Transcript
Page 1: A Small Dose of  ™  Neurotoxicity

Intro Neurotoxicity – 5/7/04

A Small Dose of ™ Neurotoxicity

An Introduction to Toxicology of the Nervous System

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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

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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?

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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

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Ancient Awareness

“LEAD MAKES THE MIND GIVE WAY”

Dioscorides - GREEK 2ND BC

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“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

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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

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Case Studies

Lead – damages developing brain

Alcohol – Fetal alcohol syndrome

MPTP – similar to Parkinson’s disease

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Lead In Homes

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Nervous Systems Effects

Developmental Neurotoxicity Reduced IQ Impaired learning and memory

Life-long effects

Lead Neurotoxicity

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Alcohol (ethanol)

CH

H

H

OH

Ethyl Alcohol

C

H

H

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Vulnerability of Developing Nervous System

FAS – Fetal Alcohol SyndromeFAE – Fetal Alcohol Effects

What is a save level of consumption during pregnancy?

Alcohol

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Effects of Prenatal Alcohol

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Intro Neurotoxicity – 5/7/04 A Small Dose of ToxicologyFAS Child

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MPTP

N

CH3

1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine

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• 1980s – Designer Drug• Caused effects similar to

Parkinson’s disease• Damaged neurons that

secrete dopamine

MPTP Effects

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• 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

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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

CNSCentral Nervous System

PNSPeripheral 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)

Autonomic Somatic

Sympathetic Parasympathetic

Afferent (sensory) Nerves(Carry sensory information to the CNS)

Efferent (motor) Nerves(Transmit information to muscles or glands)

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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

Axon

Myelin (Schwann cell)

Synapse

Dendrite

Cell Body

Nucleus

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DopamineTransmitter Cell(Excitatory Neuron)

DopamineReceptor Cell(Post-synaptic receptor)

DopamineReceptor

Synaptic Cleft

Synaptic Vesicles

Neurotransmission

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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

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• Inhalation (e.g. solvents, nicotine)

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

Exposure Issues

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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

Neuron

Normal

Neuronopathy

Axonopathy

Myelinopathy

Transmission

Axon

Synapse

Myelin

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Examples of Neurotoxicology

DiseasesParkinson's, Alzheimer's, MS, ALS..

EnvironmentalLead, Methylmercury, PCBs

OccupationalSolvents, Pesticides

Drugs - ClinicalVincristine, cisplatin

Drugs - SocialAlcohol, cocaine, nicotine

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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

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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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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

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Structure• Long cell requires extensive

intracellular transport

Blood-Brain BarrierDevelopmental stage

(lead and alcohol)

Physiological Sensitivity

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Neurons CANNOT divide and replace themselves

Neurons CAN repair limited axonal damage

Most Recovery• Redundancy of Function• Plasticity of Organization

Reversibility of Damage

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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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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

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ToxicantToxicant11

Toxicantinactivates

receptor

Toxicantinactivates

receptor

No ResponseNo Response

3322

Inactivation of Receptor by Toxicant

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Toxicant1

No Response

32

Ligand

Toxicant out competes normal ligand

Ligand cannot bind receptor

Competition For Receptor

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Who Is Vulnerable?

Young or OldMale or FemaleGenetics - Individual Diff.Species

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Fetal Nervous System

Developing Nervous System

Mature Nervous System

Aging Nervous System

Vulnerability / Sensitivity

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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: <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

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Authorship Information

For Additional Information ContactSteven G. Gilbert, PhD, DABT

E-mail: [email protected]: www.asmalldoseof.org

This presentation is supplement to “A Small Dose of Toxicology”


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