UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
December 15, 1999
EPA-SAB-EC-LTR-00-001
Honorable Carol M. Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC 20460
Subject: Science Advisory Board's review of the Draft Chloroform Risk Assessment
and Related Issues in The Proposed Cancer Risk Assessment Guidelines
Dear Ms. Browner:
The Chloroform Risk Assessment Review Subcommittee of the Science Advisory Board was
convened to review the Office of Water's draft risk assessment for chloroform, with particular attention
to the mode of action analysis for chloroform-induced cancer, and the application of the relevant
sections of the Proposed Cancer Risk Assessment Guidelines. The Subcommittee met on Wednesday
and Thursday, October 27th and 28th in Washington, DC, to address these (and related) issues (A copy
of the full Charge is provided in Appendix A).
A full report documenting the findings of the Subcommittee is currently in preparation. This
brief letter report, which addresses one element of the Charge, was developed at the request of the
Office of Water (OW) in order to provide rapid feedback on their application of a key element of the
Proposed Cancer Risk Assessment Guidelines (GLs) (section 2.5, Mode of Action Framework for
Analysis) to the chloroform risk assessment. The specific question posed by the OW asked:
"Based on its application to the chloroform risk assessment, please identify any specific
text in the draft Cancer Risk Assessment Guideline's framework for mode of action
analysis (section 2.5) which you would advise being changed prior to their publication."
After deliberating on this issue, the Subcommittee wishes to express its overall support for the
GLs' (July 1999 draft) framework for determining the importance of different modes of action. Nothing
was identified that should hold up their publication. There were, however, a few suggestions that arose
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during the Subcommittee's discussion of the Guidelines that would aid in their implementation that we
would like to convey to the Agency for consideration:
a) The Subcommittee believes that the mode of action determination should include a step
that identifies gaps in knowledge when presenting conclusions in the draft GLs' human
relevance section on page 2-35. Gaps that relate to the potential for effects in sensitive
populations and/or subpopulations are particularly important in this regard. In this vein,
the Subcommittee also suggests that the Agency consider establishing a checklist
addressing populations of concern (such as pregnant women and children), similar to
that developed by the Food and Drug Administration (FDA), to be considered in each
mode of action analysis. This would serve to identify uncertainties in the determination
that could be buttressed by further research.
b) The following statement from the draft GLs provides little guidance: "Generally,
'sufficient' support is a matter of scientific judgment in the context of the requirements
of the decision maker or in context of science policy guidance regarding a certain mode
of action." In the implementation of the GLs, it is suggested that some greater
specificity as to what the term "sufficient" means would be useful, as would a statement
to the effect that a determination of a mode of action should be based upon
experimental evidence. The fact that the hypothesis remains consistent with a number
of distinct experimental challenges builds confidence that a certain mode of action is
essential to the induction of cancer by a given chemical. Consistency between
endpoints related to mode of action and carcinogenic responses should be sought in
experiments that give both positive and negative results. The Subcommittee suggests
that the statement "Findings that show that other chemicals having parallel lexicological
properties also result in a carcinogenic response strengthen the conclusion that a
particular mode of action is causal" be included as an additional bulleted item following
line 24 of page 2-34 of the GLs.
c) Some attention needs to be paid to terms that are used in describing a mode of action.
For example, what is meant by "sustained" when referring to cytotoxicity, cell
replication, or regenerative hyperplasia? This usage seems to imply that the effect must
recur for some minimum period of time. Some guidance is needed, since most studies
of such effects are of very limited duration. The use of the terms "linear" and "non-
linear" dose-response curves in the GLs also create some confusion and should be
more clearly defined. It may be that all dose-response curves for cancer have some
non-linear character and linear relationships can have non-zero intercepts.
d) There is an implicit recognition that mutations are an inherent part of carcinogenesis in
the GLs. It would be useful to point out that the carcinogenic activity of some
chemicals appears to involve modifications of cell division and cell death processes.
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Such chemicals act to 1) permit the expression of previously experienced genetic
damage and 2) promote clonal expansion of cells containing mutations that result in
autonomous growth. In this case the mutations can be produced by a variety of
endogenous and exogenous processes, which collectively are said to arise
"spontaneously." This is a generic idea that provides some perspective with respect to
a number of modes of action that can contribute to a carcinogenic response without
direct interaction with DNA, including cytotoxicity, cell replication, and reparative
hyperplasia. Such a discussion might be usefully placed in section 2.5.3 of the GLs
where a number of potential modes of action are identified.
We appreciate this opportunity to review an application of the Agency's proposed Cancer Risk
Assessment Guidelines and look forward to receiving the responses of the Assistant Administrators of
the Offices of Water and Research and Development. The Subcommittee will work to bring our
deliberations on the other elements of the Charge for this review to an early conclusion.
