NTP center for the evaluation of risks to human reproduction reports on phthalates: addressing the data gaps.

Between 1998 and 2000 an Expert Panel convened by the National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) reviewed information related to the developmental and reproductive toxicity of seven phthalate esters; DBP, BBP, DnHP, DEHP, DnOP, DINP, and DIDP. Information on exposures was also considered. The objectives were to determine whether any of these phthalates posed potential human reproductive risks, and if so, to define the circumstances. The Expert Panel also identified some areas of uncertainty. These assessments, ultimately published in 2002, concluded that reproductive risks were minimal to negligible in most cases although some specific uses were considered potentially more problematic. Since the evaluations were completed, numerous studies dealing with both hazard characterization and underlying mechanism have been carried out. Additionally, exposures of the general population have been much better characterized through the use of urinary measurements developed by the Centers for Disease Control (CDC). This additional information makes several important points. First, calculations based on the urinary metabolite measurements indicate that exposures within the general population are at levels similar to or lower than the estimates used by the NTP-CERHR. The demonstration that exposures were not underestimated by the CERHR has removed a substantial portion of the uncertainty. Second, new hazard characterization studies on several phthalates have established NOAELs similar to or higher than those used by the Expert Panel. Thus, these data demonstrate that, to the extent that the rodent data are useful for human health risk assessment, the no effect levels and dose-response relationships are now more precisely defined. In some cases, the no effect levels may be substantially higher than those estimated by the Expert Panel. Third, studies of underlying mechanism and/or hazard characterization studies in other species suggest that primates may be less sensitive than rodents to the reproductive effects of certain phthalates. Finally, the two specific situations that the CERHR identified as potentially problematic, the exposure of young children to DINP through the use of toys or to DEHP from medical devices, have been assessed by the responsible regulatory authorities. The Consumer Product Safety Commission concluded that exposure to DINP from toys was well below effect levels in animals, and, therefore, there was no risk. The Food and Drug Administration estimates of exposures from medical devices indicated that for some limited, intensive medical procedures, DEHP exposures could be similar to or greater than the NOAELs selected by the NTP-CERHR. However, the FDA also acknowledged that more recent information indicates that the NOAELs identified in rodent studies may be substantially higher than values previously proposed by the NTP-CERHR. In summary, much of the uncertainty identified by the CERHR has now been addressed, and the overall conclusions that levels of concern are minimal to negligible in most situations are much better established. The overall objective of this report is to summarize this new research and comment on its relevance to the NTP-CERHR assessments.