Part III. Healthy or hazardous? Critics say there’s no way to know for sure

Monsanto’s new Omega-3 soybean:
Healthy or hazardous? Part III

HONOLULU—A certain kind of Omega-3 called EPA is responsible for producing compounds that reduce blood clotting, thus helping to prevent a range of ailments, like thrombosis, atherosclerosis, and heart attacks.

By 2012, we could be getting most, if not all, of our recommended EPA through Monsanto’s latest genetically modified endeavor: the Omega 3 soybean. Monsanto, in partnership with Solae, a major soy innovator, is selling the soybean oils to food companies that can add it to virtually any processed product. It’s entirely possible that you could be getting part of your daily EPA intake by eating Twinkies.

But before that happens, Monsanto must demonstrate that the new product is safe. And it’s the regulatory oversight, or rather the lack thereof, that forms the center of critics’ arguments against the safety of this eccentric soybean. 

The Omega-3 soybean seed must be inspected by two federal agencies before it can be sold and planted. The U.S. Department of Agriculture (USDA), which must determine whether to allow a crop to be planted commercially, must comply with two laws. The first is the National Environmental Policy Act, which requires that government scientists assess the plant’s potential impact on the environment. In particular, the agency evaluates company studies of its effects on animals (which is especially important for soybeans because they are a main ingredient in cattle feed) and the ecosystem the animals inhabit.

Under the second act, called the Plant Protection Act, the agency must determine the proposed crop’s likelihood of becoming a plant pest—a weed that could pose agricultural and environmental problems where its planted.

Determining which foods are safe to eat falls entirely under the aegis of the U.S. Food and Drug Administration (FDA). The agency’s biotechnology safety stance is situated in a curious limbo within the agency’s regulatory apparatus. On the one hand, it oversees companies trying to commercialize food additives (things like food coloring and artificial sweeteners), which are subject to more exhaustive safety testing, including, if necessary, cancer and other reproductive studies.

On the other hand, it requires no testing whatsoever of such traditional foods as apples, corn, and potatoes. We’ve been eating these for such a long time that history has judged them to be relatively harmless. The FDA calls these commodities GRAS (Generally Recognized as Safe).

With a genetically modified food, however, its status as either GRAS or additive hinges on whether it’s considered “substantially equivalent” to its unmodified counterpart. Born out of the FDA’s seminal—albeit controversial—1992 ruling on the subject, the oft-used industry term represents a key component of the agency’s controversial doctrine for determining the level of regulatory oversight needed for any genetically modified food. A simple question, fraught with controversy, sums it up: Does this genetically modified food affect the human body in a way that its non-genetically modified counterpart wouldn’t? If the answer is “yes,” the plant in question must undergo the more rigorous and costly testing required for additives. If the answer is “no,” it’s substantially equivalent to its unmodified GRAS counterpart and thus legally authorized to be sold in the United States.

One critical aspect of the current regulatory approach outrages critics: Companies decide if their new invention is GRAS and safe to eat.

Trusting the hand that feeds you

Determining whether a biotech product is GRAS status demands a lot of testing because many things can go wrong. Not surprisingly, the public isn’t comfortable with any company, much less one with Monsanto’s history, vouching for the safety of their own products. Consequently, Monsanto, as well as all the other biotech companies, consults voluntarily with the FDA on its studies on every one of its pre-commercial prototypes.

“People wouldn’t trust our product if we didn’t,” says Daniel Goldstein, Monsanto’s director of medical sciences and outreach. 

Some say this added assurance is virtually meaningless. Critics point out that since the FDA doesn’t require companies to consult with them, the agency isn’t really enforcing standards for safety testing protocols. What’s more, agency scientists rely mainly on companies’ testing summaries, and only sometimes do they review the actual raw data.

“The length and rigor of studies varies from company to company,” says Doug Gurian-Sherman, senior scientist at the Union of Concerned Scientists, a think tank critical of the current regulatory scheme. “Companies decide how much they want to do and what they don’t want to do.”

