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)