2. chapter principle of toxicology

BULE HORA UNIVERSITY
COLLEGE OF HEALTH AND MEDICAL
SCIENCES
DEPARTMENT OF PHARMACY
TOXICOLOGY
For 4th year Medical Laboratoy
Students
4/5/2022
Basic Principles of toxicology 1
By:Aliyi G.(B.Pharm

General Principles of
Toxicology
CHAPTER TWO
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Basic Principles of toxicology

Objectives
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At the end of this chapter, students will be able to:
 Discuss basic principles of toxicology
 Discuss toxicity parameters: the chemical form, routes and sites
of exposure, duration and frequency of exposure (acute, sub acute,
chronic), Dose- response effects.
 Discuss types of toxic reactions
 Discuss variation in toxic responses.

Outline
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 Basic principles of toxicology
 Toxicity parameters: the chemical form, routes and sites of
exposure, duration and frequency of exposure (acute, sub acute,
chronic), Dose- response effects.
 Types of toxic reactions
 Variation in toxic responses.

Principles of toxicology
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Toxicant (Poison)
 any agent capable of producing a deleterious response in a
biological system.
 Paracelsus (1493-1541) once said
 "All substances are poisons; there is none which is not a poison
The right dose differentiates a poison from a treatment’’
 It is not easy to distinguish toxic from non toxic substances.

Principles of toxicology cont’d
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therapeutic
effect
toxic
effect
increasing dose
“All things are poison and nothing is without poison, only the dose
permits something not to be poisonous
The dose makes the poison”

Exposure
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 The concentration of chemical involved and frequency of its
interaction with people.
• Degree of exposure = Determined during risk assessment
• Excessive Exposure = The amount of exposure that lead to
 injury or adverse effects .
 e.g. Median Lethal Dose (LD50) of Ethanol is
&7000 mg/kg,
 it means that by ingesting 7000 mg/kg Ethanol,
 half of the rat population in the experiment died
 LD50 : Refers to the dose of a substance that displays toxicity in that
it kills 50% of a test population.

Exposure cont’d,…
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 Adverse effects = abnormal, undesirable
harmful change following exposure.
• Reversible change
• Irreversible Change
 Injury depends on = property of chemical +
nature of exposure + health & developmental
state of the person.

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Routes and Sites of Exposure
 Ingestions (gastrointestinal tract) account for 79% of
exposures
 7% Skin (topical, percutaneous, or dermal)
 6% Eye (ophthalmologic)
 5% lungs (inhalation)
 3% bites
 0.3% injection
 intravenous, intramuscular, intraperitoneal

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Injection (intravenous route).
 Toxic agents generally produce the greatest effect and
 the most rapid response when given directly into the
bloodstream.
 Typical Effectiveness of Route of Exposure:
iv > inhale > ip > Sc> im > ingest > topical

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Skin
 direct and prolonged contact of the skin
with the substance.
• Chemicals that can penetrate healthy intact
skin
– aniline, hydrogen cyanide,
organophosphate, etc.

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Lung (Inhalation)
 Occupational exposure to toxic agents most frequently results
from breathing contaminated air.
 Depends on
 Size & Shape of particles
• Size – effective aerodynamic diameter
• Shape – dust, microorganism
 Rate of physical work
• Advice to avoid physical activity
during haze.

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 Ingestion
• Mostly we can control (unlike airborne).
• Airborne particle also can be ingested.
• Depends on
• Concentration
• Time
 The route of administration can influence the
toxicity of agents ….how????????????????

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Duration and frequency exposure
 Exposure of experimental animals to chemicals is divided into
four categories.
• Single exposure: Acute exposure - less than 24 hours
• Repeated exposures are classified as:
• Subacute - repeated for up to 30 days
• Subchronic - repeated for 30-90 days
• Chronic -repeated for over 90 days

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 For many agents, the toxic effects that follow a single
exposure are quite different from those produced by repeated
exposure.
 E.g …Benzene
 Acute exposure results in CNS depression.
 Repeated exposure results in bone marrow toxicity,
increased risk of leukemia.

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 Chronic toxic effects may occur if
 The chemical accumulates in the biological system (rate of
absorption exceeds the rate of biotransformation and/or
excretion)
 It produces irreversible toxic effects
 There is insufficient time for the system to recover from the
toxic damage within the exposure frequency interval.

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 For many agents, the toxic effects that follow a single
exposure are quite different from those produced by repeated
exposure
 E.g …Benzene
 Acute exposure results in CNS depression
 Repeated exposure results in bone marrow toxicity,
increased risk of leukemia

Dose - response effects
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 A key principle in toxicology is the
 Dose
 Dose-response relationship
 There is
 a graded dose-response relationship in individuals, and
 A quantal dose-response relationship in the population

Dose - response effects cont’d,…
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Dose
 is the actual amount of chemical entering the body,
 usually per unit body mass of a toxicant to which an
organism is exposed.
 This is usually given as
mg of chemical/kg of body weight = mg/kg.

