Regular Article
A Physiologically Based Pharmacokinetic Model for Trichloroethylene and Its Metabolites, Chloral Hydrate, Trichloroacetate, Dichloroacetate, Trichloroethanol, and Trichloroethanol Glucuronide in B6C3F1 Mice,☆☆

https://doi.org/10.1006/taap.1997.8190Get rights and content

Abstract

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.

References (60)

  • J.W Fisher et al.

    Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid

    Toxicol. Appl. Pharmacol.

    (1990)
  • J.W Fisher et al.

    Physiologically based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse

    Toxicol. Appl. Pharmacol.

    (1991)
  • M.L Gargas et al.

    Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues

    Toxicol. Appl. Pharmacol.

    (1989)
  • T Green et al.

    Species differences in response to trichloroethylene. II. Biotransformation in rats and mice

    Toxicol. Appl. Pharmacol.

    (1985)
  • S.L Herren-Freund et al.

    The carcinogenicity of trichloroethylene and its metabolites trichloroacetic acid and dichloroacetic acid, in mouse liver

    Toxicol. Appl. Pharmacol.

    (1987)
  • G.W Jepson et al.

    A partition coefficient method for non-volatile and intermediate volatility chemicals in biological tissues

    Fund. Appl. Tox.

    (1994)
  • H.J Kim et al.

    Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats

    Toxicol. Appl. Pharmacol.

    (1990)
  • J.L Larson et al.

    Metabolism and lipoperoxidation activity of trichloroacetate and dichloroacetate in rats and mice

    Toxicol. Appl. Pharmacol.

    (1992)
  • J Odum et al.

    A mechanism for the development of Clara cell lesions in the mouse lung after exposure to trichloroethylene

    Chem.–Biol. Interact.

    (1992)
  • M.V Templin et al.

    Relative formation of dichloroacetate and trichloroacetate from trichloroethylene in male B6C3F1 mice

    Toxicol. Appl. Pharmacol.

    (1993)
  • R Abbas et al.

    A physiologically based pharmacokinetic model to describe disposition of chloral hydrate and trichloroethanol in mice

    Int. Toxicol.

    (1995)
  • R Abbas et al.

    Determination of kinetic rate constants for chloral hydrate, trichloroethanol, trichloroacetic acid and dichloroacetic acid: A physiologically based modeling approach

    Toxicologist

    (1997)
  • B.C Allen et al.

    Pharmacokinetic modeling of trichloroethylene and trichloroacetic acid in humans

    Risk Anal.

    (1993)
  • J.V Bruckner et al.

    Metabolism, toxicity, and carcinogenicity of trichloroethylene

    Toxicology

    (1989)
  • H.J Clewell et al.

    Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: Examples with vinyl chloride and trichloroethylene

    Chemosphere

    (1996)
  • S.H Curry et al.

    Disposition and pharmacokinetics of dichloroacetate (DCA) and oxalate following oral DCA doses

    Biopharm. Drug Dispos.

    (1991)
  • I.W.F Davidson et al.

    Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics

    Drug Metab. Rev.

    (1991)
  • W Dekant et al.

    Absorption, elimination and metabolism of trichloroethylene: A quantitative difference between rats and mice

    Xenobiotica

    (1986)
  • P.O Droz et al.

    Variability in biological monitoring of solvent exposure. I. Development of a population physiological model

    Br. J. Ind. Med.

    (1989)
  • Cited by (0)

    Presented in part at the 35th and 36th Annual Meetings of the Society of Toxicology, Anaheim, CA, 1996 and Cincinnati, OH, 1997, respectively.

    ☆☆

    T. R. GerrityC. J. Henry, Eds.

    2

    To whom correspondence should be addressed at AL HSC/OET, Building 79, 2856 G Street, Wright–Patterson AFB, OH 45433–7400. Fax: 513–255–1474.

    View full text