Bill introduced in Senate reflects criticism of FDA GRAS program

More than six years ago, Sen. Ed Markey (D-Mass.) wrote a letter to the head of FDA, expressing concerns previously outlined by the likes of The Pew Charitable Trusts that many substances self-determined to be generally recognized as safe (GRAS) enter the U.S. food supply without review by FDA.

Members in Congress have proposed a solution in recent years: require FDA review of all GRAS substances.

In April, the “Ensuring Safe and Toxic-Free Foods Act of 2022” was introduced by Markey and co-sponsored by fellow Democratic Sens. Elizabeth Warren of Massachusetts and Richard Blumenthal of Connecticut.

Among its provisions, S.4316 would:

- Forbid manufacturers from independently designating substances as GRAS without supplying proper notice and supporting information to FDA.

- Mandate GRAS notices and supporting information be made publicly available on FDA’s website and subject to a 90-day review period by the public.

- Bar substances from receiving GRAS designation that are either carcinogenic or demonstrate evidence of reproductive or developmental toxicity.

- Prohibit individuals with conflicts of interest from serving as experts in the review and evaluation of scientific data concerning GRAS designations.

- Create an office that would reassess whether GRAS substances, food additives, food contact substances and color additives are safe.

GRAS substances must meet two criteria, according to an FDA constituent update in 2017.

1. The use of the substance must meet the same safety standard as a food additive: there must be a reasonable certainty of no harm under the conditions of its intended use; and

2. The use of the substance must meet the general recognition standard: the intended use of the substance in food must be recognized as safe by qualified experts based on publicly available scientific information.

The critics

S.4316 addresses criticism that GRAS self-determination is an inadequate process rife with conflicts of interest that deprives FDA of review and ultimately fails to protect public health.

“Americans deserve to know what they are eating, and we know that we cannot count on large corporations to put people and safety before profits,” Warren said in a May 27 news release announcing introduction of S.4316. “The bill is a step forward to help the FDA ensure the food families eat is safe.”

The nonprofit Environmental Defense Fund (EDF) is among stakeholders in favor of Markey’s bill, which has not moved to a committee vote or hearing in the Senate since its introduction.

“This bill takes needed steps to redress FDA’s failures to protect the public from chemicals added to or contaminating food and to rebuild consumer confidence in food safety,” Tom Neltner, senior director for safer chemicals at EDF, said in lawmakers’ news release.

Maricel Maffini, Ph.D., a consultant to EDF, said in an interview, “It’s imperative that we know the safety of the chemicals [in the food supply].”

The Pew Charitable Trusts found in a study that 1,000 chemicals in food have not been reviewed by FDA thanks to the “GRAS loophole,” Markey noted in a 2016 letter to Robert Califf, M.D., then and now commissioner of FDA.

“Moreover, FDA typically does not know the identity of GRAS substances, the foods in which they are used, and how much they are used,” the senator wrote to Califf. “This system challenges the statutory intent of FDA’s assignment to protect the safety of the food supply because there is no way to track the degree to which people have been exposed to these types of ingredients.”

Rep. Rosa DeLauro (D-Conn.) last year introduced the Toxic Free Food Act, which like Markey’s bill would require GRAS determinations be subject to FDA review.

“The current notification system for [GRAS] erodes the public’s trust in food safety,” DeLauro said in a June 4, 2021, news release announcing her bill. “The food industry is designating new ingredients as GRAS to take advantage of this loophole so they can rush new chemicals to market with no oversight. Those that choose to notify FDA of their new substance get to supply their own, company-funded science and keep it away from the eyes of the public. This approval process must be mandatory, transparent and independent in order to maintain the trust of American consumers. We need to close the GRAS loophole.”

Defense of GRAS

Some industry consultants who work on self-determined GRAS projects vigorously disagree the process is broken or endangers public health.

John Endres is chief scientific officer of AIBMR Life Sciences Inc., a scientific and regulatory consulting firm focused on independent GRAS conclusions and other issues. He has held his position at AIBMR since 2006 and earned a degree in naturopathic medicine two years earlier.

His response to criticism of the GRAS program is tied to the history of his employer. In the 16 years that AIBMR has prepared an independent conclusion of GRAS status and subsequently opted to notify FDA of the conclusion at the client’s request, FDA has responded each time with a “no questions” letter, said Endres.

FDA issues this type of letter when it does not question the basis for the notifier’s GRAS determination.

“Every single time, we’ve gotten a no-questions letter, which basically means that our independent conclusions of GRAS have always satisfied the FDA,” Endres said in an interview. "And therefore, the independent conclusion of GRAS … program is not rubbish.”

Of the 1,041 GRAS notices filed with FDA since 1998 and listed publicly, roughly 3% are “pending,” 78% are “FDA has no questions,” 17% are “At notifier’s request, the FDA ceased to evaluate the notice,” and 2% are “Notice does not provide a basis,” an FDA spokeswoman said.

Endres characterized Markey’s proposal to subject GRAS notices to public review as a “nightmare.”

“How are you not going to get objection every single time?” Endres asked.

He rejected the idea that an independent GRAS conclusion remains a secret.

“The client can lock that up in their safe forever and never share that with anybody,” Endres acknowledged, “but then you’re not going to be able to sell your product to anybody because people ask if you have GRAS status and they want to see and know something about” it.

To accommodate these requests, he said AIBMR Life Sciences will write a letter for a client, disclosing such details as the expert panel, their qualifications, the intended uses of the substances that were subject to an independent GRAS conclusion, and why those uses are reasonably certain to be safe for chronic consumption.

The GRAS notification system was implemented more than 20 years ago " to make the GRAS system more transparent, so both the public and the FDA would know what was being added to food,” said George Burdock, Ph.D., of the safety and regulatory consulting firm Burdock Group.

FDA posts GRAS notifications on its website even after they have been withdrawn from review, added Burdock, who questioned how much more transparency the system could provide.

“Most importantly, no one can name a notified GRAS substance that has resulted in harm to anyone or has been recalled, when used properly,” he concluded in a 2021 email to Natural Products Insider.

‘GRAS loophole’

But in his 2016 letter to Califf, Markey warned a new ingredient may show up in the food supply even when FDA’s review of a substance self-determined to be GRAS identifies safety concerns.

He cited a notice to FDA of intent to use an ingredient (sweet lupin) known to cause allergic reactions for people sensitive to peanuts. An investigation found the ingredient in more than 20 food products in the market—even after the company withdrew its notice to FDA since “other companies self-determined sweet lupin to be GRAS and chose not to voluntarily notify” FDA, according to Markey’s letter.

Some firms retained to prepare an independent GRAS conclusion may not be doing things “the right way” and fail to satisfy FDA if the agency was notified, Endres conceded, adding, “That would be disturbing for sure.”

In a series of blogs, the Environmental Defense Fund has raised concerns about firms using the “GRAS loophole” to market substances in both conventional food and dietary supplements without notifying FDA, even when the ingredients have been linked to safety concerns.

The purported problems stem from nuances in federal law.

Generally, manufacturers of “new dietary ingredients (NDIs)” must submit a notification to FDA, providing information that the dietary supplement containing the NDI “will reasonably be expected to be safe.” However, an NDI is exempt from the premarket notification requirement if it was present in the food supply in a non-chemically altered form.

Critics maintain the exemption provides companies an avenue to circumvent FDA review of ingredients marketed in both dietary supplements and food. A blog written in 2021 by Neltner highlighted Prevagen, a popular dietary supplement containing apoaequorin—a protein found from jellyfish—marketed by Quincy Bioscience to promote brain function and memory improvement.

Quincy Bioscience submitted two new dietary ingredient notifications (NDINs) to FDA in 2007 and 2012 for apoaequorin. FDA objected to the notices for several reasons, Neltner commented. In a 2012 letter to Quincy Manufacturing regarding its NDIN for apoaequorin, FDA said it was unable to establish the identity or safety of the ingredient based on the history of use provided in the notification.

“For example, Aequorea victoria, which produces apoaequorin, is not one of the jellyfish species that was identified by your referenced articles as a jellyfish that is traditionally consumed by humans,” an FDA official in the Division of Dietary Supplement Programs (now known as the Office of Dietary Supplements Programs) wrote in a response to the NDIN. “In addition, you did not provide the identity relationship between jellyfish consumed by humans and your ingredient. Moreover, you did not relate serving levels, consumption frequencies and duration of uses of ‘Apoaequorin’ with that of jellyfish that are typically consumed by humans.”

The FDA official added a single 90-day toxicology rat study was insufficient to establish safety data.

Quincy Bioscience in 2014 submitted a GRAS notice to FDA, yet the notice was withdrawn in October 2015 at the request of Quincy Bioscience, FDA records show. The notice said apoaequorin is intended for use as a food ingredient at levels up to 6 mg of apoaequorin per serving in such dairy products as milk shakes and smoothies when not prohibited by a standard of identity.

According to the notice submitted by attorney Ashish Talati, Quincy Bioscience determined apoaequorin is GRAS consistent with the law.

“The company effectively leveraged the GRAS loophole to avoid FDA review of the chemical as a new dietary supplement ingredient,” Neltner wrote in his blog.

Neltner referenced the GRAS notice’s disclosure that Quincy Bioscience had received about 2,200 adverse event reports associated with Prevagen since it began marketing the product as a dietary supplement in 2007. The adverse events included allergic reactions, chest pain, dizziness, fainting, headaches, tremors and seizures.

Adverse events don’t prove causation, according to FDA, but they may provide signals that there is a problem. And regulatory and legal experts say a review of the adverse events reported during a specific period should consider the total number of products sold during that same period: Quincy Bioscience estimated it sold about 1.96 million bottles of Prevagen through January 2014.

Of the adverse event reports received by Quincy Bioscience, 26 were deemed “serious.” However, the adverse events failed to show “any commonality in presentation or duration of exposure preceding event,” and most of them were linked to “pre-existing chronic conditions and are attributable to those conditions,” according to the GRAS notice.

Quincy Bioscience declined to comment for this article through an attorney. A spokesperson for the company told Wired in a 2020 story, “Apoaequorin is GRAS, whether it is in a food like Neuroshake or a dietary supplement like Prevagen.”

FDA had no comment when asked by Natural Products Insider whether it had any current safety concerns about apoaequorin.

Conflicts of interest

Critics have identified other problems with the GRAS program beyond the “GRAS loophole” and voluntary nature of the FDA notification program. In his 2016 letter to Califf, Markey cited a 2013 study reported in Reuters showing many GRAS notifications to FDA between 1997 and 2012 were made by individuals with ties to manufacturers of food additives.

The statistics in the study show “both the entities making GRAS determinations and those who are evaluating safety are inextricably linked by their vested interest in the perceived safety of the chemical,” Markey wrote to FDA’s commissioner.

For example, the study published in JAMA Internal Medicine found 22% of safety assessments were made by an employee of the food additive manufacturer, according to Reuters.

“How can you trust that?” Maffini, the consultant, asked. She suggested an employee is not going to make a finding contrary to the interest of the person or entity handing them a paycheck.

FDA in 2017 published a draft guidance that offers recommendations for best practices to convene a GRAS panel. An FDA spokesperson said the recommendations include: “identify GRAS panel members who have appropriate and balanced expertise; take steps to reduce the risk that bias or appearance of bias will affect the credibility of the GRAS panel’s report, including the assessment of potential GRAS panel members for conflict of interest and the appearance of conflict of interest; and limit the data and information provided to a GRAS panel to publicly available information.”

FDA has made it a priority to finalize the guidance in 2022.

Endres acknowledged the potential for a conflict of interest. However, he doesn’t believe AIBMR has a conflict and reiterated his employer’s history of successful GRAS notifications to FDA following an expert panel review and conclusion that the intended uses of the ingredients are GRAS.

“Clearly, the expert panel made the correct conclusion,” Endres said. He added expert panel members are not going to work for free and “it’s a big job.”

