Toxicity Evaluation of Chemical Contaminants, Regulations, Criteria and Standards and of Aspects of Risk Assessment and Risk Communication

Lecture Outline Regulations: TSCA, FIFRA, EPA office of Pesticide Program Definitions: Xenobiotics, Risk assessment, Toxicity, Exposure, Dose, Response Pharmacology vs Environmental Toxicology : Routes of exposure, uptake-distribution metabolism-storage-excretion, dose-response curves, interaction: additive-synergistic and antagonistic effects. Bioassays : acute-subchronic , chronic effects and safety factors

Environmental Toxicology “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

An Individual View “The sensitivity of the individual differentiates a poison from a remedy. The fundamental principle of toxicology is the individual dose response curve.” S. G. Gilbert (1997)

EPA Office of Chemical Safety and Pollution Prevention (OCSPP) OSCPP’s mission is to protect you, your family, and the environment from potential risks from toxic chemicals. Through innovative partnerships and collaboration, pollution is prevented before it begins. This reduces waste, saves energy and natural resources, and leaves our homes, schools and workplaces cleaner and safer. 

Environmental Toxicology was driven by the following acts Toxic Substances Act Resource Conservation and Recovery Act Comprehensive Environmental Response Act Federal Pesticides Act Clean Water Act Clean Air Act

The Toxic Substances Control Act (TSCA) 1976 TSCA) provides EPA with authority to require reporting, record-keeping and testing relating to chemical substances and/or mixtures. Specific Objectives To allow EPA to regulate new commercial chemicals before they enter the market To regulate existing chemicals when they pose unreasonable risk to health and/or to the environment To regulate their distribution and use

Federal Insecticide, Fungicide, and Rodenticide Act 1996 (FIFRA) The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) provides for federal regulation of pesticide distribution, sale, and use.

FIFRA All pesticides distributed or sold in the United States must be registered (licensed) by EPA. Before EPA may register a pesticide under FIFRA, the applicant must show that using the pesticide according to specifications "will not generally cause unreasonable adverse effects on the environment.''

FIFRA FIFRA defines the term ''unreasonable adverse effects on the environment'' to mean: '(1) any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide, OR (2) a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with the Federal standards

Office of Pesticide Programs Office of Pesticide Programs (OPP) OPP regulates the use of all pesticides in the United States and establishes maximum levels for pesticide residues in food, thereby safeguarding the nation's food supply.

Office of Pesticide Programs EPA has extended access to information on risk assessment and risk management actions to help increase transparency of decision making and facilitate consultation with the public.

Office of Pesticide Programs In addition to regulatory functions, information is provided on issues ranging from worker protection to misuse of pesticides.

Toxic Chemicals

Definitions Contamination. The introduction into soil, air or water of a chemical, radioactive material or live organism that will adversely affect the quality of that medium. Standards vs Criteria. Numerical standards that are established for the concentrations of chemical substances in soil, groundwater, surface water, and sediments that relate to the suitability of a site for specific land uses and land use categories. Criteria are also often referred to as guidelines.

Definitions Pathway. The route along which a chemical substance or hazardous material moves in the environment. Receptor. The person or organisms, including plants, subjected to chemical exposure.

Definitions Xenobiotics: human produced chemicals and introduced to the environment; Fate of Xenobiotics: Bioaccumulation : build up in the food chain Biotransformation : structure alteration: natural, biological Biodegradation : broken down by biological activity

Definitions Risk Assessment. The scientific examination of the nature and magnitude of risk to define the effects on both human and other receptors of the exposure to contaminant(s).

Definitions Risk Management. The selection and implementation of a strategy of control of risk, followed by monitoring and evaluation of the effectiveness of that strategy. Risk management may include direct remedial actions or other strategies that reduce the probability, intensity, frequency or duration of the exposure to contamination.

Definitions Environmental Toxicology: adverse health effects resulting from exposure to toxic chemicals via inhalation, absorption and /or ingestion Acute 96hr usually 1 exposure Sub-acute 1 month repeated doses Sub-chronic 1 year repeated doses Chronic life span repeated doses

Definitions Adverse Effect. An undesirable or harmful effect to an organism, indicated by some result such as mortality, altered food consumption, altered body and organ weights, altered enzyme concentrations or visible pathological changes.

