Synergistic effects of chemical mixtures: How frequent is rare?

Chemical pollution is characterised by sequential and simultaneous exposure to unintentional complex mixtures. The almost infinite number of real-life mixtures poses major challenges for investigations of all possible exposure scenarios through whole mixture or component-based approaches. As a pragmatic approach in data-poor situations, the application of a Mixture Assessment Factor to single substances assessments under REACH was announced in the European Chemicals Strategy for Sustainability. Current proposals for this factor are based on the assumption that mixtures behave additively, assuming that synergistic interactions are rare. This assumption is based on eight reviews published in the last 30 years. Synergistic deviations from additivity greater than two-fold were reported in roughly 5% of investigated mixtures. This was more, rather than less, frequent in the handful of suitable studies of low-dose mammalian mixture toxicity. This frequency is representative of mixtures toxicology studies in the literature and should not be interpreted as the frequency of synergisms in real-world exposures. Understanding the frequency and likelihood of synergisms would entail detailed understanding of the co-occurrence of groups of substances giving rise to such interactions in relevant environmental media. Assumptions that synergistic interactions in real-life mixtures are rare appear to be premature. While further research is required, potential synergisms should not be omitted from debates on the conservatism or otherwise of mixture allocation factor or other regulatory approaches to protect people and environment from mixture effects.