1. Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver
- Author
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Alan, Valdiviezo, Grace E, Brown, Ashlin R, Michell, Cristiana M, Trinconi, Vedant V, Bodke, Salman R, Khetani, Yu-Syuan, Luo, Weihsueh A, Chiu, and Ivan, Rusyn
- Subjects
Mice ,Tetrachloroethylene ,Liver ,Induced Pluripotent Stem Cells ,Humans ,Animals ,Glutathione ,Rats ,Trichloroethylene - Abstract
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 novelLiverWe 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 patternsFor 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.
- Published
- 2022