Toxicology- Scope and Principles

This is all about the history, principles of toxicology, and its scope.

1. SCOPE & PRINCIPLES OF TOXICOLOGY

2. 22-Mar-21 2 VPT 608 All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy Paracelsus

3. TOXICOLOGY Greek word- Toxicon = poison & Logos = to study Science of poisons Study of poisons that include their physical & chemical properties, detection & identification, biological effects, treatment & prevention of disease conditions produced by them Study of the adverse effects of xenobiotics on living systems Assimilates knowledge & techniques from biochemistry, biology, chemistry, genetics, mathematics, medicine, pharmacology, physiology & physics 22-Mar-21 3 VPT 608

4. POISON Any substance which when taken inwardly or applied in any kind of manner to body, depresses the health or entirely destroys life TOXICANT Synonym of poison TOXIN Poisons produced by living organisms in quantities- phytotoxins , mycotoxins , zootoxins, bacteriotoxins , VENOM A toxicant synthesised in specialised gland & ejected by process of biting & stinging 22-Mar-21 4 VPT 608

5. XENOBIOTICS Greek Xeno = Alien or Strange Substances which are foreign to body & are biologically active Cannot be broken down to generate energy or be assimilated in a biosynthetic pathway Natural & man made chemicals Drugs, industrial chemicals, pesticides, alkaloids, secondary plant metabolites, toxins of plants, molds & animals, environmental pollutants 22-Mar-21 5 VPT 608

6. HISTORY Ebers Papyrus (1 500 bc)- hemlock, aconite, opium, metals such as lead, copper & antimony The Book of Job (1400 bc)- poison arrows Hippocrates (400 bc) -poisons and clinical toxicology- bioavailability in therapy & overdosage Theophrastus (370–286 bc)- poisonous plants in De Historia Plantarum Dioscorides - classified poison as plant, animal, mineral De Materia Medica Mithridatic - antidote or protective mixture Sulla issued Lex Cornelia - first law against poisoning- regulatory statute directed at careless dispensing of drugs 22-Mar-21 6 VPT 608

7. Contd ….. Arsenic containing poisons- Aqua toffana ( Toffana ) Socrates executed with the extract of hemlock Catherine de Medici- La Voisine - tested toxic concoctions, rapidity of the toxic response (onset of action), the effectiveness of the compound (potency), the degree of response of the parts of the body (specificity and site of action), & the complaints of the victim ( Clinical signs and symptoms ) Writings of Maimonides - treatise on the treatment of poisonings from insects, snakes, & mad dogs (Treatise on Poisons and Their Antidotes, 1198) Described bioavailability- milk, butter & cream delay intestinal absorption 22-Mar-21 7 VPT 608

8. Contd ….. Dosis facit venenum (dose that makes a poison)- Paracelsus Focused on the primary toxic agent as chemical entity Experimentation is essential in the examination of responses to chemicals One should make distinction between therapeutic and toxic properties of chemicals These properties are sometimes but not always indistinguishable except by dose One can ascertain degree of specificity of chemicals, their therapeutic or toxic effects 22-Mar-21 8 VPT 608

9. Contd ….. Occupational Toxicology- Miners’ Sickness and Other Diseases of Miners (Paracelsus,1567) & Discourse on the Diseases of Workers (Bernardino Ramazzini , 1770) Percival Pott’s (1775) - role of soot in scrotal cancer among chimney sweeps first report of poly aromatic hydrocarbon carcinogenicity Modern Era Magendie, Orfila & Bernard lad i the ground work for pharmacology, experimental therapeutics & occupational toxicology Friedrich Serturner - isolated specific narcotic substance from Opium & called it as Morphine 22-Mar-21 9 VPT 608

10. Contd ….. M.J.B. Orfila - Father of Toxicology- Study of poisons Used autopsy material & chemical analysis systematically as legal proof for poisoning Magendie studied the mechanism of action of emetine & strychnine – Father of Experimental Pharmacology Louis Lewin - Classified drugs & plants according to their psychological effects 22-Mar-21 10 VPT 608

11. AREAS OF TOXICOLOGY 22-Mar-21 11 VPT 608

12. MECHANISTIC TOXICOLOGY Identifies the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms DESCRIPTIVE TOXICOLOGY Concerned directly with toxicity testing, which provides information or safety evaluation and regulatory requirements REGULATORY TOXICOLOGY Decides whether a drug or chemical poses a low risk to be marketed for a stated purpose based on the data provided by descriptive and mechanistic toxicology FORENSIC TOXICOLOGY Hybrid of analytic chemistry and fundamental toxicologic principles that focuses primarily on the medicolegal aspects of the harmful effects of chemicals on humans and animals CLINICAL TOXICOLOGY Concerned with disease caused by or uniquely associated with toxic substances ENVIRONMENTAL TOXICOLOGY Focuses on the impacts of chemical pollutants in the environment on biological organisms specifically studying the impacts of chemicals on nonhuman organisms such as fish, birds, terrestrial animals & plants DEVELOPMENTAL TOXICOLOGY Study of adverse effects on the developing organism that may result from exposure to chemical or physical agents before conception (either parent), during prenatal development or postnatally until the time of puberty REPRODUCTIVE TOXICOLOGY Study of the occurrence of adverse effects on the male or female reproductive system that may result from exposure to chemical or physical agents 12 VPT 608

