Principles of Toxicology

Ezra J. Mrema, Awerasia

Vera Ngowi and Bente
Moen
 Objectives

Time allotted: 120 minutes

Upon completion of this topic the students will be able to:

1. To define toxicology and other common terms used in toxicology
2. To differentiate the sub-disciplines of toxicology
3. To describe interactions of chemicals in living organisms
4. To explain the factors affecting toxicity of chemicals
5. To describe the terms used to define toxicity
 What is Toxicology?
• A basic science that deals with the poisons • Every toxicologist performs one or
and their effects both of the two basic functions
• The study of how natural or man-made • To examine the nature of the
poisons cause undesirable effects in living adverse effects produced by
organisms chemical or physical agents and
• To assess the probability of their
• The study of the adverse effects of occurrence
chemical agents on living organisms and
the assessment of the probability of their
occurrence • Ultimate Goal
• To understand toxic properties so
• The relationship between dose and its
that the adverse effects can be
effects on the exposed organism is of high
significance in toxicology
prevented…exposure guidelines
 Questions addressed by Toxicology

• In agriculture, toxicology determines the possible human health

effects from exposure to pesticides

• The effect of animal feed additives, such as growth factors, on people

• In laboratory experiments on animals, toxicology establishes dose-

response relationships

• Toxicology also deals with the way chemicals and waste products
affect the health of an individual
 Sub-disciplines of Toxicology

Clinical toxicology Forensic toxicology

• Clinical toxicologists usually are physicians or • Forensic toxicologists study the

veterinarians interested in the prevention, application of toxicology to the law
diagnosis, and treatment of poisoning cases
• Have specialized training in emergency • Use chemical analysis to determine
medicine and poison management the cause and circumstances of
• Administer antidotes to counter the specific death in a postmortem investigation
toxicity • Determine which chemicals are
• Take other measures to ameliorate the present and responsible in exposure
symptoms and signs and hasten the
elimination of the toxicant from the body
situations of abuse, overdose,
poisoning and death
 Sub-disciplines of Toxicology

Experimental Toxicology Environmental Toxicology

• Experimental toxicologists study the harmful • Environmental toxicologists study the effects of
pollutants on organisms, populations, ecosystems and
effects of chemicals on living animals the biosphere.
(mechanism of action, disposition, analytical
procedures). • Concerned with chemical exposure situations found
•
in our general living environment
• Gather toxicological information from animal • Agricultural application of chemicals (pesticides,
experimentation. These experiments are used growth regulators, fertilizers)
• Household products released into the environment
to establish how much of a chemical would • Industrial discharges into air and waterways
cause illness or death. • Non-point emission sources (e.g. automobiles)
• Concerned with the ultimate environmental fate of chemicals
• Relevant authorities use information from and their impacts upon the biological ecosystem and human
these studies to set regulatory exposure populations
limits.
 Sub-disciplines of Toxicology

Food Toxicology Analytical Toxicology

• Food toxicologists deal with the • Identify the toxicants through

possible deleterious effects of analysis of body fluids, stomach
chemicals in food for human contents, suspected containers
consumption (residue level).

Occupational (Industrial) toxicology Regulatory toxicology

• Intoxication may occur as a result of • Regulatory toxicologists use
occupational exposure to toxicants. scientific data to decide how to
This may result in acute or chronic protect humans and animals from
adverse effects. excessive risk
 Terms used in Toxicology
Harmful or adverse effects Xenobiotic (xenos-strange, bios-life)

• Effects that are damaging to • A foreign chemical substance found within an

either the survival or normal organism that is not normally naturally produced
by or expected to be present within that
function of the individual organism.
• Depends on conc. of active • Drugs such as antibiotics are xenobiotic in humans
compound at the target site for because the human body does not produce them
by itself, nor are they part of a normal food
a sufficient time
• Natural cpds can become xenobiotics if they are
taken up by another organism e.g. natural human
hormones in fish

• Xenobiotics is often used in the context of

pollutants such as dioxins and PCBs
 Terms used in Toxicology

Toxicant Poison
• Any chemical that can injure or kill humans, Poison = Toxicant
animals, or plants; a poison • Inorganic and organic lifeless substances
• Toxicant is used when talking about toxic subst. • Any substance that causes deleterious effects in a
that are produced by or are a by-product of living organism
human-made activities
• Are chemical/physical agents that produce adverse
responses in biological organisms
Toxin
• Toxic substances produced naturally by: Origin of Poisons
• Plants (phytotoxins) • Biologic origin (nicotine, botulinum toxin)
• Animals (zootoxins) • Naturally occurring chemical element (Pb, Cu)
• Microorganisms (bacteriotoxins and • Manufactured chemicals (pesticides, detergents)
mycotoxins) • Results of a physical process (CO)
Terms used in Toxicology

Poison

Father of Modern Toxicology

Areolus Phillipus Theophrastus
Bombastus von Hohenstein
Paracelsus 1493-1564

ALL SUBSTANCES ARE POISONS, THERE IS NONE

WHICH IS NOT A POISON. THE RIGHT DOSE AND
TIMING DIFFERENTIATES A POISON FROM A REMEDY
Modification of Paracelcus
 Terms used in Toxicology

An Individual
View
“The sensitivity of the individual
differentiates a poison from a
remedy. The fundamental principle
of toxicology is the individual dose
response curve.”

