Purpose and guidelines for toxicokinetic studies within the National Toxicology Program.

Toxicokinetic studies undertaken within the National Toxicology Program are intended to aid the design of toxicology and carcinogenicity studies, help interpret the results of toxicology and carcinogenicity studies with respect to the relationship between toxic effects and external exposure, and define the parameters of dose, distribution, metabolism, and elimination that can be used in human risk assessment. Descriptions of two study designs presented here represent the possible extremes in approaches to toxicokinetic studies. The comprehensive approach is geared toward the development of physiology based pharmacokinetic models that relate external exposure to target organ dosimetry and addresses the questions: Is the chemical absorbed? How is the chemical metabolized? Where are the chemical and/or metabolites distributed in the body? What are the elimination rate and route of the chemical? What is the effect of dose on absorption, distribution, metabolism, and elimination? The minimal study design is more limited in scope than the comprehensive design and addresses primarily the issues of absorption, distribution, and elimination of the parent chemical. Study protocols for most chemicals lie somewhere between these two extreme approaches. An increased understanding of the relationships between external exposure, target organ dosimetry, and adverse effects should provide greater confidence in making low-dose extrapolations of human risk. This paper focuses on the collection of data from animal toxicokinetic studies. The construction of comparable models to characterize target organ dosimetry in exposed humans would certainly require the use of human parameter values obtained from human tissue samples and volunteers.