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history & principle

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  1. 1. Dr Md Ashraful Alam
  2. 2. Toxicology Definition:  Toxicology is the study of the adverse effects of chemical, physical or biological agents on living organisms and the ecosystem, including the prevention and amelioration of such adverse effects. (Society of Toxicology)
  3. 3.  Toxicology: The study of adverse effects of xenobiotics.  Xenobiotics: From the Greek xeno (ξένο) for “foreign” and bios (βίος) for “life”).  This discipline actually has its roots in the ancient art of poisoning.  Now its scope is much broader.
  4. 4. Scope of Toxicology: Different branches  Biomedical: Mechanisms of actions Effects of exposure Understanding biological responses through model toxic compounds  Public Health: Recognition and identification of hazards Occupational exposure Development and use of pesticides
  5. 5. Scope of Toxicology: Different Branches  Regulatory: Development of exposure standards Detection methods  Environmental: Chemical effects on plants, animals & ecosystems  Clinical: Development of antidotes & treatments Recognition of exposure
  6. 6. Scope of Toxicology: How we got here  Toxicology, like other disciplines, is a mixture of science, art & creative thinking Science: The observational and data- gathering phase.
  7. 7. Scope of Toxicology: How we got here 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.
  8. 8. Scope of Toxicology: How we got here  It is important to note that facts are different from predictions.  Facts have been proven; predictions are based on probabilities. They don’t have equal value, in terms of scientific weight.  Toxicologists need to be careful when talking to the public to make sure they don’t confuse the two!
  9. 9. Historical background  Toxicology dates to the earliest humans  Poisons played an important role in the history of mankind. In most cases, poisoning is caused by people's negative characteristics  They may either be lack of information or ignorance, carelessness, untidiness, and, at worst, anger that may lead to cases of deliberate poisoning
  10. 10. History of Toxicology— Antiquity  Humans have a long history of using poisons Hemlock (Greek capital punishment) Aconite (Chinese poison arrows)  Milestones Dioscorides—Greek physician who classified poisons for Nero. He included descriptions and drawings. This was a standard text for 1600 years!
  11. 11. History of Toxicology— Antiquity  Toxicology during this time, however, mainly focused on poisoning (suicide, state-sanctioned & personal usage…)  This knowledge also lead to antidotes. Emetics (εμμετικός)—Agent to induce vomiting following poisonings
  12. 12. Most known historical persons dealing with toxicology - Dioscorides : first classification of poisons, use of emetics in treatment - Paracelsus : „All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.“ - a physician – alchemist; set the basics of pharmacology, toxicology and therapeutics; investigated the dose-response relation
  13. 13. History of Toxicology— Antiquity  King Mithridates VI of Pontus— Experimented on criminals and himself! He would drink a poison cock-tail (36 ingredients!) to prevent political enemies from being able to poison him.
  14. 14. History of Toxicology— Antiquity  Poisonings were so rampant in Rome, a law was enacted in 82BC. It made poisoning illegal, and later extended to careless dispensers of drugs (an early regulatory effort!)
  15. 15. History of Toxicology—Middle Ages  Maimonides—Concept of bioavailability: Based on the forms of toxicants, or what one eats/drinks before ingestion, the chemical can be more or less readily available in the body. Milk, butter and cream could delay intestinal absorption (due to the fat content) Full stomach also delays absorption
  16. 16. History of Toxicology—Middle Ages  The poisoner, in Renaissance Italy, was an integral part of society. Toffana—Woman who sold arsenic-laced cosmetics Hieronyma Spara—Provided ‘services’ to local young soon-to-be widows.
  17. 17. History of Toxicology—Middle Ages  Catherine de Medici—Systematic study of the effects of poisons in the sick and poor to make sure the correct concoction was delivered to her ‘customers’. Noted the following: ○ Rapidity of the toxic response (onset of action) ○ Effectiveness of the compound (potency) ○ Degree and specificity of response (site of action) ○ Complaints of victims (clinical signs and symptoms)
  18. 18. History of Toxicology—Age of Enlightenment  The age of Paracelsus (1493-1541)— Responsible for the most famous saying in all of toxicology:  All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.
  19. 19. History of Toxicology—Age of Enlightenment  Paracelsus focused on the importance of the ‘toxicon’—a primary toxic agent and a single chemical entity.  This was in contrast to previous schools of thought that included the concept of mixtures.
  20. 20. History of Toxicology—Age of Enlightenment  Fundamental contributions: Experimentation is essential in the examination of responses. There is a difference between the therapeutic and toxic properties. The above are not easily determined, except by dose. It is possible to ascertain a degree of specificity of chemicals and their therapeutic or toxic effects.
  21. 21. History of Toxicology—Age of Enlightenment  Seminal texts: On the Miners’ Sickness and other Diseases of Miners (1567) by Paracelsus ○ Included treatment and prevention strategies Discourse on the Diseases of Workers (1700) by Bernardino Ramazzini ○ Set the standard for occupational medicine. ○ Also included information about miners, midwives, printers, weavers and potters.
  22. 22. History of Toxicology—Age of Enlightenment  Major developments: 1775—Role of soot in scrotal cancer in chimney sweeps (due to polyaromatic hydrocarbons) 1825—Synthesis of phosgene and mustard gas (chemical warfare) 1880—Boom in organic chemical synthesis led to over 10,000 new compounds (no industry testing for toxicity)
  23. 23. History of Toxicology—Age of Enlightenment  Major developments: Orfila (1787-1853): Introduced the use of autopsy material to toxicology to provide legal proof of poisoning. Magendie (1783-1885): Detailed the absorption and distribution of various compounds in the body.
  24. 24. Modern Toxicology  Toxicologists must understand aspects of biology, chemistry and metabolism. They tend to function as detectives who must utilize many clues.  Initial growth in the field spurred by need to explain deaths occurring after administration of ether, chloroform and carbonic acid in iatrogenic deaths. ○ Iatrogenic: From the Greek iatros (ιατρός) for doctor
  25. 25. Modern Toxicology  1890s-1900s Discovery of vital amines (vitamins) led to the wide-spread usage of bioassays to determine whether these new chemicals were beneficial. Development of neurotoxicity field due to the production of bootleg liquor by-products (methanol & lead). Toxicology of metals due to the production of ‘the bomb’.
  26. 26. Modern Toxicology  Post World War II Discovery of organophosphates (OPs) as cholinesterase inhibitors. Today used as non-bioaccumulating pesticides  Production of quinine as an antimalarial. Based on derivative of chincona bark First use of non-human primates  Discovery of mixed-function oxidases (MFOs) Prelude to latter work on P450s
  27. 27. Modern Toxicology  Two major discoveries (1948): Paper chromatography for chemical separation. Use of blood and urine for testing presence of various chemical metabolites (biomarkers).
  28. 28. Modern Toxicology  Formalization of the experimental program for the testing of food, drug and cosmetic safety in 1955. Updated by the FDA in 1982. Basically states that any chemical found to be carcinogenic in lab animals or humans cannot be added to the US food supply.
  29. 29. Modern Toxicology  Toxicology and Applied Pharmacology started around 1958— First journal dedicated to toxicology.  Textbook of Toxicology published in 1959.  Society of Toxicology (SOT) founded in 1965.
  30. 30. Modern Toxicology  Major events in the 1960s: Thalidomide babies Silent Spring by Rachel Carson Equipment for detecting parts per billion (ppb) Genetic assays for point mutations (Ames assay)
  31. 31. Currently  Now a unique and separate discipline Offered at many graduate schools “Surprisingly, courses in toxicology are now being offered in several liberal arts undergraduate schools as part of their biology and chemistry curricula.” (p 10)
  32. 32. Famous poisonings and poisoners The King Mithridates Eupator (1st century BC)  Is said to have taken small doses of 36 poisons to build tolerance against them. When his son sent assassins to murder him, he attempted suicide by poison but the poison had no effect on him, and he had one of his servants kill him by the spear. This is where immunity from poison got its name of mithridatism. - The principle of addiction:  The organism already responds during resorption, mainly at the level of intestinal wall, and reduces the penetration of exogenous substances from the gastrointestinal tract to blood  As part of adaptation, the organism enhances the capacity of detoxification processes  The organism incorporates the poison into its biochemical processes, and the poison then becomes part of those processes. If the regular intake of the poison is interrupted, the so-called withdrawal syndrome evolves  Examples of addictive substances are arsenic (arsenic used to be given to horses as a stimulant, but interrupting the supply may have led even to the death of the horse), NaCl, morphine, some plant toxins
  33. 33. Socrates  One of the greatest ancient philosophers was executed by a solution of the hemlock plant (Conium maculatum) in 399 BC.  Poison hemlock (Conium maculatum) grows on rubbish heaps. It contains the alkaloid coniine (most of the alkaloids are in fruit). The onset of toxic effects is in 20 – 30 minutes. The death is most frequently caused by the cessation of breathing at full consciousness and before cardiac arrest.  Coniine is a curare-like poison, such alkaloids block the transmission of stimuli from motor nerve endings to striated muscles, which subsequent leads to muscle paralysis. The paralysis progresses from the lower limbs upwards to respiratory muscles, and when these muscles are paralyzed, the victim dies of asphyxia. The brain is not affected and the victim retains consciousness.
  34. 34.  In the Middle Ages, many of the greatest poisoners were women  The best known of them were Catherine de Medici and Lucrezia Borgia (a daughter of Pope Alexander VI.)  Catherine had a cabinet full of different poisons at home, and she made the use of poisons a standard political tool. She was the wife of the French king Henry II, and later became Queen of France. She tried to prevent any weakening of the royal family's political power.  In Italy, an infamous poisoner was a woman named Tofana, who made her mark by her arsenic-containing cosmetics ("Aqua Tofana"). Catherine de Medici Lucrezia Borgia
  35. 35.  There are also many examples of the use of poison in more recent history  In World War 2, German generals had a glass poison capsule (containing e.g. potassium cyanide) set in one of the tooth under a removable crown  A case from a very recently past is that of the Ukrainian president Yushchenko, who was poisoned by dioxin (which left typical symptoms of acne on his face)  Descriptions of animal poisoning also abound.  There have also been many cases of food poisoning: - Minamata Disease (Japan, 1950s – 1960s) This was a case of methylmercury poisoning of both people and animals. A chemical factory dumped its mercury-containing waste to the Minamata Bay for dozens of years. Inorganic mercury in mercury compounds that accumulated in sediments on the bay bed began to transform to methylmercury (the most toxic form of mercury) under the action of bacteria. Methylmercury penetrated to the food chain of the aquatic environment, i.e. fish and subsequently to man. People (mostly fishermen) suffered of central nervous system disorders, loss of hearing and speech disturbance. Several cases of limb paralysis and severe mental disorders were also reported. Children were born with defects. Several dozen people die.
  36. 36. - Poisoning of people in Iraq in 1960s. Poisoning was caused because seed wheat was mistaken for food wheat. The wheat had been treated with phenylmercurychloride-based fungicidal agent. Although exported as seed, the wheat was eventually by mistake used as food wheat. - Itai-Itai Disease (the ouch-ouch disease) In the 1950, Japan witnessed mass poisoned of its citizens with rice heavily contaminated with cadmium. The source of cadmium were ore dumps from which cadmium was washed by rainwater to the river. The name of the disease came from characteristic painful screams of the victims who suffered severe pain in the joints and the lower part of spine. - The oil disease (Yusho) In 1968 about 1600 people in Japan were poisoned by rice oil contaminated with polychlorinated biphenyls (PCB) during the manufacturing process. The PCB leaked into edible oil from corroded pipes of the cooling system. The main symptoms of the poisoning were impaired immunity (people died of common infectious diseases – flu, pneumonia – rather than of PCB poisoning), damage to the nervous system, hyperkeratosis, hyperpigmentation, etc.
  37. 37. Possible Short Research Topics
  38. 38. Possible Short Research Topics
  39. 39. Possible Short Research Topics
  40. 40. Methods to evaluate toxicity of chemicals 1) Based on cases of poisoning, cases studies (case histories) 2) Methods for toxicity prediction 3) Toxicity tests 1) It is not possible to perform toxicity tests or to monitor effects of chemical substances on people and most species of animals. For that reason it is important to learn as much as possible from individual cases of poisoning, and that is also the reason why we so often return to the history of toxicology
  41. 41. 2) There is a relation between the chemical structure of substances and their biological characteristics. It cannot be assumed that knowledge of the molecule structure of a new xenobiotic alone will suffice for an unambiguous evaluation of biological properties. On the other hand, it will at least allow for a group classification. Toxicity prediction may be quite successful if we are dealing with a series of substances exhibiting chemical similarities. The relationship between the chemical structure and biological activity is expressed as Quantitative Structure – Activity Relationship (QSAR). Computer programmes are developed for computer- assisted toxicity predictions. But because these predictions may differ from reality, tests on experimental animals are necessary before a final decision can be taken. Thanks to prediction processes, however, the scope of these tests can be minimized (with a minimum number of experimental animals)
  42. 42. 3) Toxicity tests are performed at the level of  cells and tissues (in vitro tests)  organisms  Biocoenoses  - For tests at the level of cells and tissues, primary cell cultures (higher sensitivity, lower reproducibility) or stable cell cultures (lower sensitivity, higher reproducibility) are used. Test can be evaluated directly (numbers of dead cells and extent of cytopathic effects) or indirectly (evaluations based on physiological reactions of the cells). - One example is the Neutral Red Test (NRT). It uses the ability of undamaged lysosomes to incorporate and bind neutral red. After a 20- hour period of exposure to the test substance, a neutral red solution is added, left there to take effect, then it is drained off and lysing solution is added. Undamaged cells are lysed, and the neutral red released is measured photocolorimetrically. - The advantage of in vitro tests is their speed, reproducibility, low financial and time demands. The disadvantage is that in vitro systems are no substitute for the enzymatic - immune system of the living organism. In spite of that, in vitro tests are suitable screening tests before animal experiments.
  43. 43.  - The most frequently performed tests are those at the level of organisms. They must include all trophic levels, i.e. bacterias, invertebrates and vertebrates (experiments on fish, birds and mammals). Methods to be used in such experiments are unified world-wide by the Organisation for Economic Cooperation and Development (OECD) and the International Organization for Standardization (ISO).  - Tests at the level of biocoenoses - these tests are very expensive and time consuming, they are used in special cases only. The preparation is applied over a defined area of land and its effects on soil microorganisms, earthworms, game, birds etc., are monitored, and its residual concentrations are studied. Similar methods are used for experiments in the aqueous environment. More info: