Organic Solvent Neurotoxicity

Updated: Dec 11, 2018
Author: Jonathan S Rutchik, MD, MPH, FACOEM; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS 



Organic solvents are a chemical class of compounds that are used routinely in commercial industries. They share a common structure (at least 1 carbon atom and 1 hydrogen atom), low molecular weight, lipophilicity, and 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 with a 6-carbon ring, such as benzene or xylene. Aliphatics 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 solvents arose 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.

Workers in industries that use these agents may have occupational exposure, whereas other individuals may have environmental exposures if they live near industrial installations and/or have contact with contaminated water, soil, air, or food. Drinking water, shower water, ambient air, indoor air, and food, among other sources, are common routes of exposure to environmental toxins.[1] Inhalation, ingestion, and dermal absorption are also important mechanisms of toxic exposure.[2, 3, 4] Exposures often involve mixtures of solvents. Some of these incidents may occur deliberately when an individual recreationally inhales paints, glues, and other products; these exposures are described in more detail in the Medscape Reference article Inhalants.

The Occupational Safety and Health Administration (OSHA) regulates worker exposure. The National Institute for Occupational Safety and Health (NIOSH) and the American Congress of Governmental Industrial Hygienists (ACGIH) also publish standards for use in occupational settings in the United States.


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 CNS and PNS. In population studies, intermediate- and long-term, low-level exposures have led to reversible and nonreversible subclinical and clinical abnormalities in the CNS and PNS. In some cases, these exposures were estimated to be below 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.



United States

In 1987, NIOSH reported that 9.8 million workers were exposed to organic solvents in occupational settings. However, 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. Table 1 lists common sources of organic solvent exposures.

Table 1. Organic Solvents and Their Common Industrial Uses (Open Table in a new window)


Industrial Uses


Cleaning solvent


Mining and tunneling, adhesives, waste treatment, ore processing


Fuel, detergents, paint removers, manufacture of other solvents

Carbon disulfide

Viscose rayon, explosives, paints, preservatives, textiles, rubber cement, varnishes, electroplating

Ethylene oxide (ETO)

Instrument sterilization

N- hexane

Glues and vegetable extraction, components of naphtha, lacquers, metal cleaning compounds

Hydrogen sulfide

Sulfur chemical manufacturing, by-product of petroleum processing, decay of organic matter


Industrial settings

Methyl mercaptan

Odorant in natural gas and fuels

Methyl-N- butyl ketone

Many industrial uses

Methylene chloride (dichloromethane)

Solvent, refrigerant, propellant






Dry cleaning, degreaser, textile industry


Fiberglass component, ship building


Paint, fuel oil, cleaning agents, lacquers, paints and paint thinners

1,1,1-Trichloroethane (methyl chloroform)

Degreaser and propellant


Cleaning agent, paint component, decaffeination, rubber solvents, varnish

Vinyl chloride

Intermediate for polyvinylchloride resins for plastics, floor coverings, upholstery, appliances, packaging


Paint, lacquers, varnishes, inks, dyes, adhesives, cements, fixative for pathologic specimens

Environmental exposures to organic solvents occur. Solvents are also present in home products. According to NIOSH, 49 million tons of organic solvents were produced in the United States in 1984. Contamination affecting community water supplies, food additives, or household chemicals is an important source of exposure. Well-water sampling, both in the United States and abroad, has revealed quantities of chlorinated hydrocarbons and other solvents. Health effects secondary to these exposures have been described.

Estimating rates of occupational exposure is difficult because of a variety of factors. Worker exposures vary even within the same job, exposures 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.


Occupational exposures affect persons of working age. Environmental exposures affect persons of all ages.




Health effects may be categorized by the neurologic system or the exposure. Neurologic systems may be divided into the CNS and the PNS and further subdivided into those exclusively affecting cerebral cortices, basal ganglia, midbrain, or spinal cord; they may also be divided by specific neurologic conditions. Symptoms may be referred from any location in the CNS or PNS.

Exposure may be categorized by duration (short or long term) and intensity (low, high). Acute effects are those that occur after short-term exposure. Very-high-intensity exposure often leads to catastrophic results. Short-term, low-intensity exposures may have subclinical or clinical and reversible or irreversible health consequences.

Chronic effects are those that result from exposures over a period of time. Authors may use this term to describe a wide variety of durations. These exposures are often low level. 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. Multiple routes of absorption are considered in these scenarios, but the level of exposure is usually lower than that of occupational exposures. Durations, however, may last a lifetime. Exposure data may be presented in units of dose per year for comparability.

The literature comprises case reports, case series, prevalence (cross-sectional) studies, and a few prospective studies. Conclusions may be simple observations, hypotheses, or evidence of association. Individual cases are not epidemiologic studies; group studies, however, are bound to the rules of statistical significance. Challenges in study design, such as confounding, recall bias, and weak exposure data have led to scrutiny by many readers. However, these studies form the basis of our knowledge of these chemicals and their characteristic health effects.

Acute effects (short-term exposures)

Immediate signs and symptoms of a CNS disturbance are common results of high-level exposure to organic solvents.

Symptoms vary somewhat depending on the solvent. However, some symptoms are typical of all solvent exposures: disorientation; giddiness; dizziness; euphoria; and confusion progressing to unconsciousness, paralysis, convulsions, and death from respiratory or cardiovascular arrest.

A metabolite may be responsible if symptoms are delayed.

When the exposure ends, symptoms abate in most of patients.

Consider the following case study:

Two workers in a headlight assembly plant had 1-2 months of dermal and inhalation exposure to nitromethane, a component in glue. One worker noted weakness in his hands, legs, and feet; the other worker noted numbness in her feet 5 months later. Each had laboratory results consistent with severe peripheral neuropathy. One had absent ankle and elbow reflexes and weakness, distally more than proximally, in the lower extremities. The other had diminished lower extremity reflexes and weakness on dorsiflexion with decreased sensation to pinprick in the midshin.

In one worker, electromyelography (EMG) and tests of nerve-conduction velocity (NCV) revealed absent motor responses in the right and left tibiae and markedly reduced peroneal amplitudes on the left with normal latencies. Ulnar motor responses were slowed and small on the left side. Sural sensation was absent. Needle EMG revealed fibrillations in several muscles: tibialis anterior, gastrocnemius, vastus medialis, abductor pollicis brevis (APB) and abductor digitorum quinti (ADQ) in the hand, and extensor indicis in the forearm. Studies also showed many polyphasic action potentials of increased amplitude and duration. This picture suggested a motor and sensory axonal and demyelinating polyneuropathy.

In the other worker, NCV and EMG findings were significant for absent motor and sensory responses and for reduced median motor amplitudes and asymmetrical slowing. EMG revealed spontaneous activity in the upper and lower extremities, with normal results in the proximal aspects of the upper limbs.

Industrial hygiene sampling for nitromethane and ethyl cyanoacrylate revealed levels in the workers' personal breathing zones of 10-20 ppm as an 8-hour time-weighted average (TWA), with a mean of 12.75 ppm. OSHA's permissible exposure limit (PEL) established is 100 ppm, and ACGIH recommends a threshold limit value (TLV) of 20 ppm. Measurements of ethyl cyanoacrylate revealed 0.04 -0.16 ppm as an 8-hour TWA with a mean of 0.09 ppm. The ACGIH TLV is 0.2 ppm.

