THE USE OF PHARMACOKINETICS AS AN INTERPRETIVE AND PREDICTIVE TOOL INCHEMICAL TOXICOLOGY TESTING AND RISK ASSESSMENT - A POSITION PAPER ONTHE APPROPRIATE USE OF PHARMACOKINETICS IN CHEMICAL TOXICOLOGY

It has been recognized for several decades in the pharmaceutical indus try that the safety evaluation of pharmacological agents must include pharmacokinetic (PK) studies, which are designed to determine the rate of absorption, distribution, metabolism, and excretion (ADME). In rec ent years the importance of such ADME studies in toxicology has also b ecome increasingly apparent to the chemical industry. This increased f ocus has led to testing strategies that can produce ADME/PK data with greater applicability to toxicity testing and risk assessment. An exam ple of such a strategy is the concept of a tiered approach to the cond uct of ADME/PK studies (Wilson, A. G. E., Frantz, S. W., and Keifer, L . C. (1994). Environ. Health Perspect., in press). However, in practic e, PK data are often viewed as being of limited usefulness and of only ancillary importance to the determination of chemical toxicity. As a consequence, the close integration of PK studies with toxicity-testing protocols is not always practiced within the chemical industry and is thus frequently scheduled independently from toxicity testing. This l ack of integration has resulted in the design of subchronic (13-week) and chronic (2-year) toxicity studies without the benefit of PK inform ation to establish the appropriate dose levels to be used, often becau se of inappropriate timing. The result is that much of the PK data whi ch have been generated is without a clear consideration of its applica tion to toxicity testing and risk assessment. This position paper is i ntended to provide recommendations for the appropriate design and inte rpretation of a PK study, as well as when and how to use PK data in th e interpretation of toxicology data. Additional issues discussed in th e paper include the design of PK studies to evaluate tissue time-cours e relationships and chemical persistence, the overall usefulness of PK data to toxicology testing, and the utility of PK as a useful interpr etive and predictive tool in toxicology and risk assessment. (C) 1994 Academic Press, Inc.