Introduction to Neurotoxicology. Functions of the Nervous System Detect sensory inputs Communication Integration and processing of responses Neuroendocrine.

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-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

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 carboxy-hemoglobin, 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.getfile?p_download_id=4555