" DISCLAIMER: The ILO does not take responsibility for content presented on this web portal that is presented in any language other than English, which is the language used for the initial production and peer-review of original content. Certain statistics have not been updated since the production of the 4th edition of the Encyclopaedia (1998)."

Thursday, 17 February 2011 23:29

Clinical Syndromes Associated with Neurotoxicity

Written by
Rate this item
(0 votes)

Neurotoxicant syndromes, brought about by substances which adversely affect nervous tissue, constitute one of the ten leading occupational disorders in the United States. Neurotoxicant effects constitute the basis for establishing exposure limit criteria for approximately 40% of agents considered hazardous by the United States National Institute for Occupational Safety and Health (NIOSH).

A neurotoxin is any substance capable of interfering with the normal function of nervous tissue, causing irreversible cellular damage and/or resulting in cellular death. Depending on its particular properties, a given neurotoxin will attack selected sites or specific cellular elements of the nervous system. Those compounds, which are non-polar, have greater lipid solubility, and thus have greater access to nervous tissue than highly polar and less lipid-soluble chemicals. The type and size of cells and the various neurotransmitter systems affected in different regions of the brain, innate protective detoxifying mechanisms, as well as the integrity of cellular membranes and intracellular organelles all influence neurotoxicant responses.

Neurons (the functional cell unit of the nervous system) have a high metabolic rate and are at greatest risk for neurotoxicant damage, followed by oligodendrocytes, astrocytes, microglia and cells of the capillary endothelium. Changes in cellular membrane structure impair excitability and impede impulse transmission. Toxicant effects alter protein form, fluid content and ionic exchange capability of membranes, leading to swelling of neurons, astrocytes and damage to the delicate cells lining blood capillaries. Disruption of neurotransmitter mechanisms block access to post-synaptic receptors, produce false neurotransmitter effects, and alter the synthesis, storage, release, re-uptake or enzymatic inactivation of natural neurotransmitters. Thus, clinical manifestations of neurotoxicity are determined by a number of different factors: the physical characteristics of the neurotoxicant substance, the dose of exposure to it, the vulnerability of the cellular target, the organism’s ability to metabolize and excrete the toxin, and by the reparative abilities of the structures and mechanisms affected. Table 1 lists various chemical exposures and their neurotoxic syndromes.

Table 1. Chemical exposures and associated neurotoxic syndromes

Neurotoxin

Sources of exposure

Clinical diagnosis

Locus of pathology1

Metals

Arsenic

Pesticides; pigments; antifouling paint; electroplating industry; seafood; smelters; semiconductors

Acute: encephalopathy

Chronic: peripheral neuropathy

Unknown (a)

Axon (c)

Lead

Solder; lead shot; illicit whiskey; insecticides; auto body shop; storage battery manufacturing; foundries, smelters; lead-based paint; lead pipes

Acute: encephalopathy

Chronic: encephalopathy and peripheral neuropathy

Blood vessels (a)

Axon (c)

Manganese

Iron, steel industry; welding operations; metal-finishing operations; fertilizers; manufacturers of fireworks, matches; manufacturers of dry cell batteries

Acute: encephalopathy

Chronic: parkinsonism

Unknown (a)

Basal ganglia neurons (c)

Mercury

Scientific instruments; electrical equipment; amalgams; electroplating industry; photography; felt making

Acute: headache, nausea, onset of tremor

Chronic: ataxia, peripheral neuropathy, encephalopathy

Unknown (a)

Axon (c)

Unknown (c)

Tin

Canning industry; solder; electronic components; polyvinyl plastics; fungicides

Acute: memory defects, seizures, disorientation

Chronic: encephalomyelopathy

Neurons of the limbic system (a & c)

Myelin (c)

Solvents

Carbon disulphide

Manufacturers of viscose rayon; preservatives; textiles; rubber cement; varnishes; electroplating industry

Acute: encephalopathy

Chronic: peripheral neuropathy, parkinsonism

Unknown (a)

Axon (c)

Unknown

n-hexane,

methyl butyl ketone

Paints; lacquers; varnishes; metal-cleaning compounds; quick-drying inks; paint removers; glues, adhesives

