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- Title
Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization.
- Authors
Valdiviezo, Alan; Brown, Grace E.; Michell, Ashlin R.; Trinconi, Cristiana M.; Bodke, Vedant V.; Khetani, Salman R.; Yu-Syuan Luo; Chiu, Weihsueh A.; Rusyn, Ivan
- 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, 푆-(1,2-dichlorovinyl)glutathione (DCVG) and 푆-(1,2,2-trichlorovinyl) glutathione (TCVG), respectively. METHODS:Â 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 human = rat = mouse, and primary hepatocytes>iHep. 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.
- Subjects
HYDROCARBON analysis; HYDROCARBON metabolism; BIOLOGICAL models; GLUTATHIONE; BIOCHEMISTRY; CELL culture; FIBROBLASTS; KIDNEYS; PHENOMENOLOGICAL biology; ANIMAL experimentation; CULTURE media (Biology); LIQUID chromatography; MATHEMATICAL models; ACCURACY; UNCERTAINTY; RATS; HYDROCARBONS; STEM cells; ENZYME-linked immunosorbent assay; MASS spectrometry; THEORY; RESEARCH funding; BIOLOGICAL assay; DATA analysis software; LIVER cells; MICE; CENTRIFUGATION
- Publication
Environmental Health Perspectives, 2022, Vol 130, Issue 11, p117009-1
- ISSN
0091-6765
- Publication type
Article
- DOI
10.1289/EHP12006