Definition of Neurotoxicity

Neurotoxicity refers to the capability of inducing adverse effects in the central nervous system, peripheral nerves or sensory organs. A chemical is considered to be neurotoxic if it is capable of inducing a consistent pattern of neural dysfunction or change in the chemistry or structure of the nervous system.

Neurotoxicity is generally manifested as a continuum of symptoms and effects, which depend on the nature of the chemical, the dose, the duration of exposure and the traits of the exposed individual. The severity of the observed effects, as well as the evidence for neurotoxicity, increases through levels 1 to 6, shown in Table 1. Short-term or low-dose exposure to a neurotoxic chemical may result in subjective symptoms such as headache and dizziness, but the effect usually is reversible. With increasing dose, neurological changes may show up, and eventually irreversible morphological changes are generated. The degree of abnormality needed for implying neurotoxicity of a chemical agent is a controversial issue. According to the definition, a consistent pattern of neural dysfunction or change in the chemistry or structure of the nervous system is considered if there is well-documented evidence for persistent effects on level 3, 4, 5 or 6 in Table 1. These levels reflect the weight of evidence provided by different signs of neurotoxicity. Neurotoxic substances include naturally occurring elements such as lead, mercury and manganese; biological compounds such as tetrodotoxin (from the puffer fish, a Japanese delicacy) and domoic acid (from contaminated mussels); and synthetic compounds including many pesticides, industrial solvents and monomers.

Table 1. Grouping neurotoxic effects to reflect their relative strength for establishing neurotoxicity

¹ Humans only
Source: Modified from Simonsen et al. 1994.

In the United States between 50,000 and 100,000 chemicals are in commerce, and 1,000 to 1,600 new chemicals are submitted for evaluation each year. More than 750 chemicals and several classes or groups of chemical compounds are suspected to be neurotoxic (O’Donoghue 1985), but the majority of chemicals have never been tested for neurotoxic properties. Most of the known neurotoxic chemicals available today have been identified by case-reports or through accidents.

Although neurotoxic chemicals often are produced to fulfil specific uses, exposure may arise from several sources—use in private homes, in agriculture and in industries, or from polluted drinking water and so on. Fixed a priori preconceptions about which neurotoxic compounds are expected to be found in which occupations should therefore be viewed with caution, and the following citations should be looked upon as possible examples including a few of the most common neurotoxic chemicals (Arlien-Søborg 1992; O’Donoghue 1985; Spencer and Schaumburg 1980; WHO 1978).

Symptoms of Neurotoxicity

The nervous system generally reacts rather stereotypically to exposure to neurotoxic substances Figure 1. Some typical syndromes are indicated below.

Figure 1. Neurological and behavioural effects of exposure to neurotoxic chemicals.

Polyneuropathy

This is caused by impairment of motor and sensory nerve function leading to weakness of the muscles, with paresis usually most pronounced peripherally in the upper and lower extremities (hands and feet). Prior or simultaneous paraesthesia (tingling or numbness in the fingers and toes) may occur. This may lead to difficulties in walking or in the fine coordination of hands and fingers. Heavy metals, solvents and pesticides, among other chemicals, may result in such disability, even if the toxic mechanism of these compounds may be totally different.

Encephalopathy

This is caused by a diffuse impairment of the brain, and may result in fatigue; impairment of learning, memory and ability to concentrate; anxiety, depression, increased irritability and emotional instability. Such symptoms may indicate early diffuse degenerative brain disorder as well as occupational chronic toxic encephalopathy. Often increased frequency of headaches, dizziness, changes in sleep pattern and reduced sexual activity may also be present from the early stages of the disease. Such symptoms may develop following long-term, low-level exposure to several different chemicals such as solvents, heavy metals or hydrogen sulphide, and are also seen in several dementing disorders not related to work. In some cases more specific neurological symptoms can be seen (e.g., Parkinsonism with tremor, rigidity of the muscles and slowing of movements, or cerebellar symptoms such as tremor and reduced coordination of hand movements and gait). Such clinical pictures can be seen following exposure to some specific chemicals such as manganese, or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in the former condition, and toluene or mercury in the latter.

