[Federal Register Volume 68, Number 41 (Monday, March 3, 2003)]
[Notices]
[Pages 10012-10015]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4912]


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ENVIRONMENTAL PROTECTION AGENCY

[FRL-7457-2]


Notice of Availability and Opportunity To Provide Comment on the 
Draft Final Guidelines for Carcinogen Risk Assessment and the Draft 
Supplemental Guidance for Assessing Cancer Susceptibility From Early-
Life Exposure to Carcinogens

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of availability and public comment period.

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SUMMARY: EPA is today announcing the availability of, and opportunity 
to comment on, the Draft Final Guidelines for Carcinogen Risk 
Assessment and the draft Supplemental Guidance for Assessing Cancer 
Susceptibility from Early-Life Exposure to Carcinogens.
    In 1996, EPA published for public comment proposed revisions to 
EPA's 1986 Guidelines for Carcinogen Risk Assessment. Since the 1996 
proposal, the Agency has benefitted from extensive public comment and 
scientific peer review, including three reviews by EPA's Science 
Advisory Board (SAB). The major issues currently being considered by 
EPA as it proceeds to issue final Guidelines are identified in the 
Supplementary Information section of this notice. As announced in 
November 2001, the July 1999 draft revised Guidelines will continue to 
serve as EPA's interim guidance to EPA risk assessors preparing cancer 
risk assessments until final Guidelines are issued.
    The Draft Final Guidelines issued today for comment explicitly call 
for consideration of possible sensitive subpopulations and/or 
lifestages (such as childhood). Therefore, concurrent with release of 
the Draft Final Guidelines, EPA is also requesting public comment on 
draft supplemental guidance describing possible approaches that could 
be used to assess risks resulting from early life exposure to potential 
carcinogens. This draft supplemental guidance will be peer reviewed by 
the Agency's Science Advisory Board at a public meeting that will be 
announced in a separate Federal Register notice. The supplemental 
guidance is separate from the Guidelines so that it may be more easily 
updated in a timely manner given the expected rapid evolution of 
scientific understanding about the effects of early-life exposures.

DATES: Comments must be received by Thursday, May 1, 2003.

ADDRESSES:

Document Availability

    The Draft Final Guidelines for Carcinogen Risk Assessment (February 
2003, NCEA-F-0644A) and the draft Supplemental Guidance for Assessing 
Cancer Susceptibility from Early-Life Exposure to Carcinogens (EPA/630/
R-03/003) are available via the Internet from http://www.epa.gov/ncea/raf/cancer2003.htm. A limited number of paper copies of the documents 
are available from the Technical Information Staff (8623D), NCEA-W, 
U.S. Environmental Protection Agency, 1200 Pennsylvania Avenue NW., 
Washington, DC 20460; telephone: 202-564-3261; facsimile: 202-565-0050.

Submitting Comments

    One of three methods may be chosen to submit comments, and comments 
may be in electronic or paper copy format. First, comments may be 
submitted through EPA's electronic public docket and comment system, 
EPA Dockets. EPA Dockets is available at http://www.epa.gov/edocket/. 
Once in the system, select ``search,'' then key in the appropriate 
docket identification number (OAR-2003-0008). Second, comments may be 
submitted via e-mail to ``[email protected].'' Third, paper copies 
of comments may be submitted (in duplicate if possible) to the Air 
Docket at the Environmental Protection Agency, EPA Docket Center (EPA/
DC), Office of Air and Radiation, Mail Code 6102T, 1200 Pennsylvania 
Avenue NW., Washington, DC 20460. Please refer to Public Docket Number 
OAR-2003-0008 in e-mail and in paper correspondence. Acknowledgments 
will not be sent for electronic or paper comment submissions. Persons 
providing information or comments should not submit personal 
information (such as medical data or home address), Confidential 
Business Information, or information protected by copyright because all 
comments will be made available for public viewing.

Viewing Public Comments

    Public comments pertaining to this notice may be viewed by using 
EPA Dockets, or by visiting EPA's Air Docket. EPA intends to make all 
comments received in response to this Federal Register Notice available 
in EPA Dockets (http://www.epa.gov/edocket/), including documents 
originally submitted in paper format. To view comments select 
``search,'' then key in the appropriate docket identification number 
(OAR-2003-0008). Also, paper copies of materials related to this notice 
are available for review under Public Docket No. OAR-2003-0008 at EPA's 
Air Docket. EPA's Air Docket also makes available for review the 
comments received on the 1996 Proposed Guidelines under Public Docket 
No. ORD-CAN-96-02 and comments received on the 1999 draft revised 
Guidelines during the November 2001 public comment period under Public 
Docket No. ORD-CAN-2001. EPA's Air Docket is located at the following 
address: U.S. Environmental Protection Agency (EPA), Public Reading 
Room, Room B102 EPA West Building, 1301 Constitution Avenue NW., 
Washington, DC 20460. The Reading Room is open between 8 a.m. and 4:30 
p.m., Monday through Friday, except on legal holidays. Visitors to the 
Public Reading Room are required to show photographic identification 
and sign the Agency's visitor log. There may be a reasonable fee for 
copying docket materials, as provided in 40 CFR part 2. You can reach 
the Air Docket by telephone at 202-566-1742, and by facsimile at 202-
566-1741.

