A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TRICHLOROETHYLENE AND ITS METABOLITES, CHLORAL HYDRATE, TRICHLOROACETATE, DICHLOROACETATE, TRICHLOROETHANOL, AND TRICHLOROETHANOL GLUCURONIDE IN B6C3F1 MICE

A six-compartment physiologically based pharmacokinetic (PBPK) model f or the B6C3F1 mouse was developed for trichloroethylene (TCE) and was linked with five metabolite submodels consisting of four compartments each. The PBPK model for TCE and the metabolite submodels described or al uptake and metabolism of TCE to chloral hydrate (CH). CH was furthe r metabolized to trichloroethanol (TCOH) and trichloroacetic acid (TCA ). TCA was excreted in urine and, to a lesser degree, metabolized to d ichloroacetic acid (DCA). DCA was further metabolized. The majority of TCOH was glucuronidated (TCOG) and excreted in the urine and feces. T COH was also excreted in urine or converted back to CH. Partition coef ficient (PC) values for TCE were determined by vial equilibrium, and P C values for nonvolatile metabolites were determined by centrifugation . The largest PC values for TCE were the fat/blood (36.4) and the bloo d/air (15.9) values. Tissue/blood PC values for the water-soluble meta bolites were low, with all PC values under 2.0. Mice were given bolus oral doses of 300, 600, 1200, and 2000 mg/kg TCE dissolved in corn oil . At various time points, mice were sacrificed, and blood, liver, lung , fat, and urine were collected and assayed for TCE and metabolites. T he 1200 mg/kg dose group was used to calibrate the PBPK model for TCE and its metabolites. Urinary excretion rate constant values were 0.06/ hr/kg for CH, 1.14/hr/kg for TCOH, 32.8/hr/kg for TCOG, and 1.55/hr/kg for TCA. A fecal excretion rate constant value for TCOG was 4.61/hr/k g. For oral bolus dosing of TCE with 300, 600, and 2000 mg/kg, model p redictions of TCE and several metabolites were in general agreement wi th observations. This PBPK model for TCE and metabolites is the most c omprehensive PBPK model constructed for P450-mediated metabolism of TC E in the B6C3F1 mouse. (C) 1997 Academic Press.