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Toxic Neuropathy Workup

  • Author: Jonathan S Rutchik, MD, MPH; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
 
Updated: Feb 03, 2016
 

Laboratory Studies

See the list below:

  • See other Medscape Reference articles on neuropathy for workup to rule out common causes of neuropathy.
  • A differential diagnosis for peripheral neuropathy with appropriate lab testing is noted in Table 4.

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

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



 

  • Neuropathies with unusual features are listed in Table 5.

Table 5. Neuropathies With Unusual Features (Open Table in a new window)

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 syndrome HIVIgM monoclonal gammopathy of undetermined significanceOsteosclerotic myelomaRefsum disease: ichthyosis
  Hereditary sensory and autonomic neuropathy Diabetic lumbar radiculoplex-opathyArsenic or thallium intoxication: Mees lines
    Hereditary motor sensory neuropathy (Charcot-Marie-Tooth)Thallium intoxication: alopecia
    LeadGiant axonal neuropathy: curled hair

 

  • Quantitative sensory testing includes vibration threshold testing, thermal threshold testing, portable motor and sensory latency tests, and current perception threshold (CPT) testing. These tests are often portable gadgets useful in the field. Each has its limitations, but some may be able to measure functions pertaining to small fiber neuropathy, such as the CPT and thermal testing devices. Others are simple versions of the NCV. The vibration testing device measures large fiber function and may be useful if NCV is not available.
  • Other techniques that help prove the presence of neuropathy include skin biopsy and intraepidermal nerve fiber density (IENF) testing. This is well reviewed in the article by Smith et al (2005).[48]
  • The sympathetic skin reflex is performed with EMG machinery, where the absence of one side's testing suggests an abnormality. This test is technically difficult. A sural nerve biopsy is invasive but may be useful. Laser evoked potential and Quantitative Sudomotor Axon Reflex Test (QSART) have been useful in research. QSART measures sweat volume.
  • IENF testing is relatively easy since it is a small punch biopsy of skin (6 mm). It has a reliable method of measuring small fiber neuropathy and has good interrater reliability. It measures intraepidermal nerve fibers, crossing the dermal, epidermal junction. It is being used in clinical trials for pharmaceuticals.
  • For patients with cryptogenic neuropathies, glucose tolerance testing makes sense because impaired glucose tolerance is prevalent in 14% of those aged 50-65 years. This is well reviewed by Sumner et al (2003).[49] It is associated with a syndrome of insulin resistance, and 25-40% of patients progress to frank diabetes. An abnormal oral glucose tolerance test result is defined as a glucose level of 140-200, 2 hours after a 75-g anhydrous load. Clinically, 86% of patients had exclusively sensory symptoms with pain and one third had otherwise idiopathic neuropathy. Oral glucose tolerance testing is more sensitive than glycosylated hemoglobin HbA1C testing.
  • For cryptogenic neuropathy, the glucose tolerance test result is abnormal in 33-61% of patients. Other important laboratory tests to consider are tests for vitamin B-12, monoclonal gammopathy of unknown significance (3% of those >70 y), axonal neuropathy (1-5%), cryoglobins and hepatitis C evaluation, and immunofixation for paraneoplastic neuropathy.
  • CSF protein level in toxic neuropathy is usually normal.
  • Consider performing serum, urine, or blood testing to assess for evidence of absorption (see Table 2). If evaluating a patient weeks or months after the exposure ceased, biological data may not yield useful information. In the case of arsenic, for example, separating inorganic from organic arsenic is important, since organic arsenic is a component of seafood and may contaminate and confuse clinicians. Patients need to refrain from seafood for 24 hour prior to urine testing. Furthermore, labs need to be instructed to perform testing for inorganic, not organic, arsenic. Some agents do not have indices that can be tested. Most need to be performed relatively soon after exposure.
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Other Tests

See the list below:

