Safety Issues Associated with Genetically Modified Foods

The main human health concerns associated with foods derived from recombinant-DNA plants variously referred to in this text as genetically modified (GM) foods, or foods derived from genetically engineered (GE) plants can be categorized into two: issues associated with the safety of the newly inserted DNA including possibility of horizontal transfer of these genes; and the impact of the product expressed by the inserted gene (typically a protein).

Questions have been raised in the public domain over the fate of the newly inserted DNA after it has been consumed by humans. For instance the possibility of transfer of the DNA from the food derived from genetically engineered plant into mammalian cells, gastrointestinal bacteria, or soil bacteria.

DNA is chemically identical regardless of its source i.e. the introduced DNA in a genetically modified organism is identical to any other DNA, regardless of which species the introduced DNA may have come from. The Food and Drugs Administration (FDA) considers all DNA from any source including genetically modified crops to be Generally Regarded as Safe (GRAS) (FDA, 2001). DNA is a completely natural and harmless component of most of the foods that we eat and is mostly degraded during industrial processing and in the gastrointestinal tract. Thus, whenever we eat those foods, we are eating the DNA that they contain.

The digestive system digests all DNA in exactly the same way whether the DNA is from GM food or conventional food. According to a report by the European Food Safety Authority (EFSA) on the fate of genes and proteins in food and feed, “After ingestion, a rapid degradation into short DNA or peptide fragments is observed in the gastro-intestinal tract of animals and humans and to date a large number of experimental studies with livestock have shown that rDNA fragments or proteins derived from GM plants have not been detected in tissues, fluids or edible products of farm animals” (EFSA, 2007). Therefore if one eats DNA in a GM food or a conventional food, it will not change their own DNA or that of their children.

1. Since food is derived from living organisms having genes, it follows that all food derived from these organisms contain DNA.
2. The daily intake of DNA by humans in the food they consume is estimated to be about 0.1-1.0 g (Flachowsky, 2007), of that even with a diet wholly composed of GM Food the transgenic DNA would < 0.0001% of the total DNA (Society of Toxicology, 2002).
3. A highly unlikely series of events would be required for this small fraction of rDNA to transfer to the mammalian or bacterial genome (WHO, 2000). The transgenic DNA would have to:
   • Survive harvest, drying, storage and milling
   • Survive food processing
   • Be present in the fraction of the plant that is consumed
   • Survive acidic pH and digestion by nuclease both in plant and in the mammalian gastrointestinal tract
   • Compete for uptake with a large excess of dietary DNA
   • Stably integrate into the host chromosome
   • Be incorporated into the host DNA and express in the new host

The other concern directly associated with inserted genes is the issue of genes that confer resistance to antibiotic or what are commonly referred to as antibiotic resistance marker (ARM) genes in GM foods. ARMs have been used in genetic engineering plant transformation processes and in some instances, the ARM genes remains in the finished product. There has been concern about the effect on human health and safety if genes present in GM foods were able to transfer to microorganisms in the human digestive tract. Of particular concern is the possibility that the genes conferring antibiotic resistance could transfer to disease-causing bacteria in the human digestive tract. If this were to happen, the concern is that it could adversely impact antimicrobial therapy. These concerns about ARMs are addressed below but the possibility of such transfer is low, and such furthermore such antibiotic resistance genes are already common in the microbes in the human gastrointestinal tract.

1. (i) Is the gene itself and the protein product produced harmful to humans or animals?

   ARM genes are not any different from other DNA present in plants and animals, and are digested and processed in the gastro intestinal tract just like DNA from any other source. In addition, ARMs are naturally present in the environment including gut bacteria (Jonas et al., 2001).

   When expressed in plant cells, the commonly used ARMs produce proteins that are digested in a similar way to other thousands of dietary proteins that humans consume everyday (Goldstein et al., 2005). The NPT II proteins, expressed by the npt IImarker gene for example are non-allergenic and non-toxic when consumed in foods in animal studies and in biotechnology pharmaceutical agents administered to human beings intravenously (Flavell et al., 1992; Fuchs et al., 1993). In addition, ARM proteins are frequently produced by human intestinal bacteria and thus humans have been exposed to these proteins throughout history. Thus it can be reasonably concluded that ARM genes themselves and the proteins they express, as with other genes and proteins in foods and feed do not pose risks to the health of humans or animals.

2. (ii) Can ARM genes transfer into bacteria and adversely impact antimicrobial therapy?

