Novel foods, produced through genetic modification, are slowly entering the market. To facilitate free trade and to increase their acceptability to consumers, the Codex Alimentarius Commission is developing international food safety guidelines. This article explains how international governmental organizations conceive the issues related to food safety.

 The properties which make a plant, animal or micro-organism desirable for use in the production and processing of food, are largely controlled, directly or indirectly, by the organism’s genes. Genetic modification provides the opportunity to alter the properties of food organisms to meet particular targets such as increased yield, increased resistance to pests and diseases, improved climatic tolerance, and improved food safety and nutritional quality.
Although enormous improvements have already been made to many food organisms using the classical techniques, genetic modification has the potential to bring about more targeted genetic alterations than traditional breeding and microbial selection. These alterations include the potential to bring into the germplasm of particular food organisms genes from entirely unrelated species and even synthetic genes.
Most properties of a particular organism result from interactions between biochemical pathways controlled by many genes. However, even specific changes to only a few genes, which are all that can be routinely achieved with current technology, can have a major impact on the properties of the organism. Many properties, but particularly those with a major agronomic impact, can be influenced significantly by modifying one or two genes.
However, the genetic influence on the properties affecting the food value of organisms is, in general, less understood than the influence on agronomic properties. Consequently, modifying these properties has lagged behind work on modifying agronomic properties.

Current applications: plants and animals
There are many genetically modified organisms (GMOs) which have been, or are close to being, commercialized for use as food or in the production of food or food ingredients. In accordance with their position in the food chain, plants have received a great deal of attention. Technically more demanding and ethically more sensitive, the genetic modification of animals used for consumption has lagged behind the development of modified plants and micro-organisms. To date, developments in this area have focused on using farm animals to produce products with medicinal rather than food uses, such as cattle and sheep capable of producing milk containing human proteins and pigs capable of producing organs suitable for use in human transplant therapy.
More than forty varieties of genetically modified crop plants are close to commercialization. A number of these have improved agronomic and breeding characteristics, such as pest and disease resistance, but in several varieties characteristics have been modified to change the food value of crop plants: delayed softening/ripening (tomato), oil modification (oilseed rape and soya bean), flavour enhancement (pepper) and reduced amylose/protein/allergen (rice).
In the USA and Canada, marketing approval has been given to certain genetically modified plants (including tomato, oilseed rape, soya bean and maize), while the UK has approved certain processed products derived from genetically modified plants (including tomato paste, rapeseed and soya oils and soya meal). Genetically modified rice is being grown on a commercial scale in China. In developing countries, including Mexico, India and Brazil, genetically modified food crops are being developed, but have not yet reached commercialization.

Current applications: micro-organisms
The genetic modification of micro-organisms for food purposes has focused particularly on those used for the production of food additives and processing aids principally enzymes, but also on some amino acids. The use of microbial GMOs for the production of enzymes has a number of advantages, including higher yields and reduced processing costs. In some instances it may also overcome shortages or other disadvantages associated with traditional sources (e.g. calves’ stomachs used for production of the ‘cheese-enzyme’ chymosin). Many countries have now approved chymosin, produced from a variety of genetically modified bacteria and fungi, for food use. In some countries, a significant proportion of cheese on the market is produced with the aid of these enzymes. Food use of certain enzymes, amylases, produced using genetically modified micro-organisms is also approved in the USA.
Yeasts used in food production have also been the subject of genetic modification to improve their processing characteristics. The UK has approved a baking yeast with improved leavening capabilities and a brewing yeast with amylolytic capabilities.

Food safety issues
For many years, many countries have required safety evaluation of food additives. However, novel foods themselves have not been required to undergo a formal pre-marketing safety evaluation and the responsibility has been on those introducing new foods to ensure that they are safe. In particular, most new strains and varieties of food organisms developed using classical selection and breeding techniques have entered the market without a formal safety evaluation. With very few exceptions, the introduction of novel foods, or of novel varieties of old foods, has been achieved without serious food safety problems. Nevertheless, there are two potential food safety hazards that might arise in applying genetic modification to food organisms. Firstly the act of genetic modification, per se, might introduce risks by interrupting existing coding sequences, for example responsible for natural detoxifying reactions.
Secondly, genetic modification might, through its intended effects, introduce a hazard. The new gene product might pose a direct risk to consumer safety by, for example increasing toxicity, decreasing nutritional value, or enhancing pathogenicity.

Process: gene interruption
In eukaryotes (organisms containing a true nucleus with a well defined membrane surrounding the nucleus), the statistical probability of gene interruption events occurring during a genetic modification procedure is small. This is due to the fact that usually a single modification is being made to a genome which is largely not coding for gene products. It is even smaller than in traditional breeding where more genetic material is being included. Any risks from such events occurring through traditional breeding are reduced to acceptable levels through selection based largely on agronomic characteristics. It is anticipated that in the unlikely event of something unexpected occurring, it would be readily revealed through phenotypic and genotypic properties. This also holds true for genetic modification.
In prokaryotes (bacteria and certain algae, whose nucleus is not surrounded by a nuclear membrane), little of the genome is non-coding, and the statistical probability of insertion into a coding sequence is much higher than for eukaryotes. However, the site of the modification and the function of the DNA around the modification site will usually be well characterized. In this way it might be possible to predict whether adverse effects will arise from the modification, and to eliminate organisms where there is a possible food safety risk.

