Journal Article
A physiologically based pharmacokinetic model for trichloroethylene and its metabolites, chloral hydrate, trichloroacetate, dichloroacetate, trichloroethanol, and trichloroethanol glucuronide in B6C3F1 mice
Abbas, R; Fisher, JW
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333
NIOSH/00241475
Toxicol. Appl. Pharmacol.
A six-compartment physiologically based pharmacokinetic (PBPK) model for 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 oral uptake and metabolism of TCE to chloral hydrate (CH). CH was further metabolized to trichloroethanol (TCOH) and trichloroacetic acid (TCA). TCA was excreted in urine and, to a lesser degree, metabolized to dichloroacetic acid (DCA). DCA was further metabolized. The majority of TCOH was glucuronidated (TCOG) and excreted in the urine and feces. TCOH was also excreted in urine or converted back to CH. Partition coefficient (PC) values for TCE were determined by vial equilibrium, and PC values for nonvolatile metabolites were determined by centrifugation. The largest PC values for TCE were the fat/blood (36.4) and the blood/air (15.9) values. Tissue/blood PC values for the water-soluble metabolites 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. The 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/kg. For oral bolus dosing of TCE with 300, 600, and 2000 mg/kg, model predictions of TCE and several metabolites were in general agreement with observations. This PBPK model for TCE and metabolites is the most comprehensive PBPK model constructed for P450-mediated metabolism of TCE in the B6C3F1 mouse. Copyright 1997 Academic Press.
Administration,Oral; Air; analogs & derivatives; Animals; August 2007 Metabolites Task; blood; chemistry; Chloral Hydrate; Corn Oil; Dichloroacetate; Ethylene Chlorohydrin; Feces; Glucuronates; Lash et al 2000 EHP; Liver; Lung; Male; metabolism; Mice; Mice,Inbred Strains; Models,Biological; mouse; NRC 2006 document; obtained; Ohio; pharmacokinetics; Research; Research Support; Solvents; Tissue Distribution; Toxicology; Trichloroacetic Acid; Trichloroethylene; urine; Chiu et al 2006 EHP Suppl; Chiu et al 2006 EHP; Hack et al 2006; Administration, Oral; Chloral Hydrate/metabolism/pharmacokinetics/urine; Dichloroacetate/metabolism/pharmacokinetics/urine; Ethylene Chlorohydrin/analogs & derivatives/metabolism/pharmacokinetics/urine; Feces/chemistry; Glucuronates/metabolism; Liver/metabolism; Mice, Inbred Strains; Models, Biological; Solvents/metabolism/pharmacokinetics; Trichloroacetic Acid/metabolism/pharmacokinetics/urine; Trichloroethylene/metabolism/pharmacokinetics; 0 (Glucuronates); 0 (Solvents); 107-07-3 (Ethylene Chlorohydrin); 115-20-8 (2,2,2-trichloroethanol); 13425-80-4 (Dichloroacetate); 302-17-0 (Chloral Hydrate); 76-03-9 (Trichloroacetic Acid); 79-01-6 (Trichloroethylene)