  • Electromyography (EMG) and nerve conduction study (NCV)
    • Using EMG and NCV, peripheral neuropathy may be separated into axonal and demyelinating forms.
    • Axonal neuropathies are more commonly the result of chronic low-level occupational or environmental toxicity.
    • Axonal neuropathies are characterized by sensory amplitude loss in the lower extremities, commonly the sural and or superficial peroneal nerves.
    • More severe axonal neuropathies may involve motor fibers and thus motor amplitudes may be small.
    • When motor fibers are involved, then fibrillation may be noted as evidence for acute denervation. For more chronic neuropathies, polyphasia and wave forms for large and long duration are evident. EMG needle assessment may then help classify duration of the neuropathy.
    • Demyelination-type neuropathies are characterized by sensory and motor slowing.
    • Some toxic neuropathies that are the result of high-level acute exposure may result in severe motor demyelinating neuropathies. However, these conditions are rare. “Ginger Jack leg” paralysis from ingestion of organophosphates is one example of this. NCV may reveal prolonged F waves initially, but then later, motor slowing.
    • EMG needle testing in these cases may be normal if the condition is purely demyelinating.
    • Characterizing a neuropathy into demyelinating or axonal may assist in identifying chemical agents responsible. (See Table 6.)
    • The differential diagnosis, however, must include inherited neuropathies as well as other common acquired neuropathies.
    • Patients with inherited demyelinating neuropathies are noted to have prolonged and symmetrical sensory and/or motor nerve conduction velocities.
    • Those with inherited axonal neuropathies may have small amplitudes that are out of proportion to their relatively minor sensory or motor findings.
    • These patients may also have high arches or other congenital physical ailments.
    • Patients with other acquired neuropathies, such as diabetes or thyroiditis, may have EMG and NCV findings that are inseparable from those with toxic neuropathy.

Table 6. Industrial Agents and Pharmaceuticals Associated With Peripheral Neuropathy (Open Table in a new window)

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) Amiodaron e (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



See the list below:

  • Neurophysiologic abnormalities in workers exposed to ethylene oxide
    • In 1993, Ohnishi and Murai reviewed polyneuropathy cases caused by EtO. Needle EMG revealed neurogenic changes in 8 of 11 patients. Conduction studies of limb nerves were abnormal in 8 of 10 patients. Relatively mild decreases of motor and sensory NCVs with decreases in the amplitudes of nerve and muscle action potentials indicated axonal degeneration of both motor and sensory nerve fibers.[50]
    • In 1983, Kuzuhara et al reported 2 patients with occupationally induced EtO polyneuropathy and their EMG and NCV results. In one patient, EMG of the limb muscles was normal except for long-duration and high-amplitude units recorded from the triceps. Motor NCVs were relatively well preserved. In the second patient, only an EMG was performed, which revealed denervation patterns in distal limb muscles.[24]
    • Finelli et al reported electrophysiological findings in 3 patients with EtO-induced neuropathy; they demonstrated mild slowing of motor conduction with positive sharp waves and fibrillation potentials on EMG during the active disease state, indicating axonal neuropathy.[25]
      • In patient 1, nerve conduction studies showed no response to stimulation of the left peroneal nerve, slowing of motor conduction over the right peroneal and the right posterior tibial nerves, and absence of the right tibial H reflex and the right sural nerve sensory potential. The EMG showed scattered positive sharp waves and fibrillation potentials with increased polyphasic activity in the intrinsic foot muscles and, to a lesser extent, in the leg muscles. Repeated examinations 5 weeks and 7 months later showed return of normal conduction velocity and disappearance of denervation potentials and the recording of giant potentials as signs of reinnervation. The left H reflex remained suppressed.
      • In patient 2, the EMG initially showed positive sharp-wave fibrillation potentials and small-amplitude motor unit potentials in leg and foot muscles. Follow-up studies showed the disappearance of the denervation potentials and the appearance of giant potentials indicating reinnervation.
      • Patient 3 showed absent potentials from the extensor digitorum brevis muscle on stimulation of the right peroneal nerve. Right tibial conduction was slowed, and the tibial H reflex was absent on the right and delayed on the left. The right sural nerve sensory potential amplitude was normal but delayed. Leg and foot muscle EMG studies showed denervation potentials. Repeat studies 7 months later showed mild slowing and active denervation on EMG with some polyphasic giant potentials.
    • In 1979, Gross et al reported 4 patients with EtO neurotoxicity and results of their nerve conduction studies. One patient had acute CNS symptoms and normal NCV. Another 2 had milder CNS symptoms with symptoms of a generalized sensorimotor polyneuropathy with fibrillations in the intrinsic muscles of the feet and abnormal NCVs (patient 2), and decreased numbers and increased amplitude and duration of motor unit potentials in the distal muscles (patient 3). Patient 4 was asymptomatic. Patients 2, 3, and 4 had decreased amplitudes of motor action potentials, moderately decreased NCVs, and signs of denervation compatible with axonal degeneration as the cause of neuropathy.[21]
    • In 1985, Schroeder et al also reported a case of EtO-induced polyneuropathy. This patient had nerve conduction study findings that showed slowed NCVs; the mean tibial NCV was 26 m/s, with normal amplitudes, 2.5 mV.[23]
    • Fukushima et al reported a 19-year-old patient with 20 days of EtO exposure who had numbness and weakness of his extremities and was noted to have a steppage gait on examination at the time of admission 1 month later. Nerve conduction study findings were abnormal; mean peroneal and tibial NCVs were 37.7 and 37.1 m/s (no normals were included), respectively. No latency potential was demonstrable for the right peroneal nerve. Neurogenic changes were demonstrated on EMG in the anterior tibial muscles.[22]
    • Deschamps et al reported a case of persistent asthma after accidental EtO exposure. They performed EMG and NCVs after an examination of the patient's lower extremities revealed abnormal findings. EMG and NCV findings were normal, but maximum amplitudes of the right and left H reflex responses were reduced significantly (ie, 6% and 2% of the maximum amplitude elicited from the direct response) without a decrease in the proximal conduction velocity. These results suggested axonal neuropathy.[51]
  • Neurophysiologic abnormalities associated with mercury exposure (inorganic and organic)
    • Inorganic mercury is noted to produce a sensory or sensorimotor polyneuropathy similar to that produced by arsenic. Chloralkali plant workers (n=138) with long-term inorganic mercury vapor exposure were noted to have elevated urine mercury levels and reduced sensation on quantitative testing, prolonged distal latencies with reduced sensory-evoked response amplitudes, and increased likelihood of abnormal needle EMG findings. Factory workers exposed to elemental mercury vapor with elevated urine mercury concentrations had prolonged motor and sensory ulnar distal latencies. Slowing of the median motor NCV was found to correlate with both increased levels of mercury in blood and urine and with increased numbers of neurological symptoms. Sensory deficits found with short-term exposure to mercury vapor, whereas motor nerve impairment occurred with longer periods of exposure.
    • Chloralkali workers exposed to inorganic mercury vapors for an average of 12.3 years were found to have median motor and sensory NCVs that were slightly reduced among the highly exposed subjects. Seventeen thermometer factory workers had high urine and blood mercury levels but no symptoms; 88% had subclinical neuropathy, mainly distal and axonal neuropathy. In another study, a sensory polyneuropathy was found in 11% of workers exposed to inorganic mercury, while a sensorimotor polyneuropathy was found in 27% of workers.
    • Chloralkali workers who were exposed to inorganic mercury for an average of 7.9 years and had ceased working in that environment an average of 12.3 years prior to the study were found to have both median sensory NCV and amplitude of the sural nerve associated with measures of cumulative exposure to mercury. A study reviewing the relationship between exposure-related indices and neurological and neurophysiological effects in workers previously exposed to mercury vapor revealed that, of 298 dentists with long-term exposure to mercury amalgam vapor evaluated for peripheral neuropathy, 30% had polyneuropathies. Another paper reported that one dentist apparently had an unelicitable sensory superficial peroneal nerve action potential that returned to normal following penicillamine treatment.
    • Industrial workers with long-term exposure to mercury were found to have performance decrements in neuromuscular functions that were reversible and correlated with blood and urine mercury levels.
  • Neurophysiological abnormalities in workers exposed to xylene
    • Nerve conduction testing was utilized in 8 studies evaluating the PNS in workers with occupational exposure to mixed organic solvents including xylene. One of these noted a prolonged refractory period in lower extremity motor and sensory nerves of 28 exposed painters compared with age-matched controls. In 1980, Elofsson found a slight decrease in NCV in the distal sensory nerves of the lower extremities of an exposed population. He concluded that these findings were consistent with an axonal polyneuropathy.
    • In 1978, Seppalainen noted that 12 of 59 car painters had abnormally slow motor and sensory NCVs, while none of the controls had slowing.[52] In 1980, Seppalainen reported that at least one abnormally slow NCV was noted in 48 of 107 subjects with a diagnosis of solvent poisoning.[53] A third publication by the same author reported a different cross-sectional study and noted that 26 of 44 (59%) subjects with a diagnosis of organic solvent intoxication, who had been exposed exclusively to mixed solvents including dimethyl benzene, were diagnosed with peripheral neuropathy by EMG.[42] Follow-up questionnaires of all subjects of the previous study, including those with mixed solvent exposure, noted that 57 of 87 subjects had symptoms referred to the PNS.
    • EMG revealed sensorimotor neuropathy in 5 of 7 painters tested in a study by Linz. Four of these 5 painters had evidence of mild distal neuropathy with reduced 2-point discrimination on neurologic examination. Temporal dispersion noted in sural SNAPs was a statistically significant finding in 50 male painters compared with controls.[54]
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Histologic Findings

