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State-of-the-Science Non-Monotonic Dose Response Curve Report

Low Dose Effects


There are tens of thousands of chemicals in the environment to which humans and wildlife may be exposed. It is important to understand how these chemicals may interact with humans and wildlife and potentially cause harmful effects. There are several ways to determine if a chemical can cause adverse (or harmful) effects. One common way is to look at the effects of chemicals on a test subject – usually an animal like a rat or fish. EPA's current chemical testing guidelines require multiple doses (amounts) of a chemical to be evaluated for potential adverse effects. Test results determine whether a chemical leads to adverse effects, such as affecting the reproductive system or causing developmental problems. Dose-response curves are drawn to show the relationship between a chemical’s concentration and an adverse effect (i.e., “the dose determines the poison”). Consequently, a typical dose response curve shows a greater response in the test subject as the dose increases. This type of dose response curve is called a monotonic dose response curve.

Some recent scientific studies show evidence of dose response curves that are not monotonic, meaning the response may be greater at lower doses than at higher doses. These types of curves depict non-monotonic dose responses (NMDR). Technically, non-monotonic dose responses (NMDR) have dose-response curves whose slope is increasing with dose at some points and decreasing as dose increases at others.

Some recent studies show NMDRs for effects on the endocrine system (endocrine disruption). If these studies prove relevant and reliable for human or environmental health assessment, it could mean concentrations of chemicals in the environment are of more concern than current testing and assessment approaches would indicate. It is therefore important to have a rigorous evaluation of the state of the science.

Why does this matter?

EPA is trying to determine if current chemical testing strategies are protective of public health for exposures to endocrine disrupting chemicals.

EPA Action

EPA is committed to incorporating scientific advances into policy developed to protect human health and the environment. Because of this commitment, EPA formed a work group to review the results from scientific studies to determine if NMDRs capture adverse effects that are not captured using current chemical testing strategies. The EPA work group reviewed the various scientific studies and the findings are detailed in the draft NMDRC state of the science report.

While EPA is interested in all aspects of NMDR, the state of the science report focuses on endocrine disruptors—estrogen, androgen and thyroid active chemicals. The work group includes 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).

The draft state of the science report focuses on the following research questions:

  • Do NMDRCs exist for chemicals and if so under what conditions do they occur?
  • Do NMDRC result in 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 NMDRCs provide key information that would alter EPA’s current weight of evidence conclusions and risk assessment determinations, either qualitatively or quantitative?

EPA contracted with the National Academies of Science's (NAS) Board on Environmental Studies and Toxicology to externally peer review the draft state of the science report. The NAS peer review includes a public comment period, and NAS will incorporate appropriate stakeholder input throughout this process. The expert peer review with public comment helps EPA develop the state of the science report in an open, public participatory and transparent process and bases policy decisions on sound science.

Next Steps

EPA sent the draft report to NAS in June 2013 and it will be available for public comment. After the NAS completes its review, the state of the science report will help EPA policy makers determine if NMDRC capture adverse effects that are not captured using current chemical testing strategies and if there are adverse effects that current EPA testing misses.

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