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Numerous chemicals can produce neurotoxic disease in humans, but only a small fraction of chemicals has been adequately evaluated for neurotoxicity. In 2009, a conservative estimate set the number of neurotoxic chemicals in the workplace at more than 1,000.
Occupationally related neurotoxic disorders have been known since antiquity and continue to occur. The presence of chemical hazards in the workplace may result in several neurologic diseases. The variety of neurotoxic disorders reflects both the nature and the size of hazards, and the complex web of nervous system’s organisations, functions, and targets. The complexity of the nervous system results in a broad range of potential targets and adverse effects, since the activity of the nervous system maintains a balance between all the various organs in the body.
The article provides a general overview of occupational exposure to dangerous substances and the link with neurotoxicity. It provides definitions and an introduction to the most relevant neurotoxic agents and neurotoxic syndromes. The heavy metals lead, arsenic, manganese and mercury are considered as the most neurotoxic agents form the occupational point of view. Exposure to plant protection products and biocides can impact plethora of severe neurological diseases. Organic solvents exposure can cause acute and long-term neurological damage.
The nervous system functions as the coordinating centre of mammals. The nervous system acts as the coordination centre of mammals. It relies on the reception of sensory information from highly specialised organs in peripheral tissues. The input is further filtered, processed and transmitted through pathways and finally leads to appropriate responses to the initial stimulus.
Two nervous systems can be distinguished:
Central Nervous System (CNS) The CNS includes the brain and the spinal cord, and is protected by the blood-brain barrier.
Peripheral Nervous System (PNS) The PNS consists of nerves outside the brain and spinal cord, including the 12 cranial nerves and motor nerves, providing sensory information to the CNS from the limbs and extremities. The PNS is divided into the somatic (motor and sensory) and the autonomic nervous system. Within the nervous system, there are mainly two general types of cells: nerve cells (neurons) and neuroglial cells (Schwann cells, oligodendrocytes, astrocytes, microglia cells). Neurons have many of the same structures found in every cell of the body.
“All agents are poisons, and only the dose makes them nonpoisonous” (Paracelsus). Chemicals with the potential to disrupt the mammalian nervous system may occur naturally (neurotoxins) or arise by synthesis (neurotoxicants). Neurotoxicology has been described as the study of “adverse effects” of chemical agents, or toxins, on the structure and/or function of the nervous system . Neurotoxicity is an adverse change in the structure or function of the central nervous system and/or peripheral nervous system, following exposure to a chemical (natural or synthetic) or physical agent . A chemical is considered ‘neurotoxic’ if it is capable of inducing a consistent pattern of neuroanatomic change or neural dysfunction that causes physiologic or behavioural effects.
Neurological work-related diseases have presumably multifactorial aetiology, and the health risk after exposure depends on age, sex, genetic factors, socioeconomic and nutritional status, and environmental factors. Only a small fraction of chemicals has been documented to cause developmental neurotoxicity in humans. Especially organic solvents, heavy metals and plant protection products and biocides are implicated.
Exposure information is still insufficient and effects of long-term and/or low-level exposure are difficult to establish, but more and more studies indicate a link with the onset or progression of neurological diseases. Only two percent of all yearly registered occupational diseases in the period 2009-2013 in The Netherlands had a neurologic origin.
The neurotoxic effects may be hidden by compensatory mechanisms and regenerative abilities because of the reserve capacity and the ability to compensate of the nervous system. Possible chemically induced neurotoxic effects can be classified as: (1) direct versus indirect effects, (2) primary versus secondary effects, and (3) transient versus persistent effects. Neurotoxic effects occur when reserve capacity is insufficient or the compensation mechanisms fail. The chemical agents can disrupt neural functions. There are several neuroprotective mechanisms provided by supporting cell types and structures such as the blood-brain barrier. This barrier and similar structures in the peripheral nervous system modulate the access of some chemicals to the nervous system. In assessing the neurotoxicity of a substance, these mechanisms must be seriously considered. Further, the long prenatal and postnatal CNS development process makes the developing nervous system susceptible to certain exposures. Early maternity protection is important in preventing maternal occupational exposures to documented and suspected neurotoxic chemicals.
