FIGURE S-3 Multiple exposures leading to common adverse outcomes.

with any risk estimates. Because issues surrounding fetal exposure are particularly important in phthalate risk assessment, research to determine prenatal exposure to phthalates at multiple relevant times during pregnancy is critical. It is especially important to determine whether metabolite concentrations in the fetal compartment vary during pregnancy; if they do, it would indicate possible metabolic differences at different gestational ages. More generally, the full spectrum of phthalate metabolites needs to be characterized, the most appropriate metabolites to use as biomarkers of human exposure need to be determined, and the most important sources of phthalate exposure in the general population need to be identified. Because differences in susceptibility clearly depend on age, species, and exposure route, research to understand why the differences occur is important. Finally, research is needed to investigate possible deviations from the dose-addition concept—that is, identification of cases of synergism or antagonism relative to dose addition.

The committee recognizes that its recommendation to move beyond the constraints of structural or mechanistic similarity for cumulative risk assessment may appear challenging. One might ask, “With so many chemicals, where do we begin?” However, the committee concludes that it is plausible and warranted to extend cumulative risk assessment to include chemicals associated with common adverse outcomes as exemplified in this report by inclusion of other antiandrogenic chemicals with phthalates. To cite another example, EPA could evaluate combined exposures to lead, methylmercury, and polychlorinated biphenyls because all contribute to cumulative risk of cognitive deficits consistent with IQ reduction in children, although the deficits are produced by different mechanisms of action. Cumulative risk assessment based on common adverse outcomes is a feasible and physiologically relevant approach to the evaluation of the multiplicity of human exposures and directly reflects EPA’s mission to pro-



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