What’s certain is the FDA does not review data with the same scrutiny as it does prospective drugs and additives. And rather than approve a modified plant’s safety, at the end of every voluntary consultation, the agency doesn’t actually certify that a modified plant is safe but instead writes a letter to the manufacturer saying that it is the company’s responsibility to guarantee safety.

“Do you think legal liability will stop them from putting harmful products in the food supply?” says William Freese, policy analyst with the Center for Food Safety, another watchdog group. “All you have to do is look at the history of companies introducing harmful products in the food supply or the environment. They’re still going to do it because they put a lot of money into their products.”

The FDA’s defends placing this heavy liability on Monsanto, stating the “existing approach protects public health.” So what possible dangers is the agency holding Monsanto legally accountable for?

Although the vast majority of the enzymes are removed through the oil-refining process, they’re still in the oil in some quantities. Furthermore, there’s a small chance that these plants could cross-pollinate other varieties of soybean out in the fields whose seeds are harvested to make protein-alternative foods, for instance. These facts are important because critics say there’s a chance that the new enzyme inserted into a plant could produce unwanted effects. Some enzymes are outright toxic, prime examples being the neurotoxins that cause botulism and the enterotoxins (that enter through the human intestine) responsible for the harmful effects of cholera.

Enzymes can also induce allergic reactions. Everyday food allergies, like those involving peanuts, shrimp, and dairy products, are in fact allergies to specific enzymes within the foods. Depending on the type of allergic enzyme, and their genetic makeup, people can suffer bouts of hives, stomachaches, asthma attacks, or, in the most acute cases, they can die.

Not only is there a precedent for inserted allergic enzymes, but the most instructive case involved a soybean. In the early 1990s, Pioneer Hi-Bred, one of Monsanto’s major biotech competitors, inserted into soybeans a Brazil nut gene that would enable them to produce an enzyme rich in methionine, an essential nutrient that helps us break down fats and cleans our livers. But the catch was that this enzyme is also a major allergen. Blood tests confirmed that people allergic to the Brazil nut were also allergic to the methionine-enhanced soybean. The project was soon scrapped. GMO opponents claim that the case highlighted the dangers inherent in genetically modified foods and should be considered a cautionary tale about the whole endeavor. Industry saw things in a different light.

“It showed how the regulatory process works,” said an emphatic Eric Sachs, Monsanto’s director of global scientific affairs, who, at a luncheon at St. Louis headquarters, was inclined to bringing up past biotech controversies only to refute them.

For Monsanto, sound safety protocol starts with knowing the kinds of enzymes they’re inserting into plants. The first line of precaution for Monsanto is its use of a software program that compares the amino acid sequence of potential transgenic protein to those of known allergens and toxins. According to Goldstein, toxins are easily identified. Identifying allergens, on the other hand, requires a little more finesse. One standard method for determining if an enzyme is a potential allergen is to compare its amino acid sequence (the building blocks of enzymes) to known allergens. It’s debatable how many identical amino acids of an allergenic enzyme need to line up with the Omega-3 soybean’s enzymes—the 446 amino acids found in the delta 6 enzyme and the 429 found in the delta 15 enzyme—for there to be concern.

“If you look for six matching acids, you’re going to pick up a lot of matches for enzymes that aren’t even known food allergens,” he said. “Eight is the generally accepted minimum number of amino acids that would give us concern. And we discard those potential enzymes right away.”

In this case, though, it turns out that delta 15 does consists of eight amino acids that match those of an allergen found in wheat. But Sachs asserts that sometimes only a part of an enzyme’s amino acid sequence is allergenic, and that the part of the delta 15 sequence that matched those of the wheat is harmless.

Another major characteristic of allergens is their resistance to digestibility. So one method for finding whether enzymes are possible allergens is to test how quickly they are dissolved in Pepsin, an enzyme our stomachs use in digestion. But critics insist that the results can’t be trusted because the typical proportion of pepsin and proteins doesn’t mimic the interactions in our stomachs.

