Principles of toxicology 1.pptx

Y

1. BASIC PRINCIPLES OF TOXICOLOGY P. E. Owusu Agyei

2. Objectives Definitions Toxicological studies Discuss the factors that affect and/or modify the actions of poisons (Dose-response correlations) Understand the toxicokinetics and toxicodynamics of toxicants.

3. Introduction Toxicology is the science of the adverse effects of chemicals, including drugs, on living organisms. descriptive toxicology mechanistic toxicology regulatory toxicology

4. Adverse effects Undesired deleterious or harmful effect in the organism caused by a medication or an intervention. Toxicant (Poison) any agent capable of producing a deleterious response in a biological system

5. So Toxicology is the study of how toxicants : enter the organism Influence the organism are eliminated from (leave) the organism All substances are toxic if taken in the wrong quantities

6. Physiological/ pharmacological classification of poisons Corrosive: strong mineral/organic acids; strong alkalis Irritant: metallic e.g. mercury vegetable e.g. castor oil gas e.g. ammonia Hypnotic/narcotic: e.g. barbiturate, morphine Deliriant / convulsant e.g. cocaine, strychnine Paralytic/anti-cholinesterase e.g. nicotine Abortifacient e.g. ergot, quinine Poisonous gases e.g. carbon monoxide, prussic acid Miscellaneous e.g. botulinum

7. Types of toxic reactions Pharmacological, Pathological, or Genotoxic Local versus Systemic Toxicity Reversible and Irreversible Toxic Effects Delayed Toxicity Idiosyncratic Reactions Interactions between chemicals

8. Types of toxic reactions (by Toxidroms) Sympathomimetics: upregulate sympathetic NS Anticholinergic Cholinergic Sedative/hypnotic opioid

9. Toxicokinetics & Toxicodynamics Toxicokinetics (Determines the no. of molecules that can reach the receptors) Uptake Transport Metabolism & transformation Sequestration Excretion Toxicodynamics (Determines the no. of receptors that can interact with toxicants) Binding Interaction Induction of toxic effects

10. Toxicodynamics Relationship between dose and intended pharmacological response and /or resultant toxicological response. Eg. Acetaminophen and ethanol

11. Target Sites: Mechanisms of Action Adverse effects can occur at the level of the molecule, cell, organ, or organism Molecularly, chemical can interact with Proteins Lipids DNA Cellularly, chemicals can interfere with receptor-ligand binding interfere with membrane function interfere with cellular energy production bind to biomolecules perturb homeostasis (Ca + )

12. Dose The amount of chemical entering the body mg/kg and/reaching the site of action. The environmental concentration The properties of the toxicant The frequency of exposure The length of exposure The exposure pathway

13. What is a Response? 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

14. Dose-Response Relationship: As the dose of a toxicant increases, so does the response. 2 3 4 1 DOSE RESPONSE 0-1 NOAEL 2-3 Linear Range 4 Maximum Response DOSE DETERMINES THE BIOLOGICAL RESPONSE

15. LD 50 Quantal responses can be treated as gradient when data from a population is used. If Mortality is the response, the dose that is lethal to 50% of the population LD 50 can be generated from the curve

16. LD 50 Comparison Chemical LD 50 (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 venom 0.24 Dioxin 0.001 Botulinum toxin 0.0001

17. Toxicokinetics Time course of blood and tissue concentration profile. Toxicokinetics and factors affecting/modifying action of poisons include: Dose/concentration age route of absorption/administration rate of administration state of poison health tolerance idiosyncrasy etc.

18. Exposure: Pathways Routes and Sites of Exposure Ingestion (Gastrointestinal Tract) Inhalation (Lungs) Dermal/Topical (Skin) Injection intravenous, intramuscular, intraperitoneal Typical Effectiveness by Route of Exposure iv > inhale > ip > im > ingest > topical

19. Exposure: Duration Acute < 24hr usually 1 exposure Subacute 1 month repeated doses Subchronic 1-3mo repeated doses Chronic > 3mo repeated doses Over time, the amount of chemical in the body can build up, it can redistribute, or it can overwhelm repair and removal mechanisms

20. Absorption, Distribution, Metabolism, and Excretion Once a living organism has been exposed to a toxicant, the compound must get into the body and to its target site in an active form in order to cause an adverse effect. The body has defenses: Membrane barriers passive and facilitated diffusion, active transport Biotransformation enzymes, antioxidants Elimination mechanisms

21. Absorption: Inhalation-- readily absorb gases into the blood stream via the alveoli. (Large alveolar surface, high blood flow, and proximity of blood to alveolar air) Ingestion-- absorption through GI tract stomach (acids), small intestine (long contact time, large surface area--villi; bases and transporters for others) 1st Pass Effect (liver can modify) Dermal-- absorption through epidermis (stratum corneum), then dermis; site and condition of skin

22. Uptake of Toxicants Passive diffusion Facilitated transport: Calmodulin for facilitated transport of Ca Active transport: P-glycoprotein pump for xenobiotics Ca-pump (Ca 2+ -ATPase) Pinocytosis: Airborne toxicants across alveoli cells Carrageenan across intestine

23. Uptake by Passive diffusion Uncharged molecules may diffuse along conc. gradient until equilibrium is reached Not substrate specific Small molecules of < 0.4 nm (e.g. CO, N 2 0) can move through cell pores Lipophilic chemicals may diffuse through the lipid bilayer

24. Distribution: Blood carries the agent to and from its site of action, storage depots, organs of transformation, and organs of elimination Rate of distribution (rapid) dependent upon blood flow characteristics of toxicant (affinity for the tissue, and the partition coefficient) Distribution may change over time

25. Distribution: Storage and Binding Storage in Adipose tissue -Very lipophylic compounds (DDT) will store in fat. Storage in Bone -Chemicals analogous to Calcium: Fluoride, Lead, Strontium Binding to Plasma proteins - can displace endogenous compounds.

26. Target Organs: Not all organs are affected equally greater susceptibility of the target organ higher concentration of active compound Liver: high blood flow, oxidative reactions Kidney: high blood flow, concentrates chemicals Lung: high blood flow, site of exposure

27. Neurons: oxygen dependent, irreversible damage Myocardium: oxygen dependent Bone marrow, intestinal mucosa -rapid divide

28. Deposition Toxicant Target organs Pb Bone, teeth, brain Cd Kidney, bone, gonad OC, PCB Adipose tissue, milk OP Nervous tissue Aflatoxin Liver

29. Metabolism & Transformation Principle of detoxification: Convert toxicants into more water soluble form (more polar & hydrophilic) Dissolve in aqueous/gas phases and eliminate by excretion (urine/sweat) or exhalation Sequestrate in inactive tissues ( e.g bone, fat)

30. Metabolism: The process by which the administered chemical (parent compounds) are modified by the organism by enzymatic reactions. 1 o objective--make chemical agents more water soluble and easier to excrete decrease lipid solubility → decrease amount at target site increase ionization → increase excretion rate → decrease toxicity

31. Biotransformation (Metabolism) Can drastically affect the rate of clearance of compounds Can occur at any point during the compound’s journey from absorption to excretion

32. Biotransformation Key organs in biotransformation LIVER (high) Lung, Kidney, Intestine (medium) Others (low) Biotransformation Pathways Phase I--make the toxicant more water soluble Phase II--Links with a soluble endogenous agent (conjugation)

33. Excretion: Urinary excretion water soluble products are filtered out of the blood by the kidney and excreted into the urine Exhalation Gas (e.g. ammonia) and Volatile compounds are exhaled by breathing

34. Excretion Biliary Excretion via Fecal Excretion Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces. Milk; Sweat; Saliva Lipid soluble and non- ionised toxicants may be reabsorbed (systemic toxicity)

35. Sequestration Animals may store toxicants in inert tissues (e.g. bone, fat, hair, nail) to reduce toxicity Lipophilic toxicants (e.g. DDT) may be stored in milk at high concentration and passed to the young

36. Individual Susceptibility Genetics: species, strain variation, interindividual variations (still can extrapolate between mammals - similar biological mechanisms) Gender (gasoline nephrotoxic in male mice only) Age -young (old too) underdeveloped excretory mechanisms underdeveloped biotransformation enzymes underdeveloped blood-brain barrier

37. Individual Susceptibility Age -old Nutritional status Health conditions Previous or Concurrent Exposures additive --antagonistic synergistic

38. Adverse drug reactions D ose-related (Augmented) N on-dose-related (Bizarre), D ose-related and time-related (Chronic), T ime-related (Delayed), W ithdrawal (End of use), **Failure of therapy (Failure).

39. Adverse drug reactions - Presentation Type I: anaphylaxis Penicillins Cephalosporins Sulphonamides Type II: Cytotoxic Haemolytic anaemia - sulphonamides, penicillin, quinidine, methyldopa Agranulocytosis - carbimazole , clozapine Thrombocytopenia - quinidine, heparin

40. Type III: Immune complex mediated Penicillins Sulphonamides thiazides Type IV: T-cell mediated Penicillins Cepholosporins Local anaesthetics phenytoin

41. Toxicant specificity/generalization Mercury readily covalent bond with sulfur Chelation with dimercaprol and penicillamine Along fluid and electrolyte ballancew Aspirin: acid-base disturbances requires urinary alkalinization, or haemodialysis botulinum toxin: neurotoxin ASAP with antibiotics