UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C, 20460
EPA-SAB-EHC-S9-Q05
October 15, 1988
Honorable Lee M. Thomas
Administrator
U.S. Environmental Protection Agency
401 M street, S*W.
Washington, D.C. 20460
Subject; Science Advisory Board's review of issues relating to
the proposed MALE AND FEMALE REPRODUCTIVE GUIDELINES
Dear Mr. Thomas,
The Science Advisory Board's Environmental Health Committee
has completed its review of the issues pertaining to the proposed
male and female reproductive guidelines at its meeting July 14-
15, 1988 in Washington, D.c..
The major recommendations of the Committee includest
combining the guidelines for male and female reproductivity into
one guideline, including illustrative examples in the support
document, expanding the weight-of-evidence section to give more
detail concerning the relative importance of different endpoints
and investigating dose-response models that may be useful
additions to the threshold no-observed level approach.
We appreciate the opportunity to conduct this particular
scientific review. We request that the Agency formally respond
to the scientific advice provided herein.
Sincerely,
Norton Nelson
Chairman, Executive committee
Richard A, Griesemer
Chairman
Environmental Health Committee
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SUBJECT: SCIENCE ADVISORY BOARD'S REVIEW OF ISSUES RELATING TO
MALE AND FEMALE REPRODUCTIVE GUIDELINES
SCIENCE ADVISORY BOARD COMMITTEE; THE ENVIRONMENTAL HEALTH
COMMITTEE
DATE OF REVIEW! JULY 14-15, 198S
PLACE OF REVIEW! HOLIDAY INN GOVERNOR'S HOUSE, WASHINGTON, DC
Introduction
Reproductive toxicology is a young field, and the process of
risk assessment for reproductive effects has yet to be developed.
Given the difficult nature of this task, the EHC believes that
the Reproductive Effects Assessment Group is to be congratulated
for their efforts in preparing this draft of the guidelines. The
evolving nature of this field will warrant frequent review and
revision of these guidelines to reflect new developments in the
science of reproductive toxicology.
Recommendations of the SAB Environmental Health Committee
l. The Environmental Health Committee (EHC) recommends that EPA
combine the guidelines for male and female reproductive risk
assessment. Eventually sufficient new information may be
obtained to justify separate guidelines* We believe the
scientific issues are best addressed with a single document*
2. EHC recommends that a technical support document be prepared
to provide illustrative examples, These examples should
illustrate the type of information available, and the scientific
judgments involved in the risk assessment process. These
illustrative examples should be used in the guidelines document
to clarify the discussion of general principles.
3. EHC recommends that the weight-of-evidence section be
expanded to include discussion of the relative importance of the
various endpoints, and the quantitative determination of what
constitutes a biologically significant change in an endpoint.
What, for example, is an acceptable reduction in reproductive
performance? Judgment on the relative importance of the
endpoints will often be critical in the risk assessment process.
Also, a single endpoint may not be sufficient for hazard
identification. It will be advisable to consider the weight-of-
evidence of related endpoints collectively.
a* SPA should designate as a research need the evaluation
of biological relevance of the various endpoints, and the
comparison of animal assays with these endpoints in humans.
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b. EPA should expand the discussion in the guidelines of
how to weigh evidence of reproductive toxicity when other
target organ or general systemic toxicity is observed.
While the EHC agrees that reproductive effects observed at
dose levels affecting other organs should not be ignored, we
conclude that the weight of evidence should be substantially
reduced if reproductive toxicity is observed only at levels
toxic to other organ systems. In any case all endpoints
should be mentioned.
4, EHC recommends that EPA refine its weight-of-evidenee
classifications in Table 2.
a. EPA should establish standards for what constitutes "a
convincing body of evidence," for both the positive and
negative categories. The technical support document should
provide examples on which such standards might be based.
Application of the standards may involve many aspects of
scientific judgment.
b. The standard for "probable negative" is particularly
difficult to define, What set of studies would provide
convincing that none of the adverse endpoints occur in
humans or in animals?
c. EPA should define what constitutes a minimal data set
for a positive, that is, identification of a reproductive
hazard based on one or more endpoints.
d. The dose at which the effect is produced must be a major
consideration in hazard identification. Because of
secondary effects, most substances will test positive at
some dose.
e. The "probable positive" category should not include
agents- for which there is convincing evidence that the
mechanism(s) by which an agent causes adverse reproductive
effects in one or more mammalian species are not applicable
to humans.
f. The difference between the "possible negative" and the
"possible positive" categories is not clear, and the
distinction between these categories may not serve a useful
purpose. We recommend that these two categories be merged
into the "no data/inadequate data11 category.
5. EHC recommends that the full set of dose-response data be
used as the basis for the risk assessment and that EPA not
restrict its approach to a reference dose based on a NOAEL. The
reference dose approach does not allow for a quantitative risk
assessment. Fitting one or more dose-response models in the risk
estimation process may be useful in addition to conventional
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NOABL approach* Extrapolation using a model can be based on the
full dose-response data set, while the NOAEL reflects one data
point. The determination of a NQAEL as the highest level failing
to yield a statistically significant response compared to
controls implies that this determination will depend on the
quality of the test and the sensitivity of the endpoint.
Uncertainties in the dose-response estimates should be made
explicit by stating confidence intervals around estimates and
discussing the assumptions and biological plausibility underlying
the choice of the dose-response model(s).
6. EEC recommends that IPA review and revise as necessary the
reproductive toxicity testing guidelines, so that the resulting
data provide the best possible basis for reproductive risk
assessment.
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U.S. QJVIROtilMEAL PROTECTION AGINCY
SCIENCE ADVISORY BOARD
ENVIROW)1QITAL HEMJH CCMHTTEE
July 14-15
Dr. Richard A. Griesemer [CHAIR], Director, Division of Toxicology Research
and Testing, NIEHS, P.O. Box 12233, Research Triangle Park, NC 27709
Dr. D. Warner North [VICE-CHAIR], Principal, Decision Focus Inc., Los Altos Office
Center, Suite 200, 4984 El Gamine- Real, Los Altos, California 94022
Dr. Gary Carlson, Department of Pharmacology and Toxicology, School of Pharmacy,
Purdue University, West Lafayette, IN 47909
Dr. Phil Enterline, Department of Biostatistics, Graduate School of Public Health,
University of Pittsburg, 130 Desoto Street, Pittsburg, PA 15261
Dr. teshall Johnson, Professor, Department of Anatomy, Jefferson Medical College,
1020 Locust Street, Philadelphia, Pennsylvania 19107
Dr. Nancy Kim, Director, New York Department of Health, Division of Environmental
Health, 2 University Plaza, Albany, New York 12203
Dr. Martha Radike, Department of Environmental Health, Medical Center, University
of Cincinnati, 3223 Eden Avenue, ML #56, Cincinnati, OH 45268
Dr. Stephen M. lappaport, Department of Momedical and Environmental Health Sciences,
Earl Warren Hal Room 317, School of Public Health, University of California,
Berkeley, California 94720
Dr. Robert Tazdiff, 1423 Trapline Court, Vienna, VA 22180
Dr. Bernard Weiss, Professor, Division of Toxicology, P.O. Box RBB, University
of Rochester, School of Medicine, Rochester, New York 14642
Dr. Ronald Wyzg^, Electric Power Research Institute, 3412 Hillview Avstue, P.O.
Box 1041, Palo Alto, California 94303
LIASON MEMBER
Dr. David Gaylor, National Center for lexicological Research, Jefferson,
Arkansas 72079
EXECUTIVE SECRETARY
Dr. C, Richard Cothern, Executive Secretary, Science Advisory Board
[A-101F] U.S. Environmental Protection Agency, Washington, D.C. 20460
MOBKSHOP GROUP
Dr, James C. Lamb, Senior Assistant, Jellmek, Schwartz, Connolly and Freshman Inc.
1350 New York Avenue NW, Suite 400, Washington, D.C. 20005
Dr. John McLachlan, Chief, Laboratory of Reproductive and Developmental Toxicology,
National Institute of Environmental Health Sciences, Research Triangle Park, NC
27709
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Dr. Bernard SeUtfetz, Chief Assistant of Toxicology Branch, NI2HS, F.O, Box 12233,
D-402, Research Triangle Park, NC 27709
Dr. Anthony Scialli, Director, Reproductive Toxicology Center, 2425 L St. NW,
Washington, D.C. 20037-1485
Dr. Peter Working, Genaitech Inc., 460 Point Bruno Blvd., South San Francisco, CA
94080
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