In Vivoandin VitroStudies of Perchloroethylene Metabolism for Physiologically Based Pharmacokinetic Modeling in Rats, Mice, and Humans

doi:10.1006/taap.1996.0036

Toxicology and Applied Pharmacology

Volume 136, Issue 2, February 1996, Pages 289-306

https://doi.org/10.1006/taap.1996.0036 Get rights and content

Abstract

In vivoexperiments in rats and mice andin vitroexperiments in rats, mice, and humans have been used to develop and validate a “2nd generation” physiologically based pharmacokinetic (PBPK) model for perchloroethylene (PERC). The refined PBPK model should be useful in the preparation of carcinogenic risk assessment based on amounts of PERC metabolites formed in the livers of rodents and humans according to procedures developed by EPA. A sensitivity analysis of the PBPK model revealed that the most significant uncertainties in this process (other than the choice of the appropriate dose/response model based on mechanism of action of PERC) were in the techniques used to estimate rates of PERC metabolism in humans.In vitrostudies with human tissues reported help define what some have called the range of “equally reasonable alternatives” for estimating human risk.

References (0)

Cited by (55)

Incorporation of the glutathione conjugation pathway in an updated physiologically-based pharmacokinetic model for perchloroethylene in mice
2018, Toxicology and Applied Pharmacology
Citation Excerpt :
In vivo data for B6C3F1 and SW strains were reviewed thoroughly and used in the previous perc PBPK model (Chiu and Ginsberg, 2011). Studies in B6C3F1 mice included inhalation, closed chamber and oil gavage administration at a range of exposure levels, and reported perc and its oxidative metabolite, TCA, in blood (Gargas, 1988; Odum et al., 1988; Gearhart et al., 1993; Reitz et al., 1996). Only data using aqueous gavage of perc was available for the SW strain, reporting concentrations of perc in blood, liver and kidney, and its oxidative metabolite, TCA, in blood and liver (Philip et al., 2007).
Perchloroethylene (perc) induced target organ toxicity has been associated with tissue-specific metabolic pathways. Previous physiologically-based pharmacokinetic (PBPK) modeling of perc accurately predicted oxidative metabolites but suggested the need to better characterize glutathione (GSH) conjugation as well as toxicokinetic uncertainty and variability.
We updated the previously published “harmonized” perc PBPK model in mice to better characterize GSH conjugation metabolism as well as the uncertainty and variability of perc toxicokinetics.
The updated PBPK model includes expanded models for perc and its oxidative metabolite trichloroacetic acid (TCA), and physiologically-based sub-models for conjugative metabolites. Previously compiled mouse kinetic data in B6C3F1 and Swiss-Webster mice were augmented to include data from a recent study in male C57BL/6J mice that measured perc and metabolites in serum and multiple tissues. Hierarchical Bayesian population analysis using Markov chain Monte Carlo was conducted to characterize uncertainty and inter-strain variability in perc metabolism.
The updated model fit the data as well or better than the previously published “harmonized” PBPK model. Tissue dosimetry for both oxidative and conjugative metabolites was successfully predicted across the three strains of mice, with estimated residuals errors of 2-fold for majority of data. Inter-strain variability across three strains was evident for oxidative metabolism; GSH conjugation data were only available for one strain.
This updated PBPK model fills a critical data gap in quantitative risk assessment by predicting the internal dosimetry of perc and its oxidative and GSH conjugation metabolites and lays the groundwork for future studies to better characterize toxicokinetic variability.
Halogenated Hydrocarbons
2018, Comprehensive Toxicology: Third Edition
Halogenated hydrocarbons (HHCs) encompass a broad group of aliphatic and aromatic chemicals. Many are environmental contaminants or industrial solvents. This article focuses on select HHCs that are known to exhibit nephrotoxicity in animals and/or humans. Chemicals that are reviewed include select examples from haloalkanes, haloacids, haloalkenes, halogenated aromatics, halogenated ethers (which include some commonly used anesthetic agents), and ifosfamide and cyclophosphamide. The article is divided into processes involved in nephrotoxicity. The first major section summarizes metabolic pathways for bioactivation and/or detoxification. Metabolism comprises two major pathways: cytochrome P450 (CYP)-dependent oxidation, which can result in bioactivation or generate substrates for Phase II conjugation reactions; and glutathione-dependent bioactivation pathways, which involve subsequent metabolism by cysteine conjugate beta-lyase or flavin-containing monooxygenase. The next major section summarizes key features of acute and chronic nephrotoxicity, which typically involve single dose or short-term, high-dose exposures for acute and long-term, low-dose exposures for chronic. The final section summarizes select human health risk assessments for HHCs.
Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet
2017, Toxicology
