I. INTRODUCTION 1. The first foods and food ingredients developed through recombinant DNA technologies have reached commercialization and more are nearing commercial distribution. In response to these developments, Member States of the Codex Alimentarius Commission (the Codex) are evaluating questions regarding appropriate labeling for these products.
Delegates to a recent meeting of the Codex Committee on Food Labeling (CCFL) agreed that this issue should be addressed, and the US Delegation to the Committee offered to draft a discussion paper on labeling issues. The discussion paper prepared by the US Delegation to the Codex Committee on Food Labeling presents a highly unbalanced view of the labeling issue that greatly favors the interests of the biotechnology industry at the expense of the broader interests of private citizens and consumers. The rationale presented in the discussion paper relies heavily on arguments that are scientifically untenable. After receiving comments on this discussion paper from a large number of organizations within the US and around the world, the US Delegation released their own comments on the discussion paper.
These comments did not incorporate any of the significant and valid comments submitted by other organizations, but merely reiterate and defend the position of the original discussion paper. In the interest of presenting a broader perspective on the labeling issue, we have prepared the following paper. This paper addresses, point by point, the issues raised in the paper prepared by the US Delegation to the CCFL, but strives to present a more balanced view of the labeling issue, one that respects and reflects the needs and concerns of a broader spectrum of the stake holders in this issue. This paper also strives to base all assessments of potential labeling policies on rigorous scientific principles and research observations. The points contained in this paper are numbered to correspond to the US Delegation's discussion paper in order to facilitate comparison of these documents. The central conclusion that emerges from this analysis is that mandatory labeling of genetically engineered foods, food constituents, and food additives is, in the long run, good for everyone, consumers and the biotech industry alike.
Labeling provides consumers with knowledge upon which to base rational choices regarding the foods they eat, and labeling provides the industry and regulators with a safety net that will allow them to quickly trace problems that arise with genetically engineered foods, thereby minimizing liability. Moreover, in the long run, if genetically engineered foods offer in practice the benefits that industry in visions, the label will become a sign of quality, which will allow industry to demand a premium for these products. 2. The term biotechnology refers to the technical use of biological processes to produce products. It is a broad term that encompasses many methods of genetic modification, including but not limited to cross-hybridization, mutagenesis, cell culture, and recombinant DNA techniques. Much of the discussion about appropriate labeling of foods and food ingredients and additives produced by biotechnology has focused on foods produced using recombinant DNA techniques.
3. Recombinant DNA techniques involve the isolation and subsequent introduction of discrete DNA segments containing the gene (s) of interest into recipient (host) organisms. The DNA segments can come from any organism (plants, animals, or microbes). In theory, essentially any trait whose gene has been identified can be introduced into any food source organism. Those who wish to minimize to the public the revolutionary nature of recombinant DNA techniques generally claim that they are a part of a continuum of methods that can be used to bring about genetic improvements in food source organisms. On this basis, they argue that it would be inappropriate to subject genetically engineered foods to additional regulatory scrutiny or to require these foods to be labeled as genetically engineered.
However, a systematic and scientific comparison of recombinant DNA technologies and other methods makes it clear that they are not part of a continuum. It is true that the goals of recombinant DNA methodologies are the same as those of traditional breeding methods, namely, the development of new varieties of food source organisms with improved characteristics. However, recombinant DNA techniques stand by themselves as a distinct and revolutionary technology for accomplishing these goals. Traditional breeding methods are designed to select preexisting genetic traits from the gene pool of a species or closely related species.
No new information is actually created in these processes. Instead, genes already existing in the gene pool of a species and its close, reproductively compatible relatives are merely brought together within the same individual. In contrast, genetic engineering alters the information content of the gene pool of a species. This is accomplished either by adding to the gene pool new genes, often derived from a widely divergent species, or by altering the information content of genes already in the gene pool. Through this powerful technology, genetic information can be transferred between species that would never exchange information under natural conditions or under traditional breeding regimes. For instance, recombinant DNA methods have made it possible to transfer the gene encoding the flounder antifreeze protein into tomatoes, in hopes of increasing resistance to freezing.
Natural genetic and reproductive boundaries normally prevent such exchanges, and even prevent crosses between close relatives such as the tomato, the potato, and the eggplant. Like traditional breeding methods, the other methods listed in the US Discussion Paper-cross-hybridization, embryo rescue, and soma clonal variation-do not involve the introduction of new genetic information into the gene pool of the food-producing organism. The first of these is a variation on traditional breeding methods, the second is a cell culture-based method for generating many genetically identical plants from a single elite specimen, and the third is a variation on this approach. Because recombinant DNA techniques introduce new genetic information into the gene pool, they do not exist on a continuum with these other methods but are of a distinctly different character and should be treated separately. 4. The biotechnology industry, research scientists, consumers and the public media frequently refer to the applied use of recombinant DNA techniques as genetic engineering.
For instance, one of the trade journals for the biotechnology industry is titled Genetic Engineering News. For this discussion, foods, food ingredients, and additives produced through recombinant DNA technologies will be referred to as 'genetically engineered,' 'recombinant,' or 'transgenic' foods. 5. Appropriate, consistent labeling of foods, food ingredients or additives produced through biotechnology, regardless of the methodology employed, will be important to Member States of the Codex for several reasons. The first of these is to protect the health of the public. The second is to provide the public with adequate information regarding their food supply.
The third is to create harmony and eliminate barriers to commercial distribution of genetically engineered foods. Appropriate labeling is also essential to ensure that consumers understand the attributes of the products they purchase. This allows them to make knowledgeable decisions regarding the potential impact of specific food products on their health. Although there are mechanisms other than labeling by which consumers can be informed and educated about genetically engineered foods, labeling is by far the most straight forward, certain, and economical method for informing the consumer that a certain food or food product has been produced through genetic engineering. II. NEW DEVELOPMENTS 6.
Several foods and food ingredients or additives developed through modern biotechnology have been commercialized. For example, tomatoes with delayed ripening characteristics and virus resistant squash have been commercialized in the USA. Other examples are the recombinant enzymes, such as alpha-amylase and, derived from various genetically engineered microbes that have been commercialized for use in industrial processes. 7.
Agricultural products, including new varieties of fruits, vegetables, grains, and by-products such as vegetable oils derives from plants modified via recombinant DNA techniques are now being distributed, and a diversity of other genetically engineered foods are under development. By far the largest class of these, accounting for nearly 50% of all genetically engineered food products, are plants resistant to chemical herbicides and fungicides such as DDT and. Others have been designed to be resistant to insects (e. g.
Bacillus delta-endotoxin) or viruses (e. g. potato Y virus), and others have been engineered to alter food or food organism characteristics in commercially useful ways. Examples of this are the development of tomatoes, mentioned above, with delayed fruit softening (anti sense), and the development of canola high in stearic acid.
Work is beginning aimed at generating foods that might have health or nutritional benefits, such as reduced all erg eric potential (e. g. rice). 8. A number of plants have been modified to express copies of animal genes, for instance a flounder antifreeze gene has been introduced into a tomato plant. Other examples which are intended for more immediate commercialization are the introduction of human and animal cytosine genes into tobacco.
It is envisioned that these plants might be used as factories for the commercial production of these polypeptide hormones for sale as drugs. Applications of genetic engineering that introduce animal genes into plants raise ethical and religious concerns with certain segments of the population in that the use of foods, and possibly medicines, produced by such plants can be in conflict with culturally- religiously- and ethically-based dietary guidelines. The commercialization of foods and food ingredients derived from plants that carry animal genetic information has not yet commenced. However, this is inevitable within the next few years.
Thus, any adequate policy regarding the labeling of genetically engineered foods must take these organisms into account. This is especially the case for an international policy, since animal-plant transgenic's conflict with the dietary restrictions of at least 30% of the world population. 9. Animals modified by modern biotechnology are rapidly approaching commercial distribution.
Fish genetically engineered for rapid growth or cold tolerance are likely to be among the first such organisms brought to market. Animals genetically engineered for the commercial production of hormones are also under development, while drugs for human use produced in genetically engineered bacteria are already in widespread use (for instance recombinant human insulin). Drugs produced using similar technologies for use in animals are also commercially available at this time. For example, recombinant bovine growth hormone (rbGH), which is produced by fermentation in bacteria and administered to dairy cows to increase milk production, is used commercially in the USA. It should be noted that a number of harmful effects of this hormone have surfaced subsequent to its commercialization, which were not anticipated during development. In addition to increased mastitis and reduced reproductive success, in rbGH-tre a ted cows, farmers have found that the metabolic demands placed on the cows physiology by rbGH-accelerated milk production can, in conjunction with climactic and other stresses, lead to wasting and death.
In response to these problems, American farmers are already reducing their use of this product. Research has also indicated that milk from rbGH-treated cows is of reduced nutritional value and safety. It contains elevated levels of white blood cells (pus) and antibiotics (used in treating mastitis). Consequently, rbGH milk is currently under review by the CODEX Committee on Residues of Veterinary Drugs in Foods. Milk from rbGH-treated cows also contains increased levels of insulin growth factor (IGF 1), which has been implicated in breast and colon cancer. The emergence of these problems subsequent to commercialization serves as an example of the tendency, inherent in genetically engineered products, to manifest unanticipated problems or side-effects.
This tendency is central to the need for mandatory label in g of genetically engineered foods and food ingredients. 10. To date the plants, animals, and microbes described above are single gene modifications accomplished via recombinant DNA techniques. Plants and microbes modified through recombinant DNA techniques also frequently contain selectable or screen able marker genes linked to the gene of interest. III. PREVIOUS DISCUSSION ON BIOTECHNOLOGY BY THE CODEX 11.
The Codex previously discussed Implications of Biotechnology on International Food Stands and Codes of Practice (ALINORM 89/39). The Codex considered general principles for the safety assessment of foods and food ingredients and additives produced through modern biotechnology. Motivated primarily by industrial interests, the discussion paper attempted to establish the similarity of conventional breeding and recombinant DNA techniques. This paper argued that genetic change brought about through recombinant DNA techniques are precise and highly controlled because they introduce into the recipient organism only one or a few genes whose DNA sequences are well characterized. This claim is, in fact, misleading as is discussed below in Point #16.
The discussion paper also noted that ' (t) he nature of these new modifications will not differ fundamentally from changes accomplished by conventional means and can be assessed by standard molecular, chemical, and toxicological methods'. This is also a misleading overstatement, as is discussed in detail below in Points #20-23. 12. The discussion paper (ALINORM 89/39) noted further that successive improvements in production microorganisms and new plant varieties have not required changes in traditional names of foods and food ingredients and additives.
It as also noted that ' (F) rom the points of view of quality and identity, however, Codex may also have to give some consideration, in specific cases, as to whether genetically altered edible fruits, vegetables or animal products essentially retain the quality factors and composition of the original product, or whether this food represents a new product or a sub-species of the original food and would therefore warrant the use of a new common name. One approach to the mandatory labeling of genetically engineered foods would be to simply give them a variant on the existent common name in which the word 'recombinant' would precede the common name of the original food. For instance, genetically engineered soy beans would be given the common name 'recombinant soy beans.' IV. LABELING ISSUES FOR MODERN Biotechnology 3.
The use of modern methods of biotechnology to make genetic modifications in organisms that will be sources of foods and food ingredients has raised several questions regarding appropriate labeling of genetically engineered foods and food ingredients and additives. Note: in the US Discussion Paper, this passage contained the phrase 'specific and directed genetic modifications,' thereby implying a precision and control in the genetic engineering process and precise predictability of the outcome of genetic manipulations accomplished using recombinant DNA techniques. This implication is far from accurate, as discussed in detail in Point #16. (i) Mandatory Genetic Engineering Labeling 14. Many scientists, including physicians, biomedical researchers, and experts in nutrition, agriculture and recombinant DNA technology, as well as consumers and public interest groups have concluded on the basis of a comprehensive knowledge of recombinant DNA methods that labeling should be required to distinguish genetically engineered foods and food ingredients and additives from other products. Based on extensive and detailed knowledge of the principles and applied practices of recombinant DNA technology and based on broad knowledge of fundamental biochemical and cell biological principles, scientists conclude that genetic engineering techniques are, in fact, fundamentally different from traditional methods of genetic modification (see Point #3).
Many scientists also recognize that the use of genetic engineering to modify food-producing organisms carries with it the risk of generating unexpected and unintended adverse changes in the composition or characteristics of foods, food ingredients, and food additives, thereby causing some genetically engineered foods to be unsafe. They locate several sources of this risk, as discussed in detail below in Points #16-23. Furthermore, based on (1) full understanding of the principles and application of recombinant DNA techniques in the agricultural sector, (2) comprehensive understanding of the limitations inherent in the research methods available for safety testing, and (3) comprehensive understanding of the commercialization process, scientists have concluded that existing testing requirements are inadequate for detecting all potentially dangerous genetically engineered foods before they are placed on the market. Thus it is likely that some genetically engineered foods that pose significant health risks will not be identified before commercialization. Based on this fact, they reason that all foods and food ingredients derived from source organisms that have been developed via genetic engineering should be required to be labeled to disclose that information to consumers.
They rightfully conclude that such information is necessary to enable consumers to make informed purchasing decisions and to help researchers as ses s the long-term safety of these products. 15. National and regional laws may differ with respect to the information that is required to be disclosed on the label or in labeling. Some Member States have labeling laws that provide for full disclosure based on consumer demand for information, while others (e. g. , U.
S. A. ) have laws that prescribe specific information which is required for labeling. It should be pointed out that US regulations regarding labeling of genetically engineered foods are likely to undergo significant change in the coming years in response to valid concerns of the scientific community and consumers (see Points #36 and 37).
16. Towards the goal of minimizing regulation and avoiding the labeling of genetically engineered foods, the US regulatory agencies encouraged by the biotechnology industry, has posed two basic arguments against the mandatory labeling of genetically engineered foods. First, they claim that there is no scientific evidence that genetic engineering per se alters the composition or character of food and additives and ingredients in a uniform manner, and that genetically engineered foods do not exhibit attributes that distinguish them uniformly from foods and food ingredients developed through other methods. This argument misses the point of the US labeling law, which is discussed in detail in Points #36 and 37, below. Quite to the contrary, the following discussion makes it clear that genetically engineered foods do, as a class, possess unique characteristics that distinguish them from foods-producing organisms developed thorough other methods, that there is risk associated with that class of food-producing organisms, and that because of that risk genetically engineered foods should be labeled.
The second argument posed by regulators and the biotech industry against the mandatory labeling of genetically engineered foods, is that they do not present unique risks or hazards. There are some scientists who support this view. However, a more balanced view held by many scientists is that, although the kinds of damage expected from genetically engineered foods are not different from those caused by other foods (namely allergic reactions and toxic or irritant responses), genetically engineered foods constitute a unique source of health risk that can be linked to the method of production of these foods (genetic engineering). Since genetic engineering constitutes a unique source of risk in the food production process, it follows that foods produced using this technology should be labeled as such to alert the consumer to this risk.
The category of risk associated with genetically engineered foods derives from the fact that, although genetic engineers can cut and splice DNA molecules with base-pair precision in the test tube, when those altered DNA molecules are introduced into a living organism, the full range of their effects on the functioning of that organism cannot be predicted or known before commercialization. What this means is that, in addition to the changes in biological function intended by the genetic engineer, the introduced DNA may bring about other, unintended changes, some of which may be damaging to health. Because all possible harmful effects cannot be tested before such a genetically altered food is placed on the market, the possibility of harm resulting from consumption of that food cannot be excluded. This is a distinct class of risk which is directly associated with the process by which genetically engineered foods are produced. Thus, foods carrying this class of risk can be easily identified, based on the process by which they were developed-genetic engineering. In light of this, it is only fair that consumers be informed of this class of risks and thereby be allowed to exercise their own judgment as to whether or not to accept that risk.
In short, genetically engineered foods should be labeled as such. The Discussion Paper argues that the risk associated with genetically engineered foods is very small, and the US Comments reiterate this position. However, there is no scientific evidence that this is the case. If one holds to the standards of the science of risk assessment, the existing body of data allows one only to state that, for a given genetically engineered food, the risk is finite, but of unpredictable magnitude.
A real risk, especially one of unpredictable probability and severity, is something that people should know about. The US Discussion Paper also attempts to infer the safety of future transgenic foods from the properties of genetically engineered foods now on the market (see Point #16). This is also invalid, based on well established principles of the science of risk assessment. Even if such comparisons were valid, the handful of examples now available do not provide a sufficient database for such estimates; the diversity of possible genetic manipulations that could be carried out in the future, and the diversity of food-producing and gene-source organisms that could be employed in the genetic engineering of future foods is extremely large.
Current examples simply are representative of the range of possibilities that will emerge in the future. The basis of this unpredictability of the risk associated with genetically engineered foods can be traced to three things: (1) the fundamental nature of genetic information, (2) the tendency of recombinant DNA manipulations to induce mutations in the genome of the recipient organism, and (3) the complexity of the recipient organism. These are discussed in detail, below. Ambiguities of Genetic Information Genes contain two basic kinds of information, structural and regulatory information. Structural information specifies the amino acid sequence of proteins, and consists of the genetic code, which was elucidated in the 1960's. This code is, with a few exceptions, identical for all terrestrial organisms.
Thus, the structural information of a particular piece of genetic material is predictable. However, the story is quite different for regulatory information. Transcription, translation, replication, recombination, and other processes involving DNA and RNA are controlled by regulatory information encoded in nucleic acid (DNA and RNA) sequences. The regulatory 'code' is much more complex and diverse than the structural code.
Furthermore, it is different in different organisms, and is often different even in different cell types of the same organism. For instance, there are many examples in the molecular biological literature in which recombinant genes, characterized in one cell type, are expressed at 100- or even 1000-fold higher levels in another cell type from the same organism. Such differences cannot be predicted simply by knowing the nucleic acid sequence of a recombinant gene. The only way to know is to gather empirical information-to actually introduce the gene into the second cell type and examine the result. If this is the case for cells within a single organism, the level of unpredictability will certainly be as great or greater for cross-species transfers of the kind commonly carried out in agricultural genetic engineering.
The underlying mechanism involved in the 'reading' of regulatory information is well understood. Regulatory proteins exist in the cell, each of which is capable of scanning DNA (or RNA) molecules. Each can recognize and bind to a single, specific nucleic acid sequence. That binding reaction triggers biochemical events leading to modulation of a process such as transcription, translation, replication, recombination, etc. In any particular cell, a given sequence can influence one of these processes only if the protein that recognizes that sequence is also present. Since different regulatory proteins are present in different cell types and different species, a given DNA sequence will function as regulatory signal only in some cell types and some species, and not in others.
Our knowledge of the 'regulatory code' is extremely incomplete. Therefore we cannot examine the sequence of a nucleic acid molecule and predict its regulatory function in a given organism. Introducing DNA sequences that possess unanticipated regulatory activities into a food-producing organism could disrupt any of the cellular processes in which DNA or RNA participate, including replication, transcription, translation, recombination, transposition. Disruption of transcription or translation could alter the level of expression or the timing of the expression of any protein that is normally expressed in a food-producing organism.
This could alter the allergenicity or toxicity of the food derived from that organism, as described below, and could also alter its nutritional or other characteristics. Disruption or alteration of replication, recombination, or transposition mechanisms could, among other things, alter the plasticity or stability of the recipient organism's genome, leading to increased rates of mutagenesis and consequently a range of problems, as described below. Mutations through Recombinant DNA Manipulations The second source of unpredictability and uncertainty regarding the effects of recombinant DNA manipulations stems from the extremely crude nature of current gene transfer techniques. The genetic information introduced into the organism may be precisely defined in sequence, but it is inserted at random into the genome of the recipient organism. Each insertion al event is in fact a random mutagenic event. Stated another way, gene transfer as it is commonly done is a mutagenic process that can disrupt any of the processes in which DNA and RNA participate.
The site at which such alterations occur is random. Therefore, there is no way to predict which gene or regulatory processes will be altered as a result of gene transfer-induced mutagenesis. By inactivating or altering the expression of genes encoding enzymes that catalyze important biosynthetic processes, mutagenic events could alter the allergenicity of a food or make it toxic as described in detail below. These mutagenic events could also alter the nutritional qualities of a food. Mutagenic events could alter regulatory sequences present normally in the recipient organism's genome. This could give rise to the range of regulatory sequence-related problems described above.
It should be pointed out that this mutational process occurs, not just sometimes, but every time a recombinant gene is inserted into the genome of an organism. Each such insertion al event disrupts some genetic locus. Many such disruptions will, fortunately, be silent or inconsequential. However, there is a finite chance that one of these will alter the structure or function of the organism in a manner that is significant to the properties of the foodstuff that is derived from it. That is, such mutations have a finite probability of altering the properties of a food so that it might become hazardous to health. In most cases, the procedures used in modification of food-producing organisms insert, not one, but several copies of a gene into the genome of the recipient organism.
Thus, multiple random mutagenic events occur, greatly increasing the probability of damaging a gene that influences the food characteristics of the organism. The risks related to manipulating the genomes of food-producing organisms are inherent in the mechanisms by which recombinant DNA techniques bring about genetic change. These risks cannot be discounted by pointing to the FlaverSaver tomato and saying that there have been no problems with it and therefore other transgenic's will probably be safe. Each transgenic food-producing organism will undergo different mutagenic events, and respond to the genetic information introduced into it differently, leading to the range of unexpected alterations described above.
Therefore there is no valid way of extrapolating from the characteristics of a particular genetically altered food to any other, as the US Discussion Paper attempts to do in Point #16. Biological complexity leads to the inability to predict the effects of recombinant DNA manipulations. A third contributor to the unpredictability of genetic engineering is the complexity of the recipient organism. The structures and functions of even the simplest single-celled microorganism are sufficiently complex that developers cannot take all components of the system into account when they consider the impact of a given genetic alteration. In such a situation, surprises are inevitable, and many of those surprises will not be advantageous. The discussions of mechanisms by which genetic manipulations can lead to increased allergenicity and toxicity, described in the following paragraphs, provide striking examples of such surprises.
17. Traditional methods of genetic improvement of plants, animals, or microbes as sources of foods and food ingredients or additives have not been considered to be information that must be disclosed on the label or in labeling (See PREVIOUS DISCUSSION ON BIOTECHNOLOGY BY THE CODEX above). This is appropriate because, as discussed in detail in Point #3, these methods do not generate new genetic information, but only select pre-existing genes from the gene pool of the food-producing organism. Labeling is not required because application of these methods is not associated with potentially large, unpredictable, harmful effects, as is the case with the use of recombinant DNA techniques. At present additives produced by fermentation by a microbe modified by chemical genesis are not required to be disclosed in labeling in the US. Such manipulations involve essentially the same risks as recombinant DNA techniques and in fact can be considered the primitive precursors to recombinant DNA technology.
Thus, it would seem more appropriate to handle the labeling of food products generated using such organisms in a manner similar to that of recombinant organisms. 18. The scientific community has embraced the use of genetic engineering methods for research purposes. However, uneasiness regarding the use of genetic engineering in food production is to be found in citizens from a wide range of backgrounds.
Within this population are many with strong scientific training, and even more with a strong layman's grasp of this technology. At present, this uneasiness is appropriate, since it is clear that there are risks associated with genetically engineered foods. Yet there is not sufficient experience with this technology to allow quantization of those risks. Labeling is of utmost importance in this situation, for several reasons.
First, it informs the consumer of the, yet unquantifiable risk associated with genetically engineered foods. Second, it facilitates the identification of the source, if it turns out that a particular genetically engineered food is harmful. Third, firms using genetic engineering have an interest in educating the public about the products that they produce to ensure consumer confidence, and labeling of genetically engineered foods serves as a very useful, effective, and economical educational tool: When consumers experience satisfaction with initial genetically engineered food purchases, confidence in these new products will grow. Through this mechanism, labeling could, in the final analysis, become high y advantageous to the biotechnology industry.
The current, ill-advised strategy of the biotechnology industry for dealing with the uneasiness of consumers regarding genetically engineered foods has been to attempt to block consumer's direct and convenient access to knowledge of whether a given food or food ingredient is genetically engineered. This approach, not only attempts to deprive consumers of knowledge that may be important for their health and safety, but also is, in the long run, highly counter productive to the interests of the biotechnology industry itself. Adoption of this strategy creates the impression that the industry lacks confidence in its own products, that the industry has something to hide. This obviously does not enhance consumer confidence in genetically engineered foods. 19. If mandatory labeling of genetically engineered foods is not mandated, it is inevitable that voluntary labeling of non-genetically engineered foods will be occur.
This is because there is, and will continue to be, a substantial demand for foods that have not been genetically engineered. Although the biotechnology industry may wish to suppress such markets by lobbying for regulations that prevent reverse labeling, such strategies are bound to fail as they already have in the US, where consumer pressure overturned attempts to prevent farmers and distributors from labeling milk as rbGH free. (ii) Safety Concerns about Allergenicity 20-22. Well qualified scientists, having extensive knowledge of molecular biology, immunology, and biochemistry, and thorough knowledge of the principles and procedures of recombinant DNA technology have identified a number of mechanisms by which allergens could be expressed in food and food ingredients through genetic engineering. They have also identified a number of molecular mechanisms through which the genetic manipulation of food producing organisms could generate new allergens or increase the allergenicity of proteins normally present in food producing organisms. These scientists, as well as consumers, point out that, without labeling of genetically engineered foods, it will be impossible for consumers to distinguish potentially allergenic genetically engineered foods from the corresponding traditional varieties and it will be much more difficult to trace problems that might arise.
At present, empirical evidence regarding the generation of allergenic foods through genetic engineering is sparse, since few of the genetically engineered foods now under development have been thoroughly tested for allergenicity. However, one example has already come to light: Pioneer Hybrid has developed soybeans with nutritionally balanced amino acid composition. They accomplished this by genetically engineering the beans' DNA to contain the gene for a brazil nut storage protein. However, these soybeans unexpectedly turned out to be allergenic to a significant proportion of the population. Thus, Pioneer Hybrid wisely decided to terminate plans to commercialize this product. Although there is limited empirical evidence regarding potential allergenicity of recombinant foods, evidence based on knowledge of the mechanics of recombinant DNA manipulations and on fundamental principles of immunology, biochemistry, cell biology, molecular biology, and physiology is compelling.
The paragraphs below clearly define molecular mechanisms by which allergenic proteins, and thus allergenic foods, can be generated using recombinant DNA methods. Based on these mechanisms, there exists a finite probability that genetic manipulations will generate allergenic foods. This probability is small but it is a very real one. The following are the most obvious mechanisms by which the use of recombinant DNA techniques could generate new food allergens: (1) It is known that many foods contain components that are low level allergens or immune-irritants.
At these low levels they produce negligible or minor problems. As discussed earlier, when recombinant DNA techniques are used to introduce new genes into a food producing organism, those manipulations can inadvertently alter the levels of proteins that are normally present in that organism. If the level of a weak allergen or immune-irritant increases substantially, it may reach concentrations within the food or food ingredient that could induce serious allergenic responses. If genetic material used in the development of a genetically engineered food producing organism is derived from a source that is known to commonly cause food allergic reactions, the genetically engineered organism containing that protein should be assumed to be allergenic unless scientific evidence demonstrates that this is not the case.
If it cannot be demonstrated that the transferred protein is not an allergen, it is obvious that it is necessary to label the genetically engineered food to alert sensitive consumers. In cases where the allergic reaction might be life threatening, the genetically engineered food should not be introduced into the market place. (2) Many of the recombinant proteins that will be expressed in food producing organisms are proteins that are not normally present in the food supply. Thus their potential allergenicity is unknown.
There is a reasonable probability that some of these proteins will be allergenic. It should be pointed out that because individuals will probably not have been previously sensitized to new allergens generated through recombinant DNA manipulations, they will probably not elicit a powerful allergenic response on first exposure. However, if such an allergen becomes a common component of the food supply, allergenicity will develop as exposure continues. It should also be pointed out that, since even trace amounts of some allergens are sufficient to induce powerful allergenic reactions, the fact that a genetically engineered substance may be present in only trace amounts does not necessarily eliminate the possibility that it could be allergenic. (3) Recombinant modifications could alter the primary or secondary structure of some proteins in such a way as to increase their allergenicity or cause them to become allergenic. Thus, even though a protein may be commonly present in food and not allergenic, when recombinant DNA techniques are used to alter the gene encoding that protein, the resultant recombinant protein could be allergenic.
(4) Many of the recombinant proteins introduced in food producing organisms will, in fact, be fusion proteins. That is, they will be proteins consisting of components derived from more than one protein. This is accomplished by using recombinant DNA techniques to fuse together pieces of the genes for two or more proteins. The potential allergenicity of fusion proteins cannot be deduced from the properties of the parental proteins from which they are derived, and thus cannot be predicted or modeled.
There is a significant probability that a given fusion protein will, in fact, be allergenic. The likelihood of generating allergenicity in fusion proteins is increased by the fact that the junctions at which two proteins are fused often assume secondary and tertiary structures that are not common in natural proteins, and are, therefore, more likely to be allergenic. (5) Even though recombinant proteins will often be expressed in food-producing organisms at low levels compared to the total protein content of a food, it is likely that even these levels will be substantially higher-orders of magnitude higher in some cases-than the naturally-occurring levels of those proteins. Thus, even if previous research fails to uncover evidence for allergenicity, a protein may behave as an allergen when expressed at higher levels through genetic engineering. (6) Different organisms possess different biochemical mechanisms for the processing of newly synthesized proteins.
Therefore, a recombinant protein may be processed differently in the genetically engineered recipient organism than it was in the organism from which the gene for that protein was isolated, and in which that protein is naturally expressed. These differences in processing could result in the transgenic form of the protein having different allergenic properties than the naturally occurring form. The risk that new allergens can be generated during the process of genetically engineering food-producing organisms leaves the developer of such organisms in a difficult position with regard to safety testing, because there is no adequate approach for generalized testing for potential allergenicity. In 1994, the US Food and Drug Administration, Environmental Protection Agency, and the Department of Agriculture hosted a 'Conference on Scientific Issues Related to Potential Allergenicity in Transgenic Food Crops.' The scientists selected by these agencies to attend this meeting and to advise them on the issue of allergenicity of genetically engineered foods indicated that it is likely that the use of recombinant DNA techniques in developing new crop varieties carries with it a significant possibility of generating unanticipated allergens. They further pointed out that this is quite problematic for safety testing.
While methods are available to assess whether a genetically engineered food contains hazardous amounts of known allergens, there are no direct or comprehensive methods for assessing the potential allergenicity of proteins derived from sources that are not known to produce food allergies. Scientists are reduced to comparing the general characteristics of such proteins to proteins that are known to cause allergic reactions, rating their similarities in terms of characteristics such as amino acid sequence, resistance to enzymatic or acidic degradation, heat stability, and molecular weight. These are of course extremely general characteristics and are unlikely to yield definitive information regarding the ability of a protein to elicit a biological reaction as complex as the immune response. Interestingly, the US Discussion Paper references this joint FDA, EPA, USDA sponsored meeting, but the conclusions found in the US Discussion Paper are contrary to the advice given by the agencies' own scientific advisors during that meeting. Whereas the scientists indicate that detection of novel allergens is problematic, the US Discussion Paper glosses over this point, implying that adequate methods for detecting such allergens are available. The lack of such methodology is a critical point, because it leaves the public vulnerable to novel allergens that have been inadvertently introduced into or generated in recombinant foods.
(iii) Safety of New Substances 23. Most substances that will occur in food and food ingredients as a result of genetic engineering will be proteins that will be present in foods in only trace concentrations. Never-the-less, it will still be necessary to label these foods and food ingredients as genetically engineered because the added components, in even trace amounts, may substantially alter either the nutritional or other biological characteristics of the food. Examples of this are presented above with regard to allergenicity. In addition to allergenicity, recombinant proteins could manifest a variety of other biological activities, and, in the case of recombinant enzymes, could catalyze the production of other compounds with biological activities not normally present in a particular food. For instance such substances could act as toxins, irritants, hormone mimetic's, etc.
, and could act at the biochemical, cellular, tissue, or organ levels to disrupt a range of physiological functions. An example of a class of genetically engineered foods that are of particular concern are those that have been modified to produce biological control agents, such as the insecticide Bt toxin. Bt toxin is considered specific for insects, and, has not been reported to be toxic to consumers when used topically, as has been done for many years in organic farming. However, it would not be surprising if a compound, such as Bt toxin, that has powerful biological activity in one class of organisms would still have some biological activity even in a distant phylum, which might become apparent if consumed in larger amounts. Normally when used topically Bt toxin is degraded to undetectable levels in just a few days. However, Bt-engineered plants produce this toxin continually, resulting in much higher stable levels.
Furthermore, the toxin will be present, not only on the surface of the plant but internally, where it may be protected from degradation and accumulated. The result is that consumers of these foods will consume much larger amounts of Bt toxin than is the case with plants treated topically. Consequently, the excellent safety record of topically applied Bt toxin does not constitute reliable evidence indicating that foods derived from plants genetically engineered to produce Bt toxin will be safe. Some of the potential biological characteristics of genetically engineered proteins or their metabolites can be assessed. However others cannot, and by the very diversity of possible effects and the complexity of the physiology, it is impossible to carry out scientific experiments that will exhaustively, thoroughly, and conclusively establish that a genetically engineered food is free of such toxins, and therefore safe, before it goes to market.
In all cases, a finite probability will remain that some toxin or other biologically active molecule has been generated in the recombinant food for which no adequate test is available. There is always an appreciable probability that the toxic properties of a certain genetically engineered food will simply not be detected in the laboratory tests carried out. Because this probability exists, there will always be a real possibility that a given recombinant food might cause harm to consumers, or at least to a subset of consumer, once that food is placed on the market. One instance that may be an example of this has already come to light. Although there is controversy regarding details, the Japanese company Showa Denk o genetically engineered a microorganism to produce tryptophan at high levels.
The enzymes expressed in this bacterium through genetic manipulations were not present in massive amounts, but they altered the cellular metabolism substantially, leading to greatly increased production of tryptophan. Many scientists suspect that these genetic manipulations also led to the production of traces of a compound formed by of tryptophan or its precursors. This compound was highly toxic, killing 37 people and causing permanent damage to 1500 more. Here, traces of a recombinant enzyme complex is likely to have led to the production of traces of a toxic substance that actually killed people. The organism was 'substantially' identical to the parental organism, and the product was 'substantially' identical to other tryptophan products, being 98. 5% pure tryptophan, but the trace constituents made all the difference.
It must be emphasized that, based on existing evidence, the magnitude of the risk associated with genetically engineered food-producing organisms is not quantifiable. Therefore there is no scientifically valid basis for arguing that this risk does not constitute valid grounds upon which to require labeling. That could only be the case if empirical evidence were available that positively demonstrated that this risk was negligible. Negative evidence is not adequate. That is, it is not valid to state that, since no problems have been reported with the few recombinant foods marketed to date, the risk must be small. In some cases, a food or food ingredient will contain a new substance that significantly alters the attributes of the product, such that the traditional name does not adequately describe it.
In such cases, in addition to being labeled as genetically engineered, it is recommended that a new common or usual name be applied to the product. For example a genetic modification could introduce a major new sweetener into a food substantially altering its composition. (iv) Ethical or Religious Concern 24. Both consumers and the biotechnology industry recognize that the transfer of genetic material / information from humans or other animals to food producing organisms will violate vegetarian, ethical, and religious beliefs of certain segments of the population. From the point of view of modern molecular biology and biochemistry, the essential component involved in such animal-plant transfers is not the material of the DNA molecule, because, of course, that material is identical in both plants and animals. The essential component is genetic information.
The biotechnology industry and regulatory bodies have attempted to skirt this issue by arguing that the recombinant gene put in the food or food ingredient is not animal material but is a copy of a gene from an animal source, claiming that no animal material has been introduced into the food. The superficial nature of this argument is obvious. It is little more than a play on words. Industrial voices elaborate on this argument stating that, indeed, many genes are common to plants, animals, and microbes, and therefore there is no real distinction between animal and plant genes. For instance they would say that both animals and plants have genes for the enzyme. This view exposes a superficial appreciation and understanding of the actual molecular biological facts.
Although genes for proteins that are common to both plants and animals are related, there are significant differences the information contained in those genes. That is, the cow gene is different from the tomato gene in information content. Therefore, the structures and functions of cow and tomato differ, as well. The fact that a change in the information content of a gene translates into a change in the function of the enzyme encoded by that gene implies that a change in genetic information, brought about through recombinant DNA manipulations, has material consequences. It should also be pointed out that, in general genes common to a wide variety of species are not the focus of agricultural genetic engineering. Instead, there is far more commercial interest in using genetic engineering to confer on a species new characteristics by transferring to it genes that are unique to some other species.
Transfer of genes that are highly similar to genes naturally present in an organism is in most cases of little commercial value. Thus, it is scientifically untenable to claim, as the biotechnology industry and regulatory agencies wish to do, that the rabbit gene is no longer a rabbit gene once it is introduced into a tomato plant. No matter how many generations the rabbit gene is propagated in tomatoes, the gene still corresponds in information content to the rabbit gene, and the catalytic and kinetic properties of the enzyme still correspond to those of rabbit, and not tomato. It may not be rabbit material, but it is still rabbit information.
We conclude that the arguments raised in the US Discussion Paper are not based on scientific fact. More to the point, purely scientific grounds are not even relevant to the issue of ethically and religiously based choices in food consumption. 25. It would be more convenient for regulators and it would seem more profitable for the biotechnology industry if arguments such as those discussed in Point #24 succeeded in explaining away the ethical and religious concerns of certain segments of the population.
However, attempts to do this will inevitably fail for the reasons discussed above. Moreover, because these arguments are transparently self-serving in their misuse of scientific argument, their use will inevitably bring into question the credibility of both regulatory agencies and the biotechnology industry. This in turn is likely to reduce the profitability of the agricultural biotechnology industry. Setting aside arguments such as those discussed in Point #24, it is a simple fact that there exists a growing segment of the population that has ethical or religious beliefs that classify genetically engineered plants carrying animal or human genes as being unacceptable as foods. This situation is not the result of misunderstanding of the nature of recombinant DNA manipulations or of ignorance of the principles of modern biology. By and large, the segment of the population holding these beliefs is among the best educated.
Lack of understanding of the technology cannot be used as an excuse for discounting the concerns of this group. A labeling policy that does not sincerely take into account the ethical and religious concerns of this growing segment of the population will not induce these individuals to ignore their beliefs and purchase plant-animal recombinant foods. Instead such a policy will cause them to restrict their food purchases even more stringently, and to promote reverse labeling, both of which are likely to impact negatively on the market share of genetically engineered foods. On the other hand, if plant-animal recombinant's are labeled as recombinant and as containing animal genetic information, individuals whose dietary guidelines proscribe such foods will be able to avoid them in a product-specific manner, thereby minimizing the impact on the market and avoiding designating reverse-labeled non-genetically engineered foods as a premium product. Thus, operationally and economically, adequate labeling is likely to be the most effective way to deal with this issue. (v) Ingredient Labeling 26.
CODEX has established a set of uniformly applied principles regarding labeling of food and food ingredients and additives. These specify that all packaged foods should be labeled with a list of ingredients. The biotechnology industry has suggested that a gene or gene product that has been introduced into a food or food ingredient through genetic engineering need not be declared as an ingredient of the food product. The only argument that the industry has raised to support this proposal is based on an inadequate or erroneous understanding of the principles and practices of recombinant DNA technology and of traditional breeding.
That argument is as follows: 'Various methods of plant breeding have introduced new genes and expression products into food crops. While such substances become components of the food, governments have not previously considered food constituents of components as substances subject to ingredient labeling.' This argument is erroneous in that plant breeding methods do not introduce new genes into food crops. They simply select from the gene pool of the crop of interest certain characteristics that already exist within that gene pool. This is discussed in detail in Point #3. This is very different from the use of recombinant DNA technologies, which do introduce new genetic information into the gene pool of the food-producing organism of interest.
The following analogy makes this distinction clear: tomato paste prepared from two varieties of tomatoes would not require labeling other than 'tomato paste.' However, if a specific protein that had been isolated from a bacterium, for instance a thickening agent, were added to the tomato paste, it would be required to list that protein on the label. Traditional breeding methods are similar to the homogenization of two tomato varieties to make a single paste, whereas the use of recombinant DNA technologies in the preparation of a genetically engineered tomato is quite analogous to the introduction of a bacterial protein into tomato paste. On the basis of this example it is clear that genetically engineered genes and their expression products should be included in the list of ingredients of food products generated through genetic engineering. (vi) Industry concerns 27. Members of the food and agriculture industry have expressed concern that mandatory labeling of genetically engineered foods, food ingredients, and food additives will be perceived by consumers to be a warning statement and will, thereby, stigmatize genetically engineered products. Although this may occur in some early cases, as time goes on and the reputation of genetically engineered food products is demonstrated in the market place as being one of high quality, high nutrition, and safety, that same label will take on a very different signification.
In this eventuality, this label will become a sign of enhanced quality and value. To the public, the unwillingness of industry to accept labeling is a sign of lack of confidence in their own products and their own huge investment in genetic engineering. 28. Although special labeling for genetically engineered food and food ingredients will involve some increased expense in order to keep these separate from similar varieties produced via traditional means, this expense is necessary for safety reasons.
Clearly, the safety concerns associated with genetically engineered foods, discussed above, are sufficiently great to justify this measure. Ordinarily foods that are separately labeled differ in quality or characteristics. The characteristics of genetically engineered foods do differ from those of traditional varieties in that their consumption carries with it a higher level of health risk, as discussed above. Thus separation of genetically engineered and traditional food products is justified. The organic food industry has succeeded in developing and implementing world wide systems that allow them to keep products with characteristics no more obvious than those of genetically engineered foods separate from foods produced by other methods. Thus a model exists for implementing such measures with genetically engineered foods.
29. Even genetic manipulations aimed at modifying the agronomic characteristics of a food producing organism may inadvertently alter other characteristics of that food or food ingredient, as discussed in detail above. In particular these manipulations may alter the impact of that food on the health of the consumer. Thus, not only would seeds from such plants need to be labeled to alert farmers to their agronomic characteristics, but also food processors and distributors would need to segregate and label such foods for the health and safety of the consumer.
30. Members of the food industry claim that separating foods that they consider 'essentially identical' would require development of new food distribution systems for each product class and would often cause major disruptions in existing national and global food distribution systems. They claim that in many cases, especially for commodity products such as grains, cereals and produce sold in bulk, the cost of such special distribution systems might exceed the value of the product. Thus, crops with attributes that may allow farmers to produce foods more economically would effectively be barred from use.
Critics of the biotechnology industry point out that it may be questionable as to whether this strategy is economically viable if the benefits that it offers are so marginal that they are obliterated by minor alterations in the distribution system. Again it should be pointed out that the organic food industry provides a clear cut successful model for separating genetically engineered from traditional foods. This system has been successful both economically and logistically. (vii) Enforcement 3 l. There are clear-cut safety and scientific reasons to enforce the segregation of genetically engineered foods and food additives from non-genetically engineered equivalents. In the past, it has been proposed that genetically engineered foods could be traced and detected, if developers were required to introduce a specific marker sequence into all recombinant food organisms, in addition to the genes of commercial interest.
However, a WHO-sponsored workshop ('Health aspects of marker genes in genetically modified plants,' WHO, l 993), concluded that such methods are not likely to work. Such methods are also unnecessary in light of well established molecular biological methodologies based on the polymerase chain reaction technique. These can be used to very specifically and precisely determine whether or not a given food is genetically engineered, given knowledge of the structures of recombinant genes introduced into the species of food-producing organism from which that food was derived. (viii) Voluntary labeling 32. If mandatory labeling of genetically engineered foods is not implemented, voluntary reverse labeling will inevitably be implemented at a grass roots level to satisfy demands of consumers to have adequate information regarding their food purchases. This was demonstrated in the US, where the biotechnology industry unsuccessfully attempted to block voluntary labeling of milk that was free of recombinant bovine growth hormone.
In the long run creating a situation where reverse labeling takes place will do far greater harm to the agricultural biotechnology industry than mandatory labeling of genetically engineered food products. V. CURRENT STATUS OF LABELING 33. Because the introduction of genetically engineered foods to the market is only in its beginning stages no member states have yet enacted legislation or mandatory regulations requiring the labeling of genetically engineered foods.
However guidelines and recommendations to that effect have been implemented in some member states and specific guidelines and regulations or legislation are under serious consideration in others. 34. The Food Advisory Committee (FAC), a non-statutory body appointed by the Minister of Agriculture, Fisheries and Food in the United Kingdom recommended proposed labeling guidance to the Food Minister following the FAC's review of comments received on a consultation paper on the subject, 'The Labeling of Foods Sourced from Genetically Modified Organisms; Revised Guidelines'. In November, l 993, The Food Minister announced the Government's proposal:' (I) t would be unrealistic to label every food whose product has involved genetic modification. It has however accepted that there should be provision for choice in relation to those foods which raise real concerns for a significant proportion of the population. It has therefore proposed that a GM (genetically modified) food should be labeled if it: contains a copy gene originally derived from a human; contains a copy gene originally derived from an animal which is the subject of religious dietary restrictions; oris plant or microbial material and containing a copy gene originally derived from an animal.
These rules would not apply if the inserted copy gene had been destroyed by processing and was not, therefore, present in the food' ('Ministry of Agriculture, Fisheries & Food News Release', 4 November l 993). 35. The European union is developing legislation that will establish regulations regarding novel foods and food ingredients. A central focus of these regulations is the labeling of genetically engineered food producing organisms as defined by directive 90/220/EEC.
However, these regulations do not apply to food additives, flavorings, extracts, solvents, and foods and food ingredients treated with ionizing radiation (14 Feb. 1994). 36. In the United States, the food labeling law (the Federal Food, Drug, and Cosmetic Act) requires that the labeling of a food or food ingredient or additive be truthful and not misleading and that the product be declared by its common or usual name. The labeling law also declares that labeling is misleading if it fails to reveal all facts that are 'material in light of representations or material with respect to consequences which may result from the use of ' the product.