Lecture 1 Outline of Current Lecture I.II. Introduction and History (People)III. Introduction and History (Toxicological Cases)IV. DefinitionsV. Branches of ToxicologyVI. Toxic Effects and Influencing FactorsVII. Dose-Response: DefinitionsVIII. Dose-Response: RelationshipsIX. Measure of ToxicityX. Evaluating SafetyCurrent LectureI. History of Toxicology: PeopleNOTE: dates are not to be focused on, merely the significance of the people and their contributiona. Hippocrates: 400BCi. Compiled a list of poisons, outlined some clinical toxicology principles (particularly bioavailability), and coined the Hippocratic Oath for doctorsb. Mithridates VI of Pontus: 134-163BCi. Discovered an antidote for poisoning thereby coining the term “Mithridatic” which is used to refer to an antidote or protective mixturec. Paracelsus: 1493-1541i. Referred to as the “father” of modern toxicology because he basically defined the word toxicology within the following quote:“All substances are poisons; there is none that is not a poison. The rightdose differentiates a poison from a remedy. The dose makes the poison.”d. Percivall Pot: 1775i. Discovered that soot was able to cause scrotal cancer in chimney sweepers (this was the first case of showing that cancer can be caused by an environmental carcinogen)a. Environmental carcinogens in soot (polycyclic aromatic hydrocarbons—PAH) have contact with the skin (chimney sweepers didn’t usually wear any form of protection)e. Rachel Carson: 1907-1964i. A marine biologist who worked for the federal government, but was also an environmental conservationistii. Her novel “Silent Spring” showed concern for environmental protection PHARM 5509 1st Edition1. Helped pave way for the creation of the EPA (Environmental Protection Agency) under president Nixon (December 1970)2. Led to the ban of the insecticide DDT due to environmental and health concerns (1972)II. History of Toxicology: Toxicological Casesa. Sulfanilamide disaster: 1937/1938i. An improperly prepared elixir of sulfanilamide diethylene glycol (diethylene glycol is a chemical analog of antifreeze) cause more than 100 deaths in 19371. This disaster led to the passing of the Federal Food, Drug, and Cosmetic Act in 1938 which, in part, stated that:“All drugs be tested for safety prior to marketing, and the resultssubmitted to the FDA in a new drug application (NDA).”b. Minamata disease: 1932-1968i. Disease caused by methylmercury toxicity (from industrial wastewater from the Chisso Corporation in Minamata City, Japan) which alters neurochemistry and neurotransmission in the brain through multiple mechanisms1. Took 2,265 victims, 1,784 of which resulted in death (>50%)2. Patients developed neurological syndromes (including: ataxia, numbness,insanity, muscle weakness, hearing and speech loss, birth defects, paralysis, coma, and death)3. Contamination: sulphuric mercury was used as a catalyst to make acetaldehyde for plastic production; the mercury contaminated water drained into the bay and worked its way up the food chain from therec. Thalidomide: 1957-1961i. Thalidomide was released into the market as a sedative named Contergan in 1957; it was also used to alleviate nausea and vomiting in pregnant women1. The drug was withdrawn in 1961 and resulted in new drug testing rules after it was discovered to be a human teratogen causing amelia (lack/deficiency of limbs) or phocomelia (reduction of long bone in limbs)in newbornsa. 10,000 cases were reported worldwide (50% survival rate)b. Note that the pathological activity of thalidomide is due to its anti-angiogenesis effect (inhibits angiogenesis or the formation of new blood cells from pre-existing vessels). This is important because when an organ needs to grow it requires vasculature to provide a blood supply to aid that growth.ii. Pomalidomide (a thalidomide derivative) was approved recently (2013) as a treatment for relapsed and refractory multiple myeloma (a cancer that attacks the plasma cells of the bone marrow; note that bone marrow helps make blood cells, and plasma helps with fighting infection)III. DefinitionsNOTE: generally not for memorization but for understanding of terminologya. Toxicology: the study of the adverse effects of chemicals on living organisms b. Toxicant (poison/toxin): any agent capable of producing a deleterious response in a biological system (the right dose differentiates a poison and a remedy)i. Toxicon: Asian/Greek word used to refer to a poisonous arrow for huntingc. Xenobiotic: chemical which is found/present in an organism but is not normally produced or expected to be present i. Note that xenobiotic has other names that are/can be used interchangeably d. Dose: the amount of a substance that enters the body which is usually expressed as mass per body weight (mg/kg)i. Dose is a measure of exposureIV. Branches of Toxicologya. Mechanistic: focuses on cellular, biochemical, and molecular mechanisms by which chemicals cause toxic responsesb. Forensic: focuses on cause of death and incorporates legal aspects (i.e. CSI: crime scene investigation)c. Clinical: focuses on treatments for poisonings and injuries that are caused by toxic substancesd. Environmental: focuses on environmental pollutants and their impact on nonhuman organismse. Descriptive: provides information for safety evaluation and regulatory requirementsf. Regulatory: assigns risk to substances of commercial importancei. i.e.: Vioxx (Rofecoxib), a selective COX2 inhibitor and NSAID, was thought to be better than nonselective NSAIDs (i.e.: Aspirin) but was found to increase the risk of heart attack; drug was recalledV. Undesired (Toxic) Effects and Factors Influencing Toxicitya. Spectrum of Undesired (Toxic) Effects:i. Allergic: immune response (can also have severe allergic reaction or hypersensitivity, i.e.: anaphylactic shock)ii. Idiosyncratic: genetically determined abnormal reactivity1. Lacking of a particular gene causes either sensitive or insensitive toxic effects (can provoke a sensitivity response, i.e. allergic reaction, or an insensitive response, i.e. resistance to adverse effect)iii. Immediate vs. Delayed: toxic effects can be immediate or delayed depending on the exposure to/nature of toxic chemical1. Some chemicals can have a long latency period (i.e.: carcinogens which can lead to the formation of cancerous tumors)iv. Reversible vs. Irreversible: effects are reversible or irreversible depending on thedamage