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National Research Council (US) Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health. Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects. Washington (DC): National Academies Press (US); 2004.
Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects.
National Research Council (US) Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health.
This chapter explores the likelihood of unintended effects from diverse methods of genetic modification of plants and animals (see Operational Definitions in Chapter 1). Specifically, it discusses unexpected outcomes of breeding methods used to develop a food crop or strain and unexpected or unintended effects recorded in the scientific literature. It also includes analyses of methods intentionally used for modifying food sources and comparing the likelihood of unintended changes resulting from the use of genetic engineering versus other methods of genetic modification discussed in Chapter 2.
Novel gene combinations arising from the genetic manipulation of existing genes through conventional breeding techniques may introduce unintended and unexpected effects. However, through the breeder”s selection process, the genetic lines that express undesirable characteristics are eliminated from further consideration, and only the best lines—those that express desirable characteristics with no additional undesirable agronomic characteristics, such as increased disease susceptibility or poor grain quality—are maintained for possible commercial release. Although plants and animals produced from conventional breeding methods are routinely evaluated for changes in productivity, reproductive efficiency, reactions to disease, and quality characteristics, they are not routinely evaluated for unintended effects at the molecular level. New varieties of food crops, other than those produced using recombinant deoxyribonucleic acid (rDNA) technologies, are rarely subjected to toxicological or other safety assessments (WHO, 2000). Previous National Academies committees have addressed the question of whether unintended effects arising from the use of rDNA-based technologies in food production and the risks potentially associated with them differ in nature and frequency from those associated with non-rDNA-based breeding methods (NRC, 1987, 2000, 2002).
There is a considerable amount of data compiled and available in the scientific literature addressing issues related to genetically modified (GM) and genetically engineered (GE) plants, including health and environmental impacts. In contrast, development of transgenic animals is a relatively new area of biotechnology, and so the amount of data collected and reported for GM animals is less than that for plants. However, the application of genetic modification techniques and the potential for unintended adverse effects are similar for both plants and animals, and much of the information obtained from plants can be applied to questions of concern in the genetic modification of animals.
Conventional Plant Breeding
Conventional plant production occasionally generates foods with undesirable traits, some of which are potentially hazardous to human health. Most crops naturally produce allergens, toxins, or other antinutritional substances (see Chapter 5). Standard practice among plant breeders and agronomists includes monitoring the levels of potentially hazardous antinutritional substances relevant to the crop. For example, canola breeders monitor levels of glucosinolates in breeding lines under consideration for prospective commercial release, while potato breeders monitor for glycoalkaloid content. If a particular breeding line generates too much of an undesirable substance, that line is eliminated from consideration for commercial release.
In the United States, the plant breeding community is largely self-monitored. Regulatory agencies do not evaluate conventional new crop varieties for health and environmental safety prior to commercial release. Some other countries require government agencies to conduct premarket evaluations for new crop varieties, both conventional and biotechnology-derived. Canada has a “merit system” for the commercial release of new varieties of major field crops, in which candidate varieties are grown in government-administered field trials. Performance data from these trials, related to agronomic factors, disease resistance, and food quality characteristics, are compiled for all candidate and standard commercial varieties. The data are collected from multiple locations over multiple years, as cereal chemists analyze the grain for chemical and nutritional composition and plant pathologists conduct tests to determine reactions to relevant diseases. These data are then evaluated by a team of experts from industry, government, and universities.
The breeder of each candidate variety must convince these experts that it is competitive and worthy relative to other commercially available varieties of that crop, based on the performance data from the trials. Only if the committee agrees is the candidate variety allowed to be registered as a new commercial variety. If the variety does not perform within prescribed parameters for all characteristics, it is not commercially released (CFIA, 2003).
Naturally Occurring Toxins
All foods, whether or not they are genetically engineered, carry potentially hazardous substances or pathogenic microbes and must be properly and prudently assessed to ensure a reasonable degree of safety. Furthermore, all crop strains, including organic strains, potentially express traits generated by various forms of induced mutagenesis. (Under organic regulations, radiation breeding and induced mutagenesis are acceptable, but irradiation of the final food itself is not. For more information on organic regulations, see USDA-AMS, 2001.)
History provides examples of traditional breeding that resulted in potentially hazardous foods (see Box 3-1). Solanaceous (tobacco family) crops, such as potato and tomato, naturally produce various steroidal glycoalkaloids. These substances are toxic not only to humans, but also to insects and pathogenic fungi. During the course of ordinary plant breeding assessments, breeding lines with increased levels of glycoalkaloids may be identified by the breeder as showing superior insect or disease resistance and retained for possible commercial release. The elevation of glycoalkaloid levels responsible for the pest tolerance may not be noted until people become ill from consuming the foods.
