APPLICATION OF US EPA IRIS SYSTEMATIC REVIEW METHODS TO THE HEALTH EFFECTS OF PHTHALATES: LESSONS LEARNED AND PATH FORWARD

This special issue presents several systematic reviews of the potential human health effects associated with exposure to phthalates and addresses some of the considerations and challenges that were encountered over the course of performing these reviews. This editorial presents the views of the lead U.S. Environmental Protection Agency (EPA) researchers on the project and the Special Issue Editors with regard to lessons learned, implications of methods, and the path forward for systematic reviews to support human health assessment. Phthalates comprise a class of alkyl diesters of phthalic acid and are used in a variety of consumer products including cosmetics, personal care, pharmaceuticals, medical devices, children’s toys, food packaging, and cleaning and building materials. Owing to this widespread use, human exposure to phthalates is ubiquitous across all life stages, including during gestation and early postnatal life (CPSC, 2014; NRC, 2008). There is a considerable body of evidence demonstrating that certain phthalates can disrupt male reproductive development through the inhibition of testosterone production as well as through mechanisms that are independent of the antiandrogenic effects (Foster and Gray, 2013; CPSC, 2014; NRC, 2008); therefore, recent assessments of phthalate toxicity have generally centered on male reproductive effects. A 2017 systematic review of the low dose toxicity of phthalates by the National Academy of Sciences (NAS) focused exclusively on three androgen-dependent male reproductive endpoints (testosterone measurements, anogenital distance, and hypospadias) that are known to be sensitive to phthalate exposure (NAS, 2017).

Antiandrogenic activity was also the basis for the US Consumer Product Safety Commission (CPSC) rule to permanently ban certain phthalates at any amount greater than 0.1% in children’s toys and childcare articles, which was expanded in 2017 to include additional phthalates that share this mode of action (CPSC, 2017). The work described in this Special Issue was designed to characterize the range of health outcomes associated with exposure to phthalates, including emerging health outcomes that were not covered by recent reports, and consists of six systematic review papers and three methodology papers. Systematic reviews of epidemiology studies were conducted for six phthalates (DEHP, DBP, BBP, DINP, DIBP, DEP) and are reported in four papers that describe associations of these chemicals with male reproductive effects (Radke et al., 2018), female reproductive and developmental effects (Radke et al., 2019a), metabolic effects (Radke et al., 2019b), and neurodevelopmental effects (Radke et al., 2020). Systematic reviews of experimental animal studies were conducted for DIBP (Yost et al., 2019) and DEP (Weaver et al., accepted for publication), with each paper describing the evidence for six major health outcome categories: male reproductive, female reproductive, developmental, liver, kidney, and cancer.

The methodology papers address issues encountered during the course of conducting these reviews that will be of broad applicability to practitioners of systematic review in environmental health, including the evaluation of epidemiological studies using outcome-specific assessment criteria (Radke et al., 2019c) and the evaluation of animal studies for reporting quality, risk of bias, and sensitivity (Dishaw et al., accepted for publication). Lastly, Blessinger et al. (2020) present an ordinal dose–response model that addresses the challenges of modeling the collection of endpoints that characterize “phthalate syndrome” in experimental animal studies. We believe this experience in applying systematic review methods to a large, complex evidence base will be informative for others in the field. Systematic review is being increasingly recognized by research and regulatory organizations as the gold standard for chemical risk assessment. Many of the benefits of systematic review, as well as the major advances and challenges facing researchers in this field, are illustrated in the July 2016 Environment International Special Issue, “Systematic Review Methods for Advancing Chemical Risk Assessment” (Whaley and Halsall 2016). Advantages of this approach include transparency and objectivity. However, challenges remain, including how to make systematic review pragmatic when applied to the broad topic areas encountered in environmental health. The methodologies for study selection, study evaluation, and evidence synthesis described in this set of papers were developed for use in the EPA’s Integrated Risk Information System (IRIS) assessments to address some of these challenges, but these papers are among the first publicly available reviews using the methodologies. It is important to note that the IRIS approach described in the systematic review protocol for these reviews has evolved since their development and it is expected this evolution will continue over time as methodologies advance and feedback is received from the scientific community. Recently posted protocols reflect the current IRIS approach and are available at https://www.epa.gov/iris/ iris-recent-additions.