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

• Published in: Environmental health perspectives Vol. 130; no. 11; pp. 117009 - 11
• Main Authors: Valdiviezo, Alan, Brown, Grace E., Michell, Ashlin R., Trinconi, Cristiana M., Bodke, Vedant V., Khetani, Salman R., Luo, Yu-Syuan, Chiu, Weihsueh A., Rusyn, Ivan
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.11.2022; Environmental Health Perspectives
• Subjects: Animal models; Animals; Biocompatibility; Carcinogens; Cell culture; Chemicals; Conjugates; Conjugation; Contamination; Environmental aspects; Enzymes; Estimates; Genotoxicity; Glutathione; Health aspects; Health risk assessment; Health risks; Hepatocytes; Humans; In vitro methods and tests; Induced Pluripotent Stem Cells; Kidneys; Laboratories; Liver; Metabolism; Metabolites; Methods; Mice; Micropatterning; Office buildings; Oxidation; Perchloroethylene; Pharmacokinetics; Physiological aspects; Plating; Pluripotency; Rats; Risk assessment; Solvents; Stem cells; Tetrachloroethylene; Tetrachloroethylene - toxicity; Toxicants; Toxicity; Trichloroethene; Trichloroethylene; Trichloroethylene - toxicity; Uncertainty; United States; United States > US
• ISSN: 0091-6765; 1552-9924; 1552-9924
• DOI: 10.1289/EHP12006

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. This study aimed to address these uncertainties using novel liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, -(1,2-dichlorovinyl)glutathione (DCVG) and -(1,2,2-trichlorovinyl) glutathione (TCVG), respectively. Liver 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). 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 data. 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.