The Story of Substantial Equivalence: Is it good enough to protect against toxic GMOs?

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During the summer of 2019, a different kind of apple dropped Apple from headlines across America. It went by the larger-than-life name, the Cosmic Crisp. Quite a name for an actual apple. The fanfare around the red-wine-colored fruit did not disappoint and the plaudits rolled in fast and furious. A website was launched complete with an array of feel-good images. Children holding apples. Children eating apples. Children and parents and apples. Children flying through the air because they ate apples because, well, that’s the power of apples.

Cosmic Crisp. (CREDIT: Proprietary Variety Management)
Cosmic Crisp. (CREDIT: Proprietary Variety Management)

And then there was the press coverage. Extensive for a fruit only scratches the surface. Martha Stewart magazine covered the Cosmic Crisp, essentially a stamp of approval. WIRED speculated that the new fruit could harken the start of a new era. Taste of Home got in on the fun, leaving no question how they felt “The Cosmic Crisp Apple Is Being Released This December—and We’re Already Obsessed.” There was even some savior talk doing the rounds. According to a Time magazine article, “The Cosmic Crisp could be a lifesaver for Washington apple growers in particular.” The apple was the state’s own creation and its champions made sure nobody forgot about it.

Meanwhile, elsewhere in Washington state, one of the nightmare scenarios often mentioned by anti-GMO activists was being being discovered in an unplanted agricultural field. Someone noticed an odd patch of wheat growing. When samples were taken to labs and analyzed, it emerged that the stalks belonged to an experimental strain of genetically modified wheat that hadn’t been approved for release. It appeared as if the glyphosate resistant wheat hadn’t been planted on purpose. According to Bayer, who recently acquired Monsanto and assumed their legacy liabilities, the field was probably an old test field and the wheat was left over from the trials. Still, officials wanted to get ahead of any panic that might begin to fester. They were adamant about establishing that the GM wheat had not entered the food supply. Everyone was safe. Nobody would be poisoned or perish.

The dichotomy of press and public reactions to the events in Washington demonstrate the way views on GMO foods diverge. Non-GMOs enjoy adulation and freedom of uncritical eyes while their genetically engineered counterparts are viewed with suspicion and revulsion. One is accepted with open arms, no questions asked, no concerns about toxicity. The other is subject to scrutiny, analyzed for its individual components, and regularly accused of needing long-term safety trials (because it’s poisonous, some claim).

Cosmic Crisp. (CREDIT: Proprietary Variety Management)

Cosmic Crisp, borne from traditional breeding techniques, is considered safe. Nobody disputes that. According Kate Evans, the person most responsible for the apple’s making it to market, she replied, “We have been eating apples produced through cross-hybridization for several thousands of years.”

But are GMOs so dangerous that they should almost cause a panic? Critics insist that the current safety mechanisms set in place for genetically modified foods are inadequate and fall far short of their stated goals. In particular, the notion of substantial equivalence — essentially the standard by which novel foods are judged — represents everything that is wrong with GMOs. They claim that the only way to really know whether consistent exposure to GMOs is harmful is to conduct long term toxicity studies. Until that is done, lives are at risk.

One of the first things taken into consideration when trying to establish the safety of a new food is its source and how it came into existence.

Is that a fact? Not at all.

Are GMOs dangerous? Many scientists with skin in the game would claim the opposite.

None of that matters though because people perceive danger. When it comes to food, perception is everything.

***

Determining how food interacts with the human body is a notoriously difficult thing to establish. So many seemingly disparate aspects of the human body intersect with one another, often in ways nobody knows about yet. Correlations are more approximations than anything else.

Eggs are a perfect example of how the inability to get a good read of how the body processes food. Their fortunes rose and fell with the scientific community’s take how dietary fat and cholesterol. For a very long time, eggs were the enemy, specifically yokes. Egg whites became a thing. Egg white omelettes. Egg white cookies. Egg whites in cartons. Indulging in yummy orange yolks made you feel the years slipping away.

But then, almost overnight, they became good for you.

So you get the picture. It’s a tricky business.

Establishing a food’s safety for consumption is no different. In fact, you can make the case that it is even more unforgiving.

One of the first things taken into consideration when trying to establish the safety of a new food is its source and how it came into existence. For GMOs, that entails taking a look at the parental varieties that give rise to the new cultivar and then the breeding method involved. According to the OECD’s Safety Evaluation of Foods Derived by Modern Biotechnology: Concepts and Principles,

  • If one considers a modified traditional food about which there is extensive knowledge on the range of possible toxicants, critical nutrients, or other relevant characteristics, the new product can be compared with the old in simple ways. These can include, inter alia, appropriate traditionally performed analytical measurements (for example, alkaloid levels in potatoes, cucurbatin in vegetable squash cultivars, and psoralens in celery) or crop-specific markers, for comparative purposes.

