?
(h) If the carcinogenic process is, in fact, not the result of the
metabolite(s) from the GST pathway alone, but is due to a combination
of metabolites or a combination of the parent compound plus the
metabolites, how would the pharmacokinetic model and the subsequent
risk assessments be affected? Can these effects be quantified?
(i) One of the assumptions made in the pharmacokinetic model is
that the target tissues for MC are liver and lung. Can this model
predict cancer incidences at other sites? If not, is there a way to
factor in consideration of possible MC-induced human cancers at other
sites than liver and lung?
(j) OSHA solicits information supporting or refuting interspecies
allometric scaling based on body weight or body surface area.
OSHA reviewed comments and testimony on these issues from an expert
witness [Ex. 25-E]; representatives of other U.S. government agencies,
including NIOSH [Exs. 19-46, 41], EPA [Exs. 25-D, 28], CPSC [Ex. 25-I]
and U.S. Navy [Exs. 19-59, 96]; the State of California [Ex. 19-17];
the Halogenated Solvents Industry Alliance (HSIA) [Exs. 19-45, 19-83,
105]; and the UAW [Exs. 19-22, 23-13, 61]. Comments and testimony from
the expert witness, the other government agencies and the Halogenated
Solvents Industry Alliance generally reflected the opinion that the
pharmacokinetic information was sufficiently developed in the case of
MC to justify its use in estimating human cancer risks. The predominant
view among these commenters and hearing participants was that the data
collected for MC and the pharmacokinetic model developed by Reitz and
Andersen adequately represented the metabolism of MC in mice. Many
commenters also believed that it was reasonable to conclude that the
lung and liver tumor incidence in the B6C3F1 mice was the result of the
GST metabolite. As described in further detail below, OSHA generally
agrees that the PBPK approach is reasonable to assess cancer risks of
MC. In fact, the Agency has evaluated the submitted PBPK models,
determined that there were several deficiences in each of those models,
and improved upon those in its final quantification of risks.
One rulemaking participant was strongly opposed to using
pharmacokinetic data in the MC risk assessment. Dr. Franklin Mirer [Ex.
61], representing the UAW, stated:
The pharmacokinetic model advanced for methylene chloride
carcinogenesis is incorrect and should not be used for quantitative
risk assessment.
Dr. Mirer was particularly concerned that the PBPK model ignored the
rat cancer bioassay data and that the model was based on a
``mechanistic hypothesis.''
Dr. Mirer reiterated his concerns in response to the October 24,
1995 reopening of the rulemaking record [Ex. 126-31], stating,
The simple message is that OSHA should give no additional weight
to the pharmacokinetic argument. For OSHA to give the argument any
additional weight would mean that OSHA was ignoring a substantial
body of evidence regarding carcinogenicity of methylene chloride in
additional animal species.
Dr. Mirer continued,
The pharmacokinetic hypothesis is unconvincing even as an
explanation of the differences in lung and liver tumors in mice and
rats.
OSHA shares Dr. Mirer's concerns that the mechanism of
carcinogenicity for MC has not been clearly established and that using
pharmacokinetic modeling may lead to risk estimates which ignore the
rat tumor data. The Agency notes that it has used the NTP rat data in
its hazard identification for MC. OSHA has also determined, however,
that the mouse data represent the strongest data set on which to base a
quantitative risk assessment, and notes that risk estimates based on
the rat data (without PBPK-based adjustment of dose) are similar to
OSHA's final risk estimates using mouse data and a PBPK analysis.
The determination that the mouse data set was the strongest on
which to base a quantitative risk assessment was made without regard to
the availability of information on pharmacokinetics. Incorporating
pharmacokinetic modeling into the risk assessment for MC is a logical
extension of OSHA's risk assessment decisionmaking process and reflects
the Agency's review of the totality of data on tumor incidence,
metabolism and mechanism of action. The extensive data base on MC
metabolism and mechanism of action, although by no means complete, was
the determining factor in the decision to incorporate pharmacokinetics
into its final risk assessment. The Agency is aware of very few
chemicals of regulatory interest for which the available data could
match this body of information. The specific criteria utilized by the
Agency in making this determination are enumerated below.
Comments on the specific issues enumerated above are discussed
under the appropriate topics in the sections that follow.
b. Criteria for using PBPK in quantitative risk assessment. OSHA
evaluated several criteria before deciding to use PBPK analysis in its
final quantitative risk assessment for MC. In future rulemakings in
which the use of pharmacokinetic information in risk assessment is at
issue, it will be necessary to evaluate at least the criteria described
below before reaching conclusions, in order to avoid adopting an
alternative hypothesis that is less (rather than more) reflective of
the true situation than the more generic applied-dose assumption.
Further, it may be appropriate to evaluate additional criteria in some
cases, depending on the metabolism and mechanism of action of the
chemical. The criteria which OSHA considered before incorporation of
PBPK in the final risk estimate for MC were:
(1) The predominant and all relevant minor metabolic pathways must
be well described in several species, including humans. (Two metabolic
pathways are responsible for the metabolism of MC in humans, mice, rats
and hamsters).
[[Page 1534]]
(2) The metabolism must be adequately modeled (Only two pathways
are responsible for the metabolism of MC as compared to several
potential routes of metabolism for other compounds, such as benzene and
the dioxins. This simplified the resulting PBPK models).
(3) There must be strong empirical support for the putative
mechanism of carcinogenesis (e.g., genotoxicity) and the proposed
mechanism must be plausible.
(4) The kinetics for the putative carcinogenic metabolic pathway
must have been measured in test animals in vivo and in vitro and in
corresponding human tissues (lung and liver) at least in vitro,
although in vivo human data would be the most definitive.
(5) The putative carcinogenic metabolic pathway must contain
metabolites which are plausible proximate carcinogens (for example,
reactive compounds such as formaldehyde or S-chloromethylglutathione).
(6) The contribution to carcinogenesis via other pathways must be
adequately modeled or ruled out as a factor. For example, there must be
a reasonable analysis of why reactive metabolites formed in a second
pathway would not contribute to carcinogenesis (e.g., formyl chloride
produced via the MFO pathway is likely to be too short-lived to be
important in MC carcinogenesis).
(7) The dose surrogate in target tissues (lung and liver in the
case of MC) used in PBPK modeling must correlate with tumor responses
experienced by test animals (mice, rats and hamsters).
(8) All biochemical parameters specific to the compound, such as
blood:air partition coefficients, must have been experimentally and
reproducibly measured. This must be true especially for those
parameters to which the PBPK model is most sensitive.
(9) The model must adequately describe experimentally measured
physiological and biochemical phenomena.
(10) The PBPK models must have been validated with data (including
human data) which were not used to construct the models.
(11) There must be sufficient data, especially data from a broadly
representative sample of humans, to assess uncertainty and variability
in the PBPK modeling.
In the case of MC, to a large extent these criteria were met. This
made evaluation of existing PBPK models and further development of the
modeling strategy a viable option. Therefore, the Agency evaluated
existing PBPK models and then contracted with Drs. Andrew Smith,
Frederic Bois, and Dale Hattis to help OSHA improve on the MC PBPK
model in the record, which would extend the application of modeling
techniques beyond those models which had been submitted to the Agency
and incorporate all of the data available and appropriate for
quantitative analysis in the record. OSHA's evaluation of existing PBPK
models, the development of a modified MC PBPK analysis, and OSHA's
final risk assessment are described later in this document.
c. Choice of GST metabolic pathway as dose surrogate. The choice of
``dose surrogate'' for the MC PBPK model is a critical factor in
estimating PBPK-based risks. The dose or ``dose surrogate'' used in a
risk assessment should be a biologically-important quantity, should
have a plausible mechanism of action at the target tissue and should
correlate with the response of interest. The simplest choice of dose is
the applied dose or ambient concentration of the contaminant measured
as ppm or as the inhaled quantity in mg/kg/day (as used in the
Preliminary Quantitative Risk Assessment in the NPRM). Such quantities
have the advantage of being easily and directly measurable during the
bioassay. Other meaningful dose surrogates could include the
concentration of parent compound in the target organ, the concentration
of specific metabolites in the target organ, the area under the time-
concentration curve (integrated dose) of each metabolite and the parent
compound, or peak blood or target organ levels of each metabolite and
parent compound. These quantities are not as easily measured. Often
only indirect measurements or computer modeling of these dose
surrogates are available.
In the PBPK model developed by Reitz et al. [Ex. 7-225], the dose
surrogates that correlated with the tumor response were the parent
compound (MC) concentration and the amount of GST metabolites formed in
the lung and liver. Reitz et al. discounted the parent compound as the
dose surrogate because MC is not a chemically reactive compound and
direct-acting carcinogens (and metabolites of carcinogenic compounds)
are generally hypothesized to be reactive (usually, electrophilic).
They also discounted the parent compound as a relevant dose surrogate
because parent MC concentration was higher in the rat blood than in the
mouse for any dose of MC, while the cancer response of the mouse was
greater than the rat. If parent MC were the critical compound for MC
carcinogenesis, one would expect the cancer response across species to
correlate with blood levels of the compound.
(1) Metabolism via GST versus MFO pathway. Human metabolism of MC
has been well studied. One clear finding from the human metabolic
studies is that humans metabolize MC by both the MFO and GST pathways,
as do mice, rats, and hamsters. Although human metabolism via the MFO
pathway has been measured in vivo as well as in vitro, human MC
metabolism via the GST pathway has been measured only in vitro.
Metabolic data on the human GST pathway have been collected from
several liver samples and one pooled lung sample (combined samples from
four human subjects). However, it has not been possible to measure
human GST metabolism of MC in vivo.
Reitz et al. measured the metabolic constants (Km and
Vmax) in vitro for the GST and the MFO metabolic pathways. Enzyme
activities were determined by measuring the conversion of 36Cl-
labeled MC to water-soluble products. Metabolic constants were then
compared across species (mouse, rat, hamster and human). In the liver,
the MFO activity was highest in the hamster, followed by the mouse,
human and rat. Human values were much more variable than those of the
rodent species. Human Vmax for the liver MFO pathway ranged
approximately an order of magnitude and human Km varied
approximately three-fold. GST activity in the liver was determined for
mouse and human tissues only. Mouse liver had approximately 18-fold
greater activity (Vmax) than human liver, but the human tissue had
about a three-fold greater affinity constant (Km) for MC than the
mouse.
In the lung, the activity of the MFO and GST enzymes was determined
for a single substrate concentration. For the MFO pathway, mouse tissue
had the highest activity, followed by hamster and rat. No MFO activity
specific for MC was detected in the human lung tissue, although other
MFO isozymes were demonstrated to be active in the tissue. For the GST
pathway in lung, mouse tissue was the most active, followed by rat and
human. No GST activity was detected in the hamster lung.
In humans, the MFO pathway has been measured in vivo as well as in
vitro [Ex. 7-225]. Human in vivo experimentation was conducted by
several investigators. Metabolism via the MFO pathway is relatively
easy to measure because the end product is carbon monoxide [Ex. 7-24].
The metabolic rates measured in vitro were not similar to those
measured in vivo after exposure to known concentrations
[[Page 1535]]
of MC, which means that in vitro measurements in human tissue (in
particular for the GST pathway for which there are no human in vivo
data) could not be used directly as a measure of metabolism. Human in
vivo and in vitro MFO metabolism data were important in developing the
pharmacokinetic models because they provided human data for MC-specific
metabolism which could be used to help validate the models.
Unfortunately, the modeling of the putative critical pathway for
carcinogenesis (the GST pathway) could not be validated for humans.
This is a weakness in the PBPK modeling for MC shared by all of the
models, including OSHA's final PBPK analysis.
In the PBPK models submitted to OSHA, the human rate of metabolism
of MC, particularly via the GST pathway, was based on data gathered
from four liver samples and one pooled lung sample. Although the liver
metabolic data were of the same magnitude as those collected by Green
et al., Green's data were not considered in Reitz's model and the
variability of those data was not assessed. Therefore, the estimates of
the dose surrogates in Reitz's model were based on the average of four
liver samples. Four liver samples are not nearly enough data to
confidently estimate and account for human variability. Considerations
of the variability and uncertainty of these data are discussed in more
detail later in this document.
The human lung data were even more limited. Four human lung samples
were pooled to provide a single data point. This lack of lung tissue
data is particularly critical in PBPK modeling when calculating the
ratios of A1 and A2 (the distribution of metabolism between liver and
lung tissue in humans). Errors in calculating these ratios will
significantly affect the final risk estimates, as discussed by Mr.
Harvey Clewell for the U.S. Navy [Ex. 96].
HSIA submitted additional data on the human metabolism of MC in the
form of a study of GST metabolism in human liver samples conducted by
Bogaards et al. [Ex. 127-16]. The human GST liver metabolism data
collected in this study were not directly comparable to the data
collected by Reitz or Green, becausethe Bogaards data were measured
using a colorimetric method which was not as sensitive as the 36Cl
method. Under contract to OSHA, Dr. Andrew Smith and Dr. Frederic Bois
compared the data from different laboratories and collected under
different methodologies and developed a correction factor across
methodologies so that they could use all of the human metabolic data
available in OSHA's final PBPK model [Ex. 128]. There are now over 30
data points for human liver in vitro metabolism by the GST pathway and
5 human lung data points (the additional lung data points were reported
in Green et al., Ex. 124A). OSHA determined that it was important to
use as much of the available human data in its PBPK model for MC as
scientifically justifiable. These data were used to estimate the
variability and uncertainty surrounding the measures of human GST
metabolism. Although the methodologies differed across studies, OSHA
has adjusted and incorporated all of the available human data in its
PBPK model.
(2) Parallelogram approach. When the metabolic rates for the MFO
pathway measured in vivo and in vitro within each species were
compared, it was determined that those rates were not equivalent. This
meant that, unlike the case for some other chemical compounds, the in
vitro GST data could not substitute directly for an in vivo measurement
of metabolism. Reitz and Andersen [Ex. 7-225] suggested a
``parallelogram'' approach to the problem of non-comparability of in
vitro and in vivo rates. This approach makes the assumption that the
ratio of in vivo to in vitro measurements is roughly comparable across
species (including humans). They measured metabolic rates of both
pathways in vitro and in vivo in rodents and then used the average
ratio of the in vitro to in vivo metabolic rate in three rodent species
to extrapolate from in vitro rates in humans [Ex. 7-225] to an
estimated in vivo value.
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Ron Brown [Ex. 25-E], an expert witness for OSHA, was concerned
that ``...the methodology used to extrapolate the in vitro data to the
in vivo state is problematic and the accuracy of the human in vitro
measurement of GST activity toward MC is uncertain.'' This may be due
to the small sample size, variability in the laboratory analysis or
inadequacy of the in vitro model. OSHA believes that this is a critical
point of uncertainty in using the PBPK model for risk assessment. The
Agency also notes that in the risk assessments using PBPK models
submitted during the MC rulemaking, none used the parallelogram
approach as the basis of determining human in vivo metabolic rates.
Instead, allometric scaling was used to estimate human values. OSHA has
conducted risk assessments using both the allometric approach (OSHA's
final risk estimates) and the parallelogram approach (OSHA's
alternative analysis). The Agency did this in order to determine what
the risk estimates would be if all possible quantitative data were used
to the fullest extent, regardless of the uncertainties in the data.
OSHA agrees that evidence presented in the record generally
supports the GST pathway as a plausible carcinogenic mechanism of
action of MC. The Agency remains concerned, however, that sole reliance
on the GST pathway may show insufficient consideration for potential
contributions of the parent compound and/or metabolites of the MFO
pathway to the carcinogenesis of MC. It is clear that ambient MC
concentration is dose-related to tumor response. It has not been shown
with any certainty that MC GST metabolites are related to tumor
response across species. Thus, there is greater confidence that the
lifetime bioassays predict MC carcinogenicity in humans than there is
that cancer occurred through a specific mechanism, and even less
confidence that the metabolic rates measured in vitro accurately
measure differences in species that correlate to tumor development.
This is particularly true for lung metabolism where only one pooled and
five individual human samples were analyzed. Notwithstanding the
uncertainties described above, the Agency believes that the hypothesis
that GST is the carcinogenic pathway presents a plausible mechanism of
action for MC and is sufficiently well-developed to warrant the use of
PBPK modeling of the GST pathway as the dose surrogate of choice in the
quantitative risk assessment for MC.
d. Structure of the MC PBPK model. The PBPK models described below
are based on the model originally submitted by Dr. Reitz on behalf of
HSIA in 1992 [Ex. 7-225]. Over the years since the first submission of
a MC PBPK model to OSHA, significant improvements have been made in
model structure and in the data collected for PBPK modeling, especially
in how the uncertainty and variability in the data are treated. The
general structure of the models submitted to OSHA are described below,
followed by a description of the parameters used in the various models.
Next follows a description of how the variability, uncertainty, and
sensitivity of the models to uncertainty have been assessed, noting the
improvements that have been made in developing methods to handle these
issues. This is followed by a comparison of the risk estimates
generated by these models. Finally, OSHA's final risk assessment is
described. This risk assessment incorporates lessons learned from
previous models and uses all of the available, appropriate,
quantifiable data in a Bayesian approach to modeling the dose metric
for MC.
In the PBPK model submitted by Dr. Reitz of HSIA [Ex. 7-225], a
series of differential equations was used to model the mass balance of
MC and its metabolites in five physiologically-defined compartments,
including the lung, liver, richly perfused tissue, slowly perfused
tissue, and fat. Metabolism via the MFO pathway was described by
saturable Michaelis-Menten kinetic equations and GST metabolism was
modeled using first-order nonsaturable kinetics. With the exception of
the PBPK model sumitted by ICI [Ex. 14A], all of the PBPK models
submitted to the Agency followed these assumptions regarding the
metabolism of MC. The rate constants for the metabolic equations were
estimated based on measurements of the partition coefficients,
allometric approximations of the physiological constants (e.g., lung
weight), and estimations (i.e., allometric scaling of rodent data,
estimations made using the parallelogram approach, etc.) of the
biochemical constants (e.g., Michaelis-Menten constants).
NIOSH presented a PBPK model in 1993 [Ex. 94], also structurally
based on the Reitz-Andersen model, but with modifications to the human
breathing rate and cardiac output to account for uptake of MC in
physically active workers, rather than at-rest humans or humans
involved in light activity, and including an analysis of the
variability of the human metabolic parameters. Specifically, NIOSH
compared estimates derived from the arithmetic average of the human GST
metabolism data with the individual human liver data points to estimate
the uncertainty in an individual's risk of cancer from occupational MC
exposure. This approach began to incorporate some necessary features,
such as a special focus on physically active workers and the
variability of human metabolic parameters, but did not attempt to
quantify the uncertainty and variability of the individual parameters
and their contribution to the uncertainty associated with the PBPK
model.
Mr. Harvey Clewell, representing the U.S. Navy, also submitted
several PBPK models to OSHA. In his initial submission (1992), Mr.
Clewell modified an existing PBPK model [Ex. 7-125] to include more
recent data on the mouse blood/air partition coefficient [Ex. 19-59].
In a second PBPK model, he ``started from scratch'' to construct a
model based on data derived from sources independent of the previous
work of Reitz and Andersen [Ex. 23-14], which was described in Mr.
Clewell's testimony [Tr. 2361,10/15/92]. This model was structurally
similar to the model presented by HSIA with the following exceptions:
it featured three lumped compartments (slowly perfused, moderately
perfused and rapidly perfused) based on tissue kinetic constants rather
than the earlier two lumped compartment models based on tissue blood
volumes; and the mouse blood/air partition coefficient was corrected to
19.4 instead of the earlier 8.29 on the basis of more recent data. A
third model submitted by Mr. Clewell was identical in structure to the
Reitz/Andersen model, but incorporated the more recent experimental
data on the partition coefficients and the more recent mouse metabolism
data [Ex. 96]. OSHA used Mr. Clewell's third model in its comparison of
PBPK-derived risk estimates because of its similarity in structure to
the original Reitz model and its incorporation of the most recent
experimental data.
In his third model, Clewell either derived probability
distributions for each parameter from the literature or estimated
distributions for those parameters for which data were not available,
and conducted Monte Carlo simulations to derive output distributions
for the dose surrogates. These distributions of dose surrogates were
then used to derive four risk estimates: the doses input into the
multistage dose-response analysis of the tumor bioassay were derived
either from the mean or from the 95th percentile of the output
distribution of PBPK parameters, and these in turn were coupled with
the either the MLE or the UCL of the distribution of possible values of
the multistage model
[[Page 1537]]
parameters. This analysis was an advance over that of previous models
because it took into account some of the uncertainty and variability
known to be associated with the data used in the PBPK model.
After evaluating these submitted models, OSHA determined that
Clewell's model provided the best prototype on which to base its final
PBPK modeling approach for MC. Therefore, the Agency worked with Drs.
Smith and Bois to review Clewell's model and with the assistance of Dr.
Hattis, to develop a refined PBPK modeling approach with a more
sophisticated analysis of variability and uncertainty (and other
refinements as described below). In this way the Agency developed an
approach which would incorporate what was learned in the development of
earlier PBPK models and make use of as much of the available
physiological and metabolic data in the record as possible. Clewell's
model was chosen for comparison, because this was the only model to
provide a systematic analysis of the uncertainty, variability and
sensitivity of the model using Monte Carlo techniques. OSHA's final
risk assessment approach is described in greater detail below.
e. Choice of parameters for PBPK modeling. The definitions of the
parameters used in the models described above are contained in Table
VI-2. Note that not all parameters were used in each model and slightly
different variable names were used by different investigators. For
example, OSHA's final analysis contains a bone marrow compartment,
while Clewell's model did not. OSHA refers to the blood flow for poorly
(or slowly) perfused tissues as ``QppC,'' while Clewell used ``QSC.''
Table VI-2.--Definitions of Pharmacokinetic Parameters
------------------------------------------------------------------------
Parameter (units) Definition
------------------------------------------------------------------------
BW (kg)...................... Body weight in kg. Human body weights
were assumed to be 70-kg (Reference
Man). Mouse body weights were the
average weight of mice in the NTP
bioassay.
QPC unscaled (1/hr, 1 kg BW). Breathing rate. QPC = QP(1/hr)/BW.75
where QP = alveolar ventilation rate.
Human QP was based on rate of 9.6 m3/8-
hr (converted 1/hr and adjusted to
alveolar ventilation (= 0.70 total
ventilation) except in NIOSH and OSHA-
modified models. Mouse QP = (24.3 1/
hr)(0.70 alveolar/total).
QCC unscaled (1/hr, 1 kg BW). Cardiac output. QCC = QC(1/hr)/BW.75
where QC = cardiac output in 1/hr. Reitz
set QC = QP. Clewell and NIOSH based
human QC on Astrand et al. [Ex. 7-120]
data on cardiac output and breathing
rate vs. workload.
VPR (ratio, unitless)........ Alveolar ventilation/perfusion ratio.
------------------------------------------------------------------------
Blood flows to tissues
------------------------------------------------------------------------
QGC or QgiC (fraction of Blood flow to gastrointestinal tract as a
cardiac output). fraction of cardiac output. QGC = QG/QC.
QLC or QliC (fraction of Blood flow to liver as a fraction of
cardiac output). cardiac output. QLC = QL/QC.
QFC or QfatC (fraction of Blood flow to fat as a fraction of
cardiac output). cardiac output. QFC = QF/QC.
QSC or QppC (fraction of Blood flow to slowly (or poorly) perfused
cardiac output). tissues as a fraction of cardiac output.
QSC = QS/QC.
QRC or QwpC (fraction of Blood flow to rapidly (or well) perfused
cardiac output). tissues as a fraction of cardiac output.
QRC = QR/QC.
QmarC (fraction of cardiac Blood flow to bone marrow as a fraction
output). of cardiac output.
------------------------------------------------------------------------
Tissue volumes
------------------------------------------------------------------------
VGC or VgiC (fraction of body Volume of GI tract as a fraction of body
weight). weight. VGC = VG/BW.
VLC or VliC (fraction of body Volume of liver as a fraction of body
weight). weight. VLC = VL/BW.
VFC or VfatC (fraction of Volume of fat as a fraction of body
body weight). weight. VFC = VF/BW.
VSC or VppC (fraction of body Volume of slowly (or poorly) perfused
weight). tissues as a fraction of body weight.
VSC = VS/BW.
VRC or VwpP (fraction of body Volume of rapidly (or well) perfused
weight). tissues as a fraction of body weight.
VRC = VR/BW.
VluC (fraction of body Volume of lung as a fraction of body
weight). weight.
VmarC (fraction of body Volume of bone marrow as a fraction of
weight). body weight.
------------------------------------------------------------------------
Partition coefficients
------------------------------------------------------------------------
PB or Pblo................... Blood/air partition coefficient.
PG or Pgi.................... GI tract/blood partition coefficient (GI
tract/air divided by PB).
PL or Pli.................... Liver/blood partition coefficient (Liver/
air divided by PB).
PF or Pfat................... Fat/blood partition coefficient (Fat/air
divided by PB).
PS or Ppp.................... Slowly (or poorly) perfused tissue/blood
partition coefficient (Slowly perfused
tissue/air divided by PB).
PR or Pwp.................... Rapidly (or well) perfused tissue/blood
partition coefficient (Rapidly perfused
tissue/air divided by PB).
PLU or Plu................... Lung/blood partition coefficient (Lung/
air divided by PB).
Pmar......................... Bone marrow:air partition coefficient.
------------------------------------------------------------------------
Metabolic parameters
------------------------------------------------------------------------
VMAXC unscaled (mg/hr, 1 kg MFO pathway Michaelis-Menten maximum
animal). velocity for MC metabolism. VMAXC = VMAX
(mg/hr)/BW.75.
KM (mg/l).................... MFO pathway Michaelis-Menten affinity
constant for MC metabolism.
[[Page 1538]]
KFC, unscaled, (/hr, 1 kg GST pathway 1st order kinetic rate
animal). constant for MC metabolism. KFC = KF (/
hr)(BW.25).
A1 (ratio)................... Ratio of distribution of MFO pathway MC
metabolism between lung and liver. A1 =
VMAXC(lung)/VMAXC(liver).
A2 (ratio)................... Ratio of distribution of GST pathway MC
metabolism between lung and liver. A2 =
KFC(lung)/KFC(liver).
B1 (ratio)................... Ratio of lung and liver tissue content of
microsomal protein.
B2 (ratio)................... Ratio of lung and liver tissue content of
cytosolic protein.
Sp--Kf....................... Allometric scaling power for body weight
scaling of KFC from mice to humans.
------------------------------------------------------------------------
The MC physiologically-based pharmacokinetic (PBPK) models
discussed here contain the following types of parameters as defined
above: body weight, breathing rate, cardiac output, blood flows to
tissue compartments (as a fraction of the cardiac output), volumes of
tissue compartments (as a fraction of body weight), partition
coefficients, the metabolic parameters (the Michaelis-Menten
parameters, Vmax and Km, for the MFO pathway and the 1st-order rate
constant, Kf, for the GST pathway) and the ratio of the pathway-
specific metabolic capacity between the major metabolic sites (lung and
liver). Differences in model structure (such as choice of lumped tissue
compartments) and differences in sources of data for individual
parameters lead to differences in the parameter values used in
different models.
The parameter values (point estimates) used in the PBPK models
reviewed by OSHA are presented in Table VI-3. The parameter
distributions used by OSHA in its analysis are presented later.
As far as OSHA could determine, the parameters chosen by HSIA were
those presented in Reitz's 1989 paper [Ex. 21-53] except that OSHA's
preferred values for breathing rates (based on 9.6 m3/workday) and
8-hour human exposures were used. The model submitted by NIOSH used the
parameters and computer code from the Reitz model, except for the human
breathing rate, human cardiac output and human metabolic parameters.
The parameters used by Clewell were summarized in his post-hearing
submission [Ex. 96], which included more recent experimental data for
the partition coefficients and mouse metabolic parameters and a
different scaling for human cardiac output.
Table VI-3.--Parameters Used in PBPK Models Reviewed by OSHA
----------------------------------------------------------------------------------------------------------------
Model Clewell [Ex. 96] NIOSH [Ex. 23-18] HSIA [Ex. 19-45]
----------------------------------------------------------------------------------------------------------------
Parameter Mouse Human Mouse Human Mouse Human
----------------------------------------------------------------------------------------------------------------
BW (kg)..................... 0.0345 70 0.0345 70 0.0345 70
QPC, unscaled alveolar
ventilation (1/hr, 1 kg
animal).................... 29.0 35 29.0 43.1 29.0 35.0
QCC, unscaled cardiac output
(1/hr, 1 kg animal)........ 16.5 18 29.0 20.9 29.0 35.0
QGC a, flow to GI tract
(fraction of cardiac
output).................... 0.165 0.195 0.0 0.0 0.0 0.0
QLC a, flow to liver
(fraction of cardiac
output).................... 0.035 0.07 0.24 0.2093 0.24 0.24
QFC a, flow to fat (fraction
of cardiac output)......... 0.03 0.05 0.05 0.040 0.05 0.05
QSC a, flow to slowly
perfused tissues (fraction
of cardiac output)......... 0.25 0.24 0.19 0.4319 0.19 0.19
QRC a, flow to rapidly
perfused tissues (fraction
of cardiac output)......... 0.52 0.445 0.52 0.3188 0.52 0.52
VGC, GI volume (fraction of
BW)........................ 0.031 0.045 0.0 0.0 0.0 0.0
VLC, liver volume (fraction
of BW)..................... 0.046 0.023 0.04 0.0314 0.04 0.0314
VFC, fat volume (fraction of
BW)........................ 0.100 0.16 0.07 0.231 0.07 0.231
VSC, slowly perfused tissue
volume (fraction of BW).... 0.513 0.48 0.75 0.621 0.75 0.621
VRC, rapidly perfused tissue
volume (fraction of BW).... 0.041 0.033 0.05 0.0371 0.05 0.0371
VLUC, lung volume (fraction
of BW)..................... 0.008 0.006 0.012 0.011 0.012 0.011
PB, blood/air part. coeff... 23.0 12.9 8.29 9.7 8.29 9.7
PG, GI tract/air part. coeff 0.52 0.93 NA NA NA NA
PL, liver/blood part. coeff. 1.6 2.9 1.71 1.46 1.71 1.46
PF, fat/blood part. coeff... 5.1 9.1 14.5 12.4 14.5 12.4
PS, slowly perf./blood part.
coeff...................... 0.44 0.78 0.96 0.82 0.96 0.82
PR, rapidly perf./blood
part. coeff................ 0.52 0.93 1.71 1.46 1.71 1.46
PLU, lung/blood part. coeff. 0.46 0.82 1.71 1.46 1.71 1.46
VMAXC mg/hr, 1 kg animal
(unscaled)................. 13.4 5.0 13.2 3.98
1.15
9.81
4.71 13.2 4.9
KM (mg/L)................... 1.35 0.4 0.396 0.72
0.55
0.26
0.79 0.396 0.580
[[Page 1539]]
KFC /hr, 1 kg animal
(unscaled)................. 1.5 1.5 1.73 1.56
0.00
1.62
1.79 1.73 1.24
A1 (Vmaxc(lung)/
Vmaxc(liver)).............. 0.41 0.015 0.416 0.00143 0.416 0.00143
A2 (KFC(lung)/KFC(liver))... 0.28 0.18 0.137 0.18 0.137 0.18
----------------------------------------------------------------------------------------------------------------
a QGC + QLC + QFC + QSC + QRC MUST = 1.00.
f. Assessment of the sensitivity and uncertainty of the PBPK model.
In the NPRM, OSHA expressed concern that, if PBPK models were used to
adjust risk assessments, the uncertainty in PBPK modeling should be
adequately addressed. Specifically, OSHA was concerned that the
uncertainty in the mechanism of action and the lack of human lung
metabolism data were the greatest obstacles to incorporation of
pharmacokinetic data into the MC final risk assessment. Many of the
uncertainties in model parameters have been quantified by various
hearing participants and are summarized below. The quantification of
these uncertainties, however, did not address OSHA's primary concerns
regarding the mechanism of action and the distribution of metabolism
between lung and liver. OSHA's analyses of the uncertainty and
variability of parameters in the PBPK model are presented with its risk
assessment later in this document.
The concepts of uncertainty, variability and sensitivity in PBPK
modeling were defined in comments submitted by the U.S. Navy [Ex. 19-
59]:
As it relates to the issue of using PBPK modeling in risk
assessment, uncertainty can be defined as the possible error in
estimating the ``true'' value of a parameter for a representative
(``average'') animal. Variability, on the other hand, should only be
considered to represent true interindividual differences.
The normalized sensitivity coefficient gives the percentage
change in a model output due to a percentage change in the parameter
value and represents the relative importance of the parameter to the
model output under the conditions of the simulation.
Each of these quantities is of concern for risk assessment and PBPK
modeling. For example, we know that there is variability or inter-
individual heterogeneity in the body weights of humans (and mice), yet
we estimate risks for an average member of the population (70 kg in
humans, average bioassay weight in mice). For many parameters, the
interindividual variability may not be known and must be estimated.
Uncertainty in estimation of the value of a parameter representing
an average member of a population is primarily due to laboratory
measurement and related errors. Measurement errors, in many cases, can
be quantified or estimated so that the potential impact of this
uncertainty on the outcome of the PBPK modeling can be assessed.
The sensitivity of the model to particular parameters is useful for
determining which experiments should be conducted to confirm parameters
and to determine the amount of confidence that PBPK model outputs
merit. For example, when a sensitivity analysis is conducted and it is
determined that the model outcomes are not very sensitive to changes in
the definitions of the lumped tissue volumes, it suggests that there is
little need to conduct experiments to describe those relationships more
precisely. Similarly, even though the lumped tissue volume does not
represent a ``true'' biological quantity, there is confidence that its
precise definition is not critically important in PBPK model outcomes.
Therefore, if the only large (quantifiable) uncertainty resides in this
measurement, one would have greater confidence that the model
predictions were reasonably accurate. Therefore, it is instructive to
understand which parameters influence the model outcomes to the
greatest degree. Conversely, if the PBPK model outputs are sensitive to
a parameter which has not been precisely described (such as the
distribution of GST metabolism between lung and liver), the confidence
in model outputs is correspondingly reduced.
Various investigators have attempted to determine the sensitivity
of the PBPK models to parameter values and to characterize the
uncertainty and variability within parameters in the models. The first
attempt to describe the sensitivity of the Reitz's original PBPK model
was performed by the Consumer Product Safety Commission (CPSC).
The CPSC conducted a sensitivity analysis of the metabolic
parameters, Km, Vmax and Kf, in the ``Updated Risk Assessment for
Methylene Chloride'' [Ex. 7-126]. They analyzed the sensitivity of the
model by selecting alternative point estimates for the metabolic
parameters and determining what the resulting ratio of GST metabolite
at 4000 ppm vs. 1 ppm would be. This analysis shows how this ratio
would vary if the metabolic parameters used in the model were higher or
lower than the measured values as selected by CPSC. The results showed
that the ratio of the GST metabolite in the liver at 4000 ppm to the
GST metabolite at 1 ppm (or the ratio of the GST metabolite in the lung
at 4000 ppm to the GST metabolite at 1 ppm) was relatively insensitive
to the value of Kf (when CPSC varied Kf from 0.01 to 5.3, while Km and
Vmax were held constant at Reitz-Andersen values).
HSIA presented a sensitivity analysis of the PBPK parameters from
the Reitz (HSIA) model in the testimony of Dr. Reitz [Ex. 23-21A].
Results were presented for mice at 4000 ppm, mice at 1 ppm, humans at
1000 ppm and humans at 1 ppm. In the first analysis (mice at 4000 ppm),
the most sensitive parameters were determined to be PB (blood:air
partition coefficient) and Kf (metabolic parameter for the GST
pathway). The authors observed that at high MC exposure levels the
model output was at least an order of magnitude less sensitive to
changes in the other sixteen parameters investigated.
When mice were exposed to lower concentrations of MC (1 ppm) Vmax
and Km for the MFO pathway were the most sensitive parameters
(sensitivity coefficient was over 120% for each of these parameters).
In addition, several other parameters were found to exert a significant
influence on model outputs: QP, QL, PB, VLu, and KF.
In humans, at high concentrations (> 1000 ppm) the results were
similar to those observed in mice: the model was most sensitive to PB
and KF, with
[[Page 1540]]
sensitivity coefficients of 87% and 97%, respectively. In addition, the
human model was also sensitive to the value chosen for the QP
(sensitivity coefficient = 43%).
In humans, at 1 ppm MC, Km and Vmax for the MFO pathway were the
most sensitive parameters out of the six parameters which had a
significant effect upon model outputs: QP, QL, PB, Vmax, Km, and KF.
This type of sensitivity analysis improves on that conducted by the
CPSC, because it looks at more of the parameters. It is still
deficient, however, because it examines the effect of each parameter
individually, and because it does not examine the effect of uncertainty
in two key parameters, A1 and A2 (the ratios of distribution of the MFO
and GST pathways between lung and liver), on the outcomes of the
modeling.
Mr. Clewell [Ex. 19-59] also conducted a sensitivity analysis to
determine the impact of uncertainty in PBPK parameters on the model
outcomes. In contrast to the HSIA analysis, he examined the sensitivity
of the outcomes to the ratios A1 and A2, and he chose a more realistic
occupational exposure level (100 ppm). He found that for mice at 4000
ppm, the most sensitive parameters for estimation of lung tumors were
KF, A2, and PB. In the liver, the most sensitive parameters were KF and
PB, which agrees with the results of the HSIA analysis. For humans at
100 ppm, the most sensitive parameters for estimating lung tumors were
KF and A2. Other parameters with significant effects on model outcomes
were PB, QPC, BW, KM, QCC, and QLC. The most sensitive parameters for
estimating liver tumors were VMAX, KF, QPC and BW, while PB, KM, QCC
and QLC also produced significant effects on model outcomes.
In all of these analyses, the PBPK models were clearly sensitive to
the values chosen for the metabolic parameters, especially the GST
metabolic parameter (KF). Other parameters with consistently
significant impact on the outcomes of the model included breathing rate
(QP) and distribution of GST metabolism between lung and liver (A2).
These analyses suggest that additional studies to quantify the
metabolic parameters (KF, KM and VMAX), breathing rates (QP) and
distribution of GST metabolism between lung and liver (A2) would
increase confidence in the model outcomes. Characterization of the
distribution of metabolism between lung and liver is particularly
critical because estimates for human lung metabolism were initially
based on one pooled sample of lung tissue, and the variability and
uncertainty of the value of this parameter has not been quantified.
Some analysts [Ex. 21-52] have suggested that the uncertainty is
increased in risk assessments based on PBPK as compared to applied-dose
risk assessments, because some methods of quantifying the uncertainty
result in rather broad distributions of uncertainties. OSHA, in
contrast, agrees with most commenters that quantifying uncertainty in a
PBPK model or risk assessment does not increase the uncertainty. The
Agency stresses that the appearance of increasing uncertainty with the
identification of sources of uncertainty almost certainly means that
the original uncertainty was underestimated. (In fact, since many
assessors have not attempted even to quantify the uncertainty in
applied-dose risk assessments, the uncertainty has often been
infinitely underestimated.) When conducting a risk assessment using
PBPK that appears to increase the uncertainty over delivered-dose
methodologies, the investigator should go back and recalibrate what the
uncertainty in the original analysis likely was, in light of the
sources of uncertainty identified using PBPK. This would tend to
broaden the confidence limits of the traditional risk assessments,
almost certainly beyond the limits generated in a thoughtful PBPK-based
assessment. For example, many analyses using delivered dose assume that
in the interspecies scaling factor, BWx, x is known with perfect
certainty (e.g., it is known to equal 2/3 or 1.0). An analysis that
uses an empirically-derived probability distribution for x, which might
reasonably extend from approximately 0.6 to approximately 1.0, would
yield a rather broad distribution of uncertainty in the resulting
estimate of risk.
The Agency also agrees that the primary uncertainties lie in the
choice of the dose surrogate and assumptions regarding cross-species
scaling. Clewell [Ex. 23-14] investigated the uncertainty of the PBPK
parameters using Monte Carlo analyses of the assumed distributions of
uncertainty of each parameter. The resulting estimates of dose
surrogate values were characterized by a mean of the distribution and
an upper 95th percentile estimate. Mr. Clewell stated [Ex. 19-59]:
[T]he use of the 95th percentile of the distribution of
estimates accounts for additional uncertainty concerning the true
values of the PBPK parameters for the bioassay animals and humans.
Mr. Clewell recommended that OSHA use the upper 95th percentile of the
Monte Carlo distribution of GST metabolites (from PBPK modeling) as an
input to the multistage model to generate risk estimates, and then use
of the MLE from the multistage model in those risk estimates, in
accordance with previous OSHA risk assessments. He remarked that use of
the upper 95th percentile of the PBPK output would be a reasonable
mechanism to account for the uncertainty quantified in these analyses.
Using the upper 95th percentile of the distribution of GST metabolites,
Mr. Clewell's risk estimate for lifetime occupational exposure to 25
ppm MC was 0.9 deaths per 1000 using the MLE of the multistage model,
and 1.1 per 1000 using the 95th percentile upper confidence limit (UCL)
from the multistage model. Using the mean of the distribtution of GST
metabolites, his MLE risk estimate was 0.28 deaths per 1000 at the same
exposure level, with an UCL of 0.35/1000.
The HSIA disagreed with using the upper 95th percentile for
estimating risks, and stated [Ex. 105]:
[T]he analyses conducted by Clewell et al. indicate that
consideration of model parameter variability does not contribute
orders of magnitude to the uncertainty associated with PB-PK risk
assessments. Further, the uncertainty associated with PB-PK risk
assessments is significantly less than that associated with risk
assessments that fail to consider pharmacokinetics. The uncertainty
in PB-PK based procedures is simply more readily available for
calculation.
OSHA disagrees with the HSIA that the uncertainty and variability
associated with PBPK risk assessments is significantly less than that
associated with risk assessments that fail to consider
pharmacokinetics. Quantification of uncertainty does not equate with
reducing uncertainty in an analysis. In fact, at a different level, the
assumptions made regarding mechanism of action of MC and extrapolation
of lung metabolic rates from one human in vitro sample may serve to
underestimate the uncertainty inherent in the PBPK-based risk
assessment if the underlying assumptions are wrong. Also, as stated
above, identification of uncertainty may lead us to recalibrate the
uncertainty associated with traditional risk assessment methods. In any
event, the possibility that using PBPK significantly reduces
uncertainty does not affect the need to account for whatever
uncertainty remains.
In addition, OSHA agrees with Clewell that using the upper 95th
percentile of the Monte Carlo distribution of GST metabolites as input
[[Page 1541]]
to the multistage model is a reasonable way to incorporate the
quantifiable uncertainty and variability into a risk assessment. In its
final risk estimates, OSHA has used the upper 95th percentile on the
distribution of GST metabolites from the Bayesian analysis as the input
to the multistage model, as described later in this document.
E. Other Risk Estimates Based on PBPK Models Prior to OSHA's Final
Analysis.
A PBPK model can produce estimates of target tissue doses (or dose
surrogates) for different hypotheses of action of a chemical. The
appropriate choice of target tissue dose can greatly influence risk
estimates based on that dose. For MC, the dose surrogate that has been
used most frequently to estimate cancer risks is the amount of GST
metabolite produced. The amount of GST metabolite can then be used to
extrapolate from a high bioassay dose of MC to a low occupational (or
environmental) dose of MC and from mouse MC metabolic rates to human
metabolic rates.
In the NPRM, OSHA reviewed available risk assessments for MC that
used PBPK modeling in a variety of ways. The Food and Drug
Administration risk assessment [Ex. 6-1] was not adjusted to account
for pharmacokinetic information. The Consumer Product Safety
Commission, in its ``Updated risk assessment for methylene chloride''
[Ex. 7-126], used pharmacokinetic data to adjust for differences in
metabolism in extrapolating from high dose (4000 ppm mouse bioassay) to
low dose (1 ppm) exposures, but did not adjust for interspecies
differences in the metabolism of MC. The resulting risk estimate was
approximately 2-fold lower than a risk estimate using applied dose.
The U.S. EPA analyzed the MC pharmacokinetic data in its documents,
``Technical analysis of new methods and data regarding dichloromethane
hazard assessment'' [Ex. 7-129] and ``Update to the Health Assessment
Document and Addendum for dichloromethane (methylene chloride):
pharmacokinetics, mechanism of action, and epidemiology'' [Ex. 7-128].
The EPA used the PBPK data to adjust its risk estimates in its
Integrated Risk Information System (IRIS) database. Adjustments were
made for high-to-low dose and cross-species extrapolation. EPA's risk
estimates for low human exposures to MC were decreased by approximately
a factor of 9 from its risk estimates made without consideration of
PBPK data.
The HSIA [Ex. 105] and ECETOC [Ex. 14] also submitted risk
assessments based on PBPK data. The primary difference between the HSIA
and the EPA risk estimates was that the HSIA did not use a surface area
correction to account for interspecies differences other than
pharmacokinetics (e.g., pharmacodynamic differences) while the EPA did.
Also, HSIA's risk estimates used OSHA's preferred breathing rates and
an occupational exposure scenario. ECETOC based its risk estimates on
different measures of human MC metabolism. In a pre-hearing submission,
``Using PB-PK Models for Risk Assessment with Methylene Chloride
(Comparison of U.S. and U.K. procedures)'' [Ex. 19-83A], scientists
from the U.S. and the U.K. compared methodologies for using PBPK data
in the MC risk assessment and presented a consensus opinion that OSHA
should use the methodology developed by Dr. Richard Reitz [Ex. 7-225]
for the U.S. For this reason, OSHA evaluated Dr. Reitz's analysis, as
presented by the HSIA, and did not separately consider the ECETOC risk
assessment.
As described previously, Clewell [Ex. 96] and NIOSH [Ex. 94] have
submitted analyses of the PBPK data and risk assessments based on those
analyses. Both of these analyses used PBPK modeling of the amount of
GST metabolites produced in their estimates of carcinogenic risks.
OSHA has evaluated the data in the rulemaking record and has
concluded that, if PBPK modeling is used to adjust estimates of risk,
the weight of evidence supports using the amount of GST metabolites as
the preferred surrogate for target tissue dose. The amount of GST
metabolites predicted by the PBPK model varies depending upon the
values or distributions chosen for the parameters in the model.
Of the risk assessments described above, OSHA has chosen to compare
risks estimated using PBPK models submitted by Reitz et al., Clewell et
al. and NIOSH with applied dose methodology using either of two scaling
assumptions: the inhaled dose in mg/kg/day (the estimates of risk
presented in the NPRM) and ppm-to-ppm extrapolation. OSHA evaluated the
methodologies used in developing these risk estimates before developing
its final risk estimates, which are presented in the next section.
The risk estimates derived from using PBPK with the multistage
dose-response model submitted to the Agency by Reitz et al., Clewell et
al., and NIOSH, and the risk estimates derived from applied dose
methodologies, are shown in Table VI-4.
Table VI-4.--Lifetime Excess Risk Estimates (per 1000) From Occupational Exposure Based on Female Mouse Lung
Tumor Data
----------------------------------------------------------------------------------------------------------------
MLE (UCL)**
Model -----------------------------------------------------------------------------
25 ppm 50 ppm 500 ppm
----------------------------------------------------------------------------------------------------------------
OSHA NPRM Risk Assessment (mg/kg/ 2.32 (2.97)............... 4.64 (5.92).............. 45.5 (57.7)
d, BW extrapolation) without PBPK
Adjustment.
PPM to PPM extrapolation without 11.3 (14.4)............... 22.4 (28.5).............. 203 (251)
PBPK Adjustment.
PBPK Reitz female mouse lung-- 0.43 (0.53)............... 0.93 (1.17).............. 14.3 (17.9)
Reitz human (HSIA assumptions).
PBPK Reitz female mouse lung-- 0.81 (1.02)............... 1.69 (2.12).............. 15.0 (18.7)
Dankovic average human (NIOSH
assumptions).
PBPK Clewell female mouse lung-- 0.91 (1.14)............... 1.88 (2.36).............. 27.5 (34.2)
Clewell human (Navy assumptions)*.
OSHA Final Risk Assessment (female 3.62...................... 7.47..................... 125.8
mouse lung with PBPK).
----------------------------------------------------------------------------------------------------------------
* Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.
** Maximum likelihood estimates and 95th percentile upper confidence limit (in parentheses) of the multistage
dose-response function.
Of those risk estimates considered by OSHA prior to its final risk
assessment, the risk estimates for lifetime occupational exposure to
the 8-hour TWA PEL of 25 ppm ranged from 0.43 per 1000 to 11.3 per
1000. The risk assessment presented in the NPRM was based on a body
weight extrapolation from mice to humans of a mg/kg/day dose of MC. Mr.
Harvey Clewell [Ex. 19-59] stated that this dose was not a useful dose
for estimating risks from volatile solvents such as MC. He suggested
that, if PBPK modeling was not used to estimate target tissue dose (his
preferred
[[Page 1542]]
method of estimating risk), then a ppm-to-ppm extrapolation would be
more appropriate. The ppm-to-ppm extrapolation resulted in an estimated
risk of 11.3 deaths per 1000 after lifetime occupational exposure to 25
ppm. However, the ppm-to-ppm extrapolation is generally preferred for
site-of-contact tumors. Although it is possible that the MC lung tumors
were the result of a site-of-contact mechanism of action, the data are
more supportive of a systemic, genotoxic mechanism mediated through
metabolites of MC. In addition, the liver tumors are clearly not the
result of a site-of-contact carcinogen because the liver is not a site
of contact during inhalation bioassays.
Several commenters [Exs. 19-26, 19-28, 19-29, 19-45, 19-48, 19-57,
19-59, 25-E, 25-I] suggested using PBPK modeling to estimate target
tissue dose and to account for differences in metabolism at high and
low doses and differences in metabolism of MC across species. OSHA
compared three sets of parameters in the PBPK models submitted by
interested parties to adjust the dose across species and across doses.
The risk estimates for those models (using the MLE of the multistage
model parameters) ranged from 0.43 to 0.91 deaths per 1000 after
lifetime occupational exposure to 25 ppm. Mr. Clewell's risk estimate
(0.91/1000 MLE), unlike the other PBPK analyses, represent the upper
95th percentile of the Monte Carlo distribution of GST metabolites as
input into the multistage model. The Monte Carlo simulation takes into
account the assumed distribution of values for each parameter,
including the parameters used to estimate human metabolism of MC. The
other PBPK models used point estimates instead of distributions for the
PBPK parameters, and therefore it is not known whether these are
central estimates or upper bounds. OSHA agrees that the distributional
approach used by Clewell is a reasonable way to account for the
uncertainty and variability inherent in PBPK modeling, and that
uncertainty and variability must be considered in any useful risk
assessment. The Agency has used the upper 95th percentile on the
distribution of GST metabolites from the Bayesian modeling, coupled
with the MLEs of the multistage model parameters, for its final
estimates of MC risk.
OSHA has concluded that all the risk estimates presented above
support an 8-hour TWA PEL of 25 ppm or lower. The risks estimated from
the PBPK models were less than an order of magnitude different from
estimates of risk based on applied dose methodology. Either with or
without PBPK modeling , the estimates of risk at 25 ppm clearly
indicate a significant risk.
The risks estimated from these PBPK models and ppm-to-ppm
extrapolation offer a range of risks which might be expected after
lifetime occupational exposure to MC. OSHA has assessed these models
and has decided to modify and expand on the submitted PBPK and
uncertainty analyses in its final estimates of cancer risk, in order to
give full consideration to all of the available data. This analysis is
presented in the next section.
F. OSHA's PBPK Analysis and Final Risk Estimates
In developing an approach to PBPK modeling for MC, OSHA wished to
use all of the available, appropriate and quantifiable biochemical and
physiological data in its PBPK modeling and in assessing the
uncertainty and variability in model parameters. The Agency determined
that this approach would provide the best characterization of the
variability and uncertainty in the data and the model. In addition,
incorporation of as much of the available data as possible should give
the most realistic PBPK model, and in turn, the most realistic risk
estimate. Before development of OSHA's PBPK model, Clewell's approach
(described above) was the most comprehensive pharmacokinetic approach
submitted to the Agency. It addressed many of the issues of concern to
the Agency, and OSHA believes that Clewell's approach was a reasonable
template for using PBPK in risk assessment. However, since Clewell's
work was done, PBPK modeling has continued to advance. Therefore OSHA
modified Clewell's model to accommodate these advances and to allow
incorporation of additional biochemical and physiological data that had
been added to the rulemaking record. The following is a summary of
OSHA's final (revised) PBPK analysis. A more detailed discussion can be
found in the reports submitted to the Agency, reflecting OSHA's
analysis in which the Agency was assisted by contractors [Ex. 128].
1. Review of Clewell's PBPK Analysis
a. Clewell's analytical approach.
Clewell et al. [Ex. 96] employed Monte Carlo techniques to
investigate imprecision in estimates of human health risk from
occupational exposure to MC, as a function of imprecision in parameter
values of the PBPK and dose-response models. (As described below, OSHA
and its contractors believe that Clewell et al. did not correctly parse
out uncertainty and variability, so their analysis is described as
accounting for ``imprecision'' rather than uncertainty or variability).
In the Clewell et al. analysis, probability distributions were
specified for each PBPK model parameter in an attempt to characterize
imprecision. Computer-based techniques were used to obtain pseudo-
random samples from these statistical distributions, generating
multiple sets of model parameter values. These sets of parameter values
were then used to obtain a corresponding distribution of PBPK model
predictions of various measures of internal dose for a simulated animal
bioassay (e.g., GST metabolism in lungs of mice exposed to 2000 ppm and
4000 ppm for 6 hrs/day, 5 days/wk). The mean of the mouse internal dose
distribution was used as the dose input to obtain the MLE and UCL on
the multistage model parameters, using the tumor incidence data from
the NTP bioassay. The multistage model was run a second time using the
upper 95th percentile of the mouse internal dose distribution as the
dose input to obtain the MLE and UCL on the multistage model
parameters. This yielded a total of four estimates of the parameters
(qo, q1, and q2) of the mouse dose-response function: 1)
Mean of internal dose distribution/MLE of multistage model parameters;
2) Mean of internal dose distribution/UCL of multistage model
parameters; 3) Upper 95th percentile of internal dose distribution/MLE
of multistage model parameters; and 4) Upper 95th percentile of
internal dose distribution/UCL of multistage model parameters.
