HLTH 340 (F24) - Section E - Week 10

HLTH 340 Section E: Toxicokinetics of Elimination

  • University of Waterloo School of Public Health Sciences

Routes of Absorption, Distribution, and Excretion

Absorption Routes

  • Ingestion: Gastrointestinal tract, with potential first-pass effect via the liver.

  • Inhalation: Absorption occurs in the lungs.

  • Intravenous: Direct entry into the bloodstream.

  • Intraperitoneal: Injection into the peritoneal cavity.

  • Subcutaneous: Under the skin.

  • Dermal: Absorption through the skin.

Distribution

  • Blood and Lymph: Within the circulatory system.

  • Bile: Transported to excrete via gastrointestinal system.

  • Extracellular fluid: Distribution in soft tissues and body fat.

  • Kidney, Lung, Secretory Organs: Involved in excretion.

Excretion Routes

  • Urine, Feces, Expired Air: Main channels for xenobiotic elimination.

  • Secretions: Also contribute to excretion (e.g., breast milk).

Elimination of Xenobiotics

  • Importance: Efficient elimination of toxic materials is vital for species survival.

    • For unicellular organisms: Passive diffusion suffices for waste elimination.

    • Complex organisms: Require sophisticated elimination systems due to larger size, compartmentalization, and enhanced membrane barriers.

  • Processes: Combo of biotransformation and excretion.

  • Metrics: Elimination rate constant, biological half-life, and clearance rate.

  • Rapid elimination reduces potential toxicity by preventing accumulation in critical cells.

Definitions: Excretion vs. Elimination

  • Excretion: Refers specifically to the removal of xenobiotics and metabolites via excretory organs.

  • Elimination: Encompasses both metabolic processing and excretion processes that clear xenobiotics from the organism.

Excretion Mechanisms

Excretion

  • Removal of xenobiotics via urine or feces.

  • Can occur actively or passively.

    • Passive excretion: Effective at high plasma concentrations (first-order elimination kinetics).

Secretion

  • Transport through specific channels (e.g., breast milk, semen).

  • Active process requiring energy (zero-order elimination kinetics).

Influence of Routes on Elimination

  • Elimination varies by exposure route, such as inhalation or systemic circulation.

    • Lungs clear toxicants through exhalation immediately; other routes undergo distribution and biotransformation first.

Factors Affecting Elimination

  1. Physico-chemical Properties: Kinetic factors (e.g., partition coefficient, pKa).

  2. Exposure Levels and Timing: Accumulation and clearance post-exposure.

  3. Route of Exposure: Direct effects on absorption and elimination.

  4. Health Status: Overall health affects metabolism and excretion.

  5. Biotransformation Rate: Alters lipophilic to hydrophilic forms for excretion.

  6. Functionality of Excretory Organs: Health of kidneys, liver, and respiratory tract impacts clearance.

  7. Presence of Other Toxicants: Can hinder elimination processes.

Elimination Routes for Xenobiotics

  • Urine: Via renal system, primarily for hydrophilic substances.

  • Feces: Involves unabsorbed materials and metabolites, in conjunction with liver metabolism.

  • Expired Air: Gases and volatile liquids are exhaled from the lungs.

  • Breast Milk, Sweat, Saliva: Other secretions contribute smaller quantities of xenobiotics.

Chelation Therapy

  • Definition: A chemical process to remove heavy metals or minerals from the bloodstream using chelating agents (e.g., EDTA).

  • Mechanism: Chelating agents bind metal ions to form non-toxic complexes.

  • Applications: Primarily effective for lead and mercury elimination; FDA-approved for lead poisoning.

    • Controversial for other metals and conditions (e.g., coronary artery disease).

Types of Chelating Agents

  1. EDTA: Common for heavy metals.

  2. DMSA: Effective against many metals but has limitations regarding Mercury elimination.

  3. Dimercaprol: Used for specific metals but may cause side effects.

Efficacy and Limitations of Chelation Therapy

Benefits

  • Effective for acute exposures.

  • Removes metals from tissues.

  • Can be administered orally.

Drawbacks

  • Potential for toxic metal redistribution.

  • Risk of losing essential metals.

  • Possible liver and kidney toxicity.

Biological Half-Life

  • Definition: Time required for the body to reduce a substance by half.

  • Examples of half-lives for various substances:

    • Chloroform: 1.5 hours

    • Lead in blood: 28-36 days

    • Cadmium in bone: 30 years

Excretion Kinetics

  • First-Order Kinetics: Rate of elimination is proportional to the concentration (log scale).

  • Zero-Order Kinetics: Rate is independent of concentration (linear scale).

Conclusion

  • Understanding toxicokinetics is essential for predicting the behavior and effects of xenobiotics in the human body. Effective management of exposures and treatments like chelation therapy require a foundational knowledge of elimination processes.