Consensus Report

Review of the Environmental Protection Agency's State-of-the-Science Evaluation of Nonmonotonic Dose-Response Relationships as they Apply to Endocrine Disrupters (2014)

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Potential health effects of endocrine-disrupting chemicals raise an environmental health concern about the chemicals' ability to interfere with normal hormone function in humans and wildlife. Some research on endocrine disruptors has identified nonmonotonic dose–response relationships; that is, lower doses are not always associated with smaller responses, nor higher doses with larger responses. Nonmonotonic dose–response curves have been a subject of debate in regulatory toxicology because of their implications for how chemicals should be tested and for how risks posed by such chemicals should be assessed.

To help to address those issues, the US Environmental Protection Agency (EPA) developed a draft state-of-the-science evaluation. The evaluation aimed to answer questions about the conditions under which nonmonotonic dose–response curves occur and what the implications of the evidence might be for its toxicity-testing strategies and weight of evidence conclusions and risk assessment determinations. EPA asked the National Research Council to review its evaluation to ensure that it is scientifically sound and of high quality.

Key Messages

  • The committee found that the process by which the agency performed its evaluations was poorly described and inconsistent. Separate groups were assigned to analyze and summarize the evidence on nonmonotonic dose–response curves for chemicals that affect the estrogen-, androgen-, and thyroid-hormone pathways, but the agency failed to establish (or enforce) a clear set of methods for collecting and analyzing the evidence to ensure that the groups conducted their assessments in a clear, consistent, and therefore replicable manner.
  • The committee recommended that an analytic plan be developed and applied consistently to the evidence on the three hormone pathways. The scope of the analytic plan should be tailored to the scope of the questions EPA seeks to answer. 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.
  • EPA's state-of-the-science evaluation addressed questions about toxicity testing without specific reference to and demonstration with its own testing strategies. The committee recommended that EPA perform a more explicit analysis by specifying the toxicity-testing strategies under consideration and evaluating them for their ability to detect nonmonotonic dose–response relationships mediated by the estrogen, androgen, and thyroid hormone pathways. The tests should be evaluated in terms of the design criteria that would be necessary to detect such relationships and the adverse effects of interest.
  • With respect to the question of whether nonmonotonic dose–response curves provide information that would alter EPA's current weight of evidence conclusions and risk-assessment determinations, EPA provided no analysis to support its conclusion that such curves can have both qualitative and quantitative effects and that current risk-assessment practices will consider the evidence appropriately. Thus, the committee recommends explicit consideration of how nonmonotonic dose–response relationships for estrogen, androgen, and thyroid pathways would be addressed under the agency’s current risk-assessment guidelines and practices.