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ARSENIC MODE OF ACTION AND DEVELOPING A BBDR MODEL
Citation:
WOLF, D. C., S. W. EDWARDS, Y. ZHAO, AND R. B. CONOLLY. ARSENIC MODE OF ACTION AND DEVELOPING A BBDR MODEL. Presented at Federal-State Toxicology and Risk Analysis Committee (FSTRAC), Durham, NC, October 17 - 19, 2007.
Impact/Purpose:
We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity to reduce uncertainty in estimates of low dose risk utilizing data on the mode of action and its human relevance.
Description:
The current USEPA cancer risk assessment for inorganic arsenic is based on a linear extrapolation of the epidemiological data from exposed populations in Taiwan. However, proposed key events in the mode of action (MoA) for arsenic-induced cancer (which may include altered DNA methylation, altered DNA repair, and induced reactive oxygen species) suggest the possibility of a nonlinear response at low doses. We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity to reduce uncertainty in estimates of low dose risk utilizing data on the mode of action and its human relevance. The Human Relevance Framework (HRF) and Mode-of-Action analysis is used to assess the relevance of an increased frequency of neoplastic lesions in rodents identified in carcinogenicity studies. This approach provides a framework for assessing possible cancer risks from exposures to pollutants or other agents in the environment. The goal is to make greater use of the scientific understanding of the process of carcinogenesis. The process includes analyzing all available information, identifying the key events in the cancer processes from exposure to adverse health consequence, describing the mode(s) of action and its biological plausibility in humans, considering differential susceptibility to subpopulations, and finally characterizing the risk to humans based on the weight of scientific evidence. The level of biological details that will be incorporated into the model will be detemined largely by the availability of data. This model development effort will increase our understanding of how biological factors determine the shape of the dose-response curves for arsenic-induced cancer. [This abstract does not represent EPA opinion or policy]