Each set of dose-response parameters obtained from the analysis of
the mouse data was then used to calculate human risk estimates. The
upper 95th percentile of the human internal dose distribution was used
to calculate the dose surrogate at 25 ppm, 8 hr/d exposure and then
substituted into the MLE and UCL of the multistage parameters to obtain
the MLE and UCL estimates of risk. Similarly the mean of the human
internal dose distribution was used in conjunction with the MLE and UCL
of the multistage model parameters. Therefore, four human risk
estimates were generated, based on the distribution of human internal
doses and the dose- response function derived from the multistage
analysis of the NTP mouse bioassay. The four human risk estimates are:
1) upper 95th percentile of the human internal dose distribution/MLE of
the multistage model parameters; 2) mean of human internal dose
distribution/MLE of the multistage model parameters; 3) upper 95th
percentile of the human internal dose
[[Page 1543]]
distribution/UCL of the multistage model parameters; and 4) mean of the
human internal dose distribution/UCL of the multistage model
parameters.
A major finding of that analysis was that the mean estimate of
added cancer risk for occupational exposure at the proposed PEL of 25
ppm based on the PBPK-derived GST-lung dose surrogate (PBPK(mean) /
potency(MLE) = 0.39 x 10 -3) was 6-fold lower than the
corresponding OSHA estimate (MLE = 2.32 x 10 -3) based on
administered dose scaled to body weight. The 95 percentile upper bound
estimate of risk using the same PBPK distributions and the distribution
of 95%UCLs on carcinogenic potency (PBPK(95%)/potency(95%) = 1.56 x 10
-3), was nearly 2-fold less than OSHA's 95%UCL on risk (2.97 x 10
-3).
b. Clewell's PBPK model. The PBPK model used by Clewell et al. in
performing their Monte Carlo analysis was slightly modified from the
PBPK model developed by Andersen et al. and submitted to OSHA by HSIA
[Ex. 328]. The primary modification was the addition of a separate
compartment for the GI-tract. The general structure of this model has
received considerable use by PBPK modelers. Nevertheless, there were
several deficiencies in this model and in the subsequent statistical
analysis that the Agency believed warranted major modification. These
are described in the following section.
c. Prior distributions for model parameters.Truncated normals were
used as the form for all probability distributions except for metabolic
constants, which were described by truncated lognormals. All
distributions were truncated to prevent sampling of nonsensical values
(e.g., negative values). Truncation in some instances was 2 standard
deviations (SDs) from mean values, in others more than 4 SDs.
A variety of sources of information were used as a basis for the
probability distributions of the PBPK parameters in Clewell's model:
literature summaries for most physiologic and anatomic parameters,
direct laboratory measurement of partition coefficients based on vial
equilibration studies, and statistical regression analyses of
experimental data for fitted metabolic constants.
Clewell et al. stated that the focus of their analysis was on
characterizing the effect of ``uncertainty'' in parameter values on
uncertainty in PBPK model predictions, uncertainty being defined as the
possible error in estimating the ``true'' value of a parameter for a
representative ``average'' animal. To maintain consistency with a focus
on investigating effects of parameter uncertainty, a logical choice
would have been to center their probability distributions using
estimates of mean values for all model parameters and to use the
standard error of the mean (SEM) to characterize dispersion. It it
unclear whether this was done for blood flows, tissue volumes,
inhalation rates or cardiac output, since Clewell et al. appear to have
relied extensively on an unpublished review of scientific literature
performed by S. Lindstedt for the ILSI Risk Science Institute
Physiological Parameter Working Group.
Based on Clewell's comments accompanying his PBPK model, it appears
that standard errors were not used to characterize variability among
individual replicates of measured equilibrium partition coefficients;
instead, standard deviations were used. Nor does it appear that Clewell
et al. consistently made use of standard errors in characterizing
imprecision in their fitted metabolic constants. Inspection of the
joint confidence region for their fitted estimates of mouse VmaxC and
Km (for the MFO pathway), shown in Figure 6 of Ex. 399, suggest
coefficients of variation (%CVs) for VmaxC of about 2%. Similarly, for
KfC, the %CV in the fitted MLE appears to be about 3%. These %CVs are
considerably smaller than the assumed values of 20% and 30%,
respectively, used by Clewell et al. in their Monte Carlo analysis. On
the other hand, their %CV for Km does coincide with that indicated by
the joint confidence regions. One should also note the high degree of
correlation among the fitted values for VmaxC and Km.
In assessing variability in the ratio of in vitro MFO and GST
metabolism in lung versus liver tissue (i.e., the A1 and A2
parameters), Clewell et al. used the in vitro MC metabolism data of
Reitz et al. (1989). Yet it appears that the %CV for these data is 24%
when one uses SDs among replicates for MFO metabolism in lung and liver
of mice. This is substantially less than the 50% assumed by Clewell.
One obtains a %CV of 9% when using SEMs.
It appears then, that some of the probability distributions used by
Clewell et al. reflect variability beyond that readily identifiable as
uncertainty in estimates of sample means. It may be that Clewell made a
subjective inflation of variances. Though ad hoc, inflating variances
would not be unreasonable given the sparse data on certain model
parameters. Another possibility is that the distributions reflect
variability due to both uncertainty and intersubject heterogeneity--
another reason to inflate variances, or alternately, use SDs rather
than SEMs to describe the distributions of the parameters. If so, then
it might be more appropriate to view the proportion of simulated
estimates of risk that fall within a specified interval as the
probability that the true risk for a randomly selected individual is in
that interval. Yet strictly speaking this would require that the
probability distributions reflect both the full range of uncertainty
and heterogeneity in the population of interest, with the latter being
unlikely based on inspection. If the analysis only considered
imprecision due to uncertainty, as suggested in Clewell et al., then
the resulting distribution should instead be viewed as describing the
uncertainty in risk for a hypothetical ``average'' individual.
2. OSHA's Modifications to PBPK Analysis
a. Basis for modifying approach of Clewell et al. In addition to
the likelihood that Clewell et al. used broader distributions than
those necessary to model uncertainty in the PBPK analysis (as opposed
to modeling some hybrid of uncertainty and variability), the analytical
approach they used (1992 and 1993) also has two well-known
methodological limitations. Their representation of imprecision in
fitted parameters (e.g., VmaxC, Km, KfC) is problematic because they
estimated the variability in these parameters by optimizing the model
fit to in vivo data, while assuming nominal values for all other model
parameters. However, the organ volumes, blood flows, and partition
coefficients for the mice used in the gas uptake studies and the humans
used in the open chamber studies are clearly not known with exact
precision, and are not, therefore, accurately represented by nominal
values. Consequently, the variances of the fitted parameters will be
underestimated with this approach, since full acknowledgment of
variability in other model parameters will have been ignored.
Furthermore, it is quite likely that the joint parameter space for
fitted PBPK model parameters will exhibit a considerable degree of
correlation. Importantly, failure to account for such covariances when
performing Monte Carlo sampling may overstate variance in some model
predictions by assuming independence where it does not exist. The
implications of these methodological limitations on predicted risk are
unclear, since they would seem to exert countervailing effects on
estimating uncertainty. Thus, OSHA decided that it was important to
perform an analysis that addressed these limitations. The
[[Page 1544]]
use of a Bayesian statistical framework provided a means of overcoming
the above limitations.
b. Bayesian Approach. A Bayesian analysis allows the logical
combination of two forms of information: ``prior knowledge'' about
parameter values drawn from the scientific literature, and data from
experimental studies (e.g., the mouse gas uptake studies, or, for
humans, the open chamber experiments performed by Dow Chemical
company), all within the context of a PBPK model. Clearly, neither
prior information about parameter values nor experimental data alone
are capable of precisely determining all parameter values in the PBPK
model. If prior information were sufficient, the additional experiments
performed by Clewell et al. and Dow Chemical Co. would not have had to
be done. But the available experimental data alone are insufficient to
pin down all parameters of the model to reasonable values (which is why
no attempt was made to simultaneously optimize all PBPK parameters to
data). Fitting only two or three parameters while holding others
constant so as to reduce dimensionality leads to the biases and
underestimation of variance mentioned above.
A second feature of this Bayesian approach is that it yields
distributions for all of the PBPK model parameters together with
information about their entire joint covariance structure. Thus, the
Bayesian analysis outputs distributions of parameter values that are
consistent with both all the available data as well as the prior
information. It is then possible to use samples from the joint
posterior distribution of the parameters to simulate formation of GST
metabolites in lung tissue from different species and cancer risk,
therefore producing posterior distributions for these endpoints. It
should be noted that if no data are available (or if the data are not
informative as to the likely value of the parameter), the posterior
distribution is equivalent to the prior distribution and this approach
is then equivalent to the standard Monte Carlo sampling from the prior
distribution, as in Clewell et al. Alternately, Bayesian updating with
a uniform prior distribution (i.e., complete ignorance about plausible
values) used in conjunction with data leads to a posterior distribution
proportional to the distribution of the data. The most important
applications of the Bayesian approach arise when informative (e.g.,
physiological, anatomical) prior distributions exist, in parallel with
experimental metabolic data. This is now the case with PBPK modeling of
MC. In this case, Bayesian modeling results in all the information
content of both prior distributions of parameter values and metabolic
data being incorporated in the posterior distribution of parameter
values, which will have reduced variance compared to the prior
distribution. Distributions of parameter values for both human and
mouse PBPK models, and the multistage cancer model, were determined
with this technique.
c. PBPK Model Modifications. OSHA's final risk estimates were based
on the Bayesian analysis described here. The Clewell model formed the
structural core of the analysis, although five additional structural
modifications were made as described below. These modifications were
necessary to make the PBPK model more physiologically realistic:
(1) Bone marrow was treated as a separate compartment. In the
Clewell model (as in many PBPK models), bone marrow tissue was combined
with other tissues into a (presumably) kinetically homologous
compartment. Based on blood perfusion rates, a reasonable choice would
be to place marrow in the well-perfused tissue compartment. However, if
the physicochemical affinity of the compartment is considered, it makes
more sense to place marrow in the adipose tissue compartment, since red
marrow (at least in humans) has a fat content of about 40% and yellow
marrow has a fat content of 80%. In comparison, liver, brain, kidney
and heart all have fat contents (in humans) well under 20% . In
addition, bone marrow accounts for a significant percentage of body
weight and receives a substantial fraction of cardiac output.
Therefore, a strong argument can be made for treating bone marrow as a
separate compartment, as OSHA has done here.
(2) Partitioning MFO and GST metabolism between the lung and liver.
Clewell made the MFO and GST metabolic constants for lung dependent on
the fitted constants for the liver, so as to reduce the number of
fitted parameters to be simultaneously estimated from rodent and human
in vivo data. For example, A1 is defined as the ratio of lung to liver
in vitro MFO enzymatic activity, normalized to microsomal protein,
[GRAPHIC] [TIFF OMITTED] TR10JA97.005
Similarly, A2 is the ratio of lung to liver in vitro GST enzymatic
activity, normalized to cytosolic protein,
[GRAPHIC] [TIFF OMITTED] TR10JA97.006
This assumes that lung and liver have equivalent mg protein per mg
tissue contents. Yet the data of Litterst et al. (1973) argue against
such an assumption. Litterst et al. measured microsomal protein and
soluble protein in lung and liver tissues of mice, rats, hamsters,
guinea pigs and rabbits. These data indicated ratios of mg microsomal
protein content of lung versus liver tissue of less than 0.3, and a
similar ratio for soluble protein of about 0.7. Thus, some adjustment
of the constants A1 and A2 are required.
The equations used to compute a lung Vmax for the MFO pathway and a
lung Kf for the GST pathway from a liver Vmax and Kf were thus modified
to include an additional proportionality factor to account for
differences in microsomal and cytosolic protein content of lung and
liver tissue. Specifically,
[[Page 1545]]
[GRAPHIC] [TIFF OMITTED] TR10JA97.007
where B1 is the ratio of [mg microsomal protein per mg of lung tissue]
to the same measure for liver tissue. A geometric mean and geometric
standard deviation for B1 were derived from the data of Litterst et al.
(1973) to use as input in the Bayesian prior distribution for this
parameter. Notably, accounting for this difference in protein content
leads to a proportionality factor approximately four-fold less than
that used by the Clewell et al. (i.e., A1 x B1 = 0.41 x 0.27 = 0.11).
Similarly, for Kflung.GST,
[GRAPHIC] [TIFF OMITTED] TR10JA97.008
Here too, the data of Litterst et al. (1973) were used to compute a
ratio of mg soluble protein per mg lung to the same measure for liver,
yielding a mean value of 0.68 for B2. For a human B2, the average of
the ratios computed for mice, rats, hamsters, guinea pigs, and rabbits
as per Litterst et al. (1973) was used.
(3) Linkage of alveolar ventilation to cardiac output. In
recognition of OSHA's interest in occupational exposures, Clewell used
values of cardiac output and alveolar ventilation rates consistent with
the performance of light work. However, they did not account for the
altered distribution of regional blood flows known to occur in response
to increases in work intensity [Exs. 7-115, 7-120, 21-81], as was done
in subsequent MC PBPK work by Dankovic and Bailer [Ex. 23-18] (1994).
In the latter analysis, alveolar ventilation (QP) was made dependent on
cardiac output (QC) by making QP = QC x VPR, where VPR is the
ventilation- perfusion ratio. VPR was treated as a random variable with
an assigned prior probability distribution.
(4) Linkage of work intensity to changes in physiology. Cardiac
output, ventilation perfusion ratio, and percent of cardiac output
delivered to tissues were made dependent on work intensity. Using the
data of Astrand (1983) [Ex. 21-81]--and similar to what was done by
Dankovic and Bailer (1994) [Ex. 23-18]--slope factors were derived to
describe change in flows per change in work intensity as measured in
watts. These slope factors were then used to modify resting flows for
varying levels of work intensity. This approach was taken so that the
influence of variability in work load (i.e, work load was treated as a
random variable)--with concomitant adjustments to regional blood flows
and ventilation rate--on delivered dose could be modeled.
(5) Maintaining mass balance in sampling of fractional blood flows
and compartment volumes. Monte Carlo sampling of fractional quantities
such as the proportion of cardiac output delivered to different
compartments, or the proportion of body weight represented by a given
compartment, requires the imposition of some type of constraint to
prevent random sampling leading to summed proportions greater than the
whole (and thus causing nonsensical departures from mass balance). The
following constraint was imposed: VppC = 0.82--ViC 's (0.82 is
a nominal value for the fraction of body weight absent bone, blood, and
stomach and intestinal contents), QwpC = 1--QiC 's (in the
mouse model), and QppC = 1--QiC 's (in the human model). The
use of either QwpC or QppC as the quantity to be made dependent on the
other fractional flows has biological appeal--one expects that higher
fractional blood flow to the poorly-perfused compartment (i.e., muscle
and skin) should be accompanied by a lower fractional flow to the well-
perfused compartment, and vice versa. The choice of QwpC versus QppC as
the one to be made dependent on others appeared to be unimportant in
work with the mouse model. The choice was important in work with the
human model. Here it was necessary to choose QppC, because of its large
variance relative to QwpC (i.e., since QppC cannot be estimated
precisely, it makes sense to let our greater knowledge of the other
fractional flows inform us about plausible values of QppC).
The above approach modifies the approach taken by Clewell et al.
[Ex. 96]. Their approach was to randomly draw from the distributions
for cardiac output and all fractional flows, use the random draws to
compute the absolute flows to the individual compartments, and then to
sum the individual flows to make a new cardiac output value for use in
the simulation. On the other hand, OSHA's final analysis avoided
arbitrarily modifying the prior distribution for cardiac output (which
happens to be one of the relatively well-known parameters).
Furthermore, Clewell did not make the fractional flows dependent on one
another.
d. Prior Probability Distributions. A skewed, lognormal-like
distribution is generally observed for biological parameters. However,
most, if not all, parameters are also positive and have physiological
bounds. Thus, truncated lognormal distributions of the parameter values
were used in this analysis. They do not differ appreciably from normal
distributions for small values of the variance.
In specifying prior distributions an attempt was made to
characterize the variability of the mean parameter values for small
groups of rodents and humans. This focus was adopted to make the prior
distribution congruent with the data sets available for Bayesian
analysis. For example, the rodent gas uptake data represent the
aggregate pharmacokinetic behavior of groups of 5 mice. Prior
distributions were therefore constructed to reflect the degree of
variability in mean physiological and anatomical PBPK parameters for
small groups of mice. A similar approach was taken in defining prior
distributions for human physiologic and anatomic parameters, since the
available experimental data reflected the averaged pharmacokinetic
behavior of 6 subjects. In practice, this meant amassing studies
reporting mean values for certain PBPK parameters (e.g., tissue
weights, blood flows, cardiac output, minute ventilation), and then
using these means as data for computing a geometric mean (GM) and
geometric standard deviation (GSD) with which to estimate the parameter
values for the truncated lognormal distributions. Sampling of all
lognormal distributions was truncated at 2 GSDs, with one exception.
Truncation of the blood:air partition coefficient was extended to 3
GSDs based on results from preliminary runs.
Table VI-5 presents a summary of the prior probability
distributions used in the Bayesian fitting of the mouse and human data
sets. The prior distributions for metabolic constants to be estimated
from in vivo data were made very broad (i.e., assigned a GSD of 10) to
reflect our ignorance of these values before examining the data.
Similarly, the prior distributions for parameters of the multistage
cancer model were broad uniform distributions, constrained to be
positive, as required by the standard model.
[[Page 1546]]
Table VI-5.--Prior Distributions Used in Bayesian Analysis of Mouse and Human In-vivo Data
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mouse priors Human priors
Parameter -----------------------------------------------------------------------------------------
GM GSD GM GSD
--------------------------------------------------------------------------------------------------------------------------------------------------------
Flows:
QCC Cardiac Output (l/hr/kg--BW).. a 34.8 1.14 4.2.......................... 1.10
VPR Alveolar Ventilation Perfusion b 1.22 1.95 1.35......................... 1.15
Rate.
Tissue Blood Flows (fraction
of cardiac output):
QgiC GI Tract...................... 0.165 1.30 0.191........................ 1.25
QliC Liver......................... 0.017 1.20 0.067........................ 1.20
QfatC Fat........................... 0.047 1.60 0.057........................ 1.45
QppC Poorly Perfused Tissues....... 0.276 1.25 0.198 c...................... 1.55
QwpC Well Perfused Tissues......... c 0.369 1.10 0.443........................ 1.25
QmarC Bone Marrow................... 0.089 1.60 0.044........................ 1.70
Tissue Volumes (fraction of
body weight):
VgiC GI Tract...................... 0.035 1.30 0.017........................ 1.10
VliC Liver......................... 0.045 1.20 0.026........................ 1.10
VfatC Fat........................... 0.077 1.40 0.204........................ 1.20
VppC Poorly Perfused Tissues....... c 0.556 1.10 0.470 c...................... 1.15
VwpC Well Perfused Tissues......... 0.065 1.15 0.044........................ 1.10
VluC Lung.......................... 0.008 1.30 0.008........................ 1.15
VmarC Bone Marrow................... 0.033 1.50 0.050........................ 1.10
Equilibrium Partition
Coefficients:
Pblo Blood:Air..................... 13.7 1.80 8.4.......................... 1.30
Pgi GI Tract:Air.................. 10.5 1.20 8.1.......................... 1.60
Pli Liver:Air..................... 22.9 2.00 9.9.......................... 1.60
Pfat Fat:Air....................... 98.2 1.40 97.6......................... 1.25
Ppp Poorly Perfused Tissues:Air... 9.5 1.30 6.8.......................... 1.60
Pwp Well Perfused Tissues:Air..... 10.2 1.20 7.6.......................... 1.40
Plu Lung:Air...................... 10.0 1.30 7.6.......................... 1.50
Pmar Bone Marrow:Air............... 62.0 1.60 48.8......................... 1.60
Metabolic Parameters:
VmaxC Maximum metabolic velocity of 750 10.00 75........................... 10.00
MFO saturable pathway (mg/hr/
kg--liver).
KM Affinity of MFO saturable 1.35 10.00 0.6.......................... 10.00
pathway (mg/l).
KFC First order rate constant for 1.5 10.00 Mouse post. d................ Mouse post. d
GST pathway (l/hr/kg-0.25).
A1 Ratio of lung to liver in- 0.405 1.67 0.0045....................... 4.50
vitro MFO metabolic
velocities (nmol/min/gm--
lung--micros.Prot)/ (nmol/min/
gm--liver--micros.Prot).
A2 Ratio of lung to liver in- 0.282 1.67 0.122........................ 3.60
vitro GST metabolic
velocities (nmol/min/gm--
lung--cytos.Prot)/ (nmol/min/
gm--liver--cytos.Prot).
B1 Ratio of lung and liver tissue 0.271 1.25 0.297........................ 1.10
content of microsomal protein.
B2 Ratio of lung and liver tissue 0.721 1.25 0.807........................ 1.20
content of cytosolic protein.
Sp--Kf Allometric scaling power for ............ ............ -0.272 e..................... 0.08 e
body weight scaling of KFC
from mice to humans.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 0.025 kg mouse, 70 kg human; (b) unitless; (c) prior distribution not used, fractional flow made functionally dependent on
others (see text); (d) human prior set equal to mouse posterior; (e) mean and standard deviation of a truncated normal distribution.
While it is desirable to separate variability into components
reflecting pure uncertainty (e.g., measurement error) versus
interindividual heterogeneity and to propagate them separately, it is
necessary to build from the start an adequate statistical model. The
problem here is complicated by the fact that both the rodent and human
in vivo data used for estimating metabolic constants reflected either
aggregated or averaged pharmacokinetic behavior. Thus the prior
distributions and the statistical model used here aggregate variability
due to both finite precision in measured values and heterogeneity among
average values for small groups of rodents or humans; they do not, it
must be emphasized, reflect heterogeneity among the individual humans
in a large, representative population.
e. In Vivo Rodent and Human data. Bayesian updating of the
distributions was performed using the same data sets used by Clewell et
al. to obtain fitted estimates of mouse and human metabolic constants;
namely, gas uptake studies with mice with or without pretreatment with
a MFO inhibitor and the human open chamber inhalation studies. All
mouse gas uptake studies were conducted with 5 female mice in
[[Page 1547]]
a single chamber. Thus, measured observations of decline in chamber
concentration of MC represent the aggregate pharmacokinetic behavior of
groups of 5 animals.
The human in vivo data were obtained from Tables 2 and 3 in
Andersen et al. (1991) [Ex. 21-94]. Briefly, these data represent
exhaled breath and venous blood concentrations of MC for 6 male human
volunteers exposed to MC concentrations of 100 or 350 ppm for a period
of 6 hours. These data have only been reported as means and standard
deviations of the six subjects, which is unfortunate. Thus, the
available data reflect the average pharmacokinetic behavior of the 6
subjects. When simulating the human data reported in Andersen et al.
(1991), the work load was assumed to be zero watts (rest) and the
averaged body weight of the 6 subjects was assumed to be known without
error (86 kg).
f. Simulating the Rodent Bioassay and Human Occupational Exposure.
Distributions for GST metabolism in the lungs of mice exposed to 2000
ppm or 4000 ppm exposures, for 6 hrs/day and 5 days/week, were obtained
by simulating these two exposures (the ones used in the NTP bioassay)
with 5000 realizations drawn from the joint posterior distribution of
the mouse PBPK parameters.
The quantity of metabolites formed during the 4th week (dynamic
equilibrium reached) was divided by 7 to give an average measure per
day. For use as an input dose to the multistage model, these posterior
distributions were approximated by truncated lognormals.
The same set of 5000 parameter vectors was used to simulate both
2000 and 4000 ppm MC exposures. The control dose was always assumed to
be 0. Thus, a 5000-by-3 matrix of doses was generated, where the three
column vectors represent different realizations of a particular dose
group (0, 2000 and 4000 ppm MC) and the row vectors represent different
realizations of bioassay doses.
This method of using the joint posterior distributions for the two
doses in the mouse bioassay implies certain assumptions about the
uncertainties. Most importantly, this approach (referred to in this
document as the ``dependence case'') assumes that the posterior
distributions primarily reflect uncertainty about a single average
value equally applicable to all groups of approximately 50 mice (i.e.,
it assumes groups of 50 mice will have the same ``average''
physiological, anatomical, physicochemical and metabolic attributes,
and that these average values are simply known to us with uncertainty).
An alternative would be to model the ``independence case'' by using a
different random draw from the vector of PBPK parameters for one dose
group than for the other. This approach assumes that the posterior
distributions primarily reflect heterogeneity in the average attributes
of groups of 50 rodents. Under the dependence case, estimates of
metabolized dose for the two exposures would tend to move in tandem for
a given simulation (i.e., when one dose is estimated to be low relative
to its average, so is the other; likewise, when one is high, so is the
other), and in principle would therefore exhibit less variability in
dose-response shape (e.g., linear, sublinear, supralinear).
It appears that the dependence case is more reasonable than the
independence case, by appealing to biological theory and by examining
the results of the sensitivity analysis conducted as part of this risk
assessment. The sensitivity analysis showed that predicted mouse GST
metabolism at 2000 ppm was most sensitive to variation in the model
parameter A2. Variability in A2 was primarily a consequence of
uncertainty in using an in vitro ratio of enzymatic activity to make
inferences about an in vivo ratio. Therefore, uncertainty rather than
heterogeneity seems to dominate the distribution of mouse GST
metabolism estimates. Besides, laboratory rodents have a carefully
controlled genetic makeup, primarily so that they will differ little
from each other physiologically; thus, groups of 50 rodents should have
extremely similar average characteristics (the variance of the mean of
a characteristic within a group of 50 rodents will be approximately 50
times smaller than the (already small) inter-individual variance). OSHA
has determined that this reasoning supports use of the dependence case
in this analysis. (Note that the excess risk estimates using the
dependence case are only about a factor of 1.5 higher than those using
the independence case).
Five human occupational exposures were simulated: constant exposure
to 10, 25, 50, 100 or 500 ppm MC for 8-hrs per day and 5 days per week.
Simulations were made up to 4 weeks of work, at which a dynamic
equilibrium was reached, and as with mice, were performed using 5000
parameter human vectors drawn from their joint posterior distribution,
augmented by allowing for additional variability in human body weight
and work intensity (the latter linked to changes in cardiac,
ventilation-perfusion and regional blood flow as described above).
g. Sensitivity Analysis. The influence of variability in mouse and
human PBPK model parameters on variability in predicted mouse and human
GST lung metabolism was assessed by computing pairwise correlation
coefficients using each parameter vector (i.e., the marginal posterior
distribution) and the corresponding vector of model predictions. For
mice, the sensitivity to predicted GST--lung metabolism in the
simulated 2000 ppm bioassay dose group was evaluated. For humans,
predicted GST--lung metabolism for an occupational exposure to 25 ppm
was considered. Pairwise correlation coefficients were computed using
5000 parameter vectors drawn from the joint posterior distribution and
the associated model output vector.
Table VI-6 presents the results from the sensitivity analysis. The
strongest pairwise correlation between predicted lung GST metabolism
and any input parameter, for either mouse or human simulations, was A2.
For the mouse simulation of a 2000 ppm exposure, B2 gave the next
strongest pairwise correlation. The mouse parameters QlivC, VlivC,
VmaxC, Pfat and QppC all exhibited more moderate (though not
negligible) correlations. For the human occupational simulation, the
parameters KfC, VmaxC, Sp__Kf, and B2 all exhibited moderate pairwise
correlations with human lung GST metabolism. For both mice and human
sensitivity analyses, there were a half-dozen or more parameters
exhibiting weak (r between 0.1 and 0.2) correlations. It is important
to note that all parameters are further correlated via their posterior
joint distribution function. This explains why the sum of the
regression coefficients (i.e., squares of the correlation coefficients)
is greater than 1. Thus considerable care should be exercised in
quantitatively estimating the ability of variability in any input
parameter to explain variability in predicted GST metabolism,
especially among parameters with similar pairwise correlation
coefficients.
[[Page 1548]]
Table VI-6.--Correlation Coefficients for Total GST Lung Metabolism From Monte Carlo Analysis Using Mouse and
Human Posterior Distributions
----------------------------------------------------------------------------------------------------------------
Mouse 2000 PPM Human 25 PPM
----------------------------------------------------------------------------------------------------------------
Correlation Correlation
Parameter coefficient Parameter coefficient
(r) (r)
----------------------------------------------------------------------------------------------------------------
A2.......................................... 0.860 A2 0.850
B2.......................................... 0.530 KfC 0.315
QliC........................................ 0.335 VmaxC -0.291
VliC........................................ -0.248 Sp--Kf 0.232
VmaxC....................................... -0.229 B2 0.221
Pfat........................................ -0.203 Pmar -0.183
QppC........................................ -0.202 QfatC 0.180
VPR......................................... 0.193 B1 0.179
Pli......................................... -0.173 VliC 0.161
A1.......................................... -0.149 VmarC 0.146
QgiC........................................ -0.145 Work 0.142
Pmar........................................ 0.144 QwpC 0.141
VwpC........................................ -0.121 VfatC 0.136
KfC......................................... 0.120 QmarC 0.136
Pwp......................................... -0.106 Km -0.095
VluC........................................ -0.120 QC -0.083
B1.......................................... -0.093 QliC -0.083
QmarC....................................... -0.083 A1 -0.071
Ppp......................................... -0.076 QgiC -0.065
VgiC........................................ 0.074 Pfat -0.061
Pgi......................................... 0.054 Pwp -0.058
QC.......................................... -0.049 VluC -0.052
BW.......................................... -0.042 Pgi -0.050
Plu......................................... 0.039 VwpC 0.041
Km.......................................... -0.035 Pblood 0.039
tVmaxC...................................... 0.024 dVPR/dW 0.039
QfatC....................................... 0.020 BW -0.038
Pblood...................................... 0.019 dQli/dW -0.033
VfatC....................................... -0.013 Plu 0.023
Vmar........................................ -0.007 Ppp 0.021
dQfat/dW 0.016
VgiC -0.012
Pli -0.010
dQgi/dW -0.010
dQmar/dW -0.009
VPR 0.006
dQC/dW -0.000
dQwp/dW -0.000
----------------------------------------------------------------------------------------------------------------
h. Posterior PBPK Parameter Distributions. Table VI-7 lists the
posterior distributions for mouse PBPK parameters obtained by Bayesian
updating of the prior distributions using the available gas uptake
data. Comparison of the prior and posterior probability distributions
reveals that the gas uptake data retain considerable influence on the
distributions of many of the important PBPK model parameters. Medians
of the posterior distributions for VPR, Qfat, Pblood, Pmar, Km, A1, and
A2 were all appreciably different than the medians for their
corresponding prior distributions. Percent CVs for nearly all posterior
distributions were considerably smaller than those of their prior
distributions. As expected, the marginal variances for the metabolic
constants were considerably greater than what was obtained under
nonlinear maximum likelihood regression analysis with all other model
parameters fixed at nominal values.
Table VI-7. Prior and Posterior (Fitted) Distributions of the Mouse Model Parameters
----------------------------------------------------------------------------------------------------------------
Central tendency Variability
------------------------------ Maximum -------------------------
Parameter Posterior posterior Posterior
Prior median median Prior %CV %CV
----------------------------------------------------------------------------------------------------------------
Flows:
QCC Cardiac Output (l/hr/ 34.8 34.4 37.6 18 9
kg__BW).
VPR Alveolar Ventilation 1.22 1.59 1.49 75 14
Perfusion Ratio.
Tissue Blood Flows
(fraction of
cardiac output):
QgiC GI Tract............ 0.165 0.140 0.175 26 16
[[Page 1549]]
QliC Liver............... 0.017 0.020 0.017 19 16
QfatC Fat................. 0.047 0.090 0.098 43 19
QppC Poorly Perfused 0.276 0.290 0.243 22 18
Tissues.
QwpC Well Perfused 0.369 a 0.360 0.378 a
Tissues.
QmarC Bone Marrow......... 0.089 0.100 0.090 51 27
Tissue Volumes
(fraction of body
weight):
VgiC GI Tract............ 0.035 0.040 0.038 26 22
VliC Liver............... 0.045 0.050 0.050 18 12
VfatC Fat................. 0.077 0.070 0.055 35 24
VppC Poorly Perfused 0.556 b 0.540 0.569 b
Tissues.
VwpC Well Perfused 0.065 0.070 0.065 14 12
Tissues.
VluC Lung................ 0.008 0.010 0.007 27 22
VmarC Bone Marrow......... 0.033 0.040 0.037 42 29
Equilibrium
Partition
Coefficients:
Pblo Blood:Air........... 13.7 18.5 13.1 66 18
Pgi GI Tract:Air........ 10.5 11.3 9.5 19 17
Pli Liver:Air........... 22.9 28.2 23.9 79 32
Pfat Fat:Air............. 98.2 100.5 106.7 35 21
Ppp Poorly Perfused 9.5 12.1 13.1 27 17
Tissues:Air.
Pwp Well Perfused 10.2 10.4 10.3 19 16
Tissues:Air.
Plu Lung:Air............ 10.0 11.3 12.5 27 22
Pmar Bone Marrow:Ait..... 62.0 70.4 89.2 50 25
Metabolic
Parameters:
VmaxC Maximum metabolic 750 718 661 1413 12
velocity of MFO
saturable pathway
(mg/hr/kg__liver).
tVmaxC Maximum metabolic 8.4 7.2 11.3 58 50
velocity of MFO
saturable pathway
in t-DCE pretreated
mice.
Km Affinity of MFO 1.35 0.04 0.03 1413 97
saturable pathway
(mg/l).
KfC First order rate 1.5 1.77 2.47 1413 24
constant for GST
pathway (l/hr/
kgcaret0.25).
A1 Ratio of lung to 0.405 0.28 0.30 54 31
liver in-vitro MFO
metabolic
velocities (nmol/
min/
gm__lung__micros.Pr
ot)/(nmol/min/
gm__liver__micros.P
rot).
A2 Ratio of lung to 0.282 0.37 0.30 55 41
liver in-vitro GST
metabolic
velocities (nmol/
min/
gm__lung__cytos.Pro
t)/(nmol/min/
gm__liver__cytos.Pr
ot).
B1 Ratio of lung and 0.271 0.26 0.29 23 18
liver tissue
content of
microsomal protein.
B2 Ratio of lung and 0.721 0.70 0.84 22 17
liver tissue
content of
cytosolic protein.
----------------------------------------------------------------------------------------------------------------
Notes: (a) functionally defined as 1__sum (other fractional flows); (b) functionally defined as 0.82__sum (other
fractional volumes).
Table VI-8 presents the corresponding set of results for human PBPK
parameters. The human in vivo data also appeared to contain
considerable information about many of the model parameters, as
evidenced by shifts in medians and tightening of posterior
distributions relative to priors. Fitted estimates of the metabolic
constants were fairly precise, even for Km (Table VI-8); indeed, the
fits were markedly superior to those shown in Andersen et al. [Ex. 21-
94] and Clewell et al. [Ex. 96].
Table VI-8.--Prior and Posterior (Fitted) Distributions of the Human Model Parameters
--------------------------------------------------------------------------------------------------------------------------------------------------------
Prior distribution Posterior distribution
----------------------------------------------------------------------------------------------
Posteriors for Bayesian Modified by exercise
Parameter fit --------------------------
GM GSD %CV ---------------------------
Median %CV Median %CV
--------------------------------------------------------------------------------------------------------------------------------------------------------
Flows:
QCC Cardiac Ouput (1/hr/ 4.2 1.10 10 4.0 6 6.2 17
kg__BW).
[[Page 1550]]
VPR Alveolar Ventilation 1.35 1.15 15 1.03 1 1.37 9
Perfusion Ratio.
Tissue Blood Flows (fraction ......................... ............ ............ ........... ............ ........... ............ ...........
of cardiac output):
QgiC GI Tract................. 0.191 1.25 23 0.149 12 0.122 14
QliC Liver.................... 0.067 1.20 19 0.063 15 0.041 24
QfatC Fat...................... .057 1.45 38 0.045 10 0.052 11
QppC Poorly Perfused Tissues.. 0.198 1.55 a 0.378 a 9 a 0.453 10
Qwpc Well Perfused Tissues.... 0.443 1.25 23 0.294 3 0.258 7
QmarC Bone Marrow.............. 0.044 1.70 57 0.071 38 0.072 38
Tissue Volumes (fraction of ......................... ............ ............ ........... ............ ........... ............ ...........
body weight):
VgiC GI Tract................. 0.017 1.10 10 0.018 8 0.018 8
VliC Liver.................... 0.026 1.10 10 0.026 8 0.026 8
VfatC Fat...................... 0.204 1.20 18 0.183 11 0.183 11
VppC Poorly Perfused Tissues.. 0.470 1.15 b 0.489 b 5 b 0.489 5
VwpC Well Perfused Tissues.... 0.044 1.10 9 0.47 7 0.047 7
VluC Lung..................... 0.008 1.15 14 0.008 11 0.008 11
VmarC Bone Marrow.............. 0.050 1.10 10 0.049 8 0.049 8
Equilibrium Partition ......................... ............ ............ ........... ............ ........... ............ ...........
Coefficients:
PC.blood Blood:Air................ 8.4 1.30 26 16.5 2 16.5 2
PC.gi GI Tract:Air............. 8.1 1.60 50 10.7 36 10.7 36
PC.li Liver:Air................ 9.9 1.60 50 13.7 33 13.7 33
PC.fat Fat:Air.................. 97.6 1.25 22 84.4 12 84.4 12
PC.pp Poorly Perfuse Tissue:Air 6.8 1.60 48 13.3 13 13.3 13
PC.wp Well Perfused Tissue:Air. 7.6 1.40 35 13.1 14 13.1 14
PC.lu Lung:Air................. 7.6 1.50 43 9.4 33 9.4 33
PC.mar Bone Marrow:Air.......... 48.8 1.60 49 47.8 27 47.8 27
Metabolic Parameters: ......................... ............ ............ ........... ............ ........... ............ ...........
VmaxC Maximum MFO metabolic 75.0 10.00 1413 97.2 11 97.2 11
rate (mg/mg/hr/kg-liver).
Km MFO Michaelis Menton 0.60 10.00 1413 0.52 39 0.52 39
constant (mg/1).
Kf 1st order rate constant 0.12 2.07 81 0.23 63 0.23 63
for GST pathway (1/hr).
A1 [V/S]-lung/[V/S-MFO-liver 0.0045 4.50 226 0.024 77 0.024 77
A2 [V/S]-lung/[V/S]-GST- 0.236 2.04 83 0.364 49 0.364 49
liver.
B1 [mg micr.Prot/gm lung]/ 0.297 1.10 10 0.300 8 0.300 8
[mg micr.Prot/gm liver].
B2 [mg cyt. Prot/gm lung]/ 0.807 1.20 18 0.845 15 0.845 15
[mg cyt.Prot/gm liver].
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes (a) operationally defined as 1--sum (other fractional flows); (b) functionally defined as 0.82--sum (other fractional volumes).
[[Page 1551]]
Tables VI-9 and VI-10 compare the posterior distributions for mice
and human PBPK parameters with the distributions used by Clewell. For
mice, there were appreciable differences in the median values for QCC,
VPR, QfatC, QwpC, VwpC, VmaxC, Km, KfC, and the apparent A1 (i.e., A1
x B1). With the exception of VliC, Pblood, Pliv, Ppp and Km, the
posterior distributions for all other parameters were tighter than the
distributions used by Clewell. The human posterior distributions in
Table VI-10 are somewhat different than those in Table VI-8, in that
they reflect the influence of modeling variable work intensity on QC,
VPR, and all regional blood flows. In comparing these modified
posterior distributions to the distributions used by Clewell, one finds
appreciable differences in median values for VPR, many of the
fractional blood flows (QgiC, QliC, QppC, QwpC), VgiC, PCblood, PCliv,
PCfat, VmaxC, KfC, and the apparent A2 (i.e., A2 x B2). All human
posterior distributions except for VliC, Pli, and Sp__Kf, had
appreciably tighter distributions than those used by Clewell et al.
[Ex. 96].
Table VI-9.--Comparison of Mouse Probability Distributions Used by Clewell et al. With OSHA's Posterior
Probability Distributions
----------------------------------------------------------------------------------------------------------------
Central tendency Variability
-----------------------------------------------------
Parameter Clewell et Clewell et
al. median OSHA median al. %CV OSHA %CV
----------------------------------------------------------------------------------------------------------------
Flows:
QCC Cardiac Output (1/hr/ a 41.5 34.4 9 9
kg__BW).
VPR Alveolar Ventilation b 1.76 1.59 58 14
Perfusion Ratio.
Tissue Blood Flows (fraction of
cardiac output):
QgiC GI Tract................. 0.165 0.14 25 16
QliC Liver.................... 0.035 0.02 96 16
QfatC Fat...................... 0.030 0.09 60 19
QppC Poorly Perfused Tissues.. 0.250 0.29 40 18
QwpC Well Perfused Tissues.... 0.520 c 0.36 50 c
QmarC Bone Marrow.............. NA 0.10 NA 27
Tissue Volumes (fraction of
body weight):
VgiC GI Tract................. 0.031 0.04 30 22
VliC Liver.................... 0.046 0.05 6 12
VfatC Fat...................... 0.100 0.07 30 24
VppC Poorly Perfused Tissues.. 0.513 d 0.54 30 d
VwpC Well Perfused Tissues.... 0.041 0.07 30 12
VluC Lung..................... 0.008 0.01 30 22
VmarC Bone Marrow.............. NA 0.04 NA 29
Equilibrium Partition
Coefficients:
Pblo Blood:Air................ 23.0 18.5 15 18
Pgi GI Tract:Air............. 11.4 11.3 30 17
Pli Liver:Air................ 38.7 28.2 20 32
Pfat Fat:Air.................. 107.0 100.5 30 21
Ppp Poorly Perfused 8.5 12.1 10 17
Tissues:Air.
Pwp Well Perfused Tissues:Air 11.4 10.4 20 16
Plu Lung:Air................. 10.0 11.3 30 22
Pmar Bone Marrow:Air.......... NA 70.4 NA 25
Metabolic Parameters:
VmaxC Maximum metabolic 970 718 20 12
velocity of MFO
saturable pathway (mg/hr/
kg__liver).
Km Affinity of MFO saturable 1.35 0.04 30 97
pathway (mg/l).
KfC First order rate constant 1.5 1.77 30 24
for GST pathway (l/hr/
kg__0.25).
A1 Ratio of lung to liver in- 0.405 0.28 50 31
vitor MFO metabolic
velocities (nmol/min/
gm__lung__micros.Prot)/
(nmol/min/
gm__liver__micros.Prot).
A2 Ratio of lung to liver in- 0.282 0.37 50 41
vitro GST metabolic
velocities (nmol/min/
gm__lung__cytos.Prot)/
(nmol/min/
gm__liver__cytos.Prot).
B1 Ratio of lung and liver 1 0.25 0 18
tissue content of
microsomal protein.
B2 Ratio of lung and liver 1 0.69 0 17
tissue content of
cytosolic protein.
----------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 0.025 kg mouse; (b) unitless; (c) functionally defined as 1--sum (other fractional
flows); (d) functionally defined as 0.82--sum(other fractional volumes); (na) not applicable.
Table VI-10. Comparison of Human Probability Distributions Used by Clewell et al. With OSHA's Posterior
Probability Distributions
----------------------------------------------------------------------------------------------------------------
Central tendency Variability
-----------------------------------------------------
Parameter Clewell et Clewell et
al. median OSHA median al. %CV OSHA %CV
----------------------------------------------------------------------------------------------------------------
Flows:
[[Page 1552]]
QCC Cardiac Output (l/hr/kg__BW) a 6.2 c 6.3 9 c 17
VPR Alveolar Ventilation b 1.95 c 1.36 18 c 9
Perfusion Ratio.
Tissue Blood Flows (fraction
of cardiac output):
QgiC GI Tract.................... 0.195 c 0.12 10 c 13
QliC Liver....................... 0.070 c 0.04 35 c 23
QfatC Fat......................... 0.050 c 0.05 30 c 15
QppC Poorly Perfused Tissues..... 0.240 c 0.46 15 c 10
QwpC Well Perfused Tissues....... 0.445 c, d 0.26 20 c, d 7
QmarC Bone Marrow................. NA c 0.07 NA c 45
Tissue Volumes (fraction of
body weight):
VgiC GI Tract.................... 0.045 0.017 10 8
VliC Liver....................... 0.023 0.026 5 8
VfatC Fat......................... 0.160 0.187 30 12
VppC Poorly Perfused Tissues..... 0.480 e 0.483 30 e 5
VwpC Well Perfused Tissues....... 0.033 0.047 10 7
VluC Lung........................ 0.006 0.008 10 12
VmarC Bone Marrow................. NA 0.050 NA 8
Equilibrium Partition
Coefficients:
Pblo Blood:Air................... 12.9 16.5 15 2
Pgi GI Tract:Air................ 12.0 13.5 30 31
Pli Liver:Air................... 37.4 13.6 20 34
Pfat Fat:Air..................... 117.0 81.2 30 13
Ppp Poorly Perfused Tissues:Air. 10.0 13.3 10 14
Pwp Well Perfused Tissues:Air... 12.0 13.0 20 14
Plu Lung:Air.................... 10.6 9.1 30 32
Pmar Bone Marrow:Air............. NA 51.2 NA 35
Metabolic Parameters:
VmaxC Maximum metabolic velocity 75.2 94.2 30 12
of MFO saturable pathway
(mg/hr/kg__liver).
Km Affinity of MFO saturable 0.4 0.49 50 35
pathway (mg/l).
KfC First order rate constant 1.5 1.82 50 24
for GST pathway (l/hr/kg-
0.25).
A1 Ratio of lung to liver in- 0.015 0.03 70 69
vitro MFO metabolic
velocities (nmol/min/
gm__lung__micros. Prot)/
(nmol/min/
gm__liver__micros.Prot).
A2 Ratio of lung to liver in- 0.18 0.45 70 71
vitro GST metabolic
velocities (nmol/min/
gm__lung__cytos.Prot)/
(nmol/min/
gm__liver__cytos.Prot).
B1 Ratio of lung and liver 1.0 0.31 0 8
tissue content of
microsomal protein.
B2 Ratio of lung and liver 1.0 0.84 0 14
tissue content of cytosolic
protein.
Sp__Kf Allometric scaling power for -0.25 -0.267 0 22
body weight scaling of KFC
from mice to humans.
----------------------------------------------------------------------------------------------------------------
Notes: (a) value computed for 70 kg human; (b) unitless; (c) posterior distributions adjusted for effects of
light activity; (d) functionally defined as 1--sum(other fractional flows); (d) functionally defined as 0.82--
sum(other fractional volumes); (NA) not applicable.
i. Alternative analysis using the ``parallelogram'' approach.
Andersen et al. [Ex. 21-94] estimated a human first order rate constant
(Kf) for glutathione (GST) metabolism of MC in the liver by allometric
scaling of a fitted estimate of an in vivo mouse rate constant
(KfCmouse). Specifically,
[GRAPHIC] [TIFF OMITTED] TR10JA97.009
where spKf was the allometric scaling power with value -0.25. In their
Monte Carlo analysis, Clewell et al. followed the approach of Andersen
et al., treating KfCmouse as a lognormally distributed random
variable and spKf as a known constant. The Bayesian analysis summarized
above also made use of the allometric scaling given by the equation
above, but prior probability distributions were specified for both
KfCmouse and spKf.
Reitz et al. (1988, 1989) [Exs. 7-225 and 21-53] proposed an
alternative approach for estimating an apparent in vivo human Kf. The
approach, referred to as the ``parallelogram method,'' assumes there is
a constant proportionality across species between in vitro and apparent
in vivo metabolic rates when normalized for substrate concentration
([S]). For example, the equation modeling the apparent in vivo rate of
GSH conjugation (dMGST/dt) is given by:
[GRAPHIC] [TIFF OMITTED] TR10JA97.010
The constant proportionality between apparent in vivo rates of
metabolism and in vitro rates implies
[[Page 1553]]
[GRAPHIC] [TIFF OMITTED] TR10JA97.011
where [V/S]GST denotes an in vitro enzymatic rate normalized to
[S] and kp the in vivo--in vitro proportionality constant. This
approach assumes a common value of kp across species, such that
knowledge of a [V/S]GST-rodent and Kfrodent (sufficient to
estimate a value for kp as the ratio of Kfrodent to [V/
S]GST-rodent)
and knowledge of [V/S]GST-human
is sufficient to estimate the remaining corner of a parallelogram,
namely Kfhuman. Therefore, this approach assumes,
[GRAPHIC] [TIFF OMITTED] TR10JA97.012
or:
[GRAPHIC] [TIFF OMITTED] TR10JA97.013
Reitz et al. [Ex. 21-53] obtained an estimate for Kfhuman
using the parallelogram method that was very similar to the estimate
obtained by Andersen et al. [Ex. 21-94] using allometric scaling.
However, Reitz and coworkers estimated a mean [V/S]GST-human based
on liver samples from only four human subjects--three of which had
appreciable enzymatic activity and one with no detectable activity.
More recent publications (Bogaards et al., 1993 [Ex. 127-16]; Graves et
al., 1995 [Ex. 122]) and unpublished data (Green et al., 1987 [Ex. 14])
provide measured values of [V/S]GST on another 35 human subjects.
These additional data demonstrate considerable variation in rates of
GST metabolism among human subjects, consistent with a known human
polymorphism for GST, described earlier in this Quantitative Risk
Assessment. Moreover, these data indicated that, putting aside
questions of interlaboratory comparability of measurements, three of
the four human samples used by Reitz et al. had GST metabolic rates
among the highest reported to date. Consequently, the mean [V/
S]GST-human used by Reitz and coworkers was greater than the mean
estimable from the full complement of data on human GST activity.
Since OSHA was interested in assessing the effect of accounting for
the full complement of data on human GST activity on estimates of
cancer risk, this additional analysis was performed, despite the
Agency's reservations concerning the appropriateness of using the
parallelogram approach in the MC risk assessment. Although this
approach allows the use of all of the available data, the uncertainties
in the ratio of in vitro to in vivo metabolic constants raise serious
questions for the utility of this analysis. OSHA is presenting this
analysis for purposes of comparison and notes that HSIA and Clewell
used allometric adjustments in their final PBPK models.
The use of a Kfhuman derived by the parallelogram method
required: (1) modification of the human PBPK model; (2) specification
of a prior probability distribution for Kfhuman; (3) replication
of the Bayesian analysis of the human in vivo open chamber data using
the new prior for Kfhuman; (4) simulation of the occupational
exposure scenario using the joint posterior distributions from the new
Bayesian analysis to obtain a posterior distribution for human GST lung
metabolism; and (5) re-estimation of the extra cancer risk.
(1) PBPK Model Modifications. The only structural modification to
the PBPK models was to replace the parameter for allometric scaling of
Kfmouse with a direct insert of a model parameter Kfhuman,
having its own prior probability distribution.
(2) Prior Probability Distributions. Mouse prior probability
distributions were unchanged. Prior probability distributions for human
model parameters were also unchanged, with the exception of prior
distributions for KfC, spKf and A2. Prior probability distributions for
KfC and spKf were replaced with a prior probability distribution for
Kfhuman. The prior probability distribution for A2 was modified to
account for additional data on human lung GST activity submitted to
OSHA by HSIA [Ex. 122].
The prior probability distribution for Kfhuman was derived
using the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.014
where errkp is an error term added to account for uncertainty in
estimating the proportionality constant kp, as kmouse. Thus,
to derive a prior probability distribution for Kfhuman, it was
necessary to derive prior distributions for Kfrodent, [V/
S]GST-rodent, [V/S]GST-human and errkp, which in turn
were propagated using Monte Carlo techniques in accordance with the
relationships specified by the equation above.
(i) Prior distribution for rodent Kf. The posterior probability
distribution used in the main analysis for the apparent in vivo rodent
KfC parameter was used as the basis for a prior probability
distribution for Kfrodent. The posterior distribution was well
described by a truncated lognormal distribution with a mean and
standard deviation of 1.8 and 0.43 l/hr/bw /-0.25, and lower and
upper truncations at 0.84 and 3.07 l/hr/bw /-0.25, respectively.
The posterior distribution was converted to units of (hour) -1 by
using Monte Carlo techniques to multiply the truncated lognormal by the
scalar, (rodent body weight) -0.25.
(ii) Prior for rodent liver GST [V/S]. A prior probability
distribution for a low dose mouse [V/S]GST was obtained as the
ratio of the fitted estimates of in vitro Vmax and Km
reported by Reitz et al. for liver glutathione conjugation of MC. The
fitted estimates of Vmax and Km and their associated standard
errors were used to set the parameters for normal distributions. Monte
Carlo techniques were used to obtain the ratio of these two
distributions (i.e., Vmax/Km), under the assumption that the
joint sample space for Vmax and Km was correlated with a
= 0.9. Correlation was induced because a reanalysis of the
mouse in vitro reported in Reitz et al. showed that the joint parameter
space for these two fitted parameters was highly correlated.
(iii) Prior distribution for human GST [V/S]. There were four data
sets reporting measured values of in vitro GST activity in liver
samples from 39 human subjects. These data reflect work from different
laboratories using (in some cases) different assay methods and
different substrate concentrations. In order to make use of all the
data to estimate central tendencies and population variability, it was
necessary that all measurements be placed on a common scale.
With respect to assay methods, two of the studies [Exs. 21-53 and
122] reported measured values of [V/S]GST based on detection of
[36]Cl from labelled MC. The other two studies [Exs. 14 and 127-16]
reported values of [V/S]GST based on detection of formaldehyde, a
known decomposition product from GSH conjugation with MC. In a
comparison of these two methods, Green et al. [Ex. 14] reported results
indicating a systematic difference in measured values of [V/S]GST,
with the [36]Cl detection method appearing to give estimates
approximately 1.7-fold higher than the formaldehyde detection method.
In this analysis, the [36]Cl method was chosen as the common scale,
since the mouse [V/S]GST data used above were based on this
method. Thus, the formaldehyde assay results were multiplied by 1.7 to
put them on the [36]Cl scale.
