Experts examine how the FDA defines and regulates cancer-causing food additives

By Srivindhya Kolluru

Pulegone, which gives candies their peppermint flavor, has been delisted from the FDA's food additives list. Photo credit: Flickr/LabyrinthX

SEATTLE — Mint candies and chewing gum get their signature peppermint flavor from a naturally occurring substance called pulegone. The synthetic version of that chemical is one of several compounds based on natural products that the U.S. Food and Drug Administration (FDA) pulled from its list of approved food additives in 2018 at the urging of several advocacy groups.

It’s not that these additives aren’t safe for human consumption at the levels used in foods. In fact, "the FDA's rigorous scientific analysis has determined that they do not pose a risk to public health under the conditions of their intended use," according to the agency's delisting announcement.

But as a matter of law, the FDA’s hands are tied due to what some consider an outdated clause in the federal act that governs substances we ingest and use on our bodies.

Toxicology and legal experts discussed the 21st-century relevance of the 1958 Delaney clause of the Federal Food, Drug, and Cosmetic Act and whether it continues to be evidence-informed, during a Feb. 16 session at the American Association for the Advancement of Science annual meeting.

The Delaney clause bans chemical additives found to induce cancer in humans or animals. It holds that there is a direct cancer risk at all, even miniscule, chemical levels — this is known as the linear non-threshold dose-response model.

The clause has long sparked debate among researchers and regulators alike.

“Science is not static, it advances regularly, and since 1958, the understanding of toxicology and risk assessments associated with suspected carcinogenic chemicals has greatly increased and will continue to increase," said Lisa Navarro a toxicologist at flavor and fragrance manufacturer Givaudan and a former officer of the Society of Toxicology.

Our understanding of how cancer progresses has advanced since the 1950s, when it was thought that a single mutation could trigger tumor formation. Today, scientists know that the process by which chemicals induce cancer, called chemical carcinogenesis, is a complex series of events involving multiple mutations before healthy cells transform into tumor cells that eventually multiply.

At specified concentrations, certain chemicals can latch onto DNA and damage it. This damaged DNA produces mutations that jumpstart the development of cancer. If there are no repair mechanisms in place to delete mutations, the affected cells proliferate and form tumors.

But the Delaney clause does not take into consideration the concentration at which a chemical produces an effect. And it prohibits compounds like citrus-flavored synthetic d-limonene, even if associated adverse effects were seen only in animal models, not in humans.

For example, studies from the 1990s found that d-limonene caused kidney tumors in male rats, but not in female rats or in mice. The researchers concluded that this was because male rats produce large quantities of a protein linked to cell proliferation when given d-limonene.

“In some of these examples, these are processes that occur in animals, but don't have a counterpart in humans based on our understanding of how these particular agents interact,” said Barbara Beck of environmental and risk sciences consulting firm Gradient.

But not everyone agrees that the Delaney clause is obsolete.

It serves to protect individuals from potentially harmful chemicals and should remain in force, said Michael L. Dourson, director of science at the non-profit Toxicology Excellence for Risk Assessment.

There’s room for interpretation, however, since the terms “induce” and “additive” are not strictly defined in the clause, according to Ricardo Carvajal, a director at the law firm Hyman, Phelps & McNamara, P.C., which specializes in FDA regulation.

It’s unclear what an alternative to the Delaney clause would look like, but suggestions abound for how it could be amended, or its execution improved. At the very least, regulators and legislators could look to studies more recent than those from the 1960s and 70s that formed the basis of the clause.

Assessment tools used to invoke the clause should be updated to reflect current understanding of chemical carcinogenesis: that not all chemical carcinogens share the same mode of action, animal studies often cannot be extrapolated to humans, and there are thresholds for cancer risk, said Suzanne Fitzpatrick, senior toxicology advisor at the FDA.

“We at the FDA are also consumers, so we are really dedicated to doing rigorous scientific assessment.”

Srivindhya Kolluru is a student at the University of Toronto studying biological chemistry and professional writing & communication. She is the former science editor of The Varsity, Canada’s largest student newspaper. See her work at and follow her on Twitter @vindhya_kolluru.