An article published on September 13, 2018, in the peer-reviewed journal Dose-Response addresses nonmonotonic dose response curves (NMDRCs) and their relevance to regulatory decision-making. Corinne Hill and Laura Vandenberg from the School of Public Health and Health Sciences, Amherst, Massachusetts, and Pete Myers from the Environmental Health Sciences, Charlottesville, Virginia, all U.S., explain that regulatory agencies commonly use the linear dose response model “to extrapolate [from high dose testing] to lower doses that are anticipated to be ‘safe’ for human exposures.” This is done with the assumption that nonmonotonicity and hence NMDRCs are “not common” and “not found for adverse outcomes.” For the same reason, regulatory agencies also argue that NMDRCs “are not relevant for the regulation of endocrine disrupting chemicals (EDCs).”

To challenge these assumptions, the authors review documented examples of NMDRCs and “discuss how their presence in different portions of the dose response curve might affect regulatory decisions.” Three cases are identified, all supported by evidence from peer-reviewed publications:

(1) NMDRCs occurring at high levels of exposure, i.e., above the No Observed Adverse Effects Level (NOAEL) dose.

In risk assessment, NOAEL dose is “typically divided by a number of uncertainty factors to determine the acceptable daily intake or reference dose” (RfD). NMDRCs that occur above the NOAEL “appear to have little consequence for the identification of a RfD” and are therefore “irrelevant when drawing extrapolations to ‘safe’ doses,” the authors conclude.

(2) NMDRCs occurring below the NOAEL, but above the RfD.

The authors argue that such NMRDCs “would likely not be revealed by conventional testing, which rarely examines sufficient doses below the NOAEL.” Moreover, the existence of such NMRDCs (which has been demonstrated in the peer-reviewed literature) would “falsify a fundamental assumption, that high dose hazards can be used to predict low dose safety.” This would “suggest that the RfD should not be calculated or extrapolated from the toxicological NOAEL, and the ‘true’ NOAEL dose may be much lower.” The authors emphasize that “it is important to evaluate each study individually and determine whether the significant effects are statistical artifacts,” but there “should not be a default assumption that these phenomena are not ‘real.’ ”

(3) NMDRCs occurring below the RfD established by extrapolation from the high-dose testing, possibly in the range of known human exposures.

The occurrence of nonmonotonicity below the calculated RfD would imply that this calculation is “scientifically flawed and insufficiently protective of public health,” the authors warn. They point to a review that summarized “more than 30 NMDRCs observed in human epidemiology studies [that] fall into this category and provide evidence that human exposure levels, which are likely below the RfD, can result in adverse health outcomes” (FPF reported). While acknowledging that “it is important to view these findings in light of the limitations of epidemiological studies,” the authors also emphasize that “epidemiology studies are not designed to evaluate NMDRCs, meaning they likely go neglected.”

The examples reviewed in cases (2) and (3) “indicate that nonmonotonicity occurs at doses/concentrations that are overlooked by regulatory toxicology as it is commonly practiced today,” the authors summarize. They further point out a large study on bisphenol A (BPA, CAS 80-05-7), the Consortium Linking Academic and Regulatory Insights on BPA toxicity (CLARITY-BPA) study, “revealed a nonmonotonic relationship between BPA and mammary adenocarcinoma” (FPF reported). Regulatory decision-making views such information as “problematic” because it “presents one of many challenges to the current practice of using high-dose studies to extrapolate to so-called ‘safe’ doses,” the authors conclude.

Based on the evidence and considerations presented, the authors argue for a need “(1) to develop agreed upon methods, using best practices, for how nonmonotonic relationships should be evaluated statistically; (2) to consider increasing number of doses, covering wider ranges, in studies used for regulatory purposes; (3) to utilize adverse effects . . . observed at low, but not higher doses, to calculate RfDs that are public-health protective.”


Hill, C., et al. (2018). “Nonmonotonic dose-response curves occur in dose ranges that are relevant to regulatory decision-making.Dose-Response 16(3): 1559325818798282.

Vandenberg, L., et al. (2012). “Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses.Endocrine Reviews 33: 378-455.