Medical Experts in Organic Solvent-induced Neurotoxicity
Organic solvents are a chemical class of compounds that are used routinely in commercial industries. They share a common structure as well as other characteristics such as, low molecular weight, lipid, volatility, and they exist in liquid form at room temperature. They may be grouped further into aliphatic-chain compounds, such as n -hexane, and as aromatic compounds, such as benzene or xylene. Aliphatic and aromatics may contain a substituted halogen element and may be referred to as halogenated hydrocarbons, such as perchloroethylene (PCE or PER), trichloroethylene (TCE), and carbon tetrachloride. Alcohols, ketones, glycols, esters, ethers, aldehydes, and pyridines are substitutions for a hydrogen group. Organic solvents are useful because they can dissolve oils, fats, resins, rubber, and plastics.
Organic solvent usage increased in the latter half of the 19th century from the coal-tar industry. Their application grew to be wide and diverse in both developed and developing countries. The introduction of chlorinated solvents in the 1920s led to reports of toxicity. Although solvents number in the thousands, only a few have been tested for neurotoxicity.
Short-term, high-level exposures such as those frequently reported in case reports can result in acute reversible and irreversible health effects that involve the central nervous system (CNS) and peripheral nervous system (PNS). In population studies, intermediate- and long-term, low-level exposures have led to reversible and nonreversible clinical abnormalities in the CNS and PNS. In some cases, these exposures were estimated to be below the then acceptable levels, as designated in regulations for workers. Neurophysiologic, neuropsychological, and neuroimaging diagnostic tools have been used to evaluate individuals and groups exposed to organic solvents.
In 1987, The National Institute for Occupational Safety and Health (NIOSH) reported that 9.8 million workers were exposed to organic solvents in occupational settings. Most occupational exposures involved solvent mixtures. Workers who use these agents include printers, paint manufacturers, painters, microelectronics workers, degreasers, dry cleaners, carpet layers, coating workers, gluers, dye workers, carpenters, anesthesia personnel, petrol filling workers, laboratory workers, inkers, and textile workers; others are those who work with polymers, pharmaceuticals, synthetic fabrics, agriculture products, refining, or in airplane refitting.
Worker exposures within the same job vary during a workday, many routes of absorption are possible, personal protective equipment (PPE) is used inconsistently, and solvents are commonly used in various mixtures. For environmental exposures, similar challenges exist. Industrial hygienists and risk-assessment scientists work to overcome these challenges.
Exposure may be measured by intensity and duration. Intensity refers to solvent concentration, which depends on many factors, such as space ventilation, temperature, surface materials, solvent volume, concentration, and method of application of the material. Personal protective equipment (PPE) and other individual variables influence absorption. For most solvents, the main route of absorption appears to be inhalation, though dermal routes are common in the workplace, and ingestion is important in accidental exposures.
Chronic effects are those that result from exposures over a period of time. These exposures are often low level. Authors may use this term to describe a wide variety of durations. Health consequences may be subclinical or clinical and/or irreversible. Environmental exposures are often grouped into this category, though high-level or acute exposures have occurred.
Inhaled agents rapidly diffuse from the alveoli to the blood. Because alveolar ventilation and pulmonary perfusion are functions of physical exertion or workload, manual labor may lead to increased absorption because of the rate and depth of respiration.
Dermal absorption occurs when liquid solvent contacts the skin. For solvents with low vapor pressure, this route of absorption may be more important than for others. Abraded or burned skin is less of a barrier to absorption than intact skin, and the risk of subsequent health effects is increased. Percutaneous absorption of solvent vapor is reportedly negligible.
Lipid solubility often allows solvents and metabolites to access structures of the CNS and the PNS. For example, the lipid solubility of TCE allows access to structures of the CNS and the PNS, where TCE produces acute effects, such as narcosis, and irreversible effects, such as demyelination and cell death.
Chronic effects of trichloroethane (TCA) have been attributed to the parent compound and its metabolites. Dechlorination of TCA occurs, and free radicals are formed during its metabolism. Because it is a saturated hydrocarbon, it has a slow rate of metabolism and lower toxicity.
The acute neurotoxic effects of organic solvent exposure in workers and laboratory animals are narcosis, anesthesia, CNS depression, respiratory arrest, unconsciousness, and death. Acute experimental exposures of human volunteers to one or several organic solvents have impaired psychomotor function as measured by reaction time, manual dexterity, coordination, or body balance. Chronic animal studies of organic solvents support the evidence for peripheral neuropathy and mild toxic encephalopathy in solvent-exposed workers.
