Principles of Toxicology

         The discipline of toxicology considers the adverse effects of chemicals, including drugs, and other agents, such as biological toxins and radiation, on biological systems.

    Toxicity associated with drug action can generally be characterized as either an extension of the therapeutic effect, such as the fatal central nervous system (CNS) depression that may follow a barbiturate overdose,or as an effect that is unrelated to the therapeutic effect,such as the liver damage that may result from an acetaminophen overdose.

     This chapter focuses on the tissue response associated with the latter type of drug toxicity and on the toxicities associated with several important classes of nontherapeutic agents.

    The target organ for the expression of xenobiotic toxicity is not necessarily the tissue or organ in which the drug produces its therapeutic effect,nor is it necessarily the tissue that has the highest concentration of the agent. For example, lead accumulates in bone but produces no toxicity there; certain chlorinated pesticides accumulate in adipose tissue but produce no local adverse effects.

     Drugs such as acetaminophen cause necrosis in the centrilobular portion of the liver at a site of the monooxygenase enzymes that bioactivate the analgesic.

      It is necessary to distinguish between the intrinsic toxicity of a chemical and the hazard it poses.While a chemical may have high intrinsic toxicity, it may pose little or no hazard if exposure is low.In contrast,a relatively nontoxic chemical may be quite hazardous if exposure is large or the route of exposure is not physiological.

 

MANIFESTATIONS OF TOXICITY:-

Organ Toxicity:-  

  The events that initiate cell death are not completely understood. The common final stages of necrotic cell death are disruption of normal metabolic processes and ensuing inability to maintain intracellular electrolyte homeostasis.If the insult is severe or prolonged enough, the cell will not regain normal function. At the same time, other cells show apoptotic cell death, characterized by cell shrinkage,cleavage of DNA between nucleosomes,and formation of apoptotic bodies.Some chemicals are metabolized to reactive products that bind to cellular macromolecules. If such binding impairs the function of crucial macromolecules,cell viability is lost. How severely organ function will be impaired depends on the reserve capacity of that organ.The ultimate outcome will depend on the affected organ’s regenerative capacity and response to damage.

Pulmonary Toxicity:-

Inhaled gases,solid particles,or liquid aerosols may deposit throughout the respiratory system, depending on their chemical and physical properties.The large surface area of the respiratory passages and alveolar region and the large volume of air delivered to that area (approximately 6–7 L/minute in a young man) provide great opportunity for interaction between inhaled materials and lung tissue.

Exposure of the lungs to xenobiotics may result in a number of disease conditions including bronchitis, emphysema, asthma, hypersensitivity pneumonitis, pneumoconiosis, and cancer. During repair, damaged lung alveolar epithelium may be replaced by fibrous tissue that does not allow for gas exchange, which intensifies the damage caused by the initial lesion.

Hepatotoxicity:-

The blood draining the stomach and small intestine is delivered directly to the liver via the hepatic portal vein, thus exposing the liver to relatively large concentrations of ingested drugs or toxicants. Hepatic exposure to agents that undergo bioactivation to toxic species can be significant.

          Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform,that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance.At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the midzonal area (midway between the portal triad and central vein).Cells around the portal triad are exposed to the highest concentrations; necrosis occurs with direct-acting agents.

     A single large dose of a hepatotoxin may cause liver necrosis yet resolve with little or no tissue scarring. Continued exposure to the toxic agent, however, can result in hepatic cirrhosis and permanent scarring.

Nephrotoxicity:-

The kidneys are susceptible to toxicity from xenobiotics  because they too have a high blood flow.Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the filtered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity,since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells,thereby concentrating these chemicals manyfold.