Update on non-monotonic dose response

A new EFSA external scientific report is “a useful contribution to the scientific debate” on non-monotonic dose response (NMDR) results from toxicity studies, according to Prof Anthony Hardy, Chair of EFSA’s Scientific Committee. “More analysis and discussion are needed to prepare for a comprehensive assessment of the evidence for non-monotonicity,” he stated.

The view “the dose makes the poison” used in conventional hazard assessment implies a consistent increase in effects along the dose range, i.e. a monotonic dose response. For an NMDR effect, however, the response could both increase and decrease as the dose increases, resulting in, for example, U-shaped or inverted U-shaped curves when plotted on a graph. 

Some evidence is available from experimental data for such NMDR relationships.  If NMDR effects were proven in the context of food safety, it could have implications for how risk assessment is carried out. 

Reviewing the evidence for NMDR

At its meeting, the Scientific Committee discussed an EFSA external scientific report, published today, that provides a review of the evidence of datasets suggesting NMDR (excluding essential nutrients).

The report details how some 10,000 studies were retrieved from a systematic review of the literature. After applying screening procedures and relevance and reliability criteria for inclusion, the authors obtained a short-list that they consider could provide some scientific evidence to support non-monotonicity:

  • 202 datasets from 49 animal studies (in vivo).
  • 311 datasets from 91 tissue/cell studies (in vitro).
  • 9 datasets from 2 studies in humans.

Due to the difficulties of extracting data from in vitro studies only 13 of these datasets could be used to analyse the dose-response relationships.

According to the report, considering the type (hormones and pharmaceuticals were excluded) and amount of data selected and analysed, NMDR as a common phenomenon is so far not supported for substances in the area of food safety.  

Scientific Committee feedback

“The report provides an extensive overview of the studies to date where indications of NMDR have been observed. It also puts forward a well substantiated set of criteria for evaluating the evidence of NMDR,” said Prof Hardy.

“It stimulated a wide-ranging discussion about the methodology the authors used, their results and how EFSA and the scientific community might be able to build on this initiative.”

The Scientific Committee discussed the need for the following additional activities:

  • Further analysis of the datasets suggesting evidence of NMDR, to confirm the reproducibility of the results if the studies were repeated, and to identify whether the effect concerned is a biochemical change (e.g. a change in the level of an enzyme) or is directly related to an adverse health outcome (e.g. cancer).
  • Review of the authors’ methodology which uses six checkpoints to characterise the strength of the evidence for NMDR.
  • Provision of guidance on which of the six checkpoints or combination of checkpoints put forward by the authors could be considered as sufficient, depending on the dataset under review, for evaluating NMDR.
  • Dose-response modelling of the human datasets and datasets related to “quantal endpoints” (i.e. effects that occur in steps such as cancer, as opposed to gradual effects like weight loss) that could not be analysed by the authors.

The report was commissioned by EFSA and carried out by four Member State organisations: the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), the Austrian Agency for Health and Food Safety (AGES), the Institute of Environmental Medicine, Karolinska Institute (KI), Sweden, and the National Institute for Public Health and the Environment (RIVM), The Netherlands.

*This story was updated on 11 May 2016.

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