1. Introduction to Neurotoxicology

2. Functions of the Nervous System Detect sensory inputs Communication Integration and processing of responses Neuroendocrine

3. Organization of the Nervous System Macroscopic organization: CNS and PNS Cellular organization –Neurons –Glial cells Astrocytes Oligodendrocytes Schwann cells Microglia

4. Structure of a Neuron

5. Neurotransmission

6. Myelin Formation

7. 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)

8. 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

9. 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

10. Cognitive deficits in lead exposed children

11. 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.

12. 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)

13. 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

14. 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

15. 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

17. Axonopathies Toxicity damages the axon The longest axons usually exhibit the greatest toxicity Chemicals include acrylamide, carbon disulfide, hexacarbons, and organophosphates

20. Myelinopathies Can affect central and peripheral nervous system Triethyltin and hexachlorophene cause CNS myelinopathies

21. Examples of Neurotoxicants

23. 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