Gases

A wide variety of chemicals with totally different chemical structures are gases at normal temperature and have been proven neurotoxic Table 3. Some of them are extremely toxic even in very small doses, and have even been used as war gases (phosgene and cyanide); others require high doses over longer periods to give symptoms (e.g., carbon dioxide). Some are used for general anaesthesia (e.g., nitrous oxide); others are widely used in industry and in agents used for disinfection (e.g., formaldehyde). The former may induce irreversible changes in the nervous system after repeated low-level exposure, the latter apparently produce only acute symptoms. Exposure in small rooms with poor ventilation is particularly hazardous. Some of the gases are odourless, which makes them particularly dangerous (e.g., carbon monoxide). As shown in Table 2, some gases are important constituents in industrial production, while others are the result of incomplete or complete combustion (e.g., CO and CO₂ respectively). This is seen in mining, steel works, power stations and so on, but may also be seen in private homes with insufficient ventilation. Essential for treatment is to stop further exposure and provide fresh air or oxygen, and in severe cases artificial ventilation.

Table 2. Gases associated with neurotoxic effects

¹ M: mechanism; A: acute effects; C: chronic effects.
Neuropathy: dysfunction of motor- and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain.
Ataxia: impaired motor coordination.

Metals

As a rule the toxicity of metals increases with increasing atomic weight, lead and mercury being particularly toxic. Metals are usually found in nature at low concentrations, but in certain industries they are used in great amounts (see Table 3) and may give rise to occupational risk for the workers. Moreover, considerable amounts of metals are found in waste water and may give rise to environmental risk for the residents close to the plants but also at greater distances. Often the metals (or, for example, organic mercury compounds) are taken up into the food chain and will accumulate in fish, birds and animals, representing a risk for consumers. The toxicity and the way in which the metals are handled by the organism may depend on the chemical structure. Pure metals may be taken up by inhalation or skin contact of vapour (mercury) and/or small particles (lead), or orally (lead). Inorganic mercury compounds (e.g., HgCl₂) are mainly taken up by mouth, while organic metal compounds (e.g., tetraethyl lead) mainly are taken up by inhalation or by skin contact. The body burden may to a certain degree be reflected in the concentration of metal in the blood or urine. This is the basis for biological monitoring. In treatment it must be recalled that especially lead is released very slowly from deposits in the body. The amount of lead in bones will normally be reduced by only 50% over 10 years. This release may be speeded up by the use of chelating agents: BAL (dimercapto-1-propanol), Ca-EDTA or penicillamine.

Table 3. Metals and their inorganic compounds associated with neurotoxicity

¹ M: mechanism; A: acute effects; C: chronic effects.
Neuropathy: dysfunction of motor- and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain.

Monomers

Monomers constitute a large, heterogeneous group of reactive chemicals used for chemical synthesis and production of polymers, resins and plastics. Monomers comprise polyhalogenated aromatic compounds such as p-chlorobenzene and 1,2,4-trichlorbenzene; unsaturated organic solvents such as styrene and vinyltoluene, acrylamide and related compounds, phenols, ɛ-caprolactam and ζ-aminobutyrolactam. Some of the widely used neurotoxic monomers and their effect on the nervous system are listed in Table 3. Occupational exposure to neurotoxic monomers may take place at industries manufacturing, transporting and using chemical products and plastic products. During handling of polymers containing rest monomers, and during moulding in boat yards and in dental clinics, a substantial exposure to neurotoxic monomers takes place. Upon exposure to these monomers uptake may take place during inhalation (e.g., carbon disulphide and styrene) or by skin contact (e.g., acrylamide). As monomers are a heterogeneous group of chemicals, several different mechanisms of toxicity are likely. This is reflected by differences in symptoms (Table 4).

Table 4. Neurotoxic monomers

¹ M: mechanism; A: acute effects; C: chronic effects.
Neuropathy: dysfunction of motor and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain.
Ataxia: impaired motor coordination.

