In the US, genetically engineered (GE) organisms are regulated by the Food and Drug Administration (FDA), the US Department of Agricultural (USDA) and the Environmental Protection Agency (EPA). Since the first commercialization of GE foods, the US National Academy of Sciences (NAS) has produced three major reports addressing the applications, risks, and benefits of GE crops and foods. A fourth comprehensive report is expected in the spring of 2016. The most recent, detailed NAS report addressing issues of food safety and human health was published in 2004.
While the NAS recognizes that genetic engineering has potentially hazardous unexpected and unintended consequences, it nonetheless states that it “is not aware of any evidence that foods on the market are unsafe to eat as a result of genetic modification” (2004 report, p. 9, bold in original). Every NAS report includes a statement to this effect, along with assurances that GE foods on the market as of 2004 pose, to the knowledge of the committees writing the reports, no different or more serious human health risks than non-engineered foods.
The absence of evidence of any food safety or nutritional risks would be reassuring if GE foods had been tested thoroughly and in accordance with the testing protocols suggested by the NAS, the international Codex Alimentarius Commission, and the many other expert bodies that have issued detailed recommendations for the testing of GE foods, both before market approval and post-commercialization. Unfortunately, not a single GE crop or food on the market today has been tested according to such recommendations.
The 2004 NAS committee offered many common-sense recommendations to improve the science base supporting GE crop and food risk assessment. These include reevaluating current research methodologies, developing new tools to assess the risk of GE foods producing novel allergens and toxins, and creating post-market evaluation tools and programs.
We hope that the NAS Committee will address the following critical points when it carries out its 2015-2016 evaluation of GE food testing, risk assessment, and regulation:

1. The reasons why the recommendations from the 2004 and earlier NAS reports have gone largely unheeded, and why state-of-the-art risk assessment science has not been applied to today’s GE foods.
2. The fact that in the years ahead, with the recent approvals of GE sweet corn, Bt eggplant, Arctic apples, Innate potatoes and AquaAdvantage salmon (although very few Americans have consumed these foods yet, with the exception of GE sweet corn which has been commercially significant in the US for only a few years), people will now begin to consume GE foods in forms likely to contain intact GE proteins.
3. The worrisome gap in knowledge regarding the potential for “cross-talk” between multiple regulatory genes and sequences created by stacking traits. For several years, most GE corn varieties, for instance, have contained multiple, “stacked” traits, and one popular brand, SmartStax, contains eight (two herbicide-tolerant traits, and six Bt traits). Such unintended impacts could increase the level of known or new allergens and/or toxins.
4. The importance of including the synergistic effects of the transgene(s), its expression, and the pesticides normally used on the crop – including the so-called inert ingredients incorporated in a given pesticide formulation – in safety evaluations and risk assessments.

The present acceptance of GE crops and foods rests on several questionable assumptions and assertions, including the belief that the FDA “approval” process is thorough and independent. It is neither. In fact, the FDA never really “approves” a GE food: it simply accepts assertions made by technology developers during the course of a “voluntary consultation.”

The FDA approval process

The FDA review process is based almost entirely on industry-sponsored studies. Information in the open, peer-reviewed scientific literature is often ignored or discounted.
The FDA does not conduct any original research or risk assessments on a newly proposed GE food. Nor does it conduct an independent assessment of the conclusions reached by technology developers and expressed in the “voluntary consultation” packages submitted to it.
When submitting a “voluntary consultation” package to the FDA, a company:

1. Summarizes their own safety assessment.
2. Asserts that the GE trait produces food that is “substantially equivalent” to the non-GE counterpart (often referred to as an “isoline”).
3. States their conclusion that the GE food poses no new or more serious food safety or nutrition-related risk compared to non-engineered food.

The FDA simply accepts the data that the company has generated, along with its conclusions regarding safety. The agency does alert technology developers that they are responsible for informing it if they become aware of any data suggesting that the GE food might not be “substantially equivalent” or as safe as non-engineered food.
One need look no further than the typical letter that the FDA sends to a technology developer when it closes out – i.e., “approves” – a new GE food technology. In a 1996 letter to Monsanto, for instance, the FDA states,
Based on the safety and nutritional assessment [Monsanto has] conducted, it is our understanding that Monsanto has concluded that corn grain and forage derived from the new variety are not materially different in composition, safety, or other relevant parameters from corn grain and forage currently on the market, and that they do not raise issues that would require premarket review or approval by FDA. (FDA website)
Because the technology developer has concluded that the FDA does not need to conduct a premarket review, and because the FDA accepts that conclusion, the FDA has no substantive basis on which to “approve” the technology. The FDA “approval” is really an exemption from the standard FDA risk assessment process, and is, regrettably, only a small step removed from a free pass.
These are among the key reasons that we hope the ongoing NAS report on the health and safety of GE crops will examine in detail the FDA review process and recommend ways to strengthen it. In the following, we propose alternatives and evaluate the likely impact of the solutions that others have suggested.
For example, the FDA needs to ensure that the toxicological tests conducted are of sufficient duration and quality to rule out, or identify, potential food safety risks. The process also badly needs, and will benefit from, a greater level of independence and oversight by scientists not affiliated with or supported by technology developers.

Have GE crops been thoroughly tested?

The claim is often made that GE-food technology has undergone extremely thorough testing. A simple comparison of the number of available health impact studies shows otherwise. More than 11,000 citations can easily be found on DDT, and more than 3,000 on the insecticides chlorpyrifos and parathion and on the herbicides atrazine and 2,4-D. There are more than 1,500 studies on glyphosate. There are hundreds of thousands of health-impact studies on “all pesticides,” a class of agricultural technology roughly equivalent to “all GE crops.”
In comparison, there are only a few hundred studies designed to identify and/or quantify human health risks from consumption of GE food. An exhaustive review of the health effects of transgenic foods published in 2011 yielded a total of 75 studies covering GE potato, corn, maize, soybeans, rice, cassava, cucumbers, tomatoes, apples, and many other crops. Most of these studies were carried out for fewer than 91 days. For each of the above crops, there are several commercially significant transgenic events, most of which have been studied by scientists working for technology developers.
There are other categories of agricultural technology that have been examined in much greater depth than GE crops. Indisputable examples are antibiotics used for disease prevention and growth promotion, food additives, hormones used to accelerate animal growth or production, and food colors.
It would be closer to the truth for the NAS to state that GE foods are among the least well-tested agricultural technologies ever adopted.
The testing of GE crops poses significant challenges, including difficulty in ensuring that control animals in fact receive feed that is free of GE ingredients and that the Bt proteins used in animal feeding studies are, in fact, identical to the ones expressed in Bt-transgenic crops (the latter is often not the case, because of the cost of extracting enough Bt proteins from plants to run an animal feed experiment).
In spite of these difficulties, some animal feeding studies to test GE crops have revealed worrisome adverse health impacts and evidence of progress toward chronic disease. However, the US government has never funded research to follow up on experiments reporting adverse impacts, nor has it pushed forward the boundaries of scientific knowledge by trying to develop new tools to understand the mechanisms in transgenic plants through which novel allergens or toxins might be formed, detected, and studied for potential toxicity.

Substantial equivalence

Although the term “substantially equivalent” has been repeatedly used to justify the paucity of nutritional and food safety research on foods from GE crops, it is not subject to a rigorous scientific definition, nor does it encompass careful research on all compositional parameters and nutrient levels that might impact animal health.
In fact, studies of GE crops and their isolines grown in properly designed, side-by-side trials in multiple locations often show statistically significant differences in the levels of many nutrients. Technology developers, however, have argued that these differences should be dismissed as “biologically not meaningful” because they fall within the range of natural variation for the crop in question. It is time to define the concept of “substantial equivalence” much more rigorously in order to gain a more reliable, science-based understanding of the impacts of genetic engineering technology on agriculture.

