What is toxicology?

2. What is toxicology? • Toxicology is the study of how natural and man made poisons cause undesirable effects in living organisms. Harmful Effects of Toxicology • It may damage the survival or normal functions of an individual.

3. What is Toxicity? • The degree to which a substance is poisonous or can cause injury. • The toxicity depends on a variety of factors. • Dose • Duration • Route of Exposure • Shape and structure of the chemical itself

4. What is Toxicant? • A toxicant is any chemical that can injure or kill humans, animals or plants. • Toxicant is the term used when talking about toxic substances that are produced by or are a by product of man-made activities. What is a Toxin? • The term toxin is used when a toxic substance is produced naturally(phytotoxin, zootoxin or bacteriotoxin) OR synthetic chemicals that alter the growth, development or kill the organism

5. Toxic Symptom • Any sign or feeling that represents or indicates the presence of a poison in the system Toxic Effect/Poisonous Effect • Health effects that occur due to exposure to a toxic substance Selective Toxicity • Means that a chemical/toxin will produce injury to one kind of living matter without harming another form of life, even though the two may exist close together

6. Types Of Toxic Effect

7. How Does Toxicity Develop? • Before toxicity can develop a substance must come in contact with the body surface or respiratory tract. • The dose or amount of a toxin also matters a lot in this case Dose • Actual amount of a chemical that enters the body • Dose received may be due to either Acute Exposure or Chronic Exposure • Acute Exposure(occurs over a short period of time, usually 24 hours) • Chronic Exposure(occurs over long period of time such as weeks, months or years) • The amount of exposure and the type of toxin will determine the toxic effect.

8. Dose–Response Curve • Direct relationship between exposure and health effect. • Greater is the exposure worst is the effect on human/living things

9. Threshold Dose • The lowest amount of exposure or dose at which no adverse effects can be seen in population

10. Field Of Toxicology • Sub disciplines of toxicology • Environmental Toxicology (study of effects of pollutants on living organisms, populations, ecosystem and the biosphere) • Regulatory Toxicology (use of scientific data to decide how to protect humans and environment from excessive risks) • Clinical Toxicology (deals with the prevention, diagnosis and treatment of different poisoning cases)

11. Food Toxicology • (study of the nature, properties, effects, and detection of toxic substances in food, and their disease manifestation in humans) • Forensic Toxicology • (deals with the study of chemical analysis to determine the cause and circumstances of death and postmortem investigations)

12. Natural toxins: • Naturally present in plants & animals • Usually, natural toxins are not acutely toxic, except in a few cases in animals.

13. Endogenous toxins of plant origin • Toxic phenolic substances: flavonoids, tannins, coumarin, safrole, and myristicin • Cyanogenic glycosides • Glucosinolates • Acetylcholinesterase inhibitors • Biogenic amines • Central stimulants • Natural contaminants • Mixing of edible plants with toxic plants • Contamination resulting from intake of toxic substances by animals • Microbial toxins

14. Endogenous Toxins of Plant Origin 1. Flavonoids: • A class of plant pigments that are widely present in human food. • These pigments are polyhydroxy-2-phenylbenzo-γ-pyrone derivatives, occurring as aglycones, glycosides and methyl ethers. • A group of yellow pigments that occurs abundantly is the flavones. • Examples • nobiletin, • tangeretin(in citrus fruits) and • 3, 3′, 4′, 5 ,6 ,7, 8-heptamethoxyflavone (in grapefruit). • The flavones are generally located in the oil vesicles of the fruit peel. Flavones are non-polar, and therefore readily soluble in the oil. • They can be found in the juice after pressing the peel.

15. 2. Tannins: • Tannins are a heterogeneous group of broadly distributed substances of plant origin. • Two types of tannins can be distinguished on the basis of degradation behaviour and botanical distribution: • hydrolysable tannins and • condensed tannins. • The hydrolysable tannins are Gallic, digallic, and ellagic acid esters of glucose or quinic acid. • Example: tannic acid, also known as Gallo tannic acid, Gallo tannin, or simply tannin. • Tannic acid has been reported to cause acute liver injury, i.e., liver necrosis and fatty liver.

16. 3. Goitergens: • Glucosinolates are a particular group of substances, occurring in cruciferous plants, such as cabbage and turnips. They can be considered as natural toxins, but also as antinutritives. • Presents in many commonly consumed plants, such as cabbage, cauliflower, Brussels sprouts, broccoli, turnip, radish, oil seed meals. • Inhibit the uptake of iodine by the thyroid iodine deficiency. • Concerning toxicity and antinutritive activity, the hydrolysis products are the active agents, not the glucosinolates themselves. • Hydrolysis of glucosinolates results in the formation of isothiocyanates and nitriles. • The enzyme becomes available for catalysis when cells are damaged on cutting or chewing. • Several isothiocyanates have been shown to be embryotoxic in rats, while in vitro studies have proved a number of them to be cytotoxic and mutagenic.

17. 4.Safrole, coumarin, myristicin 5. Mushroom Toxins • Some other natural toxins: Biogenic amines, Acetyl cholinesterase inhibitors, Cyanogenic glycosides,

18. Natural Contaminants: • Natural contaminants can also originate from biological systems different from those in which they occur. • There are three important sources: • Raw materials of plant origin can become contaminated if they are mixed with toxic non-nutritive plant species. • Raw materials of animal origin, mainly fish and milk, can also become contaminated if the animal has ingested toxic substances of natural origin. • Contaminants of natural origin can be the products of microorganisms.

19. Natural toxins in aquatic organisms • Paralytic shellfish poisoning (PSP) is attributed to the consumption of shellfish that have become contaminated with a toxin or group of toxins from the ingestion of toxic plankton, in particular toxic dinoflagellates. • The shellfish involved are pelecypods, a family of mollusks, including mussels and clams. • The dinoflagellates produce a complex mixture of toxins. One of the components has been identified as saxitoxin. • Shellfish poisoning symptoms: • tingling and burning in face, lips, tongue, and ultimately the whole body, and parathesia followed by numbness, general motor incoordination, confusion, and headache • These symptoms develop within 30 minutes after ingestion. Death, preceded by respiratory paralysis, occurs within 12 hours.

20. Mycotoxin • Mycotoxins are secondary metabolites of fungi which can induce acute as well as chronic toxic effects (i.e., carcinogenicity, mutagenicity, teratogenicity, and estrogenic effects) in animals and man. • Currently, a few hundred mycotoxins are known, often produced by the genera Aspergillus, Penicillium, and Fusarium. • Toxic syndromes resulting from the intake of mycotoxins by man and animals are known as mycotoxicoses. • Because of their chemical stability, several mycotoxins persist during food processing, while the molds are killed.

21. Aflatoxins • Aflatoxins are the most important mycotoxins, which is produced by certain species of Aspergillus (A. flavus and A. parasiticus), which develop at high temperatures and humidity levels. • Aflatoxins are carcinogenic substances and may be present in a large number of foods. This toxin can cause cancer, cirrhosis of the liver. • For substances of this type there is no threshold below which no harmful effect is observed. • The most common commodities contaminated are tree nuts, peanuts, and corn and cottonseed oil. • The major aflatoxins of concern are B1, B2, G1, and G2  usually found together in various proportions. Aflatoxin B is usually predominant, and it is the most toxic and carcinogenic. • TLC method can detect aflatoxins.

22. Process-Induced Food Toxins: • Modern processing techniques: • Heat treatments (preservation) • Flavour enhancing • Texture or appearance enhancing • Shelf-life • Changes in food • Chemical reactions between food components • Desirable and Undesirable (toxins) • generate potentially harmful compounds. • Examples: Partially hydrogenated oils, Sodium nitrate/nitrite levels, MSG, Pesticides, artificial sweeteners

23. It Involves: • naturally-occurring components in the food • food additives, ingredients, • food packaging materials that were intentionally used. • Examples of such Food process induced chemicals: • Acrylamide • Benzene • Chloropropanols • Ethyl carbamate • Furan • Heterocyclic aromatic hydrocarbons • Nitrosamines • Polycyclic aromatic hydrocarbons (PAH's) • Semicarbazide

25. Measurement of Toxicity

26. What is toxicity? • The toxicity of a substance is its capacity to cause injury to a living system. • Toxicity represents the kind and extent of damage that can be done by a chemical or how poisonous something is.

27. Kinds of toxicity: • Acute toxicity: •  Acute toxicity is used to describe effects which appear promptly, or within 24 hours of exposure.  • The acute toxicity of a pesticide is used as the basis for the warning statements on the label.  • Acute toxicity may be measured as acute oral toxicity, acute dermal toxicity, and acute inhalation toxicity.

28. Chronic toxicity: •  It is the delayed poisonous effect from exposure from a substance. • It is measured in experimental conditions after three months of either continuous or occasional exposure. • The effects of both acute toxicity and chronic toxicity are dose-related; the greater the dose, the greater the effect.

29. RISK = TOXICITY X EXPOSURE The risk of harm from a toxicant exposure is equal to how poisonous the toxicant is, multiplied by the amount and route of exposure to the toxicant

30. Measurement of Acute toxicity: • Lethal dose (LD50): • This is defined as the dose required to kill half the members of a specific animal population when entering the animal’s body. • LD50 is stated in milligrams per kilogram (mg/kg): milligram of chemical per kilogram of body weight • The lower the LD50--the lower the lethal dose-the more toxic the substance. • The term LC50-Lethal Concentration is used to measure the toxicity of gases. The LC50 is stated in milligram of chemical per liter (or cubic meter) of air.

32. Fixed dose procedure: • In 1992, the fixed-dose procedure (FDP) was proposed as an alternative test to LD50. • Fewer animals used, less pain and suffering. • Here the test substance is given at one of four fixed-dose levels (5, 50, 500 and 2000 milligrams per kilogram) to five male and five female rats.  • When a dose produces clear signs of toxicity but no death is identified, the chemical is then classified at that level.

33. Parts per million: • To compare chemicals causing toxicity at very low levels. • Parts per million (ppm), parts per billion (ppb) and parts per trillion (ppt) are the most commonly used terms. • They are measures of concentration – the amount of one substance in a larger amount of another substance. • Scientists often use these measurements when measuring a toxic chemical in a lake or toxins in the air such as greenhouse gases.

34. Measurement of Chronic toxicity: • Carcinogenic toxicity: • Carcinogenesis bioassay: • Utilizes high-dose studies on laboratory animals to look for even the rare case of cancer for 24-30 months • It may not be the best scientific approach but is an effective way to address to public concerns by generating carcinogenic risk values. • For carcinogenic toxicity, scientists try to find even the rare cases of cancer.

35. Non-carcinogenic toxicity: • Lowest Observable Effect Level (LOEL) • Looking for the smallest dose of the substance that cause a detectable change. • For dose-response studies: administering small doses to substances to several groups of test animals everyday over a lifetime. • Periodically observing animals and final autopsy to determine the effect. • LOEL is measured in milligrams (mg) of substance per kilogram (kg) of body weight, or in parts per million (ppm) of substance in food. 

36. Determining Safe Levels: • To protect the public, scientists also determine the highest dose at which no effects occur, known as No Observable Effect Level (NOEL). • The NOEL is considered the "safe level" for that chemical in the species studied. • The NOEL is not necessarily the "safe level" for humans, because:  • humans may be more/less sensitive to the substance than the animals studied. • humans have more genetic, health, age, and other variability's, which may affect individual human reactions.

37. NOAL: No observable adverse effect levelLOAEL: Low observable adverse effect level

38. Human sensitivity & Variability: • The "safe level" calculation for humans assumes that humans are more sensitive than animals, but humans are not more sensitive in all cases. • This variation is usually due to the different degrees and rates of absorption, metabolism, and/or excretion of the substance by the different species. 

39. Mathematical models vary: • A mathematical model is a set of equations that mimic a real situation and predict what will happen under different circumstances.   • For toxicity assessments, models are made to apply the values obtained from the animal studies to human conditions. • The choice of model strongly affects the outcome of the toxicity assessment.

40. Non-Threshold vs. Threshold Models: • Non-Threshold Model: • It is based on the assumption that even one molecule of a cancer-causing agent can lead to the disease. This type of model is also referred to as a "one-hit" model.  • Threshold Model: • It is based on the premise that repeated exposures to a chemical are needed before a threshold of exposure is reached and cancer follows. 

41. Risk assessment: The risk assessor estimates ‘real world’ risk by combining information on toxicity and exposure.  • A toxicity assessment provides information on how much of a chemical causes what kind of harm. • Toxicity assessment provides only an estimate of the harm to humans. 

42. Toxicokinetics & Toxicodynamics • Toxicokinetics(Determines the no. molecules that can reach the receptors) • Uptake • Transport • Metabolism & transformation • Sequestration • Excretion • Toxicodynamics (Determines the no. of receptors that can interact with toxicants) • Binding • Interaction • Induction of toxic effects

43. Important Principles - The effect which a drug produces is dependent on: • The dose • The concentration in the target organ - The kinetics of a drug may differ from therapeutic dose to its toxic dose - Toxicokinetics is important in predicting the plasma concentration of a drug

44. Uptake and Elimination K1 Biological System K2 Elimination Uptake K1 > K2 : Accumulation & Toxic effect

45. Slowing of absorption (AB) - prolonged Tp - lower Cmax In instances when the absorption rate is slower than elimination rate, the rate of washout of toxicant becomes rate-limited by absorption rather than by elimination (i.e., a depot effect).

47. Toxicokinetics • Uptake • Transport • Metabolism & Transformation • Sequestration • Excretion

48. Absorption - Uptake routes • Ingestion (toxicity may be modified by enzymes, pH and microbes) • Respiration (Air borne toxicants) • Body surface (Lipid soluble toxicants such as carbon tetra chloride and organophosphate)

50. Uptake Barriers • Cell membrane • Cell wall/cuticles/stomata • Epithelial cells of GI tract • Respiratory surface (lung, gill tracheae) • Body surface