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Non-Monotonic Dose Response Curves Research

Low Dose Effects

Displayed are three different types of NMDRCs including an inverted U-shaped curve, a U-shaped curve, and a multiphasic curve. All of these are considered NMDRCs because the slope of the curve changes sign one or more times.

Issue

Results from epidemiological studies suggest an association between environmental ("low dose") concentrations of endocrine active chemicals and reproductive or developmental health outcomes. These effects have been examined and reported with mixed results in a wide range of animal studies.

Among the scientific community there is a broad spectrum of interpretation of these findings, in particular as it relates to internal dosimetry (dose). This includes scientific discussions about the significance of these observations that seem to support non-monotonic dose response relationships at low levels of exposure. Technically, non-monotonic dose response curves (NMDRC) are defined as dose response curves whose response is increasing with dose at some points and decreasing as dose increases at others. In the context of this effort, EPA's focus is on curves that are not linear or show an effect (threshold) at a low dose concentration.

EPA Action

The diversity of scientific opinions motivated EPA's Office of Chemical Safety and Pollution Prevention (OCSPP) to ask EPA's Office of Research and Development (ORD) to work with them and other interested stakeholders to develop a state of the science paper to investigate the implications of non-monotonic dose response curves to EPA testing and risk assessment procedures. While EPA is interested in all aspects of low dose extrapolation, this short term effort is designed to meet immediate science-policy needs. The scope therefore is limited to the state of the science for non-monotonic dose response for endocrine disruptors—estrogens, androgens and thyroid active chemicals. To develop this paper, EPA formed a working group which consists of scientific experts from EPA's Office of Chemical Safety and Pollution Prevention, EPA's Office of Research Development and scientists from other federal agencies, including the Food and Drug Administration, National Institute of Environmental Health Science’s National Toxicology Program (NIEHS/NTP), and the National Institute of Child and Human Development (NICHD).

To date, the cross-program working group developed a work plan and is currently writing the state of the science paper.

The central questions being investigated by the working group that will be addressed in the state of the science paper and peer reviewed are:

  • Do NMDRC capture adverse effects that are not captured using our current chemical testing strategies (i.e. false negatives) and are there adverse effects that we are missing?
  • Do non-monotonic dose response curves (NMDRC) exist for chemicals and if so under what conditions do they occur?
  • Do NMDRCs provide key information that would alter EPA’s current weight of evidence conclusions and risk assessment determinations, either qualitatively or quantitative?

EPA bases its decisions on sound science and the development of the state of the science paper is being done in an open, public participatory and transparent process. Starting in the Spring of 2013, the National Academies of Science will coordinate the expert peer review and public comment on the state of the science paper to ensure scientific rigor and provide opportunities for public participation.

Impact

The state of the science paper findings will provide information to help inform how the safety of chemicals are assessed.

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