Neurobehavioral toxicity

Neurobehavioral toxicity can be defined as the study and assessment of adverse effects
on the structure and function of the nervous system, particularly in terms of observable
changes in behavior and performance resulting from exposure to naturally occurring or
synthetic chemical agents. Neurobehavioral toxicity falls under the purview of
neurotoxicology, a specialized branch of toxicology that focuses on understanding how
chemical and biological agents impact the nervous system.

A neurotoxin, within this context, is described as either a naturally occurring or synthetic

chemical agent capable of inducing functional or structural changes in the nervous
system. Neurotoxicologists are tasked with investigating and determining whether a
given substance has caused or contributed to neurological manifestations in
individuals. Such exposures can lead to both reversible and persistent alterations in
neurological function and behavior.

Overview of nervous system

The Nervous System: A Complex Network of Communication

The nervous system is the intricate network of specialized cells and tissues that controls
and coordinates the body's activities. It is the master conductor of our thoughts,
emotions, movements, and sensations, enabling us to perceive, adapt, and interact with
the world around us.

Structure and Organization

The nervous system is divided into two main components:

Central Nervous System (CNS)

The CNS comprises the brain and spinal cord, serving as the control center and
information processing hub.
Central Nervous System (CNS)
● Brain: The brain is the most complex organ in the human body, responsible for a
wide range of functions, including thought, emotion, memory, and movement.

●
● Spinal cord: The spinal cord is a long, slender bundle of nerves that connects the
brain to the rest of the body. It is responsible for transmitting sensory information
from the body to the brain and motor signals from the brain to the muscles.

Peripheral Nervous System (PNS)

The PNS consists of the nerves that extend from the CNS to all parts of the body,
connecting the brain and spinal cord to the muscles, sensory organs, and glands.

Peripheral Nervous System (PNS)

● Sensory nerves: Sensory nerves carry information from the body's sensory
receptors to the CNS.
● Motor nerves: Motor nerves carry signals from the CNS to the muscles, causing
them to contract.
● Autonomic nerves: Autonomic nerves control involuntary functions, such as heart
rate, breathing, and digestion.

●
● Autonomic Nervous System (ANS)

Basic Unit of the Nervous System: Neurons

The fundamental building blocks of the nervous system are neurons, specialized cells
that transmit electrical and chemical signals. Neurons consist of three main parts:
Neuron
● Cell body: The central part of the neuron, containing the nucleus and other
essential organelles.
● Dendrites: Short, branched extensions that receive signals from other neurons or
sensory receptors.
● Axon: A long, slender fiber that transmits signals to other neurons, muscles, or
glands.

Neurotransmission and Synapses

Neurons communicate with each other through a process called neurotransmission. At

junctions between neurons called synapses, the axon of one neuron releases chemicals
called neurotransmitters, which bind to receptors on the dendrites of another neuron or
effector cell. The binding of neurotransmitters triggers an electrical signal in the
receiving neuron or initiates a response in an effector cell.
Types of Neurons

There are three main types of neurons:

● Sensory neurons: Detect stimuli from the environment and transmit information to
the CNS.
● Motor neurons: Transmit signals from the CNS to muscles or glands, causing
movement or secretion.
● Interneurons: Connect sensory and motor neurons within the CNS, forming
complex circuits for processing information.

Functions of the Nervous System

The nervous system has a wide range of functions, including:

○ Sensory reception: Detecting and processing information from the internal

and external environment.
○ Integration: Combining and analyzing sensory information to create a
perception of the world.
○ Motor control: Coordinating the movement of muscles to produce actions
and responses.
○ Homeostasis: Maintaining a stable internal environment by regulating
various body functions.
○ Thought, learning, and memory: Enabling higher-order cognitive functions
such as thinking, learning, and storing memories.

BBB

The Blood-Brain Barrier

The blood-brain barrier (BBB) is a protective barrier that surrounds the brain and spinal
cord. It helps to keep harmful substances out of the brain and spinal cord, while allowing
nutrients and other essential substances in.

Structure of the Blood-Brain Barrier

The BBB is made up of several components, including:

 ● Specialized endothelial cells: These cells line the blood vessels in the brain and
spinal cord. They have tight junctions between them, which prevent substances
from passing between them.
● Transport proteins: These proteins help to move substances across the BBB.
● Astrocyte foot processes: These are extensions of astrocytes, a type of glial cell
in the brain. They help to support the BBB and provide additional protection
against harmful substances.

Function of the Blood-Brain Barrier

The BBB has several important functions, including:

● Protecting the brain from harmful substances: The BBB prevents many harmful
substances from entering the brain, including toxins, bacteria, and viruses.
● Regulating the movement of nutrients and other substances into the brain: The
BBB allows nutrients and other essential substances to enter the brain, such as
glucose, oxygen, and amino acids.
● Maintaining the brain's environment: The BBB helps to maintain the brain's
unique environment, which is essential for normal brain function.

Factors that Affect the Blood-Brain Barrier

Several factors can affect the BBB, including:

● Age: The BBB is less developed in infants and young children, making them
more susceptible to brain injury from toxins.
● Disease: Certain diseases, such as Alzheimer's disease and multiple sclerosis,
can damage the BBB.
● Infection: Infection can also damage the BBB.
● Exposure to toxins: Exposure to certain toxins, such as lead and mercury, can
damage the BBB.

Consequences of Blood-Brain Barrier Dysfunction

Damage to the BBB can allow harmful substances to enter the brain, which can lead to
serious neurological problems. These problems can include:

● Seizures
● Coma
 ● Stroke
● Dementia

Importance of the Blood-Brain Barrier

The BBB is a critical component of the nervous system. It helps to protect the brain from
harm and ensures that the brain receives the nutrients and other substances it needs to
function properly. Understanding the mechanisms of the BBB is essential for developing
effective treatments for neurological diseases.

Energy requirements

Energy Requirements of Neurons

Neurons are highly specialized cells that require a continuous supply of energy to
maintain their function. This energy is primarily derived from aerobic respiration, which
converts glucose into ATP, the cell's energy currency. The high energy demands of
neurons are due to the constant electrical activity that occurs within their membranes.
This activity includes the generation and propagation of action potentials, which are the
electrical signals that underlie communication between neurons.

Factors Affecting Energy Requirements

Several factors can affect the energy requirements of neurons, including:

● Frequency of action potentials: Neurons that fire more frequently require more
energy than neurons that fire less frequently.
● Brain region: Neurons in certain brain regions, such as the cerebral cortex, have
higher energy demands than neurons in other regions.
● Neurotransmitter activity: The release and reuptake of neurotransmitters also
contributes to the energy demands of neurons.
● Synaptic activity: The activity of synapses, the junctions between neurons, also
consumes energy.

Consequences of Energy Depletion

When neurons are deprived of oxygen or glucose, they quickly deplete their ATP stores
and become unable to function properly. This energy depletion can lead to a cascade of
events that ultimately result in neuronal death.

Examples of Toxins that Affect Energy Production

Several toxins can disrupt the energy production of neurons, leading to neurotoxicity.
These toxins include:

● Cyanide: Cyanide inhibits cytochrome oxidase, a key enzyme in the electron

transport chain.
● Carbon monoxide (CO): CO binds to hemoglobin, reducing its ability to transport
oxygen to tissues.
● 3-nitropropionic acid (3-NP): 3-NP inhibits succinate dehydrogenase, another key
enzyme in the electron transport chain.

Importance of Energy Production for Neuronal Function

The high energy demands of neurons reflect their critical role in brain function.
Disruption of energy production can lead to serious neurological impairments, including
seizures, coma, and even death. Therefore, understanding the mechanisms of energy
production in neurons is essential for developing effective treatments for neurological
diseases.

