Use of Mode of Action Information in Cancer Risk Assessment for Chloroform. D. E. Robinson and M. E. Andersen, International Life Sciences Institute, 1126 Sixteenth St., NW, Washington, DC 20036
EPA’s Proposed Guidelines for Carcinogen Risk Assessment consider the use of mode of action information to be a central part of the proposed approach for hazard characterization and dose response assessment. In particular, the use of non-tumor data in dose response assessment represents a departure from historical approaches to cancer risk assessment. With public and private sector support, ILSI convened an Expert Panel during 1996-1997 to develop several case studies on specific chemicals to utilize and evaluate the guidance provided in the proposed guidelines. Chloroform was selected as one of the case studies as a consequence of its well- developed mechanistic database. Data reviewed by the Panel included bioassay data in several strains of rats and mice following administration by gavage, drinking water and inhalation routes of exposure, results from a variety of assays on direct and indirect genotoxic potential, metabolism and disposition information, toxicokinetics and PBPK modeling, and mode of carcinogenic action data. Considering the weight of evidence for both linear and non-linear modes of action and the uncertainties associated with the available data base, the Panel provided its expert opinion regarding the likely mode of chloroform’s carcinogenic action, critical endpoint(s) for use in dose response assessment, use of PBPK modeling to select the appropriate dose measures in the target tissue(s), and recommended approaches for low dose extrapolation. The outcome of the Panel’s deliberations will be discussed. In addition, issues identified during the exercise of applying the proposed guidelines to a complex set of data will also be presented.