☣️Toxicology Unit 2 – Toxicokinetics and toxicodynamics

Key Concepts and Definitions

• Toxicology studies the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem
• Toxicokinetics describes the absorption, distribution, metabolism, and excretion (ADME) of toxicants in the body
• Toxicodynamics focuses on the mechanisms of action and the biochemical and physiological effects of toxicants on the body
• Xenobiotics are foreign substances not normally present in an organism (drugs, pollutants, food additives)
• Biotransformation is the process by which the body modifies xenobiotics to facilitate their elimination
  • Phase I reactions involve oxidation, reduction, or hydrolysis of the toxicant
  • Phase II reactions involve conjugation of the toxicant with endogenous molecules (glucuronic acid, sulfuric acid, amino acids)
• Biomarkers are measurable indicators of a biological state or condition (exposure, effect, susceptibility)
• Risk assessment evaluates the probability of adverse health effects occurring due to exposure to a toxicant

Toxicokinetics: ADME Processes

• Absorption is the process by which a toxicant enters the body through various routes (oral, dermal, inhalation, injection)
  • Factors affecting absorption include the physicochemical properties of the toxicant (solubility, molecular size, ionization) and the physiological characteristics of the absorption site (surface area, blood flow, pH)
• Distribution refers to the movement of a toxicant from the site of absorption to various tissues and organs in the body
  • Toxicants can bind to plasma proteins (albumin, globulins) or accumulate in specific tissues (fat, bone, liver, kidney)
  • The blood-brain barrier and placental barrier can limit the distribution of certain toxicants
• Metabolism is the process by which the body transforms toxicants into more water-soluble compounds to facilitate their elimination
• Excretion is the removal of toxicants and their metabolites from the body through various routes (urine, feces, sweat, breath, milk)
  • The kidneys play a major role in the excretion of water-soluble toxicants and their metabolites
  • The liver facilitates the excretion of lipophilic toxicants through bile into the feces
• Bioaccumulation occurs when the rate of absorption exceeds the rate of elimination, leading to the accumulation of a toxicant in the body over time (DDT, mercury, lead)

Toxicodynamics: Mechanisms of Action

• Receptor-mediated toxicity occurs when a toxicant binds to a specific receptor, leading to alterations in cellular function (neurotransmitter receptors, hormone receptors, enzyme inhibition)
• Enzyme inhibition can disrupt normal metabolic processes and lead to cellular dysfunction (cholinesterase inhibition by organophosphate pesticides)
• Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses, leading to cellular damage (lipid peroxidation, DNA damage, protein oxidation)
• DNA damage can lead to mutations, genomic instability, and cancer (aflatoxins, benzene, UV radiation)
• Mitochondrial dysfunction can disrupt energy production and lead to cell death (rotenone, cyanide)
• Endocrine disruption occurs when a toxicant interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones (bisphenol A, phthalates, dioxins)
• Immunotoxicity can suppress or enhance the immune system, leading to increased susceptibility to infections or autoimmune disorders (lead, mercury, PCBs)

Dose-Response Relationships

• The dose-response relationship describes the magnitude of the biological response as a function of the dose of the toxicant
• The threshold dose is the minimum dose required to produce a detectable effect
  • Some effects, such as cancer and genetic mutations, may not have a threshold dose
• The no-observed-adverse-effect level (NOAEL) is the highest dose at which no adverse effects are observed
• The lowest-observed-adverse-effect level (LOAEL) is the lowest dose at which adverse effects are observed
• The median lethal dose (LD50) is the dose that causes mortality in 50% of the exposed population
• Hormesis is a biphasic dose-response relationship characterized by a beneficial effect at low doses and a toxic effect at high doses (alcohol, radiation)
• The margin of safety (MOS) is the ratio of the NOAEL to the estimated human exposure level, used to assess the risk of adverse effects

Factors Affecting Toxicity

• Species differences in anatomy, physiology, and biochemistry can influence the toxicity of a substance (rodents vs. humans)
• Genetic factors, such as polymorphisms in metabolic enzymes (cytochrome P450) and DNA repair genes, can affect an individual's susceptibility to toxicants
• Age can influence the absorption, distribution, metabolism, and excretion of toxicants (infants, elderly)
  • The developing fetus is particularly vulnerable to toxicants due to its rapid growth and immature detoxification systems
• Gender differences in body composition, hormones, and metabolic rates can affect the toxicity of certain substances (alcohol, pharmaceuticals)
• Nutritional status can modulate the toxicity of certain substances (vitamin deficiencies, high-fat diets)
• Exposure route (oral, dermal, inhalation) and duration (acute, chronic) can influence the toxicity of a substance
• Chemical interactions, such as synergism and antagonism, can enhance or reduce the toxicity of a substance when combined with other agents (alcohol and acetaminophen)

Biomarkers and Risk Assessment

• Exposure biomarkers indicate the presence of a toxicant in the body (blood lead levels, urinary cotinine)
• Effect biomarkers reflect the biological response to a toxicant (cholinesterase inhibition, DNA adducts)
• Susceptibility biomarkers identify individuals who are more sensitive to the effects of a toxicant (genetic polymorphisms)
• Risk assessment involves hazard identification, dose-response assessment, exposure assessment, and risk characterization
  • Hazard identification determines the potential adverse health effects of a substance based on animal studies and human epidemiological data
  • Dose-response assessment quantifies the relationship between the dose of a toxicant and the incidence of adverse effects
  • Exposure assessment estimates the magnitude, frequency, and duration of human exposure to a toxicant
  • Risk characterization integrates the information from the previous steps to estimate the probability of adverse effects in a given population
• Uncertainty factors are applied to the NOAEL or LOAEL to account for interspecies and intraspecies variability, as well as other uncertainties in the risk assessment process
• The reference dose (RfD) is the estimated daily exposure to a toxicant that is likely to be without appreciable risk of adverse effects over a lifetime

Real-World Applications and Case Studies

• Environmental toxicology assesses the impact of pollutants on ecosystems and wildlife (oil spills, pesticide runoff)
• Occupational toxicology focuses on the health effects of workplace exposures (asbestos, silica dust, solvents)
  • Permissible exposure limits (PELs) are established to protect workers from adverse health effects
• Food toxicology evaluates the safety of food additives, contaminants, and naturally occurring toxins (aflatoxins, pesticide residues, acrylamide)
• Forensic toxicology applies toxicological principles to legal investigations (drug overdoses, poisonings)
• The Flint water crisis in Michigan, USA, highlighted the importance of monitoring and regulating lead levels in drinking water
• The Minamata disease in Japan was caused by the consumption of seafood contaminated with methylmercury from industrial waste
• The Love Canal disaster in New York, USA, involved the exposure of residents to various chemical waste products, leading to adverse health effects and the relocation of the affected community

Emerging Trends and Future Directions

• High-throughput screening (HTS) techniques allow for the rapid testing of large numbers of chemicals for potential toxicity using in vitro assays and computational models
• Toxicogenomics integrates genomics, transcriptomics, proteomics, and metabolomics to understand the molecular mechanisms of toxicity and identify novel biomarkers
• In silico methods, such as quantitative structure-activity relationship (QSAR) models, predict the toxicity of chemicals based on their structural features
• Organ-on-a-chip technologies mimic human physiology and allow for the testing of toxicants in a more relevant and personalized manner
• Nanotoxicology investigates the potential health and environmental risks associated with engineered nanomaterials (carbon nanotubes, silver nanoparticles)
• Epigenetic toxicology studies the impact of toxicants on epigenetic modifications (DNA methylation, histone modifications) and their role in disease development
• Microbiome toxicology explores the interactions between toxicants, the gut microbiome, and host health
• Cumulative risk assessment considers the combined effects of multiple toxicants and stressors on human health and the environment