Organic solvents

Organic solvents is a common designation for a large group of more than 200 lipophilic chemical compounds capable of dissolving fats, oils, waxes, resins, rubber, asphalt, cellulose filaments and plastic materials. They are usually fluids at room temperature with boiling points below 200 to 250°C, and are easily evaporated. They are mainly taken up via the lungs but some may penetrate the skin as well. Due to their lipophilicity they are distributed to organs rich in fat. Thus high concentrations are found in body fat, bone marrow, liver and brain, which also may act as reservoirs of solvents. The partition coefficient octanol/water can indicate whether high brain concentrations are to be expected. The mechanism of toxicity is not yet known, but several possibilities have been envisioned: blocking important enzymes in the metabolic breakdown of glucose and thus reducing energy available for neuronal processing; reducing energy formation in the mitochondria; changing neuronal membranes, leading to impairment of ion channel function; slowing of axonal flow. Methylene chloride is metabolized to CO, which blocks the transport of oxygen in the blood. Large groups of workers in a great variety of professions are exposed daily or at least frequently (see Table 5). In some countries the consumption of organic solvents has declined in some occupations due to hygienic improvements and substitution (e.g., house painters, graphic industry workers, metal workers), while in other occupations the pattern of exposure has changed but the total amount of organic solvents has remained unchanged. For example, trichloroethylene has been replaced by 1,1,1-trichloroethane and freon. So solvents are still a major hygienic problem at many workplaces. People are at particular risk when exposed in small rooms with poor ventilation and with high temperature, increasing the evaporation. Physical work increases the pulmonary uptake of solvents. In several countries (in particular the Nordic countries), compensation has been given to workers who have developed chronic toxic encephalopathy following long-term, low-level exposure to solvents.

Table 5. Organic solvents associated with neurotoxicity

 ¹ M: mechanism; A: acute effects; C: chronic effects.

Neuropathy: dysfunction of motor- and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain

Pesticides

Pesticides is used as a generic term for any chemical designed to kill groups of plants or animals that are a human health hazard or may cause economic loss. It includes insecticides, fungicides, rodenticides, fumigants and herbicides. Approximately 5 billion pounds of pesticide products made up of more than 600 active pesticide ingredients are annually used in agriculture worldwide. Organophosphorus, carbamate and organochlorine pesticides together with pyrethroids, chlorophenoxy herbicides and organic metal compounds used as fungicides have neurotoxic properties (Table 6). Among the many different chemicals used as rodenticides, some (e.g., strychnine, zinc phosphide and thallium) are neurotoxic too. Occupational exposure to neurotoxic pesticides is mainly associated with agricultural work such as pesticide handling and working with treated crops, but exterminators, pesticide manufacturing and formulating employees, highway and railway workers, as well as greenhouse, forestry and nursery workers may have a substantial risk of being exposed to neurotoxic pesticides as well. Children, who constitute a significant proportion of the agricultural workforce, are especially vulnerable because their nervous systems are not fully developed. The acute effects of pesticides are generally well described, and long-lasting effects upon repeated exposure or single high dose exposure are often seen (Table 6), but the effect of repeated subclinical exposure is uncertain.

Table 6. Classes of common neurotoxic pesticides, exposure, effects and associated symptoms

¹ M: mechanism; A: acute effects; C: chronic effects.
Neuropathy: dysfunction of motor and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain.
Ataxia: impaired motor coordination.
² Mainly phosphates or phosphonates.

Other chemicals

Several different chemicals which do not fit into the above-mentioned groups also possess neurotoxicity. Some of these are used as pesticides but also in different industrial processes. Some have well-documented acute and chronic neurotoxic effects; others have obvious acute effects, but the chronic effects are only poorly examined. Examples of these chemicals, their uses and effects are listed in Table 7.

Table 7. Other chemicals associated with neurotoxicity

¹ M: mechanism; A: acute effects; C: chronic effects.
Neuropathy: dysfunction of motor and sensory peripheral nerve fibres.
Encephalopathy: brain dysfunction due to generalized impairment of the brain.
Ataxia: impaired motor coordination

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Current knowledge of the short- and long-term manifestations of exposure to neurotoxic substances comes from experimental animal studies and human chamber studies, epidemiological studies of active and retired and/or diseased workers, clinical studies and reports, as well as large-scale disasters, such as those that occurred in Bhopal, following a leak of methyl isocyanate, and in Minamata, from methyl mercury poisoning.

