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Introduction to Neurotoxicology
Functions of the Nervous System
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Detect sensory inputs
Communication
Integration and processing of responses
Neuroendocrine
Organization of the Nervous System
• Macroscopic organization: CNS and PNS
• Cellular organization
– Neurons
– Glial cells
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Astrocytes
Oligodendrocytes
Schwann cells
Microglia
Structure of a Neuron
Neurotransmission
Myelin Formation
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)
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
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
Cognitive deficits in lead
exposed children
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.
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)
Interference with Dopamine
• MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) 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
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
Neuronopathies
• Toxicity primarily affects neurons
• Hypoxia and ischemia due to decreased
blood flow, methemoglobin and carboxyhemoglobin, and cyanide
• Hypoglycemia - neurons have little or no
anaerobic glycolysis
• Blockage of protein synthesis - Cisplatin,
methyl mercury, organomercurials
Axonopathies
• Toxicity damages the axon
• The longest axons usually exhibit the
greatest toxicity
• Chemicals include acrylamide, carbon
disulfide, hexacarbons, and
organophosphates
Myelinopathies
• Can affect central and
peripheral nervous system
• Triethyltin and
hexachlorophene cause CNS
myelinopathies
Examples of Neurotoxicants
Reading Material
• Casserett and Doull’s Toxicology
• US EPA Neurotoxicity Risk Assessment
Guidelines
http://oaspub.epa.gov/eims/eimscomm.getfil
e?p_download_id=4555