TOX4000.docx - Principles of Toxicology What is Toxicology Study of adverse effects of chemical or physical agents(ex radiation on living organisms What

TOX4000.docx - Principles of Toxicology What is Toxicology...

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Principles of Toxicology What is Toxicology? Study of adverse effects of chemical or physical agents (ex: radiation) on living organisms What is Medical Toxicology? Must consider whether drug is safe or effective --> Determining if and at what doses it is safe Why study Medical Toxicology? Mechanistic Tox o Determining how the agent causes that effect Regulatory Tox o Government agencies that determine whether product is safe & effective Descriptive Tox o Giving an agent, and seeing what effect is (Cause and effect) Risk assessment o Develop new drug --> seen effect and safety in other species --> seen toxicity at high doses o Until you give pill to human, can’t know 100% if it’s safe in humans (differences in species) o Want to do everything you can to minimize the risk o Virtually impossible to say 0% risk until you perform clinical trials Does an agent cause a toxicological response? Causation vs Correlation 1. Strength of association - Relationship between independent and dependent variables 2. Consistency of findings 3. Biological gradient - Dose response 4. Temporal sequence i. Cause before effect --> Exposure before incidence of disease 5. Biological and theoretical plausibility - Mechanism of action 6. Coherence w/ established knowledge - No competing hypothesis 7. Specificity of association - Cause is tightly linked w/ outcome Characteristics of Exposure
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Dose-Response Relationship Examples? Essential nutrients Water Ethanol Too much of anything can be toxic Ultimate Toxicological Dose- Response: LD50 Lethal dose (effective in 50% of people) Causes death in 50% of population
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What determines whether something is a toxicant or not? Depends on dose Therapeutic index o Window between an effective dose & toxic dose o Wider T.I. = greater safety o TI = TD50/ED50 10-fold diff in concentrations Lower the number, the Dose and dose rate o Consider exposure o Accumulation and frequency of exposure Acute Subchronic Chronic o Single dose Rate of elimination Concentration of 2 is toxic Fast rate of elimination means not in window of toxicity for long o Repeated doses A --> very slow metabolism/elimination B --> additive, not all eliminated in a day, same amount eliminated C --> eliminated at the end of the day Descriptive animal toxicology testing Assumptions o Biological response in animals is representative of humans o Exposure to high doses necessary + valid o Results from new genomics technology still requires verification Large screening, still have to validate that gene Acute testing o High dose o Goals Provide estimate of intrinsic toxicity of the substance (LD50) Provide info on target organs & other clinical manifestations Identify species diff and susceptible species Establish reversibility of toxic response
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Provide info that will guide dose selection for longer-term studies Chronic administration o 6 months to 2 years in rodents, 1 year in other species o
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