Acute: narcosis

Chronic: peripheral neuropathy, unknown (a) Axon (c),

 

Perchloroethylene

Paint removers; degreasers; extraction agents; dry cleaning industry; textile industry

Acute: narcosis

Chronic: peripheral neuropathy, encephalopathy

Unknown (a)

Axon (c)

Unknown

Toluene

Rubber solvents; cleaning agents; glues; manufacturers of benzene; gasoline, aviation fuels; paints, paint thinners; lacquers

Acute: narcosis

Chronic: ataxia, encephalopathy

Unknown (a)

Cerebellum (c)

Unknown

Trichloroethylene

Degreasers; painting industry; varnishes; spot removers; process of decaffeination; dry cleaning industry; rubber solvents

Acute: narcosis

Chronic: encephalopathy, cranial neuropathy

Unknown (a)

Unknown (c)

Axon (c)

 Insecticides

 Organophosphates

 Agricultural industry manufacturing and application

 Acute: cholinergic poisoning

 Chronic: ataxia, paralysis, peripheral neuropathy

 Acetylcholinesterase (a)

 Long tracts of spinal cord (c)

 Axon (c)

 Carbamates

 Agricultural industry manufacturing and application flea powders

 Acute: cholinergic poisoning Chronic: tremor, peripheral neuropathy

 Acetylcholinesterase (a)

 Dopaminergic system (c)

 1 (a), acute; (c), chronic.

Source: Modified from Feldman 1990, with permission of the publisher.

 

Establishing a diagnosis of a neurotoxicant syndrome and differentiating it from neurologic diseases of non-neurotoxicant aetiology requires an understanding of the pathogenesis of the neurological symptoms and observed signs and symptoms; an awareness that particular substances are capable of affecting nervous tissue; documentation of exposure; evidence of presence of neurotoxin and/or metabolites in tissues of an affected individual; and careful delineation of a time relationship between exposure and the appearance of symptoms with subsequent decrease in symptoms after exposure is ended.

Proof that a particular substance has reached a toxicant dose level is usually lacking after symptoms appear. Unless environmental monitoring is ongoing, a high index of suspicion is necessary to recognize cases of neurotoxicologic injury. Identifying symptoms referable to the central and/or the peripheral nervous systems can help the clinician focus on certain substances, which have a greater predilection for one part or another of the nervous system, as possible culprits. Convulsions, weakness, tremor/twitching, anorexia (weight loss), equilibrium disturbance, central nervous system depression, narcosis (a state of stupor or unconsciousness), visual disturbance, sleep disturbance, ataxia (inability to coordinate voluntary muscle movements), fatigue and tactile disorders are commonly reported symptoms following exposure to certain chemicals. Constellations of symptoms form syndromes associated with neurotoxicant exposure.

Behavioural Syndromes

Disorders with predominantly behavioural features ranging from acute psychosis, depression and chronic apathy have been described in some workers. It is essential to differentiate memory impairment associated with other neurological diseases, such as Alzheimer’s disease, arteriosclerosis or presence of a brain tumour, from the cognitive deficits associated with toxicant exposure to organic solvents, metals or insecticides. Transient disturbances of awareness or epileptic seizures with or without associated motor involvement must be identified as a primary diagnosis separate from similarly appearing disturbances of consciousness related to neurotoxicant effects. Subjective and behavioural toxicant syndromes such as headache, vertigo, fatigue and personality change manifest as mild encephalopathy with inebriation, and may indicate the presence of exposure to carbon monoxide, carbon dioxide, lead, zinc, nitrates or mixed organic solvents. Standardized neuropsychological testing is necessary to document elements of cognitive impairment in patients suspected of toxicant encephalopathy, and these must be differentiated from those dementing syndromes caused by other pathologies. Specific tests used in the diagnostic batteries of tests must include a broad sampling of cognitive function tests which will generate predictions about the patient’s functioning and daily life, as well as tests which have been demonstrated previously to be sensitive to the effects of known neurotoxins. These standardized batteries must include tests which have been validated on patients with specific types of brain damage and structural deficits, to clearly separate these conditions from neurotoxic effects. In addition, tests must include internal control measures to detect the influence of motivation, hypochondriasis, depression and learning difficulties, and must contain language that takes into account cultural as well as educational background effects.

