Download - Introduction to Neurotoxicology
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Introduction to Neurotoxicology
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Functions of the Nervous System
• Detect sensory inputs
• Communication
• Integration and processing of responses
• Neuroendocrine
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Organization of the Nervous System
• Macroscopic organization: CNS and PNS
• Cellular organization– Neurons– Glial cells
• Astrocytes
• Oligodendrocytes
• Schwann cells
• Microglia
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Structure of a Neuron
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Neurotransmission
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Myelin Formation
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Unique Features of the Nervous System
• Several features of the nervous system predispose it to chemically-induced injury– High metabolic rate
• Neurons dependent on aerobic glycolysis• Brain is 2% of body weight, but 15% of cardiac
output
– Great distance from cell body to axon– Limited capacity for repair– Blood-Brain-Barrier (incomplete)
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Evidence of Neurotoxicity
Humans• Epidemiological• Clinical case reports• Neurotoxicity first noted in humans
– Metals (lead, mercury, manganese)– Drugs (MPTP)
Animals• Experimental studies• Clinical case reports
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Evaluation of Neurotoxicity in Animals
• Structure - Neuropathology (Light and electron microscopy, and special studies)
• Functional – Neurochemistry (Neurotransmitter binding and receptor studies, and metabolism)
• Behavioral – Sensory, motor, autonomic and cognitive function
• Electrophysiology – EEG, evoked potential
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Cognitive deficits in lead exposed children
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Toxicants Affecting Neurotransmission
• Functional nervous system requires a balance of stimulatory and inhibitory signals
• Often see clinical effects without pathology• Toxic agents include organophosphates,
strychnine, DDT, MPTP, glutamine, domoic acid, and agents with anesthetic properties.
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Organophosphates and Carbamates
• Common insecticides and war gases that block acetylcholinesterase
• Acute toxicity-SLUD and tremors
• Treat with atropine and 2-PAM
• Chronic toxicity affects memory and OPIDN- delayed neuropathy. Humans, cat, chicken are sensitive (Ginger Jake)
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Interference with Dopamine
• MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetra-hydropyridine) and manganese
• Causes a Parkinson’s like disease
• Toxicity of MPTP appears to be due to the generation of free radicals that lead to the death of dopaminergic neurons
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Excitotoxicity
• Glutamate is the major excitatory amino acid in the CNS
• NMDA receptor opens and permits influx of Ca++ that leads to cell death
• Neurotoxic agents include domoic acid from shellfish, monosodium glutamate, long-term mercury, kanic and quisqualic acid
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Neuronopathies
• Toxicity primarily affects neurons• Hypoxia and ischemia due to decreased
blood flow, methemoglobin and carboxy-hemoglobin, and cyanide
• Hypoglycemia - neurons have little or no anaerobic glycolysis
• Blockage of protein synthesis - Cisplatin, methyl mercury, organomercurials
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Axonopathies
• Toxicity damages the axon
• The longest axons usually exhibit the greatest toxicity
• Chemicals include acrylamide, carbon disulfide, hexacarbons, and organophosphates
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Myelinopathies
• Can affect central and peripheral nervous system
• Triethyltin and hexachlorophene cause CNS myelinopathies
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Examples of Neurotoxicants
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Reading Material
• Casserett and Doull’s Toxicology
• US EPA Neurotoxicity Risk Assessment Guidelines
http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4555