Physiologically-based pharmacokinetic model for trichloroethylene considering enterohepatic recirculation of major metabolites.
Trichloroacetic acid (TCA) is a major metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA in rats do not occur until approximately 12 hours following an oral dose of TRI. However, blood concentrations of TRI reach a maximum within an hour and are nondetectable after 2 hours. The results of a study which examined the enterohepatic recirculation (EHC) of the principle TRI metabolites was used to develop a physiologically-based pharmacokinetic model for TRI, which includes enterohepatic recirculation of its metabolites. The model quantitatively predicts the uptake, distribution and elimination of TRI, trichloroethanol, trichloroethanol-glucuronide, and TCA and includes production of metabolites through the enterohepatic recirculation pathway. Physiologic parameters used in the model were obtained from the literature. Parameters for TRI metabolism were taken from Fisher et al. Other kinetic parameters were found in the literature or estimated from experimental data. The model was calibrated to data from experiments of an earlier study where TRI was orally administered. Verification of the model was conducted using data on the enterohepatic recirculation of TCEOH and TCA, chloral hydrate data (infusion doses) from Merdink, and TRI data from Templin and Larson and Bull.
Stenner
R D
RD
Pacific Northwest National Laboratory (operated by Battelle Memorial Institute), Richland, Washington 99352, USA. rd-stenner@prl.gov
Merdink
J L
JL
Fisher
J W
JW
Bull
R J
RJ
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D004764:Enterohepatic Circulation; D004785:Environmental Pollutants / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D012306:Risk; D014238:Trichloroacetic Acid / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity
D001798:Blood Proteins; D002273:Carcinogens; D004785:Environmental Pollutants; D014241:Trichloroethylene; D014238:Trichloroacetic Acid