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Non-Cancer Toxicology

Non-Cancer Toxicology. Introduction to the Health Effects of Chemicals Neurotoxicology. Steven G. Gilbert, PhD, DABT & www.asmalldoseof.org www.toxipedia.org. “You cannot reach your full genetic potential with a damaged nervous system.” S.G. Gilbert. Introduction. What is Neurotoxicity.

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Non-Cancer Toxicology

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  1. Non-Cancer Toxicology Introduction to the Health Effects of Chemicals Neurotoxicology Steven G. Gilbert, PhD, DABT & www.asmalldoseof.org www.toxipedia.org

  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. Developmental alterations Immunological impairment Neurobehavioral effects Kidney/liver dysfunction Mutagenesis Reproductive impairment Metabolic inhibition Examples of non-cancer toxicity

  6. General Mechanisms of Non-Cancer Toxicity Toxicant Exposure T O X I C I T Y Delivery to target tissue Interaction with target molecule Cell dysfunction and/or Injury Tissue damage

  7. Interference with receptor-ligand interactions Interference with membrane functions Interference with cellular energy production Binding to macromolecules Perturbation of calcium regulation Toxicity from selective cell loss Non-lethal genetic alterations Are there general mechanisms?

  8. Animal Cell Membrane Protein Nucleus Golgi Rough Endoplasmic Reticulum Lysosomes Peroxisomes Mitochondria Ribosomes

  9. Interference with Membrane Function Cell Transport Protein Hydrophilic head Lipid bilayer Hydrophobic tails Channel Pump

  10. Neuro Insulation

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

  12. 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

  13. 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.

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

  15. Lead In Homes

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

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

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

  19. ALCOHOL Vulnerability of Developing Nervous System FAS – Fetal Alcohol Syndrome FAE – Fetal Alcohol Effects What is a safe level of ethanol consumption during pregnancy? http://www.fetalalcohol.com/what-is-fase.htm http://www.alumni.ca/~syed4s0/discussion.htm

  20. FAS Child

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

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

  23. MPTP • MPTP – 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine: a contaminant in “synthetic heroin” • Parkinson’s Disease-like symptoms in drug addicts • Loss of neurons in the substantia nigra which synthesize and secrete dopamine • MPTP-->MPP+ ---> oxidative stress

  24. MPTP – Real People http://www.swmed.edu/stars/resources/neurodisslides.html

  25. http://www.swmed.edu/stars/images/neurodisslides/Slide26.JPG

  26. PD Brain http://www.swmed.edu/stars/images/neurodisslides/Slide29.JPG

  27. 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

  28. 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

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

  30. 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

  31. 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

  32. 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)

  33. 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

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

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

  36. 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

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

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

  39. 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

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

  41. 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

  42. 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

  43. Classification of Neurotoxicant Mechanism of action • Temporary inhibition of nerve function • Agents which alter membrane function • Agents with interfere with synaptic transmission

  44. Classification of Neurotoxicant Mechanism of action • Permanent inhibition of nerve function • Agents which cause Anoxia • Anoxic anoxia (e.g. CO2 asphyxiation) • Ischemic anoxia (e.g. blood clot) • Cytotoxic anoxia (e.g. cyanide) • 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

  45. Functional Observational Battery (FOB) 1. Autonomic function (lacrimation and salivation, piloerection and exophthalmus, urination and defecation, pupillary function, palpebral closure) 2. Convulsions, tremors, or abnormal motor movements 3. Reactivity to general stimuli such as removal from the cage or handling (no reaction to hyperreactivity) 4. Arousal level (from coma to hyperalertness) 5. Posture and gait abnormalities (home cage and open field) 6. Forelimb and hindlimb grip strength 7. Landing foot splay 8. Sensorimotor responses to stimuli (a tail-pinch, tailflick, hot-plate, acoustic startle response ) 9. Body weight 10. Any unusual or abnormal behaviors, excessive or repetitive actions (stereotypies), emaciation, dehydration, hypotonia or hypertonia, altered fur appearance, red or crusty deposits around the eyes, nose, or mouth, and any other observations that may facilitate interpretation of the data.

  46. Functional Observational Battery (FOB) 1. Count of rearing activity on the open field. 2. Ranking of righting ability. 3. Body temperature. 4. Excessive or spontaneous vocalizations. 5. Alterations in rate and ease of respiration, e.g., rales or dyspnea. 6. Sensorimotor responses to visual or proprioceptive stimuli.

  47. Other measures • Memory and learning tests (e.g. radial maze, Morris water maze) • Conditioned stimulus/responses • Other supportive techniques: • Histopathology/Quantitative Stereology • EEG, EMG, Functional MRI: CBV-fMRI of rat brain induced by electrical stimulation of both forepaws. T. Reese, A. Sauter, N. Beckmann, M. Rudin et al. Novartis Pharmaceutical, Basel, Switzerland http://www.bruker-biospin.de/MRI/applications/bio29.html

  48. WHAT IS THIS? O CH3 CH3 N N 7 1 3 N O N CH3

  49. 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

  50. Interference with Energy Production 3 ATP Intermembrane Space H+ H+ H+ +++++++++++++ +++++++ +++ +++ +++ I III IV V - - - - - - - - - - - - - - - - - - - - - - - - - - - - - O2 + 4H+ 2H2O NADH + H+ NAD+ Matrix H+

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