20 of 167 DOCUMENTS

Copyright (c) Trustees of Boston University 1998.
Boston University Law Review

April, 1998

78 B.U.L. Rev. 329

LENGTH: 37546 words

ARTICLE: STARTING FROM SCRATCH?: REINVENTING THE FOOD ADDITIVE APPROVAL PROCESS

NAME: Lars Noah * & Richard A. Merrill **

BIO: 

* Associate Professor of Law, University of Florida.
** Daniel Caplin Professor of Law, University of Virginia; Chief Counsel to the U.S. Food and Drug Administration from 1975 to 1977.
The authors would like to thank the following individuals for their comments on the manuscript: Marsha N. Cohen, Catherine L. Copp, Margaret Gilhooley, Richard L. Hall, Lisa M.W. Hillman, Peter Barton Hutt, George H. Pauli, and other participants at the Food Forum workshop (held at the National Academy of Sciences on May 6-7, 1997) where an earlier version of this paper was presented.

LEXISNEXIS SUMMARY:
 ... The safety of novel foods and food ingredients has been of intense public concern and periodic political interest at least since World War II, which inspired heroic efforts to expand, extend, and improve the products of nature. ... General recognition of safety based upon scientific procedures shall require the same quantity and quality of scientific evidence as is required to obtain approval of a food additive regulation for the ingredient. ...  The FDA has acknowledged, albeit with some reluctance, that the maker or user of a substance may reach its own conclusion that a particular food use is GRAS and, therefore, exempt from food additive approval requirements. ...  Thus, if a substance qualifies as a food additive, it may not be used unless and until the FDA specifically grants approval. ...  "Promptly upon completion of the studies undertaken on the substance, the Commissioner will review all available data, will terminate the interim food additive regulation, and will either issue a food additive regulation or will require elimination of the substance from the food supply." ...  The previous discussion has focused on which substances must undergo food additive approval and the FDA's processing of food additive and GRAS affirmation petitions. ...  In its implementing regulations, the FDA has defined GRAS status as requiring the same quantity and quality of data supporting safety as needed for food additive approval - unless the substance was in common use prior to 1958. ...  

TEXT:
 [*330]  Introduction
The safety of novel foods and food ingredients has been of intense public concern and periodic political interest at least since World War II, which inspired heroic efforts to expand, extend, and improve the products of nature. One need only recall controversies over diethylstilbestrol (DES) in beef cattle, the artificial sweeteners cyclamate and saccharin, nitrite-treated bacon, Alar on apples, and bovine growth hormone (rBST) to be impressed by the popular and journalistic salience of putative hazards created by modern food production methods. In more recent years, truly innovative technologies - such as Procter & Gamble's fat-substitute olestra and Calgene's bioengineered tomato - have attracted significant attention, and their regulation by the U.S. Food and Drug Administration (FDA) has become the focus of a complex debate. Some have criticized the FDA for its lengthy delays in reviewing these and other innovative substances added to food.   n1 Others have argued that the Agency does not adequately ensure the safety of such substances. These latest controversies pose significant questions about how best to regulate substances added to food.
This Article explores the FDA's regulation of substances purposely added to food as it has evolved over the last several decades, and it concludes with a discussion of several possible avenues for reform. Debates about proposals to modify existing approaches must start with a proper appreciation of the difficulties encountered in the past. Moreover, the history of the food ingredient approval process illuminates recurring challenges faced in the design of regulatory programs. Past studies of other federal agencies have revealed valuable lessons about regulatory performance that transcend the particular program under study.   n2
 [*331]  Part I describes the FDA's system for regulating food-use substances as it existed before the enactment of specific food additive legislation in 1958. The next three Parts explore, in turn, the definitional, procedural, and substantive provisions of this legislation as implemented over the last several decades. Part V offers three recent case studies that expose some of the special difficulties encountered in the regulation of food-use substances. Finally, Part VI identifies several problems experienced by the FDA in recent years and analyzes an accompanying range of possible reforms. The time is ripe for reinventing this country's food ingredient approval process.
I.
 
 History
 
 The federal government asserted authority over the quality and safety of food products early this century. In 1906, reacting to widely publicized examples of filth and deception, Congress prohibited the introduction of adulterated or misbranded food and drugs into interstate commerce.   n3 The 1906 Act provided that any food containing an "added poisonous or other added deleterious ingredient which may render such article injurious to health" would be deemed adulterated.   n4 If federal officials suspected a safety problem, they could initiate enforcement action to remove the product from the market, but the government would shoulder the burden of proving that the food ingredient, as consumed, posed "a reasonable possibility of injury."   n5 Congress replaced the original statute in 1938 with the Federal Food, Drug, and Cosmetic (FD&C) Act,   n6 but the newer legislation retained the same basic system of after-the-fact policing for adulterants in food. It was not until  [*332]  the Food Additives Amendment of 1958   n7 that Congress established a premarket approval system for food ingredients. The detailed requirements of these two enactments are discussed more fully below.
In the two decades that elapsed between the passage of the FD&C Act and the Food Additives Amendment, a number of developments rendered the original statutory design outdated. Indeed, the 1938 legislation, based as it was on the 1906 Act, focused on the control of "adulterants" and did not fully anticipate the rapid progress in food processing technology and the growing utilization of intentional additives that would follow.   n8 Technological advances spurred by World War II allowed processors to offer more nutritious, palatable, and convenient foods, and consumers increasingly demanded such improved products. Meanwhile, progress in the biomedical sciences increased the understanding of human nutritional needs and the causes of chronic diseases. These advances have not slowed, and, almost four decades later, Congress is being urged to consider once again updating - or overhauling - the statutory system governing food additives.   n9
A.
 
 The Food, Drug, and Cosmetic Act of 1938
 
 Under the original FD&C Act, the FDA possessed broad responsibility but comparatively weak regulatory authority over substances added to food. Section 402(a) provided that a food shall be deemed to be adulterated under the following circumstances:

(1) If it bears or contains any poisonous or deleterious substance which may render it injurious to health; but in case the substance is not an added substance such food shall not be considered adulterated under this clause if the quantity of such substance in such food does not ordinarily render it injurious to health; or

 
(2) if it bears or contains any added poisonous or added deleterious substance which is unsafe within the meaning of section 406...   n10
 
  [*333] 
 
The authority to promulgate food standards of identity under Section 401 provided the FDA with another regulatory mechanism, though cumbersome, for restricting the use of added substances; it permitted the Agency to specify what ingredients could be used in standardized food.   n11
 
 To enforce Section 402(a) of the FD&C Act, the FDA (through the Department of Justice) could initiate judicial proceedings to seize adulterated food or enjoin its continued marketing.   n12 Unless the product exceeded one of the very few tolerances ever established under Section 406, however, the Agency had to shoulder the burden of proving that the substance (1) was poi [*334]  sonous or deleterious and (2) could, in the amounts present, render the food injurious to health.   n13 As the Supreme Court held in construing the essentially identical language in the 1906 version of the statute,   n14 the government must show that the food containing a poisonous or deleterious substance creates a reasonable possibility of harm to consumers.   n15 Because of the time and effort required to undertake animal feeding studies of a substance, the FDA frequently could not satisfy this burden even if it had some legitimate basis for concern about safety.   n16
 [*335]  At the same time, another provision of the 1938 Act appeared to make the FDA's task too easy. Under Section 402(a)(2), absent a tolerance established under Section 406, any added poisonous or deleterious substance would render a food adulterated,   n17 even if the amount present was not "injurious" and it served a useful purpose.   n18 In theory, Section 402(a)(2) reduced the FDA's burden of proof in taking enforcement action against a food product by eliminating any need for it to demonstrate that an added poisonous or deleterious substance might render the food injurious to health.   n19 The Agency still would have to show that an added substance was poisonous or deleterious at some level of exposure. But if such a showing could be made, as for most ingredients it could, the FDA would have difficulty allowing use at lower levels that would be safe.
Thus, the original statute created a safety standard for substances added to food that was both unnecessarily rigid and difficult to administer. Because it shouldered the burden of proof, the FDA experienced problems in regulating the introduction and marketing of foods containing substances whose safety  [*336]  had not been established. Moreover, because the statute did not require advance notification of the introduction of a new additive, the Agency might not even learn of its use unless safety problems subsequently came to light.   n20
Although the FDA lacked the authority under the 1938 Act to insist that new additives be tested, chemical manufacturers and food processors had incentives to undertake at least limited safety assessments of new ingredients. First, they might have feared eventual enforcement sanctions under the FDA's food adulteration provisions. Second, and more importantly, they could not risk the adverse publicity that would accompany the subsequent discovery of a hazard in their products. Finally, though perhaps less of a concern at the time, they might have faced significant tort liability if consumers suffered injuries.   n21 In fact, most companies did test new additives to some extent, but nothing in the law prevented an unscrupulous firm from using an untested substance in food.   n22
B.
 
 The Food Additives Amendment of 1958
 
 In 1950, Congress turned its attention to the growing use of chemicals in food production.   n23 After two years of hearings on the subject,   n24 a House se [*337]  lect committee chaired by Representative James Delaney issued a report of its investigation. At the outset, the Committee remarked on the rapidly growing use of chemicals in the food supply: "There is hardly a food sold in the market place today which has not had some chemicals used on or in it at some stage in its production, processing, packaging, transportation, or storage."   n25 The Committee recognized the substantial value of this growing use of additives, but it also expressed concerns about the accompanying potential health hazards.   n26 According to the report, the FDA estimated that approximately 700 chemicals were used in food at the time but that only 428 were known to be safe.   n27 The Committee expressed particular concern over the lack of information about the possible chronic risks of existing food-use chemicals, and it urged Congress to amend the FD&C Act so that food additives would be required to undergo the same premarket review for safety required for drugs at that time.   n28
In the six years following the investigations by the Delaney Committee, Congress considered numerous bills and held further hearings on the subject.   n29 Unlike other legislative reforms of the FDA's enabling statutes, which were prompted by apparent public health crises, the effort to equip the  [*338]  Agency to cope with the emerging concerns about new food additives displayed little urgency. Congress proceeded incrementally to design a regulatory mechanism.   n30 Its first step was to amend the FD&C Act in 1954 to create a premarket approval system for pesticide residues in food. The Miller Pesticide Amendments required the establishment of a tolerance for any pesticide chemical intended for use on a raw agricultural commodity.   n31
Food processors and ingredient suppliers accepted the need for some method of premarket FDA review of novel ingredients in processed food,   n32 but initially they preferred a system of advance notification of an intent to market a new additive rather than a system that required the issuance of a license by the Agency.   n33 Administration officials objected that such a notification system "would give no effect, except a delaying effect, to an adverse safety evaluation of the Secretary."   n34 Such a delay would give the FDA time to institute judicial proceedings to prevent marketing, where it only would have to establish that existing studies failed to demonstrate safety. However, the Agency would have to prove more than a reasonable possibility of harm in the abstract, under any condition of use; it would shoulder the more diffi [*339]  cult burden of showing inadequate pretesting related to the safety of a substance for that particular intended use.
In contrast, the FDA's parent, the Department of Health, Education, and Welfare (HEW), sponsored a bill that would prohibit the use of a new food additive unless and until the FDA promulgated a regulation specifically authorizing its use.   n35 The Agency did not conceive of this proposal as a product-specific licensing scheme authorizing use by a particular applicant, as is the case with new drug approvals; instead, it envisaged approval as a generic authorization for use by any person.   n36 Under such a regime, the FDA would issue a nonexclusive public regulation authorizing any person to use an additive, subject only to any patent rights of the food additive petitioner. Without any recorded discussion of the choice before it, Congress ultimately opted for the Administration's proposed generic approval approach.
The various bills also included deadlines for FDA review of information about a new food additive. For instance, Representative Delaney's original bill provided that a petition would be deemed approved if the Secretary failed to act on it within sixty days of filing.   n37 Under another bill, even if the Secretary concluded that an applicant had failed to demonstrate a new additive's safety, a manufacturer or processor could still introduce it thirty days after notifying the Agency, unless the FDA first sought an injunction.   n38 The Agency favored a premarket approval system but insisted that it would need additional time to process submissions.   n39
 [*340]  Ultimately, in 1958, Congress enacted the Food Additives Amendment to the FD&C Act.   n40 By establishing a premarket review system for food additives in new Section 409, Congress shifted the burden of proof on the safety issue from the FDA to the industry.   n41 A food additive now could not be used unless and until the Agency deemed it safe for the use proposed by the sponsor. The legislation was not, however, motivated exclusively by concerns about safety. Congress believed it was promoting continued innovation in food technology by giving the FDA greater flexibility to authorize limited uses of substances in food even if shown in animal tests to be toxic at higher levels.   n42
The next three Parts, focusing in turn on definitional, procedural, and substantive issues, explore in greater detail the most important features of the food additive approval regime that Congress created in 1958.
 [*341] 
II.
 
 Definition of Food Additive
 
 Since its enactment, definitional issues have been at center stage in the application of the Food Additives Amendment. In particular, the statutory definition of the term "food additive" has posed significant interpretive difficulties. As the FDA's process for reviewing food additive petitions has become more cumbersome, industry has come to rely more heavily on exceptions enumerated in the definition. Some of the recently proposed reforms would modify the definition of "food additive" in an effort to limit the FDA's premarket role.
A.
 
 Components of Food
 
 The 1938 FD&C Act defined the term "food" as "articles used for food or drink... [and] components of any such article."   n43 Putting aside the obvious tautology in the primary definition, Congress clearly intended to subject "components" of food to regulation as food.   n44 In addition, the statute's operative provisions - namely, the often vague prohibitions against adulteration and misbranding - refer to "substances" added to food,   n45 as well as to "ingredients" from which a food has been fabricated.   n46
Although Congress did not expressly modify any of these original definitions, the Food Additives Amendment effectively displaced many of the Act's broad prohibitions against adulteration insofar as they applied to substances added to food. According to the statute:

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... , if such substance is not generally recognized... to be safe under the conditions of its intended use...   n47
 
  [*342]  By its terms, this definition does not include substances that are generally recognized as safe (GRAS), an important exception that, as discussed below, has become a central feature of the FDA's regulatory system. The definition does encompass a number of "indirect" uses,   n48 but, as a result of parallel or subsequent amendments, it also specifically excludes several important categories of purposeful substances that otherwise would be covered, including color additives, pesticide chemicals on raw agricultural commodities, new animal drugs, and ingredients of dietary supplements.   n49 Other provisions of the statute now govern each of these excluded categories.   n50
At its core, the definition of "food additive" applies to a "substance" whenever the manufacturer or food processor knows or should know that it will become a "component or otherwise affect[] the characteristics of any food."   n51 The FDA routinely grapples with questions about the intended use of an article to determine its appropriate regulatory classification as, for instance, a food, drug, medical device, or cosmetic.   n52 Although Congress in 1958 focused on "chemical" additives,   n53 items commonly available as food  [*343]  may be food additives (e.g., tomatoes in pasta sauce) unless otherwise excluded from the definition.   n54
1.
 
 Indirect Additives
 
 The definition of "food additive" clearly covers more than just intentional, functional ingredients; Congress expressly included substances that may indirectly become a component or otherwise affect the characteristics of food through their utilization in production or processing.   n55 Such "indirect" or "incidental"   n56 additives may, for instance, include substances in food packaging which unavoidably, and often at barely detectable levels, migrate into the food.   n57 Before the FDA may regulate a substance as an indirect food ad [*344]  ditive, however, the Agency must have some evidence that it may reasonably be expected to migrate into food.   n58 The Agency then may impose conditions on the use of the substance to ensure that it will not migrate into food or, if it does, only in amounts that can be considered safe.
The food additive definition appears to encompass any food-contact material that might get into food. The statute nowhere suggests that the level of migration might make a difference. As analytical methods have improved, the FDA's original view that any level of migration would render a substance a food additive (unless it were GRAS) has become increasingly problematic. The first serious test of the Agency's position came in the mid-1970s, when it confronted evidence suggesting that acrylonitrile, a polymer used to fabricate lightweight beverage bottles and other food-contact articles, might migrate into foods, albeit in parts per billion.   n59 This discovery was particularly worrisome, although the FDA did not immediately say so, because it coincided with preliminary reports of a chronic feeding study indicating that acrylonitrile was a carcinogen.   n60 After a formal hearing on the issue of migration, the FDA Commissioner decided that the acrylonitrile copolymer used to manufacture bottles qualified as a food additive which, because its safety had not been established, could no longer be used.   n61 The manufacturer immediately challenged this decision in court.
 [*345]  In Monsanto Co. v. Kennedy,   n62 the U.S. Court of Appeals for the D.C. Circuit reversed the Commissioner's decision. According to Judge Leventhal, the FDA had failed to adduce concrete evidence that some residual (unpolymerized) acrylonitrile monomer would migrate from the interior surface of the plastic container into the beverage.   n63 The court remanded the matter so that the Commissioner could consider migration studies using improved detection methods and also decide, even if migration was probable at extremely low levels, whether to exercise his discretion to disregard the amount as trivial.   n64 Relying on fresh migration data, the Agency again concluded that the acrylonitrile container was a food additive, but this time it also approved the material as safe under conditions that all but eliminated the likelihood of migration.   n65
Over the years, the FDA has approved hundreds of indirect food additives.   n66 Its historical position that any amount of migration required approval guaranteed that this part of its workload would expand inexorably with advances in analytical chemistry. According to reliable accounts, the Agency has devoted so much time and manpower to this task that it has, by comparison, neglected reviews of the less numerous direct food additives.   n67 The FDA recently established an abbreviated exemption procedure for food-contact substances where the level of potential migration is so trivial - generally less than 0.5 parts per billion (ppb) - as not to require formal approval.   n68 Except as it affects the Agency's workload, the FDA's regulation  [*346]  of indirect food additives is beyond the scope of this Article.
2.
 
 Dietary Supplements
 
 Another persistent, increasingly provocative issue is how to differentiate between food additives and food itself. Before a recent amendment to the statute, the issue arose most frequently in the context of dietary supplements, but the underlying interpretive issue is broader. Over the years, the FDA has pursued a variety of legal tactics in regulating nutritional supplements, attempting to shift the burden of proof on issues of safety to the industry. It has at various times challenged specific supplements as drugs and as food additives, both of which require premarket approval. In a pair of recent cases two federal appellate courts rejected the FDA's claim that black currant oil (BCO), sold in capsule form, was a food additive.   n69 In both instances, the Agency had seized shipments of the products on the theory that the manufacturers failed to establish BCO's safety as a component in the dietary supplement capsules.   n70 Refusing to accord deference to the FDA's interpretation of its enabling statute, both courts found the Agency's reading of the "food additive" definition unpersuasive.   n71
According to the courts, only components that somehow affect the final food may be regulated as food additives. In the challenged capsules, the courts held, the black currant oil was the sole active ingredient and, therefore, properly regarded as the food itself rather than an additive in the food.   n72 Indeed, as the courts pointed out, the FDA had conceded that BCO  [*347]  sold in bottles containing the pure liquid form would not qualify as a food additive; they ruled that replacing the bottle with a gelatin capsule as the delivery vehicle should not affect BCO's regulatory status.   n73 In the capsule form, two inert substances (gelatin and glycerin) encased the BCO. The legal dispute turned on the interpretation of the statutory phrase "becoming a component or otherwise affecting the characteristics of any food."   n74 The Agency sought to read the phrase in the disjunctive (i.e., either becoming a component or affecting the characteristics ... ); the claimants argued for an overlapping, unitary interpretation (i.e., affecting the characteristics by becoming a component or otherwise...).   n75
Both courts accepted the latter construction even though the statute could hardly be characterized as unambiguous.   n76 They observed that BCO neither logically appeared to constitute a "component" in the first place,   n77 nor was there any evidence to show that BCO affected the characteristics of the gelatin and glycerin.   n78 If the FDA's interpretation were valid, it could recharacterize every processed food as a food additive, thereby shifting the burden of proving safety onto the processor. This would effectively read the 1938 provisions governing food out of the statute even though Congress failed to amend them in 1958.
This judicial gloss on the food additive definition may well be confined to  [*348]  its facts. Insofar as it suggests that a "component" must meaningfully affect the characteristics of the food, it surely would dramatically shrink the universe of food additives. It is not clear, for instance, whether, under the courts' interpretation of the definition of food additive, the gelatin and glycerin (or an equivalent plasticizer) in the BCO capsules would fall within the FDA's premarket approval authority.   n79 Earlier cases had sustained the Agency's efforts to regulate similar products as food additives. Indeed, when a food contains more than one ingredient, each ingredient may be deemed a food additive, as the courts in the BCO cases conceded.   n80 For example, one federal district court accepted the FDA's contention that BCO was an additive when encapsulated with fish oil, vitamins, and minerals.   n81 Another court recently decided that evening primrose oil was a food additive when encapsulated with Vitamin E.   n82
Because Congress has effectively neutered the Agency's authority to  [*349]  regulate dietary supplements, these definitional issues may well become less important in the future. In 1994, Congress amended the FD&C Act to address dietary supplements.   n83 If a substance can be classified as a "dietary supplement" or as an "ingredient" in such a supplement, it is excluded by statute from the definition of the term "food additive."   n84 Unless the substance is a "new dietary ingredient" (because it was not marketed before October 15, 1994),   n85 a manufacturer or processor would only have to file a premarket notification with the FDA seventy-five days prior to commercial use.   n86 Nonetheless, skeptical judicial interpretations of the statute's food additive definition will continue to limit the FDA's choice of regulatory responses to more conventional foods and food components.
B.
 
