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PRINCIPLES OF

TOXICOLOGY

PRINCIPLES of TOXICOLOGY

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OBJECTIVES:
To explain the general nature of toxic
action of substances
 To describe the nature of toxic action and
the effects brought about by chemicals
 To explain the potential stages in the
development of toxicity

PRINCIPLES of TOXICOLOGY

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Introduction to Toxicology

Toxicology is the study of the adverse
effects of chemicals on living organisms.

Toxicologist- one who is trained to
examine the nature of those effects
( cellular, biochemical, and molecular
mechanisms of action) and assess the
probability of their occurrence
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BRANCHES OF
TOXICOLOGY
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Clinical toxicology Effects of substances to patients PRINCIPLES of TOXICOLOGY 5 .

Experimental Effects of chemicals in the biological system  Measures laboratory parameters  PRINCIPLES of TOXICOLOGY 6 .

Descriptive toxicology Toxicity testing  Provide information for safety evaluation and regulatory requirements  SET LIMITS  PRINCIPLES of TOXICOLOGY 7 .

Mechanistic toxicology Mechanism of action or MOA of poisons  Data may be useful in the design and production of safer chemicals and in rational therapy for chemical poisoning and treatment of disease  Data is useful in demonstrating that an adverse outcome observed in laboratory animals is directly relevant to humans  PRINCIPLES of TOXICOLOGY 8 .

Regulatory toxicology  Involved in the establishment of standards for the amount of chemicals permitted in foods. drugs. industrial atmosphere and drinking water PRINCIPLES of TOXICOLOGY 9 . air.

birds.Environmental toxicology  Studying the impacts of chemicals on non human organisms such as fish. terrestrial animals and plants PRINCIPLES of TOXICOLOGY 10 .

Forensic toxicology  Medico-legal cases of poisoning and intoxication PRINCIPLES of TOXICOLOGY 11 .

Paracelsus “All substances are poisons. The right dose differentiates a poison from a remedy. there is none which is not a poison.” Paracelsus (1493-1541) PRINCIPLES of TOXICOLOGY 12 .

The fundamental principle of toxicology is the individual’s response to a dose.An Individual View “The sensitivity of the individual differentiates a poison from a remedy. G.” S. Gilbert (1997) PRINCIPLES of TOXICOLOGY 13 .

Poison Any agent that may cause harm or serious injury PRINCIPLES of TOXICOLOGY 14 .

“ every known chemical has the potential to produce injury or death if it is present in a sufficient amount” PRINCIPLES of TOXICOLOGY 15 .

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 PRINCIPLES of TOXICOLOGY 16 .

4 RESPONSE 0-1 NOAEL 2-3 Linear Range 4 Maximum Response 3 2 0 1 DOSE DOSE DETERMINES THE BIOLOGICAL RESPONSE PRINCIPLES of TOXICOLOGY 17 . so does the response.Dose-Response Relationship: As the dose of a toxicant increases.

Dose response assumptions  response is due to chemical administered  the response is related to the dose  there is a receptor site with which the chemical interacts  the degree of response is related to the concentration at the site  the concentration at the site is related to the dose administered  has a quantifiable method of measuring and a precise means of expressing the toxicity PRINCIPLES of TOXICOLOGY 18 .

intramuscular.Exposure: Pathways  Routes and Sites of Exposure ◦ ◦ ◦ ◦ Ingestion (Gastrointestinal Tract) Inhalation (Lungs) Dermal/Topical (Skin) Injection  intravenous. intraperitoneal PRINCIPLES of TOXICOLOGY 19 .

Rapidity of response with respect to route of exposure  Intravenous  Inhalation  Intraperitoneal  Subcutaneous  Intramuscular  Intradermal  Topical PRINCIPLES of TOXICOLOGY 20 .

Exposure: Duration Acute Subacute Subchronic Chronic < 24hr usually 1 exposure 1 month repeated doses 1-3mo repeated doses > 3mo repeated doses Over time. the amount of chemical in the body can build up. or it can overwhelm repair and removal mechanisms PRINCIPLES of TOXICOLOGY 21 . it can redistribute.