S. G. Gilbert (1997)
 Class Task

When salt or drinking water considered a poison?

 Terms used in Toxicology

Toxicity
• The adverse effects that a chemical may produce
How Does Toxicity Develop?
• The degree to which a substance is poisonous or • Before toxicity can develop, a substance must come
can cause injury into contact with a body surface such as skin, eye or
mucosa of the digestive or respiratory tract
• The ability of the chemical to cause injury, illness • The dose of the chemical, or the amount one comes
and death into contact with, is important when discussing how
“toxic” a substance can be.
• The toxicity depends on:
• Dose
• Duration Selective toxicity
• Route of exposure A chemical will produce injury to one kind of living
• Shape and structure of the chemical matter without harming another form of life, even
• Individual human factors though the two may exist close together
 Terms used in Toxicology
Toxicity: Dose Toxicity: Duration
• Toxicity depends on the dose (the amount your • Acute exposure = short term exposure
body takes in due to either acute or chronic • Acute toxicity shows up more quickly and
exposure)
can be fatal
• Acute exposure occurs over a very short period of
time, usually 24 hours • Children are more sensitive to toxic
• Chronic exposures occur over a long periods of substances
time, (weeks, months or years) • For many substances the acute toxic effects
• The amount of exposure and the type of toxin will from single exposure (one time contact with
determine the toxic effect it) may be quite different from that of
• The higher the toxicity, the more harmful or repeated exposure
dangerous the chemical is
Very Toxic Chemicals An example is alcohol – acute effect (drunk) or
Dose : a small amount can make you ill even getting into a coma
•
 Terms used in Toxicology
Toxicity: Duration cont. Toxicity: Duration cont.
• Chronic exposure = long term exposure
Immediate Toxicity
• Chronic toxicity shows up after a long period of
time
• Develops rapidly after a single
• People can appear healthy despite having high
administration of a substance
levels of poisonous substances such as pesticides
in their blood
Delayed Toxicity
• Chronic poisoning is much more complex and its
signs are difficult to see and can develop after a • Toxic effects occur after the lapse
long time, repeated or continuous exposure to of some period of time
small amount of a substance
In the alcohol example, chronic effects are liver cells
• Carcinogenic effects have long
dying (cirrhosis) or dementia in old age latency (up to 30 years)
 Terms used in Toxicology
Toxicity: Duration cont. Toxicity: Duration
• Chronic exposure = long term exposure
Immediate Toxicity
• Chronic toxicity shows up after a long period of
time
• Develops rapidly after a single
• People can appear healthy despite having high
administration of a substance
levels of poisonous substances such as pesticides
in their blood
Delayed Toxicity
• Chronic poisoning is much more complex and its
signs are difficult to see and can develop after a • Toxic effects occur after the lapse
long time, repeated or continuous exposure to of some period of time
small amount of a substance
In the alcohol example, chronic effects are liver cells
• Carcinogenic effects have long
dying (cirrhosis) or dementia in old age latency (up to 30 years)
 Terms used in Toxicology
Toxicity: Route of exposure Toxicity: Route of exposure cont.
EXPOSURE Acute Exposure
• The actual contact of the chemical substance • A single exposure lasting less than 24 hours.
with the biological organism
Sub-acute Exposure
• Routes and Sites of Exposure • Repeated exposure lasting 1 month or less.
• Ingestion (GI – food and water)
• Inhalation (Lungs - air)
Sub-chronic Exposure
• Dermal/Topical (Skin)
• Injection (intravenous, intramuscular, • Repeated exposure lasting from 1 month to 3
intraperitoneal…) months.

• Typical Effectiveness of Route of Exposure Chronic Exposure

• i.v. > inhale > i.p. > i.m. > ingest > topical • Repeated exposure lasting more than 3
months (over months or years).
 Terms used in Toxicology
Toxicity: Route of exposure cont.
Acute Exposure Acute Poisoning
• A single exposure lasting less than 24 hours. • The body is exposed to the toxic substance
in a single high dose
Sub-acute Exposure • Symptoms of poisoning develop in close
• Repeated exposure lasting 1 month or less. relation to the exposure (within hours or
days).
Sub-chronic Exposure
• Repeated exposure lasting from 1 month to 3
Chronic Poisoning
months.
• The body is exposed repeatedly to toxic
Chronic Exposure
substance in low dose during a long period
• Repeated exposure lasting more than 3 months • Symptoms of poisoning are appeared after
(over months or years). a long period (months or years)
 Class Task

Differentiate between Exposure and Poisoning

 Interactions of chemicals
Additive Synergistic
• Chemicals with the same toxicity (i.e.,
• Chemicals with the same same target organ) that, when combined,
toxicity combine to give an cause a greater than additive effect i.e.
additive effect i.e. the • The combined effect of two chemicals are
combined effect of 2 chemicals much greater than the sum (2+2=20)
is equal to the sum of the • CCl4 and ethanol are hepatotoxic alone but
effects of each (2+3=5) when given together produce much more
liver injury than the mathematical sum of
• This is the most commonly their individual effects.
• Smoking and asbestos exposure is another
observed effect when 2 example.
chemicals are given together • Cocaine use with alcohol use is a third
example.
 Interactions of chemicals
Potentiation Antagonism

• Occurs when one compound does • Occurs when two chemicals

not have a toxic effect on a certain administered together interfere
organ or system but when added to with each other’s action.
another chemical makes that
chemical much more toxic.
• CCl4 is hepatotoxic, isopropanol is • Antagonistic interactions are
not hepatotoxic, when given very often desirable in toxicology
together the effect of CCl4 is more and are the basis of many
than expected (0 + 2 = 10). antidotes. (2 + (-2) = 0).
 Types of Antagonism
Functional antagonism Dispositional antagonism

Occurs when 2 chemicals counterbalance Occurs when the disposition of a chemical is

each other by producing opposite effects on altered so that the conc. and/or duration of the
the same physiological function chemical at the target organ are diminished. Ex.
metabolism is increased – Excretion is
increased, therefore half-life is decreased

Receptor antagonism
Chemical antagonism Occurs when 2 chemicals that bind to the same
receptor produce less of an effect when given
A chemical reaction between 2 compounds together than the addition of their separate
that produce a less toxic product. Ex. = a parts. Receptor antagonists are often called
chelator and a metal. blockers
Interactions of chemicals
 Terms used in Toxicology
Median lethal concentration (LC50
Median lethal dose (LD50)
The amount or dose of a The concentration of a chemical
chemical that produces that produces death in 50% of a
death in 50% of a population of test animals to
population of test animals which it is exposed.
to which it is administered
Expressed as mg of chemical per
by any of a variety of
methods
m3, l, g (kg) of the medium (i.e.
air, water, soil…, respectively)
Expressed as milligrams of
chemical per kilogram of
animal body weight [i.e. mg/m3, mg/l, mg/g(kg),
(mg/kg) respectively]
 Terms used in Toxicology
Effective dosage (ED50)
Therapeutic index (TI)
• Effective dosage for 50% of a A quantitative measurement of relative
population of test animals to which it safety of the drug
is administered by any of a variety of • A ratio of LD50 or TD50 to ED50
methods TI = LD50/ED50
or
Toxic dosage (TD50) TI = TD50/ED50
• Toxic dosage for 50% of a population • The larger value means the margin of
of test animals to which it is safety between the ED and TD is greater
administered by any of a variety of • Thus the larger the value means the safer
methods is the drug
 Comparison of Toxicants
Chemical substance 2 LD50 mg/kg b.w.
Ethyl alcohol 10,000.0
Sodium chloride 4,000.0
Morphin 900.0
Dithane M-45 10,700.0
Decis 2.5 EC 620.0
Temik 10 G 0.9
Nicotine 1.0
Aflatoxin B1 7.2
WX (chemical warfare) 0.015
Dioxin 0.001
Tityustoxin 0.009
Tetanus toxin 0.000002
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 Classification of chemical substances based on
toxicity
Toxicity class LD50 mg/kg b.w. Probable lethal oral dose for
humans

Super toxic <5 a taste (less than 7

drops)

Extremely toxic 5-50 between 7 drops and

teaspoonful

Very toxic 50-500 between teaspoonful

and ounce (1/3 dl)

Moderately toxic 0.5-5 (g/kg) a glass

Slightly toxic 5-15 (g/kg) 0.5-1 liter
Practical nontoxic >15 (g/kg) >1 liter
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 Terms used in Toxicology
Reversible/Irreversible Toxic Effects
Local Adverse Effects
The site of action takes places at the point
of contact • Some toxic effects are
• The site:
• skin reversible, and others are
• mucous membrane of the eyes,
nose, mouth, throat
irreversible
• along the respiratory or
gastrointestinal system
• Level of tissue injury
• Liver has high regenerative
Systemic adverse effects
• Requires absorption and distribution to a ability (most are reversible)
distant site
• Most chemical substances can produce • Central nervous system have
systemic effects
• Target organs:
differentiated cells (largely
CNS, circulatory system, blood and irreversible)
hematopoietic system, liver or GI, kidney,
lung • Carcinogenic and teratogenic
 HUMAN CARCINOGEN CLASSIFICATION BY
USEP AND IARC

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