Exposure to neurotoxic substances can produce immediate effects (acute) and/or long-term effects (chronic). In both cases, the effects can be reversible and disappear over time following reduction or cessation of exposure, or result in permanent, irreversible damage. The severity of acute and chronic nervous system impairment depends on exposure dose, which includes both the quantity and duration of exposure. Like alcohol and recreational drugs, many neurotoxic substances may initially be excitatory, producing a sensation of well-being or euphoria and/or speeding up motor functions; as the dose increases in quantity or in time, these same neurotoxins will depress the nervous system. Indeed, narcosis (a state of stupor or insensibility) is induced by a large number of neurotoxic substances, which are mind-altering and depress the central nervous system.

Acute Poisoning

Acute effects reflect the immediate response to the chemical substance. The severity of the symptoms and resulting disorders depends on the quantity that reaches the nervous system. With mild exposures, acute effects are mild and transient, disappearing when exposure ceases. Headache, tiredness, light-headedness, difficulty concentrating, feelings of drunkenness, euphoria, irritability, dizziness and slowed reflexes are the types of symptoms experienced during exposure to neurotoxic chemicals. Although these symptoms are reversible, when exposure is repeated day after day, the symptoms recur as well. Moreover, since the neurotoxic substance is not immediately eliminated from the body, symptoms can persist following work. Reported symptoms at a particular workstation are a good reflection of chemical interference with the nervous system and should be considered a warning signal for potential over-exposure; preventive measures to reduce exposure levels should be initiated.

If exposure is very high, as can occur with spills, leaks, explosions and other accidents, symptoms and signs of intoxication are debilitating (severe headaches, mental confusion, nausea, dizziness, incoordination, blurred vision, loss of consciousness); if exposure is high enough, effects can be long-lasting, possibly resulting in coma and death.

Acute pesticide-related disorders are a common occurrence among agricultural workers in food-producing countries, where large amounts of toxic substances are used as insecticides, fungicides, nematicides, and herbicides. Organophosphates, carbamates, organochlorines, pyrethrum, pyrethrin, paraquat and diquat are among the major categories of pesticides; however, there are thousands of pesticide formulations, containing hundreds of different active ingredients. Some pesticides, such as maneb, contain manganese, while others are dissolved in organic solvents. In addition to the symptoms mentioned above, acute organophosphate and carbamate poisoning may be accompanied by salivation, incontinence, convulsions, muscle twitching, diarrhoea, visual disturbances, as well as respiratory difficulties and a rapid heart rate; these result from an excess of the neurotransmitter acetylcholine, which occurs when these substances attack a chemical called cholinesterase. Blood cholinesterase decreases proportionally to the degree of acute organophosphate or carbamate intoxication.

With some substances, such as organophosphorus pesticides and carbon monoxide, high-level acute exposures can produce delayed deterioration of certain parts of the nervous system. For the former, numbness and tingling, weakness and disequilibrium can occur a few weeks after exposure, while for the latter, delayed neurologic deterioration can take place, with symptoms of mental confusion, ataxia, motor incoordination and paresis. Repeated acute episodes of high levels of carbon monoxide have been associated with later-life Parkinsonism. It is possible that high exposures to certain neurotoxic chemicals may be associated with an increased risk for neurodegenerative disorders later on in life.

Chronic Poisoning

Recognition of the hazards of neurotoxic chemicals has led many countries to reduce the permissible exposure levels. However, for most chemicals, the level at which no adverse effect will occur over long-term exposure is still unknown. Repeated exposure to low to medium levels of neurotoxic substances throughout many months or years can alter nervous system functions in an insidious and progressive manner. Continued interference with molecular and cellular processes causes neurophysiological and psychological functions to undergo slow alterations, which in the early stages may go unseen since there are large reserves in the nervous system circuitry and damage can, in the first stages, be compensated through new learning.

Thus, initial nervous system injury is not necessarily accompanied by functional disorders and may be reversible. However, as the damage progresses, symptoms and signs, often non-specific in nature, become apparent, and individuals may seek medical attention. Finally, impairment may become so severe that a clear clinical syndrome, generally irreversible, is manifest.

Figure 1 schematizes the health deterioration continuum associated with exposure to neurotoxic substances. Progression of neurotoxic dysfunction is dependent on both the duration and concentration of exposure (dose), and may be influenced by other workplace factors, individual health status and susceptibility as well as lifestyle, particularly drinking and exposure to neurotoxic substances used in hobbies, such as glues applied in furniture assembly or plastic model building, paints and paint removers.

Figure 1. Health deterioration on a continuum with increasing dosage

Different strategies are adopted for identification of neurotoxin-related illness among individual workers and for the surveillance of early nervous system deterioration among active workers. Clinical diagnosis relies on a constellation of signs and symptoms, coupled to the medical and exposure history for an individual; aetiologies other than exposure must be systematically ruled out. For the surveillance of early dysfunction among active workers, the group portrait of dysfunction is important. Most often, the pattern of dysfunction observed for the group will be similar to the pattern of impairment clinically observed in the disease. It is somewhat like summing early, mild alterations to produce a picture of what is happening to the nervous system. The pattern or profile of the overall early response provides an indication of the specificity and the type of action of the particular neurotoxic substance or mixture. In workplaces with potential exposure to neurotoxic substances, health surveillance of groups of workers may prove particularly useful for prevention and workplace action in order to avoid the development of more severe illness (see Figure 2). Workplace studies carried out throughout the world, with active workers exposed to specific neurotoxic substances or to mixtures of various chemicals, have provided valuable information on early manifestations of nervous system dysfunction in groups of exposed workers.

Figure 2. Preventing neurotoxicity at work.

Early symptoms of chronic poisoning

Altered mood states are most often the first symptoms of the initial changes in nervous system functioning. Irritability, euphoria, sudden mood changes, excessive tiredness, feelings of hostility, anxiousness, depression and tension are among the mood states most often associated with neurotoxic exposures. Other symptoms include memory problems, concentration difficulties, headaches, blurred vision, feelings of drunkenness, dizziness, slowness, tingling sensation in hands or feet, loss of libido and so on. Although in the early stages these symptoms are usually not sufficiently severe to interfere with work, they do reflect diminished well-being and affect one’s capacity to fully enjoy family and social relations. Often, because of the non-specific nature of these symptoms, workers, employers and occupational health professionals tend to ignore them and look for causes other than workplace exposure. Indeed, such symptoms may contribute to or aggravate an already difficult personal situation.

In workplaces where neurotoxic substances are used, workers, employers and occupational health and safety personnel should be particularly aware of the symptomatology of early intoxication, indicative of nervous system vulnerability to exposure. Symptom questionnaires have been developed for worksite studies and surveillance of workplaces where neurotoxic substances are used. Table 1 contains an example of such a questionnaire.

Table 1. Chronic symptoms checklist

Symptoms experienced in the past month

1.         Have you tired more easily than expected for the type of activity you do?

2.         Have you felt light-headed or dizzy?

3.         Have you had difficulty concentrating?

4.         Have you been confused or disoriented?

5.         Have you had trouble remembering things?

6.         Have your relatives noticed that you have trouble remembering things?

7.         Have you had to make notes to remember things?

8.         Have you found it hard to understand the meaning of newspapers?

9.         Have you felt irritable?

10.       Have you felt depressed?

11.       Have you had heart palpitations even when you are not exerting yourself?

12.       Have you had a seizure?

13.       Have you been sleeping more often than is usual for you?

14.       Have you had difficulty falling asleep?

15.       Have you been bothered by incoordination or loss of balance?

16.       Have you had any loss of muscle strength in your legs or feet?

17.       Have you had any loss of muscle strength in your arms or hands?

18.       Have you had difficulty moving your fingers or grasping things?

19.       Have you had hand numbness and tingling in your fingers lasting for more than a day?

20.       Have you had hand numbness and tinging in your toes lasting more than a day?

21.       Have you had headaches at least once a week?

22.       Have you had difficulty driving home from work because you felt dizzy or tired?

23.       Have you felt “high” from the chemicals used at work?

24.       Have you had a lower tolerance for alcohol (takes less to get drunk)?

Source: Taken from Johnson 1987.

Early motor, sensory and cognitive changes in chronicpoisoning

With increasing exposure, changes can be observed in motor, sensory and cognitive functions in workers exposed to neurotoxic substances, who do not present clinical evidence of abnormality. Since the nervous system is complex, and certain areas are vulnerable to specific chemicals, while others are sensitive to the action of a large number of toxic agents, a wide range of nervous system functions may be affected by a single toxic agent or a mixture of neurotoxins. Reaction time, hand-eye coordination, short-term memory, visual and auditory memory, attention and vigilance, manual dexterity, vocabulary, switching attention, grip strength, motor speed, hand steadiness, mood, colour vision, vibrotactile perception, hearing and smell are among the many functions that have been shown to be altered by different neurotoxic substances.

Important information on the type of early deficits that result from exposure has been provided by comparing performance between exposed and non-exposed workers and with respect to the degree of exposure. Anger (1990) provides an excellent review of worksite neurobehavioural research up to 1989. Table 2 adapted from this article, provides an example of the type of neuro-functional deficits that have been consistently observed in groups of active workers exposed to some of the most common neurotoxic substances.

Table 2. Consistent neuro-functional effects of worksite exposures to some leading neurotoxic substances

Source: Adapted from Anger 1990.

Although at this stage in the continuum from well-being to disease, loss is not in the clinically abnormal range, there can be health-related consequences associated with such changes. For example, decreased vigilance and reduced reflexes may put workers in greater danger of accidents. Smell is used to identify leaks and mask saturation (cartridge breakthrough), and acute or chronic loss of smell renders one less apt to identify a potentially hazardous situation. Mood changes may interfere with inter-personal relations at work, socially and in the home. These initial stages of nervous system deterioration, which can be observed by examining groups of exposed workers and comparing them to non-exposed workers or with respect to their degree of exposure, reflect diminished well-being and may be predictive of risk of more serious neurological problems in the future.

Mental health in chronic poisoning

Neuropsychiatric disorders have long been attributed to exposure to neurotoxic substances. Clinical descriptions range from affective disorders, including anxiety and depression, to manifestations of psychotic behaviour and hallucinations. Acute high-level exposure to many heavy metals, organic solvents and pesticides can produce delirium. “Manganese madness” has been described in persons with long-term exposure to manganese, and the well-known “mad hatter” syndrome results from mercury intoxication. Type 2a Toxic Encephalopathy, characterized by sustained change in personality involving fatigue, emotional lability, impulse control and general mood and motivation, has been associated with organic solvent exposure. There is growing evidence from clinical and population studies that personality disorders persist over time, long after exposure ceases, although other types of impairment may improve.

On the continuum from well-being to disease, mood changes, irritability and excessive fatigue are often the very first indications of over-exposure to neurotoxic substances. Although neuropsychiatric symptoms are routinely surveyed in worksite studies, these are rarely presented as a mental health problem with potential consequences on mental and social well-being. For example, changes in mental health status affect one’s behaviour, contributing to difficult inter-personal relationships and disagreements in the home; these in turn can aggravate one’s mental state. In workplaces with employee aid programmes, designed to help employees with personal problems, ignorance of the potential mental health effects of exposure to neurotoxic substances can lead to treatment dealing with the effects rather than the cause. It is interesting to note that among the many reported outbreaks of “mass hysteria” or psychogenic illness, industries with exposure to neurotoxic substances are over-represented. It is possible that these substances, which, for the large part, went unmeasured, contributed to the reported symptoms.

Mental health manifestations of neurotoxin exposure can be similar to those that are caused by psychosocial stressors associated with poor work organization, as well as psychological reactions to accidents, very stressful occurrences and severe intoxications, called post-traumatic stress disorder (as discussed elsewhere in this Encyclopaedia). A good understanding of the relation between mental health problems and working conditions is important to initiating adequate preventive and curative actions.