   The possibility of transferring antibiotic resistance from genetically engineered plants and food derived from them to bacteria that are naturally found in the gut of humans and animals and therefore compromising the effectiveness of antibiotics has been raised. Gene flow amongst bacteria is a well established natural process that occurs in nature (Davison, 1999). In the same vein it is theoretically possible for genes to be transferred from plant to bacteria but this would be an extremely rare occurrence. This is because for an ARM to transfer from plants to gut bacteria, the gene would have to be excised from the plant chromosome without being destroyed by cellular enzymes, survive intact in the gut environment, and be acquired in intact form by a transformation-competent bacterium (WHO, 2000; Jonas et al., 2001). Because all whole foods contain DNA, humans have been exposed to DNA from both plant and gut bacteria throughout evolutionary history and in spite of this there has been no evidence of regular incorporation of intact plant or bacterial genes into human cells (Goldstein et al., 2005).

3. (iii) Are the antibiotics important to human or animal medicine?

   It is important to note that antibiotic resistance genes currently present in GM foods code for resistance to antibiotics that are not widely used in human medicine, because resistance to them is already widespread. For example the npt II gene confers resistance to neomycin, kanamycin and other antibiotics that are not in clinical use any more, while aad-3 gene another ARM confers resistance to two-little used antibiotics, streptomycin and spectinomycin (Gilman et al., 1996). In the future, as genetic engineering techniques improve, antibiotic resistance genes will not be present in GM foods because they will either have been removed during development or have been replaced by other types of marker genes.

   In a recent publication, the European Food Safety Authority has reaffirmed that two antibiotic resistance marker genes, npt II and aadA, pose no threat to humans or the environment (EFSA, 2009).

Introducing a gene into an organism raises the possibility of the introduction of allergens leading to production of foods that can elicit allergenic reactions in humans. An estimated 3 to 4% of adults and up to 8% of children suffer from food allergies in developed countries (Kanny et al., 2000; Sicherer et al., 2004). It is estimated that 90% of the food allergies are associated with products derived from a few groups of foods including cow’s milk, eggs, fish, crustaceans, peanuts, tree nuts, soybeans, wheat and sesame seeds (FAO, 1995). Although allergies to other foods occur, they tend to be far less common.

Most foods do not cause allergenic reactions in most people, but for people who have any kind of food allergy, certain proteins in food can cause an unusual immune reaction. The proteins that provoke this reaction are known as allergens, and people with allergies generally react to just one or a few allergens in one or two specific foods. The exact site of food absorption and allergy induction is still unknown. It is believed that most food allergens are absorbed in the intestines, prior to initiating an immune response. For an immunological reaction to be triggered, allergenic proteins have to move through the stomach in an immunologically intact form. Food proteins can also be absorbed into the circulation system through the oral mucosa (Dirks et al., 2005; Untersmayr et al., 2007). The majority of ingested food proteins whether naturally present in the transgenic product or introduced through genetic engineering are extensively digested as they travel through the gastrointestinal tract and this renders the resulting peptides non-reactive for antigen recognition (York et al., 1999).

Nevertheless, since almost all allergens are proteins (Bush and Hefle, 1996), there exists a possibility that any novel food protein might be an allergen. If a conventional food that contains allergens is genetically engineered, the GM food may contain those allergens, just as the conventional food does. For example, soy naturally contains proteins that cause an allergic reaction in some people. Unless these specific proteins are removed, they will also be found in GM soy varieties. Similarly, unless their level is increased by the genetic procedures, the level of risk is altered. The possibility of introducing new proteins exhibiting allergenic properties is real but low because of the safety assessment procedures that foods derived from recombinant-DNA plants undergo. These safety assessment procedures conducted on the introduced gene and the protein expressed in the GM product are designed to identify potential allergenic effects that may be associated with the commercialized GM crop/food. In assessing the safety of a GM food, tests are carried out to ensure that the levels of naturally occurring allergens in GM foods have not significantly increased above the natural range in the conventional food and to ensure that the new proteins in GM foods are not likely to be allergenic.

Hence, it seems unlikely that an allergenic risk posed by a GM food is greater than that of conventional foods generated by traditional breeding methods that are not subjected to the same kind of stringent safety evaluation procedures. A good example is the common peanut which is generally considered a safe product but has a history of eliciting mild to severe allergenic reaction in a segment of the population that is sensitive, regardless of how it is produced.