Contaminant involvement in the pathophysiology of obesity is widely recognized. It has been shown that low dose and chronic exposure to endocrine disruptor compounds (EDCs) potentiated diet- induced obesity. High and acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant (POP) and an EDC with anti-estrogenic property, causes wasting syndrome . However at lower doses, the TCDD metabolic effects remain poorly understood. We investigated the obesogenic effect during chronic exposure of TCDD at 1 μg/kg body weight (bw)/week in adult C57BL/6J mice fed with a high fat diet (HFD) and exposed from 10 to 42 weeks old to TCDD or equal volume of vehicle by intragastric gavage. Under these conditions, TCDD was obesogenic in adult mice (7% in males and 8% in females), which was linked to fat mass. A sex effect was observed in the fat mass distribution in adipose tissue and in the hepatic triglyceride content evolution. In visceral fat pad weight, we observed a decrease (11%) in males and an increase (14%) in females. The hepatic triglyceride content increase (41%) in females only. TCDD failed to induce any change in plasma parameters regarding glucose and lipid homeostasis. Messenger ribonucleic acid (mRNA) levels involved in adipose tissue and hepatic metabolism, inflammation, xenobiotic metabolism and endocrine disruption were differently regulated between males and females. In conclusion, these results provide new evidence that dioxin, a POP and EDC can be obesogenic for adult mice with multi-organ effects.
Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans
2011, Toxicology and Applied Pharmacology
Citation Excerpt :
For rat calibration data, the poorest fits are to the fraction of retained perc metabolized and rate of perc exhalation (both from Reitz et al., 1996) and perc in various tissues (from Dallas et al., 1994a, 1994c; and Warren et al., 1996), with residual errors of 2- to 3-fold. As with mice, it is unclear how to completely reconcile the extremely well-fit closed chamber data with the more poorly fit C-14 data from Reitz et al. (1996), but inter-study variation cannot be ruled out. All the remaining data have more modest (< 2-fold) residual errors.
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 ~ 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (~ 3000-fold) and mice (~ 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.
Bioaccumulation potential of air contaminants: Combining biological allometry, chemical equilibrium and mass-balances to predict accumulation of air pollutants in various mammals
2009, Toxicology and Applied Pharmacology
In the present study we develop and test a uniform model intended for single compartment analysis in the context of human and environmental risk assessment of airborne contaminants. The new aspects of the model are the integration of biological allometry with fugacity-based mass-balance theory to describe exchange of contaminants with air. The developed model is applicable to various mammalian species and a range of chemicals, while requiring few and typically well-known input parameters, such as the adult mass and composition of the species, and the octanol–water and air–water partition coefficient of the chemical.
Accumulation of organic chemicals is typically considered to be a function of the chemical affinity for lipid components in tissues. Here, we use a generic description of chemical affinity for neutral and polar lipids and proteins to estimate blood–air partition coefficients (K_ba) and tissue–air partition coefficients (K_ta) for various mammals. This provides a more accurate prediction of blood–air partition coefficients, as proteins make up a large fraction of total blood components.
The results show that 68% of the modeled inhalation and exhalation rate constants are within a factor of 2.1 from independent empirical values for humans, rats and mice, and 87% of the predicted blood–air partition coefficients are within a factor of 5 from empirical data. At steady-state, the bioaccumulation potential of air pollutants is shown to be mainly a function of the tissue–air partition coefficient and the biotransformation capacity of the species and depends weakly on the ventilation rate and the cardiac output of mammals.
Contribution of trichloroacetic acid to liver tumors observed in perchloroethylene (perc)-exposed mice
2009, Toxicology
Perchloroethylene (perc), a solvent used in dry cleaning operations and industrial applications, has been found to produce increases in hepatocellular carcinomas and/or adenomas in mice in chronic inhalation bioassays. Perc is metabolized primarily to trichloroacetic acid (TCA), which is also a mouse hepatocarcinogen. The fractional conversion of perchloroethylene to TCA by mice was determined from physiologically based pharmacokinetic (PBPK) modeling of TCA in mouse blood at the conclusion of inhalation exposure of male and female B6C3F1 mice to 10, 50, 100, or 200 ppm perc for 6 h/day for 5 days. The dose-dependent bioavailability of TCA in B6C3F1 mice exposed to TCA in drinking water was estimated by optimizing the fit of time course blood, plasma, and liver TCA concentrations for TCA doses ranging from 12 to 800 mg/(kg day) to predictions of a previously published TCA PBPK model. Using the PBPK models, the area under the liver TCA concentration vs. time curve (liver TCA AUC) was calculated for TCA and perc bioassays. Benchmark dose analyses were conducted to determine the dose–response relationship between liver TCA AUC and the additional risk of hepatocellular adenomas or carcinomas (combined) in mice ingesting TCA. Using the dose–response relationships derived for the TCA-exposed mice, the contribution of TCA produced by metabolism to the additional risk of liver adenomas and carcinomas in mice exposed to perchloroethylene by inhalation was computed. The analysis indicated that the levels of TCA observed in perchloroethylene-exposed mice are sufficient to explain the incidence of liver adenomas and carcinomas.

View all citing articles on Scopus

View full text

Regular ArticleIn Vivoandin VitroStudies of Perchloroethylene Metabolism for Physiologically Based Pharmacokinetic Modeling in Rats, Mice, and Humans

Abstract

Regular Article
In Vivoandin VitroStudies of Perchloroethylene Metabolism for Physiologically Based Pharmacokinetic Modeling in Rats, Mice, and Humans