FOR FURTHER INFORMATION CONTACT: Dr. William P. Wood, Risk Assessment 
Forum (mail code 8601D), U.S. Environmental Protection Agency, 1200 
Pennsylvania Avenue NW., Washington, DC 20460, telephone 202-564-3361, 
or send electronic mail inquiries to [email protected].

SUPPLEMENTARY INFORMATION:

Background

    In 1983, the National Academy of Sciences/National Research Council 
(NRC) published its report entitled, Risk Assessment in the Federal 
Government: Managing the Process. In that report, the NRC recommended 
that Federal regulatory agencies establish ``inference guidelines'' to 
promote consistency and

[[Page 10013]]

technical quality in risk assessments and to ensure that the risk 
assessment process was maintained as a scientific effort separate from 
risk management. EPA responded to this recommendation by publishing a 
set of risk assessment guidelines in 1986, including Guidelines for 
Carcinogen Risk Assessment (51 FR 33992, September 24, 1986). These 
Guidelines set forth principles and procedures to guide EPA scientists 
in assessing the cancer risks from chemicals or other agents in the 
environment and to inform the public about these procedures. EPA 
continues to revise its risk assessment guidelines and to develop new 
guidelines as experience and scientific understanding evolve. Revisions 
to the Guidelines for Carcinogen Risk Assessment are intended to make 
greater use of the increasing scientific understanding of the 
mechanisms that underlie the carcinogenic process. As part of that 
process, the Agency published Proposed Guidelines for Carcinogen Risk 
Assessment in 1996 (61 FR 17960, April 23, 1996).
    The draft revisions to the Guidelines have been subject to 
extensive public comment and scientific peer review, including three 
reviews by EPA's Science Advisory Board (SAB). In 2001, EPA published a 
notice (66 FR 59593, November 29, 2001) providing an additional 
opportunity for public comment on a 1999 draft of the Guidelines. 
Comments were invited on experience gained in applying previous draft 
revised Guidelines and on issues raised in previous comments by the SAB 
and the public. EPA has also considered the recommendations of the NRC 
(Science and Judgment in Risk Assessment, 1994) in revising the 
Guidelines. EPA's approach to the recommendations is reflected in the 
Guidelines themselves. Draft EPA responses to the NRC recommendations 
were presented in the preamble to the 1996 draft of these revised 
Guidelines (61 FR 18003, April 23, 1996). EPA anticipates issuing final 
responses to the NRC recommendations when it issues final Guidelines.

Role of Risk Assessment Guidelines at EPA

    The final Guidelines will be guidance only. They will not establish 
any substantive ``rules'' under the Administrative Procedure Act or any 
other law and will have no binding effect on EPA or any regulated 
entity, but instead will represent a non-binding statement of policy. 
EPA believes that the Draft Final Guidelines represent a sound and up-
to-date approach to cancer risk assessment, and the final Guidelines 
will enhance the application of the best available science in EPA's 
risk assessments. However, EPA cancer risk assessments may be conducted 
differently than envisioned in the final Guidelines for many reasons, 
including (but not limited to) new information, new scientific 
understanding, or new science policy judgment. The science of risk 
assessment continues to develop rapidly, and specific components of the 
final Guidelines may become outdated or may otherwise require 
modification in individual settings. Use of the final Guidelines in 
future risk assessments will be based on decisions by EPA that 
approaches from the final Guidelines are suitable and appropriate in 
the context of those particular risk assessments. These judgments will 
be tested through peer review, and risk assessments will be modified to 
use different approaches if appropriate.
    Even though the final Guidelines will not be binding rules, EPA is 
issuing them in a manner consistent with the procedures in the 
Administrative Procedure Act that are generally applicable to 
rulemaking, including providing an opportunity for public comment. EPA 
will consider and respond to all significant public comments as it 
prepares the final Guidelines, and will send a copy of the final 
Guidelines to Congress. EPA certifies that the Draft Final Guidelines 
will not have a significant impact on a substantial number of small 
entities because the Guidelines are for the benefit of EPA and impose 
no requirements or costs on small entities.

Issues Identified in 2001 Public Comments

    A range of views were expressed in the comments submitted to EPA in 
response to the 2001 notice (66 FR 59593, November 29, 2001) (see the 
Addresses section for information on viewing these comments). Comments 
on four issues of interest identified by EPA in the 2001 notice 
included the following:
    (1) Default assumptions. Default assumptions are options that EPA 
can apply in risk assessments when information about the effects of a 
substance on human health is unavailable, limited, or of insufficient 
quality. (For example, if no information is available on the effects of 
a chemical on humans, a common default assumption is that adverse 
effects observed in animals due to chemical exposure have the potential 
to occur in humans as well.) Commenters differed on whether default 
assumptions should be (a) built into each risk assessment unless 
sufficient evidence is available to depart from them, or (b) invoked 
only when determined to be necessary given the data available in a 
particular risk assessment. Commenters also differed on whether EPA's 
proposed default assumptions should be more protective of public health 
versus already being excessively conservative.
    (2) Hazard descriptors. Under the 1999 draft Guidelines, one or 
more standard descriptors (e.g., ``Likely to be Carcinogenic to 
Humans'') were used to express conclusions about the weight of evidence 
for human carcinogenic potential. Many commenters generally agreed with 
EPA's approach for the descriptors, but most recommended that EPA 
refine the phrases and descriptions to enhance their clarity. Two 
commenters preferred that descriptors not be used at all. A number of 
commenters advised the Agency to use the ``Carcinogenic to Humans'' 
descriptor only when epidemiological evidence of carcinogenicity is 
conclusive.
    (3) Mode of action. EPA's draft 1999 Guidelines emphasized the 
value of understanding a chemical's ``mode of action,'' which refers to 
the series of steps and processes that lead to cancer formation. Many 
commenters disagreed with EPA's proposal that confirmatory data be 
available or a ``cogent biological rationale'' be developed before a 
mode of action identified in adults (or mature animals) could be 
considered applicable to children as well. On the other hand, several 
commenters stated that EPA should require much stronger evidence before 
concluding that a particular mode of action operates in both adults and 
children.
    (4) Margin of exposure analysis. A margin of exposure analysis is 
an approach described in the 1999 draft Guidelines to inform decision-
makers about cancer risks at relatively low levels of exposure. The 
1999 draft Guidelines suggested its use in the case of certain 
carcinogens where mode of action data support a nonlinear approach for 
describing the relationship between dose and response for the chemical. 
Several commenters expressed concern that the margin of exposure 
analysis as described by EPA would not be sufficiently protective of 
public health. Other commenters stated that it inappropriately mixed 
risk assessment and risk management considerations and was problematic 
because it removed quantitative estimation of cancer risk from risk 
assessment.

[[Page 10014]]

