3.4 Toxicokinetics and toxicodynamics

Toxicokinetics and toxicodynamics are crucial for understanding how toxicants interact with organisms. Toxicokinetics covers absorption, distribution, metabolism, and excretion, explaining how toxicants move through the body. These processes influence a toxicant's effects and persistence.

Toxicodynamics focuses on how toxicants cause harm, including receptor binding and dose-response relationships. This knowledge helps determine toxicity thresholds and identify biomarkers, which are essential for assessing risks and monitoring exposure to harmful substances.

Toxicokinetics

Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption refers to the process by which a toxicant enters the body through various routes such as ingestion, inhalation, or dermal contact
• Distribution describes how the toxicant is transported throughout the body via the bloodstream and reaches target organs or tissues
  • Factors influencing distribution include blood flow, tissue affinity, and protein binding
• Metabolism, also known as biotransformation, involves the chemical modification of the toxicant by enzymes in the body
  • Biotransformation can result in detoxification (rendering the toxicant less harmful) or bioactivation (converting the toxicant into a more toxic form)
  • Common biotransformation reactions include oxidation, reduction, and hydrolysis (cytochrome P450 enzymes play a crucial role)
• Excretion is the process by which the body eliminates the toxicant or its metabolites through various routes such as urine, feces, sweat, or exhalation
  • The primary organs involved in excretion are the kidneys and liver (biliary excretion)

Toxicokinetic Parameters and Half-Life

• Half-life is the time required for the concentration of a toxicant in the body to decrease by half
  • Determines the persistence of a toxicant in the body and the duration of its effects
  • Influenced by factors such as the rate of metabolism, excretion, and redistribution
• Other important toxicokinetic parameters include:
  • Absorption rate: the speed at which a toxicant enters the body (influenced by factors such as solubility and lipophilicity)
  • Bioavailability: the fraction of the administered dose that reaches the systemic circulation unchanged
  • Volume of distribution: the theoretical volume required to contain the total amount of a toxicant at the same concentration as in the blood (reflects the extent of distribution)
  • Clearance: the volume of blood or plasma cleared of a toxicant per unit time (a measure of the body's ability to eliminate the toxicant)

Toxicodynamics

Receptor Binding and Dose-Response Relationship

• Toxicodynamics focuses on the mechanisms by which toxicants exert their adverse effects on the body
• Receptor binding is a key concept in toxicodynamics, as many toxicants exert their effects by interacting with specific receptors in the body
  • Toxicants can act as agonists (activating receptors) or antagonists (blocking receptor activation)
  • Examples of receptor-mediated toxicity include endocrine disruption (binding to hormone receptors) and neurotoxicity (binding to neurotransmitter receptors)
• The dose-response relationship describes the relationship between the dose of a toxicant and the magnitude of the observed effect
  • Typically follows a sigmoidal curve, with increasing effects at higher doses
  • Important parameters include the median lethal dose (LD50) and the no-observed-adverse-effect level (NOAEL)

Toxicity Thresholds and Biomarkers

• The toxicity threshold is the dose or concentration of a toxicant below which no adverse effects are observed
  • Determined through dose-response studies and used to establish safe exposure levels (reference doses or concentrations)
  • Thresholds can vary depending on the endpoint (acute vs. chronic toxicity) and the sensitivity of the population (e.g., children, elderly)
• Biomarkers are measurable indicators of exposure, effect, or susceptibility to a toxicant
  • Exposure biomarkers indicate the presence of a toxicant in the body (e.g., blood lead levels)
  • Effect biomarkers reflect the biological response to a toxicant (e.g., liver enzyme levels as indicators of hepatotoxicity)
  • Susceptibility biomarkers identify individuals who are more sensitive to the effects of a toxicant due to genetic or other factors (e.g., genetic polymorphisms in detoxification enzymes)
• Biomarkers are valuable tools in risk assessment and monitoring the health effects of toxicant exposure (used in occupational and environmental settings)