Novel foods in the European Union: Scientific requirements and challenges of the risk assessment process by the European Food Safety Authority

The European Food Safety Authority (EFSA) has been involved in the risk assessment of novel foods since 2003. The implementation of the current novel food regulation in 2018 rendered EFSA the sole entity of the European Union responsible for such safety evaluations. The risk assessment is based on the data submitted by applicants in line with the scientific requirements described in the respective EFSA guidance document. The present work aims to elaborate on the rationale behind the scientific questions raised during the risk assessment of novel foods, with a focus on complex mixtures and whole foods. Novel foods received by EFSA in 2003–2019 were screened and clustered by nature and complexity. The requests for additional or supplementary information raised by EFSA during all risk assessments were analyzed for identifying reoccurring issues. In brief, it is shown that applications concern mainly novel foods derived from plants, microorganisms, fungi, algae, and animals. A plethora of requests relates to the production process, the compositional characterization of the novel food, and the evaluation of the product's toxicological profile. Recurring issues related to specific novel food categories were noted. The heterogeneous nature and the variable complexity of novel foods emphasize the challenge to tailor aspects of the evaluation approach to the characteristics of each individual product. Importantly, the scientific requirements for novel food applications set by EFSA are interrelated, and only a rigorous and cross-cutting approach adopted by the applicants when preparing the respective application dossiers can lead to scientifically sound dossiers. This is the first time that an in-depth analysis of the experience gained by EFSA in the risk assessment of novel foods and of the reasoning behind the most frequent scientific requests by EFSA to applicants is made

Safety of Lemna minor and Lemna gibba whole plant material as a novel food pursuant to Regulation (EU) 2015/2283

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on Lemna minor and Lemna gibba whole plant material as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Lemna minor and Lemna gibba are aquatic plants commonly named water lentils. The NF is produced by cultivation of Lemna minor and Lemna gibba plants, washing with water and heat treatment. The main constituents of the NF are water, protein and fibre. The Panel notes that the concentration of trace elements and contaminants in the NF is highly dependent on the conditions of cultivation of the plant and the fertiliser composition. The NF is intended to be used as a vegetable, similar to other leafy vegetables. The target population is the general population. The Panel considers that, with the exception of concerns related to the manganese intake, taking into account the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The Panel considers that the risk that the consumption of the NF may trigger allergic reactions in humans is low. The Panel concludes that the NF, in consideration of its proposed uses and the concentration of manganese as compared to the normally present concentration of manganese in other leafy vegetables, may be of safety concern, therefore, the safety of the NF cannot currently be established

Safety of Wolffia globosa powder as a Novel food pursuant to Regulation (EU) 2015/2283

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on Wolffia globosa powder as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Wolffia globosa is an aquatic plant, one out of the 38 species of the water lentil family which is composed by five genera (i.e. Spirodela, Landoltia, Lemna, Wolffiella and Wolffia). The NF is produced by cultivation of Wolffia globosa plants under controlled conditions, washing with hot water and drying. The main constituents of the NF are protein, fibre and fat. The Panel notes that the concentration of trace elements and contaminants in the NF is highly dependent on the conditions of cultivation of the plant and the fertiliser composition. The NF is intended to be used as food ingredient in a variety of food categories and as food supplement. The target population is the general population except for food supplements which are intended to be consumed exclusively by adults. The Panel considers that with the exception of concerns related to the manganese intake, taking into account the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The subchronic toxicity study provided with the NF revealed a number of significant findings and the Panel considers the middle dose (6.5 g/kg body weight (bw) per day) as the no observed adverse effect level (NOAEL). Based on the protein concentration, the Panel considers that the consumption of the NF may trigger allergic reactions. The Panel concluded that an increase in manganese intake from the NF used as food ingredient or food supplements is of safety concern and the safety of the NF cannot be established

Safety of tetrahydrocurcuminoids from turmeric (Curcuma longa L.) as a novel food pursuant to Regulation (EU) 2015/2283

