Hanif Nasiatul Baroroh

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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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CNS Central Nervous System
PNS Peripheral Nervous System
Blood brain barrier
Neuronal cells
Neurotransmitters & receptors
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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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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Neuronal Transmission
+ + - + +
+ + - + +
+ + - + +
+ + - + +
- - + - -
- - + - -
- - + - -
- - + - -
- - - - -
+ + + + +
- - - - -
+ + + + +
+
+
+
+
+ +
+
+
+ +
+
+
+
-
-
-
-
- -
-
-
-
-
-
K
+
K
+
Na
+
Cl
-
-
-
-
-
-
-
-
-
-
-
Inhibitory
Synapse
Excitatory
Synapse
+40
0
-40
-70
+40
0
-40
-70
Action Potential
IPSP
EPSP
Action Potential
No Action Potential
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Neurotransmission
Dopamine
Transmitter Cell
(Excitatory
Neuron)
Dopamine
Receptor Cell
(Post-synaptic receptor)
Dopamine
Receptor
Synaptic Cleft
Synaptic Vesicles
Neurotransmission
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EPSP=EXCITATORY POSTSYNAPTIC
POTENTIAL
Ex : ACETILCHOLINE, NOR ADRENALINE,
ADRENALIN E, GLUTAMATE

IPSP=INHIBITORY POSTSYNAPTIC
POTENTIAL
Ex :SEROTONIN, DOPAMIN , GABA, GLISIN,
ASPARTAT.
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?
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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.

Historical Events
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Case Studies
Lead damages developing brain
Alcohol Fetal alcohol syndrome
MPTP similar to Parkinsons disease
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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)
C H
H
H
O
H
Ethyl Alcohol
C
H
H
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Vulnerability of Developing
Nervous System

FAS Fetal Alcohol Syndrome
FAE Fetal Alcohol Effects

What is a save level of
consumption during pregnancy?
Alcohol
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FAS Child
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MPTP

N
CH
3
1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine
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1980s Designer Drug
Caused effects similar to
Parkinsons disease
Damaged neurons that
secrete dopamine
MPTP Effects
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Receptor
Ligand
Cell
Membrane
Signal Protein
Positive Response
Outside Cell
Inside Cell
Ligand binds to receptor
1
3
2
Normal Receptor-Ligand Interaction
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Toxicant
1
Toxicant
inactivates
receptor
No Response
3
2
Inactivation of Receptor by Toxicant
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Toxicant
1
No Response
3
2
Ligand
Toxicant
out competes
normal ligand
Ligand cannot bind
receptor
Competition For Receptor
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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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Neuronopathy
Neuronopathy refers to generalized damage to nerve cells,
with the primary damage occurring at the nerve cell body
Many neurotoxicants produce their effects by promoting
cell death in neurons.
Neurons die by one of two processes distinguished by their
morphological and molecular features: apoptosis and
necrosis.
Neurotoxicant-induced cytotoxicity has been associated
with the pathogenesis of a number of neurodegenerative
disorders, including Alzheimers disease, Parkinsons
disease, and amyotrophic lateral sclerosis (ALS)

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Axonopathy
Axonopathy is a specialized form of neuronal damage,
involving degeneration of the axon, while leaving the
cell body intact.

Axonopathy can manifest as defects in sensory or
motor functions, or a combination of the two. For most
neurotoxicants, sensory changes are noticed first,
followed by progressive involvement of motor neurons
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Demyelination
Neurotoxicants that target the synthesis or integrity of
PNS myelin may cause muscle weakness, poor
coordination, and paralysis.
The former include agents like hexachlorophene,
isoniazid, the organotins, cyanide, carbon monoxide,
and Inorganic lead
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Neurotoxicants interfere with signaling processes within
the nervous system by activating or inhibiting receptors, or
altering the amount of neurotransmitter available to
activate receptors.

This type of neurotoxicity is illustrated by the well-
characterized actions of the organophosphates and
carbamates on acetylcholine signaling.
Acetylcholine and its receptors mediate neurotransmission
in sympathetic and parasympathetic autonomic ganglia, in
the effector organs where autonomic nerves terminate, in
neuromuscular junctions, and in the brain and spinal cord.
Hyperstimulation of nicotinic receptors in neuromuscular
junctions results in muscle weakness, in rapid, localized
contractions called fasciculations, and in paralysis

Toxicant-Mediated Alterations in
Synaptic Function
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Examples of Neurotoxicology
Diseases
Parkinson's, Alzheimer's, MS, ALS..
Environmental
Lead, Methylmercury
Occupational
Solvents, Pesticides
Drugs - Clinical
Vincristine, cisplatin
Drugs - Social
Alcohol, cocaine, nicotine
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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 Barrier
Developmental 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,, 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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Mercury
Neurotoxic effects lead to,
Paresthesia
Ataxia
Neurasthenia
Vision and hearing loss
- Coma and death
Neurotoxic effects due to focal necrosis of neurons
The average long-term intake associated with
paresthesia calculated to be 300 g/day for an
adult
Poisoning therapy utilizes chelators such as
cysteine, penicillamine, thiol resins


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Bahaya toksisitas merkuri
Gejala miamata disease congenital:
- serebralpasy
- gangguan saraf
- pertumbuhan terhambat
Carbon disulfida
Used in the production of viscose rayon, cellophane,
pesticides, as a solubilizer for waxes and oils
Direct interaction with free amine and sulfhydryl groups
Microsomal activation to reactive sulfur intermediates
that bind macromolecules
Produce neuronal degeneration in CNS; in PNS produce
myelin swelling and fragmentation

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Source is from lead-based paint, contaminated drinking
water,
Encephalopathy occurs at blood lead levels of 80-100
g/dL
Symptoms of encephalopathy include lethargy,
vomiting, irritability, loss of appetite, and dizziness
Progression of symptoms lead to ataxia, reduced level
of consciousness, which may progress to coma and death
Recovery is often associated with life-long epilepsy,
mental retardation, optic neuropathy, blindness

LEAD
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Chronic toxicity affects PNS;
Schwann
cell degeneration
Mechanisms of toxicity include,
Impairment of cell-cell connections,
Alterations in neurotransmitter levels,
Disrupts calcium metabolism
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NICOTINE
Exposure from smoking
Binds to nicotinic cholinergic receptors
Increase in HR
Elevated BP
Acute overdose leads to excessive
stimulation of nicotinic receptors leading
to ganglionic paralysis
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DDT, lindane, dieldrin
High lipid solubility, low degradation rate
Produce disturbances in ion transport across
axon leading to increased excitability
ORGANOCHLORINE INSECTICIDES
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ORGANOPHOSPHOROUS PESTICIDES
Malathion, parathion, nerve
gases
Inhibits acetylcholinesterase
(AChE) leading to continuous
stimulation
Neurobehavioral, cognitive,
neuromuscular disturbances
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