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

  • Muscle and nerve biopsies were carried out by Kuzuhara et al on 2 patients who developed distal symmetrical polyneuropathies after being exposed to EtO while working as employees of a factory that produced medical supplies. The nerve biopsies of both patients implied axonal degeneration and regeneration. Swollen Schwann cell processes with numerous filaments, myelin figures, debris, and vacuoles with and without granules were seen on the electromicrogram of the sural nerve of patient 1. Growth cones of damaged axons were seen on the sural nerve of patient 2.[24]
  • Muscle biopsies revealed smearing and distortion of the Z bands. Some revealed absence of mitochondria and target or targetoid structures. Transverse sections showed atrophic fibers, scattered or grouped with many target fibers. Enzyme histochemistry of muscle from patient 2 revealed atrophy of both type 1 and type 2 fibers in the myosin adenosine triphosphatase (ATPase) reaction and dark angulated fibers, target, targetoid, and moth-eaten fibers on nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) reaction.
  • In 1993, Ohnishi and Murai reported that histologic studies of the sural nerves biopsied in 3 patients revealed decreased density of large myelinated fibers, reduction of the cross-sectional area of axons, reduction of axonal circularity, and presence of myelin ovoid and Bunger bands, which are compatible with a mild degree of axonal degeneration.[50]
  • Experimental EtO neuropathy was produced by Ohnishi in rats exposed to a one-time dose of 500 ppm for 6 hours or 5 doses of 250 ppm for 6 hours at a time over a week. In both experiments, distal axonal degeneration was found both in peripheral and central myelinated axons of lumbar primary sensory neurons of rats. In hind leg nerves and in the fasciculus gracilis, myelinated fibers showed axonal degeneration sparing the nerve cell body of the lumbar dorsal root ganglion and myelinated fibers of lumbar dorsal and ventral roots. The rats exposed to 250 ppm also showed a retardation of growth and maturation of myelinated fibers in the presence of mild axonal degeneration.
  • In a patient with EtO polyneuropathy after 5 months of exposure, Schroder et al performed a sural nerve biopsy that revealed nerve fiber degeneration of the wallerian type associated with reduction of axonal cross-sectional areas and some degree of nerve fiber regeneration. Conspicuous paranodal vesicular disintegration of individual myelin lamella also was present. Unusual cisternae with introverted hemidesmosomes were noted in endoneural fibroblasts.[23]
  • Nerve pathology was investigated in those exposed to organic mercury. Miyakawa et al reported selective swelling and degeneration of the Schwann cells, noticeable changes of both myelin sheaths and the axon. Pathologic changes began at the nodes of Ranvier. Primary site of damage was noted to be in the cell bodies of the sensory ganglion cells, with axonal degeneration occurring later in rats poisoned by methylmercury hydroxide. The largest myelinated fibers were affected to a greater extent than the smaller caliber fibers in the dorsal root.[55]
  • An autopsy performed on a descendant of a woman exposed to mercury at Minimata Bay demonstrated segmental demyelination of the PNS. In both humans and animals, the major pathologic effect of methylmercury appears to be on the dorsal root ganglion cells. Similar data are not available for inorganic or metallic mercury poisoning.
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Contributor Information and Disclosures
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)

Jonathan S Rutchik, MD, MPH is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, International Parkinson and Movement Disorder Society, Society of Toxicology, Western Occupational and Environmental Medical Association, American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS 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

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

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

Milind J Kothari, DO is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

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Table 1. Exposure Limits, Common Organic Solvents and Metals
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 oxide 1 < 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
Table 2. Agency for Toxic Substances and Disease Registry Biological Exposure Indices
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 mL Erythrocyte protopor-phyrin
Mercury, inorganicMercury: start of shift, 35 µg/gMercury: end of shift at end of work week, 15 µg/L  
Methyl n -butyl ketone 2,5 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



Table 3. Industrial Uses of Common Organic Solvents and Metals
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
Table 4. Differential Diagnosis of Peripheral Neuropathy With Selective Lab Testing (Recommended lab tests in bold.)
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



Table 5. Neuropathies With Unusual Features
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 syndrome HIVIgM monoclonal gammopathy of undetermined significanceOsteosclerotic myelomaRefsum disease: ichthyosis
  Hereditary sensory and autonomic neuropathy Diabetic lumbar radiculoplex-opathyArsenic or thallium intoxication: Mees lines
    Hereditary motor sensory neuropathy (Charcot-Marie-Tooth)Thallium intoxication: alopecia
    LeadGiant axonal neuropathy: curled hair
Table 6. Industrial Agents and Pharmaceuticals Associated With Peripheral Neuropathy
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) Amiodaron e (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



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