research about genetically modified crops

The pharmaceutical industry is another frontier for the use of GMOs. In 1986, human growth hormone was the first protein pharmaceutical made in plants (Barta et al ., 1986), and in 1989, the first antibody was produced (Hiatt et al ., 1989). Both research groups used tobacco, which has since dominated the industry as the most intensively studied and utilized plant species for the expression of foreign genes (Ma et al ., 2003). As of 2003, several types of antibodies produced in plants had made it to clinical trials. The use of genetically modified animals has also been indispensible in medical research. Transgenic animals are routinely bred to carry human genes, or mutations in specific genes, thus allowing the study of the progression and genetic determinants of various diseases.

Potential GMO Applications

Many industries stand to benefit from additional GMO research. For instance, a number of microorganisms are being considered as future clean fuel producers and biodegraders. In addition, genetically modified plants may someday be used to produce recombinant vaccines. In fact, the concept of an oral vaccine expressed in plants (fruits and vegetables) for direct consumption by individuals is being examined as a possible solution to the spread of disease in underdeveloped countries, one that would greatly reduce the costs associated with conducting large-scale vaccination campaigns. Work is currently underway to develop plant-derived vaccine candidates in potatoes and lettuce for hepatitis B virus (HBV), enterotoxigenic Escherichia coli (ETEC), and Norwalk virus. Scientists are also looking into the production of other commercially valuable proteins in plants, such as spider silk protein and polymers that are used in surgery or tissue replacement (Ma et al ., 2003). Genetically modified animals have even been used to grow transplant tissues and human transplant organs, a concept called xenotransplantation. The rich variety of uses for GMOs provides a number of valuable benefits to humans, but many people also worry about potential risks.

Risks and Controversies Surrounding the Use of GMOs

Despite the fact that the genes being transferred occur naturally in other species, there are unknown consequences to altering the natural state of an organism through foreign gene expression . After all, such alterations can change the organism's metabolism , growth rate, and/or response to external environmental factors. These consequences influence not only the GMO itself, but also the natural environment in which that organism is allowed to proliferate. Potential health risks to humans include the possibility of exposure to new allergens in genetically modified foods, as well as the transfer of antibiotic-resistant genes to gut flora.

Horizontal gene transfer of pesticide, herbicide, or antibiotic resistance to other organisms would not only put humans at risk , but it would also cause ecological imbalances, allowing previously innocuous plants to grow uncontrolled, thus promoting the spread of disease among both plants and animals. Although the possibility of horizontal gene transfer between GMOs and other organisms cannot be denied, in reality, this risk is considered to be quite low. Horizontal gene transfer occurs naturally at a very low rate and, in most cases, cannot be simulated in an optimized laboratory environment without active modification of the target genome to increase susceptibility (Ma et al ., 2003).

In contrast, the alarming consequences of vertical gene transfer between GMOs and their wild-type counterparts have been highlighted by studying transgenic fish released into wild populations of the same species (Muir & Howard, 1999). The enhanced mating advantages of the genetically modified fish led to a reduction in the viability of their offspring . Thus, when a new transgene is introduced into a wild fish population, it propagates and may eventually threaten the viability of both the wild-type and the genetically modified organisms.

Unintended Impacts on Other Species: The Bt Corn Controversy

One example of public debate over the use of a genetically modified plant involves the case of Bt corn. Bt corn expresses a protein from the bacterium Bacillus thuringiensis . Prior to construction of the recombinant corn, the protein had long been known to be toxic to a number of pestiferous insects, including the monarch caterpillar, and it had been successfully used as an environmentally friendly insecticide for several years. The benefit of the expression of this protein by corn plants is a reduction in the amount of insecticide that farmers must apply to their crops. Unfortunately, seeds containing genes for recombinant proteins can cause unintentional spread of recombinant genes or exposure of non-target organisms to new toxic compounds in the environment.

The now-famous Bt corn controversy started with a laboratory study by Losey et al . (1999) in which the mortality of monarch larvae was reportedly higher when fed with milkweed (their natural food supply) covered in pollen from transgenic corn than when fed milkweed covered with pollen from regular corn. The report by Losey et al . was followed by another publication (Jesse & Obrycki, 2000) suggesting that natural levels of Bt corn pollen in the field were harmful to monarchs.

Debate ensued when scientists from other laboratories disputed the study, citing the extremely high concentration of pollen used in the laboratory study as unrealistic, and concluding that migratory patterns of monarchs do not place them in the vicinity of corn during the time it sheds pollen. For the next two years, six teams of researchers from government, academia, and industry investigated the issue and concluded that the risk of Bt corn to monarchs was "very low" (Sears et al ., 2001), providing the basis for the U.S. Environmental Protection Agency to approve Bt corn for an additional seven years.

Unintended Economic Consequences

Another concern associated with GMOs is that private companies will claim ownership of the organisms they create and not share them at a reasonable cost with the public. If these claims are correct, it is argued that use of genetically modified crops will hurt the economy and environment, because monoculture practices by large-scale farm production centers (who can afford the costly seeds) will dominate over the diversity contributed by small farmers who can't afford the technology. However, a recent meta-analysis of 15 studies reveals that, on average, two-thirds of the benefits of first-generation genetically modified crops are shared downstream, whereas only one-third accrues upstream (Demont et al ., 2007). These benefit shares are exhibited in both industrial and developing countries. Therefore, the argument that private companies will not share ownership of GMOs is not supported by evidence from first-generation genetically modified crops.

GMOs and the General Public: Philosophical and Religious Concerns

In a 2007 survey of 1,000 American adults conducted by the International Food Information Council (IFIC), 33% of respondents believed that biotech food products would benefit them or their families, but 23% of respondents did not know biotech foods had already reached the market. In addition, only 5% of those polled said they would take action by altering their purchasing habits as a result of concerns associated with using biotech products.

According to the Food and Agriculture Organization of the United Nations, public acceptance trends in Europe and Asia are mixed depending on the country and current mood at the time of the survey (Hoban, 2004). Attitudes toward cloning, biotechnology, and genetically modified products differ depending upon people's level of education and interpretations of what each of these terms mean. Support varies for different types of biotechnology; however, it is consistently lower when animals are mentioned.

Furthermore, even if the technologies are shared fairly, there are people who would still resist consumable GMOs, even with thorough testing for safety, because of personal or religious beliefs. The ethical issues surrounding GMOs include debate over our right to "play God," as well as the introduction of foreign material into foods that are abstained from for religious reasons. Some people believe that tampering with nature is intrinsically wrong, and others maintain that inserting plant genes in animals, or vice versa, is immoral. When it comes to genetically modified foods, those who feel strongly that the development of GMOs is against nature or religion have called for clear labeling rules so they can make informed selections when choosing which items to purchase. Respect for consumer choice and assumed risk is as important as having safeguards to prevent mixing of genetically modified products with non-genetically modified foods. In order to determine the requirements for such safeguards, there must be a definitive assessment of what constitutes a GMO and universal agreement on how products should be labeled.

These issues are increasingly important to consider as the number of GMOs continues to increase due to improved laboratory techniques and tools for sequencing whole genomes, better processes for cloning and transferring genes, and improved understanding of gene expression systems. Thus, legislative practices that regulate this research have to keep pace. Prior to permitting commercial use of GMOs, governments perform risk assessments to determine the possible consequences of their use, but difficulties in estimating the impact of commercial GMO use makes regulation of these organisms a challenge.

History of International Regulations for GMO Research and Development

In 1971, the first debate over the risks to humans of exposure to GMOs began when a common intestinal microorganism, E. coli , was infected with DNA from a tumor-inducing virus (Devos et al ., 2007). Initially, safety issues were a concern to individuals working in laboratories with GMOs, as well as nearby residents. However, later debate arose over concerns that recombinant organisms might be used as weapons. The growing debate, initially restricted to scientists, eventually spread to the public, and in 1974, the National Institutes of Health (NIH) established the Recombinant DNA Advisory Committee to begin to address some of these issues.

In the 1980s, when deliberate releases of GMOs to the environment were beginning to occur, the U.S. had very few regulations in place. Adherence to the guidelines provided by the NIH was voluntary for industry. Also during the 1980s, the use of transgenic plants was becoming a valuable endeavor for production of new pharmaceuticals, and individual companies, institutions, and whole countries were beginning to view biotechnology as a lucrative means of making money (Devos et al ., 2007). Worldwide commercialization of biotech products sparked new debate over the patentability of living organisms, the adverse effects of exposure to recombinant proteins, confidentiality issues, the morality and credibility of scientists, the role of government in regulating science, and other issues. In the U.S., the Congressional Office of Technology Assessment initiatives were developed, and they were eventually adopted worldwide as a top-down approach to advising policymakers by forecasting the societal impacts of GMOs.

Then, in 1986, a publication by the Organization for Economic Cooperation and Development (OECD), called "Recombinant DNA Safety Considerations," became the first intergovernmental document to address issues surrounding the use of GMOs. This document recommended that risk assessments be performed on a case-by-case basis. Since then, the case-by-case approach to risk assessment for genetically modified products has been widely accepted; however, the U.S. has generally taken a product-based approach to assessment, whereas the European approach is more process based (Devos et al ., 2007). Although in the past, thorough regulation was lacking in many countries, governments worldwide are now meeting the demands of the public and implementing stricter testing and labeling requirements for genetically modified crops.

Increased Research and Improved Safety Go Hand in Hand

Proponents of the use of GMOs believe that, with adequate research, these organisms can be safely commercialized. There are many experimental variations for expression and control of engineered genes that can be applied to minimize potential risks. Some of these practices are already necessary as a result of new legislation, such as avoiding superfluous DNA transfer (vector sequences) and replacing selectable marker genes commonly used in the lab (antibiotic resistance) with innocuous plant-derived markers (Ma et al ., 2003). Issues such as the risk of vaccine-expressing plants being mixed in with normal foodstuffs might be overcome by having built-in identification factors, such as pigmentation, that facilitate monitoring and separation of genetically modified products from non-GMOs. Other built-in control techniques include having inducible promoters (e.g., induced by stress, chemicals, etc.), geographic isolation, using male-sterile plants, and separate growing seasons.

GMOs benefit mankind when used for purposes such as increasing the availability and quality of food and medical care, and contributing to a cleaner environment. If used wisely, they could result in an improved economy without doing more harm than good, and they could also make the most of their potential to alleviate hunger and disease worldwide. However, the full potential of GMOs cannot be realized without due diligence and thorough attention to the risks associated with each new GMO on a case-by-case basis.

References and Recommended Reading

Barta, A., et al . The expression of a nopaline synthase-human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Molecular Biology 6 , 347–357 (1986)

Beyer, P., et al . Golden rice: Introducing the β-carotene biosynthesis pathway into rice endosperm by genetic engineering to defeat vitamin A deficiency. Journal of Nutrition 132 , 506S–510S (2002)

Demont, M., et al . GM crops in Europe: How much value and for whom? EuroChoices 6 , 46–53 (2007)

Devlin, R., et al . Extraordinary salmon growth. Nature 371 , 209–210 (1994) ( link to article )

Devos, Y., et al . Ethics in the societal debate on genetically modified organisms: A (re)quest for sense and sensibility. Journal of Agricultural and Environmental Ethics 21 , 29–61 (2007) doi:10.1007/s10806-007-9057-6

Guerrero-Andrade, O., et al . Expression of the Newcastle disease virus fusion protein in transgenic maize and immunological studies. Transgenic Research 15 , 455–463(2006) doi:10.1007/s11248-006-0017-0

Hiatt, A., et al . Production of antibodies in transgenic plants. Nature 342 , 76–79 (1989) ( link to article )

Hoban, T. Public attitudes towards agricultural biotechnology. ESA working papers nos. 4-9. Agricultural and Development Economics Division, Food and Agricultural Organization of the United Nations (2004)

Jesse, H., & Obrycki, J. Field deposition of Bt transgenic corn pollen: Lethal effects on the monarch butterfly. Oecologia 125 , 241–248 (2000)

Losey, J., et al . Transgenic pollen harms monarch larvae. Nature 399 , 214 (1999) doi:10.1038/20338 ( link to article )

Ma, J., et al . The production of recombinant pharmaceutical proteins in plants. Nature Reviews Genetics 4 , 794–805 (2003) doi:10.1038/nrg1177 ( link to article )

Muir, W., & Howard, R. Possible ecological risks of transgenic organism release when transgenes affect mating success: Sexual selection and the Trojan gene hypothesis. Proceedings of the National Academy of Sciences 96 , 13853–13856 (1999)

Sears, M., et al . Impact of Bt corn on monarch butterfly populations: A risk assessment. Proceedings of the National Academy of Sciences 98 , 11937–11942 (2001)

Spurgeon, D. Call for tighter controls on transgenic foods. Nature 409 , 749 (2001) ( link to article )

Takeda, S., & Matsuoka, M. Genetic approaches to crop improvement: Responding to environmental and population changes. Nature Reviews Genetics 9 , 444–457 (2008) doi:10.1038/nrg2342 ( link to article )

United States Department of Energy, Office of Biological and Environmental Research, Human Genome Program. Human Genome Project information: Genetically modified foods and organisms, (2007)

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National and global impacts of genetically modified crops.

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Largest-Ever Study Reveals Environmental Impact of Genetically Modified Crops

• By Caroline Newman , [email protected]

According to new research from University of Virginia economist Federico Ciliberto, widespread adoption of genetically modified crops has decreased the use of insecticides, but increased the use of weed-killing herbicides as weeds become more resistant.

Ciliberto led the largest study of genetically modified crops and pesticide use to date, alongside Edward D. Perry of Kansas State University, David A. Hennessy of Michigan State University and GianCarlo Moschini of Iowa State University. The four economists studied annual data from more than 5,000 soybean and 5,000 maize farmers in the U.S. from 1998 to 2011, far exceeding previous studies that have been limited to one or two years of data.

“The fact that we have 14 years of farm-level data from farmers all over the U.S. makes this study very special,” Ciliberto said. “We have repeated observations of the same farmers and can see when they adopted genetically modified seeds and how that changed their use of chemicals.”

Associate economics professor Federico Ciliberto co-led the largest research study to date examining how genetically modified soybeans and maize have impacted pesticide use in the U.S. (Photo by Dan Addison, University Communications)

Since 2008, genetically engineered crops have accounted for more than 80 percent of maize and soybean crops planted in the U.S. Maize seeds are modified with two genes: one kills insects that eat the seed and one allows the seed to tolerate glyphosate, a herbicide commonly used in weed killers like Roundup. Soybeans are modified with just one glyphosate-resistant gene. 

Unsurprisingly, maize farmers who used the insect-resistant seeds used significantly less insecticide – about 11.2 percent less – than farmers who did not use genetically modified maize. The maize farmers also used 1.3 percent less herbicide over the 13-year period.

Soybean crops, on the other hand, saw a significant increase in herbicide use, with adopters of genetically modified crops using 28 percent more herbicides than non-adopters.

Ciliberto attributes this increase to the proliferation of glyphosate-resistant weeds.

“In the beginning, there was a reduction in herbicide use, but over time the use of chemicals increased because farmers were having to add new chemicals as weeds developed a resistance to glyphosate,” Ciliberto said.

Maize farmers, he said, have not yet had to address the same level of resistance, in part because they did not adopt genetically modified crops as quickly as their counterparts in the soy industry. However, the study did find evidence that both maize and soybean farmers increased herbicide use during the last five years of the study, indicating that weed resistance is a growing problem for both groups.

From 2006 to 2011, the percentage of hectares sprayed with only glyphosate shrunk from more than 70 percent to 41 percent for soybean farmers and from more than 40 percent to 19 percent for maize farmers. The decrease resulted from farmers having to resort to other chemicals as glyphosate-resistant weeds became more common.

“Evidence suggests that weeds are becoming more resistant and farmers are having to use additional chemicals, and more of them,” Ciliberto said.

Insects do not appear to have developed a similar resistance, in part because federal regulations require farmers to have a “safe haven” in their fields that is free of genetically modified crops. Insects and worms in those safe havens have no need to develop resistance, and because they interact and breed with insects in other parts of the field, they help prevent the development of resistant genes.

Despite the decrease in insecticide use, continued growth in herbicide use poses a significant environmental problem as large doses of the chemicals can harm biodiversity and increase water and air pollution.

Ciliberto and his colleagues measured the overall environmental impact of the changes in chemical use that have resulted from the adoption of genetically modified crops, using a measure called the environmental impact quotient, or EIQ, to account for chemicals’ impact on farmworkers, consumers and the environment. Comparing adopters to non-adopters, they found little change in the impact on farmworkers and consumers. However, the adoption of genetically modified soybeans correlated with a negative impact on the environment as increased herbicide use also increased contamination of local ecosystems.

Overall, Ciliberto said he was surprised by the extent to which herbicide use had increased and concerned about the potential environmental impact.

“I did not expect to see such a strong pattern,” he said.

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Pros and cons of gmo crop farming.

• Rene Van Acker , Rene Van Acker University of Guelph
• M. Motior Rahman M. Motior Rahman University of Guelph
•  and  S. Zahra H. Cici S. Zahra H. Cici University of Guelph
• https://doi.org/10.1093/acrefore/9780199389414.013.217
• Published online: 26 October 2017

The global area sown to genetically modified (GM) varieties of leading commercial crops (soybean, maize, canola, and cotton) has expanded over 100-fold over two decades. Thirty countries are producing GM crops and just five countries (United States, Brazil, Argentina, Canada, and India) account for almost 90% of the GM production. Only four crops account for 99% of worldwide GM crop area. Almost 100% of GM crops on the market are genetically engineered with herbicide tolerance (HT), and insect resistance (IR) traits. Approximately 70% of cultivated GM crops are HT, and GM HT crops have been credited with facilitating no-tillage and conservation tillage practices that conserve soil moisture and control soil erosion, and that also support carbon sequestration and reduced greenhouse gas emissions. Crop production and productivity increased significantly during the era of the adoption of GM crops; some of this increase can be attributed to GM technology and the yield protection traits that it has made possible even if the GM traits implemented to-date are not yield traits per se . GM crops have also been credited with helping to improve farm incomes and reduce pesticide use. Practical concerns around GM crops include the rise of insect pests and weeds that are resistant to pesticides. Other concerns around GM crops include broad seed variety access for farmers and rising seed costs as well as increased dependency on multinational seed companies. Citizens in many countries and especially in European countries are opposed to GM crops and have voiced concerns about possible impacts on human and environmental health. Nonetheless, proponents of GM crops argue that they are needed to enhance worldwide food production. The novelty of the technology and its potential to bring almost any trait into crops mean that there needs to remain dedicated diligence on the part of regulators to ensure that no GM crops are deregulated that may in fact pose risks to human health or the environment. The same will be true for the next wave of new breeding technologies, which include gene editing technologies.

• genetically modified
• herbicide tolerance
• insect resistance

Introduction

Genetically modified organisms (GMOs) result from recombinant DNA technology that allows for DNA to be transferred from one organism to another (transgenesis) without the genetic transfer limits of species to species barriers and with successful expression of transferred genes in the receiving organism (Gray, 2001 ). Four crops, maize, canola, soybean, and cotton, constitute the vast majority of GM crop production (James, 2015a ), and GM crops have been grown commercially since 1995 (Bagavathiannan, Julier, Barre, Gulden, & Van Acker, 2010 ). The acceptance of GM crops by farmers has been rapid, with the global GM production area growing from 1.7 million hectares in 1996 (International Service for the Acquisition of Agri-biotech Applications [ISAAA], 2015 ) to 182 million hectares in 2014 (James, 2014 ). Just 10 countries represent almost 98% of the GM hectares worldwide. The top GM producing countries are the United States (73.1 million ha), Brazil (42.2 million ha), Argentina (24.3 million ha), Canada (11.6 million ha), and India (11.6 million ha) (James, 2014 ). GM soybean is the most popular GM crop and almost 50% of global soybean acres are now GM soybean (James, 2015b ). For corn and cotton the global proportion of GM is 30% and 14%, respectively (James, 2015b ). GM canola occupies only 5% of the global canola hectares (James, 2015b ). GM crops are grown on only 3.7% of the world’s total agricultural land, by less than one percent of the world’s farmers. Almost 100% of GM crops on the market are either herbicide tolerant (HT) or insect resistant or have both of these two traits (Dill, CaJacob, & Padgette, 2008 ).

The production of GM crops is not equal across the world and in some jurisdictions there is little or no production. Countries in the European Union (EU) are a notable example in this regard. The near complete moratorium on the production of GM crops in the EU is based on common public view and political decisions rather than GM food safety assessment (Fischer, Ekener-Petersen, Rydhmer, & Edvardsson Björnberg, 2015 ). This is also true for Switzerland, where, for example, since 2005 GM foods and crops have been banned because of strong negative views on the part of both Swiss farmers and citizens (Mann, 2015 ). Five EU countries (Spain, Portugal, the Czech Republic, Slovakia and Romania) accounted for 116,870 hectares of Bt maize cultivation in 2015 , down 18% from the 143,016 hectares in 2014 . The leading EU producer is Spain, with 107,749 hectares of Bt maize in 2015 , down 18% from the 131,538 hectares in 2014 (James, 2015a ). Russia is the world's largest GM-free zone (James, 2015a ). Despite the claimed benefits over risks, and the wide adoption of biotech-improved crop varieties in many parts of the world, Europe and Africa still remain largely GM-free in terms of production (Paarlberg, 2008 ). This may be due in part to the relative absence of reliable public scientific studies on the long-term risks of GM crops and foods and the seed monopoly that is linked to GM technology development (Paarlberg, 2008 ). In Asia, four countries, including Turkey, have banned GM crops. The GM concerns in Europe have also slowed down the approval of GM crops in many developing countries because of impacts on agricultural exports (Inghelbrecht, Dessein, & Huylenbroeck, 2014 ). Many African governments have been slow to approve, or have sometimes even banned GM crops, in order not to lose export markets and to maintain positive relations with the EU, especially given implications for development aid (Wafula, Waithaka, Komen, & Karembu, 2012 ). In addition, a few African nations have banned GM cultivation over fears of losing European markets (ISAAA, 2015 ). Public concerns over GM crops and foods have also had an impact on production of GM crops in North America. The withdrawal of the GM Bt potato (NewLeaf™) varieties from the North American market due to the concerns of two of the largest buyers of processing potatoes (Frito-Lay and McDonalds) was the result of feared consumer rejection (Kynda & Moeltner, 2006 ).

The extensive adaptation of GM crops does, however, also have some drawbacks. The occurrence of outcrossing with non-GM crops, gene flow, and the adventitious presence of GM crops on organic farms has sparked concerns among various stakeholders, including farmers who are growing GM crops (Ellstrand, 2003 ; Marvier & Van Acker, 2005 ). Public concern over GM crops is centered in three areas: human health, environmental safety, and trade impacts (Van Acker, Cici, Michael, Ryan, & Sachs, 2015 ). GM biosafety is also forcing both agriculture and food companies to appreciate GM safety in their marketing decisions (Blaine & Powell, 2001 ; Rotolo et al., 2015 ). The adoption of GM crops in a given jurisdiction is a function of public GM acceptance as well as the level of public trust of regulatory authorities (Vigani & Olper, 2013 ). Examples of these include feeding the world, consumer choice, and seed ownership (Van Acker & Cici, 2014 ). Opponents of GM crops have questioned their necessity in terms of agricultural productivity to feed the world (Gilbert, 2013 ). They point to studies that have shown that current agricultural output far exceeds global calorie needs and that distribution, access, and waste are the key limitations to feeding those who are hungry and not gross production per se (Altieri, 2005 ).

The novelty of GM technology has been both an asset and a challenge for those companies producing GM seeds. Supporters of GM crops have asserted that GM is merely an evolution of conventional breeding approaches (Herdt, 2006 ). They have insisted that humans have been genetically modifying crops for millennia and that GM technology has been an extension and facilitation of natural breeding. At the same time, however, GM crops are patentable, emphasizing that the process is truly novel and different from the natural breeding (Boucher, 1999 ). In addition, expert technical assessments acknowledge the unique and novel nature of GM crops (Taylor, 2007 ). This situation highlights the conundrum and challenge of not only introducing disruptive new technologies into society but having such technologies accepted by society (Van Acker et al., 2015 ). The socioeconomic nature of most risks along with the continuing farm income crisis in North America has led some to argue for the adoption of a more comprehensive approach to risk assessment of GM crops and all new agricultural technologies (Mauro et al., 2009 ).

The Green Revolution was driven by global hunger, and some argue that the next agricultural production revolution, which is perhaps being sparked by the introduction of GM crops, would be driven by other global needs including sustainability and the needs of individuals (Lipton & Longhurst, 2011 ). The green revolution of the 1960s and 1970s depended on the use of fertilizers, pesticides, and irrigation methods to initiate favorable conditions in which high-yielding modern varieties could thrive. Between 1970 and 1990 , fertilizer use in developing countries rose by 360% while pesticide use increased by 7 to 8% annually. The environmental impacts, of the adoption of these technologies did in some cases override their benefits. These impacts included polluted land, water, and air, and the development of resistant strains of pests. GM crops could be used to sustain or grow production levels while diminishing environmental impacts yet despite the rapid adoption of GM crops many of the problems associated with the green revolution remain (Macnaghten & Carro-Ripalda, 2015 ). The pros and cons of GM crops are many and diverse but there is little argument over the ambiguous consequences of this comparatively new technology, and numerous critics noted the potential pros and cons of GM crops as soon as they were launched in the early 1990s (Mannion, 1995a , 1995b , 1995c ).

Pros of GMO Crop Farming

The world population has exceeded 7 billion people and is forecasted to reach beyond 11 billion by 2100 (United Nations, 2017 ). The provision of an adequate food supply for this booming population is an ongoing and tremendous challenge. The companies that develop GM seeds point to this challenge as the key rationale for their need, and they explain that GM seeds will help to meet the “feeding the world” challenge in a number of ways.

Productivity of GM Crops

GM seed companies promised to raise productivity and profitability levels for farmers around the world (Pinstrup-Andersen, 1999 ). GM seed companies had expected GM crops to be adopted by farmers because the traits they were incorporating provided direct operational benefits for farmers that could be linked to increased profits for farmers (Hatfield et al., 2014 ). The proponents of GM crops have argued that the application of GM technology would fundamentally improve the efficiency, resiliency, and profitability of farming (Apel, 2010 ). In addition GM seed companies argue that the adoption of GM crops helps to reduce the application of pesticides, which has a direct impact on the sustainability of the cropping systems (Lal, 2004 ) as well as profitability for farmers (Morse, Mannion, & Evans, 2011 ). Some have even suggested that the production of GM crops creates a halo effect for nearby non-GM crops by reducing pest pressures within regions that are primarily sown to GM crops (Mannion & Morse, 2013 ).

There is an expectation widely held by those in agriculture that GM seeds increase yields, or at least protect yield potential. GM crops with resistance to insects and herbicides can substantially simplify crop management and reduce crop losses, leading to increased yields (Pray, Jikun Huang, Hu, & Rozelle, 2002 ; Pray, Nagarajan, Huang, Hu, & Ramaswami, 2011 ; Nickson, 2005 ). GM varieties of soybean, cotton, and maize produced 20%, 15%, and 7% higher yield, respectively, than non-GM varieties (Mannion & Morse, 2013 ). The Economic Research Service (ERS) of the United States Department of Agriculture (USDA) noticed a significant relationship between increased crop yields and increased adoption of herbicide- and pesticide-tolerant GM crop seeds, and the USDA reported significantly increased yields when farmers adopted herbicide-tolerant cotton and Bt cotton (USDA, 2009 ). India cultivated a record 11.6 million hectares of Bt cotton planted by 7.7 million small farmers in 2014 , with an adoption rate of 95%, up from 11.0 million hectares in 2013 . The increase from 50,000 hectares in 2002 to 11.6 million hectares in 2014 represents an unprecedented 230-fold increase in 13 years (James, 2014 ). This rapid adoption has been attributed to the increased yields farmers in this region experienced because of the efficacy of the GM seeds on cotton bollworm and the additional income farmers received as a result (James, 2014 ; Morse & Mannion, 2009 ). Similarly, the benefits that were obtained by resource-poor cotton farmers in South Africa have led many smallholders in South Africa and elsewhere in sub-Saharan Africa to accept GM cotton (Hillocks, 2009 ). Similar benefits were also obtained by resource-poor farmers growing Bt maize in the Philippines (James, 2010 ).

Tillage Systems

The adoption of no tillage and minimum tillage practices in agriculture started in the 1980s. In fact, the largest extension of both no tillage and conservation tillage and the concomitant declines in soil erosion significantly predates the release of the first HT varieties of maize and soybean in 1996 (National Research Council [NRC], 2010 ). However, farmers in the United States who adopted HT crops were more likely to practice conservation tillage and vice versa (NRC, 2010 ). There was an increase in HT crops and conservation tillage in the United States during the period of rapid GM crop adoption from 1997–2002 (Fernandez-Cornejo, Hallahan, Nehring, Wechsler, & Grube, 2012 ). Soybeans genetically engineered with HT traits have been the most widely and rapidly adopted GM crop in the United States, followed by HT cotton. Adoption of HT soybeans increased from 17% of U.S. soybean acreage in 1997 to 68% in 2001 and 93% in 2010 . Plantings of HT cotton expanded from about 10% of U.S. acreage in 1997 to 56% in 2001 and 78% in 2010 (Fernandez-Cornejo et al., 2012 ). Some argue that the adoption of GM HT varieties resulted in farmers’ deciding to use conservation tillage, or farmers who were practicing conservation tillage may have adopted GM HT crops more readily (Mauro & McLachlan, 2008 ). Adoption of HT soybean has a positive and highly significant impact on the adoption of conservation tillage in the United States (Carpenter, 2010 ). Technologies that promote conservation tillage practices decrease soil erosion in the long term and fundamentally promote soil conservation (Montogomery, 2007 ), while reducing nutrient and carbon loss (Brookes & Barfoot, 2014 ; Giller, Witter, Corbeels, & Pablo, 2009 ; Mannion & Morse, 2013 ; Powlson et al., 2014 ). Adopting HT soybean has decreased the number of tillage operations between 25% and 58% in the United States and in Argentina (Carpenter, 2010 ). The introduction of HT soybean has been cited as an important factor in the rapid increase of no tillage practices in Argentina, and the adoption of no tillage practices in this region has allowed for wheat to be double cropped with soybean which has led to a fundamental increase in farm productivity (Trigo, Cap, Malach, & Villareal, 2009 ). Substantial growth in no tillage production linked to the adoption of GM HT crops has also been noted in Canada. Several authors have reported a positive correlation between the adoption of GM HT canola and the adoption of zero-tillage systems in western Canada (Phillips, 2003 ; Beckie et al., 2006 ; Kleter et al., 2007 ). The no tillage canola production area in western Canada increased from 0.8 million hectares to 2.6 million hectares from 1996 to 2005 . This area covers about half the total canola area in Canada (Qaim & Traxler, 2005 ). In addition, tillage passes among farmers growing HT canola in Canada dropped by more than 70% in this same period (Smyth, Gusta, Belcher, Phillips, & Castle, 2011 ). Fields planted with HT crops in this region require less tillage between crops to manage weeds (Fawcett & Towery, 2003 ; Nickson, 2005 ).

Reductions in tillage and pesticide application have great benefits because they minimize inputs of fossil fuels in farming systems and in doing so, they reduce the carbon footprint of crop production (Baker, Ochsner, Venterea, & Griffis, 2007 ). The mitigation of soil erosion is important with respect to environmental conservation and the conservation of productivity potential. The adoption of no tillage practices would also save on the use of diesel fuel, and it enriches carbon sequestration in soils (Brookes & Barfoot, 2014 ). Brookes and Barfoot ( 2008 ) suggested that the fuel reduction because of GM crop cultivation resulted in a carbon dioxide emissions savings of 1215 × 10 6 Kg. This corresponds to taking more than 500,000 cars off the road. In addition, a further 13.5 × 10 9 Kg of carbon dioxide could be saved through carbon sequestration, which is equivalent to taking 6 million cars off the road. The impact of GM crops on the carbon flows in agriculture may be considered as a positive impact of GM crops on the environment (Knox et al., 2006 ).

Herbicide Tolerance and Pest Management

Herbicide tolerance in GM crops is achieved by the introduction of novel genes. The control of weeds by physical means or by using selective herbicides is time-consuming and expensive (Roller & Harlander, 1998 ). The most widely adopted HT crops are glyphosate tolerant (Dill, CaJabob, & Padgette, 2008 ) colloquially (and commercially for Monsanto) known as “Roundup Ready” crops. Herbicide tolerant GM crops have provided farmers with operational benefits. The main benefits associated with HT canola, for example, were easier and better weed control (Mauro & McLachlan, 2008 ). The development of GM HT canola varieties has also been linked to incremental gains in weed control and canola yield (Harker, Blackshaw, Kirkland, Derksen, & Wall, 2000 ). Despite all of the weed management options available in traditional canola, significant incentives remained for the development of HT canola. The most apparent incentives were special weed problems such as false cleavers ( Galium aparine ) and stork’s bill ( Erodium cicutarium ), and the lack of low-cost herbicide treatments for perennials such as quackgrass ( Agropyron repens ) and Canada thistle ( Cirsium arvense ). Mixtures of herbicides can control many of the common annual and perennial weeds in western Canada but they are expensive and not necessarily reliable (Blackshaw & Harker, 1992 ). In addition, some tank-mixtures led to significant canola injury and yield loss (Harker, Blackshaw, & Kirkland, 1995 ). Thus, canola producers welcomed the prospect of applying a single nonselective herbicide for all weed problems with little concern for specific weed spectrums, growth stages, tank mixture interactions (i.e., antagonism or crop injury) and/or extensive consultations. Two major GM HT canola options are widely used in western Canada. Canola tolerant to glufosinate was the first transgenic crop to be registered in Canada (Oelck et al., 1995 ). Canola tolerant to glyphosate (Roundup Ready) followed shortly thereafter. The GM HT canola offers the possibility of improved weed management in canola via a broader spectrum of weed control and/or greater efficacy on specific weeds (Harker et al., 2000 ). The greatest gains in yield attributed to the adoption of GM HT crops has been for soybean in the United States and Argentina and for GM HT canola in Canada (Brookes & Barfoot, 2008 ).

The reduction of pesticide applications is a major direct benefit of GM crop cultivation: reducing farmers’ exposure to chemicals (Hossain et al., 2004 ; Huang, Hu, Rozelle, & Pray, 2005 ) and lowering pesticide residues in food and feed crops, while also releasing fewer chemicals into the environment and potentially increasing on-farm diversity in insects and pollinators (Nickson, 2005 ). Additionally, improved pest management can reduce the level of mycotoxins in food and feed crops (Wu, 2006 ). Insect resistance in GM crops has been conferred by transferring the gene for toxin creation from the bacterium Bacillus thuringiensis (Bt) into crops like maize. This toxin is naturally occurring in Bt and is presently used as a traditional insecticide in agriculture, including certified organic agriculture, and is considered safe to use on food and feed crops (Roh, Choi, Li, Jin, & Je, 2007 ). GM crops that produce this toxin have been shown to require little or no additional pesticide application even when pest pressure is high (Bawa & Anilakumar, 2013 ). As of the end of the 21st century , insect resistant GM crops were available via three systems (Bt variants). Monsanto and Dow Agrosciences have developed SmartStax maize, which has three pest management attributes, including protection against both above-ground and below-ground insect pests, and herbicide tolerance, which facilitates weed control (Monsanto, 2009 ). SmartStax maize GM varieties were first approved for release in the United States in 2009 and combine traits that were originally intended to be used individually in GM crops (Mannion & Morse, 2013 ). Significant reductions in pesticide use is reported by adoption of Bt maize in Canada, South Africa, and Spain, as well as Bt cotton, notably in China (Pemsl, Waibel, & Gutierrez, 2005 ), India (Qiam, 2003 ), Australia, and the United States (Mannion & Morse, 2013 ).

Human Health

GM crops may have a positive influence on human health by reducing exposure to insecticides (Brimner, Gallivan, & Stephenson, 2005 ; Knox, Vadakuttu, Gordon, Lardner, & Hicks, 2006 ) and by substantially altering herbicide use patterns toward glyphosate, which is considered to be a relatively benign herbicide in this respect (Munkvold, Hellmich, & Rice, 1999 ). However these claims are mostly based on assumption rather than real experimental data. There is generally a lack of public studies on the potential human health impacts of the consumption of food or feed derived from GM crops (Domingo, 2016 ; Wolt et al., 2010 ) and any public work that has been done to date has garnered skepticism and criticism, including, for example, the work by Seralini et al. ( 2013 ). However, the GM crops that are commercialized pass regulatory approval as being safe for human consumption by august competent authorities including the Food and Drug Administration in the United States and the European Food Safety Authority in Europe. Improvement of GM crops that will have a direct influence on health such as decreased allergens (Chu et al., 2008 ), superior levels of protein and carbohydrates (Newell-McGloughlin, 2008 ), greater levels of essential amino acids, essential fatty acids, vitamins and minerals including, multivitamin corn (Naqvi et al., 2009 ; Zhu et al., 2008 ), and maximum zeaxanthin corn (Naqvi et al., 2011 ) hold much promise but have yet to be commercialized. Malnutrition is very common in developing countries where poor people rely heavily on single food sources such as rice for their diet (Gómez-Galera et al., 2010 ). Rice does not contain sufficient quantities of all essential nutrients to prevent malnutrition and GM crops may offer means for supplying more nutritional benefits through single food sources such as rice (White & Broadley, 2009 ). This not only supports people to get the nutrition they require, but also plays a potential role in fighting malnutrition in developing nations (Sakakibara & Saito, 2006 ; Sauter, Poletti, Zhang, & Gruissem, 2006 ). Golden rice is one the most known examples of a bio-fortified GM crop (Potrykus, 2010 ). Vitamin A deficiency renders susceptibility to blindness and affects between 250,000 and 500,000 children annually and is very common in parts of Africa and Asia (Golden Rice Project, 2009 ). A crop like Golden rice could help to overcome the problem of vitamin A deficiency by at least 50% at moderate expense (Stein, Sachdev, & Qaim, 2008 ), yet its adoption has been hampered by activist campaigns (Potrykus, 2012 ).

Environmental Benefits

For currently commercialized GM crops the environmental benefits as previously pointed out are primarily linked to reductions in pesticide use and to reductions in tillage (Christou & Twyman, 2004 ; Wesseler, Scatasta, & El Hadji, 2011 ). Reductions in pesticide use can lead to a greater conservation of beneficial insects and help to protect other non-target species (Aktar, Sengupta, & Chowdhury, 2009 ). Reduced tillage helps to mitigate soil erosion and environmental pollution (Wesseler et al., 2011 ; Brookes & Barfoot, 2008 ) and can lead to indirect environmental benefits including reductions in water pollution via pesticide and fertilizer runoff (Christos & Ilias, 2011 ). It has been claimed that growing Bt maize could help to significantly reduce the use of chemical pesticides and lower the cost of production to some extent (Gewin, 2003 ). The deregulation process for GM crops includes the assessment of potential environmental risks including unintentional effects that could result from the insertion of the new gene (Prakash, Sonika, Ranjana, & Tiwary, 2011 ). Development of GM technology to introduce genes conferring tolerance to abiotic stresses such as drought or inundation, extremes of heat or cold, salinity, aluminum, and heavy metals are likely to enable marginal land to become more productive and may facilitate the remediation of polluted soils (Czako, Feng, He, Liang, & Marton, 2005 ; Uchida et al., 2005 ). The multiplication of GM crop varieties carrying such traits may increase farmers’ capacities to cope with these and other environmental problems (Dunwell & Ford, 2005 ; Sexton & Zilberman, 2011 ). Therefore, GM technology may hold out further hope of increasing the productivity of agricultural land with even less environmental impact (Food and Agriculture Organization [FAO], 2004 ).

Some proponents of GM crops have argued that because they increase productivity they facilitate more sustainable farming practices and can lead to “greener” agriculture. Mannion and Morse ( 2013 ), for example, argue that GM crops require less energy investment in farming because the reduced application of insecticide lowers energy input levels, thereby reducing the carbon footprint. It has been suggested by other authors that the adoption of GM crops may have the potential to reduce inputs such as chemical fertilizers and pesticides (Bennett, Ismael, Morse, & Shankar, 2004 ; Bennett, Phipps, Strange, & Grey, 2004 ). Others note that higher crop yields facilitated by GM crops could offset greenhouse gas emissions at scales similar to those attributed to wind and solar energy (Wise et al., 2009 ). Greenhouse gas emissions from intensive agriculture are also offset by the conservation of non-farmed lands. While untilled forest soils and savannas, for example, act as carbon stores, farmed land is often a carbon source (Burney, Davis, & Lobell, 2010 ).

The Economy

GM crops are sold into a market and are subject to the market in terms of providing a realized value proposition for farmers and value through the food chain in terms of reduced costs of production (Lucht, 2015 ). Currently the GM crops on the market are targeted to farmers and have a value proposition based on economic benefits to farmers via operational benefits (Mauro, McLachlan, & Van Acker, 2009 ). Due to higher yield and lower production cost of GM crops, farmers will get more economic return and produce more food at affordable prices, which can potentially provide benefits to consumers including the poor (Lucht, 2015 ; Lemaux, 2009 ). The most significant economic benefits attributed to GM crop cultivation have been higher gross margins due to lower costs of pest management for farmers (Klümper & Qaim, 2014 ; Qaim, 2010 ). GM varieties have provided a financial benefit for many farmers (Andreasen, 2014 ). In some regions, GM crops have led to reduced labor costs for farmers (Bennett et al., 2005 ). Whether GM crops have helped to better feed the poor and alleviate global poverty is not yet proven (Yuan et al., 2011 ).

Cons of GMO Crop Farming

The intensive cultivation of GM crops has raised a wide range of concerns with respect to food safety, environmental effects, and socioeconomic issues. The major cons are explored for cross-pollination, pest resistance, human health, the environment, the economy, and productivity.

Cross-Pollination

The out crossing of GM crops to non-GM crops or related wild type species and the adventitious mixing of GM and non-GM crops has led to a variety of issues. Because of the asynchrony of the deregulation of GM crops around the world, the unintended presence of GM crops in food and feed trade channels can cause serious trade and economic issues. One example is “LibertyLink” rice, a GM variety of rice developed by Bayer Crop Science, traces of which were found in commercial food streams even before it was deregulated for production in the United States. The economic impact on U.S. rice farmers and millers when rice exports from the United States were halted amounted to hundreds of millions of dollars (Bloomberg News, 2011 ). A more recent example is Agrisure Viptera corn, which was approved for cultivation in the United States in 2009 but had not yet been deregulated in China. Exports of U.S. corn to China contained levels of Viptera corn, and China closed its borders to U.S. corn imports for a period. The National Grain and Feed Association (NGFA) had encouraged Syngenta to stop selling Viptera because of losses U.S. farmers were facing, and there is an ongoing class-action lawsuit in the United States against Syngenta (U.S. District Court, 2017 ). Concerns over the safety of GM food have played a role in decisions by Chinese officials to move away from GM production. Cross-pollination can result in difficulty in maintaining the GM-free status of organic crops and threaten markets for organic farmers (Ellstrand, Prentice, & Hancock, 1999 ; Van Acker, McLean, & Martin, 2007 ). The EU has adopted a GM and non-GM crop coexistence directive that has allowed nation-states to enact coexistence legislation that aims to mitigate economic issues related to adventitious presence of GM crops in non-GM crops (Van Acker et al., 2007 ).

GM crops have also been criticized for promoting the development of pesticide-resistant pests (Dale, Clarke, & Fontes, 2002 ). The development of resistant pests is most due to the overuse of a limited range of pesticides and overreliance on one pesticide. This would be especially true for glyphosate because prior to the development of Roundup Ready crops glyphosate use was very limited and since the advent of Roundup Ready crops there has been an explosion of glyphosate-resistant weed species (Owen, 2009 ). The development of resistant pests via cross-pollination to wild types (weeds) is often cited as a major issue (Friedrich & Kassam, 2012 ) but it is much less of a concern because it is very unlikely (Owen et al., 2011 ; Ellstrand, 2003 ). There are, however, issues when genes transfer from GM to non-GM crops creating unexpected herbicide resistant volunteer crops, which can create challenges and costs for farmers (Van Acker, Brule-Babel, & Friesen, 2004 ; Owen, 2008 ; Mallory-Smith & Zapiola, 2008 ).

Some critics of GM crops express concerns about how certain GM traits may provide substantive advantages to wild type species if the traits are successfully transferred to these wild types. This is not the case for GM HT traits, which would offer no advantage in non-cropped areas where the herbicides are not used, but could be an issue for traits such as drought tolerance (Buiatti, Christou, & Pastore, 2013 ). This situation would be detrimental because the GM crops would grow faster and reproduce more often, allowing them to become invasive (FAO, 2015 ). This has sometime been referred to as genetic pollution (Reichman et al., 2006 ). There are also some concerns that insects may develop resistance to the pesticides after ingesting GM pollen (Christou, Capell, Kohli, Gatehouse, & Gatehouse, 2006 ). The potential impact of genetic pollution of this type is unclear but could have dramatic effects on the ecosystem (Stewart et al., 2003 ).

Pest Resistance

Repeated use of a single pesticide over time leads to the development of resistance in populations of the target species. The extensive use of a limited number of pesticides facilitated by GM crops does accelerate the evolution of resistant pest populations (Bawa & Anilakumar, 2013 ). Resistance evolution is a function of selection pressure from use of the pesticide and as such it is not directly a function of GM HT crops for example, but GM HT crops have accelerated the development of glyphosate resistant weeds because they have promoted a tremendous increase in the use of glyphosate (Owen, 2009 ). Farmers have had to adjust to this new problem and in some cases this had added costs for farmers (Mauro, McLachlan, & Van Acker, 2009 ; Mannion & Morse, 2013 ). The management of GM HT volunteers has also produced challenges for some farmers. These are not resistant weeds as they are not wild type species, but for farmers they are herbicide-resistant weeds in an operational sense (Knispel, McLachlan, & Van Acker, 2008 ; Liu et al., 2015 ). Pink bollworm has become resistant to the first generation GM Bt cotton in India (Bagla, 2010 ). Similar pest resistance was also later identified in Australia, China, Spain, and the United States (Tabashnik et al., 2013 ). In 2012 , army worms were found resistant to Dupont-Dow’s Bt corn in Florida (Kaskey, 2012 ), and the European corn borer is also capable of developing resistance to Bt maize (Christou et al., 2006 ).

Although the deregulation of GM crops includes extensive assessments of possible human health impacts by competent authorities there are still many who hold concerns about the potential risks to human health of GM crops. For some this is related to whether transgenesis itself causes unintended consequences (Domingo, 2016 ), while for others it is concerns around the traits that are possible using GM (Herman, 2003 ). Some criticize the use of antibiotic resistance as markers in the transgenesis procedure and that this can facilitate antibiotic resistance development in pathogens that are a threat to human health (Key, Ma, & Drake, 2008 ). Many critics of GM crops express concerns about allergenicity (Lehrer & Bannon, 2005 ). Genetic modification often adds or mixes proteins that were not native to the original plant, which might cause new allergic reactions in the human body (Lehrer & Bannon, 2005 ). Gene transfer from GM foods to cells of the body or to bacteria in the gastrointestinal tract would cause concern if the transferred genetic material unfavorably influences human health, but the probability of this occurring is remote. Other concerns include the possibility of GM crops somehow inducing mutations in human genes (Ezeonu, Tagbo, Anike, Oje, & Onwurah, 2012 ) or other unintended consequences (Yanagisawa, 2004 ; Lemaux, 2009 ; Gay & Gillespie, 2005 ; Wesseler, Scatasta, & El Hadji, 2011 ) but commentary by these authors is speculative and is not based on experimentation with current GM crops.

Environment

For currently commercialized GM crops the potential environmental impacts are mostly related to how these crops impact farming systems. Some argue that because crops like Roundup Ready soybean greatly simplify weed management they facilitate simple farming systems including monocultures (Dunwell & Ford, 2005 ). The negative impact of monocultures on the environment is well documented and so this might be considered an indirect environmental effect of GM crops (Nazarko, Van Acker, & Entz, 2005 ; Buiatti, Christou, & Pastore, 2013 ). Other concerns that have been raised regarding GM crops include the effects of transgenic on the natural landscape, significance of gene flow, impact on non-target organisms, progression of pest resistance, and impacts on biodiversity (Prakash et al., 2011 ). Again, many of these concerns may be more a function of the impacts of simple and broad-scale farming practices facilitated by GM crops rather than GM crops per se. However, there has been considerable concern over the environmental impact of Bt GM crops highlighted by studies that showed the potential impact on monarch butterfly populations (Dively et al., 2004 ). This begged questions then about what other broader effects there may be on nontarget organisms both direct and indirect (Daniell, 2002 ). In addition, there may be indirect effects associated with how GM crops facilitate the evolution of pesticide resistant pests in that the follow-on control of these pest populations may require the use of more pesticides and often older chemistries that may be more toxic to the environment in the end (Nazarko et al., 2005 ).

Bringing a GM crop to market can be both expensive and time consuming, and agricultural bio-technology companies can only develop products that will provide a return on their investment (Ramaswami, Pray, & Lalitha, 2012 ). For these companies, patent infringement is a big issue. The price of GM seeds is high and it may not be affordable to small farmers (Ramaswami et al., 2012 ; Qaim, 2009 ). A considerable range of problems has been associated with GM crops, including debt and increased dependence on multinational seed companies, but these can also be combined with other agricultural technologies to some extent (Kloppenburg, 1990 ; Finger et al., 2011 ). The majority of seed sales for the world’s major crops are controlled by a few seed companies. The issues of private industry control and their intellectual property rights over seeds have been considered problematic for many farmers and in particular small farmers and vulnerable farmers (Fischer, Ekener-Petersen, Rydhmer, & Edvardsson Björnberg, 2015 ; Mosher & Hurburgh, 2010 ). In addition, efforts by GM seed companies to protect their patented seeds through court actions have created financial and social challenges for many farmers (Marvier & Van Acker, 2005 ; Semal, 2007 ). There is considerable debate about the extent to which GM crops bring additional value to small and vulnerable farmers with strong opinions on both sides (Park, McFarlane, Phipps, & Ceddia, 2011 ; Brookes & Barfoot, 2010 ; James, 2010 ; Smale et al., 2009 ; Subramanian & Qaim, 2010 ). As the reliance on GM seeds extends, concerns grow about control over the food supply via seed ownership and the impacts on the diversity of seed sources, which can impact the resilience of farming systems across a region (Key et al., 2008 ). The risk of GM crops to the world economy can be significant. Global food production is dominated by a few seed companies, and they have increased the dependence of developing countries on industrialized nations (Van Acker, Cici, Michael, Ryan, & Sachs, 2015 ).

Productivity

Justification for GM crops on the basis of the need to feed the world is often used by proponents of the technology, but the connection between GM crops and feeding the world is not direct. GM crops are used by farmers and are sold primarily on the basis of their direct operational benefits to farmers, including the facilitation of production and/or more production (Mauro et al., 2009 ). Farmers realize these benefits in terms of cost savings or increased production or both and are looking to increase their margins by using the technology. Companies producing GM seeds can be very successful if they are able to capture a greater share of a seed market because they supply farmers with operational benefits such as simplified weed management (Blackshaw & Harker, 1992 ) even if there are no productivity gains. In addition, the traits in GM crops on the market as of the early part of the 21st century are not yield traits per se but are yield potential protection traits that may or may not result in greater productivity.

Conclusions

Genetic modification via recombinant DNA technology is compelling because it does provide a means for bringing truly novel traits into crops and the adoption of GM crops has been rapid in a range of countries around the world. Only a very limited number of traits have been incorporated to date into GM crops, the two primary traits being herbicide tolerance (HT) and insect resistance. Nonetheless, farmers who have adopted GM crops have benefited from the operational benefits they provide, and current GM crops have facilitated the adoption of more sustainable farming practices, in particular, reduced tillage. The ongoing asynchronous approvals of GM crops around the world mean that there will always be issues related to the adventitious presence of GM crops in crop shipments and trade disruptions. Pollen mediated gene flow from crop to crop, and seed admixtures are challenges of GM crop farming and agricultural marketing as a result. The adoption of GM HT crops has also accelerated the evolution of herbicide resistant weeds, which has created additional operational challenges and costs for farmers. The GM crops commercialized to date have all been deregulated and deemed to be safe to the environment and safe in terms of human health by competent authorities around the world, including the European Food Safety Association. There remain, however, critics of the technology who point to a lack of public research on the potential risks of GM and GM crops. GM crops will continue to be developed because they provide real operational benefits for farmers, who are the ones who purchase the seeds. The novelty of the technology and its potential to bring almost any trait into crops mean that there needs to remain dedicated diligence on the part of regulators to ensure that no GM crops are deregulated that may in fact pose risks to human health or the environment, but there will also remain the promise of the value of novel inventions that bring benefits to consumers and the environment. The same will be true for the next wave of new breeding technologies, which include gene editing technologies such as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) (Cong et al., 2013 ). These new technologies have even greater potential for modifying crops than GM technology and they avoid some of the characteristics of GM technology that have underpinned criticisms including, for example, the presence of foreign DNA.

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Biology, Health, Conservation, Social Studies, Economics

Tearless GM Onion

GM crops may be modified to improve yield, enhance nutrition, or better adapt to environmental conditions. They can even be altered to resist pests or eliminate unwanted effects, like this type of onion that doesn't cause people to tear up when chopped.

Photograph by Redux Pictures LLC

Hunger is one of the greatest global challenges of the 21st century. Despite some improvements within the last two decades, global hunger is again on the rise, with 2016 data indicating that more than 800 million people around the world suffer from malnutrition . Children under five years of age represent 150 million of those affected, and for roughly three million of these children every year, the struggle ends in death. When faced with such staggering statistics, it is natural to wish for one simple solution to prevent these deaths and rid the world of hunger . Use of genetically modified (GM) crops is among the proposed solutions—but is it truly a viable solution? GM crops are plants that have been modified, using genetic engineering, to alter their DNA sequences to provide some beneficial trait. For example, genetic engineering can improve crop yield , resulting in greater production of the target crop. Scientists can also engineer pest-resistant crops, helping local farmers better withstand environmental challenges that might otherwise wipe out a whole season of produce . Crops can even be engineered to be more nutritious, providing critical vitamins to populations that struggle to get specific nutrients needed for healthy living. However, GM seeds are produced primarily by only a few large companies who own the intellectual property for the genetic variations. A transition to GM crops would closely align global food production with the activities of a few key companies. From an economic standpoint, that poses a risk to long-term food security by creating the potential for a single-point failure. If that company failed, then the crop it provides would not be available to the people who depend on that crop. Moreover, a large proportion of those affected by malnutrition are small farmers in sub-Saharan Africa, where use of GM crops is less common. Since attitudes toward GM crops tend to correlate with education levels and access to information about the technology, there is a concern that sub-Saharan African farmers may be hesitant to adopt GM crops. More generally, public perception of GM foods is plagued by concerns of safety, from the potential for allergic response to the possible transfer of foreign DNA to non-GM plants in the area. None of these concerns are backed by evidence, but they persist nonetheless. Whether based on legitimate concerns or lack of scientific information and understanding, local rejection of GM crops has the potential to derail efforts to use these crops as a tool against malnutrition . However, there are case stories for success: Adoption of GM cotton in India has improved family income and, as a result, reduced hunger . While there are these controversies and complexities that pose challenges for the use of GM foods, these are secondary to a larger issue. We already live in a world that produces enough food to feed everyone. Thus, hunger results from inequity, not food shortage. Unequal distribution of quality food among communities suffering from poverty is the primary culprit in today’s world hunger , not abundance or quantity of food stocks. For those suffering from malnutrition , access to quality food depends on a variety of political, environmental, and socioeconomic factors—most notably, armed conflict and natural disasters . When viewed through this lens, GM crops may have a role to play in combatting global hunger , but merely increasing crop production or nutritional value (via any method) will not solve the larger problem of inequity in access to food. For example, farmers whose livelihoods depend on production of commercial crops rather than food staples may be able to increase their income by growing GM crops, affording them the financial resources to purchase more or higher-quality food. Moreover, GM crops might better withstand certain natural disasters , such as drought. However, since data shows that political unrest is the primary driver of hunger , it is unclear whether these farmers would be able to sell their products or use their income on nutritional food sources within a country plagued by conflict. Unfortunately, GM foods are not the cure-all to hunger the world needs. The path to eradicating global hunger is more complex than any one solution and is in fact far more complex than only addressing food quantity or quality. The United Nations Global Goals for Sustainable Development address world hunger in Goal 2: Zero Hunger , which aims to “end hunger , achieve food security and improved nutrition and promote sustainable agriculture.” This goal lays the foundation to combatting world hunger via a multipronged approach, including political action and reduction of violence, agricultural and technical innovations, efforts to end poverty , and educational initiatives. Luckily, with allies such as the United Nations Children’s Fund (UNICEF) and the World Food Programme, this grand challenge may be achievable—and maybe GM foods will play a role, but they cannot be relied upon as a magical solution.

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Genetically modified crops: current status and future prospects

Affiliations.

• 1 ICAR-Indian Institute of Maize Research, Pusa Campus, New Delhi, 110012, India. [email protected].
• 2 ICAR-Indian Institute of Maize Research, Pusa Campus, New Delhi, 110012, India.
• 3 National Institute for Research in Environmental Health, Bhopal, 462001, India.
• 4 ICAR-Indian Institute of Maize Research, PAU Campus, Ludhiana, 141004, India.
• PMID: 32236850
• DOI: 10.1007/s00425-020-03372-8

While transgenic technology has heralded a new era in crop improvement, several concerns have precluded their widespread acceptance. Alternative technologies, such as cisgenesis and genome-editing may address many of such issues and facilitate the development of genetically engineered crop varieties with multiple favourable traits. Genetic engineering and plant transformation have played a pivotal role in crop improvement via introducing beneficial foreign gene(s) or silencing the expression of endogenous gene(s) in crop plants. Genetically modified crops possess one or more useful traits, such as, herbicide tolerance, insect resistance, abiotic stress tolerance, disease resistance, and nutritional improvement. To date, nearly 525 different transgenic events in 32 crops have been approved for cultivation in different parts of the world. The adoption of transgenic technology has been shown to increase crop yields, reduce pesticide and insecticide use, reduce CO 2 emissions, and decrease the cost of crop production. However, widespread adoption of transgenic crops carrying foreign genes faces roadblocks due to concerns of potential toxicity and allergenicity to human beings, potential environmental risks, such as chances of gene flow, adverse effects on non-target organisms, evolution of resistance in weeds and insects etc. These concerns have prompted the adoption of alternative technologies like cisgenesis, intragenesis, and most recently, genome editing. Some of these alternative technologies can be utilized to develop crop plants that are free from any foreign gene hence, it is expected that such crops might achieve higher consumer acceptance as compared to the transgenic crops and would get faster regulatory approvals. In this review, we present a comprehensive update on the current status of the genetically modified (GM) crops under cultivation. We also discuss the issues affecting widespread adoption of transgenic GM crops and comment upon the recent tools and techniques developed to address some of these concerns.

Keywords: Cisgenesis; GM crops; Genome editing; Intragenesis; Public concerns; Transgenics.

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September 1, 2013

13 min read

The Truth about Genetically Modified Food

Proponents of genetically modified crops say the technology is the only way to feed a warming, increasingly populous world. Critics say we tamper with nature at our peril. Who is right?

By David H. Freedman

Robert Goldberg sags into his desk chair and gestures at the air. “Frankenstein monsters, things crawling out of the lab,” he says. “This the most depressing thing I've ever dealt with.”

Goldberg, a plant molecular biologist at the University of California, Los Angeles, is not battling psychosis. He is expressing despair at the relentless need to confront what he sees as bogus fears over the health risks of genetically modified (GM) crops. Particularly frustrating to him, he says, is that this debate should have ended decades ago, when researchers produced a stream of exonerating evidence: “Today we're facing the same objections we faced 40 years ago.”

Across campus, David Williams, a cellular biologist who specializes in vision, has the opposite complaint. “A lot of naive science has been involved in pushing this technology,” he says. “Thirty years ago we didn't know that when you throw any gene into a different genome, the genome reacts to it. But now anyone in this field knows the genome is not a static environment. Inserted genes can be transformed by several different means, and it can happen generations later.” The result, he insists, could very well be potentially toxic plants slipping through testing.

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Williams concedes that he is among a tiny minority of biologists raising sharp questions about the safety of GM crops. But he says this is only because the field of plant molecular biology is protecting its interests. Funding, much of it from the companies that sell GM seeds, heavily favors researchers who are exploring ways to further the use of genetic modification in agriculture. He says that biologists who point out health or other risks associated with GM crops—who merely report or defend experimental findings that imply there may be risks—find themselves the focus of vicious attacks on their credibility, which leads scientists who see problems with GM foods to keep quiet.

Whether Williams is right or wrong, one thing is undeniable: despite overwhelming evidence that GM crops are safe to eat, the debate over their use continues to rage, and in some parts of the world, it is growing ever louder. Skeptics would argue that this contentiousness is a good thing—that we cannot be too cautious when tinkering with the genetic basis of the world's food supply. To researchers such as Goldberg, however, the persistence of fears about GM foods is nothing short of exasperating. “In spite of hundreds of millions of genetic experiments involving every type of organism on earth,” he says, “and people eating billions of meals without a problem, we've gone back to being ignorant.”

So who is right: advocates of GM or critics? When we look carefully at the evidence for both sides and weigh the risks and benefits, we find a surprisingly clear path out of this dilemma.

Benefits and worries

The bulk of the science on GM safety points in one direction. Take it from David Zilberman, a U.C. Berkeley agricultural and environmental economist and one of the few researchers considered credible by both agricultural chemical companies and their critics. He argues that the benefits of GM crops greatly outweigh the health risks, which so far remain theoretical. The use of GM crops “has lowered the price of food,” Zilberman says. “It has increased farmer safety by allowing them to use less pesticide. It has raised the output of corn, cotton and soy by 20 to 30 percent, allowing some people to survive who would not have without it. If it were more widely adopted around the world, the price [of food] would go lower, and fewer people would die of hunger.”

In the future, Zilberman says, those advantages will become all the more significant. The United Nations Food and Agriculture Organization estimates that the world will have to grow 70 percent more food by 2050 just to keep up with population growth. Climate change will make much of the world's arable land more difficult to farm. GM crops, Zilberman says, could produce higher yields, grow in dry and salty land, withstand high and low temperatures, and tolerate insects, disease and herbicides.

Credit: Jen Christiansen

Despite such promise, much of the world has been busy banning, restricting and otherwise shunning GM foods. Nearly all the corn and soybeans grown in the U.S. are genetically modified, but only two GM crops, Monsanto's MON810 maize and BASF's Amflora potato, are accepted in the European Union. Ten E.U. nations have banned MON810, and although BASF withdrew Amflora from the market in 2012, four E.U. nations have taken the trouble to ban that, too. Approval of a few new GM corn strains has been proposed there, but so far it has been repeatedly and soundly voted down. Throughout Asia, including in India and China, governments have yet to approve most GM crops, including an insect-resistant rice that produces higher yields with less pesticide. In Africa, where millions go hungry, several nations have refused to import GM foods in spite of their lower costs (the result of higher yields and a reduced need for water and pesticides). Kenya has banned them altogether amid widespread malnutrition. No country has definite plans to grow Golden Rice, a crop engineered to deliver more vitamin A than spinach (rice normally has no vitamin A), even though vitamin A deficiency causes more than one million deaths annually and half a million cases of irreversible blindness in the developing world.

Globally, only a tenth of the world's cropland includes GM plants. Four countries—the U.S., Canada, Brazil and Argentina—grow 90 percent of the planet's GM crops. Other Latin American countries are pushing away from the plants. And even in the U.S., voices decrying genetically modified foods are becoming louder. In 2016 the U.S. federal government passed a law requiring labeling of GM ingredients in food products, replacing GM-labeling laws in force or proposed in several dozen states.

The fear fueling all this activity has a long history. The public has been worried about the safety of GM foods since scientists at the University of Washington developed the first genetically modified tobacco plants in the 1970s. In the mid-1990s, when the first GM crops reached the market, Greenpeace, the Sierra Club, Ralph Nader, Prince Charles and a number of celebrity chefs took highly visible stands against them. Consumers in Europe became particularly alarmed: a survey conducted in 1997, for example, found that 69 percent of the Austrian public saw serious risks in GM foods, compared with only 14 percent of Americans.

In Europe, skepticism about GM foods has long been bundled with other concerns, such as a resentment of American agribusiness. Whatever it is based on, however, the European attitude reverberates across the world, influencing policy in countries where GM crops could have tremendous benefits. “In Africa, they don't care what us savages in America are doing,” Zilberman says. “They look to Europe and see countries there rejecting GM, so they don't use it.” Forces fighting genetic modification in Europe have rallied support for “the precautionary principle,” which holds that given the kind of catastrophe that would emerge from loosing a toxic, invasive GM crop on the world, GM efforts should be shut down until the technology is proved absolutely safe.

But as medical researchers know, nothing can really be “proved safe.” One can only fail to turn up significant risk after trying hard to find it—as is the case with GM crops.

A clean record

The human race has been selectively breeding crops, thus altering plants' genomes, for millennia. Ordinary wheat has long been strictly a human-engineered plant; it could not exist outside of farms, because its seeds do not scatter. For some 60 years scientists have been using “mutagenic” techniques to scramble the DNA of plants with radiation and chemicals, creating strains of wheat, rice, peanuts and pears that have become agricultural mainstays. The practice has inspired little objection from scientists or the public and has caused no known health problems.

The difference is that selective breeding or mutagenic techniques tend to result in large swaths of genes being swapped or altered. GM technology, in contrast, enables scientists to insert into a plant's genome a single gene (or a few of them) from another species of plant or even from a bacterium, virus or animal. Supporters argue that this precision makes the technology much less likely to produce surprises. Most plant molecular biologists also say that in the highly unlikely case that an unexpected health threat emerged from a new GM plant, scientists would quickly identify and eliminate it. “We know where the gene goes and can measure the activity of every single gene around it,” Goldberg says. “We can show exactly which changes occur and which don't.”

And although it might seem creepy to add virus DNA to a plant, doing so is, in fact, no big deal, proponents say. Viruses have been inserting their DNA into the genomes of crops, as well as humans and all other organisms, for millions of years. They often deliver the genes of other species while they are at it, which is why our own genome is loaded with genetic sequences that originated in viruses and nonhuman species. “When GM critics say that genes don't cross the species barrier in nature, that's just simple ignorance,” says Alan McHughen, a plant molecular geneticist at U.C. Riverside. Pea aphids contain fungi genes. Triticale is a century-plus-old hybrid of wheat and rye found in some flours and breakfast cereals. Wheat itself, for that matter, is a cross-species hybrid. “Mother Nature does it all the time, and so do conventional plant breeders,” McHughen says.

Could eating plants with altered genes allow new DNA to work its way into our own? It is possible but hugely improbable. Scientists have never found genetic material that could survive a trip through the human gut and make it into cells. Besides, we are routinely exposed to—and even consume—the viruses and bacteria whose genes end up in GM foods. The bacterium Bacillus thuringiensis , for example, which produces proteins fatal to insects, is sometimes enlisted as a natural pesticide in organic farming. “We've been eating this stuff for thousands of years,” Goldberg says.

In any case, proponents say, people have consumed as many as trillions of meals containing genetically modified ingredients over the past few decades. Not a single verified case of illness has ever been attributed to the genetic alterations. Mark Lynas, a prominent anti-GM activist who in 2013 publicly switched to strongly supporting the technology, has pointed out that every single news-making food disaster on record has been attributed to non-GM crops, such as the Escherichia coli –infected organic bean sprouts that killed 53 people in Europe in 2011.

Critics often disparage U.S. research on the safety of genetically modified foods, which is often funded or even conducted by GM companies, such as Monsanto. But much research on the subject comes from the European Commission, the administrative body of the E.U., which cannot be so easily dismissed as an industry tool. The European Commission has funded 130 research projects, carried out by more than 500 independent teams, on the safety of GM crops. None of those studies found any special risks from GM crops.

Plenty of other credible groups have arrived at the same conclusion. Gregory Jaffe, director of biotechnology at the Center for Science in the Public Interest, a science-based consumer-watchdog group in Washington, D.C., takes pains to note that the center has no official stance, pro or con, with regard to genetically modifying food plants. Yet Jaffe insists the scientific record is clear. “Current GM crops are safe to eat and can be grown safely in the environment,” he says. The American Association for the Advancement of Science, the American Medical Association and the National Academy of Sciences have all unreservedly backed GM crops. The U.S. Food and Drug Administration, along with its counterparts in several other countries, has repeatedly reviewed large bodies of research and concluded that GM crops pose no unique health threats. Dozens of review studies carried out by academic researchers have backed that view.

Opponents of genetically modified foods point to a handful of studies indicating possible safety problems. But reviewers have dismantled almost all of those reports. For example, a 1998 study by plant biochemist Árpád Pusztai, then at the Rowett Institute in Scotland, found that rats fed a GM potato suffered from stunted growth and immune system–related changes. But the potato was not intended for human consumption—it was, in fact, designed to be toxic for research purposes. The Rowett Institute later deemed the experiment so sloppy that it refuted the findings and charged Pusztai with misconduct.

Similar stories abound. Most recently, a team led by Gilles-Éric Séralini, a researcher at the University of Caen Lower Normandy in France, found that rats eating a common type of GM corn contracted cancer at an alarmingly high rate. But Séralini has long been an anti-GM campaigner, and critics charged that in his study, he relied on a strain of rat that too easily develops tumors, did not use enough rats, did not include proper control groups and failed to report many details of the experiment, including how the analysis was performed. After a review, the European Food Safety Authority dismissed the study's findings. Several other European agencies came to the same conclusion. “If GM corn were that toxic, someone would have noticed by now,” McHughen says. “Séralini has been refuted by everyone who has cared to comment.”

Some scientists say the objections to GM food stem from politics rather than science—that they are motivated by an objection to large multinational corporations having enormous influence over the food supply; invoking risks from genetic modification just provides a convenient way of whipping up the masses against industrial agriculture. “This has nothing to do with science,” Goldberg says. “It's about ideology.” Former anti-GM activist Lynas agrees. He has gone as far as labeling the anti-GM crowd “explicitly an antiscience movement.”

Persistent doubts

Not all objections to genetically modified foods are so easily dismissed, however. Long-term health effects can be subtle and nearly impossible to link to specific changes in the environment. Scientists have long believed that Alzheimer's disease and many cancers have environmental components, but few would argue we have identified all of them.

And opponents say that it is not true that the GM process is less likely to cause problems simply because fewer, more clearly identified genes are replaced. David Schubert, an Alzheimer's researcher who heads the Cellular Neurobiology Laboratory at the Salk Institute for Biological Studies in La Jolla, Calif., asserts that a single, well-characterized gene can still settle in the target plant's genome in many different ways. “It can go in forward, backward, at different locations, in multiple copies, and they all do different things,” he says. And as U.C.L.A.'s Williams notes, a genome often continues to change in the successive generations after the insertion, leaving it with a different arrangement than the one intended and initially tested. There is also the phenomenon of “insertional mutagenesis,” Williams adds, in which the insertion of a gene ends up quieting the activity of nearby genes.

True, the number of genes affected in a GM plant most likely will be far, far smaller than in conventional breeding techniques. Yet opponents maintain that because the wholesale swapping or alteration of entire packages of genes is a natural process that has been happening in plants for half a billion years, it tends to produce few scary surprises today. Changing a single gene, on the other hand, might turn out to be a more subversive action, with unexpected ripple effects, including the production of new proteins that might be toxins or allergens.

Opponents also point out that the kinds of alterations caused by the insertion of genes from other species might be more impactful, more complex or more subtle than those caused by the intraspecies gene swapping of conventional breeding. And just because there is no evidence to date that genetic material from an altered crop can make it into the genome of people who eat it does not mean such a transfer will never happen—or that it has not already happened and we have yet to spot it. These changes might be difficult to catch; their impact on the production of proteins might not even turn up in testing. “You'd certainly find out if the result is that the plant doesn't grow very well,” Williams says. “But will you find the change if it results in the production of proteins with long-term effects on the health of the people eating it?”

It is also true that many pro-GM scientists in the field are unduly harsh—even unscientific—in their treatment of critics. GM proponents sometimes lump every scientist who raises safety questions together with activists and discredited researchers. And even Séralini, the scientist behind the study that found high cancer rates for GM-fed rats, has his defenders. Most of them are nonscientists, or retired researchers from obscure institutions, or nonbiologist scientists, but the Salk Institute's Schubert also insists the study was unfairly dismissed. He says that as someone who runs drug-safety studies, he is well versed on what constitutes a good-quality animal toxicology study and that Séralini's makes the grade. He insists that the breed of rat in the study is commonly used in respected drug studies, typically in numbers no greater than in Séralini's study; that the methodology was standard; and that the details of the data analysis are irrelevant because the results were so striking.

Schubert joins Williams as one of a handful of biologists from respected institutions who are willing to sharply challenge the GM-foods-are-safe majority. Both charge that more scientists would speak up against genetic modification if doing so did not invariably lead to being excoriated in journals and the media. These attacks, they argue, are motivated by the fear that airing doubts could lead to less funding for the field. Says Williams: “Whether it's conscious or not, it's in their interest to promote this field, and they're not objective.”

Both scientists say that after publishing comments in respected journals questioning the safety of GM foods, they became the victims of coordinated attacks on their reputations. Schubert even charges that researchers who turn up results that might raise safety questions avoid publishing their findings out of fear of repercussions. “If it doesn't come out the right way,” he says, “you're going to get trashed.”

There is evidence to support that charge. In 2009 Nature detailed the backlash to a reasonably solid study published in the Proceedings of the National Academy of Sciences USA by researchers from Loyola University Chicago and the University of Notre Dame. The paper showed that GM corn seemed to be finding its way from farms into nearby streams and that it might pose a risk to some insects there because, according to the researchers' lab studies, caddis flies appeared to suffer on diets of pollen from GM corn. Many scientists immediately attacked the study, some of them suggesting the researchers were sloppy to the point of misconduct.

A way forward

There is a middle ground in this debate. Many moderate voices call for continuing the distribution of GM foods while maintaining or even stepping up safety testing on new GM crops. They advocate keeping a close eye on the health and environmental impact of existing ones. But they do not single out GM crops for special scrutiny, the Center for Science in the Public Interest's Jaffe notes: all crops could use more testing. “We should be doing a better job with food oversight altogether,” he says.

Even Schubert agrees. In spite of his concerns, he believes future GM crops can be introduced safely if testing is improved. “Ninety percent of the scientists I talk to assume that new GM plants are safety-tested the same way new drugs are by the FDA,” he says. “They absolutely aren't, and they absolutely should be.”

Stepped-up testing would pose a burden for GM researchers, and it could slow down the introduction of new crops. “Even under the current testing standards for GM crops, most conventionally bred crops wouldn't have made it to market,” McHughen says. “What's going to happen if we become even more strict?”

That is a fair question. But with governments and consumers increasingly coming down against GM crops altogether, additional testing may be the compromise that enables the human race to benefit from those crops' significant advantages.

David H. Freedman is a journalist who has been covering science, business and technology for more than 30 years.

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Food, genetically modified

These questions and answers have been prepared by WHO in response to questions and concerns from WHO Member State Governments with regard to the nature and safety of genetically modified food.

Genetically modified organisms (GMOs) can be defined as organisms (i.e. plants, animals or microorganisms) in which the genetic material (DNA) has been altered in a way that does not occur naturally by mating and/or natural recombination. The technology is often called “modern biotechnology” or “gene technology”, sometimes also “recombinant DNA technology” or “genetic engineering”. It allows selected individual genes to be transferred from one organism into another, also between nonrelated species. Foods produced from or using GM organisms are often referred to as GM foods.

GM foods are developed – and marketed – because there is some perceived advantage either to the producer or consumer of these foods. This is meant to translate into a product with a lower price, greater benefit (in terms of durability or nutritional value) or both. Initially GM seed developers wanted their products to be accepted by producers and have concentrated on innovations that bring direct benefit to farmers (and the food industry generally).

One of the objectives for developing plants based on GM organisms is to improve crop protection. The GM crops currently on the market are mainly aimed at an increased level of crop protection through the introduction of resistance against plant diseases caused by insects or viruses or through increased tolerance towards herbicides.

Resistance against insects is achieved by incorporating into the food plant the gene for toxin production from the bacterium Bacillus thuringiensis (Bt). This toxin is currently used as a conventional insecticide in agriculture and is safe for human consumption. GM crops that inherently produce this toxin have been shown to require lower quantities of insecticides in specific situations, e.g. where pest pressure is high. Virus resistance is achieved through the introduction of a gene from certain viruses which cause disease in plants. Virus resistance makes plants less susceptible to diseases caused by such viruses, resulting in higher crop yields.

Herbicide tolerance is achieved through the introduction of a gene from a bacterium conveying resistance to some herbicides. In situations where weed pressure is high, the use of such crops has resulted in a reduction in the quantity of the herbicides used.

Generally consumers consider that conventional foods (that have an established record of safe consumption over the history) are safe. Whenever novel varieties of organisms for food use are developed using the traditional breeding methods that had existed before the introduction of gene technology, some of the characteristics of organisms may be altered, either in a positive or a negative way. National food authorities may be called upon to examine the safety of such conventional foods obtained from novel varieties of organisms, but this is not always the case.

In contrast, most national authorities consider that specific assessments are necessary for GM foods. Specific systems have been set up for the rigorous evaluation of GM organisms and GM foods relative to both human health and the environment. Similar evaluations are generally not performed for conventional foods. Hence there currently exists a significant difference in the evaluation process prior to marketing for these two groups of food.

The WHO Department of Food Safety and Zoonoses aims at assisting national authorities in the identification of foods that should be subject to risk assessment and to recommend appropriate approaches to safety assessment. Should national authorities decide to conduct safety assessment of GM organisms, WHO recommends the use of Codex Alimentarius guidelines (See the answer to Question 11 below).

The safety assessment of GM foods generally focuses on: (a) direct health effects (toxicity), (b) potential to provoke allergic reaction (allergenicity); (c) specific components thought to have nutritional or toxic properties; (d) the stability of the inserted gene; (e) nutritional effects associated with genetic modification; and (f) any unintended effects which could result from the gene insertion.

While theoretical discussions have covered a broad range of aspects, the three main issues debated are the potentials to provoke allergic reaction (allergenicity), gene transfer and outcrossing.

Allergenicity

As a matter of principle, the transfer of genes from commonly allergenic organisms to non-allergic organisms is discouraged unless it can be demonstrated that the protein product of the transferred gene is not allergenic. While foods developed using traditional breeding methods are not generally tested for allergenicity, protocols for the testing of GM foods have been evaluated by the Food and Agriculture Organization of the United Nations (FAO) and WHO. No allergic effects have been found relative to GM foods currently on the market.

Gene transfer

Gene transfer from GM foods to cells of the body or to bacteria in the gastrointestinal tract would cause concern if the transferred genetic material adversely affects human health. This would be particularly relevant if antibiotic resistance genes, used as markers when creating GMOs, were to be transferred. Although the probability of transfer is low, the use of gene transfer technology that does not involve antibiotic resistance genes is encouraged.

Outcrossing

The migration of genes from GM plants into conventional crops or related species in the wild (referred to as “outcrossing”), as well as the mixing of crops derived from conventional seeds with GM crops, may have an indirect effect on food safety and food security. Cases have been reported where GM crops approved for animal feed or industrial use were detected at low levels in the products intended for human consumption. Several countries have adopted strategies to reduce mixing, including a clear separation of the fields within which GM crops and conventional crops are grown.

Environmental risk assessments cover both the GMO concerned and the potential receiving environment. The assessment process includes evaluation of the characteristics of the GMO and its effect and stability in the environment, combined with ecological characteristics of the environment in which the introduction will take place. The assessment also includes unintended effects which could result from the insertion of the new gene.

Issues of concern include: the capability of the GMO to escape and potentially introduce the engineered genes into wild populations; the persistence of the gene after the GMO has been harvested; the susceptibility of non-target organisms (e.g. insects which are not pests) to the gene product; the stability of the gene; the reduction in the spectrum of other plants including loss of biodiversity; and increased use of chemicals in agriculture. The environmental safety aspects of GM crops vary considerably according to local conditions.

Different GM organisms include different genes inserted in different ways. This means that individual GM foods and their safety should be assessed on a case-by-case basis and that it is not possible to make general statements on the safety of all GM foods.

GM foods currently available on the international market have passed safety assessments and are not likely to present risks for human health. In addition, no effects on human health have been shown as a result of the consumption of such foods by the general population in the countries where they have been approved. Continuous application of safety assessments based on the Codex Alimentarius principles and, where appropriate, adequate post market monitoring, should form the basis for ensuring the safety of GM foods.

The way governments have regulated GM foods varies. In some countries GM foods are not yet regulated. Countries which have legislation in place focus primarily on assessment of risks for consumer health. Countries which have regulatory provisions for GM foods usually also regulate GMOs in general, taking into account health and environmental risks, as well as control- and trade-related issues (such as potential testing and labelling regimes). In view of the dynamics of the debate on GM foods, legislation is likely to continue to evolve.

GM crops available on the international market today have been designed using one of three basic traits: resistance to insect damage; resistance to viral infections; and tolerance towards certain herbicides. GM crops with higher nutrient content (e.g. soybeans increased oleic acid) have been also studied recently.

The Codex Alimentarius Commission (Codex) is the joint FAO/WHO intergovernmental body responsible for developing the standards, codes of practice, guidelines and recommendations that constitute the Codex Alimentarius, meaning the international food code. Codex developed principles for the human health risk analysis of GM foods in 2003.

Principles for the risk analysis of foods derived from modern biotechnology

The premise of these principles sets out a premarket assessment, performed on a caseby- case basis and including an evaluation of both direct effects (from the inserted gene) and unintended effects (that may arise as a consequence of insertion of the new gene) Codex also developed three Guidelines:

Guideline for the conduct of food safety assessment of foods derived from recombinant-DNA plants

Guideline for the conduct of food safety assessment of foods produced using recombinant-DNA microorganisms

Guideline for the conduct of food safety assessment of foods derived from recombinant-DNA animals

Codex principles do not have a binding effect on national legislation, but are referred to specifically in the Agreement on the Application of Sanitary and Phytosanitary Measures of the World Trade Organization (SPS Agreement), and WTO Members are encouraged to harmonize national standards with Codex standards. If trading partners have the same or similar mechanisms for the safety assessment of GM foods, the possibility that one product is approved in one country but rejected in another becomes smaller.

The Cartagena Protocol on Biosafety, an environmental treaty legally binding for its Parties which took effect in 2003, regulates transboundary movements of Living Modified Organisms (LMOs). GM foods are within the scope of the Protocol only if they contain LMOs that are capable of transferring or replicating genetic material. The cornerstone of the Protocol is a requirement that exporters seek consent from importers before the first shipment of LMOs intended for release into the environment.

The GM products that are currently on the international market have all passed safety assessments conducted by national authorities. These different assessments in general follow the same basic principles, including an assessment of environmental and human health risk. The food safety assessment is usually based on Codex documents.

Since the first introduction on the market in the mid-1990s of a major GM food (herbicide-resistant soybeans), there has been concern about such food among politicians, activists and consumers, especially in Europe. Several factors are involved. In the late 1980s – early 1990s, the results of decades of molecular research reached the public domain. Until that time, consumers were generally not very aware of the potential of this research. In the case of food, consumers started to wonder about safety because they perceive that modern biotechnology is leading to the creation of new species.

Consumers frequently ask, “what is in it for me?”. Where medicines are concerned, many consumers more readily accept biotechnology as beneficial for their health (e.g. vaccines, medicines with improved treatment potential or increased safety). In the case of the first GM foods introduced onto the European market, the products were of no apparent direct benefit to consumers (not significantly cheaper, no increased shelflife, no better taste). The potential for GM seeds to result in bigger yields per cultivated area should lead to lower prices. However, public attention has focused on the risk side of the risk-benefit equation, often without distinguishing between potential environmental impacts and public health effects of GMOs.

Consumer confidence in the safety of food supplies in Europe has decreased significantly as a result of a number of food scares that took place in the second half of the 1990s that are unrelated to GM foods. This has also had an impact on discussions about the acceptability of GM foods. Consumers have questioned the validity of risk assessments, both with regard to consumer health and environmental risks, focusing in particular on long-term effects. Other topics debated by consumer organizations have included allergenicity and antimicrobial resistance. Consumer concerns have triggered a discussion on the desirability of labelling GM foods, allowing for an informed choice of consumers.

The release of GMOs into the environment and the marketing of GM foods have resulted in a public debate in many parts of the world. This debate is likely to continue, probably in the broader context of other uses of biotechnology (e.g. in human medicine) and their consequences for human societies. Even though the issues under debate are usually very similar (costs and benefits, safety issues), the outcome of the debate differs from country to country. On issues such as labelling and traceability of GM foods as a way to address consumer preferences, there is no worldwide consensus to date. Despite the lack of consensus on these topics, the Codex Alimentarius Commission has made significant progress and developed Codex texts relevant to labelling of foods derived from modern biotechnology in 2011 to ensure consistency on any approach on labelling implemented by Codex members with already adopted Codex provisions.

