Toxicology Lec 1 & 2 (Principles of Toxicology) PDF

Toxicology ( Lecture 1& 2) Principles of Toxicology The Study of Poisons Suhair.A.A. A./ Toxicology &TDM 1 Objectives Suhair.A.A. A./ Toxicology &TDM 2  Origin of toxicology 400 BC: Hippocrates compiled a listing of a number of poisons and outlined some clinical toxi...

Toxicology ( Lecture 1& 2) Principles of Toxicology The Study of Poisons Suhair.A.A. A./ Toxicology &TDM 1 Objectives Suhair.A.A. A./ Toxicology &TDM 2  Origin of toxicology 400 BC: Hippocrates compiled a listing of a number of poisons and outlined some clinical toxicology principles 1493-1541: Paracelsus—physician and philosopher ……….. Suhair.A.A. A./ Toxicology &TDM 3  Origin of toxicology 1775: polycyclic aromatic hydrocarbons as carcinogen 1972: Rachel Carson/EPA led to ban of insecticide DDT for environmental and health concerns Suhair.A.A. A./ Toxicology &TDM 4  Definition of Toxicology - the basic science of poisons (old) - the study of the adverse effects of chemical agents on biological systems (new) Suhair.A.A. A./ Toxicology &TDM 5  The study of the adverse effects of a toxicant on living organisms Adverse effects – any change from an organism’s normal state – dependent upon the concentration of active compound at the target site for a sufficient time. Toxicant (Poison) – any agent capable of producing a deleterious response in a biological system Living organism – a sac of water with target sites, storage depots and enzymes 6 Suhair.A.A. A./ Toxicology &TDM  Definition of toxicology Toxicology is a science dealing with poisons, and their chemical effect on the living cells. Or Toxicology is a branch of medical sciences that deals with – Nature of poisons – Action of poisons – Symptomatology of poisons – treatment and detection of poisons. Suhair.A.A. A./ Toxicology &TDM 7  Toxicity describes the degree to which a substance is poisonous or can cause injury Depends on many factors – Dose – Duration of exposure – Route of exposure – Shape and structure of poison – Individual human factors (age , genetic , immunity, ext.) Suhair.A.A. A./ Toxicology &TDM 8  Toxicity Toxicity can be detected as : all or none responses: death; presence /absence of pathological damage , or graded responses: biochemical/ physiological changes; changes in normal status. Direct tissue lesions result in damage to a target organ: The target organ is determined by a number of factors: (i) function and position, (ii) blood supply, (iii) presence of uptake systems, (iv) pathways of intermediary metabolism, (v) absence of repair mechanisms, (vi) vulnerability to damage/disruption, (vii) biotransformation capabilities, and (viii) binding to particular macromolecules. 9 Suhair.A.A. A./ Toxicology &TDM The science of toxicology aids society by: Protecting humans and other organisms from deleterious effects of toxicants. Provide knowledge for the safer use of chemicals and radiation e.g., in medicine, foods, and agriculture. Methods Identify toxic substances. Determine mechanisms of toxicity. Develop safer and more selective substances (drugs, pesticides). determines risk associated with use of chemicals Communicate accurate information to the public, industry, and regulatory agencies. 10 Suhair.A.A. A./ Toxicology &TDM  Exposure To Toxins about 50% of poisoning cases are intentional suicide attempt – High mortality rate Accidental exposure accounts for about 30% of cases – Children – Drug over dose occupational exposure Suhair.A.A. A./ Toxicology &TDM 11 The incidences of poisoning are mainly Suicidal poisoning. Homicidal. Exhibitional, for creating sympathy. Aphrodisiacal, to arouse sexual desire. abortificient, to induce abortion. Accidental poisoning. Poisoning by substances used to kill animals. Poisoning by substances used to kill insects ( insecticides). 12 Suhair.A.A. A./ Toxicology &TDM  What is a Poison? All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy. Paracelsus (1493-1541) Suhair.A.A. A./ Toxicology &TDM 13  Dose The amount of chemical entering the body This is usually given as mg of chemical/kg of body weight = mg/kg The dose is dependent upon * The environmental concentration * The properties of the toxicant * The frequency of exposure * The length of exposure * The exposure pathway 14 Suhair.A.A. A./ Toxicology &TDM  What is a Response? The degree and spectra of responses depend upon the dose and the organism--describe exposure conditions with description of dose Change from normal state – could be on the molecular, cellular, organ, or organism level--the symptoms Local vs. Systemic Reversible vs. Irreversible Immediate vs. Delayed Graded vs. Quantal – degrees of the same damage vs. all or none Suhair.A.A. A./ Toxicology &TDM 15  Dose-Response Relationship: As the dose of a toxicant increases, so does the response. 4 RESPONSE 0-1 NOAEL 2-3 Linear Range 3 4 Maximum Response 2 0 1 DOSE DOSE DETERMINES THE BIOLOGICAL RESPONSE 16 Dose-response Relationship Dose-response is a relationship between exposure and health effect, that can be established by measuring the response relative to an increasing dose is important in determining the toxicity of a particular substance Dose : actual amount of a chemical that enters the body Suhair.A.A. A./ Toxicology &TDM 17  Dose-response Relationship Toxicity is relevant that depend on many factors – Toxic property of toxicant – as dose increase toxic response increase – Individual variation – Exposure (chronic or acute) 18 Suhair.A.A. A./ Toxicology &TDM Dose-response Relationship 19  Evaluating Dose-Response Relationships 100 ED: Effective dose (therapeutic dose of a drug) 80 50 % ED TD: Toxic dose % response response 60 (dose at which toxicity occurs) TD 40 LD LD: Lethal dose NOAEL LOAEL (dose at which death occurs) 20 NOAEL: no observed adverse effect level LOAEL: lowest observed adverse effect 0 level -2 -1 0 1 2 3 10 10 10 10 10 10 dose (mg/kg) ED50: dose at which 50% of population therapeutically responds. (In this example, ED50=1 mg/kg) TD50: dose at which 50% of population experiences toxicity (TD50=10 mg/kg). 20 LD50: dose at which 50% of population dies (LD50=100 mg/kg).  Therapeutic Index (TI) TI = LD50/ED50 or TI = TD50/ED50 TI is the ratio of the doses of the toxic and the desired responses. TI is used as an index of comparative toxicity of two different materials; approximate statement of the relative safety of a drug. The larger the ratio, the greater the relative safety. Suhair.A.A. A./ Toxicology &TDM 21  LD50 The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a variety of methods mg/kg Normally expressed as milligrams of substance per kilogram of animal body weight Suhair.A.A. A./ Toxicology &TDM 22  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 in a specified time frame mg/L Normally expressed as milligrams of substance per liter of air or water (or as ppm) Suhair.A.A. A./ Toxicology &TDM 23  Toxicity rating systems correlate the dose of a toxin that will result in a harmful response correlates a single acute oral dose range with the probability of a lethal outcome in an average 70-kg man 24  LD50 Comparison Chemical LD50 (mg/kg) Ethyl Alcohol 10,000 Sodium Chloride 4,000 Ferrous Sulfate 1,500 Morphine Sulfate 900 Strychnine Sulfate 150 Nicotine 1 Black Widow 0.55 Curare 0.50 Rattle Snake 0.24 Dioxin (TCDD) 0.001 Botulinum toxin 0.0001 25  Exposure: Pathways Routes and Sites of Exposure – Ingestion (Gastrointestinal Tract) – Inhalation (Lungs) – Dermal/Topical (Skin) – Injection intravenous, intramuscular, intraperitoneal Typical Effectiveness of Route of Exposure iv > inhale > ip > im > ingest > topical Suhair.A.A. A./ Toxicology &TDM 26  Exposure: Duration Acute < 24hr usually 1 exposure Subacute 1 month repeated doses Subchronic 1-3mo repeated doses Chronic > 3mo repeated doses Over time, the amount of chemical in the body can build up, it can redistribute, or it can overwhelm repair and removal mechanisms Suhair.A.A. A./ Toxicology &TDM 27  ADME: Absorption, Distribution, Metabolism, and Excretion Once a living organism has been exposed to a toxicant, the compound must get into the body and to its target site in an active form in order to cause an adverse effect. The body has defenses: – Membrane barriers passive and facilitated diffusion, active transport – Biotransformation enzymes, antioxidants – Elimination mechanisms 28  Absorption: ability of a chemical to enter the blood (blood is in equilibrium with tissues) Inhalation--readily absorb gases into the blood stream via the alveoli. (Large alveolar surface, high blood flow, and proximity of blood to alveolar air) Ingestion--absorption through GI tract stomach (acids), small intestine (long contact time, large surface area--villi; bases and transporters for others) – 1st Pass Effect (liver can modify) Dermal--absorption through epidermis (stratum corneum), then dermis; site and condition of skin 29  Distribution: the process in which a chemical agent translocates throughout the body Blood carries the agent to and from its site of action, storage depots, organs of transformation, and organs of elimination Rate of distribution (rapid) dependent upon – blood flow – characteristics of toxicant (affinity for the tissue, and the partition coefficient) Distribution may change over time 30 Distribution: Storage and Binding Storage in Adipose tissue--Very lipophylic compounds (DDE a metabolite of the DDT) will