On October 20, 2021, the European Food Safety Authority (EFSA) published a scientific opinion on the impacts of non-monotonic dose responses (NMDR) on human health risk assessments of chemicals. EFSA found that there is no “gold standard for the statistical assessment of NMDR” and that “understanding the underlying [biological] mechanism(s) is necessary to assess its biological plausibility.” With that in mind, the authors suggest a workflow for the evaluation of NMDRs during risk assessment with a particular focus on responses seen at the low dose end of a dose-response curve. “In cases where biological considerations or previous results suggest that NMDR may be present, any further testing should assure that a sufficient number of doses are tested at the lower end of the dose-response curve… If such design issues are not properly considered, the possible presence or non-presence of NMDR may be difficult to address.” NMDRs at the upper end of a dose-response curve are of less concern since current risk assessment procedures will likely create a limit below that level.
The definition of non-monotonicity used in the opinion comes from Vandenberg et al., that “the slope of the dose-response curve changes sign from positive to negative or vice versa at some point along the range of doses examined.” But the authors note that Vandenberg’s definition “does not cover how to formally assess… if there is a non-monotonic dose-response.” This scientific opinion is an attempt to fill that gap.
The opinion concludes that “there is a need for an international effort to provide more detailed dose-response information for risk assessment.” And the authors encourage “a concerted international effort” to develop “(i) guidance on the statistical approaches for identifying NMDR, and (ii) harmonized frameworks for addressing NMDR in the risk assessment process.”
EFSA released a draft version of this scientific opinion on NMDRs in December 2020 (FPF reported) which The Food Packaging Forum formally commented on in February 2021 (FPF reported).
Reference
EFSA Scientific Committee (October 20, 2021). “Opinion on the impact of non-monotonic dose responses on EFSA′s human health risk assessments.” EFSA Journal