 Generally Recognized as Safe
 
1.
 
 The GRAS Concept
 
 The statutory definition of "food additive" only covers, and thus the requirements for food additives only apply to, a substance that "is not gener [*350]  ally recognized... to be safe under the conditions of its intended use."   n87 Thus, in the peculiar vocabulary of the statute, a substance that becomes a component of a food (even as an ingredient) is not a "food additive" if it is generally recognized as safe for that use. A substance may be GRAS if there is "general" scientific agreement about its safety based either on appropriate testing or on common use in food prior to 1958.
The GRAS exception raises a number of obvious interpretive puzzles. The statute provides no further elaboration about the required degree of scientific agreement, the types of scientific procedures which could provide the necessary predicate for such consensus, or, for substances in use before 1958, the required nature and extent of such prior use. For instance, how could a substance become GRAS without experience based on common prior use? Did Congress intend to allow manufacturers of new food-use substances the option of asking non-FDA scientists for their evaluation and possible stamp of approval?   n88 As discussed below, this has become a frequent practice.
Because the GRAS exception was included in every one of the numerous bills considered by Congress,   n89 the legislative history sheds additional light on these and other questions. Although not technically a "grandfather clause" (which might have permanently exempted all substances used in food prior to the enactment date),   n90 the GRAS exception attempts to minimize the burden that otherwise would have fallen on both the food industry and the government if the FDA had to evaluate and affirmatively approve all common sub [*351]  stances used in food.   n91 In addition, for substances in use in 1958 that were not regarded as GRAS, and therefore were subject to regulation as food additives, Congress initially provided a transitional period of up to thirty months to satisfy the new premarket approval requirements.   n92
In adopting the GRAS concept for substances added to food, Congress was drawing on an established model. The FD&C Act already included similar GRAS language in the definition of the term "new drug"   n93 and in the Pesticide Residues Amendment of 1954.   n94 Although witnesses at the hear [*352]  ings conceded that the phrase was inherently ambiguous, they thought it could sensibly be applied to food ingredients too.   n95 Their confidence notwithstanding, the FDA and reviewing courts have struggled to make sense of the GRAS exception.   n96
It is generally agreed that GRAS requires a fairly high level of scientific consensus.   n97 The FDA's implementing regulations, promulgated nearly two  [*353]  decades after passage of the Food Additives Amendment, provide:

General recognition of safety based upon scientific procedures shall require the same quantity and quality of scientific evidence as is required to obtain approval of a food additive regulation for the ingredient. General recognition of safety through scientific procedures shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data and information.   n98
 
 In 1997, the FDA proposed clarifying amendments to these regulations, requiring that evidence of GRAS relate to the conditions of intended use.   n99 Accordingly, general recognition of the safety of a substance in a different product, or at a different level, would not suffice.   n100 Furthermore, as the  [*354]  statutory text suggests, the exception turns not on safety per se but on recognition of safety by scientific experts.   n101 Testimony that there was no evidence a substance posed any risk to health would not establish its GRAS status,   n102 at least not unless coupled with evidence of common prior use.   n103
To base GRAS status on common use prior to 1958, manufacturers would have to show extensive use.   n104 For many years, the FDA categorically refused to recognize prior use outside of the United States.   n105 This policy,  [*355]  however, ultimately did not survive judicial challenge.   n106 The revised regulations provide that foreign use before 1958 may support GRAS status, but only if the manufacturer identifies readily available and corroborated information about such use.   n107 In addition, GRAS status based on prior foreign use must satisfy domestic safety criteria.   n108 Accordingly, the FDA urges any person who wishes to predicate GRAS status on a history of prior foreign use to seek its concurrence.   n109
2.
 
 The FDA's GRAS Lists
 
 During the congressional hearings preceding enactment of the Food Additives Amendment, the FDA submitted a "partial" list of substances that it would regard as GRAS. The list included items such as butter, coffee, cream, gelatin, lard, lemon juice, margarine, molasses, mustard, olive oil, paprika, pepper, salt, sugar, vinegar and wine.   n110 And, in the first several  [*356]  years after enactment of the Food Additives Amendment, the Agency proceeded to list in its regulations hundreds of additional ingredients as GRAS.   n111 The FDA's original GRAS lists included, for example, ascorbic acid, calcium chloride, caramel, and sodium phosphate.   n112
Because these early inventories emerged without any rigorous scientific assessment of the existing safety data, much less any data derived from contemporary safety assessment methods (as exposed by the later report of a study linking the artificial sweetener cyclamate to cancer   n113 ), the FDA in 1969 initiated a systematic review to resolve the GRAS or food additive status of a number of substances commonly added to food.   n114 The Agency designated several categories of food ingredients for this review: substances  [*357]  of natural biological origin widely consumed as food before 1958 but subsequently modified by new production processes or selective breeding; distillates, isolates, extracts and reaction products of GRAS substances; and substances not of natural biological origin or intended for consumption for other than their nutrient properties.   n115
The National Academy of Sciences (NAS) undertook ingredient usage surveys,   n116 and, in 1972, at the FDA's urging, the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology (FASEB) established a Select Committee on GRAS Substances (SCOGS) to review the available scientific literature.   n117 Over a period of ten years, SCOGS forwarded to the Agency detailed reports on 468 food substances (of which 422 were direct ingredients).   n118 This Select Committee, after creating an array of five standardized recommendations,   n119 concluded that seventy-two percent of the food substances under review should remain GRAS and only one percent should immediately become subject to food additive requirements.   n120 The FDA had planned to review each of these reports and undertake appropriate rulemaking. Fifteen years after receiving the last SCOGS report, however, it has not completed its GRAS list review.   n121
A number of substances have been added to the GRAS list as a result of  [*358]  the FDA's comprehensive review. As of 1997, the Agency has formally recognized almost 200 separate ingredients as GRAS for direct use in food.   n122 It concedes, however, that its GRAS lists are not exhaustive: "Because of the large number of substances the intended use of which results or may reasonably be expected to result, directly or indirectly, in their becoming a component or otherwise affecting the characteristics of food, it is impracticable to list all such substances that are GRAS."   n123
GRAS substances are not exempt from all FDA controls.   n124 For instance, users must comply with any specific usage limitations in a GRAS affirmation regulation.   n125 If no specific limitations apply, GRAS status is lost only if the conditions of use differ significantly from those providing the basis for eligibility.   n126 In addition, the FDA cautions, "new information may at any time  [*359]  require reconsideration of the GRAS status of a food ingredient."   n127 To revise or repeal an existing GRAS regulation, the FDA would need to follow only notice-and-comment rulemaking procedures.   n128 In contrast, revision or repeal of a food additive regulation would require more cumbersome procedures, including an opportunity for a formal evidentiary hearing.   n129
3.
 
 Private GRAS Determinations
 
 The FDA has acknowledged, albeit with some reluctance, that the maker or user of a substance may reach its own conclusion that a particular food use is GRAS and, therefore, exempt from food additive approval requirements.   n130 Neither the statute nor any regulation currently requires that the Agency be advised of such private GRAS determinations. In seeking such a  [*360]  determination, manufacturers have sometimes commissioned safety reviews by nongovernmental scientific organizations. FASEB, for example, has conducted a handful of private GRAS reviews in recent years.   n131 For instance, Procter & Gamble contracted with FASEB to review the safety of caprenin, a new reduced calorie fat-substitute. On the basis of FASEB's report, the company determined that caprenin was GRAS, filed a GRAS affirmation petition with the FDA, and promptly began selling it to food processors, without any objection from the Agency.   n132 Similarly, Nabisco Foods commissioned a FASEB review of salatrim, another fat-substitute, which the company subsequently brought to market on the basis of a GRAS self-determination.   n133
To perform a commissioned review, FASEB's LSRO assembles an ad hoc panel of experts from several different scientific disciplines. These experts usually are drawn from among FASEB's more than 40,000 members, and they are retained and paid by LSRO to serve as independent consultants.   n134 The expert panels prepare study reports which are "peer-reviewed by an independent internal FASEB committee for clarity, objectivity, and scientific integrity..., [and] the reports of each study are published in scientific journals or are made available publicly."   n135
FASEB's specific procedures depend on the terms of its agreement with  [*361]  the sponsor.   n136 The FDA often has contracted with the LSRO to conduct safety reviews of particular substances or to formulate recommendations on broad scientific questions. These government contracts often set forth precise timetables for the solicitation of public input, the scheduling of meetings, and the completion of draft and final reports. As mentioned previously, the original GRAS list review required the creation of a special standing committee (SCOGS) charged with that enormous task, and FASEB managed to review almost 500 food-use substances in just ten years. The organization's more recent safety reviews of BHA and MSG, however, took more than two years to complete and each cost the Agency approximately $ 300,000.   n137
A few industry associations have created their own expert panels to assess the GRAS status of food ingredients. The most notable example is the review system operated by the Flavor and Extract Manufacturers' Association (FEMA) for nearly forty years.   n138 FEMA's project initially surveyed the industry to determine the usage of different flavoring substances. The Association then established a permanent panel - composed of independent experts from various disciplines, including toxicology and biochemistry - to evaluate scientific literature reviews (SLRs) assembled for its consideration by the FEMA staff.   n139 The objective was to assess the GRAS status of the flavoring  [*362]  substances reported to be in use. The Expert Panel's reports have been published periodically.   n140
Since the inception of this project in 1959, FEMA has considered more than a thousand flavoring substances.   n141 The Expert Panel's initial set of reviews identified 1,118 substances as GRAS based on prior safe use and six newer substances as GRAS based on the available scientific information.   n142 The FDA incorporated only 277 of these flavors in its own GRAS list,   n143 but it designated another 846 FEMA-reviewed substances as approved food additives on the strength of the existing safety data, without requiring the filing of separate petitions.   n144 Moreover, the FDA has never challenged the marketing or use of a flavor that FEMA has identified as GRAS.   n145
 [*363]  Although the law presents no impediment, making a unilateral GRAS determination carries regulatory risks. On occasion, when it has disagreed with a company's conclusion that a substance is GRAS, the Agency has pursued enforcement proceedings.   n146

The theoretical freedom of food processors to determine initially which ingredients require FDA licensure has little practical significance for widely used ingredients. Very few processors will purchase ingredients for which the supplier cannot provide documentation of FDA approval or acknowledgment as GRAS. Should a manufacturer independently conclude that an ingredient is GRAS it runs the risk that FDA may disagree and initiate regulatory action against its product.   n147
 
 There is some disagreement over which party bears the burden of proof on the question of GRAS status in such a case. A few commentators have argued that the government would have to prove that a substance is not GRAS,   n148 but the FDA believes that the burden would rest with the manufacturer to establish general recognition of safety once it was called into question.   n149 Though not authoritatively resolved, this is not a trivial issue.
 [*364]  The FDA has established a formal procedure by which an interested person may seek the Agency's affirmation that a substance qualifies as GRAS.   n150 The filing of a petition for GRAS affirmation effectively protects the user of the substance from enforcement action during the pendency of the FDA's review.   n151 Because of the costs - in money and particularly in time - of seeking food additive approval, the GRAS exception has come to play an increasingly important role in the regulatory scheme, for it permits the introduction of safe food substances without affirmative Agency action.   n152
C.
 
 Prior Sanctions Exception
 
 The statutory definition of "food additive" also excludes "any substance used in accordance with a sanction or approval granted prior to the enactment of this paragraph pursuant to this Act, the Poultry Products Inspection Act... or the Meat Inspection Act."   n153 The enactment date of the Food Additives Amendment was September 6, 1958. Accordingly, only substances "sanctioned" prior to that date (nine months later than the cut-off for prior  [*365]  use GRAS)   n154 qualify for this exclusion.   n155 A "prior sanction" may be either formal (e.g., a food standard of identity that refers to an ingredient) or informal, usually in the form of correspondence from an agency official.   n156 The burden of demonstrating that a substance is covered by a prior sanction rests on the person who seeks to make use of this exception.
Just as GRAS status is use specific, a prior sanction only covers the particular food use of a substance that was previously approved.   n157 The FDA has published regulations formally acknowledging a number of prior sanctions. Except for nitrites, which were approved by the Department of Agriculture as a color fixative and preservative in cured meats,   n158 the only prior sanctions listed by the FDA cover substances used in food packaging materials.   n159 The Agency recognizes that documentation of other sanctions may exist,   n160 and it invites interested persons to request publication of any such  [*366]  sanction, but it also asserts that a prior sanction will lapse if not brought to the FDA's attention once it undertakes consideration of a substance's food additive status.   n161
The FDA always remains free to reconsider a GRAS determination,   n162 but a prior sanction exception to "food additive" status should in principle be permanent.   n163 If the FDA once approved the use of a substance, it may reconsider that decision but it cannot change the historical fact that the decision  [*367]  was made.   n164 Even if a prior sanction may not be erased, however, it does not represent a permanent safe harbor for a substance. The FDA may seek to revoke the original approval.   n165 Moreover, if the FDA determines that a substance "may render [food] injurious to health,"   n166 it may challenge its sale even if the substance is exempt from food additive status.   n167 In short, a food containing a prior sanctioned substance remains a "food" subject to the FD&C Act's more general prohibitions against adulteration.   n168
III.
 
 Approval Procedures
 
 The definitional issues discussed above are important because they can decisively affect the regulatory status of a substance.   n169 Under the Act, a food  [*368]  shall be deemed to be adulterated, and thus subject to enforcement action, "if it is, or it bears or contains, any food additive which is unsafe within the meaning of section 409."   n170 And Section 409 provides that a food additive shall be deemed to be "unsafe" unless its particular use has been approved in a regulation.   n171 Thus, if a substance qualifies as a food additive, it may not be used unless and until the FDA specifically grants approval.
This Part describes the procedures that must be followed to secure FDA food additive approval; the safety standards that the Agency applies are discussed in the next Part. Because of the complexities of the food additive petition process, producers and users of new ingredients have begun to rely more heavily on a parallel mechanism, created by the FDA itself, that permits these producers and users to request that the Agency affirm their own judgment that a substance is safe. A comparison of the two review procedures reveals that these so-called "GRAS affirmation" petitions have not elicited more rapid administrative review. But, there is an important practical difference, because a substance whose GRAS status the FDA is asked to affirm may be used before the FDA acts on the petition. Some critics have suggested that all direct additives should undergo food additive review,   n172 but such a requirement would surely overwhelm the Agency's current resources. Others favor increased reliance on the GRAS exception to allow the FDA to allocate its resources more efficiently to review difficult food additive petitions.   n173 An evaluation of these and other suggested reforms must await a  [*369]  fuller description of existing procedures and, in Parts V and VI, of the Agency's practice over the years.
A.
 
 Food Additive Petitions
 
 Normally, in response to a petition filed by the manufacturer or other interested person requesting such an action, the Agency issues a regulation authorizing one or more uses of a food additive.   n174 A food additive petition must contain information identifying the substance, its proposed use (as reflected in its labeling), all relevant data concerning its effect on food and residue detection methodologies, and full reports of safety studies.   n175 Certain confidential information provided to the Agency, including protected trade secrets, are exempt from public disclosure.   n176
Pursuant to its regulations, which amplify the statutory procedures,   n177 the FDA must notify a petitioner within fifteen days of receipt whether it accepted the petition for filing.   n178 Within thirty days of accepting a petition for  [*370]  filing, the FDA must publish a notice of filing in the Federal Register containing the name of the petitioner and a brief description of the proposal.   n179 Neither the statute nor the FDA's regulations, however, make provision for public comment following the notice of filing and before issuance of a decision.   n180 Although the provisions governing judicial review of FDA decisions prompted substantial congressional debate,   n181 the legislative history of the Food Additives Amendment provides little guidance about the administrative procedures that the Agency must follow in reviewing food additive petitions.   n182 Over the years, the FDA has not regularly invited the submission of  [*371]  comments prior to the publication of an order.   n183
Although neither the statute nor the regulations so require, however, the Agency now tacitly allows a post-filing opportunity for public comments on petitions,   n184 and it explicitly invited such comments in the case of olestra.   n185 Preapproval comment became feasible after the Agency decided in 1974 that the safety data contained in food additive and other petitions should be made available to the public. In fact, the Agency's desire to allow public comment at this stage appears to have been one reason for changing its public information regulations.   n186
 [*372]  Upon the acceptance (or refusal) of a food additive petition for filing, virtually the entire petition is available for public disclosure.   n187 The petition thus becomes an easy target for comments from interested persons, both from concerned scientists and public interest groups and from competitors whose primary objective may be to delay approval of the petitioner's product.   n188 In several recent cases, taking advantage of the de facto comment period, parties have made anonymous submissions late in the FDA's internal review process, which have had the effect of delaying Agency decisions.   n189 If the FDA plans to accept and respond to pre-approval comments, it should impose a strict time limit for filing.   n190
 [*373]  Under the Act the FDA must, within ninety days of filing, issue a regulation approving the requested use or deny the petition and provide the petitioner with the reasons for such action. If the Agency needs more time to study the petition, it may notify the petitioner that it is extending the review period for not more than ninety additional days.   n191 Because the evaluation of a food additive petition draws on a number of scientific and technical disciplines within the Agency, meeting the statutory deadlines necessitates parallel rather than sequential reviews of a petition.   n192 Assuming that the FDA has claimed an extension, it must issue a final order granting or denying approval of a food additive petition within 180 days of filing.   n193 In practice, however, this deadline is almost never met.   n194
The primary opportunity for public debate on a food additive petition  [*374]  comes only after the FDA issues its order.   n195 Within thirty days, "any person adversely affected by such an order may file objections thereto" and request a formal evidentiary hearing.   n196 This provision does not make a hearing automatic whenever objections are filed; the FDA may dispense with a public hearing if objections fail to raise any material factual issues.   n197 In fact, very few food additive orders have triggered requests for a hearing or, for that matter, appeals for court review. In the FDA's history, only two direct food additives have been the subject of formal hearings.   n198
 [*375]  Sponsors of novel direct food additives currently must spend $ 20 million on average for toxicological and other safety research in pursuit of FDA approval.   n199 Unlike an application to market a new drug, whose approval gives the sponsor an exclusive license to sell the product, a food additive petition results in the promulgation of a public regulation authorizing the sale or use of the additive by any person who wishes to do so.   n200 In this respect, a food additive regulation more closely resembles an FDA monograph for an over-the-counter (OTC) drug product.   n201
The sponsor of a food additive may benefit from any remaining patent term, if the substance was patentable.   n202 As FDA reviews have slowed,  [*376]  however, sponsors may find relatively little patent life left after approval. Congress may extend the life of a patent for a specific food additive by special legislation, but the FD&C Act provides no period of market exclusivity for the sponsor of an approved food additive, in contrast with its treatment of approved new drugs.   n203 For this reason, it has been suggested, food ingredient manufacturers may refrain from pursuing innovations that will necessitate the filing of a food additive petition.   n204
To generate the safety data required for approval, the sponsors of an additive must be able to provide researchers access to the substance. Some of the necessary studies may be performed in-house, but more advanced toxicological studies are likely to be done by independent research facilities. An unapproved food additive may be shipped in commerce only if exempted by the Agency as "intended solely for investigational use by qualified experts when... consistent with the public health."   n205 Pursuant to FDA regulations, an exemption is automatically available if the unapproved food additive is intended only for in vitro tests or studies in laboratory animals and is labeled as "Not for use in humans."   n206 Unlike new drugs and medical devices, new food additives are not required to be administered to human subjects under an investigational use exemption.   n207 Human studies are not uncommon,  [*377]  however, and generally the FDA has not objected to such studies so long as investigators comply with its informed consent and other requirements for the protection of human subjects.
B.
 
