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

2. Leslie London, University of Cape Town
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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)
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Leslie London, University of Cape Town

3. 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
Note – can also have CNS effects of trauma, asphyxia, etc
Leslie London, University of Cape Town

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

5. Consequence of toxin exposure 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

6. 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

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

8. Exposures and effects
Varied, ubiquitous exposures - Beware fixed expectations of job exposures
Mechanisms 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

9. Hallmark 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

10. Early symptoms of chronic poisoning
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

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

12. Severity levels (Simonsen et al, 1994)
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
Leslie London, University of Cape Town

13. Biomonitoring Metals often stored in bone
Blood 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

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

15. Peripheral Neuropathy
Metals: Arsenic, Thallium, Lead, Org Mercury
Gases: Ethylene Oxide, MethylBromide
Grouting Agents: Acrylamide, Dimethylacryloprioprionitrite (DMAP)
Industrial Solvents: n-hexane, methyl-n-butyl-ketone, CS2, trichlorethylene, methanol
Pesticides: Organophosphates, Organochlorines, organotins, Pb arsenate
NB all have different mechanisms!
Leslie London, University of Cape Town

16. Encephalopathy Global cerebral impairment: Cerebellar: Parkinsoniasm:
Solvents, Heavy metals, CS2
Cerebellar:
toluene, mercury
Parkinsoniasm:
manganese, CO, CS2
Opsoclonus:
kepone
Leslie London, University of Cape Town

17. Metal Neurotoxicity Heavier the metal, more toxic (Pb, Hg)
Environmental risks NB (e.g. in water)
Bioaccumulate if organic form  food chain
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

18. NEUROTOXICITY 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 ?
SPECTRUM
Progression
SPECTRUM ? ?
Leslie London, University of Cape Town

19. Implications of the Continuum of 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