Protocol for a systematic review of ten years of research on interactions in chemical mixtures of environmental pollutants

Current chemical regulation operates almost exclusively on a chemical-by-chemical basis. There is concern that this approach may not be sufficiently protective if two or more chemicals have the same toxic effect and methods for the routine consideration of mixture effects in chemical authorisation are currently being elaborated. Particularly, component-based approaches rely on the ability to anticipate quantitatively the effects of a given mixture of chemicals from knowledge about the toxicity of its individual components. This can be achieved by assuming that several chemicals act in concert by exerting their effects without diminishing or enhancing the others’ toxicity, the so-called non-interaction or additivity assumption. Questions nonetheless remains as to the extent to which deviations from the additivity concept occur and how this should be considered further in the risk assessment of mixtures. Several publications have considered the relevance of toxic interactions, i.e. addressing how often they are reported in the literature and the magnitude of deviation from additivity-based predictions (Boobis et al., 2011; Cedergreen, 2014). Since these reviews have been published, many new publications on the topic became available in both the area of toxicology and ecotoxicology. It is therefore argued that an up-to-date and comprehensive systematic review of the latest literature on toxic interactions was both necessary and timely. This manuscript and supplementary documents in detail the protocol developed to systematically review interactions of chemical mixtures of environmental pollutant