 GRAS Affirmation Petitions
 
 As explained above, even if the maker or user of a substance is reasonably confident that scientists generally would consider it safe, there is no assurance that the FDA (or a court) will agree with such a conclusion unless the substance previously has been listed or affirmed as GRAS. Some private GRAS determinations represent a safer bet than others. The Agency appears to defer routinely to FEMA's assessments of flavoring substances, perhaps because they are unlikely to pose a serious hazard at the extremely low levels they are used in food. But a manufacturer that markets a food containing a novel and poorly studied ingredient faces a significant risk that the FDA will challenge the product on the ground that it contains an unapproved additive.
Rather than risk such a challenge, the sponsor or user of the substance is always free to seek the FDA's concurrence that it is GRAS. Indeed, food processors may demand official concurrence before agreeing to purchase a new ingredient.   n208 After several years of responding to such requests informally,   n209 the FDA published specific procedures for seeking what it called "GRAS affirmation."   n210 While food additive petitions are subject to procedures prescribed by Congress, GRAS affirmation is governed entirely by procedures developed by the FDA.   n211
A person seeking FDA affirmation that a substance is GRAS must file a citizen petition containing information demonstrating that the substance satisfies the Agency's GRAS criteria. A petition must include a detailed description of the substance (including names, formulae, food grade material speci [*378]  fications, and descriptions of its quantitative composition and the manufacturing process), a history of its use (including dates of use, data on past use, foods in which it was used, levels of use, and purposes), a description of available analytical methods, and information concerning its safety and functionality.   n212 The information concerning a substance's safety and functionality may include published scientific literature (or complete bibliographic references) or evidence that it is identical to a GRAS counterpart of natural biological origin.   n213
Within thirty days of receiving a petition, the FDA must publish in the Federal Register a notice of filing and allow a sixty-day period for public comment.   n214 After considering the petition and any comments, the FDA has a choice: If it finds the evidence of GRAS status "convincing," the Agency will publish an order adding the substance to the list of other substances whose GRAS status it has affirmed; otherwise, it will publish a ruling that the substance is considered a food additive.   n215 The regulations establish no deadline for final action on a GRAS affirmation petition,   n216 and the FDA has  [*379]  been notoriously slow in acting on such submissions.   n217 During the last decade, the Agency has taken more than seven years on average to rule on GRAS affirmation petitions.   n218 Thus, the process appears to provide no short-cut over the food additive petition process.   n219 GRAS affirmation has remained attractive, however, because a sponsor is permitted to, and typically does, market the substance while its petition is awaiting a formal decision.   n220
In early 1997, the FDA proposed to eliminate the GRAS affirmation petition procedure and replace it with a simplified GRAS notification process.   n221 Under the proposed new procedure, a sponsor could submit a GRAS exemption claim, containing specified information (both favorable and unfavorable), to which the Agency would respond within ninety days by a letter ac [*380]  knowledging receipt and identifying any questions it had about the claim.   n222 The Agency's preamble made clear, however, that an acknowledgment letter that raised no objections would have little authoritative weight. The FDA would not "conduct its own detailed evaluation of the data that the notifier relies on to support a determination that a use of a substance is GRAS or to affirm that a substance is GRAS for its intended use."   n223 Sponsors who file a notification would "receive as a benefit a response that documents the agency's awareness of the determination."   n224 The Agency emphasized that, like the procedure it would replace, the new GRAS notification procedure would be voluntary and that sponsors who submitted notifications would remain free to market or use substances without waiting for an official response.   n225 Indeed, the Agency specifically invited comment on the option of responding only to those notifications about which it had questions or concerns.   n226
The FDA contended that this notification process would encourage more firms to inform it of GRAS self-determinations,   n227 but this seems unlikely. A  [*381]  GRAS notification may require less effort to draft than an affirmation petition, but the compilation and analysis of supporting data would require comparable effort.   n228 Moreover, current petitioners for GRAS affirmation seem most interested in the FDA's acceptance of their petitions for filing, which is now essentially automatic. In contrast, the Agency would scrutinize GRAS notifications more carefully at the outset,   n229 increasing the chances that reviewers will raise questions. Of course, FDA reviewers may raise questions about GRAS affirmation petitions as well, but they allow a response from a petitioner. Under the FDA's new proposal, however, a letter raising questions about a GRAS notification apparently would not invite a response or provide any procedure for resolving disagreements. Such a communication would imperil the sponsor's assertion that the substance was GRAS, even if the FDA did not publish a notice calling for a food additive petition.   n230 Sponsors of new ingredients may regard these risks as not worth the possible benefit of a "no objection" letter from the FDA and simply decide not to notify the Agency. This behavior would, of course, reduce the Agency's workload, but this would also deprive it of information about private GRAS determinations.
 [*382] 
C.
 
 Interim Food Additives
 
 In 1972, the FDA promulgated regulations creating a new transitional category for GRAS substances whose safety has been called into question.   n231 The regulations emerged from the FDA's successful effort to deal with brominated vegetable oil (BVO), a stabilizer in fruit-flavored beverages.   n232 Under the regulations, the Agency may declare a substance previously considered GRAS to be an "interim" food additive

when new information raises a substantial question about [its] safety or functionality... but there is a reasonable certainty that the substance is not harmful and that no harm to the public health will result from the continued use of the substance for a limited period of time while the question raised is being resolved by further study.   n233
 
  [*383]  In promulgating such a regulation, the FDA must follow the procedures applicable to the issuance of a final food additive order;   n234 however, the interim order may be summarily revoked. The regulation may require compliance "with whatever limitations the Commissioner deems to be appropriate under the circumstances."   n235
The primary condition for continued marketing is a promise by at least one sponsor of the substance to undertake additional studies to resolve the open issue(s).   n236 If, within sixty days, at least one sponsor has not certified that "adequate and appropriate" studies have been undertaken to resolve the issue(s) raised, an order shall be published immediately to revoke the interim food additive regulation.   n237 The failure to submit progress reports every six months may also be the basis for revoking the regulation.   n238 "Promptly upon  [*384]  completion of the studies undertaken on the substance, the Commissioner will review all available data, will terminate the interim food additive regulation, and will either issue a food additive regulation or will require elimination of the substance from the food supply."   n239
Since 1972, the FDA has regulated the following substances as interim food additives: acrylonitrile copolymers, mannitol, brominated vegetable oil, and saccharin.   n240 In each case, the Agency's regulation called for additional toxicological studies, though with different levels of specificity.   n241 With the exception of nitrites used in certain curing premixes,   n242 no listed interim food additive has been made subject to permanent restrictions or an outright prohibition. Indeed, the FDA recently revised the mannitol regulation to authorize an additional method of manufacture without commenting on the fact that the "interim" rule was over two decades old.   n243 Apart from saccha [*385]  rin, which has been the subject of a continuing regulatory moratorium imposed by Congress,   n244 the FDA's inaction on these interim food additives seems legally problematic.   n245 Nevertheless, both the Agency and the food industry seem content to leave these substances in an indefinite regulatory limbo.   n246
 [*386] 
IV.
 
 Approval Criteria
 
 The previous discussion has focused on which substances must undergo food additive approval and the FDA's processing of food additive and GRAS affirmation petitions. Ultimately, the Agency must rule on such petitions and determine whether a substance is safe for the contemplated use in human food. The criteria for this critical determination raise fundamental questions of both science and policy. The definitional and procedural issues are not simply a prelude, however, because choices about substantive safety criteria cannot be disentangled entirely from decisions about their appropriate reach and mechanisms for their efficient application.
A.
 
 The General Safety Standard
 
 The Act provides that the FDA may not approve a food additive for a particular use unless the data presented by the sponsor establish that the additive is "safe" for that use.   n247 Unlike most medicines and medical devices, food ingredients are likely to be consumed by all segments of the population, including children and the elderly, potentially for their entire lifetimes. This difference in cumulative exposure, coupled with their less obvious, and in any case less compelling, benefits, helps explain why the FDA is more conservative in assessing the safety of food additives.   n248
The House Report accompanying the bill that would become the Food Ad [*387]  ditives Amendment of 1958 offered the following explanation of the statutory safety standard:

The concept of safety used in this legislation involves the question of whether a substance is hazardous to the health of man or animal. Safety requires proof of a reasonable certainty that no harm will result from the proposed use of an additive. It does not - and cannot - require proof beyond any possible doubt that no harm will result under any conceivable circumstance. This was emphasized particularly by the scientific panel which testified before the subcommittee. The scientists pointed out that it is impossible in the present state of scientific knowledge to establish with complete certainty the absolute harmlessness of any chemical substance.   n249
 
 Thus, for approval of a food additive, the statute does not demand confirmation of safety under all possible conditions of use or a guarantee of safety for every intended use.   n250 In its implementing regulations, the FDA has defined GRAS status as requiring the same quantity and quality of data supporting safety as needed for food additive approval - unless the substance was in common use prior to 1958.   n251
As explained previously, courts have interpreted the safety standard contained in the Act's general adulteration provisions as requiring the government to prove that an added substance poses a reasonable possibility of harm to consumers.   n252 During hearings on the food additive legislation, the Administration objected to the enactment of a definition of "safe" that explicitly used a "reasonably probable" standard for deciding whether to approve the use of a substance in food.   n253 As the sponsor of the bill reiterated on the  [*388]  floor of the House, the legislation would not require proof of safety "beyond any possible doubt" but rather a practical certainty that no harm would result.   n254
In its original implementing regulations, the FDA defined safe to demand "convincing evidence which establishes with reasonable certainty that no harm will result."   n255 In 1971, the Agency revised, and arguably relaxed, this definition to require proof of "no significant risk of harm."   n256 It revised the definition again in 1976 to track the legislative history quoted previously.   n257 The FDA's current regulations define "safe" as meaning "that there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use."   n258 Although one could well argue that the Agency's original interpretation - demanding "convincing evidence" - is entitled to greater deference,   n259 no court has di [*389]  rectly addressed the current interpretation.   n260
In explaining the safety standard applicable to food additives, the FDA's regulation tracks the factors that Congress enumerated.   n261 The Agency says it will follow "the principles and procedures for establishing the safety of food additives stated in current publications of the National Academy of Sciences-National Research Council."   n262 For example, unless presented with evidence justifying a different margin of safety, the Agency will apply a safety factor of 100 in extrapolating from studies in laboratory animals.   n263 The acceptable daily intake (ADI) of an additive is thus ordinarily set at /100th (as adjusted for body weight) of the lowest no effect level observed in animal studies.   n264 The estimated daily intake (EDI) of the additive, based  [*390]  on its intended use(s) and surveys of likely consumption patterns,   n265 may not exceed the ADI.   n266
The FDA also has described "acceptable" study designs for generating the data necessary to support the approval of a food additive, while claiming that it wished to avoid imposing rigid guidelines.   n267 Although testing methods recommended by the NAS-NRC are presumptively acceptable, a petitioner may follow alternative procedures shown to be equally reliable.   n268 In addition, the regulations provide that upon request the Agency will advise "whether [it] believes the experiments planned will yield data adequate for an evaluation of the safety of the additive."   n269 Petitioners have not, however, routinely sought, nor has the FDA customarily offered, meetings to reach agreement on the types of tests that the Agency will expect to support a decision on approval.
Several years ago, the FDA announced plans for a "cyclic review" of all approved food additives, in effect to assure that its original safety decisions were still sound.   n270 Eventually, however, it discontinued work on what very quickly became a gargantuan task.   n271 It was in the context of this aborted  [*391]  effort that the FDA in 1982 released its Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food (which is simply referred to as the Redbook).   n272 In 1993 the Agency announced the availability of a revised draft (Redbook II), which was "intended to provide guidance to petitioners regarding criteria used by FDA for toxicological safety assessment of direct food additives and color additives, and in the agency's evaluation of the generally recognized as safe (GRAS) status of food ingredients."   n273 Five years later, work to finalize Redbook II continues.
Under the FDA's procedural regulations, study guidelines of the sort embodied in the Redbook are binding on the Agency only in the limited sense that it commits itself to accept submissions that conform with the guidelines. The regulations expressly disavow any intention to impose binding obligations on regulated parties.   n274 Accordingly, the FDA has stated that the Redbook does not mandate the submission of particular toxicology information in food additive petitions.   n275 In practice, of course, petitioners hesitate to devi [*392]  ate from the guidelines for safety testing for fear that any departure might result in delay or, worse, disapproval.   n276
Agency scientists from several disciplines, including chemistry, toxicology, nutrition, and microbiology, typically are involved in the review of a food additive petition.   n277 This assessment of safety calls for the exercise of professional judgment. As one commentator explained, the "FDA's approach is better characterized as an attempt, using the best, but admittedly imperfect, tools science makes available, to manage the uncertainty inherent in food safety evaluation."   n278 Agency reviewers have been criticized, however, for excessive conservatism, even paralysis, in the face of such uncertainty.   n279 Whether or not such criticisms are well placed, the evaluation process is usually quite protracted.   n280
Both Congress and the FDA have separately wrestled with the question of  [*393]  what role, if any, a consideration of an additive's benefits should play in applying the general safety standard. Early versions of the 1958 legislation would have required the Agency to find that, in addition to being safe, an additive had some "functional value."   n281 In response to industry opposition to such a formulation,   n282 the final legislation required the FDA to consider functionality only in circumstances where assurance of safety necessitated a quantitative limitation on use. The Agency could limit use to levels sufficient to accomplish an additive's intended effect but was not to make any judgment about its social value.   n283 In short, an additive that was shown to be safe could not be refused approval on the ground that it offered no significant benefits.   n284
Nearly twenty years later, however, when it revised its food additive and GRAS regulations, the FDA suggested that social utility is "inevitably a fac [*394]  tor" in determining safety.   n285 This trial balloon had a short life. Just three years later, a new Commissioner expressly disavowed this statement in a decision withdrawing DES as a livestock growth promotant.   n286
The FDA is not faced with an all-or-nothing choice in passing on food additive petitions. Congress expressly authorized the Agency to impose conditions on its approval to ensure safe use. These may include limits on the types of food in which an additive may be used and quantitative restrictions on the amount that may be added.   n287 Labeling requirements represent another type of condition that the FDA may consider. Although the Agency relies widely on labeling requirements to control the sale and use of products subject to its jurisdiction, it has mandated warnings or special disclosure requirements for food products rather infrequently.   n288 Indeed, the FDA's  [*395]  power to impose such requirements is not clear. The Agency does enjoy broad authority to regulate the labeling of food products generally, under the statute's specific prohibitions against misbranding, but Section 409 does not appear to authorize it to condition approval of an additive on the inclusion of special labeling on the finished food.   n289
B.
 
 Carcinogenicity and the Delaney Clause
 
 The general safety standard for food additives is modified by the Delaney clause, a famous proviso which directs that "no additive shall be deemed to be 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."   n290 The Delaney clause is surely the most discussed, but perhaps the least used, provision of the FD&C Act.   n291 Recent legislation governing tolerances for pesticide residues reflects congressional skepticism about the Delaney clause's rigidities, but it left the proviso fully applicable to food additives.   n292 The interpretation and potential impact of the Delaney clause have shaped, and may continue to  [*396]  influence, the debate over the FDA's food additive approval process.   n293
The Delaney clause was added to the Food Additives Amendment late in the legislative process. The bill approved by the House Commerce Committee did not contain an anti-cancer clause, but the Committee, at Representative Delaney's persistent urging, added the proviso to the bill before it was approved on the House floor.   n294 Although drafters of the 1958 legislation assured that the Delaney clause was no stricter than the safety standard for additives,   n295 its application has proven far more troublesome in practice.
The language of the clause indicates that its congressional authors contemplated that the FDA would exercise scientific judgment in assessing the rela [*397]  tionship between exposure to a chemical and a carcinogenic response.   n296 The FDA's approach historically has conformed with this expectation. Indeed, the Agency has played a leading role within the federal government in bringing scientific advances to bear in evaluating the carcinogenicity of chemicals.   n297
The FDA's own practice over the years reveals a determination to rely on the best contemporary scientific understanding of cancer risk assessment. The Agency does not accept, or act upon, the proposition that a mere temporal association between administration of a chemical to test animals and an elevation in tumor incidence justifies, much less requires, a finding that the chemical "induces cancer." Study results suggesting such an association are subject to critical evaluation, and any conclusion is the product of an assessment of many different scientific elements. Evidence that a substance is associated with a statistically significant increase in tumors compared with concurrent controls is a necessary, but not sufficient, basis for concluding that it "induces cancer."
Single studies revealing significant carcinogenic activity are not necessarily decisive and do not obviate an assessment of the overall weight of the  [*398]  evidence. For example, if the increase of tumors in test animals falls within the range historically observed in the species, the FDA is likely to question the significance of the test results. The Agency frequently looks beyond quantitative analysis of tumor incidence to consider, based on qualitative scientific evidence, whether the effects observed are biologically significant: "Determination that the incidence of neoplasms increases as the result of exposure to the test compound requires a full biological, pathological, and statistical evaluation. Statistics assist in evaluating the biological conclusion, but a biological conclusion is not determined by the statistical results."   n298 Thus, the Agency considers relevant biological and biochemical data in determining whether a substance "induces cancer," including information on a variety of other biological functions such as dose response, tumor progression, and tumor latency, as well as the overall evidence from other studies.   n299
In approving the color additive FD&C Blue No. 2, for example, the FDA stated that it had "consistently asserted that statistical factors must be analyzed in conjunction with biological factors in determining what, if any, conclusions can be drawn from a study."   n300 The Agency relied on a similar weight-of-the-evidence analysis when it approved D&C Green No. 5.   n301  [*399]  More recently, the FDA ruled that the sweetener acesulfame potassium is not a carcinogen based on "the weight of all of the evidence; no single point provided complete proof in determining the question of carcinogenicity."   n302 In denying a hearing, the FDA defended its conclusion that the incidence of mammary gland tumors in female rats was not treatment-related by pointing out that these tumors are common in old-age rats of the strain used in the bioassays, that the incidence of these tumors fell within the range for historical controls, and that there was no evidence of a dose-response relationship or evidence of progressive tumor stages.   n303
The FDA also once explained that, although some common substances fed at exaggerated levels may cause tumors through a secondary mechanism, "these foods and drugs are not, by reason of their capacity to induce liver damage when abused by being consumed at high levels, properly classified as carcinogenic because of their potential association with a higher rate of liver cancer."   n304 Over the last two decades, the Agency has tacitly or ex [*400]  plicitly allowed the continued use of substances that appear to cause tumors only at high dose levels in animals, in part because it recognized that such substances are ubiquitous in the human diet. For instance, when the FDA approved a petition to allow selenium supplementation of livestock feed, it had to address three studies that had found neoplastic lesions in the livers of rodents fed high doses. It ultimately concluded that selenium presented no cancer risk to humans, discounting the observed tumors as linked to liver damage which occurred only at high doses.   n305 The application of the Delaney clause to substances suspected of causing cancer by a secondary mechanism continues to provoke controversy, however, and, these precedents notwithstanding, the FDA's recent policy appears equivocal.   n306
If the Agency finds that an additive has not induced cancer, but that one of the additive's constituents does, it applies the general safety standard rather than the Delaney clause.   n307 The Agency has interpreted the "reasonable cer [*401]  tainty of no harm" standard as permitting it to disregard truly negligible risks. In discussing the proper application of the Delaney clause to the use of methylene chloride to decaffeinate coffee,   n308 for example, the FDA explained that it had relied on a one-in-one million lifetime risk of cancer standard "for determining whether the calculated upper bound risk of cancer posed by an impurity is low enough to be considered "safe' within the meaning of the general safety clause."   n309
V.
 
 Case Studies
 
 None of the three precedent-setting case studies discussed below can be characterized as typical of the FDA's workload, but together they illustrate the kind of challenges the Agency faces in implementing the Food Additives Amendment. The Agency experienced special difficulties in evaluating the artificial sweetener aspartame, Calgene's bioengineered tomato, and the fat-substitute olestra. As science reveals more novel ways to produce and use food substances, however, the challenges posed by these distinctive products may in the future seem routine.   n310
A.
 
 Artificial Sweeteners: Aspartame
 
 Aspartame, a chemically bound combination of phenylalanine, aspartic acid, and methanol, is an artificial sweetener sold under the brandname Nu [*402]  traSweet<tm>. It is the first sugar substitute approved by the FDA in the wake of the controversies involving cyclamate and saccharin. G.D. Searle & Co. submitted a food additive petition for certain "dry" uses of aspartame in 1973,   n311 and more than one year later the FDA approved the petition.   n312 Because a rare genetic disorder prevents the metabolism of phenylalanine, which at very high levels poses a risk of mental retardation, the Agency required that the statement "Phenylketonurics: Contains Phenylalanine" appear on the label of products containing aspartame.   n313
Objectors to the FDA decision contended that it overlooked or misrepresented evidence that the additive caused brain damage in rodents, and they requested a hearing. The Agency agreed to hold a hearing and later decided to stay the effective date of its approval pending the hearing when it discovered discrepancies in the data reported by a contract laboratory that had tested aspartame and other substances for Searle.   n314 It was not until four years later, after the investigation of the laboratory had concluded, that the FDA convened a three-member "public board of inquiry" to conduct the hearing.   n315 The board agreed with the FDA's initial determination that aspartame posed no risk of causing brain damage or neuroendocrine dysfunction, but it recommended against approval because of unresolved questions  [*403]  about brain tumors observed in rodent studies of the sweetener.   n316 The Commissioner rejected this recommendation and in 1981 finally reaffirmed the original food additive regulation.   n317 He decided, however, to impose the following novel condition: "Searle is to monitor the actual use levels of aspartame and to provide such information on aspartame's use to the Bureau of Foods as the Bureau may deem necessary by an order, in the form of a letter, to Searle."   n318
In 1982, Searle petitioned the FDA to expand its approval to allow the use of aspartame in carbonated beverages.   n319 The Agency approved this use a year later.   n320 This action, too, precipitated formal objections and a request for an immediate stay and a public hearing. This time the Agency rejected the objections without conducting a hearing,   n321 leading one of the objectors, a consumer group, to seek judicial review of the FDA's latest approval. Affirming the FDA's decision,   n322 the court upheld its determination that the objections did not raise material issues concerning the safety of the wet use  [*404]  of aspartame and that the more general issues surrounding the additive's safety had been resolved at the time that the Agency approved aspartame for dry use.   n323
On two dozen later occasions, the FDA, in response to petitions, has amended the food additive regulation to approve additional uses of aspartame,   n324 often rejecting renewed objections and denying occasional requests for a hearing.   n325 Most recently, in 1996, the Agency approved a petition requesting that aspartame be permitted for use as a general purpose sweetener, thereby consolidating in one regulation the twenty-seven specific sweetener uses it had approved over the previous two decades.   n326 Despite the FDA's repeated reaffirmation of aspartame's safety, controversy over its action has persisted,   n327 prompting the Agency to continue monitoring consumer complaints.   n328 Meanwhile, the attention of consumer activists has shifted to the  [*405]  FDA's review of newer artificial sweeteners and other direct additives.   n329
B.
 
