Lecture 3_Toxicology_Sept 3_v2 - Introduction to Toxicology...

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Unformatted text preview: Introduction to Toxicology Christine Skibola, Ph.D. September 3, 2009 What is Toxicology? What is Toxicology? The study of the adverse effects of chemicals or physical agents on living organisms “Great-great-great grandfather of toxicology” •A Treatise of General Toxicology •Demonstrated target organ specificity Mathieu Joseph Bonaventure Orfila 20th century toxicology 20th century toxicology Discovery of DNA (the molecule of life) and various biochemicals that maintain body functions Toxic effects of xenobiotics on organs and cells are now studied at the molecular level All toxic effects are caused by changes in specific cellular molecules and biochemicals toxicants substances that cause adverse biological effects of any nature toxins specific proteins produced by living organisms poisons produce immediate death or illness when experienced in very small amounts toxic substances materials that have toxic properties xenobiotics foreign substances taken into the body may produce beneficial or toxic effects systemic affect entire body or many organs target organ specificity affect specific sites Basic Toxicology Terminology Basic Toxicology Terminology What is dose­response? What is dose­response? A correlation between an exposure and the spectrum of induced effects The D­R relationship is based on observed data from animal, human clinical or cell­based studies This relationship may be used to establish: Causal associations between toxins and biological effects The lowest dose needed to produce a biological effect Rate of accumulation of harmful effects Within a population the majority of Within a population the majority of responses to a toxicant or drug are similar The dose­response relationship The dose­response relationship Slope=potency or effect Threshold=highest dose that no toxic effect occurs The dose­response curve The dose­response curve Threshold dose = NOAEL (no observed adverse effect level) LOAEL = lowest observed adverse effect level For carcinogens, no safe level of exposure exists, since any exposure could result in cancer lowest dose that an effect is observed highest non­zero dose that no effect is observed) A common dose estimate for acute toxicity is A common dose estimate for acute toxicity is the LD50 Effective Dose Effective Dose Toxic Dose Toxic Dose Knowledge of the ED and TD aides the toxicologist and Knowledge of the ED and TD aides the toxicologist and clinician in determining the relative safety of pharmaceuticals Toxicity is complex with many Toxicity is complex with many influencing factors Xenobiotics cause many types of toxicity toxic without being metabolized toxic when metabolized Toxicity can result from adverse cellular, biochemical, or macromolecular changes Factors influencing toxicity – exposure route Factors influencing toxicity – exposure route Ingestion Inhalation Dermal contact Factors influencing toxicity (cont’d) Factors influencing toxicity (cont’d) Chemical interactions Factors influencing toxicity (cont’d) Factors influencing toxicity (cont’d) Individual susceptibility Age Exercise and Physical Stress Health Status Genetic make­up Genetic make­up (genotype) can influence: Genetic make­up (genotype) can influence: Exposure to environmental risk factors Susceptibility to environmental risk factors Gene­environment interaction Factors influencing toxicity (cont’d) Factors influencing toxicity (cont’d) Absorption nearly all alcohols are readily absorbed when ingested; virtually no absorption for most polymers rates and extent of absorption may vary depending on the form of the chemical and the route of exposure Ethanol ­ readily absorbed from GI tract, poorly absorbed through skin organic mercury ­ readily absorbed from GI tract; inorganic lead sulfate is not Metabolism (Biotransformation) Metabolism (Biotransformation) Detoxification Bioactivation Distribution Distribution The distribution of xenobiotics determines the sites where toxicity occurs Blood Lymph Lipid solubility can readily penetrate cell membranes Many toxicants are stored in the body Fat tissue, liver, kidney, and bone ­ most common storage depots Excretion Excretion amount that amount reaches the human envelope human amount that passes amount available to amount through the human interact with envelope vulnerable tissues envelope vulnerable Knowledge of toxicity is primarily Knowledge of toxicity is primarily obtained by: experimental studies using animals studies using cells (human, animal, plant) human studies Epidemiology ­the study and observation of people exposed to xenobiotics in the normal course of their lives or occupations or through accidental exposures Clinical trials ­ administration of chemicals to humans with careful clinical observations and laboratory measurements Exposure of the public to inadequately tested drugs or environmental agents has resulted in several notable disasters Thalidomide Diethylstilbestrol (DES) DES ­ a human teratogen, mutagen DES ­ a human teratogen, mutagen and carcinogen Rubin, 2007, Obstet Gynecol Surv. Cervical clear cell adenocarcinoma Main U.S. regulatory agencies Main U.S. regulatory agencies Food and Drug Administration Environmental Protection Agency pharmaceuticals, food additives, and medical devices agricultural and industrial chemicals released to environment toxins present in consumer products shipment of toxic chemicals Consumer Product Safety Commission Department of Transportation Occupational Safety and Health Administration exposure to chemicals in the workplace Toxicity testing Toxicity testing Much of the info used to estimate toxicity of chemicals or drugs comes from bioassays in animals Short lifespan in rodents makes testing practical Tiered process of standardized tox studies Acute toxicity testing­ LD50 Subchronic rodent bioassay Chronic rodent bioassay Standardized animal toxicity tests Standardized animal toxicity tests Reproductive Toxicity Developmental Toxicity Dermal Toxicity Ocular Toxicity Neurotoxicity Genetic Toxicity General principles of toxicity testing General principles of toxicity testing with animals Routes of exposure to animals should be similar to those for humans Doses should exceed those that humans will be exposed to by at least an adequate safety margin (uncertainty factor) Several groups of animals, each at different dose levels, should be used to establish dose­response and dose­ effect relationships. If practical, more than one species should be tested Toxicity testing in rodents Toxicity testing in rodents Acute Toxicity Test Yields LD50 (or LC50)—doses acutely lethal to 50% of test animals Subchronic rodent bioassay Chronic toxicity testing Chronic toxicity testing Important limitations of animal Important limitations of animal toxicology studies Difficulties in extrapolating across species to humans Difficulties in extrapolating results to lower concentrations to which humans are usually exposed Do not take into account variation in human living conditions (eg, nutrition, temperature, other exposures) or genetic variation Very limited information on interactions between chemicals Clinical studies Clinical studies Phase 1 ­ 20­80 patients Phase 2 – drug tested on several hundred patients pharmacokinetics and pharmacological effects metabolism mechanism of action Phase 3 ­ hundreds to thousands of patients short­term side effects risks effectiveness for treatment of a particular disease or condition additional information gathered on effectiveness and safety evaluate overall benefit­risk relationship of the drug provide basis for precautionary information that accompanies the drug Cohort Relative risk (RR) – ratio expressing occurrence of disease in an exposed vs. unexposed population Epidemiology studies Epidemiology studies Case­control Odds ratio (OR) – ratio of risk of disease in an exposed vs. unexposed population Cross­sectional­ prevalence of a disease or clinical outcome in 1 or more exposed groups is studied Ecological – the incidence of disease is 1 geographic location is compared to an other location Standardized mortality ratio (SMR) – the RR of death based on a comparison of exposed vs. unexposed population Schmidt, CW, EHP; 114:8, 2009 NIH Chemical Genomics Center, Rockville, MD TOX21 TOX New Dimensions of Toxicity Testing ...
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