Key Features of the Draft Final Guidelines

    EPA's guiding principle for revisions to the Guidelines is that 
Agency cancer risk assessments be both public health protective and 
scientifically sound. By public health protective, EPA means that risk 
assessments should consider a range of susceptibilities among the human 
population and, in the absence of complete knowledge, employ 
assumptions that will reflect the risks to susceptible subpopulations 
and lifestages. By scientifically sound, EPA means that risk 
assessments should reflect current and evolving scientific practice and 
describe risks in a clear, consistent, and reasonable manner. In 
particular, the revisions to the Guidelines are intended to make 
greater use of the increasing scientific understanding of the 
mechanisms that underlie the carcinogenic process. EPA has also 
designed the Guidelines to be flexible enough to accommodate future 
scientific advances in science and risk assessment practices. EPA is 
particularly interested in public comments on the following areas that 
have been the focus of the Agency's attention in preparing today's 
Draft Final Guidelines:
    (1) Use of default options. The Draft Final Guidelines clarify the 
role of default options (default assumptions) in the Agency's risk 
assessments. Rather than view default options as the starting point 
from which departures may be justified by new scientific information, 
the Guidelines emphasize that assessments begin with a critical 
analysis of the available data, and defaults would be invoked as needed 
when too much uncertainty exists or critical data are missing. In 
keeping with EPA's mission and the advice of numerous scientific 
advisory panels, the Agency's default options are constructed to be 
public health protective. The decision to invoke a default option would 
be determined on a case-by-case basis. Given the multitude of different 
types of risk assessments and potential default options, it is neither 
possible nor desirable to specify step-by-step criteria for decisions 
to invoke a default option. The Guidelines, however, identify general 
principles for invoking default options (as originally articulated by 
the National Research Council): Such decisions should be scientifically 
defensible, consistent with EPA's statutory mission, and responsive to 
the needs of decision-makers.
    (2) Hazard descriptors. The Draft Final Guidelines continue to 
emphasize the importance of weighing all of the evidence in reaching 
conclusions about the human carcinogenic potential of agents, with 
hazard descriptors used to facilitate clarity in describing 
carcinogenicity conclusions. Several of the hazard descriptors 
presented in the Draft Final Guidelines have been modified from 
previous drafts of the Guidelines, and the discussion of when they 
would apply has been strengthened. Descriptors may apply only to 
certain routes of exposure, dose ranges, and durations of exposure. The 
following five descriptors are discussed in the Guidelines: 
Carcinogenic to Humans; Likely to Be Carcinogenic to Humans; Suggestive 
Evidence of Carcinogenic Potential; Inadequate Information to Assess 
Carcinogenic Potential; and Not Likely to Be Carcinogenic to Humans.
    (3) Mode of action. The use of mode of action in the assessment of 
potential carcinogens is the main thrust of the Draft Final Guidelines. 
This area of emphasis arose because of scientific breakthroughs 
concerning the causes of cancer induction. As discussed in the Draft 
Final Guidelines, an important use of mode-of-action information is to 
identify susceptible populations and lifestages. Because it is rare to 
have epidemiologic studies or animal bioassays conducted in susceptible 
individuals, identifying the key events of the mode of action and the 
risk factors that can augment these key events can be critical in 
understanding risks to susceptible populations.
    (4) Extrapolation to lower doses. An important issue to address in 
most EPA risk assessments is the estimation of risks at levels of 
environmental exposure (doses) that are lower than the levels at which 
adverse effects (responses) have been observed. Historically, EPA used 
an approach known as linear extrapolation for all potential 
carcinogens, which involves modeling risk in an approximately straight 
line extrapolation from a particular dose level (the point of 
departure) to the zero dose/zero response point. This approach differs 
from that used by EPA in assessing risks in the case of most noncancer 
effects, which typically involve nonlinear extrapolation. The Draft 
Final Guidelines generally reaffirm the use of a linear extrapolation 
approach for carcinogens when mode of action information is limited or 
indicates a linear dose-response relationship, such as in the case of 
mutagenic agents. The Draft Final Guidelines also discuss potential 
uses of nonlinear extrapolation when consistent with understanding of 
the mode of action, and recommend the development of a reference dose 
(or reference concentration) as established by EPA for effects other 
than cancer. This default approach is in keeping with the Agency's goal 
of harmonizing the assessment of risks from agents, whether carcinogens 
or not, that operate by a nonlinear mode of action.
    (5) Susceptible populations and lifestages. The Draft Final 
Guidelines explicitly recognize that variability exists among people in 
their susceptibility to carcinogens and emphasize that this variability 
should be considered in risk assessment. Some subpopulations may 
experience increased susceptibility to carcinogens throughout their 
lives, such as people who have inherited a predisposition to certain 
cancer types or reduced capacity to repair genetic damage. Also, during 
certain lifestages the entire population may experience heightened 
susceptibility to carcinogens. In particular, the Guidelines note that 
childhood may be a lifestage of greater susceptibility for a number of 
reasons, such as susceptibility related to the rapid growth and 
development that occurs prenatally and after birth.

Supplemental Guidance on Early-Life Exposure

    The discussion of consideration of childhood risks in the Draft 
Final Guidelines has been augmented by the development of the separate 
draft document entitled ``Supplemental Guidance for Assessing Cancer 
Susceptibility from Early-Life Exposure to Carcinogens.'' This document 
contains an analysis of studies and a possible approach for how 
quantitative scientific data could inform risk assessments when 
exposure to carcinogens occurring during childhood is considered. The 
draft document will be reviewed by EPA's Science Advisory Board 
following the public comment period. After SAB recommendations and 
public comments are incorporated into the document, the supplemental 
guidance will be issued separately from the final Cancer Guidelines so 
that it may be more easily updated in a timely manner given the 
expected rapid evolution of scientific understanding about the effects 
of early-life exposures.

Request for Comment

    EPA requests comments on today's Draft Final Guidelines and will 
consider all comments in completing final Guidelines. Comments on 
earlier drafts of the revised Guidelines already submitted to EPA need 
not be resubmitted. Public comments are also invited on the draft 
supplemental guidance on early-life exposure to carcinogens. Following 
the public

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comment period, EPA's SAB will peer-review the supplemental guidance. A 
separate notice of the planned SAB meeting will also appear in the 
Federal Register.

    Dated: February 25, 2003.
Paul Gilman,
Assistant Administrator for Research and Development.
[FR Doc. 03-4912 Filed 2-28-03; 8:45 am]
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