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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