Toxicology Past Paper 2020-2019 PDF

# TOXICOLOGY ## Department of Technical Pharmacy ## Second Year ### Edit ### Pharmacist ### Abdulsattar Qasem Yaseen ### 2020-2019 ## 2020-2019 ## Lec 1 ## علم السموم ## المرحلة الثانية ### TOXICOLOGY The meaning of the term toxicology is "the study of poisons." The root word toxic entered the...

# TOXICOLOGY ## Department of Technical Pharmacy ## Second Year ### Edit ### Pharmacist ### Abdulsattar Qasem Yaseen ### 2020-2019 ## 2020-2019 ## Lec 1 ## علم السموم ## المرحلة الثانية ### TOXICOLOGY The meaning of the term toxicology is "the study of poisons." The root word toxic entered the English language around 1655 from the Late Latin word toxicus (which meant poisonous), itself derived from toxikón, an ancient Greek term for poisons into which arrows were dipped. The early history of toxicology focused on the understanding and uses of different poisons, and even today most people tend to think of poisons as a deadly potion that when ingested causes almost immediate harm or death. As toxicology has evolved into a modern science, however, it has expanded to all forms of adverse health effects that substances might produce, not just acutely harmful or lethal effects. The following definitions reflect this expanded scope of the science of toxicology: * **Toxic** - having the characteristic of producing an undesirable or adverse health effect. * **Toxicology** - the science that deals with the study of the adverse effects (toxicities) may produce in living organisms under specific conditions of exposure to chemicals or physical agents. It is a science that attempts to qualitatively identify all the hazards associated with a substance, as well as to quantitatively determine the exposure conditions under which those hazards/toxicities are induced. that experimentally investigates the occurrence, nature, incidence, mechanism, and risk factors for the adverse effects of toxic substances. * **Toxicant** - any substance that causes a harmful (or adverse) effect when in contact with a living organism at a sufficiently high concentration. * **Toxin** - any toxicant produced by an organism. ## 2020-2019 ## علم السموم ## المرحلة الثانية ## Lec 1 ### Exposure To cause an adverse effect, a toxicant must first come in contact with an organism. The means by which an organism comes in contact with the substance is the route of exposure (e.g., in the air, water, soil, food, medication) for that chemical * **Acute exposure** - exposure over a brief period of time (generally less than 24 h). Often it is considered to be a single exposure (or dose) but may consist of repeated exposures within a short time period. * **Subacute exposure** - resembles acute exposure except that the exposure duration is greater, from several days to one month. * **Subchronic exposure** - exposures repeated or spread over an intermediate time range 1-3 months. * **Chronic exposure** - exposures (either repeated or continuous) over a long (greater than 3 months) period of time * **Hazard** - the qualitative nature of the adverse or undesirable effect resulting from exposure to a particular toxicant or physical agent. For example, asphyxiation is the hazard from acute exposures to carbon monoxide (CO). * **Risk** - the measure or probability that a specific exposure situation or dose will produce a toxic effect. * **Risk assessment** - the process by which the potential (or probability of) adverse health effects of exposure are characterized. * **Safety** - the measure or mathematical probability that a specific exposure situation or dose will not produce a toxic effect. ## 2020-2019 ## علم السموم ## المرحلة الثانية ### Toxicity * **Toxicity** - any toxic (adverse) effect that a chemical or physical agent might produce within a living organism * **Toxic Symptom** - any feeling or sign indicating the presence of a poison in the system * **Selective Toxicity** - means that a chemical will produce injury to one kind of living matter without harming another form of life, even though the two may exist close together * **Acute toxicity** - an adverse or undesirable effect that is manifested within a relatively short time interval ranging from almost immediately to within several days following exposure * **Chronic toxicity** - a permanent or lasting adverse effect that is manifested after exposure to a toxicant.. * **Delayed or latent toxicity** - an adverse or undesirable effect appearing long after the initiation of exposure to the toxicant. * **Local toxicity** - an adverse or undesirable effect that is manifested at the toxicant's site of contact with the organism. Examples include an acid's ability to cause burning of the eyes, upper respiratory tract irritation, and skin burns. * **Systemic toxicity** - an adverse or undesirable effect that can be