Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

Abstract

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent speciesand sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure.

Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice

“…However, a detailed examination of the effects of NAFLD on toxicokinetics of an environmental chemical and its metabolites in multiple tissues has not yet been reported. Because delivered dose of both PERC and its major metabolites may contribute to target organ-specific toxicity (Lash and Parker, 2001;Guyton et al, 2014;Cichocki et al, 2016b), such an examination is warranted for this ubiquitous environmental contaminant.…”

“…Little is known about specific enzymes that are responsible for PERC metabolism and most of the metabolic pathways are inferred from a related chemical trichloroethylene (Cichocki et al, 2016b). Underlying disease states of NAFLD had a major impact on PERC and TCA toxicokinetics and transcriptomic data showed significant repression of biologic oxidative metabolism in HFD-and MCD-fed mice.…”

“…PERC is a high-production volume chlorinated olefin solvent, with industrial uses in dry cleaning, metal degreasing, and as a chemical feedstock (Cichocki et al, 2016b). Because of its widespread use, high production volume, and persistence in the environment, PERC has become a ubiquitous environmental contaminant of ambient air, soil, and drinking and ground water and is one of the most commonly found contaminants at hazardous waste sites (National Research Council, 2010).…”

“…Because of its widespread use, high production volume, and persistence in the environment, PERC has become a ubiquitous environmental contaminant of ambient air, soil, and drinking and ground water and is one of the most commonly found contaminants at hazardous waste sites (National Research Council, 2010). Exposure to PERC in humans and animals is associated with multiple target organ toxicity, including both cancer and noncancer toxicity (U.S. EPA, 2011;Guha et al, 2012;IARC, 2013;Guyton et al, 2014;Cichocki et al, 2016b). In mice, hepatotoxicity associated with PERC exposure is thought to be mediated by trichloroacetate (TCA), an oxidative metabolite of PERC (Bull et al, 1990;Bull, 2000;Corton, 2008).…”

“…It is known that PERC is metabolized by human and rodent hepatic cytochrome P450s (CYPs) to TCA (Cichocki et al, 2016b). Additionally, PERC can also be conjugated with glutathione through glutathione S-transferases (GSTs) to form S-(1,2,2-trichlorovinyl)-glutathione (TCVG).…”