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

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

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)

Leslie London, University of Cape Town

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

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

Leslie London, University of Cape Town

Neurotoxic syndromesNeurotoxic syndromes Peripheral neuropathy Encephalopathy Bulbar or spinal cord syndromes Extrapyramidal Psychiatric Neuropsychological Tremor Neuro-endocrine

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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

Leslie London, University of Cape Town

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

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

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)

Leslie London, University of Cape Town

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)

Leslie London, University of Cape Town

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

Leslie London, University of Cape Town

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

?

?

?

Leslie London, University of Cape Town

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