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Response
 is the effect on an organism resulting from exposure to a
toxicant.
 Change from normal state
 could be on the molecular, cellular, organ, or organism level
=> the symptoms.
 Local vs. Systemic
 Reversible vs. Irreversible
 Immediate vs. Delayed
 Graded vs. Quantal
 degrees of the same damage vs. all or none.

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 A response occurs is dependent on
The chemical and physical properties of the
agent
The exposure situation
How the agent is metabolized by the system
The overall susceptibility of the biological
system or subject

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Dose-response Relationships
 is a relationship between exposure and response,
 that can be established by measuring the response relative
to an increasing dose.
 This relationship is important in determining
 the toxicity of a particular substance.
 It relies on the concept that a dose or a time of exposure (to a
chemical, drug, or toxic substance),
 will cause an effect (response) on the exposed organism.

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 Usually, the larger or more intense the dose, the greater the
response or the effect.
 This is the meaning behind the statement “the dose makes the
poison.”

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 For most toxicants,
 at very low amounts,
 there will be no detectable effect of the chemical (NOAEL: no
observed adverse effect level)
 As the dose of a toxicant increases, so does the response,
either in terms of the proportion of the population responding
or in terms of the severity of the graded responses.
 In the middle range of doses, the amount of damage will
increase as the dose increases.

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 In the Larger amounts of chemical will cause increasingly
more severe biological responses until a maximum level of
damage is reached.
 Additional toxic effects may also appear along with
increased doses, dose - effect relationships.

Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.
2
3
4
0 1 DOSE
RESPONSE
0-1 NOAEL
2-3 Linear Range
4 Maximum Response
DOSE DETERMINES THE BIOLOGICAL RESPONSE
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 There are two types of dose–response relationships:
1. The individual dose–response relationship
 Which describes the response of an individual organism to
varying doses of a chemical
 Often referred to as a “graded” response because the
measured effect is continuous over a range of doses
2. A quantal dose–response relationship
 Which characterizes the distribution of responses to
different doses in a population of individual organisms

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Graded or Individual Dose–Response
Relationships
 Response of an individual organism to varying doses of a
chemical (also called“graded” response because effect is
continuous over a dose range) (e.g.enzyme activity, blood
pressure).
 Characterized by a dose related increase in the severity of the
response
 The dose relatedness of the response
 often results from an alteration of a specific biochemical process.

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Dose Mg/kg
Response

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Quantal Dose–Response Relationships
 Quantal or “all or none”— in nature; that is, at any given dose,
an individual in the population is classified as either a
“responder” or a “non responder”
 The quantal dose-response is the more important one, used
 to determine the median lethal dose (LDm) and
 judge what percentage of the population is affected by a
dose increase and
 comes closest to a classification of whether something is safe or
toxic.

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Diagram of a quantal dose–response relationship

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Threshold dose
 Given the idea of a dose-response, there should be a dose or
exposure level below which the harmful or adverse effects of
a substance are not seen in a population.
 That dose is referred to as the ‘threshold dose’.
 This dose is also referred to as the
 no observed adverse effect level (NOAEL), or the no effect level
(NEL).
 These terms are often used by toxicologists when discussing
the relationship between exposure and dose.

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 For chronic effects, the determination of a threshold value is
very difficult
 This is especially
 for substances causing cancer (carcinogens),
 no safe level of exposure exists, since any exposure could
result in cancer.

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Toxicity
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Def.:
 Describes the degree to which a substance is poisonous or
can cause injury.
 The toxicity depends on a variety of factors:
 dose,
 duration and route of exposure,
 shape and structure of the chemical itself, and
 individual human factors.

Toxicity cont’d
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 Different xenobiotics cause many types of toxicity
by a variety of mechanisms. So, we have to take an
idea about:
-Different types of toxic agents
-Different type of toxicity
-Different mechanisms of toxic response.

Toxicity cont’d
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Toxic Agents
Toxic agent: is anything that can produce an adverse biological
effect.
-The most common terms used to describe a toxic agent are
toxicant, toxin, poison.

Toxicity cont’d
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Toxic Agents are classified :
1-According to their nature:
1-Chemicals: as alcohols, phenols & heavy metals…
2-Physical : as radiation & heat.
2-Bilogical : Snake & scorpion venoms.

Toxicity cont’d
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2-According to their effect:
i-Systemic toxicant:
 is one that affects the entire body or many organs rather than
a specific site.
E.g.: potassium cyanide is a systemic toxicant
it affects virtually every cell and organ in the body by
interfering with the cell's ability to utilize oxygen.

Toxicity cont’d
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ii-Target organs toxicant:
 affect only specific tissues or organs while not producing
damage to the body as a whole.
Examples:
-Arsenic& paracetamol are hepatotoxic.
-Digitalis& antimony are cardiotoxic.
-Mercury & gentamycin are nepherotoxic.
-Lead is also a specific organ toxin; however, it has three target
organs (central nervous system, kidney, and hematopoietic
system).