Crops with stacked traits

Most GE corn varieties contain stacked traits. However, we are aware of only very few studies designed to test the question of whether unique risks arise as a result of stacking traits in a given cultivar. The FDA has adopted the position that if each trait is presumed safe individually, then combinations of traits will also be safe.
Until much needed science is carried out to determine whether FDA’s position on this issue is reasonable, the FDA “approval” process for GE crops/foods with stacked traits rests more on wishful thinking than on science.

Increased availability of transgenic products

We raise specific concerns over the introduction of three-trait sweet corn in the US which contains three GE traits and Bt eggplant internationally (although not yet in the US). EPA approval of Bt corn, both sweet corn and field corn, is based on data showing that Bt endotoxins are not acutely toxic to mammals and suggesting that they could be rapidly broken down in the mammalian GI tract.
However, transgenic Bt toxins can and do enter the bloodstream intact before they get to the stomach, via the gums, tongue, and throat in ways similar to sublingual medications (e.g., a pill placed under one’s tongue).
Moreover, while Bt endotoxins break down in the human stomach, very little research has been done to assess the type of elements they break down into, and whether fragments of Bt toxins might irritate the inner lining of the human GI tract. Such concern is grounded in an appreciation of the way activated Bt toxins attach to, and then create holes in, the stomachs of susceptible insects.
Furthermore, the experiment used to demonstrate Bt toxin destruction in the stomach is an in vitro assay at a highly acidic pH that does not duplicate stomach conditions for the millions of Americans on certain acid-reducing medications.
Chronic exposure to Bt toxins via crops that are ingested in minimally processed forms (such as sweet corn and eggplant) is therefore more likely to result in Bt toxins, or fragments thereof, entering the bloodstream. These fragments may then reach vital organs that might be vulnerable to such exposures, the effects of which have not been studied. We cannot responsibly accept the assertion that the consumption of these foods is safe for all humans. Such assertions might well prove correct in many, or even most cases, but for some others, particularly among individuals dealing with other, chronic conditions, or who are much more heavily exposed to GE proteins occupationally or through their diet, they may well not.

Further considerations: weed and insect resistance

Weed resistance is emerging as a critical concern for farmers planting GE, Roundup Ready® crops. The seed industry has responded by creating corn, soybean, and cotton plants genetically engineered to be tolerant of both glyphosate (the active ingredient in Roundup ®) and 2,4-D, or glyphosate and dicamba. Glyphosate and 2,4-D have been combined by Dow AgroSciences into the new product Enlist Duo®. The EPA approved the registration of Enlist Duo® in late 2014, but recently asked a court to reverse the approval, in effect banning any commercial use of the product until a set of issues involving impacts on non-target plants and endangered species are resolved.
When the EPA was first asked to approve GE Bt corn and cotton, the agency immediately recognized the risk of triggering the emergence of Bt-resistant insects. The EPA was also well aware, as were farmers, environmentalists, and ecologists, that the many natural forms of Bt play an absolutely critical role in soil food webs and in microbial biocontrol in the soil.
Moreover, several natural strains of Bt are incorporated in liquid bioinsecticides that are the backbone of Lepidopteran insect-control programs on many conventional and organic vegetable farms. Industry, farmers, environmentalists, and the EPA all agreed that the loss of Bt efficacy to resistance would be extremely costly and damaging and that strong, preventive measures should be taken if and as transgenic Bt crops were planted.
Hence, the initial approvals of Bt corn and cotton were accompanied by mandatory resistance management practices recommended by independent, mostly academic entomologists. For many years, this proactive approach worked as hoped, and the effectiveness of transgenic Bt corn and cotton did not start breaking down until industry pressure convinced the EPA to relax the preventive measures.
But in the early 1990s, when considering the first applications to approve Roundup Ready® crops, the EPA did not feel that mandatory resistance-risk prevention measures were warranted, even though the agency recognized that herbicide-tolerant crop technology would greatly increase the risk of Roundup-resistant weeds becoming a serious problem for farmers—a situation analogous to the development of Bt-resistant insects.
Why the difference in the way the EPA addressed the risk of resistance in the case of Bt crops versus herbicide-tolerant crops? In the case of Bt crops, the concern was about the future efficacy of a natural bioinsecticide of enormous value to all farmers, and indeed humankind. Since it was clear to just about everyone at the time that no company had the right to jeopardize the biological utility of such an important natural resource, the EPA felt justified in imposing mandatory resistance management practices.
But in the case of Roundup Ready® crops and their associated herbicide, glyphosate, the EPA left the management of glyphosate resistance to the manufacturer, concluding that they would believe it in their best interest to preserve the efficacy of their product.
In retrospect, the decision to leave glyphosate resistance management to market forces was one of the most costly and damaging decisions made in the 40-year history of the EPA’s Office of Pesticide Programs.