A continuum exists from mild to severe central nervous system impairment experienced by patients exposed to toxicant substances:

  • Organic affective syndrome (Type I Effect), in which mild mood disorders predominate as the patient’s chief complaint, with features most consistent with those of organic affective disorders of the depressive type. This syndrome seems to be reversible following cessation of exposure to the offending agent.
  • Mild chronic toxicant encephalopathy, in which, in addition to mood disturbances, central nervous system impairment is more prominent. Patients have evidence of memory and psychomotor function disturbance which can be confirmed by neuropsychological testing. In addition, features of visual spatial impairment and abstract concept formation may be seen. Activities of daily living and work performance are impaired.
  • Sustained personality or mood change (Type IIA Effect) or impairment in intellectual function (Type II) may be seen. In mild chronic toxicant encephalopathy, the course is insidious. Features may persist after the cessation of exposure and disappear gradually, while in some individuals, persistent functional impairment may be observed. If exposure continues, the encephalopathy may progress to a more severe stage.
  • In severe chronic toxicant encephalopathy (Type III Effect) dementia with global deterioration of memory and other cognitive problems are noted. The clinical effects of toxicant encephalopathy are not specific to a given agent. Chronic encephalopathy associated with toluene, lead and arsenic is not different from that of other toxicant aetiologies. The presence of other associated findings, however (visual disturbances with methyl alcohol), may help differentiate syndromes according to particular chemical aetiologies.

 

Workers exposed to solvents for long periods of time may exhibit disturbances of central nervous system function which are permanent. Since an excess of subjective symptoms, including headache, fatigue, impaired memory, loss of appetite and diffuse chest pains, have been reported, it is often difficult to confirm this effect in any individual case. An epidemiological study comparing house painters exposed to solvents with unexposed industrial workers showed, for example, that painters had significantly lower mean scores on psychological tests measuring intellectual capacity and psychomotor coordination than referent subjects. The painters also had significantly lower performances than expected on memory and reaction time tests. Differences between workers exposed for several years to jet fuel and unexposed workers, in tests demanding close attention and high sensory motor speed, were apparent as well. Impairments in psychological performance and personality changes have also been reported among car painters. These included visual and verbal memory, reduction of emotional reactivity, and poor performance on verbal intelligence tests.

Most recently, a controversial neurotoxicant syndrome, multiple chemical sensitivity, has been described. Such patients develop a variety of features involving multiple organ systems when they are exposed to even low levels of various chemicals found in the workplace and the environment. Mood disturbances are characterized by depression, fatigue, irritability and poor concentration. These symptoms reoccur on exposure to predictable stimuli, by elicitation by chemicals of diverse structural and toxicological classes, and at levels much lower than those causing adverse responses in the general population. Many of the symptoms of multiple chemical sensitivity are shared by individuals who show only a mild form of mood disturbance, headache, fatigue, irritability and forgetfulness when they are in a building with poor ventilation and with off-gassing of volatile substances from synthetic building materials and carpets. The symptoms disappear when they leave these environments.

Disturbances of consciousness, seizures and coma

When the brain is deprived of oxygen—for example, in the presence of carbon monoxide, carbon dioxide, methane or agents which block tissue respiration such as hydrocyanic acid, or those which cause massive impregnation of the nerve such as certain organic solvents—disturbances of consciousness may result. Loss of consciousness may be preceded by seizures in workers with exposure to anticholinesterase substances such as organophosphate insecticides. Seizures may also occur with lead encephalopathy associated with brain swelling. Manifestations of acute toxicity following organophosphate poisoning have autonomic nervous system manifestations which precede the occurrence of dizziness, headache, blurred vision, myosis, chest pain, increased bronchial secretions, and seizures. These parasympathetic effects are explained by the inhibitory action of these toxicant substances on cholinesterase activity.

