NERVOUS SYSTEM

TOXICOLOGY
 OUTLINE
Pr
od
uc
ed
w
ith
a

• Nervous system development

Tr
ia
lV
er

• Nervous system anatomy and physiology

si
on
of
PD

• Manifestations of neurotoxicity
F
An
no

– Neuronopathies
ta
to
r-

– Axonopathies
w
w
w
.P
– Myelinopathies
D
FA

– Neurotransmission-associated anomalities
nn
ot
at

• Prototypical toxicological agents

or
.c
om

– Methylmercury
– Carbon disulfide
– Lead
– Nicotine
– Organochlorine insectides
– Organophosphorous insectides
– Venoms
NERVOUS SYSTEM
NERVOUS SYSTEM
BRAIN
NERVOUS SYSTEM
SPINAL CORD
NERVOUS SYSTEM
NERVOUS SYSTEM ANATOMY
NERVOUS SYSTEM ANATOMY
NERVOUS SYSTEM ANATOMY
NERVOUS SYSTEM ANATOMY
BLOOD BRAIN BARRIER
MANIFESTATIONS OF NEUROTOXICITY
MANIFESTATIONS OF NEUROTOXICITY

• Neuronopathies
• Axonopathies
• Myelinopathies
• Neurotransmission-associated
anomalities
 MANIFESTATIONS OF NEUROTOXICITY
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od
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NEURONOPATHIES
a
Tr
ia
lV
er
si
on
of
PD

• Injury or death to neurons

F
An
no
ta
to

• Irreversible loss
r-
w
w
w
.P
D

• Initial injury followed by apoptosis or

FA
nn
ot
at
or

necrosis
.c
om

• Caused by CO, ethanol, carbon

tetrachloride, methyl mercury, lead
 MANIFESTATIONS OF NEUROTOXICITY
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od
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AXONOPATHIES
a
Tr
ia
lV
er
si
on
of
PD

• Primary site of toxicity is axon

F
An
no
ta
to

• Degeneration of axon, surrounding

r-
w
w
w
.P

myelin, but cell body remains intact

D
FA
nn
ot
at
or

• Irreversible in CNS, but reversible in

.c
om

PNS
• Caused by CS2, acrylamide, gold,
organophosphorous esters
MANIFESTATIONS OF NEUROTOXICITY
AXONOPATHIES
 MANIFESTATIONS OF NEUROTOXICITY
Pr
od
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w
ith

MYELINOPATHIES
a
Tr
ia
lV
er
si
on
of
PD

• Intramyelinic edema
F
An
no
ta
to

• Demyelination
r-
w
w
w
.P
D

• Remyelination in CNS occurs to a

FA
nn
ot
at
or

limited extent
.c
om

• Remyelination in PNS done by

Schwann cells
• Caused by amiodarone, disulfiram,Pb
 MANIFESTATIONS OF NEUROTOXICITY
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NEUROTRANSMISSION-ASSOCIATED ANOMALITIES
Tr
ia
lV
er
si
on
of

• Interruption of impulse transmission

PD
F
An
no
ta

• Blockade of transsynaptic
to
r-
w
w

communication
w
.P
D
FA
nn
ot

• Inhibition of neurotransmitter uptake

at
or
.c
om

• Interference with second-messenger

systems
• Caused by nicotine, amphetamines,
cocaine
MANIFESTATIONS OF NEUROTOXICITY
Pr
od
uc
ed
w

MERCURY
ith
a
Tr
ia
lV
er
si
on
of
PD
F

• Vapor from degassing in earth’s crust

An
no
ta
to
r-

• Methylated by microorganisms to CH3Hg

w
w
w
.P
D

– CH3Hg is most significant form of Hg in terms of

FA
nn
ot

toxicity from environmental exposure

at
or
.c
om

– Bioconcentration in aquatic food chain

– 90 to 95% absorption in GIT
– Crosses placenta
Pr
od
uc

MERCURY
ed
w
ith
a
Tr
ia
lV

METHYL MERCURY
er
si
on
of
PD

• Neurotoxic effects lead to,

F
An
no
ta
to

– Paresthesia
r-
w
w
w
.P

– Ataxia
D
FA
nn
ot
at

– Neurasthenia
or
.c
om

– Vision and hearing loss

– Coma and death
• Neurotoxic effects due to focal necrosis
of neurons
Pr
od

MERCURY
uc
ed
w
ith
a
Tr
ia
lV

METHYL MERCURY
er
si
on
of
PD
F

• The critical or lowest level of observed

An
no
ta
to

adverse health effect in adults is paresthesia

r-
w
w
w
.P

• The average long-term intake associated with

D
FA
nn
ot

paresthesia calculated to be 300 μg/day for

at
or
.c
om

an adult
• Poisoning therapy utilizes chelators such as
cysteine, penicillamine, thiol resins
Pr
od
uc
ed
w

CARBON DISULFIDE
ith
a
Tr
ia
lV
er
si
on
of
PD
F

• Used in the production of viscose rayon,

An
no
ta
to

cellophane, pesticides, as a solubilizer

r-
w
w
w
.P
D

for waxes and oils

FA
nn
ot
at
or

• Exposure is predominantly occupational

.c
om

• OSHA has established a PEL of 20 ppm

as an 8-h TWA
Pr
od
uc
ed
w

CARBON DISULFIDE
ith
a
Tr
ia
lV
er
si
on
of
PD
F

• Direct interaction with free amine and

An
no
ta
to

sulfhydryl groups
r-
w
w
w
.P
D
FA

• Microsomal activation to reactive sulfur

nn
ot
at
or

intermediates that bind macromolecules

.c
om

• Produce neuronal degeneration in CNS;

in PNS produce myelin swelling and
fragmentation
Pr
od
uc
ed
w

LEAD
ith
a
Tr
ia
lV
er
si
on
of
PD

• Ubiquitous toxic metal

F
An
no
ta
to

• Primary route of exposure is by

r-
w
w
w
.P

ingestion
D
FA
nn
ot
at

• Source is from lead-based paint,

or
.c
om

contaminated drinking water, lead-

glazed pottery
• Encephalopathy occurs at blood lead
levels of 80-100 μg/dL
Pr
od
uc
ed
w

LEAD
ith
a
Tr
ia
lV
er
si
on
of
PD

• Symptoms of encephalopathy include

F
An
no
ta

lethargy, vomiting, irritability, loss of

to
r-
w
w
w

appetite, and dizziness

.P
D
FA
nn
ot

– Progression of symptoms lead to ataxia,

at
or
.c
om

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
• Chronic toxicity affects PNS; Schwann
cell degeneration
• Mechanisms of toxicity include,
– Impairment of cell-cell connections
– Alterations in neurotransmitter levels
– Disrupts calcium metabolism
 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
 ORGANOCHLORINE INSECTICIDES

• DDT, lindane, dieldrin

• High lipid solubility, low degradation rate
• Persistence in environment,
bioconcentration and biomagnification
in food chains
• Produce disturbances in ion transport
across axon leading to increased
excitability and seizures
ORGANOPHOSPHOROUS PESTICIDES
• Malathion, parathion, “nerve gases”
• Inhibits acetylcholinesterase (AChE)
leading to continuous stimulation
• Neurobehavioral, cognitive,
neuromuscular disturbances
• Intermediate syndrome
• Death from respiratory distress
 VENOMS
ARACHNIDA

• Scorpions, spiders
• Contain low molecular weight proteins
that affect ion transport along axon
– Impairs action potential
• Symptoms include tachycardia,
respiratory distress