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Tomatine, a glycoalkaloid naturally present in tomatoes, can be produced in hazardous quantities in certain conventionally bred varieties. Ordinarily, alpha tomatine is present in immature tomato fruit, but is degraded as the fruit matures, so that by the time the fruit ripens to the preferred stage for human consumption, tomatine content is reduced to safe levels. Nevertheless, levels of naturally occurring tomatine in ordinary tomatoes bred using conventional methods can vary considerably, primarily based on maturity, type, and environmental growing conditions (Gilbert and Mohankumaran, 1969; Leonardi et al., 2000). In this respect, environment is more responsible for food hazards than genetic makeup or breeding method.
Another example of a possible effect is the unintended elevation of glycoalkaloid content in potatoes. All potatoes produce the toxic glycoalkaloid solanine, but mature potatoes from most cultivars have amounts so small as to be nonhazardous. However, some varieties produce more than others, and certain environmental stimuli, such as growing or storage conditions, can cause potentially hazardous increases in solanine content, even within a usually safe cultivar (Concon, 1988). For example, potatoes exposed to sunlight turn green, making them particularly prone to high solanine content. Dark-skinned varieties are less likely to turn green than light-skinned varieties, but in either case environment seems to be more important to solanine production than genetics.
Certain potato lines have been found to express greater disease- or pest-resistance, and they have been selected as superior, not always with favorable or intended results. The most notorious such selection was the Lenape potato, which was developed using conventional breeding methods (Akeley et al., 1968). After a successful commercial launch, it was found to have dangerously elevated solanine content in the tubers and was removed from the market (Zitnak and Johnston, 1970). More recently, a similar high-solanine potato variety was detected and withdrawn from the market in Sweden (Hellanäs et al., 1995). In this case, the potato was a heritage variety, developed in the United Kingdom during the nineteenth century, but superseded by another variety due to its susceptibility to disease (Kuiper, 2003). Nevertheless, it became popular in Sweden under the name “Magnum Bonum,” until its predilection for overexpressing solanine resulted in its commercial demise (Hellanäs et al., 1995).
In spite of occasional problems with the consumption of potato glycoalkaloids, conventional breeders continue to increase the glycoalkaloid content in the leaves to take advantage of its pest- and pathogen-deterrent properties. Consequently, the U.S. Department of Agriculture (USDA) recommends, but does not require, a limit for glycoalkaloid content in new potato varieties (Sinden and Webb, 1972).
Interestingly, the Lenape (also known as breeding line no. B5141-6) potato has been found to express some useful attributes, such as high solids content. Thus Lenape continues to be used successfully as a parent in conventional breeding programs, providing its genes to new commercial potato varieties, such as Atlantic and Denali. Progeny with genes providing the high solids content are selected or maintained, and the genes responsible for high solanine content in the tubers are selected against or rejected. Additionally, Lenape has been transformed with a genetic construct containing the solanidine glucose-adenosine diphosphate glucosyltransferase (SGT) transgene in the antisense direction, which is designed to interfere with the solanine biosynthesis (Moehs et al., 1997). In field trials, several transgenic Lenape-derived lines expressed substantially less solanine than the parent Lenape, apparently due to antisense expression, an rDNA method for “turning off” an undesirable gene (McCue et al., 2003).
Several breeding programs are developing potatoes derived from conventional crosses between the ordinary potato Solanum tuberosum and relatives of other species, such as S. acaule (Kozukue et al., 1999) or S. chacoense (Sanford et al., 1998; Zimnoch-Guzowska et al., 2000). These are conventional breeding programs in which genes from two different species are exchanged. The intent of these conventional breeding programs is to generate potato varieties with new beneficial features, while minimizing deleterious traits from the foreign species.
Breeders typically monitor levels of toxins in plants that are known to naturally contain them, even though such monitoring is only voluntary in the United States. However, an unexpected and unintended problem may result when combining different species because thousands of genes would be interacting, not just one or two genetic elements of interest. For example, hybrids of S. tuberosum and S. brevidens produced not only the usual glycoalkaloids, but also the toxin demissidine, which is not produced in either parent (Laurila et al., 1996). This singular result shows that non-genetic engineering breeding methods can have unintended effects and generate potentially hazardous new products.
Any time genes are mutated or combined, as occurs in almost all breeding methods, the possibility of producing a new, potentially hazardous substance exists. Conceivably, similar outcomes could result from using rDNA to transfer specific genes from S. brevidans to S. tuberosum, giving rise to hybrids expressing the novel toxin demissidine. In either case, the hazard lies with the presence of the toxin, and not with the method of breeding. Genetic engineering could also be used to transfer only the beneficial genes from S. brevidans, leaving behind the genes responsible for the novel toxin.
Another example of a toxic compound from traditional crops is psoralens in celery (see Box 3-2). Celery naturally produces these irritant chemicals that deter insects from feeding on the plant and also confer protection from some diseases (Beier and Oertli, 1983). Celery plants with an elevated expression of psoralens will suffer less damage from disease and insect predation and have more aesthetic appeal to consumers, who tend to reject insect- or disease-damaged produce.