If you want to explain each poison correctly, what is there that is not poison, all things are poison and nothing is without poison.

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1 Learning Objectives Environmental Toxicology "Sure, its going to kill a lot of people, but they may be dying of something else anyway." - Othal Brand, member of a Texas pesticide review board, on chlordane Discuss the history of toxicology Review methods of estimating toxicity Describe the events in toxicosis Compare approaches to estimating health effects Outline the steps of toxic risk assessment Discuss the major classes of pesticides and their environmental and human health risks Review the health risk associated with exposure to lead, cadmium, and mercury History of Toxicology History of Toxicology If you want to explain each poison correctly, what is there that is not poison, all things are poison and nothing is without poison. Solely the dose determines that a thing is not poison. Theophrastus Bombastus von Hohenheim (Parcelsus ) Today, toxicology is not the science of identifying poisons, but the science of quantifying the levels at which substances are toxic, and then describing various types of toxic effects. Death is no longer the endpoint of much interest, but rather focus on many sublethal effects.

2 What, me worry? OK, there are toxic chemicals out there; what determines if I get sick? toxicity of the agent (chemical) quantity and duration of exposure route of exposure age, sex, genetics, gender, general health, nutrition, prior conditions modifying factors (other exposures) Characteristics of Exposure: Route Rubbing alcohol applied to skin may have beneficial effect, but ingested is toxic. Oral, dermal, inhalation, injection ADMSE absorption distribution metabolism storage excretion Characteristics of Exposure: Duration Acute Exposure one or two exposures of short duration (e.g. diagnostic x-ray) Subchronic Exposure multiple exposure over days or months (e.g. pesticide exposure) Chronic Exposure long-term or lifetime exposures (e.g. radon) Acute and Chronic also characterize the time delay between exposure and effects Exposure and Dose Exposure means that the person has been in contact with a potentially toxic agent. A cup of coffee has about 100 mg of caffeine; exposure e is 100 mg per cup Dose would depend on size of individual. 155 lbs adult = 70 kg; dose = 100 mg / 70 kg or 1.4 mg/kg An 11 lb child (5 kg); 100 mg / 5 kg or 20 mg/kg For non-chemical exposures other variable and units are used.

3 Exposure and Dose Duration and frequency of exposure are important 4 beers consumed in one hour would have very different response than if consumed over 4 days. Toxic effects not only differ among individuals, but same person may show different response to same exposure at another time. Fetal Exposures Once thought that placental membranes protected developing fetus Now understand that fetus is exposed to same factors as mother Amniotic fluid will have about same concentration of chemicals as mother s blood (caffeine, nicotine, alcohol). Fetus is storage site for maternal methyl mercury. Adult brain is protected from large non water soluble chemicals, but child s blood brain barrier is more permeable. Absorption Distribution Absorption of gases through lungs is rapid. Cells of lungs are easily damaged by caustic gases or particulates Particulates are filtered and removed from lungs by ciliary action and phagocytosis. Small particles <10u penetrate to deepest regions of lungs. Healthy skin has relatively low permeability. Selective and active uptake of many chemicals in the stomach. Mercury swallowed is poorly absorbed in gut, but if allowed to evaporate and inhaled cause serious health problems. Blood carries substance to all tissues. Membranes consist of protein/lipid bi-layers. Movement across membrane determined by: lipid/water coefficient molecular size ionic charge ph of medium

4 Membrane Transport Passive Diffusion movement due to concentration gradient lipid solubility improves mobility ionized forms less lipid soluble Filtration capillaries and glomeruli have large pores (40Å) reach equilibrium between plasma and extracellular fluid Membrane Transport (cont) Carrier Mediated Transport Substance may combine with carrier molecule and is transported across the membrane into the cell. Mechanism can become saturated. Requires energy when movement is against a concentration gradient (active transport) Phagocytosis - engulfing by specialized cells removes particles to lymphatic system or dissolves them. Metabolism Refers to body s biochemical response to toxic substance. Usually involves oxidation, hydrolysis or addition of active groups to make the molecule l more water soluble so it can be removed by kidneys. Many metabolites are more toxic than precursors. parathion > paroxon elemental Hg > methyl Hg Metals can not be metabolized. Metabolism Many chemicals have a metabolic half life the time it take the body to metabolize and remove it from the body. It would take 5 hours for the typical person to eliminate about half of a given dose of caffeine. High individual variation (condition of liver, prior exposure) Half life of caffeine in typical pregnant women is about 7 hours. Half life of lead is about 30 days; PCBs even longer due storage and removal from metabolic processes.

5 Storage Excretion Very lipophilic (fat-soluble) compounds may be deposited in the fatty constituents of tissues and partitioned away from metabolic activities. (i.e. PCB s and DDT) When remobilized, chemicals in fat may achieve toxic levels. Toxicants that are chemically similar to essential nutrients may be stored (i.e. Pb, Cd, Sr). Removal from body may be active or passive process. exhaled air feces urine secretions Estimating Chemical Toxicity Information derived from: lab studies with animal models (dose - response) rodents (mice & rats), bacteria (Samonella sp.), ) fish, invertebrates t Endpoint of choice is death of test animal. Exposures may be acute or chronic. Exposure levels are varied and LD 50 or NOEL concentrations are estimated. EPA usually sets safe exposure levels at 1/100th of NOEL when uncertainty is high and there are no data on humans. Estimating Chemical Toxicity (cont) Information derived from: epidemiological studies of occupational or accidental exposures. Usually initiated by a cluster of rare diseases. Try to associate the disease with a presumed exposure.

