100%(2)2 out of 2 people found this document helpful
This preview shows page 1 - 5 out of 37 pages.
Principles of ToxicologyWhat is Toxicology?Study of adverse effects of chemical or physical agents (ex: radiation) on living organismsWhat is Medical Toxicology?Must consider whether drug is safe oreffective --> Determining if and at what doses it is safeWhy study Medical Toxicology?Mechanistic ToxoDetermining howthe agent causes that effectRegulatory ToxoGovernment agencies that determine whether product is safe & effectiveDescriptive ToxoGiving an agent, and seeing what effect is (Cause and effect)Risk assessmentoDevelop new drug --> seen effect and safety in other species --> seen toxicity at high dosesoUntil you give pill to human, can’t know 100% if it’s safe in humans (differences in species)oWant to do everything you can to minimize the riskoVirtually impossible to say 0% risk until you perform clinical trialsDoes an agent cause a toxicological response?Causation vsCorrelation1.Strength of association - Relationship between independent and dependent variables2.Consistency of findings3.Biological gradient - Dose response4.Temporal sequencei.Cause beforeeffect --> Exposure beforeincidence of disease5.Biological and theoretical plausibility - Mechanism of action6.Coherence w/ established knowledge - No competing hypothesis7.Specificity of association - Cause is tightly linked w/ outcomeCharacteristics of Exposure
Dose-Response RelationshipExamples? Essential nutrients Water EthanolToo much of anything can be toxicUltimate Toxicological Dose- Response: LD50Lethal dose (effective in 50% of people)Causes death in 50% of population
What determines whether something is a toxicant or not?Depends on doseTherapeutic indexoWindow between an effective dose & toxic doseoWider T.I. = greater safetyoTI = TD50/ED5010-fold diff in concentrationsLower the number, the Dose and dose rateoConsider exposureoAccumulation and frequency of exposureAcuteSubchronicChronicoSingle doseRate of eliminationConcentration of 2 is toxicFast rate of elimination means not in window of toxicity for longoRepeated dosesA --> very slow metabolism/eliminationB --> additive, not all eliminated in a day, same amount eliminatedC --> eliminated at the end of the dayDescriptive animal toxicology testingAssumptionsoBiological response in animals is representative of humansoExposure to high doses necessary + validoResults from new genomics technology still requires verificationLarge screening, still have to validate that geneAcute testingoHigh doseoGoalsProvide estimate of intrinsic toxicity of the substance (LD50)Provide info on target organs & other clinical manifestationsIdentify species diff and susceptible speciesEstablish reversibility of toxic response
Provide info that will guide dose selection for longer-term studiesChronic administrationo6 months to 2 years in rodents, 1 year in other specieso