He further addressed provisions in Markey’s bill that would bar substances from receiving GRAS designation if they are carcinogenic or demonstrate evidence of reproductive or developmental toxicity. He pointed to the Delaney Clause in the 1958 Food Additives Amendment to the Federal Food, Drug & Cosmetic Act (FDCA), which already requires FDA to ban substances in food additives found to cause cancer in animals or humans.

“AIBMR would never make a GRAS conclusion if something showed evidence of reproductive or developmental toxicity,” Endres added.

Endres said he has no problem with Markey’s proposal to create a procedure to reassess substances that previously received GRAS designation.

“If evidence arises that causes some question about something that receives GRAS status, it should be removed,” he said. “There’s no such thing as absolute certainty of safety because research is ongoing, and it’s possible that some research will come to light.”

History of GRAS

GRAS substances can be traced back to the mid-20th century. Congress in the late 1950s passed an amendment to the FDCA that generally characterized any new substance added to food as a “food additive” subject to premarket review—unless use of the substance is GRAS or otherwise exempt from the definition of a food additive.

“By 1961, FDA had amended its regulations to include a list of food substances that are GRAS under certain conditions of use (‘the GRAS list’),” according to an excerpt of a poster presentation at an FDA science forum in 2006.

“Although GRAS conclusions do not require FDA approval under the [FDCA], the GRAS standard requires that ingredients meet the same safety standard as food additives, and that their safe use in food is widely recognized by qualified experts based on publicly available data and information,” an FDA spokeswoman explained in an email to Natural Products Insider. “FDA can question the basis for an independent GRAS conclusion and take action as appropriate.”

Companies must ensure ingredients added to food are safe and meet the law, including either being approved by FDA as food additives or meeting the regulatory and statutory criteria for GRAS substances, she added.

“GRAS substances are distinguished from food additives in that the data and information that supports the GRAS conclusion is publicly available and generally accepted by the scientific community,” the FDA spokeswoman said. “The quantity and quality of information supporting a GRAS conclusion needs to be the same as necessary to support the safety of a food additive.”

She added the standard for GRAS additives is the same as the standard for food additives: “a reasonable certainty of no harm under the intended conditions of use.”

In 2016, FDA issued a final rule outlining the criteria for concluding use of a substance in human or animal food is GRAS.

“We continue to strongly encourage companies to inform the agency of GRAS conclusions through the notification procedure,” the FDA spokeswoman said. “While the FDA can question the basis for an independent GRAS conclusion, whether notified or not, and take action as appropriate, the notification procedure yields important information that aids the agency’s food safety monitoring efforts.”

Lawmakers behind the 1958 Food Additives Amendment understood “how slowly a bureaucracy moves and included the GRAS exemption as a remedy for what they foresaw as a glacial review process,” Burdock said.

FDA nonetheless included a review process in its regulations, subjecting GRAS substances to a rigorous assessment, according to Burdock, who’s been working on food ingredient regulatory issues related to product safety since 1988. FDA in the 1970s announced it was performing a “comprehensive review” of presumed GRAS substances and created rulemaking procedures to confirm the GRAS status of substances that were either on the GRAS list or the subject of a petition, according to FDA’s April 2006 poster presentation.

“The affirmation process soon became clogged and unresponsive to the point where there was no reason to submit a GRAS for review and affirmation,” Burdock said. “FDA eventually dropped the process. Congress’ prophecy of a plodding bureaucracy was fulfilled.”

FDA in 1997 proposed supplanting the GRAS affirmation petition process with a notification procedure to “eliminate the resource-intensive rulemaking procedures,” according to the above referenced FDA poster presentation.

EDF’s Maffini acknowledged the FDA bureaucracy described by Burdock “was not ideal," but she also countered "it’s not ideal that the agency doesn’t know what is in the food supply."

FDA, on the other hand, doesn’t seem to agree with critics that the GRAS program is broken and in need of a comprehensive overhaul.

“Through experience administering the GRAS provision over several decades, the FDA finds that substances used in food generally have wide margins of safety, and re-reviews of available information on substances generally supports the conclusion that current uses continue to be protective of public health,” the FDA spokeswoman said.