of absorption, distribution, metabolism, and excretion. Those four biologic processes characterize the disposition of a foreign substance that enters the organism. Their combination determines the concentration of the chemicals in the body and how long each organ is exposed to it and thus influences its toxic or pharmacologic activity.

Absorption is the entry of a substance into an organism, normally by uptake into the bloodstream via mucous surfaces, such as the intestinal walls of the digestive tract during ingestion. Low solubility, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a substance is absorbed after being ingested. The solubility of a chemical in fat and its hydrophobicity influence the pathways by which it is absorbed and its relative potential to be metabolized (structurally transformed) and ultimately whether it persists in the body or is excreted. Absorption is a critical determinant of a chemical’s bioavailability, that is, the fraction of it that reaches the systemic circulation. In addition to ingestion routes of exposure experienced by free-ranging humans are inhalation (entry via the airways) and dermal exposure (entry via the skin). Animal studies may involve additional routes of exposure that are not ordinarily encountered by humans, such as intravenous or intraperitoneal injection, in which a chemical is injected into the bloodstream or abdominal cavity, respectively.

Distribution refers to the travel of a substance from the site of entry to the tissues and organs where they will have their ultimate effect or be sequestered. Distribution takes place most commonly via the bloodstream.

Metabolism is the breaking down that all substances begin to experience as soon as they enter the body. Most metabolism of foreign substances takes place in the liver by the action of a number of enzymes, including cytochrome P-450s, which catalyze the oxidative metabolism of many chemicals. As metabolism occurs, the initial (parent) chemical is converted to new chemicals called metabolites, which are often more water-soluble (polar) and thus more readily excreted. When metabolites are pharmacologically or toxicologically inert, metabolism deactivates the administered dose of the parent chemical, reducing its effects on the body. Metabolism may activate a chemical to a metabolite that is more potent or more toxic than it is.

Excretion, also referred to as elimination, is the removal of substances or their metabolites from the body, most commonly in urine or feces. The relative rate of excretion of a chemical from the body is often limited by the rate of metabolism of the parent chemical into more water soluble, readily excreted metabolites. Excretion is often incomplete, especially in the case of chemicals that resist metabolism, and incomplete excretion results in the accumulation of foreign substances that can adversely affect biologic functions.

The routes and rates of absorption, distribution, metabolism, and excretion of a toxic substance collectively are termed toxicokinetics (or pharmacokinetics). Those processes determine the amount of a particular substance or metabolite that reaches specific organs or cells and that persists in the body. Understanding the toxicokinetics of a chemical is important for valid reconstruction of exposure



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