The chemical properties (e.g. solubility) of a given neurotoxic substance may indicate the resulting syndrome (e.g. inorganic and organic mercury). The same chemical may have different targets in the nervous system (e.g. acrylamide monomer effects depend on dose).
Although it is common practice to consider neurotoxic syndromes in terms of the toxic agents (e.g. heavy metals, organic solvents, plant protection products and biocides), the matching of chemical structure to neurotoxicity is imprecise and often unpredictable. The alternative is to consider neurotoxic syndromes in terms of their clinical presentation (e.g. encephalopathy, peripheral neuropathy, movement disorders).
Neurologic syndromes may also derive from working conditions related to particular occupations and tasks as explained in Table 1.
Table 1: Overview
In most cases the assessment of the neurotoxicity of chemicals needs to be based on data from animal experiments, in vitro cell cultures and in vivo. Data in humans from several epidemiological studies are infrequently available, but particularly valuable. The detection of neurotoxicity in human studies provides the most direct means of assessing health risks but is often complicated by confounding factors and inadequate data. The assessment is complicated by inter-individual and species differences in the response to toxic exposure and by the wide variety of potential effects that chemicals can have on the nervous system.
Human laboratory experiments have been performed for different combinations of solvents in experimental exposure studies. But, ethical considerations are of paramount importance in human studies.
Quite often the first information available to raise a level of concern is a single case report or a cluster of cases indicating the increased incidence of an adverse health effect. In the workplace, the occurrence of a particular neurotoxic disease in a specific occupational setting may constitute what is called a ‘sentinel health event’ (SHE). Some examples of neurotoxic SHE’s included: toxic encephalopathy due to lead exposure, parkinsonism due to manganese exposure, cerebellar ataxia due to organic mercury exposure a peripherical neuropathy due to exposure to n-hexane, methyl n-butyl ketone or other solvents. Because of the specificity of effects with these particular exposures, the occurrence of even a single case should alert (occupational health) physicians to the possibility of a neurotoxic disease . An EU-OSHA report (2018), reviewed the findings of a major project on alert and sentinel approaches to identify emerging occupational health risks and new work-related diseases .
Risk assessment is an empirically based process used to estimate the risk that exposure of an individual or population to an agent will result in an adverse effect. Hazard identification is the first stage in risk assessment, which consists of determining substances of concern and the adverse effects they may inherently have on target systems under certain conditions of exposure, taking into account toxicity data. The purpose is to evaluate the weight of evidence for adverse effects in humans based on the assessment of all available data. But collectively they permit a scientific judgement as to whether the chemical can cause adverse effects. Animal-to-human extrapolation is not without controversy. Dose-response assessment consists of analysing the relationship between the total amount of agent. Exposure assessment describes the magnitude, duration, frequency and routes of exposure (ingestion, inhalation, dermal penetration) to the agent(s) of interest. Exposure assessment is not simple and straightforward. Risk assessment is the qualitative and/or quantitative estimation, including attendant uncertainties, of the severity and probability of occurrence of known and potential adverse effects, based on hazard identification, dose-response assessment and exposure assessment. It is an integrative analysis and a summary of all findings. In the EU, the REACH Regulation (2006/1907/EC)  is a key legal instrument to improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances. One of the main reasons for developing and adopting the REACH Regulation was that a large number of substances have been manufactured and placed on the market in Europe for many years, sometimes in very high amounts, and yet there is insufficient information on the hazards that they pose to human health and the environment. There is a need to fill these information gaps to ensure that industry is able to assess hazards and risks of the substances, and to identify and implement the risk management measures to protect humans and the environment .
Carbon monoxide (CO) is a colourless, odourless, non-irritant gas absorbed through the lungs. CO is a product of incomplete combustion of hydrocarbons, leading to elevated air levels. Occupational situations in which (construction) workers may encounter significant levels of carbon monoxide include using LPG Liquefied petroleum gas (e.g. heaters, cookers) or petrol (e.g. generators, cut off saws) powered equipment in enclosed spaces, disruption of gas flues or ventilation during building refurbishment and inadequately installing new gas appliances. Also working in confined spaces may lead to CO intoxication. CO toxicity is a combination of tissue hypoxia-ischemia by the formation of COHb (carboxyhemoglobin) and direct cellular damage by CO. Described symptoms are headache, dizziness, nausea, fatigue, confusion, and memory problems. A chronic intermittent CO exposure shows cognitive impairment with neuropsychologic testing.
Metals make up the bulk of the periodic table and are therefore abundant in our environment . Toxicity to metals can result from malicious poisonings, environmental exposures, and occupational exposures. Neurotoxic effects of metals can be varied and will depend on the metal, dose, duration, and route of exposure. Reversibility of metal-induced neurotoxicity may not always be possible.
Aluminium (Al) is the third most common element on earth, found in several mineral deposits, such as mica, cryolite and bauxite. Al and Al alloys are widely used in industry, and this is the most used non-ferrous metal. Al compounds primarily occur as airborne particles in the workplace. The following operations may involve Al and lead to workers exposure to this substance: the processing and transportation of aluminium, the use in electrical transmission lines, the use in construction, manufacturing, explosives, petrochemical and paper industries, the use in sugar refining, alloying metals, as a chemical intermediate and in containers for fissionable reactor fuels, the use in testing for gold, arsenic and mercury.
There is no identified function for Al in the human body and exposure to Al can produce toxicity. While the CNS is not a target for acute Al exposures, the brain readily accumulates Al and can be affected over time. Studies in Al and steel welders have shown greater prevalence of concentration deficits, fatigue, emotional irritability, and depression in the welders exposed to Al. This shows that Al exposure can elicit specific neurotoxic effects. Al neurotoxicity does not resolve after cessation of exposure. For more than 20 years there have been much debate whether Al is involved in Alzheimer’s Disease, a very common neurodegenerative disease. Currently Al is thought to be a factor contributing to the development of Alzheimer’s Disease. However, the definite mechanism of Al toxicity is not known .
Arsenic (As) has been used since bronze age for strengthening alloys of copper and lead, an important process still in use. Manufacturing of As-containing products, mining, refining, and chemical synthesis of As compounds represent the major sources of occupational exposure. As can be found in pesticides, pharmaceuticals, pyrotechnics, glass and microelectronics. The toxicity of As has been appreciated since ancient times (‘poison of kings’, king of poisons’ because it wat the poison of choice of European royalty). Acute high exposure to As can lead to As encephalopathy, characterised by headache, confusion, seizure, coma, and death. Chronic exposure to low levels of As affect the peripherical nervous system. A peripheral neuropathy starts as a symmetric numbness of hands and feet, sensory changes, and muscle tenderness. It then progresses into muscle weakness and a painful pins-and-needles sensations   .
The toxic effects of lead (Pb) have been appreciated for centuries. While Pb occurs naturally in the environment as ores with other metals (galena, anglesite, cerussite), the highest levels occur in nature due to human activities. Professions that have the highest risk for Pb exposure include recycling of batteries, car repair, Pb paint removal, demolition, refining, welding, and smelting. Regulations have reduced the amount of Pb poisoning in the workplace, however the regulations are not strictly followed in some professions. In occupational settings exposure occurs typically through inhalation. Inorganic Pb affects several organ systems, also the CNS and the PNS. Severe chronic exposures to Pb lead to ‘Pb encephalopathy’, characterised by insomnia, poor attention, vomiting, convulsions, and coma. Chronic exposure to low levels of Pb has less severe neurologic and behavioural effects, such as decreased libido, mood changes, headache, depression, decreased dexterity and reaction time, dizziness, fatigue, forgetfulness, lethargy, and impaired concentration. Demyelination of peripheral neurons severely affects conductance and leads to incoordination, muscle weakness, and pain. Organic Pb is primarily a CNS toxin. The clinical symptoms of exposure to lead include lethargy, inappetence, tremor, hypermotility, hyperexcitability, aggression, psychosis, hypothermia, convulsion, incoordination, ataxia, and paralysis. Finally, leading to the death of the exposed individual. Lead exposure has been demonstrated to result in an acute or chronic progressive neurologic disorder in which fine tremors are a prominent feature. Tremors may manifest as an early symptom of Pb poisoning within weeks of initial exposure   .
Manganese (Mn) is the 12th most abundant element on earth and is found in a variety of ores, the most important for industry being pyrolusite (MnO2). Mn can exist in 11 different oxidation states. Mn is used in a wide range of industrial processes and commercial products. Mn is an essential element for humans (‘trace metal’), entering our diet in foods such as grains, nuts, chocolate, mussels, seeds and spices. Mn is essential for steel, and stainless-steel production and formation of aluminium alloys. Occupational exposure to Mn is the primary cause of human Mn intoxication. Exposure to Mn in occupational settings is predominantly inhalational and caused by industrial processes utilizing Mn that involve welding, smelting, or the creation of fine dusts. Exposure to high levels or chronic low-level of Mn can cause ‘manganism’ characterised by psychiatric symptoms, extrapyramidal features and dystonia. These symptoms are often preceded by other symptoms, including irritability, aggressiveness, and hallucinations. The extrapyramidal symptoms arising in Mn-exposed individuals include headaches, facial muscular cramps, fatigue, psychosis, and hypertonia with cogwheel rigidity. For manganese there is also an occupational link to parkinsonism  .
Mercury (Hg) is a highly toxic element which occurs as three different species: elemental Hg, inorganic Hg compounds and organic Hg compounds (MeHg, ethylmercury). These species have different chemical properties utilised in industrial processes. Hg is primarily used for the manufacture of industrial chemicals or for electrical and electronic applications. The use in thermometers is declining since the early 21st century. Additionally, the three species have different toxicologic effects following exposure. Acute exposures to elemental Hg vapour do not generally affect the CNS but cause respiratory distress and dyspnea. Chronic exposures, however, can induce tremors, delusions, memory loss, erethism, anxiety and cognition problems. Inorganic mercurous and mercuric compounds do not affect the CNS. Organomercury compounds have been long recognised as neurotoxic, the most well characterised being methylmercury, the most toxic among metals. It affects the CNS by causing psychiatric disturbances, ataxia, visual loss, hearing loss and neuropathy. Elemental, organic, and inorganic mercury have long been established as potent neurotoxicants capable of inducing both resting and intentional tremors. Tremors and irritability are the most prominent symptoms of inhaled elemental mercury. Similar to Pb, the tremors can occur after both acute high-concentration mercury exposures and chronic low-concentration mercury exposures   .
‘Organic solvents’ is a common designation for a large group of more than 200 chemical compounds capable of dissolving nonwatery-soluble materials such as paints and coatings, fats, oils, waxes, resins, rubber, asphalt, cellulose filaments, adhesives, inks, and plastic materials. Graphic industry, electronic industry, plastic industry, dry cleaning, industrial cleaning, polystyrene production, are also concerned . Organic solvents include aliphatic, aromatic, or chlorinated hydrocarbons and alcohols, ethers, esters, ketones, carbon disulfide, and fuels. They have one common feature, that is their lipophilicity and thereby affinity for the nervous system. Solvents are metabolised mainly in the liver and they accumulate to lipid-rich tissues such as the brain. Solvent products are often mixtures of chemical substances. They enter the body mainly by inhalation and most solvents also penetrate through the skin. In some work settings (e.g. painting, printing, cleaning), dermal exposure to certain solvents like acetone, toluene, m-xylene may be an important exposure route . Aromatic and halogenated hydrocarbons are considered more neurotoxic than other hydrocarbons and alcohols. Acute high solvent exposure causes symptoms such as nausea, headache, dizziness, disequilibrium, disorientation, euphoria, and feeling of drunkenness. Exposure to very high solvent concentrations may lead to unconsciousness, convulsions, and death . Tremors may be the first symptom reported as a result of solvent exposure. Solvents that are still widely used and are commonly associated with tremor includes carbon disulfide, toluene, xylene, n-hexane, TCE, and perchloroethylene. Chronic adverse effects of solvents were called ‘psycho-organic syndrome’ or ‘organic solvent syndrome’ in the 1960s in Finland, before adopting the name ‘chronic solvent encephalopathy’ in 1980s. Since 1990, CSE is included in the European Schedule of Occupational Diseases . Encephalopathies due to organic solvents are included under code 135 in the list with occupational diseases . Good occupational hygiene practice is the mainstay of managing solvent exposures .