 Biotechnology: Calgene's Tomato
 
 In 1994, Calgene began marketing the FLAVR SAVR<tm> tomato, a fruit engineered to remain on the vine longer, have a longer retail shelf life, and exhibit improved viscosity in processed foods. Calgene created the FLAVR SAVR<tm> by using a recombinant DNA technique, specifically by isolating the polygalacturonase gene, which is responsible for producing the enzyme that breaks down pectin in the cell walls of the tomato during the ripening process, and reintroducing the gene into the plant in the reverse or "antisense" orientation.   n330 The antisense copy suppresses the production of the polygalacturonase enzyme. In this respect, Calgene's process simply rearranged the tomato's own genetic material (it was not replaced by material from a different organism), and it reduced the levels of an existing protein (it did not introduce a new chemical or increase the levels of other naturally-occurring substances in the tomato).
The process required the insertion of a selectable "marker" gene, in this case the commonly used kanamycin resistance (kan[su'r']) gene derived from certain bacteria. Marker genes help identify those plant cells which have successfully taken up the transferred gene controlling a desired trait; in this case, cells that contain the kan[su'r'] gene synthesize a protein, aminoglycoside 3'-phosphotransferase II (APH(3')II), which renders the cell resistant to the action of antibiotics.   n331 By adding kanamycin or a similar antibiotic to the laboratory growth medium, a researcher can screen out the tomato plant cells with unsuccessful gene transfers. Although the marker gene serves no useful purpose beyond that point, it remains part of the genetic material in every cell of the growing transgenic plant.
After the completion of field testing authorized by the USDA,   n332 Calgene  [*406]  petitioned the FDA to issue advisory opinions on the regulatory status of the kan[su'r'] gene   n333 and the FLAVR SAVR<tm> tomato.   n334 Later, after the FDA's 1992 publication of a policy statement on foods derived from new plant varieties,   n335 the company converted this request into a petition seeking food additive approval of the protein from the kan[su'r'] gene as a processing aid.   n336
In 1994, following a meeting of its Food Advisory Committee, the FDA responded to Calgene's petitions. First, it "concluded that FLAVR SAVR<tm> tomatoes have not been significantly altered when compared to varieties of tomatoes with a history of safe use."   n337 Although not stated in such terms, the FDA in effect found that this tomato was GRAS and, therefore, not a food additive when used in processed foods.   n338 The Agency had once before approved a GRAS affirmation petition for bioengineered versions of a milk-clotting enzyme, chymosin, for use in making cheese and other products, as a substitute for the animal-derived version of the enzyme which previously had been affirmed as GRAS.   n339
 [*407]  Second, the FDA granted Calgene's food additive petition, approving the use of APH(3')II encoded by the kan[su'r'] gene as a processing aid for developing certain new plant varieties.   n340 The Agency concluded that the protein produced by the kan[su'r'] gene is neither toxic nor allergenic and that estimated dietary exposure would be extremely low.   n341 Although it provides antibiotic resistance and could, therefore, interfere with the therapeutic use of human antibiotics, the FDA found that the protein would be inactivated and degraded by digestion or heating.   n342 Finally, the Agency concluded that the proposed additive created no risk of horizontal transfer of the kan[su'r'] gene (and the spread of antibiotic resistance) into human cells lining the intestinal walls or into microorganisms found in the intestines or in the soil.   n343
Although the FLAVR SAVR<tm> tomato posed fairly narrow scientific issues, the FDA and Calgene spent considerable time analyzing its safety and debating how best to regulate the product. It is likely that biotechnology will become increasingly important in the future development of food products, and some innovations will pose more serious regulatory questions than the Calgene tomato.   n344
The Calgene petitions provided a major impetus for the FDA to formulate a general policy governing the regulation of food products produced using biotechnology. In 1992, the Agency published a policy statement on foods  [*408]  derived from new plant varieties,   n345 and it subsequently published notices requesting further public comment on separate aspects of the subject, including appropriate safety testing.   n346 At the outset the policy statement notes that revolutionary genetic modification techniques, such as recombinant DNA and cell fusion, will lead to the development of new varieties of food plants that would not have been possible using more traditional methods of selective breeding.   n347 It also recognizes that, because "these techniques are more precise, they increase the potential for safe, better-characterized, and more predictable foods."   n348
 [*409]  The policy statement canvasses a variety of potential safety issues posed by genetic modification - some shared with traditional selective breeding and some unique to the new methods - including unexpected chromosomal effects, changes in the levels of naturally occurring toxins in plants, reductions in nutrient bioavailability, production of new substances, introduction of allergens, and increased antibiotic resistance from marker genes.   n349 The FDA decided, however, that it need not develop a separate regulatory framework for foods derived from genetically modified plants. Instead, it preferred to "utilize an approach identical in principle to that applied to foods developed by traditional plant breeding."   n350 The policy statement embraces a functional rather than literal approach to the food additive issue.   n351 In short, according to the policy statement, the Agency plans to rely on its enforcement authority under the general adulteration provisions to ensure the safety of whole foods derived from genetically modified plants, though it pointed out that the transferred genetic material and the intended expression products could be subject to regulation as food additives if not GRAS.   n352 The FDA did not, however, explain how it would become aware of bioengineered foods for which it  [*410]  might require the submission of food additive petitions.
The intended expression product generally will not alter the GRAS status of any food derived from the new plant variety, unless it is "a protein, carbohydrate, fat or oil, or other substance that differs significantly in structure, function, or composition from substances currently found in food."   n353 Thus, if transferred genetic material introduces an unusual protein and/or alters a metabolic pathway to produce a new carbohydrate or other substance, then the FDA may call for the submission of a food additive petition. Furthermore, apart from the possibility that a new component in a whole food might be regulated as a food additive, the whole food itself could be regulated as a food additive when used as a component of a processed food. The Agency noted, however, that it rarely has ruled on the GRAS status of a whole food when used as a component in a processed food, e.g., tomatoes in vegetable soup, because most food plants "have been widely recognized and accepted as safe."   n354
The policy statement provides detailed guidance for the industry in conducting safety evaluations of new plant varieties and in determining the need for a food additive petition.   n355 It also invites companies unsure about a new  [*411]  product's regulatory status to consult with the FDA on an informal basis rather than having to submit a petition requesting an advisory opinion.   n356 In materials distributed at a 1994 meeting of its Food Advisory Committee, the Agency announced its intention to propose a regulation which would require formal premarket notification for all bioengineered foods, including the submission of available safety and nutritional information to the FDA.   n357 The mere "threat" to publish such a proposal has prompted several companies to consult with the FDA on the status of bioengineered food products that they have under development.   n358
Finally, the FDA rejected suggestions that all bioengineered foods disclose their origin in labeling. The Agency said it would require disclosure, however, if the insertion of genetic material from another source introduced a risk of allergenicity.   n359 The labeling question has proven extremely conten [*412]  tious in the wake of the Agency's approval of the new animal drug recombinant bovine somatotropin (rBST).   n360 Because it could detect no difference between milk from cows administered rBST and other milk, the FDA did not require any special disclosure statement in labeling.   n361 At the same time, it declined to prohibit nonmisleading claims that a dairy product was derived from cows that had not received rBST.   n362 In an effort to avoid controversy over the FLAVR SAVR<tm> tomato, Calgene provided point-of-sale information for consumers.   n363
Consumer and environmental groups criticized the regulatory framework described in the 1992 policy statement, arguing that the FDA should use its food additive authority to require premarket notification, safety testing, and labeling disclosures for all bioengineered foods.   n364 For the present, how [*413]  ever, the Agency continues to rely on a flexible case-by-case approach in determining whether to impose special requirements for genetically engineered foods. Although flexibility in dealing with an emerging technology has obvious advantages, there is a case to be made for establishing clearer rules for bioengineered food products. The FDA's 1992 policy statement, with its emphasis on informal, ad hoc assessment, perpetuates uncertainty for innovative companies and may weaken public confidence. Even if the FDA were to require food additive approval for all bioengineered foods, however, this would not provide certainty about the safety criteria that should apply. As the GAO concluded, debate over the FDA's policy on biotechnology is simply "reviving old questions about the adequacy of the existing regulatory framework for food and food ingredients."   n365
C.
 
 Novel Macroingredients: Olestra
 
 On January 30, 1996, the FDA approved Procter & Gamble (P&G)'s food additive petition for the noncaloric fat-substitute olestra for use in certain snack foods.   n366 Olestra's regulatory history is notable in a number of respects. Nearly twenty-five years elapsed between the sponsor's initial contacts with FDA officials and final approval, though no formal food additive petition was pending during most of that period, and P&G spent more than $ 200 million in the process.   n367 Olestra is one of the first macroingredients that the FDA has evaluated,   n368 and its final regulation conditions approval on  [*414]  special labeling, vitamin fortification, and the submission of postmarketing surveillance reports to the Agency.   n369 If the initial uses of olestra prove popular with consumers, the company will surely seek approval for additional uses in the near future.
P&G submitted its formal food additive petition for olestra in 1987.   n370 In 1991, anticipating that the FDA would not complete its review before the expiration of the various patents covering the product, the company lobbied Congress to enact special legislation to extend the patents well beyond 1994.   n371 The hearings on this legislation provided a detailed history of the company's R&D efforts.   n372 They began in 1969, when P&G scientists synthesized a new molecule with a sucrose core surrounded by six, seven, or eight medium- or long-chain fatty acids (classified as a sucrose polyester).   n373  [*415]  Triglycerides, by contrast, have a glycerol core surrounded by three fatty acids. Olestra, as the molecule was later named, tastes, smells, and cooks like ordinary fats, and can absorb fat soluble substances.   n374 The human gastrointestinal tract cannot, however, absorb olestra because it lacks enzymes capable of breaking the molecule down.   n375 Because it passes through the intestines undigested, olestra provides no calories. At the same time, olestra may interfere with the absorption of substances such as fat soluble vitamins or certain lipophilic drugs,   n376 and it may cause unpleasant gastrointestinal side effects in some individuals.   n377
After initially pursuing approval of the substance as a human drug,   n378 P&G shifted focus and filed a food additive petition in 1987. Why the company was slow to seek food additive approval remains unclear.   n379 The company soon encountered delays in discussions with the FDA to define appropriate testing protocols for a substance intended for use at a fairly high level in the diet.   n380 In 1990, the FDA convinced P&G to amend its petition to re [*416]  quest approval of only a limited use in snack foods and also asked the company to undertake one more long-term animal study.   n381
In November 1995, a majority of the Agency's Food Advisory Committee, based on discussions of an assigned subcommittee,   n382 concluded that there was a reasonable certainty that no harm would result from the use of olestra in snack foods but also recommended imposing certain conditions on any approval.   n383 After announcing a deadline for the submission of comments,   n384 the FDA approved the food additive petition less than two months after the close of the comment period.   n385 The Center for Science in the Public Interest (CSPI) promptly filed objections and requested a hearing, but it did not seek a stay of the approval.   n386 In the meantime, test marketing of  [*417]  olestra began in several cities.   n387
Shortly after its approval of olestra, the FDA invited comments on how it should assess the safety of novel macroingredients generally.   n388 It alluded to some of the difficult issues posed by substances like olestra. Because olestra is not significantly absorbed, traditional animal toxicology studies were less important and less revealing than efforts to assess digestive side effects in humans.   n389 In addition, because macroingredients are likely to be consumed by humans in relatively large amounts, it is difficult to conduct animal studies at the exaggerated intake levels that are customary in the chronic feeding tests relied on to evaluate the safety of conventional food additives.   n390 This has led some scientists to recommend greater reliance on postmarketing evaluation of macroingredients.   n391
 [*418]  In evaluating olestra, the FDA sifted through a wealth of scientific data.   n392 In approving the additive, the Agency emphasized the irrelevance to its ultimate safety assessment of both possible unpleasant (but not otherwise harmful) side effects and the social benefits of reducing levels of dietary fat.   n393 Although the Agency concluded that the use of olestra in certain snack foods was safe, it did impose several unusual conditions on its approval. First, to compensate for olestra's projected interference with the absorption of certain fat-soluble micronutrients, foods containing the ingredient must be fortified with specified quantities of vitamins A, D, E, and K.   n394
Second, the labels of foods containing olestra must bear the following statement:

This Product Contains Olestra. Olestra may cause abdominal cramping  [*419]  and loose stools. Olestra inhibits the absorption of some vitamins and other nutrients. Vitamins A, D, E, and K have been added.   n395
 
 Unlike the other labeling requirements prescribed in food additive regulations, which call for warnings or ingredient disclosures to alert consumers who may be allergic to the substance,   n396 this statement, as the FDA conceded, does not represent a condition necessary to ensure the safe use of olestra.   n397 Instead, the Agency argued that the statute's general misbranding prohibitions,   n398 which are cross-referenced in Section 409 as a ground for denying a food additive petition,   n399 authorize the imposition of such a disclosure requirement in this case.   n400 It did, however, invite further comments on  [*420]  whether it should revise what it characterized as only an "interim" labeling requirement.   n401
The third condition, a requirement for postmarketing surveillance, is one of the most interesting features of the FDA's approval. The regulation itself does not mandate further testing by the petitioner; it only provides that the Agency "will review and evaluate all data and information bearing on the safety of olestra received by the agency."   n402 In the preamble, however, the FDA explained that "as a condition of approval, Procter and Gamble is to conduct the studies that it has identified in its letter [dated January 24, 1996], consistent with the timetables identified in that letter."   n403 It went on to warn that, "if Procter and Gamble does not conduct the identified studies and does not conduct them according to the articulated timetable, FDA will consider the approval... to be void ab initio and will institute appropriate proceedings."   n404
This remarkable threat treats the approval of olestra as a private license rather than a public regulation upon which any person wishing to manufacture and sell the additive may rely.   n405 The Agency insisted that such a con [*421]  dition "is not without precedent," citing the more limited data collection requirement imposed on the manufacturer of aspartame.   n406 It also emphasized that imposition of this condition "is not, and should not be interpreted as, an indication that FDA has somehow not determined that there is a reasonable certainty that no harm will result from the use of olestra in savory snacks."   n407 Six months after approval, P&G had reported fewer consumer complaints than expected.   n408 In the meantime, the FDA has not yet responded to CSPI's year-old objections and hearing request.
VI.
 
 The Composite Picture
 
 Aggregate data provide an additional valuable perspective on the FDA's experience with the food additive approval process. Lengthy reviews of petitions for novel macroingredients may be unavoidable, but quantitative measures suggest habitual administrative delays in the handling of both simple and complex submissions. During the last decade, direct food additive petitions (original and supplemental) and GRAS affirmation petitions have languished at the Agency for an average of more than five years. As explained more fully below, a number of factors may account for these delays, especially the growing resource constraints faced by the FDA generally and its Center for Food Safety and Applied Nutrition (CFSAN) in particular.   n409 A variety of  [*422]  reforms have been proposed.
A.
 
 Track Records Compared
 
 As explained previously, the FD&C Act establishes a maximum 180-day review clock for food additive petitions. Pursuant to FDA regulations, however, this clock runs only intermittently after filing - the Agency stops the clock while awaiting additional information from the petitioner and resets it at zero whenever substantial new information arrives.   n410 No deadlines apply to action on GRAS affirmation petitions, and the FDA has been even slower in reviewing these submissions.   n411
In fact, the FDA has approved very few direct food additives during the last quarter century. In addition to aspartame and olestra, these include the antioxidant TBHQ,   n412 the multipurpose additive polydextrose,   n413 the sweetener acesulfame potassium,   n414 and the stabilizer and thickener gellan gum.   n415  [*423]  The bulk of the Agency's case load has involved petitions for indirect food additives.   n416 In addition, as illustrated by aspartame, the FDA has processed a number of supplemental petitions requesting amendments to authorize additional uses of previously approved additives.   n417 The Agency sometimes takes longer to approve these supplemental petitions than the original. For instance, the original petition for polydextrose took two years to approve, but supplemental petitions for expanded uses required up to six years.   n418
 [*424]  In the early 1990s, CFSAN undertook a series of internal management studies, including an evaluation of the food additive review process using data from 1979 through 1992.   n419 In the case of direct food additive petitions (both original and supplemental) approved during this period, the Agency found a bimodal distribution, with review times ranging from one to three years and three to six years.   n420 Of the forty-two substances affirmed as GRAS between 1979 and 1992, none took less than one year to review and more than half (twenty-six) took more than four years.   n421
In 1995, Congress held oversight hearings for the first time on the FDA's food additive approval process.   n422 As summarized in the Committee Report issued several months after their completion:

FDA has a backlog of 295 food additive petitions under review, some of which have been pending since the 1970s. Approximately 100 new food and color additive petitions are submitted to the FDA each year... Direct additives comprise approximately 17% of pending petitions and may be under review for up to 10 years... Seventy-five GRAS affirmation petitions are currently pending at FDA, the oldest of which was filed on August 31, 1972.   n423
 
 Several witnesses provided additional information about the flow of food additive approvals and GRAS affirmation petitions. They pointed out that, over the course of a decade, review times for both food additive and GRAS affirmation petitions had doubled.   n424 FDA officials conceded that significant  [*425]  delays existed and announced various initiatives to speed reviews,   n425 but they also concluded that the statute's 180-day deadline was unrealistic.   n426
In addition, Agency officials insisted that petitioners bore some of the blame for the delays because their submissions were often inadequate.   n427 Although it could reject such petitions without prejudice to future resubmission, the officials said that CFSAN generally has worked to help petitioners correct deficiencies in pending petitions.   n428 Petitioners apparently have tolerated lengthy delays rather than face the stigma associated with an FDA rejection of a food additive petition.   n429 CFSAN officials subsequently advised  [*426]  the industry that they planned to start rejecting incomplete petitions.   n430
Some members of the Subcommittee commented on the unwillingness of officials from individual companies to testify at the hearings.   n431 One witness suggested that their reluctance might reflect fear of retaliation for criticizing the FDA.   n432 Even so, representatives from several trade associations did appear at the hearings. They echoed claims of others that the FDA was congenitally risk-averse, complaining that reviewers evidently preferred to ask additional questions rather than exercise well-informed scientific judgment and recommend closure on a petition.   n433 Whether or not this charge is valid, no one seriously disputes the fact that reviews of new food additives have become extremely slow.
 [*427]  Because so few petitions are approved in any single year,   n434 aggregate measures for the last decade are more valuable than year-to-year comparisons. They afford a better picture of the average review times for (1) first approvals of direct food additives, (2) approvals of supplemental petitions for additional uses of a direct additive (sometimes referred to as follow-on petitions), and (3) affirmations of GRAS petitions for direct ingredients.
Substances Added Directly to Foods
 Average Review Times for Approvals
 (Jan. 1, 1987 - Dec. 31, 1996)
 Food Additive Petitions = 73.5 months (n=10).   n435
 Supplemental Use Petitions = 38.0 months (n=33).   n436
 GRAS Affirmation Petitions = 87.2 months (n=22).   n437 Thus, for direct food additives approved during the last decade, an average of more than six years elapsed between filing and first approval. Not surprisingly, the FDA approved follow-on uses for previously approved additives more quickly (in just over three years), though still long past the three- and six-month deadlines imposed by the FD&C Act. Finally, GRAS affirmation petitions approved during the last decade required more than seven years on average.
It is difficult, in truth, to measure petition review periods with any real precision. For example, some significant but unreported portion of the elapsed time is consumed while the FDA awaits the submission of additional  [*428]  information by the petitioner.   n438 On the other hand, because of substantial delays in publishing notices of filing after the receipt of a petition, average review times may be understated if measured from the official filing date.   n439 Although FDA officials have pointed to trend data as evidence of recent improvements,   n440 the numbers for any particular year are too limited to justify such a conclusion. Further, as the backlogs of long-pending petitions are cleared, the average review times could well worsen rather than improve.
After Congress subjected new drugs to rigorous premarket FDA review for safety and effectiveness, some critics argued that the resulting delays in approval kept valuable therapeutic agents out of the hands of needy patients.   n441 More than thirty years later, complaints about a "drug lag" continue.   n442 Although similar delays in approvals of direct food additives may  [*429]  seem less consequential,   n443 access to innovations in food technology does have some public health implications.   n444 Wholly apart from delays in reviewing particular applications, the inevitability of substantial delays and uncertainty about applicable regulatory controls may inhibit potentially valuable research and development efforts.   n445 The lengthy delays in FDA reviews of GRAS affirmation petitions pose fewer such concerns because petitioners generally proceed to market once the Agency initially accepts their submissions. Delays prior to formal affirmation have less impact on petitioners in these cases.
B.
 
 A Catalogue of Proposed Solutions
 
 A number of factors may account for the problems revealed in the FDA's handling of food additive petitions, and numerous reforms have been sug [*430]  gested. Some of the solutions would require only modest revisions in the FDA's internal procedures, but other proposals call for radical, and in most instances legislative, overhauls of the current system. This section summarizes the most serious flaws in the system and several suggested reforms.
1.
 
 Internal Management Initiatives
 
 The FDA recently reorganized CFSAN, partly in an attempt to streamline its food additive review activities,   n446 and it announced renewed efforts at publishing guidelines and tracking work flow among reviewers.   n447 The lack of coordination and frequent turn-over among reviewers has created significant administrative inefficiencies in the past.   n448 Clearer and current guidelines, and other efforts to educate sponsors, can reduce the number of petitions that are manifestly inadequate or incomplete. The Agency is wise to consider offering, perhaps even requiring, a pre-filing meeting at which petitioners can learn what is expected and have an opportunity to reach at least tentative agreement on the studies required to permit a decision on an additive's safety. This procedure has been a common and very useful feature of the FDA's new drug review process for several years.   n449
 [*431]  Such initiatives will not produce substantial gains in efficiency,   n450 however, and there are no guarantees that the FDA will make good on its promises to streamline the process.   n451 Although they would represent dramatic improvements over the existing time frames, none of the Agency's announced performance goals - to be phased in gradually only after it begins reducing the current backlog - would meet the current statutory deadlines.   n452 In November 1997, Congress enacted sweeping FDA reform legislation, including a provision calling on the Agency to develop a plan "establishing mechanisms, by July 1, 1999, for meeting the time periods specified in [the FD&C] Act for the review of all [product] applications and submissions" and "eliminating backlogs in the review of [such] applications and submissions... by January 1, 2000."   n453 Even so, the Agency would remain free  [*432]  to ignore the existing deadlines unless some action-forcing mechanism accompanied such a command.
2.
 
 Statutory Hammers
 
 Some critics of the FDA process have recommended that Congress enact a "hammer" to force the Agency to act on petitions by a specified deadline.   n454 A type of hammer appeared in some of the early food additive bills,   n455 and this mechanism enjoys popularity in Congress as a means of assuring the timely promulgation of broad regulations.   n456 Such an instrument seems ill-suited, however, to forcing expeditious action on food additive petitions.
Instead of tolling or ignoring the statutory clock as it does now, the FDA could circumvent a statutory hammer simply by repeatedly denying a petition until it received sufficient data to be satisfied about the safety of the additive.   n457 Such a practice might encourage greater initial care in preparing petitions. The sole benefit for petitioners, however, would be an earlier opportunity to demand a formal hearing or seek judicial review, an illusory  [*433]  advantage over the present system.
If a statutory hammer were drafted to foreclose such behavior by the FDA, the Agency would in theory be forced to approve some food additives about which it had genuine safety concerns. The FDA might then routinely insist on postmarketing studies, as a backstop against a rushed approval decision. Statutory hammers might have a place in a revised food additive approval system, but, as an independent reform, they suffer from significant shortcomings.
3.
 
 Prioritizing Reviews
 
 Shrinking human resources are an important cause of the delays in FDA reviews of food additive and GRAS affirmation petitions. CFSAN staffing levels have barely remained constant while food additive petitions have become more complicated and its other regulatory responsibilities have burgeoned.   n458 The Agency could improve utilization of its personnel by better prioritizing its review activities. For instance, reducing the intensity of reviews for substances likely to pose little or no public health risk, such as indirect food additives or additional uses of approved direct additives, would allow reviewers to focus on the more significant petitions involving novel ingredients.
The FDA recently promulgated criteria for exempting some indirect food additives from plenary review if estimated human exposure falls below a "threshold of regulation."   n459 This new system may allow CFSAN to allocate more of its resources to direct additives.   n460 Under this new regulation, the  [*434]  FDA may issue a letter exempting a food-contact substance from food additive petition requirements if the requestor demonstrates, through migration data and existing toxicological studies, that the likelihood or extent of migration to food will be so trivial as not to require further regulation.   n461 Although it acknowledged the need to review exemption requests promptly, the FDA declined to set any deadlines.   n462 The resulting potential for delay may limit the new policy's value as a mechanism for redirecting Agency resources to additives that present more challenging questions.   n463
 [*435]  Because it requires FDA action on exemption requests,   n464 the threshold of regulation policy is more like an abbreviated premarket review procedure than a premarket notification system - another reform option, which Congress has applied in other contexts. Congress recently enacted a simplified premarket notification procedure for "new dietary ingredients,"   n465 though its goal was to reduce regulation of the dietary supplement industry rather than to free up Agency resources for other activities. Over the last twenty years, the premarket notification system for medical devices - designed by Congress as a procedure for exempting (at least temporarily) new but "substantially equivalent" devices from full premarket approval - has become the FDA's primary mechanism for reviewing new medical devices. As a result, it has also become more rigorous and protracted than the simple notification procedure originally envisioned by Congress.   n466 A similar fate could befall the FDA's new threshold of regulation policy or any similar reform.
The FDA might consider adopting an abbreviated review process for supplemental petitions for additional uses of previously approved additives.   n467  [*436]  The Agency also might assign higher priority to the review of novel food additives that promise important public health benefits. At present, the Agency reviews submissions in the order received, and existing backlogs may mean that scientific review of a new petition does not even begin for some time.   n468 Although the statute does not authorize the FDA to consider benefits in evaluating the safety of food additives,   n469 the statute would not appear to bar it from prioritizing its reviews on the basis of such considerations.   n470 Similar prioritization systems exist for new drug reviews, though the statute expressly authorizes the consideration of benefits in approving new drugs.   n471 The FDA's announced performance goals for petition review point in quite a different direction. They classify petitions according to their length, complexity, and novelty of the issues presented, and thus appear to promise relatively faster reviews of petitions for the least complex and significant food  [*437]  additives.   n472
4.
 
 Imposing User Fees
 
 Some have recommended legislative authorization for the FDA to collect food additive user fees as a way of addressing the resource problem.   n473 Congress adopted such a system for prescription drugs in 1992.   n474 This is not a new idea. The FDA specifically sought the authority to collect user fees during the congressional hearings that preceded the enactment of the Food Additives Amendment.   n475 Such authority had been included in the Pesticide Residues Amendment of 1954,   n476 and it also appeared in Representative Delaney's food additive bills.   n477 But, for reasons that are not elaborated in the legislative history, the authority to impose such fees did not appear in the enacted legislation.
User fees are typically justified as a means of reimbursing an agency for the benefits it provides to regulated entities. More than two decades ago, the Supreme Court held that the collection of user fees from regulated companies  [*438]  for the benefit of the general public is simply a tax in another form.   n478 Approval of a food additive petition directly benefits not only the petitioner but other makers or users of the ingredient as well. Unlike a new drug application, whose approval confers on the applicant an exclusive license to sell a drug product, a food additive petition results in the publication by the FDA of a regulation authorizing use of the additive by any person wishing to do so, subject only to any remaining patent term.   n479
If the obligation to pay for an FDA "service" that benefits the food industry generally fell only on petitioners, developers of innovative additives would be unfairly penalized.   n480 Congress could avoid this problem by converting food additive approvals into a private licensing system similar to that for new drugs. In fact, in addition to attacking the causes of delay (whether by imposing user fees or otherwise), some reformers have proposed that the negative competitive effects of such delays should be compensated for by providing the petitioner a period of market exclusivity if the additive cannot be patented or patents are about to expire.   n481 Even then, however, the amount of the user fees collected from the petitioner would have to be far lower than currently charged for new drugs in recognition of the smaller R&D investment in, and limited commercial potential of, most new food additives. Otherwise, a user fee system would further discourage companies from pursuing FDA approval.
 [*439] 
5.
 
 Third Party Review of Petitions
 
 Frustration with delays in the FDA's drug and device approval processes has triggered calls for legislation authorizing applicants to resort instead to extramural reviews by non-governmental scientific organizations.   n482 A similar approach has been suggested as a way of expediting review of new food additives. This idea, too, has precedents. The FDA frequently seeks the advice of independent scientific organizations, as when it sought NAS and FASEB help during the GRAS list review.   n483 And, in 1995, the Agency announced plans to contract out reviews of routine toxicity studies in currently pending food additive petitions.   n484
Industry representatives and many academic scientists favor greater reliance on such outside organizations.   n485 Under one proposal, a petitioner willing to pay could ask the FDA to contract out the review of its safety data; both the Agency and the third party organization would have a limited op [*440]  portunity to request that the petitioner first collect additional information. This proposal would require resolution of several difficult issues, including how to satisfy or modify the Federal Advisory Committee Act (FACA),   n486 whether fees should be channeled through the Agency,   n487 and what force to give the third party's assessment and recommendation. The most controversial proposals for third-party review provide that the recommendations of the reviewing organization should be deemed adopted unless the FDA could demonstrate (within a limited period of time) that the additive posed a significant risk.   n488
In a related vein, some have suggested that the Agency place greater reliance on the GRAS exception, though not necessarily through the formalized GRAS affirmation process that exists at present.   n489 Perhaps this could be ac [*441]  complished by contracting out the review of GRAS affirmation petitions, much as the FDA did in the 1970s when it contracted out data reviews for substances appearing on the initial GRAS lists,   n490 or by giving presumptive weight to the conclusions of certain organizations when commissioned by the petitioner to review the GRAS status of a food substance.   n491
* * * * * Efforts to revise the statute and FDA regulations will surely continue and are likely to emphasize one or more of the reforms discussed above. In the meantime, the breadth of the GRAS exception provides industry the unusual opportunity to "reform" the approval process unilaterally and substantially reduce existing delays. After all, GRAS is a definitional exception (or exclusion) rather than an exemption procedure,   n492 and self-determinations of GRAS status, premised on published extramural reviews by reputable scientific organizations, could largely supplant the industry's existing dependence on the FDA. For instance, companies can and several have commissioned extramural reviews by FASEB and then submitted a GRAS affirmation petition primarily to advise the FDA of their self-determination.   n493
Although food processors traditionally have insisted on some sort of FDA seal of approval, ingredient makers need to better explain to their customers that such approvals are not necessary, expeditiously acquired, nor in many cases very meaningful.   n494 Why should processors feel more comfortable using an interim food additive such as mannitol (which theoretically could be  [*442]  withdrawn by the FDA with little or no advance warning   n495 ) than a substance that FASEB found to be GRAS under the Agency's criteria? Food processors may fear enforcement action by the FDA, but the fact is that the Agency has never challenged a self-determination of GRAS based on the published extramural review of a reputable scientific body, such as FASEB or FEMA's expert committee.
If it were genuinely disturbed by the use of an ingredient it had not approved, the FDA could initiate an administrative proceeding that could result in a determination that a food additive petition for the substance must be filed. But it could do that for a substance it had previously affirmed as GRAS. If food processors understood the limited practical value of an FDA affirmation, a market for private GRAS certifications could emerge without any change in the FD&C Act or the Agency's regulations.   n496
In some respects, privatization would bring us full circle, back to the time when food companies assured themselves of the safety of any substance used in food, and the FDA shouldered the burden of proving otherwise.   n497 But now another expert body would review, confirm, and publish the industry's judgments, applying more uniform and stringent safety assessment criteria than had existed prior to 1958.   n498
 [*443] 
Conclusion
 
 Exactly four decades after the enactment of the Food Additives Amendment and twenty years after the political controversy over saccharin, congressional and administrative attention again has focused on the regulation of food additives. Food producers have become increasingly frustrated with lengthy delays in the review process, while public interest groups vocally criticize approved additives as unsafe. The FDA is caught between these competing factions, struggling to do more with fewer resources. Out of necessity, the Agency has been forced to improvise, sometimes evading its unrealistic directives from Congress.
The GRAS exception constitutes a legitimate route to market, and the food industry could make even broader use of this definitional exclusion. For its part, the FDA could facilitate GRAS self-determinations, continue efforts at streamlining the review process, and exempt certain types of substances altogether to allow a reallocation of its scarce resources. Finally, Congress has before it a range of reform possibilities, from codifying steps the FDA has already promised to authorizing the collection of user fees in exchange for limited market exclusivity and codifying procedures for extramural review of GRAS affirmation and food additive petitions. Although controversy inevitably will surround the choice among reforms, the FDA cannot simply continue "muddling along" in its current fashion.

Legal Topics: 

For related research and practice materials, see the following legal topics:
Environmental LawHazardous Wastes & Toxic SubstancesPesticidesEvidenceScientific EvidenceGeneral OverviewGovernmentsAgriculture & FoodGeneral Overview

FOOTNOTES:

n1. See, e.g., Delays in the FDA's Food Additive Petition Process and GRAS Affirmation Process: Hearings Before the Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight, 104th Cong. (1995) [hereinafter 1995 Hearings] (examining the reasons for, and consequences of, delays in the FDA's review of food additive petitions and the GRAS affirmation process); Peter Barton Hutt, Approval of Food Additives in the United States: A Bankrupt System, Food Tech., Mar. 1996, at 118, 122 (arguing that the FDA's regulation of food additives has failed because of the Agency's sluggish review process).

n2. See, e.g., Thomas O. McGarity & Sidney A. Shapiro, Workers at Risk: The Failed Promise of the Occupational Safety and Health Administration (1993) (suggesting improvements in the Occupational Safety and Health Administration's regulatory process); Jerry L. Mashaw & David L. Harfst, The Struggle for Auto Safety (1990) (evaluating the National Highway Traffic Safety Administration's regulatory efforts to promote automobile safety); Glen O. Robinson, The Forest Service: A Study in Public Land Management (1975) (analyzing the U.S. Forest Service's organizational and administrative process in the context of general public land management); James Q. Wilson, The Politics of Regulation (1980) (collecting essays describing how various regulatory agencies ordinarily operate).

n3. See Pure Food and Drugs Act, Pub. L. No. 59-384, ch. 3915, 2, 34 Stat. 768 (1906) (superseded by the FD&C Act in 1938).

n4. Id. 7.

n5. United States v. Lexington Mill & Elevator Co., 232 U.S. 399, 411 (1914) ("If it cannot by any possibility, when the facts are reasonably considered, injure the health of any consumer, such [product], though having a small addition of poisonous or deleterious ingredients, may not be condemned under the act."); see also United States v. Coca Cola Co., 241 U.S. 265, 279-85 (1916) (holding that caffeine added to beverage syrup was an "added" ingredient and that the government's evidence that caffeine was poisonous or deleterious should have been submitted to the jury).

n6. Pub. L. No. 75-717, ch. 675, 52 Stat. 1040 (1938) (codified as amended at 21 U.S.C. 321-393 (1994)). The statute refers throughout to the Secretary of Health and Human Services (previously the Secretary of Health, Education and Welfare (HEW) and before that the Secretary of Agriculture (USDA)), see 21 U.S.C. 321(d), but the Secretary has delegated most powers under the FD&C Act to the Commissioner of Food and Drugs, see id. 393(b); 21 C.F.R. 5.10(a)(1), 5.11(a) (1997).

n7. Pub. L. No. 85-929, 72 Stat. 1784 (1958) (codified as amended in scattered sections of 21 U.S.C.).

n8. See 104 Cong. Rec. 17,417 (1958) (statement of Hon. John B. Williams) ("The 1938 law gave no recognition to substances deliberately added to food for beneficial purposes, such as retarding natural spoilage or keeping food moist or tasty. There is a gap in our pure food law as a result of advancing technology.").

n9. See, e.g., General Accounting Office, Food Safety and Quality: Innovative Strategies May Be Needed to Regulate New Food Technologies, No. RCED-93-142 (1993), at 1-2, 5 [hereinafter GAO, New Food Technologies] (discussing new food technologies, various possible responses to these new technologies, and unresolved regulatory issues).

n10. FD&C Act 402(a) (codified as amended at 21 U.S.C. 342(a)). Section 406 of the Act provided:
 
Any poisonous or deleterious substance added to any food, except where such substance is required in the production thereof or cannot be avoided by good manufacturing practice[,] shall be deemed to be unsafe for purposes of the application of [the above-quoted clause]; but when such substance is so required or cannot be so avoided, the Secretary shall promulgate regulations limiting the quantity therein or thereon to such extent as he finds necessary for the protection of public health...
 
 Id. 406(a) (codified as amended at 21 U.S.C. 346); see also H.R. Rep. No. 75-2139, at 6 (1938) (explaining that the tolerance setting provision would provide greater flexibility in dealing with pesticide residues); Richard A. Merrill, Regulating Carcinogens in Food: A Legislator's Guide to the Food Safety Provisions of the Federal Food, Drug, and Cosmetic Act, 77 Mich. L. Rev. 171, 175 (1978) ("In substance, Congress authorized the FDA to license the use of some potentially toxic substances in food, apparently in recognition of their utility or of the importance of foods from which they cannot practicably be eliminated.").

n11. FD&C Act 401 (codified as amended at 21 U.S.C. 341); see also Federal Sec. Admin. v. Quaker Oats Co., 318 U.S. 218, 227-31 (1943) (upholding "standards of identity" which were adopted in order to avoid consumer confusion); Atlas Powder Co. v. Ewing, 201 F.2d 347, 350-55 (3d Cir. 1952) (upholding FDA decision, after almost one decade of hearings, not to permit the use of certain emulsifiers in bread because of unresolved safety concerns and the risk of consumer deception); Richard A. Merrill & Earl M. Collier, Jr., "Like Mother Used to Make": An Analysis of FDA Food Standards of Identity, 74 Colum. L. Rev. 561, 600 (1974) (establishing a framework for analyzing the costs and benefits of food standards). The FDA did have limited premarket approval powers under the 1938 Act through the listing and batch certification provisions applicable to coal-tar colors used in food. See FD&C Act 406(b), 52 Stat. 1040, 1049 (1938), repealed and replaced by Color Additive Amendments of 1960, Pub. L. No. 86-618, tit. I, 74 Stat. 397 (codified as amended at 21 U.S.C. 379e).

n12. See 21 U.S.C. 331(a)-(c) (designating the adulteration of food, or its delivery or receipt, in interstate commerce as prohibited acts); id. 332(a) (authorizing injunctions to restrain violations of the Act); id. 334(a) (authorizing seizure of products in violation of the Act); see also id. 333(a) (authorizing the imposition of criminal penalties for violations of the Act); United States v. Park, 421 U.S. 658, 671-74 (1975) (affirming the imposition of strict criminal liability under the FD&C Act in a case involving food adulteration); Brenda A. Bachman & Lori Ludemann, Note, Federal Food and Drug Act Violations, 33 Am. Crim. L. Rev. 757 (1996) (examining the criminal provisions of the FD&C Act). In practice, the FDA typically sends a warning letter first, threatening to pursue formal enforcement action only if the company fails to bring itself into prompt compliance. See Warning Letters; Procedure Manual, Chapter 8-10; Availability, 56 Fed. Reg. 27,026 (1991).

n13. See, e.g., United States v. 29 Cartons of * * * An Article of Food, 987 F.2d 33, 35 (1st Cir. 1993) ("The FDA can prevent sale of bottled BCO or any other "food' only if it proves by a preponderance of the evidence that the food is "injurious to health.'"); United States v. Boston Farm Ctr., Inc., 590 F.2d 149, 153 (5th Cir. 1979) ("In this case the expert evidence is uncontradicted that 20 ppb of aflatoxin may render corn harmful."); United States v. 2,116 Boxes of Boned Beef * * *, 516 F. Supp. 321, 328-30 (D. Kan. 1981) (holding that, under the identically-phrased adulteration provision in the Federal Meat Inspection Act, the government must prove a reasonable possibility of harmfulness), aff'd, 726 F.2d 1481, 1485 (10th Cir. 1984); United States v. Anderson Seafoods, Inc., 447 F. Supp. 1151, 1155-56 (N.D. Fla. 1978) (holding that the injuriousness requirement does not mean harmfulness under any conceivable conditions of use), aff'd, 622 F.2d 157, 159 (5th Cir. 1980) ("The "may render' standard has been interpreted to mean that there is a reasonable possibility of injury to the consumer."); see also United States v. Coca Cola Co., 241 U.S. 265, 284-85 (1916) (construing similar language in predecessor statute).

n14. Pure Food and Drugs Act, Pub. L. No. 59-384, ch. 3915, 7, 34 Stat. 768 (1906) (superseded by the FD&C Act in 1938).

