Neurotoxicity in Occupational Health l Diploma in Occupational

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Neurotoxicity in Occupational Health l Diploma in Occupational Health UCT Nov 2005 Leslie London,

Neurotoxicity in Occupational Health l Diploma in Occupational Health UCT Nov 2005 Leslie London, University of Cape Town

This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2. 5 South Africa

This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2. 5 South Africa License. Under the following conditions: Attribution. You must attribute the work in the manner specified by the author or licensor (but not in any way that suggests that they endorse you or your use of the work) Non-commercial. You may not use this work for commercial purposes. Share Alike. If you alter, transform, or build upon this work, you may distribute the resulting work but only under the same or similar license to this one. • For any reuse or distribution, you must make clear to others the license terms of this work. One way to do this is with a link to the license web page: http: //creativecommons. org/licenses/by-nc-sa/2. 5/za • Any of the above conditions can be waived if you get permission from the copyright holder. • Nothing in this license impairs or restricts the authors’ moral rights. • Nothing in this license impairs or restricts the rights of authors whose work is referenced in this document. • Cited works used in this document must be cited following usual academic conventions • Citation of this work must follow normal academic conventions http: //za. creativecommons. org Source work at Vula. Permissions beyond the scope of this license may be available at www. healthedu. uct. ac. za or contact [email protected] ac. za Leslie London, University of Cape Town

Neurotoxicity Definition: “Neurotoxicity refers to the capability of inducing adverse effects in the central

Neurotoxicity Definition: “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. ” International Labour Organisation, 2003 l Note – can also have CNS effects of trauma, asphyxia, etc Leslie London, University of Cape Town

Historical Perspective l Drug-induced neurotoxicity Occupational toxins l Main categories: – metals – solvents

Historical Perspective l Drug-induced neurotoxicity Occupational toxins l Main categories: – metals – solvents – pesticides l > 100 000 chemicals in use, 2000 new chemicals / year; yet minority tested for neurotoxicity (+/- 800 recognised ntoxins) Leslie London, University of Cape Town

Consequence of toxin exposure for the nervous system: l changes in sensory input (loss

Consequence of toxin exposure for the nervous system: l changes in sensory input (loss of vision, hearing, smell, etc) l hinder the capacity to control movement and body functions l affect brain’s capacity to manage information l behavioural or psychological disorders (mood and personality changes) Leslie London, University of Cape Town

Why is the Nervous System uniquely sustainable to toxicity? – limited capacity for repair

Why is the Nervous System uniquely sustainable to toxicity? – limited capacity for repair – complex functional organisation – sensitive to other organ malfunction Leslie London, University of Cape Town

Neurotoxic syndromes l l l l Peripheral neuropathy Encephalopathy Bulbar or spinal cord syndromes

Neurotoxic syndromes l l l l Peripheral neuropathy Encephalopathy Bulbar or spinal cord syndromes Extrapyramidal Psychiatric Neuropsychological Tremor Neuro-endocrine Leslie London, University of Cape Town

Exposures and effects Varied, ubiquitous exposures - Beware fixed expectations of job exposures l

Exposures and effects Varied, ubiquitous exposures - Beware fixed expectations of job exposures l Mechanisms wide ranging: e. g. target cell processes in membrane transport, internal cellular chemical reactions, liberation of secretory substances, etc. l Specific vs Non-Specific effects l – E. g. autonomic PN due to dimethylaminoproprionitrile – e. g. purely motor neuropathy (lead, TOCP) l Neurotoxicity manifested as continuum of symptoms and effects – depend on the nature of the chemical, dose, duration of exposure and individual traits Leslie London, University of Cape Town

Hallmark is axonal damage – Central and peripheral – Typically symmetrical sensory-motor polyneuropathy –

Hallmark is axonal damage – Central and peripheral – Typically symmetrical sensory-motor polyneuropathy – (autonomic, demyelination, etc rare) – NB! Exposures are usually to cocktails of chemicals – rarely to single chemical Leslie London, University of Cape Town

Early symptoms of chronic poisoning l l l Altered mood states: Irritability, euphoria, sudden

Early symptoms of chronic poisoning l l l Altered mood states: Irritability, euphoria, sudden mood changes, excessive tiredness, feelings of hostility, anxiousness, depression and tension Cognitive: memory problems, concentration difficulties Other: drunkenness, dizziness, slowness, tingling sensation in hands or feet, loss of libido Symptoms are non-specific, usually do not interfere with work ignored, or attributed to non -occupational cause Hence NB to have high index of awareness Leslie London, University of Cape Town

