Mammalian Toxicology

							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”.
 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
 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 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 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 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 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
 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—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—Antiquity
     Mithridates VI of Pontus—
 King
 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—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 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
              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
 Theage of Paracelsus (1493-
 1541)—Responsible for the most
 famous saying in all of
 toxicology:
 Allsubstances 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
    Includedtreatment 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.
         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 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 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 Toxicology
 Two   major discoveries (1948):
 – Paper chromatography for chemical
   separation.
 – Use of blood and urine for testing
   presence of various chemical
   metabolites (biomarkers).
      Modern Toxicology
 Formalizationof 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 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 Toxicology
 Major   events in the 1960s:
 – Thalidomide babies
 – Silent Spring by Rachel Carson
    Highlightedthe ecological effects of
    pesticide usage
 – Equipment available for detecting
   parts per billion (ppb)
 – Genetic assays for point mutations
   (Ames assay)
          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.
        Recallthat this shift had already taken
        place once—move from mixtures to the
        toxicon. Now a movement back to
        mixtures.
            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)
Possible Short Research Topics
Possible Short Research Topics
Possible Short Research Topics