Keywords

1 The Safety Assessment Process in the European Union

Ensuring food safety from farm to fork is a founding principle of the European Union.Footnote 1 It is also the fundamental aim of the extensive body of EU laws and standards covering the agri-food sectors as well as imported and exported goods within the Member States. However, many foodborne illness outbreaks that have occurred in recent years compounded by the pressure—intentional or unintentional—caused by misinformation circulating through social media (so-called “fake news”), have generated an increasing mistrust among EU consumers in the capability of the food system to deliver safe food.Footnote 2,Footnote 3,Footnote 4 At the same time, global concern about climate change and the effects of globalization are driving lifestyle changes towards more sustainable patterns, and a consequent growing demand for healthier and less processed food.Footnote 5 At an industrial level, this demand translates into a need for product differentiation on the global market and, therefore, a call for innovation.

Novel Foods—especially those derived from less exploited resources or biomasses—may offer a great opportunity to the food industry for innovation while at the same time meeting sustainability needs.Footnote 6 While the potential sources of Novel Foods are countless, their safety assessment according to EU regulation requires a case-by-case approach. Safety evaluations include a toxicological and a nutritional assessment, an analysis of the way the Novel Food will be processed and used, as well as a description of its intended intake.

Although the effort required to assess and ensure the safety of Novel Foods is enormous and is encoded by a well-established process,Footnote 7 consumers still perceive these foods with distrust, often due to communication campaigns on social media. It can be noted indeed that also accountable media reporting news on Novel Foods often make use of images that can drive disgust among readers, and thus causing mistrust. A recent work based on longitudinal- and cross-cultural studies reported on the significant correlation between food disgust and risk perception among adult consumers, pointing out the importance of food disgust sensitivity for the acceptance of Novel Foods.Footnote 8 This neophobiaFootnote 9 attitude is higher for those Novel Foods obtained from sources that are alien to Europeans, such as insects or algae, or sources that are produced using radically new technologies (i.e., cultured meat). A better response is observed for Novel Foods obtained from known sources (i.e., those derived from cocoa or coffee biomasses) or resembling foods common in Europe (i.e., juices or infusions from novel berries).Footnote 10,Footnote 11 It is therefore important to provide an overview of the safety assessment required for Novel Food, to demonstrate the rigorous procedure required for approval and the high standards requested for entering the market.

2 Safety Assessment Requirements for Novel Foods

It is important to underline that Novel Foods should be at least as safe as their traditional counterparts, where extant, and should not present any dietary risks. This is the underpinning principle for the safety assessment procedure leading to the approval of a Novel Food.Footnote 12

The risk assessment performed by the European Food Safety Authority (EFSA), based on the scientific evidence provided by the food business operator, enables the European Commission to decide whether a Novel Food product or ingredient can be placed on the EU market.Footnote 13 It should be noted that such premarket authorisationFootnote 14 is not only requested for Novel Foods, but is also a prerequisite for the commercialization of other regulated products (i.e., food enzymes, improvement agents). Authorisation is also required for the use of health claims on food labels, and it is clearly aimed at both ensuring the safety of the product as well as at enabling consumers to make informed choices.

The safety assessment procedure for Novel Foods is established by law in Regulation (EU) 2015/2283, while the main scientific requirements for a Novel Food application are outlined in EFSA’s “Guidance on the preparation and presentation of an application for authorization of a Novel Food in the context of Regulation (EU) 2015/2283”. EFSA’s specific role is to identify and characterise any hazards linked to the consumption of Novel Foods, and assess the risk associated with their consumption under the proposed conditions of use. It should be noted, however, that it is the applicant’s responsibility to provide sufficient and sound evidence to support the safety of the proposed Novel Food. When scientific data provided by the applicant are not sufficient to rule out any potential health concern, the Novel Food cannot be approved for the market.

