A Small Dose of Neurotoxicity

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

• You cannot reach your full genetic potential
  with a damaged nervous system.
• S.G. Gilbert

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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.
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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.
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Ancient Awareness

• LEAD MAKES THE MIND GIVE WAY
• Dioscorides - GREEK 2ND BC

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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
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Historical Events

• 1930s 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.
• 1950s Mercury poisoning
• Methylmercury in fish cause death and sever
  nervous system damage in infants and adults.

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Case Studies

• Lead damages developing brain
• Alcohol Fetal alcohol syndrome
• MPTP similar to Parkinsons disease

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Lead In Homes
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Nervous Systems Effects
Lead Neurotoxicity

• Developmental Neurotoxicity
• Reduced IQ
• Impaired learning and memory
• Life-long effects

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Alcohol (ethanol)
H
H
C
H
OH
C
H
H
Ethyl Alcohol
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Alcohol
Vulnerability of Developing Nervous System FAS
Fetal Alcohol Syndrome FAE Fetal Alcohol
Effects What is a save level of consumption
during pregnancy?
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Effects of Prenatal Alcohol
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FAS Child
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MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine
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MPTP Effects

• 1980s Designer Drug
• Caused effects similar to Parkinsons disease
• Damaged neurons that secrete dopamine

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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

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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

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

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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)

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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

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Neuronal Cells
Myelin (Schwann cell)
Synapse
Axon
Dendrite
Nucleus
Cell Body
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Neurotransmission
Dopamine Transmitter Cell (Excitatory Neuron)
Synaptic Vesicles
Synaptic Cleft
Dopamine Receptor Cell (Post-synaptic receptor)
Dopamine Receptor
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Neuronal Transmission
40 0 -40 -70
EPSP
Action Potential
Excitatory Synapse
Inhibitory Synapse
No Action Potential
Action Potential
IPSP
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Exposure Issues

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

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What causes neurotoxicity?

• Wide ranged of agents chemical and physical

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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

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Neurotoxic Injury
Normal
Axonopathy
Transmission
Neuronopathy
Myelinopathy
Neuron
Myelin
Axon
Synapse
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Examples of Neurotoxicology

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

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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

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Classification of neurotoxicants by mechanism of
action

• Temporary inhibition of nerve function
• Agents which alter membrane function
• Agents with interfere with synaptic transmission

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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

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Physiological Sensitivity

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

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Reversibility of Damage

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

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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

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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

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Normal Receptor-Ligand Interaction
1
Ligand
Outside Cell
Receptor
Cell Membrane
2
Inside Cell
Ligand binds to receptor
3
Signal Protein
Positive Response
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Inactivation of Receptor by Toxicant
1
Toxicant
2
Toxicant inactivates receptor
3
No Response
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Competition For Receptor
Ligand
1
Toxicant
2
Toxicant out competes normal ligand
Ligand cannot bind receptor
3
No Response
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Who Is Vulnerable?
Young or Old Male or Female Genetics - Individual
Diff. Species
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Vulnerability / Sensitivity
Fetal Nervous System Developing Nervous
System Mature Nervous System Aging Nervous
System
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A Small Dose of Neurotoxicity
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Additional Information

• Web Sites
• U.S. National Institute of Health - National
  Institute of Neurological Disorders and Stroke
  (NINDS). Online. Available HTTP
  lthttp//www.ninds.nih.gov/gt (accessed 10 April
  2003).
• Natural Resources Defense Council (NRDC). Online.
  Available HTTP lthttp//www.nrdc.org/health/kids/c
  fqpa0599.aspgt (accessed 10 April 2003). NRDC
  site provides information on childrens health
  and neurotoxicology.
• Other Chapters
• Mercury, lead, pesticides

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