Review
A review of potential neurotoxic mechanisms among three chlorinated organic solvents

https://doi.org/10.1016/j.taap.2011.05.008Get rights and content

Abstract

The potential for central nervous system depressant effects from three widely used chlorinated solvents, trichloroethylene (TCE), perchloroethylene (PERC), and dichloromethane (DCM), has been shown in human and animal studies. Commonalities of neurobehavioral and neurophysiological changes for the chlorinated solvents in in vivo studies suggest that there is a common mechanism(s) of action in producing resultant neurotoxicological consequences. The purpose of this review is to examine the mechanistic studies conducted with these chlorinated solvents and to propose potential mechanisms of action for the different neurological effects observed. Mechanistic studies indicate that this solvent class has several molecular targets in the brain. Additionally, there are several pieces of evidence from animal studies indicating this solvent class alters neurochemical functions in the brain. Although earlier evidence indicated that these three chlorinated solvents perturb the lipid bilayer, more recent data suggest an interaction between several specific neuronal receptors produces the resultant neurobehavioral effects. Collectively, TCE, PERC, and DCM have been reported to interact directly with several different classes of neuronal receptors by generally inhibiting excitatory receptors/channels and potentiating the function of inhibitory receptors/channels. Given this mechanistic information and available studies for TCE, DCM, and PERC, we provide hypotheses on primary targets (e.g. ion channel targets) that appear to be most influential in producing the resultant neurological effects.

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.

References (109)

  • H.H. Chen et al.

    Behavioural effects of tetrachloroethylene exposure in rats: acute and subchronic studies

    Toxicology

    (2002)
  • K.M. Crofton et al.

    The ototoxicity of trichloroethylene: extrapolation and relevance of high-concentration, short-duration animal exposure data

    Fundam. Appl. Toxicol.

    (1997)
  • K.M. Crofton et al.

    Solvent-induced ototoxicity in rats: an atypical selective mid-frequency hearing deficit

    Hear. Res.

    (1994)
  • A.B. Elgoyhen et al.

    The nicotinic receptor of cochlear hair cells: a possible pharmacotherapeutic target?

    Biochem. Pharmacol.

    (2009)
  • E.B. Evans et al.

    CNS depressant effects of volatile organic solvents

    Neurosci. Biobehav. Rev.

    (1991)
  • L.D. Fechter et al.

    Trichloroethylene ototoxicity: evidence for a cochlear origin

    Toxicol. Sci.

    (1998)
  • K. Fuxe et al.

    Central catecholamine neurons and exposure to dichloromethane. Selective changes in amine levels and turnover in tel- and diencephalic and Na nerve terminal systems and in the secretion of anterior pituitary hormone in the male rat

    Toxicology

    (1984)
  • D.W. Herr et al.

    A comparison of the acute neuroactive effects of dichloromethane, 1,3-dichloropropane, and 1,2-dichlorobenzene on rat flash evoked potentials (FEPs)

    Fundam. Appl. Toxicol.

    (1997)
  • L.G. Isaacson et al.

    Maternal exposure to 1,1,2-trichloroethylene affects myelin in the hippocampal formation of the developing rat

    Brain Res.

    (1989)
  • L.G. Isaacson et al.

    Trichloroethylene affects learning and decreases myelin in the rat hippocampus

    Neurotoxicol. Teratol.

    (1990)
  • R.M. Jaspers et al.

    Mid-frequency hearing loss and reduction of acoustic startle responding in rats following trichloroethylene exposure

    Neurotoxicol. Teratol.

    (1993)
  • P. Kjellstrand et al.

    Effects of organic solvents on motor activity in mice

    Toxicology

    (1985)
  • B.M. Kulig

    The effects of chronic trichloroethylene exposure on neurobehavioral functioning in the rat

    Neurotoxicol. Teratol.

    (1987)
  • T. Kyrklund et al.

    Chronic effects of perchloroethylene on the composition of lipid and acyl groups in cerebral cortex and hippocampus of the gerbil

    Toxicol. Lett.

    (1984)
  • T. Kyrklund et al.

    Fatty acid changes in rat brain ethanolamine phosphoglycerides during and following chronic exposure to trichloroethylene

    Toxicol. Appl. Pharmacol.

    (1986)
  • T. Kyrklund et al.

    Long-term exposure of rats to perchloroethylene, with and without a post-exposure solvent-free recovery period: effects on brain lipids

    Toxicol. Lett.