Movement disorders

Slowness of movement, increased muscle tone, and postural abnormalities have been observed in workers exposed to manganese, carbon monoxide, carbon disulphide and the toxicity of a meperidine by-product, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At times, the individuals may appear to have Parkinson’s disease. Parkinsonism secondary to toxicant exposure has features of other nervous disorders such as chorea and athetosis. The typical “pill-rolling” tremor is not seen in these instances, and usually the cases do not respond well to the drug levodopa. Dyskinesia (impairment of the power of voluntary motion) can be a common symptom of bromomethane poisoning. Spasmodic movements of the fingers, face, peribuccal muscles and the neck, as well as extremity spasms, may be seen. Tremor is common following mercury poisoning. More obvious tremor associated with ataxia (lack of coordination of muscular action) is noted in individuals following toluene inhalation.

Opsoclonus is an abnormal eye movement which is jerky in all directions. This is often seen in brain-stem encephalitis, but may also be a feature following chlordecone exposure. The abnormality consists of irregular bursts of abrupt, involuntary, rapid, simultaneous jerking of both eyes in a conjugate manner, possibly multidirectional in severely affected individuals.

Headache

Common complaints of head pain following exposure to various metal fumes such as zinc and other solvent vapours may result from vasodilation (widening of the blood vessels), as well as cerebral oedema (swelling). The experiencing of pain is common to these conditions, as well as carbon monoxide, hypoxia (low oxygen), or carbon dioxide conditions. “Sick building syndrome” is thought to cause headaches because of excess carbon dioxide present in a poorly ventilated area.

Peripheral neuropathy

Peripheral nerve fibres serving motor functions begin in motor neurons in the ventral horn of the spinal cord. The motor axons extend peripherally to the muscles they innervate. A sensory nerve fibre has its nerve cell body in the dorsal root ganglion or in the dorsal grey matter of the spinal cord. Having received information from the periphery detected at distal receptors, nerve impulses are conducted centrally to the nerve cell bodies where they connect with spinal cord pathways transmitting information to the brain stem and cerebral hemispheres. Some sensory fibres have immediate connections with motor fibres within the spinal cord, providing a basis for reflex activity and quick motor responses to noxious sensations. These sensory-motor relationships exist in all parts of the body; the cranial nerves are the peripheral nerve equivalents arising in brain stem, rather than spinal cord, neurons. Sensory and motor nerve fibres travel together in bundles and are referred to as the peripheral nerves.

Toxicant effects of peripheral nerve fibres may be divided into those which primarily affect axons (axonopathies), those which are involved in distal sensory-motor loss, and those which primarily affect myelin sheath and Schwann cells. Axonopathies are evident in early stages in the lower extremities where the axons are the longest and farthest from the nerve cell body. Random demyelination occurs in segments between nodes of Ranvier. If sufficient axonal damage occurs, secondary demyelination follows; as long as axons are preserved, regeneration of Schwann cells and remyelination can occur. A pattern seen commonly in toxicant neuropathies is distal axonopathy with secondary segmental demyelination. The loss of myelin reduces the speed of conducting nerve impulses. Thus, gradual onset of intermittent tingling and numbness progressing to lack of sensation and unpleasant sensations, muscle weakness, and atrophy results from damage to the motor and sensory fibres. Reduced or absent tendon reflexes and anatomically consistent patterns of sensory loss, involving the lower extremities more than upper, are features of peripheral neuropathy.

Motor weaknesses may be noted in distal extremities and progress to unsteady gait and inability to grasp objects. The distal portions of the extremities are involved to a greater extent, but severe cases may produce proximal muscle weakness or atrophy as well. Extensor muscle groups are involved before the flexors. Symptoms may sometimes progress for a few weeks even after removal from exposure. Deterioration of nerve function may persist for several weeks after removal from exposure.

