As knowledge of human variation in responses increases from the results of the Human Genome Project, a risk-assessment framework is needed in which these default factors are replaced with mechanistic data on relevant toxicant-induced changes.

Molecular approaches should be useful in resolving the issue of extrapolation across species. There is general agreement that the molecular control of development is highly conserved, although the pattern of development of structures at higher levels of biological organization can be very dissimilar. The committee discusses such conservatism in Chapter 7 and suggests that models that assess a small number of those control points and pathways might be relevant for evaluating the potential for chemicals to impact the critical pathways in development, regardless of the species from which the model is derived. The same principle applies to extrapolation from rat or mouse to humans. The critical data to support predictions of ultimate effect in human embryos include a description of the pathogenetic steps that ensue from toxicant actions at the molecular level and lead to structural malformations. Pattern formation genes and signal transduction pathways are so highly conserved across groups of animals that actions of toxicants on those gene products and processes are likely to be comparable and have similar toxicodynamic impacts. The events that follow perturbations at the molecular level are likely to be more prone to interspecies variability, for example, the toxicokinetic differences observed with chemicals that require metabolic activation, as metabolic rates often vary markedly between species. At this point, the predictive value of hazard identification data in alternative models, particularly those that are phylogenetically removed from humans, becomes limited. Therefore, characterization of the pathogenetic events that result in dysmorphogenesis will lead to better prediction of (1) whether the critical events are present and when they are functional in humans, predisposing them to an adverse outcome; and (2) the kinds of adverse outcomes that are possible, based on the temporal and spatial locations of the critical events.

A better understanding of the molecular and cellular mechanisms involved in the pathogenesis of abnormal development might provide a method for answering such questions as to whether a residual level of risk exists at the RfD or ADI and what that level might be. A residual level of risk might also provide a method for determining what exposure concentration can be permitted before the probability of an adverse event begins to increase. The resolving power of animal studies to distinguish an increase in the rate of frank malformations is relatively weak. For example, in a study with 20 pregnant rats per dose group, an increase in the malformation rate must double from the background rate to be statistically significant. Mechanistic and pathogenetic events may prove to be much more sensitive and, therefore, provide a data-driven means to extend the dose-response curve below the NOAEL or BMD for malformations. Although these effects might not be adverse, they might be biomarkers or early indicators for the process of pathogenesis and might help to determine the shape and slope of the dose-

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