Toxic Neuropathy

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Practice Essentials

Toxic neuropathy refers to neuropathy caused by drug ingestion, drug or chemical abuse, or industrial chemical exposure from the workplace or the environment. Distal axonopathy, causing dying-back axonal degeneration, is the most common form.

Signs and symptoms

Patients with neuropathy typically present with symptoms of pain, tingling, or numbness in their feet, consistent with dysfunction affecting the longest and largest fibers of the peripheral nervous system (PNS). Other manifestations of neurologic dysfunction that may be present include the following:

During physical examination, the following symptoms of polyneuropathy may be found:

Central nervous system (CNS) disease can manifest as follows:

The following examples list the neuropathic signs and symptoms associated with specific toxins:

See Clinical Presentation for more detail.

Diagnosis

Take a thorough medical history, including the patient’s occupational and environmental history, to consider all sources of exposure to all possible agents. List details of all jobs and specific tasks within these jobs, as well as when various symptoms and medical problems began for the patient.

Quantitative sensory testing in the diagnosis of neuropathy includes the following:

Other studies that help to prove the presence of neuropathy include the following:

Laboratory studies in patients with neuropathy can include the following:

See Workup for more detail.

Management

In addition to advising the patient to avoid the causative drug or occupational or environmental toxin, management of toxic neuropathy can include the following:

Consistent follow-up care with a neurologist is necessary to monitor the progress of neurologic findings. Follow-up with an occupational medicine specialist may be important to assist with return to work and reduction of exposure.

See Treatment for more detail.

Background

Lewis P. Rowland, in Merritt's Textbook of Neurology, defines the terms peripheral neuropathy and polyneuropathy as describing "the clinical syndrome of weakness, sensory loss and impairment of reflexes caused by diffuse lesions of peripheral nerves." The diagnosis most often is based on the clinical picture and is confirmed with electrodiagnostic techniques, most commonly electromyography (EMG) and nerve conduction studies. Facial nerve and blink reflex testing also are used commonly. Apparatuses, such as the neurometer, vibrometer, and sensory nerve perception threshold-testing device, often are used in research settings or to evaluate clusters of patients.

Patients with toxic etiologies for neuropathy are less common than patients with other neuropathies such as those due to hereditary, metabolic, or inflammatory causes. Drug-related neuropathies are among the most common toxic neuropathies. Neuropathies from industrial agents (either from occupational or environmental sources), presenting after either limited or long-term exposure, are insidious. Patients may present with subtle pain or weakness. Subclinical abnormalities found on electrodiagnostic testing may herald a progressive neuropathy if exposure continues at a similar dose. Attributing neuropathy to such an exposure often is difficult. In some patients, extensive search for an etiology may fail to uncover the exact cause of neuropathy.

Many chemicals are known to cause neuropathy in laboratory animals. Some of these have been associated with neuropathy in clinical epidemiologic studies, confirming their ability to injure the human peripheral nervous system (PNS). Other chemicals have been reported to be associated with PNS dysfunction and neuropathy on the basis of retrospective and cross-sectional epidemiologic studies. Designs for many of these studies have been criticized. Other associations have been made from many case reports and case series.

Human studies infrequently have associated exposure to environmental sources with peripheral neuropathy. As compared to nonexposed controls, exposed individuals have statistically significant differences in nerve conduction velocity (NCV) and EMG findings. Exposures have been estimated for duration and intensity based on point source extrapolation, a common method of environmental risk assessment. When reviewing the literature, a critical analysis of study designs and electrodiagnostic techniques is important.

An algorithm to assess patients with suspected neurotoxic illness is detailed in Medical/Legal Pitfalls. It describes occupational and environmental history as an important aspect of the medical history. In cases of positive occupational or environmental exposure, estimating dose and duration of exposure and level of protection afforded by personal protective equipment is emphasized. Government and professional organizations publish exposure limits for workers using various chemicals. Physicians may use this information to compare with industrial hygiene data. These are outlined in Table 1.

Table 1. Exposure Limits, Common Organic Solvents and Metals


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Utilizing neurophysiologic testing, neuropsychological testing, and neuroimaging to support a clinical suspicion is encouraged. When the exposure has ended, retesting also is appropriate after a period of time. Perform biological testing of serum and urine to assess absorbed dose. Values have been published for these data. These are outlined in Table 2.

Table 2. Agency for Toxic Substances and Disease Registry Biological Exposure Indices


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Use of the medical literature to associate an agent with an abnormality is important. Ascertain existence of supporting evidence that suggests exposure at a specific dose and duration that can cause such dysfunction and whether animal data are helpful to extrapolate an estimated dose that may lead to a health effect in humans.

Pathophysiology

Neuropathy may be categorized by presentation (ie, motor or sensory symptoms), electrodiagnostic features, and neuroanatomical location within the peripheral nerve (ie, demyelinating or axonal, neuronopathy, ion channel neuropathy, neuromuscular transmission) or location (ie, cranial or peripheral). Toxic neuropathy refers to those presentations that are caused by drug ingestion, drug or chemical abuse, or industrial chemical exposure from the workplace or from the environment.

Kimura mentions that these may be divided into the following 3 groups based on the presumed site of cellular involvement:

Although distal axonopathy is the most common form, a few agents have been associated with the first 2 types. Antibiotic treatment or cisplatin or pyridoxine toxicity may cause sensory neuronopathy, and segmental demyelination may result from the cardiac medications perhexiline or amiodarone, tetanus toxoid or diphtheria toxin administration, or exposure to lead or arsenic.[1, 2]

Other types of neuropathy, such as sodium channel, neuromuscular transmission, or cranial neuropathies, also have toxic etiologies.

In North America, sodium channel dysfunction may be the result of ciguatera toxin from reef fish or saxitoxin from shellfish. This often presents as an acute or subacute illness. Puffer fish may be intoxicated with tetrodotoxin in Japan. Neuromuscular transmission dysfunction is associated most commonly with organophosphate intoxication; however, envenomation from snake bites or botulism may be as serious a culprit. Cranial neuropathies affecting isolated nerves are uncommon. Trichloroethylene (TCE) has been associated with trigeminal neuropathy, and ethylene glycol may affect the facial nerve. The existence of these syndromes has been revealed by facial nerve and blink electrophysiologic studies (see Causes).

Frequency

United States

In one study, 76% of 205 patients who presented with undiagnosed neuropathy had neuropathies that were classifiable. Thus, about 25% of all neuropathies have an unknown etiology. Environmental and occupational exposure may play a role in some of these undiagnosed neuropathies.

History

Patients with neuropathy typically present with symptoms of pain, tingling, or numbness in their feet, consistent with dysfunction affecting the longest and largest fibers of the PNS. In some cases, they may have weakness (distal more than proximal) or difficulty with gait. In other cases, patients may also present with symptoms of pain. This may suggest a small fiber neuropathy, which exists when small myelinated and unmyelinated fibers are involved. Clinically, pain may be accompanied by restless leg syndrome, a condition in which disagreeable leg sensations and an irresistible urge to move occur prior to sleep onset.

Additionally, other forms of autonomic dysfunction may be present such as hypohidrosis or hyperhidrosis, diarrhea or constipation, urinary incontinence or retention, gastroparesis, sicca syndrome, blurry vision, facial flushes, orthostatic intolerance, or sexual dysfunction. Autonomic dysfunction may present as cramping. In these cases, the examination reveals normal proprioception, vibration, power or bulk, reflexes, and normal findings on electromyography (EMG) or nerve conduction studies (NCS).[3]

The clinician needs to exercise a high index of suspicion to uncover toxic etiologies. A patient beginning a new medication in the last few weeks or months should raise a red flag. Certainly, the search for an underlying chronic disease is the most common workup ordered; however, new medications are commonly a culprit.

Toxic neuropathy due to recreational drug or chemical abuse may be more difficult to uncover than occupational or environmental exposures, since direct questioning of the patient may lead to incorrect information. In some cases, a dramatic systemic reaction leads to an emergency department (ED) visit because of an acute alteration of consciousness, heralding the diagnosis of drug abuse. The challenge for the ED clinician at this point is to uncover the agent of ingestion or inhalation. Neuropathy, in these cases, may present over a few days to weeks since the dose is often higher than in prescribed-medication settings.

