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Intro Neurotoxicity – 5/7/04
A Small Dose of ™ Neurotoxicity
An Introduction to Toxicology of the Nervous System
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Introduction
“You cannot reach your full genetic potential with
a damaged nervous system.”
S.G. Gilbert
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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.
What is Neurotoxicity?
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Even minor changes in the structure or function of the nervous system may have profound consequences for neurological, behavioral, and related body functions.
Nervous System Sensitivity
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Ancient Awareness
“LEAD MAKES THE MIND GIVE WAY”
Dioscorides - GREEK 2ND BC
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
“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
Current Awareness
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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.
Historical Events
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Case Studies
Lead – damages developing brain
Alcohol – Fetal alcohol syndrome
MPTP – similar to Parkinson’s disease
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Nervous Systems Effects
Developmental Neurotoxicity Reduced IQ Impaired learning and memory
Life-long effects
Lead Neurotoxicity
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Alcohol (ethanol)
CH
H
H
OH
Ethyl Alcohol
C
H
H
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Vulnerability of Developing Nervous System
FAS – Fetal Alcohol SyndromeFAE – Fetal Alcohol Effects
What is a save level of consumption during pregnancy?
Alcohol
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
MPTP
N
CH3
1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
• 1980s – Designer Drug• Caused effects similar to
Parkinson’s disease• Damaged neurons that
secrete dopamine
MPTP Effects
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
• CNS – Central Nervous System• PNS – Peripheral Nervous System• Blood brain barrier• Neuronal cells• Neurotransmitters & receptors• 10-100 billion cells with 1015
connections
Nervous System Biology
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Nervous System
Nervous System
CNSCentral Nervous System
PNSPeripheral Nervous System
Autonomic Somatic
Sympathetic Parasympathetic
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Central Nervous System
Central Nervous System (CNS)(Brain and Spinal Cord)
Peripheral Nervous System(PNS)
Autonomic Somatic
Sympathetic Parasympathetic
Afferent (sensory) Nerves(Carry sensory information to the CNS)
Efferent (motor) Nerves(Transmit information to muscles or glands)
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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)
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Neuronal Cells
Axon
Myelin (Schwann cell)
Synapse
Dendrite
Cell Body
Nucleus
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
DopamineTransmitter Cell(Excitatory Neuron)
DopamineReceptor Cell(Post-synaptic receptor)
DopamineReceptor
Synaptic Cleft
Synaptic Vesicles
Neurotransmission
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Neuronal Transmission
+ + - + +
+ + - + +
+ + - + +
+ + - + +
- - + - -- - + - -
- - + - -- - + - -
- - - - -+ + + + +- - - - -+ + + + +
++
++
+ + +++ +
++ +-
--
- -- ----
-K+
K+
Na+
Cl-
-- -
-
-
--
-
- -
Inhibitory Synapse
Excitatory Synapse
+400
-40-70
+400
-40-70
Action Potential IPSP
EPSP
Action Potential
No Action Potential
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
• Inhalation (e.g. solvents, nicotine)
• Ingestions (e.g. lead, alcohol)• Skin (e.g. pesticides, nicotine)• Physical (e.g. load noise)
Exposure Issues
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
What causes neurotoxicity?
Wide ranged of agents – chemical and
physical
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Neurotoxic Injury
Neuron
Normal
Neuronopathy
Axonopathy
Myelinopathy
Transmission
Axon
Synapse
Myelin
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Examples of Neurotoxicology
DiseasesParkinson's, Alzheimer's, MS, ALS..
EnvironmentalLead, Methylmercury, PCBs
OccupationalSolvents, Pesticides
Drugs - ClinicalVincristine, cisplatin
Drugs - SocialAlcohol, cocaine, nicotine
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Neurotoxic Effects
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Classification of neurotoxicants by mechanism of action
Temporary inhibition of nerve function• Agents which alter membrane
function• Agents with interfere with synaptic
transmission
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Dependence on oxygen• Little anaerobic capacity• CO – less available oxygen• Cyanide – inability to use oxygen
Dependence on glucose• Sole energy source
High metabolic rate
Physiological Sensitivity
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Structure• Long cell requires extensive
intracellular transport
Blood-Brain BarrierDevelopmental stage
(lead and alcohol)
Physiological Sensitivity
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Neurons CANNOT divide and replace themselves
Neurons CAN repair limited axonal damage
Most Recovery• Redundancy of Function• Plasticity of Organization
Reversibility of Damage
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
ReceptorReceptor
LigandLigand
Cell MembraneCell Membrane
Signal ProteinSignal Protein
Positive ResponsePositive Response
Outside CellOutside Cell
Inside CellInside Cell
Ligand binds to receptorLigand binds to receptor
11
33
22
Normal Receptor-Ligand Interaction
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
ToxicantToxicant11
Toxicantinactivates
receptor
Toxicantinactivates
receptor
No ResponseNo Response
3322
Inactivation of Receptor by Toxicant
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Toxicant1
No Response
32
Ligand
Toxicant out competes normal ligand
Ligand cannot bind receptor
Competition For Receptor
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Who Is Vulnerable?
Young or OldMale or FemaleGenetics - Individual Diff.Species
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
Fetal Nervous System
Developing Nervous System
Mature Nervous System
Aging Nervous System
Vulnerability / Sensitivity
Intro Neurotoxicity – 5/7/04 A Small Dose of Toxicology
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