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 <math><mrow><mtext>human</mtext><mo>≥</mo><mtext>rat</mtext><mo>≥</mo><mtext>mouse</mtext></mrow></math>, and primary hepatocytes>iHep<math><mrow><mtext>hepatocytes</mtext><mo>></mo><mtext>iHep</mtext></mrow></math>. 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.