Principles Of Toxicology PDF

University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Principles of Toxicology *Toxicology: - The science of poison and poisoning, it is the stud...

University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Principles of Toxicology *Toxicology: - The science of poison and poisoning, it is the study of undesirable effects of chemical, Biological, or even radiation on the living organism. *Toxicologist: The person who is trained to examine the nature of toxic effects including their cellular, biochemical and molecular mechanisms of action, and assess the probability of their occurrence. * Toxin: - Poison of natural origin (e.g.) insect, fungi…etc. *Poison (Toxicant)-: Any substance when applied or introduced into a living organism at a certain dose or route causes damage to life processes, and tissues or may deprive life. *Venom ;- The poisonous fluid that some animals, such as certain snakes and spiders,secrete and introduce into the bodies of their victims by biting and stinging. *Toxicosis - :The state of being poisoning or any diseased condition due to poisoning. * Toxicity is the degree to which a substance can damage an organism,i t can refer to the effect on a whole organism, human ,animal and plant or substructure of the organism like cytotoxicity , hepatotoxicity or to describe the toxic effects in a large and more complex group such as family. *Hazard: - The likelihood of occurrence of poisoning under specific conditions of use. *Pollutant substance that occurs in the environment (air, water, soil) are possibly by human activity and adversely affects the living organism that lives in this environment. 1 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 *Iatrogenic disease -:Disease condition induced by chemicals due to medical mistake. *Minimum toxic dose (MTD):- The smallest toxic dose that causes detectable signs and symptoms of toxicity in organism. * LD50 (Median lethal dose )-:The dose of a toxic agent that causes death in 50% of the test animals. *Therapeutic index -:It is the ratio of doses required to produce toxic or lethal effect and required to elicit desirable therapeutic effect. The most commonly used index of effect, weather it beneficial or toxic ,is median dose (i.e.) ED50 , TD50, LD50.Therapeutic index (TI) is approximate statement about relative safety of drug LD50 or TD50 TI = ----------------------- ED50 The highest the ratio, the safest is the drug. Types of Toxicology -:Three specialized types of toxicology 1. -Forensic Toxicology: - Mixture of analytical chemistry and fundamental toxicological principles, It is concerned with medicological assessment of the effects of toxic agent in human and animal and establish cause of death. 2. -Environmental Toxicology -:Study the effect of pollutants on living organism and to assess the risk to animal and human being that live in this environment. 3. -Clinical Toxicology -:Area of professional of medical science (clinic) concerned with disease or poisoning caused by toxic substances and their treatment. 2 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 *Mutation:-State that cause change or damage of genetic material and could transmitted during cell division leading to carcinogenesis , teratogenesis or genetic disease. *Carcinogenesis - :State in which substance (carcinogen) responsible for formation cancer. *Teratogenesis-:State in which teratogen taken by mother at some definitive stage of pregnancy and cause abnormalities or anomalies in fetus and newborn. Classification of Toxic Agents - :Toxic agents are classified in variety of ways. 1. Target organ (Liver,kidney, hematopoietic system ) 2. Use (pesticide, solvent, food additive) 3. Source (animal, plant ) 4. Effect (cancer, mutation, liver injury) 5. State -:physical ( gas , dust, liquid) 6. Chemical ( aromatic amine ,organophosph compounds (OPC),halogenated hydrocarbon). 7. Labeling requirements Oxidizer, Flammable, Irritant. 8. Poisoning potential (extremely toxic, moderately and slightly toxic) 9. Mechanism of action ( Methemoglobinemia , enzyme inhibitor). Types of toxicity-: They can be divided according to the dose and period of exposure. 1. Acute Toxicity -:Sudden violent syndrome caused by a single large dose or repeated exposure to toxicant within 24 hours 3 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 and cause high mortality and severe toxic symptoms. LD50 is a measure of acute toxicity. 2. Subacute Toxicity-: Repeated large toxic doses for a period less than one month, with severe toxic symptoms and some mortality. 3. Subchronic Toxicity -:Repeated moderate to low toxic doses for a period less than three months with moderate toxic symptoms. 4. Chronic Toxicity:-Long term condition by repeated small doses for a period more than three months with or without any toxicity symptoms , It is mainly used to study carcinogenicity and accumulation. Toward and Untoward effect of drug -Toward effect -:It is the main therapeutic or pharmacological effect of drug in the body. -Untoward effect -: This is the effect that accompanies therapeutic effect and it is may be desirable or undesirable and is include; 1-Secondary effect:-Secondary pharmacological effect that accompanied therapeutic effect and consider some times as desirable effect e.g atropine. 2-Side effect:-Secondary predicted undesirable effects that accompanied the therapeutic effect e.g (Aminoglycosides. 3-Adverse effect -: Unpredicted undesirable effect caused by drug used at recommended dose e.g. Allergy to penicillin or Idiosyncracy. a) Allergic reaction: Is an adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one, it is a result of antigen-antibody reactions and 4 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 occurs usually at low doses of the chemical, allergic reactions are often severe and many are fatal. b( Idiosyncratic reaction: Is genetically determined abnormal reactivity to a chemical, may takes extreme sensitivity to low doses or extreme insensitivity to high doses of the chemical.e.g. standard dose of succinylcholine in certains patient produces prolonged muscular relaxation and apnea because of they have an atypical pseudocholinesterase in plasma( is genetically determind). Some people sensitive to Nitrites and other chemicals that produce methemoglobinemia, this occurs due to deficiency of NADH methemoglobin reductase(autosomal recessive trait). -Toxic effect -:Damaged effect to certain biological, system or process caused by poison or drug at high doses. - Xenobiotics-:They are substances which not enter any biological processes or used as source of energy or nutrition ,so they consider as foreign compounds ,(e.g.) drugs ,heavy metals , insecticides TOLERANCE:Is 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. Two major mechanism are responsible for tolerance. i. Decreased amount of toxicant reaching the site(dispositional tolerance).e.g. CCL4( decrease formation of reactive metabolite trichloromethyl radical)and Cadmium( induce metallothioneine). ii. Reduced responsiveness of a tissue to the chemical. Role of toxicokinitic in Toxicity The interesting of toxic effect depends on the 5 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 1- concentration 2-persistent of ultimate toxicant at the site of action. Ultimate toxicant:- is chemical species that is formed by metabolic activation act to react with an endogenous target molecule or critically alter the biological environment initiating structural or functional alteration that results in toxicity. The ultimate toxicant can be the original chemical to which the organism is exposed, a metabolite (electrophile that reacts with nucleophile), or reactive oxygen or Nitrogen species(ROS or RNS) generated during the biotransformation of toxicant or endogenous molecule. The following diagram shows the potential stages in the development of toxicity. 6 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Figure: Potential stages in the development of toxicity after chemical exposure. Toxicokinitic 7 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 The concentration of the ultimate toxicant at the target molecule depends on the relative effectiveness of the processes that increase or decrease its concentration at the target site (a system that showed a higher toxic effect). The accumulation at its target is facilitated by (absorption ,distribution ,reabsorption and toxication or metabolic activation ) ,while (presystemic elimination ,distribution away from the site of action ,excretion and detoxication )oppose these processes and work against the accumulation of the ultimate toxicant at the target molecule. The following diagram shows toxicokinitic processes that increase or decrease toxicity. 8 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Figure: The role of toxicokinetics in the development of toxicity 1- Absorption versus presystemic elimination -Absorption:- is transfer of chemical from the site of exposure ,usually external or internal body surface ,into systemic circulation.Several factors influence absorption 1-concentration 2-surface area of exposure 3-Characterstic of epithelial layer through which the toxicant is being absorbed.Lipid solubility is usually the most important factor because it is the absorbable form. -Presystemic elimination :-During transport from the site of the exposure to systemic circulation , toxicant may be eliminated before enter general circulation.This is common for chemicals absorbed from GIT, because they may pass through GI mucosal cell ,liver ,and lung before being distributed to the rest of the body by systemic circulation.The GI mucosa and liver may eliminate significant fraction of toxicant during passage through those tissue by metabolism and/or excretion through bile.Presystemic or first –pass elimination contribute in reduce concentration of toxicant in general circulation and so reduce their toxic effect at the target site. 9 Page University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 2- Excretion versus reabsorption The route and speed of excretion depend largely on physiochemical properties of toxicant. The major excretory organs are (kidney ,liver ,and GIT) for removing highly hydrophilic chemical such as organic acid and bases.Lung is very important organ for excretion of irritant gases, volatile liquids or aerosol (air pollutant),while excretion in milk is important for public health interest. -Reabsorption mainly occurs in renal tubule and contribute in increase the concentration of xenobiotics in blood circulation and so increase their toxicity. 3- Distribution toward versus away from target site - Distribution toward target site(tissue or organ)by crossing their membrane mainly and binding with target molecule (protein ,nucleic acid or cell organelles )either covalently or non covalently (ionic or hydrogen bonding ).Lead to development of toxicity in the target site. The facility of distribution to target depend on the porosity of capillary of endothelium (hepatic sinusoid and kidney have large fenestrate 50-150 nm in diameter that permit even protein bound xenobiotics),accumulation in cell organelles ( xenobiotice with amine group and lipophilic character accumulate in lysosome and mitochondria) and specialized transport like Na+,K+/ATPase and endocytosis. -Distribution away from target site to a storage depot(fat or bone) will protect the target site and reduced toxicity of xenobiotic. 4-Toxication versus detoxication Page 10 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Toxication :- Biotransformation to harmful product (ultimate toxicant) capable for binding with endogenous molecule (target molecule) causing toxic effect. Detoxication: -Biotransformation that eliminates the ultimate toxicant or prevents its formation. There are several mechanisms of detoxication:- a) Addition of functional groups e.g. benzene and Toluene haven't functional group ,they are initially detoxified by introducing functional groups as hydroxyl or carboxyl and the endogenous acid such as glucoronic acid ,sulfuric acid or an amino acid is added to functional group by transferase. b) Detoxication of nucleophiles by preventing conversion to free radicals. c) Detoxication of electrophiles involves the conjugation with glutathione (anti-oxidant). d) Detoxication of free radicals to water by different enzymatic reactions. e) Detoxication of protein toxins : proteases are involved in the inactivation of toxic polypeptides and venoms.e.g. thioredoxin reduces the disulfide bond of erabutoxin and phospholipase. Log dose toxic response effect Binding of ultimate toxicant with target molecule in the target site will lead to development of toxic response ,according to log Page 11 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 doses of toxicant which lead either to graded or quantal (all or none) toxic response as in the graph. Quantal LDR mainly used for determination of ED50 ,TD50 ,LD50 and for estimation of safety of drugs. Mechanism of Toxicity of Toxicant 1-Direct damage effect by an irritant toxicant like Riot gasses or strong acid or alkalis. 2- Displacement of some important element by competition for binding in plasma or tissue protein leading to disturbance or damage of some biological system. e.g Page 12 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Lead and Calcium in children CNS leading to encephalopathy ,Sulphonamide and Hypoglycemic drugs[plasma protein (albumin)} hypoglycemic coma. 3-Inhibition of some important enzyme leading to inhibition of biological. Inhibit CN Cytochrome oxidase Histotoxic anoxia Inhibit Lead ALAD aminolivulanic acid Anemia 4-Induction and Oxidative change or lipid peroxidation in certain tissues leading to damage of cell membrane and necrosis or DNA damage (mutation ). CCL4 Liver (O3) OZONE Oxidative stress in tissues Page 13  University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 5-Binding with tissue macromolecule like protein.leading to development of allergy(ricin or phytotoxin) or may cause DNA adduct Mutation (gentoxic effect). 6-Asphyxiant effect due to binding and change in chemical structure of hemoglobin that lead to loss ability to transport oxygen to tissue. HbFe+2 Co Carboxyhemoglobin Anoxia HbFe+2 (NO3)Nitrite Methemoglobin (HbFe+3 ) & Amine(NH2) 7-Metabolic activation (toxication) to highly reactive metabolite (electrophil or nucleophil ) that covalently bind to each other leading to development of mutation ,cancer or teratogenic effects. Nitrosamine (cigarate smoke) Cancer Β-naphthalamine Bladder cancer Factors Affecting The Action of toxic Agent Page 14  University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 1-Dose ; Increase dose of toxic agent cause increase effect and toxicity symptoms especially for xenobiotic depending on period and exposure.Toxic dose usually determined by LD50 ,that used to determine toxicity rate according to oral route in rat. TOXITY RATING Rate class oral LD50 in rat mg/kg Example ------ ------ ------------------------------ ------------- 6 super toxic less than 5mg Strychnine 5 Extremely toxic 5-50 Opium toxic 50-500 phenobarbitone 3 moderately toxic 500-5000 kerosine 2 slightly toxic 5000-15000 Ehanol 1 practically non toxic over 15000 linseed oil 2-Physical and chemical nature:- physical form(gas , liquid , solid, radiation ) will effect absorption by different routes.Any change in chemical form due to metabolism or isomerization also effect toxicity (carcinogen). 3-Single or repeated exposure:- According to dose and exposure (acute ,subacute, subchronic, chronic).chronic exposure may lead to development of resistance (tolerance ),allergy ,accumulation ence in case of narcosis. Page 15 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 4-Species:-Different species with different effect due to difference in anatomy(monogastric and ruminant ) and metabolism (Lacking of some enzyme). 5-Size ,age and sex :- LD50 according to animal weight.young and old animal more susceptible to toxicity due to low metabolism ,excretion and resistance. Sex have low effect but in rat show more effect may be due to physiological performance and resistance. 6-General state of health :- Disease and debilitated animals more susceptible to toxicity. 7-Diet:-Any change in diet (vitamin.mineral , protein, fat)will effect toxicity. 8-Route of administration:- Different routes with different absorption rate ,some poisons only toxic by certain route (snake venom). 9- Strain and genetic factor :- Different strain may show different toxic susceptibility due to difference in genetic factor. Some individuals show(genetically determined abnormal reactivity to therapeutic doses of drug due to lack of some important enzyme e.g, Lack enzyme pseudocholinestrase Succinylcholine apnea this called idiosyncracy. Diagnosis of Toxicity Difficult but proceed on four to five evidence 1-Symptomatic evidence according to specific symptoms. Page 16  University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 2-Cicumstanstial evidence searching for sources of poisoning. 3-Pathological evidence gross and histopathological examination. 4-Analytical evidence analysis samples for determination of significant toxic amount in different organ and tissues. 5-Expermintal evidence by dosing of suspected material in laboratory animal to determine toxicity. Treatment of Toxicosis Treatment should be done as quickly as possible and proceed at 4 lines. 1-Prevention of further absorption of toxicant. First step;- Remove the suspected material so no more will be ingested (by washing ). Second step:- Remove any poisonous material ingested but not yet absorbed by using of emetic (1% copper sulphate or abomorphine or gastric lavage using ringer lactate or saline and adsorbent as charcoal ). In case of ruminant ,ruminatomy for removal of toxicant. Step three :- Removal of toxic material which is passed from stomach into gut by using of purgative ( Magnesium ,sodium sulphate ). Page 17 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 2-Enhancment of nonspecific elimination from the body by the use of Diuretic or ion trapping or by dialysis ( Hemodialysis , peritoneal dialysis or hemoperfussion 3-Supportive and symptomatic treatment :- Aim to keep the vital functions of body working until the poison neutralized by the anti dote or eliminated by the body defense mechanism.In general treat symptomatically.+ Coma Stimulant (amphetamine). Convulsion Anticonvulsant (phenobarbitone). Dehydration due to diarrhea or vomiting I.V physiologic sol. 4-Specific treatment by antidote:- After diagnosis,proceed by seven mechanisms. Mechanism (1) :- Antidote complex with poison making it inert. Principally make inert complex to reduce concentration of free poison and dissociate it from tissue. Ex 1- Chelating agent like (BAL , pencillamine , EDTA-Ca) are used to treat heavy metal poisoning like As ,Hg ,Cd ,Pb. Ex2-OPC insecticide (irreversible choline esterase inhibitor treatment by Pralidoxime (2PAM + atropine ). Ex3-Boyulinus ,tetanus ,Diphtheria toxin ,snake venom Specific anti toxin and antibodies. Mechanism (2):- Antidote accelerated metabolic conversion of poison (Detoxification ) to non toxic product. Ex-Cyanide treatment by Thioslfate. Page 18 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Mechanism (3):- Antidote block metabolic formation of poison (Intoxication) from less toxic precursor. Trt Ex1 – Methanol Ethanol Trt Ex2- Fluoroacetate(Rodenicide) Acetate – monocetin Mechanism(4) Antidote specifically accelerate excretion of poison. Trt Ex1- Bromide Chloride Trt Ex2-Strontium Calcium salt Mecanism (5):- Antidote compete with toxicant agent for essential receptor (Displacement competition ). Trt Ex1- CO O2 Trt Ex2-Morphine and related narcotic Nalaxone. Page 19 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Mechanism( 6 ) Antidote block receptor responsible for toxic effect (causing blocker). Ex- Cholinesterase inhibitors atropine. (Neostigmine ,Edrophonium). Mechanism(7) Antidote restore normal function by repairing of damaged process or by passing effect of poison by the compensation with the inhibited end produce. Trt Ex- Agent that produce methemoglobinemia Methylene blue (NO2 ,Cl,Sulphonamide,Acetnilide) Trt Ex- Mercaptopurine(Anticancer-DNA antagonist Purine Inhibit purine synthesis By passing Scope of toxic effect Local versus systemic effect:- local effect refer to that occur at the site of application e.g. caustic chemical ,inhalation of irritant chemical (Riot gas ). While systemic effect need absorption and distribution to the organ or site of toxic effect (target organ) e.g. Hg ,Cd. Some toxic agent show both local and systemic effect e.g. snake venom. Reversible versus irreversible effect :- The ability to regenerate will determine whether the effect is reversible or irreversible (Liver ,CNS). Page 20 University Of Baghdad Clinical Toxicology College of Vet , Medicine Prof Dr. Falah M K AL-rekabi 202 Immediate versus delayed effect:- Carcinogen need latent period (years) to exert carcinogenic effect (diethylstilbestrol, this called delayed effect.). While most toxic agent showed an immediate toxic effect depending on the dose.e.g. CN. Page 21