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on tetrahydrocurcuminoids from turmeric (Curcuma longa L.) as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Tetrahydrocurcuminoids are derivatives of curcuminoids, produced chemically by hydrogenation of curcuminoids extracted from the rhizomes of C. longa L. The NF consists of more than 95% of tetrahydrocurcuminoids. The applicant proposed to use the NF in food supplements at a maximum dose of 300 mg/day for adults excluding pregnant and lactating women. Taking into account the composition of the NF and the proposed conditions of use, consumption of the NF is not nutritionally disadvantageous. There are no concerns regarding genotoxicity of the NF. Based on a 90-day oral toxicity study and a reproduction/developmental toxicity screening test performed with the NF, the Panel derives a safe level of 2 mg/kg body weight per day. For the target population this level corresponds to 140 mg/day, which is lower than the use level as proposed by the applicant. The Panel concludes that the NF, tetrahydrocurcuminoids from turmeric (C. longa L.), is safe for the target population at 140 mg/day

Safety of glucosyl hesperidin as a Novel food pursuant to Regulation (EU) 2015/2283

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on glucosyl hesperidin (GH) as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF, which is produced from hesperidin and dextrin by enzymatic reactions, is a powder consisting mainly of monoglucosyl hesperidin (MGH) and unreacted hesperidin (flavonoid), which account in total for up to 92.8% (on dry basis) of the product. The applicant proposed to use the NF in specific drinks and food supplements leading to a maximum intake of up to 364 mg per day for adults. The target population is the general population, except for food supplements for which the proposed target population is children from 1 year onwards and adults. Taking into consideration the composition of the NF and the proposed uses, the consumption of the NF is not nutritionally disadvantageous. There are no concerns regarding genotoxicity of the NF. Based on a 90-day oral toxicity study conducted with the NF, the Panel considers the NOAEL at the mid-dose group, i.e. ~ 1000 mg/kg body weight (bw) per day. By applying an uncertainty factor of 200, the resulting intake providing sufficient margin of exposure for humans would be 5 mg/kg bw per day. The available human intervention studies did not report clinically relevant changes in haematological or clinical chemistry parameters following the administration of GH/MGH at supplemental doses of up to 3 g/day for 12 weeks. Overall, the Panel considers that the margin of exposure (~ 200) between the intake of the NF at the proposed uses and use levels and the NOAEL from the 90-day study is sufficient. The Panel concludes that the NF, glucosyl hesperidin, is safe for the target population at the proposed uses and use levels

Guidance on the scientific requirements for an application for authorisation of a novel food in the context of Regulation (EU) 2015/2283

The European Commission requested EFSA to update the scientific guidance for the preparation of applications for authorisation of novel foods, previously developed following the adoption of Regulation (EU) 2015/2283 on novel foods. This guidance document provides advice on the scientific information needed to be submitted by the applicant towards demonstrating the safety of the novel food. Requirements pertain to the description of the novel food, production process, compositional data, specifications, proposed uses and use levels and anticipated intake of the novel food. Furthermore, information needed in sections on the history of use of the novel food and/or its source, absorption, distribution, metabolism, excretion, toxicological information, nutritional information and allergenicity is also described. The applicant should integrate and interpret the data presented in the different sections to provide their overall considerations on how the information supports the safety of the novel food under the proposed conditions of use. Where potential health hazards have been identified, they are to be discussed in relation to the anticipated intake of the novel food and the proposed target populations. On the basis of the information provided, EFSA will assess the safety of the novel food under the proposed conditions of use

Safety of water lentil protein concentrate from a mixture of Lemna gibba and Lemna minor as a novel food pursuant to Regulation (EU) 2015/2283

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on water lentil protein concentrate from a mixture of Lemna gibba and Lemna minor as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Water lentil protein concentrate is produced from two water lentil species (L. gibba and L. minor) by separation of the protein fraction of the plant material from fibres, followed by pasteurisation and spray drying. The NF consists mainly of protein, fibre, fat and ash. The applicant proposed to use the NF as a food ingredient in a variety of food categories and as a food supplement. The target population is the general population when used as a food ingredient and exclusively adults when used as a food supplement. The Panel considers that taking into account the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. There are no concerns regarding genotoxicity of the NF. The Panel considers that the risk of the NF triggering allergic reactions is low. The Panel concludes that the NF, water lentil protein concentrate from a mixture of L. gibba and L. minor, is safe under the proposed conditions of use

Prospective analysis of circulating metabolites and endometrial cancer risk

Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention

Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis

As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or re-routing catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we have employed a novel phenotypic metabolic array. We have profiled fibroblasts and induced neuronal progenitor derived human iAstrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach has shown for the first time that C9orf72 human iAstrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in iAstrocytes from sporadic patients. Patient derived iAstrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control iAstrocytes led to increased motor neuron toxicity in co-cultures, similar tothe levels observed with patient derived iAstrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with iAstrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis