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Phthalates and Cumulative Risk Assessment: The Tasks Ahead 6 Data Gaps and Research Needs On review of the scientific literature on phthalates, the committee found that sufficient data are available to conduct a cumulative risk assessment of these chemicals. Accordingly, progress need not wait for data gaps identified here to be addressed. Instead, the research recommended will allow greater refinement of the cumulative risk assessment for all health outcomes associated with phthalates and reduce uncertainty associated with such an assessment. EXPOSURE ASSESSMENT As discussed in Chapter 2, phthalates are used in a wide variety of consumer products and building materials, and widespread exposure of the general population has been documented through the National Health and Nutrition Examination Surveys (NHANES) conducted by the Centers for Disease Control and Prevention. Research initiatives outlined below would answer important questions concerning human exposure and greatly refine any cumulative risk assessment of phthalates. Identify across the human life span the important sources of phthalate exposure and the migration pathways that connect the sources to members of the general population, including highly exposed or susceptible groups. Elucidate across the life span the proportional contributions of exposure media (such as toys, dust, air, food, and soil) and exposure routes (ingestion, inhalation, and dermal) and define which media and routes are most important. Define the degree to which phthalates are absorbed by the three exposure routes. Identify the full spectrum of phthalate metabolites, particularly the oxidized metabolites of DEHP and DINP; determine whether they differ by exposure route; and determine the most appropriate metabolites to use as biomarkers of human exposure and the most appropriate biologic matrices in which to measure them. Improve the understanding of metabolism and of how metabolism might change over a lifetime. For example, is metabolism in the fetus, infant, or child different from metabolism in adults?
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Phthalates and Cumulative Risk Assessment: The Tasks Ahead 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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Phthalates and Cumulative Risk Assessment: The Tasks Ahead focused solely on adult animal models, it is important to determine whether in utero exposure affects cancer outcomes and, if so, by what mechanisms. Conduct epidemiologic studies to evaluate potential health outcomes of phthalate-antiandrogen exposures. Attempt to characterize and evaluate effects in susceptible or highly exposed groups. Confirm and extend current information on the relationship between anogenital distance and infant testosterone concentration. Conduct toxicity studies of phthalate metabolites to determine potential adverse effects associated with exposure to them. CUMULATIVE RISK ASSESSMENT As discussed in Chapter 5, available data support the appropriateness of cumulative risk assessment of phthalates and other antiandrogen compounds. Research initiatives that would refine such an assessment are outlined below. Explore combination effects of phthalates, other antiandrogens, and other endocrine-disrupting agents. Investigate deviations from additivity observed when hypospadias is used as the selected outcome. Refine estimates of composite scores for disruption of androgen action. Develop approaches to the epidemiologic assessment of the cumulative effects of phthalates and other antiandrogens. DATA RESOURCES FOR CUMULATIVE RISK ASSESSMENT The committee emphasizes that the quality of results of any risk assessment is based on the data available. The U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) is the source of much of the toxicity information used in risk assessment today. Many of the chemical profiles in IRIS need to be updated; the information is no longer relevant or accurate. The phthalate profiles available in IRIS illustrate that point. The committee recognizes that the task of profile review and revision is enormous; however, linking profiles to current literature would be helpful. For example, IRIS profiles of chemicals that also are the subject of interaction profiles produced by the Agency for Toxic Substances and Disease Registry would ideally be linked to the interaction profiles. Furthermore, as EPA moves toward cumulative risk assessment, some consideration should be given to restructuring IRIS so that its process for identifying chemicals for review includes and sets priorities among chemical mixtures, as appropriate, and facilitates cumulative risk assessment conducted by using common adverse outcomes. For example, listing the no-observed-adverse-effect levels or benchmark doses for a variety of effects would facilitate that approach.