Depending on the region of the world, people often have different attitudes to food. In addition to nutritional value, food often has societal and historical connotations, and in some instances may have religious importance. Technological modification of food and food production may evoke a negative response among consumers, especially in the absence of sound risk communication on risk assessment efforts and cost/benefit evaluations.

Yes, intellectual property rights are likely to be an element in the debate on GM foods, with an impact on the rights of farmers. In the FAO/WHO expert consultation in 2003 , WHO and FAO have considered potential problems of the technological divide and the unbalanced distribution of benefits and risks between developed and developing countries and the problem often becomes even more acute through the existence of intellectual property rights and patenting that places an advantage on the strongholds of scientific and technological expertise. Such considerations are likely to also affect the debate on GM foods.

Certain groups are concerned about what they consider to be an undesirable level of control of seed markets by a few chemical companies. Sustainable agriculture and biodiversity benefit most from the use of a rich variety of crops, both in terms of good crop protection practices as well as from the perspective of society at large and the values attached to food. These groups fear that as a result of the interest of the chemical industry in seed markets, the range of varieties used by farmers may be reduced mainly to GM crops. This would impact on the food basket of a society as well as in the long run on crop protection (for example, with the development of resistance against insect pests and tolerance of certain herbicides). The exclusive use of herbicide-tolerant GM crops would also make the farmer dependent on these chemicals. These groups fear a dominant position of the chemical industry in agricultural development, a trend which they do not consider to be sustainable.

Future GM organisms are likely to include plants with improved resistance against plant disease or drought, crops with increased nutrient levels, fish species with enhanced growth characteristics. For non-food use, they may include plants or animals producing pharmaceutically important proteins such as new vaccines.

WHO has been taking an active role in relation to GM foods, primarily for two reasons:

on the grounds that public health could benefit from the potential of biotechnology, for example, from an increase in the nutrient content of foods, decreased allergenicity and more efficient and/or sustainable food production; and

based on the need to examine the potential negative effects on human health of the consumption of food produced through genetic modification in order to protect public health. Modern technologies should be thoroughly evaluated if they are to constitute a true improvement in the way food is produced.

WHO, together with FAO, has convened several expert consultations on the evaluation of GM foods and provided technical advice for the Codex Alimentarius Commission which was fed into the Codex Guidelines on safety assessment of GM foods. WHO will keep paying due attention to the safety of GM foods from the view of public health protection, in close collaboration with FAO and other international bodies.

Food, Genetically modified

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Genetically modified crops - statistics & facts

Acreage of gm crops, gm crops in the u.s., gm crops in canada, consumer attitudes and understanding, key insights.

Detailed statistics

Acreage of genetically modified crops worldwide 2003-2019

Acreage of genetically modified crops by species 2003-2019

Acreage of genetically modified crops 2015-2019, by country

Editor’s Picks Current statistics on this topic

Crop Production

Global genetically modified crops by countries 2019, based on acreage

Global adoption rate for major biotech crops worldwide 2019, by type

Biotech and non-biotech corn areas in the U.S. 2022

Further recommended statistics

Global overview.

• Premium Statistic Acreage of genetically modified crops worldwide 2003-2019
• Premium Statistic Acreage of genetically modified crops 2015-2019, by country
• Premium Statistic Global genetically modified crops by countries 2019, based on acreage
• Premium Statistic Acreage of genetically modified crops by species 2003-2019
• Basic Statistic Global adoption rate for major biotech crops worldwide 2019, by type

Acreage of genetically modified crops worldwide from 2003 to 2019 (in million hectares)

Acreage of genetically modified crops worldwide from 2015 to 2019, by leading country (in million hectares)*

Area of genetically modified (GM) crops worldwide in 2019, by country (in million hectares)

Acreage of genetically modified crops from 2003 to 2019, by species (in million hectares)

Adoption of GM technology among selected major crops worldwide in 2019, by type*

• Premium Statistic Acreage of major genetically engineered crops in the U.S. by type 2019
• Premium Statistic Percentage of genetically modified crops in the U.S. by type 1997, 2018, 2019 & 2020
• Premium Statistic U.S. acreage of genetically modified corn 2014-2019
• Premium Statistic Biotech and non-biotech corn areas in the U.S. 2022
• Basic Statistic Distribution of U.S. biotech corn acres 2006-2023
• Premium Statistic U.S. acreage of genetically modified soybeans 2014-2019
• Premium Statistic U.S. acreage of genetically modified cotton 2014-2019

Acreage of major genetically engineered crops in the U.S. by type 2019

Major genetically modified (GM) crops in the United States in 2019, by crop type (in million hectares)*

Percentage of genetically modified crops in the U.S. by type 1997, 2018, 2019 & 2020

Percentage of genetically modified crops in the U.S. in 1997, 2018, 2019, and 2020, by type (as percent of total acreage)

U.S. acreage of genetically modified corn 2014-2019

Acreage of genetically modified (GM) corn in the United States from 2014 to 2019 (in million hectares)

Biotech and non-biotech corn areas in the U.S. in 2022 (in 1,000 acres)*

Distribution of U.S. biotech corn acres 2006-2023

Distribution of U.S. biotech and non-biotech corn acreage from 2006 to 2023, by type

U.S. acreage of genetically modified soybeans 2014-2019

Acreage of genetically modified (GM) soybeans in the United States from 2014 to 2019 (in million hectares)

U.S. acreage of genetically modified cotton 2014-2019

Acreage of genetically modified (GM) cotton in the United States from 2014 to 2019 (in million acres hectares)

• Premium Statistic Seeded area of genetically engineered crops in Canada 2012-2023
• Premium Statistic Seeded area of genetically engineered canola in Canada 2012-2023
• Premium Statistic Genetically engineered canola share of seeded canola area in Canada 2012-2023
• Premium Statistic Canada's seeded area of genetically engineered soybeans 2012-2023
• Premium Statistic Genetically engineered soybeans share of seeded soybeans area in Canada 2012-2023
• Premium Statistic Seeded area of genetically engineered corn in Canada 2011-2023
• Premium Statistic Genetically engineered corn share of seeded corn area in Canada 2012-2023
• Premium Statistic Seeded area of genetically modified soybeans in Ontario 2012-2024
• Premium Statistic Seeded area of genetically modified soybeans in Quebec 2012-2024
• Premium Statistic Seeded area of genetically modified corn for grains in Ontario 2012-2024
• Premium Statistic Seeded area of genetically modified corn for grains in Quebec 2012-2024

Seeded area of genetically engineered crops in Canada 2012-2023

Seeded area of genetically engineered crops in Canada from 2012 to 2023 (in million hectares)

Seeded area of genetically engineered canola in Canada 2012-2023

Seeded area of genetically engineered canola in Canada from 2012 to 2023 (in million hectares)

Genetically engineered canola share of seeded canola area in Canada 2012-2023

Genetically engineered canola share of seeded canola area in Canada from 2012 to 2023

Canada's seeded area of genetically engineered soybeans 2012-2023

Seeded area of genetically engineered soybeans in Canada from 2012 to 2023 (in million hectares)

Genetically engineered soybeans share of seeded soybeans area in Canada 2012-2023

Genetically engineered soybeans share of seeded soybeans area in Canada from 2012 to 2023

Seeded area of genetically engineered corn in Canada 2011-2023

Seeded area of genetically engineered corn in Canada from 2011 to 2023 (in million hectares)

Genetically engineered corn share of seeded corn area in Canada 2012-2023

Genetically engineered corn share of seeded corn area in Canada from 2012 to 2023

Seeded area of genetically modified soybeans in Ontario 2012-2024

Seeded area of genetically modified soybeans in Ontario from 2012 to 2024 (in 1,000 hectares)

Seeded area of genetically modified soybeans in Quebec 2012-2024

Seeded area of genetically modified soybeans in Quebec from 2012 to 2024 (in 1,000 hectares)

Seeded area of genetically modified corn for grains in Ontario 2012-2024

Seeded area of genetically modified corn for grains in Ontario from 2012 to 2024 (in 1,000 hectares)

Seeded area of genetically modified corn for grains in Quebec 2012-2024

Seeded area of genetically modified corn for grains in Quebec from 2012 to 2024 (in 1,000 hectares)

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Genetically Engineered Crops: Experiences and Prospects (2016)

Chapter: 5 human health effects of genetically engineered crops, 5 human health effects of genetically engineered crops.

In this chapter, the committee examines the evidence that substantiates or negates specific hypotheses and claims about the health risks and benefits associated with foods derived from genetically engineered (GE) crops. There are many reviews and official statements about the safety of foods from GE crops (for example, see Box 5-1 ), but to conduct a fresh examination of the evidence, the committee read through a large number of articles with original data so that the rigor of the evidence could be assessed.

Some of the evidence available to the committee came from documents that were part of the U.S. regulatory process for GE crops conducted by the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). Other evidence came from studies published by regulatory agencies in other countries or by companies, nongovernmental organizations (NGOs), and academic institutions. The committee also sought evidence from the public and from the speakers at its public meetings and webinars. 1

The committee thinks that it is important to make clear that there are limits to what can be known about the health effects of any food, whether non-GE or GE. If the question asked is “Is it likely that eating this food today will make me sick tomorrow?” researchers have methods of getting quantitative answers. However, if the question is “Is it likely that eating

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1 The committee has compiled publicly available information on funding sources and first-author affiliation for the references cited in this chapter; the information is available at https://www.nationalacademies.org/ge-crops .

this food for many years will make me live one or a few years less than if I never eat it?” the answer will be much less definitive. Researchers can provide probabilistic predictions that are based on the available information about the chemical composition of the food, epidemiological data, genetic variability across populations, and studies conducted with animals, but absolute answers are rarely available. Furthermore, most current toxicity studies are based on testing individual chemicals rather than chemical mixtures or whole foods because testing of the diverse mixtures of chemicals experienced by humans is so challenging ( Feron and Groten, 2002 ; NRC, 2007 ; Boobis et al., 2008 ; Hernández et al., 2013 ).

With regard to the issue of uncertainty, it is useful to note that many of the favorable institutional statements about safety of foods from GE crops in Box 5-1 contain caveats, for example: “no overt consequences,” “no effects on human health have been shown,” “are not per se more risky,” and “are not likely to present risks for human health.” Scientific research can answer many questions, but absolute safety of eating specific foods and the safety of other human activities is uncertain.

The review in this chapter begins with an examination of what is known about the safety of foods from non-GE plants and how they are used as counterparts to those from GE crops in food-safety testing. U.S. food-safety regulatory testing for GE products and GE food-safety studies conducted outside the agency structure are then assessed. A variety of hypothesized health risks posed by and benefits of GE crops are examined, and the chapter concludes with a short discussion of the challenges that society will face in assessing the safety of GE foods that are likely to be developed with emerging genetic-engineering technologies.

COMPARING GENETICALLY ENGINEERED CROPS WITH THEIR COUNTERPARTS

An oft-cited risk of GE crops is that the genetic-engineering process could cause “unnatural” changes in a plant’s own naturally occurring proteins or metabolic pathways and result in the unexpected production of toxins or allergens in food ( Fagan et al., 2014 ). Because analysis of risks of the product of the introduced transgene itself is required during risk assessment, the argument for unpredicted toxic chemicals in GE foods is based on the assumption that a plant’s endogenous metabolism is more likely to be disrupted through introduction of new genetic elements via genetic engineering than via conventional breeding or normal environmental stresses on the plant. The review below begins by discussing natural chemical constituents of plants in the context of food safety to provide a background on what the natural plant toxins are and how they vary in non-GE plants. The review then goes on to explain the premise used by regulatory agencies to compare GE crops with their non-GE counterparts.

Endogenous Toxins in Plants

Most chemicals of primary metabolism (for example, those involved in the formation of carbohydrates, proteins, fats, and nucleic acids) are shared between animals and plants and are therefore unlikely to be toxic. Perceived risks associated with alterations of plant compounds arise mainly from alterations of plant-specific molecules, popularly known as plant natural products and technically named secondary metabolites. Collec-

tively, there are more than 200,000 secondary metabolites in the plant kingdom ( Springob and Kutchan, 2009 ). Crop species vary in the number of secondary metabolites that they produce. For example, potato ( Solanum tuberosum ) is known for its high diversity of secondary metabolites and can have more than 20 sesquiterpenes (a single group of related compounds), some of which are thought to confer resistance to diseases ( Kuc, 1982 ). The concentrations of these secondary metabolites within some tissues in a particular plant species may vary from high—for example, chlorogenic acids alone make up about 12 percent of the dry matter of green coffee beans ( Ferruzzi, 2010 )—to trace amounts (many minor saponins in legumes) and may be associated with particular stages of plant development (some found only in seeds) or may increase in response to external stimuli, such as pathogen or herbivore attack, drought, or altered mineral nutrition ( Small, 1996 ; Pecetti et al., 2006 ; Nakabayashi et al., 2014 ). Many secondary metabolites function as protective agents, for example, by absorbing damaging ultraviolet radiation ( Treutter, 2006 ), acting as antinutrients ( Small, 1996 ), or killing or halting insects and pathogens that damage crops ( Dixon, 2001 ). Plant secondary metabolites that protect against pathogen attack have been classified as either phytoanticipins (if they exist in a preformed state in a plant before exposure to a pathogen) or phytoalexins (if their synthesis and accumulation are triggered by pathogen attack) ( VanEtten et al., 1994 ; Ahuja et al., 2012 ). The toxic properties of some plant compounds are understood, but most of these compounds have not been studied. Some secondary metabolites and other products (such as proteins and peptides) in commonly consumed plant materials can be toxic to humans when consumed in large amounts, and examples are listed below:

• Steroidal glycoalkaloids in green potato skin, which can cause gastrointestinal discomfort or, more severely, vomiting and diarrhea.
• Oxalic acid in rhubarb, which can cause symptoms ranging from breathing difficulty to coma.
• Gossypol in cottonseed oil and cake, which can cause respiratory distress, anorexia, impairment of reproductive systems, and interference with immune function in monogastric animals.
• Nonprotein amino acid canavanine in alfalfa sprouts, which can be neurotoxic.
• Hemolytic triterpene saponins in many legume species, which can increase the permeability of red blood cell membranes.
• Cyanogenic glycosides in almonds and cassava, which can cause cyanide poisoning.
• Phototoxic psoralens in celery, which are activated by ultraviolet sunlight and can cause dermatitis and sunburn and increase the risk of skin cancer.

Friedman (2006) provided information that demonstrated that some glycoalkaloids in potato can have both harmful and beneficial effects. The Food and Agriculture Organization has recognized that foods often contain naturally occurring food toxins or antinutrients but that at naturally occurring concentrations in common diets they can be safely consumed by humans ( Novak and Haslberger, 2000 ; OECD, 2000 ). The health risks associated with some secondary metabolites in common foodstuffs are generally well understood, and the plants are either harvested at times when the concentrations of the compounds are low, the tissues with the highest concentrations of toxins are discarded, or, as in the case of cassava ( Manihot esculenta ), the food is prepared with special methods to remove the toxic compounds. In other cases, food preparation may be the cause of the presence of a toxic compound (for example, the formation of the probable carcinogen acrylamide when potatoes are fried at high temperatures or when bread is toasted). Plant breeders have generally screened for toxins that are typical of the plant group from which a crop was domesticated and have excluded plants that have high concentrations of the compounds.

Unintended changes in the concentrations of secondary metabolites can result from conventional breeding ( Sinden and Webb, 1972 ; Hellenas et al., 1995 ). In some cases, conventionally bred varieties have been taken off the market because of unusually high concentrations of a toxic compound, as in the case of a Swedish potato variety that was banned from sale in the 1980s because of high concentrations of glycoalkaloids ( Hellenas et al., 1995 ).

Rather than being a cause of worry, many secondary metabolites are perceived as having potential health benefits for humans and are consumed in increasingly large quantities ( Murthy et al., 2015 ). Examples include the isoflavone phytoestrogens found in a number of leguminous plants, such as soybean ( Glycine max ) and clover ( Trifolium spp.), which have been ascribed beneficial activities, including chemoprevention of breast and prostate cancers, cardiovascular disease, and post-menopausal ailments ( Dixon, 2004 ; Patisaul and Jefferson, 2010 ). Also, various perceived antioxidants, such as anthocyanins ( Martin et al., 2013 ), and some saponins may have anticancer activity ( Joshi et al., 2002 ). There is, however, disagreement as to whether many of the compounds are beneficial or toxic at the concentrations consumed in herbal medicines or dietary supplements (see, for example, Patisaul and Jefferson, 2010 ).

FINDING: Crop plants naturally produce an array of chemicals that protect against herbivores and pathogens. Some of these chemicals can be toxic to humans when consumed in large amounts.

Substantial Equivalence of Genetically Engineered and Non–Genetically Engineered Crops

A major question addressed in the regulation of GE crops is whether the concentrations of the toxic secondary metabolites are affected by genetic engineering. In addition to the plant toxins, nutrients, introduced genes, and proteins and their metabolic products in specific GE crops are assessed with a comparative approach that is generally encompassed by the concept of substantial equivalence.

The concept of substantial equivalence has a long history in safety testing of GE foods. The term and concept were “borrowed from the [U.S. FDA’s] definition of a class of new medical devices that do not differ materially from their predecessors, and thus, do not raise new regulatory concerns” ( Miller, 1999:1042 ). No simple definition of substantial equivalence is found in the regulatory literature on GE foods. In 1993, the Organisation for Economic Co-operation and Development (OECD) explained that the “concept of substantial equivalence embodies the idea that existing organisms used as food, or as a source of food, can be used as the basis for comparison when assessing the safety of human consumption of a food or food component that has been modified or is new” ( OECD, 1993:14 ).

The Codex Alimentarius Commission’s Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants is careful to state that “the concept of substantial equivalence is a key step in the safety assessment process. However, it is not a safety assessment in itself; rather it represents the starting point which is used to structure the safety assessment of a new food relative to its conventional counterpart” ( CAC, 2003:2 ). The Codex guideline also makes clear that a safety assessment of a new food based on the concept of substantial equivalence “does not imply absolute safety of the new product; rather, it focuses on assessing the safety of any identified differences so that the safety of the new product can be considered relative to its conventional counterpart” ( CAC, 2003:2 ). The OECD (2006) came to a similar conclusion. Conflict among stakeholders often comes into play during the determination of what constitutes evidence of differences from substantial equivalence sufficient to justify a detailed food-safety assessment.

The Codex Alimentarius Commission concluded that the concept of substantial equivalence “aids in the identification of potential safety and nutritional issues and is considered the most appropriate strategy to date for safety assessment of foods derived from recombinant-DNA plants” ( CAC, 2003:2 ). Despite some criticism of the substantial-equivalence concept itself (for example, Millstone et al., 1999 ) and operational problems (for example, Novak and Haslberger, 2000 ), it remains the cornerstone for

GE food-safety assessment by regulatory agencies. The present committee examined its use in practice and its empirical limitations.

The precautionary principle, which is described in more detail in Chapter 9 (see Box 9-2 ) is a deliberative principle related to the regulation of health, safety, and the environment and typically involves taking measures to avoid uncertain risks. The precautionary principle has been interpreted in a number of ways, but it is not necessarily incompatible with use of the concept of substantial equivalence. In the case of foods, including GE foods, it can be reasonably argued that even a small adverse chronic effect should be guarded against, given that billions of people could be consuming the foods. However, the degree of precaution taken in the face of uncertainty is a policy decision that varies among countries and according to the specific uncertainty being considered. For example, many European countries and the European Union (EU) as a whole generally take a more precautionary approach with GE foods and climate change whereas the United States has historically taken a more precautionary approach with tobacco products and ozone depletion ( Wiener et al., 2011 ). The reader is directed to Chapter 9 for further discussion of how different regulatory frameworks address uncertainty in the safety of GE foods.

Some differences between a GE food and its non-GE counterpart are intentional and identifiable (for example, the presence of a Bt toxin in maize kernels) or are due to practices directly associated with the use of the GE crops (for example, increased use of glyphosate). Some of the risks posed by the intended changes can be anticipated on the basis of the physiological and biochemical characteristics of the engineered change. There are often established protocols for assessing such risks, especially when a change involves exposure to a known toxin. However, other risks have been hypothesized for GE crops because previous uses of a trait (for example, Bt as an insecticidal spray) did not have consumption of the GE plant products as the route of exposure. New routes of exposure could result in unanticipated effects.

In contrast with such intended differences, some potential differences between GE crops and their non-GE counterparts are unintentional and can be difficult to anticipate and discern ( NRC, 2004 ). Two general sources of unintended differences could affect food safety:

• Unintended effects of the targeted genetic changes on other characteristics of the food (for example, the intended presence of or increase in one compound in plant cells could result in changes in plant metabolism that affect the abundance of other compounds).
• Unintended effects associated with the genetic-engineering process (for example, DNA changes resulting from plant tissue culture).

Much of the concern voiced by some citizens and scientists about the safety of GE foods is focused on potential risks posed by unintended differences. Some of the biochemical and animal testing done by or for government agencies is aimed at assessing the toxicity of such unintended differences, but what is adequate and appropriate testing for assessing specific toxicities is often difficult to determine. In some cases, the unintended effects are somewhat predictable or can be determined; in such cases, tests can be designed. In other cases, the change or risk could be something that has not even been considered, so the only effective testing is of the whole food itself. As discussed in Chapter 6 , there is a tradeoff between costs of such testing and societal benefits of reduction in risks.

The approach of comparing new varieties to existing varieties is just as applicable to crops developed by conventional plant breeding as it is to GE crops (see Chapter 9 ). The discussion above on endogenous toxins (see section “Endogenous Toxins in Plants”) shows that such crops pose some risks. The 2000 National Research Council report Genetically Modified Pest-Protected Plants found that “there appears to be no strict dichotomy between the risks to health and the environment that might be posed by conventional and transgenic pest-protected plants” ( NRC, 2000:4 ). Similarly, the 2004 National Research Council report Safety of Genetically Engineered Foods found that all forms of conventional breeding and genetic engineering may have unintended effects and that the probability of unintended effects of genetic engineering falls within the range of unintended effects of diverse conventional-breeding methods. The 2002 National Research Council report Environmental Effects of Transgenic Plants found that “the transgenic process presents no new categories of risk compared to conventional methods of crop improvement but that specific traits introduced by both approaches can pose unique risks” ( NRC, 2002:5 ). That finding remains valid with respect to food safety and supports the conclusion that novel varieties derived from conventional-breeding methods could be assessed with the substantial-equivalence concept.

FINDING: The concept of substantial equivalence can aid in the identification of potential safety and nutritional issues related to intended and unintended changes in GE crops and conventionally bred crops.

FINDING: Conventional breeding and genetic engineering can cause unintended changes in the presence and concentrations of secondary metabolites.

OVERVIEW OF U.S. REGULATORY TESTING OF RISKS TO HUMAN HEALTH

Although the committee agrees that crops developed through conventional breeding could result in food-safety risks, its statement of task focuses on GE crops. Furthermore, there have been claims and counterclaims about the relative safety of GE crops and their associated technologies compared with conventionally bred crops and their associated technologies. Therefore, the remainder of this chapter examines possible risks and benefits associated with GE crops and assesses the methods used to test them in and beyond government regulatory systems.

Whether testing is done for regulatory purposes or beyond the regulatory realm, it typically involves three categories of testing: acute or chronic animal toxicity tests, chemical compositional analysis, and allergenicity testing or prediction. Although the precision, transparency, specific procedures, and interpretation of results vary among countries, criticisms about the adequacy of testing are not so much country-specific as they are method- and category-specific. For example, there may be arguments about whether a 90-day whole-food animal test is more appropriate than a 28-day test, but the bigger issue is about whether whole-food testing is appropriate. The committee uses a description of the U.S. testing methods as an example, but it mostly examines the criticism of food-safety testing more broadly.

The structure of the U.S. regulatory process for GE crops based on the Coordinated Framework for the Regulation of Biotechnology is briefly reviewed in Chapter 3 and is examined in more detail in Chapter 9 . The focus in this chapter is on the testing itself. The present section provides insight into U.S. procedures by describing the risk-testing methods used for two examples of traits in commercialized GE crops: Bt toxins and crop resistance to the herbicides glyphosate and 2,4-D.

Regulatory Testing of Crops Containing Bt Toxins

EPA considers plant-produced Bt toxins to be “plant-incorporated protectants,” a class of products generally defined as “a pesticidal substance that is intended to be produced and used in a living plant, or in the produce thereof, and the genetic material necessary for the production of that pesticidal substance” (40 CFR §174.3). EPA specifically exempts plant-incorporated protectants whose genetic material codes for a pesticidal substance that is derived from plants that are sexually compatible. Bt toxin genes are not exempted because they come from bacteria (see Chapter 9 for regulatory details).

For Bt toxins produced by GE crops, EPA took into consideration that there was already toxicity testing of Bt toxins in microbial pesticides and

that the toxins were proteins that, if toxic, typically show almost immediate toxicity at low doses ( EPA, 2001a ; also see Box 5-2 ). The pesticidal safety tests mostly involved acute toxicity testing in mice and digestibility studies in simulated gastric fluids because one characteristic of food allergens is that they are not rapidly digested by such fluids.

Box 5-2 provides a verbatim example of the procedures used for testing as reported in EPA fact sheets for the Cry1F Bt toxin so that readers can see what is involved in the testing. The actual research is not typically done by EPA itself. The registrant is usually responsible for testing. Results of the tests of Cry1F show no clinical signs of any toxicity even when Cry1F protein was fed at 576 mg/kg body weight, which would be the equivalent of about ¼ cup of pure Cry1F for a 90.7-kilogram (200-pound) person. Another part of the testing described in Box 5-2 is allergenicity testing. Concerns about the EPA testing methods are discussed in sections below on each category of testing.

Regulatory Testing of Crops Resistant to Glyphosate and 2,4-D and of the New Uses of the Herbicides Themselves

The regulatory actions taken for herbicide-resistant (HR) crops are different from regulatory actions taken to assess Bt crops. With Bt crops, regulatory actions are related to the crop itself. With HR crops, there are regulatory processes for the plant itself and separate regulatory processes for the new kind of exposure that can accompany spraying of a herbicide on a crop or on a growth stage of a crop that has never been sprayed prior to availability of the GE variety.

EPA governs the registration of herbicides such as glyphosate and 2,4-D. Both glyphosate and 2,4-D were registered well before the commercialization of GE crops. However, EPA has authority to re-examine herbicides if their uses or exposure characteristics change.

A good example of such re-examination was the 2014 EPA registration of the Dow AgroSciences Enlist Duo® herbicide, which contains both glyphosate and 2,4-D for use on GE maize ( Zea mays ) and soybean. Because the glyphosate component of Enlist Duo had already been in use on GE maize and soybean, EPA did not conduct further testing of glyphosate alone. However, 2,4-D was registered previously only for applications to maize up to 20 centimeters tall and for preplant applications to soybean. The proposed use of 2,4-D on GE crops was expected to change use patterns and exposure and thereby triggered a safety assessment of the new use 2,4-D. Additionally, EPA compared the toxicity of the formulation that contained both herbicides to the toxicity of the individual herbicides and concluded the formulation did not show greater toxicity or risk compared to either herbicide alone.

In the human health risk assessment portion of the EPA Enlist Duo registration document, the following tests and results with 2,4-D were considered ( EPA, 2014a ):

• An acute dietary test in rats that found a lowest observed-adverse-effect level (LOAEL) of 225 mg/kg (about 1 ounce per 200-pound person).
• A chronic-dietary-endpoint, extended one-generation reproduction toxicity study in rats that found a LOAEL of 46.7 mg/kg-day in females and higher in males.
• Inhalation tests involving data from a 28-day inhalation toxicity study in rats that found a LOAEL of 0.05 mg/L-day.
• Dermal tests that showed no dermal or systemic toxicity after repeated applications to rabbits at the limit dose of 1000 mg/kg-day.
• Reviews of epidemiological and animal studies, which did not support a linkage between human cancer and 2,4-D exposure.

Analysis of the results of those tests and agronomic and environmental assessments resulted in the product’s registration.

EPA received over 400,000 comments in response to the initial proposal to register the new use of 2,4-D. Some of the concerns submitted to EPA were similar to ones some members of the public expressed in public comments to the committee, including questions about whether EPA had considered toxicity of only the active ingredient or of the formulated herbicide and whether it had tested for synergistic effects of 2,4-D and glyphosate. EPA (2014b:7) responded that

acute oral, dermal, and inhalation data, skin and eye irritation data, and skin sensitization data are available for the 2,4-D choline salt and glyphosate formulation for comparison with the 2,4-D parent compound and glyphosate parent compound data, and these test results show similar profiles. The mixture does not show a greater toxicity compared to either parent compound alone. Although no longer duration toxicity studies are available, toxic effects would not be expected as the maximum allowed 2,4-D exposure is at least 100-fold below levels where toxicity to individual chemicals might occur, and exposure to people is far below even that level.

