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Chemical Disposition and Toxicokinetics

The immediate goal of a chemical disposition study is to determine the fate of the chemical of interest in the animal studied. That is, to determine absorption, tissue distribution, bioaccumulation, metabolism, and excretion in the intact animal and to determine the effect of dose and/or route of exposure on each of these parameters. It may also be of interest to determine how these parameters change with age, sex or species. The long-range goal of these studies is to accumulate data to obtain a better assessment of structure-activity relationships as they determine chemical disposition in laboratory animals and to better interpret the significance of this data to humans.

Toxicokinetic studies are concerned with the change in concentration of the chemical or a metabolite with time in blood/plasma or other tissue. This information is important in relating exposure to internal dose, in determining if various biological processes, such as absorption or metabolism change as the administered dose changes, in determining if internal dose from a given exposure is different between sexes, species, old/young. Toxicokinetic data often can be extrapolated from laboratory animals to humans through mathematical modeling.

The major difference between the two is that chemical disposition studies consider what happens to the chemical and all its metabolites. Toxicokinetic studies generally just consider the parent chemical and perhaps a limited number of metabolites.

Chemical Disposition:

Disposition studies measure the Absorption, Distribution, Metabolism, and Excretion (ADME) of a chemical. ADME studies are normally done very early in the sequence of fully characterizing chemical toxicity and the data are often used to help set the route of administration for subsequent studies.

Chemicals used in these studies are usually synthesized to have a radiolabeled component in their structure, e.g. radioactive carbon (14C ) or hydrogen (3H ). Using chemicals containing a radiolabel does not require any prior knowledge about the chemical's behavior. In addition, the radioactivity can be easily detected and the parent compound or its metabolites in body fluids, tissues and excreta can be determined. However, measuring radioactivity only monitors the radiolabel and does not identify whether what is being measured is the parent chemical or one of its metabolites. Additional analysis techniques are used to differentiate between parent and metabolites.

The general outline of ADME studies is as follows:

Animals are dosed with radiolabeled chemical and placed in metabolism cages for separate collection of urine, feces and expired air. At termination, tissues are removed, the activity of the label (e.g., 14C or 3H ) is measured in the samples, and the content determined in tissues, urine, etc.

These studies usually include an intravenous (iv) administration to determine the fate of a "100% absorbed dose".

Toxicokinetic studies:

Toxicokinetic (TK) studies follow the change in concentration of parent and/or metabolite(s) with time in blood/plasma or other tissue(s).

Ideally, toxicokinetic studies are finished before the 2-year bioassay begins but data may also be obtained from animals treated in the bioassay.

TK studies are usually performed with unlabeled (no radioactivity) chemical. It is usually possible to develop an analytical method for a specific unlabeled chemical that is more sensitive than the rather general analysis that radiochemical methods allow. Data from the ADME studies are used to decide whether the analysis should be for parent or a metabolite. TK studies can use exposure routes not suitable for radiolabeled studies, for example, dosed-feed.

As with chemical disposition studies, TK studies include both iv and the anticipated routes of exposure. And, as in the disposition studies, iv gives the behavior of a "100% absorbed dose".

Bioavailability is a toxicokinetic measure that is often useful in describing the behavior of a chemical. Bioavailability is similar to absorption and is a comparison of systemic exposure between the iv dose (100 % bioavailable) and another route (oral, topical, inhalation). One usually considers bioavailability of the parent chemical, but it could refer to a metabolite. Absorption takes into consideration parent chemical and all its metabolites. Bioavailability only considers a single chemical or metabolite present in a single tissue, usually blood/plasma.

The general outline for TK studies is as follows:

Animals are dosed, blood samples are taken at predetermined times and analyzed. There are usually 3 blood samples per animal, the third sample being taken at termination. However, when more frequent sampling is required, an alternate procedure is to use a jugular vein cannula and take multiple samples from the same animal.

References

J Robert Buchanan, Leo T. Burka, Ronald L. Melnick. Purpose and Guidelines for Toxicokinetics Studies within the National Toxicology Program. Environmental Health Perspectives, Vol. 105, No. 5, pp. 468-471, 1997.