1 Andrew S. Kane, Ph.D. Department of Environmental & Global Health College of Public Health & Health Professions [email protected] Introduction to Toxicology WATER BIOLOGY PHC 6937; Section 4858 “The problem with toxicology is not the practicing toxicologists, but chemists who can detect, precisely, toxicologically insignificant amounts of chemicals” Rene Truhaut, University of Paris (1909-1994) ?Toxicology………… • Is the study of the harmful effects of chemicals and physical agents on living organisms • Examines adverse effects ranging from acute to long-term chronic • Is used to assess the probability of hazards caused by adverse effects • Is used to predict effects on individuals, populations and ecosystems2 Clinical Toxicology: Diagnosis and treatment of poisoning; evaluation of methods of detection and intoxication, mechanism of action in humans (human tox, pharmaceutical tox) and animals (veterinary tox). Integrates toxicology, clinical medicine, clinical biochemistry/pharmacology. Environmental Toxicology: Integrates toxicology with sub-disciplines such as ecology, wildlife and aquatic biology, environmental chemistry. Occupational Toxicology: Combines occupational medicine and occupational hygiene. An interdisciplinary field… Descriptive Toxicology: The science of toxicity testing to provide information for safety evaluation and regulatory requirements. Mechanistic Toxicology: Identification and understanding cellular, biochemical & molecular basis by which chemicals exert toxic effects. Regulatory Toxicology: Determination of risk based on descriptive and mechanistic studies, and developing safety regulations. An interdisciplinary field… Federal agencies: FDA (FDCA- Federal Food, Drug & Cosmetic Act) EPA (FIFRA-Federal Insecticide, Fungicide and Rodenticide Act) EPA (TSCA-Toxic Substance Control Act) PCBs, asbestos, Pb-based paint EPA (CERCLA- Comprehensive Env Response, Compensation, & Liability Act); Superfund DOL (OSHA-Occupational Safety and Health Administration) An interdisciplinary field…3 Environmental Contaminants • Inorganics (e.g., metals, N,P, ions) • Organics (e.g., solvents, hydrocarbons, pesticides, EDCs, detergents) • Particulates • Gases • Biologicals Sources of Environmental Chemicals Air Emissions Industrial Processes Incinerators Gasoline and diesel exhaust Spraying of agricultural chemicals Water Discharges Industrial effluents Sewage effluent Non-Point Sources Surface run-off from roads and agricultural land Leachate from dump-sites Accidental spills Household Chemical Use “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.” Paracelsus 1493-15414 Approximate acute LD50s for selected chemical agents!Relative Toxicity!Haber’s Law For many compounds… The toxic effect of a substance is determined by the product of the concentration and the duration of the exposure • Acute effects do not predict chronic effects • Doses causing chronic effects may not cause acute or sub-acute effects • In human and veterinary medicine, chronic effects of a chemical exposure may manifest themselves as a common disease and go unnoticed • SARs and Kow predictors Acute vs Chronic Toxicity5 Dose: Amount of chemical an organism is exposed to per unit of body weight (mg/kg b.wt) Exposure: Concentration of a chemical in either the air or water through which the exposure occurs Dose vs Exposure Concentrations in liquids or solids: ppt = parts per thousand (g/L; ‰; PSU); easily confused ppm = parts per million (µg/mL = mg/L or µg/g = mg/kg) ppb = parts per billion (ng/mL = µg/L or ng/g = µg/kg) Concentrations in air: mg vapor/m3 =molecular weight (ppm)/24.45 ppm = ug/m3 Exposure concentrations Absorption Distribution to tissues Metabolism Excretion The Dose Makes The Poison6 Primary Routes of Exposure Gastrointestinal Respiratory Dermal (skin) There are tremendous differences in the absorption of compounds depending on the route of exposure due to physiological differences between these organs. Great differences between various species. Cell Membrane Semi-permeable lipid bilayer Pharmacokinetic Parameters Octanol Water Partition Coefficient (Kow) • Ratio of the concentration of a chemical in octanol and in water at equilibrium and at a specified temperature. • Predict solubility • Predict bioaccumulation7 Metabolism Metabolites: conversion products of substances, often mediated by enzyme reactions. Bioactivation (activation): production of metabolites that are more toxic than the parent substance. Detoxication: production of metabolites that are less toxic than the parent substance. Xenobiotics!Accumulation"(storage in body fat, bone)!Phase I metabolism"(bioactivation or inactivation)"oxidation, reduction, hydrolysis!Phase II metabolism"(bioinactivation) conjugation!Extracellular mobilization!!!Biliary excretion!Plasma circulation!Renal excretion!highly lipophilic"metabolically stable!lipophilic! polar! hydrophilic!polar!hydrophilic!Metabolism8 Routes of Elimination Biliary Renal Fecal Respiratory Bioaccumulation • Accumulation of substances, such as pesticides or other organic chemicals in an organism or part of an organism. • Biological sequestering through respiration, diet, epidermal (skin) contact. • Results in the organism having a higher concentration of the substance than the concentration in the surrounding environment. • Amount depends on the rate of uptake, the mode of uptake, how quickly the substance is eliminated, transformation of the substance, the lipid content of the organism, the Kow of the substance, and environmental factors, and other biological and physical factors. • General rule: the more hydrophobic (i.e., lipophilic) a substance is the more likely it is to bioaccumulate in organisms. • Bioconcentration refers only to the uptake of substances into the organism from water alone. Bioaccumlation is the more general term because it includes all means of uptake into the organism. Biomagnification refers to increased concentration going up a food chain. Chemical Interactions Additive: 2+3=5 (parathion + diazinon) Synergistic: 2+2=20 (CCl4 + EtOH) Potentiation: 0+2=10 (isopropanol + CCl4) Antagonism: 4+6=8; 4+0=19 Diagram of quantal!dose-response!relationships!Effective, toxic and lethal