Types of Toxicity
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1-Systemic Toxicity :
 Toxicity may occur at multiple sites. This is referred as
systemic toxicity.
 The following are types of systemic toxicity:-
a-Acute Toxicity:
 It occurs almost immediately (hours/days) after an
exposure to single dose or a series of doses received
within a 24 hour period.
 Death is a major concern in cases of acute exposures.
Examples are:
-In 1989, 5,000 people died and 30,000 were
permanently disabled due to exposure to methyl
isocyanate from an industrial accident in Bhopal, India.

Types of Toxicity Cont’d
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b- Subchronic Toxicity (reversible)
 It results from repeated exposure for several weeks or months.
 This is a common human exposure pattern for
 some pharmaceuticals and
 environmental agents.
 Examples are:
-Ingestion of coumadin tablets (blood thinners) for several weeks
as a treatment for venous thrombosis
 can cause internal bleeding.
-Workplace exposure to lead over a period of several weeks can
result in anemia.

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c-Chronic Toxicity (irreversible) :
 It is a cumulative damage to specific organ or system and
 it takes many months or years to become a recognizable
clinical disease.
 This damage is so severe that the organ can no longer function
normally (irreversible) and
 a variety of chronic toxic effects may result.
 Examples are:
-Cirrhosis in alcoholics who have ingested ethanol for
several years
-Chronic bronchitis in long-term cigarette smokers
-Pulmonary fibrosis in coal mineral (black lung disease).

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d-Carcinogenicity:
 Carcinogenicity is a complex multistage process of abnormal
cell growth and differentiation which can lead to cancer.
e-Developmental Toxicity:
 Developmental Toxicity result from toxicant exposure to
either parent before conception or to the mother and her
developing embryo-fetus.
f-Genetic Toxicity:
 Genetic Toxicity results from damage to DNA and altered
genetic expression. This process is known as mutagenesis.
The genetic change is referred to as a mutation and the agent
causing the change as a mutagen.

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2- Organ Specific Toxicity :
Blood and Cardiovascular Toxicity
 Hypoxia due to carbon monoxide binding of hemoglobin
preventing transport of oxygen
Hepatotoxicity
 CCl4 causes lipid peroxidation in liver & lead to liver
necrosis.
Nephrotoxicity
 Mercury & gentamycin are nepherotoxic.
Neurotoxicity
 Organophosphorus compounds (insecticides)………damage
to sensory fibers.

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Respiratory Toxicity
 Aluminum…..emphysema……inflated lung
…….fibrosis(aluminosis).
Dermal Toxicity
 Dermal irritation due to skin exposure to gasoline
 Dermal corrosion due to skin exposure to sodium hydroxide
 Skin cancer due to ingestion of arsenic or skin exposure to UV
light.
Eye Toxicity
 Acids and strong alkalis may cause severe corneal corrosion
 Corticosteroids may cause cataracts.
 Methanol (wood alcohol) may damage the optic nerve leading
to blindness.

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Mechanisms of Toxic Effects
 Adverse effects can occur at the level of the molecule, cell,
organ, or organism
Molecular level: chemical can interact with:
Proteins / Lipids / DNA.
Cellular level: chemical can
• interfere with receptor-ligand binding
• interfere with membrane function
• interfere with cellular energy production
• bind to biomolecules

Variation in toxic responses
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Selective Toxicity
 Means that a chemical produces injury to one kind of living
matter without harming another form of life event though the
two may exist in intimate contact.
 Living matter that is injured is termed the
 uneconomic form (or undesirable) and
 the matter protected is called the
 economic form (or desirable).

Variation …
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 Drugs and other chemical agents used for selective toxic
purposes are selective for one of two reasons.
 The chemical is equitoxic to both economic and uneconomic
cells but
 is accumulated mainly by uneconomic cells or
 It reacts fairly specifically with a cytological or a biochemical
feature
 that is absent from or does not play an important role in the
economic form.

Variation ……
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Species Differences
 Both quantitative and qualitative differences in response to
toxic substances may occur among different species
 Identifying the mechanistic basis for species differences in
response to chemicals is an important part of toxicology
because
 Only through understanding of these differences can
the relevance of animal data to human response be
verified.

Variation ….
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Individual Differences in Response
 Even within a species, large inter individual differences in
response to a chemical can occur
 because of subtle genetic differences.
 Genetic polymorphism
 Hereditary differences in a single gene that occur in more than
1 percent of the population.
 Genetic polymorphism in physiologically important genes
may also be responsible for interindividual differences in
toxic responses.

Variation ….
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 In humans, there is evidence that possessing one mutated copy
of a tumor suppressor gene greatly increases the risk of
developing certain cancers.

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2. chapter principle of toxicology

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