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JOURNAL OF MEDICINAL FOOD
J Med Food 11 (4) 2008, 601–605
DOI: 10.1089/jmf.2008.0094

Perspective: The Problem with Nutritionally Enhanced Plants David R. Schubert Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California

ABSTRACT

Among the next generation of genetically modified (GM) plants are those that are engineered to produce elevated levels of nutritional molecules such as vitamins, omega-3 fatty acids, and amino acids. Based upon the U.S. current regulatory scheme, the plants and their products may enter our food supply without any required safety testing. The potential risks of this type of GM plant are discussed in the context of human health, and it is argued that there should be very careful safety testing of plants designed to produce biologically active molecules before they are commercially grown and consumed. This will require a mandatory, scientifically rigorous review process.

INTRODUCTION

The evolution of genetically modified (GM) plant production is in a new phase that could have serious health consequences if the biology of these plants and their interaction with the consumer are not better understood.

Currently the only widely planted GM crops are those engineered for insect and herbicide resistance, but there has been interest in marketing plant-based pharmaceuticals as well as nutritionally enhanced plants (NEPs), such as those producing vitamins and other food supplements. The best known example of a NEP is golden rice, which is engineered for the overproduction of beta-carotene, the precursor to retinol (vitamin A), but not yet commercialized. Other examples include plants enriched in vitamin E2,3 or omega-3 fatty acids.

Protein-based pharmaceuticals meeting Food and Drug Administration (FDA) clinical standards have been difficult to produce in plants in their native form, in part because secondary modifications, such as glycosylation, are quite distinct from those made by mammalian cells and can contribute to the proteins’ immunogenicity. In contrast to protein-based pharmaceuticals, most NEPs only necessitate the manipulation of small molecule metabolism and will, based upon current GM crop regulation, likely be viewed by U.S. government agencies as generally recognized as safe (GRAS), thereby not requiring any mandatory safety testing.

Substances produced in plants by GM technology are regulated by the food additives provision of the Federal Food, Drug and Cosmetic Act. Food additives are required to undergo extensive premarket safety testing, including long-term animal testing.

However, testing is not required for foods that are generally recognized as safe by the FDA. Furthermore, it is largely up to the producer to decide whether or not the GM product and the plant that produces it are exempt from testing. To date, the FDA has not disallowed a single favorable biotech industry safety determination in over 100 completed applications. Since a number of plants with altered small molecule metabolism, such as those producing high oleic acid, have already passed FDA’s voluntary biotechnology review, it is very likely that the FDA will accept this designation from other NEP producers. The FDA, however, has the authority to require the full testing protocol for food additives if there is evidence of possible harm.

While there has been an extensive discussion of the problems associated with aberrant secondary modifications of mammalian proteins expressed in plants, there has been no discussion about the potential harmful side effects of producing large amounts of biologically active compounds in plant hosts that have an enormous repertoire of enzymes capable of modifying small molecules in an unpredictable manner. For example, with golden rice there has been concern about beta-carotene absorption, but none about the potential for teratogenesis. Indeed, in a recent article in Science on golden rice, there was no discussion about safety, despite the fact that simple derivatives of beta-carotene are known teratogens.

NEPs are designed to make molecules that are biologically active in animals. Given that the transfection procedures used to make GM plants cause random mutations that can alter the already unpredictable plant metabolism, that there will be unforeseen pleiotropic interactions between overproduced metabolites of introduced enzymes and normal plant metabolism, and that NEPs will likely have no required safety testing, there should be significant concern about allowing the introduction of this type of GM plant product into the marketplace.

To explain the reasoning behind these concerns, several examples illustrating how altering the human diet with biologically active compounds can have clinical consequences will be used. These examples include a tryptophan food supplement to demonstrate that an extremely small amount of a metabolite contaminant in a product can be lethal, glycolysis in GM yeast to show that changes in even the best understood metabolic pathway can produce unpredicated toxins, and golden rice to demonstrate how plant-derived small molecules based upon the beta-carotene chemical scaffold may negatively influence human development.

[…]

CONCLUSIONS

The above paragraphs summarize published data that clearly show the
following: (1) Compounds structurally related to a common small molecule can have a lethal effect when present as even a minor contaminant in a food supplement. (2) The GM enhancement of a metabolic pathway by the overexpression of genes for that pathway can have unpredictable consequences in the form of synthesizing a toxin. (3) Finally, in the case of golden rice, it is argued that biologically active compounds derived from aberrant plant carotenoid synthesis could have profound effects on human development. Similar arguments can be made for NEP-derived fatty acids that are directly incorporated into brain lipids and about NEPs overproducing vitamin E. Aberrant fatty acid composition of brain lipids is implicated in Alzheimer’s disease, and vitamin E has a role similar to RA in mammalian development.

The excess consumption of a nutrient can also have negative effects. For example, a clinical trial with vitamin E supplementation showed that a relatively small dose increased the risk of heart failure, and smokers who supplemented their diet with beta-carotene had an increased risk of lung cancer. Therefore, there is a potential for nutrient toxicity in NEPs because upper tolerable levels of many nutrients are not well established and are likely to vary between individuals and lifestyles.

The information presented here shows that not only the potential harm of the product should be considered for risk assessment, but the GM process itself. The data clearly invalidate the argument that “the regulatory trigger for risk assessment should be based upon the physical features of the product rather than the process by which the product was generated.”

While it is true that traditional breeding methods can give rise to potentially hazardous products, the most recent assessment of GM food safety by the National Research Council stated that GM “has a higher probability of producing unanticipated changes than some genetic modification methods”, but it curiously concludes by stating that the risk of GM technology is no greater than conventional breeding methods. There are, in fact, no data comparing the food safety profiles of GM versus conventional breeding, and the ubiquitous argument that since there is no evidence that GM products make people sick, they are safe (see, for example, McHughen and Smyth, Bradford et al., and Miller et al.) is both illogical and false. There are, again, simply no data or even valid assays to support this contention. Without proper epidemiological studies, most types of harm will not be detected, and no such studies have been conducted. The necessity of labeling all GM products and particularly NEPs is therefore critical if there is any hope of monitoring adverse health consequences due to their consumption. For example, it would have been impossible to identify the source of the toxic tryptophan supplement if the product were not traceable through labeling.

It follows that before NEPs producing biologically active molecules such as beta-carotene, omega-3 fatty acids, or vitamin E are introduced into the food chain, great care must be taken to do rigorous, multigenerational animal safety assessments with the hope of identifying risks to health (for methods, see, for example, the 2007 publication by the National Toxicology Program and Pusztai and Bardocz). In addition, the products must be labeled and traceable, and the unpredictable and unintended metabolic changes that may occur in NEPs require the thorough testing of the entire edible portion of the plant, not just the designated product as is almost always done by biotech companies. To date there is essentially no multigenerational animal safety testing published for GM plants and no required labeling in the United States for any GM product. In an excellent review of our current GM regulatory process, Mandel concluded that for second-generation GM products, like NEPs, “it is necessary to establish a comprehensive, efficient and scientifically rigorous regulatory system.”

As discussed herein there are very valid scientific concerns to support this conclusion.