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- Absorption is the transfer of a chemical from the site of exposure, usually an external or internal body surface, into the systemic circulation.
- Toxicants are removed from the systemic circulation by biotransformation, excretion, and storage at various sites in the body.
- Excretion is the removal of xenobiotics from the blood and their return to the external environment via urine, feces, or exhalation.
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The disposition of a chemical or xenobiotic is defined as the composite actions of its absorption, distribution, biotransformation, and elimination. The quantitative characterization of xenobiotic disposition is termed pharmacokinetics or toxicokinetics (see Chapter 7).
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The toxicity of a substance depends on the dose. The concentration of a chemical at the site of action is usually proportional to the dose, but the same dose of two or more chemicals may lead to vastly different concentrations in a particular target organ of toxicity owing to differences in the disposition of the chemicals. Various factors affecting disposition are depicted in Figure 5–1. For example, (1) if the fraction absorbed or the rate of absorption is low, a chemical may never attain a sufficiently high concentration at a potential site of action to cause toxicity, (2) the distribution of a toxicant may be such that it is concentrated in a tissue other than the target organ, thus decreasing toxicity, (3) biotransformation of a chemical may result in the formation of less toxic or more toxic metabolites at a fast or slow rate with obvious consequences for the concentration and thus the toxicity at the target site, and (4) the more rapidly a chemical is eliminated from an organism, the lower will be its concentration and hence its toxicity in target tissues. If a chemical is distributed to and stored in fat, its elimination is likely to be slow because very low plasma levels preclude rapid renal clearance or other clearances.
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The skin, lungs, and alimentary canal are the main barriers that separate higher organisms from an environment containing a large number of chemicals. Exceptions are caustic and corrosive agents (acids, bases, salts, and oxidizers) that act topically. A chemical absorbed into the bloodstream through any of these three barriers is distributed throughout the body, including the site where it produces damage, the target organ or target tissue. A chemical may have one or several target organs. Because several factors other than the concentration influence the susceptibility of organs to toxicants, the organ or tissue with the highest concentration of a toxicant is not necessarily the site of toxicity.
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Toxicants usually pass through the membranes of a number of cells, such as the stratified epithelium of skin, the thin cell layers of lungs or gastrointestinal tract, the capillary endothelium, and the cells of the target organ or tissue. Proteins ...