OUTLINE

Nervous system development

Nervous system anatomy and physiology

Manifestations of neurotoxicity

Neuronopathies

Axonopathies

Myelinopathies

Neurotransmission-associated anomalities

Prototypical toxicological agents

Methylmercury

Carbon disulfide

Lead

Nicotine

Organochlorine insectides

Organophosphorous insectides

Venoms

MANIFESTATIONS OF NEUROTOXICITY

Neuronopathies

Axonopathies

Myelinopathies

Neurotransmission-associated anomalities

MANIFESTATIONS OF NEUROTOXICITY

Injury or death to neurons

Irreversible loss

Initial injury followed by apoptosis or necrosis

Caused by CO, ethanol, carbon tetrachloride, methyl mercury, lead

MANIFESTATIONS OF NEUROTOXICITY

Primary site of toxicity is axon

Degeneration of axon, surrounding myelin, but cell body remains intact

Irreversible in CNS, but reversible in PNS

Caused by CS₂, acrylamide, gold, organophosphorous esters

MANIFESTATIONS OF NEUROTOXICITY

MANIFESTATIONS OF NEUROTOXICITY

Intramyelinic edema

Demyelination

Remyelination in CNS occurs to a limited extent

Remyelination in PNS done by Schwann cells

Caused by amiodarone, disulfiram,Pb

MANIFESTATIONS OF NEUROTOXICITY

Interruption of impulse transmission

Blockade of transsynaptic communication

Inhibition of neurotransmitter uptake

Interference with second-messenger systems

Caused by nicotine, amphetamines, cocaine

MANIFESTATIONS OF NEUROTOXICITY

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MERCURY

Vapor from degassing in earth’s crust

Methylated by microorganisms to CH₃Hg

CH₃Hg is most significant form of Hg in terms of toxicity from environmental exposure

Bioconcentration in aquatic food chain

90 to 95% absorption in GIT

Crosses placenta

MERCURY

Neurotoxic effects lead to,

Paresthesia

Ataxia

Neurasthenia

Vision and hearing loss

Coma and death

Neurotoxic effects due to focal necrosis of neurons

MERCURY

The critical or lowest level of observed adverse health effect in adults is paresthesia

The average long-term intake associated with paresthesia calculated to be 300 μg/day for an adult

Poisoning therapy utilizes chelators such as cysteine, penicillamine, thiol resins

CARBON DISULFIDE

Used in the production of viscose rayon, cellophane, pesticides, as a solubilizer for waxes and oils

Exposure is predominantly occupational

OSHA has established a PEL of 20 ppm as an 8-h TWA

CARBON DISULFIDE

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

LEAD

Ubiquitous toxic metal

Primary route of exposure is by ingestion

Source is from lead-based paint, contaminated drinking water, lead-glazed pottery

Encephalopathy occurs at blood lead levels of 80-100 μg/dL

LEAD

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

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

Scorpions, spiders

Contain low molecular weight proteins that affect ion transport along axon

Impairs action potential

Symptoms include tachycardia, respiratory distress


	Nervous system development
	Nervous system anatomy and physiology
	Manifestations of neurotoxicity
		Neuronopathies
		Axonopathies
		Myelinopathies
		Neurotransmission-associated anomalities
	Prototypical toxicological agents
		Methylmercury
		Carbon disulfide
		Lead
		Nicotine
		Organochlorine insectides
		Organophosphorous insectides
		Venoms


	Injury or death to neurons
	Irreversible loss
	Initial injury followed by apoptosis or necrosis
	Caused by CO, ethanol, carbon tetrachloride, methyl mercury, lead


	Primary site of toxicity is axon
	Degeneration of axon, surrounding myelin, but cell body remains intact
	Irreversible in CNS, but reversible in PNS
	Caused by CS₂, acrylamide, gold, organophosphorous esters


	Intramyelinic edema
	Demyelination
	Remyelination in CNS occurs to a limited extent
	Remyelination in PNS done by Schwann cells
	Caused by amiodarone, disulfiram,Pb


	Interruption of impulse transmission
	Blockade of transsynaptic communication
	Inhibition of neurotransmitter uptake
	Interference with second-messenger systems
	Caused by nicotine, amphetamines, cocaine


	Vapor from degassing in earth’s crust
	Methylated by microorganisms to CH₃Hg
		CH₃Hg is most significant form of Hg in terms of toxicity from environmental exposure
		Bioconcentration in aquatic food chain
		90 to 95% absorption in GIT
		Crosses placenta


	Neurotoxic effects lead to,
		Paresthesia
		Ataxia
		Neurasthenia
		Vision and hearing loss
		Coma and death
	Neurotoxic effects due to focal necrosis of neurons


	The critical or lowest level of observed adverse health effect in adults is paresthesia
	The average long-term intake associated with paresthesia calculated to be 300 μg/day for an adult
	Poisoning therapy utilizes chelators such as cysteine, penicillamine, thiol resins


	Used in the production of viscose rayon, cellophane, pesticides, as a solubilizer for waxes and oils
	Exposure is predominantly occupational
	OSHA has established a PEL of 20 ppm as an 8-h TWA


	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


	Ubiquitous toxic metal
	Primary route of exposure is by ingestion
	Source is from lead-based paint, contaminated drinking water, lead-glazed pottery
	Encephalopathy occurs at blood lead levels of 80-100 μg/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


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


	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


	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


	Malathion, parathion, “nerve gases”
	Inhibits acetylcholinesterase (AChE) leading to continuous stimulation
	Neurobehavioral, cognitive, neuromuscular disturbances
	Intermediate syndrome
	Death from respiratory distress


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