eMedicine Specialties > Neurology > Neurotoxicology

Organic Solvents: Differential Diagnoses & Workup

Author: Jonathan S Rutchik, MD, MPH, Assistant Professor, Department of Occupational and Environmental Medicine, University of California at San Francisco
Contributor Information and Disclosures

Updated: Nov 9, 2009

Differential Diagnoses

Other Problems to Be Considered

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

Workup

Laboratory Studies

• Laboratory tests: 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 eMedicine journal. To confirm exposure to an organic solvent, monitoring of the biologic exposure index (BEI) may yield valuable information.
• Safe exposure levels: 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.¹ 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

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^* 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.⁶⁰
• 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

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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.
  • 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.²
    • 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.²⁶
  • 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.²²
    • 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.⁶
    • 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.²⁵
  • 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.
  • SPECT was used to evaluate chronic occupational exposure.¹¹ 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.⁶⁸ , 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.³⁹
  • 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.¹⁴
  • 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.⁴⁰
  • 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.²⁰ 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.²²
  • 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.⁴⁹
  • 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.⁶⁷
• 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.²²
  • 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.
  • 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.⁸³ In 1983, Karai et al used fluorescein angiography to further evaluate populations from the viscose-rayon industry.⁴²
  • 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.
• 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.⁴⁵
  • 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.³²
  • Findings from few brain pathology specimens of patients with organic solvent exposure have been reported.

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