Neuro-behavioural

toxicity
M pharm forensic
toxicology sem 1,
NFSU
 TABLE OF CONTENTS

01 02 03
All about
Introduction Targets of
nervous system toxicants
• Routes of toxicity
• PNS • Toxicants
• CNS

04
Disorders and
05 06
Assessments References
diseases
• Neurobehavioral disorders • Road side
(categories) • Bed side
• Neurodegenrative diseases • Neuropsychological
(models)
 INTRODUCTION
o Neurobehavioral toxicity refers to the adverse effects of chemicals or
other substances on the functioning of the nervous system, including
the brain, spinal cord, and peripheral nerves.
o These effects can be caused by a variety of mechanisms, such as
disruption of neural signaling pathways, damage to neurons and their
supporting cells, and alterations in neurotransmitter systems.
o Neurobehavioral toxicity can result in a wide range of cognitive,
emotional, and behavioral changes, including impaired memory and
learning, decreased attention and concentration, increased agitation
and irritability, and even psychotic symptoms.
 INTRODUCTION
o The study of neurobehavioral toxicity involves evaluation of both the
direct and indirect effects of chemicals on the nervous system.
o Direct effects occur when chemicals interact directly with neural
tissue, altering the function or structure of neurons, glial cells, or
other components of the nervous system.
o Indirect effects can result from changes in the body that are not
necessarily related to direct interactions with the nervous system but
nevertheless impact its function, such as changes in hormone levels,
metabolism, or immune response.
 DIFFERENCE
NEUROTOXICITY NEUROBEHAVIORAL TOXICITY

o Refers to the ability of a o Refers to the ability of a substance to

substance to damage or kill affect behavior, emotions, and
neurons, leading to structural cognitive function without necessarily
and functional changes in the causing direct damage to neurons or
nervous system. their supporting structures.

o Effects can include degeneration o Effects can include changes in mood,

of neurons, loss of myelin anxiety, sleep patterns, and cognitive
sheaths, and disruption of performance.
neurotransmitter systems.
TARGETS OF NERVOUS SYSTEM
PNS - PERIPHERAL NERVOUS SYSTEM

Myelinopathies : -Myelin provides

electrical insulation of neuronal
processes, and its absence leads to a
slowing of and/or aberrant conduction
of impulses between adjacent
processes, so-called ephaptic
transmission.
Myelinopathies are disorders that
affect the myelin sheath, which is a
fatty insulating substance that
surrounds and protects nerve fibers.
TARGETS OF NERVOUS SYSTEM
PNS - PERIPHERAL NERVOUS SYSTEM
Axonopathy: The neurotoxic disorders
termed axonopathies are those in
which the primary site of toxicity is
the axon itself. The axon degenerates,
and with it the myelin surrounding
that axon; however, the neuron cell
body remains intact.
Axonopathy refers to damage or
degeneration of the axons, which are
the long, slender extensions of a
neuron that transmit signals away
from the cell body.
 TARGETS OF NERVOUS SYSTEM
PNS - PERIPHERAL NERVOUS SYSTEM

THE PATIENT
Neuronopathy: Peripheral nervous system (PNS) neuronopathy refers to damage or
disease affecting the peripheral nerves outside the central nervous system (CNS).
Neuronopathy is a form of polyneuropathy and occurs as a result of neuron
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degeneration. It is a subgroup of disorders of the peripheral nervous system (PNS)
and involves the destruction of specific neurons in this area.
There are several types of neuronopathy, including sensory neuronopathy, also
known as ganglionopathy, motor neuronopathy, and autonomic neuronopathy. Each
of these types is characterized by damage to particular neurons in the PNS and can
lead to a distinct set of resulting symptoms.
 CNS- NEUROTRANSMITTER

Neurotransmission is the process by which chemical messengers

(neurotransmitters) transmit signals between neurons in the nervous system.
This process is crucial for normal brain function, including mood regulation,
movement, and cognitive processes.
 A wide variety of naturally occurring toxins, as well as synthetic chemicals, alters specific mechanisms
of intercellular communication.

