Opinion on the impact of non‐monotonic dose responses on EFSA′s human health risk assessments

Abstract

This Opinion assesses the biological relevance of the non‐monotonic dose responses ( NMDR ) identified in a previous EFSA External Report (Beausoleil et al., 2016) produced under GP / EFSA / SCER /2014/01 and the follow‐up probabilistic assessment (Chevillotte et al., 2017a,b), focusing on the in vivo data sets fulfilling most of the checkpoints of the visual/statistical‐based analysis identified in Beausoleil et al. (2016). The evaluation was completed with cases discussed in EFSA assessments and the update of the scientific literature. Observations of NMDR were confirmed in certain studies and are particularly relevant for receptor‐mediated effects. Based on the results of the evaluation, the Opinion proposes an approach to be applied during the risk assessment process when apparent non‐monotonicity is observed, also providing advice on specific elements to be considered to facilitate the assessment of NMDR in EFSA risk assessments. The proposed approach was applied to two case studies, Bisphenol A and bis(2‐ethylhexyl phthalate ( DEHP ) and these evaluations are reported in dedicated annexes. Considering the potential impact of NMDR s in regulatory risk assessment, the Scientific Committee recommends a concerted international effort on developing internationally agreed guidance and harmonised frameworks for identifying and addressing NMDR s in the risk assessment process.

Responses of animals and plants to physiological doses of ethanol: a molecular messenger of hypoxia?

“…The impact of ethanol on root growth and architecture, particularly when applied in minute concentrations, supports a hormone‐like activity in plants [65,66]. The fact that ethanol can boost metabolic activities at very low levels and inhibit them at higher doses [43,45,50,69], makes responses to ethanol resemble hormone effects, particularly nonmonotonic dose–response curves [67], matching the concept of hormesis [68,69], e.g., in this article, the germination of tomato seeds [50] or the resistance to desiccation of nematodes [43]. Cui and Koob [68] reviewed this biphasic ethanol dose effect in humans, recently.…”

Drug combinations screening using a Bayesian ranking approach based on dose–response models

“…The proposed approach has good operating characteristics in situations of limited and variable quantity of biological material and is robust to small sample sizes and increased interpatient variability. This approach demonstrates robust and consistent performance in identifying effective combinations, even in the face of unexpected patterns, such as the absence of a dose–response relationship, and violations of the assumption of monotonicity, which has been identified as a challenge in drug‐assessment paradigms by health authorities (European Food Safety Authority; Fourie Zirkelbach et al., 2022; More et al., 2021). It provides a useful tool to rank and prioritize candidate treatments in drug screening experiments, notably in oncology.…”

Re‐evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs

“…Although methodologies to assess NMDR in toxicological studies have been proposed (Beausoleil et al., 2016 ; Badding et al, 2019 ), there is currently no consensus on these methods and different approaches of varying robustness, ranging from visual inspection to fitting any non‐linear curve though data, have been applied by different researchers. In 2018, EFSA established a WG whose aim was to assess the impact of NMDRs on EFSA's human health risk assessments (EFSA Scientific Committee, 2021b ). The reader is referred to that opinion for more comprehensive review on previous activities by EFSA and other international organisations to address NMDR.…”