Before midterm Toxicology

• History of Toxicology

  • Ebers Papyrus
  • Hippocrates
  • Moses Maimonides (1134-1204)
  • Paracelsus (1493 – 1541)
  • Georgius Agricola (1494-1555)
  • Bernardino Ramazzini (1633-1714)
  • John Hill (1761)
  • Percivall Pott (1775)
  • Mathieu Orfila (1787 – 1885)
  • Rachel Carson
  • Louis Casarett and John Doull Casarett
• Ebers Papyrus


  Earliest publication on toxicology of poisons: hemlock, opium, lead, copper & antimony
• Hippocrates


  Introduced clinical toxicology principles by describing elemental concepts of bioavailability and overdose
• Moses Maimonides (1134-1204)


  Jewish Rabbi who wrote The Treatise on Poisons and Their Antidotes in 1198: insects, snakes & mad dogs
• Paracelsus (1493 – 1541)


  Father of toxicology who established a scientific basis for toxicology with his theory "All things are poison; there is none which is not a poison"
• Georgius Agricola (1494-1555)


  Published De Re Metallica (On the Nature of Metals), described diseases like silicosis in miners, prescribed preventive measures including safety, worker protection, and ventilation in mines
• Bernardino Ramazzini (1633-1714)


  Father of occupational medicine and industrial hygiene who published De Morbis Artificum (Diseases of Workers), described "asthma" in various workers, outlined health hazards of dusts, fumes, or gases
• John Hill (1761)


  Linked tobacco (snuff) to cancer
• Percivall Pott (1775)

  Linked scrotal cancer and soot in chimney sweeps
• Mathieu Orfila (1787 – 1885)

  Modern father of toxicology who systematically used autopsy material and chemical analysis as legal proof of poisoning, starting point of forensic toxicology
• Rachel Carson

  Wrote the Silent Spring in 1962, documenting the detrimental effects of DDT (dichlorodiphenyltrichloroethane), led the crusade against the use of pesticide which was eventually banned in 1972, advancing the environmental movement and raising public awareness of environmental concern
• Louis Casarett and John Doull Casarett


  First editors of the textbook Toxicology: The Basic Science of Poisons (1975), instrumental in training scientists for almost 50 years
• 1970s Popularization of Risk Assessment: A methodology for predicting the incidence of human cancers based on animal data offered quantitative estimates of risk for a given chemical dose, this model was quickly used to prioritize the regulation of dozens of substances found to be carcinogenic
• 1980s Paradigm Shift: From hazard and risk assessments based on typical end points in animal studies, toward a mechanism-driven integrated approach, incorporating population variability and susceptible population into dosimetry including in vitro studies and modelling approaches
• Principle of Toxicology


  Contact, Exposure, Magnitude of risk, Target site

  
• Adverse effect

  Undesired harmful effect resulting from a medication or other intervention, can damage the survival and normal function of a person
• Side effect

  Generally harmful but not hinder the main effect of drug, can be both therapeutic & harmful, can hinder the treatment & lead to more complications
• Toxicity

  The degree and nature of adverse effects produced by a substance (i.e. toxin) and the conditions necessary for their production

  
• Toxicant

  Substance that is produced by or a by-product of human made activities
• Toxin

  Toxic substances that are produced naturally
• Classification of Toxic agents

  • Usage (Rodenticides, Insecticides, Fungicides, Herbicides)
  • Source (Organic, Inorganic, Synthetic, Natural)
  • Target organ (Hepatotoxins, Neurotoxins, Nephrotoxins, Endocrine disruptors)
  • Physical state (Gas, Vapour, Solid, Liquid, Aerosol, Particulate)
  • Degree of toxicity (Extreme, Moderate, Slightly toxic, Non-toxic)
  • MOA (Anticholinergic, Inhibitor, Uncoupler)
  • Chemical composition (Heavy metal, Organophosphate, Dioxins)

  
• Factors that influence toxicity

  • Age
  • ADME
  • Gender
  • Individual sensitivity (Genotype, Ethnicity)
  • Species variation
  • Dose & duration of exposure
  • Chemical property
  • Nature of biological target
• Spectrum of Adverse effects

  • Delayed
  • Immediate
  • Local vs systemic
  • Reversible vs irreversible
• idiosyncratic reaction

  Unique to an individual, unpredictable reactivity to a chemical
• Idiosyncratic reaction

  Extreme sensitivity or insensitivity to doses of a chemical
• Interaction of chemicals

  • Additive effect
  • Synergistic effect
  • Antagonism effect
• Roles of toxicologists


  • Recognize, identify and quantify hazard
  • Determine risk associated with the use of chemicals
  • Develop standard and regulation to protect environment and human health
  • Involve in safety assessment and use of data as a basis for a regulatory control of hazards
• Mechanism of Action (MOA) in presence of target molecule

  1. Delivery from the site of exposure to the target

  2. Reaction of ultimate toxicant with the target molecule

  3. Cellular dysfunction and resultant toxicities

  4. Repair vs direpair
• Mine risk


  Associated with the use of chemicals
• Develop standard and regulation

  Protect environment and human health
• Involve in safety assessment and use of data

  As a basis for a regulatory control of hazards
• MOA of toxicant in presence of target molecule

  1. Delivery from the site of exposure to the target

  2. Reaction of ultimate toxicant with the target molecule

  3. Cellular dysfunction and resultant toxicities

  4. Repair vs direpair
• Delivery

  Movement of a toxicant from the site of exposure to the site of action
• Ultimate toxicant


  The chemical that reacts with the endogenous target (e.g. enzyme)
• Molecule


  The one that changes the biological environment, initiates structural and/or functional alterations, resulting in toxicity
• Reaction of ultimate toxicant with target molecule

  • Character of target molecules
  • Type of reaction between the ultimate toxicant and target molecule
  • Effect of toxicants on the target molecules
• Covalent binding


  Binding of toxicant to target molecules
• Non-covalent binding


  Binding of toxicant to target molecules
• Cell program

  • Determines the fate of cells - whether they undergo division, differentiation or apoptosis
  • Regulates activities in differentiated cells

  
• Hapten

  Small molecules that can elicit an immune response when attached to a larger carrier, usually a protein