Traditional breeding methods such as cross pollination are generally considered safe and result in foods deemed similar to those already being eaten. The same goes for accepted variation including mutation breeding through chemicals or irradiation. (How that gets a pass is anyone’s guess.)

Genetic engineering (GE), on the other hand, is considered problematic. Since the dawn of the recombinant DNA era, a level of discomfort expressed itself as distrust and regardless of how much more refined and precise technologies became. Whether it involved conventional restriction enzyme/ligation cloning or Gibson Assembly or CRISPR Cas-9, it didn’t make a difference.

At the most basic level, traditional breeding and genetic engineering rely on the same notion, namely determining a desired trait, obtaining it, and then actively selecting for it. How they approach the second step — obtaining the desired trait — is where the major difference lies and where causes for concern begin to pop up.

The major issue that emerges is the expression of unwanted genes. Most of the time, it will be self-evident. Physical differences when compared to parental lineage can appear. Upon testing, there may be differences in levels of certain chemicals. Sometimes, the entire plant will simply fail to grow or die quickly, taking that particular breed off the table immediately. What worries scientists and regulators is the so-called silent expression of genes, wherein unwanted traits that are potentially toxic are present.

As stakeholders would soon discover, proving safety was as easy as it was difficult since nobody could agree what constituted substantial equivalence.

In reality, the responsibility of determining the presence of harmful deleterious traits falls on the backs of GM breeders and them alone. This creates the potential for oversight, sloppy reporting, or just plain neglectful abuse. (We’ll deal with this in the next installment.)

When GMOs were beginning to progress beyond laboratory benches, international regulators attempted to address the nature of the new organisms. They quickly realized that conducting long-term safety studies spanning multiple decades was not feasible. Instead, regulators leaned on a vaguely defined concept called substantial equivalence which basically said that

  • …existing food sources 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.

Fred Gould, an agricultural researcher at North Carolina State University, puts it into more straight-forward terms. “Substantial equivalence is a concept that is based on the assumption that if food from a GE variety is compared to the same food from a non-GE variety and they have the same biochemical makeup, then they are equivalent, so the GE food is considered safe.”

As stakeholders would soon discover, proving safety was as easy as it was difficult since nobody could agree what constituted substantial equivalence.

***

The notion of substantial equivalence did not originate in the GMO industry or even the biotechnology field. It wasn’t some scheme pieced together by Monsanto (devil!) to advance hegemonic dreams of global domination. Far from it, actually. In the most direct sense, it was the illegitimate child of a medical device industry idea meant to make an understaffed and underfunded FDA’s job a little easier. While food regulators did not adopt the methodology used to establish substantial equivalence, the spirit and DNA of the general idea was transferred faithfully. Unfortunately, that meant its imperfections were transferred as well. In order to appreciate the nature of substantial equivalence in the GMO field, it’s instructive to look at the story of the 1976 Medical Devices Amendment first.

The history of modern medicine runs parallel to tales of quacks and charlatans eager to exploit an unsuspecting public’s desire to stay healthy. Horse and buggy travelling salesmen famously peddled all sorts of elixirs and cures. Clark Stanley, the so-called Rattlesnake King, was far from an outlier and at least his snake oil contained camphor and capsaicin.

Medical devices presented wily hucksters with another opportunity to take advantage of people’s frailties. A cure was a cure, after all, whether it came in liquid or solid form. One famous example from late 18th century America was called a Tractor and belonged to a Connecticut doctor named Dr. Elisha Perkins.

Prior to his discovery of the Tractor, Perkins was a serious surgeon with an ascendant reputation. This was during a time when doctors still struggled for respect and well over a century before serendipity smiled on Alexander Fleming and the green mold he discovered by the window of his lab window. While performing surgery, Perkins often noticed that exposed muscles would retract when touched by metal from his scalpel. Other materials like wood failed to elicit similar responses. This led him to postulate that metals held some force that had direct effects on the human body. According to one account of Perkins’ discovery,

  • He discovered that by drawing over the parts affected in particular directions certain instruments which he formed from metallic substances into certain shapes, he could remove rheumatism, gouty affections, pleurisies, inflammations in the eyes, erysipelas, and tetters; violent spasmodic convulsions, as epileptic fits; the lockjaw; the pain and swelling attending contusions; inflammatory tumours; the violent pains occasioned by a recent sprain; the painful effects of a burn or scald; pain in the head, teeth, ears, breast, side, back and limbs; and indeed most kinds of painful topical affections, which came under his care and observation. The instruments producing these effects are termed Tractors.

Perkins’ invention (and salesman routine most likely) convinced President George Washington to purchase one for his family. Not only that, the doctor even convinced Chief Justice Oliver Ellsworth to buy one. His Honor believed in the Tractor so much that he penned a letter of introduction for Perkins to John Marshall, who would later go on to succeed Ellsworth as Chief Justice of the United States.

At the turn of the 20th century, a new problem emerged. Radiation. After French chemists Pierre and Marie Curie discovered radium in 1898, health regulators became aware of its dangers. Many so-called medical devices claimed to be radioactive and curative. This set off alarm bells the size of Big Ben. According to Carol Rados, “One such device was known as a radium belt, which carried a disc alleged to contain the element. According to proponents, someone wearing the belt would never have appendicitis or gallbladder disease, or perhaps, any other Ailment.”

Congress would eventually step in and put an end to the radiation nonsense. Unfortunately, it wasn’t the end of questionable medical devices. By the 1960s, something drastic needed to be done to reign in the medical device industry. In 1962, President John F. Kennedy moved to change the way devices were regulated. Subsequent Congressional hearings resulted in changes to the way the FDA viewed medical devices. Now, (and this is key) they would be regulated comparably to, but separately from, new drugs. (Prior to this, medical devices officially considered drugs, prompting a Congressman to comment that it was like “calling a sheep’s leg a tail.”) The notion of a device being a drug was reinforced in 1969 when the Supreme Court made a decision in the Bacto-Unidisk Company case, essentially saying that an antibiotic-sensitivity disc — a lab tool that never touches the human body — was a drug.

What made Cooper’s advice so significant for GMOs in the future was that he had essentially made the case for risk-based statutes

“The Supreme Court decision stated that FDA did not have adequate device legislation and so the Court was expanding the concept of a drug so that the agency could require new drug applications for diagnostic products and other important medical items.”

At about the same time, medical devices made the leap from the outside of people’s bodies to the inside with the implantable pacemaker. This considerably upped the ante when it came to how they were regulated and when a string of pacemaker failures were reported, the U.S. government was once again forced to address how medical devices were monitored.

President Nixon appointed Ted Cooper as head of a committee established by the Department of Health, Education, and Welfare to issue a report. The so called “Cooper Committee Report” recommended the creation of three classes of medical devices contingent on the amount of regulation needed for each. What made Cooper’s advice so significant for GMOs in the future was that he had essentially made the case for risk-based statutes, something that would be the standard way of classifying things from that point forward.

There was a problem though. With so many devices in existence and an untold number of future devices, an efficient means of evaluating them had to be created. As a solution, the Health Subcommittee of the House Committee on Interstate and Foreign Commerce broke all devices into three classes with Class III devices needing close monitoring. The other two categories were considered generally regarded as safe (GRAS) and generally regarded as effective (GRAE) and would not need monitoring. For post-1976 devices, this would come to be known as the 510(k) process and consisted of a report by the medical device maker to the FDA regarding the basis of potential risks and benefits of the new devices. What’s more, the legislation made an important distinction. It stated that “A postamendment device could be marketed if it was not “significantly different” from an existing device.”

According to the International Service for the Acquisition of Agri-biotech Applications, “The drafters’ intent was that the FDA would actively set priorities and potentially revise what was considered a reasonable model for substantial equivalence.”

In other words, the Medical Devices Act of 1976 was never meant to be the be all and end all of device testing. It was designed to be a starting point that would be honed and sharpened in the future. When the bill was introduced and enacted, the term substantial equivalence was born.

***

As the 1980s rolled around, recombinant DNA technology continued to improve and gain acceptance. The technology that made genetically modified organisms possible had been in existence for over a decade and it was only a matter of time before genetically modified organisms came knocking on the mainstream’s door. When it finally did, it had nothing to do with food. The first FDA approved GMO was more medical than nutritional. Eli Lilly’s Biosynthetic Human Insulin was subjected to a detailed and conservative evaluation process because of its novelty and HUMULIN-R was officially approved on Oct 28, 1982.

That same year, the Organization for Economic Co-operation and Development (OECD) put in motion a series of events that would culminate in substantial equivalence being imported to the genetic engineering field. They released a report that explored the potential hazards of releasing GMOs into the environment. In the United States, the Office of Science and Technology was created to figure out how to regulate recombinant technology.

In 1990, the OECD, the Food and Agriculture Organization (FAO), and the World Health Organization began close collaboration aimed at codifying how to assess GM foods’ safety for consumption. The Group of National Experts on Safety in Biotechnology took a step towards establishing how GM crops should be assessed. They agreed that “work on food safety, with particular attention given to the elaboration of scientific principles for assessing the safety of new foods or food components produced by means of biotechnology, was of high priority and should be initiated as soon as possible.” Moreover, the GM organism was classified according to four categories defined by the level of risk involved. By 1993, the groups had reached an international consensus regarding how GM food safety was to be assessed. They reported their recommendations in a document called “The Safety Evaluation of Foods Derived by Modern Technology – concepts and principles.”

The substantially equivalent apple is treated as if it was its analogous conventional counterpart.

The report clearly delineated how the notion of substantial equivalence was to be applied to the regulation process and its role in the entire safety determination process. As a starting point, new food needed to be analyzed according to its chemical composition and also the expression of DNA. That information would then be compared to the makeup of a similar organism produced through traditional breeding. Any significant differences — beyond the natural amounts seen naturally — would indicate that more tests were needed. If the components matched up, it indicated that more extensive testing could be forgone. It is important to note that the establishment of substantial does not function as a safety test. According to the Codex Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants CAC GL-45-2003,

  • 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. The concept is used to identify similarities and differences between a new food and its conventional counterpart.

For example, if a genetically modified apple is created to slow browning, it is subjected to a two-step process. The first step entails a quantification of selected molecules. The new crop’s components such as nutrients, anti-nutrients, and toxic molecules are compared with existing databases for those molecules. The apple’s chemical composition will also be compared to the internationally agreed composition of the fruit. In this case, the OECD Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides, and Biotechnology issued a document, Consensus Document on Compositional Consideration for New Cultivars of Apple which provides an extensive breakdown of nutrients, minerals, fatty acids, amino acids, and vitamins found in apples. It even breaks down the composition of apple juice, apple pomace, and animal feed. If the new apple differs beyond the range of normal variability then it will indicate that further testing is needed in order to establish safety.

It is important that the new apple be compared with a suitable counterpart, technically called a comparator. Choosing a comparator can be done in various ways. The new apple tree can be planted alongside a traditionally bred, genetically-related variety. They can then be directly compared. Another approach entails comparing the new apple to publicly available data about the composition of closely-related varieties. A final option is only viable for GM crops that have been created to express improved product quality. In this case, the apple can be compared to different fruits. However, the new comparator must exhibit the desired trait being bred in the apple. So, for example, if an apple is bred to have higher levels of vitamin C comparable with oranges, the latter can be used as a comparator. In this case, comparing apples to oranges is acceptable, even desired.

Once substantial equivalence is determined, two assumptions are in play. Firstly, further safety or nutritional concerns are expected to be insignificant. Secondly, the substantially equivalent apple is treated as if it was its analogous conventional counterpart.

Subsequent documents such as the Codex Alimentarius further refined the notion of substantial equivalence. However, the 1993 OECD document and its recommendations served as the foundation that was tweaked but not changed. The process of analyzing new GM organisms won international approval and substantial equivalence became the standard. Unfortunately, what is lacking is a common consensus as to what constitutes substantial equivalence. The requirements for substantial equivalence differs from country to country, severely hindering any hope of standardization.

***

The juxtaposition of the fanfare surrounding the Cosmic Crisp’s official launch (it is considered a new technology, after all) and the discovery of rogue GM wheat stalks in the wild demonstrates the significant gap in how each one is perceived.

It’s complicated and extends well beyond the confines of the Frankenfood debate.

When asked about the commercial prospects of Cosmic Crisp apples, Aaron Clark, a fourth-generation apple grower from Washington state, replied “There’s something almost spiritual about seeing a crop grow, and being a part of it and growing a really good one.”

What is implied is that traditionally bred apples carry a mystical element, a oneness with Nature that is timeless and good. It represents an idealized and fetishized past that’s all the rage these days (See: Paleo diet, elements of the organic movement, etc.).

On the other side lies, the genetically modified creatures that embody a cold and uncertain future that causes nothing but anxiety. The term “Frankenfood” tells you everything you need to know about how about how some quarters views GMOs (a monstrosity) and how well they know Mary Shelly’s work (not well at all).

Again, perception matters most.

The fuzziness of the substantial equivalence doesn’t do GM foods any favors and its opacity opens it up to misrepresentation on both sides. It’s neither as bad as critics insist nor as fool-proof as advocates declare. It’s somewhere in the middle. It’s also the subject of the next installment of our look at the safety of genetically modified foods.

SOURCES: Martha Stewart; Time magazine; Taste of Home; WIRED; FAO; WHO; OECD; The Safety Evaluation of Foods Derived by Modern Technology – concepts and principles; Elisha Perkins and his Metallic Tractors; Medical Device and Radiological Health Regulations Come of Age; International Service for the Acquisition of Agri-biotech Applications; NPR; Reuters; FDA; Interview with Kate Evans; Interview with Fred Gould; Codex Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants CAC GL-45-2003; Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing patient safety and innovation.

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