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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

A Small Dose of ™ Neurotoxicity

An Introduction to Toxicology of the Nervous System


Introduction

“You cannot reach your full genetic potential with a damaged nervous system.”

S.G. Gilbert

Introduction


What is neurotoxicity
What is Neurotoxicity? damaged nervous system.”

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.


Nervous system sensitivity
Nervous System Sensitivity damaged nervous system.”

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


Ancient awareness

“LEAD MAKES THE MIND GIVE WAY” damaged nervous system.”

Dioscorides - GREEK 2ND BC

Ancient Awareness


Current awareness
Current Awareness damaged nervous system.”

“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


Historical events
Historical Events damaged nervous system.”

  • 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.


Case studies
Case Studies damaged nervous system.”

  • Lead – damages developing brain

  • Alcohol – Fetal alcohol syndrome

  • MPTP – similar to Parkinson’s disease


Lead in homes
Lead In Homes damaged nervous system.”


Nervous systems effects
Nervous Systems Effects damaged nervous system.”

Lead Neurotoxicity

  • Developmental Neurotoxicity

  • Reduced IQ

  • Impaired learning and memory

  • Life-long effects


Alcohol ethanol
Alcohol (ethanol) damaged nervous system.”

H

H

C

C

OH

H

H

H

Ethyl Alcohol


Alcohol
Alcohol damaged nervous system.”

Vulnerability of Developing Nervous System

FAS – Fetal Alcohol Syndrome

FAE – Fetal Alcohol Effects

What is a save level of consumption during pregnancy?


Effects of prenatal alcohol
Effects of Prenatal Alcohol damaged nervous system.”


Fas child
FAS Child damaged nervous system.”


N damaged nervous system.”

CH3

MPTP

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


Mptp effects
MPTP Effects damaged nervous system.”

  • 1980s – Designer Drug

  • Caused effects similar to Parkinson’s disease

  • Damaged neurons that secrete dopamine


Nervous system biology
Nervous System Biology damaged nervous system.”

  • CNS – Central Nervous System

  • PNS – Peripheral Nervous System

  • Blood brain barrier

  • Neuronal cells

  • Neurotransmitters & receptors

  • 10-100 billion cells with 1015 connections


Nervous system cns pns
Nervous System – CNS & PNS damaged nervous system.”

  • 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


Nervous system
Nervous System damaged nervous system.”

Nervous System

PNS

Peripheral Nervous System

CNS

Central Nervous System

Autonomic

Somatic

Sympathetic

Parasympathetic


Central nervous system
Central Nervous System damaged 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


Peripheral nervous system
Peripheral Nervous System damaged 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


Cells of the nervous system
Cells of the damaged nervous system.”Nervous System

  • Neurons

    • Information conductors

  • Supporting Cells (Glia cells)

    • Astrocytes (CNS – blood brain barrier)

    • Oligodendrocytes (CNS – link cells)

    • Schwann cells (PNS – wrap cells)


Blood brain barrier
Blood-brain Barrier damaged nervous system.”

  • 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


Neuronal cells
Neuronal Cells damaged nervous system.”

Myelin (Schwann cell)

Synapse

Axon

Dendrite

Nucleus

Cell Body


Neurotransmission
Neurotransmission damaged nervous system.”

Dopamine

Transmitter Cell

(Excitatory Neuron)

Synaptic Vesicles

Synaptic Cleft

Dopamine

Receptor Cell

(Post-synaptic receptor)

Dopamine

Receptor


Neuronal transmission

Na damaged nervous system.”+

-

-

-

+

+

+ + - + +

-

+

+

+

-

- - + - -

-

- - - - -

-

- - + - -

-

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


Exposure issues
Exposure Issues damaged nervous system.”

  • Inhalation (e.g. solvents, nicotine)

  • Ingestions (e.g. lead, alcohol)

  • Skin (e.g. pesticides, nicotine)

  • Physical (e.g. load noise)


What causes neurotoxicity

Wide ranged of agents – chemical and physical damaged nervous system.”

What causes neurotoxicity?


Types of neurotoxicity
Types Of Neurotoxicity damaged nervous system.”

  • 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


Neurotoxic injury
Neurotoxic Injury damaged nervous system.”

Normal

Axonopathy

Transmission

Neuronopathy

Myelinopathy

Neuron

Myelin

Axon

Synapse


Examples of neurotoxicology

Diseases damaged nervous system.”

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


Neurotoxic effects
Neurotoxic Effects damaged nervous system.”

  • 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


Classification of neurotoxicants by mechanism of action
Classification of neurotoxicants by mechanism of action damaged nervous system.”

  • Temporary inhibition of nerve function

    • Agents which alter membrane function

    • Agents with interfere with synaptic transmission


Physiological sensitivity
Physiological Sensitivity damaged nervous system.”

  • 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 sensitivity1
Physiological Sensitivity damaged nervous system.”

  • Structure

    • Long cell requires extensive intracellular transport

  • Blood-Brain Barrier

  • Developmental stage

    (lead and alcohol)


Reversibility of damage
Reversibility of Damage damaged nervous system.”

  • Neurons CANNOT divide and replace themselves

  • Neurons CAN repair limited axonal damage

  • Most Recovery

    • Redundancy of Function

    • Plasticity of Organization


Classification of neurotoxicants by mechanism of action1
Classification of neurotoxicants by mechanism of action damaged nervous system.”

  • 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


Neurological and behavioral effects of exposure to toxic substances
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


Normal receptor ligand interaction
Normal Receptor-Ligand Interaction Substances

1

Ligand

Outside Cell

Receptor

2

Cell Membrane

Inside Cell

Ligand binds to receptor

3

Signal Protein

Positive Response


Inactivation of receptor by toxicant
Inactivation of Receptor by Toxicant Substances

1

Toxicant

2

Toxicant

inactivates

receptor

3

No Response


Competition for receptor
Competition For Receptor Substances

Ligand

1

Toxicant

2

Toxicant

out competes

normal ligand

Ligand cannot bind

receptor

3

No Response


Who is vulnerable
Who Is Vulnerable? Substances

Young or Old

Male or Female

Genetics - Individual Diff.

Species


Vulnerability sensitivity
Vulnerability / Sensitivity Substances

Fetal Nervous System

Developing Nervous System

Mature Nervous System

Aging Nervous System


A Small Dose of Substances™ Neurotoxicity


Additional information
Additional Information Substances

  • 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


  • Authorship information
    Authorship Information Substances

    This presentation is supplement to

    “A Small Dose of Toxicology”

    For Additional Information Contact

    Steven G. Gilbert, PhD, DABT

    E-mail: [email protected]

    Web: www.asmalldoseof.org


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