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Development and Application of a Human PBPK Model for Bromodichloromethane (BDCM) to Investigate Impacts of Multi-Route Exposure
Kenyon, E., T. Leavens, C. Eklund, AND R. Pegram. Development and Application of a Human PBPK Model for Bromodichloromethane (BDCM) to Investigate Impacts of Multi-Route Exposure. JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 36(9):1095-1111, (2015).
Model applications include multi-route exposure assessment prediction of toxicity based on internal dose to target tissue, risk analysis for susceptible sub-populations, and prediction of the effect(s) of change in disinfection scenarios on tissue dosimetry and toxicity.
Due to its presence in water as a volatile disinfection byproduct, BDCM, which is mutagenic and a rodent carcinogen, poses a risk for exposure via multiple routes. We developed a refined human PBPK model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on toxicologically-relevant dose metrics in comparison to oral exposure. Results of local and global sensitivity analysis (LSA, GSA) were also compared. The model adequately predicted data from the published literature for oral, dermal, and bathing/showering exposures. In general, parameters ranked in the top and bottom one third based on the Morris GSA were also ranked as high and low influence based on the LSA. Using the drinking water equivalency level (DWEL) approach to produce by oral exposure, the same internal doses predicted to result from a 20-min bathing exposure to water containing 10 µg/L BDCM, we found that drinking a liter of water containing 605, 803, and 5 µg/L BDCM for maximum venous blood concentration (Cmax), area under the curve (AUCv), and amount metabolized in liver/hr (MBDCM) is required. For a 10-min showering exposure to 10 µg/L BDCM water, the oral DWELs are 282, 312, and 2.1 µg/L for Cmax, AUC, and MBDCM. These data demonstrate large contributions of dermal and inhalation exposures (e.g., via bathing, showering) to internal dose of BDCM reaching the systemic circulation, resulting in more BDCM available for extrahepatic metabolism to mutagenic metabolites in target tissues. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne brominated trihalomethanes is needed
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION