Toxicology

Introduction, Routes and Exposure

Prof. Shishir Sinha
Department of Chemical Engineering

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 Toxicological Studies
Significance of chemical safety
 8.3% (Ref. 2016-17 UNO) of all deaths are due to
environmental exposure to selected chemicals
each year.
 Major contributors: Indoor smoke from solid
fuel use, outdoor air pollution and second-hand
smoke, followed by occupational particulates,
chemicals involved in acute poisonings, and
pesticides involved in self-poisonings.

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 What is Toxicology?
• Involves all aspects of adverse effects of
chemicals on living system.
• Those effects which are damaging to either the
survival or normal function of the individual

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 What is Toxicity?
• The term “toxicity” is used to describe the nature
of adverse effects produced and the conditions
necessary for their production.
• Before toxicity can develop, a substance must
come into contact with a body surface such as
skin, eye or mucosa of the alimentary or
respiratory tract.

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 Toxic, Toxicant and Toxin
Toxic
• This term relates to poisonous or deadly effects on the
body
Toxicant
• The term "toxicant " refers to toxic substances that are
produced by or are a by- product of human made
activities.
Toxin
• The term "toxin " refers to toxic substances that are
produced naturally

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 History
50- 400 A.D. - Romans used poisons
for executions and assassinations.
The philosopher, Socrates, was executed
using hemlock for teaching
radical ideas to youths.
Avicenna (A.D. 980-1036) Islamic
authority on poisons and antidotes.
1200 A.D. - Spanish rabbi Maimonides
writes first-aid book for poisonings,
Poisons and Their Antidotes

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 History
Swiss physician Paracelsus (1493-1541) credited with
being
“the father of modern toxicology.”

“All substances are poisons: there is none which is

not a poison. The right dose differentiates a poison
from a remedy.”

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 An Individual View
The sensitivity of the individual differentiates a
poison from a remedy. The fundamental principle of
toxicology is the individual’s response to a dose.”
S. G. Gilbert

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 TOXICITY vs HAZARD/RISK
[an important distinction]
Toxicity
The ability of a substance to have an adverse effect
on the health or well-being of a human
The toxicity of a chemical depends on the degree of
exposure and absorption
Hazard/Risk
The probability that the concentration will occur at
that site in the body

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 TOXICITY vs HAZARD
Two chemicals can possess the same degree of
toxicity, but present different degrees of hazard.
Ex. Odorless and non-irritating vs. pungent odor
The chemical with warning properties may present a
lesser degree of hazard.

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 Toxicology
• How toxicants enter the organism?
• How toxicants effect the organism?
• How toxicants are eliminated from (leave) the
organism?
All substances are toxic if taken in the wrong
quantities

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 Toxicology
• The right dose differentiates a poison and a
remedy
Harmless substances, such as water, can become
fatal if delivered to the biological organism in large
enough doses.
• A fundamental principle of toxicology is
“There are no harmless substances, only harmless
ways of using the substances”

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 Recent Definition
• Toxicology is more adequately defined as the
qualitative and quantitative study of the adverse
effects of toxicants on biological organisms.
• A toxicant can be a chemical or physical agent,
including dusts, fibers, noise, and radiation. A
good example of a physical agent is asbestos
fiber, a known cause of lung damage and cancer.

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 Recent Definition
• Toxic hazard is the likelihood of damage to
biological organisms based on exposure due to
transport and other physical factors of usage
• The toxic hazard of a substance can be reduced
by the application of appropriate industrial
hygiene techniques
• The toxicity, however, cannot be changed

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 ROUTES OF EXPOSURE
• Inhalation
• Ingestion
• Skin contact
• Injection

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 EFFECTS OF EXPOSURE
• ACUTE - a “one-time” event
– rapid absorption of material
– exposure sudden & severe
– critical period for death/survival
• CHRONIC - small doses over long time
– rate of intake > rate of elimination
– material remains in tissue; injures

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 TYPES OF TOXIC EFFECT
• Mortality
• Pathological change
• Growth rate change
• Physiological injury
• Biochemical change
• Behavioral effects
• Reproductive system damage
• Mutagenic, etc.

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 Toxic Effect by Target Organ
• Irritant
• Anesthetic
• Hepatotoxic
• Nephrotoxic
• Neurotoxic
• Pulmonary

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 Targeted organ
• A systemic toxin is one that affects the entire
body or many organs rather than a specific site
Potassium cyanide: Toxic to every cell and organ
in the body by interfering with the cell’s ability
to utilize oxygen
• Toxins may also affect only specific tissues or
organs called as target organs or target tissues
• Benzene: Toxic to blood- forming tissues.
• Lead: Toxic to CNS, kidney and hematopoietic
system

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 Target Sites
• Adverse effects occur at the level of the molecule,
cell.
• Molecularly, chemical can interact with
– Proteins
– Lipids
– DNA
• Cellularly, chemical can
– interfere with receptor-ligand binding
– interfere with membrane function
– interfere with cellular energy production
– bind to biomolecules
• perturb homeostasis (Ca) 20
 Factors Influencing Intensity
of Toxic Action
• Route of entry
• Rate of exposure
• Age of host
• Prior exposure
• Environment
• Host factors
gender, genetics
• Other factors

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 NOTE
Gender plays a very important role in toxicology due to
the pharmacokinetic and pharmacodynamic differences
between men and women. Womens have slower
gastrointestinal mobility which leads to increased
duration of exposure to the toxic (or drug). In the same
manner both genders have different sensitivity towards
different drugs. for example, males are more sensitive
toward the exposure to DDT and lead while females are
more sensitive towards some drugs such as beta blockers.

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 How Toxicants Enter Organism
• Inhalation (mouth or nose to lungs) then into
blood(+*)
• Ingestion (mouth to stomach) then into blood(+)
• Injection (cuts, punctures in skin) into blood
• Dermal absorption (through skin) into blood(+*)
• + Involve membrane transport
• * Greatest threats in industry
Of the four routes of entry, the inhalation and dermal
routes are the most significant to industrial facilities.

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 How Toxicants Enter Organism
• 'For higher-order organisms, the path of the
chemical agent through the body is well defined
• After the toxicant enters the organism it moves
into the bloodstream and is eventually
eliminated, or it is transported to the target organ
• The damage is exerted at the target organ

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 How Toxicants Enter Organism
• Inhalation is the easiest to quantify by the direct
measurement of airborne concentrations; the
usual exposure is by vapor, but small solid and
liquid particles can also contribute.
• Injection, inhalation and dermal absorption
generally result in the toxicant entering the blood
stream unaltered.

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 ENTRY ROUTES FOR TOXICANTS AND METHODS
FOR CONTROL
Entry Route Entry Organ Method for Control
Ingestion Mouth or Enforcement of rules on
Stomach eating, drinking and
smoking
Inhalation Mouth or nose Ventilation, respirators,
hoods and other personal
protection equipments
Injection Cuts in skin Proper protective clothing
Dermal Skin Proper protective clothing
absorption

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 Entry Routes For Toxicants And Methods
For Control
• Toxicants that enter by injection and dermal
absorption are difficult to measure and quantify.
• Some toxicants are absorbed very rapidly
through the skin.
• The expected blood level concentration as a
function of time and route of entry.
• The blood level concentration is a function of a
wide range of parameters; so large variations in
this behavior are expected.

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 Entry Routes For Toxicants And Methods
For Control
• The gastrointestinal (GI) tract, the skin, and the
respiratory system play significant roles in the
various routes of entry.
The Gastrointestinal (GI) Tract
The GI tract plays the most significant role in
toxicants entering the body through ingestion.
Food or drink is the usual mechanism of exposure.
Airborne particles (either solid or liquid) can also
lodge in the ,mucous of the upper respiratory tract
and be swallowed.

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 Entry Routes For Toxicants And Methods
For Control
The rate and selectivity of absorption by the GI tract
are highly dependent on many conditions like;
• The type of chemical and its molecular weight
• molecule size and shape
• acidity
• susceptibility to attack by intestinal flora
• rate of movement through the GI tract, etc.

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 Distribution
Blood carries the agent to and from its site of
action, storage depots, organs of transformation,
and organs of elimination
Rate of distribution (rapid) dependent upon
blood flow
characteristics of toxicant (affinity for the tissue,
and the partition coefficient)
Distribution may change over time

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 The Skin
• Skin plays important roles in both the dermal
absorption and injection routes of entry.
• Injection includes both entry by absorption
through cuts and mechanical injection with
hypodermic needles

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 The Skin
Schematic representation of human skin
• Stratum corneum is the top of the five layers
making epidermis, it is composed of keratinised
dead cells glued by lipids.
• It is shed off and replaced every two weeks.
Depending on the part of the body its thickness
varies from 0.05 mm to 1.5 mm.

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 Respiratory System
The respiratory system plays a significant role in
toxicants entering the body through inhalation.
The main function of the respiratory system is to
exchange oxygen and carbon dioxide between the
blood and the inhaled air.

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 Respiratory System
The respiratory system is divided into two areas:
the upper and lower respiratory system.
The upper respiratory system is composed of the
nose, sinuses, mouth, pharynx (section between the
mouth and esophagus), larynx (the voice box), and
the trachea or windpipe.

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 Respiratory System
The lower respiratory system is composed of the
lungs and its smaller structures, including the
bronchi and alveoli.
The bronchi tubes carry fresh air from the trachea
through a series of branching tubes to the alveoli.
The alveoli are small blind air sacs where the gas
exchange with the blood occurs.
The upper and lower respiratory tracts respond
differently to the presence of toxicants.

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 Respiratory System
• The upper respiratory tract is effected mostly by
toxicants which are water soluble
• These materials either react or dissolve in the
mucous to form acids and bases.

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 Respiratory System
• Toxicants in the lower respiratory tract affect the
alveoli by physically blocking the transfer of gases
(as with insoluble dusts) or reacting with the wall
of the alveoli to produce corrosive or toxic
substances.
• Phosgene gas, for example, reacts with the water
on the alveoli wall to produce HCl and carbon
monoxide.

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 Duration of Exposure
Three terms are commonly used to describe the
duration of dose(s)

• Acute
• Chronic
• Subchronic

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 Duration of Exposure:
Acute Exposure
Application of a single or short-term (generally less
than a day) dosing by a chemical

If toxic symptoms are expressed, they are referred to

as symptoms of “acute toxicity”

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 Duration of Exposure:
Chronic Exposure
Expression of toxic symptoms only after repeated
exposure to a chemical in doses regularly applied to
the organism for a time greater than half of its life-
expectancy

If toxic symptoms are expressed, they are referred to

as symptoms of “chronic toxicity”

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 Exposure: Duration
Over time, the amount of chemical in the body can
build up, it can redistribute, or it can overwhelm
repair and removal mechanisms
Effect Time Exposure pattern
Acute <24 hours Usually 1 exposure
Subacute 1 months Repeated doses
Subchronic 1-3 months Repeated doses
Chronic >3 months Repeated doses

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Thank You

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