13. DOSE VS EXPOSURE Amount of chemical an organism is exposed to per unit body weight (mg/Kg B. W.) Concentration of chemical in either air or water through exposure occurs ppt (g/L),ppm (mg/L, μ g/mL), ppb ( μ g/L, ng /L) 22-Mar-21 VPT 608 13

14. EXPOSURE Toxic effects in a biological system are not produced by a chemical agent unless that agent or its metabolic breakdown products reach appropriate sites in the body at a concentration and or a length of time sufficient to produce a toxic manifestation Whether a toxic response occurs is dependent on the chemical and physical properties of the agent, the exposure situation, how the agent is metabolized by the system, and the overall susceptibility of the biological system or subject 22-Mar-21 14 VPT 608

15. ROUTE & SITE OF EXPOSURE Intravenous (blood stream) Inhalation (lungs) Intraperitoneal Subcutaneous Intramuscular Intradermal Oral (ingestion) Dermal 22-Mar-21 15 VPT 608 ABSORPTION Process of movement of unchanged compound from its site of administration or exposure to blood stream Rate & Extent Duration & Intensity

16. DURATION & FREQUENCY OF EXPOSURE ACUTE Exposure less than 24 h SUB-ACUTE Repeated exposure for 1 month or less SUB-CHRONIC Repeated exposure for 1 month – 3 months CHRONIC Repeated exposure for more than 3 months 22-Mar-21 16 VPT 608

17. Factors Affecting Xenobiotic Distribution Physico chemical properties of toxicant Binding to tissue & plasma proteins Blood flow & organ size Specialised compartments & barriers Availability of specialised transport system Disease status 22-Mar-21 17 VPT 608 DISTRIBUTION Process by which xenobiotics leave blood stream & enter extravascular fluid & tissues

18. CHARACTERISTICS OF TOXIC RESPONSE Every known chemical has the potential to produce injury or death if it is present in a sufficient amount Chemicals producing death in microgram doses are often considered extremely poisonous 22-Mar-21 18 VPT 608

19. BIOTRANSFORMATION Chemical transformation of xenobiotics in body/living organism Inactivation/detoxification DDT DDE & DDA Bioactivation / toxication Malathion Malaoxon Activation Thoicyanates Cyanide 22-Mar-21 19 VPT 608

20. 22-Mar-21 VPT 608 20 Active compound to equally active compound Digitoxin Digoxin Active compound to active metabolite with different pharmacological action Aflatoxin B1 Aflatoxin M1

21. EXCRETION Process by which toxicants are irreversibly transferred from body to external environment Renal excretion Extra renal excretion Faecal excretion Pulmonary excretion Mammary excretion 22-Mar-21 21 VPT 608

22. DOSE- RESPONSE RELATIONSHIP Characteristics of exposure and the spectrum of effects come together in a correlative relationship Individual dose–response relationship- Describes the response of an individual organism to varying doses of a chemical “ Graded ” response - Measured effect is continuous over a range of doses (continual change in effect with changing doses) Quantal dose–response relationship- Characterizes the distribution of responses to different doses in a population of individual organisms 22-Mar-21 22 VPT 608

23. INDIVIDUAL/GRADED DOSE-RESPONSE RELATIONSHIP Characterized by dose related increase in the severity of response Measured in a single biologic unit (a cell, a tissue or organ, or an entire organism) Measured on a continuous scale and the intensity of effect is proportional to the dose Most of the drugs fall in this category – contraction of SI produced by carbachol, inhibition of ChE by OP insecticides Dose response curve - parabola with its origin at zero on both axes Response versus log dose curve- sigmoid (s-shaped) instead of hyperbolic 22-Mar-21 23 VPT 608

24. 22-Mar-21 VPT 608 24 Ceiling dose

25. QUANTAL DOSE RESPONSE RELATIONSHIP Quantal or “all or none” in nature At any given dose, an individual in the population is classified as either a “responder” or a “ nonresponder It is always seen in a population because the assumption is made that individuals responds to maximal possible or not at all Log dose response- sigmoid Normal or gaussian distribution Quantal response is more used in toxicology to determine LD50 and ED50 22-Mar-21 25 VPT 608

26. Animals responding at high frequency at the left end of the curve- Hypersuceptible and those at right end- Resistant Flat dose response curve - large change in dose required to produce significant change in response Steep response curve - small change in dosage cause large change in response 22-Mar-21 26 VPT 608

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28. SHAPE OF DOSE- RESPONSE CURVE Essential nutrients Shape of the “graded” dose–response relationship is actually U-shaped 22-Mar-21 28 VPT 608

29. Hormesis Nonnutritional toxic substances may impart beneficial or stimulatory effects at low doses but, at higher doses, produce adverse effects U-shaped dose–response curve 22-Mar-21 29 VPT 608

30. Nonmonotonic Dose Response Curves Some chemicals, the endocrine disruptors, exert effects at low doses that are not evident at high doses Produce nonmonotonic doseresponse curves Curves may result from upregulation of some receptors at low doses with downregulation of those receptors at higher doses E.g. Bisphenol A 22-Mar-21 30 VPT 608

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32. VARIATION IN TOXIC RESPONSES 22-Mar-21 32 VPT 608 SELECTIVE TOXICITY Chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact SPECIES DIFFERENCES Both quantitative & qualitative differences in response to toxic substances may occur among different species INDIVIDUAL DIFFERENCES IN RESPONSE

33. SPECTRUM OF UNDESIRED EFFECTS Pharmacological, pathological and genotoxic Depending upon the concentration of chemical, toxic effects are usually reversible Pharmacological effects discontinue due to biotransformation, while pathological and genotoxic effects are usually reversible Allergic reactions An adverse reaction that result from previous exposure to a particular chemical or to one that is structurally similar Hapten + Endogenous protein antigen antibody complex subsequent exposure allergy 22-Mar-21 33 VPT 608

34. Idiosyncratic reactions Genetically determined abnormal reactivity to a test This response could be in the form of extreme sensitivity to low doses or increased insensitivity to high doses of a chemical These genetic polymorphism can be due to interindividual differences in drug pharmacokinetics or pharmacodynamics This knowledge is used to individualize dosages in a science known as pharmacogenomics 22-Mar-21 34 VPT 608

35. Local Vs Systemic toxicity Local toxicity occurs at the site of first contact between the toxicant and the biological system Systemic toxicity requires absorption and distribution of the toxicant A toxicant may produce both effects Severity of local toxicity depends on the portal of entry 22-Mar-21 VPT 608 35

36. Reversible Vs irreversible toxic effects Depends on the tissue capacity to regenerate at molecular, cellular and tissue levels Immediate Vs Delayed toxicity Immediate toxicity-Develops rapidly after a single administration Delayed toxicity- occur after a lapse of some time 22-Mar-21 VPT 608 36

37. XENOBIOTIC INTERACTIONS Additive When the combined effect of two chemicals is equal to the sum of the effects of each agent given alone Synergism When the combined effects of two chemicals are much greater than the sum of the effects of each agent given alone Potentiation When one substance does not have a toxic effect on a certain organ or system but when added to another chemical makes that chemical much more toxic ( Isopropanol & CCl ₄) Antagonism When two chemicals administered together interfere with each others actions or one interferes with the action of the other 22-Mar-21 37 VPT 608

38. Functional antagonism Occurs when two chemicals counterbalance each other by producing opposite effects on the same physiologic function Eg- marked fall in BP during severe barbiturate intoxication can be effectively antagonized by the intravenous administration of a vasopressor agent such as norepinephrine or metaraminol Chemical antagonism or inactivation Simply a chemical reaction between two compounds that produces a less toxic product Eg- chelators of metal ions decrease metal toxicity, antitoxins antagonize the action of various animal toxins 22-Mar-21 38 VPT 608

39. Receptor antagonism Occurs when two chemicals that bind to the same receptor produce less of an effect when given together than the addition of their separate effects or when one chemical antagonizes the effect of the second (often termed blockers) Dispositional antagonism Occurs when the absorption, biotransformation, distribution, or excretion of a chemical is altered so that the concentration and/or duration of the chemical at the target organ are diminished 22-Mar-21 39 VPT 608

40. DECSCRIPTIVE ANIMAL TOXICITY TESTS Effects produced by a compound in lab animals, when properly qualified, are applicable to humans Exposure of experimental animals to toxic agents in high doses is a necessary and valid method of discovering possible hazards in humans Toxicity tests are not designed to demonstrate that a chemical is safe but to characterize the toxic effects a chemical can produce 22-Mar-21 VPT 608 40

41. SCOPE Mixture of science, art & creative thinking Science : The observational and data gathering phase Art : Utilization of the data to predict outcomes in humans based on in vitro and in vivo studies Creative Thinking : Determining the next hypothesis and how to design experiments to actually answer the questions posed 22-Mar-21 41 VPT 608

42. Public Health: Recognition and identification of hazards Occupational exposure Development and use of pesticides Regulatory: Development of exposure standards Detection methods Environmental: Chemical effects on plants, animals & ecosystems Clinical: Development of antidotes & treatments Recognition of exposure 22-Mar-21 42 VPT 608

43. THANK YOU 22-Mar-21 43 VPT 608