Toxicity Toxicity is the ability of a chemical to damage an organ system, to disrupt a biochemical process, or to disturb an enzyme system.

Exposure Over time, The chemical might Accumulate OR re-destribute Metabolized Excreted

Routes of Exposure

Definitions Exposure : the contact with an agent : oral, dermal or by inhalation Hazard: the possibility that an agent can cause harm Risk: the possibility of adverse health effect including disease , injury or death following exposure to an agent

Definitions Dose: amount of exposure to an agent Response : reaction to the dose For example: drinking one glass of milk might be fine, but drinking a gallon of milk may result in unpleasant response.

Dose- Response Hazard+ Exposure= Risk Depends on 1- Individual sensitivity, 2- dose 3- the agent.

Dose : Body Weight For exposure to a chemical agent, dose is usually expressed in relation to body weight. This is because for a fixed amount of toxic agent, the dose, and likewise the effect, depends directly on weight. We know, for example, that one shot of alcohol would have a very big effect on a child weighting 10 lbs and a much smaller effect on an adult weighing 200 lbs.

Dose : Body Weight To take this into account, dose is measured in units of milligrams of toxicant per kilogram of body weight, abbreviated mg/kg. If someone consumed 100 mg of caffeine, approximately the amount in a cup of coffee or two cans of caffeinated soda, and if they weighed 70 kg (about 155 lbs), the dose would be 100 mg/70 kg of body weight or 1.4 mg/kg. On the other hand, if a child weighing only 10 kg (about 22 lbs) consumed the same 100 mg of caffeine, the dose would 10 mg/kg, seven times as large because the body weight is one seventh.

Dose Thus amount of exposure and the size of individual determine the dose and are critical factors in toxicology. This principle can be an extremely important factor in home lead or pesticide exposures, where the dose a child receives is far greater than the adult due to the small size and extra sensitivity of the child.

Effects of amount on response Demonstration of the importance of amount of the Dose Fill three same size glasses with approximately ¾ water. (This represents the approximate water content of an individual).

Effects of amount on response Then add 1 drop of red food color in the first glass, 3 drops in the second glass and 7 drops in the last glass.

Effects of Amount on Response

Effects of amount on response Stir with a pencil : Notice the color intensity based on number of drops. This represents Color diffusion/distribution in the body

Effects of Size on Response

Effects of Size on Response Fill one large glass and the small glass with approximately ¾ water. The small glass represents a small child in contrast to the adult size glass.

Effects of Size on Response Add one drop of food color in the each glass. The small glass will be much darker.

Effects of Size on Response

Environmental Toxicology Difference between Pharmacology and Environmental Toxicology

Definitions Pharmacology: Toxicology: the scientific study of the origin, nature, chemistry, effects, and use of drugs Toxicology: the science that investigates the adverse effects of chemicals on health Web: www.asmalldoseof.org .

Routes of Administration/Exposure Pharmacology: Routes of administration: oral, Intramascular, Intravevous, subcutaneous, topical Toxicology: Routes of exposure: oral, inhalation, dermal

Key Factors Related to Routes of Administration/Exposure In administration of medication, different routes are used based upon the efficacy of absorption of drugs from each route. In environmental health, different toxins are absorbed through different routes of exposure, which results in variations in toxicity. In administration of medication, different routes are used based upon the efficacy of absorption of drugs from each route. For example, the topical route can be used only for medication preparations that are absorbed effectively through the skin. Insulin is administered parenterally because it is broken down in the stomach and, therefore, is not absorbed well via the GI tract. In environmental health, different toxins are absorbed through different routes of exposure, which results in variations in toxicity. For example, elemental mercury (the silver-grey material in mercury thermometers and sphygmomanometers) is poorly absorbed through the GI tract but well absorbed as a vapor in the respiratory tract. If transformed to methylmercury by the action of bacteria in bodies of water, and later consumed in fish, it is readily absorbed in the GI tract and crosses the placental barrier.

Administration/Exposure Pharmacology: Administration regimen: A drug can be administered one time, short-term, or long-term. Toxicology: Exposure is the actual contact that a person has with a chemical. It can be one-time, short-term, or long-term.

