By fagoson.

WELCOME TO THE PRESENTATIONON

TOXICOLOGY

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.

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.

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

Types of Exposure

Intentional Ingestion

Occupational exposure

Environmental exposure

Accidental poisoning

Intentional poisoning

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)

Dose Response Relationship

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.

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.

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

Disposition of Toxic Compounds

The disposition of toxic compound in a biological system

may be divided into four phases:

Absorption

Distribution

Metabolism

Excretion

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)

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)

DistributionDistribution to different tissuesThrough blood flowIonization/non ionizationVd= Dose/Plasma concArea under the curve

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

Other RoutesBreast milk ( lipid soluble drug,

DDT)SweatTearsSemenStomach

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.

Drug metabolic pathway

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

Phases of Metabolism Usually two phases: Phase-1 Phase-11

Phase-1 Reactions: Functional group addition

Oxidation Reduction Hydrolysis Hydration Dealkylation Dehalogenation

Cytocrome p 450 Enzyme

Phase-11 Reactions Conjugation occurs in phase-11 reactions.

Types-

Sulphation Glucoronidation Glutathione conjugation Acetylation Amino acid conjugation Methylation

Toxication Vs DetoxicationFigure with explanation:

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

Enzyme inductionParacetamol: alcohol or

barbiturates increase the toxicity of paracetamol.

Enzyme Inhibition : Flavonoid is a potent inhibitor of cytocrome p450 3a4

Cigarette smokingAlcohol intake affects metabolism

of drug.

6. Pathological state: Disease state/influenza/liver

disease7. 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.