Carbon disulfide (CS2) is mainly used in the manufacture of viscose rayon and cellophane film. It is also used to produce rubber chemicals and pesticides. Workers exposed to concentrations of CS2 air may suffer neurotoxic diseases such as multiple brain infarctions and peripheral neuropathy. The basic mechanisms involved are atherosclerotic changes in the blood vessels resulting in clinical manifestations of vascular encephalopathy (hemiparesis, speech disturbance) are similar to those observed in patients with atherosclerotic cerebrovascular disorders .
Preventing CSE should be based on avoiding exposure to organic solvents and there are already legislative measures in place to reduce or ban the use of organic solvents. For instance, trichloroethylene (TCE) (a neurotoxic but also a carcinogenic substance) has been added to the REACH Authorisation List and in 2022 a report from ECHA concluded that over 95% of uses of TCE within the scope of authorisation have been phased out in the EU since the substance was added to the Candidate list in 2010 . Although the restrictions on its use, TCE is still widely used in the degreasing of metals, as an intermediate for hydrofluorocarbon production, and as a solvent in printing inks, paints, lacquers, varnishes, adhesives, and paint strippers. It's also used as an anaesthetic given its properties as a CNS depressant.
TCE exposure causes concentration-related CNS effects. Typical symptoms of exposure to lower levels of trichloroethylene (>500 ppm) include excitation, light-headedness, headache, nausea, incoordination, and impaired ability to concentrate. At higher doses (>1,000 ppm), lack of muscle tone, decreased deep-tendon reflexes, drowsiness, dizziness, impaired gait, and stupor may develop. Death may result from respiratory depression . If exposure cannot be avoided, appropriate control measures should be in place to minimise exposure as much as possible (e.g. reducing the amounts that are used, adapting the work techniques, local exhaust ventilation, etc.), as well as good personal hygiene practices Monitoring of workers’ solvent exposure by personal sampling and biological monitoring may be indicated .
Plant protection products and biocides
Plant protection products (PPPs) and biocides (often called “pesticides”) are a broad class of compounds used in both agricultural as well as household settings to control or eliminate various nuisance plants, insects, or animals that could impact human and crop health. Pesticides may include compounds formulated to manage rodents (rodenticides), fungi (fungicides), plants (herbicides), and insects (insecticides) through various mechanisms of action that may be specially formulated to target the CNS of pests, such as insecticides, or may affect the function of other cellular components, leading to death .
By far the most widely used pesticides are insecticides. The most prominent classes of insecticides are organochlorines, organophosphates, pyrethroids, and rotenoids. Most studies have focused on the risk of Parkinson’s Disease associated with exposure to organochlorines (DDT, dieldrin, lindane, …), but also organophosphates and rotenoids are known for their neurotoxic effects .
Herbicides are a broad class of pesticides that are used to remove nuisance plants, such as grasses and weeds, that may compromise the growth and yield of desired crops that are in close proximity. Glyphosate is used as herbicide in agriculture, horticulture and in some non-cultivated areas. This herbicide can diffuse across the blood-brain barrier and cause neurotoxic effects. Glyphosate is the subject of much debate in the EU because of its suspected link to harmful chronic health effects. Glyphosate is currently approved in the EU until 15 December 2022 and can be used as an active substance in plant protection products until that date. To evaluate its safety, the Committee for Risk Assessment (RAC) has carried out a study and concluded that the current classification of glyphosate as causing serious eye damage and being toxic to aquatic life needs no change. Based on a wide-ranging review of scientific studies, the RAC found no evidence for acute or chronic neurotoxic effects. It also concluded that classifying glyphosate as a carcinogen is not justified  .
Fungicidal compounds are used to combat fungal diseases in plants. The most widely used class of fungicides is dithiocarbamates, which include compounds such as maneb, ziram, and mancozeb. In addition, compounds like captan, folpet, and benomyl, which have a similar structure to the dithiocarbamates, have been extensively used. The neurotoxic effects of the dithiocarbamate compounds, maneb, and ziram, has been extensively studied, either as singular exposures or in conjunction with other pesticides, such as paraquat. A significant amount of data show generalised, severe toxicity of these compounds following exposure, with symptoms including dermal irritation, endocrine disruption, tremor development, some effects on the CNS. Common tremor-inducing pesticides that have been used for the past 50 years include organophosphates and carbamate agents .