Nicotine Widely available in tobacco

products and in certain pesticides,
Nicotine exerts its effects by binding to a
subset of cholinergic receptors, the
nicotinic receptors.
These receptors are located in ganglia,
at the neuromuscular junction, and also
within the CNS, where the psychoactive
and addictive properties most likely
reside
At the same time, nicotine leads to a sensation of “relaxation” and is associated with
alterations of electroencephalographic (EEG) recordings in humans. These effects are
probably related to the binding of nicotine with nicotinic receptors within the CNS, and
the EEG changes may be blocked with mecamylamine, a nicotinic antagonist.

Cocaine and Amphetamines Cocaine blocks the

reuptake of dopamine, norepinephrine, and serotonin
at the nerve terminal in the CNS, and also causes
release of dopamine from storage vesicles.
Amphetamines also affect catecholamine
neurotransmission in the CNS, but also have the
potential to damage monoaminergic cells directly.
All about neurotoxicants

Route of toxicants

Neurotoxic substances

Toxicants
 Route of Administration of Toxicants
• Neurotoxic chemicals can be absorbed via pulmonary, oral, intranasal, subcutaneous,
intravenous, and transdermal routes.
• Although some drugs of abuse are taken intravenously (eg, heroine) to avoid first pass
metabolism, most are inhaled (eg, paint thinner “huffing”), smoked (eg, marijuana), imbibed
(eg, ethanol) or snorted (eg, cocaine) making pulmonary, oral and intranasal the most
common routes of absorption of these compounds.
• On the contrary, prescription drugs are more often taken via oral, transdermal or
intravenous routes. All chemicals taken by the oral route are subject to extensive first pass
metabolism in the liver following absorption from the gastrointestinal tract.
• Occupational and environment exposures are typically associated with absorp-tion via
pulmonary and transdermal routes.
• The size of the molecule as well as the lipid solubility and charge also influence absorp-
tion, with small, lipid soluble, uncharged molecules
Neurotoxic chemical is defined as a substance that is directly and/or indirectly
capable of the following:
1. Altering the integrity of nerve cell membranes, thereby affecting neuronal
excitability, neurotransmitter release, and synaptic activity of neurons.
2. Disturbing the flow of axoplasm, thereby interfering with the transport of
neurotransmitters and nutrient substances along the axon to and from the
cell body.
3. Disrupting cellular respiration processes.
4. Disrupting protein synthesis.
5. Affecting neuronal functions indirectly by damaging Schwann cells and
peripheral myelin, oligodendrocytes, and central myelin and/or disrupting
the normal functioning of astrocytes and microglia.
6. Disturbing extracellular fluid volume and flow by damaging capillary
endothelium, thereby resulting in disruption of the integrity of the BBB.
 Neurotoxicants
Neurotoxicants Neurobehavioral effects
Carbon monoxide Encephalopathy, delayed
parkinsonism(dystonia)
Lead Encephalopathy ( acute), learning
deficits(children), myelinopathy
Manganese Emotional disturbances,
parkinsonism(dystonia)
Methanol Headache, visual loss or blindness,
coma(severe)
MPTP Parkinsonism ( dystonia)
Carbon disulfide Psychosis(acute),peripheral
neuropathy(chronic)
Organophosphorous compounds Abdominal pain(acute), peripheral
neuropathy
Mechanism of toxicity
Neuronal loss in cortex, focal
demyelination
Brain swelling,
hemorrhages(acute),axonopathy
Degeneration of straitum
Degeration of retinal ganglion cells
Neuronal degeneration of substantia
nigra
Axonal degeneration, neurofilament
swelling
Axonal degeneration
 Lead
• It result in peripheral neuropathy with prominent segmental demyelination.
• Process that bears a strong resemblance to tellurium toxicity.
• Variety of manifestation of lead toxicity is seen in other organs system also.
• In adults are exposed to lead in occupational settings through lead smelting
processes and soldering and in domestic settings through lead pipes or through
the consumption of “moon shine” contaminated with lead.
• Children,below 5 years of age have higher blood levels of lead than adults in the
same environment.
• In young children, acute massive exposures to lead result in severe cerebral
edema, perhaps from damage to endothelial cells.
• Children seem to be more susceptible to this lead encephalopathy than adults.
• Adults may also develop an acute encephalopathy in the setting of massive lead
exposure.
• Chronic lead intoxication in adults results in peripheral neuropathy , accompanied
by manifestations outside the NS. Such as gastritis, colicky abdominal pain,
anemia, and the prominent deposition of lead in particular anatomic sites, creating
lead lines in the gums and in the epiphyses of long bones in children.
• Electrophysiologic studies have demonstrated a slowing of nerve condition.
• Another finding in humans is the predominant involvement of
motor axons, creating one of the few clinical situations in which
patients present with predominantly motor symptoms.
• Another theory on the mechanisms associated with lead-
induced effects in the peripheral nervous system suggests a
toxic effect on Schwann cells, and the ensuing demyelination of
nerves.
• There is a clear association between lead level and intel lectual
performance.
• Children with higher blood levels tend to share certain other
environmental factors,
• In spite of these complex social factors, it appears that lead
exposure has an adverse effect on the intellectual abilities of
children.
 Organophosphorous compound
• The OP insecticides qnd nerve agents are designed to inhibit
acetylcholinesterase (AChE), thereby causing accumulation of acetylcholine
in cholinergic synapses resulting in cholinergic toxicity and death.
• Some OP compounds, tri-o-cresyl phosphate (TOCP), are neuropathic and
can cause a severe sensorimotor central peripheral distal axonopathy called
OP compound induced delayed neurotoxicity (OPIDN) without inducing
cholinergic poisoning.
• This condition is also referred to as a delayed neuropathy or delayed.
Polyneuropathy (OPIDP)
• Many OP compounds are hydrophobic and readily enter the NS.
 Disorders

Categories Model
Neuro-toxic behavioral Neuro-degenrative
disorders diseases
Categories
 Categories of neuro-toxic behavioral disorders
extent disorder symptoms duration neurological effects
reversible
sedation, euphoria, pharmacologic effect
attention and (gait,ataxia, dysmetria,
acute intoxication psychomotor deficits hours loss of conciousness)
cognitive deficits,
seizures,coma.
recovery in most
acute toxic cases with cessation neuronal loss due to
acute exposure encephalopathy of exposure hours-years necrosis or apoptosis
permanent cognitive
or motor deficits,
chronic toxic permanent changes in neuronal loss due to
encephalopathy mood and affect months-years necrosis or apoptosis
cerebral dysfunction
associated with
incoordination, tremor, dystonia, dyskinesis,
chronic exposure parkinsonism nystagmus depends on toxicant bradykinesis
 Difference between acute and chronic toxic encephalopathy
Feature Acute Toxic Encephalopathy
Onset Rapid (days or weeks)
Exposure Single or short-term
Range from euphoria to coma, with
varying degrees of cognitive
Clinical manifestations impairment
Complete for most cases with
Recovery potential cessation of exposure
Severity grading Not formally graded
Closer link between exposure and
Diagnosis symptoms
Chronic Toxic Encephalopathy
Insidious (months or years)
Repeated or cumulative
Primarily cognitive impairment,
including memory, attention, and
mood problems
Limited, dependent on severity and
time of diagnosis
I-III or 1, 2A, 2B, and 3 (1 and 2A
more subjective, 3 with neurological
deficits)
Requires detailed history,
neurobehavioral testing, and
exclusion of other causes
Models
Neurodegerative disease model
•MPTP is a substrate
for MAO-B, oxidized to
toxic MPP+.
•MPP+ enters
dopaminergic neurons
via DA uptake system,
causing injury or death.
•Acts as a
mitochondrial toxin,
blocking respiration at
complex I.
 Behavioral assessment

Road side Bed side

Neuropsychological
tests
 Assessment

Road side tests Features

● WAT ● Acute effects of
● One-leg stand intoxication
● Gaze-evoked ● Trained first responders
nystagmus ( police, investigators)
 Assessment

Bed side tests Features

● MMSE ● Clinically assess
● Attention and mental intoxication
control tests ● Trained clinicians
● Finger to nose test
● Sensory function
evaluation
 Neuropsychological
EEG- record brain’s Evoked RP- responses
electrical activity to stimuli( sensory and
motor) Event RP –
responses to stimuli
( cognition )

Peripheral nerve Blink reflex testing –

conduction studies- assess reflexes
speed and strength of involving facial nerves
electrical signals along
periphery
 References
● Casarett and Doull's Toxicology: The Basic Science of Poisons, 9th Edition: A
comprehensive textbook covering all aspects of toxicology, including chapters
on neurotoxicology.
● MH Ratner, JF Jabre (2017): neurobehavioral toxicology
● JB Harris, PG Blair (2004): neurotoxicology
THANK YOU!