604: Week 3

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  1. Be able to define toxicology
    (and toxins vs. toxicants)
    Study of the adverse effects of chemicals on living organisms

    • Toxins: products of living organisms (microorganisms, plants, animals)
    • Toxicants: come from non-biological sources (made on purpose)
  2. Discuss the implications of the concept "the dose makes the poison" when studying chemical toxicants
    • -A small dose of a substance may be safe, while a large dose can be toxic (e.g. we need oxygen for survival, 21% in air, but 100% oxygen atmospheres are toxic)
    • -For some drugs, the difference between a therapeutic dose and a toxic dose is small, for some the difference is large
    • -For environmental chemical exposure, there is no perceived benefit, so the toxicity is the parameter of concern
    • -Dose is a critical predictor of toxicity
  3. Be able to interpret a dose response curve and determine from it the threshold and points of toxic response (example: LD50)
    (Lecture 3 ppt: slide 13, 20, 21, 22, 30)

    • -Dose on x-axis (often in units of mg/kg), response on y-axis (e.g. mortality)
    • -LD50: Dose required to produce death in 50% of exposed animals
    • -Threshold: where effects will occur - the dose at which you first start seeing a “response” (the exception to this is carcinogens)
    • -The dose makes the poison - so we can use the dose-response curve to make determinations, and get levels of chemicals in the environment down to below the threshold
  4. Toxicity vs. Hazard vs. Risk
    • Toxicity: intrinsic property of a compound (may be naturally occurring or even endogenous compound - can still be toxic)
    • Hazard: depends on the accessibility to the person (storage conditions, amount present, etc.)
    • Risk: numerical probability of harm predicted under specified exposure conditions
  5. Gases v. Vapors V. Aerosols
    • Gases: vapor phase at room temperature
    • Vapors: come from a substance that is a liquid at room temperature — behaves like a gas (high vapor pressure = high tendency to escape, e.g. solvents)
    • Aerosols: particles suspended in air, can be liquid or solid — particle size is important for the deposition in the lung (>10 microns particles removed by the nose; 2-10 micron particles are deposited in the tracheobronchial region and can be removed by the cilia and mucous layers; particles that are 2.5 microns or less make it into the alveolar region of the lung)
  6. Be able to describe the three most important routes of exposure to humans from
    environmental chemicals and to differentiate between the physical barriers to absorption for each
    Inhalation (Lung) - nose, cilia, mucous, macrophages

    Ingestion (GI tract) -pH of the various portions is a factor (the pH of the stomach is around 2, pH of intestine is around 6 - almost neutral); compounds in the non-ionized form (not charged) are more likely to be absorbed across membranes; some compounds may be actively taken up if they mimic natural compounds

    Dermal (Skin) - skin is a good barrier, but lipid soluble components are more likely to penetrate
  7. Be able to define the partition coefficient and discuss a use for this data in determining potential of chemicals for posing a hazard through dermal absorption
    • Partition coefficient for lipid solubility: determines lipid solubility for a compound, and is an indicator of how likely the compound is to penetrate the skin (a higher partition coefficient, the more likely it is to penetrate the skin)
    • - the tendency of a compound to go into oil vs water when it is mixed an oil/water solution (e.g. concentration in octanol/concentration in water =? , a value of 1000 would mean a compound is very lipid soluble and would likely penetrate the skin)
  8. Be able to discuss the excretion of xenobiotics.
    • Xenobiotics are any substances that are foreign to the body
    • -Most xenobiotics are excreted (eliminated) by the kidneys (besides urine, toxins can also be excreted in the feces, expired air, or in other secretions such as sweat)
    • -Xenobiotics are usually made more water soluble in the body (via phase I and phase II metabolism) in order to exit via the urine. (The blood goes into the kidneys and has to cross a membrane to get back into the blood, so water soluble compounds tend to not cross the membrane but instead are excreted.)
  9. Recount what is meant by the term metabolism, and describe the two major phases of the metabolism of lipid soluble compounds in general terms, and where in the body metabolism takes place
    • Metabolism = chemical changes made by the body
    • -can make compounds LESS toxic (detoxify) or MORE toxic
    • -Most important organs in metabolism (#1 is liver; next are the kidneys, intestines, and lungs; next are the skin and gonads) - if you ingest something it goes through the liver first and is often detoxified (as opposed to if you breathe something in and it moves around more before getting to the liver)

    PHASE I Metabolism: Adds functional (reactive) groups to the absorbed compound (OH, O, etc.) — in this phase a xenobiotic (or other compound) is converted to an “intermediate product” (reactive group is what allows it to have a water soluble compound attached in Phase II)

    PHASE II Metabolism: Adds an endogenous, water soluble molecule to the compound, creating a “secondary compound”  — the secondary compound is excreted (usually by the kidneys)

    Phase I and Phase II metabolism change a lipophilic compound into a hydrophilic one that can be excreted in the urine.
  10. Explain why animals are used in toxicity tests and assumptions implicit in using them. To describe why in vivo testing is used instead of in vitro systems only.
    • In order to see how compounds are distributed and metabolized after they are absorbed.
    • (You can’t just assume toxicity from original toxin, have to look at metabolic products)
    • -Metabolism might differ between species, between genders, and between people with different genetic make-ups
  11. Be able to illustrate concept that ‘natural’ does not mean that a process or compound is less toxic
    Examples: toxic effects of natural processes (like PHASE I metabolism activating carcinogens) and natural compounds that are toxic (example: aflatoxin, botulinum toxin)

    “Natural” does not mean that something is good for you
  12. What does ADME stand for?
    absorption, distribution, metabolism, excretion
  13. Describe attributes of distribution (in the absorption, distribution, metabolism, excretion cycle)
    • -Toxicants are often concentrated in specific tissues (e.g. carbon monoxide has a high affinity for hemoglobin; lead accumulates in bone)
    • -Bioaccumulation may occur as storage depot (e.g. bone, fat, liver) removes the toxicant from the blood)
    • -Storage may be on plasma proteins (e.g. albumin)
    • -Liver and kidney have a high affinity for metal compounds
    • -Fat can concentrate lipid soluble compounds (e.g. chlorinated pesticides)
  14. Factors influencing toxic responses
    • -Dose
    • -Route of exposure
    • -Other chemical factors (e.g. interactions - synergistic, etc.)
    • -Other biological factors (e.g. genetic susceptibility, health status, age_
    • -Toxicokinetics (where it goes) and toxicodynamics (what it does)
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604: Week 3
Week 3 study guide
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