A recent review of U.S. Food and Drug Administration “Generally Recognized as Safe” (FDA GRAS) determinations has shown that, although the types of carcinogenicity data submitted to support GRAS notifications for food substances are varied, adequate evidence is typically supplied to support the conclusion that the substance is safe, as far as carcinogenicity is concerned. Still, a standardized approach defining which data is required to support a GRAS determination could be useful.

GRAS, its Requirements, and its Perceived Pitfalls

GRAS is the main premarket food substances review mechanism used by FDA, and it requires those interested in manufacturing/using food substances to demonstrate, “to a reasonable certainty, no harm under the conditions of [a substance’s] intended use prior to being added to food.” FDA is then supposed to review all available data relevant to the food substance, including (but not limited to) information provided by the submitter.

Although FDA assures constituents that all substances allowed in foods undergo review by the agency as required by federal law, some state lawmakers have pointed to GRAS as a “loophole” that enables companies to clandestinely introduce substances to the food supply, and have put forth bills to remedy what they see as an opportunity for oversight—either through bans on possibly toxic additives, such as the recently passed California Food Safety Act, or through legislation tightening the rules for GRAS notifiers, as proposed in the active New York Assembly Bill A9295. Read an overview of the evolving landscape of and debate around state food additives regulation in the U.S. here.

There is no specific guidance to GRAS notifiers about the types of data that should be submitted—although all data should be “generally available” to the public—but the 1993 Guidance for Industry and Other Stakeholders: Toxicological Principles for the Safety Assessment of Food Ingredients (also known as the FDA Redbook) does exist and recommends a set of studies to establish the safety of a substance. It has not been substantively updated since 1993, despite how scientific understanding of carcinogenicity has evolved. According to the review’s authors, the FDA Redbook’s guidance about the usefulness of 2-year rodent bioassay studies is in conflict with the modern consensus that these data are limited in their value for human carcinogenicity assessments.

Review Methods and Findings

In the present study, the researchers conducted a retrospective analysis of publicly available FDA GRAS notifications (GRNs) to identify trends in the use of data to support the carcinogenic assessment of food substances. Included in the review were a total of 187 GRNs that received “no questions” letters in response from FDA. The researchers recorded which types of scientific studies were used to evaluate the carcinogenicity potential for each notified food substance, including various methods of genotoxicity and pre-clinical repeat-dose studies, as well as the 2-year rodent bioassay. Also noted by the researchers was whether the data submitted for each GRN was for the substance itself or a related substance.

Interestingly, 25 percent of GRNs only referenced toxicity studies on a relevant substance but not the substance itself.

While the majority of GRNs for the “concentrated mixture,” “defined chemical entity,” and “isolated protein” substance categories referenced genotoxicity or pre-clinical repeat dose studies—specifically, greater than 80 percent and greater than 70 percent for genotoxicity and pre-clinical repeat dose studies, respectively—GRNs for “microorganism” substances only referenced genotoxicity or pre-clinical repeat dose studies 28 percent and 52 percent of the time, respectively.

Notably, 15 percent of GRNs for concentrated mixture, minimally processed substance, isolated protein, and/or microorganism substances did not cite any toxicity study. Instead, the safety of these substances were evidenced by well-documented, long-term dietary histories, analyses of whether the substances were in a chemical class with carcinogenic potential, and carcinogenicity assessments of relevant constituents.

All 2-year bioassays referenced in notifications were conducted prior to 1997, predating the implementation of the GRAS notification process, and the majority of notifications did not reference results from such studies. Instead, the review identified a shift from the reliance on the 2-year bioassay to a combination of the 13-week rodent study and a standard genotoxicity battery for substances of relatively low concern based on other evidence. The 13-week rat study was routinely referenced in more than 74 percent of the GRNs from the defined chemical entity, concentrated mixture, and minimally processed substance categories, whereas the 2-year bioassay was cited in less than half of the GRNs for these categories. Moreover, 69 percent and 41 percent of notifications for isolated proteins and microorganisms referenced a 13-week rat study, respectively, while none of these notifications referenced a 2-year bioassay.

The Need for a Standardized Approach

According to the authors, who reference the available literature on carcinogenicity assessments, demonstrating “reasonable certainty of no harm” includes consideration of whether the food substance has the potential to cause cancer due to 1) mutagenicity, and 2) increasing cellular proliferation. In the review of 187 GRNs, all food substances documented evidence that would rule out activity via these mechanisms.

Still, the authors argue that there could be a benefit in adopting a standardized approach to addressing these elements in the narrative of a GRAS determination. Even though flexibility in the approach to demonstrate lack of carcinogenic potential is crucial, establishing a standardized approach in which carcinogenic mechanisms are directly addressed as part of a GRAS determination would provide consistency, clarity, and transparency to the process.