Occupationally induced neuropathies may be secondary to low-level, long-term exposures. The differential diagnosis may not include a work-related exposure, since physicians often are not trained to ask questions about patients' work practices or environment. The presentation may coincide with other lifestyle and medication changes and recent medical diagnoses. After a high-level acute exposure, an occupational etiology for toxic neuropathy may be easier to consider.

Environmental exposure–induced neuropathies follow the same pattern as those from occupational exposures; however, they are omitted even more commonly from the differential diagnosis. For example, a physician is even less likely to ask questions about the patient's use of groundwater, proximity to pesticides, or household use of organic solvents than about occupational exposures. As with occupational exposure, environmental exposures often are very low level, but they are long term and more intensive than occupational exposures, lasting longer than a 40-hour workweek for the duration of employment. Patients who have had high-concentration acute exposure from an environmental accident may present with more obvious clinical symptoms. A differential diagnosis ruling out more common causes of neuropathy is mandatory to establish the cause of neuropathy.[4, 5]

Prior to appearance of symptoms, subclinical findings on EMG or NCV studies may be apparent and consistent with axonal or demyelinating abnormalities. Occupational or environmental exposure at doses approaching regulatory levels for duration or intensity may warrant such an evaluation. Often these are performed in field studies with the use of portable apparatus. Dysfunction associated with environmental exposure to TCE, mainly subclinical, is revealed by electrodiagnostic techniques.

Pain or numbness in the distribution of the trigeminal nerve suggests a disorder of that nerve.

Physical

Kimura, in Electrodiagnosis in Diseases of Nerve and Muscle, notes that polyneuropathy presents clinically as a "triad of sensory changes in a glove and stocking distribution, distal weakness, and hyporeflexia." The sensory changes include sensory loss in a stocking-glove distribution. Often, progression is distal to proximal. This is consistent with the commencement of axonal degeneration. Early loss of symmetrical ankle jerk is noted. In severe cases, motor dysfunction such as abnormal gait and foot drop also may occur. In some patients with exclusively small fiber neuropathy, the motor and reflexes examination may be normal.

Spencer and Schaumberg emphasized a gradual insidious onset, as well as slow recovery. Recovery proceeds at a rate of 2 mm/day and may take months or several years, or may never be complete. Function is restored in reverse order to the sequence of loss. Coasting may be noted, that is, intensification may occur for weeks before improvement. This often reflects continued axonal degeneration and reconstitution.

Signs of CNS disease also may be present at examination. This occurs in some patients recovering from certain toxic neuropathies. Dorsal column or corticospinal tract degeneration may be present. These clinical signs of degeneration are not prominent early in the illness; however, the patient may manifest hyperreflexia, Babinski responses, and stiff-leg ataxic gait with corticospinal tract disease or diffusely decreased proprioceptive and vibratory sensations and gait ataxia with dorsal column degeneration.

Involvement of the autonomic nerves may lead to a different clinical presentation–miosis, anhydrosis, orthostatic hypotension, sphincter symptoms, impotence, and vasomotor abnormalities. These may occur with or without evidence of a peripheral neuropathy. Tachycardia, rapid alterations in blood pressure, flushing and sweating, and abnormalities in gastrointestinal motility may be present.

Spencer and Schaumberg reported the association of sensory ganglion cell loss in pyridoxine-associated sensory neuropathy with 9 clinical features; they are as follows:

Causes

A variety of drugs and industrial chemicals cause distal axonopathy. In 1989, Kimura listed the following as potential causes of toxic neuropathy[6, 7] :

In August 2013, the US Food and Drug Administration (FDA) announced that oral or injected fluoroquinolone antibiotics can cause permanent peripheral neuropathy and that labels on the drugs will be updated to reflect this finding. (Topical fluoroquinolones have not been associated with this condition.)[8, 9]

The change strengthens the FDA’s previous warning, first added to fluoroquinolone labels in 2004, that oral and injectable fluoroquinolones carry a risk of peripheral neuropathy. The 6 FDA-approved fluoroquinolone antibiotics on the market are ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin.[8, 9]

Industrial chemicals causing toxic axonal neuropathy also are listed by Kimura; they include the following[6, 7] :

In 1999, Feldman added the heavy metals arsenic and lead, as well as the solvents n -hexane, perchloroethylene (PERC), and TCE to this list.[10] In 1995, Albers and Bromberg summarized the literature on toxic neuropathy caused by the solvents ethylene oxide (EtO), styrene, toluene, and mixed solvents.[11]

Spencer and Schaumberg listed agents that commonly are associated with peripheral neuropathy (see Table 2 in Schaumberg, 2000[12] ).

Toxic neuropathy may be the result of exposure to numerous agents and is related to dose and duration of exposures and to host factors. Most syndromes are subacute, progressing to chronic as already described. Chemicals such as thallium, dimethylaminopropionitrile (DMAP), and organophosphates (eg, parathion) produce specific syndromes associated with peripheral neuropathy; however, all of these may lead to systemic abnormalities as well.

Thallium is used in glass and in metal alloys. It had been used therapeutically to treat venereal disease, tuberculosis, and ringworm. It has also been used as a rodenticide. Accidental or homicidal abuse is a common reason for toxicity.

Acute thallium intoxication leads to pain and paresthesias in the distal extremities followed by weakness and eventual atrophy. Preservation of peripheral reflexes is a useful physical finding to differentiate thallium toxicity from Guillain-Barré syndrome. Alopecia is a clinical hallmark of thallium toxicity that may develop weeks after intoxication. Mee lines, nephropathy, anemia, and hepatotoxicity are systemic manifestations. Autonomic dysfunction also may be a part of the clinical syndrome. Thallium toxicity may be mistaken for porphyria, arsenic toxicity, or botulism. Serum thallium levels typically are elevated.

DMAP is used as a catalyst in the manufacture of polyurethane foam and in an acrylamide grouting compound. It is used as a waterproofing agent in tunnels and sewer lines. Industrial exposure has led to prominent urinary and sexual dysfunction as well as to distal sensory neuropathy.

Alcohol, by itself, is toxic to the PNS. Individuals who consume alcohol also may become nutritionally compromised. Studies have found that alcohol impairs axonal transport and that this can occur in the setting of normal nutrition. Since it may affect both the cerebellum and the autonomic nervous system, ataxia and other systemic symptoms may accompany symptoms of dysesthesia and weakness of the lower extremities. In the patient with occupational exposure to other peripheral neurotoxic agents, alcohol may act either to slow metabolism and increase toxicity or, in the case of a habitual alcohol user, promote metabolism and reduce toxicity from the agent. This is observed most clearly with toluene exposure.

A number of studies have attempted to address the type of neuropathy that occurs with alcohol exposure, as well as what amount of exposure is required before neuropathy occurs. A sensorimotor axonopathy with secondary demyelination that was not necessarily related to a deficit in thiamine was described by Mellion et al in 2011.[13] Ten ounces of whiskey per day in a 70-kg man for several years was mentioned to cause alcohol neuropathy.[14] Three liters of beer per day for 3 years was described as another threshold.[15] Wine in combination with other forms of ethanol was deemed worse, possibly due to impurities with lead.[16]

Other organic solvents have been associated with peripheral neuropathy on the basis of cross-sectional studies and animal data. Prospective data are unavailable. Solvent mixtures have been noted to be responsible for toxic neuropathies in many studies. Identifying the culpable agent has been difficult. Often, no chemical with a clear association with neuropathy is listed, suggesting that organic solvents themselves, either in mixture or individually, may cause neuropathy. Studies that have found subclinical abnormalities further support this hypothesis.

Often, study designs have been criticized for their definition of neuropathy. NCV and EMG findings in many of these studies are difficult to categorize. To ascertain whether a toxic etiology is a possibility for a patient, a clinician may need to search the literature for the agent as well as the industry. Many agents are used in many different industries. The industrial agents and some of the industries that utilize them are listed in Table 3. For information on toxic neuropathy caused by organophosphates, refer to the article Organophosphates.

Carbon disulfide and peripheral neuropathy

Carbon disulfide is an agent used in the viscose rayon industry. Refer to Table 3 for its other uses.

