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The European Food Safety Authority (EFSA) asked the Panel on Plant Protection Products and their Residues (PPR Panel) to develop a Scientific Opinion on the relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food. The present opinion was preceded by three previous opinions of the PPR Panel (EFSA, 2008, 2009, 2013). The purpose of the present opinion was to assess the relevance of dissimilar modes of action (MoA) for cumulative risk assessment, to evaluate the existing methods for assessing chemicals acting by dissimilar MoA and to identify which methods need to be considered. The PPR Panel restricted its considerations of pesticide combinations with dissimilar modes of action to substances that produce a common adverse effect on the same organ/system. The PPR Panel noted that there is no case documented in the scientific literature where independent action provided more conservative predictions of combination effects than dose addition, and where at the same time independent action also produced accurate predictions. The use of independent action as an assessment concept for combination effects requires demonstration that modes of action of individual substances in a mixture are strictly independent, a condition that can rarely be met in practice. The PPR Panel also noted that there is no cumulative risk assessment method derived from independent action. The PPR Panel therefore recommends using cumulative risk assessment methods derived from dose addition also for the assessment of mixtures of pesticides with dissimilar modes of action, provided they produce a common adverse outcome. Pesticides that produce common adverse outcomes on the same target organ/system should be grouped together in CAGs, and their combined effects assessed by using the concept of dose addition as a pragmatic and conservative default approach for the purpose of assessing cumulative risk in relation to MRL setting or risk assessment of chemical mixtures in practice.

The European Food Safety Authority asked the Panel on Plant Protection Products and their Residues to develop an Opinion on the identification of pesticides to be included in cumulative assessment groups (CAGs) on the basis of their toxicological profile. In 2008, the PPR Panel adopted an Opinion on the suitability of existing methodologies for cumulative risk assessment of pesticides and a tiered approach was proposed, which was applied to a selected group of triazole pesticides in 2009. The present Opinion suggests a methodology for grouping of pesticides based on phenomenological effects and provides CAGs for the thyroid and nervous system. This approach can be applied even when the underlying biochemical events mediating the effects are not understood, and is based on a standardised and thorough review of Draft Assessment Reports (DARs) supporting the approval of all pesticides in Europe, and on recommendations from the European Commission. Pesticidal active substances exhibiting neurotoxic properties were allocated to CAGs for acute effects on motor, sensory and autonomic divisions of the nervous system and neurochemical endpoints. Chronic effects across the same divisions/endpoints and neuropathological effects were collated. Active substances having adverse effects on the thyroid system were allocated to CAGs for effects either on C-cells/the calcitonin system or on follicular cells/the T3/T4 system. The PPR Panel notes that the resulting groups encompass many pesticides and also that individual pesticides could appear in several groups and therefore the data entries for performing cumulative risk assessment (CRA) are of considerable magnitude. Although some CAGs contain a large number of pesticides, little indication of cumulative risk may be inferred from the size of CAGs per se. The PPR Panel recommends that the methodology is implemented for all major organ/systems but the approach used should be considered specific for pesticides.