Skip to main content

Investigation of the state of the science on combined actions of chemicals in food through dissimilar modes of action and proposal for science-based approach for performing related cumulative risk assessment

EFSA Journal logo
Wiley Online Library

Meta data

The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the European Food Safety Authority is subject. It may not be considered as an output adopted by EFSA. EFSA reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.


The purpose of this project was to summarise the state of the science on combined actions of chemicals in food through dissimilar modes of action and to propose a science basedapproach for performing the related cumulative risk assessment (CRA).

A systematic literature search was carried out (Task 1) to identify relevant experimental studies of mixtures, and this served as the basis for a summary of the state of the science (Task 2). Of central importance was the confirmation that there is no current example of a situation in which the concept of independent action (IA) provides an accurate prediction that is also more conservative than dose addition (DA), supporting the use of DA as a conservative default in CRA. The quantitative difference between predictions based on DA or IA were analysed in detail, and this analysis suggested that the differences that might be expected in practice are small.

Currently used approaches to grouping (Task 3) and to CRA (Task 4) were reviewed to identify their critical features. An approach is proposed (Task 5) that unifies the assessment of similarly and dissimilarly acting chemicals based on pragmatic use of assessment approaches derived from the concept of DA. The approach incorporates a tiered framework. At lower tiers, the grouping of chemicals is driven by their co-occurrence in the exposure scenarios under investigation. At higher tiers, chemicals that evoke a common adverse outcome should be grouped together. The proposal is illustrated with three case studies.

Conclusions and recommendations

It is feasible and justified to utilise CRA methods and tiered framework analyses derived from DA also for combinations of dissimilarly acting chemicals. There can be one unified approach for dealing with mixtures in regulatory practice, irrespective of (often presumed) modes of action.