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Development of a biologically based dose response (BBDR) model for arsenic induced cancer
Zhao, Y., S. W. EDWARDS, D. C. WOLF, AND R. CONOLLY. Development of a biologically based dose response (BBDR) model for arsenic induced cancer. Presented at Toxicogenomics Integrated with Environmental Sciences, Raleigh, NC, October 25 - 26, 2007.
We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action. Expert consultation and literature review are being conducted to identify the tumor endpoints of regulatory interest and the sequence(s) of key events most likely to be linked with arsenic induced cancer. Laboratory studies will be designed that emphasize dose-response and time course behaviors for these key events. The level of biological details that will be incorporated into the model will be determined largely by the availability of data. The initial modeling effort will include a description of the pathway leading from DNA damage to activation of cell cycle checkpoints and apoptosis. The full BBDR model will consist of (1) a physiologically-based pharmacokinetic (PBPK) submodel to provide estimates of tissue-specific doses, (2) the sequence(s) of key events (mode of action) triggered by the tissue dose and, (3) a multistage clonal growth model to predict dose-responses and time-courses for tumor incidence.
This coordinated data collection – model development effort will increase our understanding of how biological factors determine the shape of the dose-response curves for arsenic-induced cancer.
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Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY