Toxicological Sciences 53, 159-172 (2000)
Copyright © 2000 by the Society of Toxicology
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Lessons Learned in Applying the U.S. EPA Proposed Cancer Guidelines to Specific Compounds
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* Department of Environmental Health, Colorado State University; Fort Collins, Colorado;
Health Canada;
National Institute of Environmental Health Sciences;
§ Covance Laboratories;
¶ University of Nebraska Medical Center;
|| Ohio State University;
||| Rohm and Haas Company;
|||| Michigan State University;
# American Health Foundation;
** University of Cincinnati; and
ILSI Health and Environmental Sciences Institute, Washington, DC
ABSTRACT
An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted.
Key Words: chloroform; dichloroacetic acid; proposed cancer guidelines, U.S. EPA; mode of action; margin of exposure; harmonization; modeling, toxicokinetic; evidence, preponderance of; risk assessment..
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