How the 62-year old Delaney Clause continues to thwart science: Case study of the flavor substance β-myrcene.

The Delaney Clause is a provision of the 1958 Food Additive Amendment to the Food, Drug and Cosmetic Act of 1938 which stipulates that if a substance is found by the Food and Drug Administration to be carcinogenic in any species of animal or in humans, then it cannot be used as a food additive. This paper presents a case study of β-myrcene, one of seven synthetic substances that was challenged under the Delaney Clause, ultimately resulting in revocation of its regulatory approval as a food additive despite a lack of safety concern. While it is listed as a synthetic flavor in 21 CFR 172.515, β-myrcene is also a substance naturally occurring in a number of dietary plants. The exposure level to naturally-occurring β-myrcene is orders of magnitude higher (estimated to be 16,500 times greater) than the exposure via β-myrcene added to food as a flavoring substance. The National Toxicology Program conducted genotoxicity testing (negative), a 13-week range-finding study, and a two-year cancer bioassay in B6C3F1 mice and F344/N rats. An increase in liver tumors was seen in male mice and kidney tumors in male rats, ultimately resulting in β-myrcene being classified by IARC as a Class 2B carcinogen and being listed on California Proposition 65; in contrast, β-myrcene is not classified as a carcinogen by any other regulatory authority. The doses administered in the NTP bioassay were five-six orders of magnitude higher than human exposures, and the FDA concluded after a thorough evaluation that there was no safety concern associated with the use of β-myrcene as a flavor substance at the current use level. The Delaney Clause, however, does not consider the exposure potential or the human health relevance of effects observed in animals. The lack of options available to the US FDA led to the 2018 decision to remove β-myrcene from the list of approved food additives. This revocation has contributed to the ongoing erosion of trust in regulatory agencies (and industry), which has both economic implications for food manufacturers and consumers alike, and implications for consumer perception of safety of the US food supply. It is time for us to reconsider the rationale behind any legislation that relies on classification alone, and whether there is, in fact, a reason to still classify nongenotoxic carcinogens at all.