All substances whether natural or human-made are potentially toxic depending on the dose received. However, substances classified as toxins are those that can be harmful to health at typical levels of exposure. Naturally occurring toxins are found in various foods, but the vast majority of these are present at concentrations well below the level that would harm the consumer. Some foods contain naturally occurring toxins that cause an adverse effect if the food is eaten in excessively high amounts e.g. cyanogenic glycosides in cassava. Other foods contain naturally occurring toxicants that elicit adverse reactions only if the food is prepared in a manner that allows for the retention of a toxicant that is normally destroyed e.g. lectins in kidney beans. Other foods may elicit deleterious effects on particular segments of the population that may be sensitive to a component in the food e.g. allergenic proteins in peanuts and soybeans. On the other hand food may become contaminated with naturally occurring toxicants produced by microorganisms e.g. botulinum toxin and aflatoxin (Taylor and Hefle, 2002). Thus, toxic substances are naturally present in many conventional foods that are subsequently genetically modified. Therefore unless any toxins present in a conventional food are specifically removed, they will remain in the GM version of the food.

For genetic engineered products the concern is the possibility of the genetic modification introducing a hitherto absent toxic substance for example a newly expressed protein or resulting into elevation of naturally occurring toxic substances. This is however precluded by the fact that as part of the safety assessment of GM foods, the levels of the naturally occurring toxins in the GM food are compared to those of the conventional food to ensure that the levels of the toxins are not elevated above their natural levels. Furthermore, the safety evaluation process requires the amino acid-sequence of a novel protein to be demonstrated not to be similar to known protein toxicants and that the protein is rapidly digested under simulated mammalian conditions. Animal bioassays are also conducted on individual proteins to reveal any potential toxicity.

The potential occurrence of ‘‘unintended effects’’ is another concern being raised regarding the application of recombinant DNA techniques in the production of foods. Unintended effects are defined as those consistent differences between the GM plant and its appropriate control line, which go beyond the primary expected effect(s) of introducing the target gene(s) (EFSA, 2006). It is important to note that unintended effects are not limited to GE crops, traditional breeders spend a considerable time in their breeding programs back crossing in an attempt to eliminate some of these undesirable characteristics (Rischer and Oksman-Caldentey, 2006). Unintended effects in modern biotechnology may arise due to the nature by which current rDNA techniques introduce genes into the plant. The genes may result in disruption of gene functions, causing changes in levels and activities of enzymes, nutrients and metabolites, or the altered production of proteins or toxins (Cellini et al., 2004). An unintended or unexpected effect does not necessarily imply a health hazard, although obviously the expression of a new trait would require thorough scrutiny to ensure that the safety of the new product is reasonably ensured before it is commercialized.

Over the years there have been documented cases where conventional plant breeding procedures have led to crops with unintended effects. For example, conventional breeding of potatoes to produce a variety with superior characteristics resulted in a variety, the Lenape variety, which had unintentionally high levels of glycoalkaloids (Beier, 1990), a class of naturally occurring toxicants typically found in low levels in commercial potato varieties (Zitnak and Johnston, 1970). On the other hand genetically engineered soybeans altered to produce enhanced levels of the amino acid lysine showed an unexpected decrease in oil content (FAO/WHO, 2000).

Recombinant DNA techniques can be considered to be more precise than conventional breeding methods because only known and precisely characterized genes are transferred (IM and NRC, 2004). In contrast conventional breeding involves transferring thousands of unknown genes with unknown function along with the desired genes. Traditional breeders observe off-types due to unintended effects regularly and they methodologically eliminate these plants through selection during the evaluation process and long before commercialization. The same scrutiny, if not more, is also applied to plants generated by rDNA techniques.

It is important to note that all foods whether derived from plants developed through conventional plant breeding or through genetic engineering, carry potential hazardous substances and must be properly and prudently assessed to ensure an acceptable degree of safety. Indeed because GM crops are regulated to a greater extent and subjected to more rigorous risk assessment procedures, than are conventionally bred, non-GM crops, it is more likely that traits with potentially hazardous characteristics will not go through early development phases (IM and NRC, 2004). Moreover, current methods are constantly being improved and new ones are being developed in an effort to improve the detection of unintended effects (Rischer and Oksman-Caldentey, 2006).

Predicting and assessing potential adverse health effects posed by foods modified by a number of methods, including genetic engineering, are challenging. Also, because any form of adverse effect developed during this modification is unintentional, they may be unexpected, which complicates matters further. Nonetheless bodies like Codex Alimentrius Commission (CAC), International Life Science Institute (ILSI), and the Organization of Economic Cooperation Development (OECD) have developed guidelines to be followed in the assessment of the safety of GM foods to be discussed in a different segment of the food safety section. Also to be discussed will be the safety assessment testing procedures and the interpretation of data generated to reasonably determine that the products developed by rDNA technology are at the very minimum as safe as their conventional counterparts.