Physiologically based pharmacokinetic modeling of inhaled trichloroethylene and its oxidative metabolites in B6C3F(1) mice

A physiologically based pharmacokinetic (PBPK) model for inhaled trichloroe thylene (TCE) was developed for B6C3F(1) mice. Submodels described four P45 0-mediated metabolites of TCE, which included chloral hydrate (CH), free an d glucuronide-bound trichloroethanol (TCOH-f and TCOH-b), trichloroacetic a cid (TCA), and dichloroacetic acid (DCA). Inhalation time course studies we re carried out for calibration of the model by exposing mice to TCE vapor c oncentrations of either 100 or 600 ppm for 4 h. At several time points, mic e were euthanized and blood, liver, kidney, lung, and fat were collected an d analyzed for TCE and its oxidative metabolites. Peak blood TCE concentrat ions were 0.86 and 7.32 mu g/mL, respectively, in mice exposed to 100 and 6 00 ppm TCE. The model overpredicted the mixed venous blood and tissue conce ntrations of TCE for mice of both exposure groups. Fractional absorption of inhaled TCE was proposed to explain the discrepancy between the model pred ictions and the TCE blood time course data. When fractional absorption (53% ) of inhaled TCE was incorporated into the model, a comprehensive descripti on of the uptake, distribution, and clearance of TCE in the blood was obtai ned. Fractional uptake of inhaled TCE was further verified by collecting TC E in exhaled breath following a 4-h constant concentration exposure to TCE and validation was provided by testing the model against TCE blood concentr ations from an independent data set. The submodels adequately simulated the distribution and clearance kinetics of CH and TCOH-f in blood and the lung s, TCOH-b in the blood, and TCA and DCA, which were respectively detected f or up to 43 and 14 h postexposure in blood and livers of mice exposed to 60 0 ppm TCE. This is the first extensive tissue time course study of the majo r metabolites of TCE following an inhalation exposure to TCE and the PBPK m odel predictions were in good general agreement with the observed kinetics of the oxidative metabolites formed in mice exposed to TCE concentrations o f 100 and 600 ppm. (C) 1999 Academic Press.