General Toxicology Concepts I & II PDF

1140-115 Principles of Toxicology General Toxicology Concepts I & II Dr. Bedoor Qabazard Learning Objectives: 1. Understand the basic principles, terminology and subdivisions of toxicology and the concept of selective toxicity....

1140-115 Principles of Toxicology General Toxicology Concepts I & II Dr. Bedoor Qabazard Learning Objectives: 1. Understand the basic principles, terminology and subdivisions of toxicology and the concept of selective toxicity. 1. Know the general classification of adverse drug reactions (ADRs). 2. Understand Paracelsus principle that every substance is a potential poison and what matters is the dose. 3. Outline the major mechanisms of toxicity (e.g. molecular, biochemical, carcinogenicity, teratogenicity, mutagenicity..etc). 4. Understand the factors determining toxicity, such as the dose, route and duration of exposure (acute/subchronic/chronic), individual susceptibility..etc. 5. Know the different types of toxic responses (immediate/delayed, reversible/irreversible, local/systemic), and target organ toxicity. 6. Understand the basics of the dose-response relationship in toxicology, the graded and quantal dose-response curves and some important toxicodynamic parameters (TD50, LD50, threshold, NOAEL, LOAEL, ADI, TLV).  What is Toxicology? Toxicology was simply regarded as the science of poisons or poisoning. Toxicology can be defined as the study of the harmful/adverse effects of chemical, physical and biological agents on living organisms and the ecosystem. It is the study of the detection, symptoms, mechanisms, treatments, prevention and regulation of toxic substances. Subdivisions of Toxicology Analytical toxicology Environmental toxicology Forensic toxicology Occupational toxicology Clinical toxicology Molecular toxicology (Toxicogenomics) Regulatory toxicology  The dose makes the poison A poison is any substance, including any drug, that is capable of e producing deleterious response in a biological system. Every known chemical has the potential to produce injury or e death if present in a sufficient amount. “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.” evenwater Paracelsus (1493 – 1541) Pharmacology Toxicology Pharmacodynamics Toxicodynamics Pharmacokinetics ED I Toxicokinetics TD, LD ADRs Toxic responses  Adverse Drug Reactions (ADRs) ADRs are noxious or unintended responses occurring at therapeutic doses (WHO definition) ~ 5% of all acute hospital admissions 2 main classifications of ADRs: classical and alphabetic Type A ▪ related to - Hemorrhage with anticoagulants (augmented) ADRs pharmacological effect - - 1 Hypoglycemia with oral hypoglycemics Bradycardia with b-blockers ≈ 80% ▪ predictable - Headache with GTN ▪ common Type B (bizarre) Be ▪ dose-related ▪ unrelated to pharmacological 1) Immunological (allergic reactions): - anaphylactic shock: penicillin ADRs effect - drug-induced lupus: hydralazine ≈ 20% ▪ unpredictable 2) Anaphylactoid reactions (pseudoallergic) ▪ rare - ACEIs- angioedema, nonimmunological ▪ dose independent 3) Genetically determined reactions - acetylator polymorphism: isoniazid neuropathy in slow acetylators and hepatotoxicity in fast acetylators 4) Idiosyncratic reactions genes - hematological idiosyncratic reactions: chloramphenicol aplastic anemia. heparin-induced thrombocytopenia Other ADRs ▪ may involve a - nephrotoxicity: aminoglycosides (unclassified) chemically reactive - hepatotoxicity: chlorpromazine metabolite - carcinogenesis: cyclophosphamide - teratogenesis: warfarin  Alphabetic classification of ADRs Type Effects A Augmented pharmacological effect, dose- related, common, often reversible, rarely fatal B Bizarre unpredictable, high rate of morbidity and mortality, uncommon C Chronic after prolonged treatment (Steroids- cushion syndrome) D Delayed- years after treatment (Cyclophosphamide- secondary carcinoma) E End of treatment when drug is stopped (b-blockers- unstable angina) Toxicological Terms and Definitions Toxic agent: is anything that can produce an adverse biological effect. Toxic agents may be chemical (e.g. cyanide, lead), physical (e.g. radiation) or biological (e.g. snake venom). Toxicant: toxic substances that are produced by or are a by-product of human-made activities Xenobiotics: include a variety of foreign synthetic chemicals with different intended purposes. Pharmaceuticals are xenobiotics developed to treat disease, whereas pesticides are used to deter pests. Toxin: a toxic substance that is a specific product of the metabolic activities of a living organism such as plants, animals, fungi and bacteria (tetanus- a neurotoxin by Clostridium tetani bacteria). The term ‘toxin’ should be used only for biologically produced substances and