History and Basic Concepts of Toxicology PDF

History and Basic Concepts, Definition of Terms, Areas of Toxicology Johnny Sagun Bacud Jr., RPh, MS Pharm  Toxicology Definition:  Toxicology is the study of the adverse effects of chemical, physical or biological agents on living organisms and the ecosys...

History and Basic Concepts, Definition of Terms, Areas of Toxicology Johnny Sagun Bacud Jr., RPh, MS Pharm  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) http://www.toxicology.org/  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. 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 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  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. 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. 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!  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 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! 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  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  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. 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!)  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  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.  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)  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.  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. 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. 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. 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) 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.  Toxicology What is toxicology? The study of the effects of poisons. Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins Toxicant - the specific poisonous chemical. Xenobiotic - man-made substance and/or produced by but not normally found in the body. Toxicology is arguably the oldest scientific discipline, as the earliest humans had to recognize which plants were safe to eat. Most exposure of humans to chemicals is via naturally occurring compounds consumed from food plants. Humans are exposed to chemicals both inadvertently and deliberately.  History 2700 B.C. - Chinese journals: plant and fish poisons 1900-1200 B.C. - Egyptian documents that had directions for collection, preparation, and administration of more than 800 medicinal and poisonous recipes. 800 B.C. - India - Hindu medicine includes notes on poisons and antidotes. 50-100 A.D. - Greek physicians classified over 600 plant, animal, and mineral poisons.  History 50- 400 A.D. - Romans used poisons for executions and assassinations. The philosopher, Socrates, was executed using hemlock (Conium maculatum) for teaching radical ideas to youths. Avicenna (Abu Ali al-Husayn ibn Abdillah ibn Al-hasan ibn Ali Ibn Sina (A.D. 980-1036) Islamic authority on poisons and antidotes. 1200 A.D. – Spanish/Jewish rabbi Maimonides Writes first-aid book for poisonings, Treatise on Poisons and Their Antidotes (Moses ben Maimon)  History Swiss physician Paracelsus (1493- 1541) credited with being “the father of ancient toxicology.” “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.” Philippus Aureolus Theophrastus Bombastus von Hohenheim  The Dose Makes the Poison An apparently nontoxic chemical can be toxic at high doses. (Too much of a good thing can be bad). Highly toxic chemicals can be life saving when given in appropriate doses. (Poisons are not harmful at a sufficiently low dose).  Lethal Doses Approximate Lethal Doses of Common Chemicals (Calculated for a 160 lb. human from data on rats) Chemical Lethal Dose Sugar (sucrose) 3 quarts Alcohol (ethyl alcohol) 3 quarts Salt (sodium chloride) 1 quart Herbicide (2, 4-D) one half cup Arsenic (arsenic acid) 1-2 teaspoons Nicotine one half teaspoon Food poison (botulism) microscopic Source: Marczewski, A.E., and Kamrin, M. Toxicology for the citizen, Retrieved August 17, 2000 from the World Wide Web: www.iet.msu.edu/toxconcepts/toxconcepts.htm.  History Spanish physician Mathieu Joseph Bonaventure Orfila (1815) established toxicology as a distinct scientific discipline.  History 20th Century Paul Ehrlich –developed staining procedures to observe cell and tissues and pioneered the understanding of how toxicants influence living organisms.  History 20th Century Rachel Louise Carson - alarmed public about dangers of pesticides in the environment. Thanks