response curve at doses that approach relevance for human exposure. It then becomes a matter of conducting further research to understand the magnitude of response on a molecular or cellular end point that is needed to produce a structural defect with adverse physiological, structural, or functional developmental effects. A method has been proposed for constructing dose-response curves that combine data on frank malformations with data on less-severe effects that are not considered adverse. For example, Allen et al. (1996) combined data on rib malformations with those on rib variations in rats prenatally exposed to boric acid. This method could easily be adapted to include molecular events.

Although it can be postulated that many molecular and cellular events that are the precedents of abnormal development are unlikely to have strictly linear dose-response curves, there is minimal information on developmental specific processes. There have been extensive discussions on the shape of receptor-versus-nonreceptor-based responses that were initiated directly from recent advances in the understanding of molecular events; yet, little is known about actual events at low-dose exposures, as opposed to generation of hypothesized dose-response relationships at low doses. Hypothetical biologically based dose-response models have been proposed on a toxicant-specific basis (Shuey et al. 1995; Leroux et al. 1996). What appears to be most relevant for this report is a call for increased understanding of toxicant-induced molecular changes and an investigation of how these early events are linked to manifestations of adverse developmental outcomes. Empirical work will be needed to establish the magnitude of response at each level of organization required to provoke a response at the next level. Such investigations should be conducted to obtain quantitative information on the kinetics of the toxicant and the dynamics of the toxicological interaction in the temporal context of development (Faustman et al. 1999; Faustman et al. 2000).

Current practices in developmental toxicity risk assessment recognize the concept of “critical windows of sensitivity” in development, but a fundamental understanding of applying the molecular and developmental biological events that define those windows is lacking. This lack of understanding again results in the application of additional child-specific uncertainty factors in efforts to address the sensitivity of the developing conceptus rather than emphasizing the search for the biological understanding of critical windows of susceptibility.

A corollary to the problem of low-dose extrapolation is the assumption that effects observed at high-dose concentrations in experimental animals are relevant to the prediction of risk of adverse effects at ambient exposure concentrations. As discussed previously, testing of chemicals has the inherent dilemma of requiring exaggerated doses and concentrations to maximize the chances of detecting the potential for adverse effects and requiring understanding that the interpretability of the results might be limited because of the possibility that physiological processes in the pregnant animal have been so overwhelmed that the observed responses are qualitatively different from the responses at lower doses. The uneasy resolution of the dilemma has been to assume that the high dose and concen-

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement