The following lecture has been approved for University Undergraduate Students

1. The following lecture has been approved for University Undergraduate Students This lecture may contain information, ideas, concepts and discursive anecdotes that may be thought provoking and challenging It is not intended for the content or delivery to cause offence Any issues raised in the lecture may require the viewer to engage in further thought, insight, reflection or critical evaluation

2. Neurotoxicants Dr. Craig Jackson Senior Lecturer in Health Psychology Faculty of Health BCU www.health.bcu.ac.uk/craigjackson craig.jackson@uce.ac.uk

3. Neurotoxins 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).

4. Neurotoxins Any substance capable of interfering with the normal function of nervous tissue Causing irreversible cellular damage Or resulting in cellular death Neurotoxin will attack selected sites or specific cellular elements of the nervous system 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.

5. Neurotoxins The type and size of cells; various neurotransmitter systems affected; different regions of the brain; innate protective detoxifying mechanisms; 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.

6. Neurotoxins Toxicant effects: alter protein form; fluid content; 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.

7. Neurotoxins • Clinical manifestations of neurotoxicity are determined by: • 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; • the reparative abilities of the structures and mechanisms affected.

8. METALS: Arsenic SOURCE Pesticides; pigments; antifouling paint; electroplating industry; seafood; smelters; semiconductors DIAGNOSIS Acute: encephalopathyChronic: peripheral neuropathy LOCUS OF PATHOLOGY Unknown (a)Axon (c)

9. METALS: Lead SOURCE Solder; lead shot; illicit whiskey; insecticides; auto body shop; storage battery manufacturing; foundries, smelters; lead-based paint; lead pipes DIAGNOSIS Acute: encephalopathyChronic: encephalopathy and peripheral neuropathy LOCUS OF PATHOLOGY Blood vessels (a)Axon (c)

10. METALS: Manganese SOURCE Iron, steel industry; welding operations; metal-finishing operations; fertilizers; manufacturers of fireworks, matches; manufacturers of dry cell batteries DIAGNOSIS Acute: encephalopathyChronic: parkinsonism LOCUS OF PATHOLOGY Unknown (a)Basal ganglia neurons (c)

11. METALS: Mercury SOURCE Scientific instruments; electrical equipment; amalgams; electroplating industry; photography; felt making DIAGNOSIS Acute: headache, nausea, onset of tremorChronic: ataxia, peripheral neuropathy, encephalopathy LOCUS OF PATHOLOGY Unknown (a)Axon (c)Unknown (c)

12. METALS: Tin SOURCE Canning industry; solder; electronic components; polyvinyl plastics; fungicides DIAGNOSIS Acute: memory defects, seizures, disorientationChronic: encephalomyelopathy LOCUS OF PATHOLOGY Neurons of the limbic system (a & c)Myelin (c)

13. SOLVENTS: Carbon Disulphide SOURCE Manufacturers of viscose rayon; preservatives; textiles; rubber cement; varnishes; electroplating industry DIAGNOSIS Acute: encephalopathyChronic: peripheral neuropathy, parkinsonism LOCUS OF PATHOLOGY Unknown (a)Axon (c)Unknown

14. SOLVENTS: n-hexane, methyl butyl ketone SOURCE Paints; lacquers; varnishes; metal-cleaning compounds; quick-drying inks; paint removers; glues, adhesives DIAGNOSIS Acute: narcosisChronic: peripheral neuropathy, unknown (a) Axon (c), LOCUS OF PATHOLOGY

15. SOLVENTS: Perchloroethylene SOURCE Paint removers; degreasers; extraction agents; dry cleaning industry; textile industry DIAGNOSIS Acute: narcosisChronic: peripheral neuropathy, encephalopathy LOCUS OF PATHOLOGY Unknown (a)Axon (c)Unknown

16. SOLVENTS: Toluene SOURCE Rubber solvents; cleaning agents; glues; manufacturers of benzene; gasoline, aviation fuels; paints, paint thinners; lacquers DIAGNOSIS Acute: narcosisChronic: ataxia, encephalopathy LOCUS OF PATHOLOGY Unknown (a)Cerebellum (c)Unknown

17. SOLVENTS: Trichloroethylene SOURCE Degreasers; painting industry; varnishes; spot removers; process of decaffeination; dry cleaning industry; rubber solvents DIAGNOSIS Acute: narcosisChronic: encephalopathy, cranial neuropathy LOCUS OF PATHOLOGY Unknown (a)Unknown (c)Axon (c)

18. INSECTICIDES: Organophosphates SOURCE Agricultural industry manufacturing and application DIAGNOSIS Acute: cholinergic poisoningChronic: ataxia, paralysis, peripheral neuropathy LOCUS OF PATHOLOGY Acetylcholinesterase (a)Long tracts of spinal cord (c)Axon (c)

19. INSECTICIDES: Carbamates SOURCE Agricultural industry manufacturing and application flea powders DIAGNOSIS Acute: cholinergic poisoning Chronic: tremor, peripheral neuropathy LOCUS OF PATHOLOGY Acetylcholinesterase (a)Dopaminergic system (c)

20. Diagnosis • Establishing a diagnosis of a neurotoxicant syndrome and differentiating it from neurologic diseases of non-neurotoxicant aetiology requires; • understanding of the pathogenesis of the neurological symptoms and observed signs and symptoms; • 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; • delineation of a time relationship between exposure and the appearance of symptoms with subsequent decrease in symptoms after exposure ends

21. Diagnosis 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

22. Diagnosis 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 all commonly reported symptoms following exposure to certain chemicals. Constellations of symptoms form syndromes associated with neurotoxicant exposure.

23. Diagnosis • Establishing a diagnosis of a neurotoxicant syndrome and differentiating it from neurologic diseases of non-neurotoxicant aetiology requires; • understanding of the pathogenesis of the neurological symptoms and observed signs and symptoms; • 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; • delineation of a time relationship between exposure and the appearance of symptoms with subsequent decrease in symptoms after exposure ends

24. Behavioural Disorders 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 tumor, 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.

25. Behavioural Disorders Subjective and behavioural syndromes; Headache Vertigo Fatigue Personality change Can all 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.

26. Behavioural Disorders Specific tests used in the diagnostic batteries of tests must include a broad sampling of cognitive function tests These 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

27. Central Nervous System impairments Organic affective syndrome (Type I Effect) 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 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.

28. Central Nervous System impairments Sustained personality or mood change (Type IIA Effect) 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. 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.

29. Chronic Symptoms Dilemma 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

30. Chronic Symptoms Dilemma Some epidemiological studies comparing house painters exposed to solvents with unexposed industrial workers showed that painters had significantly lower mean scores on psychological tests measuring intellectual capacity and psychomotor coordination than referent controls 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 also seen 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.

31. Multiple Chemical Sensitivity 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 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.

32. Disturbances of Consciousness, Seizure or Coma When the brain is deprived of oxygen (e.g. CO) disturbances of consciousness may result Loss of consciousness may be preceded by seizures in workers with exposure to anticholinesterase substances such as organophosphates 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.

33. Movement Disorders Slowness of movement, increased muscle tone, and postural abnormalities are observed in workers exposed to manganese, carbon monoxide, carbon disulphide and MPTP. Individuals may appear to have Parkinson's disease Parkinsonism secondary to toxicant exposure has features of other nervous disorders such as chorea and athetosis 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

34. Movement Disorders 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, 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

35. Headaches • 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) • 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

36. 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 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.Slowing of motor or sensory conduction velocities is generally associated with demyelination of nerve fibres

37. Conclusion The differentiation of a neurotoxicant syndrome from a primary neurological disease poses a challenge to physicians 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 Early recognition of illness related to toxicant agents in their environment or to a particular occupational exposure is critical Proper diagnosis can lead to early removal of an individual from the hazards of ongoing exposure to a toxicant substance 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.