Adjustments for both substrate concentration and nonlinear
metabolism were made by converting all the
[[Page 1554]]
reported in vitro velocity data, [V]GST, to Vmax/Km
ratios (i.e., low dose metabolic velocity), by the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.015
The above equation follows from assuming in vitro kinetics can be
reasonably modeled as a single-substrate Michaelis-Menton process
(i.e., [V]GST = {Vmax x [S]}/{Km + [S]}). In making
adjustments, assay specific substrate concentrations were used (i.e.,
[S], which ranged from 35 to 94 mM) along with the average estimate of
an in vitro Km reported by Reitz et al. [Ex. 21-53] in analysis of data
from two human subjects ( 44 mM). It is noteworthy that none of the
human in vitro [V/S]gst data reported in Reitz et al. were truly
reflective of linear kinetics, whereas the mice data were.
After the two above adjustments were made, a lognormal distribution
was fit to the transformed data yielding a GM of 0.031 l/min/mg
protein, and a GSD of 2.72. This distribution models intersubject
variability in in vitro metabolic activity. However, the prior
probability distribution for [V/S]gst-human should reflect
variation in means of six subjects, because the in vivo human data from
Dow Chemical Company reflect the averaged pharmacokinetic behavior of
tissue from six subjects. Thus, dispersion in the above distribution
was adjusted to give the corresponding sampling distribution for means
of n = 6.
(iv) Prior distribution for error term.
The in vivo and in vitro metabolic data on the MFO metabolic
pathway, reported by Reitz et al. [Ex. 21-53], were used to estimate
the uncertainty in assuming a constant kp across species. These
were the only data for which both in vivo and in vitro information was
available on several species and which was directly relevant to MC. To
avoid artifacts due to the very imprecise fitted estimates of apparent
in vivo Km's, in vivo / in vitro comparisons were constructed based on
estimates of Vmax alone. These estimates were then normalized by the
ratio obtained for mice, providing a measure of the error in using a
mouse ratio to estimate ratios in three other species: rats (1.42),
hamsters (0.64), and humans (0.41). The GM (0.72) and GSD (1.89) of
these three values were used to set parameters for a lognormal
distribution used as the prior probability distribution for errkp.
Note that the human value of 0.41 reflected an average of separate
estimates on four human subjects, with ratios ranging from 0.1 to 1.0.
(v) Monte Carlo simulation to obtain a prior for human Kf. The
above prior probability distributions for Kfmouse, [V/S]gst-
mouse, [V/S]GST and errkp were independently sampled by Monte
Carlo techniques (n = 5000) and combined to give a prior distribution
for Kfhuman for use in Bayesian analysis of the human open chamber
data.
(vi) Revised prior distribution for A2.
A2 is the ratio of in vitro GST enzymatic activity in lung tissue
to the same activity in liver tissue. In the main analysis, the prior
probability distribution for A2 was derived according to the equation:
[GRAPHIC] [TIFF OMITTED] TR10JA97.016
where errvivo/vitro is an error term to account for
uncertainty in using a ratio of in vitro activity to make inferences
about in vivo activity, and the data of Reitz et al. [Ex. 21-53] were
used to estimate prior distributions for [V/S]GST-lung and [V/
S]GST-liver. This prior distribution was revised to account for
additional human [V/S]GST-lung and [V/S]GST-liver data.
(vii) Prior for human lung GST [V/S]. Previously, only a single
measured value for [V]GST-lung from a pooled lung sample from two
human subjects was available for estimating A2. Mainwaring et al. [Ex.
124] recently submitted additional [V]GST-lung data to OSHA,
consisting of measured values on three additional human subjects (0.00,
0.06 and 0.21 nmol/min/mg protein). The value reported as 0.00 was
assumed equal to one-half the detection limit for the assay. Since
these new [V]GST-lung data were obtained using the formaldehyde
detection assay, it was necessary to transform the values to the [36]Cl
scale. Lacking direct information, it was assumed that the same HCOOH
[36]Cl correction factor derived for the liver data held for
the lung data. A correction for substrate concentration was also made,
under the assumption of equivalency in lung and liver in vitro Km's.
The resulting transformed [V]GST-lung data were used to construct
a prior probability distribution describing uncertainty in the mean of
five 1 observations (GM = 0.00082, GSD = 1.61). Note that, in this
case, an attempt was made to model pure uncertainty in a low dose [V/
S]GST-lung, without information indicating appreciable
heterogeneity in the ratio of lung and liver enzymatic activity within
an individual.
---------------------------------------------------------------------------
\1\ Since the single observation of [V]GST-lung reported by
Reitz et al. (1988) was from a pooled sample of lung tissue from two
human subjects, the data point was treated as two observations with
the same value.
---------------------------------------------------------------------------
(viii) Prior probability distribution for uncertainty in human
liver GST [V/S]. Because of the focus on uncertainty in A2, the prior
probability distribution for [V/S]GST-liver derived above was
modified to describe uncertainty about the mean, given a sample size of
39 subjects.
(ix) Uncertainty in using an in vitro ratio of lung and liver GST
activity to make an inference about the corresponding ratio for
apparent in vivo GST activity. A prior probability distribution for
errvivo/vitro was derived using data on in vivo and in vitro
ratios of liver MFO enzymatic activity for different species, as a
surrogate for intra-species lung versus liver GST enzymatic activity.
Thus, two key assumptions are made: (i) That relative enzymatic
activity for liver tissue from two species is a reasonable surrogate
for relative activities of lung versus liver tissue within a single
species, and (ii) that the degree of consistency in ratios of in vivo
versus in vitro enzymatic activity will be the same for either MFO or
GST mediated processes.
If the apparent in vivo Vmax for the MFO pathway in the lung was
modeled as:
[GRAPHIC] [TIFF OMITTED] TR10JA97.017
it follows that,
[GRAPHIC] [TIFF OMITTED] TR10JA97.018
where VmaxA denotes normalization of Vmax to unit tissue volume.
Although there were insufficient data to
[[Page 1555]]
allow for a direct evaluation of the above equation, the data tabulated
by Reitz et al. [Ex. 7-225] for MFO enzymatic activity in mice, rats
and hamsters did allow an evaluation of the equality,
[GRAPHIC] [TIFF OMITTED] TR10JA97.019
where the subscripts sp1 and sp2 denote species 1 and 2 (e.g.,
mouse and rat). Using the apparent in vivo Vmax and in vitro [V/S] data
reported in Reitz et al. [Exs. 7-225 and 21-53], it was possible to
compute mouse:rat, hamster:mouse and rat:hamster ratios for in vivo
Vmax and in vitro [V/S] as shown in table VI-11, below.
Table VI-11.--Interspecies Comparison of MFO Activity
------------------------------------------------------------------------
Ratios of MFO enzymatic
activity
------------------------------
Species ratio in
in vivo vitro Fold-
Vmax [V/S] Difference
------------------------------------------------------------------*-----
Rat: mouse............................... 0.49 0.36 1.36
Mouse: hamster........................... 1.20 0.79 1.53
Hamster: rat............................. 0.59 0.28 2.06
------------------------------------------------------------------------
* Ratio of values in in vivo Vmax column to values in in vitro [V/S]
column.
The assumption was made that the use of an in vitro ratio as a
surrogate for an in vivo ratio is unbiased (i.e., errvivo/vitro
should be centered on a value of 1). The mean of the three estimates of
fold-difference (1.65) is our best estimate of a GSD for errvivo/
vitro. Thus, the prior probability distribution for errvivo/vitro
was modeled as a lognormal variate with expected value 1.0 and GSD of
1.65.
(x) Monte Carlo simulation to obtain a prior probability
distribution for A2. The above prior probability distributions for [V/
S]GST-lung, [V/S]GST-liver and errvivo/vitro were independently
sampled by Monte Carlo techniques (n = 5000) and combined to give a
prior probability distribution for A2 for use in Bayesian analysis with
the human open chamber data. The resulting distribution was well
described as a lognormal variate with a GM of 0.236 and a GSD of 2.0.
(3) Human in vivo data and simulating occupational exposure.
Bayesian updating was performed with the same human in vivo data used
in the main analysis. These data consisted of time serial measurements
of exhaled breath and venous blood concentrations of MC for 6 human
volunteers exposed to 100 and 350 ppm MC for 6 hours. Unfortunately,
the data have only been reported as averages of the 6 subject-specific
observations at each time point. When simulating the human data,
subjects were assumed to be at rest (i.e., work load set equal to 0),
and the reported average body weight for the six subjects (86 kg) was
assumed to be known without error.
A single human occupational exposure was simulated: constant
exposure to 25 ppm MC for 8-hours per day and 5 days per week.
(4) Distribution of human metabolized dose and sensitivity
analysis. The distribution for GST metabolism in the human lung
resulting from simulated occupational exposure to 25 ppm MC had a
median and mean of 0.139 and 0.192 mg/day/liter lung, about 3-fold less
than values obtained using the allometrically scaled Kf.
From the sensitivity analysis, Kf and A2' exhibited the strongest
pairwise correlations with predicted lung GST metabolism, with all
other parameters having considerably smaller correlation coefficients.
Indeed, other than PC.mar (partition coefficient air:marrow), all other
parameters were only weakly correlated with GST lung metabolism. These
results differ somewhat from those obtained when using an
allometrically scaled Kf, and reflect the effect of greater variability
in a Kf based on the parallelogram method.
(5) Posterior distributions in the ``parallelogram method''
analysis. The posterior distributions for many model parameters were
considerably tighter than their corresponding prior distributions, most
notably for fractional blood flow and partition coefficient parameters.
Similar results were obtained in the main analysis. In general, medians
and %CVs of the posterior distributions were similar to those in the
main analysis, with the exception of Kf, which was expected, given its
revised prior distribution. However, differences among the posterior
distributions for Kf were less than expected due to an appreciable
shift toward larger values (and some tightening) in the posterior
distribution for the parallelogram-based Kf relative to its prior
distribution. Thus, it would appear that the data had some information
about plausible values of Kf.
The results of the covariance analysis indicated that the
covariance structure was fairly similar to the results from the main
analysis, with moderate to high pairwise correlations among 15 pairs of
parameters.
G. Results of OSHA's PBPK Risk Assessments; Discussion
Summary statistics for OSHA's main analysis modifying the other
analysis and the alternative (parallelogram) analysis are reported in
Table VI-12. From the main analysis, the MLE of excess cancer risk
obtained using the upper 95th percentile of the human internal dose
distribution was 3.62/1000, for an occupational lifetime exposure to 25
ppm MC. The MLE of cancer risk obtained using the mean of the human
internal dose distribution was 1.24/1000. The alternative
(parallelogram) analysis yielded slightly lower estimates of risk. In
that analysis, the MLE of cancer risk using the upper 95th percentile
of the human internal dose distribution was 1.23/1000. The MLE of
cancer risk for the alternative analysis using the mean of the human
internal dose distribution was 0.40/1000. After evaluating the
methodologies and uncertainties in the two analyses, OSHA determined
that the main analysis was most appropriate for the Agency's final risk
assessment and the MLE of cancer risk using the upper 95th percentile
of the human internal dose distribution was best supported as OSHA's
final MC risk estimate. Therefore, OSHA's final risk estimate for
occupational lifetime exposure to MC at 25 ppm is 3.62/1000.
Table VI-12.--Summary Statistics on Estimates of Extra Cancer Risk From Occupational Exposure to 25 ppm MC for 8 hrs/day, 5 days/wk for 45 years
--------------------------------------------------------------------------------------------------------------------------------------------------------
Summary statistics for distributions of extra risk
Computational approach ----------------------------------------------------------------------------------------------------------------------
95% ** Mean %CV * Skewness Kurtosis
--------------------------------------------------------------------------------------------------------------------------------------------------------
Maximum likelihood fitting: 3.62 *** per 1000..................... 1.24 per 1000......................... 103 2.2 10.2
Dependence case.
[[Page 1556]]
Maximum likelihood fitting: 2.43 per 1000......................... 0.79 per 1000......................... 113 2.3 11.3
Independence case..
--------------------------------------------------------------------------------------------------------------------------------------------------------
* %CV denotes coefficient of variation ([standard deviation/mean] x 100).
** 95% denotes the 95th percentile value of the distribution of GST matabolites for extra cancer risk.
*** OSHA's final risk estimate.
Figure VI-1 shows the end result of the main PBPK analysis: the
cumulative distribution function of excess lifetime cancer risk
(log10 scale) from exposure to 25 ppm MC, 8 hours per day, 5 days
per week for 45 years, when estimated using the MLE of the dose-
response parameters, GST lung metabolism as the dose surrogate, and a
human Kf based on allometric scaling and Bayesian prior information. As
described in the main analysis, the ``dependence case'' was used.
Several summary statistics can be discerned from this cumulative
distribution function: (1) the 95th percentile of this hybrid
distribution of uncertainty and heterogeneity gives a risk estimate of
3.62 x 10-3 (point ``A'' in the figure); (2) the mean value of the
distribution (point ``B'' in the figure) gives a risk estimate of 1.24
x 10-3.
BILLING CODE 4510-26-P
[[Page 1557]]
[GRAPHIC] [TIFF OMITTED] TR10JA97.020
BILLING CODE 4510-26-C
[[Page 1558]]
OSHA conducted the alternative analysis in order to determine the
impact of basing the human GST metabolite distribution on allometry
(human GST metabolic rates estimated based on the relative size of
animals and humans) versus the parallelogram approach (human GST
metabolic rates based on ratio of various rodent in vitro: in vivo
metabolic rates applied to human in vitro rates) on risk estimates. As
discussed in greater detail above, allometry predicts that one would
expect that humans have approximately seven-fold less GST activity than
mice. The parallelogram approach, on the other hand, predicts
approximately 18-fold less GST activity in humans than in mice. After
analyzing the available data, OSHA has determined that the allometric
assumptions are best supported by the scientific literature, primarily
because of the lack of human in vivo GST data and the lack of
validation of the parallelogram approach. The Agency has therefore used
that approach in its final (main) estimate of risk, but has also
presented an alternative analysis using the parallelogram methodology.
During the rulemaking, studies were submitted to the Agency by HSIA
challenging the relevance of the mouse data for estimating human cancer
risks. However, as described in detail previously, if one examines the
HSIA data critically, it is clear that the studies most likely could
not detect differences in metabolic activity (and hence in risk)
between mice and humans of the magnitude predicted by allometry. For
example, the lack of detection of an increase in DNA ss breaks in human
cells compared to mouse cells could be explained because the
methodology used could not detect an increase in ss breaks 7-fold
smaller than that observed in mice. Clearly, an 18-fold difference, as
predicted by the parallelogram method, would be even harder to detect.
Moreover, if the human in vitro data are examined more closely, it
becomes apparent that the in vitro: in vivo ratios calculated for the
35 individual humans who have been studied were as low as 4.6 (the
median value in this series was 24). Therefore, the use of allometry
(ratio = 7) or the parallelogram approach (ratio = 18) would lead to
risk estimates that clearly underestimate the risks for some
individuals. In addition, RNA adduct data [Ex. 126-25] indicate that
exposure of human cells to MC results in only a 3-fold lower amount of
RNA adducts than formed in mouse cells. This ratio may not be a close
surrogate for the GST ratio, but it does heighten concern that both
PBPK approaches may be underestimating cancer risks from occupational
exposure to MC, because humans may be appreciably less sensitive than
mice.
The distribution of risk presented in either the main or the
alternative analysis most closely reflects uncertainty about risk for
some randomly chosen worker (with respect to work intensity and body
weight), chosen among the population of workers with physiologic,
anatomic, and metabolic attributes similar to those of the average
subject from the Dow human study group. The Dow pharmacokinetic data
did not contain individual data on the 6 subjects, so the results
obtained and the predictions made are conditioned by the use of
averages. This means that the model is truly only applicable to people
who physiologically and biochemically resemble the Dow group of six
subjects. Although six subjects do not represent a large data base from
which to draw a representative PBPK sample, this is much more human
data than is usually available to base a risk assessment on. In fact,
in OSHA's preliminary quantitative risk assessment, point estimates
were used for body weight, breathing rates, etc. to represent the
entire working population with a single ``average'' number. Therefore,
this sample, although small, represents a significant improvement over
the point estimates of human parameter values for PBPK modeling.
Although these are the best data available, the small number of
individuals upon which the human parameter values are based increases
concern that the Agency may be underestimating risks for a significant
portion of the working population by relying upon these values and
using PBPK modeling to estimate human internal doses. OSHA considered
making an ad hoc inflation of the variance of the distributions of
human GST enzyme kinetics parameters in order to account for some of
this unmeasured heterogeneity (as recommended by the NAS Committee
report discussed above), but decided not to make this ``conservative''
choice but instead to rely on the unadjusted analyses.
OSHA has chosen for its final risk estimate to couple one measure
of central tendency (the MLE of the dose-response parameters) with a
somewhat ``conservative'' measure (the 95th percentile of the
distribution of human GST metabolites (internal dose)). Congress and
the courts have permitted--indeed, encouraged--OSHA to consider
``conservative'' responses to both uncertainty and human variability.
The OSH Act addresses the latter when it refers, for example, to OSHA's
responsibility to set standards such that ``no employee shall suffer
material impairment of health* * *;'' a standard that only considered
risk to the average employee clearly would not be responsive to the
statute. Similarly, the 1980 ``Benzene decision'' affirmed that ``the
Agency is free to use conservative assumptions in interpreting the data
with respect to carcinogens, risking error on the side of over-
protection rather than under-protection.''
In past rulemakings, OSHA has frequently estimated carcinogenic
potency via the MLE of the multistage model parameters. The Agency has
recently received comments, particularly in a public meeting in
February 1996 on risk assessment issues surrounding the first phase of
its ``PEL Update'' process, critical of the MLE on the grounds that
this estimator can be highly unstable with respect to small
fluctuations in the observed bioassay response rates. Although OSHA may
in the future move to a different estimator, such as the mean value of
the likelihood function of the multistage model parameters, such a
change would have neglible practical impact in the case of MC. The
observed data in the NTP mouse bioassay follow a nearly precisely
linear trend, so the MLE, mean and UCL estimates are all very nearly
equivalent to each other.
However, OSHA needs to take particular care not to underestimate
risk when it departs from a relatively simple methodology (in this
case, the assumption that administered dose is the most relevant
measure of exposure) in favor of a relatively more complex and
computationally- intensive methodology (in this case, that the human
lung GST metabolite, calculated via a PBPK model, is the most relevant
measure of exposure). This is even more important in this particular
PBPK analysis, because the variance of the output distributions
represents an unknown hybrid of uncertainty in the various parameters
and true heterogeneity among the humans exposed to MC. As Clewell
stated with respect to his own PBPK analysis (see discussion above),
the 95th percentile estimator provides a modicum of assurance that the
risk to the average human--and hence the population risk--is not
underestimated.
Moreover, it is critical to use an estimator other than the central
tendency here so that it will not be inevitable that the risk to a
human of above-average susceptibility (due to enzyme kinetics that
produce relatively more reactive metabolite per unit of administered
dose, or due to other attributes related to body weight, organ
[[Page 1559]]
volumes, partition coefficients, etc.) is not underestimated,
potentially by a substantial amount. Any ``conservatism'' introduced by
using the 95th percentile of the PBPK output distribution is further
attenuated by the unmeasured model uncertainty inherent in this more
complex model structure. Several aspects of the model itself are known
to be oversimplifications (e.g., assuming the lung is the only tissue
at risk); therefore, the resulting risk distributions could be biased
downward.
Finally, it is important to note that there is no risk of
``cascading conservatism'' with this 95th percentile estimator; the
individual model parameters are permitted to vary over their entire
ranges, and the selected percentile is only applied to the distribution
resulting from the combined influence of all parameters. Furthermore,
the newest refinements to the model ensure that the 95th percentile is
not affected by any probability assigned to impossible combinations of
parameters. The attention paid to issues of mass balance, covariance
structure and truncation ensures that this percentile represents a
fully plausible set of input parameters. In sum, the combination of the
MLE of the multistage parameters and the 95th percentile of the PBPK
output distribution represents a reasonable attempt to account for
uncertainty and variability without unduly exacerbating the magnitude
or the probability of underestimation of errors.
H. Comparison of Animal-Based Risk Estimates With ``Non-Positive''
Epidemiology Data
Direct comparisons between animal bioassays and human
epidemiological studies are difficult to make because experimental
protocols between animal and human studies differ substantially.
Animals are generally exposed to a fixed dose of a chemical, for
several hours per day, from approximately 6-8 weeks of age until study
termination, which is usually at 2 years. This would be chronologically
equivalent to a human exposure that starts when a human is
approximately 4-5 years old and continuing until the human is
approximately 74 years old (assuming a 74 year average life-span for
humans) [Ex. 89]. This clearly differs from the typical pattern of
occupational exposure encountered in epidemiological studies of worker
populations. For example, in the Kodak cohort, the workers were never
exposed to a constant level of MC; exposure to MC for these workers did
not start until their adult life; and most of them were exposed to the
chemical for less than one third of their life-span.
Exposure to MC has been found to induce lung and liver cancer in
mice and mammary tumors in rats. As discussed above, there are positive
epidemiology studies which suggest an association between MC exposure
and cancer risk. Because exposure data are inadequate or unavailable,
it is not possible to quantify the risks in these studies. OSHA
acknowledges that there are also non-positive epidemiology studies.
In 1986, Crump analyzed the preliminary results from the 1964-70
Kodak cohort followed through 1984 and compared them to the rodent
bioassay results. The results from the Kodak epidemiological study have
also been used by Tollefson et al. [Ex. 7-249], Hearne [Ex. 91-D], and
NIOSH to compare the predictions of excess cancer risk from the animal
risk assessment models. In addition, Hearne used data from the
cellulose triacetate fiber study in Cumberland, Maryland, and a
different analytical approach, to validate the excess cancer risk
predicted by the animal data [Ex. 91-D]. The details of these analyses
can be found in the cited exhibits. OSHA has analyzed the different
approaches to assessing the mouse bioassay in light of the epidemiology
data and has determined that the approach taken by NIOSH (summarized
below) represents the most comprehensive and clearest way to examine
those data. OSHA also agrees with the conclusions reached by NIOSH,
that the epidemiology results and the mouse bioassay data are not
inconsistent with each other.
NIOSH compared the confidence intervals for the standardized
mortality ratios (SMRs) from the Kodak study with the predicted
confidence intervals derived from OSHA's risk assessment models from
the NPRM [Ex. 89]. To estimate predicted SMRs using the multistage
model, NIOSH used the following approach:
1. The expected excess number of deaths in each of the exposure
groups was derived by multiplying the number of workers in each
exposure group by the excess risk as determined by the multistage
model (after correcting for dose equivalence between animals and
humans, and differences in length of follow-up).
2. This number of expected deaths, derived from the animal data,
was then added to the expected (denoted Ep) number of deaths
which were derived from the Kodak study, after correcting for the
HWE, (this can be viewed as the background risk) to estimate the
number of ``observed'' deaths that would have been predicted by the
multistage model assuming it was valid for humans (denoted Op).
3. Op was then divided by Ep to calculate predicted
SMRs and 95% confidence intervals, where calculated.
NIOSH's results indicated that the non-positive findings from the
Kodak study were not inconsistent with the predicted risk estimates in
OSHA's risk assessment. The predicted confidence intervals from the
animal multistage model were completely nested within the observed
confidence intervals from the Kodak study. This is not to suggest that
results from this non-positive epidemiology study are equivalent to the
positive results from the animal inhalation study. Rather, based on
these findings, one can conclude that the non-positive results from the
Kodak epidemiologic study were not of sufficient power to contradict
risk predictions of the multistage model developed from the animal
bioassay data (when appropriate adjustments for differences in study
protocol were taken into account).
Basically, the Kodak study examined approximately 1000 workers
whose average MC exposure was 26 ppm. Therefore, the animal-based
potency estimates would predict only about 3 excess cancer deaths in
that cohort (the risk at 26 ppm is approximately 3 per 1000), even if
they were followed for many decades after exposure ceased. This small
predicted excess is clearly too small an increment to be observable
with statistical confidence, considering the much larger background of
cancer present in the human population. The differences between the
NIOSH and Hearne analyses essentially represent different ways to
estimate the ``signal-to-noise'' ratio for the Kodak study; OSHA
believes that any reasonable method of estimating this ratio would
conclude that the Kodak study has insufficient power to rule out a
``signal'' of significant human risk.
NIOSH's approach for adjusting for the healthy worker effect (HWE)
was criticized in the comments to the record submitted by Hearne.
Hearne stated that the HWE is unlikely to be present in long term
cancer studies and therefore an adjustment for the HWE is not necessary
[Ex. 91-D]. Hearne argued that since the HWE diminishes with time, the
healthy worker effect would have been minimal in the 1946-70 Kodak
cohort because the median follow-up period was 32 years and that only
20% of the cohort members were still actively employed [Tr. 10/15/92].
There is evidence in the literature showing that the HWE can be
weaker for some types of cancer than for other causes of death;
however, in this case NIOSH believed and OSHA agreed that the
difference between control and
[[Page 1560]]
exposed populations reflected an HWE for cancer. In addition, results
from a similar analysis done by NIOSH without the HWE adjustment did
not contradict the results including the HWE adjustment. NIOSH
testified [Tr. 985-6, 9/21/92] that there would be a difference in the
results obtained when adjusting for HWE and the unadjusted results.
However, the conclusions reached would not be different. In other
words, the analysis still supported the conclusion that the
epidemiologic and mouse bioassay results were not inconsistent with
each other. OSHA supports NIOSH's position on the use of an adjustment
factor for HWE in this cohort. Other criticisms of NIOSH's approach can
be found in the hearing transcripts and post-hearing comments. OSHA has
evaluated these methodological criticisms and has determined that NIOSH
used the best available methodology in analyzing this issue and that
their conclusions are supported by those arrived at independently by
Crump and by Tollefson et al.
Specifically, NIOSH predicted 23.25 deaths from cancers (at all
sites) in the full cohort, after adjusting for the HWE. This value is
closer to the observed number (22) than is the unadjusted expected
number of deaths (29.61). Looking at lung cancer deaths separately,
NIOSH predicted 22.36 deaths for the entire cohort (adjusted for HWE)
compared with 22 observed and 28.67 expected by Hearne. Hearne observed
no deaths from liver cancer in the entire cohort (1.14 deaths were
expected). NIOSH predicted 0.88 deaths from liver cancer when they
adjusted for the HWE.
OSHA believes that NIOSH's approach in comparing results from an
animal bioassay to those of an epidemiological study is the most
reasonable comparison between data sets because it is more accurate and
better addresses computational and experimental issues inherent in the
data sets. The Agency has evaluated the extent to which the cancer risk
calculated using the human data is consistent with the cancer risk
calculated using animal data. Based on its review of those studies,
OSHA concluded that the human epidemiology results are not inconsistent
with the animal bioassays and has determined that the bioassays are the
appropriate basis for its quantitative risk assessment.
I. Conclusions
OSHA has determined that MC is a potential occupational carcinogen
and has conducted a quantitative risk assessment in order to estimate
human risks of cancer after occupational exposure to MC. The Agency
reviewed all of the human and animal data on MC and determined that MC
is carcinogenic in mice and in rats, causing tumors at multiple sites,
in both species, and in both sexes of animals. Some epidemiologic data
also indicate an association between MC exposure and excess cancer in
exposed workers (statistically significant increases in biliary cancers
in textile workers and astrocytic brain cancer in workers exposed to MC
in solvent applications). Mechanistic data indicate that MC is likely
to be metabolized to a genotoxic carcinogen. MC has been clearly shown
to be metabolized by similar enzymatic pathways in rodents and humans,
indicating that the metabolic processes which produce cancer in mice
and rats are also present in humans. Finally, no data have been
presented which demonstrate that the mouse is an inappropriate model
for humans because of a physiological or biochemical component or
process. Therefore, the Agency has determined that it is appropriate to
assess the carcinogenic risks of MC using the NTP mouse bioassay dose-
response.
The NTP mouse MC bioassays demonstrated a clear dose-tumor response
relationship. OSHA determined that the NTP female mouse lung tumor
response was the best data set on which to base a quantitative analysis
because there was a clear dose-response, low background tumor incidence
and it represented the most sensitive tumor site/sex combination.
After examining the PBPK models submitted to the Agency, OSHA
concluded that PBPK modeling estimates of the amount of GST metabolites
produced are reasonable dose surrogates for MC and are supported by
substantial scientific evidence in the record. For that reason, OSHA
has used PBPK modeling in its final risk assessment. OSHA reviewed
methodologies used in PBPK models submitted to the Agency and decided
to modify and expand an existing model. Specifically, a Bayesian
analysis was conducted as described above. Use of the Bayesian model
analysis was a logical next step in development and use of
pharmacokinetic models for MC. It has great advantages in accounting
for the covariance of the PBPK parameters and incorporating
distributions of physiological parameters obtained from the scientific
literature. OSHA's final estimates of risk use the PBPK analysis
described above and are based on the MLE of the dose-response
parameters using the upper 95th percentile of the human internal dose
distribution. For an occupational lifetime exposure to 25 ppm MC, OSHA
estimates an excess risk of 3.6 MC-induced cancer deaths per 1000
workers.
VII. Significance of Risk
A. Introduction.
In the 1980 Benzene decision, the Supreme Court, in its discussion
of the level of risk that Congress authorized OSHA to regulate,
indicated its view of the boundaries of acceptable and unacceptable
risk. The Court stated:
It is the Agency's responsibility to determine in the first
instance what it considers to be a ``significant'' risk. Some risks
are plainly acceptable and others are plainly unacceptable. If for
example, the odds are one in a billion that a person will die from
cancer by taking a drink of chlorinated water, the risk clearly
could not be considered significant. On the other hand, if the odds
are one in a thousand that regular inhalation of gasoline vapors
that are 2 percent benzene will be fatal, a reasonable person might
well consider the risk significant and take the appropriate steps to
decrease or eliminate it. (I.U.D. v. A.P.I., 448 U.S. 607, 655).
So a risk of 1/1000 (10-3) is clearly significant. It
represents the uppermost end of a million-fold range suggested by the
Court, somewhere below which the boundary of acceptable versus
unacceptable risk must fall.
The Court further stated that ``while the Agency must support its
findings that a certain level of risk exists with substantial evidence,
we recognize that its determination that a particular level of risk is
significant will be based largely on policy considerations.'' The Court
added that the significant risk determination required by the OSH Act
is ``not a mathematical straitjacket,'' and that ``OSHA is not required
to support its findings with anything approaching scientific
certainty.'' The Court ruled that ``a reviewing court [is] to give OSHA
some leeway where its findings must be made on the frontiers of
scientific knowledge [and that] . . . the Agency is free to use
conservative assumptions in interpreting the data with respect to
carcinogens, risking error on the side of overprotection rather than
underprotection'' (448 U.S. at 655, 656).
Nonetheless, OSHA has taken various steps that make it fairly
confident its risk assessment methodology is not ``conservative'' (in
the sense of erring on the side of overprotection). For example, there
are several options for extrapolating human risks from animal data via
interspecies scaling factors. The plausible factors range from body
weight extrapolation (risks equivalent at equivalent body weights) to
(body
[[Page 1561]]
weight)2/3 (risks equivalent at equivalent surface areas).
Intermediate values have also been used, and the value of (body
weight)3/4, which is supported by physiological theory and
empirical evidence, is generally considered to be the midpoint of the
plausible values. (Body weight)2/3 is the most conservative value
in this series. Body weight extrapolation is the least conservative.
OSHA has generally used body weight extrapolation in assessing risks
from animal data, our approach which tends to be significantly less
conservative than the other methodologies and most likely is less
conservative even than the central tendency of the plausible values.
Other examples in OSHA's risk assessment methodology where the
Agency does not use a conservative approach are selection of the
maximum likelihood estimator to parameterize the dose-response function
rather than the upper 95% confidence limit, and the use of site-
specific tumor incidence rather than pooled tumor response in
determining the dose-response function for a chemical agent.
OSHA's overall analytic approach to regulating occupational
exposure to particular substances is a four-step process consistent
with recent court interpretations of the OSH Act, such as the Benzene
decision, and rational, objective policy formulation. In the first
step, OSHA quantifies the pertinent health risks, to the extent
possible, performing quantitative risk assessments. The Agency
considers a number of factors to determine whether the substance to be
regulated poses a significant risk to workers. These factors include
the type of risk posed, the quality of the underlying data, the
plausibility and precision of the risk assessment, the statistical
significance of the findings and the magnitude of risk [48 FR 1864,
January 14, 1983]. In the second step, OSHA considers which, if any, of
the regulatory options being considered will substantially reduce the
identified risks. In the third step, OSHA looks at the best available
data to set permissible exposure limits that, to the extent possible,
both protect employees from significant risks and are also
technologically and economically feasible. In the fourth and final
step, OSHA considers the most cost-effective way to fulfill its
statutory mandate by crafting regulations that allow employers to reach
the feasible PEL as efficiently as possible.
B. Review of Data Quality and Statistical Significance
The former OSHA standard for MC was designed to prevent irritation
and injury to the neurological system of the employees exposed to MC.
In 1985, the National Toxicology Program (NTP) released the results of
their MC rodent lifetime bioassays. Those results indicated that MC is
carcinogenic to rats and mice. As discussed in the Events Leading to
the Final Standard section, based on the NTP findings, EPA now
considers MC a probable human carcinogen, and NIOSH regards MC as a
potential occupational carcinogen and recommends controlling the
exposure to MC to the lowest feasible level. In 1988, ACGIH classified
MC as an industrial substance suspected of carcinogenic potential for
humans.
As discussed in the Health Effects section, OSHA has determined,
based on the NTP data, that MC is a potential occupational carcinogen.
This conclusion is supported by high-quality data in both rodent
species. Having determined, as discussed in the Quantitative Risk
Assessment section, that the NTP study provided suitable data for
quantitative analysis, OSHA performed quantitative risk assessments to
determine if MC exposure at the current PEL presents a significant
risk.
As discussed in the Health Effects and Quantitative Risk Assessment
sections, OSHA evaluated four MC rodent bioassays [Exs. 4-35, 4-25, 7-
29, 7-30, 7-31] to select the most appropriate bioassay as the basis
for a quantitative risk assessment. These bioassays were conducted in
three rodent species (rat, mouse, and hamster) using two routes of
administration (oral and inhalation). The NTP study (rat and mouse,
inhalation) was chosen for a quantitative risk assessment because it
provides the clearest toxicological and statistical evidence of the
carcinogenicity of MC [Exs. 12, 7-127] and because the studies were of
the highest data quality. In the NTP study, MC induced significant
increases both in the incidence and multiplicity of alveolar/
bronchiolar and hepatocellular neoplasms in male and female mice. In
rats, dose-related, statistically significant increases in mammary
tumors were also observed. OSHA chose the female mouse tumor response
as the basis of its quantitative risk assessment, because of the high
quality of data, the clear dose response of liver and lung tumors and
the low background tumor incidence. OSHA chose female mouse lung tumors
as the specific tumor site for its final quantitative risk assessment.
There is no a priori reason to prefer the mouse lung tumor response
over the liver tumor response because both data sets were of high
quality, showed a clear dose-response relationship and had low
background tumor incidence. In fact, in the NPRM, the Agency reported
estimates of risk generated using both sites. However, to reduce the
complexity of the final PBPK analysis, which required highly intensive
computations, OSHA chose one site (the female mouse lung tumor
response) for its final risk estimates. The risks calculated using the
female mouse liver response would likely be only slightly lower than
those calculated using the lung tumor response. On the other hand,
pooling the total number of tumor-bearing animals having either a lung
or liver tumor (or both) would have yielded risk estimates higher than
OSHA's final values.
Once the alveolar/bronchiolar neoplasms in female mice were chosen
as the most appropriate data set, the multistage model of
carcinogenesis was used to predict a lifetime excess risk of cancer
from occupational exposure to MC at several concentration levels. The
multistage model is a mechanistic model based on the biological
assumption that cancer is induced by carcinogens through a series of
stages. The model may be conservative, in the sense that it risks error
on the side of overprotection rather than underprotection, because it
assumes no threshold for carcinogenesis and because it is approximately
linear at low doses, although there are other plausible models of
carcinogenesis which are more conservative. The Agency believes that
this model conforms most closely to what we know of the etiology of
cancer. There is no evidence that the multistage model is biologically
incorrect, especially for genotoxic carcinogens, which MC most likely
is. OSHA's preference is consistent with the position of the Office of
Science and Technology Policy which recommends that ``when data and
information are limited, and when much uncertainty exists regarding the
mechanisms of carcinogenic action, models or procedures that
incorporate low-dose linearity are preferred when compatible with
limited information'' [Ex. 7-227].
In the NPRM, OSHA solicited comment and testimony on the
application of physiologically-based pharmacokinetic (PBPK) modeling to
refine the MC risk assessment. There was an intensive discussion of
pharmacokinetic issues during the hearings and in comments and briefs
submitted to OSHA. PBPK modeling is used to account for metabolic and
pharmacokinetic differences between rodents and humans and when
extrapolating from high experimental doses to lower occupational
exposures. OSHA has evaluated several risk assessments produced using
[[Page 1562]]
pharmacokinetic models. Discussion of the major issues surrounding the
use of PBPK in risk assessment can be found in the Quantitative Risk
Assessment section. Although serious questions remain concerning the
application of these models in the MC risk assessment, the Agency has
used the estimates generated via PBPK modeling as its final estimate of
the carcinogenic risk of MC exposure.
In accepting PBPK analysis, the Agency wanted to be able to utilize
all of the data available and appropriate for the analysis. OSHA was
also concerned that the uncertainties and inter-individual
variabilities in PBPK models were insufficiently quantified to allow
analysis of the impact of those uncertainties on the risk. Several
rulemaking participants have conducted sensitivity and uncertainty
analyses, the most extensive of which was that submitted by Mr. Harvey
Clewell on behalf of the U.S. Navy. These analyses show the impact of
the variability and uncertainty of the parameters which are used in the
PBPK model and suggest methods of quantifying the impact of that
uncertainty on the risk estimates.
OSHA has determined that the PBPK data are of sufficient weight to
warrant reliance on PBPK modeling to develop a risk estimate in the
specific case of MC, a chemical with more extensive information on
metabolism than exists for most other substances. To that end, OSHA
adopted a Bayesian approach in which all of the physiological and MC-
specific data could be used to generate a distribution of estimates of
the carcinogenic risks of MC. OSHA used the mean and the upper 95th
percentile estimator of the distribution of human PBPK parameters,
coupled with the maximum likelihood estimator of cancer potency, to
generate its final estimates of risks.
As discussed in more detail in the Health Effects Section above,
human data concerning the carcinogenicity of MC were presented in
several epidemiology studies. In a study of cellulose triacetate fiber
production (MC used as solvent) workers, an increased incidence of
liver/biliary cancer [Ex. 7-260] was noted. Although the case numbers
were small and the exposure information limited, this epidemiological
evidence is consistent with findings from animal studies and indicates
that there may be an association between human cancer risk and MC
exposure. A study of workers in photographic film production was non-
positive [7-163]. However, the exposures experienced by these workers
were likely to have been much less than those in the cellulose
triacetate fiber plant and, as discussed in the quantitative risk
assessment section, the study lacked the power to detect the magnitude
of the increase in cancer deaths that would have been predicted given
only the bioassay results. A case-control study conducted by the
National Cancer Institute showed a statistically significant
association between occupational MC exposure and development of
astrocytic brain cancer. Exposure levels could not be determined in
this study. The results of the epidemiological studies summarized here
were not inconsistent with the results of the animal-based cancer
potency estimate.
C. Material Impairment of Health
MC is a potential occupational carcinogen. Cancer is a material
impairment of health. OSHA has set the 8-hour TWA PEL primarily to
reduce the risk to employees of developing cancer.
The STEL of 125 ppm averaged over 15 minutes is primarily designed
to protect against MC's non-cancer risks. As discussed in the Health
Effects section, there are substantial risks of CNS effects and cardiac
toxicity resulting from acute exposure to MC and its metabolites. CNS
effects have been demonstrated in workers at concentrations as low as
175 ppm [Ex. 7-153] and a STEL of 125 ppm for 15 minutes would thus be
protective against the CNS effects described. Metabolism of MC to CO
increases the body burden of COHb in exposed workers. Levels of COHb
above 3% COHb may exacerbate angina symptoms and reduce exercise
tolerance in workers with silent or symptomatic heart disease. Smokers
are at higher risk for these effects because of the already increased
COHb associated with smoking (COHb ranges from 2 to 10% in most
smokers). Limiting short term exposure to 125 ppm for 15 minutes will
keep COHb levels due to MC exposure below the 3% level, protecting the
sub-population of workers with silent or symptomatic heart disease and
also limiting the additional COHb burden in smokers.
In addition to protecting against CNS and cardiac effects, there is
evidence that reducing the GST metabolite production by reducing short
term exposure to high concentrations of MC may also lower the cancer
risk. This is because metabolism by the MFO pathway (not generally
believed to be associated with carcinogenesis) appears to saturate
beginning around 100 ppm. This means that exposure to higher
concentrations of MC would lead to increased metabolism by the GST
pathway (the putative carcinogenic pathway) and therefore, greater than
proportionally increased risk.
All of the health effects averted by reducing MC exposure are
potentially or likely to be fatal, and this clearly represents
``material impairment of health'' as defined by the OSH Act and case
law.
D. Risk Estimates
OSHA's final estimate of excess cancer risks at the current PEL of
500 ppm (8-hour TWA) is 126 per 1000. The risk at the new PEL of 25 ppm
is 3.62 per 1000. The risk at 25 ppm is similar to the risk estimated
in OSHA's preliminary quantitative risk assessment based on applied
dose of MC on a mg/kg/day basis (2.3 per 1000 workers) and clearly
supports a PEL of 25 ppm. Risks greater than or equal to 10-\3\ are
clearly significant and the Agency deems them unacceptably high.
However, OSHA did not collect the data necessary to document the
feasibility of a PEL below 25 ppm across all affected industry sectors,
and so the Agency has set the PEL at 25 ppm in the final rule. OSHA
intends in the future to gather more information pertaining to the
feasibility of lower PELs.
E. ``Significant Risk'' Policy Issues
Further guidance for the Agency in evaluating significant risk and
narrowing the million-fold range provided in the ``Benzene decision''
is provided by an examination of occupational risk rates, legislative
intent, and the academic literature on ``acceptable risk'' issues. For
example, in the high risk occupations of mining and quarrying, the
average risk of death from an occupational injury or an acute
occupationally-related illness over a lifetime of employment (45 years)
is 15.1 per 1,000 workers. The typical occupational risk of deaths for
all manufacturing industries is 1.98 per 1,000. Typical lifetime
occupational risk of death in an occupation of relatively low risk,
like retail trade, is 0.82 per 1,000. (These rates are averages derived
from 1984-1986 Bureau of Labor Statistics data for employers with 11 or
more employees, adjusted to 45 years of employment, for 50 weeks per
year).
Congress passed the Occupational Safety and Health Act of 1970
because of a determination that occupational safety and health risks
were too high. Congress therefore gave OSHA authority to reduce
significant risks when it is feasible to do so. Within this context,
OSHA's final estimate of risk from occupational exposure to MC at the
current 8-hour TWA PEL (126 per 1000) is substantially higher than
other risks
[[Page 1563]]
that OSHA has concluded are significant, is substantially higher than
the risk of fatality in some high-risk occupations, and is
substantially higher than the example presented by the Supreme Court.
Moreover, a risk of 3.62 per 1000 at 25 ppm is also clearly
significant; therefore, the PEL must be set at least as low as the
level of 25 ppm documented as feasible across all industries.
Further, applying the rationale of the Benzene decision, the other
risk assessments presented by OSHA and the risk estimates presented by
rulemaking participants, including the HSIA (see Table VII-1, below),
all support OSHA's conclusion that the human cancer risk for employees
exposed to MC above 25 ppm as an 8-hour TWA is significant.
Table VII-1.--Lifetime Excess Risk Estimates (per 1000) From Occupational Exposure Based on Female Mouse Lung
Tumor Data
----------------------------------------------------------------------------------------------------------------
MLE (UCL)**
Model -----------------------------------------------------------------------------
25 ppm 50 ppm 500 ppm
----------------------------------------------------------------------------------------------------------------
OSHA NPRM Risk Assessment (mg/kg/ 2.32 (2.97)............... 4.64 (5.92).............. 45.5 (57.7)
d, BW extrapolation) without PBPK
Adjustment.
PPM to PPM extrapolation without 11.3 (14.4)............... 22.4 (28.5).............. 203 (251)
PBPK Adjustment.
PBPK Reitz female mouse lung-- 0.43 (0.53)............... 0.93 (1.17).............. 14.3 (17.9)
Reitz human (HSIA assumptions).
PBPK Reitz female mouse lung-- 0.81 (1.02)............... 1.69 (2.12).............. 15.0 (18.7)
Dankovic average human (NIOSH
assumptions).
PBPK Clewell female mouse lung-- 0.91 (1.14)............... 1.88 (2.36).............. 27.5 (34.2)
Clewell human (Navy assumptions)*.
OSHA Final Risk Assessment (female 3.62...................... 7.47..................... 125.8
mouse lung with PBPK).
----------------------------------------------------------------------------------------------------------------
*Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model.
**Maximum likelihood estimates are 95th percentile upper confidence limit (in parentheses) of the multistage
dose-response function.
In addition to being 100 to 1000 times higher than the risk levels
generally regarded by other Federal Agencies as on the boundary between
significant and insignificant risk (see, e.g., Travis et al., 1987),
and 1000 times higher than the ``acceptable risk'' level Congress set
in the 1990 Clean Air Act Amendments, the level of 10-3 is within
the range where economic studies document a marked nonlinearity. In
other words, individuals regard risks this high as qualitatively
different from ``smaller'' risks. Although risks below 10-3 are
not unambiguously significant, depending on the size of the affected
population, the benefits associated with the risky activity, and other
factors, this policy determination is not relevant to this regulation,
since OSHA's final risk estimate is substantially greater than 1 per
1000. Risks at or above 10-3 are always significant by any
empirical, legal or economic argument available.2
---------------------------------------------------------------------------
\2\ OSHA also conducted an alternative PBPK analysis that uses
all of the available human data on MC metabolism, despite the very
limited quantity of data available and the additional bias
introduced by adopting the ``parallelogram'' assumptions for
interspecies scaling (see Quantitative Risk Assessment for a
discussion of this analysis and the uncertainties and biases
therein). The risk estimate using this alternative method, 1.2 per
1000, is also unambiguously significant.
---------------------------------------------------------------------------
Because of the lack of documented feasibility data for potential
PELs of less than 25 ppm, OSHA has concluded that there is not enough
information available to support lowering the 8-hour TWA PEL or STEL
further at this time. However, OSHA has integrated other protective
provisions into the final standard to further reduce the risk of
developing cancer among employees exposed to MC. Employees exposed to
MC at the 8-hour TWA PEL limit without the supplementary provisions
would remain at risk of developing adverse health effects, so that
inclusion of other protective provisions, such as medical surveillance
and employee training, is both necessary and appropriate. The action
level will encourage those employers for whom it is feasible to do so
to lower exposures below 12.5 ppm to further reduce significant risk.
Consequently, the programs triggered by the action level will further
decrease the incidence of disease beyond the predicted reductions
attributable merely to a lower PEL. As a result, OSHA concludes that
its 8-hour TWA PEL of 25 ppm and associated action level (12.5 ppm) and
STEL (125 ppm) will reduce significant risk and that employers who
comply with the provisions of the standard will be taking reasonable
steps to protect their employees from the hazards of MC.
The Agency notes that even at the final PELs, the risks to workers
remain clearly significant. OSHA will be gathering information on the
risks of, and feasibility of compliance with, PELs less than 25 ppm, to
determine whether future rulemaking is appropriate in order to further
reduce the MC risks to employees.
VIII. Summary of the Final Economic Analysis
In its Final Economic and Regulatory Flexibility Analysis document,
OSHA addresses the significant issues related to technological and
economic feasibility and small business impacts raised in the
rulemaking process. The Final Economic Analysis is also OSHA's most
comprehensive explanation of the standard's practical impact on the
regulated community; in the Final Economic Analysis, OSHA explains in
detail the Agency's findings and conclusions concerning pre-standard
(baseline) conditions, such as exposure levels, in establishments in
the regulated community, and discusses how and why the requirements of
the standard are expected to eliminate significant risk to the extent
feasible. This document also sets forth OSHA's Final Regulatory
Flexibility Analysis and the analyses required by Executive Order
12866. This Federal Register preamble and the Final Economic Analysis
are integrally related and together present the fullest statement of
OSHA's reasoning concerning this standard. The Final Economic and
Regulatory Flexibility Analysis, together with supporting appendix
material, has been placed in the rulemaking docket for methylene
chloride (Ex. 129).
The purpose of the Final Economic Analysis is to:
Describe the need for a standard governing occupational
exposure to methylene chloride;
Identify the establishments and industries potentially
affected by the standard;
Evaluate the costs, benefits, economic impacts and small
business impacts of the standard on affected firms;
Assess the technological and economic feasibility of the
standard for affected establishments, industries, and small businesses;
Evaluate the availability of effective non-regulatory
approaches to the problem of occupational exposure to methylene
chloride; and
Present changes designed to reduce the impact of the
standard on small
[[Page 1564]]
firms while meeting the objectives of the OSH Act.
Need for the Standard
OSHA's final methylene chloride (MC) standard covers occupational
exposures to this substance, one of the most widely used of all organic
solvents, in general industry, construction, and shipyard employment.
In all, about 237,000 employees are estimated to be exposed to MC.
These workers are exposed to MC in many different ways, including the
manufacturing, formulation, distribution, and use of MC-containing
products. The most common uses of MC are in paint stripping, metal
cleaning, and furniture stripping.
Workers exposed to MC are at significant risk of developing cancer,
heart and liver effects, and central nervous system impairments, as
well as eye, skin, and mucous membrane irritation. Animal bioassays
have shown MC to be carcinogenic in mice and rats of both sexes, and
epidemiologic studies in workers have produced suggestive evidence of
its carcinogenicity in humans. Acute overexposure to the vapors of MC
can lead to central nervous system depression, respiratory paralysis,
and death: OSHA receives fatality reports every year involving workers
who have died using MC to perform such tasks as stripping floors and
removing paint. To protect all MC-exposed workers from these adverse
health effects, the final standard lowers the airborne concentration of
MC to which workers may be exposed from the current permissible
exposure limit (PEL) of 500 ppm as an 8-hour time-weighted average (8-
hour TWA) to 25 ppm, and from the Agency's current short-term limit of
1000 ppm as an acceptable ceiling, or 2000 ppm as an acceptable peak
above the acceptable ceiling for 5 minutes in any 2-hour period, to a
short-term exposure limit (STEL) of 125 ppm, averaged over 15 minutes.
(For a detailed discussion of the risks posed to workers by exposure to
MC, see the Quantitative Risk Assessment and Significance of Risk
sections of the preamble, above.)
OSHA's final MC standard is similar in format and content to other
health standards issued under Section (6)(b)(5) of the Act. In addition
to setting PELs, the standard requires employers to monitor the
exposures of workers; establish regulated areas when exposures may
reasonably be expected to exceed one of these PELs; implement
engineering and work practice controls to reduce employee exposures to
MC; provide respiratory protection to supplement engineering controls
where these are not feasible, are insufficient to meet the PELs, or in
emergencies; provide other protective clothing and equipment as
necessary for employee protection; make industrial hygiene facilities
(such as eyewash and emergency showers) available in certain
circumstances; provide medical surveillance; train workers about the
hazards of MC (as required by OSHA's Hazard Communication Standard);
and keep records relating to the standard. The contents of the standard
are explained briefly in Chapter I of the Final Economic Analysis and
in detail in the Summary and Explanation (Section X of the preamble,
below).
Chapter II of the economic analysis describes the uses of methylene
chloride and the industries in which such use occurs. Employee
exposures to MC are analyzed on the basis of ``application groups,''
i.e., groups of firms that use MC to perform a particular function,
such as metal cleaning or industrial paint stripping, regardless of the
particular industry in which the use takes place. The methodology used
by OSHA in the analysis is appropriate when a ubiquitous chemical like
MC is used to perform the same function in many kinds of firms in many
industries, because the processes used, employee exposures generated,
and controls in place or needed to achieve compliance are the same,
whether the process takes place in a machine shop, on board ship, or on
a construction site. For example, because the process of using MC to
strip paint or coatings from an object is essentially the same whether
the object being stripped is a spray paint booth, boat, church pew, or
automobile, and the exposures generated during the process are similar
in important respects, it is appropriate to analyze such activities as
a group. However, OSHA's technological feasibility and cost analyses
reflect the fact that job classifications and work processes may differ
within a given application group. Table VIII-1 shows the application
groups analyzed in the economic analysis, and the numbers of MC-using
establishments, MC-exposed workers, and estimated volume of MC handled
annually by establishments in each application group.
Table VIII-1.--Methylene Chloride Application Groups
----------------------------------------------------------------------------------------------------------------
Estimated Estimated Estimated
number of MC- Estimated number of MC handled
Application group using total exposed (millions
establishments employment * workers * of lbs)
--------------------------------------------------------------*-------------------------------------------------
Methylene Chloride Manufacturing..................... 4 1,664 84 469.20
Distribution/Formulation of Solvents................. 320 84,004 1,701 189.65
Metal Cleaning:
Cold Degreasing and Other Cold Cleaning: 23,717 901,232 94,537 32.56
Open-Top Vapor Degreasing.................... 278 27,105 608 14.87
Conveyorized Vapor Degreasing................ 45 2,920 75 1.13
Semiconductors............................... 239 217,960 1,392 0.40
Printed Circuit Boards....................... 141 77,795 298 13.98
Aerosol Packaging.................................... 52 4,142 520 25.21
Paint Remover Manufacturing.......................... 80 6,134 200 136.85
Paint Manufacturing.................................. 49 8,909 229 3.54
Paint Stripping:
Aircraft Stripping............................... 300 266,826 2,470 13.17
Furniture Stripping.............................. 6,152 23,592 7,872 23.26
Other Industrial Paint Stripping................. 35,041 2,312,721 46,605 59.36
Flexible Polyurethane Foam Manufacturing............. 100 9,800 600 50.32
Plastics and Adhesives Manufacturing and Use......... 3,487 1,186,040 10,481 41.90
Adhesive Production.............................. 165 56,254 497 ...........
