Organic Solvent Neurotoxicity Clinical Presentation

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  more...
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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.