Toxicokinetics in the National Toxicology Program

Toxic responses to test chemicals are known to be dependent on the exposure route, the kinetic behavior of the chemical, and the dose used in the toxicology study. Therefore, knowledge of internal dose is indispensable for the interpretation of toxicology study results, for the facilitation of interspecies scaling, and for risk assessment. By monitoring the blood and/or tissue concentrations of test chemical and/or metabolites versus time after administration of study chemicals by different routes, the bioavailability and kinetic characteristic of test chemicals can be readily obtained. This data can define the so-called linear dose range using area under the plasma concentration versus time curve, clearance, or other related toxicokinetic parameters, and can also be used to predict the possible bioaccumulation under multiple dose regimes. Changes in kinetic parameters after multiple exposures indicate alteration in how the animal handles the chemical (e.g., that there was enzyme induction or inhibition). A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. Examples of the application of NTP toxicokinetic evaluations were also presented in this chapter, demonstrating their use in the design and interpretation of toxicology studies.