GENERAL INTRODUCTION TO TOXICOLOGY: GENERAL INTRODUCTION TO TOXICOLOGY Dr. TAHAR A. SOLIMAN MD, PhD TOXICOLOGY: TOXICOLOGY is the study of the adverse effects of chemicals on living organisms. Toxicologist is a person dealing with those adverse effects Different Areas of Toxicology : Different Areas of Toxicology 3 MAIN CATEGORIES Descriptive toxicology Mechanistic toxicology Regulatory toxicology Each has distinctive characteristics, but they are contributing each to the other, and all are vitally important to chemical risk assessment . Mechanistic Toxicologist: Mechanistic Toxicologist Concerned with identification and understanding the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms Descriptive Toxicologist: Descriptive Toxicologist Concerned with toxicity testing to provide information for safety evaluation and regulatory requirements. PowerPoint Presentation: Regulatory toxicologist responsible for deciding whether a drug (or chemical) has sufficient low risk to be marketed. The FDA is responsible for allowing drugs, cosmetics, and food additives to be sold in the market) The U.S. Environmental Protection Agency (EPA) is responsible for regulating other chemicals according to the Federal Insecticide, Fungicide and Rodenticide Act. . There are other specialized areas of toxicology : : There are other specialized areas of toxicology : Forensic toxicology : concerned with the medicolegal aspects of the harmful effects of chemicals on humans and animals. The forensic toxicologist is concerned to aid in establishing: Cause of death Determination of death circumstances in a postmortem investigation. PowerPoint Presentation: Clinical toxicology deals with diseases caused by or associated with toxic substances PowerPoint Presentation: Environmental toxicology focuses on the hazards of chemical pollutants in the environment on biological organisms. Ecotoxicology is a specialized area within environmental toxicology that focuses more specifically on the impacts of toxic substances on population dynamics in an ecosystem. The transport, fate, and interactions of chemicals in the environment constitute a critical component of both environmental toxicology and ecotoxicology . Terms & Definitions: Terms & Definitions Poison is any substance that causes a harmful effect to a living organism. Poison is a quantitative concept, almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose. Between these two limits there is a range of possible effects, from subtle long-term chronic toxicity to immediate lethality. Toxicant is any chemical, of natural or synthetic origin, capable of causing a harmful effect to a living organism. Toxin is a toxicant produced by a living organism and is not used as a synonym for toxicant all toxins are toxicants, but not all toxicants are toxins Modes of Toxic Action: Modes of Toxic Action Includes the consideration of all events leading to toxicity in vivo: uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event leading to toxicity , such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Mechanisms of toxicity: Mechanisms of toxicity 1. Biochemical and molecular toxicology consider events at the biochemical and molecular levels, including enzymes that metabolize toxicants generation of reactive intermediates modes of action, and signaling pathways in toxic action. PowerPoint Presentation: 2. Behavioral toxicology deals with the effects of toxicants on animal and human behavior This involves both the peripheral and central nervous systems, as well as effects mediated by other organ systems, such as the endocrine glands. Mechanisms of Toxicity (cont.): Mechanisms of Toxicity (cont.) 3. Nutritional toxicology deals with the effects of diet on the expression of toxicity and mechanisms of these effects. 4. Carcinogenesis includes the chemical, biochemical, and molecular events that lead to the large number of effects on cell growth collectively known as cancer. 5. Teratogenesis includes the chemical, biochemical, and molecular events that lead to deleterious effects on development. 6. Mutagenesis is concerned with toxic effects on the genetic material and the inheritance of these effects. 7. Organ toxicity considers effects at the level of organ function (neurotoxicity, hepatotoxicity , nephrotoxicity , etc.). Measurement of Toxicants and Toxicity: Measurement of Toxicants and Toxicity They deal with: analytical chemistry Bioassay applied mathematics They are designed to provide the methodology to answer certain critically important questions, such as; Is the substance likely to be toxic? How can we assay its toxic effect? what is the minimum level at which this toxic effect can be detected? Measurement of Toxicants and Toxicity: A number of important fields are included: Analytical toxicology concerned with identification and assay of toxic chemicals and their metabolites in biological and environmental materials. 2. Toxicity testing involves the use of living systems to estimate toxic effects. Measurement of Toxicants and Toxicity PowerPoint Presentation: 3. Structure-activity studies are concerned with the relationship between the chemical and physical properties of a chemical and toxicity and, particularly, the use of such relationships as predictors of toxicity. 5. Biomathematics and statistics relate to many areas of toxicology. They deal with data analysis, the determination of significance, and the formulation of risk estimates and predictive models. 6. Epidemiology as it applies to toxicology, is of great importance as it deals with the relationship between chemical exposure and human disease in actual populations rather than in experimental settings. Applied Toxicology: Applied Toxicology 1. Clinical toxicology is the diagnosis and treatment of human poisoning. 2. Veterinary toxicology is the diagnosis and treatment of poisoning in animals other than humans. 3. Forensic toxicology concerns the medicolegal aspects, including detection of poisons in clinical and other samples. 4. Environmental toxicology is concerned with the movement of toxicants and their metabolites and degradation products in the environment and in food chains and with the effect of such contaminants on individuals and, especially, populations. 5. Industrial toxicology is a specific area of environmental toxicology that deals with the work environment and constitutes a significant part of industrial hygiene . Chemical Use Classes : Chemical Use Classes Includes the toxicology aspects of the development of new chemicals for commercial use. In some of these use classes, toxicity is desirable for some organisms and not for others. PowerPoint Presentation: 1. Agricultural chemicals such as insecticides, herbicides, fungicides, and rodenticides, in which toxicity to the target organism is a desired quality whereas toxicity to “ nontarget species” is to be avoided 2. Clinical drugs 3. Drugs of abuse are chemicals taken for psychological or other effects and may cause dependence and toxicity. 4. Food additives are of concern to toxicologists only when they are toxic or being tested for possible toxicity. PowerPoint Presentation: 5. Industrial chemicals are so numerous that testing them for toxicity or controlling exposure to those known to be toxic is a large area of toxicological activity. 6. Naturally occurring substances include many phytotoxins , mycotoxins , and minerals, all occurring in the environment. 7. Combustion products are not properly a use class but are a large and important class of toxicants, generated primarily from fuels and other industrial chemicals. Dose-Response Relationships : Dose-Response Relationships Toxicity is a relative event that depends on: Toxic properties of the chemical Dose Individual variation Inter-specific variation Paracelsus (1493–1541) laid the groundwork for the later development of modern toxicology by recognizing the importance of the dose-response relationship. His famous statement—“All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy”. : Paracelsus (1493–1541) laid the groundwork for the later development of modern toxicology by recognizing the importance of the dose-response relationship. His famous statement—“ All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy ”. Paracelsus in Bavaria Paracelsus in Switzerland Types of dose-response relationships : Types of dose-response relationships Individual (graded) dose-response relationships These are characterized by an increase in the severity of the response by increasing the dose. It is called “graded” response because the measured effect is continuous over a range of doses. 2. Quantal Dose–Response Relationships In contrast to the “graded” or continuous-scale dose–response relationship that occurs in individuals, the dose–response relationships in a population are by definition quantal —or “all or none”—in nature; that is, at any given dose, an individual in the population is classified as either a “responder” or a “ nonresponder .” In toxicology, the quantal dose response is widely used. PowerPoint Presentation: Threshold dose: a dose below which no effect or response is observed. This concept is of significance because it implies that a no observed effect level (NOEL) can be determined and that this value can be used to determine the safe intake for food additives and contaminants such as pesticides. Generally this is accepted for most types of chemicals but not for carcinogens acting by non-threshold genotoxic mechanism median lethal dose (LD50): median lethal dose (LD 50 ) The 1 st . Experiment performed to a new chemical is determination of the median lethal dose ( LD 50 ). LD 50 is the statistically derived single dose of a substance that can be expected to cause death in 50% of the tested animals. Groups of animals are dosed at different levels, and the mortality that results in each dose group is recorded. The quantal all-or-none response is not limited to lethality. Similar dose–response curves can be used for cancer, liver injury, and other types of toxic responses as well as for beneficial therapeutic responses such as anesthesia or lowering of blood pressure. Evaluating Dose-Response Relationships : Evaluating Dose-Response Relationships By determining chemical: Effective dose (ED), which gives good effects & Toxic dose (TD), in which undesirable effects appear, & Lethal dose (LD), we can calculate: TI= LD 