Abstract
In the United States, the Food and Drug Administration (FDA) regulates the safe use of food ingredients, including food additives. Food additives are subject to FDA premarket review and approval, a process conducted by FDA scientists to evaluate the additive’s safety for the intended conditions of use. Typically, an acceptable daily intake level is established by toxicologists based on the highest no observable adverse effect level for the most sensitive noncancer toxicity end point determined from a pivotal nonclinical study with application of an appropriate safety factor. Utilizing other information, including the additive’s use and exposure levels, a safety determination (reasonable certainty of no harm) is made. During ongoing safety assessments, pathologists are often consulted by toxicologists for case-specific reasons, which may include verifying that an observed pathological effect is treatment related and adverse, confirming the determination of the pivotal study, endorsing a mode of action, or evaluating the human relevance of a toxicological effect found in experimental animals. Last year, the FDA took regulatory action to no longer allow the use of the food additive myrcene, a synthetic flavoring agent, based on results from National Toxicology Program carcinogenicity studies. The cancer and noncancer end points from the rat studies are discussed.
Safety Assessment of Food Additives
The safe use of food ingredients and food packaging in the United States is regulated by the Food and Drug Administration (FDA) through the Center for Food Safety and Applied Nutrition (CFSAN), Office of Food Additive Safety (OFAS). In general, regulatory submissions reviewed by OFAS include (1) food additive petitions, (2) color additive petitions, (3) food contact substance notifications, (4) generally recognized as safe (GRAS) notices, and (5) consultations for foods derived from bioengineered plants. The FDA’s regulatory (safety) review process for submissions under the purview of OFAS is conducted by multiple scientific disciplines, including consumer safety officers, chemists, toxicologists, and pathologists.
A food additive, as defined in Section 201(s) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), is a substance in which the intended use results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food. Any substance added to food is a food additive, subject to FDA premarket safety review and approval, unless the substance is designated to be GRAS, or meets one of the other exclusions specified in the FD&C Act. A direct food additive, such as a sweetener, preservative, or emulsifier, is deemed unsafe unless there is a food additive regulation permitting its use and the additive is used in conformance with the provisions of that regulation (FD&C Act, Section 409). Any food that contains an unsafe food additive is considered adulterated [FD&C Act, Section 402(a)(2)(C)]. 1 The responsibility for demonstrating to FDA that a food additive is safe under the conditions of its intended use rests with the sponsor (eg, industrial companies, organizations, individuals) of the petition seeking approval. Petitions also may be submitted to FDA to repeal an existing food additive regulation based on either safety reasons or abandonment of use. During the review of a food additive petition, FDA toxicologists conduct a comprehensive review of the safety of the additive for the specific use. For all food ingredients, FDA’s safety standard is “reasonable certainty of no harm.” 2,3 However, the Delaney Clause in the FD&C Act limits FDA’s discretion to determine the safety of a food additive in that it prevents FDA from finding a food additive to be safe if it is found to induce cancer when ingested by man or animal, or it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal, regardless of the probability or risk of cancer in humans from the use of the additive. 1 –3
Typically, for the food additive safety evaluation, an acceptable daily intake (ADI) level is established by the toxicology reviewer based on the highest no observable adverse effect level (NOAEL) for the most sensitive noncancer toxicity end point determined from a pivotal nonclinical study with application of an appropriate safety factor. The chemistry reviewer is responsible for the exposure assessment and determining the estimated daily intake (EDI) level. Comparing the ADI to the EDI, a safety determination (reasonable certainty of no harm) can be made. 2,3
In the regulatory review (safety and carcinogenicity assessment) process, pathologists are often consulted by toxicologists to verify that an observed pathological finding or effect is treatment related. In many complex review cases, pathologists are also consulted by toxicologists during regulatory reviews to determine whether an observed effect is adverse (eg, increased organ weight), evaluate and define adverse effects and assist in determining the NOAEL, confirm the pivotal study choice, weigh the scientific evidence and provide input on mode of action (eg, thyroid hormonal, inflammatory, cytotoxic), and evaluate the human relevance of a histopathological effect found in experimental animals (eg, rodent renal tumors).
Pathology Consultation Review for Myrcene, a Synthetic Flavoring Agent
Myrcene (β-myrcene) is an aroma chemical used in soaps, detergents, and cosmetics as well as a flavoring agent (food additive) used in foods and beverages. It is also a major natural constituent found in hops, hop and bay oils, citrus fruits and citrus juices, and lemongrass tea. The natural constituent food source exposure to myrcene is much higher (estimated to be 16,500 times greater) than the synthetic use (flavoring substance and adjuvant) exposure. 4
Myrcene was nominated by the National Institute of Environmental Health Sciences in 1997 for study by the National Toxicology Program (NTP) based on its high production volume, high level of human exposure, and a structural relationship to
In 2015, a Food Additive Petition (FAP 5A3810) was submitted to the FDA to revoke the synthetic use of myrcene and 6 other flavoring substances listed in 21 CFR 172.515. 4 The petition relied primarily on results from studies conducted by NTP. For myrcene, the pathologists at CFSAN/OFAS were consulted on the array of complex renal histopathology reported in the rat for neoplastic findings and an associated triad of non-neoplastic lesions (an “unusual or unique” nephrosis in both sexes, α2u-globulin nephropathy in lower dose male rats only, and chronic progressive nephropathy or CPN in both sexes). The scientific evaluation by FDA pathologists of the kidney precancer and cancer end points reported by the NTP in the myrcene rat studies was complex and involved the utilization of some key literature references. 5 –9
Food and Drug Administration pathologists concluded that both male and female rats had treatment-related increased incidences of combined renal tubule adenomas and carcinomas. This conclusion took under special consideration that renal tubule neoplasia is a “rare” spontaneous tumor in the F344 rat strain. The 2016 pathology consultation memorandum was cited in the toxicologist’s 2018 cancer risk assessment review memorandum, included as reference 14 in the Federal Register 4 and the publicly available docket. 10
Based on the consultation opinions from FDA pathologists, the toxicology reviewer concluded that synthetic myrcene was shown to cause cancer in laboratory animals under the conditions of the NTP carcinogenicity studies. 4,10 Food and Drug Administration concluded that myrcene is not genotoxic, yet definitive modes of action were not established for rodent carcinogenicity. After a thorough weight-of-evidence analysis and a science-based estimation of the margin of safety, FDA also concluded that myrcene is unlikely to induce tumors in humans at its current exposure level as a synthetic food flavoring agent. However, despite FDA’s determination that myrcene did not pose a risk to public health under the conditions of its intended use, FDA could not, as a matter of law under the Delaney Clause, maintain the listing of myrcene (and the other synthetic flavoring substances) in the food additive regulations. Consequently, in 2018, the FDA issued a final rule that amended 21 CFR 172.515 to no longer provide for the use of the food additive myrcene as a synthetic flavoring agent. 4
Footnotes
Authors’ Note
This work was authored as part of the contributor’s official duties as an employee of the US Government and is therefore a work of the US Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under US Law.
Acknowledgments
The authors would like to acknowledge the intellectual contribution of Dr Abu Khan (US FDA, toxicology review of myrcene) and Dr Sabine Francke (US FDA, pathology review of myrcene). This is a synopsis of our presentation at the 2019 Society of Toxicologic Pathology Annual Symposium.
Declaration of Conflicting Interests
The authors declared no potential, real, or perceived conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