not as a synonym for toxicant  Toxicity Toxicity: is the cascade of events starting with exposure, proceeding through distribution and metabolism, and ending with various toxic endpoints. Selective toxicity: – Differences in susceptibility to toxic effects between different species – The basis for designing antibacterial and anticancer drugs and pesticides. an insecticide is lethal to insects but relatively nontoxic to animals antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans Penicillin is active against bacteria (interferes with cell wall synthesis) but not mammalian cells (no cell wall) Types of Toxicity Molecular toxicity: interaction of xenobiotics or their metabolites with macromolecules (DNA, RNA, protein, lipids), deleterious effects on gene expression and signaling pathways Biochemical toxicity: deleterious effects on enzymes that metabolize xenobiotics, generation of reactive intermediates and ROS, damage to normal cellular function, premature or accelerated death of cells in tissues (necrosis/apoptosis), depletion of cellular protective abilities (glutathione depletion). Target organ toxicity: deleterious effects at the level of organ function leading to impaired organ function (e.g., neurotoxicity, hepatotoxicity, nephrotoxicity) Behavioral toxicity: harmful effects on animal and human behavior; mainly involves PNS and CNS and other organs such as muscles and endocrine glands  Types of Toxicity Carcinogenicity: a specific toxic effect that leads to uncontrolled proliferation of cells in a tissue or organ. Teratogenicity: includes the biochemical and molecular events that lead to deleterious effects on the development of the embryo or fetus. Mutagenicity: toxic effects on the genetic material and the inheritance of these effects. Immunotoxicity: toxic reactions involving the immune system Adverse drug reactions (ADRs) : toxic reaction to a specific drug occurring at therapeutic doses * most toxic substances have multiple mechanisms of toxicity Classification of Toxic Agents Food additives (e.g. aspartame, sodium nitrite) Pesticides (e.g DDT –banned, paraquate) Industrial chemicals (lead, cadmium) Environmental pollutants (SO2, CO) Natural toxins (botilinium toxin, tetanus, fungal aflatoxin, snake venoms) Household poisons (solvents, benzene, bleach) Drugs and drugs of abuse - Every drug is a potential poison, and several factors contribute to the ability of the drug (or any agent) to achieve its adverse potential  Factors that Determine Toxicity 1. Dose and concentration (see Paracelsus principle) – The amount of the xenobiotic administered to or reaching the living system 2. Route of exposure 3. Duration of exposure 4. Physicochemical properties (composition, chemical activity) 5. Metabolism of the toxic agent (toxicokinetics) 6. Individual susceptibility, e.g. genetics, race, age, gender, diet, pregnancy, overall health, etc. – Race: Chinese are more susceptible to alcohol toxicity – Genetic: rate of acetylation of isoniazid (genetic polymorphism) Routes of Exposure The route of administration can influence the toxicity of agents. The major routes (pathways) by which toxic agents gain access to the body are: – Gastrointestinal tract (ingestion) – lungs (inhalation) – skin (topical or dermal) – parenteral (IV, IP, IM) Exposure to a toxic agent can occur via: – Intentional ingestion (oral- drugs or drugs of abuse or food additives) – Accidental poisoning (e.g. inhalation of gas) – Intentional poisoning (suicide, homicide) – Occupational exposure (e.g. asbestos inhalation, skin contact) – Environmental exposure (inhalation of pollutants, pesticides)  Duration and Frequency of Exposure Acute exposure: a single episode (or repeated in less than 24h) whereby a particular amount of a substance enters the body (e.g. an overdose of a drug). – May result in acute or chronic effects (e.g. acute exposure to asbestos may cause lung cancer) Subacute & Subchronic: occurring repeatedly over several weeks and up to 3 months. Chronic exposure: repeated exposure to a substance for many months or years which may then accumulate or cause a cumulative toxic effect. Single Dose Repeated Dose Benzene CNS Depression Leukemia Types of Toxic Responses-1 Classification based on onset of toxic effect – Acute toxicity (immediate): a toxic event that develops rapidly after a single administration (acute exposure) of a substance. E.g., hydrogen cyanide or nerve gases such as sarin – Delayed toxicity (chronic): a toxic event which occurs after the lapse of some time-weeks, months or years- following exposure. E.g., vaginal cancer in daughters of women who took diethylstilbestrol (DES) during pregnancy (in utero exposure to DES). Toxicant Acute toxicity Chronic toxicity Ethanol CNS