seen throughout the organism or in an organ with distant from the point of entry of the toxicant. Examples would be adverse effects on the kidney or central nervous system resulting from the chronic ingestion of mercury. ## 2020-2019 ## علم السموم ## المرحلة الثانية * **Reversible toxicity** - an adverse or undesirable effect that can be reversed once exposure is stopped. Reversibility of toxicity depends on a number of factors, including the extent of exposure (time and amount of toxicant), ability of the affected tissue to repair or regenerate. * **Allergic reaction** - a reaction to a toxicant caused by an altered state of the normal immune response. The outcome of the exposure can be immediate (anaphylaxis) or delayed (cell-mediated). * **Idiosyncratic reaction** - a response to a toxicant occurring at exposure levels much lower than those generally required to cause the same effect in most individuals within the population. This response is genetically determined, * **Dose** - the total amount of a toxicant administered to an organism at specific time intervals. The quantity can be further defined in terms of quantity per unit body weight or per body surface area. * **Dose-response** - is a relationship between exposure and effect, that can be established by measuring the response relative to an increasing dose. This relationship is important in determining the toxicity of a particular substance ## 2020-2019 ## Lec 2 ## علم السموم ## المرحلة الثانية ### WHAT TOXICOLOGISTS DO * Recognition, identification, and quantitation of hazard * Develops standards and regulations to protect health and the environment * Involved in safety assessment and use of data as basis for regulatory control of hazards * Determines risk associated with use of chemicals ### Divisions of toxicology * **Descriptive** - concerned directly with toxicity testing, to evaluate the risk of exposure to specific chemicals. * **Mechanistic** - concerned with the mechanisms by which chemicals exert their toxic effects on living organisms. * **Regulatory** - establishment of standards for the amount of chemicals permitted in air, in the environment, in the workplace, or in drinking water Other divisions of toxicology may be based on the classes of chemicals dealt with or application of knowledge from toxicology for a specific field * **Forensic toxicology** - It is concerned with the legal aspects of the harmful effects of chemicals on humans, establishing the cause of death and elucidating its circumstances in a postmortem investigation. * **Clinical toxicology** - recognizes and treats poisoning, and development of new techniques to treat these intoxications. * **Environmental toxicology** - is a relatively new area that studies the effects of chemicals on wildlife * **Drug toxicology** - Drug toxicology o elucidates the mechanisms of side effects observed during clinical application. * **Occupational toxicology** - studies toxicity of chemicals encountered in the occupational environment. * **Pesticide toxicology** - is involved in the development of new pesticides and the safety of pesticide formulations. ## Classification of Toxic Agents There are many types of Classification according to their : * **Effect on target organs** (liver, kidney, hematopoietic system), * **Use** (pesticide, solvent, food additive), * **Source of the agent** (animal and plant toxins), * **Effects** (cancer mutation, liver injury,,,,,,,,), * **Physical state** (gas, dust, liquid), * **Labeling requirements** (explosive, flammable, oxidizer), * **Chemistry** (aromatic amine, halogenated hydrocarbon), * **Poisoning potential** (extremely toxic, very toxic, slightly toxic) ## 2020-2019 ## علم السموم ## المرحلة الثانية ### Toxic substances are classified into the following: * **Heavy Metals** - differ from other toxic substances in that they are neither created nor destroyed by humans.. * **Solvents and Vapors.** * **Radiation and Radioactive Materials** * **Pesticides** * **Plant Toxins** * **Animal Toxins** ### Interaction of chemical **Antagonism**: antagonist desirable in toxicology (antidote). There are 4 types of antagonist : * **Functional**: 2 chemicals counter balance each other by producing opposite effect on the same physiological function * **Chemical reaction** between 2 compound produce less toxic effect * **Dispositional** - when that the absorption, distribution, biotransformation or excretion is altered so that the concentration and or duration are diminish * **Receptor antagonist** - Occur when 2 chemical that bind to the same receptor produce less effect than give each one alone ## 2020-2019 ## علم السموم ## المرحلة الثانية ### MAJOR FACTORS THAT INFLUENCE TOXICITY * **Route of administration:** * **Duration and frequency of exposure** * **Dose or concentration** ### DOSE RESPONSE RELATIONSHIP It's the relation between the degree of response of biological system and the amount of toxicant administration. Is related * **the dose** * **there is a receptor site with which the chemical interacts** * **the concentration at the site (related to dose administered)** ### Measures of Toxicity * **Mortality (death)** * **Teratogenicity (ability to cause birth defects)** * **Carcinogenicity (ability to cause cancer), and,** * **Mutagenicity (ability to cause heritable change in the DNA)** ### The Median Lethal Dose LD50 The amount (dose) of a chemical which produces death in 50% of a population of test animals mg/kg Normally expressed as milligrams of substance per kilogram of animal body weight ## 2020-2019 ## علم السموم ## المرحلة الثانية ### The Median Lethal Concentration LC50 The concentration of a chemical in an environment (generally air or water) which produces death in 50% of an exposed population of test animals mg/L. Normally expressed as milligrams of substance per liter of air or water (or as ppm) ### Signal Words The three possible signal words * **CAUTION** "Caution" reflects the lowest degree of relative toxicity All pesticides with an LD50 of greater than 500 mg/kg must display this word on their label * **WARNING** "Warning" reflects an intermediate degree of relative toxicity All pesticides with an LDso of greater than 50 and less than 500 mg/kg must display this word on their label * **DANGER** "Danger" reflects the highest degree of relative toxicity All pesticides with an LD50 of less than 50 mg/kg must display this word on their label ## 2020-2019 ## علم السموم ## المرحلة الثانية ### POISON! Legally defined term - not just anything you don't like Any pesticide with an LD50 of 50 mg/kg or less Labels must reflect this classification * Label must have the signal word "DANGER" plus the word "POISON" ### Units Used to Measure Chemicals in the Environment * **PPM** - Parts per million * **PPB** - Parts per billion * **PPT** - Parts per trillion One part per million is **PPM** * 1 minute in two years * 1 cent in $10,000 * 1 g of salt in 1 tons of potato chips One part per billion is **PPB** * 1 second in 32 years * 1 cent in $10,000,000 * 1 g of salt in 1000 tons of potato chips One part per trillion is **PPT** * 1 second in 320 centuries * 1 mg of salt in 1000 tons of potato chips * 1 part per trillion is 1000 smaller than 1 part per billion * 1 part per billion is 1000 smaller than 1 part per million * 1 part per million 1000 smaller than 1 part per thousand ## 2020-2019 ## Lec 3 ## علم السموم ## المرحلة الثانية ### TOXICOKINETICS & TOXICODYNAMICS The term **toxicokinetics** (the absorption, distribution, excretion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites). The term **toxicodynamics** is (the injurious effects of these substances on vital function.) ### How Does Toxicity Develop Before toxicity can develop, a substance must come into contact with a body surface such as skin, eye or mucosa of the digestive or respiratory tract. ### Step 1 - delivery from the site of exposure to the target * The intensity of toxic effect depend on concentration and persistence of the toxicant at the site of action. * After absorption of toxicant the rate of absorption is related to the concentration at the absorbing surface, **lipid soluble**(lipid soluble more absorb than water soluble) ### Step 2: Reaction of toxicant with target molecule Types of reaction : * **Noncovalent binding :** * **Covalent binding :** * **Hydrogen abstraction** * **Electron transfer** * **Enzyme reaction :** ### Step 3- Cellular dysfunction and result toxicity * **Dysfunction of target molecules** * **Destruction of target molecules** * **New antigen formation** ### Step 4- Inappropriate repair and adaptation ### HOW DOES THE POISONED PATIENT DIE? Many toxins depress CNS resulting in coma. Comatose patients frequently lose their airway protective reflexes and their respiratory drive. Thus, they may die as a result of airway obstruction, respiratory arrest. These are the most common causes of death due to overdoses of narcotics and sedative-hypnotic drugs * **Seizures, muscular hyperactivity, and rigidity may result in death** * **Cardiovascular toxicity** is also frequently. Hypotension may be due to depression of cardiac contractility; **hypovolemia** resulting from vomiting, diarrhea, **Lethal arrhythmias** can occur with overdoses of cardioactive drugs such as ephedrine, amphetamines, cocaine, digitalis, and theophylline; * **Other organ system damage** may occur after poisoning and is sometimes delayed in onset. lung tissue, resulting in **pulmonary fibrosis**, beginning several days after ingestion. **Massive hepatic necrosis** due to poisoning by acetaminophen or certain mushrooms results in **hepatic encephalopathy** and death 