Labeling

In the US, foods from GE crops are not labeled as such. This impedes efforts by doctors and epidemiologists to trace any possible connections between consumption of GE foods and adverse health outcomes. Some consumers support labeling because of religious or cultural norms, while others want labeling so they can preferentially seek out or avoid GE foods. Consumer surveys consistently show 85% or more support for GE-food labeling.
Labeling also comes into play in an important way in the flow of agricultural commodities in world markets. Nearly 70 countries have made international sales of non-labeled GE crops illegal. The decision by a country, or a company, to not label GE food fosters mistrust, which can be costly when trying to secure or hold export market share.
Because of the need for labeling to conduct post-approval market surveillance and secure and retain access to many sensitive foreign markets, it is only a matter of time before all foods derived from US-grown GE crops will be labeled. In the interim, expect a lively debate over what sorts of labels should be required, who should impose the requirements, and who should oversee compliance (public versus private entity; states vs. the federal government).

Overcoming objections to GE foods

Several major changes in the way GE crops and foods are tested, analyzed, regulated, and marketed are going to be necessary to improve market acceptance. Substantial progress will take time, consistency, and transparency. Essential building blocks needed to resolve lingering risk assessment issues and gain consumer trust and acceptance include:

1. Labeling of GE foods and associated public information campaigns.
2. Risk assessment that conforms to a high standard of excellence. Given our present understanding, such assessment ought to include cutting-edge techniques, e.g. genomics, transcriptomics, proteomics, metabolomics, immune system parameters, as well as siRNA/miRNA profiling.
3. Long-term animal-feeding studies. These should include multiple arms of investigation addressing toxicity, carcinogenicity, reproduction, and multigenerational effects, several physiologically relevant doses, and comparisons to isogenic, non-GMO-only controls. This testing should be based on real-world conditions, including the use of formulated pesticides where relevant.
4. Long-term studies that define toxicokinetics and produce information sufficient to complete a comprehensive anatomical, histological, physiological, and biochemical analysis of major organs, blood, and urine.
5. Post-market surveillance similar to that available for new medications. Until much more is known about the human health risks posed by GE crops, post-market surveillance must be carefully structured as part of government approval, and particular consideration should be accorded to the ways in which it will be carried out and paid for.

A transparent, comprehensive effort, demonstrating a real commitment to discovering harmful effects, if any, should be undertaken. In health care, we well understand the directive to “do no harm.” This should also pervade regulatory decision-making—especially when it comes to human food. Many members of the public erroneously believe that government agencies are acting in accordance with this directive in the case of agricultural biotechnology. We wish it were true and, because it is not, we will work to make it so.
For more information on this topic:
Druker, S. 2015. Altered Genes, Twisted Truth: How the venture to genetically engineer our food has subverted science, corrupted government and systematically deceived the public. Clear River Press.
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