depression Liver cirrhosis Arsenic GI damage Skin/liver cancer  Types of Toxic Responses-2 Classification based on nature of toxic effect: – Reversible toxic effects (inflammation, liver injury) e.g. Acetaminophen - systemic, reversible toxicity (liver damage) – Irreversible toxic effects (CNS injury, carcinogenic, teratogenic) e.g. asbestos (asbestosis, lung cancer, mesothelioma) lead (cognitive impairment) thalidomide (phocomelia) Types of Toxic Responses-3 Classification based on general site of action: – Local: occur at the site of first contact between the biological system and the toxic agent. E.g., chlorine gas reacts with lung tissue at the site of contact, causing damage and swelling of the lungs – Systemic: require absorption and distribution of a substance from its entry point to a distant site, at which deleterious effects are produced (most substances produce systemic effects). E.g., kidney damage after a severe acid burn is an indirect systemic effect because the toxicant does not reach the kidney.  Target Organ Toxicity A target organ is an organ that is damaged by the xenobiotic or its metabolite (e.g. alcohol targets CNS and liver) Target organs most affected by toxicants - CNS - Visceral organs (liver, kidney, lung) - CVS - Muscle and bone Many toxins do not produce general effects but are specific to only one or more organs – Asbestos: lung cancer - Cadmium: kidney toxicity Target organ of toxicity is not always the site of the highest concentration of the toxicant. – Lead concentrates in bones (act as reservoir) but its toxic effects occur mainly in soft tissues (brain, kidney, liver, blood cells). – DDT accumulates in adipose tissue but affects CNS and female reproductive system Mechanisms of Toxicity (1) delivery of the toxicant to its target (2) interactions between the toxicant and its target (3) progression to cellular dysfunction (4) inappropriate repair or adaptation  Toxicological Interactions Additive effect: the combined responses of two chemicals is equal to the sum of the responses to each chemical given alone (2 + 3 = 5). E.g., when two organophosphorous insecticides are given together, inhibition of acetylcholinesterase enzymes (AChE) is usually additive. Synergistic effect: the combined responses of two chemicals are much greater than the sum of the response to each chemical when given alone (2 + 2 = 20). E.g., both carbon tetrachloride (CCl4) and ethanol are hepatotoxic compounds, but together they produce much more liver injury. Potentiation: one substance does not produce any toxicity but when added to another chemical makes that chemical much more toxic (e.g., 0 + 2 = 10). E.g., Isopropanol is not hepatotoxic on its own, but when combined with CCl4, hepatotoxicity of CCl4 is much greater than when it is given alone. Antagonism: two chemicals administered together interfere with each other's actions or one interferes with the action of the other (4 + 6 = 8; 4 + (−4) = 0; 4 + 0 = 1). E.g., Antidotes. Four major types: receptor, chemical, dispositional & functional Types of Toxicity Antagonism Receptor antagonism (blockers) Two chemicals bind to the same receptor, one chemical blocks the receptor and antagonizes the effect of the second chemical. E.g., the receptor antagonist naloxone treats the respiratory depressive effects of morphine narcotic by competitively binding to the same receptor. Treatment of organophosphorus insecticide poisoning with atropine by blocking “ligand–receptor interaction.” Chemical antagonism (inactivation) A direct chemical reaction between two compounds that produces a less toxic product. The direct binding or sequestration of the two chemicals prevents the toxicant from interacting with its receptor and in turn reduces downstream signaling and cellular damage. E.g., DMSA (succimer) chelates or binds to metal ions, such as arsenic, mercury, and lead, decreasing their toxicity. The strongly basic protein protamine sulfate form a stable complex with heparin, which abolishes its anticoagulant activity.  Types of Toxicity Antagonism Dispositional antagonism Occurs when the disposition—ADME of a chemical—is altered such that the concentration and/or duration of the chemical at the target organ is reduced. Prevention of absorption of a toxicant by activated charcoal Increased excretion of a chemical by administration of an osmotic diuretic or alteration of the pH of the urine (NaHCO3urine alkalinization to enhance salicylates excretion). Functional (physiological) antagonism Occurs when two chemicals counterbalance each other by producing opposing effects on the same physiological function, often through different signaling pathways. Glucagon and insulin have opposing effects on blood sugar level. Antagonism of Toxic Effects