• Determine the basis of differences observed in children’s vs adults’ urinary concentrations. For example, are the observed differences related to differences in exposure or to differences in metabolism?

  • Determine prenatal exposure by using phthalate-exposure biomarkers (that is, urine and amniotic fluid) at multiple relevant times during pregnancy. It is especially important to determine whether the various metabolite concentrations vary with time; if so, it might indicate differences in metabolism according to gestational age.

  • Determine the relationship between maternal urinary phthalate metabolite concentrations and those in the fetal compartment (for example, concentrations in amniotic fluid), with an emphasis on understanding the pharmacokinetics of phthalates in the fetal compartment.

  • Characterize human exposure to other antiandrogens and other factors that contribute to disturbed androgen action. Determine the possibility of coexposure, in which case the chemicals would exhibit joint action.

  • Use existing large databases, such as NHANES, to assess exposure to multiple phthalates and other chemicals that may contribute to common biologic outcomes. Incorporate state-of-the-art exposure-assessment strategies for multiple phthalates and other chemicals in large or planned epidemiologic studies, such as the National Children’s Study.

  • Develop pharmacokinetic models that can allow better predictions of human fetal exposure on the basis of animal studies.

TOXICITY ASSESSMENT

As discussed in Chapter 3, although few human data are available, rats exposed to a variety of phthalates have exhibited reproductive developmental effects that mirror the hypothesized testicular dysgenesis syndrome in humans. The research initiatives outlined below would add substantially to the scientific database and enable better prediction of effects of phthalate exposure.

  • Conduct studies to determine whether there are multigenerational effects of specific phthalates, phthalate-antiandrogen mixtures, and antiandrogen mixtures that have not yet been tested.

  • Elucidate the mechanisms of phthalate action in fetal vs adult tissue, mechanistic differences between species, and any potential for differences in effects related to exposure route.

  • Determine whether in utero exposure combined with lifetime exposure affects the incidence and severity of cancer outcomes. As discussed in Chapter 3, hepatic, testicular, and pancreatic cancers have been associated with activation of the peroxisome-proliferator-activated receptor-α (PPARα), but there is evidence that these cancer types may be mediated by mechanisms independent of PPARα. Because fetuses and neonates may exhibit sensitivity to PPARα ligands different from that exhibited by adults and the majority of studies have



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