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Neurotoxicity in Occupational Neurotoxicity in Occupational HealthHealth
Diploma in Occupational Health
UCT
Nov 2005
Leslie London, University of Cape Town
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Leslie London, University of Cape Town
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NeurotoxicityNeurotoxicityDefinition:
“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, 2003Note – can also have CNS effects of
trauma, asphyxia, etc
Leslie London, University of Cape Town
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Historical PerspectiveHistorical Perspective
Drug-induced neurotoxicity Occupational toxins
Main categories:– metals– solvents– pesticides
> 100 000 chemicals in use, 2000 new chemicals / year; yet minority tested for neurotoxicity (+/- 800 recognised ntoxins)
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Consequence of toxin exposure Consequence of toxin exposure for the nervous system:for the nervous system:
changes in sensory input (loss of vision, hearing, smell, etc)
hinder the capacity to control movement and body functions
affect brain’s capacity to manage information
behavioural or psychological disorders (mood and personality changes)
Leslie London, University of Cape Town
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Why is the Nervous System Why is the Nervous System uniquely sustainable to uniquely sustainable to
toxicity?toxicity?
– limited capacity for repair
– complex functional organisation
– sensitive to other organ malfunction
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Neurotoxic syndromesNeurotoxic syndromes Peripheral neuropathy Encephalopathy Bulbar or spinal cord syndromes Extrapyramidal Psychiatric Neuropsychological Tremor Neuro-endocrine
Leslie London, University of Cape Town
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Exposures and effectsExposures and effectsVaried, ubiquitous exposures - Beware fixed expectations of job
exposuresMechanisms wide ranging: e.g. target cell processes in membrane
transport, internal cellular chemical reactions, liberation of secretory substances, etc.
Specific vs Non-Specific effects– E.g. autonomic PN due to dimethylaminoproprionitrile– e.g. purely motor neuropathy (lead, TOCP)
Neurotoxicity manifested as continuum of symptoms and effects– depend on the nature of the chemical, dose, duration of exposure and
individual traits
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Hallmark is axonal damageHallmark is axonal damage
– Central and peripheral
– Typically symmetrical sensory-motor polyneuropathy
– (autonomic, demyelination, etc rare)
– NB! NB! Exposures are usually to cocktails of chemicals – rarely to single chemical
Leslie London, University of Cape Town
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Early symptoms of chronic Early symptoms of chronic poisoningpoisoning
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
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Early motor, sensory and Early motor, sensory and cognitive changes cognitive changes
Reaction time hand-eye coordination short-term memory visual and auditory
memory attention and vigilance
manual dexterity, grip strength
motor speed, hand steadiness,
Vocabulary colour vision, vibrotactile perception Hearing, smell
With increasing exposure, changes in:
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Severity levels Severity levels (Simonsen et al, 1994)(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
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BiomonitoringBiomonitoring
Metals often stored in boneBlood or urine concentrations may reflect
body burden = basis for biological monitoring (bone fluoroscopy for Pb)
Release from storage sites may be very slow (e.g. Pb burden 50% over 10 years. (Can be accelerated with chelating agents = treatment)
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Clinical vs Sub clinical effects Clinical vs Sub clinical effects HistologicElectrophysiologicalClinical – Sign
– SymptomsSubclinical Sensory Testing
– vibration sense (esp long nerves in feet)
– colour vision
– postural swayNeurobehavioural: Cognitive domains etc(Population shifts, accelerated aging, compensatory capacity,
etc)
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Peripheral NeuropathyPeripheral NeuropathyMetals: Arsenic, Thallium, Lead, Org MercuryGases: Ethylene Oxide, MethylBromideGrouting Agents: Acrylamide,
Dimethylacryloprioprionitrite (DMAP)Industrial Solvents: n-hexane, methyl-n-butyl-
ketone, CS2, trichlorethylene, methanolPesticides: Organophosphates,
Organochlorines, organotins, Pb arsenateNB all have different mechanisms!
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EncephalopathyEncephalopathyGlobal cerebral impairment:
– Solvents, Heavy metals, CS2
Cerebellar: – toluene, mercury
Parkinsoniasm:– manganese, CO, CS2
Opsoclonus:– kepone
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Metal NeurotoxicityMetal Neurotoxicity
Heavier the metal, more toxic (Pb, Hg)Environmental risks NB (e.g. in water)Bioaccumulate if organic form food chainRoutes absorption:
– pure metal: inhalation or skin contact (e.g. Hg)– Inorganic metal: oral– Organic metal: inhalation or skin contact
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NEUROTOXICITY OF CHEMICALSNEUROTOXICITY OF CHEMICALS
EXPOSURE – EFFECT RELATIONSHIPS
What sort of Exposure? What sort of Effect?
ACUTE INTOXICATION ACUTE EFFECTS
EPISODIC
Reversible
LONG-TERM LOW DOSE CHRONIC EFFECTS
Irreversible
SP
EC
TR
UM
SP
EC
TR
UM
Progression
?
?
?
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Implications of the Continuum Implications of the Continuum of effectsof effects
Early alterations in groups of exposed workers using sensitive measures of impairment can be used to prompt preventive actions.
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