This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.

Methods for the assessment of ecological risks associated with exposure to defined mixtures of toxicants are reviewed and formalized for single-species toxicity. Depending on the modes of action of toxicants in a mixture, these methods apply either the model for concentration additivity (CA) or the model for response additivity (RA). For complex mixtures, the present paper advocates the use of a new, two-step, mixed-model approach as a logical extension of model selection: Mixture toxicity for individual modes of action is evaluated with the CA model, and the toxicities of different modes of action are combined using the RA model. Using comparable mixture toxicity strategies in combination with the concept of species-sensitivity distributions, we develop a method to address and predict the risk for direct effects on the composition of species assemblages and biodiversity. The data needed for modeling can be obtained from existing databases, and lack of data can, in part, be addressed by the use of toxicity patterns in those databases. Both single- and multiple-species methods of mixture risk prediction are useful for risk management, because they allow ranking of polluted sites and affected species as well as identification of the most hazardous contaminants, at least in a comparative way. Validation of the proposed methods is feasible but currently limited because of a lack of appropriate data.

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Climate and land-use change drive a suite of stressors that shape ecosystems and interact to yield complex ecological responses, i.e. additive, antagonistic and synergistic effects.Currently we know little about the spatial scale relevant for the outcome of such interactions and about effect sizes. This knowledge gap needs to be filled to underpin future land management decisions or climate mitigation interventions, for protecting and restoring freshwater ecosystems. The study combines data across scales from 33 mesocosm experiments with those from 14 river basins and 22 cross-basin studies in Europe producing 174 combinations of paired-stressor effects on a biological response variable. Generalised linear models showed that only one of the two stressors had a significant effect in 39% of the analysed cases, 28% of the paired-stressor combinations resulted in additive and 33% in interactive (antagonistic, synergistic, opposing or reversal) effects. For lakes the frequency of additive and interactive effects was similar for all spatial scales addressed, while for rivers this frequency increased with scale. Nutrient enrichment was the overriding stressor for lakes, generally exceeding those of secondary stressors. For rivers, the effects of nutrient enrichment were dependent on the specific stressor combination and biological response variable. These results vindicate the traditional focus of lake restoration and management on nutrient stress, while highlighting that river management requires more bespoke management solutions.

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