[Federal Register Volume 65, Number 4 (Thursday, January 6, 2000)]
[Notices]
[Pages 784-787]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-228]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health service
National Institute of Environmental Health Sciences, NIH;
National Toxicology Program; Solicitation of Comments on Proposed Peer
Review of Low-Dose Issues for Endocrine Disruptors
SUMMARY: NTP is soliciting comments on the planned scope and process
for a proposed peer review of studies bearing on the question of
whether endocrine disruptors may cause effects at doses lower than are
tested using standard toxicological testing procedures. Nominations for
peer reviewers, as well as nominations for studies to be reviewed, are
also being solicited. Results from the peer review will help the U.S.
Environmental Protection Agency (a member agency of the NTP) and, in
particular the EPA's Endocrine Disruptor Screening Program, determine
how to address low-dose questions in endocrine disruptor screening,
testing, and hazard assessment.
Background
The U.S. Environmental Protection Agency (EPA) is implementing an
Endocrine Disruptor Screening Program as required by the Food Quality
Protection Act of 1996 (See 63 FR 71542-71568, Dec. 28, 1998). The EPA
is in the process of choosing appropriate assays to use in this
screening program and is also developing standardized, validated
protocols for these assays. A critical aspect of protocol development
is dose-setting. In recent years, there have been suggestions that
hormonally active agents may cause effects at doses lower than those
normally selected for toxicological testing. A review of the issue can
be found in the National Academy of Science's recently-released report
Hormonally Active Agents in the Environment (NRC [National Research
Council]. 1999. Washington, DC: National Academy Press, pp. 103-111).
The EPA has asked the National Toxicology Program to establish an
independent panel of scientists to review the evidence related to low-
dose effects and consider their implications for the development,
validation, and interpretation of test protocols. If this Panel
concludes that significant effects at low doses occur and that the
standard dose-setting paradigm is inadequate to detect such effects,
the EPA intends to pursue in a separate forum the question of how to
test for such effects, including endpoints to be tested, dose-setting
protocols and appropriate test methods. If the Panel believes the
current data to be inconclusive, it will be asked to describe specific
research that would resolve the ambiguities.
Proposed Scope and Process for the review
A. Scope of the Review
Analysis will focus on interpretation of the major data sets
showing or refuting effects at low doses. ``Low doses'' are defined for
the purposes of discussion as ``doses below the currently accepted No
Observed Adverse Effect Level for that substance''. The intent is to
evaluate the presence or absence of low-dose effects in specific
studies, then evaluate the likelihood and significance of these and/or
other potential low-dose effects to humans.
The main topic to be addressed is evidence for defining the shape
of the dose/response curves for endocrine-active substances in the low-
dos region.
The review is expected to examine all evidence, including such
things as relevant pharmacokinetic and mechanistic information, which
may have a bearing on the low-dose issue. In order to come to
disclosure on the central issue of whether there are sufficient grounds
to change the traditional dose-setting paradigm for endocrine-active
substances, it will not be possible to go into the details of non-
central issues. Issues which may enter the discussion but which are not
the central forcus and will not get exhaustive review include:
--existence of inverted U-shaped dose/response curves as a general
phenomenon in toxicology;
--completeness of the list of endpoints examined in two-generation
toxicity tests;
--definition of ``adversity''.
B. Selection of Studies for Review
Given the breadth of the scope, many studies are likely to be
considered relevant to the discussion. NTP proposes to divide studies
into two categories: those which provide background information and
those which hare critical to the resolution of the issue. Hard copies
of both the background information and critical studies will be
provided to the Panel in advance of the Peer Review Meeting. For the
critical studies, principal investigators will be invited for in-depth
discussions with the Panel, and the data sets from these critical
studies will be subjected to independent analyses by the panel. NTP
anticipates that approximately 10 to 12 studies might be designated
critical.
C. Criteria for Selection of Studies for Review
Studies which provide direct evidence for the presence of effects
related to the endocrine system at doses below the No Observed Adverse
Effect Level will generally be considered critical. Studies which
provide direct evidence against such effects at similar doses for the
same chemical will also generally be considered critical. Studies which
provide direct evidence for endocrine-related effects for chemicals for
which NOAELs have not been established will generally be considered
critical if there is reason to believe that normal procedures for
establishing a NOAEL would set NOAELs at a higher level than those
indicated by the study in question, as long as the difference in
putative NOAELs would be due to dose/response considerations rather
than to definitions of adversity or selection of endpoints for
observation. Studies which provide direct evidence against effects at
similar doses from chemicals for which such claims have been made will
also generally be considered critical.
Pharmacokinetic and mechanistic studies which provide insight into
the plausibility or relevance of effects established in the direct
studies may be either critical or background information depending on
how closely they address low-dose issues.
Studies of other endocrine effects caused by a substance for which
a low-dose endocrine effect is established will be considered
background information unless mechanistic information establishes a
relevant relationship to the low-dose effect.
In general, potency per se, is not a central issue. Studies which
show effects at low doses but whose central issue in setting a NOAEL is
either the definition of adversity or the completeness of the list of
endpoints for which observations are made will not be considered
relevant to the dose/response issues that this peer review will
address.
For background information, well-written reviews will be preferred
over individual studies. Only studies or reviews which have been
published in standard, peer-reviewed scientific journals or books will
be considered.
[[Page 785]]
Critical studies must be accepted for publication in a standard,
peer-reviewed scientific journal or book by April 1, 2000. Studies
presented at scientific meetings but not formally accepted for
publication in a peer-reviewed journal will not be accepted.
Raw data for critical studies must be available for the Panel to
review and analyze. ``Raw data'' includes data on individual laboratory
animals, prior to aggregation by statistical or other methods. Data
reported under Good Laboratory Practices, for example, will generally
be considered ``raw data''.
D. Selection Procedure
An NTP interagency workshop organizing committee will choose the
studies to be considered by the Panel.
NTP recognizes that the date of acceptance for publication cannot
be predicted with accuracy. Similarly, co-operation by principal
investigators to include a study in this review cannot be guaranteed.
For planning purposes, it may become necessary to designate certain
studies as ``likely to be critical'' before April 1 and to treat them
as if they will be examined at the Panel meeting. However, the criteria
will be applied on April 1.
E. Preliminary List of Published Studies To Be Considered by the Low-
Dose Peer Review Panel
The NTP has compiled the attached preliminary list of relevant
studies and invites public comment on the list.
F. Peer Review Panel Members
A panel of 16 to 20 members is anticipated. NTP is soliciting
nominations for the Panel from the public. (See Guidelines for
Submission of Comments below). Kinds of expertise that are likely to be
relevant include reproductive biology (male and female, whole animal
and cellular), endocrinology, pharmacology, statistical data analysis,
and dose/response modeling. Expertise need not be limited to these
areas, nor will these areas necessarily all be included on the Panel.
NTP will try to ensure an appropriate breadth of expertise across the
Panel. If there are particular kinds of expertise that you feel the
Panel should include, please provide a justification in your comments,
especially if the expertise is not covered in the list above.
Nominations should be accompanied by complete contact information,
including name, address, institutional affiliation, telephone number,
and e-mail address. Where possible, a Web page address for research
interests and/or curriculum vitae should be included. To avoid the
potential for candidates being contacted by a large number of
nominators, candidates need not be contacted prior to nomination. NTP
will solicit curricula vitae and interest in participation at an
appropriate time.
G. Criteria for Selection of Panel Members
Expertise in a scientific field relevant to the low-dose issue is
required.
Investigators associated with critical studies will not be
considered for the Panel. Principal investigators (or their designated
co-authors) for critical studies will be asked to present their data
and be available for discussion at the Peer Review Panel meeting, but
will not be asked to be part of the Panel itself.
H. Selection Procedure
Panelists will be chosen after critical studies have been selected.
An NTP interagency organizing committee will select panel members
considering all nominations received from the public as well as
nominations developed internally. All nominees will be contacted for
interest and availability, and curricula vitae will be solicited from
the nominees. Selection will be based on the CVs and accompanying
information such as statements of research interest. Official
invitations to participate will be sent out in approximately April of
2000. The final list of Peer Review panel members will be available to
the public through the Endocrine Disruptor Screening Program's Interent
Web site (http://www.epa.gov/scinpoly/oscpendo/index.htm). Panel
members will be paid as consultants, and candidates will be required to
disclose potential conflicts of interest.
I. Subcommittee Structure
NTP proposes to have Subcommittees of the Peer Review Panel examine
specific aspects of the low-dose issue. Subcommittee topics will be
determined after studies for review have been selected. Topics that may
be appropriate for Subcommittees include:
Data Analysis and Statistics
Pharmacokinetics, Receptor Binding, and Modeling
Effects on Males
Effects on Females
Comments on the appropriateness of having Subcommittees, and of the
specific topics suggested, are welcome.
Approximate Schedule for the Review
A meeting of the Peer Review Panel is tentatively planned for late
July 2000 in the Research Triangle Park, NC area. The entire peer
review panel meeting will be open to the public, limited only by space
available. Details of the meeting location, dates, and times will be
announced at a later time.
In order to meet this deadline, designation of critical studies
will take place in March, with Panel selection to begin in the March/
April time frame.