General considerations in assessing early neurotoxicdysfunction

When evaluating early nervous system dysfunction among active workers, a number of factors must be taken into account. Firstly, many of the neuropsychological and neurophysiological functions that are examined diminish with age; some are influenced by culture or educational level. These factors must be taken into account when considering the relation between exposure and nervous system alterations. This can be done by comparing groups with similar socio-demographic status or by using statistical methods of adjustment. There are, however, certain pitfalls that should be avoided. For example, older workers may have longer work histories, and it has been suggested that some neurotoxic substances may accelerate ageing. Job segregation may confine poorly educated workers, women and minorities in jobs with higher exposures. Secondly, alcohol consumption, smoking and drugs, which all contain neurotoxic substances, may also affect symptoms and performance. A good understanding of the workplace is important in unravelling the different factors that contribute to nervous system dysfunction and the implementation of preventive measures.

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A worker not exposed to a neurotoxic substance will never develop any adverse neurotoxic health effects from that substance. Zero exposure leads to total protection against neurotoxic health effects. This is the essence of all primary prevention measures.

Toxicity Testing

New chemical compounds introduced into the workplace and in occupational settings should have already been tested for neurotoxicity. Failure to do pre-market toxicity testing can lead to workers’ contact and potentially severe adverse health effects. The introduction of methyl n-butyl ketone into a workplace in the United States is a classic example of the possible hazards of untested neurotoxicants being introduced into the workplace (Spencer and Schaumburg 1980).

Engineering Controls

Engineering controls (e.g., ventilation systems, closed production facilities) are the best means for keeping workers’ exposures below permissible exposure limits. Closed chemical processes that keep all toxicants from being released into the workplace environment are the ideal. If this is not possible, closed ventilation systems that exhaust ambient air vapours and are designed so as to pull contaminated air away from workers are useful when well designed, adequately maintained, and properly operated.

Personal Protection Equipment

In situations where engineering controls are unavailable to reduce workers’ contact with neurotoxicants, personal protective equipment must be provided. Because workplace neurotoxicants are many, and routes of exposure differ across workplaces and work conditions, the kind of personal protective equipment must be carefully selected for the situation at hand. For example, the neurotoxicant lead can exert its toxicity when lead-laden dust is breathed and when lead particles are ingested in food or water. Therefore, personal protective equipment must protect against both routes of exposure. This would mean respiratory protection equipment and adoption of personal hygiene measures to prevent consumption of lead-contaminated food or beverages. For many neurotoxicants (like industrial solvents), absorption of the substance through intact skin is a main route of exposure. Impermeable gloves, aprons and other appropriate equipment must therefore be provided to prevent skin absorption. This would be in addition to engineering controls or personal respiratory protection equipment. Considerable planning must be given to match personal protective equipment to the specific work being performed.

Administrative Controls

Administrative controls consist of managerial efforts to reduce workplace hazards through planning, training, employee rotation on job sites, changes in production processes, and product substitution (Urie 1992), as well as strict adherence to all existing regulations.
Workers’ Right-to-Know

While the employer bears the responsibility for providing a workplace or work experience that does not harm workers’ health, workers have the responsibility to follow workplace rules that are intended to protect them. Workers must be in a position to know what actions to take in protecting themselves. This means workers have the right to know about the neurotoxicity of substances with which they come into contact, and what protective measures they can take.

Worker Health Surveillance

Where conditions permit, workers should be regularly given medical examinations. A regular evaluation by occupational physicians or other medical specialists constitutes worker health surveillance. For workers known to be working with or around neurotoxicants, physicians should be knowledgeable of the effects of exposure. For example, low-level exposure to many organic solvents will produce symptoms of fatigue, sleep disorders, headaches and memory disturbances. For heavy doses of lead, wrist drop and peripheral nerve impairment would be signs of lead intoxication. Any signs and symptoms of neurotoxicant intoxication should result in reassignment of the worker to an area free of the neurotoxicant, and efforts to reduce workplace levels of the neurotoxicant.

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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

 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.

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