Application of pharmacokinetic principles to exposure to chemical mixtures.

Kinetic interactions among chemicals present in a mixture can influence the relationship between administered and delivered or effective dose; these interactions are distinct from dynamic interactions such as, for example, competition between two chemicals for receptor binding sites. The relationship between administered and effective dose depends on a number of biochemical, physiological, and physical factors such as age, sex, level of physical activity, route of administration, dose pattern, and bioavailability. In addition, interactions among chemicals may limit or increase the effective dose relative to the administered dose for any of the chemicals of a mixture. If the mechanism of the interaction is known, the direction and general magnitude of its effects may be predictable. A variety of potential interactions is briefly reviewed, and selected illustrations of these interactions are given. Two types of interactions likely to be pervasive in mixtures of chemically related bioactive materials are considered in greater detail. These interactions are induction of metabolizing enzymes such as the mixed-function oxidases, and competition of structurally similar chemicals for active sites on metabolizing enzymes. Simulations are presented to illustrate the consequences of these interactions, and examples of their occurrence are given.