Carbon disulfide has been deemed a peripheral neurotoxin in both animals and humans by the Agency for Toxic Substances and Disease Registry (ATSDR). Consistency has been established for effect (ie, neurophysiological impairment and pathologic changes) but not for dose. The pathophysiology for toxic neuropathy is an axonal neuropathy in a distal dying back pattern. Reduced or absent sensory nerve action potentials (SNAPs) are common. Conduction velocities are usually normal, but they may be borderline low owing to selective involvement of large fibers. Metabolic abnormalities from coexisting diseases may be associated with reduced conduction velocities and may contribute to electrophysiologic abnormalities.

In humans, neurophysiological effects have been demonstrated at low levels of occupational exposure. In 1974, Seppalainen and Tolonen demonstrated a decrease in maximal motor NCV in the median, ulnar, peroneal, and posterior tibial nerves in 118 viscose rayon workers who had exposure to an average of 10-20 parts per million (ppm) of carbon disulfide for an average of 15 years. No improvement was noted after removal from exposure, but a follow-up study by these authors demonstrated that fewer workers who had retired 10-15 years prior had decreased NCVs than those who had been removed from their work 0-4 years prior to the study. (These abnormalities were in workers who had no subjective complaints.)[17]

In 1990 and 1993, Ruitjen et al demonstrated that 44 viscose rayon workers exposed to 1-30 ppm of carbon disulfide for at least 10 years had somewhat slower slow motor fiber conduction velocities than 31 controls, based on the antidromic collision technique. Symptoms of clinical neuropathy related to cumulative exposures were absent in the patients in this study. This study revealed that a decrease in the conduction velocity occurs at low levels of exposure to carbon disulfide. Extrapolation of these results suggests that small effects may occur after a mean cumulative exposure of 165 ppm-years, which would be equivalent to a concentration of 4 ppm over an 8-hour time-weighted average (TWA). At this exposure level over a lifetime of employment, the observed effects would be expected.

The authors explained that the significance of these effects on health would be that these observed changes might reduce reserve capacity to cope with other noxious influences. They concluded that these changes are undesirable until they are shown to be not detrimental to health in the long term.

The second study to verify these findings reexamined these workers 4 years later and found a statistically significant decrease in velocities in the slow as well as the fast motor nerve fibers of the peroneal nerve. Weighted cumulative exposures correlated less well with the peripheral nerve indices and revealed no evidence that the effects were reversible. The authors reiterated their concerns for the neurotoxic effects of carbon disulfide at these exposure levels.[18, 19]

In 1983, Johnson et al examined 189 workers from a viscose rayon plant; 245 workers in polyester-nylon filament and staple plants were used as controls.[20] Confounding exposures were hydrogen sulfide, tin oxide, zinc oxide and sulfate, sodium hydroxide, and sulfuric acid. At no point in time did hydrogen sulfide levels exceed 1 ppm.

Carbon disulfide exposure was divided into high (median >7.1 ppm), medium (median 3-7.1 ppm), and low (median < 3 ppm). Exclusion criteria were alcohol consumption >35 U, blood glucose >110 mg/dL, or blood lead >40 mcg/L. Mean duration of exposure for all exposed subjects was 12.1 years; for the high-exposure group it was 13.6 years; for the medium-exposure group it was 12.3 years; and for the low-exposure group it was 10.5 years. The average age of exposed individuals was 38.5 years and of controls, 33.9 years.

The study assessed NCV of motor (ie, peroneal, ulnar) and sensory (ie, sural) nerves. A reduction in peroneal nerve mean conduction velocity (MCV) was found to be related, in a dose-response sense, to cumulative exposure to carbon disulfide.

Ethylene oxide and peripheral neuropathy

EtO is a sterilizing agent with an epoxide structure often used in hospital settings. Refer to Table 3 to review other industrial uses of EtO. Symptoms suggestive of neuropathy, such as numbness and weakness of extremities, leg cramps, and gait difficulties, are reported mostly after long-term EtO exposures. In 1979, Gross et al reported 4 cases of peripheral neuropathy caused by EtO resulting from a large EtO sterilizer leak that was not noticed for 2 months.[21] These patients were working as sterilizer operators and had exposures of 3 weeks to 8 years. One operator was asymptomatic; 3 had headaches; and 2 developed fatigue, numbness, and muscle weakness in the extremities. In 1983, 5 of 6 sterilizer operators of a factory producing medical appliances were poisoned by EtO gas.

In 1986, Fukushima et al examined 4 operators who had exposures to the chemical ranging in duration from 20 days to 8 months. Gait disturbance was noted in all 4 operators. All 4 complained of numbness and muscle weakness in the feet and numbness of the fingers. Two operators had pain in the calf muscles and 3 had muscle weakness of the fingers. A 23-year-old man had been exposed 2-3 times a day for 5 months to high levels of EtO, up to 500 ppm, while working in a food and medical supply sterilization factory prior to his admission to a hospital. He complained of increasing weakness in his lower extremities.[22]

Schroder and Kuzuhara reported 2 patients with long-term EtO exposure. Both had difficulty in walking. One had been an operator of a sterilizer for 3 months before noting paresthesias and weakness in the distal limbs with staggering. After he returned to work, his symptoms worsened, and 3 months later he was admitted to a local hospital. His symptoms cleared entirely after 2 months. The second patient noted paresthesias in his feet 6 months after he had started to load and unload the sterilizers with medical supplies. Staggering followed the numbness and tingling of both hands and feet. Symptoms cleared 1 month later.[23, 24]

Finelli et al reported another case series of 3 males with toxicity from EtO. Two of these had been operators of sterilizers. One worked for a year and the other worked part-time for 1.5 years before developing symptoms. Both had difficulties with their gait after developing numbness and weakness in their lower extremities. One operator reported numbness in his feet and buckling of his right leg, and the other complained of cramps in his calf muscles. Both reported an odor; the part-time operator also reported headaches, burning eyes, and nausea.[25]

The third patient worked for 6 days a week at a plastic manufacturing company, where several times a day he worked in a sterilizing tank for about 40 minutes; he also unloaded materials in a decontamination area for half an hour each day. His chief complaints were leg cramps and a sense of heaviness of the feet. He first noted difficulty with sleeping, nervousness, and cramps in his hands and calf muscles. One month later, he noted poor balance and repeated stumbling. He also was aware of odd tingling sensations in both feet that had been present for longer than 3 months.

Two women workers developed symptoms referred to the PNS after chronic EtO exposure. Both had been part of a group of 12 sterilizer workers in a hospital in Italy who were tested 2 years after the commencement of this exposure. Four of these 12 women complained of paresthesias and fatigue. Two were found to have peripheral neuropathy. Complete remission of these symptoms was reported for most of these women approximately 6 months after removal from exposure.

Mercury (inorganic and organic) and peripheral neuropathy

Inorganic mercury is used in the chloralkali industry. Other uses are noted in Table 3. Neuropathy and PNS dysfunction, often motor more than sensory, were noted in the cases summarized here.

Albers et al reported 138 chloralkali plant workers with long-term exposure to inorganic mercury vapor who were found to have elevated urine mercury levels and reduced sensation on quantitative testing. Subjects exposed to mercury for 20-35 years who had urine mercury levels greater than 0.6 mg/L demonstrated significantly less strength, poorer coordination, more severe tremor, more impaired sensation, and higher prevalence of Babinski and snout reflexes than controls. Subjects with polyneuropathy had higher peak levels of mercury than healthy subjects.[11]

In another study by Andersen et al, chloralkali workers exposed to inorganic mercury vapor for an average of 12.3 years revealed a higher prevalence of reduced distal sensation, postural tremor, and impaired coordination than controls.[26] Barber reported 2 employees of a chloralkali plant who had findings suggestive of amyotrophic lateral sclerosis (ALS). Signs, symptoms, and laboratory findings returned to normal 3 months after withdrawal from exposure.[27] Adams et al reported a 54-year-old man with a brief but intense exposure to mercury vapor, which led to a syndrome resembling ALS that resolved as urinary mercury levels fell.[28] Ross reported that prolonged application of an ammoniated ointment to the skin was a cause of motor polyneuropathy, with cerebrospinal fluid (CSF) findings suggestive of Guillain-Barré syndrome.[29]