The committee did not have access to the actual data from the registrant. 2

EPA does not regulate the commercialization of the GE herbicide-resistant crops themselves. That is the role of USDA’s Animal and Plant Health Inspection Service (APHIS) under the Plant Protection Act. Under its

2 In November 2015, EPA took steps to withdraw the product’s registration in light of new information that indicated there could be synergistic effects of the two herbicides, which could possibly result in greater toxicity to nontarget plants ( Taylor, 2015 ). A court ruling in January 2016 allowed the herbicide to remain on the market while EPA considered other administrative actions ( Callahan, 2016 ).

statutory authority, APHIS controls and prevents the spread of plant pests (see Box 3-5 ). On the basis of a plant-pest risk assessment ( USDA–APHIS, 2014a ), APHIS concluded that Enlist™ GE herbicide-resistant maize and soybean engineered to be treated with the Enlist Duo herbicide (containing glyphosate and 2,4-D) were unlikely to become plant pests and deregulated them on September 18, 2014 ( USDA–APHIS, 2014b ). In its document on the decision to deregulate Enlist GE herbicide-resistant maize and soybean ( USDA–APHIS, 2014a:ii ), APHIS states a general policy that “if APHIS concludes that the GE organism is unlikely to pose a plant pest risk, APHIS must then issue a regulatory determination of nonregulated status, since the agency does not have regulatory authority to regulate organisms that are not plant pests. When a determination of nonregulated status has been issued, the GE organism may be introduced into the environment without APHIS’ regulatory oversight.”

FDA did not identify any safety or regulatory issues in its consultation with Dow AgroSciences on the Enlist maize and soybean varieties ( FDA, 2013 ). FDA also explained the basis of Dow’s conclusion that Enlist soybean is not “materially different in composition” from other soybean varieties ( FDA, 2013 ):

Dow reports the results of compositional analysis for 62 components in soybean grain, including crude protein, crude fat, ash, moisture, carbohydrates, [acid detergent fiber] ADF, [neutral detergent fiber] NDF, total dietary fiber (TDF), lectin, phytic acid, raffinose, stachyose, trypsin inhibitor, soy isoflavones (i.e., total daidzein, total genistein, total glycitein), minerals, amino acids, fatty acids, and vitamins. No statistically significant differences in the overall treatment effect and the paired contrasts between each of the DAS-44406-6 soybean treatment groups and the control were observed for 29 of the components. A statistically significant difference in the overall treatment effect was observed for 16 components (crude protein, carbohydrates (by difference), NDF, calcium, potassium, cystine, palmitic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, folic acid, γ-tocopherol, total tocopherol, lectin, and trypsin inhibitor). However, differences between the control and the DAS-44406-6 treatment groups were small in magnitude. Differences between DAS-44406-6 soybean and the control were considered not biologically relevant because the mean values were either within the ranges generated using the reference lines, consistent with the ranges of values in the published literature, or both.

FINDING: U.S. regulatory assessment of GE herbicide-resistant crops is conducted by USDA, and by FDA when the crop can be consumed, while the herbicides are assessed by EPA when there are new potential exposures.

FINDING: When mixtures of herbicides are used on a new GE crop, EPA assesses the interaction of the mixture as compared to the individual herbicidal compounds.

Technical Assessment of Human Health Risks Posed by Genetically Engineered Crops

As explained in Chapter 2 , the development and use of GE crops is governed by more than national and regional regulatory standards. In the cases of the GE crops commercially available in the United States and some other countries in 2015, inputs from many public and private institutions regarding their specific concerns have influenced the type and extent of GE crop food-safety tests conducted by companies, agencies, and other researchers. Many stakeholders have criticized the testing used by U.S. and other national regulatory agencies for lacking rigor (for example, Hilbeck et al., 2015 ). Researchers in companies, NGOs, and universities have sometimes conducted more extensive safety tests than are required by national agencies or have reanalyzed existing data, as described below. All testing as of 2015 fell into three categories: animal testing, compositional analysis, and allergenicity testing and prediction.

Animal Testing

Short-Term and Long-Term Rodent Testing with Compounds and Whole Foods . One common criticism of the animal testing conducted by or for regulatory agencies in the United States and elsewhere is related to its short duration (for example, Séralini et al., 2014 ; Smith, 2014 ). Indeed, there is a range in the duration and doses within the test protocols used by regulatory agencies that depends in part on the product. Doses for subchronic and chronic toxicity studies are such that the lowest dose (exposure level), which is many times higher than expected for human exposure, is set to ensure that it does not elicit acute adverse effects that would interfere with examining the potential chronic-effect endpoints. As can be seen in the discussion above, EPA conducted an extended one-generation reproduction toxicity study in male and female rats in its assessment of 2,4-D, and it relied on previous long-term studies for the assessment of cancer risk associated with it. For assessment of the Bt toxin Cry1F and for the bacterially derived proteins in 2,4-D-resistant maize and soybean, company testing submitted to EPA, FDA, and USDA relied on acute toxicity testing. In all the cases above, the experiments were conducted by adding large amounts of a single test chemical to an animal’s diet. Tests with high concentrations of a chemical are typical of EPA testing protocols for pesticides.

What is different between GE crop evaluation and that of general agri-

cultural chemicals is the use of “whole food” tests. These tests are aimed at assessing potential hazards due to the combined intentional and unintentional changes that might have been caused by the genetic engineering of the crop. In such tests, it is not possible to use concentrations higher than what is in the crop itself because potential unintended effects are not typically known. Thus, it is impossible for a researcher to know what compounds should be increased in concentration in a fabricated diet, and the only way to assess such unintended effects is to feed the actual GE crop to test animals. For testing GE maize, soybean, and rice ( Oryza sativa ), 3 flour from kernels or seed is added to an animal’s diet and constitutes between about 10–60 percent of the diet. The high percentages can be used because the crop products are nutritious for the animal. In the case of whole foods that are not typically part of a rodent’s diet, whether GE or non-GE, it is impossible to achieve very high concentrations of the test food because it would cause nutritional imbalance. The whole-food tests done for regulatory agencies are generally conducted for 28 or 90 days with rats, but some researchers have run tests for multiple generations.

The utility of the whole-food tests has been questioned by a number of government agencies and by industry and academic researchers (for example, Ricroch et al., 2014 ), and they are not an automatic part of the regulatory requirements of most countries that have specific GE food-testing requirements ( CAC, 2008 ; Bartholomaeus et al., 2013 ). However, in its 2010 report A Decade of EU-Funded GMO Research (2001–2010) , the European Directorate-General for Research and Innovation concluded that “the data from a well-designed 90-day rodent feeding study, together with data covering the gene insert, the compositional analysis, and the toxicity of the novel gene product, form the optimal basis for a comparative assessment of the safety of [genetically engineered] food and its conventional counterpart in the pre-market situation” ( EC, 2010a:157 ). The European Food Safety Authority (EFSA) developed principles and guidance for establishing protocols for 90-day whole-food studies in rodents at the European Commission’s request ( EFSA, 2011b ), and 90-day, whole-food studies were made mandatory by the European Commission ( EC, 2013 ). Most studies reported in the peer-reviewed literature have concluded that there was a lack of adverse effects of biological or toxicological significance (see, for example, Knudsen and Poulsen, 2007 ; MacKenzie et al., 2007 ; He et al., 2008 , 2009 ; Onose et al., 2008 ; Liu et al., 2012 ), even though some of the studies found statistically significant differences between the GE and non-GE comparator in toxicity.

The criticisms of whole-food tests come from two perspectives. One perspective is that whole-food studies cannot provide useful tests of food

3 GE rice was not commercialized in 2015, but GE varieties in development have been tested.

safety because they are not sensitive enough to detect differences (see, for example, Bartholomaeus et al., 2013 ; Kuiper et al., 2013 ; Ricroch et al., 2013a , 2014 ) and that animal testing is not needed because other types of required testing ensure safety ( Bartholomaeus et al., 2013 ; Ricroch et al., 2014 ). Ricroch et al. (2014) pointed to the costs of the 90-day tests, which they reported as being €250,000 (in 2013 money). The second perspective is that whole-food tests could be useful, but there is concern about their design and conduct or about the parties who conduct them (the companies commercializing the GE crops). That perspective is evident in Séralini et al. (2007) , Domingo and Bordonaba (2011) , Hilbeck et al. (2015) , and Krimsky (2015) . Boxes 5-3 and 5-4 describe some of the specific procedures and practices involved in doing these tests.

The committee heard from invited speakers ( Entine, 2014 ; Jaffe, 2014 ) and members of the public who provided comments at meetings and it received a number of written public comments highlighting the work of one research group ( Séralini et al., 2012 , 2014 ) that has conducted a number of whole-food studies of GE herbicide-resistant and insect-resistant crops and

of direct consumption of glyphosate. Some comments made to the committee pointed to the publications of that research group as evidence that GE crops and foods derived from GE crops were deleterious to human health; other comments questioned the robustness and accuracy of the research. The committee also heard from the lead researcher himself at one of its meetings ( Séralini, 2014 ). Because of the attention garnered by this specific research group, the committee examined the primary research paper from the group and many articles related to it ( Box 5-5 ).

A general question that remains for all whole-food studies using animals is, How many animals, tested for how long, are needed to assess food safety when a whole food is tested? That question is related to the question of how large an effect the tested food would have to have on the animal for it to be detected with the experiment. The statistical procedure called power analysis can answer the first question, but the committee did not find such analyses in articles related to GE crop whole-food studies. The EFSA scientific committee ( EFSA, 2011b ) provided general guidance on power analysis. Figure 5-2 , from the EFSA report, shows the relationship between the number of experimental units (cages with two animals) per treatment group and the power of an experiment in standard-deviation units. Standard deviations quantify how much the measurement of a trait or effect varies among animals that have been given the same diet. The report concluded that, if researchers follow OECD Test No. 408 of 10 males and 10 females per treatment ( OECD, 1998a ), a test should be able to detect a difference equal to about 1 standard deviation (with 90-percent confidence) unless the food has a different effect on males and females, in which case, the smallest difference that could be detected would be about 1.5 standard deviations from the experimental mean.

Because the relationship is quite abstract for the nonstatistician, the committee examined the size of the standard deviations in a number of whole-food safety articles. It found that the sizes of the standard deviations compared with the mean value of a measured trait depended heavily on the trait being measured and on the specific research article. For example, in the Hammond et al. (2004) study, the average white blood cell count for the four treatments, each with 9 or 10 female Sprague-Dawley rats, is 6.84 10 3 /µl, and the average standard deviation is 1.89 10 3 /µl. On the basis of rough calculations, this test would have the power to discern statistically whether the GE food caused an increase in white blood cell count of about 35 percent with about 90-percent confidence. If the male white blood cell count effects and standard deviations were similar to those in females, the test could have found about a 25-percent increase.

OECD (1998a) made general recommendations, such as those used in

Hammond et al. (2004) , for the number of units (cages with two animals) per treatment. Following these guidelines leads to the assumption that less than a 25-percent change in the white blood cell count was not biologically relevant. The EU Standing Committee on the Food Chain and Animal Health adopted the mandatory use of 90-day whole-food testing of GE crops, and its protocols generally follow OECD guidelines for the testing of chemicals ( EC, 2013 ).

EFSA also published a document ( EFSA, 2011c ) that focused specifically on the questions, What is statistical significance? and What is biological relevance? The accessibly written document makes clear that the two are very different and that it is important to decide how large a difference is biologically relevant before designing an experiment to test a null hypothesis of no difference. The problem in most whole-food animal studies is in determining how large a biological difference is relevant. Most of the statistically significant differences observed in the literature on the animal-testing data were around a 10- to 30-percent change, but the authors do not give detailed explanations of why they conclude that a statistically significant difference is not biologically relevant. A general statement is sometimes made that the difference is within the range for the species, but because the range of values for the species typically come from multiple laboratories, such a statement is not useful unless the laboratories, instrumentation, and health of the animals were known to be comparable.

Clearly, the European Commission relied on both expert judgment and citizen concerns in making its assessment of biological relevance of the effects of GE foods in requiring 90-day testing. It is reasonable to ask what balance of the two is the basis for this judgment. As pointed out by the 2002 National Research Council report, “risk analysis of transgenic plants must continue to fulfill two distinct roles: (1) technical support for regulatory decision making and (2) establishment and maintenance of regulatory legitimacy” ( NRC, 2002:6 ). Fulfilling the two roles can lead to different country-specific and region-specific decisions. This issue is discussed further in Chapter 9 .

One specific criticism of the 90-day whole-food studies revolves around an EU-funded project conducted by Poulsen et al. (2007) in which rice was genetically engineered to produce the kidney bean lectin, agglutinin E-form, which is known to have toxic properties. In a 90-day test, rats were fed diets of 60-percent rice with the lectin gene or 60-percent rice without the lectin gene. The researchers concluded that they did not find any meaningful differences between the two treatments. However, in a treatment in which the diets were spiked with 0.1-percent recombinant lectin (a high dose), biological effects including significant differences in weight of small intestines, stomach, and pancreas and in plasma biochemistry were found. Poulsen et al. included results from a preceding 28-day feeding study and

compositional analyses of the rice diets. The criticism involves the question, If a whole-food study with a known toxin does not demonstrate effects, how can the test be considered useful? ( Bartholomaeus et al., 2013 ). If a whole-food study with an animal finds statistically significant effects, there is obviously a need for further safety testing, but when there is a negative result, there is uncertainty as to whether there is an adverse effect on health. In the specific case of lectin gene in rice, one could argue that the statistical power of the whole-food test was insufficient or that, when the toxin is in the structure of the food, it is no longer toxic so the food is safe.

Other Long-Term Studies with Rodents . In addition to the work of Séralini et al. (2012 , 2014 ), there have been other long-term rodent studies, some of which included multiple generations. Magana-Gomez and de la Barca (2009) , Domingo and Bordonaba (2011) , Snell et al. (2012) , and Ricroch et al. (2013b) reviewed the studies. Some found no statistically significant differences, but quite a few found statistically significant differences that the authors generally did not consider biologically relevant, typically without providing data on what was the normal range. In the multigeneration studies, the sire and dam are dosed via the diet before conception, and the parent generation and pups are dosed via the diet throughout the duration of the study to determine multiple generational outcomes, including growth, behavior, and phenotypic characteristics. Some studies have looked at three or four generations. For example, Kiliç and Akay (2008) conducted a three-generation rat study in which 20 percent of the diet was Bt maize or a non- Bt maize that otherwise was genetically similar. All generations of female and male rats were fed the assigned diets, and the third-generation offspring that were fed the diets were sacrificed after 3.5 months for analysis. The authors found statistical differences in kidney and liver weights and long kidney glomerular diameter between the GE and non-GE treatments but considered them not biologically relevant. Similarly, statistically significant differences were observed in amounts of globulin and total protein between the two groups. There was no presentation of standards used for judging what would be a biologically relevant difference or for what the normal range was in the measurements.

The standard deviations in measurements of the traits (that is, effects) of individual animals in a treatment in the long-term studies were similar to those of studies of shorter duration. Therefore, the power of the tests to detect statistically significant differences was in the range of 10–30 percent. The committee could not find justification for considering this statistical power sufficient. It can be argued that the number of replicates (number of units of two animals per treatment) in the studies should be substantially increased, but one argument against an increase in numbers is related to the ethics of subjecting more animals to testing ( EC, 2010b ). One could

also argue that it is unethical to conduct an underpowered study. However, most if not all of the rodent studies are based on widely accepted safety evaluation protocols with fixed numbers of animals per treatment. Cultural values regarding precaution for human safety and those regarding the number of animals subjected to testing are in conflict in this case. As pointed out by Snell et al. (2012) , a close examination of the long-term and multigenerational studies reveals that some have problems with experimental design, the most common being that the GE and non-GE sources were not isogenic and were grown in different locations (or unknown locations). Those problems in design make it difficult to determine whether differences are due to the genetic-engineering process or GE trait or to other sources of variation in the nutritional quality of the crops.

In cases in which testing produces equivocal results or tests are found to lack rigor, follow-up experimentation with trusted research protocols, personnel, and publication outlets is needed to decrease uncertainty and increase the legitimacy of regulatory decisions. There is a precedent of such follow-up studies in the literature on GE crop environmental effects that could serve as a general model for follow-up food-safety testing (see Chapter 4 section “Genetically Engineered Crops, Milkweed, and Monarch Butterflies”). The USDA Biotechnology Risk Assessment Research Grants Program has enabled this approach in a few cases.

Beyond Rodent Studies. Mice and rats are typically used in toxicity studies because of their general physiological similarities to humans and their small size, but some farm animals are considered to be better models of human physiology than rodents. The best example is the pig, which is considered to be better than rodents as a model, especially with respect to nutritional evaluations ( Miller and Ullrey, 1987 ; Patterson et al., 2008 ; Litten-Brown et al., 2010 ). Porcine insulin has been used for decades to control blood sugar in patients who have childhood-onset diabetes mellitus (type I diabetes). Pig heart valves are used for human mitral valve replacement, and pig skin has been investigated as a possible donor tissue. The pig is monogastric as is the human, and its gastrointestinal tract absorbs and metabolizes nutrients (lipids and micronutrients) in the same manner as in humans.

Reviews of studies with animals fed GE foods have included studies using both rodents and farm animals ( Bartholomaeus et al., 2013 ; DeFrancesco, 2013 ; Ricroch et al., 2013a , b , 2014 ; Swiatkiewicz et al., 2014 ; Van Eenennaam and Young, 2014 ). Those animal studies have taken advantage of the fact that maize and soybean are major components of the diets of many farm animals. Some of the reported studies that used farm animals have designs similar to those of rodent studies and have variation in duration and replicates similar to that of the rodent experiments. Some of the tests were run for 28 days (for example, Brouk et al.,

2011 ; Singhal et al., 2011 ), others for a long term ( Steinke et al., 2010 ) or in multiple generations ( Trabalza-Marinucci et al., 2008 ; Buzoianu et al., 2013b ).

The experiments with pigs are especially relevant. Most of them were conducted in one prolific laboratory ( Walsh et al., 2011 , 2012a , b , 2013 ; Buzoianu et al., 2012a , b , c , d , 2013a , b ). The studies range from examination of short-term growth of piglets to multigenerational studies of sows and piglets, with mixed designs having either generation or both exposed to Bt maize and non- Bt maize. Characteristics measured included food consumption and growth, assessment of organ size and health, immunological markers, and microbial communities. The authors of the studies generally concluded that Bt maize does not affect health of the pigs, but they reported a number of statistically significant differences between Bt maize treatment and control maize treatment. In one experiment ( Walsh et al., 2012a ), the weaned piglets that were fed Bt maize had lower feed-conversion efficiency during days 14–30 (P > 0.007) but no significant effect over the full span of the experiment. In another experiment ( Buzoianu et al., 2013b ), there was lower efficiency in the Bt treatment during days 71–100 (P > 0.01) but again no effect over the full span of the experiment.

In those experiments with pigs and experiments with other farm animals and rodents, there was apparently one source of the GE food and one source of the non-GE food per study, and it is generally not clear that the food sources were isogenic or grown in the same location. That makes it difficult to determine whether any statistical differences found were due to the engineered trait or to the batches of food used, which in at least some experiments varied in nutrient content and may have differed in bioactive compounds (produced in response to plant stressors), which may have a profound effect on outcomes of nutritional studies. Another issue is that many statistical tests were performed in most studies. That could result in accumulation of false-positive results ( Panchin and Tuzhikov, 2016 ). Although this is not a situation in which a stringent correction for doing multiple tests is called for ( Dunn, 1961 ), there is reason to be cautious in interpretation of statistical significance of individual results because multiple tests can lead to artifactual positive results. The issue of multiple test results is common in many fields, and one approach used in genetics is to use the initial tests for hypothesis generation with follow-up experiments that test an a priori hypothesis (for example, Belknap et al., 1996 ). If a straightforward application of Bonferonni correction is used, each animal study that measures multiple outcomes, whether for GE crops or any other potential toxicant, could require over 1,000 animals to obtain reasonable statistical power ( Dunn, 1961 ).

In addition to the literature on controlled experiments with livestock, Van Eenennaam and Young (2014 ) reviewed the history of livestock health

and feed-conversion ratios as the U.S. livestock industry shifted from non-GE to GE feed. Producers of cattle, milk cows, pigs, chickens, and other livestock are concerned about the efficiency of conversion of animal feed into animal biomass because it affects profit margins. The data examined start as early as 1983 and run through 2011. Therefore, livestock diets shifted from all non-GE feed to mostly GE feed within the duration of the study. Van Eenennaam and Young found that, if anything, the health and feed-conversion efficiencies of livestock had increased since the introduction of GE crops but that the increase was a steady rise, most likely because of more efficient practices not associated with use of GE feed. In the studies that they reviewed, the number of animals examined was large (thousands). Of course, most livestock are slaughtered at a young age, so that data cannot address the issue of longevity directly. However, given the general relationship between general health and longevity, the data are useful.

FINDING: The current animal-testing protocols based on OECD guidelines for the testing of chemicals use small samples and have limited statistical power; therefore, they may not detect existing differences between GE and non-GE crops or may produce statistically significant results that are not biologically meaningful.

FINDING: In addition to experimental data, long-term data on the health and feed-conversion efficiency of livestock that span a period before and after introduction of GE crops show no adverse effects on these measures associated with introduction of GE feed. Such data test for correlations that are relevant to assessment of human health effects, but they do not examine cause and effect.

RECOMMENDATION: Before an animal test is conducted, it is important to justify the size of a difference between treatments in each measurement that will be considered biologically relevant.

RECOMMENDATION: A power analysis for each characteristic based on standard deviations in treatments in previous tests with the animal species should be done whenever possible to increase the probability of detecting differences that would be considered biologically relevant.

RECOMMENDATION: In cases in which early published studies produced equivocal results regarding health effects of a GE crop, followup experimentation using trusted research protocols, personnel, and publication outlets should be used to decrease uncertainty and increase the legitimacy of regulatory decisions.

RECOMMENDATION: Public funding in the United States should be provided for independent follow-up studies when equivocal results are found in reasonably designed initial or preliminary experimental tests.

Compositional Analysis

Compositional Analysis of Genetically Engineered Crops. As part of the regulatory process of establishing substantial equivalence, GE crop developers submit data comparing the nutrient and chemical composition of their GE plant with a similar (isoline) variety of the crop. In the United States, submitting such data to FDA is voluntary, although as of 2015 this seems to always be done by developers. Developers and regulators compare key components of the GE variety with published reference guides that list the concentrations and variabilities of nutrients, antinutrients, and toxicants that occur in crops already in the food supply. 4 The section “Regulatory Testing of Crops with Resistance to Glyphosate and 2,4-D and the New Uses of the Herbicides Themselves” earlier in this chapter gives an example of the types of nutrients and chemicals that are generally measured. In the specific case of the soybean resistant to 2,4-D and glyphosate, measurements of 62 components in the soybean were submitted by Dow AgroSciences. There were statistically significant differences between the GE and comparison varieties in 16 of the 62. The differences were considered to be small and within the range of published values for other soybean varieties. They were therefore “considered not biologically relevant.” In compositional analysis, as in some of the whole-food animal testing, it is difficult to know how much of the variance and range in values for the components is due to the crop variety, the growing conditions, and the specific laboratory experimental equipment. In the United States, regulatory agencies require that the comparison be between the GE crop and its isogenic conventionally bred counterpart grown in side-by-side plots. In those cases, it is hard to attribute differences to anything but the genetic-engineering process.

FINDING: Statistically significant differences in nutrient and chemical composition have been found between GE and non-GE plants by using traditional methods of compositional analysis, but the differences have been considered to fall within the range of naturally occurring variation found in currently available non-GE crops.

4 OECD develops consensus documents that provide reference values for existing food crops ( OECD, 2015 ). These are publicly available online at http://www.oecd.org/science/biotrack/consensusdocumentsfortheworkonthesafetyofnovelfoodsandfeedsplants.htm (accessed May 9, 2016). The International Life Science Institute (ILSI) also maintains a crop composition database at www.cropcomposition.org (accessed May 9, 2016). ILSI reports that in 2013 the database contained more than 843,000 data points representing 3,150 compositional components.

Composition of Processed Genetically Engineered Foods . General compositional analysis and the specific content of the introduced proteins are typically conducted on raw products, such as maize kernels or soybean seed. However, much of the human consumption of these products occurs after substantial exposure to heat or other processing. If in processing of foods the amounts of GE proteins substantially increase, consumers are potentially exposed to a risk that is different from that anticipated from testing the raw material. In the production of oil, for example, the goal is to separate the oil from other compounds in the raw crop, such as proteins and carbohydrates. Crude oils can contain plant proteins ( Martín-Hernández et al., 2008 ), but in highly purified oils even sophisticated approaches have failed to find any nondegraded proteins ( Hidalgo and Zamora, 2006 ; Martín-Hernández et al., 2008 ). Those results are reflected in the fact that people who are allergic to soybean are not affected by purified oils ( Bush et al., 1985 ; Verhoeckx et al., 2015 ).

A few studies have searched for a means of finding DNA in plant-derived oils to identify the origin of the oil as GE or non-GE for labeling purposes ( Costa et al., 2010a , b ) or to identify the origin of olive oil ( Muzzalupo et al., 2015 ). It is possible to detect DNA, but the amounts are typically diminished in purified oils to 1 percent or less of the original content. Similarly, Oguchi et al. (2009) were not able to find any DNA in purified beet sugar. Some countries exempt products from labeling if GE protein or DNA is not detectable. For example, in Japan, where foods with GE ingredients typically require labeling, oil, soy sauce, and beet sugar are excluded because of degradation of GE proteins and DNA ( Oguchi et al., 2009 ). Australia and New Zealand have similar exemptions from labeling for such highly refined foods as sugars and oils ( FSANZ, 2013 ).

The detection of GE protein and DNA in other processed foods depends on the type of processing. For example, the amount of the Bt protein Cry1Ab detected by immunoassay in tortillas depends on cooking time ( de Luis et al., 2009 ). The detected amount of Cry9C protein remaining in samples of corn bread, muffins, and polenta was about 13, 5, and 3 percent of the amount in the whole-grain maize ( Diaz et al., 2002 ). For Cry1Ab in rice, Wang et al. (2015) found that baking was more effective in lowering the detection using polyclonal antibodies of the Cry1Ab protein than microwaving, but 20 minutes of baking at 180ºC left almost 40 percent of the protein intact. Heat denaturation of proteins can lower antibody binding to epitopes and cause lower detection of GE proteins.

FINDING: The amount of GE protein and DNA in food ingredients can depend on the specific type of processing; some foods contain no detectable protein and little DNA. In a few countries that have manda-

tory labeling of GE foods, that is taken into account, and food without detectable GE DNA or GE protein is not labeled.

Newer Methods for Assessing Substantial Equivalence . As explained in Chapter 2 , governance of GE crops includes regulatory governance. Although not required to by governing bodies, companies and academic researchers have moved beyond the typical measurements of food composition to newer technologies that involve transcriptomics, proteomics, and metabolomics. The new methods provide a broad, nontargeted assessment of thousands of plant characteristics, including the concentrations of most of the messenger RNAs, proteins, and small molecules in a plant or food. These methods are more likely to detect changes in a GE crop than the current regulatory approaches. If a GE crop has been changed only as intended, any changes observed in these -omics measurements theoretically should be predictable in a given environment. The science behind the methods, including the current limitations of their interpretation, is discussed in Chapter 7 . The discussion here focuses on how the methods have already been applied in the assessment of risk of health effects of currently commercialized GE crops.

Ricroch et al. (2011) reviewed -omics data from 44 studies of crops and detailed studies of the model plant Arabidopsis thaliana . Of those studies, 17 used transcriptomics, 12 used proteomics, and 26 used metabolomic methods. Ricroch (2013) updated the number of studies to 60. The committee found that many more studies had been done since those reviews were published, and many of them have used multiple -omics approaches. The sophistication of the studies has increased ( Ibáñez et al., 2015 ) and is likely to increase further. As recommended in Chapter 7 , there is a need to develop further and share databases that contain detailed -omics data ( Fukushima et al., 2014 ; Simó et al., 2014 ).