Sincerely,
/s/
Dr. Joan M. Daisey, Chair
Science Advisory Board
/s/ /s/
Dr. Richard J. Bull, Co-chair, Dr. Mark J. Utell, Co-chair,
Chloroform Risk Assessment Chloroform Risk Assessment
Review Subcommittee Review Subcommittee
Science Advisory Board Science Advisory Board
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APPENDIX A - CHARGE
General Purpose: Review the Mode of Action Determination and Selection of Nonlinear Dose-
Response Approach for Chloroform under EPA's Proposed Cancer Risk
Assessment Guidelines Revisions, and identify specific statements or text in
section 2.5 of the draft Cancer Risk Assessment Guidelines which, based on its
application to the chloroform risk assessment, you would advise be changed
prior to final publication.
Charge 1: Based on its application to the chloroform risk assessment, please identify any specific
text in the draft Cancer Risk Assessment Guideline's framework for mode of action
analysis (section 2.5) which you would advise be changed prior to their publication.
Charge 2: Specific questions:
a) In the draft chloroform risk assessment document, are the conclusions as to the
following issues adequately supported by the analyses presented in the health
risk assessment/characterization (as supported by the ILSI report) and the
framework analysis?
(1) chloroform' s mode of action
(2) consideration of a nonlinear approach to dose-response, and the
possibility that mutagenesis might play a role in the carcinogenic
response.
(3) the relationship of low-dose pathology to the doses that induce tumors.
(4) epidemiologic evidence on chlorinated drinking water as to the
carcinogenicity of chloroform, including comment on any conclusion to
be drawn from the epidemiologic data about mode of action.
b) Does the assessment of children's risk for chloroform appropriately address the
risk concerns, including ontogeny of drug metabolizing enzymes), given the data
available?
A-l
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SCIENCE ADVISORY BOARD
CHLOROFORM RISK ASSESSMENT REVIEW SUBCOMMITTEE
CO-CHAIRS
Dr. Richard J. Bull, Senior Staff Scientist, Battelle Pacific Northwest National Laboratory, Molecular
Biosciences, Richland, WA
Dr. Mark J. Utell, Director, Pulmonary Unit, and Professor of Medicine and Environmental Medicine,
University of Rochester Medical Center, Rochester, NY
MEMBERS
Dr. Mary Davis, Professor of Pharmacology and Toxicology, West Virginia University, Morgantown,
WV
Dr. George Lambert, Associate Professor of Pediatrics and Director of Pediatric Pharmacology and
Toxicology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical
School, New Brunswick, NJ
Dr. Lauren Zeise, Chief, Reproductive and Cancer Hazard Assessment Section, Office of
Environmental Health Hazard Assessment, California Environmental Protection Agency,
Oakland, CA
CONSULTANTS
Dr. James E. Klaunig, Division of Toxicology, Department of Pharmacology and Toxicology, Indiana
University, School of Medicine, Indianapolis, IN
Dr. Richard Okita, College of Pharmacy, Washington State University, Pullman, WA
Dr. David Savitz, Professor and Chair, Department of Epidemiology, School of Public Health, University
of North Carolina, Chapel Hill, NC
Dr. Verne Ray, Groton, CT
FEDERAL EXPERT
Dr. Robert Maronpot, title, National Institute of Environmental Health Sciences, 111 Alexander Drive,
Research Triangle Park, NC
SCIENCE ADVISORY BOARD STAFF
Mr. Samuel Rondberg, Designated Federal Officer, U.S. Environmental Protection Agency, Science
Advisory Board (1400A), Washington, DC
Mr. Thomas Miller, Designated Federal Officer, U.S. Environmental Protection Agency, Science
Advisory Board (1400A), SW, Washington, DC
Ms. Dorothy Clark, Management Assistant, U.S. Environmental Protection Agency, Science Advisory
Board (1400A), Washington, DC
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NOTICE
This report has been written as part of the activities of the Science Advisory Board, a public
advisory group providing extramural scientific information and advice to the Administrator and other
officials of the Environmental Protection Agency. The Board is structured to provide balanced, expert
assessment of scientific matters related to problems facing the Agency. This report has not been
reviewed for approval by the Agency and, hence, the contents of this report do not necessarily
represent the views and policies of the Environmental Protection Agency, nor of other agencies in the
Executive Branch of the Federal government, nor does mention of trade names or commercial products
constitute a recommendation for use.
Distribution and Availability: This Science Advisory Board report is provided to the EPA
Administrator, senior Agency management, appropriate program staff, interested members of the
public, and is posted on the SAB website (www.epa.gov/sab). Information on its availability is also
provided in the SAB's monthly newsletter (Happenings at the Science Advisory Board). Additional
copies and further information are available from the SAB Staff.
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