UNIT-1- TOXICOLOGY DEFINITION

 Toxicology is the 'science of poisons'.

 Poisons are defined as naturally occurring or man-made chemicals,
which, following their entry via any route and in relatively small
quantities into the body, produce biochemical abnormalities and/or
physical lesions. Poisons are also known as toxicants or toxic agents.
 Like medicine, toxicology is both a science and an art.
 The science of toxicology is the phase involving observational and data-
gathering, while the art of toxicology consists of utilization of data to
arrive at the outcome to exposure in human and animal populations.
 A more descriptive definition of toxicology can be 'the study of the
adverse effects of chemicals or physical agents on living organisms and
the ecosystems, including the prevention and amelioration of such
adverse effects'.
 Adverse effects may occur in many forms, ranging from immediate death
to subtle changes not realized until months or years later. They may
occur at various levels within the body, such as an organ, a type of cell, or
a specific biochemical. Knowledge of how toxic agents damage the body
has progressed along with medical knowledge. It is now known that
various observable changes in anatomy or body functions actually result
from previously unrecognized changes in specific biochemicals in the
body.
 A toxic agent is anything that can produce an adverse biological effect. It
may be chemical, physical, or biological in form. For example, toxic
agents may be chemical (such as cyanide), physical (such as
radiation)and biological(such as snake venom).
 A distinction is made for diseases due to biological organisms. Those
organisms that invade and multiply within the organism and produce their
effects by biological activity are not classified as toxic agents. An
example of this is a virus that damages cell membranes resulting in cell
death.
 If the invading organisms excrete chemicals which is the basis for
toxicity, the excreted substances are known as biological toxins. The
organisms in this case are referred to as toxic organisms. An example is
tetanus. Tetanus is caused by a bacterium, Clostridium tetani. The
bacteria C. tetani itself does not cause disease by invading and

1
 destroying cells. Rather, it is a toxin that is excreted by the bacteria that
travels to the nervous system (a neurotoxin) that produces the disease.
 A toxic substance is simply a material which has toxic properties. It may
be a discrete toxic chemical or a mixture of toxic chemicals. For
example, lead chromate, asbestos, and gasoline are all toxic substances.
Lead chromate is a discrete toxic chemical. Asbestos is a toxic material
that does not consist of an exact chemical composition but a variety of
fibers and minerals. Gasoline is also a toxic substance rather than a toxic
chemical in that it contains a mixture of many chemicals. Toxic
substances may not always have a constant composition. For example,
the composition of gasoline varies with octane level, manufacturer, time
of season, etc. toxic substances may be organic or inorganic in
composition
 Thus toxicology is the science dealing with properties, action, toxicity,
fatal dose, detection, estimation, interpretation of their results of
toxicological analysis and management of poison.
 Toxicology is concerned with all aspects of poisons and poisoning.
 It includes the identification, chemical properties and biological effects of
poisons as well as the treatment of disease conditions they cause.
 The science of toxicology helps people make informed decisions and
balance RISKS vs. BENEFITS.
 Toxin is the word reserved to poisons produced by a biological source
like venoms and plant toxins. Toxins from plants are called phytotoxins.
Toxins from bacteria are called bacterial toxins. Endotoxins are those
toxins found within the bacteria and exotoxins are those toxins elaborated
from bacterial cells. Toxins from fungi are called mycotoxins. Toxins
from lower animals are called as zootoxins. Toxins that are transmitted by
a bite or sting are called venoms.
 Toxinology deals with the study of toxic effects of toxins.
 Toxicity is the term used to describe the amount of a poison that, under a
specific set of conditions causes toxic effects or results in detrimental
biologic changes. It is the inherent capacity of a substance to produce
toxic effects or detrimental changes on the organism. Toxicity is the
adverse end product of a series of events that is inhibited by exposure to
chemical, physical or biological agents. Toxicity can manifest itself in a
wide array of forms, from mild biochemical functions to serious organ
damage and death.

2
  Toxicosis is the term used to describe the condition resulting from
exposure to poisons. This term is frequently used interchangeably with
poisoning and intoxication.
 Xenobiotic is the general term that is used for a foreignsubstance taken
into the body. It is derived from the Greek term xeno which
means"foreigner."Xenobiotics may produce beneficial effects(such as a
pharmaceuticals)or they may be toxic(such as lead).

Toxicants Substances that produce adverse

biological effect on any nature.
May be chemical or physical in nature
toxin Specific protein produced by living
organisms
Mushroom toxin, Tetanus toxin
Most exhibit immediate effect
Poison Toxicant that cause immediate death or
illness when experience in very small
amount

Three phases under which toxicology is studied are:

exposure phase,

toxicokinetic phase and

toxicodynamic phase

Toxic substances may be systemic toxins or organ toxins.

A systemic toxinis one that affects the entire body or many organs rather than a
specific site. For example, potassium cyanide is a systemic toxicant in that it
affects virtually every cell and organ in the body by interfering with the cell's
ability to utilize oxygen.

Toxicants may also affect only specific tissues or organs while not producing
damage to the body as a whole. These specific sites are known as the target
organs or target tissues. Some examples: Benzene is a specific organ toxin in
that it is primarily toxic to the blood-forming tissues. Lead is also a specific
organ toxin; however, it has three target organs (central nervous system, kidney,
and hematopoietic system).
3
HISTORICAL DEVELOPMENTS

Historical developments in toxicology during various periods

Antiquity

Middle Ages

Age of enlightenment

Modern Toxicology

After World War II

1. Antiquity

Shen
Shen Nung - 2696 BC
Shen Nung the father of Chinese medicine is noted for tasting 365 herbs and he
died of a toxic dose and wrote treatise on ‘Herbal Medical Experiment Poisons’.

Homer

Homer (about 850 BC) wrote of the use of arrows poisoned with venom in the
epic tale of ‘ The Odyssey’ and ‘ The Iliad’.

Hippocrates

Hippocrates (460-337 BC)

Hippocrates in his writings (400 BC) showed that the ancient Greeks had a
professional awareness of poisons and of the principles of toxicology,
particularly with regard to the treatment of poisoning by influencing absorption.

Theophrastus (370–286 BC), a student of Aristotle, included numerous

references to poisonous plants in 'De Historia Plantarum'.

Nicander of Colophon (185-135 BC), physician to Attalus, King of Bythnia,

was allowed to experiment with poisons using condemned criminals as subjects.
As a result of his studies he wrote a treatise on 'antidotes to poisonous reptiles
and substances' and mentioned 22 specific poisons including white lead, lead
oxide, aconite, cantharides, hemlock, hyoscyamus and opium. He recommended

4
linseed tea to induce vomiting and sucking the venom from the bite of a
venomous animal as treatments.

Sulla

Sulla 82 BC: The first known law against poisoning was issued in Rome by
Sulla in 82 BC to protect against careless dispensing. The law prevented people
from buying, selling or processing poisons .

Pedanius

Pedanius Dioscorides (40-90 AD)

The Greek physician Dioscorides made a particularly significant contribution

to toxicology by classifying poisons as animal, plant or mineral and recognizing
the value of emetics in the treatment of poisoning. The classification was
accompanied by descriptions and drawings.

Middle Ages

The writings of Maimonides (AD 1135–1204) included a treatise on the

treatment of poisonings from insects, snakes and mad dogs. His 'Treatise on
Poisons and Their Antidotes' is an early toxicology textbook that remained
popular for centuries. Maimonides also refuted many of the popular remedies of
the day and stated his doubts about others.

During the middle ages more of misuse of poisons to kill enemies was on the
rise.

Age of Enlightenment

More recently, in 1945, Sir Rudolph Peters studied the mechanism of action of
arsenical war gases and so was able to devise an effective antidote known as
British Anti-Lewisite for the treatment of soldiers exposed to these gases.

Modern toxicology

It is a continuation of the development of the biological and physical sciences

in the late nineteenth and twentieth centuries.

During this period the world witnessed an explosion in science that paved way
for the beginning of the modern era of various aspects of science.

5
 The introduction of ether, chloroform, and carbonic acid led to several
iatrogenic deaths.

These unfortunate outcomes spurred research into the causes of the deaths and
early experiments on adverse and toxic effects.

After World War II

The 20th century is marked by an advanced level of understanding of

toxicology.

DNA (molecule of life) and various biochemicals that maintain body functions
were discovered.

Our level of knowledge of toxic effects on organs and cells is now being
revealed at the molecular level.

It is recognized that virtually toxic effects are caused by changes in specific

cellular molecules and biochemical moiety.

INCIDENTS OF IMPORTANCE IN HISTORY OF TOXICOLOGY

 The early cave dwellers recognized poisonous plants and animals and
used their extracts for hunting or in warfare.
 By 1500 B.C, written recordings like Ebers papyrus indicated that
hemlock, opium, arrow poisons and certain metals were used to poison
enemies or for state executions.
 Poisons such as arsenic, aconite and opium were also known to Hindu
medicine as recorded in the Vedas.
 The ancient Chinese used aconite as an arrow poison.
 Greeks, Romans and Italians used poison for execution and murder of
their political opponents.
 Socrates was charged with religious heresy and corrupting the morals of
local youth and was executed with extract of hemlock (Conium
maculatum) and Greeks recognized hemlock as the state poison. The
active chemical in hemlock was the alkaloid coniine which, when
ingested causes paralysis, convulsions and eventually death.