Warkany and Hubbard reported the association of acrodynia and symmetrical flaccid paralysis with mercury toxicity.[30]

Organic mercury was deemed the culprit in a number of historic environmental accidents. One noted catastrophe, reported by Yoshida et al, occurred in Minimata Bay, Japan, and involved organic mercury. The majority of Minimata patients with methylmercury intoxication had elevated pain thresholds but suffered from glove and stocking hyperesthesia in the extremities.[31]

Lead and neuropathy

A review of the literature reported that acute, high-level lead exposure has been described to cause motor neuropathy with minimal sensory involvement and rarely the textbook-described wrist drop. Chronic, lower-level exposures lead to axonal dying back neuropathies that appear similar to neuropathies from diabetes or alcohol. Chronic exposures, depending on the length of exposure, may have poorer prognoses but may present with a slower and more gradual onset. High–level, acute exposures are more likely to cause motor neuropathies, and recovery may be complete if termination of exposure is prompt. Because neuropathies have not seemed to correlate with blood lead levels, interference with porphyrin metabolism has been proposed as the etiology.[32]

Xylene and neuropathy

Xylene often is a component of paints and other industrial processes (see Table 3 for other uses of xylene). A literature search using Medline uncovered 11 epidemiologic studies of painters or other subjects with occupational exposure to organic solvents, including xylene, that found positive associations between exposure and PNS dysfunction. Two studies reported that vibration sensation was significantly less acute in 102 painters than in 102 age- and sex-matched controls. Four studies utilized quantitative sensory test (QST) methods.

In 1991, Bleecker found a correlation between increasing exposure dose and elevated vibration sensation thresholds in 187 workers from 2 paint-manufacturing plants.[33] A second study noted higher vibration thresholds in 80 exposed painters than in controls.[34] Demers et al noted statistically significant differences in vibrotactile measurements by QST of upper and lower extremities between 28 painters and 20 nonexposed controls.[35] In 1989, Bove et al compared 93 painters to a nonexposed control population of 105 construction workers.[36] Subjects were tested by 2 QST devices, a vibrometer and a temperature sensitivity tester. Painters had significantly higher temperature sensation thresholds, and exposure intensity and cumulative exposure over the past month and year were associated positively with vibration thresholds.

In 1989, Padilla et al performed an important animal study in which axonal transport was noted to be decreased by 30-50% in the rat optic nerve system immediately and 13 hours after inhalation exposure to xylene. Exposure was subacute; 800 and 1600 ppm for 6 hours/day, 5 days a week for 8 days led to these abnormalities. The authors concluded that the decreased supply of cellular materials to the axon and nerve-ending regions could initiate the neuronal malfunction reported in solvent-exposed animals and humans.[37] As axonal transport is a process common to all nerves, any perturbation in these processes may disrupt the structure and functional integrity of the neuron. This mechanism has been used to explain both the CNS and PNS toxicity from organic solvents.

Seven men aged 17-22 years developed severe distal symmetrical polyneuropathy after repeatedly inhaling a commercially available brand of lacquer thinner that was composed predominantly of xylene. All 7 were disabled permanently with motor weakness. One man died, 3 remained wheelchair bound, and 3 could walk but demonstrated varying degrees of weakness. Pathologic specimens revealed evidence of peripheral neuropathy.

Perchloroethylene and neuropathy

PERC is an agent used in the dry-cleaning industry. Its various other uses are listed in Table 3. Peripheral neuropathy is a clinical diagnosis that is listed as secondary to chronic PERC exposure by Feldman.[38, 39] Neither article refers to specific study results. Spencer and Schaumberg list neuropathy with a question mark as an effect of tetrachloroethylene (ie, perchloroethylene) toxicity. This article refers to 2 articles by Antti-Poika and Juntunen et al that reported sensory trigeminal (fifth cranial nerve) defects in those exposed to mixed solvents. A 1978 National Institute for Occupational Safety and Health (NIOSH) publication on PERC remarked that "various disturbances of the peripheral nervous system such as tremors and numbness have also been associated with exposure to tetrachloroethylene."

Juntunen et al studied 87 patients from Finland diagnosed as having chronic intoxication caused by exposure to a mixture of solvents or to TCE and PERC between 1970 and 1974. Of these, 14 had been exposed to TCE or PERC alone, 53 to solvent mixtures, and 13 to all of them. Disturbances of cutaneous sensation and the sense of vibration were encountered frequently as clinical signs.[40]

The Antti-Poika article of the same year (1982) discussed the EMG findings of this same group. Electroneuromyography ([ENMG], including NCV and EMG) revealed 64 patients with signs positive for PNS disease and 34 patients with subjective symptoms. Signs of polyneuropathy were reported in 13 subjects. In the discussion, the author remarked that the number of patients with clinical polyneuropathy was so small that a trend could not be evaluated definitively.[41]

A publication the following year (1983) by Seppalainen and Antti-Poika categorized the specific ENMG findings of each of the 3 groups in the previously mentioned 2 studies. Of 18 patients in the group exposed to either TCE or PERC alone, 9 (50%) were deemed to have neuropathy on the first ENMG examination. On the second ENMG, 15 of 21 (71%) patients had this diagnosis. For those exposed to TCE or PERC or a mixture, 10 of 11 (91%) patients and 11 of 13 (85%) patients had this diagnosis, as opposed to 26 of 44 (59%) and then 38 of 53 (72%) of those exposed only to a mixture excluding chlorinated hydrocarbons (ie, TCE or PERC). The authors concluded that those patients with exposure to a mixture of solvents and to TCE or PERC tended to have neuropathic findings more often than patients exposed to either TCE or PERC alone or to a solvent mixture that did not include TCE or PERC. Findings on ENMG in these patients suggested axonal changes rather than segmental demyelination.[42]

One toxicology text remarked that neuropathy may present following solvent exposures because the solvent (ie, PERC) often is mixed with amines, epoxides, and esters to protect it from moisture and light. Some of these compounds are known to cause neuropathy. Two European articles report PERC as being associated with neuropathy. In 1989, Herruzo-Perez et al described one case in which the authors suspected that a sensitive painful polyneuropathy probably was caused by poisoning with PERC.[43] In 1989, Muller et al found slight derangements in neural functions in 130 dry-cleaning workers with long-term exposure to PERC during a 5-year follow-up study.

Baker reported in a review from 1994 that recent studies suggested that mild subclinical disruption of PNS function does occur in workers exposed to solvent mixtures.[44] In 1988, Orbaek et al studied patients with long-term exposures to organic solvents and found evidence of PNS dysfunction and slowing of the median nerve that was more pronounced in follow-up testing 22-72 months later. Slowing in the peroneal nerve was observed only at the follow-up NCV examination. Sensory conduction studies showed substantially reduced amplitudes in median and sural nerves with a prolongation of the distal latency in comparison with a control group; sensory conduction velocity in the median nerve also was slowed in the follow-up examination.[45]

Whether this and other studies of mixed organic solvent exposures suggesting neuropathy with various neurophysiological tests can implicate PERC is not clear, since PERC, its metabolites, or chemicals of similar structure may or may not have been a component of the solvent mixture. Maizlish et al refer to chlorinated aliphatic and chlorinated hydrocarbon solvents as components of paint vehicles and glues to which their subject population was exposed[46] ; other authors do not specify the composition of the substances to which their subjects were exposed.

Trichloroethylene and neuropathy

TCE is used as degreaser in many industrial processes (refer to Table 3 above to review its other industrial uses). Bernad et al evaluated 22 persons in a cohort of Michigan residents exposed for 5-20 years to well water with a low level of TCE contamination; 8-14 ppm of TCE was measured in the well water. Questionnaire, examination, and computer current perception-threshold testing (CPT) was performed. Results revealed hyperesthesia in 21 of 22 persons by CPT. Fatigue, lack of energy, somnolence, numbness, and tingling were reported by all 10 adults.