The history of acute-onset, severe peripheral neuropathy temporarily associated with exposure to nitromethane is suggestive of toxic neuropathy. Occupational exposure to nitromethane appears to be the most likely etiology.[5]

Chronic effects (short- and long-term exposures)

Symptoms may be of slow onset and difficult to associate with a chemical exposure.

Headache, fatigue, sleep disturbances, achiness, numbness, tingling, mood changes, and other generalized symptoms are common.

Usually no event or incident is clearly responsible.

A keen history is necessary.

Consider the following case studies:

A 57-year-old man had worked as a painter for 30 years for the same employer, primarily spraying the exteriors of gasoline storage tanks and assisting welders. He did not use a respirator. For 1 year, he painted residential buildings. When he was 22-24 years old, he painted the insides of university and commercial buildings. He was often in unventilated areas and often had nausea and dizziness and gait difficulties.[6]

The California Department of Health Services investigated a report about a 24-year-old man who developed peripheral neuropathy after 2 years of exposure to n -hexane while working as an automotive technician.[7] He developed numbness and tingling and was found to have reduced biceps, patellar, and Achilles reflexes. During the 22 months of his employment, he used 1-9 aerosol cans of brake cleaner per day. Each 15-oz can contained 50-60% hexane (20-80% n -hexane), 20% toluene, 10% methyl ethyl ketone, acetone, isopropanol, methanol, and mixed xylenes.

At another automotive facility, 15 technicians were screened for neuropathy. One met the criterion for peripheral neuropathy related to n- hexane exposure. Three had detectable 2,5-hexane dione levels of 7%, 26%, and 6.4% of the BEI for n -hexane. California neurologists were surveyed n- hexane–related peripheral neuropathy. One case in an automotive technician was identified and verified.

In another study, 1424 male veterans of the Australian Gulf War were compared with a randomly sampled military group to determine the prevalence of neurologic symptoms and diagnoses by means of questionnaires and examinations. Exposure to immunizations, pyridostigmine bromide, antimalarials, anti–biologic warfare tablets, solvents, pesticides, and insect repellant was considered. Although reporting of exposure increased, the objective physical signs provided no evidence of increased effects.[8]

Acute, high-dose exposure and neurologic dysfunction

According to Longstreth, neurologic dysfunction from acute, high-dose organic solvent exposure is commonly reported in patients who have a history of the following:[9]

  • Acute onset of symptoms including fatigue, headache, dizziness, giddiness, disorientation, confusion, hallucination, and/or seizure; other neurologic consequences; coma; or death

  • Reported acute exposure to an organic solvent from any source, such as food, water, pharmaceutical, or workplace

  • Symptoms of raised intracranial pressure (ICP), such as headache, nausea, or vomiting, which may be consistent with acute toxic exposure

  • Work in a confined space

  • Noted a foul odor before the onset of symptoms

  • Worked with little or no PPE

  • Did not use industrial hygiene data to assess the level of exposure of work setting

  • Among those in the United States, unfamiliarity with the English language and lack of proper training in confined-space or PPE procedures

  • Drug abuse or dependence (nonoccupational)

  • Depression, suicidal ideation, or history of psychological disorder (nonoccupational)

  • Fatigue, dizziness, or giddiness that may disappear after exposure stops

  • Effects consistent with known acute effects of the neurotoxin

Long-term, low-dose exposure and neurologic dysfunction

According to LaDou, neurologic dysfunction from long-term, low-dose exposure to organic solvents may be suspected in patients with the following conditions or histories:[10]

  • Reversible, static, or progressive neurologic symptoms after removal from exposure

  • Symptoms of slow or intermittent onset

  • Symptoms referable to the CNS, such as headache, confusion, disorientation, behavior changes, or memory problems that are intermittent or of slow onset

  • Symptoms referable to the PNS, such as numbness in the feet and hands, pain, weakness, or difficulty walking that are intermittent or of slow onset[11]

  • Other neurological symptoms

  • No focality on neurologic examination: This observation may suggest other neurologic diagnoses.

  • Long-term employment in industrial processes in which organic solvents are used

  • Many occasions of symptoms associated with brief, high-dose exposures at work

  • Progressive fatigue and symptoms, such as memory and concentration difficulties, that dissipate over the weekend but reappear as the workweek begins

  • Limited PPE use or training

  • Evidence of household water contamination with an organic solvent above levels permitted by state or federal drinking-water or exposure regulations

  • Evidence of ambient air contamination with an organic solvent above levels permitted by state or federal ambient-air regulations

  • Subclinical dysfunction noted by abnormal neurophysiologic, neuropsychological, or neuroimaging results with a notable occupational or environmental

To determine whether a symptom or finding is associated with an exposure, pertinent to a history, the following steps must be taken:

  • Devise a timeline of when symptoms began.

  • Include significant dates from medical, social, birth, and family histories and medications.

  • Include dates of items such as head trauma, psychological history, and drug dependence.

  • Include dates of past and present occupations and exposures and specific day-to-day tasks.

  • Include dates of symptoms from short-term exposures from present job.

  • Include dates of present and past residences.

  • Gather information about the following:

    • Education

    • Birth history

    • Past and present specific job tasks, chemical agents used, and hours spent at a task

    • Material Safety Data sheets of chemical agents from employer

    • Other employment records, time sheets, and process records (if and when available)

    • PPE (eg, gloves, gowns, breathing apparatus, eye shields, masks) used in past and present jobs

    • Previous occupational injuries

    • Alcohol, smoking, and recreational drug intake

    • Emotional and psychological history

    • Colleagues and cohabitants' medical histories and health status

    • List of past and present residences, drinking and washing water supplies of each

    • Proximity to power lines and plants, well water, lakes, ponds, and streams

    • Dietary and exercise habits, commercial products, and vitamins (supplement and traditional uses)

Overview of occupational and environmental neurologic evaluation

An occupational and environmental history is useful to a neurologist in 1 of 3 settings: (1) referral for diagnosis and treatment of a clinically noted neurologic problem, (2) referral after an occupational or environmental exposure to a specified neurotoxin for an assessment of the neurologic system, and (3) referral requesting information about whether a neurologic problem is associated with an exposure in the patient's history.

Begin the evaluation with a medical history that includes a thorough occupational and environmental history. Include the birth, pregnancy, and extensive family history. Did the individual have an exposure of concern? Is it ongoing? If exposure is ongoing, be specific and detailed about when, how often, where, and how long (eg, months or years), and consider biologic monitoring. Determine whether other medical records help to confirm and clarify the timing of other events.

In one report, a 57-year-old man had a history of being a painter for 30 years. He had cognitive difficulties and a history of consuming 1-3 alcoholic drinks each evening for 20 years. He stopped drinking 10 years before his presentation. He had no family history of dementia, psychiatric illness, or other neurologic illnesses. He had episodes of dizziness and numbness of the right arm, which were often aggravated by painting in the 6 years before this presentation. He was found to have subclavian steal syndrome and occlusion of the right subclavian artery.[6]

Perform a neurologic examination. A general medical examination including an assessment of the hair, teeth, nails, skin color, and lymph system is important. Determine the objective findings on examination and determine whether they support the reported symptoms.

Arrange for confirmatory neurophysiologic, neuropsychological, and imaging tests.

Arrange for serum and biologic monitoring, when appropriate.

Consider contacting an industrial hygienist for air and water sampling.

Consider removing the patient from the exposure, or consider contacting the employer or representative to discuss the specific concerns.

Consider whether exposure and problem are historically correct.

Exclude all other common causes of diagnosis.

Search the literature for epidemiologic and case studies that describe an association between exposure and dysfunction. Search for case reports that have exposure scenarios and for case studies or epidemiologic findings (eg, age, exposure characteristics) that are similar to the patient's.

Determine whether the dose and duration of exposure are consistent with the described dysfunction.

Determine the proposed mechanism for the exposure-induced dysfunctions.

Reexamine the patient and repeating neurologic tests that previously yielded positive results. Are the results consistent?


Physical findings from short-term high-level exposure depend on the dose and duration of exposure.

The half-life of the agent plays a role in the symptoms, as does synergism and antagonism of mixed-solvent exposures.

Tolerance may also be a factor. Patients with withdrawal and "hangovers" may present with symptoms and findings on weekends or on vacations that may be alleviated by alcohol ingestion.

Mental-status changes may begin as mild disorientation and memory disturbances and lead to changes in mood, speech, and consciousness; generalized seizures; coma; and death. Brainstem signs such as nystagmus may be noted.

Trigeminal neuropathy may be a sequela of high-dose or long-term low-dose exposure to TCE. Trichloroethylene is the most important cause of trigeminal neuropathy among workers. Diabetes, AIDS, lymphoma, and trauma are other important etiologic agents for this condition.

Motor signs, sensory findings, and reflex changes may be signs of central or peripheral dysfunction.

Case study

A 49-year-old machinist presents with burning feet over the last 5 years. PMH is questionable for significant alcohol, some reports of 1 bottle of gin per week, then 4 bottles in 8 months, self-reported weekends. Examination reveals sensory deficits in the lower extremities and absent ankle reflexes. EMG and NCV reveals small sensory amplitudes in the lower extremities consistent with a sensory axonopathy. Lab testing revealed a HbA1C of 5.6 and inconsistent glucose tolerance tests.

He is a machinist who uses blocks of metals (aluminum, brass, copper and stainless steel) to creates parts in aerospace and defense industry. He cleans and degreases with lineum, containing n- propyl bromide. He uses the agent for mins each hour, 2-12 x per day. The workspace is a 40 x 40 foot garage type bay where window was installed during last yr. PPE included gloves, protective shield hood. He did experience dizziness and seeing spots on occasions. He reported that the company had used an agent that contained freon in the past and he was told by EHS that the chemical was unsafe but no changes were made.

1- bromopropane, 1-BP is a substitute for chloroflourocarbons due to lack of ozone depleting abilities. In its liquid form, it is used for cleaning metals, precision instruments, electronics, optical instruments, and ceramics in US and Japan. It is also a spray adhesive in US and an alternative to PER in the dry cleaning industry and used by foam cushion workers.

Biological indices include urinary N acetyl cysteine, in foam cushion workers with high-dose exposures and urinary Bromide and N Acetyl cysteine in degreasers and adhesive users.[12, 13]

A paper in Environmental Health Perspectives in 2004 and another in 2010 JOEM by the same authors reported data from an evaluation of workers in a Chinese 1BP factory. They found differences in neurophysiological measures of female workers comparing to controls in vibration sense, motor and sensory distal latency, Benton test scores, and depression and fatigue in the POMS test. Their TWA avg was between 0.34–49.19 ppm .

Regarding neuropathy, a paper by Raymond and Ford, JOEM 2007, reported high dose exposures to adhesives in four workers with confounding As urine levels. Initial case presented with flu like syndrome, balance issues painful feet and later was found to have EMG evidence of motor neuropathy with no data reported. An estimate of exposure was 80 ppm in the work setting.

There was no evidence for peripheral neuropathy in a NJ Human Health Evaluation by NIOSH regarding symptoms of workers in dry cleaner facilities using bromopropane. The estimate for these exposures was 40 ppm in the operator and 17 ppm in the cashiers with no elevated urine bromide found.

Distal sensory loss and hyperreflexia was noted in patients with high level 1 bp use with a TWA of 108 ppm reported by Majersik et al.[14] Serum bromide concentrations ranged from 44 to 170 mg/dL (reference 0–40 mg/dL.

Lower extremity weakness and sensory loss along with NCV revealing diffuse symmetric motor and sensory slowing was noted in patient reported by Sclar G.[15] CNS involvement was also reportedly evidence from contrast enhanced MRI; patchy areas of increased T2 signal in the periventricular white matter and Spinal cord MRI revealing root enhancement at several lumbar levels.

Te-Hoa Wang, et al. reported on 6 workers in a golf club cleaning factory confirmed with daily exposure to 1-BP for 3–10 months. Their primary presenting symptoms included tingling pain, soreness in the lower extremities, and paresthesia. It was found that 1-BP poisoning was a result of recurrent power outages, condenser and exhaust fan malfunction, and inadequate PPE. Nerve condutction testing was normal, but SSEP (somatosensory evoked potential) testing was abnormal in some patients.

Lastly JAMA Internal Medicine in 2012, by Samukawa et al, reported a propyl bromide neuropathy with positive sural nerve biopsy with increased motor tone, sensory loss p/t/vib on exam. EMG NCV revealed sensory nerve action potential reduced. The exposure to 1 bp was estimated to be 500 ppm. Removal from exposure for 4 months led to improvement of gait and reappearance of ankle reflexes?

In this case, a worker has had exposure to 1-BP and has developed a sensory neuropathy and MRI changes. Exposure estimates were not clearly accomplished. The literature is convincing using animal data. For humans, a case in 2012 reveals sural nerve evidence for axonal neuropathy which would be consistent with this patients presentation however previous studies reported sensory slowing and a mixed central and peripheral picture on examination. The evaluation of a patient with objective findings and solvent exposure is always challenging and requires detailed investigation.

Increased motor tone, rigidity or tremor or difficulties with gait and station may suggest a movement disorder. A complete family history would be warranted for neurodegenerative disease. While some medications may cause atypical parkinsonism, literature is developing such that a consensus is developing that supports that solvents may lead to Parkinsonism or Parkinson’s Disease in some patients.

Case Study

A 53-year-old female first reported symptoms of Parkinson's disease in 1997. Prior to 1998, she had occupational exposures to solvents over a 30-year period while working in a factory; many years in areas of the plant where PPE and ventilation were inadequate. Solvent exposures included methyl ethyl ketone (MEK), styrene, toluene, phenolic compounds, and 111 trichloroethane (TCA). Styrene, toluene, TCA, and MEK 1.5 -5 times that of the 8-hour exposure limits (PELs), some even above the STELs. Trichloroethylene, (TCE) present in the plant, 6 and 29 times above the TLV.

Literature support for solvent induced Parkinsonism stems from individual case reports of solvent induced atypical parkinsonism.[16, 17, 18, 19]

Also, research identified a mitochondrial neurotoxic metabolite, known as MPP+, as a causative agent of the clinical and pathological features of Parkinson's disease (PD), when drug abusers in the 1980s developed idiopathic type PD.[20]

Exposures to lead, manganese, solvents, and some pesticides have been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis, and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies, which is a crucial factor in PD pathogenesis.

Literature reported associations with TCE and atypical forms as well as PD.[21, 22, 23] and a toxic metabolite of TCE has demonstrated mitochondrial impairment in the midbrain leading to loss of dopamine the neurons in animal studies. This metabolite of trichloroethylene, is called TaClo, or 1- trichloromethyl 1,2,3,4 tetrahydro- beta carboline.[24]

In epidemiological studies, Pezzoli in 2000 in Neurology, studied those with PD and hydrocarbon exposure and found that that they had a younger onset of disease compared to controls and that exposure severity directly correlated to disease severity and inversely correlated to a latency period.

In 2011, Goldman[25] then demonstrated that exposure to TCE was associated with a statistically significant odds ratio > 6! Risk of PD from exposure to PER, and carbon tetrachloride was also elevated and tended toward statistical significance. In a twin study of Veterans of WWII, also in 2011, Goldman et al, demonstrated that those exposure to any solvent, including toluene, was associated with a greater risk for PD but tended toward statistically significance.

Again in 2014, Goldman conducted an analytic epidemiologic study of TCE in 99 twin pairs discordant for PD. Industrial hygienists blinded to disease status estimated exposures using detailed job task-specific occupational questionnaires. They found a 6-fold increased risk in twins exposed to TCE, and a near-significant association with the similar solvent perchlorpethylene (PERC) (OR 10.5, 95% CI 0.97–113) as well as with carbon tetrachloride (OR 2.3, 95% CI 0.9–6.1).

A case-control study conducted in the Netherlands looked at 444 PD patients and 876 age- and sex-matched controls. Exposures to aromatic solvents, chlorinated solvents, and metals were estimated by linking the ALOHA+ job-exposure matrix (JEM) to the patients’ occupational histories. Researchers found no increased risk of developing PD with occupational exposure to aromatic solvents, chlorinated solvents, or exposure to metals; however, study results did show, interestingly, reduced risk estimates for welding. Researchers did note several limiting factors such as recall bias and limitations of the JEM, which assigns exposures as no, low, or high using arbitrary weights for intensity and probability of exposure.

When patients present with tremor only, a diagnosis of essential tremor (ET) may be indicated. There is also epidemiological literature that has implicates harmane, a tremor inducing solvent agent in animals. Harmane is found in animal protein, increased with cooking, coffee, ethanol, tobacco and has been found to be elevated in those with ET. Males with ET have been found to have eat more meat consumption that those without ET. Harmane has a toxic metabolite that is similar in structure to MPTP, 1 methyl 9H pyrole (3,4-6) indole, which is in the carboline alkaloid family, similar to TCE, mentioned above. In 2014, harmane has recently been found to be elevated in those with PD compared to controls.

Cerebellar signs such as ataxia, dystaxia, or dysmetria may be noted in acute exposure settings and have been noted as subclinical abnormalities in populations.



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. 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. All routes of exposure should be considered in an assessment of occupational or environmental exposure.

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. Skin surface area, thickness, and physical characteristics, along with the duration of solvent contact, are important variables. 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.

The distribution of solvents depends on the blood supply and the lipid content of the organ system. Cardiac output controls the blood supply to an organ. Solvent half-life in a tissue and the volume of adipose tissue are important parameters. Half-lives for solvents vary widely, ranging from 3 hours for toluene to more than 12 hours for benzene. The blood-air partition coefficient of the agent is another variable for solvents. This coefficient determines the rate at which the agent enters an organ from the blood. It is directly related to the time necessary for a specific agent to cause symptoms. For solvents with high partition coefficients, increased solubility of a gas in the blood is associated with slowed onset of symptoms. The CNS, which is rich in both blood supply and lipid content, is a common target of solvent distribution.

The liver is where most solvents are metabolized. Specifically involved is the cytochrome P450 mixed-function oxidase system, which varies by ethnicity and age. Many solvents or drugs often cause enzyme competition and induction of this system occur. Induction may increase toxicity if a metabolite is responsible for the health effects, or toxicity may be reduced if the parent compound alone is responsible. Examples of solvents metabolized in this way are n -hexane and methyl-tert -butyl ketone, both of which metabolized to 2,5-hexane dione, a peripheral neurotoxin.

The cytochrome P450 enzymatic system also generates reactive intermediates. Inactivation by antioxidants, such as glutathione and ascorbic acid, is necessary to prevent cellular damage. These intermediates may covalently bind to proteins, lipids, DNA, or RNA, and they may inactivate receptors and proteins, damage cellular membranes, or initiate mutagenic reactions.

Saturation of detoxification pathways may result from high-dose exposures. Parent compounds or reactive metabolites may accumulate. This effect has been demonstrated for a number of solvents. Reactive oxygen species, such as free radicals, may result from metabolism of organic solvents. These may attack cellular macromolecules by means of mechanisms different from those of reactive metabolites. DNA structure may be altered.

Current concepts of the mechanisms of neurotoxicity are based on hypotheses and neuropathologic findings from animal studies and case reports.

Mechanism of toxicity

Lipid solubility often allows solvents and metabolites to access structures of the CNS and the PNS. The lipid solubility of TCE allows it to access to structures of the CNS and the PNS, where it produces acute effects, such as narcosis, and irreversible effects, such as demyelination and cell death. Demyelination and axonal pathology of the trigeminal nerve have been experimentally reproduced with TCE and its breakdown product dichloroethylene (DCA). Vascular permeability of the trigeminal-nerve nucleus has been suggested as the basis for relative selectiveness. Many authors consider DCA the main cause of the neurotoxic effect of TCE. The asymmetrical molecular conformation of TCE may also lead to the generation of free radicals. TCE epoxide irreversibly binds to cellular macromolecules and may be a toxic compound. Electrophilic compounds such as these alter protein transport in neurons and cause fragmentation of DNA.

PCE or its tetrachloroethylene metabolite, PCE epoxide, reacts with membrane lipids, cytoskeleton proteins, and nucleic acids of DNA and RNA. Exposure is associated with alterations in the fatty-acid composition of phospholipids. PCE epoxide is an electrophilic alkylating agent and covalently binds to the nucleophilic centers of cellular macromolecules such as cytoskeletal proteins and to nucleic acids such as DNA. DNA altered by covalent binding of PCE epoxide may decrease cellular adenosine triphosphate (ATP) content and increase intracellular free calcium content, possibly damaging neurons.

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 relatively low toxicity.

Acute and chronic effects of toluene have been attributed to the metabolites benzyl alcohol and benzaldehyde, to free radicals, and to the parent compound. Benzyl alcohol reversibly blocks neuronal action potentials in vitro; chronic in vitro exposure of rat nerve roots resulted in scattered demyelination and axonal degeneration. In 1993, Mattia et al suggested that free radicals induce lipid peroxidation during metabolism. Exposure alters membrane composition, function, and fluidity.[26]

Xylene can interact with membrane-bound integral proteins, and these interactions may be the critical factor in determining the anesthetic effects of xylene on the CNS. Animal studies indicate that xylene disrupts fast axonal transport; such disruption has been associated with peripheral neuropathy after exposure to other solvents and polymers. Methyl benzaldehyde covalently binds to cellular macromolecules and interferes with axonal transport.

N -hexane exposure has been associated with central and peripheral distal dying back neuropathy. The neurotoxic properties have been attributed to 2,5-hexane dione, a gamma diketone. Methyl-n -butyl ketone forms more 2,5-hexane dione than n -hexane and thus is more toxic. Fast anterograde and retrograde axonal transport were slowed in experimental studies. Disruption of axonal transport and induction of a distal central dying back axonal neuropathy appear to result from the formation of chemical cross-links between axonal neurofilaments. Progression of neuropathy after cessation of exposure results from the subsequent oxidation of pyrroles formed during exposure.

Styrene oxide is thought to be the ultimate toxin. Free radicals may be responsible for the neurotoxicity of styrene. Monamine oxidase B (MAO-B) levels are depressed in people exposed to styrene.

The mechanism of toxicity of acrylamide includes a direct toxic effect on the perikaryon, inhibition of glycolysis, interference with synthesis of microtubule-associated proteins (MAPs), alteration in calcium homeostasis, alteration of phosphorylation of neurofilament proteins (by acrylamide or glycinamide), and depletion of glutathione stores with increase in lipid peroxidation.

Neuropathologic changes in the CNS and the PNS are documented after ETO exposure. ETO exposure is associated with a distal axonopathy. The mechanism is unknown, but its epoxide structure is thought to be responsible. Its electrophilic properties make it a highly reactive alkylating agent, and it directly reacts with the nucleophilic centers of macromolecules such as DNA and RNA, proteins, and lipids of biologic systems without requiring metabolic activation. ETO binds covalently to DNA; this may be the basis for its induction of sister chromatid exchanges (SCEs) and chromosomal aberrations. Impairment of creatine kinase activity may be involved in the genesis of encephalopathy and distal axonopathy associated with exposure to ETO. Another possibility is that lipid peroxidation occurs, as evidenced by increased levels of the biologic marker malondialdehyde. The acid and aldehyde metabolites are also implicated in neurotoxicity.

Carbon disulfide is thought to interfere with lipid metabolism, chelation of copper, and binding to intercellular molecules. Induction of hypercoagulation of blood is likely related to lipid metabolism. Morphologic changes in the brain are associated with arteriopathic effects. Carbon disulfide readily crosses the blood-brain barrier. Chromatolysis of neurons occurs in response to axonal damage, reflecting interrupted axonal transport of neurofilaments, a phenomenon associated with peripheral neuropathy. Carbon disulfide does not require metabolism to become electrophilic. Dithiocarbamates are thought to chelate copper, which may lead to the inactivation of enzymes important to norepinephrine synthesis. Carbon disulfide also inhibits norepinephrine synthesis and lowers dopamine levels. Metabolites may also bind covalently and are associated with hepatotoxicity.



Diagnostic Considerations

Additional conditions to consider include the following:

  • Acute CNS symptoms (rapid onset)
  • Cerebral anoxia
  • Cerebral ischemia
  • Drug overdose
  • Drug toxicity
  • Hyperglycemia or hypoglycemia
  • Metabolic derangements
  • Postictal
  • Thyroid storm
  • Wernicke encephalopathy
  • Meningitis
  • Encephalitis
  • Central pontine myelinolysis Chronic CNS symptoms (slow onset)
  • Pseudodementia (depression)
  • Dementia of Alzheimer type
  • Dementia of multiinfarct type
  • Dementia of normal pressure hydrocephalus (NPH) variant
  • Dementia pugilistica
  • Drug toxicity
  • Nutritional excess of deficit
  • Multiple sclerosis
  • Epilepsy
  • Brain tumor or metastasis
  • Carcinomatous meningitis
  • Encephalitis or meningitis
  • Chronic drug abuse
  • Multiple head trauma history
  • Hepatocerebral syndrome
  • Krabbe leukodystrophy
  • Adult adrenoleukodystrophy Chronic PNS symptoms
  • Diabetes
  • Thyroid disease
  • Uremia
  • Liver disease
  • HIV infection
  • Medication toxicity
  • Lymphoma or other neoplasm
  • Nutritional deficit or excess
  • Syphilis
  • Familial neuropathy
  • Myasthenia gravis
  • Amyotrophic lateral sclerosis
  • Mononeuritis multiplex Other diagnoses to consider
  • Occupational exposures from previous employment
  • Environmental exposures from residence (indoor) and neighborhood (ambient) air and household water
  • Other environmental exposures from commercial products routinely used
  • Exposures from food and food preservatives
  • Paraproteinemic neuropathy

Differential Diagnoses



Laboratory Studies

Many laboratory tests should be routinely performed to rule out common diagnoses in the differential. Detailed discussions of these may be found in other articles in the Medscape Reference journal. To confirm exposure to an organic solvent, monitoring of the biologic exposure index (BEI) may yield valuable information.

Large proportions of many organic solvents are removed unchanged by means of exhalation; however, metabolism of the fraction that is absorbed often yields a water-soluble conjugate that is excreted mainly in the urine. Urinary or biliary excretion of the unchanged compound or metabolite is also common. These compounds are often measured in the urine and are the basis for BEIs. The levels of the metabolite or urinary compound are correlated with an exposure that is thought to be safe for a worker for 8 hours a day, 5 days a week. The ACGIH publishes these indices, which are only guidelines.[27] They are not enforceable by law (see Table 2 below). Monitoring is often impossible because exposure may have occurred in the distant past, or a specimen may be unobtainable.

Table 2. Exposure levels Believed Safe for Workers (Open Table in a new window)




Expired Air


Acetone, formic acid 100 mg/L




Total phenol 50 mg/g at the end of the shift, trans-trans- muconic acid


Benzene before shift, 0.08 ppm; end exhaled, 0.12 ppm

Carbon disulfide

2-TTCA 5 mg/g*

Carbon disulfide

Carbon disulfide





N- hexane

2,5-hexanediol 5 mg/g at the end of the shift, 2-hexanol, total metabolites

N- hexane

N- hexane

Hydrogen sulfide








Methyl mercaptan





Formic acid 80 mg/g at the start of the work week, methanol 15 mg/g at the end of the shift



Methyl-N- butyl ketone


2,5-hexane dione


Methylene chloride













PCE, trichloroacetic acid

PCE 1 mg/L

PCE 10 ppm before the last shift of the week


End of the shift: mandelic acid (MA) 800 mg, phenylglyoxylic acid (PGA) 240 mg/g)

Before shift: MA 300 mg/g or PGA 100 mg/g

Styrene 0.02 mg/L at the start of the shift, 0.55 mg/L at the end of the shift



Hippuric acid



1,1,1-Trichlorethane (methyl chloroform)

TCA 10 mg/L at the end of the work week; total trichloroethanol at the end of the shift and at the end of the work week, 30 mg/L

Total trichloroethanol 1 mg/L

Methyl chloroform 40 ppm before the last shift of the work week


TCE, TCA 100 mg/g at the end of the work week or TCA plus trichloroethanol 300 mg/g

TCE at the end of the work week 4 mg/L


Vinyl chloride





Methylhippuric acid 1.5 g/g at the end of the shift



* TTCA - 2-thiothiazolidine 4-carboxylic acid.

Formal standards

Industrial hygiene data are important to consider in setting standards for occupational settings. Industrial hygienists may take samples of air or other media to determine potential exposure.

In the United States, OSHA is the regulatory body that publishes and enforces standards or PELs for 8-hour-per-day, 5-day-per-week exposure.

NIOSH is the section of the Centers for Disease Control and Prevention (CDC) that performs research and publishes recommended exposure limits (RELs) that may be more conservative than OSHA's limits.[28]

The ACGIH publishes recommended TLVs that often are even more conservative than other standards.

The US Environmental Protection Agency (EPA) monitors ambient air and drinking water and sets standards for lifetime and shorter-term environmental exposures.

Individual states often set standards that are at or below EPA or OSHA standards.

Risk assessment

Risk assessment takes into account a data point and assumes toxicologic properties and chemical characteristics and models to determine potential exposure. This statistical method is used to develop exposure measurements to which regulations and recommended standards are compared. This method can be used to determine whether an exposure is likely to lead to health effects. Table 3 lists limits (eg, PELs, recommended exposure limits [RELs], and TLVs) from several agencies (eg, OSHA, NIOSH, and ACGIH) for specific organic solvents.

Table 3. Recommended Exposure Limits, Organic Solvents (Open Table in a new window)


ppm, mg/m,3





1000 (2400)

250 (590), 2500

750 (1780) ceiling, 1000 (2380)



(0.03), 60 level for carcinogenicity



10, 25 ceiling, 50 for 10 min

0.1, STEL 1, 500

10 (32)

Carbon disulfide

20, 30, 100 for 30 min

1 (3), 10 STEL (30), 500

10 (31)



< 0.1, < 0.18, 5 ceiling, 800

1 (1.8)

N- hexane

500 (1800)

50 (180), 1100

50 (176)

Hydrogen sulfide

20 ceiling, 50 for 10 min once only

10 ceiling, (15) for 10 min, 100


Methyl mercaptan

10 ceiling (20)

0.5 ceiling, (1) for 15 min, 150



200 (260)

200 (260), 250 STEL (325), 6000

262 (200), 328 (250)

Methyl-n- butyl ketone

100 (410)


5 (20)

Methylene chloride

25, 15 STEL for 15 min

2300 level for carcinogenicity

50 (174) ceiling


100, 200 ceiling, 300 for 5 min in 3 h

150 level for carcinogenicity

25 (170), 100 (685)


100, 200 ceiling, 600 for 5 min in 3 h

50 (215), 100 ST (425), 700

50 (213), 100 (428)


200, 300, 500 for 10 min

100 (375), 150 STEL (560), 500

50 (188)

1,1,1-Trichlorethane (methyl chloroform)

350 (1900)

Ceiling 350 (1900) for 15 min, 700

350 (1910), 450 (2460)


100, 200 ceiling, 300 for 5 min in 2 h

1000 level for carcinogenicity

50 (269), 100 (1070)

Vinyl chloride

1, 5 for 15 min

Not determined



100 (435)

100 (435), 150 STEL (655)

100 (434),150 (651)

Abbreviations—ACGIH = American Congress of Governmental Industrial Hygienists, IDLH = Immediately dangerous to life or health; NIOSH = National Institute for Occupational Safety and Health, OSHA = Occupational Safety and Health Administration, PEL = permissible exposure limit, REL = recommended exposure limit; STEL = short-term exposure limit; TWA = time-weighted average.

Imaging Studies

CT, MRI, positron emission tomography (PET), and single-photon emission CT (SPECT) have been used to evaluate patients with organic solvent neurotoxicity, but no specific abnormalities are consistently demonstrated. MRI and CT have been used to differentiate encephalopathy due to organic solvent exposure from other causes of dementia or neurologic diseases (eg, normal-pressure hydrocephalus, multiple-infarct dementia, Alzheimer disease, multiple sclerosis, many others). Although images are often normal, many demonstrate focal abnormalities.

Pneumoencephalography was performed in the past. Brain atrophy was noted in 64% of 37 patients undergoing pneumoencephalography in a Scandinavian study. Slight asymmetric central atrophy and slight local cortical atrophy were the most common findings. Pneumoencephalography is no longer performed.

Computerized tomography

CT has been used to investigate the sequelae of chronic recreational inhalation of organic solvents consisting mainly of toluene.

In one study, 8 of 9 subjects had evidence of diffuse cerebellar and cerebral atrophy. Another study revealed that impairment on examination was correlated with CT findings. Cerebral atrophy was noted on CT scans in 5 of 6 workers after 6-27 years of occupational exposure to styrene vapor. In 1990, Aaserud demonstrated that 13 of 16 workers with long-term exposure to carbon disulfide in the viscose rayon industry had cerebral atrophy on CT scans.[29]

A 26-year-old woman presented with altered mental status 36 hours after ingesting methanol. She reported blurred vision then nausea and vomiting. CT scanning revealed mild cerebral edema on admission, but 48 hours later, scans revealed hypoattenuations in the putamen and in the peripheral white matter.[30]


MRI has also been applied to examine patients exposed to organic solvents.

MRI revealed olivopontocerebellar atrophy in a worker exposed to carbon disulfide for 30 years. MRI demonstrated mild cortical atrophy in a patient exposed to PCE for 30 years. Another study showed that increased signal intensity periventricular white matter on T2-weighted images was significantly correlated with neuropsychologic deficits.

MRI revealed global symmetrical volume loss involving white matter more than gray matter in a 57-year-old painter exposed to mixed organic solvents for 30 years. Eight years earlier, his brain CT scans had been normal.[6]

A Turkish medical journal published a case series of 4 patients who chronically abused thinner containing toluene. White-matter lesions were noted in 46%. These lesions began in the deep periventricular white matter and spread to the peripheral white matter, causing the loss of gray matter–white matter differentiation with continued abuse. The deposition of iron due to demyelination and axonal loss is the most probably mechanism for the thalamic hypointensity found in solvent abusers.[31]

A 40-year-old experimental physicist noticed a tremor in her right hand when she was writing. Her work was performing research on the optical properties of mixed single crystals that she thinned by etching them with bromine diluted in methanol. She did not use appropriate personal protection, but had no episodes of acute intoxication. The initial diagnosis was hemiparkinsonism, which became bilateral. T2-weighted MRI revealed bright, bilateral foci in the subcortical white matter near the left basal ganglia and in the right occipital region. Long tract signs were noted with bilateral hyperreflexia. Levodopa provided a partial benefit, and dystonia was noted with the peak dose. This case illustrated a delayed neurotoxic effect of a long-term exposure to methanol.[32]


SPECT was used to evaluate chronic occupational exposure.[33] It increased the sensitivity of detecting CNS abnormalities. SPECT findings were abnormal in 31 of 33 workers who developed clinical toxic encephalopathy. The most frequent abnormalities were noted in the temporal lobes, frontal lobes, basal ganglia, and thalamus. MRI demonstrated abnormal findings in 28% of patients.

Other Tests

Neurophysiologic testing

EMG and NCS abnormalities have been demonstrated in individuals exposed to ETO, carbon disulfide, and mixed solvents (including xylene, TCE, PCE, toluene, and styrene, among others). Evidence of a mixed sensorimotor neuropathy has been found in many studies. Some have demonstrated a dose response when the exposure dose was compared with physiologic abnormalities. Other population studies revealed inconsistent results.

Gross et al reported 4 cases of peripheral neuropathy in workers who operated a leaky ETO sterilizer. Three had abnormal NCS and/or EMG results. The findings of muscle action potentials with decreased amplitude, signs of denervation, and moderately decreased conduction velocities were consistent with an axonal degenerative type of neuropathy.[34] Studies have revealed similar findings. Exposures varied in intensity and duration.

Viscose rayon workers examined 10 years after their exposure to carbon disulfide ceased had EMG and/or NCS findings suggestive of permanent axonal neuropathy. About 67% had evidence of neuropathy. In 1993, Ruijten et al performed a second study of the same workers, and exposed workers had abnormal motor NCSs of the peroneal nerve and abnormal sensory NCSs in the hand and arm segments of the median nerve and ulnar nerve and in the sural nerve.[35] , Johnson et al noted substantial abnormalities in sural sensory NCSs and peroneal motor NCSs in 156 male viscose rayon workers compared with control subjects. These changes were related in a dose-response manner to the workers' cumulative exposure to carbon disulfide.[36]

Scandinavian investigators assessed 87 patients with chronic solvent intoxication after occupational exposure. Abnormal EMG and/or NCS results were observed in 62% on the first evaluation, and in 74% on second evaluation 3-9 years later. Fibrillations were noted in 54% on initial examination and in 61% on reexamination. Exposures were to TCE, PCE, both, or other mixed solvents. Other populations of workers also had EMG and/or NCV abnormalities. The authors found a high percentage of slow motor and sensory conduction velocities and/or prolonged motor distal latencies in car painters but none in nonexposed controls subjects.

In another study, 28 exposed painters were compared with age-matched subjects and were found to have significantly prolonged refractory periods in lower-extremity motor and sensory nerves.

A high prevalence of slowed conduction velocity in the radial and peroneal nerves was observed in 490 workers exposed to styrene. A consistent decrement in peripheral-nerve conduction velocity was noted with duration of occupational exposure.

Mild sensory NCS deficits were found in men exposed to various levels of styrene in 4 Canadian factories.

A 55-year-old woman developed Guillain-Barré syndrome with nephrotic syndrome after exposure to an occupational solvent containing acetone.[37]

Croatian researchers studied the effects of mixed solvents in the painting and lacquer industries on the PNS. They assessed the BEIs for toluene (hippuric acid) and xylene (methyl hippuric acid), as well as sensory and motor conduction velocities for the radial and tibial nerves along with the distal tibial motor latency. Slowing was observed in workers and worse than findings in control subjects, with a clear trend of further deterioration with prolonged exposure. Subjects had more than 2 months of exposure and had no previous neurologic conditions or significant medical history.[38]

Environmental exposure has been implicated in EMG and NCS abnormalities. Three populations with exposure to organic solvents, including TCE, in well water were reported by to have evidence of subclinical peripheral neuropathy.[39] Blink-reflex testing showed considerable abnormalities, which was evidence for trigeminal neuropathy attributed to TCE toxicity. Abnormal blink-reflex testing has also been reported in populations with occupational TCE exposures.

Investigators in field studies have used quantitative sensory testing, such as vibrometry and current perception threshold (CPT) testing. Vibrometry is used to assess large-fiber function by simulating vibration. CPT is used to assess all 3 populations of nerve fibers: large myelinated, small myelinated, and small unmyelinated.

Neuropsychological testing

Many investigators from many international institutions have conducted neuropsychological testing in subjects with long-term occupational and environmental exposures to organic solvents from various industries. Some have performed behavioral testing after short-term experimental exposures. Different test batteries have been used, depending on the investigator, exposure, and sample size.

Testing may be performed to assess for neurologic dysfunction, consistency with deficits reported from specific exposures, or clinical progress (ie, comparison with previous findings in an individual).

Neurobehavioral effects of exposure to neurotoxins are characterized by impairments in 1 or more of the following functional areas: intelligence, attention, executive function, fluency, motor abilities, visuospatial skills, learning and short-term memory, and mood and adjustment. Variables, including age and maturity at the time of exposure, and individual subject variables, such as cognitive skills, preceding deficits, education, and socioeconomic status, are important to consider in assessing a subject with chemical exposure.

Neuropsychological studies of persons with the following occupations have been conducted:

  • House and car spray painters

  • Viscose rayon workers

  • Hospital and machine sterilization workers

  • Hospital workers

  • Histology technicians

  • Screen printers

  • Rotogravure printers

  • Ammunitions plant workers

  • Floor layers

  • Sewer workers

  • Hazardous waste workers

  • Microelectronics workers

  • Automotive carburetor plant workers

  • Varnishing industry workers

  • Dry cleaning workers

  • Chemical cleaning workers

  • Domestic appliance manufacturing workers

  • Fiberglass boat builders

  • Polyester and polyvinyl chloride factory workers

  • Plastics workers

  • Dockyard workers

  • Metal degreasers

Exposures to mixed solvents, as well as exposures to carbon disulfide, ETO, styrene, xylene, toluene, TCE, PCE, and vinyl chloride, have been investigated.

Both positive and negative findings are reported for many populations. Studies vary widely in exposure intensity and duration and in epidemiologic study design (eg, sample size, sensitivity and specificity of testing batteries, ages, exclusion and inclusion criteria, comparability of control populations).

Case study

A 57-year-old painter with more than 30 years of mixed solvent exposure had stopped working 4 years before presentation. Impairments were noted on tests of verbal and nonverbal memory, attention, execution, and visuomotor coordination. A second test, including the Boston Naming test, revealed normal language and spontaneous speech. Persistent static deficits were deemed not consistent with Alzheimer disease or multiinfarct dementia.[6]

Case study

In 1 study, 180 shipyard painters and 60 reference workers completed questionnaires about their symptoms and history. Exposure was estimated by industrial-hygiene measurements of the ambient air. Results for symbol-digit substitution and finger-tapping speed for both the dominant and the nondominant hand were affected. The duration of work was also associated with abnormal results.[40]

Case study

In another study, 55 chronic solvent abusers underwent MRI and neuropsychological testing, and their results were compared with those who abused other drugs, such as cocaine and alcohol. Both groups had abnormal MRIs, but the group abusing solvents had more abnormalities than the other. They also performed more poorly than the other group in terms of working memory and executive functions. No clear dose response was noted between solvent exposure and neuropsychological abnormalities, but a strong dose-response relationship was observed in the presence of MRI abnormalities. MRI may be more useful than other tools in evaluating these types of patients.[41]

Neuropathologic testing

Sural-nerve biopsy was reviewed in a number of studies of subjects exposed to ETO or carbon disulfide. Findings were consistent with axonal neuropathy, Wallerian degeneration, and some nerve-fiber regeneration.

In 1983, Kuzuhara et al noted mild degeneration of the myelin sheath in 2 workers.[42]

In 1985, Gottfried et al described the morphology of carbon disulfide neurotoxicity in peripheral nerves of rats. Experimental application of TCE to rat trigeminal nerves led to focal myelin and axon loss.[43]

Findings from few brain pathology specimens of patients with organic solvent exposure have been reported.

Electroencephalography (EEG)

Abnormalities have been demonstrated in many populations exposed to organic solvents.

Case study

Excessive theta activity was noted in a patient exposed to mixed solvents for more than 30 years who had memory difficulties, disorientation, irritability and insomnia. Sharp activity of low-to-medium voltage was noted in the posterior occipital area. A moderate amount of fast beta activity was superimposed over the background activity. About 4 years after the patient stopped working, his condition had not substantially progressed.[6]

Case study

Acute effects of xylene exposure were assessed in 9 volunteers with short-term exposure of < 400 ppm. Exposure increased the dominant alpha frequency and the alpha percentage during the early phase of exposure and counteracted the effect of exercise. These effects were deemed minor and not deleterious. About 65% of 107 patients with solvent poisoning after long-standing occupational exposure had abnormal EEGs. Excessive beta activity was noted in 54%. Focal slow-wave activity was correlated with inaccurate hand movements detected by using a motor test. Among patients assessed by the same author, 67% had abnormal EEG findings, predominantly diffuse slow-wave activity, on the first examination; on a second examination, 47% had abnormalities (more paroxysmal abnormalities than before).

Case study

Thirty-three styrene-exposed workers were evaluated with EEG. Three groups of exposure were assessed: at the TLV, clearly below the TLV, and clearly above the TLV. EEGs of these groups, of nonexposed individuals, and of those with exposure to mixed organic solvents were compared. Increased diffuse slow activity was seen in some of the styrene-exposed group and in many for the mixed-exposure group. No clear relationship to exposure was noted. An increased occurrence of fast activity in central and precentral areas was noted in the groups. Twenty-three of 98 male workers exposed to styrene in the reinforced plastics industry had abnormal EEGs. This was deemed a high prevalence.

Other tests to consider

Color-vision testing by using the Lanthony D-15 and the FM-100 tests has been useful in exposed populations. Long-term occupational exposure is associated with blue-yellow color loss (dyschromatopsia) that progresses to red-green color loss with continued exposure. Styrene, carbon disulfide, n -hexane, PCE, and other solvents are positively associated with these effects in populations working in many industries: microelectronics, paint manufacturing, airline mechanic, dry cleaning, plastics, shipbuilding, viscose rayon, adhesive bandage processing, and vegetable-oil extraction. Authors have postulated that subclinical findings may herald more drastic nervous system dysfunction.[44]

Occupational exposure to n-hexane has also been associated with acquired color vision defects. Blue-yellow defects are the most common and may be due to either neurotoxicity or retinal damage. In a cross-sectional study of 835 auto repair workers in the San Francisco Bay Area between the years 2007 and 2013, acquired color defects were present in 29% of participants, 70% of which were blue-yellow. Among participants aged ≤50 years, the prevalence ratio for blue-yellow defects was 1.62 (95% CI: 0.97–2.72) in the highest category of exposure to hexane with acetone co-exposure.[45]

Color fundal photography and ophthalmoscopy have been used to assess specific populations. In 1978, Sugimoto et al reported the association between retinopathy and carbon disulfide.[46] In 1983, Karai et al used fluorescein angiography to further evaluate populations from the viscose-rayon industry.[47]

Oculomotor and cerebellar function have also been studied in exposed populations. Electronystagmography (ENG) eye-movement testing and body-sway posturography have been some modalities used. These studies are performed mainly in subjects acutely exposed to styrene, xylene, and toluene. Both positive and negative associations have been found.

Case reports describe subjects with visual-field abnormalities. A 26-year-old man with high-dose acute occupational exposure to TCE had constricted visual fields. A 20-year-old man who intentionally abused toluene had reduced and constricted visual fields. Both patients recovered after many months. In 2 workers in a viscose rayon factory, carbon disulfide lead to visual-field narrowing and enlargement of the blind spot.

Evoked potentials have been used to assess many populations. Positive associations are reported in workers at printing presses workers and rotogravure printers, manufacturers of adhesive bandage, and vegetable-old extractors (n -hexane exposure), as well as in volunteers with short-term PCE exposure.

Contrast sensitivity and critical flicker fusion are included in many test batteries to assess exposed subjects. Positive associations are reported for contrast sensitivity with mixed solvent exposures in the microelectronics industry.

Tremometer has been used to assess populations with exposures to carbon disulfide.



Medical Care

For acute or emergency scenarios, symptomatic treatment is usually the mainstay of medical care. After emergency issues are addressed, reducing the intensity or eliminating exposure is the appropriate goal.

  • Reducing inhalation, ingestion, or dermatologic exposures may be accomplished by not eating or smoking in the workplace and by improving use of PPE, including masks and breathing apparatuses. Other protective measures are wearing gloves made of latex, Vicryl, or other impermeable material to limit skin absorption and by showering and changing clothes on completion of job tasks.

  • Changing the duration of exposure is also important. This may be accomplished by changing shifts and rotating jobs in a department.

  • Engineering controls, such as improving ventilation or shifting chemical processes to less-toxic substitutes, are other actions that the clinician might suggest.

  • Removal from exposure may follow a reduction of exposure if symptoms are severe, life threatening, or persistent. Reduction and/or removal are important diagnostic and treatment options. If symptoms abate after these steps, they better support the diagnosis of sequelae secondary to exposure than if they persist.

  • Clinicians should be willing to follow up their patients and to determine if their symptoms are improving compared with their relative exposure. A clinician must be willing to consider recommending a job change (eg, modified or restricted duty) to the employer. At that point, referral to appropriate specialists may be indicated.

  • Antidepressant medication, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, have been helpful for managing the alterations of mood that may be part of the syndrome, as well as for reducing pain in patients with symptoms of peripheral neuropathy.

  • Psychological counseling, brain rehabilitation, and physical and occupational therapy may be appropriate.


The patient may be referred to an internist, occupational medicine specialist, ophthalmologist, neuropsychologist, neuromuscular or behavioral neurologist, or other specialists depending on the specifics of the case.



Medication Summary

Many classes of medications may be appropriate for patients exposed to organic solvents. The selection is case specific. Antianxiety medication in the form of benzodiazepines, tricyclic antidepressants, and SSRIs, as well as other categories of pharmaceuticals, may be appropriate.



Further Outpatient Care

See the list below:

  • Examinations and neurophysiologic and neuropsychological testing should be repeated 9 months to 1 year after the exposure is reduced or ceased.

  • Neuropsychological testing results generally stay the same or improve with time, though some authors (eg, Seppalainen) have reported that a substantial percentage worsen over time.


See the list below:

  • Exposure is prevented with appropriate use of PPE for those who work with organic solvents.

    • Industrial hygienists are vital members of any company occupational health and safety department.

    • Engineering controls are further steps that can be taken to decrease exposure. Choosing a less-toxic chemical as an alternative to in process, increasing ventilation, and adjusting shifts so that workers are exposed to toxins for less time than before are some engineering controls.

  • Environmental exposure may be reduced by means of community education, which may lead to local, state, and national regulation and increased policing. Education may also improve epidemiologic research, which may prove or disprove the relationship between exposure to a solvent and health consequences.