Epidemiologic studies of various groups of solvent-exposed workers have demonstrated statistically significant chronic changes in peripheral nerve function (sensory and motor nerve conduction velocities and electromyography abnormalities) that persisted for months to years following cessation of exposure. Epidemiologic studies have also shown statistically significant increases in neurobehavioral effects in workers chronically exposed to organic solvents.
These effects include disorders characterized by reversible subjective symptoms such as fatigability, irritability, and memory impairment, sustained changes in personality or mood, emotional instability and diminished impulse control and motivation, and impaired intellectual function, decreased concentration ability, memory, and learning ability. Among organic solvent abusers, the most severe disorders reported are characterized by irreversible deterioration in intellect and memory (dementia) accompanied by structural CNS damage.
Chronic solvent encephalopathy or “chronic painters’ syndrome” refers to a central nervous system disorder that can follow many years of heavy exposure to solvents. A study of 85 painters by Mikkelsen showed that changes in neurobehavioral dysfunction were related to the degree of past solvent exposure. There was little risk of organic brain damage in workers with fewer than 13 years of exposure to the equivalent of a time-weighted average of 40 ppm of white spirit.
Neuropsychological performance testing has been the primary method of assessing chronic solvent effects on exposed workers. Workers who reach the criteria for exposure, and show positive cognitive and/or psychological effects of exposure on clinical interview, should undergo a neuropsychological assessment by a qualified clinical neuropsychologist.
Two international workshops have categorized solvent-induced CNS disorders according to their severity. Correspondence between the two systems of nomenclature is not exact, but the categories produced by these two workshops do help clarify the chronic effects of solvents on the CNS. Each workshop identified three categories of effect, varying from minimal and reversible to pronounced and irreversible. Using the nomenclature from either workshop will be useful in classifying effects in future epidemiologic and clinical studies.
The mildest type of disorder is the organic affective syndrome (WHO Workshop), or the Type I disorder (International Solvent Workshop). This disorder is characterized by fatigue, memory impairment, irritability, difficulty in concentrating, and mild mood disturbance.
The second level of disorder is described as mild chronic toxic encephalopathy (WHO Workshop), or the Type II disorder (International Solvent Workshop). This level involves both symptoms of neurotoxicity and abnormalities of performance on formal neuropsychological testing. The Type II disorder has been divided into Type IIA (sustained personality or mood changes such as emotional instability and diminished impulse control and motivation) and Type IIB (impairment in intellectual function with diminished concentration, memory, and learning).
The third and most pronounced level of disorder is described as severe chronic toxic encephalopathy (WHO Workshop), or the Type III disorder (International Solvent Workshop). The condition is characterized by global deterioration in intellectual and memory functions (dementia) that may be irreversible, or at best, only poorly reversible.
Types I and II disorders are the most likely to be reported among solvent-exposed workers. Type III disorders to date have been seen only in individuals who have abused solvent-containing products (i.e., by deliberately inhaling organic solvent vapors for their euphoric properties). For example, persons who abusively inhaled toluene almost daily for one to seven years showed evidence of severe, multifocal CNS damage with cortical, cerebellar, and brain stem atrophy, electrophysiological abnormalities, and neuropsychological deficits.
Chronic neurotoxicity in workers exposed to organic solvents over a period of months to years includes (1) peripheral neuropathies such as axonal degeneration seen in workers exposed to hexacarbon solvents (e.g., n-hexane, methyl n-butyl ketone), (2) Type I CNS symptoms such as fatigability irritability, and memory impairment, and (3) Type II mild toxic encephalopathy, including sustained personality or mood changes such as emotional instability, diminished impulse control and motivation, and impairment in intellectual function manifested by diminished concentration, memory, and learning capacity. Epidemiologic studies have demonstrated correlations of workplace solvent exposures with the types of solvent-related CNS dysfunctions noted above and changes in neurophysiologic parameters such as nerve conduction velocities. Studies have demonstrated that these effects can persist for months to years after removal of workers from solvent exposure. The extent to which chronic neurotoxicity is reversible remains to be established; peripheral nerves have the capacity to regenerate, but damage to the CNS is more often permanent.
The NIOSH believes that the collective toxicologic and epidemiologic data on organic solvent neurotoxicity provide sufficient evidence to warrant concern about adverse health effects from occupational exposure to these chemicals.
References are available upon request.