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Safety, regulation and innovation in the food sector David Jonas

Address Wayborough Bungalow, Wayborough Hill, Minster, Ramsgate, Kent CT12 4HR, UK Current Opinion in Biotechnology 1996, 7:262-264 Current Biology Ltd ISSN 0958-1669 Abbreviations CAC CodexAlimentarius Commission FAO Food and Agriculture Organization ILSI International Sciences Institute Life OECD Organisation for Economic Cooperation and Development SAFEST safety assessment of food through equivalence and similarity targeting WHO World Health Organization

pace of developments in food production and processing, including the application of modern biotechnology, and a growing consumer interest in food-safety issues have prompted some regulatory agencies to consider the need for more formalized safety assessment and regulatory procedures for new foods. Member States of the European Union have adopted a common position on a proposal for a 'Regulation on Novel Foods and Novel Food Ingredients' that would require the pre-marketing approval of such products [3]. Canada, the Netherlands and the UK are amongst those countries that already have in place procedures for the pre-marketing clearance of new foods. In relation to a new food, safety has been defined as 'a reasonable certainty of no harm under the anticipated conditions of use' [4]. Establishing procedures for the safety assessment of new foods that do not inhibit unnecessarily the application of new technology and that ensure, as far as is practical, new foods are safe poses a considerable challenge. Procedures used for the safety evaluation of food additives are often not applicable to foods for a number of reasons. T h e s e include the difficulty of feeding foods to test animals at sufficiently high dose rates to establish a level of 'no adverse effect' from which acceptable daily intakes are calculated, and the chemical complexity of many new foods, which makes it difficult to balance test and control diets and thus to correctly attribute any effects observed on feeding the new food. Attempts have been made to develop systematic safety assessment procedures covering a diverse range of new foods in the UK [5], Canada [6], the European Union (G Pascal, personal communication), the International Life Sciences Institute (ILSI) Europe [7] and the United Nations University [8]. More attention has been given to developing procedures for specific groups of novel foods (e.g. novel protein foods [9]) and, most recently, for the safety evaluation of foods obtained from organisms developed using modern biotechnology. In 1990, a joint consultation on biotechnology and food safety was sponsored by the World Health Organization (WHO) and the United Nations Food and Agriculture Organization (FAO). This consultation concluded that the use of the newer techniques of biotechnology did not result in food that is inherently less safe than food produced by conventional technologies [10]. It advocated a case by case comparative approach, based on sound scientific principles, to the safety evaluation of foods produced through the application of modern biotechnology. T h e comparative approach was taken further by the Organisation for Economic Cooperation and Development (OECD) and enunciated as the concept of substantial equivalence [4]. This concept was considered to be

Introduction

Recent years have seen an explosion in the number of new foods and food ingredients approaching commercialization. In the past five years alone, the UK's Advisory Committee on Novel Foods and Processes has reviewed the safety of more than 35 new foods [1]. T h e s e new foods vary widely in their nature and anticipated uses. Some, such as the synthetic fat replacers, may be chemically well defined and have clearly identifiable applications, whereas others, such as 'Mycoprotein', which is produced from a filamentous fungus, are chemically very complex and have a range of applications. Other recent developments include the use of exotic fruits and vegetables as well as products obtained using entirely new food production processes. These include processes such as ohmic heating, in which sterilization is achieved by passage of an electric current through the food, and sterilization using ultra high pressures, alone or in combination with heat. T h e diverse range of innovative new foods also includes foods obtained from organisms developed using the modern techniques of biotechnology rather than the more traditional processes of breeding and strain selection. Several such products have been approved by regulatory agencies in the USA and Europe and either are being marketed or are expected to reach the market within the next few months [2].
Procedures for the assessment of food safety

Whenever any new food is introduced on to the market or the process by which a food is produced is changed, a food-safety assessment should be made. T h e nature of this assessment will depend on the properties of the food and the perceived concerns. Traditionally, new foods have not been subjected to a formal safety assessment and approval process, although food additives are rigorously controlled in many countries. In the past, evidence of previous human exposure allowed a presumption of safety for many new foods and, as new foods were introduced slowly to the market, any adverse reactions could be followed up and appropriate measures taken. However, the increasing

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the most practical approach to the determination of the safety of foods derived by modern biotechnology. Initially developed for foods of terrestrial origin, substantial equivalence was concluded by an O E C D workshop in 1992 to be equally valid for foods of aquatic origin, although the shortage of data on conventional foods of this origin could hinder application [11].

Substantial equivalence Essentially, the concept of substantial equivalence, as conceived by O E C D and reviewed in detail in relation to plant-derived foods by a W H O workshop in 1994 [12], focuses the safety evaluation of a new food obtained from an organism developed using modern biotechnology on any differences between the new food and its traditional counterpart. T h e counterpart will often be another edible strain of the host organism for the genetic modification. If the new food can be shown to be substantially equivalent to the conventional counterpart after taking into account processing, the way in which the food is used and its likely route of intake, then no further evaluation is necessary to establish its safety. T h e W H O workshop concluded that, to show substantial equivalence, the new food and the counterpart should be compositionally and nutritionally similar within the limits of the normal biological variation in edible varieties of the plant. If well defined differences exist between the new food and the conventional counterpart, these should be the focus of the safety evaluation. If the differences between the new food and its conventional counterpart cannot be defined, or if there is no counterpart, this does not mean that the new food is unsafe, although an in-depth safety evaluation is likely to be required that takes into account the properties of the new food.
Many genetically modified organisms intended for use in food production are likely to fall into the class of organisms where substantial equivalence to a conventional food organism exists apart from well defined differences. These differences may be the intended result of the genetic modification; for example, the introduction of genes encoding pesticidal proteins or proteins affecting quality attributes such as softening. T h e y may also be a result of the presence of marker genes and their products, which have no function in the food product. T h e food safety aspects of marker genes used in plant biotechnology were reviewed by a W H O workshop in 1995 which concluded that they raise no unique food-safety concerns [13]. Differences between the new food and its counterpart might also arise from secondary effects of the intentionally introduced gene products or as the result of insertional mutagenesis during the act of genetic modification affecting the normal metabolism of the organism.

its conventional counterpart, if the differences can be defined the food safety evaluation will often require a relatively straightforward evaluation of a specific chemical component. Traditional approaches may be used. T h e evaluation will need to address nutrition, potential allergenicity, toxicity and interactions between the chemical component and other components of the new food. If the chemical tested is obtained from a source other than the genetically modified organism being evaluated, it will be essential to show that the chemical tested is identical to that produced in the genetically modified organism.

Codex Alimentarius Commission T h e comparative approach advocated by WHO, FAO and O E C D for the safety evaluation of foods derived using biotechnology has been widely adopted in many countries [14]. It is likely that the approach will be developed further at a second FAO/WHO consultation in 1996 and incorporated into guidelines for the safety assessment for foods produced by biotechnology to be elaborated by the Codex Alimentarius Commission (CAC).
T h e CAC, which currently has a membership of more than 150 countries, was established by FAO and W H O in 1962 to guide and promote the elaboration and establishment of definitions and standards for foods, to assist in their harmonization and, in doing so, to facilitate international trade [15]. Guidelines elaborated by the CAC have assumed added importance since the Uruguay Round of agreements under the General Agreement on Tariffs and Trade (GATT) because, in the food sector, they are recognized as benchmarks in resolving international trade disputes. Thus, if the CAC is able to reach a consensus on guidelines for the safety assessment of foods produced by biotechnology, international trade in such products should be greatly facilitated.

