Guidelines for Canadian Drinking Water Quality

Industrial solvents and liver toxicity: risk assessment, risk factors and mechanisms.

Background: The U.S. EPA’s Integrated Risk Information System (IRIS) completed an updated toxicological review of dichloromethane in November 2011.

Objectives: In this commentary we summarize key results and issues of this review, including exposure sources, identification of potential health effects, and updated physiologically based pharmacokinetic (PBPK) modeling.

Methods: We performed a comprehensive review of primary research studies and evaluation of PBPK models.

Discussion: Hepatotoxicity was observed in oral and inhalation exposure studies in several studies in animals; neurological effects were also identified as a potential area of concern. Dichloromethane was classified as likely to be carcinogenic in humans based primarily on evidence of carcinogenicity at two sites (liver and lung) in male and female B6C3F1 mice (inhalation exposure) and at one site (liver) in male B6C3F1 mice (drinking-water exposure). Recent epidemiologic studies of dichloromethane (seven studies of hematopoietic cancers published since 2000) provide additional data raising concerns about associations with non-Hodgkin lymphoma and multiple myeloma. Although there are gaps in the database for dichloromethane genotoxicity (i.e., DNA adduct formation and gene mutations in target tissues in vivo), the positive DNA damage assays correlated with tissue and/or species availability of functional glutathione S-transferase (GST) metabolic activity, the key activation pathway for dichloromethane-induced cancer. Innovations in the IRIS assessment include estimation of cancer risk specifically for a presumed sensitive genotype (GST-theta-1+/+), and PBPK modeling accounting for human physiological distributions based on the expected distribution for all individuals 6 months to 80 years of age.

Conclusion: The 2011 IRIS assessment of dichloromethane provides insights into the toxicity of a commonly used solvent.

Citation: Schlosser PM, Bale AS, Gibbons CF, Wilkins A, Cooper GS. 2015. Human health effects of dichloromethane: key findings and scientific issues. Environ Health Perspect 123:114–119; http://dx.doi.org/10.1289/ehp.1308030

Human Health Effects of Tetrachloroethylene: Key Findings and Scientific Issues

The purpose of this report is to present toxicological benchmarks for assessment of effects of certain chemicals on mammalian and avian wildlife species. Publication of this document meets a milestone for the Environmental Restoration (ER) Risk Assessment Program. This document provides the ER Program with toxicological benchmarks that may be used as comparative tools in screening assessments as well as lines of evidence to support or refute the presence of ecological effects in ecological risk assessments. The chemicals considered in this report are some that occur at US DOE waste sites, and the wildlife species evaluated herein were chosen because they represent a range of body sizes and diets.

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Toxicological benchmarks for wildlife: 1996 Revision

Trichloroethylene (TCE) induces liver cancer in mice but not in rats Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA) CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well The concentrations of TCA in blood required to induce liver cancer approach the mM range Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA TCA is a peroxisome proliferator in the same dose range that induces liver cancer Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators Human cells do not display the responses associated with PPAR-alpha that are observed in rodents This may be attributed to lower levels of expressed PPAR-alpha in human liver DCA treatment produces liver tumors with a different phenotype than TCA Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis Growth of DCA-induced tumors has been shown to arrest after cessation of treatment The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE Low-level exposure to TCE is not likely to induce liver cancer in humans Higher exposures to TCE could affect sensitive populations Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis

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Ja Buben

Papers

Delineation of the role metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene : a dose-effect study