Product: unintended effects
Possible food safety risks from effects of new gene products, or from altered levels of existing gene products, include the gene product acting as a substrate for toxin-producing pathways latent in the organism or inhibiting natural detoxifying mechanisms. In the case of conventional food organisms such risks are managed by strain or variety selection and except for a few cases such as the intentional production of hormones, there is no reason to suppose that the risks will be higher with recombinant organisms. Reassurance also comes from long familiarity with many food organisms.
Other potential risks from genetically modified food organisms are those from the new gene and its gene product. Risks from the new gene, per se, can be discounted since new genes are composed of the same building blocks as the organisms’ existing genes. In assessing the food safety implications of new gene products, or altered levels of existing gene products, existing safety information on the gene product as well as information on its levels in the food generally consumed, will be important. It may be necessary to generate new data, using either the novel food or the gene product itself.

International safety evaluation guidelines
The potential of genetic modification in the development of novel food organisms has led several countries to consider whether there is a need to evaluate the safety of such foods prior to marketing. In some countries, notably the USA, it is felt that genetic modification is only an extension of traditional procedures for strain improvement. Therefore, the same lack of a formal review process is acceptable for foods obtained using genetic modification. In Europe, however, and to some extent in parts of Asia, safety review is regarded as necessary for foods obtained from organisms developed using recombinant DNA techniques. This view stems from a number of factors including a growing consumer interest in food safety issues, the fact that novel foods may be consumed at much higher levels than food additives (which are being reviewed) and apprehension about the application of new technology in food production and processing in general.

CAC
The Codex Alimentarius Commission (CAC) was established in 1962 to implement the joint Food Standards Programme of the UN Food and Agriculture Organization (FAO) and the World Health Organization (WHO). The purpose of the programme is to protect the health of consumers, to ensure fair practices in the food trade, and to promote the coordination of all food standards work undertaken by international governmental and non-governmental organizations. Codex standards, recommendations and guidelines have assumed new importance as a result of the completion of the General Agreement on Tariffs and Trade Uruguay Round as they will be the basis for the resolution of any trade disputes.
The CAC has announced that it intends to develop international guidelines for the safety assessment of food produced by modern biotechnology. The development of such guidelines is intended to minimize potential barriers to trade in biotechnologically produced foods which might otherwise arise from the application of different safety assessment procedures in different countries. Some of the international initiatives which should pave the way for the development of Codex guidelines are described below.

Other initiatives
Only in the late 1980s did modern biotechnology start to be applied to food production and processing. Few products, apart from some food additives, were close to commercialization, although the potential for novel products had been recognized. FAO and WHO convened a consultation meeting on the use of biotechnology in food production and processing as related to food safety in Geneva in 1990. The consultation concluded that there was no reason to assume that foods produced by modern biotechnology are inherently less safe than those produced by other technologies. Nevertheless, it was concluded that this needs to be demonstrated through evaluations comparing them to conventional foods, covering both safety and nutritional value.
Also in 1990, the Group of National Experts on Safety in Biotechnology, established by the Committee for Science and Technology Policy of the Organisation for Economic Cooperation and Development (OECD), agreed to set up a food safety working group to give priority attention to the elaboration of scientific principles for assessing the safety of novel foods or food components produced by means of biotechnology. In line with the outcome of the FAO/WHO consultation, this working group concluded that the most practical approach to determine the safety of foods and food components developed through the application of modern biotechnology is to consider whether they are substantially equivalent to analogous conventional foods where such exist. Account should be taken of the way in which the food would be processed as well as the intended uses and intakes. This approach provided a basis for an evaluation of both safety and nutritional value.

Safety of marker gene products
The safety of some of the marker genes used in modern biotechnology has received considerable attention. These genes are inserted into the GMO as part of the modification in order to facilitate identification of the GMO from amongst the many unmodified organisms produced in attempts at genetic modification. They serve no practical function in the food organism once selection of the GMO has taken place. The WHO convened a workshop on the health aspects of marker genes in genetically modified plants in Copenhagen in 1993. Here it was concluded that: there is a need for marker genes in plant biotechnology and it is impractical at the present time to remove them from modified plants after they have fulfilled their function;  the presence of marker genes per se in food plants is not a safety concern; in judging the safety of the expressed proteins the assessment should focus on the function of the protein rather than its structure since there is no reason to suppose that marker gene proteins pose a greater allergenic concern than other expressed proteins; and there are no characteristics of marker genes or their products that suggest that their site of insertion into the plant genome will give rise to additional secondary and/or pleiotropic effects. The Workshop also concluded that there is no recorded evidence of the transfer of genes from plants to micro-organisms in the human gut. However, if it did occur, health concerns would depend on a number of factors including the ability of any transformed micro-organisms to replicate in the gut and to express the gene product. Unless the gene was under the control of a bacterial promoter there was no mechanism for its expression in gut bacteria.
As these examples show, there has already been a considerable amount of work at the international level aimed at developing a consensus on how to assess the safety of genetically modified genes and their products. Although much of this work has been oriented towards plants, many of the principles are also valid for micro-organisms and animals.
D. Jonas*/F. Käferstein**

 * Independent consultant, Wayborough Bungalow, Wayborough Hill, Minster, Ramsgate, Kent CT12 4HR, United Kingdom. Phone/Fax (+44) 1843 821745

** Chief Food Safety Unit, World Health Organization, CH-1211 Geneva 27, Switzerland.
Phone (+41) 22 7912111; Fax (+41) 22 7910746; E-mail kafersteinf@who.ch

Sources
Safety evaluation of foods derived by modern biotechnology. Concepts and principles (1993). Paris: Organisation for Economic Cooperation and Development.

Several reports of the World Health Organization, Geneva.