Axonal transport

Axonal transport is a cellular process that allows neurons to transport materials over
long distances. This process is essential for the survival and function of neurons, as it
allows them to maintain their structure and function at the distal ends of their axons.
Axonal transport is divided into two main components:

● Fast axonal transport: This is the fastest component of axonal transport, and it
carries a large number of proteins, many of which are associated with vesicles.
Fast axonal transport is ATP-dependent and reaches a rate of 400 mm/d.
● Slow axonal transport: This is the slowest component of axonal transport, and it
carries the cytoskeleton, which is composed of neurofilaments and microtubules.
Slow axonal transport moves at a rate of approximately 1 mm/d.
The function of axonal transport is to transport materials from the cell body to the distal
end of the axon. These materials include:

● Proteins: Proteins are essential for the structure and function of neurons. They
are also needed for the synthesis of new proteins and for the repair of damaged
proteins.
● Organelles: Organelles are specialized structures that carry out specific functions
within the cell. Mitochondria, for example, are the powerhouses of the cell, and
they produce ATP, which is the energy currency of the cell.
● Lipids: Lipids are essential for the structure of the cell membrane and for the
formation of myelin, which is the insulating sheath that surrounds some axons.

The importance of axonal transport is evident from the consequences of disruption to

this process. When axonal transport is disrupted, the distal end of the axon
degenerates, a process known as axonal degeneration. This is a unique feature of the
nervous system, and it is due to the fact that neurons are unable to regenerate their
axons.

Axonal transport is a complex process that is dependent on a number of factors,

including:

● Microtubules: Microtubules are the tracks along which vesicles are transported.
● Motor proteins: Motor proteins, such as kinesin and dynein, are the enzymes that
provide the force for axonal transport.
● ATP: ATP is the energy currency of the cell, and it is required for axonal
transport.

Disruption of axonal transport can be caused by a number of factors, including:

● Trauma: Trauma, such as a spinal cord injury, can sever axons and disrupt
axonal transport.
● Disease: Diseases, such as Alzheimer's disease and Parkinson's disease, can
disrupt axonal transport.
● Toxins: Toxins, such as lead and mercury, can disrupt axonal transport.

Axonal degeneration

Axonal degeneration is the process by which an axon dies. This can happen after an
injury to the axon, or it can be caused by a disease. When an axon degenerates, it
breaks down into smaller pieces and is eventually removed by the body.
Wallerian degeneration is a type of axonal degeneration that occurs after an axon is
transected, or cut. This type of degeneration is named after Augustus Waller, who first
described it in the 1850s.

The sequence of events that occur in Wallerian degeneration is as follows:

1. Degeneration of the distal nerve stump: The distal nerve stump is the part of the
axon that is farthest from the cell body. After an axon is transected, the distal
nerve stump undergoes a series of changes that lead to its death.
2. Generation of a microenvironment supportive of regeneration: After the distal
nerve stump degenerates, the body begins to generate a microenvironment that
is supportive of regeneration. This microenvironment includes Schwann cells,
macrophages, and growth factors.
3. Regeneration of the axon: If the conditions are right, the axon can regenerate
and reconnect with its target. However, regeneration is often incomplete or
unsuccessful in the CNS.

Factors that affect axonal regeneration include:

● The type of injury: Some types of injuries are more likely to result in regeneration
than others.
● The age of the organism: Younger organisms are generally more likely to
regenerate than older organisms.
● The location of the injury: Injuries to the PNS are more likely to regenerate than
injuries to the CNS.

The clinical relevance of axonal degeneration is that it can lead to a loss of function. For
example, if an axon in the optic nerve degenerates, it can lead to blindness. In some
cases, axonal degeneration can be irreversible. However, in other cases, it is possible
for the axon to regenerate and function normally again.

Myelin formation and maintenance

Myelin formation and maintenance is a complex process that is essential for normal
nervous system function. Myelin is a sheath of fatty tissue that surrounds axons, the
long, slender fibers that transmit nerve impulses. Myelin helps to insulate axons and
speed the transmission of nerve impulses.
In the central nervous system (CNS), myelin is formed by oligodendrocytes. These cells
wrap their cytoplasmic processes around axons, forming concentric layers of myelin.
The cytoplasm is eventually excluded from the inner surface of the membranes, forming
the major dense line of myelin.

In the peripheral nervous system (PNS), myelin is formed by Schwann cells. These cells
also wrap their cytoplasmic processes around axons, forming concentric layers of
myelin. However, in the PNS, the cytoplasm is not completely excluded from the inner
surface of the membranes. Instead, it forms a spiral around the axon, forming the inner
and outer loops of myelin.

The formation and maintenance of myelin requires metabolic and structural proteins that
are unique to the nervous system. Some of the most important myelin proteins include:

● Myelin basic protein (MBP): This protein is closely associated with the
intracellular space (at the major dense line of myelin) in the CNS.
● P1 protein: This protein is located in the PNS and is analogous to MBP.
● Proteolipid protein (PLP): This protein is located on the extracellular surface of
the lipid bilayers in the CNS and is at the intraperiod line of myelin.

Mutations in these genes can result in disorders in which myelin is either poorly formed
from the outset or maintained after its formation. These disorders are known as
demyelinating diseases. Some examples of demyelinating diseases include:

● Multiple sclerosis (MS): This is an autoimmune disease that attacks the myelin
sheath of the CNS.
● Guillain-Barré syndrome: This is an autoimmune disease that attacks the myelin
sheath of the PNS.
● Krabbe disease: This is a genetic disorder that causes the breakdown of myelin
in the CNS.

There are a variety of toxic compounds that can also interfere with myelin formation and
maintenance. These compounds can cause the toxic "myelinopathies". Some examples
of myelinopathies include:

● Lead poisoning: Lead poisoning can cause demyelination of both the CNS and
PNS.
● Mercury poisoning: Mercury poisoning can cause demyelination of the CNS.
● Alcohol poisoning: Alcohol poisoning can cause demyelination of the CNS.
The loss of myelin with the preservation of axons is referred to as demyelination.
Demyelination can cause a variety of symptoms, including:

● Muscle weakness: Demyelination of the nerves that control muscles can cause
muscle weakness.
● Sensory problems: Demyelination of the nerves that carry sensory information to
the brain can cause sensory problems, such as numbness, tingling, and pain.
● Vision problems: Demyelination of the nerves that carry visual information to the
brain can cause vision problems, such as blurred vision, double vision, and loss
of vision.

Treatment for demyelination depends on the underlying cause. Some demyelinating

diseases can be treated with medication, while others cannot. In some cases, physical
therapy can help to improve muscle function after demyelination.

Neurotransmission

Neurotransmission is the process by which neurons communicate with each other. This
communication is essential for the normal functioning of the nervous system.

Neurotransmission occurs at synapses. These are specialized junctions between

neurons where neurotransmitters are released from the presynaptic neuron and bind to
receptors on the postsynaptic neuron.

Neurotransmitters are chemicals that are released from neurons. They act as the first
messenger in neurotransmission.

Binding of a neurotransmitter to a receptor on a postsynaptic neuron can have two main

effects:

● It can open or close ion channels. This changes the electrical potential of the
neuron and can either excite or inhibit the neuron.
● It can activate a second messenger system. This leads to a cascade of events
that can have a variety of effects on the neuron, including changes in gene
expression.

There are many different types of neurotransmitters. Some of the most important ones
include:
 ● Acetylcholine (ACh): This neurotransmitter is involved in muscle contraction, as
well as memory and learning.
● Dopamine: This neurotransmitter is involved in movement, reward, and
motivation.
● GABA: This neurotransmitter is the main inhibitory neurotransmitter in the brain.
It helps to calm the brain down and prevent seizures.
● Glutamate: This neurotransmitter is the main excitatory neurotransmitter in the
brain. It is involved in learning, memory, and thinking.

Neurotransmission can be disrupted by a variety of factors, including:

● Drugs: Some drugs, such as cocaine and heroin, can block the reuptake of
neurotransmitters, leading to increased levels of neurotransmitters in the brain.
Other drugs, such as barbiturates, can open ion channels, leading to increased
inhibition of neurons.
● Diseases: Some diseases, such as Alzheimer's disease and Parkinson's
disease, can cause the death of neurons that produce neurotransmitters. This
can lead to a decrease in the levels of neurotransmitters in the brain.
● Toxins: Some toxins, such as lead and mercury, can damage neurons and
disrupt neurotransmission.

