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A Small Dose of ™ Neurotoxicity

A Small Dose of ™ Neurotoxicity. An Introduction to Toxicology of the Nervous System. “You cannot reach your full genetic potential with a damaged nervous system.” S.G. Gilbert. Introduction. What is Neurotoxicity?.

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A Small Dose of ™ Neurotoxicity

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  1. A Small Dose of ™ Neurotoxicity An Introduction to Toxicology of the Nervous System

  2. “You cannot reach your full genetic potential with a damaged nervous system.” S.G. Gilbert Introduction

  3. What is Neurotoxicity? An adverse change in the chemistry, structure or function of the nervous system during development or at maturity, following exposure to a chemical or physical agent.

  4. Nervous System Sensitivity Even minor changes in the structure or function of the nervous system may have profound consequences for neurological, behavioral, and related body functions.

  5. “LEAD MAKES THE MIND GIVE WAY” Dioscorides - GREEK 2ND BC Ancient Awareness

  6. Current Awareness “The upsurge of interest in recent years in academia, industry, and government on the effects of toxic chemicals on the nervous system has created a new discipline of neurotoxicology.” Peter S. Spencer & Herbert H. Schaumberg, in Experimental and Clinical Neurotoxicology, 1980

  7. Historical Events • 1930’s – Ginger-Jake Syndrome • During prohibition, an alcohol beverage was contaminated with TOCP (triorthocresyl phosphate) causing paralysis in 5,000 with 20,000 to 100,000 affected. • 1950’s – Mercury poisoning • Methylmercury in fish cause death and sever nervous system damage in infants and adults.

  8. Case Studies • Lead – damages developing brain • Alcohol – Fetal alcohol syndrome • MPTP – similar to Parkinson’s disease

  9. Lead In Homes

  10. Nervous Systems Effects Lead Neurotoxicity • Developmental Neurotoxicity • Reduced IQ • Impaired learning and memory • Life-long effects

  11. Alcohol (ethanol) H H C C OH H H H Ethyl Alcohol

  12. Alcohol Vulnerability of Developing Nervous System FAS – Fetal Alcohol Syndrome FAE – Fetal Alcohol Effects What is a save level of consumption during pregnancy?

  13. Effects of Prenatal Alcohol

  14. FAS Child

  15. N CH3 MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine

  16. MPTP Effects • 1980s – Designer Drug • Caused effects similar to Parkinson’s disease • Damaged neurons that secrete dopamine

  17. Nervous System Biology • CNS – Central Nervous System • PNS – Peripheral Nervous System • Blood brain barrier • Neuronal cells • Neurotransmitters & receptors • 10-100 billion cells with 1015 connections

  18. Nervous System – CNS & PNS • Central Nervous System (CNS) • Brain & Spinal Cord • Peripheral Nervous System (PNS) • Afferent (sensory) Nerves – Carry sensory information to the CNS • Efferent (motor) Nerves – Transmit information to muscles or glands

  19. Nervous System Nervous System PNS Peripheral Nervous System CNS Central Nervous System Autonomic Somatic Sympathetic Parasympathetic

  20. Central Nervous System Central Nervous System (CNS) (Brain and Spinal Cord) Peripheral Nervous System (PNS) Afferent (sensory) Nerves (Carry sensory information to the CNS) Efferent (motor) Nerves (Transmit information to muscles or glands) Autonomic Somatic Sympathetic Parasympathetic

  21. Peripheral Nervous System • Peripheral Nervous System (PNS) • Efferent (motor) Nerves – • Transmit information to muscles or glands • Somatic Nervous System • Stimulates Skeletal muscles • Autonomic Nervous System • Stimulates Glands and Organs (e.g. heart) • Sympathetic • - Adrenergic – stress response • Parasympathetic • - Cholinergic – basic functions

  22. Cells of the Nervous System • Neurons • Information conductors • Supporting Cells (Glia cells) • Astrocytes (CNS – blood brain barrier) • Oligodendrocytes (CNS – link cells) • Schwann cells (PNS – wrap cells)

  23. Blood-brain Barrier • Not an absolute barrier • Caffeine (small) • Methylmercury cysteine complex • Lipids (brain is a ball of fat) • Anatomic Characteristics • Capillary endothelial cells are tightly joined – no pores between cells • Capillaries in CNS surrounded by astrocytes • Low protein concentration in CNS fluid • Active ATP-dependent transporter – moves chemicals into the blood

  24. Neuronal Cells Myelin (Schwann cell) Synapse Axon Dendrite Nucleus Cell Body

  25. Neurotransmission Dopamine Transmitter Cell (Excitatory Neuron) Synaptic Vesicles Synaptic Cleft Dopamine Receptor Cell (Post-synaptic receptor) Dopamine Receptor

