The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity

doi:10.1016/0041-008X(80)90082-4

Toxicology and Applied Pharmacology

Volume 55, Issue 2, 15 September 1980, Pages 207-219

https://doi.org/10.1016/0041-008X(80)90082-4 Get rights and content

Abstract

The pharmacokinetic and macromolecular interactions of perchloroethylene were evaluated in B₆C₃F₁ mice and Sprague-Dawley rats in an attempt to explain, mechanistically, the sensitivity of the mouse and the resistance of the rat to perchloroethylene-induced hepatocellular carcinoma. When compared to rats, mice were found to metabolize 8.5 and 1.6 times more perchloroethylene per kilogram of body weight following inhalation of 10 ppm or a single oral dose of 500 mg/kg perchloro[¹⁴C]ethylene, respectively. Since the initial metabolism of perchloroethylene is an activation process, the increased extent of metabolism in the mouse resulted in a greater extent of irreversible binding of radioactivity in hepatic macromolecules of the mouse compared to that in the rat after inhalation of 10 or 600 ppm or a single oral dose of 500 mg/kg perchloro[¹⁴C]ethylene. Repeated oral administration of perchloroethylene for 11 days resulted in histopathological changes in the liver of mice at doses as low as 100 mg/kg/day, while minimal treatment-related effects were observed in the liver of rats only at the 1000 mg/kg/day level. Approximately a twofold increase in hepatic DNA synthesis, indicative of hepatic regeneration, was observed in mice but not in rats after repeated oral administration of perchloroethylene at dose levels which are tumorigenic to mice in lifetime studies. The absence of any pronouced direct interaction of perchloroethylene with hepatic DNA in mice at times of peak hepatic macromolecular binding suggests that hepatic tumors are induced in B₆C₃F₁ mice by recurrent cytotoxicity which enhances the spontaneous incidence of liver tumors in this highly susceptible strain of mouse. The implication of these results for hazard assessment is that recurrent tissue damage is necessary for tumors to be induced. Thus, levels of perchloroethylene which do not induce organ toxicity are not likely to pose a carcinogenic risk to man.

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Citation Excerpt :
Most of each parent compound (TCE and PCE) remained unmetabolized until excretion, the fraction of the total administered dose ranged from 61.7% to 84.3% for TCE, and from 90.3% to 93.5% for PCE. The unmetabolized fractions of TCE and PCE are likely cleared via exhalation, as shown in mice orally dosed with 500 mg/kg 14C-labelled PCE where exhalation fraction of PCE was 82.6% (Schumann et al., 1980). Excreted TCA accounted for 3.5%–7.1% of the total dose for TCE, and 6.4–9.4% for PCE.
Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar chemicals that are metabolized through oxidation and glutathione conjugation pathways. Both chemicals have been shown to elicit liver and kidney toxicity in rodents and humans; however, TCE has been studied much more extensively in terms of both metabolism and toxicity. Despite their qualitative similarities, quantitative comparison of tissue- and strain-specific metabolism of TCE and PCE has not been performed. To fill this gap, we conducted a comparative toxicokinetic study where equimolar single oral doses of TCE (800 mg/kg) or PCE (1000 mg/kg) were administered to male mice of C57BL/6J, B6C3F1/J, and NZW/LacJ strains. Samples of liver, kidney, serum, brain, and lung were obtained for up to 36 h after dosing. For each tissue, concentrations of parent compounds, as well as their oxidative and glutathione conjugation metabolites were measured and concentration-time profiles constructed. A multi-compartment toxicokinetic model was developed to quantitatively compare TCE and PCE metabolism. As expected, the flux through oxidation metabolism pathway predominated over that through conjugation across all mouse strains examined, it is 1,200–3,800 fold higher for TCE and 26–34 fold higher for PCE. However, the flux through glutathione conjugation, albeit a minor metabolic pathway, was 21-fold higher for PCE as compared to TCE. The degree of inter-strain variability was greatest for oxidative metabolites in TCE-treated and for glutathione conjugation metabolites in PCE-treated mice. This study provides critical data for quantitative comparisons of TCE and PCE metabolism, and may explain the differences in organ-specific toxicity between these structurally similar chemicals.
Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans
2011, Toxicology and Applied Pharmacology
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.
Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice
2007, Toxicology
The aim was to study the subchronic toxicity of perchloroethylene (Perc) by measuring injury and repair in liver and kidney in relation to disposition of Perc and its major metabolites. Male SW mice (25–29 g) were given three dose levels of Perc (150, 500, and 1000 mg/kg day) via aqueous gavage for 30 days. Tissue injury was measured during the dosing regimen (0, 1, 7, 14, and 30 days) and over a time course of 24–96 h after the last dose (30 days). Perc produced significant liver injury (ALT) after single day exposure to all three doses. Liver injury was mild to moderate and regressed following repeated exposure for 30 days. Subchronic Perc exposure induced neither kidney injury nor dysfunction during the entire time course as evidenced by normal renal histology and BUN. TCA was the major metabolite detected in blood, liver, and kidney. Traces of DCA were also detected in blood at initial time points after single day exposure. With single day exposure, metabolism of Perc to TCA was saturated with all three doses. AUC/dose ratio for TCA was significantly decreased with a concomitant increase in AUC/dose of Perc levels in liver and kidney after 30 days as compared to 1 day exposures, indicating inhibition of metabolism upon repeated exposure to Perc. Hepatic CYP2E1 expression and activity were unchanged indicating that CYP2E1 is not the critical enzyme inhibited. Hepatic CYP4A expression, measured as a marker of peroxisome proliferation was increased transiently only on day 7 with the high dose, but was unchanged at later time points. Liver tissue repair peaked at 7 days, with all three doses and was sustained after medium and high dose exposure for 14 days. These data indicate that subchronic Perc exposure via aqueous gavage does not induce nephrotoxicity and sustained hepatotoxicity suggesting adaptive hepatic repair mechanisms. Enzymes other than CYP2E1, involved in the metabolism of Perc may play a critical role in the metabolism of Perc upon subchronic exposure in SW mice. Liver injury decreased during repeated exposure due to inhibition of metabolism and possibly due to adaptive tissue repair mechanisms.
Glutathione conjugation of perchloroethene in subcellular fractions from rodent and human liver and kidney
1998, Chemico-Biological Interactions
Perchloroethene (Per) is a widely used industrial solvent and common environmental contaminant. In rats, long-term inhalation of Per is known to cause a small increase in the incidence of renal tubule cell tumors in males only; renal toxicity is seen in female rats and in both sexes of mice after prolonged Per exposure. The renal toxicity of Per is likely mediated by a glutathione-dependent bioactivation reaction. Glutathione S-transferase mediated formation of S-(1,2,2-trichlorovinyl)glutathione is the first step in a sequence of reactions finally resulting in the formation of reactive intermediates in the kidney. In this study, we compared the enzymatic rates of formation of S-(1,2,2-trichlorovinyl)glutathione in liver and kidney subcellular fractions from rats, mice, and from both sexes of humans (n=11). In microsomal fractions from the liver and kidney of all three species, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione from Per could not be observed. S-(1,2,2-Trichlorovinyl)glutathione formation (the structure was confirmed by electrospray mass spectrometry) was observed in liver cytosol from both male and female rats and mice. However, the rates of S-(1,2,2-trichlorovinyl)glutathione formation in liver cytosol from male rats (84.5±12 pmol/mg per min) were approximately four times higher than from female rats (19.5±8 pmol/mg per min) and from both sexes of mice (27.9±6 and 26.0±4 pmol/mg per min). Low rates of S-(1,2,2-trichlorovinyl)glutathione formation were also seen in kidney cytosol from mice (12±6 pmol/mg per min), but not from rats. In human liver subcellular fractions, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione could not be detected. The human liver cytosolic fractions, however, exhibited glutathione S-transferase activity (as determined using 1-chloro-2,4-dinitrobenzene and hexachlorobutadiene as marker substrates) in the same order of magnitude as rat and mouse liver cytosol. In contrast to other marker activities for glutathione S-transferases, the ability of all human liver cytosol samples to catalyze the glutathione conjugation of 1,2-dichloro-4-nitrobenzene was three orders of magnitude lower compared to rat and mouse liver cytosol. 1,2-Dichloro-4-nitrobenzene conjugation was also four times higher in liver cytosol from male rats compared to female rats. The results suggest that the ability of the human liver to catalyze the formation of S-(1,2,2-trichlorovinyl)glutathione from Per is at least two orders of magnitude lower than that of rat liver, and that sex-specific differences in the extent of hepatic conjugation of Per with glutathione, which may be relevant for nephrotoxicity, occur in rats.
In vivo and in vitro studies of perchloroethylene metabolism for physiologically based pharmacokinetic modeling in rats, mice, and humans
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The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity

Abstract

Cancer Lett.

Fd. Cosmet. Toxicol.

Lancet

J. Biol. Chem.

Mutat. Res.

Toxicol. Appl. Pharmacol.

Fd. Cosmet. Toxicol.

Toxicol. Appl. Pharmacol.

Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadines and dichlorobutenes by rodent or human liver tissues

Arch. Toxicol.

Tumor-formation following freezing with carbon dioxide snow

Brit. J. Exp. Pathol.

Irritation and carcinogenesis

Arch. Pathol.

A study of the conditions and mechanism of the diphenylamine reaction for the estimation of deoxyribonucleic acid

Biochem. J.

Defective repair replication of DNA in Xeroderma pigmentosum

Nature (London)

Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective

Effect of partial hepatectomy on tumor incidence and metabolism of mice fed thioacetamide

J. Nat. Cancer Inst.

Comparison and evaluation of some experimental designs for use in carcinogen screening

J. Nat. Cancer Inst.

Experimental human exposures to tetrachloroethylene vapor and elimination in breath after inhalation

Amer. Ind. Hyg. Assoc.

Persistance of 0-6-ethylguanine in rat brain DNA: correlation with nervous system specific carcinogenesis by ethylnitrosourea