Doug Gurian-Sherman, senior scientist at the Union of Concerned Scientists, noted in a report that, in one particular test done for one of Monsanto’s Roundup Ready soybeans, scientists dissolved the enzymes—the ones that give those soybeans resistance to the company’s herbicide—in pepsin concentrations 120 times greater than the recommended international standards. At that level, Gurian-Sherman suggests, potential allergens might not be found because they can break down as fast as a non-allergenic protein would.

“With Monsanto, it’s hard to think they weren’t being devious when they did these things,” Gurian-Sherman said.

Goldstein concedes that Gurian-Sherman is right about pepsin levels not always replicating the acidity of the human stomach. Acknowledging that there’s room for debate regarding such levels, he contends an enzyme’s resistance to digestion is only one of several factors that are taken into account, noting that there is debate as to the appropriate pH levels and enzyme amounts. Adding to the complexity is the fact that some allergens are easily digestible while some hard-to-digest enzymes aren’t allergens. To address the uncertainty, other factors are considered, such as heat stability and whether the enzyme in question contains an amino acid sequence similar to other known allergens. Goldstein is confident in the corporation’s methods for avoiding what, in his view, amounts to a very isolated group of problematic enzymes.

“Out of the millions of enzymes out there, only about fifty known allergens exist,” he says. “We know which ones to look out for.” 

Nature always finds a way, doesn’t it?

Beyond questioning testing protocol, critics are concerned about the actual enzymes used in all the company’s tests, including the animal feeding trials, because they’re not derived from the transgenic crop—in other words, the soybean itself. Instead, they are derived from bacteria (usually E. coli), which are engineered to produce the enzyme in bulk amounts to make testing easier. According to the opposition, plants and bacteria process enzymes differently. Plants can glycosylate, or add sugar molecules to their enzymes, something bacteria normally do not do. And sometimes those extra sugar molecules can spur allergic reactions, and, in the event that they do, we’d never know beforehand because those enzymes are not the ones being tested.

Monsanto official Goldstein says that using bacterial surrogates is a matter of efficiency, noting that it’s extremely time-consuming and costly to extract enough of the enzymes directly from plants, which are present only in tiny amounts—a few micrograms at most. Using bacteria, scientists are able to produce concentrated amounts. In an attempt to dispel concerns about glycosylation, they change the sequence of the enzymes’ amino acids so they’re prevented from manufacturing those potential allergy-producing sugars.

But in keeping with the novelty of the Omega-3 soybean, Monsanto didn’t use protein surrogates for safety testing. The corporation had no choice but to extract the enzymes directly from the genetically modified plants because bacteria, lacking the right structures to produce these fats, can’t manufacture the enzymes successfully. Plant cells are specially designed to process these fat-producing enzymes. And that’s the source of another controversy that’s unique to the new nutritionally enhanced crops: Not only can plants utilize these unique enzymes to produce Omega-3’s fats—they can also produce potentially other dangerous byproducts. 

And that’s the source of another controversy that’s unique to the new nutritionally enhanced crops: Not only can plants utilize these unique enzymes to produce Omega-3’s fats—they can also produce potentially other dangerous byproducts.

Fear of these mystery enzymes being inserted into food crops has been a focus of contention since before Roundup Ready soybeans entered the market as the country’s first commercial biotech crop in 1996. But Monsanto’s newest invention—a soybean engineered to improve cardiovascular health—has some opponents ironically even more worried, and it’s because of fears that the omega-3 fatty acid SDA isn’t the only novel oil being produced.

In the complex world of plant metabolism, enzymes normally initiate or accelerate multiple chemical reactions. For example, a certain enzyme can convert ALA (our mother Omega-3) into Jasmonic acid, a critical defense compound that acts as a toxin to plant insect pests. Policy analyst William Freese says he’s not sure if Monsanto, in touting their new nutritional wonder, is aware of all those possible secondary reactions, much less studying their effects on human health. 