50 /ED 50 Variation in Toxic Responses: Variation in Toxic Responses Selective toxicity It means that a chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in contact. The living matter that is injured is termed the uneconomic form (or undesirable) the matter protected is called the economic form (or desirable). They may be related to each other as parasite and host or may be two tissues in one organism. This biological diversity is used to develop agents that are lethal for an undesired species and harmless for other species. PowerPoint Presentation: Species Differences Both quantitative and qualitative differences responses to toxic substances may occur among different species Individual Differences in Response Even within a species, large inter-individual differences in response to a chemical can occur because of subtle genetic differences. CHARACTERISTICS OF EXPOSURE : CHARACTERISTICS OF EXPOSURE Toxic effects depend on The Concentration The duration Chemical & physical properties of the substance Exposure situation Susceptibility of the biological system or subject . To characterize the possible hazard of a chemical agent, we need to know: Type of effect it produces The dose required to produce that effect Information about the agent Information about the exposure Its disposition by the subject. The major factors that influence toxicity as it relates to the exposure situation for a specific chemical are the route of administration and the duration and frequency of exposure. Route and Site of Exposure : Route and Site of Exposure The major routes are Ingestion Inhalation skin (topical, percutaneous , or dermal) Other parenteral (other than intestinal canal) routes. PowerPoint Presentation: Toxic agents generally produce the greatest effect and the most rapid response when given directly into the bloodstream (the intravenous route). An approximate descending order of effectiveness for the other routes would be inhalation, intraperitoneal, subcutaneous, intramuscular, intradermal, oral, and dermal. PowerPoint Presentation: The route of administration can influence the toxicity of agents. For example, an agent that is detoxified in the liver would be expected to be less toxic when given via the portal circulation (oral) than when given via the systemic circulation (inhalation). PowerPoint Presentation: Occupational exposure most frequently results from: Inhalation Skin contact Accidental and suicidal poisoning occurs most frequently by oral ingestion. PowerPoint Presentation: Comparison of lethal dose of a toxic chemical by different exposure routes provides information about its extent of absorption. When the LD is similar after oral or dermal administration is or IV administration, the assumption is that the toxic agent is absorbed readily and rapidly. Conversely, in cases where LD by dermal route is higher than oral LD, it is likely that the skin provides an effective barrier to absorption of the agent. Duration and Frequency of Exposure : Duration and Frequency of Exposure Acute exposure : exposure to a chemical for less than 24 h or repeated exposures within a 24-h period and the adverse effects occur within 14 days. Subacute exposure : repeated exposures to a chemical for 1 month or less. Subchronic exposure : for 1 to 3 months. Chronic exposure : more than 3 months. SPECTRUM OF UNDESIRED EFFECTS : SPECTRUM OF UNDESIRED EFFECTS Therapeutic drug produces one desirable effect associated with the primary objective of the therapy; all the other effects are referred to as undesirable effects or side effects PowerPoint Presentation: Sometimes the side effects may be desired for another therapeutic indication. Diphenhydramine (Benadryl) is antihistamine but cause mild CNS depression. It is still used as OTC sleep remedy in combination with analgesics Some side effects of drugs are never desirable and are always deleterious to the well-being of humans. These are referred to as the adverse, deleterious, or toxic effects of the drug. Allergic Reactions : Allergic Reactions Chemical allergy is immunologically mediated adverse reaction resulting from previous sensitization The term hypersensitivity , allergic reaction and sensitization reaction are used to describe this situation. Because most chemicals and their metabolites are not sufficiently large to be recognized by the immune system as a foreign substance, they combine with endogenous protein to form an antigen. A molecule that must combine with an endogenous protein to elicit an allergic reaction is called a hapten . The hapten -protein complex (antigen) is then capable of eliciting the formation of antibodies, and usually at least 1 or 2 weeks is required for the synthesis of significant amounts of antibodies. Subsequent exposure to the chemical results in an antigen–antibody interaction, which provokes the typical manifestations of allergy. Idiosyncratic Reactions : Idiosyncratic Reactions Chemical idiosyncrasy : genetically determined abnormal reactivity to a chemical. The response observed is usually qualitatively similar to that observed in all individuals but may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of the chemical. A classic example of an