Depending on the type and severity of neuropathy, an electrophysiological examination of the peripheral nerves is useful to document impaired function. Slowing of conduction velocity, reduced amplitudes of sensory or motor action potentials, or prolonged latencies can be observed. Slowing of motor or sensory conduction velocities is generally associated with demyelination of nerve fibres. Preservation of normal conduction velocity values in the presence of muscle atrophy suggests axonal neuropathy. Exceptions occur when there is progressive loss of motor and sensory nerve fibres in axonal neuropathy which affects the maximal conduction speed as a result of the dropping out of the larger diameter faster conducting nerve fibres. Regenerating fibres occur in early stages of recovery in axonopathies, in which conduction is slowed, especially in the distal segments. The electrophysiological study of patients with toxicant neuropathies should include measurements of motor and sensory conduction velocity in the upper and lower extremities. Special attention should be given to the primarily sensory conducting characteristics of the sural nerve in the leg. This is of great value when the sural nerve is then used for biopsy, providing anatomical correlation between the histology of teased nerve fibres and the conduction characteristics. A differential electrophysiological study of the conducting capabilities of proximal segments versus distal segments of a nerve is useful in identifying a distal toxicant axonopathy, or to localize a neuropathic block of conduction, probably due to demyelination.

Understanding the pathophysiology of a suspected neurotoxicant polyneuropathy has great value. For example, in patients with neuropathy caused by n-hexane and methylbutyl ketone, motor nerve conduction velocities are reduced, but in some cases, the values may fall within the normal range if only the fastest firing fibres are stimulated and used as the measured outcome. Since neurotoxicant hexacarbon solvents cause axonal degeneration, secondary changes arise in myelin and explain overall reduction in conduction velocity despite the value within the normal range produced by the preserved conducting fibres.

Electrophysiological techniques include special tests other than the direct conduction velocity, amplitude and latency studies. Somatosensory evoked potentials, auditory evoked potentials, and visual evoked potentials are ways of studying the characteristics of the sensory conducting systems, as well as specific cranial nerves. Afferent-efferent circuitry can be tested by using blink reflex tests involving the 5th cranial nerve to 7th cranial innervated muscle responses; H-reflexes involve segmental motor reflex pathways. Vibration stimulation selects out larger fibres from smaller fibre involvements. Well-controlled electronic techniques are available for measuring the threshold needed to elicit a response, and then to determine the speed of travel of that response, as well as the amplitude of the muscle contraction, or the amplitude and pattern of an evoked sensory action potential. All physiological results must be evaluated in light of the clinical picture and with an understanding of the underlying pathophysiological process.

Conclusion

The differentiation of a neurotoxicant syndrome from a primary neurological disease poses a formidable challenge to physicians in the occupational setting. Obtaining a good history, maintaining a high degree of suspicion and adequate follow-up of an individual, as well as groups of individuals, is necessary and rewarding. Early recognition of illness related to toxicant agents in their environment or to a particular occupational exposure is critical, since proper diagnosis can lead to early removal of an individual from the hazards of ongoing exposure to a toxicant substance, preventing possible irreversible neurological damage. Furthermore, recognition of the earliest affected cases in a particular setting may result in changes that will protect others who have not yet become affected.

 

Back

Read 5483 times Last modified on Tuesday, 11 October 2011 20:40

Contents

Preface
Part I. The Body
Blood
Cancer
Cardiovascular System
Digestive System
Mental Health
Musculoskeletal System
Nervous System
Resources
Renal-Urinary System
Reproductive System
Respiratory System
Sensory Systems
Skin Diseases
Systematic Conditions
Part II. Health Care
Part III. Management & Policy
Part IV. Tools and Approaches
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides

Nervous System Additional Resources

Click the Button below to view additional resources for this topic.

button

Nervous System References

Amaducci, L, C Arfaioli, D Inzitari, and M Marchi. 1982. Multiple sclerosis among shoe and leather workers: An epidemiological survey in Florence. Acta Neurol Scand 65:94-103.

Anger, KW. 1990. Worksite neurobehavioral research: Result, sensitive methods, test batteries and the transition from laboratory data to human health. Neurotoxicology 11:629-720.

Anger, WK, MG Cassitto, Y Liang, R Amador, J Hooisma, DW Chrislip, D Mergler, M Keifer, and J Hörtnagel. 1993. Comparison of performance from three continents on the WHO-recommended neurobehavioral core test battery (NCTB). Environ Res 62:125-147.

Arlien-Søborg, P. 1992. Solvent Neurotoxicity. Boca Raton: CRC Press.
Armon, C, LT Kurland, JR Daube, and PC O’Brian. 1991. Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology 41:1077-1084.

Axelson, O. 1996. Where do we go in occupational neuroepidemiology? Scand J Work Environ Health 22: 81-83.

Axelson, O, M Hane, and C Hogstedt. 1976. A case-referent study on neuropsychiatric disorders among workers exposed to solvents. Scand J Work Environ Health 2:14-20.

Bowler, R, D Mergler, S Rauch, R Harrison, and J Cone. 1991. Affective and personality disturbance among women former microelectronics workers. J Clin Psychiatry 47:41-52.

Brackbill, RM, N Maizlish, and T Fischbach. 1990. Risk of neuropsychiatric disability among painters in the United States. Scand J Work Environ Health 16:182-188.

Campbell, AMG, ER Williams, and D Barltrop. 1970. Motor neuron disease and exposure to lead. J Neurol Neurosurg Psychiatry 33:877-885.

Cherry, NM, FP Labrèche, and JC McDonald. 1992. Organic brain damage and occupational solvent exposure. Br J Ind Med 49:776-781.

Chio, A, A Tribolo, and D Schiffer. 1989. Motorneuron disease and glue exposure. Lancet 2:921.

Cooper, JR, FE Bloom, and RT Roth. 1986. The Biochemical Basis of Neuropharmacology. New York: Oxford Univ. Press.

Dehart, RL. 1992. Multiple chemical sensitivity—What is it? Multiple chemical sensitivities. Addendum to: Biologic markers in immunotoxicology. Washington, DC: National Academy Press.

Feldman, RG. 1990. Effects of toxins and physical agents on the nervous system. In Neurology in Clinical Practice, edited by WG Bradley, RB Daroff, GM Fenichel, and CD Marsden. Stoneham, Mass: Butterworth.

Feldman, RG and LD Quenzer. 1984. Fundamentals of Neuropsychopharmacology. Sunderland, Mass: Sinauer Associates.

Flodin, U, B Söderfeldt, H Noorlind-Brage, M Fredriksson, and O Axelson. 1988. Multiple sclerosis, solvents and pets: A case-referent study. Arch Neurol 45:620-623.

Fratiglioni L, A Ahlbom, M Viitanen and B Winblad. 1993. Risk factors for late-onset Alzheimer’s disease: a population-based case-control study. Ann Neurol 33:258-66.

Goldsmith, JR, Y Herishanu, JM Abarbanel, and Z Weinbaum. 1990. Clustering of Parkinson’s disease points to environmental etiology. Arch Environ Health 45:88-94.

Graves, AB, CM van Duijn, V Chandra, L Fratiglioni, A Heyman, AF Jorm, et al. 1991. Occupational exposure to solvents and lead as risk factors for Alzheimer’s disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 20 Suppl. 2:58-61.

Grönning, M, G Albrektsen, G Kvåle, B Moen, JA Aarli, and H Nyland. 1993. Organic solvents and multiple sclerosis. Acta Neurol Scand 88:247-250.

Gunnarsson, L-G, L Bodin, B Söderfeldt, and O Axelson. 1992. A case-control study of motor neuron disease: Its relation to heritability and occupational exposures, particularly solvents. Br J Ind Med 49:791-798.

Hänninen, H and K Lindstrom. 1979. Neurobehavioral Test Battery of the Institute of Occupational Health. Helsinki: Institute of Occupational Health.

Hagberg, M, H Morgenstem, and M Kelsh. 1992. Impact of occupations and job tasks on the prevalence of carpal tunnel syndrome. Scand J Work Environ Health 18:337-345.

Hart, DE. 1988. Neuropsychological Toxicology: Identification and Assessment of Human Neurotoxic Syndromes. New York: Pergamon Press.

Hawkes, CH, JB Cavanagh, and AJ Fox. 1989. Motorneuron disease: A disorder secondary to solvent exposure? Lancet 1:73-76.

Howard, JK. 1979. A clinical survey of paraquat formulation workers. Br J Ind Med 36:220-223.

