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Mammalian Toxicology: History & Principles. Lecture 1, Fall 2006. History and Scope of Toxicology: How we got here. Toxicology : The study of adverse effects of xenobiotics. Xenobiotics : From the Greek xeno ( ξένο ) for “foreign” and bios ( βίος ) for “life”.

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history and scope of toxicology how we got here
History and Scope of Toxicology: How we got here
  • 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.
history and scope of toxicology different branches
History and 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
history and scope of toxicology different branches1
History and 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
history and scope of toxicology how we got here1
History and 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.
history and scope of toxicology how we got here2
History and 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.
history and scope of toxicology how we got here3
History and 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!
history of toxicology antiquity
History of Toxicology—Antiquity
  • Humans have a long history of using poisons
    • Hemlock (Greek capital punishment), made famous by death of Socrates.
  • 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 antiquity1
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
history of toxicology antiquity2
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.
    • When ultimately captured, he had to resort to using his sword.
history of toxicology antiquity3
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
History of Toxicology—Middle Ages
  • Maimonides—Concept of bioavailability: Based on the forms of toxicant, 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 ages1
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 ages2
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
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 enlightenment1
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 enlightenment2
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 enlightenment3
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 enlightenment4
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)
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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.
modern toxicology
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
modern toxicology1
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’.
modern toxicology2
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
modern toxicology3
Modern Toxicology
  • Two major discoveries (1948):
    • Paper chromatography for chemical separation.
    • Use of blood and urine for testing presence of various chemical metabolites (biomarkers).
modern toxicology4
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.
modern toxicology5
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.
modern toxicology6
Modern Toxicology
  • Major events in the 1960s:
    • Thalidomide babies
    • Silent Spring by Rachel Carson
      • Highlighted the ecological effects of pesticide usage
    • Equipment available for detecting parts per billion (ppb)
    • Genetic assays for point mutations (Ames assay)
modern toxicology7
Modern Toxicology
  • In the 1970s:
    • “Discovery” of Love Canal as a major dumping site for toxic chemicals.
    • Push for toxicology to consider exposures to complex mixtures.
      • Recall that this shift had already taken place once—move from mixtures to the toxicon. Now a movement back to mixtures.
  • 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)