n15. See United States v. Lexington Mill & Elevator Co., 232 U.S. 399, 411 (1914) ("If it cannot by any possibility, when the facts are reasonably considered, injure the health of any consumer, such [bleached] flour, though having a small addition of poisonous or deleterious ingredients, may not be condemned under the [1906] act."); see also Flemming v. Florida Citrus Exch., 358 U.S. 153, 161 (1958) (applying the holding of Lexington Mill to the adulteration provisions of the FD&C Act). The FDA shouldered an even greater burden of proof in the case of non-added substances (i.e., "ordinarily render it injurious to health"). See Merrill, supra note 10, at 189 ("The sparse case law suggests that the agency would have to demonstrate a probability of harm to some significant number of consumers."). Thus, the FDA often has stretched the concept of "added" so that it could act against harmful substances even though they were not intentionally added to food. See, e.g., Continental Seafoods, Inc. v. Schweiker, 674 F.2d 38, 42-43 (D.C. Cir. 1982) (salmonella in shrimp); United States v. Anderson Seafoods, Inc., 622 F.2d 157, 160-61 (5th Cir. 1980) (mercury contamination in fish); Richard A. Merrill & Michael Schewel, FDA Regulation of Environmental Contaminants of Food, 66 Va. L. Rev. 1357, 1372-75 (1980) (discussing the judicial acceptance of the FDA's expansive interpretation of the term "added"); James D. Poliquin, Comment, The Incremental Development of an Extra-Statutory System of Regulation: A Critique of Food and Drug Administration Regulation of Added Poisonous and Deleterious Substances, 33 Me. L. Rev. 103, 108-15 (1981) (describing some of the purposes behind the FDA's expansive interpretation of the term "added").

n16. See H.R. Rep. No. 85-2284, at 1 (1958) ("To prove an untested substance poisonous or deleterious may require approximately 2 years or more of laboratory experiments with small animals and during this period the Government cannot prevent the use of such a substance in food."); Federal Food, Drug, and Cosmetic Act (Chemical Additives in Food): Hearings Before a Subcomm. of the House Comm. on Interstate and Foreign Commerce, 84th Cong. 71 (1956) [hereinafter 1956 Hearings] (statement of Glenn G. Paxton, appearing as counsel for various food industry associations) ("Today FDA must do its own testing and experimentation on an additive - admittedly a difficult task - and must sustain the burden of proof that it is poisonous or deleterious - admittedly a difficult burden - before it can obtain a court order to restrain its use."); Merrill, supra note 10, at 194 ("To enforce section 402(a)(1), the FDA ordinarily must locate contaminated food, conduct chemical analyses, find witnesses prepared to testify that the amount of the contaminant is potentially harmful to some portion of consumers, and prove these facts in court.").

n17. See 21 U.S.C. 342(a)(2), 346 (1994); Young v. Community Nutrition Inst., 476 U.S. 974, 977, 981-84 (1986) (noting that any added poisonous or deleterious substance for which no tolerance existed would be unsafe, but holding that the statute did not compel the Agency to regard such a substance as adulterated); United States v. Ewig Bros. Co., 502 F.2d 715, 720 (7th Cir. 1974) (describing the "per se" adulteration approach established by Section 406 for any poisonous or deleterious substance for which no tolerance had been promulgated). The phrase "poisonous or deleterious" is not separately defined in the statute, and the FDA has declined to include a definition in its implementing regulations. See Poisonous or Deleterious Substances, 42 Fed. Reg. 52,814, 52,816 (1977).

n18. See H.R. Rep. No. 85-2284, at 1-2 ("Present law entirely prohibits the use of these additives even if their use at safe levels would advance our food technology and increase and improve our food supplies."); 1956 Hearings, supra note 16, at 194 (statement of George P. Larrick, Comm'r, FDA) ("Once it was shown that the proposed additive was a poison, it was excluded unless it was necessary in production or unavoidable in good manufacturing practice. Over the years, only the pesticide chemicals have met this test of necessity.").

n19. See Merrill, supra note 10, at 195-98 & nn.89 & 92 (discussing the regulatory framework provided by Sections 402(a)(2) and 406); Poliquin, supra note 15, at 111-15 (applying Sections 402(a)(2) and 406 to five fact patterns).

n20. See 1956 Hearings, supra note 16, at 112 (statement of J.M. Gillet, Mfg. Chemists' Ass'n) ("Under the present law there is no requirement that the [FDA] be advised in advance of the use of any new chemical, and it has been up to them to find out that such chemical is being used," though most manufacturers voluntarily provide notification.).

n21. See, e.g., Robert C. Brown, The Liability of Retail Dealers for Defective Food Products, 23 Minn. L. Rev. 585, 596-610 (1939); R.D. Hursh, Annotation, Liability of Manufacturer or Seller for Injury Caused by Food or Food Product Sold, 77 A.L.R.2d 7 (1961). For a more recent survey of decisions in this area, see Jane M. Draper, Annotation, Liability for Injury or Death Allegedly Caused by Spoilage, Contamination, or Other Deleterious Condition of Food or Food Product, 2 A.L.R.5th 1, 41-82 (1992).

n22. See Food Additives: Hearings Before a Subcomm. of the House Comm. on Interstate and Foreign Commerce, 85th Cong. 421-22 (1957) [hereinafter 1957 Hearings (even though the final session of the hearings took place in 1958)] (statement of Elliot L. Richardson, Asst. Secretary, Health, Education & Welfare (HEW)) ("The commendable actions of the great majority [of companies], however, cannot provide protection against the minority. We have had some narrow escapes in the food field.").

n23. See 96 Cong. Rec. 8933 (1950). Congress called for an investigation into
 
the nature, extent, and effect of the use of chemicals, compounds, and synthetics in the production, processing, preparation, and packaging of food products to determine the effect of such chemicals, compounds, and synthetics (A) upon the health and welfare of the Nation and (B) upon the stability and well-being of our agricultural economy.
 
 Id.

n24. See Chemicals in Foods and Cosmetics: Hearings Before the House Select Comm. to Investigate the Use of Chemicals in Foods and Cosmetics, 82d Cong. (1952); Chemicals in Food Products: Hearings Before the House Select Comm. to Investigate the Use of Chemicals in Food Products, 82d Cong. (1951); Chemicals in Food Products: Hearings Before the House Select Comm. to Investigate the Use of Chemicals in Food Products, 81st Cong. (1950).

n25. H.R. Rep. No. 82-2356, at 4 (1952); see also National Academy of Sciences, The Use of Chemical Additives in Food Processing, NAS Pub. No. 398 (1956); Report of the Joint FAO/WHO Expert Committee on Food Additives, General Principles Governing the Use of Food Additives (1956).

n26. See H.R. Rep. No. 82-2356, at 3-4; see also 1957 Hearings, supra note 22, at 421 (statement of Elliot L. Richardson, Asst. Secretary, HEW) ("The potential danger of food additives, indeed, is more insidious [than untested drugs] because it is a danger from the daily intake of small amounts of chemical substances...."); cf. id. at 167 (statement of Hon. Leonor K. Sullivan) ("Seldom do the chemicals add anything of nutritional value. Mostly, they are intended to cut costs, or to cut corners, or to cut spoilage or waste. They are put into the foods mostly for the manufacturer's benefit... rather than the consumer's.").

n27. See H.R. Rep. No. 82-2356, at 4. Subsequent estimates ran much higher. See, e.g., Food Additives: Competitive, Regulatory, and Safety Problems: Hearings Before the Senate Select Comm. on Small Bus., 95th Cong. 52 (1977) (statement of Sherwin Gardner, Acting Comm'r, FDA) ("There are over 400 nonflavor GRAS substances; approximately 1,650 flavors and spices, some of which are GRAS and some regulated additives; about 400 regulated direct food additives and on the order of 10,000 GRAS and regulated indirect additives.").

n28. See H.R. Rep. No. 82-2356, at 27. Some scientists viewed the Committee's conclusions as largely unsupported and inappropriately alarmist. See, e.g., Maurice H. Seevers, Perspective Versus Caprice in Evaluating Toxicity of Chemicals in Man, 153 JAMA 1329, 1331-32 (1953) ("[Representative Delaney's] lurid article, a masterpiece of innuendo and fantasy, based principally on conjecture, was designed for the one purpose of frightening the [consumer] into demanding further legislation.").

n29. See, e.g., 1957 Hearings, supra note 22, at 43-49 (reproducing a chart prepared by subcommittee staff comparing the various food additive bills introduced in 1957).

n30. See S. Rep. No. 85-2422, at 3-4 (1958) (describing extensive hearings leading up to the consideration of the final bill); 1957 Hearings, supra note 22, at 50 (statement of Hon. John B. Williams, Subcomm. Chairman) ("It seems to me that a 10-year period is a sufficiently long incubation period even for difficult legislation."); Vincent A. Kleinfeld, "Chemicals in Foods" - A Legal Viewpoint, 9 Food Drug Cosm. L.J. 115 (1954) (discussing the initial efforts at drafting legislation to regulate food additives).

n31. See Pub. L. No. 83-518, 3 (408(a)), 68 Stat. 511 (1954) (codified at 21 U.S.C. 346a(a) (1994)), repealed and replaced by Food Quality Protection Act of 1996, Pub. L. No. 104-170, 405, 110 Stat. 1514.

n32. See 104 Cong. Rec. 19,359 (1958) (statement of Sen. Hill) ("This measure now has the overwhelming support of the major industrial and business concerns which would be affected by it."). As the Committee Chairman reported:
 
The industries concerned - those who manufacture the chemicals in question and those who use them in connection with food products - and the Government agencies are in agreement that an advance determination by the Government as to the acceptability of a chemical in connection with foods is desirable from the point of view both of the industries concerned, the Government, and the consumer.
 
 1956 Hearings, supra note 16, at 1-2 (statement of Hon. J. Percy Pierce).

n33. See, e.g., 1956 Hearings, supra note 16, at 73 (statement of Glenn G. Paxton, appearing as counsel for various food industry associations) (observing that "the consensus among the food group was that this is a subject that does not require a strict licensing arrangement by the [FDA]"); id. at 91 (supporting a "provision to the effect that after an unfavorable opinion by the Secretary the proponent may not use the additive without first giving to the Secretary at least 30 days notice of intended use, which would enable the Secretary to institute any type of legal action which he deems advisable").

n34. 1957 Hearings, supra note 22, at 21 (letter from M.B. Folsom, Secretary, HEW) ("Moreover, as the bill is drawn, the requirement to notify us of an intended shipment would apply only to the person submitting the pretesting data, and our adverse evaluation would not legally operate to prevent shipment by others.").

n35. See H.R. 6747, 85th Cong. 5 (1957); 1957 Hearings, supra note 22, at 28-36 (letter and memorandum from M.B. Folsom, Secretary, HEW).

n36. See 1957 Hearings, supra note 22, at 447 (statement of George P. Larrick, Comm'r, FDA). Commissioner Larrick stated:
 
When issued, the regulation would give all food manufacturers who might wish to use a new chemical in their foods official assurance that its safety has been established under the precise conditions set out in the regulation; the regulation would be a rule for all to follow, not a license to a single manufacturer.
 
 Id.; see also id. at 423 (statement of Elliot L. Richardson, Asst. Secretary, HEW) ("Such determinations should have the maximum possible future value in regulating the use of the substance... [by] prescribing conditions for its use by all others in the same segment of the food industry."); cf. id. at 141 (testimony of Lawrence A. Coleman, appearing on behalf of the Mfg. Chemists' Ass'n) (declining to take a position on the relative merits of licensing for an individual applicant rather than issuing a generally-applicable regulation).

n37. See H.R. 2245, 83d Cong. 6 (407(d)) (1953). Such a passive approval approach resembled that used by the FDA for new drug approvals before passage of the Drug Amendments of 1962.

n38. See H.R. 10,404, 85th Cong. 5 (409(e)) (1958); see also H.R. 8390, 85th Cong. 5 (409(f)) (1957) (requiring notification 90 days before use); H.R. 7607, 84th Cong. 5 (409(e)) (1955).

n39. As HEW explained:
 
We believe that the time limit which the bills would allow for initial action by the Secretary should be extended to 120 days, with authority to the Secretary to extend it to 180 days when found necessary... Consideration of the adequacy of testing of additives will be no less difficult and time consuming than passing on a new-drug application.
 
 1956 Hearings, supra note 16, at 141 (HEW memorandum).

n40. Food Additives Amendment of 1958, Pub. L. No. 85-929, 72 Stat. 1784 (codified as amended in scattered sections of 21 U.S.C.). The bill passed unanimously in the House of Representatives. See, e.g., 104 Cong. Rec. 19,359 (1958) (statement of Sen. Hill).

n41. See S. Rep. No. 85-2422, at 2 (1958) ("The processor who wants to add a new and unproven additive [must] accept the responsibility now voluntarily borne by all responsible food processors of first proving it to be safe for ingestion by human beings."). As one commentator explained, "often this allocation of the burden of proof determines substantive outcomes." Peter Huber, The Old-New Division in Risk Regulation, 69 Va. L. Rev. 1025, 1034 (1983) ("Even when the substantive standard for acceptability is the same in the two systems, some sources of hazard will be excluded under the screening system, but tolerated under the standard-setting one because degrees of hazard can never be evaluated with absolute precision."). In addition, the cost of acquiring necessary information and the risks associated with delay are shouldered by the regulated entity rather than the agency under a screening system. See id. at 1034-36.

n42. See H.R. Rep. No. 85-2284, at 1 (1958) ("The purpose of the legislation is twofold: (1) To protect the health of consumers... ; and (2) to advance food technology by permitting the use of food additives at safe levels.").
 
The second flaw in existing law which has proved detrimental to consumers, to processors, and to our national economy and which this bill seeks to remove is a provision which has inadvertently served to unnecessarily proscribe the use of additives that could enable the [consumer] to safely keep food longer, the processor to make it more tasteful and appetizing, and the Nation to make use of advances in technology calculated to increase and improve our food supplies.
 
 S. Rep. No. 85-2422, at 2, 3 (noting that the legislation "could materially advance our ability to make more wholesome foods available to more people at all seasons"); see also Continental Chemiste Corp. v. Ruckelshaus, 461 F.2d 331, 340 (7th Cir. 1972) (describing the "two broad purposes to be accomplished by the food additive legislation").

n43. 21 U.S.C. 321(f) (1994); see also Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 337 (7th Cir. 1983) ("This definition is not too helpful, but it does emphasize that "food' is to be defined in terms of its function as food, rather than in terms of its source, biochemical composition or ingestibility."); id. (noting that the definition "is a term of art and is clearly intended to be broader than the common-sense definition of food").

n44. See 1957 Hearings, supra note 22, at 456 (HEW memorandum) ("The purpose of clause (3), of course, is to subject all intentional additives, as soon as offered for introduction into interstate commerce, to all the act's requirements for food...."); id. at 219 (testimony of H.T. Austern, appearing on behalf of the Nat'l Canners Ass'n) (noting that there is no difference between an "ingredient" and an "additive").

n45. 21 U.S.C. 342(a)(1).

n46. Id. 343(i)(2); see also id. 341 (governing optional ingredients in standards of identity for fabricated foods).

n47. Id. 321(s); see also 21 C.F.R. 170.3(e) (1997) (tracking the statutory definition). The United States Department of Agriculture (USDA) regulates food additives to the extent that they are used in meat products. See 9 C.F.R. 318.7(a)(2) (1997). The statutory definition of adulteration largely defers, however, to FDA decisions regarding the safety of such additives. See 21 U.S.C. 601(m)(2)(C).

n48. See 21 U.S.C. 321(s) (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").

n49. See id. 321(s)(1)-(6). One of the other exceptions covers certain substances approved prior to 1958. See id. 321(s)(4); see also infra Part II.C (discussing the "prior sanctions" exception). Many of these exceptions have been modified over the years, most recently by the Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103-417, 3(b), 108 Stat. 4325, 4327-28, and the Food Quality Protection Act of 1996, Pub. L. No. 104-170, 402(b), 110 Stat. 1489, 1513.

n50. See 21 U.S.C. 346a (establishing a regulatory framework for setting tolerances for pesticide residues); id. 350b (requiring premarket notification for new dietary ingredients unless an enumerated exception applies); id. 360b (requiring premarket review of drugs for food-producing animals unless an enumerated exception applies); id. 379e (addressing the listing of color additives). Recently, Congress substantially amended the provision authorizing tolerances for pesticide residues in or on raw agricultural commodities to also include processed foods. See Food Quality Protection Act of 1996, Pub. L. No. 104-170, 405, 110 Stat. 1489, 1514.

n51. 21 U.S.C. 321(s).

n52. See S. Rep. No. 73-493, at 2-3 (1934) ("The use to which a product is put will determine the category into which it will fall... The manufacturer of the article, through his representations in connection with its sale, can determine the use to which the article is to be put."); United States v. Undetermined Quantities of "Cal-Ban 3000," 776 F. Supp. 249, 253-55 (E.D.N.C. 1991) (holding that guar gum product advertised as interfering with the absorption of food was a drug); cf. Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 337 (7th Cir. 1983) (noting that the statutory definition of food, unlike other articles subject to FDA regulation, does not explicitly refer to intended use); Lars Noah & Barbara A. Noah, Nicotine Withdrawal: Assessing the FDA's Effort to Regulate Tobacco Products, 48 Ala. L. Rev. 1, 9-10 (1996).

n53. See 1957 Hearings, supra note 22, at 62 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.) ("We presume that the FDA gave this amendment a chemical additive name to emphasize that it mainly applies to such industrial additives... and to give it a strong congressional and popular appeal.").

n54. See, e.g., id. at 209 (statement of H.T. Austern, appearing on behalf of the Nat'l Canners Ass'n) ("Although some of these bills are titled as "chemical additive' proposals, every one of them covers every new food ingredient - animal, vegetable, chemical, biological, natural, or even something not found in nature...."); United States v. An Article of Food* * * FoodScience Lab., 678 F.2d 735, 738 (7th Cir. 1982) ("Had Congress intended the [FDA] and the courts to rely on common parlance it would not have so carefully crafted the foregoing definition of the term ["food additive']."); National Nutritional Foods Ass'n v. Kennedy, 572 F.2d 377, 391 (2d Cir. 1978) (doubting that "a substance gains immunity from this [food additive] criterion merely because it also qualifies as a food"); see also 21 U.S.C. 342(a)(2)(C) (providing that a food shall be deemed to be adulterated "if it is or it bears or contains any food additive which is unsafe" (emphasis added)). It is a popular misconception
 
that "food additives" are artificial substances used in food production while natural ingredients, such as salt or potatoes, are simply that - ingredients. In fact, not every artificial substance used to make food is a food additive. Moreover, the Act does not distinguish between ingredients produced by chemical synthesis and those produced naturally by agriculture.
 
