Scientific Opinion on the relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food

Abstract

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

Gender and Age Related Modulation of Xenoestrogen-Induced Tumorigenesis

“…structure would be different, as pointed by the European Food Safety Authority with regard to the cumulative effects of pesticides [99,100] may exert effects through mechanisms that are different from the traditional ERrelated pathways, i.e., rapid membrane receptor-related pathways or gender-and age-relate epigenetic modulation [101].…”

Endocrine Disrupters and the Safety of Food Chains

“…The research needs for risk assessments involve a number of areas, such as: the mechanisms underlying combined effects [17,18,19,24,25,27,28]; the assessment of long-term effects on the programming of target organs and systems upon prenatal exposure [41,44,45,46,47,48] as well as during the postnatal developmental windows through to adolescence [13,34,38,39,40], and, last but not least, the interactions between contaminants and natural food components [60,61,62,64,68,70], in particular to support the risk-benefit analysis of whole foods [21,59]. …”

“…On the other hand, the EFSA has made an important step forward, concluding that, based on the available knowledge, the most robust and conservative approach is the assumption of effect additivity: compounds that have the same effect in the same target organ (e.g., causing hypothyroidism) are assumed to act in an additive way [27]. This holds true also when pesticides eliciting the same effect have different chemical structures and molecular mechanisms [28], in agreement with a number of previous experimental data [17,18,19]. The ensuing phase in the risk assessment of multiple pesticide residues will be the identification of ‘risk drivers', i.e., those chemicals that make up most of the risk associated with a given cumulative assessment group because of their potency and/or exposure.…”

Establishment of cumulative assessment groups of pesticides for their effects on the nervous system

“…The rationale of using dose addition to perform CRA of pesticide residues was given in the Scientific Opinions of the PPR Panel on the identification of pesticides to be included in CAGs on the basis of their toxicological profile (EFSA PPR Panel, 2013a) and on the relevance of dissimilar MoA and its appropriate application for CRA of pesticides residues in food (EFSA PPR Panel, 2013b). Where possible, clusters of ASs for which dose addition is virtually certain should be defined.…”