The SAFEST concept Although the concept of substantial equivalence was developed by O E C D specifically for food products derived using biotechnology, a Working Party set up by ILSI Europe has taken the concept further and has applied it to the safety evaluation of all novel foods [7]. T h e Working Party has proposed the concept of safety assessment of foods through equivalence and similarity targeting (SAFEST) that, in part, clarifies uncertainties that have arisen in the application of substantial equivalence [16].
In applying the SAFEST concept, a novel food is allocated to one of three classes on the basis of certain background information. In the first class are those novel foods that can be shown to be substantially equivalent to their conventional counterparts, for which no further information is required to establish safety. Foods in the second class differ from their conventional counterparts only in well defined ways and are thus sufficiently similar to their conventional counterparts for the safety evaluation to focus on these differences. Novel foods that cannot be

Chemical analysis o f f o o d s Whatever the origins of the defined differences between a food obtained from a genetically modified organism and

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shown to be either substantially equivalent or sufficiently similar to their conventional counterparts are in the third S A F E S T class and require an in-depth safety evaluation. T h e ILSI Working Party has discussed the nutritional and toxicological tests that may need to be applied to establish the safety of novel foods not shown to be in the first SAFEST class. In the case of novel foods falling into the second SAFEST class, these tests will usually be targeted at specific chemical components of the novel food. In contrast, those foods that fall neither into SAFEST class 1 nor into SAFEST class 2 may require the tests to be applied to the whole food or to extracts and concentrates.

2.

Engel K-H, Takeoka G, Teranishi R: Foods and food ingredients produced via recombinant DNA techniques. In Genetically Modified Foods - Safety Aspects. Edited by Engel K-H, Takeoka G, Teranishi R, Washington, DC: American Chemical Society; 1995:1-10. European Council: Common position No 25/95 concerning a proposal for a regulation on novel foods and novel food ingredients. Off J Eur Communities 1995, C320:1-8. Organisation for Economic Cooperation and Development: Safety Evaluation of Foods Derived by Modern Biotechnology: Concepts and Principles: Paris: OECD; 1993. Anon: Structured approach to safety assessment of novel foods and processes. In Annual Report for 1994; Advisory Committee on Novel Foods and Processes. London: MAFF Publications; 1995:67-91. Food Directorate: Draft Guidelines for the Safety Assessment of Novel Foods: Ottawa; Health Canada; 1993.
The International Life Sciences Institute Europe: The Safety Assessment of Novel Foods: Brussels: ILSI Europe; 1995.

3.

4.

5.

6.
7,

Conclusions
T h e concept of substantial equivalence was initially developed to facilitate the food safety evaluation of products of biotechnology. Since it was initially proposed, it has been refined using the SAFEST concept and the scope of application enlarged to include all novel foods, including those produced by innovative technologies. These concepts provide frameworks within which to conduct a comparative safety evaluation of a novel food. With the diversity of products that might be considered to be novel, however, any systematic approach should be applied cautiously because over-reliance could lead to potential problems being overlooked. There is no substitute for intuitive scientific appraisal by those familiar with the product concerned. For the foreseeable future, a case by case approach will be needed.

8. 9.

Anon: PAG/UNU guideline no 6: preclinical testing of novel sources of food. United Nat Univ Bull 1983, 5:60-63. Protein-Calorie Advisory Group of the United Nations System: Guideline Number 6 on the Preclinical Testing of Novel Sources of Protein. New York: United Nations; 1972. World Health Organization: Strategies for Assessing the Safety of Foods Produced by Biotechnology. Geneva: WHO; 1991. Organisation for Economic Cooperation and Development: Aquatic Biotechnology and Food Safety. Paris: OECD; 1994. World Health Orgainization: Application of the Principles of Substantial Equivalence to the Safety Evaluation of Foods or Food Components from Plants Derived by Modern Biotechnology. Geneva: WHO; 1995. World Health Organization: Health Aspects of Marker Genes in Genetically Modified Plants. Geneva: WHO; 1993. Kok E: Evaluation of Strategies for Food Safety Assessment of Genetically Modified Agricultural Products. Wageningen: RIKILTDLO; 1992. Food and Agriculture Organization of the United Nations: This is Codex Alimentarius, cdn2. Rome: FAO; 1994. Organisation for Economic Cooperation and Development: Proceedings of the OECD Workshop on Food Safety Evaluation. Paris: OECD; 1996:in press.

10. 11. 12.

13. 14.

References
1. Anon: Cumulative index. In Annual Report for 1994: Advisory Committee on Novel Foods and Processes. London: MAFF Publications; 1995:92-93.

15. 16.