store in fat. Rapid mobilization of the fat (starvation) can rapidly increase blood concentration Storage in Bone--Chemicals analogous to Calcium--Fluoride, Lead, Strontium Binding to Plasma proteins--can displace endogenous compounds. Only free is available for adverse effects or excretion 31 Suhair.A.A. A./ Toxicology &TDM  Target Organs: adverse effect is dependent upon the concentration of active compound at the target site for enough time Not all organs are affected equally – greater susceptibility of the target organ – higher concentration of active compound Liver--high blood flow, oxidative reactions Kidney--high blood flow, concentrates chemicals Lung--high blood flow, site of exposure Neurons--oxygen dependent, irreversible damage Myocardium--oxygen dependent Bone marrow, intestinal mucosa--rapid divide 32  Target Sites: Mechanisms of Action Adverse effects can occur at the level of the molecule, cell, organ, or organism Molecularly, chemical can interact with Proteins Lipids DNA Cellularly, chemical can – interfere with receptor-ligand binding – interfere with membrane function – interfere with cellular energy production – bind to biomolecules – perturb homeostasis (Ca) 33  Excretion: Toxicants are eliminated from the body by several routes Urinary excretion – water soluble products are filtered out of the blood by the kidney and excreted into the urine Exhalation – Volatile compounds are exhaled by breathing Biliary Excretion via Fecal Excretion – Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces. Milk Sweat Saliva 34  Metabolism: adverse effect depends on the concentration of active compound at the target site over time The process by which the administered chemical (parent compounds) are modified by the organism by enzymatic reactions. 1o objective--make chemical agents more water soluble and easier to excrete – decrease lipid solubility --> decrease amount at target – increase ionization --> increase excretion rate --> decrease toxicity Bioactivation--Biotransformation can result in the formation of reactive metabolites 35  Biotransformation (Metabolism) Compound Without With Can drastically Metabolism Metabolism effect the rate of Ethanol 4 weeks 10mL/hr clearance of compounds Phenobarbital 5 months 8hrs Can occur at any DDT infinity Days to weeks point during the compound’s journey from absorption to Suhair.A.A. A./ Toxicology &TDM 36 excretion  Biotransformation Key organs in biotransformation – LIVER (high) – Lung, Kidney, Intestine (medium) – Others (low) Biotransformation Pathways * Phase I--make the toxicant more water soluble * Phase II--Links with a soluble endogenous agent (conjugation) Suhair.A.A. A./ Toxicology &TDM 37  Individual Susceptibility --there can be 10-30 fold difference in response to a toxicant in a population Genetics-species, strain variation, interindividual variations (yet still can extrapolate between mammals--similar biological mechanisms) Gender (gasoline nephrotox in male mice only) Age--young (old too) – underdeveloped excretory mechanisms – underdeveloped biotransformation enzymes – underdeveloped blood-brain barrier 38 Suhair.A.A. A./ Toxicology &TDM  Individual Susceptibility Age – changes in excretion and metabolism rates, body fat Nutritional status Health conditions Previous or Concurrent Exposures – additive --antagonistic – synergistic Suhair.A.A. A./ Toxicology &TDM 39  Age The two extremes of age are more susceptible to toxic agents in general. Risk groups Pregnant women Fetus Infant Child, adolescent Higher breathing volumen compared to body surface Different metabolism Typical childhood habits. Suhair.A.A. A./ Toxicology &TDM 40  Disciplines of toxicolology –mechanistic, – descriptive, –forensic, –Regulatory –Clinical toxicology Suhair.A.A. A./ Toxicology &TDM 41  Mechanistic toxicology Concerned with identification of cellular , biochemical and molecular mechanism by which chemical exerts toxic effect on living cells Suhair.A.A. A./ Toxicology &TDM 42  Descriptive toxicology uses the results from animal experiments to predict what level of exposure will cause harm in humans Toxicity testing or risk assessment Provide information for – Safety evaluation – Regulatory requirement Suhair.A.A. A./ Toxicology &TDM 43  Regulatory toxicologist Responsible for interpreting the data from mechanistic and descriptive studies to establish standards that define the level of exposure that will not pose a risk to public health or safety – FDA – USA Environmental protection agency Suhair.A.A. A./ Toxicology &TDM 44  Forensic toxicology Concerned with medicolegal consequences of toxin exposure Establishing and validating the analytic performance of the methods used to generate evidence in legal situations, including the cause of death Suhair.A.A. A./ Toxicology &TDM 45  Clinical toxicology is the study of interrelationships between toxin exposure and disease states Suhair.A.A. A./ Toxicology &TDM 46  Types of toxicants Carcinogens: cause cancer Mutagens: cause mutations in DNA Teratogens: cause birth defects Allergens: cause unnecessary immune response Neurotoxins: damage nervous system Endocrine disruptors: interfere with hormones Suhair.A.A. A./ Toxicology &TDM 47  Interaction of Chemicals - Additive - Synergistic - Potentiation - Antagonism ( functional, chemical, dispositional, receptor) Suhair.A.A. A./ Toxicology &TDM 48  General and Specific Management of Poisoning General measures should be followed in any case of poisoning. These measures are life saving regardless of the availability on an antidote Suhair.A.A. A./ Toxicology &TDM 49  Two main principles should be considered in management, these are ; – Stop administration and exposure. – Elimination of the poison. Suhair.A.A. A./ Toxicology &TDM 50  Stop administration and exposure.  If a patient under medical treatment swallows any toxic agent, the drug should be stopped immediately.  Exposure to industrial or agricultural toxicants needs removal from the contaminated environment. Suhair.A.A. A./ Toxicology &TDM 51  Elimination of Ingested poisons: Induction of emesis: evacuation of the stomach by emesis is a very rapid, easy and safe method. It is contraindicated in: Corrosive poisons. convulsing patients. Comatose patients to avoid pulmonary aspiration of the vomitus Suhair.A.A. A./ Toxicology &TDM 52  Excretion of poisons in urine by increasing urine out put (Diuresis): It is not wise to administer diuretics alone to increase the urine out put, since this will lead to dehydration and hence more concentration of the poisonous material in the plasma  Fluid Diuresis:  5% glucose in physiological saline solution (1000ml). Avoid over hydration and keep fluid chart. This is useful in mild cases of poisoning. Suhair.A.A. A./ Toxicology &TDM 53  Specific Management of acute poisoning the use of Antidotes These are substances which abolish or counter act the poison and its harmful effects They are generally classified into : – Physical – Chemical – physiological Suhair.A.A. A./ Toxicology &TDM 54  Physical Antidotes:- These agents interfere with the ingested poisons through physical means only and do not change its nature. – Adsorbing: Activated charcoal 50 gm shaken in 400 ml water, given orally or in gastric lavage fluid. useful in all ingested poisons. – Delaying absorption and coating Milk and egg are used. – Diluting: Water dilutes all poisons especially corrosives. 55 Suhair.A.A. A./ Toxicology &TDM  Chemical Antidotes:- Interfere with the poison by chemical means. They include: 1/ Neutralizing agents:- Weak acids lemon or orange juice orally for corrosive alkalies Weak alkalies as Mg oxide or soap solution for corrosive acids were used. the use of milk is more safe. Sodium bicarbonate 1.26% 500 ml I/V Suhair.A.A. A./ Toxicology &TDM 56 2/ Oxidizing agents:- – Potassium permanganate 150 ml orally oxidizes most alkaloids – Oxygen 100% is the specific antidote for CO poisoning to provide adequate tissue oxygenation through saturation of plasma, and fastens the dissociation of carbon monoxide from haemoglobin. 3/ Reducing agents:- – Ascorbic acid (Vit C): 1mg I/V for treating methaemoglobinemia – Sodium thiosulphate 100 ml of 1% solution orally in iodine poisoning to reduce it to iodide. Suhair.A.A. A./ Toxicology &TDM 57  Physiological (Pharmacological) Antidotes:- 1/ Antagonists:- Anticonvulsants: Ether inhalation, barbiturates as pentothal, diazepam.  Digitalis: 1 mg digoxin I/V repeated according to the condition.  Choline esterase inhibitors: physostigamine 1-5 mg I/V.  Antisera: For snake bites & scorpion stings; 10 ml of antiserum in 500 ml 5% glucose by I/V drip.  Potassium chloride: 1 gm orally digitalis toxicity. Suhair.A.A. A./ Toxicology &TDM 58 Physiological (Pharmacological) Antidotes:- 2/ Competitives:-  Narcotic antidotes: as Nalorphine & Naloxone, competes with morphine at target tissues have a similar but weaker action than morphine.  Ethyl alcohol for methyl alcohol : 500 ml of 5% ethanol orally or I/V to be repeated after 4 hours to reduce the metabolism of methyl alcohol. Ethanol competes with the enzyme because it is oxidized more easily to acetaldehyde, acetic acid then CO2 + H2O. so methanol is excreted unchanged instead of changing to its more toxic oxidation products (formaldehyde and formic acid)  Chelators:- Desferroxamine in chelation of iron. 59 Suhair.A.A. A./ Toxicology &TDM Suhair.A.A. A./ Toxicology &TDM 60