Dose Pharmacology: Toxicology: Dose refers to the amount of a drug absorbed from an administration. Toxicology: Dose refers to the amount of a chemical absorbed into the body from an exposure.

Key Factors Related to Dose In pharmacology, we have good control over who receives what dosage of what substance. In environmental health, it is usually difficult to control or determine who receives what dose of which toxin(s). In pharmacology, we have very good control over who receives what dosage of what substance (as described by the 5 “R”s: you are responsible for giving the right medication, to the right patient, in the right dose, at the right time, by the right route). In environmental health, though, it is usually very difficult to control or determine who receives what dose of which toxin(s). For environmental exposures, we are often left “reconstructing” a dose based on the best information we can gather.

Key Factors Related to Administration/Exposure Drugs are taken voluntarily. Hazardous chemical exposures are often involuntary. With both drugs and hazardous chemicals, children’s behavior entails special exposure risks. Drugs are taken voluntarily, often under the supervision of a licensed health care provider…. Children are at high risk for poisoning from drugs and hazardous chemicals because of their curiosity and hand-to-mouth behavior. With regard to environmental hazards, children are at greater risk because they spend more time on or near the ground, which increases their exposure to residues (including residues from airborne toxicants that settle on the ground). With regard to foodborne toxicants, children have greater food intake per kilogram of body weight than adults, and they eat a smaller range of foods (which leads to increased risk from contaminants on certain foods). With regard to airborne toxicants, children breathe proportionately more air than adults.

Distribution, Metabolism and Excretion Pharmacology and Toxicology: Distribution, metabolism and excretion describe what happens to the drug or toxin in the body. Distribution: organs that are reached Metabolism: chemical transformation metabolites Excretion: elimination . Distribution refers to the organs that are reached by the drug or toxin. Metabolism is the chemical transformation of the substance that occurs. Metabolism produces products called metabolites, which may be more or less toxic than the original substance. Excretion refers to the elimination of the substance, usually by way of the kidneys.

Dose-Response Curve Dose-response curve graphically represents Pharmacology: Dose-response curve graphically represents the relationship between the dose of a drug and the response elicited

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Dose-Response Curve Toxicology: Dose-response curve describes the relationship of the body’s response to different amounts of an agent Beyond a certain dose (the threshold), the response increases with increasing dose. At some point, this effect may “level off.”

Toxicology

Key Factors Related to Dose Response The dose-response curve may differ for different populations. Individuals vary with regard to response to drugs or toxins. In pharmacology as well as environmental health, the dose-response curve may differ for different populations. Children, for example, are not just little adults. Because of differences in development and function of organs, they may metabolize drugs or toxins differently from adults. Therefore, effects may increase for children at lower (or occasionally higher) doses. For example, children absorb lead from the GI tract much more efficiently than adults. With nitrate in drinking water, the higher pH in the digestive system of an infant allows proliferation of bacteria which transform nitrate into toxic nitrite. In pharmacology as well as environmental health, individuals vary with regard to response to drugs or toxins. This is due to factors such as: age, gender, genetic variations, weight, drug that the person may be taking, pregnancy status.

Responses - Pharmacology Low dose no observable response (subtherapeutic) dose -- therapeutic response (and side effects) > therapeutic dose --- toxicity At low doses or concentrations, there is no observable response (dose is subtherapeutic). With increased dosage, there are therapeutic responses (which are desirable) and side effects (which are generally undesirable). Beyond the therapeutic dose, a drug may become toxic. (Note: The graph on this slide is a “compressed” representation of therapeutic and toxic responses. Actually, there is an S curve for each effect (therapeutic or toxic). Generally, though, toxic effects occur at higher doses—ideally, at doses that exceed those required for maximal therapeutic effect.)

Responses - Toxicology Only toxic effects are of concern. Low doses NOEL (no observable effect level) Exceeding the NOEL ------ toxicity In toxicology, only the toxic effects are of concern. At low doses, there may be no effect (called NOEL – no observable effect level). At levels greater than NOEL, toxicity occurs.

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Interactions Pharmacology: Toxicology: Drug interactions define the effect one drug has on another. Toxicology: Toxicological interactions define the effect one chemical has on another. Toxicological interactions include interactions between drugs and environmental pollutants.

Interactions 3 types of effects: Additive: the sum = the whole Synergistic or potentiated: one enhances the other’s effect Antagonistic: one reduces the effect of the other These effects may be additive (the sum of the effects = the whole, or the total toxicity of the two)…….

Potency Pharmacology: Toxicology: Potency refers to the relative amount of drug required to produce the desired response. Toxicology: The potency of a toxic chemical refers to the relative amount it takes to elicit a toxic effect compared with other chemicals.

Biological Monitoring Pharmacology: Biological monitoring is done for some drugs. Toxicology: Biological monitoring is done for some toxic exposures. In pharmacology, clotting time is monitored in patients on anticoagulants like coumadin. Actual drug levels are measured for some drugs like digoxin. In environmental health, blood lead levels, or metabolites of chemicals such as cotines for environmental tobacco smoke, may be monitored.

The Regulatory Process The regulatory process for approval to sell a medication includes several stages of testing on animals and humans. The regulatory process for food, drug, cosmetic, or pesticide in nature require original testing for human health risks. When testing is done, it tends to be focused on the effects on middle-aged white males. In recent years (notably with the Food Quality Protection Act of 1996), the effects on children have begun to be taken into consideration.

Bioassays The measurement of biological system responses resulting from an exposure to a chemical substance such as a drug or a pesticide. Testing can be done by exposing body cells, worms, fish, and other animals .

into Research/ Assessment Research Assessment Management EPA Scientific Research/ Data Collection Risk Assessment Animal Toxicology Clinical Studies Epidemiology Cell/Tissue Experiments Computational Methods Monitoring/ Surveillance Dose-Response Characterization Risk Management Control Options Research Needs Decisions Risk Characteri- zation Hazard Characterization Collaboration Exposure Characterization Other Federal Agencies States/Local Agencies Academia Industry Public Interest/Environmental Groups Collaboration Non-risk Analyses External Input into Research/ Assessment

Evaluation of Chemical Toxicity The main objective is to be able to project animal results to humans. The TEST chemical is labeled (radioactive) and fed to laboratory animals. It is assumed that metabolism of the compound in animals follow the same patterns in humans. (It is not always the case, byproducts might not be the same).

Evaluation of Chemical Toxicity A) Acute Toxicities (96hrs) The US federal regulations require that an acute test of the chemical in question be determined in at least two animal species, with one species being a non-rodent. Test results are reported as LD 50/LC50 which stands for Lethal Dose/Lethal Concentration which kills 50% of Test animals. ThThe US federal regulations require that an acute test of the chemical in question be determined in at

B) Subacute toxicity:(3 months) Chemical is fed to animals for three months at different doses. A Dose response curve is developed. The highest dose which produces no adverse effects is used to estimate for a safe dose for human consumption.

Evaluation of Chemical Toxicity C : Sub-chronic Exposure for one year

D) Chronic Toxicity Testing (Animal life span) It follows the acute and subacute testing. Rodents are normally used because their life is about four years life span. Testing lasts for three generations . The dose where animals produce normally and their off springs show no mutagenic or teratogenic effects is used to estimate the safe dose for humans.

Toxicity Testing This dose will be divided by a safety factor of 10, 100, 1000, or 10,000 depending on the toxicity of the compound.

Bioassay Curve

Dose-Response Curves

Chronic Toxicity/Safety Factors a) Divide by 10 when chronic or subchronic human exposure data identifying a NOAEL (NO Observed Adverse Effect Levels) are available, and are supported by chronic or subchronic Toxicity in other species.

Safety Factors(cont.) b) Divide by 100 When good chronic Toxicity data identifying NOAEL are available for one or more animal species ( and human data are not available) OR when good chronic or subchronic Toxicity data identifying a LOAEL(lowest) in humans are available

Safety Factors(cont.) c) Divide by 1000 When limited or incomplete chronic or subchronic Toxicity data are available , OR when good chronic data that identify a LOAEL but not NOAEL for one or more animal species are available.

Safety Factors(cont.) d) Divide by 10,000 When a subchronic study identifying a LOAEL BUT NOT a NOAEL