idiosyncratic reaction is provided by patients who exhibit prolonged muscular relaxation and apnea (inability to breathe) lasting several hours after a standard dose of succinylcholine . Succinylcholine usually produces skeletal muscle relaxation of only short duration because of its very rapid metabolic degradation by an enzyme that is present normally in the bloodstream called plasma butyrylcholinesterase (also referred to as pseudocholinesterase ). Patients exhibiting this idiosyncratic reaction have a genetic polymorphism in the gene for the enzyme butyrylcholinesterase , which is less active in breaking down succinylcholine . Immediate versus Delayed Toxicity : Immediate versus Delayed Toxicity Immediate toxic effects: occur rapidly after a single administration Delayed toxic effects: occur after some time Carcinogenic effects of chemicals usually have a long latency period, often 20 to 30 years after the initial exposure, before tumors are observed in humans. Reversible versus Irreversible Toxic Effects : Reversible versus Irreversible Toxic Effects Depend on the ability of the injured tissue to regenerate: Liver can regenerate, most injuries are reversible, whereas injury to the CNS is largely irreversible because it cannot regenerate. Carcinogenic and teratogenic effects of chemicals are irreversible toxic effects. Local versus Systemic Toxicity : Local versus Systemic Toxicity Local effects are those that occur at the site of first contact between the biological system and the toxicant. Such effects are produced by the ingestion of caustic substances or the inhalation of irritant materials. Systemic effects require absorption and distribution of a toxicant from its entry point to a distant site, at which deleterious effects are produced. Local & systemic effects INTERACTION OF CHEMICALS : INTERACTION OF CHEMICALS effects of 2 chemicals given simultaneously produce a response that may simply be: Additive Effect : the combined effect of 2 chemicals is equal to the sum of the effects of each agent given alone (example: 2 + 3 = 5). Synergistic Effect : the combined effects of 2 chemicals are much greater than the sum of the effects of each agent given alone (example: 2 + 2 = 20). For example, carbon tetrachloride & ethanol are hepatotoxic , but together they produce much more liver injury than the mathematical sum of their individual effects on liver at a given dose would suggest. INTERACTION OF CHEMICALS : INTERACTION OF CHEMICALS Potentiation occurs when one substance does not have a toxic effect on a certain organ or system but when added to another chemical makes that chemical much more toxic (example: 0 + 2 = 10). Isopropanol is not hepatotoxic , but when it is administered in addition to carbon tetrachloride, the hepatotoxicity of carbon tetrachloride is much greater than that when it is given alone. PowerPoint Presentation: Antagonism occurs when 2 chemicals administered together interfere with each other's actions or one interferes with the action of the other (example: 4 + 6 = 8; 4 + (–4) = 0; 4 + 0 = 1). Antagonistic effects of chemicals are often very desirable in toxicology and are the basis of many antidotes. There are 4 types of antagonism Functional antagonism occurs when 2 chemicals counterbalance each other by producing opposite effects on the same physiologic function. Hypotension in phenothiazine toxicity can be effectively by IV vasopressor agent such as norepinephrine . PowerPoint Presentation: Chemical antagonism or inactivation : chemical reaction between 2 compounds that produces a less toxic product. For example, dimercaprol chelates with metal ions. PowerPoint Presentation: Dispositional antagonism occurs when the disposition is altered so that the concentration and duration at the target organ are diminished. Prevention of absorption by ipecac or charcoal and the increased excretion of a chemical by administration of an osmotic diuretic or alteration of the pH of the urine are examples of dispositional antagonism. PowerPoint Presentation: Receptor antagonism occurs when 2 chemicals that bind to the same receptor produce less of an effect when given together than the addition of their separate effects (example: 4 + 6 = 8) or when one chemical antagonizes the effect of the second chemical (example: 0 + 4 = 1). Receptor antagonists are often termed blockers. This concept is used to advantage in the clinical treatment of poisoning. For example, the receptor antagonist naloxone is used to treat the respiratory depressive effects of morphine and other morphine-like narcotics by competitive binding to the same receptor. TOLERANCE : TOLERANCE A state of decreased responsiveness to a toxic effect of a chemical resulting from prior exposure to that chemical or to a structurally related chemical. Mechanisms of tolerance: Mechanisms of tolerance 1) Decreased amount of toxicant reaching the site where the toxic effect is produced ( dispositional tolerance ) Carbon tetrachloride dcreses formation of hepatotoxic metabolite Cadmium tolerance induces binding to metallothionein rather than to critical macromolecules thus decreases its toxicity. 2) Reduced responsiveness of a tissue to the chemical.