In order to ensure the overall transparency of the process, all Novel Food applications received by EFSA are publicly available via the EFSA Register of Questions (ROQ) database,Footnote 15 while all the published technical reports on the risk assessment of these products are published in the EFSA Journal.Footnote 16 In addition, all the Novel Foods in the European Union authorised so far are compiled into the Union List,Footnote 17 which includes their conditions of use, labelling requirements, and their specifications. Moreover, the EU Commission also makes publicly available the summaries of applications and notifications.Footnote 18

Certain background information on the denomination/identity of the Novel Food or ingredients, its source, and intended use, is necessary to establish its safety profile. This information also helps to identify potential knowledge gaps, and any ensuing need for additional toxicological or nutritional studies. A Novel Food or ingredient can be obtained from a plant, animal, or micro-organism, or can derive from chemical synthesis. Accordingly, different strategies should be put in place for the assessment of the safety profile. For Novel Foods or ingredients obtained from biological sources, details of any previous use as a food or feed should be provided, together with information about the history of use outside the EU. Such information will help in the evaluation of previous adverse effects in the target human population, and in the definition of the boundaries of the intended use.

Novel Foods can be ingredients with complex mixtures or whole foods. Examples of whole foods are the recently authorised lyophilised pulp and skin of pitted fruits of Synsepalum dulcificum,Footnote 19 intended as a food supplement, or the partially defatted rapeseed powder from Brassica rapa L. and Brassica napus L.Footnote 20 On the contrary, extracts or fractions can be regarded as complex mixtures, i.e., the recently authorised astaxanthin-rich oleoresin from Haematococcus pluvialis algae.Footnote 21

The complex nature of such systems, usually formed by hundreds of different substances over a large range of concentrations, is the main constraint to providing a comprehensive chemical characterization of the Novel Food. A comprehensive (physico)-chemical characterization of the Novel Food is indeed the groundwork for a critical evaluation of any possible adverse health effects in humans, providing essential information for the design and interpretation of toxicological studies.

In addition to proximate analysis, the applicant should provide qualitative and, when possible, quantitative data on components of biological interest, so as to minimize the percentage of unidentified substances. In addition, chemical information about the potential occurrence of residues, contaminants, or inherent compounds of biological interest are required. For instance, the applicant should provide data about residues, natural toxins, nutrients, and antinutritional factors known to be associated with the source of the Novel Food or ingredient, or contaminants that might arise from the production process. The analytical plan should be decided on a case-by-case basis, taking into account the source of the Novel Food or ingredient and its processing history.

As an example, in the recently authorised Coffea arabica L. and/or Coffea canephora Pierre ex A. Froehner dried cherry pulp,Footnote 22 caffeine was clearly the main inherent compound of interest. An accurate quantification in different batches allowed for the extrapolation of potential intake in the target population according to the proposed use. The provisional intake was then compared to the caffeine threshold of concern according to EFSA to assess any potential risk deriving from the consumption of the Novel Food. When the Novel Food has had, instead, a high fat content which is known to be highly degradable, as in the case of coriander seed oil,Footnote 23 the possible formation of hazardous compounds during storage following lipid peroxidation was thoroughly assessed.

In addition to its composition, the production process can significantly impact the safety profile of a Novel Food, leading to changes in composition (i.e., dilution and/or concentration of compounds of interest in extracts) or degradation of unstable compounds. Therefore, production processes cannot be overlooked in the safety assessment.

The toxicological profile of a Novel Food is probably the most cumbersome step in the safety assessment, especially when there is no substantial information available about the history of use. Methodologies for the evaluation of toxicokinetic, toxicological, and allergenic aspects are not univocally defined.Footnote 24,Footnote 25 To properly guide the process, EFSA has recently proposed a tiered approach based on the use of in silico, in vitro and in vivo studies.Footnote 26,Footnote 27 In particular, the integration of computational approaches and physicochemical data can support a more precise design of experimental trials, thus allowing for the limitation of the number of animal trials according to the 3R principle.Footnote 28

Finally, all the data obtained from the (physico)-chemical characterization and the toxicological assessment is used to set appropriate specifications and to define the intended role of the Novel Food or ingredient in the diet as well as its potential intake and target population. The specification is aimed at ensuring the observance of the general conditions of inclusion of Novel Foods in the Union list, as established by Regulation (EU) 2015/2283.