Disruption of neurotransmission can lead to a variety of neurological symptoms,

including:

● Muscle weakness or paralysis: This can occur if the neurotransmitters that

control muscle movement are disrupted.
● Seizures: These are caused by excessive excitation of neurons in the brain.
● Cognitive problems: These can occur if the neurotransmitters that are involved in
learning, memory, and thinking are disrupted.
● Mood disorders: These can occur if the neurotransmitters that are involved in
mood regulation are disrupted.

Mechanisms of neurobehavioral toxicity

○ neurotransmitter imbalance
○ oxidative stress
○ excitotoxicity
○ endocrime disruption
○ epigenetic changes
 ○ bbb disruption
○ neuroinflammation
○ neurotrophic factor disruption
○ mitochondrial dysfunction

Major toxicants
Neurotoxicant Mechanisms of Physiological
Category Subcategory Examples Neurotoxicity Effects Behavioral Effects
Altered
Dopamine-indu dopamine
ced signaling,
excitotoxicity, neurodegenera
neuroinflammat tion,
Amphetamines, ion, oxidative mitochondrial Anxiety, psychosis,
Drugs Psychostimulants Cocaine stress dysfunction addiction
Opioid receptor
desensitization,
tolerance, and Impaired pain
dependence, perception,
Neurotrophic respiratory
Heroin, factor depression, Sedation, analgesia,
Opioids Morphine dysregulation addiction euphoria
GABA receptor
downregulation Enhanced
, tolerance, and GABAergic
dependence, neurotransmiss
Impaired ion, reduced Anxiety relief,
Diazepam, memory neuronal sedation, cognitive
Benzodiazepines Lorazepam consolidation excitability impairment
Dopamine
receptor
blockade, Reduced
Extrapyramidal dopamine Decreased
Haloperidol, symptoms, signaling, hallucinations and
Chlorpromazin tardive altered motor delusions, movement
Antipsychotics e dyskinesia control disorders
Selective Serotonin or
serotonin norepinephrine Altered
reuptake reuptake serotonin or
inhibitors inhibition, norepinephrine
(SSRIs), increased signaling, Improved mood,
Tricyclic neurotransmitte potential reduced anxiety,
Antidepressants antidepressant r levels neurotoxicity cognitive side effects
 s (TCAs)
Altered ion
channel
function,
neurotransmitte
r system
modulation, Mood
Neurotrophic stabilization, Altered neuronal
Mood Stabilizers factor potential excitability, cognitive
(Lithium) Lithium dysregulation neurotoxicity impairment
Serotonin
receptor Neurotransmitt
agonism, er system
Altered modulation, Altered perception,
perception and altered sensory hallucinations,
Hallucinogens LSD, Psilocybin consciousness processing mystical experiences
Serotonin,
norepinephrine, Increased energy,
and dopamine Altered mood enhancement,
release neurotransmitte cognitive impairment
(MDMA), r levels, (MDMA); Mood
Club Drugs NMDA receptor glutamate elevation,
(MDMA, MDMA, blockade signaling dissociation, learning
Ketamine) Ketamine (Ketamine) disruption difficulties (Ketamine)
Acetylcholinest
erase inhibition
(Pesticides),
Pesticides Hormone Muscle weakness,
(Organophosph mimicry and Altered tremors, seizures
ates), neurotransmitte neurotransmitte (Pesticides);
Polychlorinated r system r signaling, Cognitive deficits,
Biphenyls disruption neurodegenera behavioral
(PCBs), (PCBs, tion, oxidative abnormalities (PCBs,
Heavy Metals Organic Dioxins Dioxins) stress Dioxins)
Cognitive impairment,
motor deficits,
Altered developmental delays
neurotransmiss (Mercury, Lead);
Protein function ion, Cognitive deficits,
disruption, neurodegenera behavioral
Mercury, Lead, oxidative tion, abnormalities
Manganese, stress, mitochondrial (Manganese,
Inorganic Arsenic excitotoxicity dysfunction Arsenic)
 ● Major neurotoxic behavioral disorders
Methodological aspects ( detection, testing, etc)

Neurobehavioral Testing: Assessing the Effects of Neurotoxicants

Neurobehavioral testing is a specialized assessment approach that evaluates the

functioning of the nervous system, particularly in the context of potential exposure to
neurotoxicants. These chemicals, including solvents, pesticides, and heavy metals, can
have detrimental effects on the brain and nervous system, leading to impairments in
cognitive function, behavior, and emotion.

Purposes of Neurobehavioral Testing

Neurobehavioral testing serves several crucial purposes in healthcare and research:

● Early Detection of Neurotoxicant Exposure: Subtle changes in cognitive function

may be the earliest indicators of neurotoxicant exposure. Neurobehavioral tests
can detect these subtle impairments before they become apparent in daily life,
allowing for early intervention and prevention of further damage.
● Evaluation of Neurotoxicant Effects: Neurobehavioral testing provides a
standardized and objective assessment of the impact of neurotoxicants on
various cognitive domains, including attention, memory, processing speed, and
motor skills.
● Monitoring Treatment Outcomes: Neurobehavioral testing can be used to track
the effectiveness of treatments for neurotoxicant-induced impairments, helping to
guide treatment decisions and assess patient progress.
● Worker's Compensation Evaluation: In cases of suspected neurotoxicant
exposure in the workplace, neurobehavioral testing plays a critical role in
determining whether a worker has suffered a work-related injury.

Common Neurobehavioral Tests

A wide range of neurobehavioral tests is available, each assessing specific cognitive

functions:

● Tests of Cognitive Ability: These tests measure overall intellectual functioning,

such as vocabulary, comprehension, and reasoning. Examples include the
Wechsler Adult Intelligence Scale (WAIS) and the Raven's Matrices.
 ● Tests of Psychomotor Skills: These tests assess the coordination and integration
of sensory and motor functions. Examples include simple reaction time tests and
the Purdue Pegboard Test.
● Tests of Attention and Concentration: These tests evaluate the ability to focus on
tasks and resist distractions. Examples include the Digit Span Test and the
Continuous Performance Test.
● Tests of Memory and Learning: These tests assess the ability to encode, store,
and retrieve information. Examples include the Rey Auditory-Verbal Learning
Test and the California Verbal Learning Test.

Interpretation and Clinical Considerations

Interpreting neurobehavioral test results requires careful consideration of several

factors, including:

● Individual Factors: The individual's age, education level, pre-exposure cognitive

functioning, and overall health status must be considered.
● Neurotoxicant Exposure: The type of neurotoxicant, the duration and level of
exposure, and potential co-exposures to other substances are crucial factors.
● Clinical Presentation: The individual's subjective symptoms, observed behavioral
changes, and medical history should be integrated into the interpretation.
● Test Administration and Scoring: Proper test administration procedures and
accurate scoring are essential for reliable interpretation.

Neurobehavioral Testing in Research

Neurobehavioral testing plays a vital role in research on neurotoxicants, contributing to:

● Understanding Neurotoxicant Mechanisms: Studies using neurobehavioral tests

help elucidate the mechanisms by which neurotoxicants exert their effects on the
nervous system.
● Developing Neuroprotective Strategies: Research involving neurobehavioral
testing can guide the development of interventions to mitigate or prevent
neurotoxicant-induced impairments.
● Establishing Safety Limits: Neurobehavioral data is crucial for setting exposure
limits and safety standards for neurotoxicants in the workplace and environment.

Neurobehavioral testing is an essential tool for assessing the effects of neurotoxicants

on the nervous system. Early detection of neurotoxicant-induced impairments allows for
timely intervention and prevention of further damage. Neurobehavioral testing also plays
a critical role in research, contributing to our understanding of neurotoxicant
mechanisms, developing neuroprotective strategies, and establishing safety limits. As
research continues to advance, neurobehavioral testing will remain an invaluable tool
for protecting human health from the harmful effects of neurotoxicants.