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A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the I nternational ST akeholder NET work (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23–24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

The margin of exposure (MOE) is a risk assessment tool used to evaluate the safety of substances in food and feed. Adopted by the European Food Safety Authority (EFSA) in 2005, the MOE is calculated as the ratio between a Reference Point (RP) and the estimated exposure. While some regulatory bodies use ‘margin of safety’ (MOS) interchangeably with MOE, others define it differently, leading to inconsistencies in interpretation. To address this, EFSA has standardised its terminology, establishing MOE as a primary metric for safety assessments across human and animal health evaluations. In addition, the meaning and interpretation of terms used to qualify a ‘concern’ is elaborated. The EFSA definitions will come into force from when this statement is published. By refining these definitions and ensuring consistent terminology across sectors, EFSA aims to improve clarity and transparency in its risk assessments, facilitating effective communication.

The present opinion deals with the re‐evaluation of thaumatin (E 957) when used as a food additive. Thaumatin is a natural plant protein, consisting of thaumatin I and thaumatin II proteins together with minor amounts of plant constituents, obtained by acidic aqueous extraction of the arils of the fruit of Thaumatococcus daniellii plant. The Panel followed the conceptual framework for the risk assessment of certain food additives and considered that thaumatin is a digestible protein; adequate exposure estimates were available; there was no concern with respect to the genotoxicity; no conclusion on oral allergenicity could be drawn from the available human data; no adverse effects were observed in sub‐chronic toxicity studies in rats and dogs at the highest dose tested of up 5,200 and 1,476 mg/kg bodyweight (bw) per day, respectively, and in a prenatal developmental toxicity study up to 2,000 mg/kg bw per day; moderate confidence in the body of evidence supported the absence of association between exposure to thaumatin and adverse health outcomes. Therefore, the Panel concluded that there is no need for a numerical acceptable daily intake (ADI) for thaumatin (E 957) and, based on a margin of safety (MOS) of 5,417, considered to be an underestimate and derived using the highest 95th percentile (P95) exposure of 0.48 mg/kg bw per day in consumers only, there is no safety concern for thaumatin (E 957) at the regulatory maximum level exposure assessment scenario, which was considered the most appropriate. The Panel recommended that European Commission considers introducing in the EU specifications for thaumatin (E 957) a new specification limit for the minimum combined content of thaumatin I and II proteins in E 957, a specification limit for yeast, mould counts and Salmonella spp and lowering the existing maximum limit for arsenic along with the inclusion of maximum limits for mercury and cadmium. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2021.EN-6918/full

Prior to being applied to the new bisphenol A (BPA) re‐evaluation, the study appraisal methodology described in the 2017 BPA hazard assessment protocol, i.e. the so‐called ‘2017 methodology’, was tested on a selection of studies that had been previously appraised by EFSA in the context of its 2015 and 2016 assessments of BPA. This report describes this testing phase, its outcome and the resulting refinement of the 2017 methodology. The goals of this testing phase were to i) test the functioning of the 2017 internal validity appraisal tools for human and animal studies, and specifically (a) to verify whether the final tier of internal validity (on a three‐tier scale, with Tier 1 being the highest) automatically assigned to each study on the basis of pre‐defined criteria after answering the questions of the risk of bias tool reflected the internal validity according to expert judgement and (b) to fine‐tune and calibrate the 2017 appraisal tool on a sufficiently large study sample (development of the ‘2019 methodology’); ii) assess the comparability of the study appraisal outcome by the 2019 methodology against the ‘2015 methodology’ applied in the EFSA BPA assessments of 2015 and 2016. Concerning the first goal, the automatic allocation of epidemiological studies to an internal validity tier,based on pre‐defined criteria for combining the appraisal questions'scores, resulted in ranking them exclusively in Tier 3 (the lowest tier), in full accordance with expert judgment. For animal studies, to enable discrimination of studies into three tiers, the appraisal tool was refined; thereafter, comparability between automatic allocation‐based and expert judgement‐based scoring reached 91% (43 out of 47 appraisals). Concerning the second goal, it is acknowledged that the 2015 and 2019 methodologies present some differences with respect to the elements considered for assessing the study quality (i.e. reliability vs. internal validity). Nonetheless, the key study used to derive BPA's tolerable daily intake in the 2015 Opinion was also considered to be of high quality according to the 2019 methodology. In addition, the outcome of the appraisal of the papers by the 2019 methodology versus the 2015 methodology was overall comparable or more stringent in 92% of the cases (24 out of 26 appraisals). It follows that despite some intrinsic differences, the 2015 methodology previously used by EFSA to appraise the BPA evidence is considered sufficiently robust, even though not as structured as the 2019 methodology. Overall, the two goals of the testing phase have been achieved. The amendments of the appraisal methodology are being implemented for the full re‐evaluation of the new BPA literature and will be fully documented in the final version of the protocol annexed to the new BPA Opinion.

In 2015, EFSA established a temporary tolerable daily intake (t‐TDI) for BPA of 4 μg/kg body weight (bw) per day. In 2016, the European Commission mandated EFSA to re‐evaluate the risks to public health from the presence of BPA in foodstuffs and to establish a tolerable daily intake (TDI). For this re‐evaluation, a pre‐established protocol was used that had undergone public consultation. The CEP Panel concluded that it is Unlikely to Very Unlikely that BPA presents a genotoxic hazard through a direct mechanism. Taking into consideration the evidence from animal data and support from human observational studies, the immune system was identified as most sensitive to BPA exposure. An effect on Th17 cells in mice was identified as the critical effect; these cells are pivotal in cellular immune mechanisms and involved in the development of inflammatory conditions, including autoimmunity and lung inflammation. A reference point (RP) of 8.2 ng/kg bw per day, expressed as human equivalent dose, was identified for the critical effect. Uncertainty analysis assessed a probability of 57–73% that the lowest estimated Benchmark Dose (BMD) for other health effects was below the RP based on Th17 cells. In view of this, the CEP Panel judged that an additional uncertainty factor (UF) of 2 was needed for establishing the TDI. Applying an overall UF of 50 to the RP, a TDI of 0.2 ng BPA/kg bw per day was established. Comparison of this TDI with the dietary exposure estimates from the 2015 EFSA opinion showed that both the mean and the 95th percentile dietary exposures in all age groups exceeded the TDI by two to three orders of magnitude. Even considering the uncertainty in the exposure assessment, the exceedance being so large, the CEP Panel concluded that there is a health concern from dietary BPA exposure. This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2023.p210401/full

The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO2 NPs < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2 NPs (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.

Processed meat (PM) intake is associated with health risks, but data are lacking in Switzerland. Using national representative data from a recent menuCH Survey, we first aimed to quantify intake of PM and its subtypes, and second to investigate associations with sociodemographic and lifestyle factors by multivariable regression analysis. PM was consumed by 72% of the population, and mean daily intake was 42.7 g/day (standard error of the mean (SEM) 1.2 g/day), ranging considerably across PM subtypes: highest intake of sausages 18.1 g/day (SEM 0.7 g/day) and lowest of bacon 2.0 g/day (SEM 0.2 g/day). PM intake by women was 4.7 g/1000 kcal lower than men (95% confidence interval (CI): −6.7; −2.7) and 2.9 g/1000 kcal lower in the French- language region compared with the German region (95% CI: 2.4; 8.7). Among sociodemographic and lifestyle factors examined, BMI (obese vs. normal: 5.5 g/1000 kcal, 95% CI: 2.4; 8.7) and current smoking (vs. never smoked: 3.1 g/kcal, 95% CI: 0.6; 5.6) were independently associated with PM intake. The results are a first description of PM intake, separate from other meat types, and which identified associations with two unhealthy lifestyle factors in Switzerland. Such data will contribute to better nutritional recommendations and guidance for public health interventions.

Following a request from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for manganese. Systematic reviews of the literature of human and animal data were conducted to assess evidence regarding excess manganese intake (including authorised manganese salts) and the priority adverse health effect, i.e. manganese‐induced neurotoxicity. Available human and animal studies support neurotoxicity as a critical effect, however, data are not sufficient and suitable to characterise a dose–response relationship and identify a reference point for manganese‐induced neurotoxicity. In the absence of adequate data to establish an UL, estimated background dietary intakes (i.e. manganese intakes from natural dietary sources only) observed among high consumers (95th percentile) were used to provide an indication of the highest level of intake where there is reasonable confidence on the absence of adverse effects. A safe level of intake of 8 mg/day was established for adults ≥ 18 years (including pregnant and lactating women) and ranged between 2 and 7 mg/day for other population groups. The application of the safe level of intake is more limited than an UL because the intake level at which the risk of adverse effects starts to increase is not defined. This publication is linked to the following EFSA Journal article: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2023.p211201