The typical signs and symptoms of possible exposure to neurotoxic agents must be identified and recognised in order to a better handling of occupational neurologic diseases. An early recognition of toxicity, decreasing sources of exposure through the implementation of recommended exposure limits, protective protocol, and safety measures. The Chemical Agents Directive (98/24/EC – CAD) contains obligations for employers to control risks associated with exposure to hazardous substances. These include the responsibility to carry out risk assessments in order to identify and evaluate the risks of exposure to hazardous substances, and the responsibility to take appropriate preventive measures that effectively control exposure. Occupational exposure limits (OELs) play a key role in prevention strategies. The CAD defines an OEL as the limit of the time-weighted average of a chemical agent in the air within the breathing zone of a worker in relation to a specified reference period. In the framework of the CAD, specific directives provide indicative occupational exposure limits (IOELs). IOELs determine threshold exposure levels below which exposure is not expected to lead to adverse effects. The IOELs provide valuable information for workplaces for developing prevention strategies and IOELs have been set for many neurotoxic substances. An example is Carbon Monoxide (CO). The Long-Term Exposure Limit (LTEL) of CO is 23 mg/m3 (or 20 ppm, parts per million), and the Short-Term Exposure Limit (STEL) is 117 mg/m3 (or 100 ppm) . Since 2019, the scientific evaluation of the relationship between the health effects of hazardous chemical agents and the level of occupational exposure in order to determine OELs is conducted by the Risk Assessment Committee (RAC) of the European Chemicals Agency (ECHA) . Some neurotoxic chemicals are also known carcinogens (e.g. Trichloroethylene (TCE)), and some of these chemicals are considered as non-threshold chemicals (if it is not possible to determine a threshold below which adverse effects may occur). A more stringent legislation applies to CMR (The Carcinogens, Mutagens and Reprotoxins Directive 2004/37/EC – CMRD) . For carrying out a workplace risk assessment, information on chemicals available on the label and in the Safety Data Sheet is crucial. The labelling of chemicals is governed by the CLP regulation (Classification, Labelling and Packaging of substances and mixtures Regulation 1272/2008/EC) . CLP does not have a specific classification for neurotoxins but depending on their chemical characteristics these chemicals are classified as chronic hazardous to health (Specific Target Organ Toxicity – Single Exposure (STOT-SE), Specific Target Organ Toxicity – Repeated Exposure (STOT-RE) or Carcinogenic/Mutagenic/Reprotoxic). The Hazard-sentence, H372 ‘Causes damage to organs through prolonged or repeated exposure – Affected organs: cardiovascular system, nervous system, eyes, peripheral nervous system’, is an example for a neurotoxic agent. Prevention relies on strategies designed to control exposure. These strategies need to focus especially on substitution of neurotoxic chemicals by less hazardous chemicals. Substitution requires a thorough understanding of the potential risks of the current chemical and the alternative product. Deciding on substituting a neurotoxic substance by a less hazardous one requires a step-by-step approach. The SUBSPORT webportal  provides practical information and case studies with exampled of workplace that have replaced neurotoxins by less hazardous products. If a substitute is not available or if the alternative product does not eliminate all risks, engineering controls (e.g. ventilation systems, closed production facilities) should be used to prevent or minimise exposure. As a last resort and if needed to prevent health effects, workers should wear personal protective equipment (PPE) to reduce skin and respiratory absorption. Workers should undergo initial and periodic medical examinations during the worker health surveillance to evaluate both the acute and chronic effects of exposure to known and suspected neurotoxic agents. Occupational health physicians should be knowledgeable of these effects.
The potential health risks from exposure to omnipresent toxic occupational agents is a major health issue. Numerous chemicals can produce direct or indirect effects neurotoxic disease in humans. Toxicology is becoming one of the most prominent fields of interest in occupational settings. Neurotoxicology is the study that studies these adverse effects on the structure and/or function of the nervous system. More attention is needed in at least two areas: the long-term exposure to low concentrations of neurotoxins, and the long-term health effects of acute poisoning. Prevention relies on strategies designed to control exposure at the workplace. Especially organic solvents, metals and pesticides are involved in occupational neurological diseases. However, of the thousands of chemicals in use today, only a small fraction has been documented to cause neurotoxicity in humans. Exposure information is still insufficient and effects of low-level exposure are difficult to establish, but more and more studies indicate a link with the onset or progression of neurological diseases.
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