Toxico C2

• Toxicokinetics


  The study of the time course of toxicant absorption, distribution, metabolism, and elimination
• Toxicological Paradigm


  • Exposure
  • Internal Dose
  • Biologically Effective Dose
  • Early Biological Effect
  • Altered Structure & Function
  • Disease
• Xenobiotic


  A chemical substance found within an organism that is not normally produced or expected to be present in the organism
• Toxicokinetic (TK) processes


  1. Absorption

  2. Distribution

  3. Metabolism

  4. Excretion
• Absorption


  The first step in the TK process, where exposure (ingestion/inhalation) leads to intake into the GI tract or lungs, and then absorption into the blood
• Major routes of exposure

  • Oral - ingestion (gut)
  • Respiratory - inhalation (lung)
  • Dermal - percutaneous (skin)
• Artificial routes of uptake

  • Injection = parenteral (not through the gut)
  • IV intravenous
  • IM intramuscular
  • IP intraperitoneal
• Uptake barriers


  • Cell membrane
  • Cell wall
  • Epithelial cells of GI tract
  • Respiratory surface
  • Body surface
• Passive transport


  No energy source is required, determined by permeability of surface, concentration gradient, and surface area
• Facilitated transport


  Carried by trans-membrane carrier along concentration gradient, energy independent, may enhance transport up to 50,000 folds
• Active transport


  Independent of or against concentration gradient, require energy, substrate-specific, rate limited by number of carriers
• Cation transport channels


  Selective channels for transcellular transport of positively charged ions (cations)
• Anion transport channels


  Transport of negative charged ions (anions)
• Lead (Pb) causes neurologic damage in children, including IQ reduction, mild retardation, hyperactivity and behavioral disorders
• Prevention of chronic lead poisoning includes calcium supplements, diet with milk, high protein intake, adequate vitamin D
• The Fukushima I Nuclear Power Plant accident in 2011 released radioactive caesium-137 and iodine-131, which were detected worldwide
• Factors affecting absorption


  • Lipid solubility
  • pH
  • Surface area
  • Concentration gradient
  • Blood flow
  • Dissolution in aqueous medium
• Bioavailability


  The fraction of the administered dose reaching the systemic circulation
• First pass effect


  Extent of absorption or bioavailability reduced due to destruction in the gut or liver before reaching systemic circulation
• Distribution


  The second phase of toxicokinetic process, defining where in the body a xenobiotic will go after absorption
• Factors affecting distribution


  • Size and molecular weight of molecule
  • Lipid solubility
  • Plasma protein or RBC binding
  • Tissue binding
  • Blood flow to target tissue
  • Internal membrane barriers
• Plasma binding of chemicals

  Extent of binding to plasma proteins like albumin affects the free, pharmacologically active concentration
• Sequestration


  Animals may store toxicants in inert tissues (e.g. bone, fat, hair, nail) to reduce toxicity
• Target tissue distribution


  Xenobiotics often produce effects on specific body tissues or organs, requiring bioavailability to that target tissue
• Elimination


  Includes all mechanisms for removing xenobiotics from the body
• Elimination routes


  • Kidney
  • Liver
  • Biliary secretion
  • Lung
  • Mother's milk
  • Other secretions (sweat, saliva)