Toxicology

• Mechanism of Toxicity


  The process by which a toxicant causes harmful effects in an organism
• Toxicants


  Substances that can cause harmful effects in living organisms
• Understanding mechanisms of toxicity

  • Provides rational basis for interpreting toxicity data, estimating probability of harmful effects, establishing prevention/antagonism procedures, designing less hazardous chemicals, and developing more selective pesticides

  
• Potential stages in development of toxicity after chemical exposure

  1. Delivery of toxicant to target

  2. Interaction with endogenous target molecules or alteration of biological environment

  3. Triggering perturbations in cell function/structure

  4. Initiation of repair mechanisms

  
• Ultimate toxicant


  The chemical species that reacts with the endogenous target molecule or critically alters the biological (micro)environment, initiating structural and/or functional changes
• Ultimate toxicants


  • Original compound (e.g. carbon monoxide)
  • Metabolite of parent compound (e.g. acetaldehyde)
  • Reactive oxygen/nitrogen species generated during biotransformation (e.g. hydrogen peroxide, hydroxyl radicals)
• Factors affecting accumulation of ultimate toxicant at target

  Facilitated by: Absorption, Distribution to site of action, Reabsorption, Toxication (metabolic activation)

  Inhibited by: Presystemic elimination, Distribution away from site of action, Excretion, Detoxification

  
• Absorption


  The rate depends on concentration at absorbing surface, area of exposed site, characteristics of epithelial layer, intensity of subepithelial microcirculation, and physicochemical properties of toxicant
• Lipid soluble chemicals are absorbed more readily than water-soluble substances
• Presystemic elimination


  Toxicants may be eliminated during transfer from site of exposure to systemic circulation, e.g. ethanol metabolized in stomach, liver, and lungs
• Presystemic elimination


  Can reduce systemic exposure but may also contribute to injury of digestive mucosa, liver, and lungs
• Distribution of toxicants


  Lipid soluble compounds move readily into cells by diffusion, while highly ionized/hydrophilic xenobiotics are largely restricted to extracellular space
• Mechanisms facilitating distribution to target

  Porosity of capillary endothelium, Specialized membrane transport, Accumulation in cell organelles, Reverse intracellular binding
• Mechanisms hindering distribution to target

  Binding to plasma proteins, Specialized barriers (e.g. blood-brain barrier), Distribution to storage sites, Association with intracellular binding proteins
• Strong binding to plasma proteins delays and prolongs the effects and elimination of toxicants
• The blood-brain barrier prevents access of hydrophilic chemicals to the brain except for those that can be actively transported
• Highly lipophilic chemicals can concentrate in adipocytes, while lead is deposited in bone
• Blood-brain barrier


  • Limits the access of hydrophilic chemicals to the brain, protecting it from potential harm
  • Not completely impermeable and allows essential nutrients and molecules required for brain function to enter through active transport mechanisms
• Distribution to storage sites

  Some chemicals accumulate in tissues (i.e., storage sites) where they do not exert significant effects
• Chemicals that accumulate in storage sites

  • Highly lipophilic such as chlorinated hydrocarbon insecticides concentrate in adipocytes
  • Lead is deposited in the bone by substituting for Ca2 in hydroxyapatite
• Chemicals with specific properties, such as lipophilicity or the ability to substitute for essential ions, can accumulate in storage sites within the body without exerting immediate toxic effects. However, the long-term presence of these chemicals in storage sites can pose risks if they are released back into circulation or undergo metabolic activation over time.
• Association with intracellular binding proteins

  Binding to non target intracellular sites also reduces the concentration of toxicants at the target site, at least temporarily
• Metallothionein


  • A cysteine-rich cytoplasmic protein that serves such a function in acute cadmium intoxication
  • Metallothionein- family of cysteine-rich proteins found in the cytoplasm of cells, particularly in the liver and kidneys. These proteins have a high affinity for heavy metals such as cadmium, zinc, and copper.
• Exports from cells


  Intracellular toxicants may be transported back into the extracellular space for reasons of cellular detoxification, maintaining cellular homeostasis, protection of organelles, and facilitating elimination
• Excretion


  • Renal transporters have a preferential affinity for smaller (300-Da), and hepatic transporters for larger (400 Da), amphiphilic molecules
  • The route and speed of excretion depend largely on the physicochemical properties of the toxicant
  • Only highly hydrophilic, usually ionized chemicals such as organics acids and bases can be efficiently removed
• Reabsorption


  • There are no efficient elimination mechanisms for nonvolatile, highly lipophilic chemicals such as polyhalogenated biphenyls and chlorinated hydrocarbon insecticides
  • Reabsorption by diffusion is dependent on the lipid solubility of the chemical
  • For organic acids and bases, diffusion is inversely related to the extent of ionization, because the nonionized molecule is more lipid-soluble
  • Reabsorption of substances in the kidneys, particularly by diffusion, is influenced by factors such as lipid solubility and the presence of specific transporters or carriers. Lipophilic molecules, including nonionized forms of organic acids and bases, can undergo passive diffusion across renal tubule cells and be reabsorbed into the bloodstream.
• Toxication


  • Biotransformation to harmful products
  • Leads to harmful effects on the body
  • Results in toxicity or adverse health effects
  • Involves absorption, distribution, and action of toxicants within the body
  • Negative impact on health and well-being
• Detoxication


  • Process of metabolizing and eliminating toxicants
  • Aims to neutralize or eliminate harmful substances
  • Reduces toxicity or renders toxicants inert
  • Involves biotransformation and elimination of toxicants from the body
  • Positive impact on health by reducing toxic effects
• Detoxication may be insufficient for several reasons: toxicants may overwhelm detoxication processes leading to exhaustion of the detoxication enzymes, a reactive toxicant may inactivate a detoxicating enzyme, some conjugation reactions can be reversed, and sometimes detoxication generates potentially harmful by products.
• Reaction of the Ultimate Toxicant with the Target Molecule


  The attributes of target molecules, the types of reactions between ultimate toxicants and target molecules, and the effects of toxicants on the target molecules are considered.

  
• The most prevalent and toxicologically relevant targets are macromolecules such as nucleic acid (especially DNA and proteins), and among the small molecules, membrane lipids are frequently involved, whereas cofactors such as coenzyme A and pyridoxal rarely are involved.
• To identify a target molecule as being responsible for toxicity, it should be demonstrated that the ultimate toxicant: reacts with the target and adversely affects its functions, reaches an effective concentration at the target site, and alters the target in a way that is mechanistically related to the observed toxicity.

  
• Effects of toxicants on target molecules

  Reaction of the ultimate toxicant with endogenous molecules may cause dysfunction; in the case of proteins, it may render them foreign (i.e., antigen) to the immune system.
• Dysfunction of target Molecules

  Some toxicants activate protein target molecules, mimicking endogenous cells and acting as agonists, binding to specific protein receptors and activating them, mimicking the action of endogenous molecules.
• Repair


  Process of restoring normal structure or function after damage or injury, restoring cellular homeostasis and functionality, including DNA repair mechanisms (e.g., base excision repair, nucleotide excision repair).

  
• Dysrepair


  Result of failed or aberrant repair processes, leading to persistent damage or dysfunction, such as necrosis, fibrosis, and chemical carcinogenesis.

  
• Repair fails most typically when the damage overwhelms the repair mechanisms.