Hutchinson, LJ, RW Amsler, JA Lybarger, and W Chappell. 1992. Neurobehavioral Test Batteries for Use in Environmental Health Field Studies. Atlanta: Agency for Toxic Substances and Disease Registry (ATSDR).

Johnson, BL. 1987. Prevention of Neurotoxic Illness in Working Populations. Chichester: Wiley.

Kandel, ER, HH Schwartz, and TM Kessel. 1991. Principles of Neural Sciences. New York: Elsevier.

Kukull, WA, EB Larson, JD Bowen, WC McCormick, L Teri, ML Pfanschmidt, et al. 1995. Solvent exposure as a risk factor for Alzheimer’s disease: A case-control study. Am J Epidemiol 141:1059-1071.

Landtblom, A-M, U Flodin, M Karlsson, S Pålhagen, O Axelson, and B Söderfeldt. 1993. Multiple sclerosis and exposure to solvents, ionizing radiation and animals. Scand J Work Environ Health 19:399-404.

Landtblom, A-M, U Flodin, B Söderfeldt, C Wolfson and O Axelson. 1996. Organic solvents and multiple sclerosis: A synthesis of the cement evidence. Epidemiology 7: 429-433.

Maizlish, D and O Feo. 1994. Alteraciones neuropsicológicas en trabajadores expuestos a neurotóxicos. Salud de los Trabajadores 2:5-34.

Mergler, D. 1995. Behavioral neurophysiology: Quantitative measures of sensory toxicity. In Neurotoxicology: Approaches and Methods, edited by L Chang and W Slikker. New York: Academic Press.

O’Donoghue, JL. 1985. Neurotoxicity of Industrial and Commercial Chemicals. Vol. I & II. Boca Raton: CRC Press.

Sassine, MP, D Mergler, F Larribe, and S Bélanger. 1996. Détérioration de la santé mentale chez des travailleurs exposés au styrène. Rev epidmiol med soc santé publ 44:14-24.

Semchuk, KM, EJ Love, and RG Lee. 1992. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 42:1328-1335.

Seppäläinen, AMH. 1988. Neurophysiological approaches to the detection of early neurotoxicity in humans. Crit Rev Toxicol 14:245-297.

Sienko, DG, JD Davis, JA Taylor, and BR Brooks. 1990. Amyotrophic lateral sclerosis: A case-control study following detection of a cluster in a small Wisconsin community. Arch Neurol 47:38-41.

Simonsen, L, H Johnsen, SP Lund, E Matikainen, U Midtgård, and A Wennberg. 1994. Evaluation of neurotoxicity data: A methodological approach to classification of neurotoxic chemicals. Scand J Work Environ Health 20:1-12.

Sobel, E, Z Davanipour, R Sulkava, T Erkinjuntti, J Wikström, VW Henderson, et al. 1995. Occupations with exposure to electromagnetic fields: A possible risk factor for Alzheimer’s disease. Am J Epidemiol 142:515-524.

Spencer, PS and HH Schaumburg. 1980. Experimental and Clinical Neurotoxicology. Baltimore: Williams & Wilkins.

Tanner, CM. 1989. The role of environmental toxins in the etiology of Parkinson’s disease. Trends Neurosci 12:49-54.

Urie, RL. 1992. Personal protection from hazardous materials exposures. In Hazardous Materials Toxicology: Clinical Principles of Environmental Health, edited by JB Sullivan and GR Krieger. Baltimore: Williams & Wilkins.

World Health Organization (WHO). 1978. Principles and Methods of Evaluating the Toxicity of Chemicals, Part 1 and 2. EHC, No. 6, Part 1 and 2. Geneva: WHO.

World Health Organization and Nordic Council of Ministers. 1985. Chronic Effects of Organic Solvents On the Central Nervous System and Diagnostic Criteria. EHC, No. 5. Geneva: WHO.

Zayed, J, G Ducic, G Campanella, JC Panisset, P André, H Masson, et al. 1990. Facteurs environnementaux dans l’étiologie de la maladie de Parkinson. Can J Neurol Sci 17:286-291.