2. Introduction to Toxicology
Toxicology
Toxicology is the study of the harmful interactions between chemicals
and biological systems. Man, other animals and plants in the modern
world are increasingly being exposed to chemicals of an enormous
variety. These chemicals range from metals and inorganic chemicals
to large complex organic molecules, yet they are potentially toxic.
3. Historical Aspects
Poison: A poison is any substance which has a harmful effect on a living
system. Poisons range from a naturally occurring plant alkaloid to a
synthetic nerve gas.
Primitive man were aware of natural poisons from animals and plants
and indeed used these on his weapons. The word toxicology is derived
from toxicon. The study of poisons must have started by 1500 BC.
Hipocrates in his writings showed that the ancient Greeks had a
professional awareness of poisons and the principles of toxicology.
So, the origins of toxicology lie in the use of poisons for murder , suicide
and political assassination. It is well known for example that Socrates
committed suicide by taking hemlock.
Toxicology has now become much more than the use of poisons for
nefarious purposes and the production of antidotes to them.
One of the worst example of industrial disasters occurred at Bhopal in
Indiain1984 where a large amount of methyl isocyanate was leaked.
4. Types of Toxic Substances
Toxic substances fall into several classes in relation to the way man
is exposed to them:
A) Drugs
B) Food additives
C) Pesticides
D) Industrial chemicals
E) Environmental pollutants
F) Natural toxins
G) Household poisons
6. Selective Toxicity
This is a very important concept in toxicology. It encompasses the
difference in susceptibility to toxic effects between species of plants or
animal or between different cells such as between tumor cell and
normal cell.
Reasons: Due to ADME difference among different species.
Example: DDT
Insects are more susceptible to the toxicity of DDT than mammalians
for two reasons:
1. Insects cuticle allows DDT to penetrate more rapidly than
mammalian skin.
2. Insects has greater surface area , therefore absorbs relatively more
DDT
Norbormide ( rodenticide), Penicillin ( antibiotic)
8. Assumptions of dose response
relationship
The response is proportional to the concentration at the target
site.
The concentration at the target site is related to the dose.
The response is causally related to the compound
administered.
9. Synergy & Potentiation
Synergist Effect: When two substances may cause a greater response
together than the sum of the individual responses, is termed as
synergist effect.
For example: Carbon tetrachloride and alcohol together are more toxic
to the liver than expected from the sum of the two individual effects.
Potentiation: It is also similar effect except that the two compounds in
question may have different toxic effects or only one may be toxic.
Disulphiram potentiates the toxicity of alcohol.
10. Approximate LD50 values of some
chemical substances
Compound LD 50 mg/kg
Ethanol 10,000
DDT 100
Nicotine 1
Tetrodotoxin 0.1
Dioxin .001
Botulinus toxin .00001
11. Disposition of Toxic Compounds
The disposition of toxic compound in a biological system may be
divided into four phases:
Absorption
Distribution
Metabolism
Excretion
12. Absorption of Toxic compounds
Before a substance can exert a toxic effect, it must come into contact
with a biological system.
The way in which foreign substance may pass through biological
membrane are as follows:
Filtration through pores ( ethanol, urea)
Passive diffusion ( Ficks law: Rate= KA ( C2-C1)
Active transport ( uniport, symport, antiport)
Facilitated diffusion ( glucose)
Phagocytosis/ Pinocytosis ( uranium dioxide, asbestos)
13. Sites of Absorption
There are three major sites for the absorption of foreign compounds:
1. Skin ( Ex: parathion, lipid soluble substance)
Poor blood supply
Dead cell
Keratin layer
2. Lungs ( Ex: carbon monoxide, methylene chloride, aerosol, lead)
Large surface area
Excellent blood supply
Rapid & efficient absorption
3. GIT ( most of the orally ingested drugs)
Orally ingested drugs
Blood flow and ph ( ionization)
14. Distribution
Distribution to different tissues
Through blood flow
Ionization/non ionization
Vd= Dose/Plasma conc
Area under the curve
15. Excretion
1. Urinary ( kidney) excretion
Filtration, diffusion, active transport
Ex- phenobarbital, aspirin, amphetamine
2. Biliary excretion ( liver)
Active process
Large polar substances
Fecally excreted
Ex- Biphenyl compound, furesemide
3. Excretion by lungs:
Gaseous/vplatile compound
Efficient route of excretion
16. Other Routes
Breast milk ( lipid soluble drug, DDT)
Sweat
Tears
Semen
Stomach
17. Metabolism of Foreign
compounds
Definition:
Drug metabolism also known as xenobiotic metabolism is the biochemical
modification of pharmaceutical substances or xenobiotics respectively by living
organisms, usually through specialized enzymatic systems. Drug metabolism often
converts lipophilic chemical compounds into more readily excreted hydrophilic products.
The rate of metabolism determines the duration and intensity of a drug's
pharmacological action.
Metabolism leads to:
1. Transformation of molecule into a more polar metabolite
2. Possible increase in molecular weight & size
3. Facilitation of excretion
The consequences of the changes are:
1. Half life of the compound is decreased.
2. The exposure time is shortened
3. possibility of accumulation is reduced.
4. a probable change in biological activity
5. a change in the duration of the biological activity.
19. Some exceptions of drug
metabolism
1. producing more toxic compound.
( ethylene glycol-----oxalic acid)
2. Decrease solubility (Acetylation of
sulphonamides , crystallization in
kidney and tissue necrosis occurs)
3. Decrease excretion
20. Phases of Metabolism
Usually two phases:
Phase-1
Phase-11
Phase-1 Reactions: Functional group addition
Oxidation
Reduction
Hydrolysis
Hydration
Dealkylation
Dehalogenation
24. Factors affecting toxic
response
1. Species( human beings, cat, rat, cow etc)
Example: cat suffers by paracetamol due to deficiency of
glucoronic acid. Another example: DDT
2. Strain of animals: (Strain of mice-metabolism of
barbiturates)
3. Sexual variation: Male & Female.( dinitrotoluene induced
hepatic tumors occurs mostly in male due to difference in
route of excretion/ biliary excretion if glucoronide conjugate in
males)
4. Genetic factors: (acetylation reaction-slow acetylator/rapid
acetylators due to mutation in acetyl transferase enzyme).
More example: CYP 2D6/P450 2D6/P450 2C etc.
5. Environmental factors: Chemicals in the diet, air or water
may influence the toxic response to another chemicals.
Enzyme induction & enzyme inhibition
25. Enzyme induction
Paracetamol: alcohol or barbiturates
increase the toxicity of paracetamol.
Enzyme Inhibition : Flavonoid is a
potent inhibitor of cytocrome p450 3a4
Cigarette smoking
Alcohol intake affects metabolism of
drug.
26. 6. Pathological state:
Disease state/influenza/liver disease
7. Human variability:
North american indians-reduced
alcohol metabolism due to slow
metabolic rate of alcohol
dehydrogenase.
Japanese population – cytocrome
p450 2C polymorphism is commonly
seen.