    (1990)
  • G.F. Lopreato et al.

    Inhaled drugs of abuse enhance serotonin-3 receptor function

    Drug Alcohol Depend.

    (2003)
  • J.L. Mattsson et al.

    Neurotoxicologic evaluation of rats after 13 weeks of inhalation exposure to dichloromethane or carbon monoxide

    Pharmacol. Biochem. Behav.

    (1990)
  • J.L. Mattsson et al.

    Neurotoxicologic examination of rats exposed to 1,1,2,2-tetrachloroethylene (perchloroethylene) vapor for 13 weeks

    Neurotoxicol. Teratol.

    (1998)
  • M.J. McKenna et al.

    The pharmacokinetics of inhaled methylene chloride in rats

    Toxicol. Appl. Pharmacol.

    (1982)
  • V.C. Moser et al.

    Neurobehavioral evaluations of mixtures of trichloroethylene, heptachlor, and di(2-ethylhexyl)phthlate in a full-factorial design

    Toxicology

    (2003)
  • Y. Motohashi et al.

    Assessment of behavioral effects of tetrachloroethylene using a set of time-series analyses

    Neurotoxicol. Teratol.

    (1993)
  • M. Niklasson et al.

    Effects of toluene, styrene, trichloroethylene, and trichloroethane on the vestibulo- and opto-oculo motor system in rats

    Neurotoxicol. Teratol.

    (1993)
  • K.D. Nitschke et al.

    Methylene chloride: a 2-year inhalation toxicity and oncogenicity study in rats

    Fundam. Appl. Toxicol.

    (1988)
  • W.M. Oshiro et al.

    Characterization of the effects of inhaled perchloroethylene on sustained attention in rats performing a visual signal detection task

    Neurotoxicol. Teratol.

    (2008)
  • C.S. Rebert et al.

    Acute effects of inhaled dichloromethane on the EEG and sensory-evoked potentials of Fischer-344 rats

    Pharmacol. Biochem. Behav.

    (1989)
  • C.S. Rebert et al.

    Sensory-evoked potentials in rats chronically exposed to trichloroethylene: predominant auditory dysfunction

    Neurotoxicol. Teratol.

    (1991)
  • C.S. Rebert et al.

    Combined effects of solvents on the rat's auditory system: styrene and trichloroethylene

    Int. J. Psychophysiol.

    (1993)
  • C.S. Rebert et al.

    Combined effects of paired solvents on the rat's auditory system

    Toxicology

    (1995)
  • H. Savolainen et al.

    Dose-related effects of dichloromethane on rat brain in short-term inhalation exposure

    Chem. Biol. Interact.

    (1981)
  • C.L. Shih et al.

    Acute exposure to trichloroethylene differentially alters the susceptibility to chemoconvulsants in mice

    Toxicology

    (2001)
  • R.R. Albee et al.

    Lack of trigeminal nerve toxicity in rats exposed to trichloroethylene vapor for 13 weeks

    Int. J. Toxicol.

    (2006)
  • G.V. Alexeeff et al.

    Learning impairment in mice following acute exposure to dichloromethane and carbon tetrachloride

    J. Toxicol. Environ. Health

    (1983)
  • H. Arito et al.

    Effect of subchronic inhalation exposure to low-level trichloroethylene on heart rate and wakefulness-sleep in freely moving rats

    Sangyo Igaku

    (1994)
  • ATSDR

    Toxicological Profile for Trichloroethylene

    (1997)
  • ATSDR

    Toxicological Profile for Tetrachloroethylene

    (1997)
  • ATSDR

    Toxicological Profile for Methylene Chloride

    (2000)
  • A.S. Bale et al.

    Evaluating the NMDA-glutamate receptor as a site of action for toluene, in vivo

    Toxicol. Sci.

    (2007)
  • L. Barret et al.

    Morphometric and biochemical studies in trigeminal nerve of rat after trichloroethylene or dichloroacetylene oral administration

    Neurotoxicology

    (1992)
  • M.J. Beckstead et al.

    Glycine and gamma-aminobutyric acid(A) receptor function is enhanced by inhaled drugs of abuse

    Mol. Pharmacol.

    (2000)
  • Cited by (0)

    The views in the manuscript are those of the authors and do not reflect views or policy of the US EPA.

    View full text