Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization

Abstract

Background: Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein. Objectives: This study aimed to address these uncertainties using novel in vitro liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, S -(1,2-dichlorovinyl)glutathione (DCVG) and S -(1,2,2-trichlorovinyl) glutathione (TCVG), respectively. Methods: Liver in vitro models used herein were suspension, 2-D culture, and micropatterned coculture (MPCC) with primary human, rat, and mouse hepatocytes, as well as human induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep). Results: We found that, although efficiency of metabolism varied among models, consistent with known differences in their metabolic capacity, formation rates of DCVG and TCVG generally followed the patterns , and primary . Data derived from MPCC were most consistent with estimates from physiologically based pharmacokinetic models calibrated to in vivo data. Discussion: For TCE, the new data provided additional empirical support for inclusion of GSH conjugation-mediated kidney effects as critical for the derivation of noncancer toxicity values. For PCE, the data reduced previous uncertainties regarding the extent of TCVG formation in humans; this information was used to update several candidate kidney-specific noncancer toxicity values. Overall, MPCC-derived data provided physiologically relevant estimates of GSH-mediated metabolism of TCE and PCE to reduce uncertainties in interspecies extrapolation that constrained previous risk evaluations, thereby increasing the precision of risk characterizations of these high-priority toxicants. https://doi.org/10.1289/EHP12006

Invited Perspective: Improved Risk Characterization for Trichloroethylene and Perchloroethylene Based on New Analyses of Glutathione Conjugation Rates

“…In summary, the work by Valdiviezo et al. 12 validated several in vitro liver models, particularly the micropatterned coculture model, and provided metabolism data for GSH conjugation of TCE and PCE that generally agree with those that my colleagues and I reported. 8 , 17 – 21 These new findings thereby provide greater confidence in using these data for physiologically based pharmacokinetic models and human health risk assessment.…”

“…In a study reported in this issue of Environmental Health Perspectives , Valdiviezo et al. 12 performed new analyses of the metabolism of TCE and PCE by the GSH conjugation pathway. Their goal was to resolve uncertainties in quantitative data for risk assessment.…”

“…highlighted these differences, as well as the values they themselves obtained for rates of TCE and PCE GSH conjugation, in Figure 4 of their paper. 12 …”

Establishment of Co-Culture Model of Primary Mature Adipocytes and Hepatocytes in Non-Alcoholic Fatty Liver Model Rats and its Effect on Hepatocyte Steatosis

“…Therefore, how to stably extract primary adipocytes and hepatocytes in NAFL pathological conditions has become an urgent technical difficulty to be solved. The isolation methods of primary hepatocytes and precursor adipocytes included mechanical isolation, simple enzymatic digestion, collagenase digestion [14,15] , etc. In this study, NAFL model was established by feeding SD rats with HFD and optimized in the traditional isolation method.…”

Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents

“…In addition, interspecies variability in the oxidative metabolism of TCE indicates that rodents metabolize TCE more rapidly than humans 40 . Mice even exhibit strain-dependent variability of metabolism in [41][42][43][44] , suggesting that greater doses beyond simple allometric scaling would be necessary in laboratory animals to accurately replicate exposure. Thus, dose conversions of TCE exposure from animal to human and vice versa, are complex, rely on imperfect conversion assumptions, and should be considered in the temporal context of a human lifespan.…”