In some studies of GE plants in which simple marker genes were added, there were almost no changes in the transcriptome ( El Ouakfaoui and Miki, 2005 ), but use of other -omics methods has revealed changes ( Ren et al., 2009 ). For example, in a comparison of glyphosate-resistant soybean and non-GE soybean, García-Villalba et al. (2008) found that three free amino acids, an amino acid precursor, and flavonoid-derived secondary metabolites (liquiritigenin, naringenin, and taxifolin) had greater amounts in the GE soybean and 4-hydroxy-l-threonine was present in the non-GE soybean, but not in the GE variety. They hypothesized that the change in the flavonoids may have been because the modified EPSPS enzyme (a key enzyme of the shikimate pathway leading to aromatic amino acids) introduced to achieve glyphosate resistance could have different enzymatic properties that influenced the amounts of aromatic amino acids. The committee was not aware of such a hypothesis before this metabolomic study. (A concern was expressed in a comment submitted to the committee that

the EPSPS transgene would cause endocrine disruption. The committee found no evidence to suggest that the changes found by García-Villalba et al. would have such an effect.)

On the basis of previous experimentation, it is predicted that, when a gene for a nonenzymatic protein (such as a Bt toxin gene) is added to a plant, there will be very few changes in the plant’s metabolism ( Herman and Price, 2013 ). However, when a gene has been added specifically to alter one metabolic pathway of a plant, a number of predicted and unpredicted changes have been found. For example, Shepherd et al. (2015) found that, when they downregulated enzymes (that is, decreased expression or activity) involved in the production of either of two toxic glycoalkaloids (alpha-chaconine and alpha-solanine) in a GE potato with RNA-interfering transgenes that regulated synthesis of one toxic glycoalkaloid, the other compound usually increased. When they downregulated production of both compounds, beta-sitosterol and fucosterol increased. Neither of these compounds has the degree of toxicity associated with alpha-chaconine and alpha-solanine. Other compounds also differed from controls in concentration, but some of the changes may have been due to products generated during the tissue-culture process used in these experiments and not to the transgenes.

Many of the studies have found differences between the GE plants and the isogenic conventionally bred counterparts, but for many components there is more variation among the diverse conventionally bred varieties than between the GE and non-GE lines ( Ricroch et al., 2011 , Ricroch, 2013 ). Furthermore, the environmental conditions and the stage of the fruit or seed affect the finding. Chapter 7 addresses the future utility of the -omics approaches in assessing the biological effects of genetic engineering.

FINDING: In most cases examined, the differences found in comparisons of transcriptomes, proteomes, and metabolomes in GE and non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties due to genetics and environment.

FINDING: If an unexpected change in composition beyond the natural range of variation in conventionally bred crop varieties were present in a GE crop, -omics approaches would be more likely to find the difference than current methods.

FINDING: Differences in composition found by using -omics methods do not, on their own, indicate a safety problem.

Food Allergenicity Testing and Prediction

Allergenicity is a widespread adverse effect of foods, several plants, tree and grass pollens, industrial chemicals, cosmetics, and drugs. Self-reporting of lifetime allergic responses to each of the most common food allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish) ranges from 1 to 6 percent of the population ( Nwaru et al., 2014 ). Allergies are induced in a two-step process: sensitization from an initial exposure to a foreign protein or peptide followed by elicitation of the allergic response on a second exposure to the same or similar agent. Sensitization and elicitation are generally mediated by immunoglobulins, primarily IgE, and the responses may range from minor palatal or skin itching and rhinitis to severe bronchial spasms and wheezing, anaphylaxis, and death. In addition to IgE responses to food allergens, IgA has been identified as an inducible immune mediator primarily in the gastrointestinal mucosa in response to foods, foreign proteins, pathogenic microorganisms, and toxins. The role of IgA in classical allergy has been investigated ( Macpherson et al., 2008 ).

Assessment of the potential allergenicity of a food or food product from a GE crop is a special case of food-toxicity testing and is based on two scenarios: transfer of any protein from a plant known to have food-allergy properties and transfer of a protein that could be a de novo allergen. Predictive animal testing for allergens in foods (GE and non-GE) is not sufficient for allergy assessment ( Wal, 2015 ). Research efforts are ongoing to discover or develop an animal model that predicts sensitization to allergy ( Ladics and Selgrade, 2009 ), but so far none has proved predictive ( Goodman, 2015 ). Therefore, researchers have relied on multiple indirect methods for predicting whether an allergic response could be caused by a protein that is either added to a food by genetic engineering or appears in the food as an unintended effect of genetic engineering. Endogenous protein concentrations with known allergic properties also have to be monitored because it is possible that their concentration could increase due to genetic engineering.

A flow diagram of the interactive approach to allergen testing recommended by the Codex Alimentarius Commission ( CAC, 2009 ) and EFSA (2010 , 2011a ) is presented in Figure 5-3 ( Wal, 2015 ); Box 5-2 describes the EPA testing of the Bt toxin Cry1F that generally follows this approach. The logic behind the approach starts with the fact that any gene for a protein that comes from a plant that is known to cause food allergies has a higher likelihood of causing allergenicity than any gene from a plant that does not cause an allergic response. If the introduced protein is similar to a protein already known to be an allergen, it becomes suspect and should be tested in people who have an allergy to the related protein. Finally, if a protein fits none of the above characteristics but is not digested by simulated gastric fluid, it could be a novel food allergen. The latter factor comes from

research demonstrating that some, but not all, proteins already known to be food allergens are resistant to digestion by gut fluid.

There is one case in which that approach was used and a GE crop with allergenicity issues was detected early and prevented from being commercialized, and a second case in which a GE crop was withdrawn from the market based on the possibly that it included a food allergen. In the first case, research was conducted on a soybean line genetically engineered to produce a Brazil nut ( Bertholletia excelsa ) protein, which was a known allergen. Sera from patients allergic to Brazil nut protein were available and tested positive for activity against the GE soybean protein. Because the segregation from the human food supply of GE soybean with that protein could not be guaranteed, the project was halted ( Nordlee et al., 1996 ). The soybean variety was never commercialized.

In the second case, EPA allowed a Bt maize variety developed by Aventis CropScience with a potential for allergenicity (due to decreased digestion of the protein Cry9c in simulated gastric fluid) to be sold as cattle feed under the name StarLink™; because of the potential for allergenicity, the variety was not approved for direct human consumption. However, the Bt protein was found in human food, so the maize variety was removed from all markets. After that incident, EPA no longer distinguished between Bt proteins in human food versus in animal feed ( EPA, 2001b ). Bt crop varieties are approved in the United States for all markets or none.

The interactive approach for testing should work for GE crops when the testing is for a transgene that is expressed by the plant as a protein that does not affect its metabolism (for example, Bt toxins). The testing does not cover endogenous allergens whose concentrations have been increased by unintended effects of genetic engineering. In 2013, the European Commission set a requirement for assessing endogenous allergens in GE crops ( EC, 2013 ). A number of articles since then have supported the approach ( Fernandez et al., 2013 ) or have found it unnecessary and impractical ( Goodman et al., 2013 ; Graf et al., 2014 ). Soybean is an example of a crop that has endogenous allergens. A paper on endogenous soybean allergens concluded that there is enough knowledge of only some soybean allergens for proper testing ( Ladics et al., 2014 ). As emphasized by Wal (2015) , there is considerable variation among conventionally bred varieties in the concentrations of endogenous allergens, especially when they are grown under different conditions. Therefore, the existing variation must be taken into consideration in assessing a GE variety. Of course, the issue is not only the magnitude of variation but the potential change in the overall exposure of the global human population to the allergen.

One example of an existing potential allergen of concern is gamma-zein, one of the storage proteins produced in the maize kernel that is a comparably hard-to-digest protein ( Lee and Hamaker, 2006 ). Concern was expressed to the committee that GE maize may have higher amounts of gamma-zein, which could be allergenic ( Smith, 2014 ). Krishnan et al. (2010) found that young pigs consuming maize generate antibodies against gamma-zein. That observation and the fact that the protein withstands pepsin digestion suggest that gamma-zein could be an allergen. In a comparison of the Bt maize line MON810 with non- Bt maize, known maize allergens, including the 27-kDa and 50-kDa gamma-zein proteins, were not found to be in significantly different amounts ( Fonseca et al., 2012 ). On the other hand, conventionally bred Quality Protein Maize is reported to have a 2 to 3 fold higher

concentration of the 27-kDa gamma-zein protein ( Wu et al., 2010 ). There is one patent for decreasing gamma-zein through genetic engineering. 5

There can be a connection between immune response and allergenicity. One well-cited study brought up in the public comment period was that by Finamore et al. (2008) , who assessed the effect of Bt maize ingestion on the mouse gut and peripheral immune system. They found that Bt maize produced small but statistically significant changes in percentage of T and B cells and of CD4+, CD8+, γδT, and αβT subpopulations at gut and peripheral sites and alterations of serum cytokines in weanlings fed for 30 days and in aged mice. However, there was no significant response in weaning mice that were fed for 90 days, which they related to further maturation of the immune system. They concluded that there was no evidence that the Bt toxin in maize caused substantial immune dysfunction. Similarly, Walsh et al. (2012a) did not find immune function changes in a long-term pig feeding study (80 or 110 days) on Bt MON810 maize compared with non-GE maize. Overall, no changes of concern regarding Bt maize feeding and altered immune response have been found.

At a public meeting that the committee held on health effects of GE foods, a question was raised about whether current testing for allergenicity is insufficient because some people do not have acidic conditions in their stomachs. Regarding that issue, digestibility of the proteins is assessed with simulated gastric fluid (0.32 percent pepsin, pH 1.2, 37ºC), under the premise that an undigested protein may lead to the absorption of a novel allergenic fragment ( Astwood et al., 1996 ; Herman et al., 2006 ). Stomach fluid is typically acidic, with a pH of 1.5–3.5, which is the range at which pepsin (the digestive enzyme of the stomach) is active, and the volume of stomach fluid is 20–200 mL (about 1–3 ounces). Simulated gastric fluid was developed to represent human gastric conditions in the stomach and is used in bioavailability studies of drugs and foods ( U.S. Pharmacopeia, 2000 ).

In general, if the pH of the stomach is greater than 5, pepsin will not be active, and less breakdown of large proteins will take place. Hence, the usefulness of simulated gastric fluid in the case of a less acidic (higher pH) stomach is questionable, whether used for non-GE foods or GE foods. Untersmayr and Jensen-Jarolim (2008:1301) concluded that “alterations in the gastric milieu are frequently experienced during a lifetime either physiologically in the very young and the elderly or as a result of gastrointestinal pathologies. Additionally, acid-suppression medications are frequently used for treatment of dyspeptic disorders.” Trikha et al. (2013) used a group of 4,724 children (under 18 years old) who had received a

5 Jung, R., W.-N. Hu, R.B. Meeley, V.J.H. Sewalt, and R. Nair. Grain quality through altered expression of seed proteins. U.S. Patent 8,546,646, filed September 14, 2012, and issued October 1, 2013.

diagnosis of gastroesophageal reflux disease (GERD) and who were treated with gastric acid-suppressive medication and matched with 4,724 children who had GERD but were not so treated. Those treated with acid-reducing medicine were more than 1.5 times as likely to have a diagnosis of food allergy as those who were not so treated. The difference between the two GERD groups was statistically significant (hazard ratio, 1.68; 95-percent confidence interval, 1.15–2.46).

The National Research Council report Safety of Genetically Engineered Foods pointed out that there were important limitations in allergenicity predictions that could be done before commercialization ( NRC, 2004 ). Since that report was published, there have been improvements in the allergen database, and research has been funded to improve precommercialization prediction. However, as the committee heard from an invited speaker, “no new methods have been demonstrated to predict sensitization and allergy in the absence of proven exposure” ( Goodman, 2015 ). Before commercialization, the general population will probably not have been exposed to an allergen similar enough to an allergen in a GE plant to cause cross-reactivity, so it would be useful to use the precommercialization tests only as a rough predictor. To ensure that allergens did not remain in the food system, the Safety of Genetically Engineered Foods report called for a two-step process of precommercialization testing and post-commercialization testing. Even though progress has been made on allergenicity prediction since that report was published in 2004, the committee found that post-commercialization testing would be useful in ensuring that no new allergens are introduced. There have been no steps toward post-commercialization testing since 2004. The committee recognized that such testing would be logistically challenging, as described in a scientific report to EFSA ( ADAS, 2015 ). Post-commercialization surveillance of such specific agents as drugs and medical devices is difficult, but there is generally a well-defined endpoint to look for in patients. In the case of food, the detection of an allergic response to a particular protein would be confounded by multiple exposures in the diet. However, several region-wide human populations have been exposed to GE foods for many years whereas others have not; this could enable an a priori hypothesis to be tested that populations that have been exposed to foods from specific GE crops will not show a higher rate of allergic response to such foods.

FINDING: For crops with endogenous allergens, knowing the range of allergen concentrations in a broad set of crop varieties grown in a variety of environments is helpful, but it is most important to know whether adding a GE crop to the food supply will change the general exposure of humans to the allergens.

FINDING: Because testing for allergenicity before commercialization could miss allergens to which the population had not previously been exposed, post-commercialization allergen testing would be useful in ensuring that consumers are not exposed to allergens, but such testing would be difficult to conduct.

FINDING: There is a substantial population of persons who have higher than usual stomach pH, so tests of digestibility of proteins in simulated acidic gastric fluid may not be relevant to this population.

GENETICALLY ENGINEERED CROPS AND OCCURRENCE OF DISEASES AND CHRONIC CONDITIONS

The overall results of short-term and long-term animal studies with rodents and other animals and other data on GE-food nutrient and secondary compound composition convinces many (for example, Bartholomaeus et al., 2013 ; Ricroch et al., 2013a , b ; Van Eenennaam and Young, 2014 ) but not all involved researchers (for example, Dona and Arvanitoyannis, 2009 ; Domingo and Bordonaba, 2011 ; Hilbeck et al., 2015 ; also see DeFrancesco, 2013 ) that currently marketed GE foods are as safe as foods from conventionally bred crops. The committee received comments from an invited speaker ( Smith, 2014 ) and from the public regarding the possible relationship between increases in the incidence of specific chronic diseases and the introduction of GE foods into human diets. Appendix F includes a representative list of the comments about GE food safety that were sent to the committee through the study’s website. The comments mentioned concerns about such chronic diseases as cancers, diabetes, and Parkinson’s; possible organ-specific injuries (liver and kidney toxicity); and such disorders as autism and allergies. Smith (2003:39) made the claim that “diabetes rose by 33 percent from 1990 to 1998, lymphatic cancers are up, and many other illnesses are on the rise. Is there a connection to [genetically modified] foods? We have no way of knowing because no one has looked for one.”

As part of the committee’s effort to respond to its task to “assess the evidence for purported negative effects of GE crops and their accompanying technologies,” it used available peer-reviewed data and government reports to assess whether any health problems may have increased in frequency in association with commercialization of GE crops or were expected to do so on the basis of the results of toxicity studies. The committee presents additional biochemical data from animal experiments but relies mostly on epidemiological studies that used time-series data. The epidemiological data for some specific health problems are generally robust over time (for example, cancers) but are less reliable for others. The committee presents the available data knowing that they include a number of sources of bias,

including changes over time in survey methods and in the tools for detection of specific chronic diseases. As imperfect as the data may be, they are in some cases the only information available beyond animal experiments for formulating or testing hypotheses about possible connections between a GE food and a specific disease. The committee points out that the lack of rigorous data on incidence of disease is not only a problem for assessing effects of GE foods on health. More rigorous data on time, location, and sociocultural trends in disease would enable better assessment of potential health problems caused by environmental factors and other products from new technologies.

Cancer Incidence

A review of the American Cancer Society’s database indicates that mortality from cancers in the United States and Canada has continued to decrease or stabilized in all categories except cancers of the lung and bronchus attributable to smoking. The decreases in mortality are due in part to early detection and improved treatment, so mortality data can mask the rate at which cancers occur. For that reason, the committee sought data on cancer incidence rather than cancer mortality. Figures 5-4 and 5-5 show

changes in cancer incidence in U.S. women and men, respectively, from 1975 to 2011 ( NCI, 2014 ). If GE foods were causing a substantial number of specific cancers, the incidence of those cancers would be expected to show a change in slope in the time series after 1996, when GE traits were first available in commercial varieties of soybean and maize. The figures show that some cancers have increased and others decreased, but there is no obvious change in the patterns since GE crops were introduced into the U.S. food system. Figures 5-6 and 5-7 show cancer incidence in women and men in the United Kingdom, where GE foods are not generally being consumed. For the specific types of cancers that are reported in both the United States and the United Kingdom, there is no obvious difference in the patterns that could be attributed to the increase in consumption of GE foods in the United States. (The absolute numbers cannot be compared because of differences in methodology.)

Forouzanfar et al. (2011) published data on breast and cervical cancer incidence worldwide from 1980 to 2010. As can be seen in Figure 5-8 , the global incidence of those two cancers has increased. An examination of the plots for North America (high income) (Canada and the United States), where GE foods are eaten, compared with the plots for western

Europe, where GE foods generally are not eaten, shows similar increases in incidence of breast cancer and no increase in cervical cancer. The data do not support the hypothesis that GE-food consumption has substantially increased breast and cervical cancer. (The data for North America [high

income] and western Europe are different from those in the studies above on the incidence of cancer in the United States and the United Kingdom.)

Taken together, Figure 5 through Figure 8 do not support the hypothesis that GE foods have resulted in a substantial increase in the incidence of cancer. However, they do not establish that there is no relationship between cancer and GE foods because there can be a delay in the onset of cancer that would obscure a trend, and one could hypothesize that something else has occurred with GE foods in the United States that has lowered cancer incidence and thus obscured a relationship. The committee had limited evidence on which to make its judgments, but the evidence does not support claims that the incidence of cancers has increased because of consumption of GE foods.

There is ongoing debate about potential carcinogenicity of glyphosate in humans. Assessment of glyphosate is relevant to the committee’s report because it is the principal herbicide used on HR crops ( Livingston, et al. 2015 ), and it has been shown that there are higher residues of glyphosate in HR soybean treated with glyphosate than in non-GE soybean ( Duke et al., 2003 ; Bøhn et al., 2014 ). Box 5-5 provides details about a study by Séralini et al. (2012 , 2014) that concluded that glyphosate causes tumors in rats. The committee found that this study was not conclusive and used incorrect statistical analysis. The most detailed epidemiological study that tested for a relationship between cancer and glyphosate as well as other agricultural chemicals found “no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate” ( Mink et al., 2012:440 ; also see section below “Health Effects of Farmer Exposure to Insecticides and Herbicides”).

In 1985, EPA classified glyphosate as Group C (possibly carcinogenic to humans) on the basis of tumor formation in mice. However, in 1991, after reassessment of the mouse data, EPA changed the classification to Group E (evidence of noncarcinogenicity in humans) and in 2013 reaffirmed that “based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, glyphosate is not expected to pose a cancer risk to humans” ( EPA, 2013:25399 ).

In 2015, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) issued a monograph on glyphosate as part of its volume on some organophosphate insecticides and herbicides ( IARC, 2015 ). In the monograph, IARC classified glyphosate in Group 2A (probably carcinogenic to humans). A summary and reasons for the classification were published in Lancet Oncology ( Guyton et al., 2015 ).

The 2015 IARC Working Group found that, although there is “ limited evidence in humans for the carcinogenicity of glyphosate,” there is “ sufficient evidence in experimental animals for the carcinogenicity of glyphosate”

( IARC, 2015:78 ). Furthermore, IARC noted that there is mechanistic support in that glyphosate induces oxidative stress, which could cause DNA damage, and some epidemiological data that support the classification.

EFSA (2015) evaluated glyphosate after the IARC report was released and concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. Canada’s health agency concluded that “the level of human exposure, which determines the actual risk, was not taken into account by WHO (IARC)” ( Health Canada, 2015 ). The Canadian agency found that current food and dermal exposure to glyphosate even by those who work directly with glyphosate is not a health concern as long as it is used as directed on product labels ( Health Canada, 2015 ). EPA (2015) found that glyphosate does not interact with estrogen, androgen, or thyroid systems.

A comment to the committee expressed concern that glyphosate breaks down to formaldehyde, which was classified as a known human carcinogen by IARC (2006) . However, this hypothesis was not supported; Franz et al. (1997) used radiolabeled glyphosate and failed to show formation of formaldehyde in the normal environmental degradation of glyphosate.

FINDING: The incidence of a variety of cancer types in the United States has changed over time, but the changes do not appear to be associated with the switch to consumption of GE foods. Furthermore, patterns of change in cancer incidence in the United States are generally similar to those in the United Kingdom and Europe, where diets contain much lower amounts of food derived from GE crops. The data do not support the assertion that cancer rates have increased because of consumption of products of GE crops.

FINDING: There is significant disagreement among expert committees on the potential harm that could be caused by the use of glyphosate on GE crops and in other applications. In determining the risk from glyphosate and formulations that include glyphosate, analyses must take into account both marginal exposure and potential harm.

Kidney Disease

It has been hypothesized that kidney disease may have increased because GE proteins reached the kidney. The committee examined epidemiological data to determine whether there was a correlation between the consumption of GE foods and the prevalence of chronic kidney disease (CKD).

The total prevalence of all stages of CKD in the United States increased 2 percent from about 12 percent in 1988–1994 to 14 percent in 1999–2004, but the total prevalence has not increased significantly since then.

Figure 5-9 presents prevalence data on the five progressively more serious, recognized stages of CKD ( USRDS, 2014 ). The greatest percent increase is seen in Stage 3, and based on the study ( USRDS, 2014 ), a large amount of the increase occurred in people with comorbidity of cardiovascular disease. Prevalence of CKD increases substantially with age ( Coresh et al., 2003 ), so the aging of the U.S. population may contribute to the overall increase ( U.S. Census Bureau, 2014 ), as does the increase in diabetes and hypertension ( Coresh et al., 2007 ).

FINDING: The available data on prevalence of chronic kidney disease in the United States show a 2 percent increase from 1988 to 2004, but the increase does not appear to be attributable to consumption of GE foods.

Obesity in humans is a complex condition associated with several genetic and environmental factors—including geography, ethnicity, socioeconomic status, lack of exercise, availability of fresh fruits and vegetables, and less nutritional meals ( Thayer et al., 2012 )—and an altered functioning microbiome ( Turnbaugh et al., 2009 ).

Studies of various species examined body-weight gain when animals were fed a GE crop, a non-GE isogenic comparator, or a non-GE, nonisogenic control. The authors concluded that there were no biologically relevant differences in body-weight gain regardless of the length of the studies ( Rhee et al. 2005 ; Hammond et al., 2006 ; Arjó et al., 2012 ; Buzoianu et al., 2012b ; Ricroch et al., 2013a , b ; Halle and Flachowsky, 2014 ; Nicolia et al. 2014 ).

Human population studies have shown that obesity has become more prevalent in the United States (for example, Fryar et al., 2014 ). An (2015) provided a graphic of the change in U.S. adults (sorted by education level) from 1984 to 2013 ( Figure 5-10 ). As can be seen in the figure, the percentage of obese U.S. adults increased until about 2009, at which time it appears to level off. Because there is no increase in the slope after commercialization of GE crops, these data do not support the hypothesis that GE crops have increased obesity. These time-series data do not prove that there is no association, but if one is present, it is not strong.

Those statistics on obesity coincide with those on the incidence of type II diabetes in the United States ( Abraham et al., 2015 ) and therefore do not support a relationship between GE crops and type II diabetes.

FINDING: The committee found no published evidence to support the hypothesis that the consumption of GE foods has caused higher U.S. rates of obesity or type II diabetes.

Gastrointestinal Tract Diseases

Although the gastrointestinal tract has evolved to digest dietary proteins in the stomach and small intestine effectively for absorption and use of amino acids, it is normal for some full proteins or their fragments to cross the gut barrier through a paracellular route (between cells) or damaged mucosa and for the immune system, which has a high presence at the interface of the gut wall and the internal circulation, to respond accordingly. It is also not unusual, given the high sensitivity of today’s analytical equipment, for proteins or fragments to be detected in minute amounts in different body fluids. Detection methods are not specific to transgene-produced proteins but can find any dietary protein or fragment that is able to pass from the gastrointestinal tract into the bloodstream and tissues. The presence

of a dietary protein or its fragment in the bloodstream or in tissues is not unusual or a cause for health concerns.

About 60–70 percent of the body’s immune system is in the gastrointestinal tract’s gut-associated lymphoid tissue, which has an interface with the gut luminal contents, including toxins, allergens, and the associated microbiota. For GE crops, a public concern has been that the immune system is compromised through ingested transgenic proteins. That possibility has been investigated in animal studies that examined immune system bio-markers and epithelial cell integrity (see section “Beyond Rodent Studies” above and Walsh et al., 2011 ).

It was suggested to the committee in presentations and public comments that fragments of transgenes may have some special properties that would result in human diseases if they were absorbed into the body through

the digestive tract. The mechanism by which such genes or proteins would affect the body is not clear, although Smith (2013) hypothesized that consuming GE foods increased gut permeability.

FINDING: The committee could find no published evidence supporting the hypothesis that GE foods generate unique gene or protein fragments that would affect the body.

Celiac Disease

Celiac disease is an autoimmune disorder that affects about 1 percent of the population of western countries. It is triggered in susceptible people by consumption of gluten-containing cereal grains ( Fasano et al., 2003 ; Catassi et al., 2010 ). Symptoms of celiac disease are the result of an immune reaction that causes marked gastrointestinal inflammation in persons susceptible to gliadin, a component of gluten protein found in wheat, rye ( Secale cereale ), and barley ( Hordeum vulgare ) ( Green and Cellier, 2007 ). In addition to exposure to gluten, the etiology of celiac disease is multifactorial and includes genetic predisposition, microbial infection of the gastrointestinal tract, antibiotic exposure, and gastrointestinal erosion ( Riddle et al., 2012 ). Diagnosis is based on detection of serum concentrations (serotypes) of IgA tissue transglutaminase and endomysial antibody IgA, the relief of symptoms upon gluten avoidance, and tissue biopsy. The genetic changes related to the serotyped IgAs are found in about 30 percent of the Caucasian population, but susceptibility to celiac disease is found in only 1 percent of this population ( Riddle et al., 2012 ).

The committee was able to find data on the incidence of celiac disease in the United Kingdom ( West et al., 2014 ; Figure 5-11 ) and a detailed study conducted by the Mayo Clinic in one county in Minnesota ( Murray et al., 2003 ; Ludvigsson et al., 2013 ). In the Minnesota and UK studies, there is a clear pattern of increase in celiac-disease incidence (or at least its detection or the extent of self-reports) that started before 1996 ( Catassi et al., 2010 ), when U.S. citizens began to consume more GE foods and the use of glyphosate increased in the United States but not in the United Kingdom. The increases are similar in magnitude to that found in U.S. military personnel, in whom prevalence increased from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008 ( Riddle et al., 2012 ). The authors cautioned that most cases of celiac disease are undiagnosed. Some of the observed increase may be related to improvements in diagnostic criteria, greater awareness of the disease in physicians and patients, better blood tests, and increases in the number of biopsies. However, recent observations point to an increase in incidence beyond those factors (J. A. Murray, Mayo Clinic, personal communication, February 1, 2016).

On the basis of data collected in the 2009–2010 National Health and Nutrition Examination Survey, Rubio-Tapia et al. (2012) reported a prevalence of celiac disease of 0.71 percent with 1.01 percent in non-Hispanic whites in a sample of 7,798 subjects. It should be noted that there has not been any commercial production of GE wheat, rye, or barley in the world. The committee found no evidence that the introduction of GE foods affected the incidence or prevalence of celiac disease worldwide.

FINDING: Celiac-disease detection began increasing in the United States before the introduction of GE crops and the increased use of glyphosate. It appears to have increased similarly in the United Kingdom, where GE foods are not typically consumed and glyphosate use did not increase. The data are not robust, but they do not show a major difference in the rate of increase in incidence of celiac disease between the two countries.

Food Allergies

Speakers and some members of the public suggested that the prevalence of food allergies has increased because of GE crops. The committee examined records on the prevalence of food allergies in the United States over time. As is clear from Figure 5-12 and Jackson et al. (2013) , the prevalence of food allergies in the United States is rising. For a rough comparator, the committee examined data on hospital admissions for food allergies in the United Kingdom over time ( Figure 5-13 ). UK citizens eat far less food derived from GE crops. The data ( Gupta et al., 2007 ) suggest that food allergies are increasing in the United Kingdom at about the same rate as in the United States (but the types of measurement are different).

FINDING: The committee did not find a relationship between consumption of GE foods and the increase in prevalence of food allergies.

Autism Spectrum Disorder

Autism is often described by such symptoms as difficulty in communicating, forming personal relationships, and using language and abstract concepts. According to the American Psychiatric Association (2013) , autism spectrum disorder (ASD) encompasses the previous diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified, and childhood disintegrative disorder. Accurate diagnosis of ASD can be difficult, but efforts to identify children with ASD have increased in the United States over the last three decades ( CDC, 2014 ).

In the 2010 Centers for Disease Control and Prevention (CDC) survey of ASD in 11 regions of the United States ( CDC, 2014 ), the overall prevalence in children 8 years old was about 1 in 68 (1.47 percent), but there was wide variation among regions and sociocultural groupings of children. The CDC report stated that “the extent to which this variation might be

attributable to diagnostic practices, under-recognition of ASD symptoms in some racial/ethnic groups, socioeconomic disparities in access to services, and regional differences in clinical or school-based practices that might influence the findings in this report is unclear” ( CDC, 2014:1 ). The degree to which the increase in ASD prevalence since 1990 is due to improved diagnosis is also unclear.

Before 1990, few children in the United States or the United Kingdom had diagnoses of ASD ( Taylor et al., 2013 ), but the prevalence has increased dramatically in both countries. Researchers in the United States and United Kingdom wrote a report that examined prevalence of ASD in the United Kingdom over time and compared it with that in the United States ( Taylor et al., 2013 ). They concluded that “a continuous simultaneous extraordinary rise in the number of children diagnosed as autistic began in both countries in the early 1990s and lasted for a decade. The distribution of first time diagnosis according to age and gender was the same. These similarities between countries as well as within different locations in each country point to a common etiology for this extraordinary medical case” ( Taylor et al., 2013:5 ). There is a higher prevalence in the United States, but it is difficult to evaluate whether it is because of differences in efforts in and approaches to diagnosis and in sociocultural factors that seem to influence prevalence. The overall similarities in prevalence of ASD in the United Kingdom, where GE foods are rarely eaten, and in the United States, where GE foods are commonly eaten, suggest that the major rise in ASD is not associated with consumption of GE foods.

FINDING: The similarity in patterns of increase in autism spectrum disorder in children in the United States, where GE foods are commonly eaten, and the United Kingdom, where GE foods are rarely eaten, does not support the hypothesis of a link between eating GE foods and prevalence of autism spectrum disorder.

OTHER HUMAN HEALTH CONCERNS RELATED TO GENETICALLY ENGINEERED CROPS

The committee heard from some members of the public and some invited speakers that ailments of gastrointestinal origin could be caused by GE crops or their associated technologies or by foods derived from GE crops. The committee investigated the evidence available for that hypothesis.

Gastrointestinal Tract Microbiota

The committee received comments from the public that foods derived from GE crops could change the gut microbiota in an adverse way. Three

scenarios can be considered as related to the potential effects of GE crops on the gut microbiota: the effect of the transgene product (for example, Bt toxin), unintended alteration of profiles of GE plant secondary metabolites, and herbicide (and adjuvant) residue (for example, glyphosate) and its metabolites in HR crops.

Research on the human gut microbiota (the community of microorganisms that live in the digestive tract) is rapidly evolving with recent reports ( Dethlefsen and Relman, 2011 ; David et al., 2014 ) that suggest that microbiota perturbations occur fairly quickly owing to dietary components or antibiotic treatment. Microbiota composition and state are now well recognized to be linked to noncommunicable chronic diseases and other health problems, so factors that cause either beneficial or adverse changes in the microbiota are of interest to researchers and clinicians. However, the science has not reached the point of understanding how specific changes in microbiota composition affect health and what represents a “healthy” microbiota. The effect of different dietary patterns (for example, high-fat versus high-carbohydrate diets) on the gut microbiota has been linked to metabolic syndrome ( Ley, 2010 ; Zhang et al., 2015 ).

As discussed above, most proteins, including those in GE and conventionally bred crops, are at least partially digested in the stomach by the action of pepsin that is maintained by the acidic pH of the stomach in most people. Further digestion and absorption are a function of the small intestine, where amino acids and dipeptides and tripeptides are absorbed. Therefore, an effect of a dietary protein on the microbiota, whether from GE or non-GE foods, is unlikely. However, there is some evidence that Bt proteins can be toxic to microorganisms ( Yudina et al., 2007 ), and some nondegraded Bt protein is found within the lumen of the gut but not in the general circulation of pigs ( Walsh et al., 2011 ). Buzoianu et al. (2012c , 2013a ) studied the effect of Bt maize feeding on microbiota composition in pigs. In their 2012 study, 110-day feeding of Bt maize (variety MON810) and of isogenic non-GE maize diets led to no differences in cultured Enterobacteriaceae, Lactobacillus , and total anaerobes from the gut; 16S rRNA sequencing showed no differences in bacterial taxa, except the genus Holdemania with which no health effects are associated ( Buzoianu et al., 2012c ). In the follow-up study in which intestinal content of sows and their offspring were examined with 16S rRNA gene sequencing, the only observed difference for major bacterial phyla was that Proteobacteria were less abundant in sows fed Bt maize before farrowing and in offspring at weaning compared with the controls ( Buzoainu et al., 2013a ). Fecal Firmicutes were more abundant in offspring fed GE maize. There were other inconsistent differences in mostly low-abundance microorganisms. On the basis of the overall results from their studies, the authors concluded that none of the changes seen in the animals was expected to have biologically relevant health effects on the animals.

Relatively few studies have examined the influence of plant secondary metabolites from any crop on the gut microbiota. The review of Valdés et al. (2015) highlighted investigations on polyphenol-rich foods—such as red wine, tea, cocoa, and blueberries—on the microbiota. Effects were considered minor. As discussed above (see the section “Endogenous Toxins in Plants”), current commercialized GE crops do not have distinctly different secondary metabolite profiles that would lead one to think that they would affect the gut microbiota.

No studies have shown that there are perturbations of the gut microbiota of animals fed foods derived from GE crops that are of concern. However, the committee concluded that this topic has not been adequately explored. It will be important to conduct research that leads to an understanding of whether GE foods or GE foods coupled with other chemicals have biologically relevant effects on the gut microbiota.

FINDING: On the basis of available evidence, the committee determined that the small perturbations found in the gut microbiota of animals fed foods derived from GE crops are not expected to cause health problems. A better understanding of this subject is likely as the methods for identifying and quantifying gut microorganisms mature.

Horizontal Gene Transfer to Gut Microorganisms or Animal Somatic Cells

Horizontal (or lateral) gene transfer is “the stable transfer of genetic material from one organism to another without reproduction or human intervention” ( Keese, 2008:123 ). Since GE crops were commercialized, concern has been voiced by some scientists and some members of the public that foreign DNA introduced into plants through genetic-engineering technologies might, after ingestion, be transferred to the human gut microbiota and directly or indirectly (that is, from bacteria) into human somatic cells. Although most of the concern regarding horizontal gene transfer has been focused on antibiotic-resistance genes used as markers of the transgenic event, other transgenes, such as those with Bt toxins, have also been of concern.

A prerequisite for horizontal gene transfer is that the recombinant DNA must survive the adverse conditions of both food processing and passage through the gastrointestinal tract. Netherwood et al. (2004) showed in patients with a surgically implanted exiting tube placed at the end of the small intestine (an ileostomy) that a small amount of the GE soybean transgene EPSPS passed through the upper gastrointestinal tract to the point of the distal ileum; in subjects without an ileostomy, no transgene was recovered from their feces. In their review on stability and degradation of

DNA from foods in the gastrointestinal tract, Rizzi et al. (2012) noted that recombinant plant DNA fragments were detected in the gastrointestinal tracts of nonruminant animals but not detected in blood or other tissues, although some nonrecombinant plant DNA could be found. The authors concluded that some natural plant DNA fragments persist in the lumen of the gastrointestinal tract and in the bloodstream of animals and humans.

For an event to be considered horizontal gene transfer, DNA must be in the form of a functional (rather than fragmented) gene, enter into bacterial or somatic cells, and be incorporated into the genome with an appropriate promoter, and it must not adversely affect the competitiveness of the cells; otherwise, the effect would be short-lived.

Plant DNA has not been demonstrated to be incorporated into animal cells; however, it has been shown to be transferred in prokaryotes (bacteria). Indeed, molecular geneticists had to find genetic-engineering approaches for getting DNA to be taken into eukaryote cells and incorporated into a genome. The report A Decade of EU-Funded GMO Research (2001–2010) ( EC, 2010a ) described a study that shows that rumen ciliates (a type of microorganism) exposed to Bt 176 maize for 2 or 3 years did not incorporate the Bt 176 transgene. There are no reproducible examples of horizontal gene transfer of recombinant plant DNA into the human gastrointestinal microbiota or into human somatic cells. Three independent reviews of the literature on the topic ( van den Eede et al., 2004 ; Keese, 2008 ; Brigulla and Wackernagel, 2010 ) concluded that new gene acquisition by the gut bacteria through horizontal gene transfer would be rare and does not pose a health risk.

FINDING: On the basis of its understanding of the process required for horizontal gene transfer from plants to animals and data on GE organisms, the committee concludes that horizontal gene transfer from GE crops or conventionally bred crops to humans does not pose a substantial health risk.

Transfer of Transgenic Material Across the Gut Barrier into Animal Organs

Conflicting reports exist regarding the question of intact transgenes and transgenic proteins from foods crossing the gut barrier. Spisák et al. (2013) published results that indicate that complete genes in foods can pass into human blood. That is plausible, but Lusk (2014) examined the approach used by Spisák et al. and found it more likely that the findings were due to contaminants. Lusk emphasized the need for negative controls in such studies. Placental transfer of foreign DNA into mice was found by Schubbert et al. (1998) by detection in the mouse fetus, but a later report

from the same laboratory ( Hohlweg and Doerfler, 2001 ) did not find the transfer in an eight-generation study.

Studies with dairy cows and goats did not find transgenes or GE proteins in milk, although chloroplast DNA fragments were detected in milk ( Phipps et al., 2003 ; Nemeth et al., 2004 ; Calsamiglia, et al., 2007 ; Rizzi et al., 2008 ; Guertler et al., 2009 , Einspanier, 2013 ; Furgał-Dierżuk et al., 2015 ). That makes it clear that there is no apparent potential for trangenes or transgenic proteins to be present in dairy products. However, these animals are ruminants, and their digestive systems are different from that of humans.

Walsh et al. (2012a) studied the fate of a Bt gene and protein in pigs that have digestive systems that are more similar to that of humans. They found no evidence of the gene or protein in any organs or blood after 110 days of feeding on Bt maize, but they did find them in the digestive contents of the stomach, cecum, and colon. Fragments of Cry1Ab transgene (as well as other common maize gene fragments) but not the intact Bt gene were found in blood, liver, spleen, and kidney of pigs raised on Bt maize ( Mazza et al., 2005 ).

FINDING: Experiments have found that Cry1Ab fragments but not intact Bt genes can pass into organs and that these fragments present concerns no different than other genes that are in commonly consumed non-GE foods and that pass into organs as fragments.

FINDING: There is no evidence that Bt transgenes or proteins have been found in the milk of ruminants. Therefore, the committee finds that there should be no exposure to Bt transgenes or proteins from consuming dairy products.

OVERALL FINDING ON PURPORTED ADVERSE EFFECTS ON HUMAN HEALTH OF FOODS DERIVED FROM GE CROPS: On the basis of detailed examination of comparisons of currently commercialized GE and non-GE foods in compositional analysis, acute and chronic animal-toxicity tests, long-term data on health of livestock fed GE foods, and human epidemiological data, the committee found no differences that implicate a higher risk to human health from GE foods than from their non-GE counterparts.

ASSESSMENT OF HUMAN HEALTH BENEFITS FROM GENETICALLY ENGINEERED CROPS

There are now a number of examples of crops, either commercialized or in the pipeline toward commercialization, that have GE traits that could improve human health. Improvement of human health can be the sole moti-

vation for development of a specific crop trait, or it can be the secondary effect of a crop trait that is developed primarily for another reason. For example, the genetic engineering of rice to have higher beta-carotene has the specific goal of reducing vitamin A deficiency. GE maize that produces Bt toxins is engineered to decrease insect-pest damage, but a secondary effect could be a decrease in contamination of maize kernels by fungi that produce mycotoxins, such as fumonisins, that at high concentrations could impair human health. Beyond the direct effects of the crops on improvement of human health, there is also a potential indirect benefit associated with a decline in the exposure of insecticide applicators and their families to some insecticides because some GE plants decrease the need for insecticidal control.

Foods with Additional Nutrients or Other Healthful Qualities

Improved micronutrient content.

According to WHO, some 250 million preschool children are vitamin A–deficient. Each year, 250,000–500,000 vitamin A–deficient children become blind, and half of them die within 12 months of losing their sight. 6 Unlike children in wealthier societies, those children have diets that are restricted mostly to poor sources of nutrients, such as rice ( Hefferon, 2015 ). Overall improvement of the diets of the children and their parents is a goal that has not been reached; measures that improve the nutritional quality of their food sources are desirable although not optimal, as a diverse, healthy diet would be.

Crop breeders have used conventional breeding to improve the concentrations of beta-carotene in maize ( Gannon et al., 2014 ; Lividini and Fiedler, 2015 ), cassava, banana and plantain ( Musa spp.) ( Saltzman et al., 2013 ), and sweet potato ( Ipomoea batatas ) ( Hotz et al., 2012a , b ). There is some loss of beta-carotene during storage and cooking, but bioavailability is still good ( Sanahuja et al., 2013 ; De Moura et al., 2015 ). The most rigorous assessments of the effects of those high–beta-carotene varieties were conducted with orange-fleshed sweet potato (high in beta-carotene) in farming areas of Mozambique and Uganda. In both countries, there was increased beta-carotene intake. In Uganda, there was a positive relationship between consumption of high–beta-carotene sweet potato and positive vitamin A status ( Hotz et al., 2012a ). A more recent study in Mozambique found a decrease in diarrhea prevalence associated with consumption of the high–beta-carotene sweet potato ( Jones and DeBrauw, 2015 ).

6 Micronutrient deficiencies. Available at http://www.who.int/nutrition/topics/vad/en/ . Accessed October 30, 2015.

No reported experiments have tested any crop with high–beta-carotene for unintended effects. There has been concern about the potential for too high a concentration of beta-carotene in crops because of the hypervitaminosis A syndrome that can be caused by direct intake of too much vitamin A, but that is not a problem when the source is beta-carotene ( Gannon et al., 2014 ).

Golden Rice, which was produced through genetic engineering to increase beta-carotene content, is one of the most recognized examples of the use of genetic-engineering technology to improve a crop’s nutritional value. It is based on the understanding that rice possesses the entire machinery to synthesize beta-carotene in leaves but not in the grain. The breakthrough in the development of Golden Rice was the finding that only two genes are required to synthesize beta-carotene in the endosperm of the rice grain ( Ye et al., 2000 ). The first version of Golden Rice had a beta-carotene content of 6 µg/g. To raise the content to a point where it could alleviate vitamin A deficiency without consumption of very large amounts of rice, a second version of Golden Rice was produced by transforming the plant with the psy gene from maize. The carotene content was thereby raised above 30 µg/g ( Paine et al., 2005 ). Varieties that yield well, have good taste and cooking qualities, and cause no adverse health effects from unintended changes in the rice could have highly important health effects ( Demont and Stein, 2013 ; Birol et al., 2015 ). There have been claims that Golden Rice was ready for public release for well over a decade ( Hefferon, 2015 ), but this is not the case.

There is a publication on a field test of the first version of Golden Rice ( Datta et al., 2007 ), but the committee could not find information on the newer, higher–beta-carotene Golden Rice in the peer-reviewed literature. Therefore, it contacted the International Rice Research Institute (IRRI) Golden Rice project coordinator, Violeta Villegas, for an update on the status of the project. In discussions with Dr. Villegas (IRRI, personal communication, 2015), it was clear that the project is progressing with a new lead transgenic event, GR2-E, because of difficulties with the previous lead event, GR2-R. The GR2-E event has been backcrossed into varieties that have been requested by several countries including the Philippines, Bangladesh, and Indonesia. As of March 2016, Golden Rice GR2-E in PSBRc82 and BRRI dhan20 genetic backgrounds was being grown in confined field tests in the Philippines and Bangladesh, respectively. Both Golden Rice varieties underwent preliminary assessment inside the greenhouse prior to planting in confined field tests. If performance is good, the varieties will be moved to open field-testing on multiple locations. Once a food regulatory approval is received in one of the participating countries, IRRI will supply the rice with the GR2-E event to an independent third party to assess its efficacy at alleviating vitamin A deficiency.

Past issues with persons and organizations opposed to Golden Rice for a myriad of reasons may have affected IRRI’s work on the rice, but the overall project status 7 points out that development of Golden Rice varieties that meet the needs of farmers and consumers and that are in full compliance with the regulatory systems of the partnering countries remains the primary objective. IRRI’s summary statement on its Golden Rice project was that “Golden Rice will only be made available broadly to farmers and consumers if it is successfully developed into rice varieties suitable for Asia, approved by national regulators, and shown to improve vitamin A status in community conditions. If Golden Rice is found to be safe and efficacious, a sustainable delivery program will ensure that Golden Rice is acceptable and accessible to those most in need.” 8

Increasing concentrations of beta-carotene is only one goal of conventional crop breeding and genetic engineering. Projects for increasing iron and zinc in crops as different as wheat, pearl millet ( Pennisetum glaucum ), and lentil ( Lens culinaris ) are at varied stages of development ( Saltzman et al., 2013 ).

FINDING: Experimental results with non-GE crop varieties that have increased concentrations of micronutrients demonstrate that both GE and non-GE crops with these traits could have favorable effects on the health of millions of people, and projects aimed at providing these crops are at various stages of completion and testing.

Altering Oil Composition

Substantial efforts have been made to increase the oxidative stability of soybean oil, a major cooking oil all over the world, as a means of avoiding trans-fats generated through the hydrogenation process and enhancing omega-3 fatty acid content of the oil for use in both food and feed applications. Soybean oil is composed principally of five fatty acids: palmitic acid (16:0, carbon number:double bond number), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), and linolenic acid (18:3) in approximate percentages of 10, 4, 18, 55, and 13. High content of unsaturated fats creates a disadvantage in industrial processing because they are susceptible to oxidation and trans-fat generation during hydrogenation, whereas oils with a high percentage of oleic acid (about 80 percent) require less processing and offer another route to decrease concentrations

7 What is the status of the Golden Rice project coordinated by IRRI? Available at http://irri.org/golden-rice/faqs/what-is-the-status-of-the-golden-rice-project-coordinated-by-irri . Accessed October 30, 2015.

of trans-fats in food products. High-oleic acid-containing soybean was produced by downregulating expression of the fatty acid desaturating enzymes FAD2-1A and -1B to decrease the concentration of trans-fats in soybean ( EFSA, 2013 ). In 2015, high-oleic acid soybean was commercially available in North America and was produced on a small area in the United States for specialty-product contracts (C. Hazel, DuPont Pioneer, personal communication, December 14, 2015).

Canola ( Brassica napus ), known in Europe as rapeseed, is the major oilseed crop in Canada. Canola was developed through conventional breeding at the University of Manitoba, Canada, by Downey and Stefansson in the early 1970s and had a good nutritional profile—58-percent oleic acid and 36-percent polyunsaturated fatty acids—in addition to low erucic acid and a moderate concentration of saturated fatty acid (6 percent). Because of demand for saturated functional oils for the trans - fat–free market, high-lauric acid GE canola was created in 1995 through an “ Agrobacterium mediated transformation in which the transfer-DNA (T-DNA) contained the gene encoding the enzyme 12:0 ACP thioesterase ( bay TE ) from the California Bay tree ( Umbellularia californica ). In addition, the T-DNA contained sequences that encoded the enzyme neomycin phosphotransferase II (NPTII). The expression of NPTII activity was used as a selectable trait to screen transformed plants for the presence of the bay TE gene. No other translatable DNA sequences were incorporated into the plant genome” ( Health Canada, 1999:1 ). The presence of lauric acid (12:0) in the oil allows it to be used as a replacement for other types of oils with lauric acid (for example, coconut and palm kernel oil) in such products as “confectionery coatings and fillings, margarines, spreads, shortenings, and commercial frying oils. It has also been used as a substitute for cocoa butter, lard, beef fats, palm oil, and partially or fully hydrogenated soybean, maize, cottonseed, peanut, safflower, and sunflower oils” ( Health Canada, 1999:2 ). However, low yield and comparably poor agronomic traits have removed high-lauric acid canola from the commercial market. The long-term use of crops with altered oil content is uncertain.

FINDING: Crops with altered oil composition might improve human health, but this will depend on the specific alterations, how the crops yield, and how the products of the crops are used.

Genetically Engineered Foods with Lower Concentrations of Toxins

Acrylamide is produced in starchy foods when they are cooked at high temperatures. Processing of potatoes for French fries and potato chips generates acrylamide. Toasting bread also produces acrylamide. That is viewed as a problem because the U.S. National Toxicology Program (2014)

concluded that acrylamide “is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals” and causes neurological damage at high exposure. Acrylamide is produced from a chemical reaction between asparagine and a reducing sugar, so decreasing the concentration of either is expected to decrease acrylamide. A potato line was genetically engineered to have low amounts of free asparagine and in early tests had as little as 5 percent of the acrylamide compared with non-GE potatoes when cooked at high temperatures ( Rommens et al., 2008 ).

In 2014, USDA deregulated a low-acrylamide potato produced by Simplot Plant Sciences ( USDA–APHIS, 2014c ) on the basis of nonplant pest status. The company also provided information to FDA. No problems were found by FDA with respect to the company’s assessment of composition or safety ( FDA, 2015 ). It should be noted that for many people reduced acrylamide in potatoes is expected to lower overall acrylamide intake substantially, but many foods contain acrylamide ( FDA, 2000b , revised 2006). An FDA survey of commonly consumed foods showed French fries at seven McDonald’s locations had an average acrylamide concentration of 288 parts per billion (ppb), whereas Gerber Finger Foods Biter Biscuits had 130 ppb and Wheatena Toasted Wheat Cereal had 1,057 ppb, which is much more than from fast-food French fries ( FDA, 2002 , revised 2006). 9 Any toasted bread is expected to be high in acrylamide. Therefore, how much low-acrylamide potato decreases total exposure depends on individual diets. Furthermore, EPA has established limits for exposure to acrylamide, and current actual exposures are generally below the limits.

Although the low-acrylamide potato is the only GE crop with a lower food-toxin concentration that has been deregulated in the United States, other GE crops with lower natural toxin concentrations are in the pipeline. Potatoes and other crops in the “deadly nightshade” family (Solanaceae, which includes tomato and eggplant) produce glycoalkaloids, some of which have human toxicity, as described above (see the section “Endogenous Toxins in Plants” in this chapter). Langkilde et al. (2012) conducted a compositional and toxicological analysis of the potatoes with lower solanine and higher chaconine. The study used Syrian golden hamsters instead of rats because the hamsters are very sensitive to the glycoalkaloids. There were some statistically significant differences, but they were considered not of biological relevance. At this point, the evidence is not sufficient to conclude that a low-glycoalkaloid potato would be healthier for humans.

Highly toxic chemicals (aflatoxins and fumonisins) are produced by Fusarium and Aspergillis fungi on the kernels of maize ( Bowers et al.,

9 Acrylamide concentrations reported by FDA were for individual purchased food products and were not adjusted for unit-to-unit variation.

2014 ). Aflatoxins are considered by the U.S. National Toxicology Program (2014) to be “human carcinogens based on sufficient evidence of carcinogenicity from studies in humans.” They are also associated with many other illnesses and considered a global health problem ( Wild and Gong, 2010 ). Fumonisins cause a number of physiological disorders and are considered possibly carcinogenic to humans ( IARC, 2002 ). Several investigators have reported a substantial decrease in fumonisins in Bt maize compared with conventionally bred varieties ( Munkvold and Desjardins, 1997 ; Bowers et al., 2014 ). However, there is no clear association between Bt maize and aflatoxin concentrations ( Wiatrak et al., 2005 ; Abbas et al., 2007 ; Bowen et al., 2014 ).

Research continues on how to use genetic engineering to develop varieties of maize and peanut ( Arachis hypogaea ) that inhibit aflatoxin production, but a GE solution has so far been elusive ( Bhatnagar-Mathur et al., 2015 ). A reduction in aflatoxin in both maize and peanut would have substantial health benefits in some developing countries ( Williams et al., 2004 ; Wild and Gong, 2010 ).

FINDING: It is possible that GE crops that would result in improved health by lowering exposure of humans to plant-produced toxins in foods could be developed, but there is insufficient information to assess the possibility. However, GE plants that indirectly or directly reduce fungal-toxin production and intake would offer substantial benefits to some of the world’s poorest populations, which have the highest dietary intake of food-associated fungal toxins.

Health Effects of Farmer Exposure to Insecticides and Herbicides

Chapter 4 presents data that demonstrate substantially lower use of insecticides in some Bt crops than in conventionally bred crops. There is a logical expectation that a decrease in the number of insecticide applications would lead to lower farm-worker exposure and therefore lower health burden, especially in countries where acute poisonings due to applicator exposure are common. Racovita et al. (2015) reviewed five studies of Bt cotton in China, India, Pakistan, and South Africa that ranged from one to four growing seasons. All reported a decline in the number of insecticide applications to Bt versus non- Bt cotton. In a study in China by Huang et al. (2002) , Bt cotton was treated with insecticides 6.6 times and non- Bt cotton was treated 19.8 times during the growing season. The frequency of Bt and non- Bt cotton farmers reporting poisonings were 5 percent and 22 percent, respectively in 1999, 7 percent and 29 percent in 2000, 8 percent and 12 percent in 2001. Kouser and Qaim (2011) found fewer overall insecticide treatments in a study conducted in India: 1.5 treatments

of Bt cotton and 2.2 treatments of non- Bt cotton. In this study, the farmers who used Bt cotton reported 0.19 poisonings per season while those with conventionally bred cotton reported 1.6 poisonings. Bennett et al. (2006) studied the same types of farmers in South Africa. Bt cotton was not yet widely available in the beginning of the experiment, but eventually some farmers adopted Bt cotton and decreased spraying. The study looked at overall poisonings according to hospital records over time; there were 20 poisonings in the year before common availability of Bt cotton and four in a later year, when there was 60 percent adoption of Bt cotton.

The findings of those and other studies (for example, Huang et al., 2005 ; Dev and Rao, 2007 ; Kouser and Qaim, 2013 ) are in line with an expectation of a decrease in poisonings when Bt cotton is grown instead of non- Bt cotton. However, Racovita et al. (2015:15) , who carefully assessed each of the studies, found many shortcomings that led them to conclude that “the link between [genetically modified] crop cultivation and a reduction in number of pesticide poisonings should be considered as still circumstantial.” The shortcomings include the fact that the number of poisonings is based on farmer recall of incidents sometimes more than a year after the field season or, in the Bennett et al. (2006) study, simply based on hospital cases. Another issue was that there may have been differences in risk–avoidance behavior between farmers who did and did not plant Bt cotton. Finally, the studies focused on farmers, not farm workers, who do not control farm operations. Racovita et al. (2015) called for more rigorous studies that would address the shortcomings of previous studies, given the politicized nature of the use of Bt crops.

Farm-worker exposure to insecticides and herbicides is lower in the United States and some other developed countries than is the case for farm workers on resource-poor farms. However, there is substantial exposure, and any effects seen in the United States would be of global concern. Prospective cohort studies of health are the high benchmark of epidemiology studies, and the Agricultural Health Study (AHS) funded by the U.S. National Institute of Environmental Health Sciences used this approach to evaluate private and commercial applicators in Iowa and North Carolina. The landmark study resulted in two peer-reviewed articles on glyphosate exposure and cancer incidence ( De Roos et al., 2005 ; Mink et al., 2012 ) and one on glyphosate exposure and non-cancer health outcomes ( Mink et al., 2011 ). De Roos et al. (2005:49) concluded that “glyphosate exposure was not associated with cancer incidence overall or with most cancer subtypes we studied.” The data suggested a weak association with multiple myeloma on the basis of a small number of cases, but that association was not found in a follow-up study ( DeRoos et al., 2005 ; Mink et al., 2012 ). Mink et al. (2012:440) reported on the continuation of the AHS cohort study and found “no consistent pattern of positive associations indicating a causal relationship between total

cancer (in adults or children) or any site-specific cancer and exposure to glyphosate.” Mink et al. (2011) reviewed noncancer health outcomes that included respiratory conditions, diabetes, myocardial infarction, reproductive and developmental outcomes, rheumatoid arthritis, thyroid disease, and Parkinson’s disease. They reviewed cohort, case–control, and cross-sectional studies within the AHS study and found “no evidence of a consistent pattern of positive associations indicating a causal relationship between any disease and exposure to glyphosate” ( Mink et al., 2011:172 ).

FINDING: There is evidence that use of Bt cotton in developing countries is associated with reduced insecticide poisonings. However, there is a need for more rigorous survey data addressing the shortcomings of existing studies.

FINDING: A major government-sponsored prospective study of farm-worker health in the United States does not show any significant increases in cancer or other health problems that are due to use of glyphosate.

ASSESSMENT OF FOOD SAFETY OF CROPS TRANSFORMED THROUGH EMERGING GENETIC-ENGINEERING TECHNOLOGIES

Increased precision and complexity of genetic-engineering alterations.

At the time that the committee wrote its report, major commercialized GE crops had been engineered by using Agrobacterium tumefaciens mediated or gene gun-mediated transformation, both of which result in semirandom insertion of the transgene into the genome. Variation in expression of the transgene was routinely observed because of the specific genomic characteristics of the insertion sites. Because of that variation, there was a need to screen large numbers of transgenic plants to identify the optimal transgenic individual. Regulations in the United States require approval of each transformation event regardless of whether the transgene itself was previously approved for release in that crop. That is at least in part because of the potential for unintended effects of each insertion.

Precision genome-editing technologies now permit insertion of single or multiple genes into one targeted location in the genome and thereby eliminate variation that is due to position effects (see Chapter 7 ). Such precision is expected to decrease unintended effects of gene insertion, although it will not eliminate the effects of somaclonal variation (discussed in Chapter 7 ).

Consider, for example, the engineering of completely new metabolic pathways into a plant for nutritional enhancement. The simplest example

would be a set of two genes, such as has been used to create Golden Rice to deliver precursors of vitamin A. A more complex example would be engineering of fish oils (very long-chain unsaturated fatty acids) to improve the health profile of plant oils; depending on the target species, this process has required introduction of at least of three and at most nine transgenes ( Abbadi et al., 2004 ; Wu et al., 2005 ; Ruiz-Lopez et al., 2014 ). If each of those transgenes is integrated into the genome on a different chromosome on the basis of separate insertion events, it will require a number of generations of crosses to put them all together in one plant. If, instead, all the transgenes could be targeted at the same site on a chromosome either simultaneously or one after another, they would not segregate from each other as they were moved into elite varieties. From a food-safety perspective, engineering transgenes into a single target locus also ensures that expression of the whole pathway is preserved so that the correct end product accumulates. Emerging genetic-engineering technologies currently enable insertion of a few genes in one construct, but in the future that number may increase dramatically.

In the future, the scale of genetic-engineering alterations may go much further than just manipulating oil profiles. The committee heard from speakers about projects aimed at changing the entire photosynthetic pathway of the rice plant ( Weber, 2014 ) to create an entirely novel crop ( Zhu et al., 2010 ; Ruan et al., 2012 ). The committee also heard from researchers interested in developing cereal crops with nitrogen fixation. Those projects are discussed further in Chapter 8 . Although the precision of future genetic-engineering alterations should decrease unintended effects of the process of engineering, the complexity of the changes in a plant may leave it not substantially equivalent to its non-GE counterpart.

It is also important to note that crops that use RNA interference (RNAi) were coming on the market when the committee was writing its report. EPA convened a science advisory panel to evaluate hazards that might arise from use of this genetic-engineering approach. The panel concluded that “dietary RNA is extensively degraded in the mammalian digestive system by a combination of ribonucleases (RNases) and acids that are likely to ensure that all structural forms of RNA are degraded throughout the digestive process. There is no convincing evidence that ingested [double-stranded] RNA is absorbed from the mammalian gut in a form that causes physiologically relevant adverse effects” ( EPA, 2014c:14 ). When the committee was writing its report, deployment of dietary RNAi was a new technology. EPA’s panel made a number of recommendations, including investigating factors that may affect absorption and effects of dietary double-stranded RNAs and investigating the stability of double-stranded RNA in people who manifest diseases.

FINDING: The precision of emerging genetic-engineering technologies should decrease some sources of unintended changes in the plants, thus simplifying food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites.

Increased Diversity of Crops To Be Engineered

The most far-ranging effects of emerging genetic-engineering technologies may be the diversity of crops that will be engineered and commercialized. Commercial GE crops at the time the committee conducted its review were mainly high-production commodity crops (maize, soybean, and cotton) engineered with trans-kingdom genes, but the applications of emerging genetic-engineering technologies are much broader: these technologies can be easily applied to any plant species that can be regenerated from tissue culture. Furthermore, the emerging technologies described in Chapter 7 can focus on any gene in which an altered nucleotide sequence results in a desired trait.

As a consequence, the committee expects a sizable increase in the number of food-producing crop species that are genetically altered. Examples of new target crops include forages (grasses and legumes), beans, pulses, a wide array of vegetables, herbs, and spices, and plants grown for flavor compounds. New traits will probably include fiber content (either increased to add more fiber or decreased to improve digestibility), altered oil profiles, decreased concentrations of antinutrients, increased or more consistent concentrations of such phytochemicals as antioxidants (for example, flavonoids) and phytoestrogens (for example, isoflavones or lignans), and increased mineral concentrations. Some of these are considered further in Chapter 8 .

From a food-safety perspective, the increase in crops and traits presents a number of challenges. First is the need to develop better and more detailed baseline data on the general chemical composition and probably the transcriptomic profiles of currently marketed conventionally bred varieties of the crops (see Chapter 7 ). Perhaps more problematic will be designing whole-food animal-testing regimens if the food from the crop cannot be used as a major component of the test animals’ diet. Maize, rice, soybean, and other grains can be added to diets at up to 30 percent without adverse effects on animal health. That is unlikely to be the case with new spices or some vegetables. It would be beneficial if new, publicly acceptable approaches for testing could be developed that do not require animal testing ( NRC, 2007 ; Liebsch et al., 2011 ; Marx-Stoelting et al., 2015 ). Chapter 9

addresses the potential need to move to an entirely product-based approach to regulation and testing based on the novelty of a new crop or food.

FINDING: Some future GE crops will be designed to be substantially different from current crops and may not be as amenable to animal testing as currently marketed GE crops.

RECOMMENDATION: There is an urgent need for publicly funded research on novel molecular approaches for testing future products of genetic engineering so that accurate testing methods will be available when the new products are ready for commercialization.

CONCLUSIONS

The committee’s objective in this chapter was to examine the evidence that supports or negates specific hypotheses and claims about the risks and benefits associated with foods derived from GE crops. As acknowledged at the beginning of the chapter, understanding the health effects of any food, whether non-GE or GE, can be difficult. The properties of most plant secondary metabolites are not understood, and isolating the effects of diet on animals, including humans, is challenging. Although there are well-developed methods for assessing potential allergenicity of novel foods, these methods could miss some allergens. However, the research that has been conducted in studies with animals and on chemical composition of GE foods reveals no differences that would implicate a higher risk to human health from eating GE foods than from eating their non-GE counterparts. Long-term epidemiological studies have not directly addressed GE food consumption, but available time-series epidemiological data do not show any disease or chronic conditions in populations that correlate with consumption of GE foods. The committee could not find persuasive evidence of adverse health effects directly attributable to consumption of GE foods.

New methods to measure food composition that involve transcriptomics, proteomics, and metabolomics provide a broad, nontargeted assessment of thousands of plant RNAs, proteins, and compounds. When the methods have been used, the differences found in comparisons of GE with non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties. Differences that are detected by using -omics methods do not on their own indicate a safety problem.

There is some evidence that GE insect-resistant crops have had benefits to human health by reducing insecticide poisonings and decreasing exposure to fumonisins. Several crops had been developed or were in development with GE traits designed to benefit human health; however, when the committee was writing its report, commercialized crops with health benefits

had been only recently introduced and were not widely grown, so the committee could not evaluate whether they had had their intended effects.

New crops developed with the use of emerging genetic-engineering technologies were in the process of being commercialized. The precision associated with the technologies should decrease some sources of unintended changes that occur when plants are genetically engineered and thus simplify food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites. Therefore, publicly funded research on novel approaches for testing future products of genetic engineering is needed so that accurate testing methods will be available when the new products are ready for commercialization.

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Genetically engineered (GE) crops were first introduced commercially in the 1990s. After two decades of production, some groups and individuals remain critical of the technology based on their concerns about possible adverse effects on human health, the environment, and ethical considerations. At the same time, others are concerned that the technology is not reaching its potential to improve human health and the environment because of stringent regulations and reduced public funding to develop products offering more benefits to society. While the debate about these and other questions related to the genetic engineering techniques of the first 20 years goes on, emerging genetic-engineering technologies are adding new complexities to the conversation.

Genetically Engineered Crops builds on previous related Academies reports published between 1987 and 2010 by undertaking a retrospective examination of the purported positive and adverse effects of GE crops and to anticipate what emerging genetic-engineering technologies hold for the future. This report indicates where there are uncertainties about the economic, agronomic, health, safety, or other impacts of GE crops and food, and makes recommendations to fill gaps in safety assessments, increase regulatory clarity, and improve innovations in and access to GE technology.

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Genetically Modified Crops and Food Security

1 Department of Agricultural Economics and Rural Development, Georg-August-University of Goettingen, Goettingen, Germany

Shahzad Kouser

2 Institute of Agricultural and Resource Economics, University of Agriculture, Faisalabad, Pakistan

Analyzed the data: MQ SK. Wrote the paper: MQ SK. Conceived and designed the survey: MQ.

Associated Data

The role of genetically modified (GM) crops for food security is the subject of public controversy. GM crops could contribute to food production increases and higher food availability. There may also be impacts on food quality and nutrient composition. Finally, growing GM crops may influence farmers’ income and thus their economic access to food. Smallholder farmers make up a large proportion of the undernourished people worldwide. Our study focuses on this latter aspect and provides the first ex post analysis of food security impacts of GM crops at the micro level. We use comprehensive panel data collected over several years from farm households in India, where insect-resistant GM cotton has been widely adopted. Controlling for other factors, the adoption of GM cotton has significantly improved calorie consumption and dietary quality, resulting from increased family incomes. This technology has reduced food insecurity by 15–20% among cotton-producing households. GM crops alone will not solve the hunger problem, but they can be an important component in a broader food security strategy.

Introduction

Food security exists when all people have physical and economic access to sufficient, safe, and nutritious food. Unfortunately, food security does not exist for a significant proportion of the world population. Around 900 million people are undernourished, meaning that they are undersupplied with calories [1] . Many more suffer from specific nutritional deficiencies, often related to insufficient intake of micronutrients. Eradicating hunger is a central part of the United Nations’ Millennium Development Goals [2] . But how to achieve this goal is debated controversially. Genetically modified (GM) crops are sometimes mentioned in this connection. Some see the development and use of GM crops as key to reduce hunger [3] , [4] , while others consider this technology as a further risk to food security [5] , [6] . Solid empirical evidence to support either of these views is thin.

There are three possible pathways how GM crops could impact food security. First, GM crops could contribute to food production increases and thus improve the availability of food at global and local levels. Second, GM crops could affect food safety and food quality. Third, GM crops could influence the economic and social situation of farmers, thus improving or worsening their economic access to food. This latter aspect is of particular importance given that an estimated 50% of all undernourished people worldwide are small-scale farmers in developing countries [7] .

In regard to the first pathway, GM technologies could make food crops higher yielding and more robust to biotic and abiotic stresses [8] , [9] . This could stabilize and increase food supplies, which is important against the background of increasing food demand, climate change, and land and water scarcity. In 2012, 170 million hectares (ha) – around 12% of the global arable land – were planted with GM crops, such as soybean, corn, cotton, and canola [10] , but most of these crops were not grown primarily for direct food use. While agricultural commodity prices would be higher without the productivity gains from GM technology [11] , impacts on food availability could be bigger if more GM food crops were commercialized. Lack of public acceptance is one of the main reasons why this has not yet happened more widely [12] .

Concerning the second pathway, crops with new traits can be associated with food safety risks, which have to be assessed and managed case by case. But such risks are not specific to GM crops. Long-term research confirms that GM technology is not per se more risky than conventional plant breeding technologies [13] . On the other hand, GM technology can help to breed food crops with higher contents of micronutrients; a case in point is Golden Rice with provitamin A in the grain [14] . Such GM crops have not yet been commercialized. Projections show that they could reduce nutritional deficiencies among the poor, entailing sizeable positive health effects [15] , [16] .

The third pathway relates to GM crop use by smallholder farmers in developing countries. Half of the global GM crop area is located in developing countries, but much of this refers to large farms in countries of South America. One notable exception is Bacillus thuringiensis (Bt) cotton, which is grown by around 15 million smallholders in India, China, Pakistan, and a few other developing countries [10] . Bt cotton provides resistance to important insect pests, especially cotton bollworms. Several studies have shown that Bt cotton adoption reduces chemical pesticide use and increases yields in farmers’ fields [17] – [20] . There are also a few studies that have shown that these benefits are associated with increases in farm household income and living standard [21] – [23] . Higher incomes are generally expected to cause increases in food consumption in poor farm households. On the other hand, cotton is a non-food cash crop, so that the nutrition impact is uncertain.

Here we address this question and analyze the impact of Bt cotton adoption on calorie consumption and dietary quality in India. Bt cotton was first commercialized in India in 2002. In 2012, over 7 million farmers had adopted this technology on 10.8 million ha – equivalent to 93% of the country’s total cotton area [10] . For the analysis, we carried out a household survey and collected comprehensive data over a period of several years. This is the first ex post study that analyzes food security effects of Bt cotton or any other GM crop with micro level data.

Materials and Methods

Ethics statement.

Our study builds on data from a socioeconomic survey of farm households in India. Details of this survey are explained further below. The institutional review board of the University of Goettingen only reviews clinical research; our study cannot be classified as clinical research. We consulted with the Head of the Research Department of the University of Goettingen, who confirmed that there is no institutional review board at our University that would require a review of such survey-based socioeconomic research.

Farm Household Survey

We carried out a panel survey of Indian cotton farm households in four rounds between 2002 and 2008. We used a multistage sampling procedure. Four states were purposively selected, namely Maharashtra, Karnataka, Andhra Pradesh, and Tamil Nadu. These four states cover a wide variety of different cotton-growing situations, and they produce 60% of all cotton in central and southern India [23] . In these four states, we randomly selected 10 cotton-growing districts and 58 villages, using a combination of census data and agricultural production statistics [18] , [19] , [23] . Within each village, we randomly selected farm households from complete lists of cotton producers. Sample households were visited individually, and the household head was taken through a face-to-face interview, for which we used a structured questionnaire. The questionnaire covered a wide array of agricultural and socioeconomic information, such as input-output details in cotton production, technology adoption, other income sources, and household living standards. The interviews were carried out in local languages by a small team of enumerators, who were trained and supervised by the researchers.

Prior to starting each interview, the study objective was explained. We also clarified that the data collected would be treated confidentially, analyzed anonymously, and be used for research purposes only. Based on this, the interviewees were asked for their verbal informed consent to participate. We decided not ask for written consent, because the interviews were not associated with any risk for participants. Furthermore, many of the sample farmers had relatively low educational backgrounds and were not used to formal paperwork. Very few households did not agree to participate; they were replaced with other randomly selected households in the same villages.

The first-round survey interviews took place in early 2003, shortly after the cotton harvest for the 2002 season was completed. The same survey was repeated at two-year intervals in early 2005 (referring to the 2004 cotton season), early 2007 (referring to the 2006 season), and early 2009 (referring to the 2008 season). In total, 533 households were interviewed during the 7-year period. Most of these households were visited in several rounds. The total sample consists of 1431 household observations ( Table 1 ). In 2002, the proportion of Bt adopters was still relatively small, but it increased rapidly in the following years. By 2008, 99% of the sample households had adopted this technology. To our knowledge, this is the only longer-term panel survey of Bt cotton farm households in a developing country (the data set with the variables used in this article is available as Data S1 ).

Calorie Consumption Data

The survey questionnaire included a detailed food consumption recall, which is a common tool to assess food security at the household level [24] . For a 30-day recall period, households were asked about the quantity consumed of different food items and the corresponding monetary value. The questions covered food consumed from own production, market purchases, gifts, and transfers.

The quantity data for the different food items were converted to calories consumed by using calorie conversion factors for India [25] , [26] . The total household calorie consumption from the 30-day recall was then divided by 30 to obtain a calorie value per day. Taking into account the age and gender structure of households, as well as physical activity levels of household members, the number of adult equivalents (AE) was calculated for each household. Male adults involved in farming count as 1.0 AE, female adults involved in farming as 0.8 AE. Male and female adults with lower physical activity levels count as 0.8 and 0.7, respectively. For children and adolescents, appropriate adjustments were made [25] – [27] . The daily household calorie consumption was divided by the number of AE in a household to obtain the calories consumed per AE and day.

Values for minimum dietary energy requirements found in the literature vary, which is due to several reasons [24] . Values stated per capita are lower than those stated per AE, because children have lower calorie requirements than adults. Moreover, not all studies take physical activity levels into account already in the AE calculations, as we do. The average daily calorie requirement for a moderately active AE in India is 2875 kcal/day [25] . According to the World Health Organization, a safe minimum daily intake should not fall below 80% of the calorie requirement, meaning 2300 kcal per AE. Minimum values around 2300 kcal per day for adult men are also found in other studies [28] . Based on this, we take 2300 kcal per AE as the threshold, that is, households with daily calorie consumption below 2300 kcal per AE are considered food insecure.

Most of the calories consumed in rural India are from cereals such as wheat, rice, millet, and sorghum that are rich in carbohydrates but less nutritious in terms of protein and micronutrient contents. Hence, in addition to total calories consumed we calculated the number of calories consumed from more nutritious foods to assess dietary quality. In the category “more nutritious foods”, we include pulses, fruits, vegetables, and all animal products (i.e., milk, milk products, meat, fish, and eggs). Recent research suggests that the share of calories consumed from higher value, non-staple foods can also be used as an indicator of nutritional sufficiency [29] . The reason is that poor and undernourished households will largely choose foods that are the cheapest available sources of calories, namely cereals in the context of rural India. Only when they have surpassed subsistence, consumers will begin to substitute towards foods that are more expensive sources of calories [29] .

It should be mentioned that food consumption data from household surveys may not provide very accurate data to measure nutritional status [24] , [30] . Sometimes, consumption data overestimate calorie intakes, because food losses, waste, and other uses within the household cannot be properly accounted for. However, this limitation applies to both adopters and non-adopters of Bt, so that the comparison between Bt and non-Bt, which is relevant for the impact assessment, is unaffected.

Regression Models

To estimate the impact of Bt cotton adoption on calorie consumption, we regress total daily calorie consumption per AE on Bt adoption, measured as the number of hectares of Bt cotton grown by a household in a particular year. Since Bt adoption increases farm profits and household incomes [23] , we expect a positive and significant treatment effect. However, calorie consumption is also influenced by other factors that need to be controlled for. We control for education of the household head (measured in terms of the number of years of schooling); education plays an important role for both income generation and consumption behavior. We also include a variable for household size (measured in terms of AE). Moreover, we control for farm size in terms of area owned, which is a proxy for agricultural asset ownership more generally. Farm income is not included in the model, as this is directly influenced by Bt adoption. However, off-farm income, measured in US$ per year, is controlled for. We also include state dummies for Karnataka, Andhra Pradesh, and Tamil Nadu (Maharashtra is the reference state), capturing climatic and agroecological differences. Given the panel structure of the data with four survey rounds, we use year dummies for 2004, 2006, and 2008 (2002 is the reference year).

Panel data models are often estimated with a random effects estimator [31] . However, a random effects estimator can lead to biased impact estimates when there is unobserved heterogeneity between Bt adopting and non-adopting households. Such bias resulting from endogeneity of the treatment variable is referred to as selection bias in the impact assessment literature [23] , [31] . Unobserved heterogeneity may potentially result from differences in household characteristics (e.g., Bt adopting farmers may have higher motivation, better management skills, or better access to information) or farm characteristics (e.g., differences in soil quality, or water access). Our panel data allow us to control for such unobserved heterogeneity. Since we surveyed the same households repeatedly over a 7-year period when Bt adoption increased, for many households we have observations with and without Bt adoption. Hence, we rely on a within household estimator, which is also called a fixed effects estimator. Differencing within households with the fixed effects estimator eliminates time-invariant unobserved factors, so that they can no longer bias the impact estimates [31] . A Hausman test is used to confirm the appropriateness of the fixed effects specification [19] , [31] .

We estimate an additional model using calories from more nutritious foods (i.e., pulses, fruits, vegetables, and animal products) instead of total calorie consumption as dependent variable. This additional model helps to analyze impacts of Bt cotton adoption on dietary quality. A positive coefficient for the treatment variable would indicate that Bt adoption increases the consumption of more nutritious foods, thus not only contributing to more calories but also to better dietary quality.

Results and Discussion

Descriptive statistics are shown in Table 2 . The average farm household owns 5 ha of land, without a significant difference between Bt adopters and non-adopters. Around half of this area is grown with cotton. Other crops cultivated include wheat, millet, sorghum, pulses, and in some locations rice, among others. Households are relatively poor; average annual per capita consumption expenditures range between 300 and 500 US$.

Mean values are shown with standard deviations in parentheses. N: Number of observations; AE: adult equivalent.

Bt adopting households consume significantly more calories than non-adopting households, and a smaller proportion of them is food insecure ( Figure 1 , Table 2 ). This suggests that the cash income gains through Bt adoption may have improved food security among cotton-producing households. Yet, this simple comparison does not yet prove a causal relationship.

Functions were estimated non-parametrically using the Epanechnikov kernel with 1085 and 346 observations for adopting and non-adopting households, respectively. AE: adult equivalent.

Impact of Bt Cotton Adoption on Food Security

To further analyze the relationship between Bt adoption and calorie consumption, we use panel regression models, as explained above. The main explanatory variable of interest is the Bt cotton area of a farm household, for which descriptive statistics are shown in Table 3 . The average Bt area among technology adopters in the sample is close to 2 ha, which is equivalent to 85% of the total cotton area of these farms. A breakdown by survey year shows that the average Bt area increased from less than 1.0 ha in 2002 to 2.4 ha in 2008. Hence, not only the number of Bt adopters but also the Bt area per adopting household increased considerably over time.

The regression results are shown in Table 4 . Each ha of Bt cotton has increased total calorie consumption by 74 kcal per AE and day. For the average adopting household, the net effect is 145 kcal per AE ( Figure 2 ), implying a 5% increase over mean calorie consumption in non-adopting households. Most of the calories consumed in rural India stem from cereals that are rich in carbohydrates but less nutritious in terms of protein and micronutrients. Yet the results show that Bt adoption has significantly increased the consumption of calories from more nutritious foods, thus also contributing to improved dietary quality.

Results based on calorie consumption regression models estimated with panel data and household fixed effects (within estimator). Full model results are shown in Table 4 . Calories from more nutritious foods include pulses, fruits, vegetables, and animal products. Effects for the average adopting household take into account the number of ha of Bt cotton actually grown. **Significant at the 5% level. ***Significant at the 1% level.

The dependent variable in models (1) and (2) is the total number of kcal consumed per AE and day. The dependent variable in model (3) is the number of kcal consumed from more nutritious foods (i.e., pulses, fruits, vegetables, and animal products) per AE and day. All coefficient estimates can be interpreted as marginal effects; robust standard errors are shown in parentheses. AE: adult equivalent; RE: random effects; FE: fixed effects.

We applied the total calorie consumption effect of Bt to the subsample of non-adopters to simulate the food security impact of adoption: if all non-adopters switched to Bt, the proportion of food insecure households would drop by 15–20% ( Table 5 ). Most of these nutritional benefits have materialized already, as over 90% of all cotton farm households in India have adopted Bt technology by now.

The proportion of food insecure households in the status quo refers to the subsample of 346 non-adopters. For these households, changes in calorie consumption through Bt adoption were simulated, assuming full Bt adoption (on 100% of their cotton area) and partial Bt adoption (on 85% of their cotton area, as observed in the subsample of Bt adopters). For the simulations, the net effect of Bt on total calorie consumption per ha was used ( Figure 2 ).

Robustness Checks

We tested the robustness of the Bt effects by estimating calorie consumption models with alternative specifications. These additional estimates are shown in Table 6 . We first look at possible changes in impact over time. In model (1), the Bt area variable is split into two periods, namely 2002–04 and 2006–08. In both periods, the Bt impact on calorie consumption was positive and significant, but the effect was bigger in 2002–04 than in 2006–08. The reason for this change is not that income effects of Bt adoption would shrink; recent research showed that the profit gains of Bt cotton in India were constant or even increased over time [23] . The change in the calorie effect per ha of Bt is rather due to the fact that the Bt area per farm increased considerably in the later period, as was shown above. Measured per farm household, the calorie consumption effect of Bt was actually very similar in 2002–04 and 2006–08.

All models are estimated with household fixed effects. Other explanatory variables were included in estimation, as in Table 4 , but are not shown here for brevity. The dependent variable in all models is calorie consumption measured in kcal per AE and day. Coefficient estimates can be interpreted as marginal effects; robust standard errors are shown in parentheses.

The smaller calorie consumption effect per ha of Bt with an increasing Bt area on a farm is consistent with Engel’s law, which states that the proportion of the household budget spent on food decreases as income rises [32] . Unsurprisingly, the same trend is not observed when we focus on higher value, non-staple foods. The results of model (2) in Table 6 suggest that the Bt effect on calories from more nutritious foods has been increasing over time. Hence, Bt cotton adoption leads to a lower staple calorie share, implying higher nutritional sufficiency and better dietary quality [29] .

In model (3) of Table 6 , we analyze whether the Bt effect is cumulative, meaning that households that have adopted Bt earlier or on larger areas benefit over-proportionally. This might be the case when profit gains from Bt adoption are reinvested, possibly entailing larger consumption benefits in subsequent periods. To test for this option, we constructed a cumulative Bt area variable, adding up the Bt area on a farm in a particular year and Bt areas on the same farm in previous survey rounds. The coefficient of this variable is insignificant; cumulative effects do not seem to be important. If we include this variable together with the standard Bt area variable, the cumulative coefficient turns negative while the actual treatment effect increases (model 4). Again, this is consistent with Engel’s law, implying that larger areas with Bt lead to lower proportions of the income gains being spent on calories.

In models (6) and (7), we analyze to what extent changes in the sample affect the estimation results. For easy comparison, results from the full-sample reference model, which were discussed above, are repeated in model (5). It is sometimes observed that early adopters of a new technology benefit more than late adopters. This may be due to cumulative effects, which we already tested for. In addition, general equilibrium adjustments may contribute to differential impacts between early and late adopters [33] . In model (6), we exclude all households that had adopted Bt already in the first survey round in 2002. The change in the Bt effect is very small, so we conclude that late adopters enjoy the same nutritional benefits per ha of Bt as early adopters.

This specification in model (6) with early adopters excluded is also an additional robustness check for possible issues of endogeneity and selection bias. The fixed effects panel estimator controls for time-invariant heterogeneity between adopters and non-adopters of Bt. But it cannot control for possible time-variant differences, which might play a role if early adopters are more innovative also with respect to other opportunities not captured in our data. The similarity of the results in models (5) and (6) substantiates that the estimated Bt impacts do not suffer from selection bias. In model (7), we exclude all observations of households that had adopted Bt in all survey rounds, so that the results are purely based on within household comparisons. The treatment effect remains highly significant. It even increases in magnitude, suggesting that the full-sample result is rather a cautious, lower-bound estimate. Finally, model (8) includes a dummy for Bt adoption in addition to the Bt area variable used before. The dummy produces a large coefficient, underlining the positive food security impact of Bt adoption. But the Bt area effect remains positive and significant, too, which confirms that using a continuous treatment variable is appropriate.

Overall, the additional results with alternative specifications strengthen the findings and show that the positive impacts of Bt cotton adoption on food security in India are very robust.

Conclusions

The results of this research confirm that the income gains through Bt cotton adoption among smallholder farm households in India have positive impacts on food security and dietary quality. GM crops are not a panacea for the problems of hunger and malnutrition. Complex problems require multi-pronged solutions. But the evidence suggests that GM crops can be an important component in a broader food security strategy. So far, food security impacts are still confined to only a few concrete examples. The nutritional benefits could further increase with more GM crops and traits becoming available in the future. Appropriate policy and regulatory frameworks are required to ensure that the needs of poor farmers and consumers are taken into account and that undesirable social consequences are avoided.

Supporting Information

Acknowledgments.

We thank Vijesh Krishna and two anonymous reviewers of this journal for very useful comments.

Funding Statement

This research was supported by the German Research Foundation (DFG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.