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  2. 2. Introduction to Toxicology Toxicology Toxicology is the study of the harmful interactions between chemicalsand biological systems. Man, other animals and plants in the modernworld are increasingly being exposed to chemicals of an enormousvariety. These chemicals range from metals and inorganic chemicalsto large complex organic molecules, yet they are potentially toxic.
  3. 3. Historical Aspects Poison: A poison is any substance which has a harmful effect on a livingsystem. Poisons range from a naturally occurring plant alkaloid to asynthetic nerve gas. Primitive man were aware of natural poisons from animals and plantsand indeed used these on his weapons. The word toxicology is derivedfrom toxicon. The study of poisons must have started by 1500 BC.Hipocrates in his writings showed that the ancient Greeks had aprofessional awareness of poisons and the principles of toxicology.So, the origins of toxicology lie in the use of poisons for murder , suicideand political assassination. It is well known for example that Socratescommitted suicide by taking hemlock. Toxicology has now become much more than the use of poisons fornefarious purposes and the production of antidotes to them. One of the worst example of industrial disasters occurred at Bhopal inIndiain1984 where a large amount of methyl isocyanate was leaked.
  4. 4. Types of Toxic Substances Toxic substances fall into several classes in relation to the way manis exposed to them: A) Drugs B) Food additives C) Pesticides D) Industrial chemicals E) Environmental pollutants F) Natural toxins G) Household poisons
  5. 5. Types of Exposure Intentional Ingestion Occupational exposure Environmental exposure Accidental poisoning Intentional poisoning
  6. 6. Selective Toxicity This is a very important concept in toxicology. It encompasses thedifference in susceptibility to toxic effects between species of plants oranimal or between different cells such as between tumor cell andnormal cell. Reasons: Due to ADME difference among different species. Example: DDT Insects are more susceptible to the toxicity of DDT than mammaliansfor two reasons: 1. Insects cuticle allows DDT to penetrate more rapidly thanmammalian skin. 2. Insects has greater surface area , therefore absorbs relatively moreDDT Norbormide ( rodenticide), Penicillin ( antibiotic)
  7. 7. Dose Response Relationship
  8. 8. Assumptions of dose responserelationship The response is proportional to the concentration at the targetsite. The concentration at the target site is related to the dose. The response is causally related to the compoundadministered.
  9. 9. Synergy & Potentiation Synergist Effect: When two substances may cause a greater responsetogether than the sum of the individual responses, is termed assynergist effect. For example: Carbon tetrachloride and alcohol together are more toxicto the liver than expected from the sum of the two individual effects. Potentiation: It is also similar effect except that the two compounds inquestion may have different toxic effects or only one may be toxic. Disulphiram potentiates the toxicity of alcohol.
  10. 10. Approximate LD50 values of somechemical substancesCompound LD 50 mg/kgEthanol 10,000DDT 100Nicotine 1Tetrodotoxin 0.1Dioxin .001Botulinus toxin .00001
  11. 11. Disposition of Toxic Compounds The disposition of toxic compound in a biological system may bedivided into four phases: Absorption Distribution Metabolism Excretion
  12. 12. Absorption of Toxic compounds Before a substance can exert a toxic effect, it must come into contactwith a biological system. The way in which foreign substance may pass through biologicalmembrane 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. 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. 14. Distribution Distribution to different tissues Through blood flow Ionization/non ionization Vd= Dose/Plasma conc Area under the curve
  15. 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. 16. Other Routes Breast milk ( lipid soluble drug, DDT) Sweat Tears Semen Stomach
  17. 17. Metabolism of Foreigncompounds Definition: Drug metabolism also known as xenobiotic metabolism is the biochemicalmodification of pharmaceutical substances or xenobiotics respectively by livingorganisms, usually through specialized enzymatic systems. Drug metabolism oftenconverts lipophilic chemical compounds into more readily excreted hydrophilic products.The rate of metabolism determines the duration and intensity of a drugspharmacological 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.
  18. 18. Drug metabolic pathway
  19. 19. Some exceptions of drugmetabolism 1. producing more toxic compound.( ethylene glycol-----oxalic acid) 2. Decrease solubility (Acetylation ofsulphonamides , crystallization inkidney and tissue necrosis occurs) 3. Decrease excretion
  20. 20. Phases of Metabolism Usually two phases: Phase-1 Phase-11 Phase-1 Reactions: Functional group addition Oxidation Reduction Hydrolysis Hydration Dealkylation Dehalogenation
  21. 21. Cytocrome p 450 Enzyme
  22. 22. Phase-11 Reactions Conjugation occurs in phase-11 reactions. Types- Sulphation Glucoronidation Glutathione conjugation Acetylation Amino acid conjugation Methylation
  23. 23. Toxication Vs Detoxication Figure with explanation:
  24. 24. Factors affecting toxicresponse 1. Species( human beings, cat, rat, cow etc) Example: cat suffers by paracetamol due to deficiency ofglucoronic acid. Another example: DDT 2. Strain of animals: (Strain of mice-metabolism ofbarbiturates) 3. Sexual variation: Male & Female.( dinitrotoluene inducedhepatic tumors occurs mostly in male due to difference inroute of excretion/ biliary excretion if glucoronide conjugate inmales) 4. Genetic factors: (acetylation reaction-slow acetylator/rapidacetylators 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 watermay influence the toxic response to another chemicals. Enzyme induction & enzyme inhibition
  25. 25. Enzyme induction Paracetamol: alcohol or barbituratesincrease the toxicity of paracetamol. Enzyme Inhibition : Flavonoid is apotent inhibitor of cytocrome p450 3a4 Cigarette smoking Alcohol intake affects metabolism ofdrug.
  26. 26.  6. Pathological state: Disease state/influenza/liver disease 7. Human variability: North american indians-reducedalcohol metabolism due to slowmetabolic rate of alcoholdehydrogenase. Japanese population – cytocromep450 2C polymorphism is commonlyseen.