Physiologically Based Pharmacokinetic Modeling of Inhaled Trichloroethylene and Its Oxidative Metabolites in B6C3F1Mice

Abstract

A physiologically based pharmacokinetic (PBPK) model for inhaled trichloroethylene (TCE) was developed for B6C3F1mice. Submodels described four P450-mediated metabolites of TCE, which included chloral hydrate (CH), free and glucuronide-bound trichloroethanol (TCOH-fand TCOH-b), trichloroacetic acid (TCA), and dichloroacetic acid (DCA). Inhalation time course studies were carried out for calibration of the model by exposing mice to TCE vapor concentrations of either 100 or 600 ppm for 4 h. At several time points, mice were euthanized and blood, liver, kidney, lung, and fat were collected and analyzed for TCE and its oxidative metabolites. Peak blood TCE concentrations were 0.86 and 7.32 μg/mL, respectively, in mice exposed to 100 and 600 ppm TCE. The model overpredicted the mixed venous blood and tissue concentrations of TCE for mice of both exposure groups. Fractional absorption of inhaled TCE was proposed to explain the discrepancy between the model predictions and the TCE blood time course data. When fractional absorption (53%) of inhaled TCE was incorporated into the model, a comprehensive description of the uptake, distribution, and clearance of TCE in the blood was obtained. Fractional uptake of inhaled TCE was further verified by collecting TCE in exhaled breath following a 4-h constant concentration exposure to TCE and validation was provided by testing the model against TCE blood concentrations from an independent data set. The submodels adequately simulated the distribution and clearance kinetics of CH and TCOH-fin blood and the lungs, TCOH-bin the blood, and TCA and DCA, which were respectively detected for up to 43 and 14 h postexposure in blood and livers of mice exposed to 600 ppm TCE. This is the first extensive tissue time course study of the major metabolites of TCE following an inhalation exposure to TCE and the PBPK model predictions were in good general agreement with the observed kinetics of the oxidative metabolites formed in mice exposed to TCE concentrations of 100 and 600 ppm.