☣️Toxicology Unit 4 – Mechanisms of toxicity

Key Concepts and Definitions

• Toxicology studies the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem
• Toxicants are substances that can cause harm or death to living organisms when ingested, inhaled, or absorbed through the skin
• Toxicity refers to the degree to which a substance can damage an organism and depends on factors such as dose, route of exposure, and individual susceptibility
• Acute toxicity results from a single exposure to a toxicant and can cause immediate effects (cyanide poisoning)
• Chronic toxicity develops over time from repeated or continuous exposure to a toxicant and may have delayed onset of symptoms (lead poisoning)
  • Chronic toxicity can be more difficult to detect and treat compared to acute toxicity
• Bioaccumulation occurs when a toxicant is absorbed by an organism at a rate faster than it can be metabolized or excreted, leading to a buildup in tissues over time (mercury in fish)
• Biomagnification is the increasing concentration of a toxicant in the tissues of organisms at successively higher levels in a food chain (DDT in birds of prey)

Toxicant Entry and Distribution

• Toxicants can enter the body through various routes, including ingestion, inhalation, dermal absorption, and injection
• Ingestion involves the consumption of a toxicant through the mouth and gastrointestinal tract (contaminated food or water)
• Inhalation occurs when a toxicant is breathed into the lungs and absorbed into the bloodstream (airborne pollutants, gases)
  • Particle size and solubility of the toxicant influence the extent of inhalation and absorption
• Dermal absorption happens when a toxicant penetrates the skin and enters the circulatory system (pesticides, solvents)
  • Factors affecting dermal absorption include skin integrity, hydration, and the chemical properties of the toxicant
• Injection introduces a toxicant directly into the body through a break in the skin (drug abuse, animal bites)
• Once absorbed, toxicants are distributed throughout the body via the bloodstream and can accumulate in specific organs or tissues (liver, kidneys, fat)
• Toxicants may cross biological barriers, such as the blood-brain barrier or placenta, affecting sensitive organs or developing fetuses
• Protein binding can influence the distribution and toxicity of a substance by altering its availability to target sites

Cellular and Molecular Targets

• Toxicants can interact with various cellular and molecular targets, disrupting normal biological processes
• Cell membrane integrity can be compromised by toxicants, leading to cell lysis or altered permeability (surfactants, organic solvents)
• Mitochondria, the powerhouses of the cell, can be targeted by toxicants, resulting in impaired energy production and oxidative stress (rotenone, cyanide)
• Enzymes, which catalyze biochemical reactions, may be inhibited or activated by toxicants, disrupting cellular metabolism (heavy metals, pesticides)
  • Enzyme inhibition can be competitive, non-competitive, or irreversible, depending on the toxicant's mechanism of action
• DNA damage caused by toxicants can lead to mutations, chromosomal aberrations, and cancer (aflatoxins, UV radiation)
• Endocrine disruptors can mimic or block the actions of natural hormones, interfering with normal endocrine function (bisphenol A, phthalates)
• Neurotransmitter systems, such as acetylcholine and dopamine, can be affected by toxicants, resulting in neurotoxicity (organophosphate pesticides, MPTP)
• Immune system components, including lymphocytes and cytokines, may be targeted by toxicants, leading to immunosuppression or autoimmunity (dioxins, silica)

Mechanisms of Cell Injury

• Toxicants can cause cell injury through various mechanisms, ultimately leading to cell death or dysfunction
• Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the cell's antioxidant defenses, leading to damage of cellular components (lipid peroxidation, protein oxidation)
  • Toxicants can increase ROS generation or deplete antioxidants (glutathione), exacerbating oxidative stress
• Mitochondrial dysfunction can result from toxicant-induced damage to mitochondrial DNA, proteins, or lipids, impairing energy production and triggering apoptosis (rotenone, doxorubicin)
• Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded proteins, which activates the unfolded protein response and can lead to apoptosis if unresolved (tunicamycin, thapsigargin)
• Lipid peroxidation is the oxidative degradation of lipids in cell membranes, leading to altered membrane fluidity and permeability (carbon tetrachloride, iron)
• DNA damage and genotoxicity can result from direct interactions between toxicants and DNA or indirectly through the generation of ROS, leading to mutations and genomic instability (aflatoxins, benzo[a]pyrene)
• Apoptosis, or programmed cell death, can be triggered by toxicants through the activation of death receptors or the mitochondrial pathway (dioxins, cisplatin)
• Necrosis is a form of cell death characterized by cell swelling, organelle dysfunction, and membrane rupture, often resulting from severe toxicant-induced damage (high doses of acetaminophen)

