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U.S. EPA framework for determining mutagenic mode of action for carcinogens
Citation:
SCHOENY, R. S., N. MCCARROLL, R. D. OWEN, N. KESHAVA, A. D. KLIGERMAN, K. L. DEARFIELD, M. CIMINO, R. PUTZRATH, AND T. MCMAHON. U.S. EPA framework for determining mutagenic mode of action for carcinogens. Presented at Society for Risk Analysis Annual meeting, Baltimore, MD, December 06 - 09, 2009.
Impact/Purpose:
This presentation will help risk assessors understand the process in deterrnining when a mode of action should be deemed "mutagenic".
Description:
U.S. EPA's Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) specify that information on a chemical's mode of action (MOA) is key to the risk assessment process. MOA determines conditions under which a chemical is considered to be carcinogenic, appropriate low dose extrapolation, and whether a default procedure is used to account for early Ilfestage susceptibility. EPA recommends that, in the absence of data to support life stage-specific cancer slope factors, slope factors calculated from adult data be increased when early Ilfestage exposure isbeing assessed. This adjustment is done only for carcinogens shown to have a mutagenic MOA. EPA has developed a draft framework for organizing and evaluating data in support of a mutagenic MOA. This relies heavily on data from genotoxicity data, but emphasizes that the MOA ajudgment use all relevant data (e.g., pharmacokinetics, tumor data, structure activity relationships). The draft Framework identifies four steps in the iterative MOA process. 1. Assemble relevant data. All available information on the mutagenic and genotoxic effects o fa chemical is obtained to ensure as full a mutagenicity assessment as possible. 2. Evaluate data against current acceptance and quality criteria. It is recommended that all studies be included in a data comparison table that is described in the framework. 3. Judge weight of evidence (WOE) that the chemical is mutagenic. WOE is judged based on several factors such as the type of assays, results, effects, endpoints, etc.The framework provides a hierarchy of preference for assays to be used in the WOE. 4.Once it Is decided that the chemical or its metabolite is mutagenic,apply the Cancer Guidelines framework for determining any MOA. Two brief case studies (cyclophosphamide and chloroform) will be used to demonstrate use of these steps. Disclaimer: The views represented in this abstract are those of the authors and do not represent the policies of EPA.