Technical Report

TR 070 – Chronic Neurotoxicity of Solvents

TR 070 : Chronic Neurotoxicity of Solvents | February 1996

This review addresses the question whether a discrete specific neurological syndrome that is casually related to chronic low-level exposure to organic solvents actually occurs. The review discusses the available information on solvent exposure, human neurotoxicology and animal neurotoxicology and demonstrates that only a small proportion of it is relevant to this particular question. Chronic low-level exposure has only been experienced in a few well controlled environments, sub-clinical effects in subjects exposed to these environments have only been investigated in a few studies and most animal work has been conducted at high levels of exposure.

A secondary objective is to review the natural history of those adverse effects that have been attributed to solvents, whatever the levels and frequency of exposure may have been. Several studies have been published which examine these effects are stable, reversible or progressive.

Thirdly, the information on specific solvents has been summarised within a framework for critical appraisal of the epidemiological literature on solvent neurotoxicity.

For a chemical to be considered neurotoxic, in contrast to narcotic, evidence needs to be obtained for a consistent pattern of neurological dysfunction in man or animals. Lesions may be shown in the nervous system or sense organs which account for the neurobehavioural disorder. Five solvents have previously been shown to cause structural lesions, namely, carbon disulphide, n-­hexane, methyl n-butyl ketone, toluene and impure thricholorethylene.

The industrial exposure data, both in manufacture and use, have been examined for the above solvents (except carbon disulphide) together with that obtained for 1,1,2-trichloro-1,2,2-trifluoroethane, methyle ethyl ketone, styrene, tetrachloroethylene, white spirit and xylenes. The above thirteen solvents represent those most commonly used in industry. Historical data on industrial exposure has been generally inadequate for the investigation of possible neurotoxicity. Recent data revealed that there are circumstances where short-term exposures can exceed occupational exposure limits, often markedly so, but that on a time weighted average basis exposure levels were below the OEL with a tendency to progressively lower exposures over recent years.

The earlier epidemiological data (pre-1984) suggested that professional house painters and varnishers exposed to high doses suffer more from dizziness, forgetfulness, irritability and fatigue compared with those either not or minimally exposed to solvents. The data suggested that at high dose levels there was evidence of minor, non progressive deficits for memory, perception and coordination in some solvent exposed workers.

Epidemiological data since 1984 have been reviewed against two criteria, their ability to tackle the objective of this review, and the validity of their conclusions. Many studies are irrelevant because they consider populations exposed to high concentrations of solvents, because the populations studied have not had lengthy exposure, or because the health condition studied has many known causative factors other than solvent exposure. The remainder have been assessed as to their treatment of bias and confounding factors, their estimates of exposure levels and the validity of their investigative techniques. Criteria for the assessment of the neurobehavioural and neurophychological content of study protocols have been defined by WHO. Confirming to these can be regarded as a necessary minimum but since they have subsequently been enhanced and extended by several investigators they cannot be regarded as a standard requirement.

A single neurotoxicological syndrome, as claimed by some to exist in man, does not occur in laboratory animals as a consequence of solvent exposures. The limited animal neurotoxicological data related to solvents has been reviewed in terms of chronic neurotoxicity or other evidence that would support the hypothesis that long-term low-level solvent exposure is causally related to chronic exposure to solvents, at or below the recent or current OELs, causes encephalopathy and irreversible behaviour changes in the case of impure trichloroethylene and toluene. Exposure pattern is important for the induction of peripheral nervous system damage caused by n-hexane and methyl n-butyl ketone.

It is concluded that there is no basis for a neurological syndrome in man that is causally related to low level organic solvent exposure (as defined by recent or current OELs).

Whilst it is likely that further epidemiological studies will be reported it is doubtful whether they will be of any great value unless rigorous attention is paid to confirming with the WHO protocols coupled with adequate characterisation of exposure. It is recommended that resources are better deployed on the control of exposure rather than conducting further epidemiological examinations.