Between May and late June, the data analysis subcommittee will be
asked to review the data on critical studies. Investigators may be
asked to run analyses of their own data according to the specifications
of the Data Analysis Subcommittee. Approximately four weeks before the
Peer Review, this Subcommittee will have the opportunity to meet with
the investigators by conference call (or, if necessary, at a central
location) to ask questions and obtain additional data that might be
needed in preparation for the Panel meeting. The findings of the Data
Analysis Subcommittee will be made available to the full Peer Review
Panel for discussion at the meeting.
On the first day of the Peer Review Meeting, presentation from
principal investigators for the critical studies will be heard by the
entire Panel. Also, the Data Analysis and Statistics Subcommittee will
present its analysis of the data to the remainder of the Low-Dose
Panel. Principal investigators of the critical studies will be
available for comment.
On the second day, the remaining Subcommittee will meet separately
for discussion. Members of the Data Analysis and Statistics
Subcommittee will be asked to split up between the remaining
subcommittees.
On the third day, the entire Panel will reconvene as a group to
discuss the deliberations of each of the Panels and to integrate the
separate aspects into a report.
Each of the Subcommittees, as well as the full Panel, will produce
a written Report following the meeting, documenting the discussions and
explaining reasons for the scientific judgments made. These reports
will be submitted for publication in an appropriate peer-reviewed
scientific journal. Reports will also be made on the NTP and EPA
(Endocrine Disruptor Screening Program) Web sites.
Public Input Solicited
As described above, the NTP solicits comments on the scope and
process for the review; comments on the NTP preliminary list of studies
for review; the nomination of studies to be considered for review; and
the nomination of peer review panel members. Comments, identified by
docket control number OPPTS-42208A,
[[Page 786]]
must be received on or before February 22, 2000.
Guidelines for Submission of Public Comments
EPA will manage the record-keeping aspects of the Peer Review as
part of the Endocrine Disruptor Screening Program.
You man obtain electronic copies of this document, and certain
other related documents that might be available electronically, from
the EPA Internet Home Page at http://www.epa.gov/. To access this
document, on the Home Page select ``Laws and Regulations'' and then
look up the entry for this document under the ``Federal Register--
Environmental Documents.'' You can also go directly to the Federal
Register listings at http://www.epa.gov/fedrgstr/.
For general information about the Endrocrine Disruptor Screening
Program go to http://www.epa.gov/scipoly/oscpendo/index.htm.
The EPA has established an official record for this action under
docket control number OPPTS-42208A. The official record consists of the
documents specifically referenced in this action, any public comments
received during an applicable comment period, and other information
related to this action. This official record includes the documents
that are physically located in the docket, as well as the documents
that are referenced in those documents. The public version of the
official record does not include any information claimed as CBI. The
public version of the official record, which includes printed, paper
versions of any electronic comments submitted during an applicable
comment period, is available for inspection in the TSCA Nonconfidential
Information Center, North East Mall Rm. B-607, Waterside Mall, 401 M
St., SW, Washington, DC. The Center is open from noon to 4 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
Center is (202) 260-7099.
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number OPPTS-42208A in the subject line on
the first page of your response.
1. By mail. Submit your comments to: Document Control Office
(7407), Office of Pollution Prevention and Toxics (OPPT), Environmental
Protection Agency, 401 M St., SW, Washington, DC 20460.
2. In person or by courier. Deliver your comments to: OPPT Document
Control Office (DCO) in East Tower Rm. G-099, Waterside Mall, 401 M St.
SW, Washington, DC. The DCO is open from 8 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
DCO is (202) 260-7093.
3. Electronically. You may submit your comments electronically by
e-mail to: ``[email protected],'' or mail your computer disk to the
address identified above. Do not submit any information that you
consider to be CBI. Electronic comments may be submitted in WordPerfect
6.1/8.0 or as an ASCII file avoiding the use of special characters and
any form of encryption. Comments and data will also be accepted on
standard disks in WordPerfect 6.1/8.0 or ASCII file format. All
comments in electronic form must be identified by docket control number
OPPTS-42208A. Electronic comments may also be filed online at many
Federal Depository Libraries.
Do not submit any information that you consider to be Confidential
Business Information. If you believe that relevant information will be
overlooked because of this restriction, please consult the person
identified under FOR FURTHER INFORMATION CONTACT.
FOR FURTHER INFORMATION CONTACT:
James P. Kariya, Office of Science Coordination and Policy (7203),
Office of Prevention, Pesticides, and Toxic Substances, Environmental
Protection Agency, 401 M St. SW, Washington, DC 20460; telephone
number: (202) 260-2916; e-mail address: [email protected].
Dated: December 28, 1999.
Kenneth Olden,
Director, National Toxicology Program, Department of Health and Human
Services.
Attachment--Preliminary List of Published Studies to Be Considered
by the Low-dose Peer Review Panel
The NTP has compiled a preliminary list of relevant studies. The
public is invited to comment on this list; suggestions for
additions, deletions, and substitutions may be submitted. (See
Section of this FR announcement on Guidelines for Submission of
Public comments.) Submission of a complete copy of the journal
article in which the study and its results are described is
preferred, but a complete reference (authors' names, name of
journal, volume, issue, pages, title, date) will be sufficient if
the complete article cannot be submitted. Include a brief narrative
explaining the reason for each addition, deletion, or substitution.
Raw data need not be submitted at this stage.
Studies which are as yet unpublished but which are expected to
be accepted for publication before April 1, 2000 may be nominated.
An abstract of the study describing highlights of the study
(including species and strain, dosing regimen, duration of study,
number of animals per dose, endpoints evaluated and, if available,
results) must be submitted in order for the Selection Committee to
be able to evaluate the likelihood that the study will be a critical
study. As with published studies, a brief narrative explaining the
significance of as yet unpublished studies should be included.
Studies which are completed but not published are not included
here. This list is being provided as an example of the kinds of
studies that may be appropriate for the Panel to consider. Final
selection of studies has not been made.
Ashby J, Elliott BM. 1997. Reproducibility of endocrine
disruption data. Reg Toxicol Pharmacol 26:94-95.
Ashby J, Tinwell H, Lefevre PA et al. 1997. Normal sexual
development of rats exposed to butyl benzyl phthalate from
conception to weaning. Reg Toxicol Pharmacol 26:102-118.
Boettger-Tong H, Murthy L, Chiapetta C, et al. 1998. A case of a
laboratory animal feed with high estrogenic activity and its impact
on in vivo responses to exogenously administered estrogens. Environ
Health Perspect 106(7):369-373.
Cagen SZ, Waechter JM Jr, Dimond SS, et al. 1999. Normal
reproductive organ development in CF-1 mice following prenatal
exposure to bisphenol A. Toxicol Sci 50:36-44.
Colerangle JB, Roy D. 1997. Profound effects of the weak
environmental estrogen-like chemical bisphenol A on the growth of
the mammary gland of Noble rats. J Steroid Biochem Molec Biol 60(1-
2), 153-160.
Makela SI, Pylkkanen LH, Santti RSS, Adlercreutz H. 1995.
Dietary soybean may be antiestrogenic in male mice. J Nutr 125:437-
445.
Nagel SC, vom Saal FS, Thayer KA, et al. 1997. Relative binding
affinity-serum modified access (RBA-SMA) assay predicts the relative
in vivo bioactivity of the xenoestrogens bisphenol A and
octylphenol. Environ Health Perspect 105:70-76.
Odum J. Pyrah ITG, Foster JR, et al. 1999. Comparative
activities of p-nonylphenol and diethylstilbestrol in Noble rat
mammary gland and uterotrophic assays. Reg Toxicol Pharmacol 29:184-
195.
Portier C, Tritscher A, Kohl M. et al. 1993. Ligand/receptor
binding for 2,3,7,8-TCDD: implications for risk assessment.
Fundamental and Applied Toxicol 20:48-56.
Sharpe RM, Fisher JS, Millar MM, et al. 1995. Gestational and
lactational exposure of rats to xenoestrogens results in reduced
testicular size and sperm production. Environ Health Perspect
103(12): 1136-1143.
Sharp R, Turner KJ, Sumpter JP. 1998. Endocrine disruptors and
testis development [letter]. Environ Health Perspect 106(5): A220-
A221.
Sheehan DM, Willingham E, Gaylor D, et al. 1999. No threshold
dose for estradiol-induced sex reversal of turtle embryos: how
little is too much? Environ Health Perspect 107:155-159.
Spearow J, Doemeny P, Sera R, et al. 1999. Genetic variation is
susceptibility to endocrine disruption by estrogen in mice. Science
285:1259-1261.
vom Saal FS, Quadagno DM, Even MD, et al. 1990. Biology of
Reproduction 43:751-761.
vom Saal FS, Timms BG, Montano MM, et al. 1997. Prostate
enlargement in mice due to
[[Page 787]]
fetal exposure to low doses of estradiol or diethylstilbestrol and
opposite effects at high doses. Proc Natl Acad Sci USA 94:2056-2061.
vom Saal FS, Cooke PS, Buchanan DL, et al. 1998. A
physiologically based approach to the study of bisphenol A and other
estrogenic chemicals on the size of reproductive organs, daily sperm
production, and behavior. Toxicol Indust Hlth 14(__):239-260.
Welshons WV, Nagel SC, Thayer KA, et al. 1999. Low-dose
bioactivity of xenoestrogens in animals: fetal exposure to low doses
of methoxychlor and other xenoestrogens increases adult prostate
size in mice. Toxicol Indust Health 15:12-25.
[FR Doc. 00-228 Filed 1-5-00; 8:45 am]
BILLING CODE 4140-01-M