6 Health Effects Toxic effects can take many forms. sudden death or illness (CO, cyanide, etc.) genetic mutation cancer (carcinogen) birth defects (teratogen) sterility brain damage Effects of toxicants can be additive, antagonistic, synergistic. Carcinogens Any agent that causes cancer. chemical (cigarette smoke) biological (viruses) physical (ultraviolet light) One of several models of cancer formation: initiator (carcinogen) alters DNA molecule of growth-regulating gene (oncogene) prolonged exposure to another carcinogen (promoter) may activate the oncogene causing unregulated cell growth. Teratogens Pests Agents that cause abnormalities in a developing fetus. thalidomide (deformed arms and legs) rubella (cardiac defects and deafness) DES (abnormal reproductive systems in daughters) Timing of exposure critical to effects on developing fetus Mutagenicity of toxic agent estimates by the Ames Test. Pest has no biological meaning. Undesirable plant or animal. Direct hazard to commodity production or health Many are man-made or introduced. r-selected

7 Pesticides Chemical purposely created and released into environment to kill something. Safety to humans and non-targeted species is uncertain. occupational exposures best documented cases. U.S. mortality rate = 0.65/million/yr.. non fatal poisonings 100x more common. teratogenic, carcinogenic, mutagenic Use of some pesticides banned in U.S. due to health and environmental risks. Classification of Pesticides insecticides, herbicides, rodenticides etc. chlorinated hydrocarbons carbamates organophosphates botanicals others (mercurials, etc) Chlorinated Hydrocarbons (a.k.a. organochlorides, organohalides) Include DDT, chlordane, aldrin, dieldrin, heptachlor, endrin, toxaphene, lindane, mirex, 2,4,5-T, 2,4-D, TCDD (dioxin), PCB In wide use U.S. from 1940 s tomid60 s A neurotoxin, but mechanisms are not well known. Considered less of an acute but more of a chronic threat than organophosphates and carbamates. Associated with liver cancer, CNS damage, muscles damage, teratogenic in test animals. Chlorinated Hydrocarbons (cont) Herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) Silvex NCI study of Kansas working with 2,4-D showed occurrence of nonhodgkins lymphoma 6 to 8 times that of unexposed. 2,4,5-T contaminated with TCDD (dioxin) Silvex is less toxic and is excreted in urine unchanged.

8 Chlorinated Hydrocarbons (cont) Polychlorinated Biphenyl's > 200 isomers, 50 in common use before plastics, heat transfer, hydraulic fluids, dielectrics, flame retardants. Biomagnifies strong evidence of toxicity from animal studies and human exposures. Thought to be carcinogens (promoter) Clean-up very expensive Organophosphate Pesticides Evolved from production of nerve gas in WW II - high mammalian toxicity. Malathion, parathion, TEPP, diazinon, Mevinphos Under biodegradation - do not bioaccumulate High acute toxicity 120 mg of parathion kill adult, 2 mg a child Readily absorbed through the skin. acetylcholinesterase inhibitor Carbonate Pesticides Include baygon, carbaryl (sevin), mobam, aldicarb, carbofuran (systemic). Not broad spectrum insecticides - roaches and houseflies are immune, but toxic to bees. Acetylcholinesterase inhibitor Biodegradable All but Aldicarb have low dermal toxicity. Detoxified in liver Botanicals Derived from plants or synthetic analogs. Varying toxicities and mode of action Nicotine has low LD50 (high acute toxicity); mimics acetylcholine. Rotenoids low mammalian toxicity blocks NAD oxidation - fish poison, kill head lice. Strychnine highly toxic to mammals Warfarin low toxicity anticoagulant Pyrethrin/pyrethroids = moderately toxic neurotoxin - insecticide

9 What are the problems with chemical pesticides? Nontarget toxicity Contamination of food and water Expensive Bioaccumulation Evolved immunity Secondary pest outbreaks Mercury Heavy, silver metal liquid at room temperature Manufacture of chlorine, plastics, caustic soda Elemental mercury will vaporized and can be inhaled. Present in environment in metallic, inorganic salts, or organic. Hatter s disease - nervous disorders due to chronic exposure to inorganic mercury Concentrates in kidney, liver and brain Methyl mercury more toxic - concentrates in RBC s and attack nerve cells. Minimata tragedy is classic example. Cadmium Chemically and biologically similar to zinc Small quantities cause kidney and bone demineralization. Inhaled causes fibrosis, and emphysema Animals - teratogen t and carcinogen Used in electroplating, plastics, pigments, alloys and batteries. Can bioaccumulate Toxic effects documented in factory workers and villagers in Japan drinking contaminated water (Itai-Itai disease) Lead Lead used extensively in industry and home. Considered by EPA the greatest chemical risk to health Stored in bone Bioaccumulates Most exposure from leaded gasoline and leaded paints. Lead poisoning from chronic exposures Children are at greatest risk Low levels of blood lead associated with learning disabilities

10 Regulatory Agencies U.S. Food and Drug Administration (FDA) ensure all food and drugs are safe and efficacious. Occupational Health and Safety Administration (OSHA) sets rules to control exposures to chemicals in the workplace. Environmental Protection Agency (EPA) protects human health and environmental quality by regulating use and disposal of chemicals in environment.