Concepts in Toxicology

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Define toxicology and toxicity. Discuss different types of toxic responses. Explain how toxicants are classified. Describe the phases of toxicosis. Explain how concomitant exposure influences toxicity. Develop an introductory understanding of toxicity testing.

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Principles of Environmental Toxicology Learning Objectives • Define toxicology and toxicity. • Discuss different types of toxic responses. • Explain how toxicants are classified. Concepts in Toxicology • Describe the phases of toxicosis. • Explain how concomitant exposure influences toxicity. Principles of Environmental Toxicology • Develop an introductory Instructor: Gregory Möller, Ph.D. understanding of toxicity University of Idaho testing. 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Toxicology Definition of Toxicity • The science that deal with the • Toxicity: The degree to which a substance can adverse effects of chemicals on harm humans or animals. living systems. • Toxicity can be acute, subchronic, or chronic. • Classifications. – Descriptive toxicology. • What? – Mechanistic toxicology. • Why? – Analytical toxicology. • How much? 3 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Acute Toxicity Subchronic Toxicity • Involves harmful effects in an organism through • The ability of a toxic substance to cause effects a single or short-term exposure. for more than one year but less than the lifetime of the exposed organism. The Death of Socrates, 1787 Jacques-Louis David (Metropolitan Museum of Art, New York) 5 6 1
Principles of Environmental Toxicology Principles of Environmental Toxicology Specialty Areas in Toxicology Chronic Toxicity • Target Organ/System. • The ability of a substance or mixture of – Neurotoxicology, Genetic Toxicology, substances to cause harmful effects over an Reproductive Toxicology, Immunotoxicology, extended period, usually upon repeated or Endocrine Toxicology. continuous exposure, sometimes lasting for the • Target Species/Systems. entire life of the exposed organism. – Aquatic Toxicology, Environmental Toxicology, Wildlife Toxicology, Veterinary Toxicology. • Selected Responses. – Teratology, Carcinogenesis. 7 8 Principles of Environmental Toxicology Principles of Environmental Toxicology Applied Toxicology Classification of Toxicants • Occupational toxicology. • Target organ. • Clinical toxicology. – Hepatotoxin, neurotoxin. – Toxic induced diseases and antidotes. • Intended use. • Forensic toxicology. – Pesticide, solvent. – Determining causes of death. • Source. • Regulatory toxicology. – Natural, synthetic. – Risk assessment from • Special effect. descriptive tests • Developmental toxicology. – Carcinogen, mutagen, endocrine disruptor. – New chemicals and uses. 9 10 Principles of Environmental Toxicology Principles of Environmental Toxicology Classification of Toxicants, 2 Types of Toxic Responses • Physical state. • Local. • Immediate. – Gas, solid. – Effect at site of contact. – Minutes to hours – GIT, lungs. after a single • Toxicity. exposure. • Systemic. – Extremely, slightly. • Delayed. – Effect distant from • Chemical composition. exposure site. – Days to years after – Heavy metal, – CNS, kidney, lungs. exposure. organophosphate. • Some both. • Some both. • Mechanism of action. – Anticholinergic, inhibitor, uncoupler. 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology Types of Toxic Responses, 2 Bioavailability • Octanol-Water Partition Coefficient, Kow • Reversible vs. Irreversible • Largely determined by • An empirical solubility term that can be used to assess transmembrane movement – Tissue involved, length of exposure and magnitude of toxic insult. potential. • Reversible - rapidly regenerating tissue. • Kow = 102 to 103 indicates – Liver, intestinal mucosa, blood cells. good chemical for absorption • Irreversible (Log Kow = 2 to 3). – CNS damage, – OK lipid solubility and carcinogenesis, OK water solubility. mutagenesis, teratagenesis. Kow = [T]octanol / [T]water 13 14 Principles of Environmental Toxicology Principles of Environmental Toxicology N,N-diethyl-3-methylbenzamide Three Phases of Toxicology • Exposure phase. • Toxicodynamic phase. Diethyltoluamide,DEET • Toxicokinetic phase. N – Absorption. – Distribution. O – Metabolism. – Excretion. Poison hemlock Conium maculatum Experimental Log Kow = 2.18 15 16 Principles of Environmental Toxicology Principles of Environmental Toxicology Exposure Phase Exposure Phase, 2 • Bioavailability. Ukrainian President Viktor Yushchenko – Dose. Dioxin Poisoning – The fraction of a dose available for absorption. – Physical and chemical form of the toxicant. • Main factors. • Particle size, – Time and frequency of exposure, e.g. acute, solubilization. subchronic… – Route of administration. • Animal: oral, lung, skin, injection. • Plant: roots, leaves. –Host related factors. –Pre-absorption metabolism. 17 18 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Absorption Phase Absorption Phase, 2 • Comparative aspects. • Transmembrane movement. – Cellular to organism. – Simple diffusion – Fick’s Law. • Membrane morphology. – Filtration – aqueous pores. – Lipoprotein bilayer. – Carrier mediated. • Physiochemical processes that govern • Sites of Absorption. transmembrane movement. – Animals – GIT, dermal, lung. – Lipid-water solubility, Kow – Plants – stomatal pores, cuticle, roots. – Ionization (pKa), functional groups – Insects – pore canals, oral. – Molecular size and – Fish – gills, GIT, dermal. conformation. 19 20 Principles of Environmental Toxicology Principles of Environmental Toxicology Distribution Phase Distribution Phase, 2 Sea snake neurotoxin • Four fates. • Factors affecting distribution. – Site of toxic action, storage, – Affinity of tissues for the xenobiotic. metabolism, excretion. – Blood flow, protein binding. • How it occurs. – Route of administration, rate of metabolism. – Animals – blood, lymph. • Redistribution. – Plants – xylem and/or phloem. – Enterohepatic recirculation. • Barriers of toxicological significance. – Blood/brain. – Placental (maternal - fetal). – Mammary (blood - milk). 21 22 Principles of Environmental Toxicology Principles of Environmental Toxicology Metabolism Phase Factors Influencing Toxicity Concomitant Exposure • Phase I – Bioconversion. • Additive 2+2=4 – Factors affecting toxicity and metabolism. – 2 OP’s leading to cholinesterase inhibition. • Environmental, genetic… • Synergistic 2 + 2 = 10 • Phase II – Conjugation. – CCl4 with ethanol leading to hepatotoxicity. – “Grease to salt” • Potentiation 2+0=6 – Isopropanol with CCl4, tumor promoters. • Antagonism 2 +2 = 0 – BAL with heavy metals, antidotes. Dioxin 23 24 4
Principles of Environmental Toxicology Principles of Environmental Toxicology Excretion Toxicodynamics Dose - Response Relationships • Toxicological significance. • Renal excretion. Toxic Chemical • Non-renal excretion. Key interaction – Biliary, expiration, gastric secretion… Critical Target • Comparative aspects. – Animals, plants. Modified Critical Target (Key lesion) Progression Overt Biological Response or Effect 25 26 Principles of Environmental Toxicology Principles of Environmental Toxicology Intrinsic Activity Oxygen Transport Toxicants • Intrinsic activity: • Methemaglobin formation T+R TR response (Fe2+ to Fe3+). – Agonist - substances "Response" – Nitrate, nitrite. with intrinsic activity, – Naphthalene. e.g. O2 Drugs – Typically reversible. Toxicants – Typically non-reversible. – Chlorate. – Antagonist - – Acetominophen. substances that work • O2 competition at Fe2+ against agonist, e.g. CO – CO, carbon monoxide. – CN-, cyanide. 27 28 Principles of Environmental Toxicology Principles of Environmental Toxicology Methemaglobin Formation O2 Transport, Hemoglobin Bar-headed goose Hemoglobin (oxy form) 29 30 5
Principles of Environmental Toxicology Principles of Environmental Toxicology Toxicity Rating – Oral Human Dose Spectrum of Toxic Dose Fish berry Agent LD50 (mg/kg) Class Dose For Average Ethanol 10,000 Adult NaCl 4,000 Practically non-toxic >15 g/kg More than a quart Ferrous sulfate 1,500 Morphine sulfate 900 Slightly toxic 5-15 g/kg Between a pint and a quart Phenobarbitol 150 Moderately toxic 0.5-5 g/kg Between an ounce and DDT 100 a pint Picrotoxin 5 Very toxic 50-500 mg/kg Between a teaspoonful Strychnine sulfate 2 and an ounce Nicotine 1 Extremely toxic 5-50 mg/kg Between 7 drops and a d-Tubocurarine 0.5 teaspoonful Tetrodotoxin 0.1 Supertoxic