3 Assessing the Allergenic Potential: The Big Constraint

As required by Regulation (EU) No 1169/2011, allergens must be indicated on food product labels to provide consumers with information about potential allergens. Therefore, the evaluation of potential allergens occurring in Novel Foods is essential to carrying out an accurate risk assessment and meeting the general conditions of inclusion in the Union list. However, there are no validated predictive tests for assessing the allergenicity of proteins from sources that are not commonly recognized as allergens.

While a comprehensive and robust chemical characterization is possible, and the methodologies for a sound toxicological evaluation are often available, the allergenic potential of a certain food or ingredient is still difficult to be defined in the absence of a history of use. For this reason, the assessment of allergenic potential is the main bottleneck and one of the major limitations in the risk assessment of many Novel Food candidates.

Since food allergens are mainly proteins, any Novel Food containing proteins or protein fractions may elicit an allergenic response. Therefore, as a general assumption, when proteins are determined in the compositional analysis of a Novel Food or ingredient, these proteins must be regarded as potentially allergenic.Footnote 29 A novel protein may present a risk due to de novo sensitisation or cross reactivity.Footnote 30,Footnote 31 The term sensitisation refers to the initiation of an allergic immune response following from the intake of an allergen. It can be caused via multiple routes of exposure, i.e., ingestion, respiratory tract, or dermal exposure. In terms of mechanism, the allergen intake leads to a hypersensitive immune response, which in typical food allergies is IgE mediated. De novo sensitisation indicates that a new protein causes such an allergic reaction, while in cross-reactivity, a protein which is homologous to a known allergen causes an allergic reaction similar to that of the known allergen (i.e., birch pollen allergens cross-reacting with apple allergens). If the Novel Food or ingredient is expected to contain proteins from sources known to be associated with food allergy, more information can be collected from specific chemical and immunological tests. In case of a positive result, the Novel Food should be labelled to indicate the source of the allergenic protein in question.

If the history of the Novel Food or ingredient does not suggest the presence of proteins from sources known to be associated with food allergy, an alternative strategy is required. While it is unlikely that a new protein will elicit an allergic reaction in a large proportion of the population, a comparison of the properties of any new proteins in the Novel Food with those of known allergens may prove valuable in assessing the likelihood that the new protein will express allergenic potential. Potential cross-reactivity can be analysed by homology searches, i.e., the comparison of the protein chemical structure with a dataset of sequences of known allergens, and serological testing such as immunoblotting. Once novel proteins are introduced in the diet, however, their capability to cause de novo sensitisation is difficult to analyse.Footnote 32

A consensus protocol for determining the allergenicity of Novel Foods is still lacking. However, current approaches are based on weight-of-evidence.Footnote 33 A sound evaluation of the history of use of the protein (or the source material containing the protein), also in relation to the specific environmental and geographical factors, is of upmost importance. A taxonomical analysis of the source organism (i.e., plants, microorganisms, or animals) may reveal a relationship with sources of known allergens, thus indicating potential allergens. This can be also supported by the structural characterization of the protein and its comparison to known allergens. In addition, the IgE-binding capacity of the Novel Food should be tested using human sera from allergic patients to check possible cross-reactivity or following a primary sensitisation. When an IgE-binding protein is identified, its biological activity should be carefully assessed so as to clarify whether it could activate an immunologic response. As a complementary strategy, protein thermal stability and its resistance to enzymatic digestion should be also considered.Footnote 34,Footnote 35

