Human Health Effects of Tetrachloroethylene: Key Findings and Scientific Issues

Abstract

Background: The U.S. Environmental Protection Agency (EPA) completed a toxicological review of tetrachloroethylene (perchloroethylene, PCE) in February 2012 in support of the Integrated Risk Information System (IRIS).Objectives: We reviewed key findings and scientific issues regarding the human health effects of PCE described in the U.S. EPA’s Toxicological Review of Tetrachloroethylene (Perchloroethylene).Methods: The updated assessment of PCE synthesized and characterized a substantial database of epidemiological, experimental animal, and mechanistic studies. Key scientific issues were addressed through modeling of PCE toxicokinetics, synthesis of evidence from neurological studies, and analyses of toxicokinetic, mechanistic, and other factors (tumor latency, severity, and background rate) in interpreting experimental animal cancer findings. Considerations in evaluating epidemiological studies included the quality (e.g., specificity) of the exposure assessment methods and other essential design features, and the potential for alternative explanations for observed associations (e.g., bias or confounding).Discussion: Toxicokinetic modeling aided in characterizing the complex metabolism and multiple metabolites that contribute to PCE toxicity. The exposure assessment approach—a key evaluation factor for epidemiological studies of bladder cancer, non-Hodgkin lymphoma, and multiple myeloma—provided suggestive evidence of carcinogenicity. Bioassay data provided conclusive evidence of carcinogenicity in experimental animals. Neurotoxicity was identified as a sensitive noncancer health effect, occurring at low exposures: a conclusion supported by multiple studies. Evidence was integrated from human, experimental animal, and mechanistic data sets in assessing adverse health effects of PCE.Conclusions: PCE is likely to be carcinogenic to humans. Neurotoxicity is a sensitive adverse health effect of PCE.Citation: Guyton KZ, Hogan KA, Scott CS, Cooper GS, Bale AS, Kopylev L, Barone S Jr, Makris SL, Glenn B, Subramaniam RP, Gwinn MR, Dzubow RC, Chiu WA. 2014. Human health effects of tetrachloroethylene: key findings and scientific issues. Environ Health Perspect 122:325–334; http://dx.doi.org/10.1289/ehp.1307359

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.…”

“…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).…”

Hepatocellular carcinoma and the risk of occupational exposure

“…A high prevalence of liver cancer was found in animal models exposed to PCE (CAS 127-18-4) [138,139] . Porru et al [140] showed that, in workers chronically exposed to organic solvents (toluene and xylene), there is an increased risk of HCC and that the risk is timedependent.…”

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

“…Table 3 summarizes the target organ carcinogenesis associated with TCE or PCE exposure. These data are derived from previous reports for TCE (Zhu et al, 2008;US EPA, 2011b;Chiu et al, 2013;IARC, 2014;National Toxicology Program, 2015) and PCE (US EPA, 2011a; IARC, 2014; Guyton et al, 2014).…”

“…There is some epidemiologic evidence for TCE-and PCE-associated noncancer hepatotoxicity (EPA, 2011a,b;Guyton et al, 2014). In most studies of TCE, liver dysfunction was monitored by serum liver enzyme levels and/or serum bile acid levels (Driscoll et al, 1992;Nagaya et al, 1993;Rasmussen et al, 1993b;Neghab et al, 1997;Davis et al, 2005;Kamijima et al, 2007;Xu et al, 2009).…”