Basic concept of toxicology_introduction.pptx

Basic concept of toxicology

1. Basic Concepts in Toxicology PHA-3216: Toxicology

2. Toxicology Toxicology is the study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem , including the prevention and reduction of such adverse effects. Branches of Toxicology Descriptive toxicology Clinical Toxicology Mechanistic Toxicology Occupational Toxicology Forensic Toxicology Environmental Toxicology Regulatory Toxicology

3. Descriptive Toxicology Descriptive toxicology is concerned with gathering toxicological information from animal experimentation . Focuses on toxicity testing of chemicals , usually on animals and then correlates to human conditions. US Environmental Protection Agency ( EPA ), the Food and Drug Administration ( FDA ) use information from these studies to set regulatory exposure limits . Clinical Toxicology Clinical toxicology refers to health problems caused by or associated with abnormal exposure to chemical substance . Clinical toxicology includes physicians and scientists involved with the understanding of the diagnosis and treatment of poisoning .

4. Mechanistic Toxicology Mechanistic toxicology makes observations on how toxic substances cause their effects . The effects of exposure can depend on a number of factors, including the size of the molecule, the specific tissue type, or cellular components affected. Occupational (industrial) toxicology is concerned with health effects from exposure to chemicals in the workplace . It deals with the clinical study of workers of industries and environment around them. Occupational Toxicology

5. Forensic Toxicology Forensic toxicology is the application of toxicology to the field of law . Forensic toxicology is a multidisciplinary field involving the detection and interpretation of the presence of drugs and other potentially toxic compounds in bodily tissues and fluids . Environmental Toxicology This deals with the effects of pollutants on the environment (food, water, air, or soil) and their prevention. Its specialties could include ecotoxicology, aquatic toxicology , and others.

6. It deals with administrative functions concerned with the development and interpretation of mandatory toxicology testing programs and controlling the use, distribution, and availability of chemicals used commercially and therapeutically. For example, Food and Drug Administration ( FDA ) regulates drugs, cosmetics, and food additives . Regulatory Toxicology

7. History of Toxicology Ebers Papyrus (circa 1500 B.C.) Contains information pertaining to many recognized poisons Example of poisons: Hemlock (State poison of Greeks) Aconite (a Chinese arrow poison) Opium (used as both a poison and antidote) Metals (arsenic, lead, copper and antimony)

8. Socrates (470-399 B.C.) One of the greatest ancient philosophers was executed by a solution of hemlock plant (Conium maculatum). Poison Hemlock contains the alkaloid coniine. Hippocrates (460-370 B.C.) Added a number of poisons and clinical toxicology principles pertaining to bioavailability in therapy and overdose. Cleopatra (69-30 B.C.) is often best known for her dramatic suicide, allegedly from the fatal bite of a venomous snake .

9. Dioscorides (40-90 AD) A Greek physician in the court of the roman emperor Nero, made the first attempt at a classification of poisons, which was accompanied by descriptions and drawings. Paracelsus (1493- 1541 AD) Formulated many revolutionary views that remain an integral part of structure of toxicology today. Responsible for the most famous saying in all of toxicology: All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy .

10. Routes of Toxicity Ingestion The toxin is taken in in the body through the oral route . Toxin enters the blood through walls of gastrointestinal tract. Chemical properties of toxin will determine whether it will be absorbed in stomach acid or the nearly neutral intestine. Inhalation Many toxins as gases and aerosols are inhaled and enter the blood through lungs. Absorption and excretion of the toxic gases and vapours depend primarily on their aqueous solubilities.

11. Topical The toxins enters through the skin and moves into the bloodstream. Epidermis largely limits absorption. Parenteral administration Routes of Toxicity

12. Toxicodynamics It deals with the study of biochemical and physiological effects of toxic agents and their mechanism of action. Toxicokinetics It deals with the study of absorption, distribution, metabolism, and excretion of toxicants in the body.

13. Step 1 Delivery Step 2 Interaction with target molecule Step 3 Cellular dysfunction, injury Step 4 Disrepair Absorption Distribution Metabolism Excretion Cell regulation (signaling) Cell maintenance Dysregulation of gene expression Dysregulation of ongoing function Impaired internal maintenance Impaired external maintenance Molecular Cellular Tissue Protein DNA Lipid Apoptosis Proliferation

14. Step 1: Delivery from the site of exposure to the target Exposure site Skin, GI tract. Respiratory tract, injection Toxicant Delivery Absorption Distribution towards the target Reabsorption Toxication Detoxication Excretion Distribution away from target Presystemic elimination

15. Ultimate toxicant is the chemical that reacts with endogenous target molecule (e.g. receptor, enzyme, DNA, protein, lipid) or critically alters the biological environment, initiating structural and/or functional alterations that result in toxicity. The accumulation of ultimate toxicant at its target is- Facilitated by Inhibited by Absorption Presystemic elimination Distribution towards the site of action Distribution away from the site of action Reabsorption Excretion Toxication Detoxification

16. Absorption versus Presystemic Elimination Absorption: transfer of a chemical from the site of exposure into the systemic circulation. Presystemic Elimination: the GI mucosa and the liver may eliminate a significant fraction of a toxic agent during its passage through tissues, decreasing its systemic availability.

17. Distribution to and away from the target Mechanisms facilitating distribution to a target: Porosity of the capillary endothelium Specialized membrane transport Reversible intracellular binding Mechanisms opposing distribution to a target Binding to plasma proteins Specialized barriers Distribution to storage sites Export from cells

18. Excretion vs Reabsorption Excretion: Physical removal of xenobiotics from the blood and their return to the external environment. Reabsorption: diffusion of toxicants in the renal tubules and the GI tract across the tubular cells and intestinal mucosa back into the circulation.

19. Toxication versus Detoxication Toxication: Biotransformation of xenobiotics to harmful products, also called activation. Detoxication: Biotransformation which eliminate the ultimate toxicant or prevent its formation.

20. Step 2: Reaction of the ultimate toxicant with the target molecule Target molecule Ultimate toxicant Reaction types: Noncovalent binding Covalent bonding Hydrogen abstraction Electron transfer Enzymatic reaction Attributes of target: Reactivity Accessibility Critical function Outcomes: Dysfunction Destruction Neoantigen formation

21. Step 3: Toxic alteration of cellular maintenance Cell regulation Inappropriate- Cell division: neoplasia, teratogenesis Apoptosis: tissue involution, teratogenesis Protein synthesis: peroxisome proliferation Inappropriate neuromuscular activity Tremor, convulsion, spasm, cardiac arrhythmia Narcosis, paralysis, paresthesia Dysregulation of gene expression Dysregulation of ongoing cell activity

22. Step 3: Toxic alteration of cellular maintenance Cell maintenance Inappropriate- ATP synthesis Ca 2+ regulation Protein synthesis Microtubular function Membrane function Impaired function of integrated systems E.g. hemostasis→ bleeding Impaired internal maintenance Impaired external maintenance

23. Step 4: Disrepair Repair of proteins : enzymatic reduction Repair of lipids : reductants and reductase Repair of DNA : Direct repair Excision repair Recombinational repair

24. Cellular repair In most cases injured cells die with the survivors dividing to replace the lost cells. An exception: nerve tissues - A strategy in peripheral neurons - Axonal damage repairs require macrophages and Schwann cells (NGF)

25. Tissue Repair Apoptosis: an active deletion of damaged cells Proliferation: regeneration of tissue Replacement of lost cells by mitosis Replacement of extracellular matrix

26. Toxicity resulting from Disrepair Tissue necrosis Fibrosis-excessive disposition of an extracellular matrix of abnormal composition. Carcinogenesis : Failure of DNA repair : mutation, the initiating event in carcinogenesis Failure of apoptosis : promotion of mutation and clonal growth Failure to terminate proliferation : promotion of mutation, protooncogene expression, and clonal growth Nongenotoxic carcinogen : promoters of mitosis and inhibitors of apoptosis