L1 Princ of Toxicology DG.pdf

Principles of Toxicity 1. Defining toxicology 2. History of toxicology Lecture 1: Principles of Toxicology...

Principles of Toxicity 1. Defining toxicology 2. History of toxicology Lecture 1: Principles of Toxicology 3. Dose response 4. Evaluating safety Toxicology Toxicology is the study of adverse effects of chemicals on living systems, Recognition, identification, quantification of including: hazards from occupational exposure to chemicals. Mechanisms of action and exposure to chemicals as a cause of acute and Discovery of new drugs and pesticides. chronic illness. Development of standards and regulations to protect humans and the environment from Understanding physiology and adverse effects of chemicals. pharmacology by using toxic agents as chemical probes.  Branches of Toxicology Origins of Toxicology 1. Mechanistic—cellular, biochemical and Earliest humans used animal venoms and molecular mechanisms by which plant extracts for hunting, warfare and chemicals cause toxic responses assassination. 2. Forensic—cause of death, legal aspects 400 BC: Hippocrates compiled a listing of a 3. Clinical—treatments for poisonings and number of poisons and outlined some clinical injuries caused by xenobiotics toxicology principles. 4. Environmental—environmental pollutants, effects on flora and fauna 1493-1541: Paracelsus—physician and 5. Food—adverse effects of processed or philosopher natural food components All substances are poisons; the right dose 6. Regulatory—assigns risk to substances differentiates a poisons from a remedy. of commercial importance. “Dose determines toxicity.” Examples of Toxicological Cases 399 B.C. Socrates, a Greek Philosopher died of Hemlock 1775: Percival Pott found that soot caused poisoning (according to Plato) scrotal cancer in chimney sweeps. Much later Coniine is the active toxic the carcinogens in soot found to be polycyclic ingredient aromatic hydrocarbons. Antagonist for the nicotinic 1972: Rachel Carson/EPA led to ban of acetylcholine receptor, insecticide DDT for environmental and health leading to cessation of concerns neurotransmission, muscular and respiratory coniine collapse and death  Examples of Toxicological Cases April 30th, 1945, Eva Braun, long-time companion of Hitler October 20th, 1740 Charles VI, Holy committed suicide with a Roman Emperor, King of Bohemia, cyanide capsule Hungary, and Croatia died from eating death Inhibitor of cytochrome c cap mushrooms oxidase, part of complex IV Active ingredient is alpha-amanitin that of the electron transport inhibits RNA polymerase inhibiting protein chain and inhibits ATP synthesis leading to hepatocellular lysis, liver production leading to brain failure, kidney failure, coma, respiratory death and heart cessation, failure, and death hypoxia, and death Examples of Toxicological Cases 1932-1968: Minamata disaster—caused by methylmercury toxicity from industrial wastewater from Chisso Corporation in Jan 16th, 1975 Bando Mitsugoro VIII, a famous Minamata City in Japan Japanese Kabuki actor died from eating 4 2265 victims livers of pufferfish Caused neurological syndrome Active toxic ingredient is tetrodotoxin associated with methyl mercury poisoning including ataxia, numbness, Methyl mercury Tetrodotoxin blocks voltage-gated sodium insanity, muscle weakness, hearing channels leading to suppression of and speech loss, birth defects, neurotransmission, numbness, paralysis, coma, death bronchospasms, coma, respiratory Alters neurochemistry and failure, death neurotransmission through multiple mechanisms  Dose-Response Individual dose-response Response of an individual organism to varying doses of a chemical (also called “graded” response because effect is continuous over a dose range) (e.g. 1988, Saddam Hussein used sarin on enzyme activity, blood pressure). Kurds, 1995, Japanese subway sarin Y-axis: % of max. response attack by terrorist group; 2013 Assad uses 100 (linear in middle range) sarin against rebels X-axis: dose (e.g. mg/kg or molar Sarin and VX are an organophosphorus 80 concentration) (plotted as log chemical warfare agents that inhibits % maximal A response base 10) acetylcholinesterase, leading to excess 60 Can derive lethal dose (LD50), acetylcholine and hyperstimulation of 40 toxic dose (TD50), effective dose neurons, resulting in seizures, tremoring, (ED50) values from dose- convulsions, excess salivation, excess B % response 20 response data. tearing, urination, defecation, bronchoconstriction, respiratory failure, 0 Inhibitory concentration (IC50) can also be determined from death 10-1 100 101 102 103 104 dose, mg/kg concentration-response curves. Dose-Response Curves for Beneficial Substances Evaluating Dose-Response Relationships death 100 ED: Effective dose threshold for (therapeutic dose of a drug) 80 toxicity TD: Toxic dose adverse response 50 % ED % response response region of homeostasis 60 TD (dose at which toxicity occurs) LD: Lethal dose response 40 NOAEL LOAEL LD (dose at which death occurs) deficiency toxicity 20 NOAEL: no observed adverse effect level dose LOAEL: lowest observed adverse effect 0 level For substances required for normal physiological function and 10-2 10-1 100 101 102 103 survival, the dose-response curves will be U- or J-shaped. dose (mg/kg) At very low doses, there is an adverse effect (deficiency), which decreases with increasing dose (homeostasis). At very high ED50: dose at which 50% of population therapeutically responds. doses, an adverse response appears from toxicity. (In this example, ED50=1 mg/kg) For example, vitamin A can cause liver toxicity and birth defects TD50: dose at which 50% of population experiences toxicity (TD50=10 mg/kg). at high doses and vitamin A deficiency is lethal. LD50: dose at which 50% of population dies (LD50=100 mg/kg).  Comparing Toxicity of Compounds Example of using TI to compare relative safety of 2 drugs. Therapeutic Index (TI) 100 100 TI = LD50/ED50 80 80 % effect % effect ED ED or TI = TD50/ED50 60 60 40 TD 40 TD TI is the ratio of the doses of the toxic and the desired % reponse % response 20 20 responses. 0 0 TI is used as an index of comparative toxicity of two different 10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 materials; approximate statement of the relative safety of a drug A dose (mg/kg) drug B dose (mg/kg) drug. Drug A: TI = TD50/ED50 = 100/0.01= 10000 The larger the ratio, the greater the relative safety. Drug B: TI = TD50/ED50 = 1/0.01 = 100 Which drug is safer? Disadvantages of Using TI Margin of Safety 100 100 99 % response 99 % response ED LD 80 ED LD 80 A A and B % effect A and B A % effect 60 60 50 % response 50 % response 40 LD 40 LD 20 B % response 20 B 1 % response % response 0 1 % response 10-3 10-2 10-1 100 101 102 103 0 10-3 10-2 10-1 100 101 102 103 dose (mg/kg) dose (mg/kg) Margin of safety can overcome this deficiency by using ED99 for Drug A: ED50 = 2 mg/kg; LD50= 100 mg/kg the desired effect and LD1 for the undesired effect. Drug B: ED50 = 2 mg/kg; LD50= 100 mg/kg Margin of safety = LD1/ED99 Drug A: LD1/ED99 = 10 / 10 = 1 Drugs A and B both have the same TI = 100/2 = 50 Drug B: LD1/ED99 = 0.002 / 10 = 0.0002 Therapeutic index does not take into account the slope Thus, Drug B is much less safe than Drug A. of the dose-response curves.  Toxic Potency Agent LD50 (mg/kg) Ethyl alcohol 10,000 Sodium chloride 4,000 slight BHA/BHT (antioxidants) 2,000 Morphine sulfate 900 moderate Caffeine 200 Nicotine 1 high Curare 0.5 Shellfish toxin 0.01 Extremely high sarin 0.001 (