Transcript 11/19/08-B
Introduction to Neurotoxicology Functions of the Nervous System • • • • 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 • • • • 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