Toxins = toxic substances produced naturally PRINCIPLES of TOXICOLOGY 22 .

Toxicants = toxic substances that are produced or a by-product of human activities PRINCIPLES of TOXICOLOGY 23 .

PRINCIPLES of TOXICOLOGY 24 .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.

reduced responsiveness of a tissue PRINCIPLES of TOXICOLOGY 25 . a decreased amount of drug reaching the site  cellular.Tolerance  state of decreased responsiveness to a toxic effect of a chemical. resulting from previous exposure  dispositional tolerance.

Toxicity  describes the degree to which a substance is poisonous or can cause injury. PRINCIPLES of TOXICOLOGY 26 .

and individual human factors.Major factors that influence toxicity  route of administration  duration and frequency of exposure  dose or concentration  shape and structure of the chemical itself. PRINCIPLES of TOXICOLOGY 27 .

PRINCIPLES of TOXICOLOGY 28 .

development or reproduction PRINCIPLES of TOXICOLOGY 29 .What is toxicodynamics ?  It examines the mechanism by which toxicants produce unique cellular effects within the organism Mechanism of toxic action  The alteration to the cell’s plasma membrane. organelles. biosynthetic pathways. cytoplasm. nucleus. enzyme systems.

One toxicant may exert several mechanisms of toxic action. The mechanisms of toxic action in acute exposure may differ from those in chronic exposure. 5. Toxic action of a drug is not necessarily an exaggeration of its therapeutic action. 3. Intensity of a toxic effect depends primarily on the concentration and persistence of the ultimate toxicant at its site of action. The toxic action may be brought about by the parent compound and/or its metabolites. PRINCIPLES of TOXICOLOGY 30 .1. 4. 2.

Allergic Reactions Chemical allergy : immunologically mediated adverse reaction to a chemical or to structurally similar one PRINCIPLES of TOXICOLOGY 31 .1.

Nitrites : deficiency in NADH-methemoglobin reductase PRINCIPLES of TOXICOLOGY 32 . the response observed may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of a chemical E.2. Idiosyncratic Reactions: Chemical idiosyncrasy : refers to a genetically determined abnormal reactivity to a chemical.g.

Delayed Toxicity: Immediate : occurs or develops rapidly after a single administration of a substance Delayed: occurs after a lapse of some Time (months or years) PRINCIPLES of TOXICOLOGY 33 .3. Immediate vs.

4. Reversible: injury to the liver by paracetamol Irreversible: injury to the CNS by ethanol PRINCIPLES of TOXICOLOGY 34 . Irreversible Toxic Effects: E.g. Reversible vs.

5.g. gastrointestinal mucosa Chlorine gas – lung tissue Systemic: absorption and distribution of toxicant from its entry point to a distant site at which deleterious effects are produced E. Caustics (phenol) – kidney damage PRINCIPLES of TOXICOLOGY 35 .g. Systemic Toxicity: Local : site of first contact between biological system and toxicant E. Caustics – skin. Local vs.

th edition CasarettPRINCIPLES & Doull’s.of7TOXICOLOGY 36 .

TOXICATION

Biotransformation to
harmful products

E.g. Ethylene glycol converted to
oxalic acid which produces
acidosis and hypercalcemia

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Non-covalent binding
Covalent binding
Electron transfer
Enzymatic reaction

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Third step: Alteration of regulatory
or maintenance function of the cell

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CELLULAR REGULATION
1. Dysregulation of gene expression

 Dysregulation of transcription
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2. Dysregulation of on-going cellular activity  Alteration in neurotransmitter levels •Methamphetamine/amphetamine increases release and inhibit reuptake of norepinephrine. dopamine and serotonin • Organophosphates decrease hydrolysis of acetylcholine PRINCIPLES of TOXICOLOGY 41 .

Dysregulation of on-going cellular activity  Toxicant-neurotransmitter receptor interaction  INHIBITION Atropine & atropine-like drugs produce inhibitory effect on the muscarinic receptors (M2 and M3) Increased heart rate Decreased bowel sounds Decreased salivation Decreased perspiration  STIMULATION Benzodiazepine stimulating GABA A receptor Sedation PRINCIPLES of TOXICOLOGY 42 .2.

Dysregulation of on-going cellular activity  Toxicant-signal transducer interactions DDT. pyrethroids act on Voltage-gated Na+ channels Neuronal activation Overexcitation Convulsion PRINCIPLES of TOXICOLOGY 43 .2.

Dysregulation of on-going cellular activity  Enzyme reactions Enzyme Inhibition • Pyridoxine kinase • Glutamic acid decarboxylase • Monoamine oxidase • Nicotinamide adenine dinucleotide (NAD) (co-enzyme) EFFECTS: • Seizure • Acidosis • Increased sympathetic activity PRINCIPLES of TOXICOLOGY 44 .2.

CO inhibits cytochrome oxidase) Inhibition of oxygen delivery to electron transport chain (3) (CO. hydrogen sulfide.CELLULAR MAINTENANCE 1. Impaired Internal Maintenance  IMPAIRED ATP SYNTHESIS  Inhibition of hydrogen delivery to ETC (1) (fluoroacetate inhibits aconitase enzyme) Inhibition of electron transport complexes (2) (Cyanide. nitrites) Inibition of ADP phosporylation (4) (DDT & chlordecone inhibit ATP synthase ) PRINCIPLES of TOXICOLOGY 45 .

tissues or whole organism • Inhibition of hepatic synthesis of coagulation factors by coumarin PRINCIPLES of TOXICOLOGY 46 .CELLULAR MAINTENANCE 1. Impaired External Maintenance  Toxicities interfering with cells specialized to provide support to other cells. Impaired Internal Maintenance  Impaired membrane function • Ethanol and organic solvents increase membrane fluidity • Lipid solvents destroy plasma membrane • Hydrocarbons destroy lysosomal membranes 2.

REPAIR Molecular Protein Cellular DNA Tissue Apoptosis Proliferation Lipid Cells ECM Repair Mechanisms PRINCIPLES of TOXICOLOGY 47 .

Tissue necrosis Fibrosis Cancer PRINCIPLES of TOXICOLOGY 48 .

DYSREPAIR • Failure of DNA repair • Failure of apoptosis • Failure to terminate cell proliferation PRINCIPLES of TOXICOLOGY 49 .

SIGNIFICANCE OF TOXICODYNAMICS: Choice of antidotal therapy  Determine magnitude and extent of toxicity  More effective and adequate treatment plan PRINCIPLES of TOXICOLOGY 50 .

PRINCIPLES of TOXICOLOGY 51 .

Study of how a substance gets into the body and what happens to it in the body Modeling and mathematical description of the time course of disposition of toxicants in the whole organism PRINCIPLES of TOXICOLOGY 52 .

Toxicokinetics Only the absorbed dose that makes it to the target organ is capable of producing an effect Xenobiotic Excretion .

PRINCIPLES of TOXICOLOGY 54 . • The concentration in turn depends on the disposition of the chemical.• The effect which a chemical produces is not only dependent on the dose administered but more on the concentration of the chemical in the target organ. • The study of toxicokinetics is important in predicting plasma concentration of a chemical. • The kinetics of a chemical/drug may differ from therapeutic dose to its toxic dose.

A result of a number of opposing actions Some promotes delivery of the Toxicant towards the target Others promote toxicant delivery Away from the target The net effect determines how much of the toxicant makes it to its site of action PRINCIPLES of TOXICOLOGY 55 .

Concentration at site of action Intensity of toxic action Duration of the Ultimate Toxicant At Its Site of Action The Ultimate Toxicant is the species that interacts with the target or critically modifies the biological microenvironment PRINCIPLES of TOXICOLOGY 56 .

The ultimate toxicant can be: The parent compound  A metabolite of the parent  A reactive Oxygen or Nitrogen species  An endogenous compound  PRINCIPLES of TOXICOLOGY 57 .

FOUR PROCESSES IN TOXICOKINETICS ABSORPTION is the process by which a chemical enters the body DISTRIBUTION is the stage when a substance moves from the site of entry to other organs/areas of the body METABOLISM is when the body transforms the chemical into metabolites EXCRETION is the process wherein the parent chemical and its metabolites leave the body PRINCIPLES of TOXICOLOGY 58 .

Distribution. antioxidants ◦ Elimination mechanisms .  The body has defenses:  ◦ Membrane barriers  passive and facilitated diffusion. active transport ◦ Biotransformation enzymes. and Excretion Once a living organism has been exposed to a toxicant.Absorption. Metabolism. the compound must get into the body and to its target site in an active form in order to cause an adverse effect.

FACTORS AFFECTING KINETIC PROCESSES • Duration and concentration at the portal of entry the higher the concentration. the organ in which a chemical is most highly concentrated is not necessarily the organ where most tissue damage occurs. the greater will the damage be • Rate and amount of chemical absorbed rate of absorption is slow and the amount absorbed is small. the toxicity will be low • Distribution of the toxicant within the body  most of the toxicants are distributed in highly perfused organs which have vital functions such as the brain and the kidneys. PRINCIPLES of TOXICOLOGY 60 .

FACTORS AFFECTING KINETIC PROCESSES • Efficiency of biotransformation and nature of metabolites a chemical maybe converted to a toxic metabolite which is more toxic than the parent compound •Ability of the chemical or its metabolites to pass through cell membranes and come into contact with specific cell components a chemical can pass through the placenta or the blood brain barrier • Amount and duration of storage of the chemical or its metabolites in body tissues some chemicals are stored in body tissues for a long period of time and would produce its effect long after the initial exposure PRINCIPLES of TOXICOLOGY 61 .

PRESYSTEMIC ELIMINATION First pass effect DISTRIBUTION AWAY FROM THE TARGET SITE Binding to plasma proteins because protein-bound chemicals do not exert toxic action Specialized barriers such as blood-brain barrier which prevent entry of hydrophilic chemicals into the brain Storage sites which are not target sites of chemicals and where the chemicals are highly concentrated Association with intracellular binding proteins which are non-target intracellular sites Export from cells wherein chemicals are transported back into the extracellular space PRINCIPLES of TOXICOLOGY 62 .

usually ionized chemicals such as weak acids and bases. PRINCIPLES of TOXICOLOGY 63 .DETOXIFICATION Biotransformation of chemical prevents its formation I nto ultimate toxic metabolites and enhances its elimination EXCRETION The liver and the kidneys can remove efficiently highly hydrophilic. gastrointestinal tract and the breastmilk. Other processes include the bile.

Involves the movement of chemcials across cell membranes Phospholipid bilayer PRINCIPLES of TOXICOLOGY 64 .

Factors affecting gastrointestinal absorption of drugs/ chemicals in their toxic states • Type of cells at the specific site • Contact time • pH of the stomach and small intestine • Concentration of the drug/chemical at absorption site • Presence of food or binding substances • Rate of gastric emptying • Gastrointestinal motility • Large absorbing surface of the small intestines • Blood flow to the site • Intestinal microflora and GI enzymes • General condition of the patient • Product formulation PRINCIPLES of TOXICOLOGY 65 .

rate of transfer from alveoli to blood is dependent on perfusion If high.• Solubility of the chemical in the blood (blood/gas coefficient) If low. rate of transfer from alveoli to blood is dependent on ventilation • Particle size • Water solubility PRINCIPLES of TOXICOLOGY 66 .

• Condition of the skin • Body region • Lipid solubility PRINCIPLES of TOXICOLOGY 67 .

Movement of chemicals throughout the body within the bloodstream PRINCIPLES of TOXICOLOGY 68 .

• Blood flow/perfusion limitation • Permeability limitation Capillary membrane passage Cell membrane passage • Apparent volume of distribution • Protein binding • Effect of pH • Age • Tissue reservoir/depots Plasma proteins Liver and kidneys Fat Bone PRINCIPLES of TOXICOLOGY 69 .

PRINCIPLES of TOXICOLOGY 70 . typically for energy production • Biotransformation process by which both endogenous.• Process by which the body alters chemicals. and exogenous substances that enter the body are changed from hydrophobic to hydrophilic molecules to facilitate elimination.

PRINCIPLES of TOXICOLOGY 71 .The highest capacity for biotransformation is the liver.

Metabolism = Toxification /Detoxification Toxication = increase in toxicity Detoxification = decrease in toxicity PRINCIPLES of TOXICOLOGY 72 .

Toxication Change in Structure increases interaction with target molecule Changes in general reactivity lead to the formation of • electrophiles • free radicals • nucleophiles PRINCIPLES of TOXICOLOGY 73 .

addition of endogenous acid (conjugation) Product: hydrophilic organic acids  Electrophiles – conjugation with glutathione – a thiol nucleophile  PRINCIPLES of TOXICOLOGY 74 .oxidation via CYP450 ◦ Phase II .Detoxication To be eliminated from the body more efficiently – must be hydrophilic and ionized  Compounds with no functional groups  ◦ Phase I .

sulfation TOXICANT PHASE I PRIMARY PRODUCT PHASE II SECONDARY PRODUCT ELIMINATION FROM BODY PRINCIPLES of TOXICOLOGY 75 . hydration • Phase II reactions Glucuronidation. reduction.• Phase I reactions Oxidation. hydrolysis.

When does detoxication fail? Toxicants overwhelm the detoxication processes Reactive toxicants deactivate a detoxicating enzyme Conjugation reactions are reversed Reactive degradation products are formed by detoxicating enzymes PRINCIPLES of TOXICOLOGY 76 .

         Age Sex Pharmacogenetic factors Pregnancy Nutritional status/ body size and weight Disease states Bioactivation Enzyme induction/inhibition Changes in kinetic mechanisms PRINCIPLES of TOXICOLOGY 77 .

Process by which the body separates and discharges wastes or toxic substances from the body PRINCIPLES of TOXICOLOGY 78 .

• Other routes: Fecal Respiratory Cerebrospinal fluid Milk Sweat Saliva PRINCIPLES of TOXICOLOGY 79 .• Most important organ for excretion is the kidney.

• Age • Disease states • Rate of excretion • Enterohepatic recirculation • Ion trapping PRINCIPLES of TOXICOLOGY 80 .

Phenomenon by which drugs emptied through the bile into the small intestine can be reabsorbed from the intestinal lumen into systemic circulation. bacterial flora convert the parent drug and its active metabolites back into lipophilic states PRINCIPLES of TOXICOLOGY 81 . When reaching the distal ileum.

persistent molecules Some volatiles and non-reactives may leave via the lung PRINCIPLES of TOXICOLOGY 82 . weak acids and bases No effective removal of lipophilic.Removal of Chemicals from the body Primary Structures: • Kidney • Glomerular filtration • Tubular excretion • Liver Usually water soluble and ionic.

compounds secreted as ionics can be modified by gut bacteria – then reabsorbed  Enterohepatic Recirculation  PRINCIPLES of TOXICOLOGY 83 .Retention of Chemicals in the Body In the renal tubule. toxicants can be reabsorbed prior to excretion:  In the GI tract.

• Aspirin • Carbamazepine • Dapsone • Digoxin • Methamphetamine • Paracetamol • Phencyclidine • Phenothiazine • Phenobarbital • Phenytoin • Quinine • Rifampicin • Salicylates • Theophylline • Anticoagulants • Naphthalene • Organochlorine pesticides PRINCIPLES of TOXICOLOGY 84 .

Winston Churchill PRINCIPLES of TOXICOLOGY 85 .