Feldman et al evaluated 21 residents of a Massachusetts community with alleged long-term exposure to TCE through drinking water and laboratory controls. The wells in question had 256 and 111 parts per billion (ppb) mean concentrations of TCE (maximum contaminant level [MCL] recommended by the Environment Protection Agency [EPA] is 0.5 ppb) and 26 and 24 ppb mean concentrations of PERC; duration of exposures was less than 1 to 12 years. Blink reflexes revealed differences in conduction latency of the reflex for the exposed population versus the controls, suggesting a subclinical alteration in the function of the fifth cranial nerve.[47]

In 1994, Feldman et al published a study that compared this population to 2 other populations that had been exposed to environments contaminated with TCE and PERC and included more details of the population's neurologic examinations. The Massachusetts group was found to have sensory impairment and reflex abnormalities as evidence of peripheral neuropathy.

The second group was 12 residents from an Ohio community who had been exposed to well water contaminated by wastewater deposited in a nearby creek by a company that fabricated sheet metal and precision-formed metal tubes. Their exposure was 3.3-330 ppb of TCE for 5-17 years. PERC also was found in the contaminated water. Nerve conduction studies (including blink reflexes) were performed. Reflex abnormalities were the most prevalent examination finding. Abnormal ulnar sensory latencies were noted in 81% of the group.

The third group comprised 14 residents from a Minnesota community who had been exposed to well water contaminated by a nearby army ammunitions plant. Exposure to TCE was between 261 and 2440 ppb in wells. 1,1-dichloroethane (DCE), 1,2-DCE, and 1,2-trans -DCE were identified in some wells. Questionnaires, examinations, and nerve conduction studies (including blink reflexes) were performed. Reflex abnormalities were the most common finding on neurologic examination. Approximately 70.6% had abnormal ulnar sensory latency, while 21% had abnormal blink reflex studies.[47]

Table 3. Industrial Uses of Common Organic Solvents and Metals


View Table

See Table

Laboratory Studies

Table 4. Differential Diagnosis of Peripheral Neuropathy With Selective Lab Testing (Recommended lab tests in bold.)


View Table

See Table

Table 5. Neuropathies With Unusual Features


View Table

See Table

Other Tests

Table 6. Industrial Agents and Pharmaceuticals Associated With Peripheral Neuropathy


View Table

See Table

Histologic Findings

Muscle and nerve pathology findings associated with ethylene oxide or mercury exposure include the following:

Medical Care

Consultations

Diet

Although diet does not play a specific role in reparation of the PNS, a balanced diet is important for various reasons related to general health. Since various B vitamins have been implicated in the development of neuropathies, some physicians suggest supplementation.

Further Outpatient Care

Prognosis

Each patient's prognosis depends on the severity of the neuropathy when exposure is ceased or reduced to levels that will not affect health negatively.

Author

Jonathan S Rutchik, MD, MPH, Associate Clinical Professor, Division of Occupational Medicine, Department of Medicine, University of California, San Francisco, School of Medicine; Neurology, Environmental and Occupational Medicine Associates (www.neoma.com)

Disclosure: Nothing to disclose.

Specialty Editors

Milind J Kothari, DO, Professor, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Amgen Grant/research funds None

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Consulting; Sunovion Consulting fee None; Supernus Speaking, consulting; Upsher-Smith Grant/research funds None

Chief Editor

Tarakad S Ramachandran, MBBS, FRCP(C), FACP, FRCP, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Boeringer-Ingelheim Honoraria Speaking and teaching

References

  1. Barton A, McLean B. An unusual case of peripheral neuropathy possibly due to arsenic toxicity secondary to excessive intake of dietary supplements. Ann Clin Biochem. May 29 2013;[View Abstract]
  2. Liu J, Chen B, Lu Y, Guan Y, Chen F. JNK-dependent Stat3 phosphorylation contributes to Akt activation in response to arsenic exposure. Toxicol Sci. Oct 2012;129(2):363-71. [View Abstract]
  3. Hoitsma E, Reulen JP, de Baets M, et al. Small fiber neuropathy: a common and important clinical disorder. J Neurol Sci. Dec 15 2004;227(1):119-30. [View Abstract]
  4. Vegosen L, Davis MF, Silbergeld E, Breysse PN, Agnew J, Gray G, et al. Neurologic symptoms associated with cattle farming in the agricultural health study. J Occup Environ Med. Oct 2012;54(10):1253-8. [View Abstract]
  5. Samukawa M, Ichihara G, Oka N, Kusunoki S. A case of severe neurotoxicity associated with exposure to 1-bromopropane, an alternative to ozone-depleting or global-warming solvents. Arch Intern Med. Sep 10 2012;172(16):1257-60. [View Abstract]
  6. Kimura J. Polyneuropathies. In: Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. 1989. 2nd ed. Philadelphia: FA Davis; 462-81.
  7. Kimura J. Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. 2nd ed. Philadelphia: FA Davis; 1989:149-162.
  8. Lowes R. FDA Strengthens Neuropathy Warning for Fluoroquinolones. Medscape Medical News. Aug 15 2013. Available at http://www.medscape.com/viewarticle/809520. Accessed August 20 2013.
  9. FDA. FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection. US Food and Drug Administration. Aug 15 2013. Available at http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm. Accessed August 20 2013.
  10. Feldman RG. Occupational and Environmental Neurotoxicology. Philadelphia: Lippincott-Raven; 1999.
  11. Albers J, Bromberg MB. Chemically induced toxic neuropathy. In: Rosenberg NL, ed. Occupational and Environmental Neurology. Boston: Butterworth-Heinemann; 1995:175-234.
  12. Schaumberg HH. Human neurotoxic disease. In: Spencer P, Schaumberg HH, eds. Experimental and Clinical Neurotoxicology. 2nd ed. New York: Oxford University Press; 2000.
  13. Mellion M, Gilchrist JM, de la Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic, or both?. Muscle Nerve. Mar 2011;43(3):309-16. [View Abstract]
  14. Monforte R, Estruch R, Valls-Solé J, Nicolás J, Villalta J, Urbano-Marquez A. Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Arch Neurol. Jan 1995;52(1):45-51. [View Abstract]
  15. Behse F, Buchthal F. Alcohol Neuropathy: Clinical, Electrophysiological and Biopsy Findings. Ann Neurol. 1977;2:95-110.
  16. Vittadini G, Buonocore M, Colli G, Terzi M, Fonte R, Biscaldi G. Alcoholic polyneuropathy: a clinical and epidemiological study. Alcohol Alcohol. Sep-Oct 2001;36(5):393-400. [View Abstract]
  17. Seppalainen AM, Tolonen E. Neurotoxicity of long term effects of carbon disulfide in the viscose rayon industry. Scand J Work Environ Health. 1974;1:145-153.
  18. Ruijten MW, Salle HJ, Verberk MM, Muijser H. Special nerve functions and colour discrimination in workers with long term low level exposure to carbon disulphide. Br J Ind Med. Sep 1990;47(9):589-95. [View Abstract]
  19. Ruijten MW, Salle HJ, Verberk MM. Verification of effects on the nervous system of low level occupational exposure to CS2. Br J Ind Med. Apr 1993;50(4):301-7. [View Abstract]
  20. Johnson BL, Boyd J, Burg JR, et al. Effects on the peripheral nervous system of workers' exposure to carbon disulfide. Neurotoxicology. 1983;4(1):53-65. [View Abstract]
  21. Gross JA, Haas ML, Swift TR. Ethylene oxide neurotoxicity: report of four cases and review of the literature. Neurology. Jul 1979;29(7):978-83. [View Abstract]
  22. Fukushima T, Abe K, Nakagawa A, et al. Chronic ethylene oxide poisoning in a factory manufacturing medical appliances. J Soc Occup Med. 1986;36(4):118-23. [View Abstract]
  23. Schroder JM, Hoheneck M, Weis J, Deist H. Ethylene oxide polyneuropathy: clinical follow-up study with morphometric and electron microscopic findings in a sural nerve biopsy. J Neurol. 1985;232(2):83-90. [View Abstract]
  24. Kuzuhara S, Kanazawa I, Nakanishi T, Egashira T. Ethylene oxide polyneuropathy. Neurology. Mar 1983;33(3):377-80. [View Abstract]
  25. Finelli PF, Morgan TF, Yaar I, Granger CV. Ethylene oxide-induced polyneuropathy. A clinical and electrophysiologic study. Arch Neurol. Jul 1983;40(7):419-21. [View Abstract]
  26. Andersen A, Ellingsen DG, Morland T, Kjuus H. A neurological and neurophysiological study of chloralkali workers previously exposed to mercury vapour. Acta Neurol Scand. Dec 1993;88(6):427-33. [View Abstract]
  27. Barber TE. Inorganic mercury intoxication reminiscent of amyotrophic lateral sclerosis. J Occup Med. Oct 1978;20(10):667-9. [View Abstract]
  28. Adams CR, Ziegler DK, Lin JT. Mercury intoxication simulating amyotrophic lateral sclerosis. JAMA. Aug 5 1983;250(5):642-3. [View Abstract]
  29. Ross AT. Mercuric polyneuropathy with albumino-cytologic dissociation and eosinophilia. JAMA. Jun 1 1964;188:830-1. [View Abstract]
  30. Warkany J, Hubbard DM. Acrodynia and mercury. J Pediatr. 1953;42:365-386.
  31. Yoshida Y, Kamitsuchibashi H, Hamada R, et al. Truncal hypesthesia in patients with Minamata disease. Intern Med. Feb 1992;31(2):204-7. [View Abstract]
  32. Thomson RM, Parry GJ. Neuropathies associated with excessive exposure to lead. Muscle Nerve. Jun 2006;33(6):732-41. [View Abstract]
  33. Bleecker ML, Bolla KI, Agnew J, Schwartz BS, Ford DP. Dose-related subclinical neurobehavioral effects of chronic exposure to low levels of organic solvents. Am J Ind Med. 1991;19(6):715-28. [View Abstract]
  34. Bleeker ML. Clinical presentations of selected neurotoxic compounds. In: Bleeker ML, Hansen JA, eds. Occupational Neurology and Clinical Neurotoxicology. Baltimore: Williams & Wilkins; 1994:207-234.
  35. Demers RY, Markell BL, Wabeke R. Peripheral vibratory sense deficits in solvent-exposed painters. J Occup Med. Oct 1991;33(10):1051-4. [View Abstract]
  36. Bove FJ, Letz R, Baker EL. Sensory thresholds among construction trade painters: a cross-sectional study using new methods for measuring temperature and vibration sensitivity. J Occup Med. Apr 1989;31(4):320-5. [View Abstract]
  37. Padilla SS, Lyerly DP. Effects of p-xylene inhalation on axonal transport in the rat retinal ganglion cells. Toxicol Appl Pharmacol. Dec 1989;101(3):390-8. [View Abstract]
  38. Feldman RG. Effect of toxins and physical agents on the nervous system. In: Bradley WG et al, eds. Neurology in Clinical Practice. Boston: Butterworth-Heinemann; 1991:1185-207.
  39. Feldman RG. The recognition and differentiation of neurotoxic and non-neurotoxic syndromes. In: Chang LW, Slikker W, eds. Neurotoxicology: Approaches and Methods. San Diego: Academic Press; 1995:689-694.
  40. Juntunen J, Antti-Poika M, Tola S, Partanen T. Clinical prognosis of patients with diagnosed chronic solvent intoxication. Acta Neurol Scand. May 1982;65(5):488-503. [View Abstract]
  41. Antti-Poika M. Overall prognosis of patients with diagnosed chronic organic solvent intoxication. Int Arch Occup Environ Health. 1982;51(2):127-38. [View Abstract]
  42. Seppalainen AM, Antti-Poika M. Time course of electrophysiological findings for patients with solvent poisoning. A descriptive study. Scand J Work Environ Health. Feb 1983;9(1):15-24. [View Abstract]
  43. Herruzo Perez A, Linares del Rio F, Moniche García-Pumarino M. [Sensitive painful polyneuropathy probably caused by poisoning by perchloroethylene. Apropos of 1 case]. Rev Esp Anestesiol Reanim. May-Jun 1989;36(3):180-1. [View Abstract]
  44. Baker EL. A review of recent research on health effects of human occupational exposure to organic solvents. A critical review. J Occup Med. Oct 1994;36(10):1079-92. [View Abstract]
  45. Orbaek P, Rosen I, Svensson K. Electroneurographic findings in patients with solvent induced central nervous system dysfunction. Br J Ind Med. Jun 1988;45(6):409-14. [View Abstract]
  46. Maizlish NA, Fine LJ, Albers JW, Whitehead L, Langolf GD. A neurological evaluation of workers exposed to mixtures of organic solvents. Br J Ind Med. Jan 1987;44(1):14-25. [View Abstract]
  47. Feldman RG. Neurotoxic effects of trichloroethylene in drinking water. In: Isaacson RL, Jensen KF, eds. The Vulnerable Brain and Environmental Risks: Toxins in Air and Water. Vol 3. Plenum Press; 1994.
  48. Smith AG, Howard JR, Kroll R, et al. The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci. Jan 15 2005;228(1):65-9. [View Abstract]
  49. Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. Jan 14 2003;60(1):108-11. [View Abstract]
  50. Ohnishi A, Murai Y. Polyneuropathy due to ethylene oxide, propylene oxide, and butylene oxide. Environ Res. Feb 1993;60(2):242-7. [View Abstract]
  51. Deschamps D, Rosenberg N, Soler P, Maillard G, Fournier E, Salson D, et al. Persistent asthma after accidental exposure to ethylene oxide. Br J Ind Med. Jul 1992;49(7):523-5. [View Abstract]
  52. Seppalainen AM, Husman K, Martenson C. Neurophysiological effects of long-term exposure to a mixture of organic solvents. Scand J Work Environ Health. Dec 1978;4(4):304-14. [View Abstract]
  53. Seppalainen AM, Lindstrom K, Martelin T. Neurophysiological and psychological picture of solvent poisoning. Am J Ind Med. 1980;1(1):31-42. [View Abstract]
  54. Linz DH, de Garmo PL, Morton WE, et al. Organic solvent-induced encephalopathy in industrial painters. J Occup Med. Feb 1986;28(2):119-25. [View Abstract]
  55. Miyakawa T, Deshimaru M, Sumiyoshi S, et al. Experimental organic mercury poisoning--pathological changes in peripheral nerves. Acta Neuropathol (Berl). 1970;15(1):45-55. [View Abstract]
  56. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract. Jan-Feb 2003;16(1):47-57. [View Abstract]
  57. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. Jan 11 2005;64(1):26-31. [View Abstract]
  58. Adams RD, Victor M, Ropper AH. Principles of Neurology. 6th ed. New York: McGraw-Hill; 1997:1278-1369.
  59. Albers JW, Cavender GD, Levine SP, Langolf GD. Asymptomatic sensorimotor polyneuropathy in workers exposed to elemental mercury. Neurology. Oct 1982;32(10):1168-74. [View Abstract]
  60. Albers JW, Kallenbach LR, Fine LJ, et al. Neurological abnormalities associated with remote occupational elemental mercury exposure. Ann Neurol. Nov 1988;24(5):651-9. [View Abstract]
  61. American Conference of Governmental Industrial Hygienist. Threshold Limit Values and Biological Exposure Indices. 1999.
  62. Angotzi G, Battistini N, Carboncini F, et al. Impairment of nervous system in workers exposed to inorganic mercury. Toxicol Eur Res. Nov 1981;3(6):275-8. [View Abstract]
  63. ATSDR. Toxicological profile for carbon disulphide. US Department of Health and Human Services;1994.
  64. Berger AR, Schaumberg HH. Disorders of the peripheral nervous system. In: Rosenstock L, Cullen MR, eds. Textbook of Clinical Occupational and Environmental Medicine. Philadelphia: Saunders; 1994:482-513.
  65. Bernad PG, Newell S, Spyker DA. Neurotoxicity and behavior abnormalities in a cohort chronologically exposed to trichloroethylene. Vet Hum Toxicol. 1987;29:475.
  66. Boggs W. IV Calcium, Magnesium Don't Prevent Oxaliplatin Neurotoxicity. Medscape Medical News. Available at http://www.medscape.com/viewarticle/818344. Accessed December 30, 2013.
  67. Dyck PJ. Diabetic Neuropathy. Philadelphia: WB Saunders Co; 1998.
  68. Dyck PJ. Peripheral Neuropathy. Philadelphia: WB Saunders Co; 1993.
  69. Ellingsen DG, Morland T, Andersen A, Kjuus H. Relation between exposure related indices and neurological and neurophysiological effects in workers previously exposed to mercury vapour. Br J Ind Med. Aug 1993;50(8):736-44. [View Abstract]
  70. Elofsson SA, Gamberale F, Hindmarsh T, et al. Exposure to organic solvents. A cross-sectional epidemiologic investigation on occupationally exposed care and industrial spray painters with special reference to the nervous system. Scand J Work Environ Health. Dec 1980;6(4):239-73. [View Abstract]
  71. Eto K, Oyanagi S, Itai Y, et al. A fetal type of Minamata disease. An autopsy case report with special reference to the nervous system. Mol Chem Neuropathol. Feb-Apr 1992;16(1-2):171-86. [View Abstract]
  72. Feldman RG, White RF. Role of the neurologist in hazard identification and risk assessment. Environ Health Perspect. Apr 1996;104 Suppl 2:227-37. [View Abstract]
  73. Gilioli R, et al. Horvath M, ed. Adverse Effects of Environmental Chemicals and Psychotropic Drugs. Vol 2. Amsterdam: Elsevier Science; 1976:157-164.
  74. Iyer K, Goodgold J, Eberstein A, Berg P. Mercury poisoning in a dentist. Arch Neurol. Nov 1976;33(11):788-90. [View Abstract]
  75. Juntunen J. Neurotoxic syndromes and occupational exposure to solvents. Environ Res. Jan 1993;60(1):98-111. [View Abstract]
  76. Levine SP, Cavender GD, Langolf GD, Albers JW. Elemental mercury exposure: peripheral neurotoxicity. Br J Ind Med. May 1982;39(2):136-9. [View Abstract]
  77. Loprinzi CL, Qin R, Dakhil SR, Fehrenbacher L, Flynn KA, Atherton P, et al. Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium and Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity (N08CB/Alliance). J Clin Oncol. Dec 2 2013;[View Abstract]
  78. Miller JM, Chaffin DB, Smith RG. Subclinical psychomotor and neuromuscular changes in workers exposed to inorganic mercury. Am Ind Hyg Assoc J. Oct 1975;36(10):725-33. [View Abstract]
  79. National Institute for Occupational Safety and Health (NIOSH). Tetrachloroethylene. Current Intelligence Bulletin; January 1978;number 20.
  80. Occupational Medicine Physician's Guide to Neuropathy in the Workplace Part 3: Case Presentation. J Occup Environ Med. Jul 2009;51(7):861-2. [View Abstract]
  81. Pleasure DE, Schotland DL. Peripheral neuropathies. In: Rowland LP, ed. Merritt's Textbook of Neurology. 8th ed. Philadelphia: Lea & Febiger; 1989:601-26.
  82. Rowland LP, ed. Merritt's Textbook of Neurology. 8th ed. Philadelphia: Lea & Febiger; 1989.
  83. Rutchik J. Occupational medicine physician's guide to neuropathy in the workplace, part 2: electromyography and cryptogenic and toxic neuropathy. J Occup Environ Med. May 2009;51(5):622-5. [View Abstract]
  84. Rutchik JS. Occupational medicine physician's guide to neuropathy in the workplace, Part 1. J Occup Environ Med. Mar 2009;51(3):390-3. [View Abstract]
  85. Schaumberg HH, Spencer PS. Clinical and experimental studies of distal axonopathy- A frequent form of brain and nerve damage produced by environmental chemical hazards. Ann NY Acad Sci. 1979;14-29.
  86. Schaumburg HH, Spencer PS. The neurology and neuropathology of the occupational neuropathies. J Occup Med. Nov 1976;18(11):739-42. [View Abstract]
  87. Shapiro IM, Cornblath DR, Sumner AJ, et al. Neurophysiological and neuropsychological function in mercury-exposed dentists. Lancet. May 22 1982;1(8282):1147-50. [View Abstract]
  88. Singer R, Valciukas JA, Rosenman KD. Peripheral neurotoxicity in workers exposed to inorganic mercury compounds. Arch Environ Health. Jul-Aug 1987;42(4):181-4. [View Abstract]
  89. Somjen S, Mercury. Schaumberg HH and Spencer PS, eds. Clinical Neurotoxicology. Baltimore: Lippincott Williams & Wilkins; 1980.
  90. Wang MS, Fang G, Culver DG, et al. The WldS protein protects against axonal degeneration: a model of gene therapy for peripheral neuropathy. Ann Neurol. Dec 2001;50(6):773-9. [View Abstract]
  91. Zampollo A, Baruffini A, Cirla AM, et al. Subclinical inorganic mercury neuropathy: neurophysiological investigations in 17 occupationally exposed subjects. Ital J Neurol Sci. Jun 1987;8(3):249-54. [View Abstract]
Compound OSHA

PEL TWA:

ppm (mg/m3)

NIOSH REL

TWA: ppm (mg/m3),

IDLH

ACGIH

ppm (mg/m3) TLV,

STEL

Acrylamide(0.3)(0.03), 60 Ca
Arsenic, inorganic(0.01)C (0.002)(0.01), -
Arsenic, organic0.5 mg/m3
Carbon disulfide20, 30, 100 for 30 min1 (3),

10 STEL (30),

500

10 (31)
Ethylene oxide1 < 0.1,

< 0.18, 5 C,

800

1 (1.8)
n -hexane500 (1800)50 (180), 110050, (176)
Lead0.05 mg/m30.100 mg/m3(0.05), -
Mercury, inorganicC 0.1 mg/m30.05 mg/m3,

C 0.01 mg/m3,

10 mg/m3

0.025 mg/m3
Mercury, organic0.01 mg/m3,

C 0.04 mg/m3

0.01 mg/m3,

ST 0.03 mg/m3,

2 mg/m3

0.01 mg/m3,

0.03 mg/m3

Methyl n -butyl

ketone

100 (410)5 (20)
Perchloroethylene100, 200 C,

300 for 5 min

in 3 h

150 Ca25 (170),

100 (685)

Styrene100, 200 C,

600 for 5 min

in 3 h

50 (215),

100 ST (425), 700

50 (213),

100 (428)

Thallium0.1 mg/m3 skin0.1 mg/m3,

15 mg/m3

0.1 mg/m3
Toluene200, 300, 500 for 10 min100 (375),

150 ST (560),

500

50 (188)
1,1,1

Trichloroethane

(methyl chloroform)

350 (1900)C 350(1900)

for 15 min,

700

350 (1910),

450 (2460)

Trichloroethylene100, 200 C,

300 for 5 min

in 2 h

1000 Ca50 (269),

100 (1070)

Vinyl chloride1, 5 for 15 minND
Xylene100 (435)100 (435),

150 ST (655)

100 (434),

150 (651)

Abbreviations: OSHA - Occupational Safety and Health Association; NIOSH - National Institute of Occupational Safety and Health; ACGIH - American Congress of Governmental Industrial Hygienists; TWA - time-weighted average; TLV - threshold limit value; PEL - permissible exposure limit; REL - recommended exposure limit; ppm - parts per million; STEL - short-term exposure limit; Ca - level for carcinogenicity; C - ceiling, should never be exceeded; ND - not determined
Compound Urine Blood Expired

Air

Other
Acrylamide
ArsenicInorganic arsenic: end of work week, 50 µg/g

monomethyl-arsonic acid, cacodylic acid (days)

Hair (ingestion chronic)
Carbon disulfide2-TTCA* 5 mg/gCarbon disulfideCarbon disulfide
Ethylene oxide
n -hexane2-5 hexanediol: end of shift, 5 mg/g

2 hexanol, total metabolites

n -hexanen -hexane
LeadLeadLead 30 μg/100 mLErythrocyte protopor-phyrin
Mercury, inorganicMercury: start of shift, 35 µg/gMercury: end of shift at end of work week, 15 µg/L
Methyl n -butyl ketone2,5 hexane dione
Perchloro-ethylenePerchloro-ethylene, trichloroacetic acidPerchloroethylene 1 mg/LPerchloro-ethylene: before last shift of week, 10 ppm†
StyreneMandelic acid: start of shift, 300 mg/g; end of shift, 800 mg/g

