U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Presentation: July 1996

Safety Assurance of Foods Derived by Modern Biotechnology in the United States


In 1992, the Food and Drug Administration (FDA) published a policy statement (the 1992 policy) clarifying its legal and regulatory framework for oversight of food and animal feed (fruits, vegetables, grains, and their by-products) derived from new plant varieties developed by conventional and new breeding techniques. The 1992 policy explains how foods and feeds are regulated in the United States (U.S.) under the Federal Food, Drug, and Cosmetic Act (the act). The "guidance to industry" section of the 1992 policy discusses a comprehensive approach to food safety assessment.


This year, June 26th, marked the tenth anniversary of publication of the U.S. government's comprehensive federal regulatory policy for ensuring the safety of biotechnology research and products. That policy, the Coordinated Framework for Regulation of Biotechnology1 described how the various agencies would exercise their regulatory oversight for products developed through biotechnology, including newly emerging technologies such as recombinant DNA (rDNA) techniques (bioengineered) and cell fusion. After careful consideration of the potential impact of rDNA technology on the food supply, the FDA concluded that the the act provided adequate authority and flexibility to enable the agency to regulate products of this new technology as it regulates other products under its authority.

The FDA has authority under the act to ensure the safety of most domestic and imported foods in the U.S. market, except meat and poultry which are regulated by the Department of Agriculture. Pesticides are regulated primarily by the Environmental Protection Agency (EPA), which reviews safety and sets tolerances (or establishes exemptions from tolerance) for pesticides. FDA monitors foods to enforce the tolerances set by EPA for pesticides.

Bioengineered foods and food ingredients (including food additives) must comply with the same standards of safety under the act that apply to other food products. This means that these products must be as safe as the products in our grocery stores today. The FDA has broad authority to initiate regulatory action if a product fails to meet the safety standards under the act.

This year is also significant for U.S. agricultural biotechnology. It will be th e first year that bioengineered food crops will be a significant part of the total U.S. production of food crops, even though the total acreage of bioengineered crops will be a fraction of the production of commodity products such as soybean and corn. These bioengineered varieties include soybeans, corn, canola, tomato, squash, cotton, and potato. The plants and the foods and feeds derived from them have been tested extensively in the U.S. for environmental safety and for consumption as human food and feed for animals. Several firms have completed all necessary regulatory requirements for commercial distribution of these crops in the U.S. These bioengineered crops are the second major category of bioengineered food products in the U.S. that follows the earlier food processing enzymes such as chymosin (rennet) that was first approved in the U.S. in 1990.2


FDA's 1992 policy clarified the agency's authority over food and animal feed derived from new plant varieties developed by both conventional and new breeding techniques, including rDNA techniques.3 The FDA published its 1992 policy to assist developers in addressing food safety and regulatory issues before products reach the market. The FDA's 1992 policy explains how whole foods, including animal feeds, derived from fruits, vegetables, grains, and by-products such as vegetable oils and food starch are regulated under the act.

The FDA relies primarily on two sections of the act to ensure the safety of foods and food ingredients. The first is the adulteration provisions of section 402(a)(1). Generally, whole foods, such as fruits, vegetables, and grains, are not subject to premarket approval. The act places a legal duty on developers to ensure that the foods they market to consumers are safe and comply with all legal requirements. The FDA has authority to remove a food from the market if it poses a risk to public health. This is the primary legal tool that the FDA intends to rely on to ensure the safety of bioengineered foods.

The second section of the act that the FDA relies on is the food additive provision (section 409). Under this section, substances that are intentionally added to food are food additives, unless the substance is generally recognized as safe (GRAS) or is otherwise exempt (e.g., a pesticide). Food additives are subject to review and approval by the FDA before they may be used in food. The FDA also reviews and affirms the GRAS status of food ingredients when there is a question regarding the regulatory status of a substance intended for use in food. The legal basis of the FDA's policy may be found in the 1992 policy.

The centerpiece of our 1992 policy is a comprehensive "guidance to industry" section that discusses scientific issues regarding safety and identifies circumstances when firms should consult with the FDA. The agency's guidance to industry establishes a "standard of care" for developers. The scientific principles of the FDA's policy have been published in Science magazine4 and are consistent with the principles for safety assessment discussed by the U.S. National Research Council,5,6 the World Health Organization and the Food and Agriculture Organization of the United Nations,7 and the Organization of Economic Cooperation and Development.8


Under the FDA's 1992 policy, safety assessment considers changes in food crops that are both intended and unintended modifications of the finished food. We begin with the premiss that many varieties of food crops have been developed through plant breeding and that the foods derived from these varieties are generally safe for consumption, although there have been rare exceptions. Our guidance through flow charts and text covers the food crop being modified, the source(s) of any introduced genetic material, and new substances intentionally added to the food as a result of the genetic modification (i.e., proteins, fatty acids, and carbohydrates), and the composition the food such as known plant toxicants and important nutrients.


One important feature of the FDA's policy is that we will regulate proteins (or other added substances such as fatty acids and carbohydrates) produced by genes, that have been intentionally added to food crops, as new food additives, unless such proteins have been safely consumed in food or are substantially similar to proteins found in food. Based on our present knowledge of developments in agricultural research, we believe that most of the substances that are being introduced into food by genetic modification have been safely consumed as food or are substantially similar to such substances. Therefore, we do not anticipate that most newly added substances in bioengineered foods will require premarket approval.


One scientific issue related to the transfer of genetic material between organisms that deserves particular attention is the possibility that proteins that have been introduced into a new food could cause allergenic reactions in sensitive individuals. We believe that the sources of genetic material that are most likely to present this issue are those foods to which humans are commonly allergic, such as milk, eggs, wheat, fish, tree nuts, and legumes. In such cases, the developer should demonstrate scientifically that the allergenic substance is not present in the new food. Otherwise, the FDA will require labeling to alert sensitive consumers.

