A small dose of neurotoxicity
This presentation is the property of its rightful owner.
Sponsored Links
1 / 46

A Small Dose of ™ Neurotoxicity PowerPoint PPT Presentation


  • 87 Views
  • Uploaded on
  • Presentation posted in: General

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?.

Download Presentation

A Small Dose of ™ Neurotoxicity

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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?

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

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”

Dioscorides - GREEK 2ND BC

Ancient Awareness


Current awareness

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


Historical events

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.


Case studies

Case Studies

  • Lead – damages developing brain

  • Alcohol – Fetal alcohol syndrome

  • MPTP – similar to Parkinson’s disease


Lead in homes

Lead In Homes


Nervous systems effects

Nervous Systems Effects

Lead Neurotoxicity

  • Developmental Neurotoxicity

  • Reduced IQ

  • Impaired learning and memory

  • Life-long effects


Alcohol ethanol

Alcohol (ethanol)

H

H

C

C

OH

H

H

H

Ethyl Alcohol


Alcohol

Alcohol

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


Fas child

FAS Child


A small dose of neurotoxicity

N

CH3

MPTP

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


Mptp effects

MPTP Effects

  • 1980s – Designer Drug

  • Caused effects similar to Parkinson’s disease

  • Damaged neurons that secrete dopamine


Nervous system biology

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


Nervous system cns pns

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


Nervous system

Nervous System

Nervous System

PNS

Peripheral Nervous System

CNS

Central Nervous System

Autonomic

Somatic

Sympathetic

Parasympathetic


Central nervous system

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


Peripheral nervous system

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


Cells of the nervous system

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)


Blood brain barrier

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


Neuronal cells

Neuronal Cells

Myelin (Schwann cell)

Synapse

Axon

Dendrite

Nucleus

Cell Body


Neurotransmission

Neurotransmission

Dopamine

Transmitter Cell

(Excitatory Neuron)

Synaptic Vesicles

Synaptic Cleft

Dopamine

Receptor Cell

(Post-synaptic receptor)

Dopamine

Receptor


Neuronal transmission

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


Exposure issues

Exposure Issues

  • 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

What causes neurotoxicity?


Types of neurotoxicity

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


Neurotoxic injury

Neurotoxic Injury

Normal

Axonopathy

Transmission

Neuronopathy

Myelinopathy

Neuron

Myelin

Axon

Synapse


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

Examples of Neurotoxicology


Neurotoxic effects

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


Classification of neurotoxicants by mechanism of action

Classification of neurotoxicants by mechanism of action

  • Temporary inhibition of nerve function

    • Agents which alter membrane function

    • Agents with interfere with synaptic transmission


Physiological sensitivity

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


Physiological sensitivity1

Physiological Sensitivity

  • Structure

    • Long cell requires extensive intracellular transport

  • Blood-Brain Barrier

  • Developmental stage

    (lead and alcohol)


Reversibility of damage

Reversibility of Damage

  • 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

  • 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

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

1

Toxicant

2

Toxicant

inactivates

receptor

3

No Response


Competition for receptor

Competition For Receptor

Ligand

1

Toxicant

2

Toxicant

out competes

normal ligand

Ligand cannot bind

receptor

3

No Response


Who is vulnerable

Who Is Vulnerable?

Young or Old

Male or Female

Genetics - Individual Diff.

Species


Vulnerability sensitivity

Vulnerability / Sensitivity

Fetal Nervous System

Developing Nervous System

Mature Nervous System

Aging Nervous System


A small dose of neurotoxicity

A Small Dose of ™ Neurotoxicity


Additional information

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


  • Authorship information

    Authorship Information

    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


  • Login