  26. Na+ - - - + + + + - + + - + + + - - - + - - - - - - - - - - - + - - - K+ + + + + + + + - + + - - - - - - - + + + + + + + - + + - K+ + - - - - + - - - - - - - + - - - + - - - - + + + - + + + Cl- + + + + +40 0 -40 -70 Neuronal Transmission +40 0 -40 -70 EPSP Action Potential Excitatory Synapse Inhibitory Synapse No Action Potential Action Potential IPSP

  27. Exposure Issues • Inhalation (e.g. solvents, nicotine) • Ingestions (e.g. lead, alcohol) • Skin (e.g. pesticides, nicotine) • Physical (e.g. load noise)

  28. Wide ranged of agents – chemical and physical What causes neurotoxicity?

  29. Types Of Neurotoxicity • Neuronopathy • Cell Death. Irreversible – cells not replaced. • MPTP, Trimethytin • Axonopathy • Degeneration of axon. Reversible. • Hexane, Acrylamide • Myelinopathy • Damage to myelin (e.g. Schwann cells) • Lead, Hexachlorophene • Transmission Toxicity • Disruption of neurotransmission • Organophosphate pesticides, Cocaine, DDT

  30. Neurotoxic Injury Normal Axonopathy Transmission Neuronopathy Myelinopathy Neuron Myelin Axon Synapse

  31. Diseases Parkinson's, Alzheimer's, MS, ALS.. Environmental Lead, Methylmercury, PCBs Occupational Solvents, Pesticides Drugs - Clinical Vincristine, cisplatin Drugs - Social Alcohol, cocaine, nicotine Examples of Neurotoxicology

  32. Neurotoxic Effects • Cognitive Effects - memory, learning, confusion • Motor Effects - weakness, convulsion, paralysis • Sensory Effects - vision, auditory, touch, balance • Mood and Personality Effects • - sleep, depression, irritability, excitability • General Effects - loss of appetite, fatigue

  33. Classification of neurotoxicants by mechanism of action • Temporary inhibition of nerve function • Agents which alter membrane function • Agents with interfere with synaptic transmission

  34. Physiological Sensitivity • Dependence on oxygen • Little anaerobic capacity • CO – less available oxygen • Cyanide – inability to use oxygen • Dependence on glucose • Sole energy source • High metabolic rate

  35. Physiological Sensitivity • Structure • Long cell requires extensive intracellular transport • Blood-Brain Barrier • Developmental stage (lead and alcohol)

  36. Reversibility of Damage • Neurons CANNOT divide and replace themselves • Neurons CAN repair limited axonal damage • Most Recovery • Redundancy of Function • Plasticity of Organization

  37. Classification of neurotoxicants by mechanism of action • Permanent inhibition of nerve function • Agents which cause Anoxia • Anoxic anoxia • Ischemic anoxia • Cytotoxic anoxia • Agents which damage myelin formation • Oligodendroglia (CNS) • Schwann cells (PNS) • Agents which damage peripheral axons • Agents which damage nerve cell body • Agents which cause localized CNS lesions

  38. Neurological and Behavioral Effects of Exposure to Toxic Substances • Motor Effects - Convulsions, weakness, tremor, twitching, lack of coordination, unsteadiness, paralysis, reflex abnormalities, activity changes • Sensory Effects - Equilibrium changes, vision disorders, pain disorders, tactile disorders, auditory disorders • Cognitive Effects - Memory problems, confusion, speech impairment, learning impairment • Mood and personality effects - Sleep disturbances, excitability, depression, irritability, restlessness, nervousness, tension, delirium, hallucinations • General effects - Loss of appetite, depression of neuronal activity, narcosis stupor, fatigue, nerve damage

  39. Normal Receptor-Ligand Interaction 1 Ligand Outside Cell Receptor 2 Cell Membrane Inside Cell Ligand binds to receptor 3 Signal Protein Positive Response

  40. Inactivation of Receptor by Toxicant 1 Toxicant 2 Toxicant inactivates receptor 3 No Response

  41. Competition For Receptor Ligand 1 Toxicant 2 Toxicant out competes normal ligand Ligand cannot bind receptor 3 No Response

  42. Who Is Vulnerable? Young or Old Male or Female Genetics - Individual Diff. Species

  43. Vulnerability / Sensitivity Fetal Nervous System Developing Nervous System Mature Nervous System Aging Nervous System

  44. A Small Dose of ™ Neurotoxicity

  45. Additional Information • Web Sites • U.S. National Institute of Health - National Institute of Neurological Disorders and Stroke (NINDS). Online. Available HTTP: <http://www.ninds.nih.gov/> (accessed: 10 April 2003). • Natural Resources Defense Council (NRDC). Online. Available HTTP: <http://www.nrdc.org/health/kids/cfqpa0599.asp> (accessed: 10 April 2003). NRDC site provides information on children’s health and neurotoxicology. • Other Chapters • Mercury, lead, pesticides

  46. Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org

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