Phenylglyoxylic acid: start of shift, 100 mg/g; end of shift, 240 mg/g

Styrene: start of shift, 0.02 mg/L; end of shift, 0.55 mg/L
ThalliumThallium
TolueneHippuric acidTolueneToluene
1,1,1 Trichloroethane (methyl chloroform)Trichloroacetic acid: end of work week, 10 mg/L

total trichloroethanol: end of shift at end of work week, 30 mg/L

Total trichloroethanol

1 mg/L

Methyl chloroform: prior to last shift of work week, 40 ppm†
Trichloro-ethyleneTrichloroethylene, trichloroacetic acid: end of work week, 100 mg/g or trichloroacetic acid plus trichloroethanol, 300 mg/gTrichloroethylene: end of work week, 4 mg/LTrichloro-

ethylene

Vinyl chloride
XyleneMethylhippuric acid: end of shift, 1.5 mg/gXyleneXylene
*2-TTCA - 2-thiothiazolidine-4-carboxylic acid

† ppm - parts per million

Compound Industrial Uses
AcrylamideMining and tunneling, adhesives, waste treatment, ore processing, paper, pulp industry, photography, dyes
ArsenicPesticides, pigments, antifouling paint, electroplating, seafood, smelters, semiconductors, logging
Carbon disulfideViscose rayon, explosives, paints, preservatives, textiles, rubber cement, varnishes, electroplating
Ethylene oxideInstrument sterilization, chemical precursor
n -hexaneGlues and vegetable extraction, components of naphtha, lacquers, metal-cleaning compounds
LeadSolder, lead shot, illicit whiskey, insecticides, auto body shops, storage batteries, foundries, smelters, lead-based paint, lead stained glass, lead pipes
MercuryScientific instruments, electrical equipment, amalgams, electroplating, photography, felt making, taxidermy, textiles, pigments, chloroalkali industry
Methyl n -butyl ketonePaints, varnishes, quick-drying inks, lacquers, metal-cleaning compounds, paint removers
OrganochlorineInsecticides
OrganophosphatesInsecticides
PerchloroethyleneDry cleaning, degreaser, textile industry
StyreneFiberglass component, ship building, polyester resin
ThalliumRodenticides, fungicides, mercury and silver alloys, lens manufacturing, photoelectric cells, infrared optical instruments
ToluenePaint, fuel oil, cleaning agents, lacquers, paints and paint thinners
1,1,1

Trichloroethane (methyl chloroform)

Degreaser and propellant
TrichloroethyleneCleaning agent, paint component, decaffeination, rubber solvents, varnish
Vinyl chlorideIntermediate for polyvinyl chloride (PVC) resins for plastics, floor coverings, upholstery, appliances, packaging
XyleneFixative for pathologic specimens, paint, lacquers, varnishes, inks, dyes, adhesives, cements
Inflam-matory Metabolic and Nutritional Infective and Granulo-matous Vasculitic Neoplastic and Para-proteinemic Drug-Induced and Toxic Hereditary
Acute idiopathic polyneuro-pathy (Anti-Gm1, anti-Gd1a, anti-GQ1b)Diabetes ( Fasting blood glucose, 2-hour glucose tolerance test) AIDS ( HIV) Mixed CT disease (ESR)Compression and infiltration ( chest radiograph) AlcoholHMSN
Chronic inflammatory demyelin-ating polyneuro-pathyEndocrino-pathies: hypo-thyroidism, acromegaly ( TSH, Electrolytes, GH) Leprosy, syphilis ( RPR, FTA, MHA-TP) Poly-arteritis nodosaParaneo-plastic syndromes (anti-Hu, anti-RII, etc; CBC)See TableHSN
Uremia ( BUN/CR) Diphtheria, Lyme ( Serology) Rheu-matoid arthritis ( RF) Paraprotein-emias ( SPEP, immuno-fixation, anti-MAG, M protein) Friedreich ataxia
Liver disease ( LFTs) Sarcoidosis ( ACE) SLE ( ANA) Amyloidosis (nerve biopsy)Familial amyloid (nerve biopsy)
Vitamin B-12 deficiency ( B12) Sepsis and multi-organ failure ( ESR) Porphyria (porphobil-inogen, amino-levulinic acid),

meta-chromatic leukodys-trophy, Krabbe, abetalipo-proteinemia, Tangier disease, Refsum disease, Fabry disease

Small Fiber Neuropathies Facial Nerve Involvement Autonomic Involvement Sensory Ataxia Pure Motor Involvement Skin, Nail, or Hair Manifestation
DiabetesGuillain-BarréParaneo-plasticPolyganglio-nopathiesMotor neuron diseaseVasculitis: purpura, livedo reticularis
AmyloidCIDPGBSParaneo-plasticMultifocal motor neuropathyCryoglo-binemia: purpura
HIV-associatedLyme diseasePorphyriaSjögren syndromeGBsFabry disease: angiokera-tomas
Hereditary sensory and autonomic neuropathySarcoidosisVincristine, vacorCisplatin analogsAcute motor axonal neuropathyLeprosy: skin hypopig-mentation
Fabry diseaseHIVDiabetesVitamin B-6 toxicityPorphyriaOsteo-sclerotic myeloma: skin hyperpig-mentation
Tangier diseaseTangierAmyloidGBS (Miller-Fisher variant) CIDPVariegate porphyria: bullous lesions
Sjögren syndromeHIVIgM monoclonal gammopathy of undetermined significanceOsteosclerotic myelomaRefsum disease: ichthyosis
Hereditary sensory and autonomic neuropathyDiabetic lumbar radiculoplex-opathyArsenic or thallium intoxication: Mees lines
Hereditary motor sensory neuropathy (Charcot-Marie-Tooth)Thallium intoxication: alopecia
LeadGiant axonal neuropathy: curled hair
Almitrine (s)“Spanish toxic oil”
Arsenic (s)(d) 2-t-Butylazo- 2- hydroxyl- 5 methylhexane
CapsaicinAcrylamide
Carbamate pesticides (nm) Allyl chloride
Carbon disulfide (m)(d) Amiodarone (d)
Chloramphenicol (s) Amitriptyline
Cimetidine (m)Carbamates (nm)
Cisplatin (s)Carbon monoxide
CyanateChloroquine
CycloleucineColchicine
CytarabineDichloroacetic acid
Dapsone (m) Disulfiram (m)
Dichloroacetylene (cr)Ethionamide
Didoxynucleosides (s) (ddC, ddI, d4T) Ethyl alcohol
DimethylaminopropionitrileEthylene glycol (cr)
Doxorubicin (m)Ethylene oxide
Ethambutol (s) Germanium dioxide
Etoposide (s)Gold
GlutethimideHexamethylmelamine
HexachloropheneHydrazine
Hydralazine (s) Indomethacin
Hyperinsulinemia/ hypoglycemia (m)Isoniazid
Imipramine (m)Lincomycin (nm)
Interferon alpha (nm)Lithium
Lead (m) L-Tryptophan
LidocaineMercury, inorganic
Methyl n-butyl ketone (m)(d)Mercury, organic
Metronidazole (s) Methaqualone
Misonidazole (s) Methyl bromide
MuzolimineMethyl methacrylate
Nitrous Oxide (s) N hexane (d)
Organophosphates (m) Naproxen
Organophosphorus compounds (nm) Nitrofurantoin (m)
Polychlorinated biphenyls (s)Penicillamine (nm)
Polymyxin (nm)Perhexiline (d)
Pyrethroids (ic) Phenol
Pyridoxine (s) Phenytoin
SarinPyriminil
Succinylcholine (nm)Quinine (nm)
Sulfonamides (m), sulfasalazineStatins
TacrolimusStilbamidine (cr)
Taxanes (paclitaxel, docetaxel) (s) Suramin
Thalidomide (s) Tetrachloroethane
Thallium (s) Tetracyclines (nm)
Trimethaphan (nm) Trithiozine
VidarabineTubocurarine (nm)
Vincristine (m) Vincristine (m), Vinca alkaloids
ZimeldineVinyl chloride
(s): Predominantly sensory

(m): Predominantly motor

(d): Possibly demyelination with conduction block

(cr): Associated with cranial neuropathy

(nm): Associated with neuromuscular transmission syndromes

(ic): Associated with axon ion channel syndromes

Bold: A rating for common or strong association

Unbolded: B rating for less common or less than strong association