Making Decisions about the Risks of Chemicals in Foods with Limited Scientific Information

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The FD&C Act provides that the FDA shall issue no food additive regulation if "a fair evaluation of the data … fails to establish that the proposed use of the food additive, under the conditions of use to be specified in the regulation, will be safe" (21 U.S.C. § 348(c)(3)(A)). This is the general safety standard applied to food additives. For this purpose, the FDA defines safe as "a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use" (21 CFR § 170.3(i.)). The FDA recognizes that "it is impossible in the present state of scientific knowledge to establish with complete certainty the absolute harmlessness of the use of any substance" (21 CFR § 170.3(i)). In its risk assessment of food additives, the FDA must consider, among other relevant factors, the estimated consumption of the additive and of any substance formed in foods due to use of the additive, the cumulative effect of such substances and any chemically or pharmacologically related substances in the diet, and the appropriate safety factors for interpretation and extrapolation of animal data. In applying animal experimental data to man, the FDA typically uses a safety factor of 100 unless scientific evidence justifies a different safety factor (21 CFR § 170.22).

The 1958 amendment added the food additive Delaney Clause, which is also known as the anti-cancer clause, to the FD&C. The food additive Delaney Clause provides that no food additive shall be deemed safe if "it is found to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal" (21 USC § 348(c)(3)(A)). The FDA has no discretion to permit use of a food additive for human food use once a finding of carcinogenicity is made regardless of the degree of risk involved. However, the Delaney Clause applies to the food additive itself and not to constituents of the additive. As the FDA has acknowledged, if a food additive has not been shown to cause cancer even though it contains a carcinogenic impurity, then the food additive Delaney Clause does not apply and the additive is properly evaluated under the general safety standard using risk assessment procedures to determine whether there is a reasonable certainty that no harm will result from the proposed use of the additive (FDA 2003). (See Les v. Reilly, 968 F.2d 985 (9th Cir. 1992); Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).

GRAS substances. GRAS substances are not regulated as food additives and do not require FDA approval prior to use. Shortly after enactment of the 1958 amendment to the FD&C Act, FDA published a list of many, but not all, substances believed to be GRAS for use in food (FDA 1958, 1959). These regulations are known informally as the FDA's GRAS list. However, the agency explicitly recognizes that it is impracticable for the FDA to publish regulations identifying all substances that are GRAS for use in food. The FDA also acknowledges that "a substance that is GRAS for a particular use may be marketed for that use without agency review and approval" (FDA 1997). Additionally, FDA recognizes that companies "have the right to make independent GRAS determinations on food substances" (FDA 1988). Manufacturers may notify the FDA of their GRAS determinations, but such notifications are completely voluntary (FDA 1997). (See 21 CFR Parts 182, 184, and 186; 21 CFR §§ 170.30(d), 182.1(a).)

A determination of the GRAS status of the use of a substance may be based either on common use in food prior to January 1, 1958 or on scientific procedures. Establishment of GRAS status through common use is ordinarily based on generally available data and information and does not require the same quantity or quality of scientific evidence needed for food additive approval. The common use in food may occur outside of the United States, provided that documentation and independent corroboration of such use is both widely available in the country of use and readily accessible to interested, qualified scientific experts in the United States. However, in Fmali Herb Inc. v. Heckler, the 9th Circuit U.S. Court of Appeals cautioned that "evidence of foreign use of an ingredient, standing alone, may rarely or never be enough to establish safety."(See 21 CFR §§ 170.35(c)(1), 170.35(c)(2); Fmali Herb Inc. v. Heckler, 715 F.2d 1385, 1390–1 (9th Cir. 1983)).

Establishing GRAS status through scientific procedures requires both technical evidence of safety and evidence of common knowledge or general recognition among qualified experts. As to technical evidence of safety, the FDA's position is that "a GRAS substance is neither more nor less safe than an approved food additive" (FDA 1997). Therefore, the same quantity and quality of scientific evidence is required (at least in theory) to demonstrate safety of a substance that is GRAS based on scientific procedures as is required for a food additive. The common knowledge element is an important distinguishing factor between a substance that is GRAS based on scientific procedures and a safe food additive. To satisfy the common knowledge requirement, the data and information relied on to establish the safety of the substance must be generally available to the scientific community, and there must be a basis to conclude that a consensus exists among qualified experts about the safety of the substance for its intended use. (See 21 CFR § 170.30(b).)

A conclusion that a substance is actually safe is not sufficient to support the GRAS status of a food ingredient. Rather, the conclusion of safety must be supported by evidence that the substance is generally recognized among experts as safe under the conditions of intended use. While unanimity is not required, there must be evidence of a consensus among qualified experts and pivotal safety data must be publicly available. In this respect, it is a much higher standard than the general safety standard applied to food additives. (See United States v. An Article of Food … Coco Rico Inc., 725 F.2d 11 (first Cir. 1985); United States v. Articles of Food … Coli-Trol, 518 F.2d 743 (5th Cir. 1975); United States v. Articles of Food … Sodium Pangamate, (1978 to 1979 Transfer Binder) Food Drug Cosm. L. Rep. (CCH) 38,226.)

Color additives. The Color Additive Amendment of 1960 added FDA premarket approval and, for certain dyes, certification, requirements to the FD&C Act. A color additive is defined in the FD&C Act as a material that

  • is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived, with or without intermediate or final change of identity, from a vegetable, animal, mineral, or other source, and

  • when added or applied to a food … is capable (alone or through reaction with other substance) of imparting color thereto: except that such term does not include any material which (FDA), by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. … The term color includes black, white, and intermediate grays. (See 21 USC §321(t).)

There are no exemptions from the color additive definition, and GRAS does not apply to color additives. Even if a color additive is generally recognized among qualified experts as safe for use as a color additive, it must first be approved and listed by the FDA before it may be used as a color additive in food.

The FD&C Act provides that the FDA "shall not list a color additive for a proposed use unless the data before (the FDA) establish that such use, under the conditions of use specified in the regulations will be safe … " (21 USC § 379e(b)(4)). For purposes of determining safety of a color additive, safe means that "there is convincing evidence that establishes with reasonable certainty that no harm will result" from such use in foods (21 CFR § 70.3(i)). Among other factors pertinent to safety, the FDA must consider the probable consumption of the color additive or any substances formed in food from the additive; the cumulative effect, if any, of the additive in the diet of man or animals, taking into account background dietary exposure and chemically or pharmacologically related substances; appropriate safety factors for application of animal data; and availability of practicable methods of analysis for identifying and quantifying the color additive in foods. (See 21 USC §§ 342(c), 379(e), 379e(b)(4), 379e(b)(5).)

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