ReviewA review of potential neurotoxic mechanisms among three chlorinated organic solvents☆
Research highlights
► Comparison of neurological effects among TCE, PERC, and DCM. ► Correlation of mechanistic findings to neurological effects. ► Data support that TCE, PERC, and DCM interact with several ion channels to produce neurological changes.
Introduction
Chlorinated solvents such as trichloroethylene (TCE), perchloroethylene (PERC), and dichloromethane (DCM) have been used for a variety of industrial and consumer cleaning purposes due to their ability to dissolve organic substances. Collectively for TCE, PERC, and DCM, exposure can occur through inhalation due to volatilization of the solvent or ingestion primarily from groundwater contamination. Primary exposure concerns result from inhalation exposure from occupational work such as metal degreasing operations and/or residential exposures resulting from off gassing from the factories using these agents or from groundwater (ATSDR, 1997a, ATSDR, 1997b, ATSDR, 2000). These three chlorinated solvents are among the most widely used in this solvent class. In 2008, according to the EPA's Toxic Release Inventory (TRI) database, DCM, TCE and PERC were released at higher levels than any other chlorinated solvent at levels of 5.1 million, 3.6 million, and 2.2 million pounds, respectively in the United States. The prevalence of DCM, TCE, and PERC and the resultant potential for exposure represent a concern and it is important to understand potential health effects resulting from these three chlorinated solvents. Many varied health effects including toxicity to the liver, kidney, lungs, and carcinogenic effects have been reported in the literature. This review will focus on neurotoxicological effects reported from exposure to the three chlorinated solvents.
Neurotoxicological changes represent one of the most pronounced health concerns following exposure to these chlorinated solvents in experimental studies. Several central nervous system effects have been reported following acute, subchronic, or chronic exposure to each of these three compounds. In rodent studies several neurological changes are commonly observed among TCE, PERC, and DCM. These effects include changes in spontaneous activity, impaired motor coordination, and visual and auditory dysfunction.
A number of studies have been conducted to better understand the mechanisms behind neurobehavioral effects of TCE, PERC, and DCM. Most of the mechanistic studies used acute exposure methods to ascertain the responses. Earlier studies (1970s–1990s) concentrated primarily on neuropathological changes following solvent exposures and indicated that brain regions such as the cerebellum and hippocampus were targeted by these chlorinated solvents. Later studies (1998–present) have focused on neurological molecular targets, especially the function of ligand and voltage-gated ion channels that may be associated with neurobehavioral effects. Collectively, these types of studies provide a better understanding of the neurobehavioral, pathological and mechanistic changes.
The purpose of this article is to review the neurotoxicological studies in animals (primarily rats and mice) conducted with TCE, PERC, and DCM and to propose potential neurological mechanism(s) for the varied effects. For many of the hypothesized neurological mechanisms, studies from a related aromatic solvent, toluene, were reviewed since it is well characterized and studied at the molecular, physiological, and behavioral level. The findings from toluene suggest approaches to evaluate potential neurotoxic mechanisms for DCM, TCE, and PERC. Targeted studies were also proposed to further understand the hypothesized mechanisms. This review is based on publications found through searches of the PubMed database for relevant articles using the combination search terms of (dichloromethane or methylene chloride, trichloroethylene, perchloroethylene or tetrachloroethylene) and (central nervous system, brain, neurotoxicity). References within these selected reports were also reviewed.
Section snippets
Comparison of neurological effects
Endpoints in studies were categorized according to 1) neurobehavioral or neurophysiological changes, 2) neuropathological or neurochemical changes, and 3) mechanistic endpoints. In the three categories, comparisons were made among TCE, PERC, and DCM for similarities and differences of effects. Some of the differences noted either between solvents or within one solvent could be partially attributed to exposure route (e.g. oral versus inhalation), duration (acute versus chronic), species used,
Discussion of mechanisms for neurotoxicological changes
Earlier studies hypothesized that metabolites such as carbon monoxide and trichloroethanol, both resulting from cytochrome P450 (CYP) pathways, produce some of the neurotoxicological effects observed after DCM and TCE exposure, respectively. For DCM, the CYP2E1 pathway is saturated at exposures of 500 ppm and higher in rats, for exposure durations of 6 h to 2 years (Burek et al., 1984, McKenna et al., 1982, Nitschke et al., 1988). Similarly, it has been predicted with a rat physiologically based
Summary of hypothesized molecular targets
TCE, PERC, and DCM exposure results in some common neurological outcomes, including changes in spontaneous activity, impaired motor coordination, and visual and auditory function. The pattern of changes suggests that these chlorinated solvents may act on several molecular targets in the central nervous system; likely, through several possible mechanisms. Drawing analogy to a closely related aromatic solvent, toluene, we hypothesize which molecular targets may be involved in the resultant
Relevance of the hypothesized mechanisms to humans
The proposed mechanisms for the observed neurological effects of the three chlorinated solvents as outlined here are based on animal mechanistic studies and correlated to reported neurobehavioral and neurophysiological changes in animal studies. Animal mechanistic studies are primarily focused on short-term and/or acute exposures, which are lacking for humans. There is limited information with regard to potential neurotoxic mechanisms of chlorinated solvents in humans in comparison to the
Conclusions
The majority of these proposed mechanisms were based on acute exposure studies and extrapolated to neurotoxicological effects following a chronic exposure. As a result, there is some uncertainty regarding this extrapolation. At present, there are no long-term animal models for investigating chronic mechanisms and this represents a data gap in correlating mechanistic information to neurological effects. More mechanistic studies evaluating the targets and their pathways are needed especially
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors would like to acknowledge Drs. William Boyes and Philip Bushnell for reviewing and providing highly useful comments on an earlier version of this manuscript.
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The views in the manuscript are those of the authors and do not reflect views or policy of the US EPA.