“What it all comes down to is the wrong fatty acids in cell membranes of plants can cause problems,” he said.

Dave Schubert, a cell neurobiologist at the Salk Institute and an outspoken critic of biotechnology, believes this next generation of nutritionally altered crops could open a Pandora’s Box of new toxic compounds. His 2008 article, “The Problem with Nutritionally Enhanced Plants,” published in the Journal of Medicinal Food, cites examples where enzymes, taken from one plant, produce unexpected byproducts when inserted into another.

But his most high-profile claim was launched against another nutritionally altered food famously (or infamously) known as Golden Rice. In the 1990’s, scientists genetically engineered rice kernels to produce beta carotene, an important precursor to Vitamin A. The discovery of these grains (named for their cornfield yellow color) was touted as a momentous benefit for the poor in South East Asian countries who often go blind because their diets lack this critical nutrient. But biotechnology is particularly controversial internationally, and it took the better part of a decade to convince beneficiary countries of its safety. China only accepted Golden Rice technology last year (now called Golden Rice II because scientists found an enzyme that could produce more Beta Carotene than its predecessor). One reason for the long deliberation might be due to concerns voiced by scientists like Schubert, who argues that the enzymes used to increase Beta Carotene intake in rice could also produce other similar compounds like retinoid that are toxic in excessive amounts. 

“Six-hundred naturally occurring compounds exists in the Carotene family, and at least 60 can be precursors to retinoids,” he writes. “Therefore, plants have the potential to make many potentially harmful retinoid-like compounds when there are increased levels of synthetic intermediates to Beta Carotene as in Golden Rice” [namely those produced by the newly-inserted enzymes].       

Goldstein agrees that these are “absolutely things that could conceivably happen.” But they don’t happen, he hastens to add, because of scientific thoroughness. Although Monsanto was not directly involved with the Golden Rice project (it was supported by rival company Syngenta), he defends the product as being thoroughly tested, that the Beta Carotene—as produced in the grain—was extensively studied and already widely consumed in the human diet. He is equally confident about the safety of SDA oil, and the evidence that supports the assertion.

“We’re very familiar with the metabolic pathway,” he says, “with what these enzymes are set to do.”

Where are our safeguards?

By engineering a nutritionally modified plant that is not substantially equivalent to its unmodified counterpart, Monsanto finds itself in new regulatory territory. To vouchsafe for the novelty of this new fat, in addition to the usual biotech consultation studies, the corporation submitted a GRAS notification to the FDA in February 2009 to prove that the oil contains nothing new or dangerous. And much like how Monsanto self-affirmed the safety of its previous biotech crops, the company could also have made its own determination that the Omega-3 oil is GRAS by submitting the supporting evidence.

But, for further validation, Monsanto chose a more thorough approach, by convening a panel of independent experts who reviewed and validated the existing data. In accordance with all notifications, the FDA then made the submission publicly available on its website, making the documents far more accessible than the biotech consultation studies, which are accessible only by submitting a Freedom of Information Act request. Those can take months to process.

After reviewing the dossier, the FDA then delivered a decision to the company. Two responses by the agency are possible at this point. The agency could demand more data to support the safety determination, and, if that’s not persuasive, relegate the product to the status of a food additive, which means further testing leading up to a pre-market approval. Or the agency could state that it “does not question the basis for the notifier's GRAS determination,” meaning that the major concerns have been satisfied. Goldstein -- and the panel, for that matter -- believes that Monsanto has answered all relevant concerns.

And in April, the FDA agreed, for now: “Based on the information provided by Monsanto, as well as other information available to FDA, the agency has no questions at this time regarding Monsanto’s conclusion that soybean oil-RP/RL/IO is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of soybean oil-RP/RL/IO.

More than one thing

As both Freese and Goldstein acknowledge, enzymes used in metabolism can do more than one thing. And in the case of the two novel enzymes inserted into the SDA soybean seed, they do produce other fats, but, according to the company, they’re fats that we already consume. The Delta-6 enzyme, in addition to producing SDA oil, also manufactures a common fat called Gamma Linolenic Acid (GLA) that’s not normally found in soybeans. Delta-15 doesn’t synthesize any fats not naturally found in soybean oil, but, along with increasing the amount of ALA, the enzyme does increase the amount of palmitic oil, a fat already found in soybeans.

To make sure no other potentially harmful acids were produced, Monsanto identified 99 percent of the chemical components in the SDA oil extracted from the Omega 3 soybean.

“This oil is far more better known than any other commercial oil on the market,” Goldstein says, noting that other oil companies typically account for only 96 to 98 percent of their oils. And as for the remaining one-percent?

“Other trace amounts of fats,” he said.

And how can we be sure that one percent doesn’t contain something toxic? Dave Schubert, the Salk Institute neurobiologist, says that the smallest amounts of an unknown compound can be very dangerous. But to make up for that uncertainty, Monsanto performed toxicity tests. Some critics have criticized the company’s methods.

“They look at how quickly animals gain weight, look for any deformities, it’s more like a performance feeding trial,” Freese says, saying that these studies, submitted as part of the biotech consultation process, is not rigorous enough. “A real feeding trial is a toxicological feeding trial with laboratory animals. Tissues need to be looked at in the gastrointestinal tract. There should be multigenerational trials with several litters, affecting their ability to reproduce.”

Goldstein says that Monsanto does conduct performance feeding trials with broiler hens, but he says the tests are only used to assure the USDA that its crops—particularly its soybeans, which are used as cattle feed—are safe for animals. To vouch for human safety, the corporation typically carries out a 90-day toxicity study with mice, complete with tissue and blood analysis consistent with other toxicological trials.

For the GRAS notification, Monsanto conducted a more robust set of studies than it did with its biotech consultations. There were not one but three distinct studies with mice, the first involving a 28-day study and the second a 90-day one, with the latter doubling as a two-generation reproductive trial that is usually reserved for certain food additives to test for possible birth anomalies. This is the first time the corporation has conducted a reproductive study on a gene-inserted crop as part of its packet of submissions to the FDA. But Goldstein chalks the test up to being an extra insurance of safety rather than an investigation into a serious concern, stating the argument could be made that SDA oil is already found in our bodies. Nonetheless, he says substantially increasing the public’s intake of a nutrient is something the agency takes seriously.

“We figured the FDA was probably going to ask for this anyway because we’re producing a lot of this oil, so we decided to just go ahead and do it,” he says.

For the 90-day studies, the mice were fed the human equivalent of a half a pound of SDA oil a day, which adds up to about 42 grams of SDA—roughly 28 times the recommend daily intake of 1.5 grams (Goldstein notes that it’s standard practice to test rats with many times the amount used for human feeding trials to account for the differences between species). Scientists found no noteworthy toxicological effects in their organs, no unusual body weight fluctuations, and no birth defects in the litter.

Monsanto also conducted a human feeding trial—another first for a genetically engineered crop.

Monsanto also conducted a human feeding trial—another first for a genetically engineered crop. Though Goldstein says the study was mainly used to show that Omega 3 soybean oil gives people meaningful amounts of EPA, he insists that the study also verified the product’s safety. Subjects were given 3.66 grams of SDA oil per day (roughly three times the recommended serving of 1.5 grams) for 16 weeks. Measuring for changes in blood pressure, weight, and cholesterol, among others, researchers found no significant differences, besides the expected increase in EPA.

Marc Hallerstein, professor of nutritional biochemistry at UC Berkeley, disagrees that the human study should only play a supporting role in safety evaluations. While he thinks the oil is a good idea, and that he wouldn’t tell people not to consume this “slightly peculiar kind of Omega-3,” as he calls it, the product should still be tested longer for safety, noting that Monsanto’s study didn’t account for the oil’s long-term effects on cancer, blood disease, or stroke.

“If they’re going to be making billions of dollars on this stuff, and before the world switches to it, they [Monsanto] should do a two or three year study and publish the findings in the American Journal of Public Health,” he says. “Then I think people would be fine with it. Then, I’d say, ‘Good product guys.’”

However Hallerstein’s sees things, the FDA decided the evidence cited in the GRAS notification was compelling enough to earn Monsanto a letter stating it had no further questions regarding the safety of the new oil. What if someone wanted to appeal the FDA’s decision? Gurian-Sherman says people can always request another review, but the agency won’t likely change its mind, and he believes a major reason for this is because the critics do not have a compelling legal argument to make.

“If biotech crops were under a mandatory regulation, watchdogs could say, ‘Here’s the law, and we think you’re in violation,’” he said. “But with no publicly agreed upon criteria, no one’s going to pay any attention to a complaint.”

Drawing from his experience as a former scientist with the Environmental Protection Agency, Gurian-Sherman also says that, given the internal culture of the FDA, the agency is not likely to scrutinize the studies.

“The federal agencies, as a whole, believe these crops are inherently safe,” he says. “That’s the baseline they’re working from.”

What’s at the top of this magic beanstalk?

The Omega-3 soybean is waiting for two regulatory replies. The USDA, which received the environmental studies from the corporation in July of last year—has yet to deregulate the plants so they can be legally planted in open fields. Monsanto expects that process to take two to three years. The corporation is also still waiting for the FDA to finish reviewing the biotech consultation studies Monsanto submitted in the middle of last year, which could take equally as long. But, considering that the FDA has already acknowledged the company’s GRAS notification for its new nutritionally altered oil, and also the fact that not once in the technology’s 14 years presence in the market did the agency, after reviewing consultation studies, relegate a GRAS-submitted genetically modified crop to food additive status, it’s safe to say its possible the Omega-3 soybean could arrive on grocery shelves by as early as 2012.

It isn’t hard to be buttered up by the allure of this heart-healthy oil: the most touted fat of recent times. More enticing is the fact that the ocean’s fish stocks are already threatened, and an increase in demand for EPA would only worsen the problem. Algae pills that contain EPA are also on the market, but they can be prohibitively expensive. Consuming the daily recommended dose through soybean oil would be more affordable and it probably wouldn’t take too much of a diet change since the oil can be blended into just about any processed food. 

Yet the same tradeoff remains. In exchange for something beneficial, this time for the consumer rather than the farmer, an almost unsettling degree of discretion is granted to Monsanto. The corporation personally ensures the safety of these modified plants, which, once released into the fields and food supply, will be impossible to rein in. And Monsanto is known for zealously guarding its proprietary information. Even members of the National Academy of Sciences, a renowned research institution whose members were hired by the USDA to evaluate the agency’s regulatory process, commented in their report that the amount of data the company classified as Confidential Business Information—and therefore removed from public view—hampers transparency and external review.

For those who want to study the seeds for themselves, there’s another roadblock: Because the company owns the patents, it has the legal authority to prevent anyone from growing, and, therefore, being able to test them, without its permission. 

Gary Barton, Monsanto’s director of communications, summed up the slideshow nicely when he said, “We’re looking at delivering technology in seed,” he said, “not investing in chemicals.”

Monsanto seems serious about its new focus. Gone are the company’s ties to pharmaceuticals, and, with the exception of its financial liabilities, so is the direct link to its notorious past. But the seeds it now specializes in pose their own potentially disastrous risks. Before we imagine a world that benefits from built-in pesticides, drought tolerant crops, and nutritionally enhanced plants, the question remains: Are we willing to permit the company that manufactures genetically altered crops to be the final arbiter of their safety?

Read Part I of “Monsanto’s new Omega-3 soybean: Healthy or hazardous?” by Samson Kaala Reiny here.

Read Part II of “Monsanto’s new Omega-3 soybean: Healthy or hazardous?” by Samson Kaala Reiny here.