4 New Methodologies to Improve Risk Assessment

The EFSA guidance documentFootnote 36 provides suggestions for which tests can be used to evaluate the kinetic, toxicological, and allergenic properties of the Novel Food, as well as its chemical characterization. Suggested methodologies are usually based on well-established approaches with a large consensus within the scientific community. However, a range of novel methods based on cutting edge technologies—with high potential to improve the chemical and toxicological characterization of a food—are becoming available to the scientific community. Among them, in silico modelling and omics technologies are already considered by the EU animal welfare Directive.Footnote 37 The integration of in vitro and in silico methods to evaluate the biological activity of certain food components is widely suggested in the recent literature, especially to refine the identification of potential biological targets and reduce the number of animal experiments.Footnote 38,Footnote 39,Footnote 40 Computational methods based on quantitative structure-activity relationship (QSAR) analysis,Footnote 41 physiologically based toxicokinetic modelling (PBTK),Footnote 42 and the Threshold of Toxicological Concern (TTC)Footnote 43 have recently been included in EFSA guidance documents, attesting to the great potential for their exploitation in risk assessment.Footnote 44 These alternative methods take advantage of the computational calculation available in the “big data” era, allowing for the high throughput safety evaluation of large batches of chemicals. Although animal studies cannot be completely replaced by computational modelling, such alternative methods may provide a prioritization criterion, thus contributing to the identification of the main biological targets and endpoints to be further tested. In the end, this may lead to a significant reduction in animal testing, as well as reducing the cost and effort required for toxicological studies.

The combination of data from in vitro toxicity experiments, ADME data, in silico experiments, and in vivo dose-response curves may represent an innovative pipeline to reduce or replace tests with experimental animals while providing a robust risk assessment; the main limitation is so far still represented by the difficulty of the in vitro–in vivo extrapolation of toxicological data. The integration of system biology and toxicogenomics is also increasingly gaining interest in risk assessment work, although the lack of consensus workflow is constraining the wide uptake of such methodologies into general risk assessment processes.Footnote 45 Once the predictive capacity of these methodologies is improved and consensus workflows are available for the scientific community, the inclusion of alternative methods into the current risk assessment procedure will pave the road to more informed and thorough safety and nutritional assessment.Footnote 46

5 Safety Assessment of Insects As Novel Food

Insects are probably among the most controversial Novel Foods in terms of consumer perception. While their relevance for sustainability from a circular economy perspective is undeniable,Footnote 47 their acceptance as food or food ingredients among consumers is low, also due to the wide use of misleading and disgust-provoking images in social media communication campaigns.Footnote 48

Three insect species have been approved as Novel Foods so far, namely Tenebrio molitor larva,Footnote 49 Locusta migratoria,Footnote 50 and Acheta domesticus.Footnote 51 For all of them a sound safety assessment has been performed before authorization based on a wide body of evidence from the scientific literature. Due to controversies in consumer perception and wide debate around them, the number of studies published in scientific journals over the past decade significantly exceeds those related to any other Novel Food. Therefore, the risk assessment performed by EFSA has strong foundations, and the uncertainties around insect safety profiles are limited to a few specific issues.

The advantages related to the use of edible insects as a source of alternative proteins for humans have been widely discussed and demonstrated in the scientific literature, from low input farming requirements to the nutritional and technological values of the protein and lipid fractions of interest. A comprehensive overview, which is beyond the scope of this chapter, can be found in recent reviews from Gravel and Doyen,Footnote 52 Baiano,Footnote 53 and van Raamsdonk and coauthors,Footnote 54 as well as in the fourth chapter of this volume, where Sforza focuses on the importance of these proteins for global human health.

Concerning the safety aspects, the risk assessment process of authorised edible insects is described in detail elsewhere this volume.Footnote 55 However, it is worth noting that the safety profile of edible insects has already been challenged on several occasions, mainly focusing on the accumulation of contaminants from substrates in reared insects.Footnote 56,Footnote 57,Footnote 58 Although available data are often fragmented over a wide range of contaminants and insect species, there is general agreement that limiting the uptake of contaminants from the rearing substrate during the rearing phase is crucial towards ensuring insect safety. While the occurrence of pesticides and veterinary drugs in the rearing substrate may affect insect growth, bioaccumulation of heavy metals, cadmium, and lead has been proven to vary based on the insect species. Bioaccumulation may occur to a certain extent also for environmental residues, such as dioxins and PAH. As for mycotoxins, several species of edible insects have demonstrated the ability to decrease their amount in the biomass without giving rise to significant bioaccumulation. This could be explained through the uptake and further metabolization of mycotoxins, although the biological pathways are still unknown.Footnote 59,Footnote 60,Footnote 61 Whether this metabolization leads to a bioactivation or a detoxification needs further attention, not only for a better safety assessment of edible insects, but mainly in view of the biotechnological exploitation of insect enzymes in the detoxification of non-compliant batches.

When edible insects are reared on biomasses compliant with EU regulations, the main food and feed contaminants such as pesticides, mycotoxins, heavy metals, or industrial residues are not accumulated in the fractions of interest. As with any other food of animal origin, the crucial point in the safety of edible insects is the implementation of severe controls for the rearing of biomasses, and not on the insects themselves.

On the contrary, it must be underlined that the main safety issue related to edible insects is their allergenic potential.Footnote 62,Footnote 63 A paradigmatic example of the challenges in assessing allergenic potential is represented by edible insects such as the recently authorised Tenebrio molitor.Footnote 64 Although no specific information can be derived about the allergenic potential of Yellow mealworm based on the history of use, the taxonomical analysis returned a proximity with shrimp and house dust mites, well known allergenic agents.Footnote 65 Experimental trials were performed on human sera by immunoblotting and basophil activation, showing that there is a realistic possibility that house dust mites and crustacean allergic patients may react to food containing yellow mealworm proteins as a cross-reactivity effect. Based on this evidence, proper labelling should be implemented when dried yellow mealworm is commercialised as Novel Food. A similar approach can be extended to other edible insects, as well as Novel Foods in general, as reported by the recent ImpARAS COST action.Footnote 66

With respect to the safety assessment of edible insects, gaps in the understanding of allergenic potential, especially in terms of de novo sensitization, are probably in most urgent need of addressing. However, considering the current regulation on food allergens in the European Union, providing accurate information to consumers and applying correct labelling are appropriate measures to limit adverse allergic effects.

6 Is an Approved Novel Food Really Safe?

As described in the previous sections, the safety assessment of a Novel Food is a structured process, aimed at providing a comprehensive evaluation of the risk posed by the Novel Food to the target population. The applicant is asked to collect and provide scientific evidence supporting the safe placing on the market of the Novel Food. Given the thorough regulatory umbrella and the accurate risk assessment required for premarket authorisation, there is no coherent reason to undermine consumer confidence towards an approved Novel Food.

Although the current safety assessment procedure for Novel Foods has some limitations and bottlenecks, mainly in the evaluation of allergenic potential and in the comprehensive toxicological assessment, innovative cutting-edge methodologies based on the integration of system biology, omics techniques, and computational approaches may offer great opportunities for a relevant improvement in better informed risk assessment.

However, it should be said that it is impossible to ensure that a food will never pose a risk to any consumer. This consideration, inherently linked to the dynamism of science, is often the basis for a misleading perception of risk that is hard for consumers to accept.

As the Organisation for Economic Co-operation and Development (OECD) stated in 1993, food safety policies are designed to establish “a reasonable certainty that no harm will result from the intended uses”.Footnote 67 The risk assessment of a certain food is therefore based on the scientific evidence available within a specific timeframe. Any further change in the body of evidence resulting from advancements in the scientific community may therefore lead to different conclusions. For this reason, risk assessment is often repeated over time (e.g., regulated contaminants for which maximum permitted limits are issued are reassessed in due time), or whenever relevant scientific data are made available.

It is important that the regulator and the scientific community pay close attention to the proper communication of this continuous refinement process through public engagement initiatives. At the same time, the industry is asked to describe the innovation strategies at the basis of the introduction of Novel Foods to the market, while also providing unbiased information about technological opportunities and benefits in relation to sustainability. Only through a transparent and open narrative of the risk assessment process and its limitations will the food system be able to restore consumer trust and dismantle misperceptions of Novel Food.