6
  Demosthenes committed suicide by consuming a poison hidden in his
pen.
 Cleopatra, the Queen of Egypt experimented with strychnine and other
poisons on prisoners and poor. She committed suicide with Egyptian Asp
(Egyptian cobra sometimes used in executions).
 Cleopatra - Queen of Egypt (69-30 BC)

 King Nero used poisons to eliminate his stepbrother Brittanicus and

employed his slaves as food tasters to differentiate edible mushrooms
from their more poisonous kin.
 King Mithridates VI of Pontus, was afraid that he would be assassinated
by his enemies. He used his prisoners as guinea pigs to test the poisons.
He started taking antidotes for many poisons. He consumed a mixture
containing about 36 ingredients. But, when he was caught by his enemies
and wanted to commit suicide, he could not do so and he took the help of
one of his slaves to stab himself to death. The term mithridatic (meaning
antidote) is derived from his name.
 A lady named Toffana prepared arsenic containing perfumes and such
cosmetics were named as Aqua toffana. These perfumes were used to kill
enemies.
 In France, a lady named Catherine de Medici along with Marchioners de
Brinvillen used most effective poisons in the name of providing treatment
to sick and poor people. Later she was imprisoned for killing 2000
infants.
BRANCHES OF TOXICOLOGY

 Veterinary toxicology - Veterinary toxicology deals with the poisons

causing toxicity in animals.
 Immuno toxicology - This branch deals with toxins that impair the
functioning of the immune system - for example, the ability of a toxicant
to impair resistance to infection.
 Forensic toxicology - It is the study of unlawful use of toxic agents and
their detection for judicial purposes. Forensic toxicology is concerned
with the medicolegal aspects of the adverse effects of chemicals on
humans and animals. Although primarily devoted to the identification of
the cause and circumstances of death and the legal issues arising there
from, forensic toxicologists also deal with sub lethal poisoning cases.

7
 (Forensic Toxicology is a branch of Forensic Medicine dealing with
Medical and Legal aspects of the harmful effects of chemicals on
humanbeings.)
 Molecular toxicology - Molecular toxicology focuses on why and how
chemicals cause harm to life. The basis of cellular and molecular
processes leading to toxic effects is studied under molecular toxicology.
 Clinical toxicology – It is the study of the effects of poisons/toxicants on
human beings, animals and other living organisms, their diagnosis and
treatment and methods for their detection etc.
 Nutritional toxicology – It is the study of toxicological aspects of
food/feed stuffs and nutritional habits.
 Environmental toxicology – It is the study of the effects of toxicants,
whether used/applied purposely (e.g. pesticides, herbicides) or as
industrial effluents or pollutants/contaminants, on the health of organisms
and environment.
 Analytical toxicology – It is the application of analytical chemistry tools
in the quantitative and qualitative estimation of the agents involved in the
process of toxicity.
 Occupational toxicology – It is the study of occupational hazards
associated with individuals working in a particular industry/occupation
and their correlation with the possible toxicants and also the possible
remedial measures.
 Ecotoxicology – It is the study of fate and effects of toxic substances on
ecosystem.
 Regulatory toxicology – It is the conduct of toxicological studies as per
the content and characteristics prescribed by regulatory agencies.
 Developmental toxicology – It is the study of adverse effects on the
developing organisms occurring any time during the life span of the
organism due to exposure to chemical or physical agents before
conception (either parent), during prenatal development or postnatal until
the time of puberty.
 Toxicoepidemiology – This refers to the study of quantitative analysis of
the toxicity incidences in organisms, factors affecting toxicity, species
involved and the use of such knowledge in planning of prevention and
control strategies.

8
Poison: A poison is defined as any substance ( Solid, liquid, gaseous) which
when administered in living body through any route ( inhalation, ingestion,
surface absorption etc) will produce ill health or death by its action which is
due to its physical, chemical or physiological properties . eg. alphos, sulphuric
acid, arsenic.

Acute toxicity : Acute toxicity describes the adverse effects of a substance

that result either from a single exposure or from multiple exposures in a short
period of time (usually less than 24 hours). To be described as acute toxicity,
the adverse effects should occur within 14 days of the administration of the
substance.

Acute toxicity is distinguished from chronic toxicity, which describes the

adverse health effects from repeated exposures, often at lower levels, to a
substance over a longer time period (months or years).

CLASSIFICATION OF POISONS

Based on their toxic effects in the body as:

Poisons which cause death by anoxia

Poisons which make haemoglobin incapable of transporting oxygen

(Heamotoxin)

e.g. Carbon monoxide, nitrites

Poisons which inhibit cellular respiratory enzymes

e.g. Cyanides

Poisons which destroy haemopoietic organs

e.g. Radioactive substances

 Poisons, which on contact cause irritation or corrosiveness of the organs

(skin) or damage the organ through which they are excreted (GI tract,
respiratory tract, urinary tract) e.g. Irritant gases, alkaline corrosives,
corrosive inorganic acids, corrosive organic acids and heavy metals
 Poisons, which damage protoplasm or parenchyma. These poisons
produce local irritation and after absorption cause damage to the cells and
capillaries e.g. Phosphorus and carbon tetrachloride

9
  Poisons, which affect the nerve cells and fibres e.g. Hypnotics, narcotics,
anesthetics, alcohol, some alkaloids and glycosides
 Based on their chemical and physical nature as, organic poisons,
inorganic poisons, gaseous poisons, nitrogenous and non-notrogenous
organic poisons etc.
 Based on their behaviour during separation procedures as volatile
poisons, non-volatile organic poisons isolated by solvent extraction,
metallic poisons and miscellaneous poisons.
 Based on their origin as plant poisons, toxins, venoms etc.
 Based on their use as antimicrobials, anticoccidials, anthelmintics,
anaesthetics etc.
 Based on the source as naturally occurring and man-made.

GUIDELINES FOR THE CLASSIFICATION OF POISONS BASED ON THE

DOSE
Extremely toxic <1mg/kg
Highly toxic 1-50 mg/kg
Moderately toxic 50-500 mg/kg
Slightly toxic 0.5-5 g/kg
Practically non toxic 5-15 g/kg
Relatively harmless > 15 g/kg
The following is a list of types of poison by intended use:

 Avicide – substance which can be used to kill birds

 Biocide – a chemical substance capable of killing living organisms,
usually in a selective way
 Fungicide – a chemical compound or biological organism used to kill or
inhibit fungi or fungal spores
 Microbicide – any compound or substance whose purpose is to reduce the
infectivity of microbes
 Germicide – a disinfectant
o Bactericide – a substance that kills bacteria
o Viricide – a chemical agent which "kills" viruses outside the body

10
 Herbicide – a substance used to kill unwanted plants
 Parasiticide – any substance used to kill parasites
 Pesticide – a substance or mixture of substances used to kill a pest
 Acaricide – pesticides that kill mites
 Insecticide – a pesticide used against insects
 Molluscicide – pesticides against molluscs
 Nematocide – a type of chemical pesticide used to kill parasitic
nematodes (roundworms)
 Rodenticide – a category of pest control chemicals intended to kill
rodents
 Spermicide – a substance that kills sperm

TOXICITY TESTING
 Different types of testing methods are undertaken to test the toxicity of
drugs and chemicals.
 This includes acute toxicity, subchronic toxicity, chronic toxicity,
developmental toxicity, reproductive toxicity, phototoxicity, behavioural
toxicity, hypersensitivity, ocular and skin irritation tests, mutagenicity,
teratogenicity and carcinogenicity.
 In addition, toxicokinetic studies are conducted to estimate the toxicity.
In many of these studies rodents are used as experimental animals.
 Subacute and subchronic differ in duration of exposure. Subacute
systemic toxicity is defined as adverse effects occurring after multiple or
continuous exposure between 24 h and 28 days. Subchronic systemic
toxicity is defined as adverse effects occurring after the repeated or
continuous administration of a test sample for up to 90 days or not
exceeding 10% of the animal's lifespan.
 Chronic toxicity, the development of adverse effects as a result of long
term exposure to a contaminant or other stressor, is an important aspect of
aquatic toxicology.Adverse effects associated with chronic toxicity can
be directly lethal but are more commonly sublethal, including changes in
growth, reproduction, or behavior. Chronic toxicity is in contrast to acute
toxicity, which occurs over a shorter period of time to higher
concentrations. Various toxicity tests can be performed to assess the
chronic toxicity of different contaminants, and usually last at least 10% of
an organism’s lifespan. Results of aquatic chronic toxicity tests can be
11
 used to determine water quality guidelines and regulations for protection
of aquatic organisms.
 Phototoxicity: The skin exposure to solar irradiation and photoreactive
xenobiotics may produce abnormal skin reaction, phototoxicity.
Phototoxicity is an acute light-induced response, which occurs when
photoreacive chemicals are activated by solar lights and transformed into
products cytotoxic against the skin cells. Multifarious symptoms of
phototoxicity are identified, skin irritation, erythema, pruritis, and edema
that are similar to those of the exaggerated sunburn. Diverse organic
chemicals, especially drugs, are known to induce phototoxicity, which is
probably from the common possession of UV-absorbing benzene or
heterocyclic rings in their molecular structures. Both UVB (290~320 nm)
and UVA (320~400 nm) are responsible for the manifestation of
phototoxicity.

12
UNIT-1- TOXICOLOGY DEFINITION

 Toxicology is the 'science of poisons'.

 Poisons are defined as naturally occurring or man-made chemicals,
which, following their entry via any route and in relatively small
quantities into the body, produce biochemical abnormalities and/or
physical lesions. Poisons are also known as toxicants or toxic agents.
 Like medicine, toxicology is both a science and an art.
 The science of toxicology is the phase involving observational and data-
gathering, while the art of toxicology consists of utilization of data to
arrive at the outcome to exposure in human and animal populations.
 A more descriptive definition of toxicology can be 'the study of the
adverse effects of chemicals or physical agents on living organisms and
the ecosystems, including the prevention and amelioration of such
adverse effects'.
 Adverse effects may occur in many forms, ranging from immediate death
to subtle changes not realized until months or years later. They may
occur at various levels within the body, such as an organ, a type of cell, or
a specific biochemical. Knowledge of how toxic agents damage the body
has progressed along with medical knowledge. It is now known that
various observable changes in anatomy or body functions actually result
from previously unrecognized changes in specific biochemicals in the
body.
 A toxic agent is anything that can produce an adverse biological effect. It
may be chemical, physical, or biological in form. For example, toxic
agents may be chemical (such as cyanide), physical (such as
radiation)and biological(such as snake venom).
 A distinction is made for diseases due to biological organisms. Those
organisms that invade and multiply within the organism and produce their
effects by biological activity are not classified as toxic agents. An
example of this is a virus that damages cell membranes resulting in cell
death.
 If the invading organisms excrete chemicals which is the basis for
toxicity, the excreted substances are known as biological toxins. The
organisms in this case are referred to as toxic organisms. An example is
tetanus. Tetanus is caused by a bacterium, Clostridium tetani. The
bacteria C. tetani itself does not cause disease by invading and

1
 destroying cells. Rather, it is a toxin that is excreted by the bacteria that
travels to the nervous system (a neurotoxin) that produces the disease.
 A toxic substance is simply a material which has toxic properties. It may
be a discrete toxic chemical or a mixture of toxic chemicals. For
example, lead chromate, asbestos, and gasoline are all toxic substances.
Lead chromate is a discrete toxic chemical. Asbestos is a toxic material
that does not consist of an exact chemical composition but a variety of
fibers and minerals. Gasoline is also a toxic substance rather than a toxic
chemical in that it contains a mixture of many chemicals. Toxic
substances may not always have a constant composition. For example,
the composition of gasoline varies with octane level, manufacturer, time
of season, etc. toxic substances may be organic or inorganic in
composition
 Thus toxicology is the science dealing with properties, action, toxicity,
fatal dose, detection, estimation, interpretation of their results of
toxicological analysis and management of poison.
 Toxicology is concerned with all aspects of poisons and poisoning.
 It includes the identification, chemical properties and biological effects of
poisons as well as the treatment of disease conditions they cause.
 The science of toxicology helps people make informed decisions and
balance RISKS vs. BENEFITS.
 Toxin is the word reserved to poisons produced by a biological source
like venoms and plant toxins. Toxins from plants are called phytotoxins.
Toxins from bacteria are called bacterial toxins. Endotoxins are those
toxins found within the bacteria and exotoxins are those toxins elaborated
from bacterial cells. Toxins from fungi are called mycotoxins. Toxins
from lower animals are called as zootoxins. Toxins that are transmitted by
a bite or sting are called venoms.
 Toxinology deals with the study of toxic effects of toxins.
 Toxicity is the term used to describe the amount of a poison that, under a
specific set of conditions causes toxic effects or results in detrimental
biologic changes. It is the inherent capacity of a substance to produce
toxic effects or detrimental changes on the organism. Toxicity is the
adverse end product of a series of events that is inhibited by exposure to
chemical, physical or biological agents. Toxicity can manifest itself in a
wide array of forms, from mild biochemical functions to serious organ
damage and death.

2
  Toxicosis is the term used to describe the condition resulting from
exposure to poisons. This term is frequently used interchangeably with
poisoning and intoxication.
 Xenobiotic is the general term that is used for a foreignsubstance taken
into the body. It is derived from the Greek term xeno which
means"foreigner."Xenobiotics may produce beneficial effects(such as a
pharmaceuticals)or they may be toxic(such as lead).

Toxicants Substances that produce adverse

biological effect on any nature.
May be chemical or physical in nature
toxin Specific protein produced by living
organisms
Mushroom toxin, Tetanus toxin
Most exhibit immediate effect
Poison Toxicant that cause immediate death or
illness when experience in very small
amount

Three phases under which toxicology is studied are:

exposure phase,

toxicokinetic phase and

toxicodynamic phase

Toxic substances may be systemic toxins or organ toxins.

A systemic toxinis one that affects the entire body or many organs rather than a
specific site. For example, potassium cyanide is a systemic toxicant in that it
affects virtually every cell and organ in the body by interfering with the cell's
ability to utilize oxygen.

Toxicants may also affect only specific tissues or organs while not producing
damage to the body as a whole. These specific sites are known as the target
organs or target tissues. Some examples: Benzene is a specific organ toxin in
that it is primarily toxic to the blood-forming tissues. Lead is also a specific
organ toxin; however, it has three target organs (central nervous system, kidney,
and hematopoietic system).
3
HISTORICAL DEVELOPMENTS

Historical developments in toxicology during various periods

Antiquity

Middle Ages

Age of enlightenment

Modern Toxicology

After World War II

1. Antiquity

Shen
Shen Nung - 2696 BC
Shen Nung the father of Chinese medicine is noted for tasting 365 herbs and he
died of a toxic dose and wrote treatise on ‘Herbal Medical Experiment Poisons’.

Homer

Homer (about 850 BC) wrote of the use of arrows poisoned with venom in the
epic tale of ‘ The Odyssey’ and ‘ The Iliad’.

Hippocrates

Hippocrates (460-337 BC)

Hippocrates in his writings (400 BC) showed that the ancient Greeks had a
professional awareness of poisons and of the principles of toxicology,
particularly with regard to the treatment of poisoning by influencing absorption.

Theophrastus (370–286 BC), a student of Aristotle, included numerous

references to poisonous plants in 'De Historia Plantarum'.

Nicander of Colophon (185-135 BC), physician to Attalus, King of Bythnia,

was allowed to experiment with poisons using condemned criminals as subjects.
As a result of his studies he wrote a treatise on 'antidotes to poisonous reptiles
and substances' and mentioned 22 specific poisons including white lead, lead
oxide, aconite, cantharides, hemlock, hyoscyamus and opium. He recommended

4
linseed tea to induce vomiting and sucking the venom from the bite of a
venomous animal as treatments.

Sulla

Sulla 82 BC: The first known law against poisoning was issued in Rome by
Sulla in 82 BC to protect against careless dispensing. The law prevented people
from buying, selling or processing poisons .

Pedanius

Pedanius Dioscorides (40-90 AD)

The Greek physician Dioscorides made a particularly significant contribution

to toxicology by classifying poisons as animal, plant or mineral and recognizing
the value of emetics in the treatment of poisoning. The classification was
accompanied by descriptions and drawings.

Middle Ages

The writings of Maimonides (AD 1135–1204) included a treatise on the

treatment of poisonings from insects, snakes and mad dogs. His 'Treatise on
Poisons and Their Antidotes' is an early toxicology textbook that remained
popular for centuries. Maimonides also refuted many of the popular remedies of
the day and stated his doubts about others.

During the middle ages more of misuse of poisons to kill enemies was on the
rise.

Age of Enlightenment

More recently, in 1945, Sir Rudolph Peters studied the mechanism of action of
arsenical war gases and so was able to devise an effective antidote known as
British Anti-Lewisite for the treatment of soldiers exposed to these gases.

Modern toxicology

It is a continuation of the development of the biological and physical sciences

in the late nineteenth and twentieth centuries.

During this period the world witnessed an explosion in science that paved way
for the beginning of the modern era of various aspects of science.

5
 The introduction of ether, chloroform, and carbonic acid led to several
iatrogenic deaths.

These unfortunate outcomes spurred research into the causes of the deaths and
early experiments on adverse and toxic effects.

After World War II

The 20th century is marked by an advanced level of understanding of

toxicology.

DNA (molecule of life) and various biochemicals that maintain body functions
were discovered.

Our level of knowledge of toxic effects on organs and cells is now being
revealed at the molecular level.

It is recognized that virtually toxic effects are caused by changes in specific

cellular molecules and biochemical moiety.

INCIDENTS OF IMPORTANCE IN HISTORY OF TOXICOLOGY

 The early cave dwellers recognized poisonous plants and animals and
used their extracts for hunting or in warfare.
 By 1500 B.C, written recordings like Ebers papyrus indicated that
hemlock, opium, arrow poisons and certain metals were used to poison
enemies or for state executions.
 Poisons such as arsenic, aconite and opium were also known to Hindu
medicine as recorded in the Vedas.
 The ancient Chinese used aconite as an arrow poison.
 Greeks, Romans and Italians used poison for execution and murder of
their political opponents.
 Socrates was charged with religious heresy and corrupting the morals of
local youth and was executed with extract of hemlock (Conium
maculatum) and Greeks recognized hemlock as the state poison. The
active chemical in hemlock was the alkaloid coniine which, when
ingested causes paralysis, convulsions and eventually death.

6
  Demosthenes committed suicide by consuming a poison hidden in his
pen.
 Cleopatra, the Queen of Egypt experimented with strychnine and other
poisons on prisoners and poor. She committed suicide with Egyptian Asp
(Egyptian cobra sometimes used in executions).
 Cleopatra - Queen of Egypt (69-30 BC)

 King Nero used poisons to eliminate his stepbrother Brittanicus and

employed his slaves as food tasters to differentiate edible mushrooms
from their more poisonous kin.
 King Mithridates VI of Pontus, was afraid that he would be assassinated
by his enemies. He used his prisoners as guinea pigs to test the poisons.
He started taking antidotes for many poisons. He consumed a mixture
containing about 36 ingredients. But, when he was caught by his enemies
and wanted to commit suicide, he could not do so and he took the help of
one of his slaves to stab himself to death. The term mithridatic (meaning
antidote) is derived from his name.
 A lady named Toffana prepared arsenic containing perfumes and such
cosmetics were named as Aqua toffana. These perfumes were used to kill
enemies.
 In France, a lady named Catherine de Medici along with Marchioners de
Brinvillen used most effective poisons in the name of providing treatment
to sick and poor people. Later she was imprisoned for killing 2000
infants.
BRANCHES OF TOXICOLOGY

 Veterinary toxicology - Veterinary toxicology deals with the poisons

causing toxicity in animals.
 Immuno toxicology - This branch deals with toxins that impair the
functioning of the immune system - for example, the ability of a toxicant
to impair resistance to infection.
 Forensic toxicology - It is the study of unlawful use of toxic agents and
their detection for judicial purposes. Forensic toxicology is concerned
with the medicolegal aspects of the adverse effects of chemicals on
humans and animals. Although primarily devoted to the identification of
the cause and circumstances of death and the legal issues arising there
from, forensic toxicologists also deal with sub lethal poisoning cases.

7
 (Forensic Toxicology is a branch of Forensic Medicine dealing with
Medical and Legal aspects of the harmful effects of chemicals on
humanbeings.)
 Molecular toxicology - Molecular toxicology focuses on why and how
chemicals cause harm to life. The basis of cellular and molecular
processes leading to toxic effects is studied under molecular toxicology.
 Clinical toxicology – It is the study of the effects of poisons/toxicants on
human beings, animals and other living organisms, their diagnosis and
treatment and methods for their detection etc.
 Nutritional toxicology – It is the study of toxicological aspects of
food/feed stuffs and nutritional habits.
 Environmental toxicology – It is the study of the effects of toxicants,
whether used/applied purposely (e.g. pesticides, herbicides) or as
industrial effluents or pollutants/contaminants, on the health of organisms
and environment.
 Analytical toxicology – It is the application of analytical chemistry tools
in the quantitative and qualitative estimation of the agents involved in the
process of toxicity.
 Occupational toxicology – It is the study of occupational hazards
associated with individuals working in a particular industry/occupation
and their correlation with the possible toxicants and also the possible
remedial measures.
 Ecotoxicology – It is the study of fate and effects of toxic substances on
ecosystem.
 Regulatory toxicology – It is the conduct of toxicological studies as per
the content and characteristics prescribed by regulatory agencies.
 Developmental toxicology – It is the study of adverse effects on the
developing organisms occurring any time during the life span of the
organism due to exposure to chemical or physical agents before
conception (either parent), during prenatal development or postnatal until
the time of puberty.
 Toxicoepidemiology – This refers to the study of quantitative analysis of
the toxicity incidences in organisms, factors affecting toxicity, species
involved and the use of such knowledge in planning of prevention and
control strategies.

8
Poison: A poison is defined as any substance ( Solid, liquid, gaseous) which
when administered in living body through any route ( inhalation, ingestion,
surface absorption etc) will produce ill health or death by its action which is
due to its physical, chemical or physiological properties . eg. alphos, sulphuric
acid, arsenic.

Acute toxicity : Acute toxicity describes the adverse effects of a substance

that result either from a single exposure or from multiple exposures in a short
period of time (usually less than 24 hours). To be described as acute toxicity,
the adverse effects should occur within 14 days of the administration of the
substance.

Acute toxicity is distinguished from chronic toxicity, which describes the

adverse health effects from repeated exposures, often at lower levels, to a
substance over a longer time period (months or years).

CLASSIFICATION OF POISONS

Based on their toxic effects in the body as:

Poisons which cause death by anoxia

Poisons which make haemoglobin incapable of transporting oxygen

(Heamotoxin)

e.g. Carbon monoxide, nitrites

Poisons which inhibit cellular respiratory enzymes

e.g. Cyanides

Poisons which destroy haemopoietic organs

e.g. Radioactive substances

 Poisons, which on contact cause irritation or corrosiveness of the organs

(skin) or damage the organ through which they are excreted (GI tract,
respiratory tract, urinary tract) e.g. Irritant gases, alkaline corrosives,
corrosive inorganic acids, corrosive organic acids and heavy metals
 Poisons, which damage protoplasm or parenchyma. These poisons
produce local irritation and after absorption cause damage to the cells and
capillaries e.g. Phosphorus and carbon tetrachloride

9
  Poisons, which affect the nerve cells and fibres e.g. Hypnotics, narcotics,
anesthetics, alcohol, some alkaloids and glycosides
 Based on their chemical and physical nature as, organic poisons,
inorganic poisons, gaseous poisons, nitrogenous and non-notrogenous
organic poisons etc.
 Based on their behaviour during separation procedures as volatile
poisons, non-volatile organic poisons isolated by solvent extraction,
metallic poisons and miscellaneous poisons.
 Based on their origin as plant poisons, toxins, venoms etc.
 Based on their use as antimicrobials, anticoccidials, anthelmintics,
anaesthetics etc.
 Based on the source as naturally occurring and man-made.

GUIDELINES FOR THE CLASSIFICATION OF POISONS BASED ON THE

DOSE
Extremely toxic <1mg/kg
Highly toxic 1-50 mg/kg
Moderately toxic 50-500 mg/kg
Slightly toxic 0.5-5 g/kg
Practically non toxic 5-15 g/kg
Relatively harmless > 15 g/kg
The following is a list of types of poison by intended use:

 Avicide – substance which can be used to kill birds

 Biocide – a chemical substance capable of killing living organisms,
usually in a selective way
 Fungicide – a chemical compound or biological organism used to kill or
inhibit fungi or fungal spores
 Microbicide – any compound or substance whose purpose is to reduce the
infectivity of microbes
 Germicide – a disinfectant
o Bactericide – a substance that kills bacteria
o Viricide – a chemical agent which "kills" viruses outside the body

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 Herbicide – a substance used to kill unwanted plants
 Parasiticide – any substance used to kill parasites
 Pesticide – a substance or mixture of substances used to kill a pest
 Acaricide – pesticides that kill mites
 Insecticide – a pesticide used against insects
 Molluscicide – pesticides against molluscs
 Nematocide – a type of chemical pesticide used to kill parasitic
nematodes (roundworms)
 Rodenticide – a category of pest control chemicals intended to kill
rodents
 Spermicide – a substance that kills sperm

TOXICITY TESTING
Toxicology testing, also known as safety assessment, or toxicity testing,
is conducted to determine the degree to which a substance can damage a
living or non-living organisms. It is often conducted by researchers using
standard test procedures to comply with governing regulations, for
example for medicines and pesticides.
 Different types of testing methods are undertaken to test the toxicity of
drugs and chemicals.
 This includes acute toxicity, subchronic toxicity, chronic toxicity,
developmental toxicity, reproductive toxicity, phototoxicity, behavioural
toxicity, hypersensitivity, ocular and skin irritation tests, mutagenicity,
teratogenicity and carcinogenicity.
 In addition, toxicokinetic studies are conducted to estimate the toxicity.
In many of these studies rodents are used as experimental animals.
 Acute Systemic Toxicity: Adverse effects occurring within a relatively
short time after administration of a single (typically high) dose of a
substance via one or more of the following exposure routes: oral,
inhalation, skin, or injection.
 Acute toxicity testing is carried out to determine the effect of a single
dose on a particular animal species. In general, it is recommended that
acute toxicity testing be carried out with two different animal species
(one rodent and one nonrodent). In acute toxicological testing, the
investigational product is administered at different dose levels, and the
effect is observed for 14 days. All mortalities caused by the
11
 investigational product during the experimental period are recorded and
morphological, biochemical, pathological, and histological changes in the
dead animals are investigated. Acute toxicity testing permits the 50%
lethal dose (LD50) of the investigational product to be determined. The
LD50 was used as an indicator of acute toxicity previously.
 Subacute and subchronic differ in duration of exposure.
 Subacute systemic toxicity is defined as adverse effects occurring after
multiple or continuous exposure between 24 h and 28 days.
 Subchronic systemic toxicity is defined as adverse effects occurring after
the repeated or continuous administration of a test sample for up to 90
days or not exceeding 10% of the animal's lifespan.
 Repeated dose toxicity testing
 Repeated dose toxicity testing is carried out for a minimum of 28 days.
The test substance is administered daily for a certain period through the
oral route. The test substance is administered regularly at a specific time.
Usually, a rodent of any gender and age 5–6 weeks is used for repeated
dose toxicity testing. There should be little individual variation between
the animals: the allowable variation in the weight is ±20%.
 Baseline parameters such as the behavioural and biochemical parameters
of the animals should be recorded. These will be helpful in calculating
percentage changes. The interpretation of human safety details is essential
in repeated dose toxicity studies.[14] At the end of the study, tissues from
most of the organs are removed, and histological changes are recorded. If
possible, immunotoxicity (adverse effects on the immune system) studies
are performed on the same animals.
 The major difference between repeated dose and subchronic toxicity
studies is the duration: repeated dose toxicity studies are conducted over a
duration of 28 days,and subchronic toxicity studies are carried out over
90 days.