In one case published recently, a developer, following the FDA's guidance, demonstrated that a protein transferred from Brazil nut to soybean caused an allergic reaction (via skin-prick test) in individuals who are sensitive to Brazil nut.9 Consequently, development of this modified soybean has been discontinued.

Many genes introduced into plants are obtained from sources that are less frequently or are not known to be associated with allergic reactions. There is no test that will predict potential allergenicity for proteins derived from sources that are not known to cause allergic reactions. However, steps can be taken to reduce the possibility that a newly introduced protein will be an allergen. The protein's structure can be compared to the reported structures for allergenic proteins, and, if similarity is found and if sera from sensitive individuals are available, an analysis of possible cross reaction can be conducted. Many proteins in bioengineered foods have been derived from microbial sources, and developers have demonstrated that these proteins do not have characteristics associated with food allergens, i.e. they do not share structural similarity to allergens and they are not resistant to digestive enzymes and acid.


All methods of plant breeding can induce unexpected or unintended changes in plants, including pleiotropic effects. It is not possible to design a test to identify these effects. Instead, the FDA has encouraged developers to examine whether important nutrients, toxicants, and other components are present in the new plant variety at levels that are within the range expected for commercial varieties.


Selectable marker genes that encode resistance to antibiotics are frequently used in the development of genetically modified plants and microorganisms. It is important to ensure that these marker genes will not spread to pathogenic microorganisms leading to a significant increase in resistance to clinically important antibiotics. Care must also be taken to ensure that enzymes that inactivate antibiotics and that are present in food will not significantly reduce the efficacy of orally administered drugs.

For food ingredients produced via fermentation using microorganisms that contain antibiotic resistance marker genes, such as chymosin, manufacturing and purification steps must inactivate viable organisms and produce a finished product that is free of transforming DNA.

The issues regarding the use of antibiotic resistance marker genes in food crops are more complex and to some extent hypothetical because there is no known mechanism for transfer of a plant gene to a microorganism. Calgene, Inc. requested that the FDA review the use of kanamycin resistance (kanr) the development of several crops including tomato. The firm also requested that the FDA regulate the enzyme expressed by kanr, aminoglycoside 3'phosphotransferase II (APH3'II), as a food additive in order to demonstrate that the only newly added substance in the Flavr SavrTM tomato meet the stringent standard for food additives. Calgene submitted extensive data and information to the FDA to support the safe use of kanr in tomato, cot canola. FDA concluded that the use of kanr in these crops was safe.10


The FDA conducted a comprehensive scientific review of Calgene's data on the Flavr SavrTM tomato and kanamycin resistance. There were several opportunities for the scientific community to comment on the FDA's approach to assessing safety. Before the FDA reached its final decision on the Flavr SavrTM tomato, the agency held a public meeting of our Food Advisory Committee, a group of experts from outside the FDA. Committee members agreed with the FDA that all safety questions regarding the Flavr SavrTM had been addressed and suggested that the FDA develop a more expedited process for the FDA and the industry to reach decisions on the marketing of other bioengineered foods that do not raise substantive scientific issues.

Subsequently, the FDA established an informal process by which firms can inform the FDA that they have completed a food and feed safety assessment. The FDA requests that firms submit a summary of their assessment to the agency. The FDA does not request the original data and, therefore, does not conduct a scientific review of the firm's decision. This informal process has worked well to date and permits the FDA to identify any unresolved safety or regulatory issues before products reach the market.

As summarized in our paper in Science, "FDA's science-based approach for ensuring the safety of foods from new plant varieties focuses safety evaluation on the objective characteristics of the food: The safety of any newly introduced substances and any unintended increased concentrations of toxicants beyond the range known to be safe in food or alterations of important nutrients that may occur as a result of genetic modification. Substances that have a safe history of use in food and substances that are substantially similar to such substances generally would not require extensive premarket safety testing. Substances that raise safety concerns would be subjected to closer inquiry. This approach is both scientifically and legally sound and should be adequate to fully protect public health while not inhibiting innovation" (see reference 4).


  1. U.S. Food and Drug Administration, Federal Register, June 26, 51: 23309-23313 (1986).
  2. U.S. Food and Drug Administration, Federal Register, March 23, 57:10932-10936 (1990).

  3. U.S. Food and Drug Administration, Federal Register, May 29, 57:22984-23005 (1992).

  4. Kessler D.A., et al, Science, 256:1747 (1992).

  5. National Research Council, Introduction of recombinant DNA- engineered organisms into the environment: key issues, National Academy Press, Washington, D.C (1987).

  6. National Research Council, Field testing genetically modified organisms: framework for decisions, National Academy Press, Washington, D.C (1989).

  7. Report of a Joint FAO/WHO Consultation, Strategies for assessing th safety of foods produced by biotechnology, World Health Organization, Geneva (1991).
  8. Organization for Economic Cooperation and Development, Safety evaluation of foods derived by modern biotechnology, Paris (1993).

  9. Nordlee, J.A., et al, N.Eng.J.Med., 334:688-692 (1996)

  10. U.S. Food and Drug Administration, Federal Register, May 23, 59: 26700-26711 (1994).

Biotechnology Strategic Manager
Center for Food Safety and
Applied Nutrition (HFS-13)
U.S. Food and Drug Administration
Washington, D.C. 20204 U.S.A.

Presented at the BioJapan '96 Symposium held on July 24-27, 1996 in Tokyo, Japan.

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