Organ-Specific Toxicity

• Toxicants can exhibit organ-specific toxicity due to differences in absorption, distribution, metabolism, and excretion among tissues
• Hepatotoxicity affects the liver, which is a primary site of toxicant metabolism and is susceptible to damage (acetaminophen, alcohol)
  • Mechanisms of hepatotoxicity include oxidative stress, mitochondrial dysfunction, and immune-mediated injury
• Nephrotoxicity targets the kidneys, which are responsible for filtering toxicants from the blood and can accumulate high concentrations of toxicants (aminoglycosides, cadmium)
  • Toxicants can cause acute kidney injury, chronic kidney disease, or specific damage to the glomeruli or tubules
• Neurotoxicity involves damage to the nervous system, including the brain, spinal cord, and peripheral nerves (lead, mercury)
  • Neurotoxicants can affect neurotransmitter systems, cause oxidative stress, or induce neuroinflammation
• Cardiotoxicity affects the heart and cardiovascular system, leading to arrhythmias, cardiomyopathy, or vascular damage (doxorubicin, cocaine)
• Pulmonary toxicity targets the lungs and respiratory system, causing inflammation, fibrosis, or impaired gas exchange (asbestos, silica)
• Reproductive toxicity can affect fertility, sexual function, or fetal development (phthalates, lead)
  • Toxicants may disrupt hormonal signaling, cause oxidative stress, or directly damage reproductive organs
• Immunotoxicity involves the suppression or dysregulation of the immune system, increasing susceptibility to infections or autoimmune disorders (dioxins, pesticides)

Detoxification and Biotransformation

• Biotransformation is the process by which the body modifies toxicants to facilitate their elimination and reduce their toxicity
• Phase I reactions, primarily carried out by cytochrome P450 enzymes, introduce or expose functional groups on toxicants through oxidation, reduction, or hydrolysis
  • These reactions can activate or detoxify toxicants, depending on the specific chemical and enzyme involved
• Phase II reactions involve the conjugation of toxicants with endogenous molecules, such as glucuronic acid, sulfate, or glutathione, to increase their water solubility and facilitate excretion
  • Conjugation reactions are catalyzed by transferase enzymes, such as UDP-glucuronosyltransferases and glutathione S-transferases
• Toxicants can induce or inhibit the expression of biotransformation enzymes, affecting their own metabolism and that of other substances (polycyclic aromatic hydrocarbons, St. John's wort)
• Genetic polymorphisms in biotransformation enzymes can influence an individual's susceptibility to toxicants and response to drugs (CYP2D6, NAT2)
• Excretion of toxicants occurs primarily through the kidneys (urine) and liver (bile), with minor routes including the lungs, sweat, and breast milk
• Toxicants that are poorly absorbed, highly bound to proteins, or extensively metabolized may have limited systemic toxicity but can still cause local effects at the site of exposure

Dose-Response Relationships

• The dose-response relationship describes the magnitude of a toxicant's effect on an organism as a function of the dose
• The dose is the amount of a toxicant administered or received, usually expressed as a concentration or mass per unit of body weight (mg/kg)
• The response can be any measurable biological effect, such as mortality, enzyme activity, or tumor incidence
• The threshold dose is the minimum dose required to produce a detectable effect and is used to establish safe exposure levels (reference dose, acceptable daily intake)
• The median lethal dose (LD50) is the dose that causes mortality in 50% of the exposed population and is used to compare the acute toxicity of different substances
  • LD50 values are species-specific and depend on factors such as route of exposure and duration
• The no-observed-adverse-effect level (NOAEL) is the highest dose at which no adverse effects are observed in exposed organisms
• The lowest-observed-adverse-effect level (LOAEL) is the lowest dose at which adverse effects are observed
• Hormesis is a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition (alcohol, radiation)
• Individual variability in response to toxicants can be influenced by factors such as age, sex, health status, and genetic background

Emerging Topics and Research

• Nanotoxicology studies the toxicity of nanomaterials, which have unique properties and can interact with biological systems in novel ways (carbon nanotubes, silver nanoparticles)
  • Nanomaterials can cross biological barriers, accumulate in tissues, and generate oxidative stress or inflammation
• Epigenetic toxicology investigates the impact of toxicants on epigenetic mechanisms, such as DNA methylation and histone modifications, which can alter gene expression without changing the DNA sequence (bisphenol A, arsenic)
  • Epigenetic changes can be heritable and may contribute to long-term health effects or transgenerational toxicity
• Microbiome-toxicant interactions explore how toxicants can disrupt the gut microbiome and how the microbiome can modulate toxicant metabolism and toxicity (pesticides, heavy metals)
• High-throughput toxicity screening uses automated methods to rapidly test large numbers of chemicals for potential toxicity, helping prioritize compounds for further testing (Tox21, ToxCast)
  • These methods often employ in vitro assays, computational models, and omics technologies to assess multiple toxicity endpoints
• Alternatives to animal testing, such as in vitro cell culture models, organoids, and in silico computational approaches, are being developed to reduce, refine, and replace the use of animals in toxicity testing (3D cell cultures, quantitative structure-activity relationships)
• Exposome research aims to characterize the totality of environmental exposures an individual experiences from conception onwards and how these exposures interact with the genome to influence health (pesticides, air pollution)
  • The exposome includes both external exposures (toxicants, diet, lifestyle) and internal factors (metabolism, microbiome, oxidative stress)
• Personalized toxicology seeks to understand individual differences in susceptibility to toxicants based on genetic, epigenetic, and environmental factors, enabling tailored risk assessment and interventions (pharmacogenomics, precision medicine)