 Chronic toxicity, the development of adverse effects as a result of long

term exposure to a contaminant or other stressor, is an important aspect of
aquatic toxicology. Adverse effects associated with chronic toxicity can
be directly lethal but are more commonly sublethal, including changes in
growth, reproduction, or behavior. Chronic toxicity is in contrast to acute
toxicity, which occurs over a shorter period of time to higher
concentrations. Various toxicity tests can be performed to assess the

12
 chronic toxicity of different contaminants, and usually last at least 10% of
an organism’s lifespan. Results of aquatic chronic toxicity tests can be
used to determine water quality guidelines and regulations for protection
of aquatic organisms.
 Phototoxicity: The skin exposure to solar irradiation and photoreactive
xenobiotics may produce abnormal skin reaction, phototoxicity.
Phototoxicity is an acute light-induced response, which occurs when
photoreacive chemicals are activated by solar lights and transformed into
products cytotoxic against the skin cells. Multifarious symptoms of
phototoxicity are identified, skin irritation, erythema, pruritis, and edema
that are similar to those of the exaggerated sunburn. Diverse organic
chemicals, especially drugs, are known to induce phototoxicity, which is
probably from the common possession of UV-absorbing benzene or
heterocyclic rings in their molecular structures. Both UVB (290~320 nm)
and UVA (320~400 nm) are responsible for the manifestation of
phototoxicity.
 Reproductive & Developmental Toxicity:

Mutagenicity testing

 Mutagenicity testing is used to assess submicroscopic changes in the base

sequence of DNA, chromosomal aberrations, and structural aberrations in
DNA including duplications, insertions, inversions, and translocations.
Certain types of mutations result in carcinogenesis (alteration in proto-
oncogenes of tumor suppressor gene mutation), and so the determination
of the mutagenicity is essential in the drug development process.

Carcinogenicity testing

Both rodents and nonrodent animal species may be used in carcinogenicity

testing. The tests are carried out over the greater portion of an animal's lifespan.
During and after exposure to test substances, the experimental animals are
observed for signs of toxicity and development of tumors. If these are not found,
a test may be terminated after 18 months in the case of mice and hamsters and
after 24 months with rats. If the animals are healthy, hematological analysis is
performed after the 12 months and the 18 months, respectively, and the study is
terminated. The animals are sacrificed, and gross pathological changes are noted
and histopathological studies are carried out on all the tissues.

13
Toxicokinetics: which is an extension of pharmacokinetics deals with the
kinetic patterns of higher doses of chemicals/toxins/xenobiotics. Toxicokinetics
helps study the metabolism and excretion pattern of xenobiotics. Animal
toxicokinetic data help extrapolate physiologically based pharmacokinetics in
humans. In toxicological testing, pharmacokinetic studies are usually carried out
in rodents, rabbits, dogs, nonhuman primates and swine using many routes of
administration.

14
Toxicokinetics and Toxicodynamics

Xenobiotic is a general term referring to any chemical foreign to an organism or, in

other words, any compound not occurring within the normal metabolic pathways of a
biologic system.Depending on the compound and the level of exposure, interactions
between xenobiotics and animals can be benign, therapeutic, or toxic in nature.

The pharmacokinetics and pharmacodynamics of a therapeutic xenobiotic influence

the time course and efficacy of that compound in a pharmacologic setting. Likewise,
the toxicokinetics and toxicodynamics of a toxic xenobiotic determine the “when,”
“how long,” “what,” and “why” for the adverse effects of that toxicant.

The disposition of a xenobiotic is what the animal’s body does to that compound
following exposure. The disposition or fate of a xenobiotic within the body consists of
the chemical’s absorption, distribution, metabolism (biotransformation), and excretion
characteristics (ADME).

Toxicokinetics refers to the quantitation and determination of the time course of the
disposition or ADME for a given toxic xenobiotic.

There are a variety of specialized toxicokinetic terms, including bioavailability,

volume of distribution (Vd), clearance, half-life, one-compartment model, and first-
and zero-order kinetics.

The term toxicodynamics describes what a toxicant does physiologically,

biochemically, and molecularly to an animal’s body following exposure.

The toxicodynamics of a given toxic xenobiotic depend on the mechanism of action

of that toxicant and the relationship between toxicant concentration and the observed
effects of the toxicant on biologic processes in the animal (i.e., the dose-response
relationship). The disposition and toxicokinetics of a particular xenobiotic also play a
role in determining the organs or tissues affected by a toxicant, and the clinical
presentation and time course of a toxicosis resulting from excessive exposure to that
compound.

1
Toxicokinetics and Disposition
Xenobiotic Absorption:
 With the exception of caustic and corrosive toxicants that cause adverse
effects at the site of exposure, a toxic xenobiotic is generally first “absorbed”
or taken up into the body.
 Absorption involves crossing cellular membranes, which are typically
composed of phospholipid bilayers containing various sized pores and
embedded proteins.
 The route of exposure and physiochemical properties of a toxicant, such as its
resemblance to endogenous compounds, its molecular size and relative lipid
and water solubilities.

Routes of Xenobiotic Exposure and Xenobiotic Bioavailability

 The most common routes of exposure for xenobiotics in small animal

toxicology are oral (gastrointestinal), dermal (percutaneous), and inhalation
(pulmonary).
 In rare instances of iatrogenic intoxications, xenobiotics can be injected
subcutaneously, intramuscularly, intraperitoneally, or even intravenously.
 There are unique aspects to the absorption of xenobiotics associated with
each route of exposure, especially with regard to the bioavailability of potential
toxicants.
 Bioavailability (often represented by F in toxicokinetic equations) represents
the fraction of the total dose of a toxic xenobiotic that is actually absorbed by
an animal.In intravenous exposures, the bioavailability of a toxic xenobiotic is
100% because the entire dose of the toxicant reaches the peripheral
circulation.
 The absorption of gases and vapors in the respiratory tract largely depends
on the ratio (blood-to-gas partition coefficient) between the equilibrium
concentrations of the toxicant dissolved in the blood and the gaseous phase
of the toxicant in the alveolar spaces.
 Dermal absorption frequently depends on the vehicle in which a toxicant is
dissolved and is generally greater for lipid-soluble compounds as compared
with chemicals that are highly soluble in water.

2
  The bioavailability of toxic xenobiotics that are ingested can be negatively
affected by acidic degradation in the stomach and enzymatic breakdown in
the small intestine.
 Decreased gastrointestinal transit time can diminish xenobiotic bioavailability
by limiting the access of toxicants to those regions of the digestive tract where
rates of absorption are greatest.
 Some potential toxicants, especially certain heavy metals (e.g., lead and
cadmium), resemble essential minerals such as calcium and zinc,
respectively. The gastrointestinal absorption of these toxic nonessential
metals involves interactions with dietary levels of the corresponding essential
metals and regulated mechanisms of gastrointestinal uptake designed for
these required minerals.
 Hepatic biotransformation of xenobiotics can also influence the apparent
bioavailability of ingested toxicants.
 Following oral exposure, xenobiotics absorbed from the gastrointestinal tract
are transported to the liver via the hepatic portal circulation.
 For some xenobiotics, rapid hepatic degradation (and in some instances prior
biotransformation in gastrointestinal cells) prevents access of the compound
to the systemic circulation, resulting in an apparently decreased bioavailability
from what is termed the first-pass effect or presystemic elimination.
 In contrast, the bioavailability of some chemicals is enhanced by a cycle of
biliary excretion and subsequent reuptake from the intestines referred to as
enterohepatic recirculation.

Mechanisms of Xenobiotic Absorption

 The passage of xenobiotics through cellular membranes can be either energy-

independent (passive transport) or can require the expenditure of energy
through specialized or active transport systems.
 Passive transport of xenobiotics can be accomplished through simple
diffusion or filtrationwhich do not require the expenditure of energy to
transport xenobiotics across cellular membranes.

