FDA’s Hostile Take-Over of GRAS, Part III: It Started Earlier Than We Think

You would think any application of the GRAS1 process would be a legitimate pathway to federal compliance unless expressly prohibited by statute (e.g., color additives, dietary supplements) or by regulation (e.g., 21CFR2§184.1(b)(2));3 the latter of which requires a food additive petition (FAP) be filed for any additional use, use levels or changes to the manufacturing process of an otherwise GRAS affirmed substance.4 So far, so good for many food ingredients, until you get to the subject of irradiation5 of foods — as a process in and of itself or even a means to an end.

A Short History of Food Irradiation

The idea of the benefits of irradiation of foods became popular in the early 1950s although it had been used as early as the 1920s to kill insects in cigars (use for cigars was discontinued as the source of irradiation was from x-ray machines that constantly broke down from the work load). The use of ionizing radiation of food became popular once again under President Eisenhower’s “Atoms for Peace” program initiated in 1953. High energy (ionizing) radiation was applied to food using gamma rays (e.g., cobalt-60 or cesium-137), electron beams and improved x-ray equipment. Initial results were successful with demonstrable delays in ripening of food, pathogen reduction and food-borne illness, controlling pests and allowing long-term food storage. However, when tests were initiated on the effects on food, it was found that in response to high energy irradiation, “radiolytic products” were formed and some B-type vitamins were destroyed. Although many of the same effects were seen in conventional food processing involving heat, revelations of less nutritious food and myths about “radioactive food” were enough (even in a pre-internet world) for timorous souls to prod Congress to include a mention of irradiation in the Food Additives Amendment of 1958. Congress defined “…any source of radiation…” as a food additive, unless it is generally recognized as safe (GRAS). However, FDA has declared that all forms of irradiation, including all sources of high energy (ionizing) radiation, ultraviolet (UV), microwave and even radio frequency irradiation are food additives which, in the absence of a regulation or notice and comment period for a proposed regulation, is a clear disregard of administrative law.

That is, according to the FDA in recent correspondence, [The] “use of UV radiation is not in compliance with the applicable food additive regulation in Title 21 of the Code of Federal Regulations (21 CFR) §179.39, and under section 4026 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) uses of radiation must be authorized by regulation7 or exemption pursuant to section 409 of the FD&C Act.” We maintain the GRAS provision in 201(s) of the FD&C Act is just such an exemption.

Mandatory Food Additive Petitions in Place of GRAS an Overreach

The author disagrees with the rationale by FDA that the use of any irradiation requires a food additive petition (FAP) because (1) the rationale is clearly an erroneous interpretation of the FD&C Act relative to the nature of the definition of a “food additive” vs. GRAS (2) the scientifically invalid equivalence between ionizing and non-ionizing radiation; (3) the erroneous supposition that because some applications of UV irradiation have been the subject of a regulation (21CFR§179.39), that all must be handled though the FAP route and; (4) the FDA rationale embodies a profound departure from FDA historical oversight, by attempting to regulate a process rather than the safety of the product offered to the public. These points of disagreement are based on the following facts and observations.

(1) The mistaken use of the term “food additive” as applied to irradiation in the production and processing of a food. The term “food additive” is applied to any substance that is not generally recognized as safe — a concept made abundantly clear in the FFDCA8 §201(s):

The term “food additive” means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use), if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety … [emphasis added]

This concept of GRAS is also captured in FDA ‘s recent draft guidance, Best Practices for Convening a GRAS Panel: Guidance for Industry (November, 2017), wherein the statement is made: “Under this definition [in which the statute was quoted], a substance that is GRAS under the conditions of its intended use is not a ‘food additive’ and is therefore not subject to a mandatory premarket review by FDA under section 409 of the FD&C Act.”9

This concept of irradiation (ionizing or non-ionizing) as GRAS and therefore excluded from the food additive regulation process was discussed in the Hutt et al (2007)10 text on food and drug law as follows:

The fact that radiation is specifically included within the definition of a food additive does not mean that it could not be found to be GRAS and thus excluded from the requirement for a food additive regulation. The GRAS exclusion from the requirement of a food additive regulation applies to all substances that fall within the broad food additive definition in section 201(s).

There is no mention of compulsory FAP submission in final rule for “Irradiation in the Production, Processing, and Handling of Food” (Federal Register 70(157):48057; August 16, 2005) or that ultraviolet radiation may not be part of a GRAS submission.

However, there is precedent in the regulations precluding a GRAS conclusion and mandating a food additive petition; a circumstance plainly described in 21CFR§184.1(b)(2) as follows:

184.1(b)(2) If the ingredient is affirmed as GRAS with specific limitation(s), it shall be used in food only within such limitation(s), including the category of food(s), the functional use(s) of the ingredient, and the level(s) of use. Any use of such an ingredient not in full compliance with each such established limitation shall require a food additive regulation.

Clearly, there is no similar mandate requiring an FAP for UV irradiation — not in the regulations, nor in any current (official) guidance(s).11 Likewise, there is no prohibition for the use of UV irradiation in the Final Rule [for] Substances Generally Recognized as Safe (Federal Register 81(159):54960; August 17, 2016); that is, the GRAS Final Rule does not state that UV irradiation as a process could not be part of a GRAS Notification.

Therefore, because an ingredient is identified as having GRAS status, it is therefore exempt from food additive status and because there is no mandate for an FAP for a food involving ultraviolet irradiation and as part of an exempt process, an exemption as described in §409 is moot.

(2) The scientifically invalid equivalence between ionizing and non-ionizing radiation. On its website, FDA has posted, “Understanding Food Irradiation: What Industry Needs to Know.”12 Within this document is the following paragraph:

There are two categories of radiation — ionizing and non-ionizing — with the difference being the amount of energy emitted. Ionizing radiation emits enough energy to remove tightly bound electrons from an atom thus creating ions (i.e., atoms with a charge). Non-ionizing radiation does not have sufficient energy to cause ionization. Examples of ionizing radiation include gamma rays, x-rays, and electron beam radiation. Examples of non-ionizing uses of radiation include sound waves, visible light, and microwaves.

It is ionizing or high energy radiation that produces radiolytic products, including nutritional degradation (e.g., depletion of B-vitamin) or even toxic reaction products (e.g., furan derivatives). On the other hand, low energy irradiation (see diagram above), includes UV, infrared (IR), microwave and, at best, can produce changes analogous with the application of heat, such as cooking. However, regardless of the amount of energy injected into the system, the production of a substantive change may well require a confirmation of safety, but still the GRAS process as an avenue for compliance cannot be precluded. However, UV has too little energy to initiate a change in food and is not even comparable to changes possible by gamma-rays, X-rays or electron beam or even thermal processes such as retort cooking or pasteurization.

(3) The erroneous assumption that because some uses of UV are the subject of an FAP, all others must follow, but maybe not all the time: There have been three food additive petitions approved for UV irradiation (i.e., food and food products, potable water and juice products), all for which the control of microorganisms was the goal (21 CFR §179.39). However, simply because there are three examples of record that have gone through the FAP process, these actions do not preclude the use of the GRAS process for compliance of another use of UV application. If precedent was the controlling mechanism, then the several hundred flavor ingredients adopted as food additives (e.g., 21 CFR §170.510) would mandate that no additional flavor ingredients could be made compliant through the GRAS process.

Further, there is an uneven application of regulations; that is, 21 CFR §179.30 grants a blanket use of radiofrequency radiation and microwave, for the heating or processing of food — obviously, at least microwave could be a “process” to reduce the number of organisms present, as does ultraviolet. Likewise, 21 CFR §179.41 allows for pulsed light from xenon flash lamps at 200 to 1100 nm (which includes the visible light spectrum) to be used on food specifically for microorganism control. Why then does visible light, microwave and radio wave frequencies receive a green light for use on food, but another non-ionizing wavelength (i.e., ultraviolet) must be approved via a specific FAP designating the food type? This inconsistency would seem to be an unequal application of administrative law.

Lastly, in FDA’s “Statement of Policy – Foods Derived from New Plant Varieties”13 the policy statement includes (within “VI. Labeling):

To date, FDA has not considered the methods used in the development of a new plant variety (such as hybridization, chemical or radiation- induced mutagenesis, protoplast fusion, embryo rescue, somaclonal variation, or any other method) to be material information within the meaning of section 201(n) of the act (21 U.S.C. 321(n)). As discussed above, FDA believes that the new techniques are extensions at the molecular level of traditional methods and will be used to achieve the same goals as pursued with traditional plant breeding…

That is, in terms of developing new plant varieties, the use of radiation-induced mutagenesis is permissible even in the absence of a food additive petition and, in fact, a significant portion of GRAS determinations for new plant varieties are likely via a radiation-induced mutagenesis, but in GRAS Notifications are often referred to euphemistically as “conventional processes.”

(4) A requirement for a FAP for ultraviolet irradiation process would mark a significant change in FDA’s historical governance over safety of a product, not the process, thus stifling innovation. Historically, FDA has regulated products, not processes. If FDA were to change course and regulate according to processes, then FDA would be obligated for instance, to set limits for time and temperatures in the manufacture of reaction (process) flavors; however, to do so, would tend to stifle innovation. Staying with the flavor analogy (above), food additive regulations for flavors specify that Artemisis spp. (worm wood) extractives be thujone-free, but they do not specify which extraction process must be used, just so the job gets done (21 CFR §172.510). To go one step further, if a fruit or vegetable was known to contain a toxic agent, such as worm wood (containing thujone), and was required to undergo a specific type of detoxifying extraction, what would happen if selective breeding could eliminate the offending agent? It is very possible there would be considerable angst in the regulatory community for waiving the extraction requirement for one variety of Artemisis and not another. Clearly, regulating the end product is more favorable than dictating the process by which the product may become compliant.

The argument for increased regulatory oversight would be more palatable if UV irradiation initiated a substantive change in food such as seen with ionizing radiation, possibly a nutritional deficiency or even production of a toxic product. That is, the production of a substantive change having been initiated, would still require the substance to be safe as intended, but still the GRAS process as a method for compliance could not be ruled out. Ultraviolet is a comparatively “gentle” process, as it does not initiate a change in food and is not comparable to changes produced by gamma-rays, X-rays or electron beam or even thermal processes such as retort cooking or pasteurization.

Because of the rigorous nature of high energy radiation or thermal processes (such as retort cooking and pasteurization), breakdown of many valuable proteins in food is routine. On the other hand, UV pasteurization (i.e., “cold pasteurization) could be a viable alternative for those who want “clean food” or “minimally processed” food and who might otherwise be tempted to consume raw milk or other dangerous foods. However, given this dangerous precedent of requiring a FAP for all types of irradiation of food, it is logical that sun-drying fruits or vegetables would require submission of an FAP.

Time for FDA to Take New Look at Food Irradiation

Historically, the argument for FDA review of irradiation has been based on the concept that a change occurs in the food subjected to the irradiation, but clearly, the energy level used for UV and the time of exposure for UV-irradiation does not initiate a change in the food. According to Pauli and Takeguchi14 in their discussion of irradiated food, “[A] reading of the legislative history of the 1958 Amendment makes clear that both Congress and the Administrative agencies were well aware that food irradiation is a process and never gave any indication otherwise.”

It is time to follow through on what Pauli and Takeguchi made obvious 30 years ago, that food irradiation is a process, not an additive and its application should be subject to a GRAS conclusion.

References:

1. Generally Recognized As Safe

2. Code of Federal Regulations

3. This regulation prohibits certain GRAS affirmed substances from being GRASed for other uses or additional food groups. Any changes to the GRAS status of these ingredients requires a food additive petition. The exact rationale for this carve-out has been lost to time.

4. For additional information on this provision, refer to Limitations of GRAS Substances: Not All Created Equal.

5. The preferred term over “radiation,” although the terms “cold pasteurization” “electronically pasteurized” have also been used.

6. According to Pauli and Takeguchi (now retired from FDA), “This provision is different from the adulteration provision for other food additives, which states that a food is adulterated if it is, or if it bears or contains, any unsafe food additive (i.e., a food additive not permitted for use by regulation). This distinction is necessary because an irradiated food would not contain the food additive, namely, the source of radiation”. Pauli, G.H. and Takeguchi, C.A. (1986). Irradiation of foods – an FDA Perspective. Food reviews International 2(1):79-107.

7. Which could only arise via a food additive petition.

8. Federal Food Drug and Cosmetic Act

9. Page 7 Best Practices for Convening a GRAS Panel: Guidance for Industry (November, 2017)

10. Hutt, PB; Merrill, RA and Grossman, LA (2007). Cases and Materials. Food and Drug Law 3rd edition, Foundation Press p. 495.

11. Which have fulfilled administrative law requirements of a notice and comment period.

12. Understanding Food Irradiation: What Industry Needs to Know. Site accessed April 29, 2018.

13. Statement of Policy — Foods Derived from New Plant Varieties. Site accessed April 29, 2018.

14. Pauli, G.H. and Takeguchi, C.A. (1986). Irradiation of foods — an FDA Perspective. Food reviews International 2(1):79-107.

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