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Development of a Multiroute Human PBPK Model for Bromodichloromethane (BDCM)
Citation:
KENYON, E. M., T. L. LEAVENS, AND R. A. PEGRAM. Development of a Multiroute Human PBPK Model for Bromodichloromethane (BDCM). Presented at 2009 Annual Society of Toxicology meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This PBPK model allows estimation of internal dose as a result of exposure to the disinfection byproduct, BDCM, in drinking water considering all routes of exposure - dermal, oral, inhalation.
Description:
BDCM is an animal carcinogen and developmental toxicant. Due to its presence as a disinfection byproduct in finished drinking water, BDCM may pose a risk for exposure via ingestion, inhalation or dermal exposure. Utilizing a unique data set in which human subjects were exposed to BDCM by both the dermal and oral routes (Leavens et al., 2007), we have developed a refined human multi-route PBPK model. Compartments in the model are skin, liver, gut, fat, brain, kidney, and slowly and rapidly perfused tissue groups; tissue transport is blood-flow limited and metabolism occurs in the liver by a single pathway. Chemical-specific parameters for tissue solubility and metabolism as well as initial organ volumes and blood flow rates were obtained from the literature; subject-specific values were available for height, weight and fat volume. The preliminary model adequately predicted individual blood time course data following dermal exposure, whereas the same model poorly predicted blood time course data following oral exposure. Sensitivity analysis (SA) allowed identification of parameters that were uniquely sensitive for dermal compared to oral exposure and identification of parameters most appropriate to estimate from the available human data. Based on SA, parameters governing oral absorption and metabolism were critical for the oral route, whereas for the dermal route skin permeability was the single most influential parameter. Model-based analysis suggests the need for a second pathway for metabolic clearance (a mechanism not included in other PBPK models for BDCM). Preliminary in vitro studies support this conclusion. These results point to the critical role for model-based analysis in both the design and interpretation of data from human studies. (This abstract does not necessarily reflect Agency policy).