3
  Specialized, energy-dependent, cellular transport systems include the process
specifically referred to as active transport, along with facilitated transport and
pinocytosis.
 Passive transport depend on the concentration gradient for a given xenobiotic,
with the rate of transport being proportional to the difference in that chemical’s
concentration between the two sides of a particular membrane
 Simple diffusion is the most common mechanism by which xenobiotics cross
cellular membranes.
 Uncharged (nonionized), lipid-soluble molecules, especially small molecules,
are more readily diffusible across the phospholipid bilayers membranes than
charged (ionized) molecules, which are generally less lipid-soluble.
 Filtration involves the passage of xenobiotics through potencies or pores
within cellular membranes and is determined, in large part, by the size of the
xenobiotic molecule and pore size, which varies in different organs and
tissues.
 Specialized Transport of Xenobiotics -Active transport is an energy-
dependent, saturable process by which xenobiotics are transported across
biologic membranes against electrochemical or concentration gradients.
 Pinocytotic transport involves cellular engulfment of small amounts of
xenobiotics and the transfer of this amount of chemical through the cellular
membrane.

Xenobiotic Distribution

 Distribution refers to the translocation of a xenobiotic from the site of

absorption to various body organs and tissues and involves both transport of
the chemical within the circulation and cellular uptake of the xenobiotic.
 The rate of xenobiotic transfer into a particular organ or tissue is determined
by the physiochemical properties of the specific xenobiotic (e.g., lipid solubility
and molecular weight), the blood flow to the organs or tissues in question, and
the rate of diffusion of the xenobiotic across the endothelial walls of the
capillary bed into cells within a particular organ or tissue.
 The Vd for a given xenobiotic represents the quotient of the total amount of
that chemical in the body divided by the concentration of the xenobiotic within

4
 the blood and is used to describe the extent to which a xenobiotic is
distributed within the body.
 The Vd is a clinically relevant indicator as to whether a chemical is primarily
contained within the plasma compartment (relatively low Vd) or whether a
compound is widely distributed throughout the body within the interstitial or
intracellular compartments of various organs and tissues (relatively high Vd).

Xenobiotic Storage Depots

 Xenobiotics can be stored within a variety of different body organs and

tissues.
 Depending on the anatomic and physiologic relationships between the
storage depot and the target organs and tissues for a specific toxicant,
storage of toxic xenobiotics can function as either a protective mechanism or
as a means by which the toxic effects of a xenobiotic are potentiated.
 An understanding of the storage sites of toxic xenobiotics can provide
additional insight about circumstances that would be expected to exacerbate
a particular toxicosis and can indicate which organs or tissues would be
expected to have the highest concentrations for diagnostic sampling.
 Plasma proteins represent a storage site for many xenobiotics (e.g.,
salicylates, barbiturates, cardiac glycosides) and important physiologic
constituents, including steroid hormones, vitamins, and various essential
minerals.
 Displacement of toxic xenobiotics from plasma proteins can greatly increase
the amount of unbound toxicant distributed to target organs or tissue.
 A wide variety of xenobiotics accumulate in the liver and kidneys, making
these organs ideal sites for postmortem sample collection in cases of
suspected toxicosis.
 Some toxic metals, such as cadmium, accumulate in the liver and kidneys.
 Fat and bone are storage depots for a variety of different xenobiotics. and
rapid depletion of body fat stores (weight loss) or increased remodeling of
bone during growth or pregnancy have the potential to increase the exposure
of target organs or tissue to previously stored toxicants.

5
Biotransformation

 It is a general term referring to the metabolic conversion of both endogenous

and xenobiotic chemicals into more water-soluble forms. For the purposes of
this chapter, xenobiotic metabolism and biotransformation are synonymous
and refer to the generally two-phase process by which chemicals are
converted to more water-soluble forms for excretion from the body.
 In xenobiotic metabolism or biotransformation, the lipophilic (lipid-soluble)
properties of xenobiotics that favor absorption are biotransformed into
physiochemical characteristics (hydrophilicity or water solubility) that
predispose compounds to excretion in the urine or feces.
 Although multiple organs within the body have biotransformation capabilities,
most xenobiotics are biotransformed in the liver.

Phase I and Phase II Xenobiotic Biotransformation

 Xenobiotics are usually biotransformed in two phases (I and II), which involve
enzymes having broad substrate specificity.
 Phase I reactions generally involve oxidation, hydrolysis, or reduction, and
convert apolar, lipophilic xenobiotics into metabolites, which have greater
polarity and hydrophilicity. In these instances, hydroxyl, amino, carboxyl, or
thiol moieties are usually either exposed or added to increase water solubility.
 Oxidation reactions, especially those catalyzed by cytochrome P450
enzymes, are the phase I biotransformations most commonly involved in
xenobiotic metabolism, and many xenobiotics are able to induce cytochrome
P450 activity.
 During phase II biotransformation, the xenobiotic or its metabolites are
conjugated with a functional group (e.g., glucuronide, sulfate, amino acids,
glutathione, or acyl or methyl groups), resulting in a compound with
dramatically increased water solubility.
 Most xenobiotic biotransformations result in less toxic metabolites.
 However, there are xenobiotics (e.g., acetaminophen and aflatoxin B1) for
which the products of hepatic phase I metabolism are actually more toxic than
the parent xenobiotic.

6
Xenobiotic Excretion

 The final step in the disposition of a xenobiotic is excretion, whereby the

xenobiotic or its metabolites are removed from the body via a number of
different routes.
 Renal excretion is the most common means by which xenobiotics and the
products of their biotransformation are eliminated from the body, but toxicants
can also be excreted in the feces (biliary excretion or elimination of
unabsorbed xenobiotic), saliva, sweat, cerebrospinal fluid, or even the milk.
 In instances of exposures to toxic vapors or volatile xenobiotics, exhalation
can also be a major route of elimination from the body.
 Xenobiotics and their metabolites can be excreted by more than one route of
elimination, and the total excretion is generally broken down into renal and
nonrenal routes.
 Xenobiotic Elimination With regard to toxicokinetics, generally incorporates
both the processes of biotransformation and excretion.

Toxicodynamics

 In contrast to toxicokinetics, the toxicodynamics of a particular xenobiotic

describe what that compound actually does to adversely affect an animal’s
health rather than how the animal handles the exogenous chemical.
 However, a xenobiotic’s toxicodynamics and toxicokinetics are not mutually
exclusive. What a toxicant does physiologically, biochemically, and
molecularly to a living organism following exposure not only depends on that
xenobiotic’s mechanism of action and its dose-response relationship, but also
on its disposition or toxicokinetics within an exposed animal.
 The first step in the development of a toxicosis is the delivery of the “ultimate
toxicant” to its site of action or “target.
 Ultimate toxicant refers to the parent xenobiotic, its metabolite, or even a
generated reactive oxygen species that actually causes cellular damage.
 The term target is often used to describe a molecule that interacts with the
ultimate toxicant, resulting in adversely affected biologic processes within an
organism.

7
  Targets can also be an inclusive term referring to the cell types, organs, or
tissues most susceptible to the effects of a toxic xenobiotic.
 The distribution and biotransformation of a xenobiotic often limit the delivery of
the ultimate toxicant to susceptible target cells, organs, or tissues. Distribution
of xenobiotics to storage depots that are physically removed from potential
target sites is one means by which the disposition of a toxicant can be
protective and can limit the adverse effects of a particular xenobiotic on an
animal.
 Presystemic elimination or the first-pass effect prevents toxic xenobiotics from
ever reaching the general circulation and therefore many potential sites of
action.
 Most biotransformation’s produce metabolites that are more water soluble and
as a result more readily eliminated from the body.
 In contrast to circumstances in which the disposition of a xenobiotic
decreases the risk of toxicosis, there are also instances in which the
distribution and biotransformation of a given toxicant actually increase the
likelihood that an ultimate toxicant will be delivered to the site of action.
 A chemical’s toxicity can be enhanced by specialized transport mechanisms
and by physiochemical characteristics that facilitate the accumulation of
ultimate toxicants within susceptible cells.
 The toxicity of a xenobiotic can also be facilitated by processes, such as
enterohepatic recirculation, that increase its bioavailability.

Toxicodynamics :

Toxicodynamic refers to the molecular, biochemical, and physiological

effects of toxicants or their metabolites in biological systems.

These effects are result of the interaction of the biologically effective

dose of the ultimate (active) form of the toxicant with a molecular target.

Molecular Targets Concept

8
The toxic action of a chemical is a consequence of the physical/chemical
interaction of the active form of that chemical with a molecular target
within the living organism.

Examples of Molecular Targets

Proteins

 Aryl hydrocarbon (Ah) receptor—Dioxin

 Hemoglobin—CO

Lipids-Carbon tetrachloride

DNA -Aflatoxin

Dose-Response Concept

The magnitude of the toxic effect will be a function of the concentration of altered
molecular targets, which in turn is related to the concentration of the active form of

9
the toxicant(biologically effective dose) at the site where the molecular targets are
located.

10
CLASSIFICATION OF TOXICOLOGY

Basic classification of toxicology: Toxicology is broadly divided into different classes

depending on research methodology, socio-medical & organ/specific effects.

I. Based on research methodology

A. Descriptive toxicology

Descriptive toxicology deals with toxicity tests on chemicals exposed to human

beings and environment as a whole.

B.Mechanistic toxicology

Mechanistic toxicology deals with the mechanism of toxic effects of chemicals on

living organisms. This is important for rational treatment of the manifestations of
toxicity (e.g. organophosphate poisoning reversed by oximes), prediction of risks
(e.g. organophosphate poisoning →leads to accumulation of acetylcholine→activate
muscarinic and nicotinic receptors respiratory failure) & facilitation of search for
safer drugs (e.g. Instead of organophosphates, drugs which reversibly bind to
cholinesterase would be preferable in therapeutics).

C.Regulatory toxicology

Regulatory toxicology studies whether the chemical substances has low risk to be used
in living systems E .g - Food and drug administration regulates drugs, food,
cosmetics medical devices &supplies in USA.- Environmental protection agency
regulates pesticides, toxic chemicals, hazardous wastes and toxic pollutants in USA-
Occupational safety and health administration regulates the safe conditions for
employees in USA-Drug administration & control authority (DACA) - regulates drugs,
cosmetics and medical devices &supplies in Ethiopia.

D.Predictive toxicology

Predictive toxicology studies about the potential and actual risks of chemicals /drugs.
This is important for licensing a new drug/chemical for use.

II. Based on specific socio-medical issues

A)Occupational toxicology

Occupational toxicology deals with chemical found in the workplace E.g. –

Industrial workers may be exposed to these agents during the synthesis,
manufacturing or packaging of substances Agricultural workers may be exposed to
harmful amounts of pesticides during the application in the field.
B)Environmental toxicology

Environmental toxicology deals with the potentially deleterious impact of chemicals,

present as pollutants of the environment, to living organisms. Ecotoxicology has evolved
as an extension of environmental toxicology. It is concerned with the toxic effects of
chemical and physical agents on living organisms, especially in populations and
communities with defined ecosystems.

C) Clinical toxicology

Clinical toxicology deals with diagnosis and treatment of the normal diseases or
effects caused by toxic substances of exogenous origin i.e. xenobiotics.

D) Forensic toxicology

Forensic toxicology closely related to clinical toxicology. It deals with the medical and
legal aspects of the harmful effects of chemicals on man, often in post mortem
material, for instance, where there is a suspicion of murder, attempted murder or
suicide by poisoning.

III. Based on the organ/system effect

1. Cardiovascular toxicology

2. Renal toxicology

3. Central nervous system toxicology

4. Gastrointestinal toxicology

5. Respiratory toxicology etc

UNIT-I Toxicology
Toxicokinetics is essentially the study of "how a substance gets into the body and what
happens to it in the body."Thustoxicokinetics refers to the study of absorption, distribution,
metabolism/biotransformation, and excretion (ADME) of toxicants/xenobiotics in relation to
time. The basic kinetic concepts for the absorption, distribution, metabolism, and excretion of
chemicals in the body system initially came from the study of drug actions or pharmacology;
therefore, this area of study is traditionally referred to as pharmacokinetics.

Four processes are involved in toxicokinetics:

1. Absorption — the substance enters the body.

2. Distribution — the substance moves from the site of entry to other areas of the body.
3. Biotransformation — the body changes (transforms) the substance into new
chemicals (metabolites).
4. Excretion — the substance or its metabolites leave the body.

Frequently the terms toxicokinetics, pharmacokinetics, or disposition have the same meaning.
Disposition is often used in place of toxicokinetics to describe the movement of chemicals
through the body over the course of time, that is, how the body disposes of a xenobiotic.

UNTOWARD EFFECTS DUE TO POISONOUS SUBSTANCES

There are other untoward effects caused by poisonous substances irrespective of the
poisoning being acute, sub-acute or chronic. These may be produced by certain drugs even at
therapeutic dose levels.

 Allergy –The individual becomes sensitized to a previous dose of the same material.
 Teratogenicity (Greek word meaning monster) – The exposure to certain naturally
occurring or man-made agents during certain stages of gestation results in
malformations of the offspring. Teratogen is defined as an agent which, when
administered during gestation, produces nonlethal structural or functional
changes in the embryo or fetus. Some plants and drugs have been identified to cause
teratogenicity. For example: plants like Veratrum and Lupinus and drugs like
thalidomide and colchicine.
 Carcinogenicity – The agent after a considerable delay may induce neoplasia. The
compound has the ability to transform normal cell into progressively and
uncontrollably proliferating ones.
 Mutagenicity – The agent induces mutation or changes through a change in the
genotype or genetic material of a cell by covalent modification of bases in DNA
particularly generation of DNA, which passes on when the cell divides.
Certain common terms used in toxicology studies include Parts Per Million (ppm) is
the term commonly used to express the quantity of toxicant mixed within another
substance (e.g., feed) 1 ppm = 0.0001% = 1 mg toxicant/kg feed.
 Lethal concentration (LC) is the lowest concentration of compound in feed, water or

even in air that causes death. It is expressed as milligrams of compound per kilogram of
feed (parts per million or billion as ppm or ppb)
 Toxic concentration (TC) relates to the first recognition of toxic effects. The specific

(threshold) toxic effects should be identified when a toxic concentration is given.

 Highest nontoxic dose (HNTD) is the largest dose that does not result in clinical or

pathologic drug-induced alterations.

 Toxic-dose-low (TDL) is the lowest dose that will produce alterations; administration
of twice this dose is not lethal.
 Toxic-dose-high (TDH) is the dose that will produce drug-induced alterations and
administration of twice this dose is lethal.
 Lethal dose (LD) is the lowest dose that causes death in any animal during the period
of observation. LD50 is a commonly used measure of toxicity.
 Median Lethal Dose (LD50) is the dose at which a toxicant causes lethality in 50% of
the population or animals exposed to that particular agent/compound.
 No observed adverse effect level (NOEL or NOAEL) is the largest dose that will
produce no deleterious effects when administered over a given period of time. This
study is generally conducted in two species (rats and dogs) at three doses by the route
of choice.
 Reference dose (RfD) is the highest dose expected to have no effect on the species of
interest (often human beings) despite a lifetime of exposure. The RfD may be set at
1/10 of the HNTD or 1/10 of the NOAEL.
 Maximum tolerated dose (MTD) is sometimes used to indicate maximum tolerated
dose (highest dose not causing death). Other times it is used to indicate minimum
 toxic dose (lowest dose causing any abnormality). Thus, it is best to ask what is meant
by MTD.
 Safety factor (SF) reflects the quality of the toxicological investigation and the degree
of certainty with which the results can be extrapolated to human beings.

COMMON CAUSES OF POISONING

 The materials causing intoxication in animals may be naturally occurring or man-

made.
 Naturally-occurring - These are either inorganic materials or minerals, plants
and the products of moulds, venomous snakes, toads and insects. The
inorganic materials include fluoride, nitrates, copper, molybdenum, selenium
and lead.
 Man-made hazards – Man made hazards may cause accidental, malicious or
intentional and occupational poisoning. The agents of interest include
industrial products or by-products, domestic materials, pharmaceutical
preparations and feed additives.
 Industrial materials
 Proximity of industrial and agricultural operations in association with
inadequate control of emissions. The harmful agents, which may be involved,
include inorganic materials arsenic, lead, molybdenum, fluoride, cadmium,
mercury, copper and chromium and the organic substances ethanol, cyanide
and fluoroacetamide. Discharge of sulphur dioxide and acid rain, accidental
discharge of radioactive material and the disposal of radioactive material and
industrial waste chemicals.
 Domestic materials
 Lead in roofing felt, linoleum, piping, paint, accumulators, used engine oil,
golf balls, fishing weights and shot, phenolic materials in bituminous floor
coverings, discarded clay pigeons, creosote and disinfectants, toxic plants
incorporated into or used as bedding, house plants, gases such as ammonia,
carbon monoxide or hydrogen sulphide, fuel oils, herbicides and human
medicaments.
 Pesticides
 This includes herbicides, fungicides, molluscicides, insecticides and
rodenticides.
 Medicaments
 Misuse or over dosage of pharmaceutical material can produce intoxication.
 Dietary constituents
 Inadequate cooking or poor storage of diets or their constituents, addition of
excessive quantities or inadequate mixing of the recommended quantities of
preservatives or growth-promoter feed additives, and either the incorporation
of toxic materials into the diet or their use in feedstuffs.