Adhesive Use..................................... 1,753 596,291 5,269 ...........
Injection Molding................................ 80 27,211 240 ...........
[[Page 1565]]
Lamination....................................... 1,323 450,031 4,070 ...........
Mold Release..................................... 165 56,254 497 ...........
Ink Use:
Ink and Ink Solvent Manufacturing................ 15 2,010 58 3.68
Ink Solvent Use in Printing...................... 11,869 197,619 39,481 3.68
Pesticide Manufacturing and Formulation.............. 60 1,440 120 9.58
Pharmaceutical Manufacturing......................... 108 70,223 1,431 39.53
Solvent Recovery..................................... 34 932 137 32.10
Film Base Manufacturing.............................. 1 45,000 500 8.90
Polycarbonate Manufacturing.......................... 4 1,898 67 6.70
Construction......................................... 9,504 63,115 24,896 2.44
Shipyards............................................ 25 85,212 3,040 0.47
Total, all application groups.................. 91,624 5,598,293 237,496 **
----------------------------------------------------------------------------------------------------------------
* In most cases, the estimated number of establishments in each application group was based on the volume flow
of MC in 1990 divided by the estimated MC use per facility. The estimated number of establishments was
multiplied by the total number of employees per establishment and exposed employees per establishment as
reported in CONSAD's survey.
** Netting out rehandling, estimated total consumption equals 469.2 million pounds manufactured, minus 129.1
million pounds exported, + 19.3 million pounds imported, + 32.10 million pounds recovered from used solvent.
The column does not sum to 391.5 million pounds because non-consumptive uses such as production, distribution
and formulation, and solvent recovery are included.
Sources: CONSAD, HSIA, PRMA, Office of Regulatory Analysis.
In all, OSHA analyzed 28 application groups. These application
groups include, among others, methylene chloride manufacturing, paint
manufacturing, metal cleaning, polyurethane foam manufacturing,
plastics and adhesives manufacturing, ink use, pharmaceuticals, and
construction and shipyards. A total of 91,624 establishments are
estimated to be potentially affected by the standard. These
establishments employ a total of 5.6 million employees, of whom 237,496
are estimated to be exposed to MC in the course of their work. The
application groups with the largest numbers of directly exposed
employees are the Metal Cleaning, All Other Industrial Paint Stripping,
and Ink Solvent Use groups. In many facilities, MC is used only by a
small number of employees; the average number of MC-exposed employees
per establishment covered by the final rule is only 2.6 employees.
Chapter III of the analysis assesses the technological feasibility
of the final standard's requirements, and particularly its PELs, for
firms in the 28 application groups identified in the Industry Profile.
OSHA finds, based on an analysis of exposure data taken on workers
performing the MC-related tasks identified for each application group,
that compliance with the standard is technologically feasible for
establishments in every application group studied. With few exceptions,
employers will be able to achieve compliance with both PELs through the
use of engineering controls and work practices. The few exceptions are
certain maintenance activities, such as vessel cleaning, which have
traditionally involved the use of respiratory protection, and
operations in two applications where the supplemental use of
respirators may be necessary. These operations are centrifuge unloading
and dryer loading at one bulk pharmaceutical manufacturing facility
operated by Abbott Laboratories, and operations involving access to and
entering of the roll coating machine used by the Eastman Kodak Company
to make film base.
The exposure data relied on by OSHA in making its technological
feasibility determinations have been compiled in a database that
contains thousands of MC exposure results (see Appendix B of this
analysis) taken by OSHA compliance officers, consultation program
consultants, MC-using companies, and interested parties. These data
show that many facilities in many of the affected application groups
have already achieved the reductions in employee exposures required by
the final rule. In addition, the exposures of many employees in many
job categories in a number of the application groups have been reduced
to levels that are close to those required by the standard. OSHA's
analysis of technological feasibility analyzes employee exposures at
the operation or task level to the extent that such data are available.
In other words, the analysis identifies relevant exposure data on a
job-category-by-job category basis to permit the Agency to pinpoint
those MC-exposed workers and job operations that are not yet under good
process control and will thus need additional controls (including
improved housekeeping, maintenance procedures, and employee work
practices) to achieve compliance. Costs are then developed (see Chapter
V of the economic analysis) for the improved controls needed to reach
the new levels.
The benefits that will accrue to MC-exposed employees and their
employers are substantial and take a number of forms. Chapter IV of the
analysis describes these benefits, both in quantitative and qualitative
form. First, based on a physiologically-based pharmacokinetic (PBPK)
model, OSHA estimated that, if all 237,000 employees were exposed at
the existing 8-hour TWA exposure limit of 500 ppm for an occupational
lifetime of 45 years, a total of 29,862 excess cancer deaths would
occur, or 126 excess cancer deaths per 1,000 workers. If, however, the
237,000 employees were exposed to the final standard's PEL of 25 ppm
for 45 years, 8533 excess cancer deaths would be expected (3.6 per
thousand workers). However, few workers are currently being exposed to
500 ppm of MC as an 8-hour TWA. The actual exposure levels of most
affected workers are considerably lower, and, when these exposure
levels, rather than 500 ppm, are used as the baseline, the PBPK model
estimates that 1405 cancer deaths will be averted over a 45-year
period. By reducing the total number of MC-related cancer deaths from
1,804 deaths to 399 deaths over 45 years, the standard will
[[Page 1566]]
save an average of 31 cancer deaths per year. Table VIII-2 shows these
risk estimates.
Table VIII-2.--Lung Cancer Risk Over 45 Years for Workers Exposed At Current Exposure Levels and at the Levels Expected After Implementation of the Final Standard
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0-12.5 12.5-25 25 25-50 50-100 100-200 200-350 350-500 500+*** Total
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Lifetime Excess Cancer Risk (per thousand workers)*............. 0.91 2.71 3.60 5.53 11.98 28.45 61.75 104.44 125.78 ..................
Baseline Number of Workers Exposed.............................. 141,323 26,464 162 22,839 23,903 14,803 3,281 1,297 3,422 237,495
Estimated Excess Deaths in Baseline (Existing PEL)**............ 129 72 1 126 286 421 203 135 430 1,804
Predicted Number of Workers Exposed at New PEL.................. 159,825 28,441 49,229 0 0 0 0 0 0 237,495
Predicted Excess Deaths at New PEL**............................ 146 77 176 0 0 0 0 0 0 399
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*Based on OSHA's final estimate using the PBPK model, as presented in the Quantitative Risk Assessment section of the Preamble.
**Computed as level of lifetime risk times the number of exposed workers.
***For workers exposed to levels of greater than the current PEL of 500 ppm, the risk estimate is that associated with a lifetime exposure to 500 ppm.
Source: Office of Regulatory Analysis; OSHA; Department of Labor.
In addition to cancer deaths, the standard is estimated to prevent
3 deaths per year from MC's acute central nervous system and
carboxyhemoglobinemic effects. (Carboxy-hemoglobinemia is the inability
of the blood to carry sufficient oxygen to supply the heart muscle;
because methylene chloride interferes with the blood's ability to carry
oxygen, exposure to it places susceptible individuals, such as those
with silent cardiovascular disease, pregnant women, and smokers, at
greater risk.) OSHA receives reports every year of workers who have
succumbed to MC's acute CNS toxicity while they were engaged in such
tasks as floor stripping. For example, the Agency recently received a
fatality report on two young workers who died after pouring 14 gallons
of MC on a squash court they were refinishing. Both of these employees
lost consciousness, collapsed, and subsequently died of respiratory
failure. In addition, MC exposures above the level at which the final
rule's STEL is set--125 ppm--are also associated with acute central
nervous system effects, such as dizziness, staggered gait, and
diminished alertness, all effects that can lead to workplace accidents.
OSHA estimates that as many as 30,000 to 54,000 workers will be
protected by the final rule's STEL from experiencing CNS effects and
episodes of carboxyhemoglobinemia every year. Moreover, exposure to the
liquid or vapor forms of MC can lead to eye, skin, and mucous membrane
irritation, and these material impairments will also be averted by
compliance with the final rule. Finally, contact of the skin with MC
can lead to percutaneous absorption and systemic toxicity and thus lead
to additional cases of cancer that have not been taken into account in
the benefits assessment presented in Chapter IV of the Final Economic
Analysis.
The costs employers in the affected application groups are
estimated to incur to comply with the standard total $101 million in
1994 dollars. These costs, which are presented in Chapter V of the full
economic analysis, are annualized over a 10-year horizon at a discount
rate of 7 percent. Table VIII-3 shows annualized costs by provision of
the standard; the most costly
[[Page 1567]]
provisions are those requiring engineering controls, protective
clothing and eye protection, and medical surveillance for MC-exposed
workers. These three provisions together account for approximately 75
percent of the standard's compliance costs.
Table VIII-3.--Annualized Costs by Provision
------------------------------------------------------------------------
Annualized
Provision Costs
------------------------------------------------------------------------
Engineering Controls...................................... $38,773,642
Respirators............................................... 6,374,083
Monitoring................................................ 9,849,577
Protective Clothing and Eye Protection.................... 29,578,340
Emergency Eyewash and Shower.............................. 3,183,486
Medical Surveillance...................................... 7,986,493
Leak and Spill Detection Program.......................... 3,703,286
Regulated Areas........................................... 150,884
Recordkeeping............................................. 652,121
Training.................................................. 196,656
Understanding Regulation and Developing Training.......... 777,132
-------------
Subtotal............................................ 101,225,701
Costs of Substitution..................................... 237,336
-------------
Total............................................... 101,463,037
------------------------------------------------------------------------
Source: Office of Regulatory Analysis; OSHA; Department of Labor.
Table VIII-4 analyzes compliance costs by application group and
shows that the Cold Cleaning application group, which is in the larger
Metal Cleaning grouping, and the Furniture Stripping application group,
which is in the larger Paint Stripping category, will incur the largest
costs of compliance (though not necessarily the largest economic
impacts). These costs reflect the high exposures and relative lack of
control measures currently existing in many establishments in these two
application groups. In other words, because MC exposures are poorly
controlled in so many cold cleaning and furniture stripping facilities,
employers in these industries will be required by the standard to
implement control measures to protect their employees from the
significant risk of MC exposure.
Table VIII-4.--Annualized Costs by Methylene Chloride Application Groups
------------------------------------------------------------------------
Annualized
Application group costs
------------------------------------------------------------------------
Methylene Chloride Manufacturing.......................... 8,150
Distribution/Formulation of Solvents...................... 794,099
Metal Cleaning:
Cold Degreasing and Other Cold Cleaning................. 26,950,869
Open-Top Vapor Degreasing............................... 371,096
Conveyorized Vapor Degreasing........................... 97,253
Semiconductors.......................................... 247,666
Printed Circuit Boards.................................. 217,479
Aerosol Packaging......................................... 297,999
Paint Remover Manufacturing............................... 229,724
Paint Manufacturing....................................... 89,697
Paint Stripping:
Aircraft Stripping...................................... 8,148,754
Furniture Stripping..................................... 10,689,840
All Other Industrial Paint Stripping.................... 24,413,924
Flexible Polyurethane Foam Manufacturing.................. 4,252,861
Plastics and Adhesives Manufacturing and use.............. 5,417,950
Adhesive Production
Adhesive Use
Injection Molding
Lamination
Mold Release
Ink and Ink Solvent Manufacturing......................... 23,518
Ink Solvent Use........................................... 3,360,723
Pesticide Manufacturing and Formulation................... 106,060
Pharmaceutical Manufacturing.............................. 311,708
Solvent Recovery.......................................... 49,829
Film Base Manufacturing................................... 47,454
Polycarbonate Manufacturing............................... 4,651
Construction.............................................. 14,922,000
Shipyards................................................. 518,544
-------------
Total, all application groups....................... 101,463,037
------------------------------------------------------------------------
Source: Office of Regulatory Analysis; OSHA; Department of Labor.
Chapter VI of the economic analysis analyzes the impacts of
compliance costs on firms in affected application groups. The standard
is clearly economically feasible: on average, annualized compliance
costs amount only to 0.18 percent of estimated sales and 3.79 percent
of profits. For all but three application groups--polyurethane foam
blowing, furniture stripping, and construction--compliance costs are
less than 3 percent of profits, and for all but one application group--
furniture stripping--annualized compliance costs are less than 0.5
percent of the value of sales. Table VIII-5 shows average compliance
cost impacts across the many Standard Industrial Classification (SIC)
codes potentially involved in the application groups studied.
Table VIII-5.--Screening Analysis to Identify Possible Economic Impact
of the Final MC Standard
------------------------------------------------------------------------
Annualized costs of
Number of compliance
Application group establishments -------------------------
complying As percent As percent
of sales of profit
------------------------------------------------------------------------
Manufacture of MC............. 4 (*) 0.04
Distribution/Formulation of
Solvents..................... 320 0.04 0.55
Metal Cleaning:
Cold Degreasing and Other
Cold Cleaning............. 23,717 0.01 0.18
Open-Top Vapor Degreasing. 278 0.01 0.22
Conveyorized Vapor
Degreasing............... 45 0.02 0.35
Semiconductors............ 239 (*) 0.05
Printed Circuit Boards.... 141 0.02 0.41
Aerosol Packaging............. 50 0.01 0.13
Paint Remover Manufacturing... 80 0.02 0.06
Paint Manufacturing........... 49 0.01 0.04
Paint Remover Use (Paint
Stripping):
Aircraft Stripping (Large
Firms)................... 75 0.07 1.34
Aircraft Stripping ( Small
Firms)................... 225 0.08 2.12
Furniture Stripping....... 6,152 2.04 **39.40
[[Page 1568]]
All Other Industrial Paint
Stripping................ 35,041 0.01 0.11
Flexible Polyurethane Foam
Manufacturing................ 100 0.32 **9.23
Plastics and Adhesives
Manufacturing and Use........ 3,487 0.03 0.52
Ink and Ink Solvent
Manufacturing................ 15 (*) 0.03
Ink Solvent Use............... 11,869 0.03 0.05
Pesticide Manufacturing and
Formulation.................. 60 0.01 0.35
Pharmaceutical Manufacturing.. 108 (*) 0.03
Solvent Recovery.............. 37 0.05 0.85
Film Base..................... 1 (*) 0.01
Polycarbonates................ 4 (*) (*)
Construction.................. 9,504 0.35 **9.67
Shipyards..................... 25 0.07 1.72
All Application groups........ 91,625 0.18 3.79
------------------------------------------------------------------------
* = less than .005%.
** These relatively high impacts on profits assume that no price
increase is possible. In all three cases, price increases of 2.1
percent or less would fully restore profits. In all of these
application groups, most firms will be able to increase prices to
offset their regulatory costs. In furniture stripping, a substantial
portion of the market is for antique refinishing that involves MC use,
a service which is relatively price insenstive. Soft flexible foam of
the kind MC is used to make is an essential material in the
construction of cushions of all types. In the construction sector, MC
based paint stripping and foam blowing are essential operations of
many of the jobs in which they are used.
Sources: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA,
Department of Labor.
It is important to understand that OSHA's methodology tends to
overestimate the economic impacts of the standard, for a number of
reasons. For example, OSHA's cost methodology does not take into
account the many simple and virtually cost-less improvements in
employee work practices and housekeeping procedures that would enable
many employers to achieve compliance with the final rule's PELs. In
flexible polyurethane foam manufacturing, for example, OSHA's costs may
be overestimated because it was assumed that no firms would substitute
away from MC entirely, even though some firms have already done so (as
described in Chapter III, Technological Feasibility). Despite the fact
that OSHA's cost estimates are likely to be overestimates, OSHA decided
to examine in greater detail the three application groups shown by the
economic analysis to have the highest costs as a percentage of profits,
i.e., furniture stripping, polyurethane foam manufacturing, and
construction.
In the furniture refinishing application group, compliance costs
are 2.0 percent of the value of revenues and 39 percent of the value of
before-tax profits. Approximately half of all furniture refinishing
sales derive from antique refinishing, a market niche that is unlikely
to be sensitive to a 2.0 percent change in price. Even in the area of
used furniture refinishing, which constitutes the remaining half of the
furniture refinishing market, a 2.0 percent price increase would be
unlikely to significantly alter the amount of furniture being
refinished. In general, price increases of this magnitude would be
expected to result only in a very small drop in the demand for
furniture refinishing. If this were not the case, normal business
fluctuations, such as drops in the relative cost of new furniture or a
major increase in the price of methylene chloride (such as has occurred
in recent years) would also have had major impacts on the industry.
In construction and polyurethane foam manufacturing, compliance
costs for the average firm are 9.2 and 9.7 percent of profits,
respectively. However, to offset these costs, construction firms would
need only to increase their revenues by 0.35 percent and foam blowing
operations would need only to increase the price of their products by
0.32 percent. In construction, such price increases are unlikely to
present a problem, since the use of MC is essential on many larger
construction projects. For example, it is difficult to believe that
demand for remodeling or renovation projects would be seriously altered
by a 0.35 percent increase in the cost of the paint stripping portion
of the job. In flexible polyurethane foam manufacturing, either MC or
an appropriate substitute is essential to the production of low
density, or soft, foam, and foam, in turn, is essential to the
production of many kinds of furniture. Demand for such products is
unlikely to change as a result of an 0.32 percent increase in the price
of flexible foam. OSHA therefore concludes that even marginal firms in
these three sectors--furniture stripping, construction, and flexible
foam blowing-- are unlikely to close as a result of the compliance
costs of this standard.
To ensure that the analysis of average impacts presented in the
economic analysis did not obscure potentially significant economic
impacts at the 4-digit SIC level, OSHA performed an in-depth analysis
of the 4-digit SICs potentially involved in the Cold Cleaning and All
Other Industrial Paint Stripping application groups. The results of
this in-depth analysis are presented in Appendix D of the full economic
analysis. In all, a total of 162 4-digit SICs potentially impacted by
the standard in the Cold Cleaning group and more than 200 4-digit SICs
in the Other Industrial Paint Stripping group were analyzed. Across all
of the Cold Cleaning SICs, the average impact of the costs of
compliance is 0.06 percent of revenues and 1.12 percent of profits. The
largest impacts on profits occur in SIC 3412, Metal Barrels, Drums, and
Pails, and SIC 3494, Valves and Pipe Fittings not elsewhere classified;
in these cases, impacts on profits are 13.3 and 15.1 percent,
respectively. In both of these cases, however, these impacts are
explained by extremely low profit margins (less than .02 percent of
sales, i.e., less than $2 per $10,000 in sales, in 1994). As a result,
a price increase of less than one cent per $100 of revenue would leave
profits unchanged. Such a price increase is feasible because an
[[Page 1569]]
increase of this magnitude is unlikely to lead to significant changes
in the demand for metal barrels or valves and pipe fittings. In no
other 4-digit Cold Cleaning SIC did impacts reach even 5 percent of
profits.
Across all 200-plus Industrial Paint Stripping SICs, the average
impact of the costs of compliance on revenues is 0.03 percent. The
largest impact of costs on sales is 0.33 percent and occurs in SIC
7532, Auto Top, Body Repair, and Paint Shops (discussed further below).
The average impacts of costs on profits across these SICs is 0.17
percent. The largest impacts on profits occur in SIC 3412, SIC 3494
(both discussed above), and in SIC 7532, Auto Tops, Body Repair and
Paint Shops; in all three of these SICs, cost impacts are between 6 and
8 percent of profits. Again, the explanation for these impacts in SICs
3412 and 3494 is that their profit margin in 1994 was vanishingly low.
The resulting price increases required to maintain profits are also
extremely small, and OSHA concludes that such an increase is likely to
take place in these cases. In SIC 7532, the other relatively high
impact SIC, profit margins are relatively high (approximately 4.4
percent), and thus a small decline of this magnitude would have
relatively little impact.
Summary of the Regulatory Flexibility Analysis
In its 1991 proposal, OSHA requested comments and information that
would assist the Agency in identifying small-business users of MC and
in structuring the final standard so that these users would be able to
achieve the standard's worker protection goals in ways that would be
technologically and economically feasible for them (56 FR 57041 to
57043). OSHA anticipated that, as stated in the proposal, the standard
might have a significant economic impact on small entities in at least
two application groups: firms with fewer than 20 employees that engage
in stripping of paint from aircraft, and firms with fewer than 20
employees that engage in furniture stripping.3 OSHA also requested
comment concerning the standard's impact on small employers in light of
the Regulatory Flexibility Act's mandate to consider and minimize
impacts on small businesses, consistent with the purposes and criteria
of the standard's enabling legislation (56 FR 57115 to 57121).
---------------------------------------------------------------------------
\3\ As a result of data and information received from commenters
and other information in the record, the Final Economic Analysis
does not identify significant impacts or technologic or economic
feasibility problems for aircraft stripping operations of any size.
---------------------------------------------------------------------------
Many commenters identified additional application groups that
include small establishments likely to have difficulty achieving all of
the standard's protective goals if the requirements of the standard
were structured in a one-size-fits-all manner. These commenters
provided considerable data and identified many possible modifications
and alternatives to the proposed standard that they believed would
facilitate compliance and mitigate the standard's impact on MC-using
establishments with fewer than 20 employees.
None of the comments concerning small employer issues, whether in
the context of economic or technological feasibility or the Regulatory
Flexibility Act, disagreed with OSHA's basic premise that the fewer-
than-20-employee cut-off was appropriate to distinguish between large
and small MC-using businesses, was a useful way of characterizing the
compliance abilities and limitations of affected employers and is an
appropriate definition for purposes of the Regulatory Flexibility Act.
Use of this numerical cut-off point captures 61 percent of all
establishments potentially affected by the final rule. MC-users with
fewer than 20 workers tend to have the characteristics of ``mom-and-
pop'' businesses, whereas establishments with 20 or more workers are
generally more sophisticated in terms of the technology they use and
their management resources. The 20-employee threshold has also proved
to be an agreed-on and useful cut-off point in past OSHA rulemakings
(see, for example, the permit-required confined spaces standard (58 FR
4547) and the process safety management standard (57 FR 6402)).
During Executive Order 12866 review, the Office of Advocacy of the
Small Business Administration expressed its views concerning OSHA's
small business definition. In a letter to OMB, the SBA's Chief Counsel
for Advocacy stated in a letter dated August 16, 1996, that ``[t]he
regulatory alternatives developed, using OSHA's size standard of less
than 20 employees, were somewhat beneficial to two of the three
industries [furniture stripping, polyurethane foam blowing, and
construction]. These industries, i.e., furniture stripping and
construction, are predominantly micro businesses that fall into OSHA's
definition of small'' (Ex. 130). The Office of Advocacy was concerned,
however, that the 20-employee cut-off did not adequately deal with the
MC-using polyurethane foam manufacturing sector. (In this application
group, the majority of establishments likely to experience significant
economic impacts fall into the 20 to 99- employee size category.)
``[T]he characteristics of the manufacturing sector indicate that the
[20 employee] size standard was not appropriate in that industry for
the purposes of regulatory flexibility.'' Id. The SBA concluded that
OSHA should consider taking additional steps to address implementation
burdens and the needs of the polyurethane foam manufacturing sector.
Working with OMB and the SBA's Office of Advocacy to resolve this
concern, OSHA reexamined the potential impacts of the standard on
polyurethane foam manufacturing establishments in the 20 to 99 employee
size category in the context of economic impact issues. As explained
more fully in the Final Economic and Regulatory Flexibility Analysis,
OSHA concluded that, even though members of this group were not small
employers, some accommodation would be necessary to assure that
employees working in establishments of this size in this industry would
not receive less protection than all other MC-exposed employees.
Accordingly, OSHA extended the engineering control implementation date
for this group of establishments by one year. This extended phase-in is
designed to enable this group of employers to plan for and accumulate
the capital to finance needed controls, install them, and ensure their
effective and consistent operation before the compliance deadline.
OSHA's extensive feasibility studies and focus on small business
issues resulted in a number of modifications that have made the
standard more cost-effective for business while maintaining protection
for workers. In addition, OSHA conducted an alternative screening
analysis to measure the final rule's potential impacts on
establishments in the regulated community using the SBA's size
standards. For most application groups, this meant that OSHA examined
the standard's economic impacts on firms at the 500 employee level.
(Financial data are not available for cut-off points higher than 500
employees; thus, OSHA used that cut-off for all application groups.) In
some cases, the SBA size standards are defined in terms of annual
revenues, and for SICs so defined, OSHA translated these revenue
figures into the appropriate employee size category. This SBA-based
alternative screening analysis enabled the Agency to determine whether,
by failing to look
[[Page 1570]]
at potential impacts among firms in other size classes, significant
impacts had been overlooked. The analysis conducted using the SBA size
standards confirmed that any potentially significant economic impacts
associated with the final rule occur among firms in the fewer-than-20-
employee category, with one exception, i.e., firms in the 20-99
employee size category in the polyurethane foam manufacturing industry.
(See the full Final Economic Analysis for additional detail.)
For the final rule, OSHA has analyzed the costs of compliance as a
percentage of profits, and costs as a percentage of revenues, for firms
with fewer than 20 employees in every application group. This analysis
identified significant economic impacts on a substantial number of
small entities, and the Agency has accordingly conducted a full Final
Regulatory Flexibility Analysis in accordance with the Regulatory
Flexibility Act, as amended in 1996. The three application groups for
which such impacts were identified were Furniture Stripping,
Polyurethane Foam Blowing, and Construction. Table VIII-6 shows the
results of this analysis in detail.
The full regulatory flexibility analysis is presented in Chapter VI
of the Final Economic and Regulatory Flexibility Analysis. The
remainder of this section briefly summarizes that analysis.
This rule is needed to prevent cancer deaths and other illnesses,
as discussed in greater detail in the Health Effects Section (Section V
of this Preamble). Section III of this preamble, Events Leading to the
Final Standard, summarizes OSHA's efforts to assure input to this
rulemaking by affected small firms. Table VIII-6 identifies the
affected small firms by sector. OSHA estimates that a total of 56,000
small firms will be affected by this standard.
Table VIII-6.--Sceening Analysis of Potential Economic Impacts on Small
Firms
------------------------------------------------------------------------
Costs as a Costs as a
Number of percentage percentage
Application group small of profits of sales
establishments for small for small
affected firms firms
------------------------------------------------------------------------
Manufacture of MC............. 0 NA NA
Distribution/Formulation of
Solvents..................... 139 3.0% 0.2
Metal Cleaning:
Cold Degreasing and Other
Cold Cleaning............ 9,223 0.9 0.0
Open-Top Vapor Degreasing. 0 NA NA
Conveyorized Vapor
Degreasing............... 11 2.4 0.1
Semiconductors............ 0 NA NA
Printed Circuit Boards.... 20 2.0 0.1
Aerosol Packaging............. 10 0.7 0.1
Paint Remover Manufacturing... 34 0.3 0.1
Paint Manufacturing........... 7 0.1 0.0
Paint Remover Use (Paint
Stripping):
Aircraft Stripping (Large
Firms)................... 0 NA NA
Aircraft Stripping ( Small
Firms)................... 75 4.5 0.1
Furniture Stripping....... 5,901 41.5* 2.2
All Other Industrial Paint
Stripping................ 25,441 0.8 0.0
Flexible Polyurethane Foam
Manufacturing................ 8 60.3* 1.7
Plastics and Adhesives
Manufacturing and Use........ 498 1.8 0.1
Ink and Ink Solvent
Manufacturing................ 3 NA NA
Ink Solvent Use............... 5,395 0.1 0.1
Pesticide Manufacturing and
Formulation.................. 40 6.6 0.2
Pharmaceutical Manufacturing.. 0 NA NA
Solvent Recovery.............. 17 2.7 0.1
Film Base..................... 0 NA NA
Polycarbonates................ 0 NA NA
Construction.................. 9,085 19.9* 0.5
Shipyards..................... 0 NA NA
All Application groups........ 55,908 8.2 0.3
------------------------------------------------------------------------
NA=No small firms in this application group.
* These relatively high impacts on profits assume that no price increase
is possible. In all three cases, price increases of 2.1 percent or
less would fully restore profits. In all of these application groups,
most firms will be able to increase prices to offset their regulatory
costs. In furniture stripping, a susbtantial portion of the market is
for antique refinishing that involves MC use, a service which is
relatively price insensitive. Soft flexible foam of the kind MC is
used to make is an essential material in the construction of cushions
of all types. In the construction sector, MC based paint stripping and
foam blowing are essential operations of many of the jobs in which
they are used.
Sources: CONSAD; Dun & Bradstreet; Office of Regulatory Analysis, OSHA,
Department of Labor.
The Summary and Explanation section of this preamble provides a
description of the compliance requirements associated with this rule,
and a paperwork burden analysis of the record keeping requirements is
provided in the Collection of Information Request for Comment section
at the beginning of this preamble. Based on comments regarding
anticipated effects on small businesses, OSHA has reduced the final
rule's overall paperwork requirements from those proposed and has
refined some paperwork requirements to simplify compliance for small
entities.
OSHA considered numerous regulatory alternatives and modifications
to the requirements of the proposed standard (ranging from higher PELs,
to 40-hour rather than 8-hour time weighted average exposure limits, to
delayed implementation dates) that commenters believed might minimize
significant economic impacts on small businesses. OSHA rejected those
alternatives that clearly decreased the safety of workers in small
establishments, but the Agency also adopted many regulatory changes
that will improve small employers' ability to provide their employees
with the same level of protection as that afforded workers in larger
establishments. As
[[Page 1571]]
explained more fully in the Final Economic Analysis and summarized in
Table VIII-7, the final standard contains delayed implementation dates,
reduced paperwork requirements, streamlined medical surveillance
provisions and other accommodations that, in the Agency's judgment,
will minimize any significant economic impacts of the standard on small
employers to the extent necessary to enable them to meet the standard's
protective goals.
Table VIII-7. Changes Made Since the Proposed Regulation To Reduce the
Final Standard's Impacts on Small Businesses
------------------------------------------------------------------------
Change to proposed regulation Impact on small businesses
------------------------------------------------------------------------
Firms with fewer than 20 employees More performance oriented and
given 3 years (rather than 1) to flexible, reduces costs to
achieve PEL using engineering controls. small businesses in first two
years by 30 to 40 %, allows
small businesses time to plan
major expenditures.
Allows the use of licensed health care Provides greater flexibility.
professionals in addition to
physicians for medical surveillance.
Laboratory tests are at the discretion Reduces costs of medical
of physician rather than automatically surveillance by more than 14
required. percent, more performance
oriented.
Employees under 45 are required to have Reduces costs of medical
a physical every three years rather surveillance by 30 percent.
than annually.
Respirators required in regulated areas Decreases respirator use and
only when PEL is likely to be exceeded. costs for small business.
If MC is used less than 30 days per Significantly reduces costs of
year, monitoring may be conducted with monitoring for establishments
direct reading instruments. making limited use of MC; this
provision will be especially
helpful in construction.
Written compliance plans are no longer Reduces paperwork.
required.
Hazard communication requirements do Reduces paperwork and costs.
not go beyond what is already required
by hazard communication standard.
Employee re-training only as needed More performance oriented,
rather than annually. reduces costs of training 80
percent.
Simplified recordkeeping for small Reduces paperwork.
businesses for exposure monitoring
data.
------------------------------------------------------------------------
IX. Environmental Impact
This section analyzes the impact on the environment of changing the
standard for methylene chloride (MC) to an eight-hour time weighted
average (TWA8) permissible exposure limit (PEL) of 25 parts per million
(ppm), with a 125 ppm 15-minute short-term exposure limit (STEL) and
ancillary requirements. It is based principally on information
collected for OSHA by CONSAD Research Corporation and its
subcontractor, PEI Associates Inc., and reported in Economic Analysis
of Draft Regulatory Standard for Methylene Chloride, 1990, OSHA Docket,
Ex. 15, and also draws upon other materials in the OSHA docket.
Current uses of methylene chloride involve releases to the air
through venting of storage tanks or drums and through evaporation of MC
during the performance of various activities such as paint stripping
and cold cleaning indoors or outdoors. The volume of MC emitted as a
percentage of MC used varies greatly among industries. Some processes,
such as polyurethane foam manufacturing and paint stripping, typically
release 100 percent of the MC to the atmosphere (Ex. 15). Other uses,
such as solvent recovery and the manufacture of methylene chloride,
involve less than 1 percent of the MC used being emitted to the
atmosphere (Ex. 15). In addition, air, water, or solid waste pollution
may occur as a result of the disposal of waste residues containing MC.
Additional details by application group are presented in CONSAD's
report [Ex. 15].
Future environmental releases of methylene chloride resulting from
the final standard will largely be a function of how it affects the
demand for methylene chloride and for its substitutes. The demand for
methylene chloride has been declining (e.g., generally, it is no longer
being used in formulating hairsprays). Any regulatory action by OSHA is
expected to further reduce the demand for MC and thus the extent of its
environmental releases.
Although it is technically possible to substitute
chlorofluorocarbons (CFCs) for methylene chloride in electronics and
foam blowing, OSHA does not expect the revision of the MC standard to
have any such effect. CFC products are significantly more expensive
than MC products and are themselves being phased out or banned because
of their effects on the environment.
To the extent that firms might have to use greater quantities of
substitute chemicals to get the same effects formerly obtained with MC,
waste residues and disposal costs would increase. On the other hand,
increases in MC leak prevention and recycling would improve the
environment.
The Paint Remover Manufacturers Association (PRMA) has charged that
the standard would cause ``massive amounts'' of methylene chloride to
be emitted into the atmosphere (Ex. 19-11). In Chapter III, OSHA noted
that it could find no convincing argument by PRMA as to why the total
amount emitted after installation of exhaust ventilation would differ
significantly from the amount now simply leaking into the atmosphere.
At informal public hearings, PRMA stated that ``an exposure level
of 25 PPM is so low that it brings into the issue the formation of
vapor clouds with levels of greater than 25 PPM that could move in and
around the neighborhood,'' allegedly through decomposition of the MC
[Tr. 245, 9/17/92]. There is no evidence that this hypothetical
situation has ever occurred. PRMA may have confused decomposition with
diffusion [Tr. 940-941, 9/21/92]. At Eastman Kodak Company, which
currently emits more methylene chloride into the atmosphere than any
furniture stripper possibly could, the chemical has diffused so rapidly
that no clouds of MC have been formed [Tr. 1237-1238, 9/22/92].
Generally, it is not expected that any significant environmental
impact will result from revision of the methylene chloride standard.
X. Summary and Explanation of the Final Standard
Introduction
The final standard for occupational exposure to methylene chloride
(MC) is different in several important respects from the proposed MC
standard
[[Page 1572]]
published in the Federal Register in 1991 (56 FR 57036). For example,
the standard has been written in plain language, is more performance-
oriented than the proposal, and substantially reduces the amount of
paperwork employers will have to complete. Employers will thus find
compliance with the standard easier, their paperwork less extensive,
and their obligations clearer and less burdensome. These changes are
discussed in greater detail in the appropriate sections of this Summary
and Explanation. OSHA seeks input from users of the standard on whether
these changes are helpful and what other changes could be made to
future standards to increase their user-friendliness. OSHA will also be
conducting a number of compliance assistance and outreach projects in
connection with this standard to assist employers and employees to
comply.
As part of the Agency's new approach to standards writing, OSHA has
included an introductory paragraph in the standard to provide readers
with information on MC, its health effects and principal uses, and the
reasons OSHA is regulating this toxic substance. This introductory
language is non-mandatory and is intended only to provide information
and enhance compliance.
This final rule is an occupational health standard that establishes
requirements to control employee exposure to MC, a chemical compound
found in many different types of industries. OSHA has determined that
this standard is necessary because exposure to MC places employees at
significant risk of developing exposure-related adverse health effects.
These effects include cancer, effects on the heart and central nervous
system, and skin and eye irritation. Employee exposure to MC can occur
through inhalation or through skin absorption or contact with the skin.
This substance is frequently used as a solvent in many different kinds
of jobs, including furniture stripping, foam blowing, film
manufacturing and metal degreasing.
Although the final rule covers many different types of workplaces
where MC is used, the extent of coverage depends on the magnitude of
employee exposure. Although all covered employers, i.e., those with MC
in the workplace, must determine initially the extent to which their
employees are exposed to MC, those with exposures at or below the
action level will only have to document the results of this initial
determination, provide employee information and training, and provide
means of protecting employees from contact with liquid MC. The
standard's other requirements, such as those for engineering controls,
medical surveillance, etc. apply only to workplaces where employee
exposures to MC exceed the action level.
Paragraph (a) Scope and application
This standard applies to all occupational exposures in workplaces
covered by OSHA in general industry, construction and shipyards where
MC is produced, released, stored, handled, or used.
As discussed in the Health Effects and Significance of Risk
sections of this preamble, OSHA has determined that exposure to MC at
the former PEL creates a significant risk that employees' health will
be materially impaired. Possible adverse health effects include cancer,
cardiac effects, central nervous system effects, and skin or eye
irritation. Exposures to MC are found in various general industry,
construction, and shipyard facilities, and OSHA has determined that
there are feasible measures to control them in each of these types of
employment.
In the proposal's Authority section, OSHA preliminarily determined,
under Section 4(b)(2) of the OSH Act, that it would be appropriate for
the MC standard to supersede any corresponding longshoring standards in
Sec. 1910.16 and 29 CFR part 1918. The Agency therefore proposed to add
a new paragraph (m) to Sec. 1910.19. In addition, in questions raised
by the Agency in its Notice of Public Hearing, OSHA requested input
regarding the use of MC in longshoring. However, OSHA has subsequently
proposed (59 FR 28594, June 2, 1994) to revise its marine terminal
(part 1917) and longshoring (part 1918) standards. Those proposed
standards (proposed Secs. 1910.16(b)(2), 1917.1(b)(2)(xiv), and
1918.1(b)(1)) would apply OSHA's toxic substance standards (part 1910,
subpart Z) only when the packaging in which a substance is being
transported in the maritime environment has broken open. This language,
based on the existing marine terminal standard
(Sec. 1910.16(b)(2)(ii)), reflects the view that hazardous substances,
when properly packaged, do not pose significant exposure risks for the
shipyard employees transporting them in closed packages.
Therefore, as revised, final rule Sec. 1910.19(m) states that
Sec. 1910.1052 will address MC exposure in marine terminal and
longshore employment only where leaking or broken packages allow MC
exposure that is not addressed through compliance with 29 CFR parts
1917 and 1918. Given the promulgation of Sec. 1910.19(m), the Agency
has determined that it is unnecessary to mention marine terminals and
longshoring in final rule Sec. 1910.1052(a), Scope and application.
OSHA has not learned of any circumstances in which marine terminal
or longshore employees have been exposed to MC because of damage to
packaging. The Agency, accordingly, anticipates that the MC final rule
will have little or no impact on the marine terminal and longshoring
industries.
In developing this rule, OSHA has consulted with its Shipyard
Employment Standards Advisory Committee (SESAC) to obtain information
on MC use and exposure in shipyards and has taken the Committee's input
into consideration in developing the standard. In particular, OSHA has
relied on data provided by SESAC in assessing the technological
feasibility and costs of compliance of the standard for shipyards
covered by the rule.
Since the construction industry is also included in the scope of
the final rule, OSHA is required to consult the Advisory Committee on
Construction Safety and Health (ACCSH) in accordance with section 107
of the Contract Work Hours and Safety Standards Act (40 U.S.C. 333)
(the Construction Safety Act) and 29 CFR 1911.10. On July 28, 1992,
OSHA formally consulted with ACCSH regarding the construction-specific
aspects of occupational exposure to MC. The Agency solicited comment
and testimony regarding ACCSH's recommendations through a Federal
Register notice (57 FR 36964, August 17, 1992). One of ACCSH's
suggestions was that the rule specifically require originators of
contract bids to stipulate a requirement for compliance with the MC
standard in their bids. OSHA has not adopted this suggestion in the
final rule because construction contracts already require compliance
with all relevant Federal regulations. The specific suggestions made by
ACCSH and OSHA's responses to ACCSH's input are discussed below in the
relevant paragraphs of the Summary and Explanation.
In the proposal, the scope and application paragraph included an
exemption for employers with workplaces where MC products were present
but objective data were available to demonstrate that the product could
not release MC above the action level or STEL under those foreseeable
conditions of processing, use, and handling that would cause the
greatest possible release. This concept remains in the final standard,
although the provision has been moved to the
[[Page 1573]]
exposure monitoring section (paragraph (d)), because this provision
constitutes, in effect, an exception to the standard's requirement for
initial monitoring.
The Air Transport Association [Ex. 19-75] requested that airlines
be excluded from the general industry standard, and that a separate
standard covering MC use in the airline industry be developed. OSHA has
specifically determined that the exposures, work operations, and means
of compliance for aircraft-related MC uses are similar to those in many
other establishments and thus that there is no substantive basis for
the requested exemption. Consequently, OSHA has concluded that no
industry-specific standard for airlines is warranted. MC uses in the
airline industry are discussed in the section of the final economic
analysis entitled ``Aircraft Stripping.''
Paragraph (b) Definitions
This paragraph includes definitions of a number of terms used in
the regulatory text of the final standard. Although some of these terms
are in common use, OSHA believes that these definitions will help to
ensure that their meaning in the context of the standard is clear.
Action level means an airborne concentration of MC of 12.5 ppm,
measured as an 8-hour time-weighted average. One purpose of the action
level is to relieve the burden on employers by providing a cut-off
point below which many of the compliance activities in the standard are
not required. In addition, due to the variable nature of employee
exposures to airborne concentrations of MC, compliance with an action
level provides employers with greater assurance that their employees
will not be exposed to MC concentrations above the permissible exposure
limits.
The action level also increases the cost-effectiveness and
performance orientation of the standard while improving employee
protection. The standard will encourage employers who can, in a cost-
effective manner, identify approaches or innovative methodologies to
reduce their employees' exposures to levels below the action level,
because this will eliminate the costs associated with exposure
monitoring and medical surveillance, two provisions of the standard
that are triggered by exposure exceeding the action level. At the same
time, the employees of such employers will be protected because their
MC exposures will be less than half of those permitted by the
permissible exposure limit. Employees of those employers who are not
able to lower exposures below the action level will have the additional
protection provided by medical surveillance, exposure monitoring, and
the other provisions of the standard that are triggered by the action
level.
The statistical basis for using an ``action level'' has been
discussed in connection with several other OSHA health standards [see,
for example, acrylonitrile (29 CFR 1910.1045) and ethylene oxide (29
CFR 1910.1047)]. In brief, although all employee exposure measurements
on a given day may fall below the permissible exposure limit, some
probability exists that on unmeasured days the employee's actual
exposure may exceed the permissible exposure limit. Where exposure
measurements are above the action level, the employer cannot reasonably
be confident that the employee may not be overexposed on a given day.
Therefore, requiring periodic employee exposure measurements to begin
at the action level provides the employer with a reasonable degree of
confidence in the results of his or her exposure measurement program
[Ex. 7-248]. OSHA's decision to set the action level at one-half the
PEL is based on its successful experience using this fraction as the
action level in many standards, such as arsenic, ethylene oxide, vinyl
chloride and benzene.
OSHA received comments from a number of rulemaking participants
[Exs. 19-16, 19-20, 19-22, 19-31, 19-47, 19-75] suggesting that the
proposed PELs and, by association, the action level, be revised. For
instance, Hukill Chemical Corporation [Ex. 19-47] argued that the
action level should be set at 100 ppm because it believes that: 1) CNS
effects from MC are not observed in humans until 300 ppm; and 2) there
is no evidence of excess cancer mortality in humans up to a level of
475 ppm. As explained in the Health Effects and Quantitative Risk
Assessment sections of this preamble, OSHA disagrees with this
commenter because the Agency has determined that significant risks
exist at levels substantially below those referred to by the commenter
and therefore that the suggested levels would not be adequately
protective.
The Pharmaceutical Manufacturers Association (PMA) [Ex. 19-25]
commented that the action level of 12.5 ppm is appropriate, but
requested an exemption from ``various requirements of the standard'' if
exposure occurs on fewer than 30 days a year. In particular, PMA
suggested that periodic monitoring be required only when there is
exposure above the PEL or STEL for at least 10 days a year or at or
above the action level for at least 30 days a year. OSHA has considered
this issue, along with similar concerns raised by ACCSH, and agreed
that in cases where exposure occurs only on a few days per year, it was
appropriate to alter the exposure monitoring requirements.
Specifically, paragraph (d)(2)(iii) would permit employers whose
employees are exposed to MC on fewer than 30 days per year to forego
the initial monitoring required by paragraph (d)(2), provided that the
employer has taken measurements that give immediate results (such as
those taken by detector tube) and that provide sufficient information
about exposures to determine what (if any) control measures are
necessary. In addition, the medical surveillance requirement (paragraph
(j)), with the exceptions described in the final rule, applies only
where employees are exposed above the action level on at least 30 days
within a year or above the PELs on at least 10 days within a year.
Newport News Shipbuilding [Ex. 19-37] suggested that the action
level be set at 15 ppm. However, adopting this suggestion would not be
consistent with the statistical basis for establishing the action level
at one-half the PEL, as described above. In addition, Markey
Restoration Company [Tr. 2671-72,
10/16/92] recommended that the action level be eliminated based on the
costs of medical surveillance triggered by that level. As noted above,
an action level is based on the probability of exceeding the PEL and is
designed to enhance both employee protection and the standard's cost-
effectiveness, and OSHA does not believe it would serve either
employers or employees to eliminate this concept from the final rule.
The UAW [Tr. 1885-86, 9/24/92] questioned the statistical arguments
underpinning the action level that OSHA has used for some years.
According to the UAW's calculations, the action level should actually
be set at one-tenth the PEL to accomplish the purpose OSHA intended.
Accordingly, the UAW argued that: ``[I]f you leave it [the action
level] at 1/2, [there is] almost the virtual certainty that workers are
overexposed on that job.'' In response, OSHA notes that its experience
with action levels set at one-half the 8-hour TWA PEL has been
favorable and that employers and employees have benefitted from the use
of the action level concept. In particular, it is OSHA's experience
that, for most workplaces, variability is normally such that an action
level set at one-half the TWA PEL is appropriate. The final standard
thus continues this practice.
Emergency means any occurrence, such as but not limited to,
equipment failure, rupture of containers, or failure of control
equipment, which results, or is likely to result in an uncontrolled
[[Page 1574]]
release of MC. The word ``uncontrolled'' was changed from
``unexpected'' in the proposal to be more descriptive and to be
consistent with the Hazard Communication Standard (29 CFR 1910.1200)
and the Hazardous Waste Operations and Emergency Response Standard (29
CFR 1910.120). Incidental releases of MC--i.e., those where the
substance can be absorbed, neutralized, or otherwise controlled at the
time of release by maintenance personnel or other employees working in
the immediate release area--are not considered to be emergencies within
the scope of this standard. Dow Chemical Company [Ex. 19-31] indicated
that the examples of emergencies provided in the proposal (purging
lines and cleaning sludge from tanks) should not be included in the
final rule. Other commenters [Exs. 19-25, 19-28, 19-57] agreed with Dow
that the examples provided with the definition in the proposal were
inappropriate. In particular, Eli Lilly and Company [Ex. 19-28, p. 7]
stated
Lilly agrees with the concept that an emergency should be tied
to unexpected releases. It is therefore curious and illogical that
the examples given--purging of lines and cleaning tanks--are not
unexpected events. To the contrary, in the pharmaceutical industry
these are planned events which could even occur daily.
On the other hand, the Upjohn Company [Ex. 19-49] commented as
follows:
The language ``unexpected significant release'' is very vague
and will not result in any consistent interpretation as to what type
of a release meets this definition. We would recommend that the
language be changed to ``* * * which may lead to employee exposure
at or above the eight hour, timed-weighted average (TWA) or at or
above the short-term exposure limit (STEL).''
OSHA acknowledges that the language in question could be
misunderstood and has deleted the parenthetical listing of some
examples of emergency situations. Furthermore, the Agency recognizes
that emergency situations, by their very nature, are difficult to
anticipate and describe. Therefore, OSHA has not provided examples of
emergency situations in the final rule. Instead, the final rule lists
situations that OSHA does not consider emergencies, because these will
help employers to identify situations in their workplaces that do
constitute emergencies. OSHA recognizes that emergencies have certain
aspects in common but that other aspects are specific to a given
workplace. For example, employee exposure must be uncontrolled for an
emergency to exist. Provisions of the standard that include
requirements that employers must meet in case of an emergency include
Methods of Compliance, Respiratory Protection, Medical Surveillance,
and Employee Information and Training.
Employee exposure is defined as that exposure to airborne MC which
occurs or which would occur if the employee were not using respiratory
protective equipment. This definition is consistent with OSHA's
previous use of the term ``employee exposure'' in other health
standards.
Methylene chloride (MC), or dichloromethane, means an organic
compound with the chemical formula, CH2Cl2. Its Chemical Abstracts
Registry Number is 75-09-2. Its molecular weight is 84.9 g/mole. Other
information regarding the characteristics of MC may be found in the
appendices to the final standard. MC is a colorless, volatile, liquid
with a chloroform-like odor and is not flammable by standard tests in
air, but will burn under extreme conditions. It has a boiling point of
39.85 C (104 F) at standard atmospheric pressure, a lower explosive
limit of 12% and an upper explosive limit of 19.5% in air. It is
completely miscible with most organic solvents but is sparingly soluble
in water (1.3% by weight at room temperature). It has an extensive oil
and fat solubility. Decomposition products during combustion or fire
include phosgene, hydrochloric acid and carbon monoxide.
Physician or other licensed health care professional is defined as
a person whose legally permitted scope of practice allows him or her to
independently provide or be delegated the responsibility to provide
some or all of the health care services required by final rule
paragraph (j), Medical Surveillance. Use of this phrase is designed to
increase the flexibility of the standard; the proposal used the more
restrictive term ``physician.'' OSHA intends that employers should
consider the opinion of the applicable state licensing board, which
defines the scope of practice for licensed health care professionals,
when they are determining the appropriate provider to supply some or
all of the medical services required by the standard. The new
terminology recognizes that there are many services that non-physicians
can provide, that some non-physicians have particular expertise in
diagnosing and treating occupationally related diseases, and that the
use of these providers is often a cost-effective and protective
approach to the provision of medical care.
Regulated area means an area, demarcated by the employer, where an
employee's exposure to airborne concentrations of MC exceeds or can
reasonably be expected to exceed either the eight (8)-hour time-
weighted average limit or the short-term exposure limit. The wording of
this definition has been changed slightly from that in the proposal for
clarity. The requirements for regulated areas are discussed below in
relation to paragraph (e).
OSHA has added a definition for symptom to the final rule to
clarify what is meant by that term when it is referred to in the
regulatory text. MC has a wide range of possible adverse health
effects. This definition clarifies what portion of that range would be
considered a symptom for purposes of the standard. The covered symptoms
would include indications of central nervous system effects, such as
headaches, disorientation, dizziness, fatigue, and decreased attention
span; cardiac effects, such as chest pain and shortness of breath; and
skin effects, such as chapping, erythema, or skin burns.
The definitions of ``Assistant Secretary,'' ``Authorized Person,''
``Director'' and ``This section'' are consistent with OSHA's previous
uses of these terms in other health standards.
The Boeing Company [Ex. 19-26] suggested that a definition be added
for ``work area'' to preclude unnecessary monitoring in areas that do
not contain MC. OSHA does not believe that this is necessary. If there
is no MC present in an area, no monitoring needs to be performed for
MC. In addition, the focus of this standard is employee exposure, as
measured by personal monitoring, and not particular locations.
Paragraph (c) Permissible Exposure Limits
OSHA is promulgating an 8-hour time-weighted average (TWA)
permissible exposure limit (PEL) of 25 ppm, and a short-term exposure
limit (STEL) of 125 ppm averaged over 15 minutes, as proposed. OSHA has
determined, based on evidence in the record, that occupational exposure
to MC at the current 500 ppm 8-hour TWA PEL presents a significant risk
of material health impairment, and particularly of cancer, to exposed
employees and that compliance with the new standard will substantially
reduce that risk. In combination with the STEL, the 8-hour TWA PEL and
the other industrial hygiene provisions of the standard will also
protect exposed employees from the other health effects caused by
exposure to MC.
The basis for the 8-hour permissible exposure limit is discussed
above in the sections on Health Effects and Significance of Risk, as
well as in the economic analysis. OSHA believes that
[[Page 1575]]
compliance with the new 25 ppm 8-hour TWA PEL is feasible and necessary
to protect exposed employees from this significant risk of material
health impairment.
OSHA received comments from a number of rulemaking participants
suggesting that the proposed PELs and, by association, the action level
be revised. The arguments for revising the proposed PELs were based on
interpretations of the scientific support for given PELs and the
feasibility of particular PELs in certain situations. Some commenters
felt that the current level of 500 ppm does not provide adequate
protection for employees and agreed that the PEL should be set at 25
ppm [Exs. 19-15, 19-49]. Specifically, Striptech International, Inc.
[Ex. 19-15] stated:
The OSHA proposed 25 ppm standard for MC does substantially
eliminate significant risk and it is feasible and definitely
appropriate. The technology exists to enable the industries using MC
to comply or to use an alternate method.
However, a number of rulemaking participants [Exs. 19-22, 19-23,
19-36, 19-38, Tr. 530, 9/18/92, Tr. 1776, 9/24/92, Tr. 1869, 9/24/92]
suggested that OSHA set the 8-hour TWA PEL below 25 ppm, because they
believe that the proposed 25 ppm limit would not adequately protect
workers. For example, the UAW stated that setting a PEL at 25 ppm
``will permit too much exposure to methylene chloride, therefore
placing workers at great risk, contrary to the requirements of the OSHA
Act'' [Tr. 1869, 9/24/92]. The UAW stated that the proposed limit
``would permit 2 deaths per thousand workers,'' and therefore suggested
setting a PEL of 10 ppm, which the union felt would be feasible through
specified engineering and work practice controls [Ex. 19-22, Tr. 1869,
9/24/92]. Scott Schneider, representing the IUE, also suggested that
``because of the evidence of health effects from low level exposures''
to MC, the PEL should be lowered below 25 ppm [Ex. 19-38]. The IUE and
the ACTWU both supported the UAW recommendation of 10 ppm [Tr. 530, 9/
18/92, Tr. 1776, 9/24/92].
The Laborers' Safety and Health Fund of North America [Ex. 19-36]
suggested that worker exposure should be controlled to the lowest
feasible level, which is consistent with NIOSH's position. NIOSH
recommended ``that occupational exposure to methylene chloride, which
is a potential occupational carcinogen and may induce ischemic heart
disease, be reduced below the proposed PEL to the lowest feasible
level'' [Tr. 868, 9/21/94]. OSHA agrees with these commenters that a
significant risk remains at 25 ppm, but believes that this level is the
lowest level for which OSHA can currently document feasibility across
the affected application groups and industries.
OSHA's primary justification for the new standard is the risk of
cancer associated with exposure to MC. Some commenters stated that the
carcinogenicity of MC has not been proven and therefore that
carcinogenicity should not be the basis for setting the PEL [Exs. 19-
18, 19-29, 19-31, 19-45]. In particular, Kodak [Ex. 19-18] stated that
it ``does not believe that the human or animal data demonstrate a need
to establish methylene chloride exposure limits at the levels proposed
by OSHA in order to adequately protect employee health.'' Mr. Bixenman,
representing Benco Sales, testified [Tr. 2638, 10/16/92] ``And surely
with our current level of technology, if methylene chloride were a
human carcinogen, it could be established without question with actual
diagnosed cases.'' Also, the Air Transport Association stated [Ex. 19-
75]:
[T]he limited findings regarding cancer in mice at high MC
dosage is weak justification for the proposed regulatory action.
None of our members have found permanent health symptoms related to
the use of MC, while usage at some facilities goes back at least 30
years. We have no data or experience connecting heart disease with
MC use.
As discussed more extensively in the Quantitative Risk Assessment
section, above, OSHA has based its assessment of MC cancer risk on the
determination (supported by the NTP, EPA, and other agencies) that
there is clear evidence of MC carcinogenicity in mice and rats.
Although there are a few substances for which clear evidence of
carcinogenicity in rodents has been deemed to be irrelevant to humans
due to compelling evidence of mechanisms of action unique to the
species tested, no such evidence exists for MC. In fact, as discussed
in the Risk Assessment section, mechanistic evidence adds to the
weight-of-the-evidence suggesting that MC is also carcinogenic in
humans.
OSHA's final risk estimate indicates a risk of 7.5 deaths per 1000
workers exposed to MC at 50 ppm over a working lifetime and a risk of
3.6 deaths per thousand workers exposed to MC at 25 ppm over a working
lifetime. OSHA has determined, using quantitative risk assessment, that
the estimated risk of developing cancer warrants setting the 8-hour TWA
PEL at 25 ppm and a 15-minute STEL at 125 ppm; in fact, at the 25 ppm
PEL the residual risk still greatly exceeds any significant risk
threshold, and only the lack of documentation of the feasibility of
lower PELs across the affected industries has convinced the Agency not
to reduce the PEL even further at this time.
OSHA disputes the contention of Mr. Bixenman that ``actual
diagnosed cases'' are a precondition for establishing that a particular
substance is carcinogenic to humans. Due to the natural background rate
of all cancers, epidemiologic studies of groups are the only way to
analyze human cause-effect relationships. As discussed in the
Quantitative Risk Assessment section, OSHA has concluded that some of
the available epidemiologic studies suggest a positive association
between MC exposure and human cancer and that no epidemiologic studies
of sufficient power exist to cast serious doubt on such conclusions.
Several commenters preferred a PEL of 50 ppm, which is the current
ACGIH threshold limit value for MC, because they felt that a 25 ppm PEL
would be either too costly to implement or the technology to achieve
such a level of control was not available [Exs. 19-2, 19-3, 19-12, 19-
14, 19-15, 19-29, 19-31, 19-35, 19-37, 19-39, 19-48, 19-50, 19-56, 19-
57]. For example, Abbott Laboratories [Ex. 19-29] commented that
specific processes in the pharmaceutical industry ``cannot be
controlled through existing conventional engineering controls.'' Also,
AMETEK [Ex. 19-12] stated that ``It will be hard for many industries to
reach the 50 ppm level and extremely difficult, if not, impossible, for
most to reach the 25 ppm level.'' Therefore, this commenter proposed
``that OSHA set the PEL for methylene chloride at 50 ppm (8-hour TWA)
with no AL [action level] and leave the STEL at 125 ppm (15-minute
average) as originally written.'' AMETEK contended that this approach
``combines aspects of both ACGIH guidelines and OSHA's proposed
standard into a regulation which would be both protective of worker
health and economically feasible for industry'' [Ex 19-12].
Many other commenters argued for a PEL of at least 100 ppm [Exs.
19-1, 19-4, 19-10, 19-11, 19-16, 19-24, 19-47, 19-51, 19-52, 19-53, 19-
54, 19-67, 19-75, 19-79, 98, 115-3, Tr. 397, 9/17/92, Tr. 2216, 10/14/
92, Tr. 2627, 10/16/92, Tr. 2671, 10/16/92, Tr. 2702, 10/16/92]. For
example, Besway Systems, Inc., testified [Tr. 397, 9/17/92]: ``We would
like to see a PEL for these companies of 200 ppm, which we've been able
to show is safe and economically attainable in our real life
experience. We
[[Page 1576]]
believe that the absolute maximum PEL for our industry should be set at
100 ppm eight hour time weighted average. . . .'' Also, Benco Sales
[Tr. 2627, 10/16/92] stated ``We feel the American workers would
receive more benefit by implementation of an exposure level of 100
parts per million, which is achievable, and the subsequent enforcement
of that level.'' ChemDesign Corporation [Ex. 19-24] believes that the
``sharp reduction in the exposure limit is unjustified based on lack of
credible data that this chemical has the potential to cause cancer in
humans.'' This commenter therefore suggested that the PEL be ``lowered
by a factor of five to 100 parts per million'' [Ex. 19-24].
Other commenters supported a variety of PEL values. One suggested
that a lower PEL be phased in over time, with 75 ppm for two years,
then 50 ppm for two years, and finally 30 ppm [Ex. 19-20]. The
reasoning behind this suggestion was that, during this period,
alternative options to best fit specific operations could be evaluated
and implemented and sufficient time provided to gather the funds
necessary to implement the entire system [Ex. 19-20]. OSHA holds,
however, that the types of engineering controls required under this
standard are relatively simple and that engineering to 75 ppm, then 50
ppm, then 30 ppm is likely to be more costly in time and money than
engineering to or below 25 ppm initially. The suggested phase-in would
also be administratively burdensome for employers, who would be subject
to changing OSHA requirements over the years, with no clear advantage
in reducing the costs of compliance. In addition, if OSHA allowed such
a phase-in period, workers would be exposed to MC at higher levels than
would occur if OSHA required no phase-in period. Therefore, the Agency
sees no advantage to using the phased-in approach described. Moreover,
the Agency notes that the time-frames for compliance with the
provisions of the standard, including implementation of engineering
controls, have been tailored to the size of the establishments, in
order to give all employers a reasonable amount of time to gather
resources and information necessary to comply with this regulation. See
the discussion of start-up dates later in this document.
Smith Fiberglass Products, Inc. suggested that the PEL should
remain at 500 ppm because there is no evidence of human harm at the
present PEL and STEL, since ``studies with rats and mice show that only
a serious overdose far above the present STEL can cause carcinogenic
effects'' [Ex. 19-82]. Another commenter [Ex. 19-86] stated that ``The
present PEL of 500 parts per million (ppm) is not protective enough of
employees based on toxicological data developed since the PEL was
established.'' This commenter therefore suggested that the PEL should
be lower than 500 ppm but higher than 25 ppm (no specific value
identified). As discussed above, however, OSHA has determined that
exposure to MC above 25 ppm poses significant cancer risks and that it
is feasible to protect affected employees from those risks (see the
Significance of Risk section of the preamble).
A number of commenters addressed the availability of suitable
substitutes for MC in their concerns about feasibility [see, e.g., Exs.
19-6, 19-8, 19-37, 19-43, 19-55, 19-74, 19-79, 19-84, 115-3; Tr. 433,
9/17/92; Tr. 1591, 9/23/92; Tr. 1712-13, 9/24/92; Tr. 2636-38, 10/16/
92]. Substitution is often a valid means of controlling exposures to a
particular hazardous chemical when a less hazardous substitute is
available that can be used to perform a similar function. In
particular, some commenters stated that there are no viable substitutes
for MC products used to perform particular tasks. These participants
argued that companies would go out of business because they would be
unable to comply with the final standard in a feasible way [Exs. 19-6
and 19-8]. In addition, one commenter [Ex. 19-8] expressed concern that
substitute products would pose fire hazards. The National Tank Truck
Carriers, Inc. testified [Tr. 1712, 9/24/92]:
One company which discontinued the use of methylene chloride
found it necessary to supplement the methylene chloride substitute
with even more hazardous acetone and toluene in order to remove the
residues from the trailers and containers and properly service the
industry by providing clean trailers.
OSHA has determined that for all application groups, compliance
with this regulation can generally be achieved through the use of
engineering controls and work practices. The Agency's Final Economic
Analysis estimated the cost of compliance assuming that almost all
firms would continue using MC and that only a small fraction of firms
would substitute away from MC. OSHA agrees that, in an individual
establishment, the potential use of substitution as a means of control
must be evaluated carefully to ensure that the magnitude of the hazard
posed is not the same or increased as a result of the substitution. For
some applications described in this regulation, many substitutes for MC
are available for specific applications that do not pose increased
health or safety hazards. In general, however, OSHA has based it
findings of feasibility not on the ability of companies in the affected
sectors to substitute away from MC but on their ability to implement
conventional engineering and work practice controls.
In addition to the 8-hour TWA PEL, OSHA is promulgating a short-
term exposure limit (STEL) of 125 ppm, measured over a 15-minute
period, to protect employees from the acute toxicity of MC and its
metabolites. The acute toxicity of MC is characterized primarily by CNS
effects, such as decreased alertness and coordination, headaches, and
dizziness, which may lead, in turn, to accidents on the job as well as
material impairment of health. Absence of a STEL would mean that
employees could be exposed to up to 800 ppm for 15 minutes. Such levels
are clearly associated with central nervous system effects.
MC is also metabolized to carbon monoxide (CO). CO produced from MC
exposure has the same toxic effects in the body as direct exposure to
CO does. The primary toxic effect of CO is reduction of the ability of
the blood to carry oxygen to the tissues of the body.
In the body, carbon monoxide is converted to carboxyhemoglobin.
Background levels of carboxyhemoglobin in the non-smoking U.S.
population vary from approximately 0.5% to 2.0%. Carboxyhemoglobin in
smokers ranges from approximately 3% to 10%. Additional body burden of
CO (carboxyhemoglobin) due to MC or direct CO exposure can have adverse
health effects on affected individuals. For example, exposure to
relatively low levels of carbon monoxide (for example, levels which
increase carboxyhemoglobin by 2%) reduced time to angina in patients
with pre-existing heart disease exposed to occupational levels of CO
[Ex. 21-93]. Exposure of pregnant women to CO has been shown to produce
adverse health effects on the developing fetus. Workers with anemia or
other blood abnormalities may be at increased risk of material
impairment to health because of an already decreased oxygen-carrying
capacity.
The carbon monoxide-mediated cardiac effects of MC exposure are of
particular concern in the occupational setting because a significant
fraction of the U.S. working population (some investigators estimate
30% of the U.S. population) has silent or symptomatic heart disease.
NIOSH has expressed concern that the STEL proposed by OSHA is not low
enough to protect
[[Page 1577]]
workers from the adverse central nervous system and cardiac effects of
MC.
In addition to reducing risks of cardiac and CNS effects, the STEL
will also enhance employee protection from MC-induced carcinogenesis by
reducing total exposure to MC and by limiting the metabolism of MC by
the GST pathway (the putative carcinogenic metabolic process).
Metabolic evidence suggests that the GST pathway produces more than
proportionately greater quantities of the putative carcinogenic
metabolite when MC concentrations reach levels of about 100 ppm. For
this reason, it is important to limit high concentration, short
duration exposures to MC. Thus the STEL will reduce the exposure-
related risks of acute CNS effects, episodes of carboxyhemoglobinemia,
and cancer.
Another advantage in requiring a STEL is that it focuses attention
on sources of MC exposure in the workplace. General industrial hygiene
principles state that a well-controlled process should have peaks no
higher than five times the 8-hour TWA. Measurement of STEL exposures
can indicate point sources which have unacceptably high MC emissions
and help the employer target those processes for abatement. This can be
an efficient mechanism to concentrate industrial hygiene resources on
those emission sources which, when controlled, will reduce total
employee MC exposure.
In addition, it has been established that ``[i]f in fact a STEL
would further reduce a significant health risk and is feasible to
implement, then the OSH Act [section 6(b)(5)] compels the agency to
adopt it barring alternative avenues to the same result.'' (emphasis in
the original) Public Citizen Health Research Group v. Tyson, 796 F.2d
1479, 1505 (D.C. Cir. 1986) (Ethylene oxide). See also Building and
Construction Trades Department, AFL-CIO v. Brock, 838 F.2d 1258, 1271
(D.C. Cir. 1988) (Asbestos).
In summary, many commenters questioned the need for a reduced PEL,
for a PEL of 25 ppm, and for the particular 8-hour TWA PEL-STEL
combination proposed by OSHA, citing concerns about the feasibility of
these limits and the ability of companies to identify controls and/or
substitutes to comply with them. However, as discussed in the final
economic analysis, OSHA has determined that it is both technologically
and economically feasible for facilities in all affected sectors to
comply with the final rule. In almost every case, companies will be
able to use conventional engineering controls and work practices to
reduce their employees'' exposures to these levels. In addition, many
employers will find that substitution is a viable approach to
eliminating the significant risk posed to workers by MC. As the
economic analysis points out, many firms in many of the covered
industries have already substituted away from MC, and have enjoyed
considerable cost savings in the process. Finally, it is important not
to lose sight of the reasons for regulating MC in the first place: this
substance poses a significant risk of cancer, central nervous system
and cardiac effects, and sensory irritation to the quarter of a million
workers who manufacture, formulate, use, or transport this substance in
the workplace.
As the Quantitative Risk Assessment and Significance of Risk
sections of the preamble demonstrate, the cancer risk remaining at an
8-hour TWA PEL of 25 ppm is clearly of great concern, in that it
exceeds the 1/1000 level indicated by the Supreme Court to be clearly
significant. OSHA therefore encourages employers to further reduce the
MC exposures of their employees wherever it is feasible to do so.
Because the residual risk remaining at 25 ppm is great, the Agency
intends to gather data and information on the feasibility of reducing
the 8-hour TWA PEL to reduce remaining significant risk in a future
rulemaking action. The priority assigned to any future rulemaking
activity will depend in large measure on the prevailing exposure
levels, feasibility, scientific advances and other information, at the
time OSHA considers further proposals; to the extent prevailing levels
are significantly below 25 ppm, the need for subsequent proposals will
diminish.
Paragraph (d) Exposure Monitoring
Paragraph (d) addresses the employee exposure monitoring
requirements for workplaces where employees are exposed to MC. As
discussed in the preamble to the proposed rule (57 FR 57118-20), OSHA
requires employee monitoring to facilitate compliance with the PELs. As
a general matter, exposure monitoring of employee exposure to toxic
substances is a well-recognized and accepted risk management tool. The
monitoring provisions of this final MC standard are consistent with the
monitoring provisions of other OSHA standards. Section 6(b)(7) of the
OSH Act, which addresses rulemaking requirements for hazardous
chemicals, requires health standards to include provisions for
monitoring employee exposures. In the final rule, the exposure
monitoring provisions have been reorganized and rewritten to improve
their clarity and readability. The substance of the requirements is
essentially the same, with the few exceptions noted below.
The provisions of proposed paragraph (d) elicited a considerable
amount of comment and testimony. Several rulemaking participants [Ex.
19-57; Tr. 249, 9/17/92; Tr. 458, 9/17/92; Tr. 1711, 9/24/92] stated
that the proposed requirements for exposure monitoring would impose
excessive economic burdens on some employers (e.g., paint strippers,
tank cleaners). However, in the final rule OSHA has structured the
exposure monitoring requirements to minimize the burden for employers
whose employees have lower exposures and for workplaces where groups of
employees have similar exposures. In addition, the Agency has included
some alternatives to the initial monitoring provisions that will reduce
the amount of monitoring required for some workplaces. Ultimately,
however, the Agency has determined that it is essential to the
protection of exposed employees that exposure levels be quantified in
order to select and implement the proper measures to reduce employee
exposures to MC.
The overall rulemaking record supports the need for exposure
monitoring to ascertain exposure levels for the purpose of designing
appropriate protective measures for employees. In addition, evidence in
the record indicates that the exposure monitoring requirements are
economically and technologically feasible for firms in all of the
affected industry sectors. (See the discussion in the Final Economic
Analysis [Ex. 129].)
Paragraph (d)(1) sets forth the general requirements that apply to
all monitoring provisions. Paragraph (d)(1)(i) states that employers
must characterize the MC exposure of each employee. Employers may chose
one of two ways to determine an employee's MC exposure level. First,
the employer can take a personal air sample in the breathing zone of
each affected employee. This approach is the most precise method of
exposure monitoring because it allows each employee's exposure to be
individually ascertained. However, OSHA recognizes that this approach
may be burdensome for employers with many employees. Therefore,
paragraph (d)(1)(ii) permits employers to establish a representative
monitoring scheme.
Under this option, a personal breathing zone air sample may be
considered representative of another employee's 8-hour TWA or STEL
exposure if the following conditions are met. First, the sampled
employee must
[[Page 1578]]
be that employee who is likely to have the highest MC exposure among
the employees included in the group that is to be represented by the
sample. Second, if the employer wishes a sample taken on an employee in
a given job on one work shift to represent the exposure of another
employee in the same job classification on another shift, the employer
must sample at least one employee in each job classification in each
work area during every work shift. Paragraph (d)(1)(ii) also contains
an exception under which a personal breathing zone sample taken on one
employee in one job classification in a given work area and on a
particular shift will be considered representative of the exposure of
employees on other shifts, where the employer documents that the tasks
performed and conditions in the workplace are similar for all employees
whose exposures are represented.
The provision for representative sampling, which is very similar to
the corresponding provision of the proposed rule, eliminates
unnecessary monitoring and thus further improves the cost-effectiveness
of the standard. In a change from the proposal, the final standard also
allows employers to use representative monitoring to comply with the
standard's requirement for initial monitoring. OSHA believes that
representative initial monitoring is appropriate in those cases where
the employer can accurately determine which employees are likely to
have similar exposures.
The accuracy of the methods used to perform exposure monitoring is
addressed under paragraph (d)(1)(iii). For monitoring of airborne
concentrations above the 8-hour TWA PEL or the STEL, the results must
be accurate within plus or minus 25 percent at a confidence level of 95
percent. Where concentrations are above the action level but at or
below the PEL, the accuracy must be within plus or minus 35 percent at
a confidence level of 95 percent.
Methods of measurement are presently available that can detect MC
within these limits. One such method is OSHA method 80, which has a
limit of detection of 0.201 ppm. Copies of this method are available
from OSHA and can be downloaded from OSHA's World Wide Web site on the
Internet at ``http.www.osha.gov/.'' Sampling and analysis may also be
performed by portable direct reading instruments, real-time continuous
monitoring systems, passive dosimeters or other methods that meet the
accuracy and precision requirements of the standard under the
particular conditions which exist at the employer's worksite.
Paragraph (d)(2) requires employers to make an initial
determination of affected employees' exposure to MC. OSHA anticipates
that most employers will need to perform monitoring in order to
characterize employee exposure and has framed the rule accordingly. The
standard allows employers to characterize their employee exposures
using other means, providing that they can meet the requirements for
such other means presented in the standard. For example, as discussed
above, some employers may have objective data that establishes that
employees will not be exposed above the action level or the STEL under
reasonably foreseeable circumstances. Some employers generate such data
themselves, while others rely on information provided by the
manufacturer or supplier. Accordingly, paragraph (d)(2)(i) provides
that employers can rely on objective data in certain circumstances in
lieu of performing initial monitoring. The objective data must
represent the highest MC exposures likely to occur under reasonably
foreseeable conditions of proccessing, use, or handling in the
workplace, and the employer must document the objective data relied on
(see paragraph (m)). This provision corresponds to proposed paragraph
(a)(2), which was the subject of several comments [Exs. 19-14. 19-31,
19-57].
Occidental Chemical testified [Tr. 2010 and 2023, 10/14/92] that
OSHA should expand the proposed objective data exemption so that
mixtures with less than one percent MC would be excluded from the scope
of the MC standard. The Hazard Communication Standard (HCS) addresses
mixture composition for the purpose of identifying those constituents
and concentrations that impart their hazardous characteristics to the
mixture as a whole. According to the HCS, carcinogenic substances such
as MC are considered to impart their carcinogenic characteristics to
the mixture if they are present in concentrations of more than one-
tenth of one percent or can be released in concentrations that exceed
an existing PEL. This is a much more protective requirement than that
suggested by Occidental, and the Agency believes it would be
inappropriate to lessen the protections provided to employees under the
HCS in this substance-specific MC standard. Therefore, OSHA has not
made the suggested change.
In addition, OSHA recognizes that it would be unreasonable to
require initial monitoring under this standard where employers have
already performed the monitoring needed to characterize employee
exposure. Paragraph (d)(2)(ii) allows employers who have monitored
their employees' exposures to MC within one year prior to April 10,
1997 and that monitoring complies with the accuracy and other
requirements for monitoring contained in the final rule, to designate
such monitoring results as sufficient in lieu of performing the initial
monitoring.
Dow Chemical Co. [Ex. 19-31] commented that OSHA should allow
monitoring data collected as much as two years prior to the effective
date of the final rule to qualify as initial monitoring data. The
Agency believes that data more than a year old would be unlikely to
provide a reliable basis for characterizing employee exposure, because
workplace conditions may well have changed since such data were
collected. Accordingly, the Agency has not made the suggested change.
Addressing this point, Scott Schneider of the International Union
of Electronic, Electrical, Salaried, Machine and Furniture Workers
(IUE) testified [Tr. 531, 9/18/92] as follows:
While we support the requirements for exposure monitoring that
were proposed, we have reservations about section (d)(2)(ii)
regarding the use of ``earlier monitoring results'' to satisfy the
initial monitoring requirements. OSHA must specify exactly which
requirements the data must meet, in terms of both quality and
quantity. Otherwise, it will be an enormous loophole for companies
to avoid monitoring.
The International Brotherhood of Painters & Allied Trades (IBPAT)
agreed with Mr. Schneider; the union stated that the use of
``historical monitoring data to characterize exposures for similar
processes * * * may lead to erroneous estimates of actual exposures''
[Ex. 19-23]. OSHA believes that the concerns of these commenters have
been addressed in the final rule because, to be acceptable under the
standard, any previously gathered exposure data must meet the
analytical, sampling, and other requirements specified for initial
monitoring.
A number of commenters addressed the application of monitoring
requirements in construction [Ex. 19-23; Tr. 544-45, 9/18/92; Tr. 814-
17, 9/21/92; and Tr. 1377-80, 9/23/92]. OSHA agrees that conditions on
construction sites often present special industrial hygiene and
monitoring problems, particularly since the job may be completed before
sampling results taken by conventional personal monitoring methods have
been returned from the laboratory. For example, IBPAT [Ex. 19-23]
pointed to the exposure variability that typifies construction sites,
noting that weather, a highly transient workforce, and other factors
often
[[Page 1579]]
complicate accurate characterization of construction worker exposures.
OSHA's Advisory Committee for Construction Safety and Health (ACCSH)
and other participants suggested that OSHA allow the use of direct-
reading instruments to address this problem [ACCSH Tr. 100-103, 7/28/
92; Workgroup report, pp. 3-4; Tr. 814-818, 9/21/92; Tr. 1377-1382, 9/
23/92].
In response to these comments, the final rule has been revised to
allow the use of such instruments where employees are exposed to MC on
fewer than 30 days within a given year. This means that construction
employers who are involved in short-term construction projects will be
able to use these instruments to characterize the MC exposures of their
employees. Paragraph (d)(2)(iii), which addresses transient workplaces
or work operations where employees are exposed on fewer than 30 days a
year, permits employers to use direct reading instruments such as
detector tubes to estimate exposure and determine what protective
measures to provide to their MC-exposed employees. Although these
simple measurement tools often do not meet the accuracy requirements
that other types of monitoring methods do, they have the advantage of
immediate results and thus allow employers to provide protection
immediately. OSHA believes that this provision is responsive to the
comments discussed above and represents an effective solution to a
difficult worker protection problem.
Paragraph (d)(3) addresses periodic monitoring. Table X-1, below,
which corresponds to Table 1 of paragraph (d)(3), displays the various
monitoring scenarios possible under the final rule's periodic
monitoring requirements. When the initial determination shows employee
exposures to be at or above the action level or above the STEL, the
employer is required to establish a periodic monitoring program. The 8-
hour TWA monitoring is to be done every six months if exposures are at
or above the action level but at or below the 8-hour TWA PEL and the
STEL. The 8-hour TWA or STEL monitoring must be done every three months
if the initial determination or subsequent monitoring shows results
that are above the 8-hour TWA PEL or the STEL, respectively. If two
consecutive subsequent monitoring results taken at least seven days
apart show that exposures have decreased to or below the 8-hour TWA
PEL, but above the action level, the frequency may be decreased to
every six months. Eight-hour TWA monitoring may be terminated when two
consecutive monitoring results taken at least seven days apart show
that exposures are below the action level. STEL monitoring may be
terminated when two consecutive monitoring results taken at least seven
days apart show that exposures are at or below the STEL (See note to
paragraph (d)(3)).
There are six possible initial determination exposure scenarios, or
combinations of 8-hour TWA and short-term exposures, that determine the
frequency of required monitoring. Table X-1 below lists these six
exposure scenarios, along with their monitoring frequencies. As shown
by Table X-1, the action level trigger largely determines whether
employers must monitor employee exposure to MC. The only exception is
the scenario in which 8-hour TWA exposures are below the action level
and short-term exposures are above the STEL. In this case, exceeding
the STEL obligates employers to monitor short-term exposures four times
per year at those job locations where the STEL was exceeded, but
employers are not required to monitor 8-hour TWA exposures at those job
locations.
Table X-1.--Six Initial Determination Exposure Scenarios and Their
Associated Monitoring Frequencies
------------------------------------------------------------------------
Exposure Scenario Required Monitoring Activity
------------------------------------------------------------------------
Below the action level and at or below No 8-hour TWA or STEL
the STEL. monitoring required.
Below the action level and above the No 8-hour TWA monitoring
STEL. required; monitor STEL
exposures every three months.
At or above the action level, at or Monitor 8-hour TWA exposures
below the TWA, and at or below the every six months.
STEL.
At or above the action level, at or Monitor 8-hour TWA exposures
below the TWA, and above the STEL. every six months and monitor
STEL exposures every three
months.
Above the TWA and at or below the STEL. Monitor 8-hour TWA exposures
every three months.
Above the TWA and above the STEL....... Monitor 8-hour TWA exposures
and STEL exposures every three
months.
------------------------------------------------------------------------
Several commenters stated that the proposal required unnecessarily
frequent monitoring [Exs. 19-25, 19-26, 19-28, 19-30, 19-31, and 19-
57]. Some commenters [Exs. 19-30, 19-31] said that the frequency of
monitoring should be the same as that in the benzene standard (29 CFR
1910.1028 (e)(3)), since frequent monitoring does nothing to reduce or
control exposures. The benzene standard requires monitoring at least
every six months if employee exposure exceeds the 8-hour TWA, at least
every year if exposure is at or above the action level but at or below
the 8-hour TWA, and ``as necessary'' to evaluate short-term exposures.
OSHA believes that MC exposure is highly variable due to the
substance's volatility (vapor pressure = 350 mmHg at 20 C, compared
with a vapor pressure for benzene of 75 mmHg at the same temperature)
and the way that it is commonly used (e.g., in manual applications),
and that reducing the frequency of exposure monitoring could therefore
result in inadequate employee protection. The frequency of monitoring
required by this MC standard is similar to that in other OSHA standards
such as Ethylene Oxide (29 CFR 1910.1047), and is sufficient to
characterize employee exposure and to evaluate the effectiveness of
exposure control strategies.
The Advisory Committee on Construction Safety and Health suggested
that OSHA trigger exposure monitoring by frequency of use as well as
the exposure level. OSHA believes, however, that the magnitude of an
employee's exposure is the appropriate determinant of monitoring
frequency (and the selection of protective measures based on the
results of that monitoring) because it is cumulative MC dose, not
frequency of use, that determines the significance of the risk to which
employees are exposed. Therefore, the Agency has not made the suggested
change.
The Polyurethane Foam Association (PFA) [Ex. 19-39] questioned the
necessity of requiring exposure monitoring at the action level.
According to the PFA [Ex. 19-39], ``An action level of 12.5 ppm would
require
[[Page 1580]]
that workers be monitored at a level that has only a remote health risk
associated with it. The costs of such monitoring, however, would be
significant.'' OSHA disagrees strongly with the PFA's analysis of the
significance of the risk remaining at the action level. As discussed in
the Significance of Risk and Economic Analysis sections of this
preamble, only feasibility has constrained the Agency from reducing the
8-hour TWA PEL in the final rule to levels below the action level,
because even at 10 ppm, the risk remaining is significant. That is, an
employee exposed to an MC concentration of 10 ppm as an 8-hour TWA over
a working lifetime would still be at significant risk of dying of MC-
induced cancer.
Under paragraph (d)(4)(i), employers are required to perform
additional monitoring when workplace conditions change or there is an
indication that employee exposures may have increased. Paragraph
(d)(4)(ii) requires that, where exposure monitoring is performed due to
a spill, leak, rupture or equipment breakdown, the employer must clean
up the MC and perform repairs and then monitor MC levels. The changes
referred to in these provisions would include deliberate changes, such
as a process or production change, or unexpected changes, such as a
leak, rupture, or other breakdown. In the case of the latter, the
employer is to perform the monitoring after taking whatever immediate
action is required to clean-up or repair the equipment or source of
exposure. OSHA recognizes that such occurrences can result in very high
exposures. Several rulemaking participants [Exs. 19-31, 19-57, Tr.
2035, 10/14/92] stated that remonitoring is not necessary after a spill
or leak since MC has a high vapor pressure, there would be no visible
residual MC and no opportunity for significant exposure. However, OSHA
believes that such remonitoring is an appropriate way to ascertain if
proper corrective methods have been instituted and if the magnitude of
an employee's exposure has changed significantly as a result of the
leak or spill.
Employees are to be notified in writing of the results of exposure
monitoring under paragraph (d)(5). This is to be done within 15 working
days of the time the employer receives the monitoring results, and can
be done either individually or by posting. When the results show that
the 8-hour TWA PEL or the STEL has been exceeded, the employer must
also notify employees of the corrective action being taken, and the
schedule for completion of the action. This provision is effectively
identical to the corresponding provision of the proposed rule.
One commenter [Ex. 19-49] argued that 15 working days is not enough
time to develop corrective actions, especially where engineering
controls are involved. OSHA believes that this comment misunderstands
the requirement, which merely states that employers are required to
``describe the corrective action being taken * * * and the schedule for
completion of this action.'' The Agency believes that 15 working days
is adequate time for the employer to make a preliminary assessment that
includes the immediate steps being taken to reduce employee exposure,
such as utilization of air-supplied respirators, and the employer's
plan for implementing permanent controls and/or work practices. This
requirement is necessary to assure employees that the employer is
making efforts to furnish them with a safe and healthful work
environment, in accordance with section 8(c)(3) of the Act. OSHA would
expect employers to update the notification when plans for permanent
controls are made.
Employees or their designated representatives are provided by
paragraph (d)(6) with the opportunity to observe any required
monitoring of employee exposure to MC. This provision is required by
section 8(c)(3) of the Act (29 U.S.C. 657(c)(3)). It was relocated to
paragraph (d)(6) of the final rule from proposed paragraph (l) to
consolidate all of the exposure monitoring requirements in one place.
The observer, whether an employee or a designated representative, must
be provided (at no cost to the observer) with any personal protective
clothing or equipment required to be worn by employees working in the
area that is being monitored, and must additionally comply with all
other applicable safety and health procedures. These provisions of the
final rule are identical to those of the proposed rule.
As noted above, OSHA received a number of comments on the
monitoring provisions proposed in the NPRM. For example, Occidental
Chemical Corporation requested that OSHA consider using what they
termed ``exposure assessment'' rather than monitoring, testifying [Tr.
2012-2013, 10/14/92] as follows:
[I]nstead of just looking at monitoring, which is in the middle
of the process, exposure assessment looks at a basic * * *
characterization: What is the characterization of the work force?
What is the characterization of the workplace? What is the
characterization of the contaminants in the workplace? All of that
is weighed together; it's a collection of information.
The next step, then, is to interpret that information and
determine what are the actual exposure levels, what category would
they fit into * * *. If, at that point, and this is still just a
paper exercise based on that information, you * * * conclude that
exposures [are] unacceptable * * * you act. You may conclude that
you have insufficient data and you'd like to monitor. Or you may
conclude the data are acceptable; in this case, you would act and *
* * change something and go through the process again. Or, in the
case they [employee exposures] are acceptable, * * * you would
document that it is acceptable and then reevaluate at some regular
frequency, say annually or something like that.
In response to this comment, OSHA notes that nothing in the
standard prevents employers from conducting exposure assessments.
Indeed, the fact that the final standard allows employers to use
objective data and recent (within the past year) exposure data are both
examples of the kinds of evaluation made by industrial hygienists
performing exposure assessments. An employer unable to avail himself or
herself of the exclusions to initial monitoring offered by the standard
would logically move to the next step in the exposure assessment
process: the direct monitoring of employees' exposures to MC. Thus the
final rule, far from interfering with exposure assessment, actually
both reflects this process and encourages employers to engage in such
assessments themselves.
Paragraph (e) Regulated Areas
Paragraph (e)(1) requires employers to establish a regulated area
wherever an employee's exposure to airborne concentrations of MC
exceeds or can be reasonably expected to exceed either the 8-hour TWA
PEL or the STEL. This paragraph was changed slightly from the proposal
to clarify that OSHA is concerned with employee exposures that can
reasonably be anticipated to exceed one of the PELs, rather than
excessive exposures that ``may'' occur. Regulated areas can be either
temporary or permanent, depending on the characteristics of a given
workplace. Such areas are required by the standard to reduce employee
exposures and to alert employees to those areas in the workplace that
present the greatest danger of MC overexposures.
Paragraph (e)(2) limits access to regulated areas to authorized
persons (a term which is defined in the definitions paragraph (b)).
This provision applies when either the TWA PEL or STEL is exceeded or
can reasonably be expected to be exceeded. OSHA believes that the
establishment of a regulated area will help to ensure that employees
are aware of areas in the workplace where MC
[[Page 1581]]
levels are above the 8-hour TWA PEL or STEL. OSHA believes that
regulated areas are an effective means of limiting the risks of high
exposures to substances suspected of being carcinogenic to humans to as
few employees as possible.
Comments from Bristol-Myers Squibb [Ex. 19-14] suggested that OSHA
delete the regulated area concept from the standard and replace it with
a ``regulated job classification'' for jobs exceeding the PEL and a
``regulated procedure'' for procedures exceeding the STEL. This
commenter's rationale was that since airborne concentrations are
measured by personal monitoring and by job classification, it does not
make sense to define an ``area'' of exposure. OSHA does not agree, for
a number of reasons. First, in many workplaces, specific areas, such as
quality control monitoring stations, mixing tanks, cutoff saw stations,
spray booths, etc., are known to be associated with high levels of MC
on a routine basis, and demarcating these areas protects employees by
making them aware of the potential for these exposures in these
locations. Second, it is standard industrial hygiene practice to use
area monitoring to identify areas of exceptionally high exposures so
that all non-authorized employees can be protected from overexposure.
Finally, OSHA does not believe that the approach suggested by Bristol-
Myers has the same potential to alert employees to the presence of high
airborne concentrations that a demarcated area does, and therefore
believes that the suggested change would not provide equivalent
protection from overexposure.
The Laborers' Safety and Health Fund of North America [Tr. 1378-79,
9/23/92] testified that, in construction, a regulated area should be
established wherever MC is used. Although there are many uses of MC on
construction sites that may warrant establishing regulated areas, there
are also engineering controls available (for example, portable
ventilation) which may reduce employee exposures so that a regulated
area would be unneccessary. OSHA believes that employers should not be
required to establish regulated areas unless potential exposure levels
warrant them. The Agency also believes that the employer is in the best
position to determine whether the exposures from a particular MC
application will warrant establishing regulated areas at a particular
work site. The Advisory Committee on Construction Safety and Health
also suggested that the establishment of regulated areas could replace
some of the standard's monitoring requirements [Ex. 21-69]. As
discussed previously, however, OSHA believes that both employers and
employees benefit from knowing what exposures to MC are in a given
workplace or on a specific job assignment. OSHA has therefore not
revised the final rule's requirement for regulated areas in locations
where exposures exceed or can reasonably be expected to exceed either
or both of the PELs.
The proposal would have required that employers supply employees
entering regulated areas with appropriate respiratory protection and
ensure its use in such areas at all times. Several commenters [Exs. 19-
25, 19-31 and 19-49] argued that respirator use in such areas should be
required only if occupational exposures in such areas either exceeded
the 8-hour TWA PEL or the STEL or could reasonably be expected to
exceed one or both of these limits. OSHA agrees with these commenters
and has revised the final rule accordingly. Paragraph (e)(3) states
that employers must supply a respirator to each person who enters a
regulated area, but shall require each affected employee to use that
respirator only if MC exposures are likely to exceed the 8- hour TWA
PEL or STEL. Thus, not all workers in regulated areas will be required
to wear respirators in regulated areas at all times.
For example, under the final rule, an employer would be required to
demarcate the area around a cutoff saw operator's work station in a
foam blowing plant as a regulated area and to train the operator to
recognize the area as regulated; however, the operator would only be
required to wear a respirator in the area at times when the foam
``bun'' was coming out of the tunnel for cutting. The employer would
demarcate the area because he or she recognizes, based on monitoring
results for the cutoff saw operator, that this work station is one
where the 8-hour TWA PEL is regularly exceeded during foam blowing
operations. Because of the intermittent nature of many foam blowing
operations, however, respirators would need to be worn by the operator
(or other workers assisting the operator) only when foam was actually
being blown. This example assumes that foam blowing operations are
intermittent and that exposures at the cutoff saw would exceed the PELs
only during foam blowing, although this may not be the case in all
plants or at all times. In facilities where foam is blown continually
and the saw operator is stationed at the end of the tunnel over the
full shift, respiratory protection would likely be required to be worn
in the regulated area at all times because exposures would routinely
exceed the PEL in that area.
Under paragraph (e)(4), which has been added to the final rule, the
employer shall ensure that, within a regulated area, employees do not
engage in non-work activities which may increase dermal or oral MC
exposure. This provision indicates that such non-work activities as
eating, drinking, smoking, taking medication, applying lotions or
cosmetics or storing such products in regulated areas are prohibited.
Proposed paragraph (e)(4) has been promulgated as final rule paragraph
(e)(6), as discussed below.
In addition, under paragraph (e)(5), which has been added to the
final rule, the employer shall ensure that employees who are wearing
respirators do not engage in activities (such as taking medication or
chewing gum or tobacco) which interfere with respirator seal or
performance. Proposed paragraph (e)(5) has been promulgated as final
rule paragraph (e)(7), as discussed below.
Final rule paragraphs (e)(4) and (e)(5) are based on the response
to NPRM Issue 41 (56 FR 57043) which indicated that OSHA was
considering a provision to prohibit activities such as eating,
drinking, smoking, etc. in regulated areas and asked for comments on
this subject. This prohibition was supported by some rulemaking
participants [Ex. 19-36, Tr. 1379, 9/23/92]. OSHA notes that it is
standard industrial hygiene practice to limit such activities in
regulated areas, both because employees should be aware at all times
that they are working in a high- exposure area and because of health
concerns. Among other things, since respirators are generally (although
not always) required to be worn in regulated areas, engaging in the
prohibited activities while wearing respirators might interfere with
the respirator seal, placement or performance, thus reducing the
effectiveness of the respirator. Furthermore, in the case of MC,
smoking while being exposed to high MC concentrations (such as those
prevailing in regulated areas) is particularly hazardous because MC is
metabolized to CO in the body and leads to carboxyhemoglobinemia, a
potentially life-threatening condition for some individuals, e.g.,
those with silent or symptomatic heart disease. Other OSHA health
standards (e.g., asbestos, cadmium, ethylene oxide) have included
similar prohibitions, and OSHA has concluded, based on the reasons
discussed above and the Agency's experience with other standards, that
including these
[[Page 1582]]
provisions in the final MC standard is appropriate.
OSHA has broadened the language and separated it into two
provisions (paragraphs (e)(4) and (e)(5)) to differentiate the types of
activities which would generally not be allowed in a regulated area and
those which would interfere with the effective use of respiratory
protection. This is consistent with OSHA's intent in this rule to allow
establishment of regulated areas, but require respirator use only when
the 8-hour TWA PEL or STEL is likely to be exceeded.
Paragraph (e)(6), which is essentially unchanged from the proposed
provision, requires employers to demarcate their regulated areas, but
it does not specify how this is to be done as long as employees are
aware of the location of the area and access to it is thus minimized.
Factors that the Agency believes are appropriate for employers to
consider in determining how to demarcate their areas include the
configuration of the area, whether the regulated area is permanent, the
airborne MC concentration present in the area, the number of employees
in adjacent areas, and the period of time the area is expected to have
exposure levels above the PEL or STEL. Permitting employers to choose
how to identify and limit access to regulated areas is consistent with
OSHA's belief that employers are in the best position to make such
determinations, based on the specific conditions of their workplaces.
This performance-oriented approach gives employers compliance
flexibility without compromising employee health.
Paragraph (e)(7), proposed as paragraph (e)(5), requires employers
at multi-employer worksites who establish a regulated area to
communicate information to other potentially affected employers at the
worksite about the location and access restrictions pertaining to the
regulated area. OSHA believes that such communication will reduce the
likelihood that unauthorized persons will enter the area or that
workers not involved in MC-related operations will be exposed
inadvertently. Those employers whose employees are exposed to MC at
concentrations above either or both of the PELs must coordinate their
operations with other employers whose employees could suffer excessive
exposure because of their proximity to a regulated area where MC is
being used. Compliance with this provision will ensure that only those
employees at multi-employer worksites who are properly authorized,
trained, and equipped enter regulated areas. This provision also
recognizes OSHA's awareness that, although multi- employer worksites
are common in construction, they are also increasingly found in other
industry sectors.
Paragraph (f) Methods of Compliance
Paragraph (f) addresses the means by which employers are to reduce
employee exposures to or below the 8-hour time-weighted average (TWA)
PEL or the STEL. Under paragraph (f)(1), employers are required to
institute and maintain the effectiveness of engineering controls and
work practices to reduce employee exposure to or below the PEL and
STEL, except to the extent the employer can demonstrate such controls
are not feasible. Where these measures cannot reduce the concentration
of airborne MC to or below the TWA PEL and STEL, the employer is
nevertheless required to implement them to achieve the lowest feasible
level. The employer is required to supplement these controls with
respirators where necessary to ensure that employees are not exposed to
MC at levels above either the 8-hour TWA PEL or the 15-minute STEL.
Section 1910.134(a)(1) of the respiratory protection standard requires
respirators to be used where effective engineering controls are not
feasible.
One commenter [Ex. 19-57] indicated that it should be left to
professional judgment to determine whether engineering controls or
respirators are the best method for protecting employees. OSHA does not
agree with this comment because it fails to acknowledge the industrial
hygiene hierarchy of controls, which places engineering controls ahead
of administrative or personal protective equipment as methods of
protecting employees from hazardous exposures. The hierarchy of
controls has been established industrial hygiene practice since the
1950s and is based on the fact that engineering controls are the most
effective method of protecting employees because they remove the hazard
from the workplace. In contrast, respirators merely prevent employees
from breathing the contaminant--it remains in the workplace air.
Effective respirator use also requires constant supervision, extensive
employee training and fit testing, and regular (often daily) care and
maintenance of the respirator. Consequently, respirators should only be
used as a means of achieving the PELs where feasible engineering
controls are not available (such as in some vessel cleaning and non-
stationary maintenance operations) or are not sufficient to control
exposures to required levels. All OSHA substance-specific health
standards have recognized and required employers to observe the
hierarchy of controls, and OSHA's enforcement experience with these
standards has reinforced the importance of this concept to the
protection of employee health.
In the Final Economic Analysis, OSHA has described feasible control
technologies for each industry affected by the final MC standard. Many
employers have already implemented such controls in their workplaces
and are currently achieving the MC levels required by the final rule.
Examples of such feasible control strategies include dilution and local
exhaust ventilation, chilling coils, magnetic pumps and magnetic
floating gauges, exhausted lances for drum filling, and inline quality
control sampling equipment.
OSHA acknowledges that there may be a few operations where the use
of engineering and work practice controls to control exposure to MC is
infeasible because exposures are highly intermittent in nature and
limited in duration. In particular, OSHA is aware that the use of
engineering and work practice controls to comply with the PELs is
infeasible for some maintenance and repair operations and during
emergency situations. Where it is infeasible to reduce workplace MC
levels below the PELs through engineering and work practice controls,
the employer is required to protect employees from excess exposure by
providing and requiring the proper use of personal protective
equipment, in this case supplied-air respirators.
As discussed in the NPRM (56 FR 57120-21), OSHA asked for comments
on whether employers should be allowed to place increased reliance on
the use of respirators to protect employees exposed to MC. The
International Brotherhood of Painters and Allied Trades [Ex. 19-23]
commented that ``[w]ith the exception of emergencies that require use
of a SCBA respirator, engineering and work practice controls should be
the sole method of compliance.''
In addition, the IUE [Tr. 530, 9/18/92] testified as follows:
[R]equirements to control those exposures using engineering
controls are particularly important because of the lack of adequate
chemical cartridge respirators for methylene chloride. For that
reason, we reject the question posed by OSHA regarding the
provisions to allow greater use of respirators which came from
earlier proceedings on revisions to 1910.1000.
Also, NIOSH [Tr. 884, 9/21/92] testified as follows:
NIOSH supports the existing OSHA policy on methods of
compliance, that is the
[[Page 1583]]
hierarchy of controls for controlling exposures to hazardous agents.
Generally, this policy states that whenever feasible, engineering
controls and work practices should be used to prevent exposures, and
that personal protective equipment, including respiratory
protection, should be used only when engineering controls are not
feasible.
As discussed above, OSHA agrees with these comments. The Agency
considers the use of respirators to be the least satisfactory approach
to exposure control because respirators provide adequate protection
only if employers ensure, on a constant basis, that they are properly
fitted and worn. Also, unlike engineering and work practice controls,
respirators protect only the employees who are wearing them from a
hazard, rather than reducing or eliminating the hazard from the
workplace as a whole. Moreover, respirators are uncomfortable to wear,
cumbersome to use, and interfere with communication in the workplace,
which can often be critical to maintaining safety and health. As
mentioned above, OSHA has reached similar conclusions for other
standards promulgated to protect employees from exposure to toxic
substances. Paragraph (g) of the final standard discusses respiratory
protection requirements.
The NPRM also proposed requirements for a written compliance
program that would have required employers to detail their plans for
implementing engineering and other controls. However, OSHA has decided
to eliminate these provisions from the final rule for MC to reduce the
amount of paperwork employers would be required to complete. The
Paperwork Reduction Act of 1995 (PRA 95), (44 U.S.C. 3501 et seq.),
requires agencies to minimize the paperwork burdens on the public.
Preparation of written compliance plans would be classified as
paperwork under the new Act. OSHA believes that the lack of a written
compliance plan will not substantially reduce the effectiveness of the
standard; the Agency solicits comment on this point. One of the primary
benefits of a written plan is that it encourages employers to consider
remedial actions soon after the standard is promulgated. For MC,
however, this may not be an issue because the necessary control
measures are not complex and, except for the very smallest employers,
the period for compliance allowed by the standard is relatively short.
Nevertheless, OSHA believes that many employers will voluntarily
develop these plans because they make it easier for employers and
employees to monitor progress toward compliance. OSHA will be
considering including compliance plans in its standards on a case-by-
case basis in future rulemakings when they are appropriate. The Agency
believes that employers benefit from having a plan to meet the start-up
dates, and has included examples of how this might be done in Appendix
B. There were very few comments about the written compliance plan
requirements, other than one stating that a written plan is reasonable
but annual review and update of it is not [Ex. 19-26].
Paragraph (f)(2), proposed as paragraph (f)(1)(iv), precludes use
of a schedule of employee rotation as a means of compliance with the
PELs. Employee rotation reduces the extent of exposure to individual
employees, but increases the number of employees exposed. OSHA is
regulating MC as an occupational carcinogen, and the Agency therefore
prohibits practices that would place more employees at risk. No
threshold has been demonstrated for the carcinogenic action of MC, and
it is therefore prudent public health policy to limit the number of
workers exposed. In addition, since the dose-response relationship for
MC is convex, exposure to higher concentrations for shorter periods of
time is riskier than exposure to the equivalent ppm-hour concentration
spread over 8 hours (when rotation is used as a method of employee
exposure control, employees tend to be exposed to higher concentrations
for shorter durations).
Paragraph (f)(3) requires employers to address leak and spill
detection in the workplace. Employers must implement procedures to
detect leaks and contain spills as well as follow appropriate methods
to dispose of contaminated materials and clean-up or repair the spill
or leak. These requirements were addressed in proposed paragraph
(f)(1)(iii), but in the final rule have been separated out and
clarified to emphasize their importance. Appendix A provides examples
of procedures that would meet these requirements. Liquid MC has a high
vapor pressure (350 mm Hg at 20 C). Accordingly, leaks and spills of
MC-containing products could generate high airborne MC levels. The leak
and spill detection program reduces the possibility of worker
overexposure to MC.
Bristol-Myers Squibb (BMS) [Ex. 19-14] and Dow [Ex. 19-31]
supported OSHA's performance-oriented requirement for a program to
detect leaks and spills. For example, BMS stated:
[T]here are many ways in which this can be done (e.g. monitoring
of tank levels, walks through areas where leaks may occur). In some
cases, continuous monitoring can be done to detect leaks, however,
this is not always feasible. Monitoring equipment may be very
difficult and expensive to maintain and may not provide the
sensitivity needed for early detection. We recommend that OSHA leave
this section as it is and not specify the system or the equipment
which should be used for the detection program.
Proposed paragraph (h) required employers to develop emergency
plans, implement those plans when necessary, equip employees correcting
emergency situations with appropriate PPE, and alert and evacuate
employees potentially affected by emergencies, as necessary. In
reviewing the proposed rule, OSHA concluded that the proposed
requirements duplicated provisions of the Hazardous Waste Operations
and Emergency Response (HAZWOPER) standard (Section 1910.120). The
Agency has therefore deleted the separate MC requirement for an
emergency plan, and has added a note to final rule paragraph (f)(3)(ii)
which refers employers to the HAZWOPER standard for the applicable
requirements.
Paragraph (g) Respiratory Protection
Paragraph (g) of the final rule addresses requirements for
respiratory protection allowed to be used to comply with the MC
standard. Paragraph (g)(1) requires that employers provide respirators
at no cost to each affected employee, and to ensure that each affected
employee uses a respirator under the following conditions:
(1) Whenever an employee's exposure to MC exceeds or can reasonably
be expected to exceed the 8-hour TWA PEL or the STEL;
(2) During the time interval necessary to install or implement
feasible engineering and work practice controls;
(3) In a few work operations, such as some maintenance operations
and repair activities, for which the employer demonstrates that
engineering and work practice controls are infeasible;
(4) Where feasible engineering and work practice controls are not
sufficient to reduce exposures to or below the PELs; or
(5) In emergencies.
These limitations on the required use of respirators are consistent
with OSHA's longstanding position on the hierarchy of controls in the
workplace, as reflected in the respiratory protection requirements in
other OSHA health standards (e.g., asbestos, Sec. 1910.1001; ethylene
oxide, Sec. 1910.1047; benzene, Sec. 1910.1028; cadmium,
Sec. 1910.1027) and with good industrial hygiene practice. They reflect
OSHA's determination that respirators are inherently less reliable in
providing protection to exposed
[[Page 1584]]
employees than engineering and work practice controls.
However, to reflect the changes made to the final rule's regulated
area provision (paragraph (e)(1)), the final rule's respiratory
protection requirements differ somewhat from those in proposed
paragraph (g). In the NPRM, OSHA proposed to require that employers
provide respirators in the following circumstances: (1) During the time
interval necessary to install or implement feasible engineering and
work practice controls; (2) in work operations, such as maintenance and
repair activities, vessel cleaning, or other activities for which
engineering and work practice controls are demonstrated to be
infeasible, and when exposures are intermittent in nature and limited
in duration; (3) in work situations where feasible engineering controls
are not yet sufficient to reduce exposure to or below the PELs; and (4)
in emergencies. In the final rule, another situation where respirator
use is appropriate is acknowledged: whenever an employee's exposure to
MC exceeds or can reasonably be expected to exceed either or both of
the PELs.
The Building and Construction Trades Department, AFL-CIO, testified
[Tr. 816-17, 9/21/92] that proposed paragraph (g)(1)(ii) could be
interpreted by construction contractors ``as an exemption from the
requirement for adopting a control strategy that places engineering and
work practice controls above that of the PPE.'' In response, OSHA has
revised final rule paragraph (g)(1)(ii) to clarify OSHA's intent. OSHA
recognizes that it may be infeasible to control MC exposure with
engineering and work practice controls during certain maintenance and
repair operations, although OSHA is also aware that portable local
exhaust, ``elephant trunks,'' and other means of providing ventilation
to, and removing contaminated air from, process vessels and other
difficult-to-reach work spaces are widely used in construction and
elsewhere. The Agency also recognizes that there may be other MC-
related activities where an employer could establish the infeasibility
of controls, particularly where employee exposure is highly
intermittent or of short duration. Accordingly, OSHA has revised
proposed paragraph (g)(1)(ii) as described above. This change also
addresses comments made by the Pharmaceutical Manufacturers Association
(PMA) [Ex. 19-25; Tr. 1430, 9/23/92], which stated that it was
infeasible for employers to protect employees during manual unloading
of batch operated centrifuges and manual loading of dryers from MC
exposure with engineering and work practice controls. The PMA suggested
that OSHA revise proposed paragraph (g)(1)(ii) to include those loading
and unloading activities in the list of operations allowed to protect
affected employees through the use of air-supplied respirators.
