species differences in susceptibility to developmentally toxic effects can frequently be due to differences in absorption, fate, or elimination of the agent of interest rather than to fundamental species-specific differences in biological response. Examples of embryotoxic drugs that have undergone detailed comparative evaluations are valproic acid (Nau 1986) and retinoids (Kraft et al. 1993; Kraft and Juchau 1993; Nau et al. 1994).

Regulatory authorities have required that the highest dose administered in animal toxicity studies in support of product registration be the estimated MTD. The administration of the MTD serves to maximize the likelihood of manifestation of a biological and possibly adverse response and ensure detection of all inherent toxicities. However, very large doses of environmental agents might be required in animals to reach the MTD, compared with anticipated human exposures at low concentrations. Such high doses of a test agent in animals can result in different kinetic and dynamic processes than those occurring at lower, more environmentally relevant exposures. For example, high doses can saturate elimination or repair processes or stimulate cell division or apoptosis, which might result in grossly exaggerated target organ concentrations and manifestations of toxicity. Indeed, toxicokinetic studies conducted in past decades have elucidated those phenomena for numerous therapeutic and environmental agents. The insights gained have led to the simplistic subdivision of linear and nonlinear classification of kinetics. Toxicokinetic data are essential to ascertain whether similar intervals or concentrations of the chemical or its metabolites result from different doses. High doses often result in nonlinear kinetics and subsequently elicit toxic effects that are not observed at low doses associated with linear toxicokinetics. Consideration of these kinetic and dose-response relationships is needed as new information is evaluated for use in risk assessment.

Toxicokinetic considerations are not only important in the interpretation of potential health effects and their relevance across species but they are also important in the determination of a developmental toxicity study design. For example, in one type of conventional developmental toxicology study design, studies initiate dosing at the beginning of organogenesis of the chosen test species. The study design might be flawed for compounds that have a long half-life, because steady-state concentrations are reached only after dosing for approximately four half-lives. Thus, a compound that has a half-life of 24 hr will not reach steady-state concentrations until 4 days after four consecutive daily administrations. Such a toxicokinetic property might miss the window of susceptibility to chemical perturbation of a specific developmental process in a long half-life test species. In animals with short gestation durations, such as the mouse or rat, the embryo might reach a developmental stage of decreased teratogenic sensitivity by the time the toxicologically critical steady-state concentration is achieved. For some agents, it may be possible to overcome this problem by starting exposure of the dam earlier in pregnancy. Toxicokinetic information can thus aid in the proper design of new studies or more accurately interpret results from inves-

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement