Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans

Journal Article · Wed Jun 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.020· OSTI ID:21587763

Chiu, Weihsueh A., E-mail: [e-mail] ^[1]; Ginsberg, Gary L., E-mail: [e-mail] ^[2]

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1. National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC 20460 (United States)
2. Connecticut Department of Public Health, Hartford, CT 06106 (United States)

This article reports on the development of a 'harmonized' PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or 'baseline,' parameter estimates, and in vivo datasets separated into those used for 'calibration' and those used for 'evaluation.' Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of {approx} 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans ({approx} 3000-fold) and mice ({approx} 60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity between those previously published PBPK models that concluded low perc metabolism in humans and those that predicted high perc metabolism in humans. In essence, both conclusions are consistent with the data if augmented with some additional qualifications: in humans, oxidative metabolism is low, while GSH conjugation metabolism may be high or low, with uncertainty and/or interindividual variability spanning three orders of magnitude. More direct data on the internal kinetics of perc GSH conjugation, such as trichlorovinyl glutathione or tricholorvinyl cysteine in blood and/or tissues, would be needed to better characterize the uncertainty and variability in GSH conjugation in humans. - Research Highlights: >We analyze perchloroethylene (perc) toxicokinetics with a physiological model. >Results from previous analyses lumping metabolic pathways are inconsistent. >Separately tracking oxidation and conjugation pathways reconciles these results. >Available data are adequate for predicting perc blood levels and oxidation by P450. >High uncertainty remains for human conjugation of perc with glutathione.

• OSTI ID: 21587763
• Journal Information: Toxicology and Applied Pharmacology, Vol. 253, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.03.020; PII: S0041-008X(11)00114-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL PATHWAYS
BLOOD
CHLORINATED ALIPHATIC HYDROCARBONS
CYSTEINE
EVALUATION
EXHALATION
GLUTATHIONE
HUMAN POPULATIONS
IN VITRO
IN VIVO
METABOLISM
METABOLITES
MICE
MONTE CARLO METHOD
OXIDATION
RATS
RISK ASSESSMENT
AMINO ACIDS
ANIMALS
BIOLOGICAL MATERIALS
BODY FLUIDS
CALCULATION METHODS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
CLEARANCE
DRUGS
EXCRETION
HALOGENATED ALIPHATIC HYDROCARBONS
MAMMALS
MATERIALS
ORGANIC ACIDS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PEPTIDES
POLYPEPTIDES
POPULATIONS
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
THIOLS
VERTEBRATES