Toxicology Lecture PDF

Toxicology DR.MAMDOUH ORABY  Introduction Mechanism of toxicity A. Toxicokinetic: Refers to how the body affects the poison through absorption & distribution & metabolism & excretion (ADME) B. Toxicodynamic: Refers to how the toxin a...

Toxicology DR.MAMDOUH ORABY  Introduction Mechanism of toxicity A. Toxicokinetic: Refers to how the body affects the poison through absorption & distribution & metabolism & excretion (ADME) B. Toxicodynamic: Refers to how the toxin affects the body (mechanism of toxin action & signs and symptoms of toxicity)  Introduction Mechanism of toxicity ❑ Factors determining the severity of toxicity: 1) Concentration (dose) of the toxin. 2) Duration of the organ exposure to the toxin 3) Rate and amount of toxin absorption at the site of absorption. 4) Ability of the toxin or its metabolite to pass through cell membranes 5) Rate of toxin biotransformation & nature of metabolite 6) Rate of toxin excretion 7) Age & and health status of the predisposed individuals  Introduction A-Toxicokinetic (disposition) 1- Absorption Absorption of a chemical is performed through Skin, GIT, or lung into the systemic circulation.  Introduction A-Toxicokinetic 1.1. Absorption from GIT: ❑ pH: Weak acidic agents (ex: aspirin) are highly absorbed from the stomach (unionized form → lipid soluble). Weak basic agents (ex: amphetamine) are highly absorbed from the intestine (unionized form → lipid soluble).  Introduction A-Toxicokinetic ❑ Amount and type of food: Presence of food in stomach delays the absorption of poisons. Empty stomach → ↑ toxicity of the poison ❑ Proteins & fats Delays the absorption of chemicals 1.2. Absorption from Skin: Factors affecting absorption of a chemical (xenobiotic) from the skin;  Introduction Toxicokinetic I. Condition of the skin (such as cuts, abrasions). II. Thickness of the skin (arms are thin whereas palms are thick) III. Presence of corrosives (ex: acids and alkalis) → ↑ the permeability of the skin → ↑ absorption of chemicals. IV. Nature of the skin: DDT is more easily absorbed from the chitinous exoskeleton of insect skin than mammalian ҆s skin.  Introduction Toxicokinetics 1.3. Absorption from lung: ❑ Factors affecting absorption of chemicals from the lung: Particle size of the chemical: Small particle size xenobiotics (< 1 μm) pass through alveoli to blood stream.  Introduction Toxicokinetics 2- Distribution: Distribution of chemicals from plasma to extracellular space and then into cells. Factors affecting distribution of a chemical; 2-1. Volume of distribution (Vd): is the apparent volume into which a chemical is distributed. ▪ Chemicals with Small Vd = high plasma concentration ▪ Chemicals with Large Vd = low plasma concentration  Introduction Toxicokinetics ❑ Vd Decides whether the toxicant can be eliminated from systemic circulation (such as dialysis) or not depends on Vd of the chemical. ❑ N.B: Chemicals with small Vd can be easily eliminated from systemic circulation and vice versa.  Introduction Toxicokinetics 2.2. Plasma protein binding: ❑ Xenobiotics with strong plasma protein binding, cannot leave the capillaries by diffusion. ❑ Dissociation from plasma proteins (free form of the chemical) is required for most xenobiotics to leave the blood and enter tissues. Therefore, strong binding to plasma proteins delays and prolongs the effects and elimination of toxicants and vice versa  Introduction Toxicokinetic ❑ Ex: DDT has delayed & prolonged toxicity and elimination rate (high protein binding activity). 2.3. Affinity of a chemical to specific tissues: Liver & kidney: ▪ Concentrate most toxicants for elimination and are highly affected by toxins. Bone: ▪ Ex; fluoride & lead & tetracycline are stored in the bone. ▪ N.B: Lead can be mobilized from the bones during pregnancy.  Introduction Toxicokinetic Adipose tissues: ▪ Concentrate highly lipid-soluble chemicals (act as a temporary protective mechanism). ▪ In certain cases (ex; starvation & fasting) toxins may be released into circulation → harmful effects (Ex: insecticides). 2.4. Physiological barriers: Placental barrier: prevents the transfer of hydrophilic substances but it is ineffective against lipophilic substances.  Introduction Toxicokinetic Blood-brain barrier (BBB): ❖ Has extremely tight junctions which don’t allow hydrophilic substances to penetrate unless carrier-mediated, or active transport is involved. ❖ Highly lipophilic substances can cross the BBB.  Introduction Toxicokinetic 2.5. Regional blood flow: ❑ Organs that are rich in blood supply (ex; heart, liver, kidney) tend to accumulate toxins more than poorly perfused organs such as skin & bone.  Introduction Toxicokinetic 3- Metabolism: The process by which the chemical is modified through enzymatic reactions. Chemicals may be converted to more soluble metabolites by enzymatic oxidation, reduction, hydrolysis, or conjugation and therefore easily excreted.  Introduction Toxicokinetics ↑ the polarity of the compound → ↓ its concentration at target organs → ↑ its excretion & ↓ toxicity. Some chemicals may be converted to more active and toxic metabolite than parent compound. ❖ Ex; Methanol is converted to more toxic metabolite formic acid & formaldehyde.  Introduction Toxicokinetic 4- Excretion: ❑Excretion is a physical mechanism where xenobiotics are removed from the blood to the external environment. Toxicants may be eliminated through: ❖ Kidney ❖ Liver ❖ Lung ❖ Sweat ❖ Saliva ❖ Tears  Introduction Toxicokinetic 4.1. Excretion from kidneys ▪ Kidney is main excretion organ and includes glomerular filtration, tubular secretion, and reabsorption.  Introduction Toxicokinetic ❑ Factors affecting excretion from kidney: 1. Urinary pH trapping: ❖ Chemicals can be excreted or reabsorbed from the kidney depending on urinary pH. More ionized chemicals are water soluble → easily excreted in urine. Non-ionized ones are more lipid soluble → easily reabsorbed to the circulation from renal tubules → prolonged toxicity.  Introduction Toxicokinetic I. Alkalinization of urine facilitates excretion of weak organic acids (more ionized). ▪ Ex: Aspirin excretion is promoted by Na bicarbonate. II. Acidification favors excretion of weak organic bases (more ionized). ▪ Ex: Amphetamine & quinidine excretion is promoted by ammonium chloride.  Introduction Toxicokinetic 2. Reabsorption ✓Reabsorption of a toxicant from renal tubules can be promoted by specific transporters. Ex 1: Peptide transporters (PEPT) can move some β-lactam antibiotics & ACEIs from renal tubules to plasma → delayed excretion & enhanced toxicity. Ex 2: Metal transporters (ex; phosphate T) can reabsorb some metals (e.g.; arsenate) → ↑ toxicity  Introduction Toxicokinetic 4.2. Excretion form the liver: Excretion of xenobiotics by hepatocytes is initiated through the bile duct which then flows into GIT for excretion of xenobiotics in the stools (ex: bilirubin, lead). Reabsorption of toxicants from bile occurs if they are sufficiently lipophilic or converted to more lipid-soluble form by conjugation in the intestine.  Introduction Toxicokinetic Ex: Intestinal flora produces β- glucuronidases enzymes that hydrolyze various weak organic acids → more lipid soluble compounds → reabsorption into portal circulation → ↑ the toxicity.  Introduction Toxicodynamic Interaction of toxicants with target organs can lead to: I. Alteration of cell membrane permeability II. Alteration in enzyme activity III. Interference with coenzymes IV. Production of reactive metabolites V. Immunotoxicity VI. Depletion of the antioxidant defense mechanism (ex; glutathione, GSH) VII.Toxicity to DNA and nucleic acids VIII. Disruption of protein synthesis  Introduction Toxicodynamics I. Alteration of cell membrane permeability Ex: Mercury & Arsenic bind to cell membrane proteins containing SH-group. Ex: CCl4 causes lipid membrane peroxidation Ex: Digoxin binds to Na+/K+ ATPase pump → inhibition of cell membrane transport of Ca+2 (out of the cell).  Introduction Toxicodynamics II. Alteration in enzyme activity Toxicants may interact with specific enzymes, causing their inhibition or activation with subsequent changes in resultant biochemical functions. Ex: Carbamate & organophosphate reversibly inhibit cholinesterase enzyme → ↑ Ach.  Introduction Toxicodynamics Ex: Hydrocyanic acid binds to iron in the cytochrome c oxidase → cessation / arrest aerobic respiration. III. Interference with coenzymes Ex: CCl4 produces free radicals that destroy the coenzyme NADPH.  Introduction Toxicodynamics IV. Production of reactive metabolites Some xenobiotics can be metabolized in the liver to reactive toxic metabolite → interference with DNA, RNA, proteins, and lipids. Ex: Paracetamol is oxidized in the liver to the hepatotoxic metabolite NAPQI (N-acetyl- p-bezoquinone imine).  Introduction Toxicodynamics v. Immunotoxicity (allergic reactions): ▪ Results from repeated exposure to chemical or structurally related compounds. ▪ For large polypeptide chemicals, act as antigens that can stimulate toxic immunological reactions. ▪ For other substances with a small molecular structure (Ex; penicillin), act as hapten that can bind to endogenous body proteins to become antigen → stimulating toxic allergic reaction.  Introduction Toxicodynamics VI. Depletion of the antioxidant defense mechanism such as GSH ❑ GSH is an antioxidant enzyme that prevents oxidative stress reactions induced by certain toxicants that lead to destruction of proteins, lipids, cell membranes and DNA. ❑ Some toxicants may lead to depletion of GSH → impairment of cellular defense mechanism against toxicants (e.g. paracetamol).  Introduction Toxicodynamics VII.Toxicity to DNA and nucleic acids ❑ Some toxicants cause damage to DNA & RNA, leading to interference with transcription and translation processes which can induce either mutation or cell death. VIII.Disruption of protein synthesis: ❑ Some toxicants inhibit protein synthesis (ex: Ethionine; antimetabolite). Thank You