TOXICODYNAMICS
(Mechanism of action)

 Cellular basis for toxic injury – Cellular damage is the basis for most toxicological
injury.
 Toxic injury involves quantitative differences in the function of cells, tissues and
organs.
 Cellular response of chemical toxicants occurs through both structural and metabolic
mechanism of the cell, like altered membrane integrity, altered cell volume regulation,
 abnormal accumulation of lipids and pigments, altered protein synthesis and altered
growth regulation.
 Mixed function oxidases play a role in biotransforming xenobiotics to electrophilic
intermediates.
 Mixed function oxidsases are a family of non specific enzymes that act primarily in
the endoplasmic reticulum to promote phase I metabolism, which prepares
xenobiotics for conjugation and excretion. These electrophilic intermediates are
believed to bind covalently to important cellular macromolecules. These
macromolecules may be denatured by binding.
 Elecrophiles also bind to reduced glutathione which is considered to be a protective
mechanism in the cell.
 Cellular macromolecules may also be damaged by free radicals.
 A free radical is a compound with an unpaired electron a result of an enzyme-
catalyzed addition of electron to a carbon bond, with subsequent cleavage.
 Superoxide (active oxygen) is formed when some compounds are oxidised by mixed
function oxidases to free radical, with electrons transferred to oxygen. This active
oxygen reacts with polysaturated lipids, initiating an autocatalytic chain reaction,
leading to lipid-free radicals and then lipid peroxidation.
 Glutathione can be depleted which enhances oxidative damage and leads to cell death.
Agents that deplete glutathione, increase cell susceptibility to lipid peroxidation.
 Several major effects are initiated after free radical formation. Defenses against free
radicals are built into cells as antioxidants like superoxide dismutase, catalase,
glutathione peroxidase and vitamin E.

CHARACTERISTICS OF TOXIC METALS

 Toxic metals may be cumulative and stored in definite tissue locations.

 Although metals may be cumulative in nature, toxicosis is not necessarily due to
storage.
 This is because some storage sites are toxicologically inert.
 Route of exposure may be important in modifying toxicosis.
 Metallic compounds can bind to enzymes, membrane proteins, or other essential
structural proteins.
  Metals may complex with one another or with the same protein molecule resulting in
altered toxicity.
 Organic and inorganic forms of metals may result in marked variation in expression
of toxicity.
 Organomercurials result in clinical signs and lesions commonly affecting the central
nervous system while inorganic mercury results in acute gastroenteritis and renal
damage.

SOURCES OF ARSENIC POISONING

Among heavy metals, arsenic plays a major role in causing toxicological hazards .

Sources

 The most common arsenic compound in general use is arsenic trioxide.

 With alkalies, arsenic trioxide forms various arsenites.
 Heating of metal ores results in the production of arsenic trioxide some of which is
carried to the surrounding in dust or smoke.
 Copper arsenite was formerly used as a cheap pigment for colouring wall papers,
artificial flowers etc. But it has been discontinued, as it was the cause of many deaths.
 Copper acetoarsenite (Paris green) was used as an insecticide.
 Sodium and potassium arsenite are extensively used as weed killers, dressings for
grains, insect poison, sheep dip and wood preservative.
 Arsenical dips are usually combined with sulphur for the use in sheep and cattle.
 Organic arsenicals are used in the treatment of blackhead (histomoniasis) in turkey
and also as general tonics and skin alteratives.
 Acetarsol, neoarsphenamine, sulpharsphenamine and liquor arsenicals (Fowler’s
solution) were used in the treatment of certain skin conditions and as skin alteratives.
 Arsenic poisoning in animals is practically always due to human carelessness.
o Animals gaining access to receptacles that contained arsenical dips, weed
killers or insecticides.
o Contamination of herbage by lead and calcium arsenate sprays.
o Contamination of water and herbage in the neighbourhood of metal smelting
works.
o Animals licking wood preserved with an arsenical preparation.
 o Inadvertent use of arsenicals because of their resemblance to other
preparations.
o Ingestion of arsenical rat poison.
o Following dipping in arsenical baths.
o Use of contaminated deep well water

FACTORS AFFECTING TOXICITY

 Trivalent compounds are more toxic than pentavalent compounds.

 Pentavalent compounds are said to exhibit their toxic effects only after conversion to
trivalent form.
 The other factors, which affect the toxicity of arsenic, are:
o The physical state – whether solid, coarse powder or fine powder or solution –
finely divided soluble forms are more toxic.
o The condition of the digestive tract.
o Nature of ingesta.
o Method of application.
o Weak, debilitated and dehydrated animals are more susceptible.
o Poisoning is more common in bovines and felines. Poisoning is also noticed in
horses and sheep. It is occasional in dogs and rare in swine and poultry.
 Herbivores are commonly poisoned as they eat contaminated forage.
 Chronic poisoning can occur due to long continued small doses.

ABSORPTION AND FATE

 The rate of absorption of inorganic arsenicals from the digestive tract depends on their
solubility.
 Soluble salts are more toxic and are absorbed through skin also. Absorption is very
rapid from a fresh wound.
 After absorption, arsenicals tend to accumulate in liver.
 After continued administration, there is a tendency for arsenic to be stored in the
bones, skin and keratinized tissue such as hair and hoof.
 Arsenic stored in the tissues may be found there for a long time, even after it has
disappeared from the faeces and urine.
  Once arsenic is deposited in the keratinized cells of hair, it is irremovable, moving
slowly along the hair as the hair grows.
 Arsenic is excreted in urine, faeces, sweat and milk.
 In the body, arsenic is found in association with protein and it is believed that it
attaches to the sulphydryl groups of the sulphur containing aminoacids.

MECHANISM OF TOXICITY

 Arsenic reacts with the sulphydryl group of lipoic acid.

 Lipoic acid is an essential co-factor for the enzymatic decarboxylation of keto acids
such as pyruvate, ketoglutarate and ketobutyrate.
 By inactivating lipoic acid, arsenic inhibits formation of acetyl, succinyl and
propionyl coenzymes A.
 So there is inhibition or slowing of glycolysis and of the citric acid cycle.
 Arsenic also inactivates sulphydryl groups of oxidative enzymes and glutathione.
 Pentavalent arsenate is a well-known un-coupler of mitochondrial oxidative
phosphorylation.

CONSEQUENCES OF TOXICITY

 Arsenic affects those tissues which are rich in oxidative enzymes especially in the
alimentary tract, kidney, liver, lungs and epidermis.
 It is a potent capillary poison. Although all beds are affected, the spalnchnic areas are
more sensitive.
 Loss of capillary integrity and dilatation allows transudation of plasma fluid into the
intestinal mucosa and lumen which results in sharply reduced blood volume,
hypotension, shock and circulatory collapse.
 Toxic arsenic nephrosis is common in small animals and man.
 Glomerular capillaries dilate, swell and varying degree of degeneration occur. This
results in oliguria and urine contains red blood cells and casts.
 Following percutaneous absorption, capillaries dilate and arsenic causes blistering and
oedema.
 Skin becomes dry, papery and may crack, bleed and develop secondary infection.
 Tolerance to arsenite: Habitual use of small quantities of arsenic is said to render the
body tolerant much larger doses.
CLINICAL SYMPTOMS

 Per-acute – In per-acute poisoning death is rapid. The symptoms noticed are intense
abdominal pain, staggering gait, collapse, paralysis and death.
 Acute – In acute cases the symptoms are salivation, thirst, vomition in possible
species, violent colic, watery diarrhoea with peel off mucous membrane sometimes
haemorrhagic, exhaustion, collapse and death.
 Sub-acute – Sub-acute cases may live for several days and there may be additional
symptoms of depression, loss of appetite, staggering gait, apparent paralysis of the
hind quarters, trembling, stupor, convulsions, coldness of the extremities and sub-
normal temperature. Proteinuria and haematuria may also occur. Arsenical dermatitis
is common in man.
 Chronic – The symptoms include indigestion, thirst, wasting and general appearance
of unthriftiness, dry staggering coat, brick red colour of visible mucous membrane,
weak and irregular pulse.
 Some organic arsenicals have been used as production aids in poultry and pigs.
 Pigs in particular have suffered damage to peripheral nerves characterized as
demyleination following repeated ingestion of medicated feeds. This problem is not
amenable to BAL but is sometimes slowly reversible following withdrawal of
medicated feed.

PM LESIONS

 Intense rose-red inflammation of the alimentary tract.

 Soft and yellow liver.
 Edematous and congested lungs.
 Haemorrhages in the heart, peritoneum, kidneys and liver.
 Inflammation of proventriculus and gizzard in birds. Horny layer of the gizzard may
be sloughing off.

DIAGNOSIS AND TREATMENT

Diagnosis

 Symptoms like colic, thirst, straining and purgation and vomiting occur suddenly.
This might give a suspicion for some irritant poisoning like arsenic. Chronic
poisoning is difficult to diagnose.

Treatment

 Induction of emesis.
 Gastric lavage with warm water.
 Enema in carnivores.
 Purgatives in ruminants.
 Use of demulcents to reduce irritation.
 Freshly prepared ferric hydroxide can be given but its use is doubtful.
 Sodium thiosulphate (hypo) can be given orally and intravenously.
o Horse and cattle – 8 to 10 g as 10-20% solution i/v 20 to 30 g orally in about
300 ml of water.
 Dimercaprol (BAL-British Anti Lewisite)
o Dimercaprol binds with arsenic-lipoic acid complex and forms arsenic-
mercaptide complex. This complex is non-toxic and easily excreted from the
body.
o BAL is relatively ineffective unless given prior to onset of clinical symptoms.
Overdosage of arsenic is common in horses and is known as ‘tying up’ in
animals.
o Water soluble BAL compounds like DMSA (Succimer) and DMPS (Unithiol)
are found to be effective.
 Thioctic acid (lipoic acid) can also be administered.
 d-Penicillamine is also useful as a chelating agent.