Early motor, sensory and cognitive changes l With increasing exposure, changes in: l l

Early motor, sensory and cognitive changes l With increasing exposure, changes in: l l l Reaction time hand-eye coordination short-term memory visual and auditory memory attention and vigilance l l l manual dexterity, grip strength motor speed, hand steadiness, Vocabulary colour vision, vibrotactile perception Hearing, smell Leslie London, University of Cape Town

Severity levels (Simonsen et al, 1994) Level Grouping Explanation 6 Morphological Cell death, axonopathy,

Severity levels (Simonsen et al, 1994) Level Grouping Explanation 6 Morphological Cell death, axonopathy, and s/clinical 5 Neurological Abn findings on examination 4 Physiological / behavioural Experimental findings in groups: EEG, evoked potentials, neuropsych tests 3 Biochemical Neurotransmitters, proteins 2 Irreversible symptoms Subjective symptoms. No abn on exam / tests 1 Reversible symptoms Subjective symptoms. No abn on exam / tests Leslie London, University of Cape Town

Biomonitoring l Metals often stored in bone l Blood or urine concentrations may reflect

Biomonitoring l Metals often stored in bone l Blood or urine concentrations may reflect body burden = basis for biological monitoring (bone fluoroscopy for Pb) l Release from storage sites may be very slow (e. g. Pb burden 50% over 10 years. (Can be accelerated with chelating agents = treatment) Leslie London, University of Cape Town

Clinical vs Sub clinical effects Histologic l Electrophysiological l Clinical – Sign – Symptoms

Clinical vs Sub clinical effects Histologic l Electrophysiological l Clinical – Sign – Symptoms l Subclinical Sensory Testing – vibration sense (esp long nerves in feet) – colour vision – postural sway l Neurobehavioural: Cognitive domains etc l (Population shifts, accelerated aging, compensatory capacity, etc) l Leslie London, University of Cape Town

Peripheral Neuropathy l Metals: Arsenic, Thallium, Lead, Org Mercury l Gases: Ethylene Oxide, Methyl.

Peripheral Neuropathy l Metals: Arsenic, Thallium, Lead, Org Mercury l Gases: Ethylene Oxide, Methyl. Bromide l Grouting Agents: Acrylamide, Dimethylacryloprionitrite (DMAP) l Industrial Solvents: n-hexane, methyl-n-butylketone, CS 2, trichlorethylene, methanol l Pesticides: Organophosphates, Organochlorines, organotins, Pb arsenate NB all have different mechanisms! Leslie London, University of Cape Town

Encephalopathy l Global cerebral impairment: – Solvents, Heavy metals, CS 2 l Cerebellar: –

Encephalopathy l Global cerebral impairment: – Solvents, Heavy metals, CS 2 l Cerebellar: – toluene, mercury l Parkinsoniasm: – manganese, CO, CS 2 l Opsoclonus: – kepone Leslie London, University of Cape Town

Metal Neurotoxicity l Heavier the metal, more toxic (Pb, Hg) l Environmental risks NB

Metal Neurotoxicity l Heavier the metal, more toxic (Pb, Hg) l Environmental risks NB (e. g. in water) l Bioaccumulate if organic form food chain l Routes absorption: – pure metal: inhalation or skin contact (e. g. Hg) – Inorganic metal: oral – Organic metal: inhalation or skin contact Leslie London, University of Cape Town

NEUROTOXICITY OF CHEMICALS EXPOSURE – EFFECT RELATIONSHIPS What sort of Exposure? What sort of

NEUROTOXICITY OF CHEMICALS EXPOSURE – EFFECT RELATIONSHIPS What sort of Exposure? What sort of Effect? ACUTE INTOXICATION ACUTE LONG-TERM LOW DOSE ? ? Progression SPECTRUM EPISODIC SPECTRUM ? EFFECTS Reversible CHRONIC EFFECTS Irreversible Leslie London, University of Cape Town

Implications of the Continuum of effects l Early alterations in groups of exposed workers

Implications of the Continuum of effects l Early alterations in groups of exposed workers using sensitive measures of impairment can be used to prompt preventive actions. l In later stages, a good clinical knowledge is required and differential diagnosis is essential to the adequate treatment and care of disabled workers Leslie London, University of Cape Town