48-72 hours or longer after ingestion. ## 2020-2019 ## علم السموم ## المرحلة الثانية ### Management of the Poisoned Patient Over a million cases of acute poisoning occur in the would each year, although only a small fraction are fatal. Most deaths are due to suicidal overdose by an adolescent or adult. Childhood deaths due to accidental ingestion of a drug or toxic household product Even with a serious exposure, poisoning is rarely fatal if the victim receives prompt medical attention and good supportive care. Attempting to the application of supportive measures that form the basis ("ABCDs") of poisoning treatment. * **Airway** should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. * **Breathing**. Patients with respiratory insufficiency should be intubated and mechanically ventilated. * **Circulation** - continuous monitoring of pulse rate, blood pressure, urinary output, and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determinations.At this point, every patient with altered mental status should receive a Dextrose, unless blood glucose test demonstrates that the patient is not **hypoglycemic**. * **HISTORY**, Family members, police, and fire department or paramedical personnel should be asked to describe the environment in which the toxic emergency occurred and should bring to the emergency department any syringes, empty bottles, household products, or over-the-counter medications in the possibly poisoned patient. ## 2020-2019 ## علم السموم ## المرحلة الثانية ### PHYSICAL EXAMINATION 1. **Vital signs** - Careful evaluation of vital signs (blood pressure, pulse, respirations, and temperature) 2. **Eyes** - Constriction of the pupils (miosis) is typical of opioids, cholinesterase inhibitors (eg, organophosphate insecticides),. Dilation of the pupils (mydriasis) is common with amphetamines, cocaine and atropine and other anticholinergic drugs.. 3. **Mouth** - The mouth may show signs of burns due to corrosive substances,. Typical odors of alcohol, hydrocarbon solvents, or ammonia may be noted.. 4. **Skin** - The skin often appears flushed, hot, and dry in poisoning with atropine and other antimuscarinics. Excessive sweating occurs with organophosphates, nicotine. 5. **Abdomen** - abdominal cramping, and diarrhea are common in poisoning with organophosphates, iron, arsenic, theophylline,. 6. **Nervous system** - A careful neurologic examination is essential. ### Decontamination involves removing toxins from the skin or gastrointestinal tract. **SKIN** - Contaminated clothing should be completely removed and double-bagged to prevent illness in health care providers and for laboratory analysis. Wash contaminated skin with soap and water. ## 2020-2019 ## علم السموم ## المرحلة الثانية ### GASTROINTESTINAL TRACT 1. Emesis 2. Gastric lavage 3. Activated charcoal 4. Cathartics ### SPECIFIC ANTIDOTES Specific antidotes reduce or abolish the effects of poisons through a variety of mechanisms, which may be categorised as follows: * receptors, which may be activated, blocked or by passed * enzymes, which may be inhibited or reactivated * displacement from tissue binding sites * exchanging with the poison * replenishment of an essential substance * binding to the poison (including chelating). ### Methods of Enhancing Elimination of Toxins It is important to consider whether measures for enhancing elimination, such as hemodialysis, Peritoneal dialysis or urinary alkalinization, forced diuretics can improve clinical outcome ## 2020-2019 ## علم السموم ## المرحلة الثانية | Antidote | Indication | Mode of action | |---|---|---| | acetylcysteine | paracetamol, chloroform, carbon tetrachloride | Replenishes depleted glutathione stores | | atropine | cholinesterase inhibitors, e.g. organophosphorus insecticides | Blocks muscarinic cholinoceptors | | benzatropine | drug-induced movement disorders | Blocks muscarinic cholinoceptors | | benozapine | B-blocker poisoning | Vagal block accelerates heart rate | | calcium gluconate | hydrofluoric acid, fluorides | Binds or precipitates fluoride ions | | desferrioxamine |iron | Chelates ferrous ions | | dicobalt edetate | cyanide and derivatives, e.g. acrylonitrile | Chelates to form nontoxic cobalti-and cobalto-cyanides | | digoxin-specific antibody fragments (FAB) | digitalis glycosides | Binds free glycoside in plasma, complex excreted in urine | | dimercaprol (BAL) | arsenic, copper, gold lead, inorganic mercury | Chelates metal ions | | ethanol | ethylene glycol, methanol | Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites | | flunsazenil | benzodiazepines | Competes for benzodiazepine receptors | | folinic acid | folic acid antagonists.e.g. methotrexate, trimethoprim | Bypasses block in folate metabolism | | glucagon | B-adrenoceptor antagonists | Bypasses blockade of the B-adrenoceptor: stimulates cyclic AMP formation with positive cardiac inocropic effect | | isoprenaline | B-adrenoceptor antagonists | Competes for B-adrenoceptors | | methionine | paracetamol | Replenishes depleted glutathione stores | | miloxone | opioids | Competes for opioid receptors | | neostigmine | antimuscurnic drugs | Inhibits acetylcholinesterase, causing acetylcholine to accumulate at cholinoceptors | | охудев | carbon monoxide | Competitively displaces carbonmonoxide from binding sites on haemoglobin | | pencillamine | copper, gold, lead, elemental mercury (vapour), zinc | Chelates metal ions | | phenoxybenzamine | hypertension due to a-adrenoceptor agonists, e.g. with MAOI, clonidine, ergotamine | Competes for -adrenoceptors (long-acting) | | phentolamine | as above | Competes for -adrenoceptors (short-acting) | | phytomenadione (vitamine K) | coumarin (warfarin) and indandione anticoagulants | Replenishes vitamin K | | pralidoxime | cholinesterase inhibitors.e.g. organophosphorus insecticides | Competitively reactivates cholinesterase | | propranolol | B-adrenoceptor agonists, ephedrine, theophylline, thyroxine | Blocks B-adrenoceptors | | protimine | heparin | Binds ionically to neutralise | | Prussian blue (potassium ferri hexacyanoferrate) | thallium (in rodenticides) | Potassium exchanges for thallium | | sodium calciumedetate | lead | Chelates lead ions | | unithiol | lead, elemental and organic mercury | Chelates metal ions | ## 2020-2019 ## Lec 4 ## علم السموم ## المرحلة الثانية ### Toxicokinetics Is the quantitative study of uptake and movement of an chemical from site of entry into the body, through its uptake, distribution to organ and tissue by the blood circulation and its final disposition by way of biotransformation Sequestration and excretion. * **Uptake** * **Transport** * **Metabolism & transformation** * **Sequestration** * **Excretion** ### Uptake routes * **Ingestion** * **Respiration** * **Body surface** ### Uptake Barriers toxicant must cross one or several of barriers to produce toxic effect * **Cell membrane** * **Epithelial cells of GI tract** * **Respiratory surface** * **Body surface** ### Uptake of Toxicants 1. **Passive diffusion** 2. **Facilitated transport** 3. **Active transport** 4. **Pinocytosis** ### Uptake by Passive diffusion Molecules may diffuse along conc. gradient until equilibrium is reached which depends on: 1. Concentration gradient 2. Surface area 3. Thickness 4. Lipid solubility & ionization 5. Molecular size ### Uptake by Facilitated Transport Carried by trans-membrane carrier along conc. Gradient. Energy independent - limited number of substance similar chemical structure, these substance can compete of the binding site and may be inhibit the binding of another,. This called competitive inhibition which could be used to prevent uptake of toxicant. ### Uptake by Active Transport * **Independent of or against conc. Gradient** - Require energy (ATP) * **Substrate - specific** ### Uptake by Pinocytosis * **Pinocytosis** - contribute to the transport of substance across the intestinal wall For large molecules * **Outside** - Infolding of cell membrane * **Inside** - release of molecules ### Transport & Deposition * **Transport** - Blood Lymph, Water * **Deposition** * Pb - Bone, teeth, brain * OP - Nervous tissue ## 2020-2019 ## علم السموم ## المرحلة الثانية ### Metabolism & Transformation Convert toxicants into more water-soluble form (polar & hydrophilic) dissolve in aqueous phases and eliminate by excretion. * **Phase I Transformation** Oxidation, Reduction or Hydrolysis * **Phase II transformation** Covalent conjugation to water soluble endogenous metabloites (e.g. sugars, glucuronic acid, glutathione, phosphates & sulphate) Further increase hydrophilicity for excretion in bile, urine and sweat ### Important Phase II enzymes * **Glutathion S-transferases (GST)** * **UDP-glucuronosyltransferase (UDP-GTS)** * **Sulfotransferase (ST).** ### Sequestration Animals store toxicants (bone, fat, hair, nail) reduce toxicity Plants may store toxicants in bark, leaves, Lipophilic toxicants (e.g. DDT,) may be stored in milk at high conc and pass to the young ### Excretion 1. in urine depend on GFR, lipid soluble, pH 2. bile 3. expired air 4. sweat 5. milk (lipid soluble toxicant) 6. saliva 7. GIT secretion 8. genital secretion 9. by normal turnover of hair skin (arsenic and mercury) ## 2020-2019 ## علم السموم ## المرحلة الثانية ### Excretion * **Gas** (e.g. ammonia) and volatile (e.g. alcohol) toxicants may be excreted from the lung by simple diffusion * **Water soluble toxicants** excreted through the kidney by active or passive transport * **Conjugates with high molecular wt.** may be excreted into bile through active transport * **Lipid soluble and non-ionised toxicants** may be reabsorbed (systematic toxicity)