NAS/NRC Publishes Review of EPA Paper on NMDRs

The National Academy of Science’s National Research Council has published its report entitled: Review of the Environmental Protection Agency’s State-of-the-Science Evaluation
of Nonmonotonic Dose–Response Relationships as They Apply to Endocrine Disruptors. This NAS/NRC report has obvious implications for EPA’s Endocrine Disruptor Screening Program.  Click here for report.

This report includes the following conclusions:

 “Recommendation: An analytic plan should be developed and applied consistently to the evidence on the three hormone pathways. Important elements of the plan include predefining and documenting the literature-search strategies and their results, establishing criteria for selecting studies for analysis, establishing criteria for determining study quality, using templates for presenting evidence consistently in tabular and graphic form, and documenting approaches to integration of evidence. Guidance on these elements is provided below [in following sections of the report].”


“Recommendation: If EPA wishes to determine the conditions under which NMDR curves occur, it should expand its evaluation to include evidence from epidemiologic and clinical studies and include chemicals that have a variety of potential MOAs for the different hormone pathways. If such a broad analysis is not feasible in light of the agency’s immediate needs, consideration should be given to narrowing the questions and their answers.”


“Recommendations: EPA should consistently use a more systematic approach to evaluating the literature on NMDR curves for all three hormone pathways. Guidance for such approaches is available from clinical guidelines, other National Research Council reports, and guidelines being developed in other government agencies. In developing an approach for the literature on NMDR relationships, special consideration should be given to the following:

Ÿ The methodologic features that would be necessary for a study to be able to detect an NMDR relationship should be identified. Ideally, multiple dose groups would be spaced across a defined exposure domain, including doses below those typically tested. Statistical design, biologic plausibility, and replicability should be factored into interpreting and weighing the evidence from such studies.

Ÿ Study exclusion and inclusion criteria should be established. Although statistical significance is an important consideration, it should not be an absolute criterion for including or excluding studies, inasmuch as standard toxicity-testing strategies generally do not have sufficient sensitivity and statistical power to detect NMDR curves.

Ÿ Study quality criteria should be established. Statistical criteria should be given particular attention. It will be important to balance study quality criteria that are based on statistical significance and those based on biologic plausibility.

Ÿ Secondary analyses of other studies may be necessary. Current methods for performing post hoc analysis of data and for combining evidence from multiple studies might be adapted for such purposes but would require research and development before implementation. EPA should consider soliciting input from the biostatistics community on the best methods to pursue in the long term and on what measures to take to complete the SOTS evaluation.

Justifying the use of definitions that are not consistent with those used by EPA programs or that are controversial, such as definitions of low-dose effect, resilience, and adverse effect.”


“The document will probably be a milestone event in the history of EPA’s engagement with endocrine disruptors because it draws conclusions about the existence of NMDR curves and the conditions under which they occur that will to be used to inform decisions about the agency’s toxicity-testing strategies and risk-assessment practices. Given its importance and its broad use, the committee judges that the SOTS evaluation should meet a higher standard of evaluation, particularly given the heated controversy surrounding this issue. Methods that provide a more systematic approach and greater transparency are necessary, or it will be too easy to dismiss the analysis as superficial or even biased in the literature selection and evaluation. Although it is clear that the authors spent enormous time and energy in developing the evaluation, it is fundamentally compromised, at least in appearance.

EPA has acknowledged the lack of a consistent and transparent process for data identification, selection, and evaluation and is actively engaged in establishing new procedures on the basis of recommendations from other National Research Council reports (NRC 2009, 2011). An upcoming National Research Council report will address methods specifically for performing evidence evaluations and evidence integration for EPA’s Integrated Risk Information System. EPA has already taken steps to address shortcoming in the current SOTS evaluation by developing a Performance Work Statement for subcontractors to conduct systematic literature searches, data extraction, and evaluation of the evidence on NMDR relationships (EPA, unpublished material, September 6, 2013). However, the results of this activity were not available to the committee, so recommendations are restricted to what was presented in the SOTS evaluation.”


“The committee found that EPA’s approach to evaluating whether NMDR curves exist for endocrine disruptors was not systematic, consistent, or transparent, especially with regard to the literature on estrogen and androgen effects.”




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