However, OSHA included examples in the proposal only to provide a
general indication of the situations where the Agency would accept the
use of air-supplied respirators in lieu of engineering and work
practice controls. OSHA believes that the examples suggested by the PMA
are too narrowly focused for inclusion in such a list. It would not be
possible for OSHA to enumerate in the final rule all of the workplace-
specific operations where engineering and work practice controls may be
infeasible. Therefore, in accordance with longstanding OSHA practice,
employers claiming that engineering and work practice controls are
infeasible must establish infeasibility on an objective basis.
Other commenters were concerned about requiring respirators during
emergency escape situations, noting the time involved in donning a
respirator in an emergency. The Dow Chemical Company stated ``Dow
believes the respiratory protection requirements for emergency escape
are excessive. For the short period of time it takes to escape a
release of MC, considering the minor acute effects of the material, it
is excessive to require, as a minimum, a gas mask with an organic vapor
canister'' [Ex. 19-86].
Similarly, comparing escaping right away or first finding a
respirator and then escaping during an emergency situation, Occidental
Chemical testified [Tr. 2041, 10/14/92]:
Methylene chloride is not incapacitating so the goal should be
to escape as fast as possible not trying to find a device--and it
may be close, it may be further--and then put it on, which could
take a minute or so, 30 seconds or a minute, and then decide about
escape. That whole process becomes much longer. So I'm not
advocating we don't have escape respirators, just that the process
should be, escape should be the number one priority.
OSHA agrees that escape is the first priority for employees exposed
to MC in an emergency situation. Furthermore, the Agency has
determined, in general, that the ready availability of escape
respirators is essential to ensure that employees are able to escape
safely. To that end, emergency plans must provide for fast access to
escape respirators where the potential for emergency exposure
situations has been identified by the employer. In addition, employees
must be trained to don those respirators properly and quickly and to
recognize any foreseeable situations where taking the time to obtain
and put on their respirators would significantly reduce their ability
to escape or where they can safely escape an emergency situation
without using respirators. OSHA recognizes that immediate escape is not
always possible, so respirators are needed to protect those employees
while they are still in the exposure area.
Paragraph (g)(2), proposed as paragraph (i)(1)(ii), requires
employers to determine that any employee required by this standard to
wear a supplied-air respirator in the negative pressure mode or a
negative-pressure respirator for escape purposes is medically fit to
use such a respirator. This provision has been changed from the
proposal to recognize that medical fitness for respirator users under
this standard is appropriate only for negative-pressure respirators or
those operated in that mode. This change will assist employers to
direct their medical surveillance resources effectively. In addition,
in keeping with the greater flexibility provided by this standard to
employers in selecting an appropriate health care professional,
paragraph (g)(2) uses the final rule's language, ``Physician or other
licensed health care professional,'' in lieu of the proposal's
exclusive use of ``physician.''
Paragraph (g)(3), proposed as paragraph (g)(2), requires employers
to select appropriate atmosphere-supplying respirators from among those
listed in Table 2 (Table 1 in the proposed rule), which sets forth the
minimum requirements for respiratory protection and is unchanged from
the proposal. Employers may use respirators approved for a higher level
of protection in lower concentrations of MC. Employers are required to
select atmosphere-supplying respirators that have been approved by
NIOSH under the provisions of 42 CFR Part 84. Also, employers must
select vapor canisters which have been approved by NIOSH when they
provide gas masks with organic vapor canisters for use in emergency
escape. The final rule differs from proposed paragraph (g)(2) in that
it does not require employers to give employees who cannot wear
negative pressure air-supplied respirators or who cannot wear a
negative pressure (organic vapor canister) during an emergency escape
the option of wearing a respirator with less breathing resistance. OSHA
believes that the respirators required by the final rule will not
strain an employee's respiratory system during such use.
Issue 30 (56 FR 57042) asked if the proposed respirator selection
table
[[Page 1585]]
(Table 1 in the proposal) appropriately regulated the choice of
respirators. Several commenters suggested changes. For example, Abbott
Laboratories [Ex. 19-29] suggested that OSHA allow the use of a
continuous flow air-supplied hood or helmet for exposures up to 5,000
ppm instead of 625 ppm of MC. On the other hand, the Laborers' Health &
Safety Fund of North America [Ex. 19-36] suggested that OSHA require
employers to provide positive pressure SCBAs or airline positive-
pressure full facepieces with auxiliary escape for all exposures over
25 ppm, instead of allowing any flexibility, in keeping with NIOSH
recommendations for respiratory protection against carcinogens. The
Advisory Committee on Construction Safety and Health [Ex. 21-69]
recommended that respirators, when used, be pressure-demand, supplied
air respirators with an auxiliary self-contained breathing apparatus,
because of MC's fast cartridge/canister breakthrough and the lack of
effective end-of-service-life indicators.
OSHA is currently in the process of developing a final standard to
revise its general respiratory protection provisions in 29 CFR
1910.134. Until that rulemaking is completed the Agency will continue
to rely on NIOSH's Assigned Protection Factors (APF) for determining
the types of respirators required for protection to airborne
concentrations of MC. The APF for continuous flow hoods/helmets is 25
in the NIOSH Respirator Decision Logic. The maximum specified use
concentration for a respirator is generally determined by multiplying
the exposure limit, in this case 25 ppm, by the protection factor,
which is 25; therefore, these hood/helmets could be used only up to 625
ppm of MC. Using the same decision logic, OSHA believes that adequate
protection can be provided by the respirators described in Table 2 when
they are used under appropriate exposure conditions.
Some commenters questioned the reliability of atmosphere-supplying
respirators. For example, in the furniture stripping industry
commenters noted that MC could cause damage or potential damage to the
hoses, the plastic lens, and the gasket of the facepiece of air line
respirators or other kind of respirators, resulting in inadequate
protection. [Ex. 19-11; Tr. 348-9, 9/17/92; Tr. 2146-7, 10/14/92; Tr.
2505-2506, 10/15/92]. In addition, the Occidental Chemical Corporation
[Tr. 2115, 10/14/92] noted that none of the manufacturers contacted had
hoses resistant to MC-induced corrosion. The Agency acknowledges that
MC may damage respirator components, if the MC is left on them for
extended periods of time. However, existing Sec. 1910.134 (f) already
requires employers to inspect respirators frequently and to maintain
respirators at their original effectiveness. In addition, MC does not
damage rubber components which are available. Most importantly, if
feasible engineering controls and work practices are not available,
properly utilized air-supplied respirators are the only way to protect
employee health from significant risk.
Issue 30 also requested information on the circumstances under
which air-purifying respirators may be used. Dr. Morton Corn of Johns
Hopkins University testified [Tr. 2352, 10/15/92] that ``* * * with the
current state of knowledge and the breakthroughs I indicated, [allowing
gas masks with organic canisters for emergency escape only] is a
prudent restriction at this time.''
Several commenters disagreed with Dr. Corn and remarked that there
are some situations where air-purifying respirators may be appropriate
in addition to emergency situations, and recommended that OSHA expand
the provision to allow the use of air-purifying (filter) respirators.
For example, Occidental Chemical testified [Tr. 2113-4, 10/14/92] as
follows:
Transportation workers who make deliveries in trucks can have
intermittent exposure to methylene chloride inside the truck and, if
you set the PEL too low, and in that emergency situation * * * you
can't have engineering controls on some types of trucks, especially
if they are rented. You ought to allow the use of respirators in
that case; it's a very short type exposure, goes in, takes the drum
out, and then gets back in the truck. Now it may be possible to
schedule operations in certain industries where the PEL is exceeded
for short periods of time. Filter cartridge respirators could be
used to protect the worker during the short periods of time without
the use of cumbersome supplied-air respirators. Of course, you have
to have changes in the regulated areas in the rules also if you're
going to allow the use of respirators where you have intermittent
exposures above the PEL.
And a short breakthrough time does not mean a respirator is
useless. If you use the NIOSH calculations, at 200 parts per million
which might be typical of paint stripping, you ought to have about
118 minutes worth of time before you get breakthrough; and that may
be enough in paint stripping operations.
Similarly, Bristol-Myers Squibb stated that air-purifying
respirators may be appropriate in certain circumstances [Ex. 19-14]:
Based upon the scientific information now in the record, BMS
requested that OSHA consider allowing chemical cartridge air-
purifying respirators for specific types of activities (lower MC
concentrations, shorter durations).
Organic vapor cartridges can be used for protecting employees
against exposures to MC where using an air-supplied respirator would
not be feasible due to costs or process (e.g. multiple working
areas). Only air-supplied respirators should be used for operations
involving the need for extended wear (e.g. greater than several
hours).
The Eastman Kodak Company [Ex. 102] also requested that OSHA allow
air-purifying respirators ``in circumstances where their effectiveness
can be adequately demonstrated, engineering controls are not feasible
and supplied-air respirators are impractical or potentially unsafe.
OSHA also should permit the use of half mask respirators'' [Tr. 1196-7,
9/22/92]. In addition, Kodak described specific situations where it
believed the use of air-purifying respirators was appropriate:
The use of air-supplied respirators must be an essential
component of the exposure-control strategies for both the Roll
Coating Division and the Dope Department. Moreover, the evidence
demonstrates that air-purifying canister or cartridge-type
respirators may appropriately be used in some operations, such as
certain dope maintenance tasks. The use of air-purifying respirators
is appropriate where: (1) air-supplied respirators or other controls
are impractical or potentially unsafe, (2) personal monitoring of
employees is conducted regularly, (3) the extremes and conditions of
the exposure potential are well characterized, and (4) used
cartridges are tested after use to verify the absence of
unacceptable breakthrough. It is essential that OSHA permit the use
of air-purifying respirators under these circumstances so that Kodak
can control employee exposure when engineering and work practice
controls and air-supplied respirators are infeasible, ineffective or
potentially unsafe.
OSHA considered including a provision in the final rule to allow
exceptions for the use of air-purifying respirators in limited
circumstances where very tight control of the respirator program is
implemented. However, the Agency has rejected this alternative for
several reasons. First, the record strongly supports the inadequacy of
such respirators for employee protection. Consequently, the use of air-
purifying respirators should only be considered when the use of air-
supplied respirators presents major disadvantages. Second, a program to
use air-purifying respirators would have to be very detailed and be
tailored to a specific workplace. It would be difficult, if not
impossible, to list all of the relevant factors and criteria for such a
program in the regulatory text, which must necessarily be appropriate
to apply to many workplaces. (Below, OSHA discusses the Agency's
variance procedures, which employers wishing to use air-purifying
respirators may use to apply for a variance.)
[[Page 1586]]
While there may be circumstances when the use of filter respirators
may seem preferable to the use of atmosphere-supplied respirators, OSHA
has concluded, as a general matter, that air- purifying respirators do
not provide sufficient, consistent, and reliable protection to
employees exposed to MC. In support of this conclusion, NIOSH testified
as follows [Tr. 887-89, 9/21/92]:
At the request of OSHA, NIOSH has completed an in-depth study of
the breakthrough characteristics of MC for organic vapor respirator
cartridges and canisters under a variety of test conditions. This
work was undertaken to determine MC breakthrough time for
commercially available, organic vapor respirator cartridges and
canisters. Several MC challenge concentrations were studied, ranging
from 50 ppm to 1,000 ppm. As received cartridges and canisters were
tested at equivalent flow rates of 64 Lpm through the respirator and
at both 50% and 80% relative humidities (RHs). Breakthrough times
were determined for individual cartridges and canisters, as well as
stacked cartridges. The results of this study show rapid
breakthrough of MC for organic vapor cartridges even for low
concentrations of MC (e.g., 5 ppm breakthrough at approximately 30
minutes for 50 ppm challenge concentration and 80% RH). Appendix D
is a detailed report of this study. At 125 ppm challenge
concentration, 5 ppm breakthrough, and 80% RH, one brand of
cartridge showed breakthrough times of approximately 40 minutes. The
same brand of chin-style canister, that contains approximately 2 and
\1/2\ to 3 times more sorbent than two cartridges (i.e., two
cartridges per respirator) showed breakthrough times of
approximately 100 minutes when tested at the same conditions. The
same brand of front- or back-mounted canister, that contains
approximately 10 times more sorbent than two cartridges, showed
breakthrough times of approximately 600 minutes. Based on the
results of this study, NIOSH supports the OSHA proposal to require
the use of air-supplied respirators in lieu of air-purifying
respirators. However, because of the potential carcinogenicity of
MC, NIOSH continues to recommend only the most protective positive-
pressure respirators as noted previously.
The NIOSH study indicated that MC quickly penetrates organic vapor
cartridges (in a fraction of a typical work shift), contrary to the
assertions of Occidental Chemical and the other commenters mentioned
above. Larger canisters, which contain greater amounts of absorbent,
last longer, but are still effective for less than a work shift (except
for very large canisters). Another problem with organic vapor
cartridges and canisters is that MC migrates through the absorbent even
when the respirator is not being used. This further decreases the
breakthrough time and raises the possibility that the employee will be
exposed to significant concentrations of MC. Also, humidity decreases
the amount of MC collected by the absorbent.
Another problem with air-purifying respirators in the case of MC is
this substance's poor warning properties, which mean that workers will
not be able to smell or sense the presence of MC when breakthrough
occurs. OSHA believes that employees wearing air-purifying respirators
could easily have a false sense of security and be lulled into
believing that they were being protected against MC when it could
already have broken through the absorbent. Accordingly, OSHA has
concluded that it would be inappropriate to allow broad-scale use of
air-purifying respirators because of MC's quick breakthrough time and
its carcinogenic health effects.
Employers who believe that the use of filter respirators is
appropriate for their operations may apply for a permanent variance
from the requirements of paragraph (g)(3) of this section, pursuant to
the authority granted by Sec. 6(d) of the Occupational Safety and
Health Act and the procedures set out in 29 CFR part 1905. In
particular, an applicant would need to establish that the use of filter
respirators in a specific workplace would provide employee protection
equivalent to that which would be provided through compliance with
final rule paragraph (g)(3). As discussed below, the respirator
program, procedures, and data needed to support the use of such
respirators under a variance are extensive.
A successful variance application for an exception that would allow
air-purifying respirators would have to address a number of the
characteristics that employers such as Eastman-Kodak [Ex. 102] indicate
they have undertaken with regard to the use of such equipment. For
example, extensive exposure monitoring would have to be done to
accurately characterize employee MC exposure levels. Furthermore, the
breakthrough time for MC when used in the airborne concentrations
expected in the workplace would have to be known, and cartridges would
have to be changed before employees are unacceptably exposed. The
program would have to be carefully monitored by a trained and
experienced individual such as a certified industrial hygienist or the
equivalent. Finally, the respirators would have to be appropriately fit
tested for each affected employee. For all of the reasons stated above,
OSHA has determined that the interests of employee protection will be
best served by requiring all employers, except those whose respiratory
program, procedures, and exposure data can support a variance request,
to provide their employees with the respirators shown in Table 2.
Paragraph (g)(4), which is identical to the proposed (g)(3),
requires employers to implement a respiratory protection program in
accordance with 29 CFR 1910.134 whenever respirator use is required by
this standard. The respiratory protection program must include basic
requirements for proper selection, fit, use, training of employees,
cleaning, and maintenance of respirators. For employers to ensure that
employees use respirators properly, OSHA has found that the employees
need to understand the respirator's limits and the hazard against which
it is providing protection in order to appreciate why specific
requirements must be followed.
Paragraph (g)(5) (effectively identical to proposed paragraph
(g)(4)) requires that employers allow employees wearing respirators to
leave the regulated area to readjust the respirator facepiece to their
faces for proper fit. In addition, employers must permit employees who
wear respirators to leave the regulated area to wash their faces as
necessary to prevent skin irritation associated with respirator use.
These requirements encourage the proper use of respirators by
authorizing employees to take specific actions that ensure the
effective functioning of respirators and reduce the likelihood that
employees will experience adverse side effects from wearing
respirators.
Paragraph (g)(6), which is essentially the same as the
corresponding proposed paragraph, addresses situations where employers
provide gas masks with organic vapor cartridges for purposes of
emergency escape. If gas masks are used, the canisters are to be
replaced before the gas masks are returned to service. This requirement
is necessary because actual MC exposures during emergencies are
generally not known, so the expected service life of the canister
cannot be determined. In addition, the migration of MC within the
canister after emergency exposure further reduces the amount of useful
life remaining, posing exposure risks for subsequent users.
Paragraph (g)(7) addresses respirator fit and is essentially
identical to the corresponding provision of the proposal. It requires
the employer to ensure that each respirator issued is properly fitted
and has the least possible facepiece leakage.
Under paragraph (g)(7)(ii), the employer must perform qualitative
or quantitative fit testing initially and at
[[Page 1587]]
least annually thereafter for each employee wearing a negative pressure
respirator, including those employees for whom emergency escape
respirators of this type are provided. A note has been added to this
provision to indicate clearly that the only supplied-air respirators to
which this provision would apply are SCBAs operated in the negative
pressure mode and full facepiece supplied-air respirators operated in
negative pressure mode. Quantitative fit testing relies on objective
data generated by measurements of facepiece seal leakage, in contrast
to qualitative fit testing, which is based on subjective observations
made by the respirator wearer. Many commenters expressed a preference
for quantitative fit testing over qualitative fit testing. For example,
Newport News Shipbuilding (NNS) [Ex. 19-37, p. 2] stated:
``Quantitative respirator fit testing is the method of choice. At NNS
we use quantitative fit testing exclusively, as this method is more
definitive than qualitative fit testing and provides a record of the
fit test.'' The Shipbuilders Council of America [Ex. 19-56, p. 11] took
the same view.
Several commenters noted the importance of proper selection and fit
testing of respirators [Exs. 19-12, p. 3; 19-31, pp. 15-17; 19-71, p.
4]. Dr. David Newcombe of the Department of Environmental and Health
Sciences at The Johns Hopkins University testified as follows:
I think that's [quantitative fit testing] a very important
parameter because, first of all, respiratory protection when it's
required takes a reasonable amount of time to ensure that the
individual is properly fitted so that the mask fits if that's the
piece that's going to be used and is protective against the
substance that you're protecting against and, in addition, I think
it's important to note that some people may have deformities that
cause a poor fit and, therefore, don't protect and so I would think
that you have to have a careful assessment of the type of
respiratory protection you're going to use, its fit in a single
individual as well [Tr. 800, 9/18/92].
In most cases, OSHA has determined that positive pressure
respirators are the respirators of choice for MC exposure, especially
loose-fitting models such as hoods or helmets; for these respirators,
fit testing is generally not needed. However, for those situations
where negative pressure respirators are used, fit testing is needed.
Qualitative or quantitative fit testing allows the employer to test
various respirators on the employee until the appropriate fit is
identified and selected for the employee.
Paragraph (h) Protective Work Clothing and Equipment
Paragraph (h) requires that, where needed, employers provide and
ensure the use of the appropriate protective clothing and equipment.
The requirements for protective work clothing and equipment were
separated from proposed paragraph (g) (respiratory protection and
personal protective equipment) and moved to paragraph (h) to facilitate
compliance. Proposed paragraph (g)(6) was effectively identical to this
paragraph.
Protective clothing used during exposure to MC, such as gloves or
aprons, must be resistant to MC. The Building and Construction Trades
Department, AFL-CIO [Tr. 832, 9/21/92] suggested that OSHA codify
NIOSH's recommendations for protective clothing materials suitable for
use with MC. MC is a constituent of so many different products that a
codification of guidance regarding appropriate protective clothing
would be unwieldy and unlikely to be complete. Further, the continual
formulation and reformulation of MC products virtually ensures the
early obsolescence of any protective clothing guidelines.
Therefore, OSHA believes that it is appropriate for paragraph (h)
to set general criteria and for the Agency to adopt the NIOSH
recommendations in a nonmandatory appendix so employers will have more
detailed guidance and so OSHA can update that guidance, without
rulemaking, as advances in PPE technology cause existing guidance to
become outdated. As discussed above, this performance-oriented approach
reflects OSHA's belief that employers are in the best position to
select protective measures that are tailored specifically to the needs
of their workplaces.
Paragraph (h) requires the employer to provide all necessary
protective clothing and equipment at no cost to the employee and to
launder, repair, replace and safely dispose of that clothing and
equipment. The final rule is performance-oriented so the employer has
the flexibility to provide only the protective clothing and equipment
necessary to protect employees in each particular work operation from
MC exposure. The generic requirements for PPE in the general industry,
construction, and shipyard standards also apply to PPE for MC, except
where a specific provision of the MC standard applies.
Paragraph (i) Hygiene Facilities
Paragraph (i) of the final rule establishes requirements for
hygiene facilities in establishments where it is reasonably foreseeable
that an employee's eyes or skin may contact solutions containing 0.1
percent or greater MC. Although such provisions were not part of the
proposed rule, OSHA requested comment on the appropriateness of
including such requirements in Issue 38 (56 FR 57122). Specifically,
the Agency requested comment on the appropriateness of including
requirements for quick-drench showers and eye-wash facilities in the
final rule. OSHA described quick-drench showers as,'' * * * showers
that could drench an employee with piped-in water applied with force,''
and eyewash facilities as devices ``that could flush the eyes
repeatedly with a great amount of water.'' In response to comments,
described below, the Agency has decided that it is not necessary to
specify in the final rule when showers and eyewash facilities are
required to protect employees from skin or eye contact with MC, because
employers are in the best position to determine whether the MC used in
their establishments meets the 0.1 percent cutoff specified in this
provision and whether contact of the eyes or skin with MC can
reasonably be foreseen.
Paragraph (i)(1) requires employers to provide conveniently located
washing facilities appropriate to removing MC if it is reasonably
foreseeable that the employee's skin may contact a solution containing
0.1 percent or greater MC through splashes or spills. MC can be
absorbed into the body through skin contact (percutaneous absorption),
which would add to the dose employees receive via inhalation and thus
increase the risk of cancer and other adverse health effects. However,
MC is not a corrosive chemical, and, if left on the skin for short
periods, is not likely to cause long-term or irreversible damage.
Therefore, it is important that employers make provisions to remove MC
from the skin of employees quickly, although immediate drenching is not
usually required. This requirement has been stated in performance-
oriented language in the final rule to allow employers to determine
what type of washing facilities are needed and at what distance from
affected employees. This provision thus recognizes that employers in
some facilities, such as furniture stripping shops where a thick MC gel
is used that may burn the skin on contact, employers need to position
washing facilities in closer proximity to affected employees than is
the case where less hazardous solutions of MC are used. OSHA believes
that this requirement of the final rule strikes the
[[Page 1588]]
right balance between employee protection and employer flexibility by
ensuring that washing facilities for the skin will be available and
appropriately placed in workplaces where such contact is likely.
MC splashed into the eyes will cause irritation if the MC is not
promptly washed out, and immediate flushing is therefore required.
Paragraph (i)(2) requires employers to provide appropriate eyewash
facilities within the immediate work area for emergency use if it is
reasonably foreseeable that an employee's eyes will contact solutions
containing 0.1 percent or greater MC through splashes or spills.
Existing OSHA requirements at Sec. 1910.141 and Sec. 1926.51
establish generic provisions for hygiene facilities but do not focus on
MC-specific situations. Existing Sec. 1910.151(c) and Sec. 1926.50 (g)
require employers to provide suitable facilities for quick-drenching or
flushing of body and eyes within the immediate work area for immediate
emergency use, when the body or eyes may be exposed to injurious
corrosive materials. However, because MC is not classified as a
corrosive material, these existing requirements would not apply. Thus
the final rule's performance-oriented requirements will provide
guidance to employers about what facilities and access distances are
appropriate for conditions in their workplaces. In addition, Appendix A
provides examples of both washing facilities and eyewash facilities
that would satisfy this requirement.
The response to Issue 38 emphasized the need for eyewash and shower
facilities [Exs. 19-37, 19-56; Tr. 2644-2645, 10/16/92; Tr. 1942-1943,
9/24/92]. For example, PRMA testified [Tr. 348, 9/17/92] that MC
splashes happen ``almost every day'' in furniture stripping workplaces.
Commenters also addressed the health effects associated with such
accidental exposures. The Amalgamated Clothing and Textile Workers
Union testified [Tr. 1825, 9/24/92]:
I would advocate including it [the provisions for showers and
eyewash facilities]. It [methylene chloride] has skin effects.
Anyone who's ever stripped paint can tell you about what it's like
to get it on their skin or their eyes. So it's very important to be
able to irrigate an affected area promptly.
One means to provide protection from prolonged skin or eye exposure
to MC from accidents is to specifically require quick-drench showers
and eyewashes. The NPRM sought comments on whether or not the final
rule should require employers to provide quick-drench showers and
eyewash facilities. Many commenters recommended that the final rule
contain such provisions [Exs. 19-15; 19-36; Tr. 532, 9/18/92; Tr. 1380,
9/23/92; Tr. 2352-53, 10/15/92]. For example, PRMA [Ex. 19-11] favored
a requirement for eyewash/ quick drench facilities, stating as follows:
An eyewash station is a safety device that should be required in
any work environment where there is the possibility of splashing
chemicals into ones eyes. Quick drench showers are also a safety
device that should be standard equipment in every facility. MC paint
removers are one of the few paint removers that are easily rinsed
from one's eyes.
The Dow Chemical Company commented [Ex. 19-31]:
Washing facilities are always a good idea when working with any
material, however, it is not always necessary to have quick-drench
showers, etc. Incidentally, quick-drench showers do not deliver
water ``applied with force.'' They work on a deluge system
delivering a large amount of water to wash off the material, not
force it off. Installing showers and eyewash fountains in all
workplaces may not be economically feasible. There are other systems
such as water hoses, portable eye-washes, etc. that work effectively
for MC. MC is a material that, in some cases, may be painful if held
against the skin for a period of time, but is not eye nor skin nor
life threatening. Therefore, an immediate shower is not required.
OSHA agrees that quick drench and eyewash facilities are effective
means for treating employees who have been accidentally exposed to MC
by spills or splashes. However, the Agency agrees with Dow Chemical
that quick drench showers are not the only means to ensure proper first
aid treatment for MC exposure due to accidental splashes or spills and
believes that other types of washing facilities can also provide
effective treatment for accidental exposure.
In some cases, the availability of a hose attached to a potable
water supply would enable employers to provide effective first aid
treatment. This could be an especially effective means of protection at
a construction worksite. Several commenters [Ex. 19-23, 19-38; Tr. 859,
9/21/92] agreed that construction employers should have potable water
at the worksite in case of accidental exposure. For example, the
Building and Construction Trades Department, AFL-CIO, testified [Tr.
817, 9/21/92]:
The standard does not address the need for available hygiene
facilities. Since methylene chloride can damage the skin and eyes
and potable water is often in limited supply on construction sites,
the requirement for potable washing areas must be clearly stated in
the standard. Potable water supplies should be of sufficient volume
to provide at least 15 minutes of continuous flushing.
The Occupational Health Foundation testified that the MC standard
should require that hygiene facilities be provided within a reasonable
distance at construction worksites [Tr. 858-859, 9/21/92]:
Unlike in a lot of other work sites where at least there's a
sink nearby, in construction you really need to specifically mandate
that provision to be sure that there's going to be water anywhere
remote, you know, within a reasonable distance to the work site.
Issue 38 also requested information on the extent to which MC-
exposed employees are already provided with quick drench showers and
eye wash facilities. Several commenters described workplaces that have
emergency shower or eyewash facilities in place. The United Automobile,
Aerospace and Agricultural Implement Workers of America (UAW) testified
[Tr. 1942-1943, 9/24/92] ``[t]here are a lot of showers and eye washes
in areas where you have open-top chemicals or use of chemicals.'' In
addition, the Occidental Chemical Corporation testified [Tr. 2159, 10/
14/92]:
. . . we conducted a survey of our customers that were not CMA
and not NACCD members recently and asked them questions like that.
We have some information on that. It doesn't necessarily mean that
we hit a large percentage of our methylene chloride customers,
though.
. . . we have safety shower[s] and eyewash[es] [in our plants],
certainly. We have . . . recommendations on it and we certainly
follow the ANSI standards on it.
Newport News Shipbuilding (NNS) and the Shipbuilders Council for
America both commented [Exs. 19-37 and 19-56] that ``[p]rocedures at
NNS now require eyewash units. For the most part we use portable (5
gallon) units. Plumbed combination units would be better.'' The
National Tank Truck Carriers, Inc. also indicated that their facilities
are already equipped with emergency showers [Tr. 1750-51, 9/24/92].
With regard to the proximity of employees to emergency showers and
eye washes, commenters and testimony indicated that, depending on the
work operation, shower facilities have been installed as close as eight
feet or as far away as 100 feet. For example, the J. M. Murray Center,
testified [Tr. 1047-48, 9/21/92] that they have both eye washes and
showers that are ten to twelve feet from the employees.
The Polyurethane Foam Association (PFA) testified [Tr. 1630, 9/23/
92] that the proximity of shower facilities and eye washes depends on
the plant and
[[Page 1589]]
operation within the plant, stating as follows:
We've got methylene chloride in bulk storage area and we also
use it at the foam machine. The total range from those things that
you might be would be anywhere from eight feet to may be 60 feet.
And I'm guessing at the 60 feet. That, again, is specific for those
plants that I am responsible for. There are 80-some-odd plants out
there, and I can't speak for that particular physical setup in each
one of those plants.
The PFA further stated in its post hearing comment:
Eye wash and drench showers are available in the production
areas. These are located within 10 to 15 feet of the work stations,
such as near bulk storage tanks and the mixing head, where a higher
risk of employee exposure exists. Hygiene facilities may be 50 to 75
feet away from other work areas [Ex. L-100A].
The Eastman Kodak Company testified [Tr. 1259, 9/22/92] that
emergency eye-wash and quick-drench showers are available in their
workplaces, and that such stations are between 50 and 100 feet from all
work areas where exposure to chemicals may occur.
Striptech International, which advocated requirements for pressure
showers and eyewash facilities where workers are exposed to MC [Ex. 19-
15], also testified that hygiene facilities are not readily accessible
in the aircraft paint stripping industry [Tr. 1834-35, 9/24/92]:
I've heard people ask about deluge in eye wash. Does it exist in
aircraft maintenance hangars? Yes, it surely does; but you also have
to look at where they normally are. They're normally on the walls.
When a man or a lady is on top of an aircraft, on the tail of an
aircraft, they may be nine stories in the air. If they get methylene
chloride in their eyes or really a bad shot of it, they've got to
come down nine stories and may be cross a 400 to 600-foot-long
hangar to get to it. Deluge showers, yes; all aircraft people have
them. Are they readily accessible? No.
It is important for the employer to evaluate the potential hazard
posed by the particular use of MC and to provide appropriate washing
facilities within a reasonable distance and eyewash facilities within
immediate reach. In addition, employers are required to provide
employees who are at risk of skin and/or eye contact with MC with
appropriate protective clothing and eye protection. Portable eyewash
units, which would significantly reduce any delay in irrigating the
eyes, are available and can be located within easy access distance of
affected employees. As described above, access to washing facilities
should be quick, but immediate showering is not generally necessary to
address the MC skin hazard. Therefore, an employee stripping an
airplane would likely have time to get to the showers located along the
walls of the hangar to wash MC from the skin. (Note: Some paint
stripping compounds do contain corrosives, and immediate access to
quick-drench facilities is essential in such cases.) Based on a review
of the rulemaking record, the Agency has determined that performance-
oriented provisions for hygiene facilities are reasonably necessary to
supplement the other requirements of the final rule and has promulgated
paragraph (i) accordingly.
Paragraph (j) Medical Surveillance
Section 6(b)(7) of the OSH Act requires that, where appropriate,
occupational health standards shall prescribe the type and frequency of
medical exams or other tests to be made available, by the employer or
at the employer's cost, to exposed employees in order to determine if
the employee's health is being adversely affected by exposure to
workplace hazards.
A medical surveillance program that complies with paragraph (j)
enables the employer to:
(1) Determine if an employee has an underlying health condition
that places the employee at increased risk from the effects of exposure
to MC;
(2) detect, insofar as possible, early or mild clinical conditions
arising as a result of MC exposure, so that appropriate preventive
measures can be taken;
(3) identify any occupational diseases that occur as a result of MC
exposure; and
(4) help to evaluate possible trends in the incidence of these
diseases.
The most serious health effect that may result from MC exposure is
cancer. Although a medical surveillance program cannot detect MC-
induced cancer at a preneoplastic stage, OSHA anticipates that, as in
the past, methods for early detection and treatments leading to
increased survival rates will continue to evolve. Moreover, the
cardiovascular disease, central nervous sytem and dermal irritation
effects caused by MC exposure can already be detected at early or mild
stages by medical surveillance provisions such as a medical history and
a medical exam. MC has not been tested adequately for the full range of
possible health effects that may result from exposure, so it is also
not presently possible to identify all diseases that may be associated
with exposure to MC. The specific level of protection afforded the
worker by the final standard cannot be predicted with certainty,
although the risk of exposure for those effects that have been
identified are significant, and the record shows that reducing the
exposure of employees will significantly reduce that risk. An important
goal of the medical surveillance program is to provide information
related to the adequacy of the PELs for MC by documenting the health
condition of exposed employees, particularly in the area of
carcinogenicity.
Several rulemaking participants [Exs. 19-31, 19-83, Tr. 1802-3, 9/
24/92] stated that the proposed medical surveillance provision should
be deleted from the final rule because it would not detect employee
exposure to harmful levels of MC. In addition participants contended
[Ex. 19-83, Tr. 458, 9/17/92] that the medical surveillance provision
is too expensive and burdensome. OSHA has determined that the medical
surveillance program required by the final rule is reasonably necessary
for the protection of workers. In particular, medical surveillance will
directly benefit workers with cardiovascular disease, central nervous
system effects, and dermal irritation. These conditions can be detected
by the medical surveillance program required by this paragraph of the
final rule, and the detection of such conditions can, in turn, alert
the employer to potential overexposures to MC in the workplace and to
the need to limit MC exposures for certain employees with underlying
heart disease or other conditions.
In addition, by increasing the performance orientation of the rule,
OSHA has minimized the costs of medical surveillance while maintaining
its effectiveness. For example, the final rule leaves the content of
laboratory surveillance for individual employees to the discretion of
the physician or other licensed health care professional. Also, the
requirement for a physical examination has been tailored to the age of
the employee, so that employees younger than 45 generally receive an
exam only every three years, instead of annually. The medical
surveillance program also will aid in the evaluation of cancer
incidence in the workplace and temporal trends therein.
Paragraph (j)(1) specifies the circumstances under which employers
must provide medical surveillance for employees who are or may be
exposed to MC. Under paragraph (j)(1)(i), employers must make medical
surveillance available to all employees who are exposed to MC at or
above the action level for 30 days or more in any year or above either
of the PELs for at least 10 days in any year. This provision is
effectively identical to the corresponding provision of the
[[Page 1590]]
proposed rule. Also, this requirement is consistent with the approach
taken by OSHA in the benzene standard (29 CFR 1910.1028). OSHA
recognizes that the health effects associated with MC exposure are, in
general, the result of chronic exposures to MC. Accordingly, employees
exposed only for a few days in any year will be at relatively low risk
of developing MC-induced disease. The exposure duration thresholds in
the final rule will thus enable employers to focus valuable medical
resources on high-risk employees.
Some commenters were concerned about the use of the PELs and action
level as triggers for medical surveillance. The Building and
Construction Trades Department, AFL-CIO [Tr. 817, 9/21/92] was
concerned that this provision would preclude medical surveillance for
some employees with MC exposures that exceeded the PELs on fewer than
10 days in a given year but who might nonetheless be at risk of adverse
health effects. OSHA has determined that employees who have been
identified by a physician or other licensed health care professional as
being at risk for cardiac disease or some other serious MC-related
health condition and who are exposed to MC at levels that exceed the
PELs on fewer than 10 days in any year should have the option of
participating in a medical surveillance program. Accordingly, paragraph
(j)(1)(ii) has been added to the final rule. This provision states that
medical surveillance must be provided to any employee (1) who is
exposed above the 8-hour TWA PEL or STEL for any time period, and (2)
who has been identified by a physician or other licensed health care
professional as being at risk from cardiac disease or from some other
serious MC-related health condition, and (3) who requests inclusion in
the medical surveillance program. As noted in the Health Effects
section, above, OSHA is concerned that any MC exposure above either of
the PELs could exacerbate cardiac problems. This paragraph enables such
high-risk employees to participate in a medical surveillance program.
Under paragraph (j)(1)(iii), appropriate surveillance is required
to be made available to employees exposed in an emergency regardless of
the airborne concentrations of MC normally present in the workplace.
Where very large amounts of materials are kept in a sealed system,
routine exposure may be very low. However, rupture of the container
might result in extremely high MC exposures. Thus, it is appropriate
for employers who have identified operations where there is a potential
for an emergency involving MC to plan ahead so that emergency medical
surveillance would be available if needed. This provision is
effectively identical to proposed paragraph (i)(1)(iii).
Proposed paragraph (i)(1)(ii) would have required that the employer
have the examining physician or other licensed health care professional
determine if affected employees are physically fit to wear respirators.
OSHA has placed this requirement with the other respiratory protection
provisions in paragraph (g) of this final rule.
Paragraph (j)(2) requires that employers offer examinations without
cost to employees, at a reasonable time and place, and without loss of
pay. OSHA believes that this provision is necessary to encourage
employees to participate in the medical surveillance program. Final
rule paragraph (j)(2), which is essentially identical to proposed
paragraph (i)(2), is also consistent with other OSHA health standards
and with provisions contained in the OSH Act.
Paragraph (j)(3) requires that all medical procedures be performed
by or under the supervision of a physician or other licensed health
care professional, defined as ``an individual whose legally permitted
scope of practice (i.e., license, registration, or certification)
allows him or her to independently provide or be delegated the
responsibility to provide some or all of the health care services
required by paragraph (j) of the standard.'' The proposal required that
all medical procedures be performed only by or under the supervision of
a physician. Only one commenter [Ex. 19-31] specifically supported this
provision.
OSHA has long considered the issue of whether and how to identify
the particular professionals who are to perform the medical
surveillance required by its health standards. The Agency has
determined that other professionals who are licensed under state laws
to provide medical surveillance services would also be appropriate
providers of such services for the purposes of the MC standard. The
Agency recognizes that the personnel able to provide the required
medical surveillance may vary from state to state, depending on state
licensing laws. Under the final rule, an employer has the flexibility
to retain the services of a range of qualified licensed health care
professionals, thus potentially reducing costs, increasing flexibility,
and allowing employers to identify those professionals, who may not
necessarily be physicians, with the greatest expertise in diagnosing
and treating occupational diseases. In future rulemakings, OSHA may
attempt, with the cooperation of interested stakeholders, to specify
which licensed health care professionals are the most appropriate to
perform each of the diagnostic, therapeutic, medical management and
other services required by the Agency's standards.
Paragraph (j)(4) of the final standard addresses when medical
examinations and consultations are to be provided.
Initial surveillance. Under paragraph (j)(4)(i), initial medical
surveillance must be provided before an employee's initial assignment
to work in an area where they would be exposed to MC or by the start-up
dates described in paragraph (n)(2)(iii) of the final MC standard,
whichever is later. The employer need not repeat equivalent medical
surveillance if it has already been provided within the past 12 months.
OSHA's requirement for a preplacement examination is intended to
determine if an individual is at increased risk of adverse effects from
exposure to MC. It also establishes a general baseline for future
reference. The provisions of final rule paragraph (j)(4) are
effectively identical to those in proposed paragraph (i)(3), except
that the proposed rule did not take into account medical surveillance
provided prior to the effective date of this section. In the preamble
to the NPRM (56 FR 57124), OSHA stated that it was considering a
provision that would give employers credit for medical examinations
provided within one year of the standard's effective date. The Agency
requested comment on the usefulness of such a provision. Commenters
[Exs. 19-31, 19-55b, 19-83] supported such a provision. In particular,
Dow Chemical [Ex. 19-31] stated ``[i]f this is not done this section
will be unfair to those employers who have on-going health surveillance
programs.'' OSHA agrees with these commenters and has promulgated the
final rule accordingly.
Periodic surveillance. Paragraph (j)(4)(ii) addresses periodic
medical surveillance. OSHA proposed to require annual medical
surveillance for all affected employees. In the final rule, this has
been changed so that the employer is required to update the medical and
work history for each affected employee every year but must only
provide physical examinations on a schedule that varies with the age of
the employee. For affected employees 45 years of age or older, the
physical examination must be conducted every year. For employees less
than 45 years of age, the examination need only be done every three
years.
[[Page 1591]]
OSHA differentiated these groups of employees in an effort to
target surveillance resources effectively. The probability of
developing heart disease (which can be exacerbated by MC exposure)
increases as employees age. Age 45 is a rough approximation of the
point at which medical professionals would have heightened concern for
cardiac effects. In other words, it is generally more likely that
employees 45 years and older would experience the adverse cardiac
effects of MC exposure. Three-year intervals between physical
examinations for workers younger than 45 seemed the proper interval to
balance the conservation of valuable medical resources and the
provision of a medical surveillance program that is useful for
detecting adverse MC health effects. The annual updates on medical and
work history will enable the physician or other licensed health care
professional to identify those individuals for whom more frequent
examinations would be appropriate.
To a lesser extent, this would be true for the detection of MC-
induced cancer as well. Although MC-induced cancer cannot currently be
detected at the pre-neoplastic stage, early detection of cancer
generally increases the survival rate, so it is important to include
employees exposed to MC in a medical surveillance program that may
detect tumors. Since any cancers caused by MC are more likely to be
found in older employees and employees exposed to MC for longer
durations, it is reasonable to concentrate medical surveillance
resources on older employees.
The main goal of periodic medical surveillance for workers is to
detect adverse health effects at an early, and potentially still
reversible, stage. The intervals chosen based on the age of the
employee are consistent with this purpose and with other OSHA health
standards. The Agency believes that these periodic surveillance
requirements strike a proper balance between the need to diagnose
health effects, such as cancer, at an early stage, thus increasing the
effectiveness of medical intervention, and the expectation that a
limited number of cases will be identified through the surveillance
program. This approach decreases the cost burden of surveillance by
lengthening the period of time between examinations for younger
employees who have fewer years of exposure and thus have a lower risk
of adverse health effects.
Termination of employment or reassignment. Paragraph (j)(4)(iii)
requires the employer to provide medical surveillance when an employee
terminates employment or is reassigned to an area where exposure is
consistently at or below the action level and the STEL. The termination
examination need not be conducted if medical surveillance has been
performed within the past six months. This requirement reduces the
likelihood that an employee who terminates employment has an active,
but undiagnosed, disease related to his or her MC exposure. In the
NPRM, OSHA had proposed that the termination examination be performed
unless medical surveillance had been conducted on that employee within
the past three months. The Motor Vehicle Manufacturers Association [Ex.
19-42] requested that the exam should only be required if the employee
has not had a medical exam within six months of termination or
reassignment, instead of three months as had been proposed. The MVMA
stated that ``six months is adequate and consistent with other OSHA
health standards (Cadmium, Sec. 1910.1027(l)(8)). We see no
contribution to reducing employee risk from examining such employees at
an earlier date, especially since the exposure to methylene chloride
has been removed.'' Upon reconsideration of the issue, OSHA has adopted
this suggestion in the final rule.
The Agency requested public comment on whether continued annual
surveillance should be offered to employees who have left employment,
retired, or transferred to other areas within the employer's
operations. Such an approach would be consistent with the requirement
in the Benzene standard (29 CFR 1910.1028), which makes medical
surveillance available to certain employees who have been exposed to
benzene during their employment with their current employer. Several
commenters [Exs. 19-31, 19-38, 19-42, 19-48, 19-55b, 19-58] stated that
there should be no medical surveillance after an employee leaves a job
in an exposure area or for employees previously exposed to MC. In
particular, Dow Chemical [Ex. 19-31] stated: ``[W]e do not believe that
the employer should be responsible for continued medical surveillance
for employees who leave MC exposure areas * * *. [T]he continued
surveillance does nothing more than divert occupational medical
resources from more important work.'' Taking a different view, the IUE
[Tr. 533, 9/18/92] testified that formerly exposed retirees should be
included in the medical surveillance program. They also stated that
retirees, presently employed workers formerly exposed to MC in previous
jobs, and workers relocated to nonexposed areas should be included in
the medical surveillance program. The ACTWU agreed, testifying [Tr.
1763-1764, 9/24/92] that employees who continue to work for the same
employer after their exposure to MC is terminated should be entitled to
participate in the medical surveillance program.
OSHA has decided that it would be inappropriate to include retirees
and other formerly exposed employees in the medical surveillance
program. A major value of medical surveillance is to detect the acute
heart disease and CNS effects associated with MC exposure. Workers no
longer exposed to MC, or retirees, would be at much less risk of
experiencing these effects.
Additional surveillance. Paragraph (j)(4)(iv) requires employers to
provide additional surveillance when the physician or other licensed
health care professional recommends that it be provided. This may be
warranted, for example, for an employee who is under 45 years of age
but has a health condition that requires surveillance more frequently
than every 3 years. Inclusion of this provision in the final rule will
ensure that all employees receive the most appropriate level of
surveillance for their particular health situation. The proposed
provision was essentially identical.
Paragraph (j)(5) of the final rule, like paragraph (i)(4) of the
proposal, establishes the requirements for the content of medical
exams. This provision requires a comprehensive medical and work
history, a physical examination, laboratory surveillance, and any
additional information determined to be necessary by the physician or
other licensed health care professional. The language in the proposed
rule, which was similar, has been revised for clarity and to provide
guidance about what constitutes adequate medical surveillance. For
example, the final rule addresses medical and work history in greater
detail than the proposal because, in some cases, three years may elapse
before a subsequent physical examination is provided. On the other
hand, the specific content of the physical examination and laboratory
surveillance has been left largely to the discretion of the physician
or other licensed health care professional.
Paragraph (j)(5)(i) requires that a comprehensive medical and work
history be obtained from each participating employee. This paragraph
requires a medical evaluation that includes a comprehensive medical and
work history with special emphasis on neurological symptoms, skin
conditions, history of hematologic or liver disease,
[[Page 1592]]
signs or symptoms suggestive of heart disease (angina, coronary artery
disease), risk factors for heart disease, MC exposures, and the work
practices and personal protective equipment used to control exposures.
OSHA has included an example of a medical and work history format that
would satisfy this requirement in non- mandatory Appendix B of the
standard. The proposed provision required a comprehensive or interim
medical and work history with emphasis on neurological symptoms, mental
status, and cardiac health. Final rule paragraph (j)(5)(i) has been
revised to indicate clearly what is required.
The medical and work history component of the initial medical
evaluation will assist the physician or licensed health care
professional in identifying pre-existing conditions that might place
the employee at increased risk when exposed to MC. It also establishes
a health baseline for future monitoring. The subsequent annual updates
will identify changes in neurological symptoms, skin conditions or
cardiac health, and, in combination with laboratory analyses and
information on exposure history, may provide early warnings of MC
toxicity. The information derived from a medical evaluation assists the
physician or other licensed health care professional in distinguishing
between MC-related effects and those effects that are unrelated to MC
exposure. This information is particularly important because the health
effects associated with MC exposure are not unique to such exposure.
For example, the proposed requirement to assess mental health status
has been eliminated from the final rule because no specific correlation
has been demonstrated between mental health status and MC exposure.
Paragraph (j)(5)(ii) requires that the extent and nature of the
required physical examinations be determined by the physician or
licensed health care professional based on the health status of the
employee and analysis of the medical and work history for that
employee. The standard also requires that the examiner give particular
attention to the lungs, cardiovascular system (including blood pressure
and pulse), liver, nervous system and skin. Proposed paragraph
(i)(4)(ii) specifically would have required that the examination
address the lungs, liver, nervous system and breast. OSHA has
determined that, in order to indicate clearly that the physician or
licensed health care professional should assess the potential cardiac
health impacts of MC, the medical exam should give attention to the
cardiovascular system, blood pressure and pulse. In addition, the
Agency has decided that, because of the skin irritation effects of MC,
it is necessary to include evaluation of the skin in the medical exam.
Two hearing participants [Tr. 803, 9/18/92; Tr. 2434-35, 10/15/92]
testified that men over 40 years old should be given electrocardiograms
(ECGs), which should be repeated every 1 to 3 years. OSHA is not
requiring ECGs because there is no evidence in the record that
associates specific changes in ECGs with MC exposures. However, the
physician or licensed health care professional has the discretion to
order an ECG for any employee where it is deemed appropriate.
Proposed paragraph (i)(4)(iv) also required the physician to make a
determination of any reproductive difficulties of the employee. Vulcan
Chemicals [Ex. 19-48] and Organization Resources Counselors (ORC) [Ex.
19-51] commented that the evidence for a relationship between
reproductive effects and MC exposure did not warrant inclusion of such
a provision in the final rule. OSHA agrees with these commenters that
the evidence associating MC exposure and specific reproductive health
effects is sparse. Therefore, the Agency has not included reproductive
effects in the list of effects the physician or other licensed health
care professional should focus on. However, the Agency will continue to
monitor the literature to determine if future evidence indicates that
inclusion of this provision is warranted.
Two commenters [Exs. 19-28, 19-42] stated that the breast
examination requirement should be eliminated from the final rule
because breast exams would be highly unlikely to identify effects
related to exposure to MC. In the proposal OSHA placed attention on the
breast because of concern raised by the increased number of breast
tumors in the rat bioassay. Upon further consideration, OSHA has
dropped the requirement for breast exams. The Agency notes that rats
are particularly sensitive to mammary tumors and it is unclear that
humans have similar risks of developing breast cancer after exposure to
MC. The Agency remains concerned about the potential for MC
carcinogenicity evidenced by the rat mammary tumors, however, and has
relied, in part, on mammary tumor data in identifying MC as a cancer
hazard.
In final rule paragraph (j)(5)(iii), laboratory surveillance of
employees is to be conducted as the examining physician or licensed
health care professional determines to be necessary and appropriate,
based on the employee's health status and the medical and work history.
This is a more performance-oriented provision than the corresponding
provision of the proposed rule. The proposal would have required
several specific laboratory tests, while the final rule leaves
laboratory test requirements to the discretion of the physician or
other licensed health care professional. Non-mandatory Appendix B
includes guidance regarding the types of tests that may be appropriate.
Some commenters [Exs. 19-28, 19-42, 19-48, 19-49] stated that COHb
levels, which had been included among the tests in the NPRM, are not a
good measure of toxic exposure to MC. In particular, the MVMA [Ex. 19-
42] stated that it is difficult to determine the COHb level
attributable to MC exposure for employees who are smokers or who may
have other exposures to CO. Several other participants [Exs. 19-25, 19-
57, 19-83 and Tr. 1438, 9/23/92] suggested that COHb testing should be
done only after over-exposure to MC, such as after an emergency. The
Laborers Health and Safety Fund [Tr. 1386, 9/23/92] testified,
[W]e're not convinced that that's [COHb monitoring] an
appropriate and accurate measure of exposures, given other sources
of carbon monoxide on construction sites as well as the issue of
smokers versus non-smokers.
However, the Department of the Army [Ex. 19-55b] suggested that
COHb levels are a more cost-effective measurement of the oxygen-
carrying capacity of blood than a complete blood count. Similarly, the
California Department of Health Services [Ex. 19-17] requested that
references to COHb testing be moved from the appendix to the regulatory
text.
COHb levels greater than 3% can exacerbate angina symptoms,
decrease exercise tolerance and increase risks for myocardial
infarctions (heart attacks) in susceptible individuals. COHb
concentrations can also be used as a rough estimate of worker exposure
to MC (taking into consideration smoking behavior, time since exposure,
and exposure to other CO sources) to calibrate personal MC monitoring
measurements. Before- and after-shift COHb determinations can be useful
in correlating recent MC exposures with COHb levels. The Agency is not
requiring COHb testing, however, because confounding factors, such as
smoking or exposure to a CO source, can reduce the usefulness of the
results of the tests and, in addition, COHb does not measure a health
effect per se but is instead a surrogate measure of MC exposure.
However, COHb testing may
[[Page 1593]]
be clinically important in the evaluation of a symptomatic worker and
therefore remains an option for the physician or other licensed health
care professional to pursue. Exposure monitoring (see paragraph (d) of
the final rule) must be performed to quantify an employee's exposure to
MC.
In the comments received subsequent to publication of the ANPR for
MC [Exs. 10-3, 10-10, 10-28], several industry commenters indicated
that urine analysis, liver function tests and chest X-rays are commonly
performed as part of the medical surveillance programs of these
companies. OSHA believes that annual urine analysis or chest X-ray
would not be relevant to detection of MC-related health effects. Liver
function tests have also been evaluated for inclusion as a requirement
in the medical surveillance provision. As discussed above in the Health
Effects section, animal studies and human clinical studies show an
association between chronic MC exposure and some changes in liver
enzymes, particularly after high exposures or doses of MC for prolonged
periods of time. The changes in liver enzyme levels after MC exposure
are not consistent in the human clinical studies, however, and in
general, changes in liver enzymes are not specific or unique to MC
exposure. Therefore, the Agency believes that it should be left to the
physician's or other licensed health care professional's discretion to
determine if laboratory analysis of liver enzymes is warranted.
Several commenters [Exs. 19-11, 19-26, 19-42, 19-48, 19-55b] agreed
that routine use of all of the tests included in the proposal would not
be appropriate or necessary for the detection of MC-related health
effects. The Agency also sought comments on the inclusion of other
medical tests in the final MC rule. Two commenters [Exs. 19-31, 19-48]
stated that a complete blood count was not necessary because the
results of this test may not correlate with MC overexposure. In
particular, the Dow Chemical Co. [Ex. 19-31] commented that a complete
blood count is not necessary because blood cell volume and hemoglobin
findings would suffice. OSHA has reevaluated the utility of the
proposed tests and has decided that leaving laboratory surveillance to
the discretion of the physician or licensed health care professional is
more cost-effective than the approach taken in the proposal and will
not negatively impact worker health.
In paragraph (j)(5)(iv), the final rule requires the medical
surveillance program of the employer to include any other information
or reports the physician or other licensed health care professional
determines are necessary. This is to ensure that a complete medical
profile is available to the physician or licensed health care
professional to make decisions regarding the employee's health and
exposure status. This provision is essentially identical to that
proposed.
Paragraph (j)(6) of the final rule describes the required contents
of emergency medical surveillance. The proposed rule did not specify
what elements should be included in an emergency medical exam. The
final rule clarifies that emergency medical surveillance should include
any appropriate emergency treatment and decontamination of the exposed
employee, a comprehensive physical exam, an updated medical and work
history, and laboratory surveillance, if needed.
The Dow Chemical Company [Ex. 19-31] commented that employees
exposed to MC during an emergency should not automatically be included
in the regular medical surveillance program. Instead, this commenter
argued that only those components of a medical examination that are
appropriate in a given situation should be conducted. OSHA believes
that it is important for an employer to provide medical examinations
and appropriate follow-up to employees exposed to MC during an
emergency. After considering the issue and comments raised during the
rulemaking, the Agency agrees with Dow that employees exposed to MC
during an emergency should not necessarily be enrolled in the
continuing medical surveillance program provided to employees routinely
exposed to MC. To that end, OSHA has added language to the final rule
that clearly indicates what emergency medical surveillance is required.
OSHA believes that final rule paragraph (j)(6) allows the employer
appropriate flexibility, while at the same time ensuring that those
employees exposed to MC during an emergency receive appropriate medical
surveillance.
Paragraph (j)(7) requires the employer to provide medical
surveillance services, in addition to those specified in final rule
paragraphs (j)(5) and (j)(6), when the physician or other licensed
health care professional determines that they are necessary. Compliance
with this requirement will ensure that the information needed to
evaluate the effects of MC exposure on employees is available. This
provision is essentially the same as proposed paragraph (i)(5).
Paragraph (j)(8) requires that the employer provide the physician
or other licensed health care professional with (1) a copy of the
standard, including the relevant appendices; (2) a description of the
affected employee's past, current, and anticipated future duties as
they relate to the employee's MC exposure; (3) a description of former,
current or anticipated exposure levels (including the frequency and
exposure levels anticipated to be associated with emergencies), as
applicable; (4) a description of any PPE that the employee must use or
will use, such as respirators; and (5) information from any previous
medical examinations that would not otherwise be available to the
examining physician or other licensed health care professional. OSHA
has determined that the physician or other licensed health care
professional needs the above-listed background information in order to
place the information derived from medical surveillance in the proper
context. For example, a well-documented exposure history assists the
physician or other licensed health care professional in determining
whether an observed health condition may be related to MC exposure. It
also helps this individual to determine if the results of medical
surveillance indicate a need to limit an employee's occupational
exposure to MC. This paragraph is essentially the same as proposed
paragraph (i)(6).
Paragraph (j)(9) of the final rule requires employers to ensure
that the examining physician or other licensed health care professional
provides the employer and the affected employee with a written opinion
that addresses (1) the physician's or other licensed health care
professional's opinion as to whether the employee has any detected
medical condition that would place the employee at increased risk of
material health impairment as a result of exposure to MC; (2) any
recommended limitations on the employee's exposure or use of personal
protective clothing or equipment and respirators; (3) a statement that
the employee has been informed of the potential carcinogenicity of MC,
the risk factors for heart disease, and the potential for exacerbation
of underlying heart disease associated with exposure to MC; and (4) a
statement that the employee has been informed of the results of the
medical examination and any medical conditions related to MC exposure
that require further explanation or treatment.
The physician or other licensed health care professional must
provide copies of the written medical opinion to the employee and the
employer within 15 days after completion of the evaluation of medical
and laboratory findings, but no later than 30 days after the medical
examination. This
[[Page 1594]]
requirement was included to ensure that the employee and the employer
have been informed of the above-mentioned results of the medical
examination in a timely manner. This requirement differs slightly from
that in proposed paragraph (i)(7)(i). Instead of the physician
providing a copy of the written medical opinion to the employer, who
then provides a copy to the employee, the final rule requires the
physician or other licensed health care professional to supply a copy
of the written medical opinion directly to both the employer and the
employee. In addition, the time allowed for providing the opinion has
been changed to recognize that time may be needed to receive and
evaluate laboratory or other medical findings. The Agency believes that
notifying both the employer and affected employees of the MC-related
results of the medical surveillance at the same time is an efficient
approach to disseminating this information to the appropriate parties.
Providing copies of the same written opinion both to the employer and
the employee ensures that the employer is aware of any factors that may
influence work assignments or choice of personal protective equipment.
OSHA has added a requirement to the final rule that the physician
or other licensed health care professional inform the employee of the
carcinogenic and cardiac effects of MC to reinforce the information on
MC's serious health effects that was transmitted during training. The
Agency believes that this reinforcement will help to ensure that
employees are aware of the potential effects of MC and take appropriate
precautions when using this toxic substance.
OSHA received several comments on different aspects of paragraph
(j)(9). For example, the UAW [Tr. 1884, 9/24/92] testified that the
written opinion transmitted to the employer by the physician or other
licensed health care professional should only state the limitations on
the employee's exposure or use of respiratory or other personal
protective equipment recommended by the physician or other health care
professional, and should not include the medical or other reasons
behind the recommended limitations.
OSHA agrees with the UAW that it is important to protect the
privacy of employees enrolled in medical surveillance programs.
Consequently, OSHA health standards have traditionally included a
statement to the effect that no findings or diagnoses should be
included in the physician's written opinion that are unrelated to
occupational exposure. This requirement is intended both to protect the
employee's privacy and to encourage employees to participate in the
employer's medical surveillance program. The restriction on what may be
revealed in the written opinion appears in the final rule as paragraph
(j)(9)(ii), and is intended to apply to all of the information provided
in the physician's or other licensed health care professional's written
opinion, including that related to recommended limitations.
The MVMA [Ex. 19-42] and ORC [Ex. 19-57] stated that the proposed
15-day requirement for providing the employer with a copy of the
written opinion should be 15 days from the physician's or other
licensed health care professional's receipt of the test results rather
than 15 days from the date of the examination. The Agency agrees and,
as described above, has changed the requirement so that the written
opinion must be provided within 15 days of completion of evaluation of
medical findings, but not more than 30 days after the examination. OSHA
believes that this strikes the proper balance between allowing
sufficient time for the physician or other licensed health care
professional to evaluate any laboratory findings while still providing
the information to the employer and the employee in a timely manner.
Newport News Shipbuilding [Ex. 19-37] and the Shipbuilders Council
of America [Ex. 19-56] stated that the written opinion should require
only that employees be notified of abnormal test results, not normal
results. In response to these comments, OSHA notes that such a
provision would actually require many physicians and other licensed
health care professionals to change their current practice because it
would require them specifically to delete normal results from printouts
of laboratory and other findings. Such reports routinely display all
results, both normal and abnormal, for a given individual. In addition,
OSHA believes that employees benefit from knowing which of their blood
parameters and other test results are normal and which are abnormal.
OSHA does not believe that requiring medical personnel to increase the
amount of paperwork they perform is a good use of medical resources,
and has therefore not revised the final rule to respond to these
comments.
Under paragraph (j)(9)(ii) of the final rule, the physician or
other licensed health care professional must exclude findings or
diagnoses that are unrelated to MC exposure from the written opinion
provided to the employer. As discussed above, OSHA has included this
provision in the final rule to reassure employees participating in
medical surveillance that they will not be penalized or embarrassed by
the employer's obtaining information about them that is not directly
pertinent to MC exposure. The above provisions are identical to those
in proposed paragraph (i)(7)(ii). A note has been added to the final
rule that states that the written opinion developed to comply with the
MC standard may also contain information related to other OSHA
standards. For example, an employer whose employees are enrolled in
medical surveillance due to their exposure to benzene, formaldehyde and
MC could receive a single, consolidated written opinion that addressed
findings related to all three substances. This performance-oriented
provision could result in reduced paperwork burdens for employers.
NPRM Issue 3 solicited input regarding whether the Agency should
add a provision for Medical Removal Protection (MRP). Medical removal
protection encourages employee participation in (and therefore
increases the effectiveness of) the medical surveillance program by
ensuring that reporting symptoms or health conditions to the physician
or licensed health care professional will not result in loss of job or
pay. Several rulemaking participants expressed support for the
inclusion of MRP in the final rule [Exs. 19-23, 19-38; Tr. 1787, 9/24/
92; Tr. 1802, 9/24/92; Tr. 1869, 9/24/92; and Tr. 1883, 9/24/92]. For
example, the Amalgamated Clothing and Textile Workers (ACTWU) [Tr.
1793, 9/24/92] testified that OSHA should require MRP based on clinical
judgment, as OSHA allowed in the final rule for formaldehyde (29 CFR
1910.1048). They also stated that they believed it was critical to have
a medical removal protection provision in the MC standard in order to
ensure worker participation. Mr. Frumin of the ACTWU testified as
follows [Tr. 1792-1793, 9/24/92]:
As I say, the problems that employers, physicians and, for that
matter, OSHA confront in trying to assure the integrity of medical
surveillance programs are not limited to a particular substance.
They deal with the general perception--these problems arise from the
general perception of workers, which is widespread through industry,
that if they submit to a medical examination and it's not
confidential, and employers could get the results of the medical
findings, that health problems may result in some negative action.
You have a symptom-based medical surveillance program, at least
for the non-cancer effects. And if workers are supposed to report
the types of symptoms, for instance, that Dr. Soden was looking for,
shortness of breath, things of that nature--and they're
[[Page 1595]]
concerned that reporting that might involve some negative action
against them: either their job security or their pay. You know, they
will be discouraged from participating in medical surveillance, and
the whole structure of the program is undermined. So the fact that
these health effects are symptom-based rather than, say, based on
laboratory tests alone, makes it all the more important to include
medical removal protection and multiple physician review in the
final rule.
Two commenters [Exs. 19-23, 19-38] suggested that MRP should be
based on COHb levels. However, Dr. Mirer of the UAW [Tr. 1940, 9/24/92]
disagreed with this idea and concurred with Mr. Frumin's remarks that
medical removal protection should be based on symptoms and professional
discretion. He stated,
* * * the guidance for the physicians, once the physician
decides this employee is at increased risk, if they continue in this
exposure and I want to remove him or her from the job, that's the
trigger. At this moment, I would leave it that way. Increased
carboxyhemoglobin is more an index of exposure than an adverse
clinical effect, so I don't have any particular guidance. If the
doctor wants to pull that man or woman out of a job, that's where I
am now.
He continued,
* * * the other benefit of protecting the disclosure of symptoms
is that it's going to identify sources of exposure, because one of
the ways of determining exposure is by the presentation of symptoms.
So the benefit of having them disclose symptoms is it will lead to
lower exposure.
I can't think of anything much else that you would need to get
out of MRP than improved participation, although at least our
experience in lead is that MRP has been the driving force to reduce
exposures independent of that.
OSHA considered the issues raised during the MC rulemaking and in
general agrees with these worker representatives that MRP increases
employee participation in medical surveillance. OSHA remains concerned
about several issues, however. The Agency recognizes that employees may
hesitate to participate in medical surveillance if they have reason to
expect that the results may adversely affect them economically.
However, OSHA has determined that there is no substantive guidance that
it could give a physician or other licensed health care professional to
indicate when it might be appropriate to remove an employee temporarily
from the workplace, or what an appropriate trigger for return to work
might be. Accordingly, OSHA has decided to promulgate the final rule
for MC without including MRP provisions. The Agency will continue to
monitor compliance with the medical surveillance and PPE provisions of
this standard and the experience in industries subject to standards
with medical removal protection provisions to determine whether any
further action is warranted.
Paragraph (k) Hazard Communication
The requirements for hazard communication have been changed from
proposed paragraph (j) (Communication of MC hazards to employees) and
promulgated in paragraph (k) of the final rule. The paragraph
addressing hazard communication in the final MC rule is consistent with
the requirements of OSHA's Hazard Communication Standard (HCS). The HCS
requires all chemical manufacturers and importers to assess the hazards
of the chemicals they produce or import. It also requires all employers
to provide information concerning the hazards of such chemicals to
their employees. The transmittal of hazard information to employees is
to be accomplished by such means as container labeling and other forms
of warning, material safety data sheets and employee training.
Since the HCS ``is intended to address comprehensively the issue of
evaluating the potential hazard of chemicals and communicating
information concerning hazards and appropriate protective measures to
employees'' (52 FR 31877), OSHA is including paragraph (k) in the final
rule only to reference the HCS requirements for labels and material
safety data sheets, and to indicate specifically the MC health effects
that are required to be addressed under that rule. This additional
guidance to employers simply reiterates the requirements of the HCS to
convey information to affected employees about all health hazards to
which they are potentially exposed. The health effects addressed by the
final MC rule are cancer, cardiac effects (including elevation of
carboxyhemoglobin), central nervous system effects, and skin and eye
irritation. There may also be other health hazards or physical hazards
associated with MC that meet the definitions of coverage under the HCS.
These should be addressed appropriately on the label and MSDS as well.
Employers who have already met their longstanding requirements to
comply with the HCS will have no additional duties with regard to
labels and MSDSs under the MC final rule. This is consistent with the
suggestions of some commenters that no requirements should be mandated
beyond those listed in the HCS [Exs. 19-25, 19-31, 19-42]. OSHA agrees
that the HCS addresses the issue comprehensively, and additional
requirements are not necessary to protect MC-exposed employees
specifically. As a result, the Agency has deleted the proposed
requirement for warning signs. Such signs are not required under the
HCS, although they may be useful in some situations and employers may
choose to use them. The Organization Resources Counselors [Ex. 19-57]
commented that the required signs should say ``warning'' and not
``danger'' as proposed, and suggested consistency with the benzene and
ethylene oxide standards. It should be noted that the terms ``warning''
and ``danger'' have specific meaning in the context of labels, and
there are criteria for their application under voluntary consensus
standards such as the ANSI Z129.1 standard for precautionary labeling.
ORC's comment is otherwise moot at this point since the relevant
requirement has been deleted.
Paragraph (l) Employee Information and Training
The requirements for employee information and training, which were
part of proposed paragraph (j) (Communication of MC hazards to
employees), have been separated from the hazard communication
requirements for labels and data sheets described above, and
promulgated as paragraph (l) in the final MC rule. Some of the training
provisions that were proposed duplicated requirements of the HCS. These
have been removed, and a reference to the information and training
required under the HCS has been added to simply remind employers of
their longstanding obligations under that rule to ensure that employees
are apprised of the hazards of the chemicals in their workplaces, as
well as appropriate protective measures. The information and training
requirements in the final MC rule build upon those requirements with
additional information specific to MC that will help employees
understand the risks of exposure and the means to prevent adverse
health effects from occurring in their particular workplaces.
It should be noted that the information and training requirements
in the final rule have been separated from each other rather than being
addressed together, because they deal with different ways of conveying
information. ``Information'' transmittal is simply that--a passive
process of making information available to employees should they choose
to use it. In some cases, this may be done in writing or some other
simple manner of information transfer. ``Training,'' on the other hand,
is not a passive process. The
[[Page 1596]]
information provided to employees in training requires them to
comprehend it and subsequently to use it in the performance of their
duties in the workplace. There are many different ways to accomplish
training effectively, but it cannot be a simple transfer of information
such as handing someone a written document. OSHA's voluntary training
guidelines, which are found in OSHA Publication No. 2252, are available
to provide employers additional guidance in setting up and implementing
an appropriate employee training program. An effective training program
is a critical component of any safety and health program in the
workplace. Workers who are fully informed and engaged in the protective
measures established by the employer will play a significant role in
the prevention of adverse health effects. Ineffective training will not
serve the purpose of making workers full participants in the program,
and the likelihood of a successful program for safety and health in the
absence of an effectively trained workforce is remote.
Paragraph (l)(1) requires employers to provide all employees who
are potentially exposed to MC with information and training on MC prior
to or at the time of initial assignment to a job involving MC exposure.
Thus employees will have the information they need to protect
themselves before they are actually subject to exposure. The final rule
further indicates in paragraph (l)(2) that employers shall ensure that
the information and training is presented in a manner that is
understandable to employees and that employees have received the
information and training required under the HCS.
Paragraph (l)(3) addresses the information to be provided to
affected employees. This includes the requirements of the final MC
standard and information available in its appendices, as well as how
the employee can access or obtain a copy of it in the workplace. This
will ensure that MC-exposed employees are aware that specific
requirements have been established to protect them from adverse health
effects, and give them an opportunity to review those requirements
themselves if they so desire. Wherever employee exposures exceed or can
reasonably be expected to exceed the action level, the employer is
required to inform employees about the location of MC in the workplace,
what operations may be affected, particularly noting where in the
workplace there may be exposures above the permissible exposure limits.
Paragraph (l)(4) requires each employer to train each affected
employee as required under the Hazard Communication Standard (29 CFR
1910.1200, 29 CFR 1915.1200 or 29 CFR 1926.59, as appropiate). This
provision simply reminds employers of their obligation to train
employees regarding the hazards of MC under the Hazard Communication
Standard.
The final rule does not provide a specific time period for updating
the training, whereas the proposed standard included a requirement for
annual retraining. Instead, the final rule indicates in paragraph
(l)(5) that the employer shall re-train each affected employee as
necessary to ensure that employees exposed above the action level or
the STEL maintain a good understanding of the principles of safe use
and handling of MC in the workplace. Employers can assess whether this
understanding is generally present in exposed employees in various
ways, such as by observing their actions in the workplace. For example,
if an employee is not using appropriate protective equipment or
following safe work practices routinely, this may be an indication that
additional training is required. This provision of the final rule is a
performance-oriented requirement that allows each employer to determine
how much or how often training is needed.
Paragraph (l)(6) requires that the employer do additional training
when the workplace is modified or changed in such a way that employees
are subject to greater exposures and those exposures exceed or can
reasonably be expected to exceed the action level and those employees
need information and training to understand how to implement the
modifications or training successfully. This provision was not in the
proposal, but the Agency considers it necessary to further protect
employees from the hazards of MC when significant changes in workplace
conditions occur.
Paragraph (l)(7) requires the employer whose employees are exposed
to MC at a multi-employer worksite to notify the other employers with
work operations at that site regarding the use of MC-containing
materials, the hazards associated with the use of those materials and
the control measures implemented to protect affected employees from MC
exposure, in accordance with the requirements of the Hazard
Communication Standard (HCS). The HCS addresses sharing information at
multi-employer worksites, and since this final rule covers construction
where most of the sites are multi-employer, this provision was added to
remind such employers of these requirements. OSHA is also aware that an
increasing number of manufacturing worksites involve more than one
employer.
In paragraph (l)(8) of the final rule, OSHA has indicated that the
Assistant Secretary or the Director may access all materials relating
to employee information and training in the workplace. This would be
done in conjunction with an inspection to ascertain compliance with the
rule, or in the event of a NIOSH health hazard evaluation. Review of
the available materials regarding information and training will help
assess whether the program has been properly conducted, as well as
evaluate what could be improved if employees do not appear to be
effectively trained.
The information and training provisions of this standard are
performance-oriented, because employees are exposed to MC in a wide
variety of circumstances and the best method of conveying the necessary
data may vary from site-to-site. The standard lists the categories of
information to be transmitted to employees but does not specify the
ways in which it is to be transmitted.
Some commenters [Tr. 531-32, 9/18/92; Tr. 545-49, 9/18/92; Tr. 828-
32, 9/21/92; Tr. 1380, 1384-85, 9/23/92] suggested that OSHA make the
proposed training provisions more specific, such as by including
requirements for length of training, qualifications of instructors, or
requirements for interactive training. In addition, hearing
participants and commenters suggested that OSHA require employers to
monitor the effectiveness of training [Ex. 19-38, Tr. 531-32, 9/18/92].
These participants suggested that provisions be made, as well, for
training of workers in languages other than English and for training of
workers with limited literacy [Ex. 19-38, Tr. 531-32, 9/18/92; Tr. 831-
32, 9/21/92].
The International Brotherhood of Painters and Allied Trades, AFL-
CIO, testified [Tr. 830-831, 9/21/92]:
We urge OSHA to promulgate a standard that requires that workers
receive a minimum of 16 hours training. Such training would include
at the minimum information on the hazards of methylene chloride and
how it harms the body. Engineering controls that can be implemented
in the field should be described and demonstrated. We will submit
information on one such control to the record. Training should also
include information on work practices associated with specific job
assignments, methods by which workers can protect themselves, the
limits of respirators use, appropriate procedures for work in
confined spaces, employee rights under the standard, the
[[Page 1597]]
purpose of medical surveillance and other elements of training as
enumerated in Section (j)(4).
OSHA does not agree that specifying a time frame for training
ensures that it will be complete, appropriate, or effective. The amount
of training required will depend to a large extent on the conditions of
use in a given workplace. It will also be related to the extent of
training on MC that has already been done by the employer under the
HCS. Therefore, the final rule provisions remain performance-oriented
with regard to the time needed to convey the information and training.
With regard to the issues of literacy and language, these remain a
significant consideration in the proper design and implementation of
any training program. Because working safely with MC is such a
significant concern, the employer must make every effort to ensure that
the training is presented in such a way that employees can understand
and act on the information.
OSHA expects that employers will ensure that the information and
training is effective. Any good training program should include an
evaluation component to help ensure effectiveness. The voluntary
training guidelines previously recommended can provide additional
guidance in this respect.
OSHA received comments that indicated that the MC standard should
simply refer to the HCS rather than having separate requirements [Exs.
19-25; 19-49]. While the Agency agrees with these comments in reference
to the label and MSDS requirements, it does not appear that this is the
appropriate approach to training. While the HCS addresses training
about the hazards of a chemical and appropriate precautionary measures,
there are other items of training that are specific to the MC standard
requirements and the determinations made in this rulemaking regarding
MC. As such, it is important to ensure that the already-required HCS
training is supplemented with information and training specific to MC.
Paragraph (m) Recordkeeping
Paragraph (m) of the final rule addresses requirements for
employers to create and maintain records of their compliance with some
of the provisions of this section. Section 8(c)(1) of the OSH Act
authorizes the Agency to promulgate regulations requiring employers to
keep necessary and appropriate records regarding activities to permit
the enforcement of the Act or to develop information regarding the
causes and prevention of occupational accidents and illnesses. Section
8(c)(3) of the Act specifically addresses the promulgation of
``regulations requiring employers to maintain accurate records of
employee exposures to potentially toxic materials or harmful physical
agents which are required to be monitored or measured under section
6.''
Paragraph (m)(1) requires that employers who rely on objective data
to characterize potential exposures to MC, rather than conducting
initial monitoring under paragraph (d) of this section, maintain
records that show the information and methodology used in reaching
their conclusion that exposures are at or below the action level and no
additional monitoring is required. The record must include the MC-
containing material evaluated; the source of the objective data; the
testing protocol, and the results or analysis of the testing; a
description of the operation(s) exempted from monitoring, and how the
data support the exemption; and other relevant data.
Since the use of objective data exempts the employer from
conducting monitoring, as well as establishing that most of the other
provisions need not be complied with due to the low level of potential
exposure, it is critical that this determination be carefully
documented. Compliance with the requirement to maintain a record of
objective data protects the employer at later dates from the contention
that initial monitoring was improperly omitted. The record will also be
available to employees so that they can examine the determination made
by the employer. The employer is required to maintain the record for
the duration of the employer's reliance upon objective data. This
provision is effectively identical to proposed paragraph (k)(1).
Paragraph (m)(2) requires that employers establish and keep an
accurate record of all measurements taken to monitor employee exposure
to MC. For employers with 20 or more employees, the record must include
at least: the date of measurement for each sample taken; the operation
involving exposure to MC which is being monitored; sampling and
analytical methods used and evidence of their accuracy; number,
duration and results of samples taken; the type of personal protective
equipment, such as respiratory protective devices worn (if any); and
name, social security number, and job classification and exposure of
all the employees deemed to be represented by such monitoring,
indicating which employees were actually monitored. For employers with
fewer than 20 employees, the record shall include, at a minimum: the
date of measurement for each sample; the number, duration and results
of samples taken; and name, social security number, job classification
and exposure of all the employees deemed to be represented by such
monitoring, indicating which employees were actually monitored. OSHA
believes it is necessary to maintain these records so that employers,
employees and OSHA can determine the extent to which MC exposure has
been identified and subsequently controlled. Over time, the exposure
records can help determine if additional measures are needed for
employee protection. OSHA has reduced the amount of information
required for small businesses in recognition of the more limited
variety of operations and exposure levels there. This should ease these
employers' recordkeeping burden without compromising employee safety
and health in these types of facilities.
Two commenters [Exs. 19-25, 19-49] suggested that such
documentation should only be required for each person actually
monitored (paragraph (d)(1) provides for representative monitoring).
However, OSHA believes that it is necessary for records to be kept for
each employee represented by the exposure monitoring so that individual
employees can access information that characterizes their own exposures
to MC. If records were kept only for those actually monitored, it would
be unreasonably difficult for an employee to identify the exposure
measurement that is intended to represent his or her experience.
Accordingly, OSHA has not made the suggested change.
Paragraph (m)(3) requires that the employer keep accurate medical
records for each employee subject to medical surveillance. The
information to be included in the record addresses identification of
the employee; the physician's or other licensed health care
professional's written opinions; and documentation of any employee
medical conditions that are found to be related to MC exposure.
Maintenance of employee medical records is necessary for the proper
evaluation of the employee's health, as well as for appropriate
followup.
Proposed paragraph (k)(3)(ii)(D) required that a copy of the
information provided to the physician or other licensed health care
professional be included in the employee record. The Dow Chemical
Company [Ex. 19-31] requested that, because many larger companies have
company medical facilities, some provision be made so that records do
not have to be maintained in medical department records and duplicated
in the personnel record of every employee potentially
[[Page 1598]]
exposed to MC. The information required under paragraph (j)(8) of this
section includes a copy of this section including its appendices, a
description of duties involving MC exposure, exposure levels, personal
protective equipment, and previous medical surveillance information.
Since this information is available to the employee through other
means, OSHA believes that the requirements under proposed paragraph
(k)(3)(ii)(D) were unnecessarily burdensome, and OSHA has therefore
deleted this paragraph from the final rule. OSHA has also deleted
proposed requirements for maintaining records of employee fit testing
as being unnecessarily burdensome. Dow also suggested that an employee
identification number be permitted in lieu of social security number
[Ex. 19-31]. OSHA does not agree with this suggestion. Social security
numbers have much wider application, and are correlated to employee
identity in other types of records. These numbers are a more useful
differentiation among employees since each number is unique to an
individual for a lifetime and does not change as an employee changes
employers.
Paragraph (m)(4) of the final rule specifies that access to
exposure and medical records by employees, employees'' designated
representatives, NIOSH and OSHA shall be provided in accordance with 29
CFR 1910.1020. OSHA promulgated 29 CFR 1910.1020 as the generic rule
for access to employee exposure and medical records on May 23, 1980 (45
FR 35212). It applies to records created under specific OSHA standards
and to records that are voluntarily created by employers. OSHA retains
unrestricted access to medical and exposure records but its access to
personally identifiable records is subject to the Agency's rules of
practice and procedure concerning OSHA access to employee medical
records, which have been published at 29 CFR 1913.10.
The time periods required for retention of exposure records and
medical records is thirty years and the period of employment plus
thirty years, respectively. These retention requirements are consistent
with those in the OSHA records access standard and with pertinent
sections of the Toxic Substances Control Act. It is necessary to keep
records for extended periods of time because of the long latency
periods commonly observed for the induction of cancer caused by
exposures to carcinogens. Cancer often cannot be detected until 20 or
more years after onset of exposure. The extended record retention
period is therefore needed for two purposes. First, possession of past
and present exposure data and medical records furthers the diagnosis of
workers' ailments. In addition, retaining records for extended periods
makes possible a review at some future date of the effectiveness and
adequacy of the standard.
Paragraph (m)(5) requires employers to comply with the requirements
of 29 CFR 1910.1020(h). That provision requires the employer to notify
the Director of NIOSH in writing at least 90 days prior to the disposal
of records and to transfer those records to NIOSH unless told not to do
so by NIOSH. The employer is required to comply with any other
applicable requirements set forth in the records retention standard.
Paragraph (n) Dates
This paragraph establishes the effective date for the MC final
rule, and the start-up dates for the various provisions of the
standard. The start-up dates allow employers additional time to comply
with some of the provisions of the standard that require more effort to
accomplish. It is expected that such work will commence by the
effective date, and be completed as soon as possible but in no case
later than the compliance deadline established by the effective date.
All other obligations imposed by the standard become effective on the
effective date unless otherwise indicated.
Paragraph (n)(1) of the final rule provides that this standard will
become effective on April 10, 1997. This date is 90 days from the date
of publication in the Federal Register. Proposed paragraph (m)(1) had
provided that the final rule would become effective 60 days after
publication in the Federal Register. OSHA stated in the preamble to the
proposed rule [56 FR 57128] that the proposed effective date, in
conjunction with the proposed start-up dates, would allow sufficient
time for employers to achieve compliance with the substantive
requirements of the proposed rule.
Although no commenters directly addressed the 60-day period
proposed in paragraph (m)(1), several commenters addressed the
reasonableness of the start-up dates in proposed paragraph (m)(2).
Those comments, discussed below, indicated that some employers would
need more time to comply than the proposed rule would have allowed.
The Agency sets the effective date to allow sufficient time for
employers to obtain the standard, read and understand its requirements,
and undertake the necessary planning and preparation for compliance.
Section 6(b)(4) of the OSHA Act provides that the effective date of an
OSHA standard may be delayed for up to 90 days from the date of
publication in the Federal Register. Given the concerns expressed by
commenters, OSHA's interest in having employers implement effective
compliance efforts, and the minimal effect of the additional 30 day
delay, the Agency has decided that it is appropriate to set the
effective date at 90 days from publication, rather than at 60 days.
Paragraph (n)(2) of the final rule establishes the start-up dates
for compliance with the provisions of the MC standard. The start-up
dates are based on information in the record about the state of the art
with regard to the types of provisions employers are expected to
implement, such as available control measures, their complexity, and
the time that is reasonably necessary to complete their installation
and implementation. In the case of MC, the types of provisions included
in the rule, such as requirements that will require conventional
controls, are identical to the elements included in all OSHA health
standards.
Proposed paragraphs (m)(2)(i), (ii) and (iii) required that initial
monitoring be completed by all employers within 120 days of the
effective date of the MC standard, engineering controls within one year
of the effective date and all other requirements within 180 days of the
effective date. As described below, OSHA received numerous comments on
the appropriateness of the start-up dates, especially for small
businesses. Given the large number of small employers covered by the
requirements, and the special problems of many of those employers in
identifying and implementing appropriate control measures, OSHA has
decided to phase-in compliance and to permit these employers a longer
time period in which to comply with the requirements of the standard.
The schedule for compliance with the provisions of the standard are
described below.
OSHA received a number of comments on the proposed periods for
compliance with the control requirements. In 1992, Kodak [Exs. 19-18
and 19-102] described circumstances at its film base production
facility that would prevent compliance with the PELs through
engineering controls before mid-1995. Kodak stated ``[it] is essential
that OSHA be responsive to these considerations in promulgating the
final rule. OSHA should permit adequate time for Kodak to implement
feasible engineering controls in an orderly and minimally disruptive
schedule.'' Considering the effective
[[Page 1599]]
date and start-up dates in this regulation, OSHA has determined that
affected parties will have sufficient time to comply with the standard.
Similar requests for longer time periods for compliance were also
received from a variety of other commenters [Exs. 19-55, 19-57, 19-67,
19-72, 19-75, 115-3, 115-28, 115-33, 115-37, Tr. 1422, 1427-29, 9/23/
92, Tr. 2103, 10/14/92, Tr. 2291-92, 2300, 10/15/92]. However, OSHA's
Final Economic Analysis for this rulemaking indicates that readily
available control measures can be used to control exposure in many of
the operations where MC is present. In general, compliance will not
require the development of new or novel control technology.
Accordingly, OSHA believes that more extended time periods for
compliance are not necessary for all affected industries. However, as
discussed below, small businesses (for example, those with fewer than
20 employees and polyurethane foam manufacturers with 20 to 99
employees) have been granted additional time to comply.
As discussed above in Section VIII, several commenters [Exs. 19-14,
19-25, 19-28 and 19-29] stated that engineering controls to achieve
compliance were not available. These commenters further stated that the
development and implementation of the process changes and engineering
controls needed to achieve compliance would take four years from the
effective date, not the single year proposed. For example, the
Pharmaceutical Manufacturers Association and Abbott Laboratories [Exs.
19-25 and 19-29] stated as follows:
[I]f the agency should rule that the exposure level to MC be
reduced to 25 ppm for an 8-hour TWA and a 125 ppm STEL, a minimum of
1 year from the effective date must be allowed for identification of
the engineering controls. A minimum of 3 years from the effective
date must be allowed for compliance with paragraph (f)(1) of the
proposed rule.
Those commenters and the HSIA [Ex. 19-45] also indicated that FDA
approval is needed in the pharmaceutical industry for any alteration of
manufacturing processes, substitution for MC, or modification of work
practices to achieve compliance with OSHA's MC standard, and requested
that OSHA consider the FDA's regulatory requirements when establishing
start-up dates. In particular, Abbott Laboratories described how it
took three years to obtain FDA approval for the substitution of
hydroalcoholic or aqueous solutions for MC in tablet coating
operations, stating ``[p]resently, completion of required testing and
obtaining FDA approval for production of a single product can take 3
months to three years, depending upon the extent of the change.''
Abbott also commented as follows [Ex. 19-29]:
As stated previously, feasible engineering controls do not exist
for the present bulk pharmaceutical centrifugal separation and
drying equipment. Implementation of engineering controls would
therefore require the use of a different process or a different
production method. Changes of that degree require Abbott
Laboratories to complete development work on an alternative process
and/or identify new production equipment; erect a building to house
the equipment; purchase, receive and install the equipment; train
employees; and validate the process. This cannot be accomplished in
one year.
OSHA is aware that pharmaceutical manufacturers must comply with
other regulatory requirements, including those set by the FDA. The
Agency has considered how affected employers, in general, need to
coordinate their OSHA compliance efforts with their other regulatory
compliance activities, that this regulation does not require
implementation of particularly complicated or novel control
technologies, and that the compliance time frames are in keeping with
those in other OSHA standards. OSHA views the coordination of OSHA
compliance with other regulatory compliance activities as an ongoing
employer effort, not just an ad hoc response to a particular OSHA
action (such as the revision of a PEL). For example, a pharmaceutical
manufacturer would need to consider the implications for OSHA
compliance of process changes undertaken due to FDA requirements or for
other reasons, whether those changes were to be made during the MC
standard's ``start-up'' period or subsequently.
Accordingly, the Agency has determined that the commenters have not
established a need for the requested extension of the start-up dates.
OSHA believes that the proposed one-year period in which to implement
controls will, in general, be adequate and, therefore, has not made the
suggested change. However, as discussed elsewhere, OSHA has tailored
the compliance schedule to the size of the establishment and
anticipated impact of the standard on those businesses.
Dow [Ex. 19-31] also expressed concern that many employers would be
unable to meet the start-up dates, focusing on the time and resources
that would be required to conduct initial monitoring. In addition, Dow
stated as follows ``OSHA should require that certain actions be
completed within the stated time periods and that if the actions can
not be completed, the employer should have a written plan and
corresponding actions to show a good faith effort to meet the
requirements.'' OSHA agrees that there may be circumstances where,
despite good faith efforts, employers cannot achieve compliance within
the time periods specified by paragraph (n)(2). OSHA further agrees
that developing a written plan and taking other ``good faith'' actions
towards compliance would be appropriate measures to mitigate any
circumstances of non-compliance with the regulation. Indeed, the
suggested procedure closely resembles the temporary variance process
already established by OSHA.
Under section 6(b)(6) of the OSH Act, an employer can obtain a
temporary variance from compliance with an OSHA standard if it shows
that it cannot achieve compliance by the effective date; is taking all
available steps to safeguard its employees from the pertinent hazard;
and has an effective program for coming into compliance with the
standard. The implementing regulations for the temporary variance
process appear at 29 CFR part 1905. Employers who experience
difficulties in meeting the start-up dates should contact OSHA and
apply for a temporary variance.
The HSIA [Ex. 19-45] recommended that OSHA ``provide a compliance
schedule similar to that provided in the generic PEL update * * *
[which] in some circumstances allows employers until December 31, 1993
to comply (a total of 4 years and 10 months).'' In addition to
mentioning the lengthy FDA approval process, the HSIA noted that ``DCM
users, particularly many of the smaller companies, will find compliance
technologically and economically difficult at best.''
As stated above, OSHA believes that the sort of extended compliance
schedule set through the generic PEL update is unnecessary for the MC
standard. Based on its review of the rulemaking record, the Agency has
reached the general conclusion that employers will be able to achieve
compliance within the time frames established in paragraph (n).
However, OSHA is concerned that some small facilities affected by
this rulemaking, such as many of those in the furniture refinishing
industry and the polyurethane foam manufacturing industry, may have
difficulties determining the appropriate control measures to use and
also may not be able to absorb the costs of compliance, particularly
those associated with implementing the appropriate
[[Page 1600]]
engineering controls within the time frames initially proposed. The
Agency has estimated (see Section VIII, Summary of the Final Economic
Analysis) that allowing a variable schedule of compliance, based upon
size of establishment, will enable firms in all impacted sectors to
absorb many of the compliance costs without endangering their financial
health.
Based on these considerations, OSHA has determined that the
following implementation schedule is reasonable and appropriate for
businesses of all sizes:
----------------------------------------------------------------------------------------------------------------
Implementation of
Initial monitoring engineering controls All other provisions must be
Establishment size provisions must be must be completed complied with within
complied with within within
----------------------------------------------------------------------------------------------------------------
Fewer than 20 employees........... 300 days of the 3 years of the 1 year of the effective date.
effective date. effective date.
Polyurethane foam manufacturers 210 days of the 2 years of the 270 days of the effective date.
with 20 to 99 employees. effective date. effective date.
All other employers............... 120 days of the 1 year of the 180 days of the effective date.
effective date. effective date.
----------------------------------------------------------------------------------------------------------------
The Agency is promulgating paragraph (n) accordingly.
The schedule of intermediate start-up dates (210 d, 270 d and 2
years) for polyurethane foam manufacturers with 20 to 99 employees was
limited to this application group because this group has the highest
potential economic impacts except for the furniture stripping and
construction groups. In both of the latter groups, most firms have
fewer than 20 employees, and thus would already be allowed additional
time to comply with the final rule's start-up dates. In contrast, in
the flexible polyurethane foam manufacturing group, even firms with
fewer than 100 employees will need to install several types of
engineering controls and are likely to have unusually high capital
expenditures in order to meet the requirements of the regulation. This
extension of compliance deadlines will allow those firms that need
extensive engineering controls time to adequately plan for and
implement their system of controls. This modification will thus also
help to ensure adequate protection for workers.
Paragraph (o) Appendices
The final paragraph of the standard simply states that the
appendices which follow are not intended to create any additional
obligations beyond those already specified in the standard. They are
basically intended as non-mandatory guidance documents to supplement
and complement the regulatory requirements in the standard, and to
provide additional information about MC and its safe handling and use
to exposed employees, employers, and health care professionals.
A few comments were received by OSHA regarding the text of the
appendices as proposed. These addressed the need for additional
information [Ex. 57, Tr. 832, 9/21/92, Tr. 1380 and 1384-85, 9/23/92],
or whether information should appear in an appendix or in the
regulatory text itself [see, e.g., Tr. 2435-36 and 2448-49, 10/15/92].
OSHA has reviewed and updated the text in the appendices to address
these comments and ensure that they are consistent with the new
regulatory text in the final standard.
Also, proposed Non-mandatory Appendix C, which addressed respirator
fit testing, has not been included in the final rule, because OSHA has
determined that very few of the respirators used to comply with this
standard will require fit testing. In addition, OSHA's revision of the
generic respirator standard (29 CFR 1910.134) will contain an up-to-
date appendix that addresses fit testing for all respirators.
XI. Authority and Signature
This document was prepared under the direction of Joseph A. Dear,
Assistant Secretary of Labor for Occupational Safety and Health, U.S.
Department of Labor, 200 Constitution Avenue, NW., Washington, DC
20210.
Pursuant to sections 4, 6(b), 8(c) and 8(g) of the Occupational
Safety and Health Act (29 U.S.C. 653, 655, 657), section 107 of the
Contract Work Hours and Safety Standards Act (the Construction Safety
Act) (40 U.S.C. 333); the Longshore and Harbor Workers' Compensation
Act (33 U.S.C. 941); the Secretary of Labor's Order No. 1-90 (55 FR
9033); and 29 CFR part 1911; 29 CFR parts 1910, 1915 and 1926 are
amended as set forth below.
List of Subjects in 29 CFR Part 1910, 1915 and 1926
Chemicals, Cancer, Health risk-assessment, Methylene chloride,
Occupational safety and health.
Signed at Washington, D.C., this 31st day of December 1996.
Joseph A. Dear,
Assistant Secretary of Labor.
XII. Final Standard Regulatory Text
Parts 1910, 1915, and 1926 of Title 29 of the Code of Federal
Regulations are amended as follows:
PART 1910--[AMENDED]
Subpart B--[Amended]
1. The authority citation for subpart B of part 1910 continues to
read as follows:
Authority: Secs. 4, 6 and 8 of the Occupational Safety and
Health Act, 29 U.S.C. 653, 655, 657; Walsh-Healey Act, 29 U.S.C. 35
et seq; Service Contract Act of 1965, 41 U.S.C. 351 et seq; Contract
Work Hours and Safety Standards Act (Construction Safety Act), 40
U.S.C. 333; Sec 41 Longshore and Harbor Worker's Compensation Act,
33 U.S.C. 941; National Foundation on Arts and Humanities, 20 U.S.C.
951 et seq; Secretary of Labor's Order No, 12-71 (36 FR 8754); 8-76
(41 FR 25059); 9-83 (48 FR 35736); 1-90 (55 FR 9033); and 29 CFR
part 1911.
2. By adding a new paragraph (m) to Sec. 1910.19 to read as
follows:
Sec. 1910.19 Special provisions for air contaminants.
* * * * *
(m) Methylene Chloride (MC): Section 1910.1052 shall apply to the
exposure of every employee to MC in every employment and place of
employment covered by Sec. 1910.16 in lieu of any different standard on
exposure to MC which would otherwise be applicable by virtue of that
section when it is not present in sealed, intact containers.
Subpart Z--[Amended]
3. The authority citation for subpart Z of 29 CFR part 1910
continues to read, in part, as follows:
Authority: Secs. 6 and 8 Occupational Safety and Health Act, 29
U.S.C. 655, 657; Secretary of Labor's Orders 12-71 (36 FR 8754), 8-
76 (41 FR 25059), 9-83 (48 FR 35736) or 1-90 (55 FR 9033), as
applicable; and 29 CFR part 1911.
* * * * *
Sec. 1910.1000 [Amended]
4. By removing the entire entry for Methylene Chloride (Z37.23-
1969) in Table Z-2 of Sec. 1910.1000 and adding the
[[Page 1601]]
following entry in its place in the substance column: ``Methylene
chloride: see Sec. 1910.1052''.
5. By adding a new Sec. 1910.1052 to read as follows:
Sec. 1910.1052 Methylene Chloride.
This occupational health standard establishes requirements for
employers to control occupational exposure to methylene chloride (MC).
Employees exposed to MC are at increased risk of developing cancer,
adverse effects on the heart, central nervous system and liver, and
skin or eye irritation. Exposure may occur through inhalation, by
absorption through the skin, or through contact with the skin. MC is a
solvent which is used in many different types of work activities, such
as paint stripping, polyurethane foam manufacturing, and cleaning and
degreasing. Under the requirements of paragraph (d) of this section,
each covered employer must make an initial determination of each
employee's exposure to MC. If the employer determines that employees
are exposed below the action level, the only other provisions of this
section that apply are that a record must be made of the determination,
the employees must receive information and training under paragraph (l)
of this section and, where appropriate, employees must be protected
from contact with liquid MC under paragraph (h) of this section. The
provisions of the MC standard are as follows:
(a) Scope and application. This section applies to all occupational
exposures to methylene chloride (MC), Chemical Abstracts Service
Registry Number 75-09-2, in general industry, construction and shipyard
employment.
(b) Definitions. For the purposes of this section, the following
definitions shall apply:
Action level means a concentration of airborne MC of 12.5 parts per
million (ppm) calculated as an eight (8)-hour time-weighted average
(TWA).
Assistant Secretary means the Assistant Secretary of Labor for
Occupational Safety and Health, U.S. Department of Labor, or designee.
Authorized person means any person specifically authorized by the
employer and required by work duties to be present in regulated areas,
or any person entering such an area as a designated representative of
employees for the purpose of exercising the right to observe monitoring
and measuring procedures under paragraph (d) of this section, or any
other person authorized by the OSH Act or regulations issued under the
Act.
Director means the Director of the National Institute for
Occupational Safety and Health, U.S. Department of Health and Human
Services, or designee.
Emergency means any occurrence, such as, but not limited to,
equipment failure, rupture of containers, or failure of control
equipment, which results, or is likely to result in an uncontrolled
release of MC. If an incidental release of MC can be controlled by
employees such as maintenance personnel at the time of release and in
accordance with the leak/spill provisions required by paragraph (f) of
this section, it is not considered an emergency as defined by this
standard.
Employee exposure means exposure to airborne MC which occurs or
would occur if the employee were not using respiratory protection.
Methylene chloride (MC) means an organic compound with chemical
formula, CH2Cl2. Its Chemical Abstracts Service Registry
Number is 75-09-2. Its molecular weight is 84.9 g/mole.
Physician or other licensed health care professional is an
individual whose legally permitted scope of practice (i.e., license,
registration, or certification) allows him or her to independently
provide or be delegated the responsibility to provide some or all of
the health care services required by paragraph (j) of this section.
Regulated area means an area, demarcated by the employer, where an
employee's exposure to airborne concentrations of MC exceeds or can
reasonably be expected to exceed either the 8-hour TWA PEL or the STEL.
Symptom means central nervous system effects such as headaches,
disorientation, dizziness, fatigue, and decreased attention span; skin
effects such as chapping, erythema, cracked skin, or skin burns; and
cardiac effects such as chest pain or shortness of breath.
This section means this methylene chloride standard.
(c) Permissible exposure limits (PELs). (1) Eight-hour time-
weighted average (TWA) PEL. The employer shall ensure that no employee
is exposed to an airborne concentration of MC in excess of twenty-five
parts of MC per million parts of air (25 ppm) as an 8-hour TWA.
(2) Short-term exposure limit (STEL). The employer shall ensure
that no employee is exposed to an airborne concentration of MC in
excess of one hundred and twenty-five parts of MC per million parts of
air (125 ppm) as determined over a sampling period of fifteen minutes.
(d) Exposure monitoring. (1) Characterization of employee exposure.
(i) Where MC is present in the workplace, the employer shall determine
each employee's exposure by either:
(A) Taking a personal breathing zone air sample of each employee's
exposure; or
(B) Taking personal breathing zone air samples that are
representative of each employee's exposure.
(ii) Representative samples. The employer may consider personal
breathing zone air samples to be representative of employee exposures
when they are taken as follows:
(A) 8-hour TWA PEL. The employer has taken one or more personal
breathing zone air samples for at least one employee in each job
classification in a work area during every work shift, and the employee
sampled is expected to have the highest MC exposure.
(B) Short-term exposure limits. The employer has taken one or more
personal breathing zone air samples which indicate the highest likely
15-minute exposures during such operations for at least one employee in
each job classification in the work area during every work shift, and
the employee sampled is expected to have the highest MC exposure.
(C) Exception. Personal breathing zone air samples taken during one
work shift may be used to represent employee exposures on other work
shifts where the employer can document that the tasks performed and
conditions in the workplace are similar across shifts.
(iii) Accuracy of monitoring. The employer shall ensure that the
methods used to perform exposure monitoring produce results that are
accurate to a confidence level of 95 percent, and are:
(A) Within plus or minus 25 percent for airborne concentrations of
MC above the 8-hour TWA PEL or the STEL; or
(B) Within plus or minus 35 percent for airborne concentrations of
MC at or above the action level but at or below the 8-hour TWA PEL.
(2) Initial determination. Each employer whose employees are
exposed to MC shall perform initial exposure monitoring to determine
each affected employee's exposure, except under the following
conditions:
(i) Where objective data demonstrate that MC cannot be released in
the workplace in airborne concentrations at or above the action level
or above the STEL. The objective data shall represent the highest MC
exposures likely to occur under reasonably foreseeable conditions of
processing, use, or handling. The employer shall document the objective
data exemption as specified in paragraph (m) of this section;
[[Page 1602]]
(ii) Where the employer has performed exposure monitoring within 12
months prior to April 10, 1997 and that exposure monitoring meets all
other requirements of this section, and was conducted under conditions
substantially equivalent to existing conditions; or
(iii) Where employees are exposed to MC on fewer than 30 days per
year (e.g., on a construction site), and the employer has measurements
by direct-reading instruments which give immediate results (such as a
detector tube) and which provide sufficient information regarding
employee exposures to determine what control measures are necessary to
reduce exposures to acceptable levels.
(3) Periodic monitoring. Where the initial determination shows
employee exposures at or above the action level or above the STEL, the
employer shall establish an exposure monitoring program for periodic
monitoring of employee exposure to MC in accordance with Table 1:
Table 1.--Six Initial Determination Exposure Scenarios and Their
Associated Monitoring Frequencies
------------------------------------------------------------------------
Exposure scenario Required monitoring activity
------------------------------------------------------------------------
Below the action level and at or below No 8-hour TWA or STEL
the STEL. monitoring required.
Below the action level and above the No 8-hour TWA monitoring
STEL. required; monitor STEL
exposures every three months.
At or above the action level, at or Monitor 8-hour TWA exposures
below the TWA, and at or below the every six months.
STEL.
At or above the action level, at or Monitor 8-hour TWA exposures
below the TWA, and above the STEL. every six months and monitor
STEL exposures every three
months.
Above the TWA and at or below the STEL. Monitor 8-hour TWA exposures
every three months.
Above the TWA and above the STEL....... Monitor 8-hour TWA exposures
and STEL exposures every three
months.
------------------------------------------------------------------------
[Note to paragraph (d)(3): The employer may decrease the
frequency of exposure monitoring to every six months when at least 2
consecutive measurements taken at least 7 days apart show exposures
to be at or below the 8-hour TWA PEL. The employer may discontinue
the periodic 8-hour TWA monitoring for employees where at least two
consecutive measurements taken at least 7 days apart are below the
action level. The employer may discontinue the periodic STEL
monitoring for employees where at least two consecutive measurements
taken at least 7 days apart are at or below the STEL.]
(4) Additional monitoring. (i) The employer shall perform exposure
monitoring when a change in workplace conditions indicates that
employee exposure may have increased. Examples of situations that may
require additional monitoring include changes in production, process,
control equipment, or work practices, or a leak, rupture, or other
breakdown.
(ii) Where exposure monitoring is performed due to a spill, leak,
rupture or equipment breakdown, the employer shall clean-up the MC and
perform the appropriate repairs before monitoring.
(5) Employee notification of monitoring results. (i) The employer
shall, within 15 working days after the receipt of the results of any
monitoring performed under this section, notify each affected employee
of these results in writing, either individually or by posting of
results in an appropriate location that is accessible to affected
employees.
(ii) Whenever monitoring results indicate that employee exposure is
above the 8-hour TWA PEL or the STEL, the employer shall describe in
the written notification the corrective action being taken to reduce
employee exposure to or below the 8-hour TWA PEL or STEL and the
schedule for completion of this action.
(6) Observation of monitoring. (i) Employee observation. The
employer shall provide affected employees or their designated
representatives an opportunity to observe any monitoring of employee
exposure to MC conducted in accordance with this section.
(ii) Observation procedures. When observation of the monitoring of
employee exposure to MC requires entry into an area where the use of
protective clothing or equipment is required, the employer shall
provide, at no cost to the observer(s), and the observer(s) shall be
required to use such clothing and equipment and shall comply with all
other applicable safety and health procedures.
(e) Regulated areas. (1) The employer shall establish a regulated
area wherever an employee's exposure to airborne concentrations of MC
exceeds or can reasonably be expected to exceed either the 8-hour TWA
PEL or the STEL.
(2) The employer shall limit access to regulated areas to
authorized persons.
(3) The employer shall supply a respirator, selected in accordance
with paragraph (h)(3) of this section, to each person who enters a
regulated area and shall require each affected employee to use that
respirator whenever MC exposures are likely to exceed the 8-hour TWA
PEL or STEL.
[Note to paragraph (e)(3): An employer who has implemented all
feasible engineering, work practice and administrative controls (as
required in paragraph (f) of this section), and who has established
a regulated area (as required by paragraph (e)(1) of this section)
where MC exposure can be reliably predicted to exceed the 8-hour TWA
PEL or the STEL only on certain days (for example, because of work
or process schedule) would need to have affected employees use
respirators in that regulated area only on those days.]
(4) The employer shall ensure that, within a regulated area,
employees do not engage in non-work activities which may increase
dermal or oral MC exposure.
(5) The employer shall ensure that while employees are wearing
respirators, they do not engage in activities (such as taking
medication or chewing gum or tobacco) which interfere with respirator
seal or performance.
(6) The employer shall demarcate regulated areas from the rest of
the workplace in any manner that adequately establishes and alerts
employees to the boundaries of the area and minimizes the number of
authorized employees exposed to MC within the regulated area.
(7) An employer at a multi-employer worksite who establishes a
regulated area shall communicate the access restrictions and locations
of these areas to all other employers with work operations at that
worksite.
(f) Methods of compliance. (1) Engineering and work practice
controls. The employer shall institute and
[[Page 1603]]
maintain the effectiveness of engineering controls and work practices
to reduce employee exposure to or below the PELs except to the extent
that the employer can demonstrate that such controls are not feasible.
Wherever the feasible engineering controls and work practices which can
be instituted are not sufficient to reduce employee exposure to or
below the 8-TWA PEL or STEL, the employer shall use them to reduce
employee exposure to the lowest levels achievable by these controls and
shall supplement them by the use of respiratory protection that
complies with the requirements of paragraph (g) of this section.
(2) Prohibition of rotation. The employer shall not implement a
schedule of employee rotation as a means of compliance with the PELs.
(3) Leak and spill detection. (i) The employer shall implement
procedures to detect leaks of MC in the workplace. In work areas where
spills may occur, the employer shall make provisions to contain any
spills and to safely dispose of any MC-contaminated waste materials.
(ii) The employer shall ensure that all incidental leaks are
repaired and that incidental spills are cleaned promptly by employees
who use the appropriate personal protective equipment and are trained
in proper methods of cleanup. [Note to paragraph (f)(3)(ii): See
Appendix A of this section for examples of procedures that satisfy this
requirement. Employers covered by this standard may also be subject to
the hazardous waste and emergency response provisions contained in 29
CFR 1910.120 (q).]
(g) Respiratory protection. (1) General requirements. The employer
shall provide a respirator which complies with the requirement of this
paragraph, at no cost to each affected employee, and ensure that each
affected employee uses such respirator where appropriate. Respirators
shall be used in the following circumstances:
(i) Whenever an employee's exposure to MC exceeds or can reasonably
be expected to exceed the 8-hour TWA PEL or the STEL (such as where an
employee is using MC in a regulated area);
(ii) During the time interval necessary to install or implement
feasible engineering and work practice controls;
(iii) In a few work operations, such as some maintenance operations
and repair activities, for which the employer demonstrates that
engineering and work practice controls are infeasible;
(iv) Where feasible engineering and work practice controls are not
sufficient to reduce exposures to or below the PELs; or
(v) In emergencies.
(2) Medical Evaluation. Before having any employee use a supplied-
air respirator in the negative pressure mode, or a gas mask with
organic vapor canister for emergency escape, the employer shall have a
physician or other licensed health care professional ascertain each
affected employee's ability to use such respiratory protection. The
physician or other licensed health care professional shall provide his
or her findings to the affected employee and the employer in a written
opinion.
(3) Respirator selection. The appropriate atmosphere-supplying
respirators, as specified in Table 2, shall be selected from those
approved by the National Institute for Occupational Safety and Health
(NIOSH) under the provisions of 42 CFR Part 84, ``Respiratory
Protective Devices.'' When employers elect to provide gas masks with
organic vapor canisters for use in emergency escape, the organic vapor
canisters shall bear the approval of NIOSH.
Table 2.--Minimum Requirements for Respiratory Protection for Airborne
Methylene Chloride
------------------------------------------------------------------------
Methylene chloride airborne
concentration (ppm) or condition of use Minimum respirator required \1\
------------------------------------------------------------------------
Up to 625 ppm (25 X PEL)............... (1) Continuous flow supplied-
air respirator, hood or
helmet.
Up to 1250 ppm (50 X 8-TWA PEL)........ (1) Full facepiece supplied-air
respirator operated in
negative pressure (demand)
mode.
(2) Full facepiece self-
contained breathing apparatus
(SCBA) operated in negative
pressure (demand) mode.
Up to 5000 ppm (200 X 8-TWA PEL)....... (1) Continuous flow supplied-
air respirator, full
facepiece.
(2) Pressure demand supplied-
air respirator, full
facepiece.
(3) Positive pressure full
facepiece SCBA.
Unknown concentration, or above 5000 (1) Positive pressure full
ppm (Greater than 200 X 8-TWA PEL). facepiece SCBA.
(2) Full facepiece pressure
demand supplied-air respirator
with an auxiliary self-
contained air supply.
Fire fighting.......................... Positive pressure full
facepiece SCBA.
Emergency escape....................... (1) Any continuous flow or
pressure demand SCBA.
(2) Gas mask with organic vapor
canister.
------------------------------------------------------------------------
\1\ Respirators assigned for higher airborne concentrations may be used
at lower concentrations.
(4) Respirator program. Where respiratory protection is required by
this section, the employer shall institute a respirator program in
accordance with 29 CFR 1910.134.
(5) Permission to leave area. The employer shall permit employees
who wear respirators to leave the regulated area to readjust the
facepieces to their faces to achieve a proper fit, and to wash their
faces and respirator facepieces as necessary in order to prevent skin
irritation associated with respirator use.
(6) Filter respirators. Employers who provide gas masks with
organic vapor canisters for the purpose of emergency escape shall
replace those canisters after any emergency use before those gas masks
are returned to service.
(7) Respirator fit testing. (i) The employer shall ensure that each
respirator issued to the employee is properly fitted and exhibits the
least possible facepiece leakage from among the facepieces tested.
(ii) The employer shall perform qualitative or quantitative fit
tests at the time of initial fitting and at least annually thereafter
for each employee wearing a negative pressure respirator, including
those employees for whom emergency escape respirators are provided.
[Note to paragraph (g)(7)(ii): The only supplied-air respirators
to which this provision would apply are SCBA in negative pressure
mode and full facepiece supplied-air respirators operated in
negative pressure mode. The small business compliance guides will
contain examples of protocols for qualitative and quantitative fit
testing.]
(h) Protective Work Clothing and Equipment. (1) Where needed to
prevent
[[Page 1604]]
MC-induced skin or eye irritation, the employer shall provide clean
protective clothing and equipment which is resistant to MC, at no cost
to the employee, and shall ensure that each affected employee uses it.
Eye and face protection shall meet the requirements of 29 CFR 1910.133
or 29 CFR 1915.153, as applicable.
(2) The employer shall clean, launder, repair and replace all
protective clothing and equipment required by this paragraph as needed
to maintain their effectiveness.
(3) The employer shall be responsible for the safe disposal of such
clothing and equipment. [Note to paragraph (h)(4): See Appendix A for
examples of disposal procedures that will satisfy this requirement.]
(i) Hygiene facilities. (1) If it is reasonably foreseeable that
employees' skin may contact solutions containing 0.1 percent or greater
MC (for example, through splashes, spills or improper work practices),
the employer shall provide conveniently located washing facilities
capable of removing the MC, and shall ensure that affected employees
use these facilities as needed.
(2) If it is reasonably foreseeable that an employee's eyes may
contact solutions containing 0.1 percent or greater MC (for example
through splashes, spills or improper work practices), the employer
shall provide appropriate eyewash facilities within the immediate work
area for emergency use, and shall ensure that affected employees use
those facilities when necessary.
(j) Medical surveillance. (1) Affected employees. The employer
shall make medical surveillance available for employees who are or may
be exposed to MC as follows:
(i) At or above the action level on 30 or more days per year, or
above the 8- hour TWA PEL or the STEL on 10 or more days per year;
(ii) Above the 8-TWA PEL or STEL for any time period where an
employee has been identified by a physician or other licensed health
care professional as being at risk from cardiac disease or from some
other serious MC-related health condition and such employee requests
inclusion in the medical surveillance program;
(iii) During an emergency.
(2) Costs. The employer shall provide all required medical
surveillance at no cost to affected employees, without loss of pay and
at a reasonable time and place.
(3) Medical personnel. The employer shall ensure that all medical
surveillance procedures are performed by a physician or other licensed
health care professional, as defined in paragraph (b) of this section.
(4) Frequency of medical surveillance. The employer shall make
medical surveillance available to each affected employee as follows:
(i) Initial surveillance. The employer shall provide initial
medical surveillance under the schedule provided by paragraph
(n)(2)(iii) of this section, or before the time of initial assignment
of the employee, whichever is later. The employer need not provide the
initial surveillance if medical records show that an affected employee
has been provided with medical surveillance that complies with this
section within 12 months before April 10, 1997.
(ii) Periodic medical surveillance. The employer shall update the
medical and work history for each affected employee annually. The
employer shall provide periodic physical examinations, including
appropriate laboratory surveillance, as follows:
(A) For employees 45 years of age or older, within 12 months of the
initial surveillance or any subsequent medical surveillance; and
(B) For employees younger than 45 years of age, within 36 months of
the initial surveillance or any subsequent medical surveillance.
(iii) Termination of employment or reassignment. When an employee
leaves the employer's workplace, or is reassigned to an area where
exposure to MC is consistently at or below the action level and STEL,
medical surveillance shall be made available if six months or more have
elapsed since the last medical surveillance.
(iv) Additional surveillance. The employer shall provide additional
medical surveillance at frequencies other than those listed above when
recommended in the written medical opinion. (For example, the physician
or other licensed health care professional may determine an examination
is warranted in less than 36 months for employees younger than 45 years
of age based upon evaluation of the results of the annual medical and
work history.)
(5) Content of medical surveillance. (i) Medical and work history.
The comprehensive medical and work history shall emphasize neurological
symptoms, skin conditions, history of hematologic or liver disease,
signs or symptoms suggestive of heart disease (angina, coronary artery
disease), risk factors for cardiac disease, MC exposures, and work
practices and personal protective equipment used during such exposures.
[Note to paragraph (j)(5)(i): See Appendix B of this section for an
example of a medical and work history format that would satisfy this
requirement.]
(ii) Physical examination. Where physical examinations are provided
as required above, the physician or other licensed health care
professional shall accord particular attention to the lungs,
cardiovascular system (including blood pressure and pulse), liver,
nervous system, and skin. The physician or other licensed health care
professional shall determine the extent and nature of the physical
examination based on the health status of the employee and analysis of
the medical and work history.
(iii) Laboratory surveillance. The physician or other licensed
health care professional shall determine the extent of any required
laboratory surveillance based on the employee's observed health status
and the medical and work history. [Note to paragraph (j)(5)(iii): See
Appendix B of this section for information regarding medical tests.
Laboratory surveillance may include before- and after-shift
carboxyhemoglobin determinations, resting ECG, hematocrit, liver
function tests and cholesterol levels.]
(iv) Other information or reports. The medical surveillance shall
also include any other information or reports the physician or other
licensed health care professional determines are necessary to assess
the employee's health in relation to MC exposure.
(6) Content of emergency medical surveillance. The employer shall
ensure that medical surveillance made available when an employee has
been exposed to MC in emergency situations includes, at a minimum:
(i) Appropriate emergency treatment and decontamination of the
exposed employee;
(ii) Comprehensive physical examination with special emphasis on
the nervous system, cardiovascular system, lungs, liver and skin,
including blood pressure and pulse;
(iii) Updated medical and work history, as appropriate for the
medical condition of the employee; and
(iv) Laboratory surveillance, as indicated by the employee's health
status. [Note to paragraph (j)(6)(iv): See Appendix B for examples of
tests which may be appropriate.]
(7) Additional examinations and referrals. Where the physician or
other licensed health care professional determines it is necessary, the
scope of the medical examination shall be expanded and the appropriate
additional medical surveillance, such as referrals for consultation or
examination, shall be provided.
[[Page 1605]]
(8) Information provided to the physician or other licensed health
care professional. The employer shall provide the following information
to a physician or other licensed health care professional who is
involved in the diagnosis of MC-induced health effects:
(i) A copy of this section including its applicable appendices;
(ii) A description of the affected employee's past, current and
anticipated future duties as they relate to the employee's MC exposure;
(iii) The employee's former or current exposure levels or, for
employees not yet occupationally exposed to MC, the employee's
anticipated exposure levels and the frequency and exposure levels
anticipated to be associated with emergencies;
(iv) A description of any personal protective equipment, such as
respirators, used or to be used; and
(v) Information from previous employment-related medical
surveillance of the affected employee which is not otherwise available
to the physician or other licensed health care professional.
(9) Written medical opinions. (i) For each physical examination
required by this section, the employer shall ensure that the physician
or other licensed health care professional provides to the employer and
to the affected employee a written opinion regarding the results of
that examination within 15 days of completion of the evaluation of
medical and laboratory findings, but not more than 30 days after the
examination. The written medical opinion shall be limited to the
following information:
(A) The physician's or other licensed health care professional's
opinion concerning whether the employee has any detected medical
condition(s) which would place the employee's health at increased risk
of material impairment from exposure to MC;
(B) Any recommended limitations upon the employee's exposure to MC
or upon the employee's use of protective clothing or equipment and
respirators;
(C) A statement that the employee has been informed by the
physician or other licensed health care professional that MC is a
potential occupational carcinogen, of risk factors for heart disease,
and the potential for exacerbation of underlying heart disease by
exposure to MC through its metabolism to carbon monoxide; and
(D) A statement that the employee has been informed by the
physician or other licensed health care professional of the results of
the medical examination and any medical conditions resulting from MC
exposure which require further explanation or treatment.
(ii) The employer shall instruct the physician or other licensed
health care professional not to reveal to the employer, orally or in
the written opinion, any specific records, findings, and diagnoses that
have no bearing on occupational exposure to MC. [Note to paragraph
(j)(9)(ii): The written medical opinion may also include information
and opinions generated to comply with other OSHA health standards.]
(k) Hazard communication. The employer shall communicate the
following hazards associated with MC on labels and in material safety
data sheets in accordance with the requirements of the Hazard
Communication Standard, 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR
1926.59, as appropiate: cancer, cardiac effects (including elevation of
carboxyhemoglobin), central nervous system effects, liver effects, and
skin and eye irritation.
(l) Employee information and training. (1) The employer shall
provide information and training for each affected employee prior to or
at the time of initial assignment to a job involving potential exposure
to MC.
(2) The employer shall ensure that information and training is
presented in a manner that is understandable to the employees.
(3) In addition to the information required under the Hazard
Communication Standard at 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR
1926.59, as appropiate:
(i) The employer shall inform each affected employee of the
requirements of this section and information available in its
appendices, as well as how to access or obtain a copy of it in the
workplace;
(ii) Wherever an employee's exposure to airborne concentrations of
MC exceeds or can reasonably be expected to exceed the action level,
the employer shall inform each affected employee of the quantity,
location, manner of use, release, and storage of MC and the specific
operations in the workplace that could result in exposure to MC,
particularly noting where exposures may be above the 8-hour TWA PEL or
STEL;
(4) The employer shall train each affected employee as required
under the Hazard Communication standard at 29 CFR 1910.1200, 29 CFR
1915.1200, or 29 CFR 1926.59, as appropiate.
(5) The employer shall re-train each affected employee as necessary
to ensure that each employee exposed above the action level or the STEL
maintains the requisite understanding of the principles of safe use and
handling of MC in the workplace.
(6) Whenever there are workplace changes, such as modifications of
tasks or procedures or the institution of new tasks or procedures,
which increase employee exposure, and where those exposures exceed or
can reasonably be expected to exceed the action level, the employer
shall update the training as necessary to ensure that each affected
employee has the requisite proficiency.
(7) An employer whose employees are exposed to MC at a multi-
employer worksite shall notify the other employers with work operations
at that site in accordance with the requirements of the Hazard
Communication Standard, 29 CFR 1910.1200, 29 CFR 1915.1200, or 29 CFR
1926.59, as appropiate.
(8) The employer shall provide to the Assistant Secretary or the
Director, upon request, all available materials relating to employee
information and training.
(m) Recordkeeping. (1) Objective data. (i) Where an employer seeks
to demonstrate that initial monitoring is unnecessary through
reasonable reliance on objective data showing that any materials in the
workplace containing MC will not release MC at levels which exceed the
action level or the STEL under foreseeable conditions of exposure, the
employer shall establish and maintain an accurate record of the
objective data relied upon in support of the exemption.
(ii) This record shall include at least the following information:
(A) The MC-containing material in question;
(B) The source of the objective data;
(C) The testing protocol, results of testing, and/or analysis of
the material for the release of MC;
(D) A description of the operation exempted under paragraph
(d)(2)(i) of this section and how the data support the exemption; and
(E) Other data relevant to the operations, materials, processing,
or employee exposures covered by the exemption.
(iii) The employer shall maintain this record for the duration of
the employer's reliance upon such objective data.
(2) Exposure measurements. (i) The employer shall establish and
keep an accurate record of all measurements taken to monitor employee
exposure to MC as prescribed in paragraph (d) of this section.
(ii) Where the employer has 20 or more employees, this record shall
include at least the following information:
(A) The date of measurement for each sample taken;
(B) The operation involving exposure to MC which is being
monitored;
[[Page 1606]]
(C) Sampling and analytical methods used and evidence of their
accuracy;
(D) Number, duration, and results of samples taken;
(E) Type of personal protective equipment, such as respiratory
protective devices, worn, if any; and
(F) Name, social security number, job classification and exposure
of all of the employees represented by monitoring, indicating which
employees were actually monitored.
(iii) Where the employer has fewer than 20 employees, the record
shall include at least the following information:
(A) The date of measurement for each sample taken;
(B) Number, duration, and results of samples taken; and
(C) Name, social security number, job classification and exposure
of all of the employees represented by monitoring, indicating which
employees were actually monitored.
(iv) The employer shall maintain this record for at least thirty
(30) years, in accordance with 29 CFR 1910.1020.
(3) Medical surveillance. (i) The employer shall establish and
maintain an accurate record for each employee subject to medical
surveillance under paragraph (j) of this section.
(ii) The record shall include at least the following information:
(A) The name, social security number and description of the duties
of the employee;
(B) Written medical opinions; and
(C) Any employee medical conditions related to exposure to MC.
(iii) The employer shall ensure that this record is maintained for
the duration of employment plus thirty (30) years, in accordance with
29 CFR 1910.1020.
(4) Availability. (i) The employer, upon written request, shall
make all records required to be maintained by this section available to
the Assistant Secretary and the Director for examination and copying in
accordance with 29 CFR 1910.1020. [Note to paragraph (m)(4)(i): All
records required to be maintained by this section may be kept in the
most administratively convenient form (for example, electronic or
computer records would satisfy this requirement).]
(ii) The employer, upon request, shall make any employee exposure
and objective data records required by this section available for
examination and copying by affected employees, former employees, and
designated representatives in accordance with 29 CFR 1910.1020.
(iii) The employer, upon request, shall make employee medical
records required to be kept by this section available for examination
and copying by the subject employee and by anyone having the specific
written consent of the subject employee in accordance with 29 CFR
1910.1020.
(5) Transfer of records. The employer shall comply with the
requirements concerning transfer of records set forth in 29 CFR
1910.1020(h).
(n) Dates. (1) Effective date. This section shall become effective
April 10, 1997.
(2) Start-up dates.
(i) Initial monitoring required by paragraph (d)(2) of this section
shall be completed according to the following schedule:
(A) For employers with fewer than 20 employees, within 300 days
after the effective date of this section.
(B) For polyurethane foam manufacturers with 20 to 99 employees,
within 210 days after the effective date of this section.
(C) For all other employers, within 120 days after the effective
date of this section.
(ii) Engineering controls required under paragraph (f)(1) of this
section shall be implemented according to the following schedule:
(A) For employers with fewer than 20 employees, within three (3)
years after the effective date of this section.
(B) For polyurethane foam manufacturers with 20 to 99 employees,
within two (2) years after the effective date of this section.
(C) For all other employers, within one (1) year after the
effective date of this section.
(iii) All other requirements of this section shall be complied with
according to the following schedule:
(A) For employers with fewer than 20 employees, within one (1) year
after the effective date of this section.
(B) For polyurethane foam manufacturers with 20 to 99 employees,
within 270 days after the effective date of this section.
(C) For all other employers, within 180 days after the effective
date of this section.
(3) Transitional dates. The exposure limits for MC specified in 29
CFR 1910.1000 (1996), Table Z-2, shall remain in effect until the
start-up dates for the exposure limits specified in paragraph (n) of
this section, or if the exposure limits in this section are stayed or
vacated.
(o) Appendices. The information contained in the appendices does
not, by itself, create any additional obligations not otherwise imposed
or detract from any existing obligation.
Appendix A to Section 1910.1052: Substance Safety Data Sheet and
Technical Guidelines for Methylene Chloride
I. Substance Identification
A. Substance: Methylene chloride (CH2Cl2).
B. Synonyms: MC, Dichloromethane (DCM); Methylene dichloride;
Methylene bichloride; Methane dichloride; CAS: 75-09-2; NCI-C50102.
C. Physical data:
1. Molecular weight: 84.9.
2. Boiling point (760 mm Hg): 39.8 deg.C (104 deg.F).
3. Specific gravity (water=1): 1.3.
4. Vapor density (air=1 at boiling point): 2.9.
5. Vapor pressure at 20 deg. C (68 deg. F): 350 mm Hg.
6. Solubility in water, g/100 g water at 20 deg. C (68 deg.
F)=1.32.
7. Appearance and odor: colorless liquid with a chloroform-like
odor.
D. Uses:
MC is used as a solvent, especially where high volatility is
required. It is a good solvent for oils, fats, waxes, resins,
bitumen, rubber and cellulose acetate and is a useful paint stripper
and degreaser. It is used in paint removers, in propellant mixtures
for aerosol containers, as a solvent for plastics, as a degreasing
agent, as an extracting agent in the pharmaceutical industry and as
a blowing agent in polyurethane foams. Its solvent property is
sometimes increased by mixing with methanol, petroleum naphtha or
tetrachloroethylene.
E. Appearance and odor:
MC is a clear colorless liquid with a chloroform-like odor. It
is slightly soluble in water and completely miscible with most
organic solvents.
F. Permissible exposure:
Exposure may not exceed 25 parts MC per million parts of air (25
ppm) as an eight-hour time-weighted average (8-hour TWA PEL) or 125
parts of MC per million parts of air (125 ppm) averaged over a 15-
minute period (STEL).
II. Health Hazard Data
A. MC can affect the body if it is inhaled or if the liquid
comes in contact with the eyes or skin. It can also affect the body
if it is swallowed.
B. Effects of overexposure:
1. Short-term Exposure:
MC is an anesthetic. Inhaling the vapor may cause mental
confusion, light-headedness, nausea, vomiting, and headache.
Continued exposure may cause increased light-headedness, staggering,
unconsciousness, and even death. High vapor concentrations may also
cause irritation of the eyes and respiratory tract. Exposure to MC
may make the symptoms of angina (chest pains) worse. Skin exposure
to liquid MC may cause irritation. If liquid MC remains on the skin,
it may cause skin burns. Splashes of the liquid into the eyes may
cause irritation.
2. Long-term (chronic) exposure:
The best evidence that MC causes cancer is from laboratory
studies in which rats, mice and hamsters inhaled MC 6 hours per day,
[[Page 1607]]
5 days per week for 2 years. MC exposure produced lung and liver
tumors in mice and mammary tumors in rats. No carcinogenic effects
of MC were found in hamsters.
There are also some human epidemiological studies which show an
association between occupational exposure to MC and increases in
biliary (bile duct) cancer and a type of brain cancer. Other
epidemiological studies have not observed a relationship between MC
exposure and cancer. OSHA interprets these results to mean that
there is suggestive (but not absolute) evidence that MC is a human
carcinogen.
C. Reporting signs and symptoms:
You should inform your employer if you develop any signs or
symptoms and suspect that they are caused by exposure to MC.
D. Warning Properties:
1. Odor Threshold:
Different authors have reported varying odor thresholds for MC.
Kirk-Othmer and Sax both reported 25 to 50 ppm; Summer and May both
reported 150 ppm; Spector reports 320 ppm. Patty, however, states
that since one can become adapted to the odor, MC should not be
considered to have adequate warning properties.
2. Eye Irritation Level:
Kirk-Othmer reports that ``MC vapor is seriously damaging to the
eyes.'' Sax agrees with Kirk-Othmer's statement. The ACGIH
Documentation of TLVs states that irritation of the eyes has been
observed in workers exposed to concentrations up to 5000 ppm.
3. Evaluation of Warning Properties:
Since a wide range of MC odor thresholds are reported (25-320
ppm), and human adaptation to the odor occurs, MC is considered to
be a material with poor warning properties.
III. Emergency First Aid Procedures
In the event of emergency, institute first aid procedures and
send for first aid or medical assistance.
A. Eye and Skin Exposures:
If there is a potential for liquid MC to come in contact with
eye or skin, face shields and skin protective equipment must be
provided and used. If liquid MC comes in contact with the eye, get
medical attention. Contact lenses should not be worn when working
with this chemical.
B. Breathing:
If a person breathes in large amounts of MC, move the exposed
person to fresh air at once. If breathing has stopped, perform
cardiopulmorary resuscitation. Keep the affected person warm and at
rest. Get medical attention as soon as possible.
C. Rescue:
Move the affected person from the hazardous exposure
immediately. If the exposed person has been overcome, notify someone
else and put into effect the established emergency rescue
procedures. Understand the facility's emergency rescue procedures
and know the locations of rescue equipment before the need arises.
Do not become a casualty yourself.
IV. Respirators, Protective Clothing, and Eye Protection
A. Respirators:
Good industrial hygiene practices recommend that engineering
controls be used to reduce environmental concentrations to the
permissible exposure level. However, there are some exceptions where
respirators may be used to control exposure. Respirators may be used
when engineering and work practice controls are not feasible, when
such controls are in the process of being installed, or when these
controls fail and need to be supplemented. Respirators may also be
used for operations which require entry into tanks or closed
vessels, and in emergency situations.
If the use of respirators is necessary, the only respirators
permitted are those that have been approved by the Mine Safety and
Health Administration (MSHA) or the National Institute for
Occupational Safety and Health (NIOSH). Supplied-air respirators are
required because air-purifying respirators do not provide adequate
respiratory protection against MC.
In addition to respirator selection, a complete written
respiratory protection program should be instituted which includes
regular training, maintenance, inspection, cleaning, and evaluation.
If you can smell MC while wearing a respirator, proceed immediately
to fresh air. If you experience difficulty in breathing while
wearing a respirator, tell your employer.
B. Protective Clothing:
Employees must be provided with and required to use impervious
clothing, gloves, face shields (eight-inch minimum), and other
appropriate protective clothing necessary to prevent repeated or
prolonged skin contact with liquid MC or contact with vessels
containing liquid MC. Any clothing which becomes wet with liquid MC
should be removed immediately and not reworn until the employer has
ensured that the protective clothing is fit for reuse. Contaminated
protective clothing should be placed in a regulated area designated
by the employer for removal of MC before the clothing is laundered
or disposed of. Clothing and equipment should remain in the
regulated area until all of the MC contamination has evaporated;
clothing and equipment should then be laundered or disposed of as
appropriate.
C. Eye Protection:
Employees should be provided with and required to use splash-
proof safety goggles where liquid MC may contact the eyes.
V. Housekeeping and Hygiene Facilities
For purposes of complying with 29 CFR 1910.141, the following
items should be emphasized:
A. The workplace should be kept clean, orderly, and in a
sanitary condition. The employer should institute a leak and spill
detection program for operations involving liquid MC in order to
detect sources of fugitive MC emissions.
B. Emergency drench showers and eyewash facilities are
recommended. These should be maintained in a sanitary condition.
Suitable cleansing agents should also be provided to assure the
effective removal of MC from the skin.
C. Because of the hazardous nature of MC, contaminated
protective clothing should be placed in a regulated area designated
by the employer for removal of MC before the clothing is laundered
or disposed of.
VI. Precautions for Safe Use, Handling, and Storage
A. Fire and Explosion Hazards:
MC has no flash point in a conventional closed tester, but it
forms flammable vapor-air mixtures at approximately 100 deg.C
(212 deg.F), or higher. It has a lower explosion limit of 12%, and
an upper explosion limit of 19% in air. It has an autoignition
temperature of 556.1 deg.C (1033 deg.F), and a boiling point of
39.8 deg.C (104 deg.F). It is heavier than water with a specific
gravity of 1.3. It is slightly soluble in water.
B. Reactivity Hazards:
Conditions contributing to the instability of MC are heat and
moisture. Contact with strong oxidizers, caustics, and chemically
active metals such as aluminum or magnesium powder, sodium and
potassium may cause fires and explosions.
Special precautions: Liquid MC will attack some forms of
plastics, rubber, and coatings.
C. Toxicity:
Liquid MC is painful and irritating if splashed in the eyes or
if confined on the skin by gloves, clothing, or shoes. Vapors in
high concentrations may cause narcosis and death. Prolonged exposure
to vapors may cause cancer or exacerbate cardiac disease.
D. Storage:
Protect against physical damage. Because of its corrosive
properties, and its high vapor pressure, MC should be stored in
plain, galvanized or lead lined, mild steel containers in a cool,
dry, well ventilated area away from direct sunlight, heat source and
acute fire hazards.
E. Piping Material:
All piping and valves at the loading or unloading station should
be of material that is resistant to MC and should be carefully
inspected prior to connection to the transport vehicle and
periodically during the operation.
F. Usual Shipping Containers:
Glass bottles, 5- and 55-gallon steel drums, tank cars, and tank
trucks.
Note: This section addresses MC exposure in marine terminal and
longshore employment only where leaking or broken packages allow MC
exposure that is not addressed through compliance with 29 CFR parts
1917 and 1918, respectively.
G. Electrical Equipment:
Electrical installations in Class I hazardous locations as
defined in Article 500 of the National Electrical Code, should be
installed according to Article 501 of the code; and electrical
equipment should be suitable for use in atmospheres containing MC
vapors. See Flammable and Combustible Liquids Code (NFPA No. 325M),
Chemical Safety Data Sheet SD-86 (Manufacturing Chemists'
Association, Inc.).
H. Fire Fighting:
When involved in fire, MC emits highly toxic and irritating
fumes such as phosgene, hydrogen chloride and carbon monoxide. Wear
breathing apparatus and use water spray to keep fire-exposed
containers cool. Water spray may be used to flush spills away from
exposures. Extinguishing media are dry
[[Page 1608]]
chemical, carbon dioxide, foam. For purposes of compliance with 29
CFR 1910.307, locations classified as hazardous due to the presence
of MC shall be Class I.
I. Spills and Leaks:
Persons not wearing protective equipment and clothing should be
restricted from areas of spills or leaks until cleanup has been
completed. If MC has spilled or leaked, the following steps should
be taken:
1. Remove all ignition sources.
2. Ventilate area of spill or leak.
3. Collect for reclamation or absorb in vermiculite, dry sand,
earth, or a similar material.
J. Methods of Waste Disposal:
Small spills should be absorbed onto sand and taken to a safe
area for atmospheric evaporation. Incineration is the preferred
method for disposal of large quantities by mixing with a combustible
solvent and spraying into an incinerator equipped with acid
scrubbers to remove hydrogen chloride gases formed. Complete
combustion will convert carbon monoxide to carbon dioxide. Care
should be taken for the presence of phosgene.
K. You should not keep food, beverage, or smoking materials, or
eat or smoke in regulated areas where MC concentrations are above
the permissible exposure limits.
L. Portable heating units should not be used in confined areas
where MC is used.
M. Ask your supervisor where MC is used in your work area and
for any additional plant safety and health rules.
VII. Medical Requirements
Your employer is required to offer you the opportunity to
participate in a medical surveillance program if you are exposed to
MC at concentrations at or above the action level (12.5 ppm 8-hour
TWA) for more than 30 days a year or at concentrations exceeding the
PELs (25 ppm 8-hour TWA or 125 ppm 15-minute STEL) for more than 10
days a year. If you are exposed to MC at concentrations over either
of the PELs, your employer will also be required to have a physician
or other licensed health care professional ensure that you are able
to wear the respirator that you are assigned. Your employer must
provide all medical examinations relating to your MC exposure at a
reasonable time and place and at no cost to you.
VIII. Monitoring and Measurement Procedures
A. Exposure above the Permissible Exposure Limit:
1. Eight-hour exposure evaluation: Measurements taken for the
purpose of determining employee exposure under this section are best
taken with consecutive samples covering the full shift. Air samples
must be taken in the employee's breathing zone.
2. Monitoring techniques: The sampling and analysis under this
section may be performed by collection of the MC vapor on two
charcoal adsorption tubes in series or other composition adsorption
tubes, with subsequent chemical analysis. Sampling and analysis may
also be performed by instruments such as real-time continuous
monitoring systems, portable direct reading instruments, or passive
dosimeters as long as measurements taken using these methods
accurately evaluate the concentration of MC in employees'' breathing
zones.
OSHA method 80 is an example of a validated method of sampling
and analysis of MC. Copies of this method are available from OSHA or
can be downloaded from the Internet at http://www.osha.gov. The
employer has the obligation of selecting a monitoring method which
meets the accuracy and precision requirements of the standard under
his or her unique field conditions. The standard requires that the
method of monitoring must be accurate, to a 95 percent confidence
level, to plus or minus 25 percent for concentrations of MC at or
above 25 ppm, and to plus or minus 35 percent for concentrations at
or below 25 ppm. In addition to OSHA method 80, there are numerous
other methods available for monitoring for MC in the workplace.
B. Since many of the duties relating to employee exposure are
dependent on the results of measurement procedures, employers must
assure that the evaluation of employee exposure is performed by a
technically qualified person.
IX. Observation of Monitoring
Your employer is required to perform measurements that are
representative of your exposure to MC and you or your designated
representative are entitled to observe the monitoring procedure. You
are entitled to observe the steps taken in the measurement
procedure, and to record the results obtained. When the monitoring
procedure is taking place in an area where respirators or personal
protective clothing and equipment are required to be worn, you or
your representative must also be provided with, and must wear,
protective clothing and equipment.
X. Access To Information
A. Your employer is required to inform you of the information
contained in this Appendix. In addition, your employer must instruct
you in the proper work practices for using MC, emergency procedures,
and the correct use of protective equipment.
B. Your employer is required to determine whether you are being
exposed to MC. You or your representative has the right to observe
employee measurements and to record the results obtained. Your
employer is required to inform you of your exposure. If your
employer determines that you are being over exposed, he or she is
required to inform you of the actions which are being taken to
reduce your exposure to within permissible exposure limits.
C. Your employer is required to keep records of your exposures
and medical examinations. These records must be kept by the employer
for at least thirty (30) years.
D. Your employer is required to release your exposure and
medical records to you or your representative upon your request.
E. Your employee is required to provide labels and material
safety data sheets (MSDS) for all materials, mixtures or solutions
composed of greater than 0.1 percent MC. An example of a label that
would satisfy these requirements would be:
Danger Contains Methylene Chloride Potential Cancer Hazard
May worsen heart disease because methylene chloride is converted
to carbon monoxide in the body.
May cause dizziness, headache, irritation of the throat and
lungs, loss of consciousness and death at high concentrations (for
example, if used in a poorly ventilated room).
Avoid Skin Contact. Contact with liquid causes skin and eye
irritation.
XI. Common Operations and Controls
The following list includes some common operations in which
exposure to MC may occur and control methods which may be effective
in each case:
------------------------------------------------------------------------
Operations Controls
------------------------------------------------------------------------
Use as solvent in paint and varnish General dilution
removers; manufacture of aerosols; cold ventilation; local exhaust
cleaning and ultrasonic cleaning; and as ventilation; personal
a solvent in furniture stripping. protective equipment;
substitution.
Use as solvent in vapor degreasing........ Process enclosure; local
exhaust ventilation;
chilling coils;
substitution.
Use as a secondary refrigerant in air General dilution
conditioning and scientific testing. ventilation; local exhaust
ventilation; personal
protective equipment.
------------------------------------------------------------------------
Appendix B to Section 1910.1052: Medical Surveillance for Methylene
Chloride
I. Primary Route of Entry
Inhalation.
II. Toxicology
Methylene Chloride (MC) is primarily an inhalation hazard. The
principal acute hazardous effects are the depressant action on the
central nervous system, possible cardiac toxicity and possible liver
toxicity. The range of CNS effects are from decreased eye/hand
coordination and decreased performance in vigilance tasks to
narcosis and even death of individuals exposed at very high doses.
Cardiac toxicity is due to the metabolism of MC to carbon monoxide,
and the effects of carbon monoxide on heart tissue. Carbon monoxide
displaces oxygen in the blood, decreases the oxygen available to
heart tissue, increasing the risk of damage to the heart, which may
result in heart attacks in susceptible individuals. Susceptible
individuals include persons with heart disease and those with risk
factors for heart disease.
Elevated liver enzymes and irritation to the respiratory
passages and eyes have also been reported for both humans and
experimental animals exposed to MC vapors.
MC is metabolized to carbon monoxide and carbon dioxide via two
separate pathways. Through the first pathway, MC is metabolized to
carbon monoxide as an end-product via the P-450 mixed function
oxidase pathway located in the microsomal
[[Page 1609]]
fraction of the cell. This biotransformation of MC to carbon
monoxide occurs through the process of microsomal oxidative
dechlorination which takes place primarily in the liver. The amount
of conversion to carbon monoxide is significant as measured by the
concentration of carboxyhemoglobin, up to 12% measured in the blood
following occupational exposure of up to 610 ppm. Through the second
pathway, MC is metabolized to carbon dioxide as an end product (with
formaldehyde and formic acid as metabolic intermediates) via the
glutathione dependent enzyme found in the cytosolic fraction of the
liver cell. Metabolites along this pathway are believed to be
associated with the carcinogenic activity of MC.
MC has been tested for carcinogenicity in several laboratory
rodents. These rodent studies indicate that there is clear evidence
that MC is carcinogenic to male and female mice and female rats.
Based on epidemiologic studies, OSHA has concluded that there is
suggestive evidence of increased cancer risk in MC-related worker
populations. The epidemiological evidence is consistent with the
finding of excess cancer in the experimental animal studies. NIOSH
regards MC as a potential occupational carcinogen and the
International Agency for Research Cancer (IARC) classifies MC as an
animal carcinogen. OSHA considers MC as a suspected human
carcinogen.
III. Medical Signs and Symptoms of Acute Exposure
Skin exposure to liquid MC may cause irritation or skin burns.
Liquid MC can also be irritating to the eyes. MC is also absorbed
through the skin and may contribute to the MC exposure by
inhalation.
At high concentrations in air, MC may cause nausea, vomiting,
light-headedness, numbness of the extremities, changes in blood
enzyme levels, and breathing problems, leading to bronchitis and
pulmonary edema, unconsciousness and even death.
At lower concentrations in air, MC may cause irritation to the
skin, eye, and respiratory tract and occasionally headache and
nausea. Perhaps the greatest problem from exposure to low
concentrations of MC is the CNS effects on coordination and
alertness that may cause unsafe operations of machinery and
equipment, leading to self-injury or accidents.
Low levels and short duration exposures do not seem to produce
permanent disability, but chronic exposures to MC have been
demonstrated to produce liver toxicity in animals, and therefore,
the evidence is suggestive for liver toxicity in humans after
chronic exposure.
Chronic exposure to MC may also cause cancer.
IV. Surveillance and Preventive Considerations
As discussed above, MC is classified as a suspect or potential
human carcinogen. It is a central nervous system (CNS) depressant
and a skin, eye and respiratory tract irritant. At extremely high
concentrations, MC has caused liver damage in animals.
MC principally affects the CNS, where it acts as a narcotic. The
observation of the symptoms characteristic of CNS depression, along
with a physical examination, provides the best detection of early
neurological disorders. Since exposure to MC also increases the
carboxyhemoglobin level in the blood, ambient carbon monoxide levels
would have an additive effect on that carboxyhemoglobin level. Based
on such information, a periodic post-shift carboxyhemoglobin test as
an index of the presence of carbon monoxide in the blood is
recommended, but not required, for medical surveillance.
Based on the animal evidence and three epidemiologic studies
previously mentioned, OSHA concludes that MC is a suspect human
carcinogen. The medical surveillance program is designed to observe
exposed workers on a regular basis. While the medical surveillance
program cannot detect MC-induced cancer at a preneoplastic stage,
OSHA anticipates that, as in the past, early detection and
treatments of cancers leading to enhanced survival rates will
continue to evolve.
A. Medical and Occupational History:
The medical and occupational work history plays an important
role in the initial evaluation of workers exposed to MC. It is
therefore extremely important for the examining physician or other
licensed health care professional to evaluate the MC-exposed worker
carefully and completely and to focus the examination on MC's
potentially associated health hazards. The medical evaluation must
include an annual detailed work and medical history with special
emphasis on cardiac history and neurological symptoms.
An important goal of the medical history is to elicit
information from the worker regarding potential signs or symptoms
associated with increased levels of carboxyhemoglobin due to the
presence of carbon monoxide in the blood. Physicians or other
licensed health care professionals should ensure that the smoking
history of all MC exposed employees is known. Exposure to MC may
cause a significant increase in carboxyhemoglobin level in all
exposed persons. However, smokers as well as workers with anemia or
heart disease and those concurrently exposed to carbon monoxide are
at especially high risk of toxic effects because of an already
reduced oxygen carrying capacity of the blood.
A comprehensive or interim medical and work history should also
include occurrence of headache, dizziness, fatigue, chest pain,
shortness of breath, pain in the limbs, and irritation of the skin
and eyes.
In addition, it is important for the physician or other licensed
health care professional to become familiar with the operating
conditions in which exposure to MC is likely to occur. The physician
or other licensed health care professional also must become familiar
with the signs and symptoms that may indicate that a worker is
receiving otherwise unrecognized and exceptionally high exposure
levels of MC.
An example of a medical and work history that would satisfy the
requirement for a comprehensive or interim work history is
represented by the following:
The following is a list of recommended questions and issues for
the self-administered questionnaire for methylene chloride exposure.
Questionnaire For Methylene Chloride Exposure
I. Demographic Information
1. Name
2. Social Security Number
3. Date
4. Date of Birth
5. Age
6. Present occupation
7. Sex
8. Race
II. Occupational History
1. Have you ever worked with methylene chloride,
dichloromethane, methylene dichloride, or CH2Cl2 (all are
different names for the same chemical)? Please list which on the
occupational history form if you have not already.
2. If you have worked in any of the following industries and
have not listed them on the occupational history form, please do so.
Furniture stripping
Polyurethane foam manufacturing
Chemical manufacturing or formulation
Pharmaceutical manufacturing
Any industry in which you used solvents to clean and degrease
equipment or parts
Construction, especially painting and refinishing
Aerosol manufacturing
Any industry in which you used aerosol adhesives
3. If you have not listed hobbies or household projects on the
occupational history form, especially furniture refinishing, spray
painting, or paint stripping, please do so.
III. Medical History
A. General
1. Do you consider yourself to be in good health? If no, state
reason(s).
2. Do you or have you ever had:
a. Persistent thirst
b. Frequent urination (three times or more at night)
c. Dermatitis or irritated skin
d. Non-healing wounds
3. What prescription or non-prescription medications do you
take, and for what reasons?
4. Are you allergic to any medications, and what type of
reaction do you have?
B. Respiratory
1. Do you have or have you ever had any chest illnesses or
diseases? Explain.
2. Do you have or have you ever had any of the following:
a. Asthma
b. Wheezing
c. Shortness of breath
3. Have you ever had an abnormal chest X-ray? If so, when,
where, and what were the findings?
4. Have you ever had difficulty using a respirator or breathing
apparatus? Explain.
5. Do any chest or lung diseases run in your family? Explain.
[[Page 1610]]
6. Have you ever smoked cigarettes, cigars, or a pipe? Age
started:
7. Do you now smoke?
8. If you have stopped smoking completely, how old were you when
you stopped?
9. On the average of the entire time you smoked, how many packs
of cigarettes, cigars, or bowls of tobacco did you smoke per day?
C. Cardiovascular
1. Have you ever been diagnosed with any of the following: Which
of the following apply to you now or did apply to you at some time
in the past, even if the problem is controlled by medication? Please
explain any yes answers (i.e., when problem was diagnosed, length of
time on medication).
a. High cholesterol or triglyceride level
b. Hypertension (high blood pressure)
c. Diabetes
d. Family history of heart attack, stroke, or blocked arteries
2. Have you ever had chest pain? If so, answer the next five
questions.
a. What was the quality of the pain (i.e., crushing, stabbing,
squeezing)?
b. Did the pain go anywhere (i.e., into jaw, left arm)?
c. What brought the pain out?
d. How long did it last?
e. What made the pain go away?
3. Have you ever had heart disease, a heart attack, stroke,
aneurysm, or blocked arteries anywhere in you body? Explain (when,
treatment).
4. Have you ever had bypass surgery for blocked arteries in your
heart or anywhere else? Explain.
5. Have you ever had any other procedures done to open up a
blocked artery (balloon angioplasty, carotid endarterectomy, clot-
dissolving drug)?
6. Do you have or have you ever had (explain each):
a. Heart murmur
b. Irregular heartbeat
c. Shortness of breath while lying flat
d. Congestive heart failure
e. Ankle swelling
f. Recurrent pain anywhere below the waist while walking
7. Have you ever had an electrocardiogram (EKG)? When?
8. Have you ever had an abnormal EKG? If so, when, where, and
what were the findings?
9. Do any heart diseases, high blood pressure, diabetes, high
cholesterol, or high triglycerides run in your family? Explain.
D. Hepatobiliary and Pancreas
1. Do you now or have you ever drunk alcoholic beverages? Age
started: ________ Age stopped: ________.
2. Average numbers per week:
a. Beers: ________, ounces in usual container:
b. Glasses of wine: ________, ounces per glass:
c. Drinks: ________, ounces in usual container:
3. Do you have or have you ever had (explain each):
a. Hepatitis (infectious, autoimmune, drug-induced, or chemical)
b. Jaundice
c. Elevated liver enzymes or elevated bilirubin
d. Liver disease or cancer
E. Central Nervous System
1. Do you or have you ever had (explain each):
a. Headache
b. Dizziness
c. Fainting
d. Loss of consciousness
e. Garbled speech
f. Lack of balance
g. Mental/psychiatric illness
h. Forgetfulness
F. Hematologic
1. Do you have, or have you ever had (explain each):
a. Anemia
b. Sickle cell disease or trait
c. Glucose-6-phosphate dehydrogenase deficiency
d. Bleeding tendency disorder
2. If not already mentioned previously, have you ever had a
reaction to sulfa drugs or to drugs used to prevent or treat
malaria? What was the drug? Describe the reaction.
B. Physical Examination
The complete physical examination, when coupled with the medical
and occupational history, assists the physician or other licensed
health care professional in detecting pre-existing conditions that
might place the employee at increased risk, and establishes a
baseline for future health monitoring. These examinations should
include:
1. Clinical impressions of the nervous system, cardiovascular
function and pulmonary function, with additional tests conducted
where indicated or determined by the examining physician or other
licensed health care professional to be necessary.
2. An evaluation of the advisability of the worker using a
respirator, because the use of certain respirators places an
additional burden on the cardiopulmonary system. It is necessary for
the attending physician or other licensed health care professional
to evaluate the cardiopulmonary function of these workers, in order
to inform the employer in a written medical opinion of the worker's
ability or fitness to work in an area requiring the use of certain
types of respiratory protective equipment. The presence of facial
hair or scars that might interfere with the worker's ability to wear
certain types of respirators should also be noted during the
examination and in the written medical opinion.
Because of the importance of lung function to workers required
to wear certain types of respirators to protect themselves from MC
exposure, these workers must receive an assessment of pulmonary
function before they begin to wear a negative pressure respirator
and at least annually thereafter. The recommended pulmonary function
tests include measurement of the employee's forced vital capacity
(FVC), forced expiratory volume at one second (FEV1), as well as
calculation of the ratios of FEV1 to FVC, and the ratios of measured
FVC and measured FEV1 to expected respective values corrected for
variation due to age, sex, race, and height. Pulmonary function
evaluation must be conducted by a physician or other licensed health
care professional experienced in pulmonary function tests.
The following is a summary of the elements of a physical exam
which would fulfill the requirements under the MC standard:
Physical Exam
I. Skin and appendages
1. Irritated or broken skin
2. Jaundice
3. Clubbing cyanosis, edema
4. Capillary refill time
5. Pallor
II. Head
1. Facial deformities
2. Scars
3. Hair growth
III. Eyes
1. Scleral icterus
2. Corneal arcus
3. Pupillary size and response
4. Fundoscopic exam
IV. Chest
1. Standard exam
V. Heart
1. Standard exam
2. Jugular vein distension
3. Peripheral pulses
VI. Abdomen
1. Liver span
VII. Nervous System
1. Complete standard neurologic exam
VIII. Laboratory
1. Hemoglobin and hematocrit
2. Alanine aminotransferase (ALT, SGPT)
3. Post-shift carboxyhemoglobin
IX. Studies
1. Pulmonary function testing
2. Electrocardiogram
An evaluation of the oxygen carrying capacity of the blood of
employees (for example by measured red blood cell volume) is
considered useful, especially for workers acutely exposed to MC.
It is also recommended, but not required, that end of shift
carboxyhemoglobin levels be determined periodically, and any level
above 3% for non-smokers and above 10% for smokers should prompt an
investigation of the worker and his workplace. This test is
recommended because MC is metabolized to CO, which combines strongly
with hemoglobin, resulting in a reduced capacity of the blood to
transport oxygen in the body. This is of particular concern for
cigarette smokers because they already have a diminished hemoglobin
capacity due to the presence of CO in cigarette smoke.
C. Additional Examinations and Referrals
1. Examination by a Specialist
When a worker examination reveals unexplained symptoms or signs
(i.e. in the physical examination or in the laboratory tests),
follow-up medical examinations are necessary to assure that MC
exposure is not
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adversely affecting the worker's health. When the examining
physician or other licensed health care professional finds it
necessary, additional tests should be included to determine the
nature of the medical problem and the underlying cause. Where
relevant, the worker should be sent to a specialist for further
testing and treatment as deemed necessary.
The final rule requires additional investigations to be covered
and it also permits physicians or other licensed health care
professionals to add appropriate or necessary tests to improve the
diagnosis of disease should such tests become available in the
future.
2. Emergencies
The examination of workers exposed to MC in an emergency should
be directed at the organ systems most likely to be affected. If the
worker has received a severe acute exposure, hospitalization may be
required to assure proper medical intervention. It is not possible
to precisely define ``severe,'' but the physician or other licensed
health care professional's judgement should not merely rest on
hospitalization. If the worker has suffered significant
conjunctival, oral, or nasal irritation, respiratory distress, or
discomfort, the physician or other licensed health care professional
should instigate appropriate follow-up procedures. These include
attention to the eyes, lungs and the neurological system. The
frequency of follow-up examinations should be determined by the
attending physician or other licensed health care professional. This
testing permits the early identification essential to proper medical
management of such workers.
D. Employer Obligations
The employer is required to provide the responsible physician or
other licensed health care professional and any specialists involved
in a diagnosis with the following information: a copy of the MC
standard including relevant appendices, a description of the
affected employee's duties as they relate to his or her exposure to
MC; an estimate of the employee's exposure including duration (e.g.,
15hr/wk, three 8-hour shifts/wk, full time); a description of any
personal protective equipment used by the employee, including
respirators; and the results of any previous medical determinations
for the affected employee related to MC exposure to the extent that
this information is within the employer's control.
E. Physicians' or Other Licensed Health Care Professionals' Obligations
The standard requires the employer to ensure that the physician
or other licensed health care professional provides a written
statement to the employee and the employer. This statement should
contain the physician's or licensed health care professional's
opinion as to whether the employee has any medical condition placing
him or her at increased risk of impaired health from exposure to MC
or use of respirators, as appropriate. The physician or other
licensed health care professional should also state his or her
opinion regarding any restrictions that should be placed on the
employee's exposure to MC or upon the use of protective clothing or
equipment such as respirators. If the employee wears a respirator as
a result of his or her exposure to MC, the physician or other
licensed health care professional's opinion should also contain a
statement regarding the suitability of the employee to wear the type
of respirator assigned. Furthermore, the employee should be informed
by the physician or other licensed health care professional about
the cancer risk of MC and about risk factors for heart disease, and
the potential for exacerbation of underlying heart disease by
exposure to MC through its metabolism to carbon monoxide. Finally,
the physician or other licensed health care professional should
inform the employer that the employee has been told the results of
the medical examination and of any medical conditions which require
further explanation or treatment. This written opinion must not
contain any information on specific findings or diagnosis unrelated
to employee's occupational exposures.
The purpose in requiring the examining physician or other
licensed health care professional to supply the employer with a
written opinion is to provide the employer with a medical basis to
assist the employer in placing employees initially, in assuring that
their health is not being impaired by exposure to MC, and to assess
the employee's ability to use any required protective equipment.
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PART 1915--[AMENDED]
6. The authority citation for 29 CFR part 1915 continues to read as
follows:
Authority: Sec. 41, Longshore and Harbor Workers Compensation
Act (33 U.S.C. 941); secs. 4, 6, 8, Occupational Safety and Health
Act of 1970 (29 U.S.C. 653, 655, 657); Secretary of Labor's Order
No. 12-71 (36 FR 8754), 8-76 (41 FR 25059), 9-83 (48 FR 35736) or 1-
90 (55 FR 9033), as applicable; 29 CFR part 1911.
7. In Table Z of section 1915.1000, Air Contaminants, the entire
entry for methylene chloride is removed and replaced with the following
entry added in the substance column: ``Methylene chloride: see
Sec. 1910.1052''.
8. Subpart Z of part 1915 is amended by adding Sec. 1915.1052, as
follows:
Sec. 1915.1052 Methylene chloride.
Note: The requirements applicable to shipyard employment under
this section are identical to those set forth at 29 CFR 1910.1052.
PART 1926--[AMENDED]
Subpart D--[Amended]
9. The authority citation for subpart D of part 1926 continues to
read as follows:
Authority: Sec. 107, Contract Work Hours and Safety Standards
Act (40 U.S.C. 333), secs. 4, 6, and 8, Occupational Safety and
Health Act of 1970 (29 U.S.C. 653, 655, 657); Secretary of Labor's
Orders No. 12-71 (36 FR 8754), 8-76 (41 FR 25059), 9-83 (48 FR
35736), or 1-90 (55 FR 9033), as applicable.
10. In Appendix A of section 1926.55, Gases, vapors, fumes, dusts
and mists, the entire entry for methylene chloride is removed and
replaced by the following entry added in the substance column:
``Methylene chloride: see Sec. 1910.1052''.
Subpart Z--[Amended]
11. The authority citation for subpart Z of part 1926 continues to
read as follows:
Authority: Secs. 6 and 8, Occupational Safety and Health Act (29
U.S.C. 655, 657); section 41, Secretary of Labor's Orders Nos. 12-71
(36 FR 8754), 8-76 (41 FR 25059), 9-83 (48 FR 35736), or 1-90 (55 FR
9033), as applicable; and 29 CFR part 1911.
12. Subpart Z of part 1926 is amended by adding Sec. 1926.1152, as
follows:
Sec. 1926.1152 Methylene chloride.
Note: The requirements applicable to construction employment
under this section are identical to those set forth at 29 CFR
1910.1052.
[FR Doc. 97-198 Filed 1-9-97; 8:45 am]
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