PHARMACOLOGY -IV

Lecture-1

Dr. Fawad Ali

Principles of Toxicology:
The Study of Poisons
 The study of the adverse effects of a
toxicant on living organisms
• Toxicant (Poison)
– any agent capable of producing an adverse effect in a
biological system

• Adverse effects
– any change from an organism’s normal state
– dependent upon the concentration of active
compound at the target site for a sufficient time.
 What is a Poison?
All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy.

Paracelsus (1493-1541)
 From Exposure to Toxicity
• Exposure: applied dose, from outside
• Absorption: internal dose
• Distribution: target organ dose
• Biological effect:
– Biochemical changes
– Symptoms
– Health effect—obvious, not so obvious;
specific, non-specific
– Late disease?
 Dose and toxicity
• Amount, timing, pattern, duration
• Health effects
– depend on exposure and susceptibility of the
individual or population.
– depend on interaction of genetics, nutrition, social
environment, cumulative exposures.
– one chemical may have a variety of health effects
that occur at different doses, timing, and patterns
of exposure (dose-response)
 Dose
The amount of chemical entering the body
This is usually given as
mg of chemical/kg of body weight = mg/kg
The dose is dependent upon
* The environmental concentration
* The properties of the toxicant
* The frequency of exposure
* The length of exposure
* The exposure pathway
 What is a Response?
The degree and spectra of responses depend upon
the dose and the organism--describe exposure
conditions with description of dose

• 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
 Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.
4

RESPONSE

0-1 Lag phase 2

2-3 Linear Range
4 Maximum Response
0 1 DOSE
DOSE DETERMINES THE BIOLOGICAL RESPONSE
 Measures of Toxicity

• Toxicity of chemicals is determined in the laboratory

• The normal procedure is to expose test animals

– By ingestion, application to the skin, by inhalation, gavage, or
some other method which introduces the material into the
body, or
– By placing the test material in the water or air of the test
animals’ environment
 Measures of Toxicity

• Toxicity is measured as clinical “endpoints” which

include
– Mortality (death)
– Teratogenicity (ability to cause birth defects)
– Carcinogenicity (ability to cause cancer), and,
– Mutagenicity (ability to cause heritible change in the DNA)
• At this time we will discuss 2 measures of mortality –
the LD50 and the LC50
 Measures of Toxicity:
The Median Lethal Dose
LD50
The amount (dose) of a chemical which produces death
in 50% of a population of test animals to which it is
administered by any of a variety of methods

mg/kg
Normally expressed as milligrams of substance per
kilogram of animal body weight
 Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.

LETHAL
RESPONSE

0-1 Lag phase LD50

2-3 Linear Range
4 Maximum Response
DOSE
DOSE DETERMINES THE BIOLOGICAL RESPONSE
 Measures of Toxicity:
The Median Lethal Concentration

LC50
The concentration of a chemical in an environment
(generally air or water) which produces death in 50%
of an exposed population of test animals in a
specified time frame

mg/L
Normally expressed as milligrams of substance per liter
of air or water (or as ppm)
 LD50 Comparison
Chemical LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 0.50
Rattle Snake 0.24
Dioxin (TCDD) 0.001
Botulinum toxin 0.0001
 POISON!!!

• Legally defined term – not just anything you don’t like

• Any pesticide with an LD50 of 50 mg/kg or less

• Labels must reflect this classification

• Label must have the signal word “DANGER” plus the word
“POISON”

• Label also must display the skull and crossbones icon

 Relative toxicity

• Organisms can’t differentiate between “natural” and

“synthetic” chemicals
• “Synthetic” does not mean toxic or poisonous
• “Natural” does not mean safe or even low risk
• Chemicals must be evaluated in their biological
context of behavior in organisms
• Mode of action, not source, is the concern of
toxicologists and informed users of pesticides
 Relative toxicity

• Most herbicides act on biological pathways not present in

humans

• Those approved for use in the Region (much more about

these later!!) have LD50s of 50 mg/kg or greater – they
have intermediate or relatively low toxicity

• Some of the insecticides used are highly toxic

 Relative Toxicity:
Are all substances toxic?

YES!
 All are toxic to some quantifiable degree
 Sugar has an LD50 of 30,000 mg/kg
 The foresters favorite – ethanol has an LD50 of only
13,700 mg/kg
 Even water has a recognized LD50 of slightly greater
than 80,000 mg/kg
 Relative Toxicity:
The Last Word

 Pesticides are chemicals introduced into the environment

to perform a function

 The source of a chemical (synthetic vs. natural) is irrelevant

when considering its toxicity

 Pesticides should be treated with care and proper respect –

but so should household cleaners, gasoline and kerosene,
bleaches, paints and all other chemicals