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PHARMACOKINETIC AND MECHANISTIC RESEARCH TO IMPROVE CANCER RISK ASSESSMENT FOR DICHLOROACETIC ACID
Impact/Purpose:
This project includes research to develop a mechanistic biologically based dose-response (BBDR) model for dichloroacetic acid (DCA) based on rat and mouse tumor studies and 2). The Stage 1 DBP rule proposed an MCLG for DCA and an MCL for haloacetic acids (five) (HAA5). The results of this study could increase our understanding of the mechanisms involved in carcinogenesis, and lead to a more accurate estimation of the carcinogenic hazard to humans exposed to DCA in drinking water. These results could be used for the Stage 2 DBP rule.In addition, the purpose of this project is to gain an improved understanding of the effects of DBPs in humans by conducting pharmacokinetic and pharmacodynamic investigations and to facilitate the extrapolation of data across different species, exposure routes, and doses. The results of these studies may strengthen or weaken the Agency's concern for a chemical's carcinogenic potential. The data may be used to adjust proposed MCLGs/MCLs for particular DBPs in the Stage 1 DBP rule, or to develop MCLGs/MCLs for other DBPs in the Stage 2 rule.
Description:
Chlorination of water containing organic material (humic, fulvic acids) results in the generation of many organic compounds, including DCA. DCA is commonly found in finished drinking water at concentrations ranging from 10-50 micrograms/liter. Several studies indicate that DCA is a carcinogen in both mice and rats exposed via drinking water lifetime studies. These studies indicate that DCA induces liver tumors. EPA has classified DCA in Group B2: probable human carcinogen, based on positive carcinogenic findings in two animal species exposed to DCA in drinking water. In the DBP proposed rule, EPA proposed an MCLG for DCA of zero based on the strong evidence of carcinogenicity via drinking water. EPA proposed to set the Stage 1 MCL for HAA5 at 0.060 mg/L. Research on pharmacokinetics (distribution, metabolism and elimination) and mechanisms of action is necessary to interpret the biological significance of an effect and to provide a sound scientific basis for assessing risk. By describing metabolism, tissue dosimetry and tissue response, physiologically based pharmacokinetic (PBPK) models and biologically based dose-response (BBDR) models permit a more accurate prediction of the shape of the dose-response curve for humans exposed to a particular contaminant. The proposed Guidelines for Carcinogen Risk Assessment describe the use of BBDR models as the preferred approach when extrapolating from animal studies. However, when this type of detailed information is not available, other approaches, such as the linear default approach or a margin of exposure analysis may be used. DCA is considered to be one of the more important DBPs and detailed information on its carcinogenic effects are especially valuable for assessing human risk.