 Merrill, supra note 10, at 203.

n55. See 21 U.S.C. 321(s) (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").

n56. See S. Rep. No. 85-2422, at 5 (1958) (explaining that the legislation covers both "intentional" and "incidental" additives but not "accidental" additives); cf. H.R. 8112, 85th Cong. 5 (1957) (proposing a separate review mechanism for incidental additives). For purposes of the FDA's ingredient labeling regulations, "incidental additives" are defined to include processing aids such as "substances that are added to a food during processing, are converted into constituents normally present in the food, and do not significantly increase the amount of the constituents naturally found in the food." 21 C.F.R. 101.100(a)(3)(ii)(b) (1997).

n57. See, e.g., Gerber Prods. Co. v. Fisher Tank Co., 833 F.2d 505, 508 (4th Cir. 1987) (holding that liner on hot water storage tank used in processing baby foods constituted a food additive); Natick Paperboard Corp. v. Weinberger, 525 F.2d 1103, 1106-07 (1st Cir. 1975) (holding that PCB contamination in paperboard packaging material constituted a food additive if likely to migrate into food); United States v. Articles of Food Consisting of * * * Pottery, 370 F. Supp. 371, 373 (E.D. Mich. 1974) (holding that lead in pottery dinnerware could constitute a food additive); see also Jerome H. Heckman, Fathoming Food Packaging Regulation: A Guide to Independent Industry Action, 42 Food Drug Cosm. L.J. 38, 39 (1987) (explaining that food packaging materials, reasonably expected to migrate into foods, constitute food additives).

n58. See 21 C.F.R. 170.3(e)(1) ("If there is no migration of a packaging component from the package to the food, it does not become a component of the food and thus is not a food additive."); Monsanto Co. v. Kennedy, 613 F.2d 947, 955 (D.C. Cir. 1979) ("Congress did not intend that the component requirement of a "food additive' would be satisfied by a mere recitation of the diffusion principle, a mere finding of any contact whatever ... [A substance's] presence in food [must] be predicted on the basis of a meaningful projection from reliable data.").

n59. See Food Additives Resulting from Contact with Containers or Equipment and Food Additives Otherwise Affecting Food, 40 Fed. Reg. 6489, 6489 (1975) (finding that, because of the possibility of significant migration from a food-contact surface, acrylonitrile copolymer was a food additive when used to manufacture beverage containers, and setting tolerances for acceptable levels of migration).

n60. See Indirect Food Additives: Polymers; Acrylonitrile/Styrene Copolymers, 49 Fed. Reg. 36,635, 36,635-36 (1984) (summarizing the regulatory history); Acrylonitrile Copolymers Used to Fabricate Beverage Containers, 42 Fed. Reg. 17,529, 17,529 (1977) (announcing a formal evidentiary hearing on the matter); Acrylonitrile Copolymer Beverage Containers; Stay of Regulations, 42 Fed. Reg. 13,546, 13,546 (1977) (staying approval of acrylonitrile in the production of beverage bottles).

n61. See 42 Fed. Reg. 48,528, 48,543 (1977).

n62. 613 F.2d 947 (D.C. Cir. 1979).

n63. See id. at 952 ("The Commissioner had made a projection of migration from 3.3 ppm RAN containers without the support of any actual data showing that migration had occurred from such containers.").

n64. See id. at 954-56. The court explained that the Commissioner ultimately may determine "that the level of migration into food of a particular chemical is so negligible as to present no public health or safety concerns... This authority derives from the administrative discretion, inherent in the statutory scheme, to deal appropriately with de minimis situations." Id. at 955 (footnote omitted).

n65. See Indirect Food Additives: Polymers; Acrylonitrile/Styrene Copolymers, 49 Fed. Reg. at 36,642 (codified as amended at 21 C.F.R. 177.1040 (1997)); see also Indirect Food Additives; Polymers, 52 Fed. Reg. 33,802, 33,803 (1987) (approving acrylonitrile for use in certain alcoholic beverage containers).

n66. See 21 C.F.R. pts. 175-178 (1997) (listing all approved indirect additives); see also id. pt. 186 (listing GRAS affirmations for indirect food-use substances).

n67. See 1995 Hearings, supra note 1, at 31 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("About 75 percent [of all applicants] are the indirects."); Hutt, supra note 1, at 122 ("It is easy to be misled about the efficiency of FDA regulation of food additives by counting the Federal Register food additive notices... More than 80% of these notices relate to obscure indirect food additives that have no possible bearing on the public health.").

n68. See Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. 36,582, 36,595 (1995) (codified at 21 C.F.R. 170.39(a)(2)(i) (1997)). This "threshold of regulation" policy is discussed more fully at infra notes 459-64 and accompanying text.

n69. See United States v. 29 Cartons of * * * An Article of Food, 987 F.2d 33, 37-39 (1st Cir. 1993); United States v. Two Plastic Drums, 984 F.2d 814, 820 (7th Cir. 1993).

n70. See 29 Cartons, 987 F.2d at 35; Two Plastic Drums, 984 F.2d at 815. Evidently, the FDA harbored concerns about the product's safety but was not able to shoulder the burden of proving that the substance was poisonous and deleterious such that it might render the food injurious to health. See 29 Cartons, 987 F.2d at 35 ("Although the FDA suspects that BCO may be unhealthful, it is unable at the present time to translate this suspicion into legally competent proof.").

n71. See 29 Cartons, 987 F.2d at 37 ("We are reluctant to believe that Congress traffics in absurdities... The FDA's reading of the Act is nonsensical, and, hence, must be incorrect."); id. at 39 (concluding that the Agency's reading "perverts the statutory text, undermines legislative intent, and defenestrates common sense"); Two Plastic Drums, 984 F.2d at 819 ("The only justification for this Alice-in-Wonderland approach is to allow the FDA to make an end-run around the statutory scheme and shift to the processors the burden of proving the safety of a substance in all circumstances.").

n72. See 29 Cartons, 987 F.2d at 37; Two Plastic Drums, 984 F.2d at 819-20. Although not discussed in these terms, the courts' interpretation helps make sense of the previously mentioned incongruity between the definitions of "food" (including "components") and "food additive" (including "components"). See United States v. 29 Cartons of * * * An Article of Food, 792 F. Supp. 139, 141 (D. Mass. 1992), aff'd, 987 F.2d 33 (1st Cir. 1993); cf. Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 337 (7th Cir. 1983) (concluding that the statutory definition of "food" is broad enough to encompass "food additives").

n73. See 29 Cartons, 987 F.2d at 35, 37; Two Plastic Drums, 984 F.2d at 816-17, 819. In fact, the FDA originally premised its seizure on a claim that the gamma linolenic acid in the BCO constituted an unapproved food additive component of the BCO capsules. See 29 Cartons, 987 F.2d at 38-39 n.6 (adding that the Agency's shifting litigation position made judicial deference to its interpretation of the statute even less appropriate).

n74. 29 Cartons, 987 F.2d at 36.

n75. See id. at 36-37 (elucidating the Agency's "mere presence" position versus the claimant's "affirmative use" stance).

n76. See Two Plastic Drums, 984 F.2d at 817 ("This language is very broad, and thus, the general rule is that a component of an article of food is a food additive, even if the component in question is the "principal component,' i.e., the ingredient sought when purchasing the food.").

n77. See 29 Cartons, 987 F.2d at 37 (suggesting that such an interpretation would create "a bizarre paradox"); Two Plastic Drums, 984 F.2d at 817 ("To hold that BCO is a component of the dietary supplement would be to find that BCO is a component of itself.").

n78. See 29 Cartons, 987 F.2d at 38 ("In the final analysis, what counts is the use of an ingredient for its effect on food. Here... BCO is not being used for its effect on gelatin and glycerine... If the BCO is removed, one is left with nothing but an empty capsule."); Two Plastic Drums, 984 F.2d at 818 ("Even if we were to find that BCO was a component of the BCO dietary supplement capsules, the language of the Act indicates that it is not a food additive because, as the single active ingredient, it does not affect the characteristics of any food.").

n79. Cf. 29 Cartons, 987 F.2d at 35 (noting that these ingredients "have no independent nutritional value" and may not therefore meaningfully affect the food's characteristics); Two Plastic Drums, 984 F.2d at 816-17 & n.2 (mentioning that gelatin and glycerin are functional insofar as they prevent the black currant oil from becoming rancid, but then explaining that they "do not interact with or change the character of the BCO," and noting that gelatin and glycerin do not qualify as food additives for a different reason, namely, because they are generally recognized as safe).

n80. See 29 Cartons, 987 F.2d at 38 n.5 ("We do not quarrel with those courts that have held, when confronted with multi-ingredient products containing two or more active ingredients, that each active ingredient is potentially a food additive."); Two Plastic Drums, 984 F.2d at 818 ("When two or more active ingredients comprise a food, each component is arguably different from the food in such a way that the addition of each has affected the characteristics of the other components and of the food."); see also 21 C.F.R. 170.3(g) (1997) ("The word substance in the definition of the term "food additive' includes a food component consisting of one or more ingredients."); United States v. An Article of Food * * * FoodScience Lab., 678 F.2d 735, 738 (7th Cir. 1982) (rejecting claimant's argument that the definition of "food additive" applied only to minor rather than principal ingredients, and observing that the "term "component' of course includes large quantities of unsafe substances as well as small").

n81. See United States v. 21 Appx. 180 Kg. Bulk Metal Drums, 761 F. Supp. 180, 182, 185 (D. Me. 1991).

n82. See United States v. 45/194 Kg. Drums of Pure Vegetable Oil, 961 F.2d 808, 812 & n.3 (9th Cir. 1992); see also Dietary Supplement Coalition, Inc. v. Sullivan, 978 F.2d 560, 563-64 (9th Cir. 1992) (holding that FDA action against the makers of Co-enzyme Q10 was not ripe for judicial review, in part because the distinction between "food" and "food additive" was not a pure legal question but would depend on Agency findings of fact); FoodScience Lab., 678 F.2d at 737-38 (holding that the "principal ingredient" in a dietary supplement nonetheless constituted a food additive because it was combined with another active ingredient); United States v. 42/30 Tablet Bottles, 779 F. Supp. 253, 255 (E.D.N.Y. 1991) ("Both CoQ10 and Germanium satisfy the plain meaning of the "component' requirement of the food additive definition because they are one or two of several ingredients in each of the dietary supplements produced by claimants.").

n83. See Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103-417, 108 Stat. 4325 (codified in scattered sections of 21 U.S.C.). Among other things, the Act places on the FDA the burden of proof in an adulteration proceeding against a dietary supplement product, and the Agency must prove that the supplement "presents a significant or unreasonable risk of illness or injury." 21 U.S.C. 342(f)(1)(A) (1994). In addition, a 75-day premarket notification requirement applies to "new dietary ingredients." Id. 350b(a)(2). Finally, the statute authorizes special labeling claims under certain circumstances. See id. 343(r)(6), 343-2; see also Food Labeling; Statement of Identity, Nutritional Labeling and Ingredient Labeling of Dietary Supplements, 60 Fed. Reg. 67,194 (1995); Margaret Gilhooley, Herbal Remedies and Dietary Supplements: The Boundaries of Drug Claims and Freedom of Choice, 49 Fla. L. Rev. 663 (1997); Robert G. Pinco & Paul D. Rubin, Ambiguities of the Dietary Supplement Health and Education Act of 1994, 51 Food & Drug L.J. 383 (1996); Jennifer J. Spokes, Note, Confusion in Dietary Supplement Regulation: The Sports Products Irony, 77 B.U. L. Rev. 181 (1997).

n84. See 21 U.S.C. 321(s)(6); see also United States v. Ten Cartons * * * Ener-B Nasal Gel, 888 F. Supp. 381, 395 (E.D.N.Y. 1995) (holding that a product intended for parenteral administration did not satisfy DSHEA's definition of dietary supplement).

n85. See 21 U.S.C. 350b(c). A person wishing to use a "new dietary ingredient" would first have to petition the Agency, "proposing the issuance of an order prescribing the conditions under which a new dietary ingredient under its intended conditions of use will reasonably be expected to be safe." Id. 350b(b) (adding that the Agency "shall make a decision on such petition within 180 days").

n86. See id. 350b(a)(2) (the notification would have to demonstrate that "there is a history of use or other evidence of safety"). If the FDA were not persuaded by the notification, it could prevent marketing only by initiating (or threatening) formal enforcement proceedings, and the Agency would shoulder the burden of proving that the product is adulterated. See id. 342(f)(1).

n87. Id. 321(s). Congress elaborated on this concept by stipulating that the substance be
 
generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use.
 
 Id.; see also 21 C.F.R. 170.30(a) (1997) (tracking the statutory definition).

n88. At least one witness at the congressional hearings apparently thought so, for he suggested that a company could seek the advice of private or academic consultants on whether a substance was GRAS based on existing data. See 1957 Hearings, supra note 22, at 94-95 (statement of Robert B. Smith, Jr., President, Med. College of Va.).

n89. See 1956 Hearings, supra note 16, at 66 (statement of Glenn G. Paxton, appearing as counsel for various food industry associations) ("All of the bills that I have seen which have ever been written on this subject have had a general exception for substances generally recognized by the experts to be safe."); Frederick H. Degnan, Rethinking the Applicability and Usefulness of the GRAS Concept, 46 Food Drug Cosm. L.J. 553, 556-61 (1991).

n90. See 104 Cong. Rec. 17,420 (1958) (letter from John L. Harvey, Deputy Comm'r, FDA) (explaining that GRAS is not "a grandfather clause as that term is normally used"); 104 Cong. Rec. 17,415 (1958) (letter from Elliot L. Richardson, Asst. Secretary, HEW) ("The grandfather clause, as proposed in some of the bills before your committee would have exempted substances used in food prior to enactment of the legislation from having to meet its requirements at all. This Department opposed such a provision....").

n91. See, e.g., 1956 Hearings, supra note 16, at 40 (statement of Hon. A.L. Miller) ("Legislation requiring exhaustive laboratory analysis, pretesting and reporting of the old, recognized, safe additives would serve no useful purpose and would be unduly burdensome upon both industry and Government."); id. at 228 (statement of William W. Goodrich, FDA Counsel) (arguing that the GRAS exception was necessary "to make the legislation reasonable"); see also GAO, New Food Technologies, supra note 9, at 62 (noting that defenders of the exception "believe that the GRAS provisions give FDA a flexible mechanism to rank-order expenditures of limited resources and to focus its efforts on food additives posing the greatest concern to public health"); Huber, supra note 41, at 1038-39 (arguing that the GRAS exception "mandated that old additives should be regulated less strictly than new ones").

n92. See Food Additives Amendment of 1958, Pub. L. No. 85-929, 6, 72 Stat. 1784, 1788. Some members of Congress criticized the transitional provisions and (correctly) feared future extensions:
 
Experience has shown us that an extended grace period in any legislation affecting a long overdue reform in existing practices almost always seems to lead to additional moratoriums and delays and there always seems to be a good reason for allowing the industry affected more and more time in which to comply with the law.
 
 104 Cong. Rec. 17,424 (1958) (statement of Hon. Leonor K. Sullivan). Congress subsequently extended this phase-in period by almost five additional years. See Food Additives Transitional Provisions Amendment of 1964, Pub. L. No. 88-625, 2, 78 Stat. 1002 (granting extension until December 31, 1965); Food Additives Transitional Provisions Amendment of 1961, Pub. L. No. 87-19, 2, 75 Stat. 42 (granting extension until June 30, 1964); see also Degnan, supra note 89, at 561 (explaining that the FDA allowed the marketing of more than 3000 substances on a transitional basis); Hutt, supra note 1, at 120-21 (praising the "heroic effort by FDA" during this transitional period, adding that its productivity "at that time in history stands in stark contrast to the inefficiency and paralysis of today").

n93. See 21 U.S.C. 321(p)(1) (1994) (excluding from the definition of "new drug" any drug "generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof"). Unlike the definition for food additives, a GRAS/GRAE drug also must have "been used to a material extent or for a material time under such conditions." Id. 321(p)(2); see also Kenneth C. Baumgartner, Getting a Grip on Material Time and Extent, 49 Food & Drug L.J. 433 (1994) (addressing the definition of "new drug").

n94. See Pub. L. No. 83-518, 3 (408(a)), 68 Stat. 511, 511 (1954) (codified at 21 U.S.C. 346a(a)), repealed and replaced by Food Quality Protection Act of 1996, Pub. L. No. 104-170, 405, 110 Stat. 1489, 1514. Interestingly, just two years after enacting the Food Additives Amendment of 1958, Congress failed to include a GRAS exception in the Color Additive Amendments. See Color Additive Amendment of 1960, Pub. L. No. 86-618, 101(c), 74 Stat. 397, 397 (codified at 21 U.S.C. 321(t)). Instead, Congress authorized a transitional category, allowing the FDA to include color additives in use in 1960 on a "provisional list" pending further safety testing. See id. 203, 74 Stat. 397, 404; see also 21 U.S.C. 379e(b)(4) (excluding a color additive if listed by the FDA as a GRAS food substance); Postponement of Closing Dates, 42 Fed. Reg. 6992 (1977) (requiring further testing); McIlwain v. Hayes, 690 F.2d 1041, 1046-49 (D.C. Cir. 1982) (upholding the FDA's authority to continue postponing final action on provisionally listed color additives, especially where made necessary by improvements in safety testing standards); Certified Color Mfrs. Ass'n v. Mathews, 543 F.2d 284, 286-88 (D.C. Cir. 1976) (describing provisional listing system); Hutt, supra note 1, at 126 (explaining that the FDA repeatedly extended the transitional period as it imposed additional testing requirements).

n95. See 1956 Hearings, supra note 16, at 203-05 (testimony of George P. Larrick, Comm'r, FDA) (describing the FDA's experience in applying the GRAS exception for drugs); see also 1957 Hearings, supra note 22, at 65 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.) (declining to propose alternative GRAS language "because these laws have been practically successful, notwithstanding the obscurity of this clause and because it has been given a reasonable construction of necessity"); Degnan, supra note 89, at 557-60 (describing the debate over whether to adopt GRAS language).

n96. See Degnan, supra note 89, at 570-80 (describing evolution from a flexible and informal concept to a more rigidly defined category). For instance, the Agency modified its implementing regulations on several occasions. See, e.g., Eligibility for Classification of Food Substances as Generally Recognized as Safe, 53 Fed. Reg. 16,544 (1988); General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600 (1976); Eligibility of Substances for Classification as Generally Recognized as Safe in Food, 36 Fed. Reg. 12,093 (1971).

n97. See 21 C.F.R. 170.30(a) (1997) ("[GRAS] requires common knowledge about the substance throughout the scientific community knowledgeable about the safety of substances directly or indirectly added to food."); see also United States v. An Article of Food * * * FoodScience Lab., 678 F.2d 735, 740 (7th Cir. 1982) (holding that the trial judge "was entitled to credit the testimony of the government's five doctors that DMG is not" GRAS as against the claimant's single expert who testified to the contrary); United States v. Articles of Food & Drug, 518 F.2d 743, 746 (5th Cir. 1975) ("What is required is not unanimous recognition but general recognition."); United States v. 41 Cases, More or Less, 420 F.2d 1126, 1130 (5th Cir. 1970) ("The absence of scientific knowledge on the part of an expert and his colleagues is sufficient to show lack of general recognition of safety."). But cf. United States v. An Article of Food, 622 F.2d 768, 772-73 (5th Cir. 1980) (reversing order granting the government's motion for summary judgment in an action for seizure of gentian violet pre-mix, finding a genuine issue of material fact concerning this substance's GRAS status because the claimant countered the FDA's two experts with references to 23 studies and 40 scientists or veterinarians who purportedly recognized its safety).

n98. 21 C.F.R. 170.30(b); see also id. 170.3(h) ("Scientific procedures include those human, animal, analytical, and other scientific studies, whether published or unpublished, appropriate to establish the safety of a substance."); United States v. 45/194 Kg. Drums of Pure Vegetable Oil, 961 F.2d 808, 813 (9th Cir. 1992) (rejecting claimant's expert testimony asserting that evening primrose oil was GRAS because the data relied upon concerned its use in drugs rather than dietary supplements and the "other data was based on unpublished materials, which were not subjected to peer evaluation"); cf. Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579, 587-95 (1993) (rejecting the general acceptance standard as the sole test for the admissibility of scientific evidence, but suggesting additional factors such as peer review and publication as bases for ensuring reliability).

n99. See Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,960 (1997). The Agency explained that publication in a peer-reviewed scientific journal usually is necessary but may not be sufficient to establish general recognition, adding that common knowledge may be demonstrated by:
 
(1) Publication of data and information in the secondary scientific literature, such as scientific review articles, textbooks, and compendia; (2) documentation of the opinion of an "expert panel" that is specifically convened for this purpose; or (3) the opinion or recommendation of an authoritative body such as the National Academy of Sciences.
 
 Id. at 18,941; see also id. at 18,943 (elaborating on these bases for claiming GRAS status); Lars Noah, Sanctifying Scientific Peer Review: Publication as a Proxy for Regulatory Decisionmaking, 59 U. Pitt. L. Rev. 677, 700-01 (1998) (arguing that administrative agencies should more carefully distinguish between the primary and secondary scientific literature and recognize that the latter provides a more reliable basis for making regulatory decisions).

n100. See, e.g., Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,939 (emphasizing that "it is the use of a substance, rather than the substance itself, that is eligible for the GRAS exemption"); United States v. An Article of Food * * * Coco Rico, Inc., 752 F.2d 11, 15 (1st Cir. 1985) ("The substance must be generally recognized as safe under the conditions of its intended use."); National Nutritional Foods Ass'n v. Kennedy, 572 F.2d 377, 392 (2d Cir. 1978) ("We see no reason why [the Commissioner] cannot determine that too much of even a good thing [i.e., use of high potency vitamins and minerals with a history of common use at lower levels] may come within the definition of a "food additive.'"); United States v. Naremco, Inc., 553 F.2d 1138, 1143 (8th Cir. 1977) (holding that the definition "refers to experience based on common use as a food additive or under conditions producing long-term ingestion," and, therefore, that "the pre-1958 use of gentian violet as an animal drug cannot be considered probative"); United States v. Articles of Food * * * Buffalo Jerky, 456 F. Supp. 207, 209 (D. Neb. 1978) ("While the claimant points to other uses of sodium nitrate and sodium nitrite which have been recognized as being safe, these examples are not comparable to the use in this case...."), aff'd, 594 F.2d 869 (8th Cir. 1979) (per curiam); cf. 21 C.F.R. 170.30(c)(1) (Prior use GRAS "shall be based solely on food use of the substance prior to January 1, 1958, and shall ordinarily be based upon generally available data and information.").

n101. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,940 ("[The] FDA has defined "safe'... as a reasonable certainty in the minds of competent scientists that the substance is not harmful under its intended conditions of use."). The Agency explained that GRAS requires "consensus" but not "unanimity" among experts. See id. at 18,941 (adding that "a single published report questioning the safety of use" would not "automatically disqualify the substance from satisfying the GRAS standard").

n102. See, e.g., Coco Rico, 752 F.2d at 15.

n103. See 21 C.F.R. 170.30(c)(1) ("General recognition of safety through experience based on common use in food prior to January 1, 1958, may be determined without the quantity or quality of scientific procedures required for approval of a food additive regulation."); see also General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,600 (1976) ("For those substances that were widely used before 1958, under the terms of the statute FDA must consider available data and may not prohibit use of a substance merely because tests that would be required for new food additives have not been performed.").

n104. See 21 C.F.R. 170.3(f) ("Common use in food means a substantial history of consumption of a substance for food use by a significant number of consumers."); Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,949-50 ("[A] substance is not eligible for the GRAS exemption merely because it was used in food before January 1, 1958, if such use were not sufficiently widespread."); Coco Rico, 752 F.2d at 15 n.7 ("Use in one manufacturer's product does not constitute "common use' in that food."); Naremco, 553 F.2d at 1143 n.7 ("Testimony that prior to 1958 one particular gentian violet drug was recommended for continuous use... is patently insufficient....").

n105. See 21 C.F.R. 170.3(f) (1982); General Recognition of Safety and Prior Sanctions for Food Ingredients, 39 Fed. Reg. 34,194, 34,195 (1974) (explaining that "use in foreign countries often cannot be verified, and in any event the experience based upon such use cannot be monitored or evaluated"). At least one of the food additives bills would have defined GRAS by reference to prior use only in the United States. See H.R. 7764, 84th Cong. 1 (1955).

n106. See Fmali Herb, Inc. v. Heckler, 715 F.2d 1385, 1390 (9th Cir. 1983). The Court stated:
 
It is an illogical and, we think, unwarranted constriction of the statute to rule that evidence of long use of a substance in food outside the United States can never provide probative evidence of safety... The statute provides no basis for a purely ethnocentric distinction of this kind, divorced from demographic considerations.
 
 Id.

n107. See 21 C.F.R. 170.30(c)(2); see also Eligibility for Classification of Food Substances as Generally Recognized as Safe, 53 Fed. Reg. 16,544, 16,544-45 (1988) (defending the revised regulation as consistent with the court's holding in Fmali Herb); Eligibility for Classification of Food Substances as Generally Recognized as Safe, 50 Fed. Reg. 27,294, 27,295 (1985) (explaining the need to require ready availability of information concerning the foreign use).

n108. See 21 C.F.R. 170.30(c)(2) (requiring that "the information about the [foreign] experience establish[] that the use of the substance is safe within the meaning of the act"); see also Eligibility for Classification of Food Substances as Generally Recognized as Safe, 50 Fed. Reg. at 27,296 ("The review needs to be performed to assure that the substance has been shown to be safe, as that term is understood in this country."); id. at 27,295-96 (explaining that different societies have differing conceptions of safety).

n109. See 21 C.F.R. 170.30(c)(2); Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,943-44 (1997) (proposing that manufacturers utilize the new GRAS notification procedure to seek concurrence when GRAS status is based on prior foreign use); see also Maltodextrin Derived from Potato Starch; Affirmation of GRAS Status as Direct Human Food Ingredient, 60 Fed. Reg. 48,890, 48,891 (1995) (affirming GRAS status based in part on consumption in Europe prior to 1958); Substances Affirmed as Generally Recognized as Safe: Hydrogenated and Partially Hydrogenated Menhaden Oils, 54 Fed. Reg. 38,219, 38,220, 38,223 (1989) (codified at 21 C.F.R. 184.1472 (1997)) (affirming GRAS status based on extensive consumption in Europe prior to 1958); cf. Eligibility for Classification of Food Substances as Generally Recognized as Safe, 53 Fed. Reg. at 16,545-46 (emphasizing that FDA concurrence is not mandatory but strongly preferred).

n110. See 1957 Hearings, supra note 22, at 461-62 (statement of George P. Larrick, Comm'r, FDA); see also id. at 464 ("There are literally thousands of substances in that category."). One witness read the GRAS exception to mean that "this amendment would not apply to normally safe food additives of agricultural and farm origin; it would principally apply to food chemical additives in an industrial sense." Id. at 64 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.).

n111. See, e.g., Lists of Substances, 26 Fed. Reg. 938 (1961); Substances That Are Generally Recognized as Safe, 24 Fed. Reg. 9368 (1959); see also Arthur A. Checchi, Food-Additives Amendment - Requirements and Proposed Regulations, 13 Food Drug Cosm. L.J. 765, 767 (1958) (discussing the preparation of the partial GRAS list); William W. Goodrich, The Beginning Point Under the Food-Additives Amendment - What Substances Do Qualified Experts Generally Recognize as Safe?, 14 Food Drug Cosm. L.J. 584, 587 (1959) (describing the publication and circulation of the list of substances with GRAS status); George P. Larrick, Status of Food-Additives Control, 15 Food Drug Cosm. L.J. 268, 269-70 (1960) (noting that several hundred substances have been designated as GRAS). One of the earlier bills would have required the issuance and periodic revision of a GRAS list. See H.R. 366, 85th Cong. 5 (409(h)) (1957).

n112. See 21 C.F.R. 121.101(d) (1965).

n113. See Cyclamic Acid and Its Salts, 34 Fed. Reg. 17,063 (1969) (deleting cyclamates from the GRAS list); see also H.R. Rep. No. 91-1585 (1970) (detailing the history and use of cyclamates from 1940 to 1970). Most scientists now conclude that cyclamates pose no significant human cancer risk. See Malcolm Gladwell, FDA Confirms Cyclamate Ban May End, Wash. Post, May 17, 1989, at A5.

n114. See 21 C.F.R. 170.30(e) (1997); see also id. 182.1(d) ("When the status of a substance has been reevaluated, it will be deleted from [the original GRAS list], and will be issued as a new regulation under the appropriate part...."); Eligibility of Substances for Classification as Generally Recognized as Safe in Food, 36 Fed. Reg. 12,093, 12,093 (1971) ("A current review of GRAS substances is necessary because of new scientific knowledge, the development of modern toxicological techniques, and the expanded usage of some GRAS substances beyond the exposure patterns considered when the GRAS list was originally promulgated."); Eligibility of Substances for Classification as Generally Recognized as Safe in Food, 35 Fed. Reg. 18,623 (1970) (announcing prior GRAS criteria for the comprehensive review). President Nixon ordered the FDA to undertake this review. See Consumer Protection, 5 Wkly. Comp. Pres. Doc. 1516, 1522 (1969) ("I have already asked the Secretary of [HEW] to initiate a full review of food additives..., re-examining the safety of [GRAS] substances....").

n115. See 21 C.F.R. 170.30(f); see also Roger D. Middlekauff, Food Safety Review - New Concepts for GRAS, 30 Food Drug Cosm. L.J. 288, 291 (1975) (commenting that "the FDA believed that some GRAS substances are more GRAS than others").

n116. See Industry Survey of Production and Use of GRAS Substances, 36 Fed. Reg. 20,546 (1971); NAS, A Comprehensive Survey of Industry on the Use of Food Chemicals Generally Recognized as Safe (1972); see also Survey and Availability of Questionnaire, 42 Fed. Reg. 30,894 (1977) (announcing follow up NAS survey).

n117. See Select Committee on GRAS Substances, 38 Fed. Reg. 20,054, 20,055 (1973). The FDA initiated similar reviews in the drug area. See Kenneth C. Baumgartner, A Historical Examination of the FDA's Review of the Safety and Effectiveness of Over-the-Counter Drugs, 43 Food Drug Cosm. L.J. 463 (1988); Gary L. Yingling, Are We on the Road to a Single Drug Approval Process?, 45 Food Drug Cosm. L.J. 235 (1990).

n118. See 1995 Hearings, supra note 1, at 114 (statement of Kenneth D. Fisher, former Dir., LSRO).

n119. See id. at 115 (describing the advantages of using this approach).

n120. See id. at 117. In addition, SCOGS concluded that 15% should remain GRAS but with use limitations because of the need for additional safety information for new uses; that 7% should lose GRAS status unless data is submitted for review; and that 5% should become subject to an interim food additive regulation to resolve uncertainties. See id.; see also H.R. Rep. No. 104-436, at 5 (1995) (summarizing FASEB's GRAS list review); Stephen Breyer, Regulation and Its Reform 142-47 (1982) (discussing some of the difficulties encountered in FASEB's GRAS list review); Sheila Jasanoff, The Fifth Branch: Science Advisers as Policymakers 218-22 (1990) (praising FASEB's review).

n121. See Hutt, supra note 1, at 121 ("In spite of the fact that FASEB completed its work several years ago, not only has FDA failed to complete its much more limited role in this process, but the end is not even in sight.").

n122. See 21 C.F.R. 184.1005-.1985 (1997). In addition, numerous substances remain on the original GRAS list pending the completion of the Agency's review of each substance. See id. 182.10-.8997.

n123. Id. 170.30(d). Thus, it acknowledges that a substance "of natural biological origin that has been widely consumed for its nutrient properties in the United States prior to January 1, 1958, without known detrimental effects, which is subject only to conventional processing... will ordinarily be regarded as GRAS without specific inclusion" in one of the GRAS lists. Id.; see also id. 170.30(k) ("In addition to the use(s) specified in [a GRAS affirmation] regulation, other uses of such an ingredient may also be GRAS."); GAO, New Food Technologies, supra note 9, at 28 ("[The] FDA estimates that approximately 1,450 of about 2,700 substances that it knows are added directly to food are GRAS and prior sanctioned substances. The majority of these substances have not been reviewed by FDA."); Merrill, supra note 10, at 214 n.160 (noting that the FDA "has been unable to devise a procedure to force users of unlisted ingredients to seek review and confirmation of their safety"). "By way of illustration, the Commissioner regards such common food ingredients as salt, pepper, vinegar, baking powder, and monosodium glutamate as safe for their intended use." 21 C.F.R. 182.1(a). This language first appeared in the FDA's original notice of proposed rulemaking. See Food Additives: Proposed Definitions and Procedural and Interpretive Regulations, 23 Fed. Reg. 9511, 9516 (1958).

n124. At a minimum, a GRAS substance must comply with any applicable food grade specifications appearing in the Food Chemicals Codex, a compilation of monographs published by NAS. See 21 C.F.R. 170.30(h)(1). A GRAS substance also must perform an appropriate function (and be used at a level no higher than necessary to fulfill that function) in the food (or food-contact article) in which it is used. Id. 170.30(h)(2)-(3).

n125. See id. 170.30(j) ("Any use of such an ingredient not in full compliance with each such established limitation shall require a food additive regulation."); see also id. 184.1(b)(2); Substances Generally Recognized as Safe, 48 Fed. Reg. 48,457, 48,458 (1983) ("The agency has determined that a GRAS affirmation regulation should only include those CGMP conditions of use that are necessary to ensure the continued safe use of the ingredient... and to discourage any potentially unsafe proliferation in the use of these substances.").

n126. See 21 C.F.R. 170.30(i) ("In such a case a manufacturer may not rely on the regulation as authorizing the use but must independently establish that the use is GRAS or must use the substance in accordance with a food additive regulation."); see also id. 184.1(b)(1),(3); id. 184.1(a) (providing that substances affirmed as GRAS as direct ingredients also are GRAS as indirect ingredients); Substances Generally Recognized as Safe, 48 Fed. Reg. at 48,458 ("The existence of a GRAS affirmation regulation that contains conditions of use does not bar a manufacturer from expanding the use of a GRAS ingredient beyond the conditions described in the regulation if the manufacturer makes its own GRAS determination."); General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,601 (1976) (noting that a substance may be GRAS for some uses and also be covered by a food additive regulation for other uses).

n127. 21 C.F.R. 170.30(l); see, e.g., Saccharin and Its Salts: Removal from Generally Recognized as Safe List; Provisional Regulation Prescribing Conditions of Safe Use, 36 Fed. Reg. 12,109, 12,110 (1971) (proposing to revoke saccharin's GRAS status and substitute a provisional food additive regulation); Cyclamic Acid and Its Salts, 34 Fed. Reg. 17,063 (1969) (revoking cyclamate's GRAS status); Jane E. Henney, Food Safety Challenges and the New Center, 48 Food & Drug L.J. 473, 477 (1993) (describing ongoing safety reviews of BHA and MSG).

n128. See 21 C.F.R. 170.30(l) (cross-referencing 21 C.F.R. 170.38).

n129. See id. 171.130(a) (cross-referencing the procedures specified in 21 C.F.R. pt. 10); id. 10.50(c)(5) (providing for an opportunity for a formal evidentiary hearing to the extent required for the issuance, amendment, or repeal of food additive regulations under the statute); see also infra Part III.C (describing the use of "interim" food additive status when the safety of a food-use substance is brought into question).

n130. See, e.g., Eligibility for Classification of Food Substances as Generally Recognized as Safe, 53 Fed. Reg. 16,544, 16,545 (1988). Under the regulations promulgated in 1971, "no substance will be eligible for GRAS status if it has no history of food use." Eligibility of Substances for Classification as Generally Recognized as Safe in Food, 36 Fed. Reg. 12,093, 12,094 (1971) (codified at 21 C.F.R. 121.3(c) (1972)). Just five years later, the FDA deleted this restriction. See General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,605 (1976) (codified at 21 C.F.R. 170.30).
 
GRAS status may be achieved for post-1958 food ingredients on the basis of scientific procedures even prior to any significant history of marketing and use. Unlike the definition of "new drug"... , section 201(s) does not require that a food ingredient be used "to a material extent or for a material time' before it may become GRAS.
 
 General Recognition of Safety and Prior Sanctions for Food Ingredients, 39 Fed. Reg. 34,194, 34,194 (1974).

n131. See 1995 Hearings, supra note 1, at 116 (statement of Kenneth D. Fisher, former Dir., LSRO); id. at 170 (estimating that FASEB had conducted five or six private GRAS reviews). A company may also choose to sponsor studies of a substance for eventual publication. See, e.g., Safety Evaluation of Erythritol, 24 Reg. Toxicology & Pharmacology S191 (1996) (assembling 15 studies of one substance). Another potential source of expertise resides in the Joint Expert Committees on Food Additives (JECFA), first organized in 1956 by the United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO) and now associated with these organizations' Codex Alimentarius Commission. See Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives (1994). JECFA reports have influenced decisions by the FDA and other regulatory bodies, and its recommendations concerning particular additives might be relied upon by companies in making GRAS self-determinations.

n132. See Procter & Gamble Co.; Filing for Affirmation of GRAS Status, 56 Fed. Reg. 37,712 (1991) (announcing the filing of a GRAS affirmation petition for caprenin); Joel G. Brenner, New Ingredient Enables Mars to Unveil a Leaner Milky Way, Wash. Post, Jan. 16, 1992, at D11; FASEB Panel Finds New Fat Substitute GRAS, Food Chem. News, Feb. 3, 1992, at 50; P&G Disputes Liver Damage Implication in Caprenin Study, Food Chem. News, Mar. 13, 1995, at 17.

n133. See Nabisco, Inc.; Filing of Petition for Affirmation of GRAS Status, 59 Fed. Reg. 33,774, 33,774 (1994); Salatrim Should Receive GRAS Status, FASEB Ad Hoc Panel Says, Food Chem. News, July 25, 1994, at 19.

n134. See 1995 Hearings, supra note 1, at 113-14 (statement of Kenneth D. Fisher, former Dir., LSRO).

n135. Id. at 114. "Where appropriate, reports include new research opportunities, specific recommendations, a comprehensive literature review, and reflect the knowledge and experience of the scientists who participate in the study and those of the LSRO staff." Id.

n136. See, e.g., id. at 114-15, 118 (describing SCOGS); see also Food Chem. News, Inc. v. Young, 900 F.2d 328, 329-30 (D.C. Cir. 1990) (describing the creation and operations of another ad hoc FASEB panel under a contract with the FDA).

n137. See BHA Poses No Human Risk at Current Exposure Levels: FASEB, Food Chem. News, July 25, 1994, at 3; FASEB to Study MSG, BHA Under New Contracts with FDA, Food Chem. News, Nov. 2, 1992, at 3; MSG Adverse Effect on Subgroups Demonstrated: Final FASEB Report, Food Chem. News, Sept. 4, 1995, at 51. Information about the schedule and cost of FASEB's occasional private GRAS reviews is unavailable.

n138. See, e.g., GAO, New Food Technologies, supra note 9, at 28 ("For example, the expert panel of the Flavor and Extract Manufacturers' Association has asserted the GRAS status of hundreds of synthetic flavoring chemicals."); Degnan, supra note 89, at 566-67 (describing the FEMA GRAS review and the FDA's reaction); see also Robert S. McCaleb, Food Ingredient Safety Evaluation, 47 Food & Drug L.J. 657, 661-63 (1992) (describing GRAS "self-affirmation" project undertaken by the Herb Research Foundation).

n139. See Degnan, supra note 89, at 567; John B. Hallagan & Richard L. Hall, FEMA GRAS - A GRAS Assessment Program for Flavor Ingredients, 21 Reg. Toxicology & Pharmacology 422, 423, 425 (1995) (outlining FEMA's efforts over the past four years); Bernard L. Oser & Richard A. Ford, FEMA Expert Panel: 30 Years of Safety Evaluation for the Flavor Industry, Food Tech., Nov. 1991, at 84, 86. A company desiring an opinion about the potential GRAS status of a new flavoring substance must submit an application form and literature search to FEMA's staff. After a preliminary check for completeness, the staff forwards the request and information to the Expert Panel for consideration at its next regularly scheduled meeting. See Lauren A. Woods & John Doull, GRAS Evaluation of Flavoring Substances by the Expert Panel of FEMA, 14 Reg. Toxicology & Pharmacology 48, 51 (1991). The available literature is evaluated against FEMA's published criteria, and a GRAS designation requires a unanimous vote by the Panel; otherwise, the flavoring substance will be placed in a hold category for further study or be designated as not GRAS. See id.; Bernard L. Oser & Richard L. Hall, Criteria Employed by the Expert Panel of FEMA for the GRAS Evaluation of Flavoring Substances, 15 Food & Chem. Toxicology 457 (1977).

n140. See, e.g., Richard L. Hall & Bernard L. Oser, Recent Progress in the Consideration of Flavoring Ingredients Under the Food Additives Amendment, Food Tech., Feb. 1965, at 151; Robert L. Smith et al., GRAS Flavoring Substances 17, Food Tech., Oct. 1996, at 72. In addition, the SLRs on which the Panel based its GRAS determinations were made available to the public and forwarded to the FDA. See Hallagan & Hall, supra note 139, at 423, 425.

n141. See Woods & Doull, supra note 139, at 48.

n142. See Lawrence J. Lin, Interpretation of GRAS Criteria, 46 Food Drug Cosm. L.J. 877, 881-82 (1991). In 1985, FEMA finished a comprehensive reevaluation of its original GRAS determinations, dropping three flavoring substances from the list. See Woods & Doull, supra note 139, at 56. In 1993, FEMA began a second reevaluation process, coupled with an effort to update and reformat all existing SLRs. See Hallagan & Hall, supra note 139, at 428, 430; Smith, supra note 140, at 74.

n143. See Lin, supra note 142, at 882; see also Substances That Are Generally Recognized as Safe, 26 Fed. Reg. 5222 (1961) (finalizing the GRAS list of natural flavors); Substances That Are Generally Recognized as Safe, 26 Fed. Reg. 3991 (1961) (finalizing the GRAS list of synthetic flavors). Notably, the GRAS list review initiated in 1969 explicitly excluded flavors, spices, and essential oils. The GRAS lists of natural and synthetic flavoring substances now appear at 21 C.F.R. 182.10, 182.60 (1997).

n144. See, e.g., Synthetic Flavoring Substances and Adjuvants: Proposal to Establish List of Safe Additives, 29 Fed. Reg. 6957 (1964) (proposing to approve numerous synthetic flavors based on prior use in food but not deemed eligible for GRAS status because the evidence of safety was not readily available to the scientific community); Lin, supra note 142, at 882 (citing the decision to list the substances as food additives because of "significant differences between FEMA and the FDA in the interpretation of GRAS criteria"). The lists of approved natural and synthetic flavoring substances now appear at 21 C.F.R. 172.510, 172.515.

n145. See Degnan, supra note 89, at 567; Hallagan & Hall, supra note 139, at 429; Lin, supra note 142, at 882. The Agency once went out of its way to describe the FEMA list as one of the "reliable industry association GRAS lists." Food Flavoring; Additional Flavoring Substances in GRAS Review; Extension of Effective Date for Compliance With Bulk Flavor Ingredient Declaration Requirements, 44 Fed. Reg. 71,460, 71,461 (1979). The FDA also occasionally refers to FEMA's GRAS listing of a flavor to support a GRAS affirmation proposal. See, e.g., 48 Fed. Reg. 4486, 4486 (1983) (affirming stearic acid); Thiamine Hydrochloride and Thiamine Mononitrate; Proposed Affirmation of GRAS Status as Direct Human Food Ingredient, 47 Fed. Reg. 47,438, 47,439 (1982).

n146. See supra notes 97-103 (citing cases). A similar question might arise when trying to determine whether a new substance is covered by an existing GRAS or food additive regulation. See General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,604 (1976) ("The manufacturer may solicit an advisory opinion from the agency," for instance, "if there is a question whether the ingredient he is using differs from the ingredient identified" in a GRAS affirmation regulation.); GAO, Food and Drug Administration: Carrageenan Food Additive from the Philippines Conforms to Regulations, No. HEHS-94-141 (1994).

n147. Peter Barton Hutt & Richard A. Merrill, Food and Drug Law 332-33 (2d ed. 1991).

n148. See id. at 333 ("In such an action, however, the agency would have to prove that the ingredient was not GRAS. Neither the ingredient's absence from FDA's GRAS lists nor the manufacturer's failure to consult the agency in advance would be relevant."); 1957 Hearings, supra note 22, at 455 (HEW memorandum) ("The burden would be on the Government, in an enforcement proceeding, to prove that a substance is not [GRAS] and is therefore within the scope of the bill."); 1956 Hearings, supra note 16, at 226 (statement of William W. Goodrich, FDA Counsel) ("We have the burden... of proving that a product is not [GRAS] in the courts."); see also Director, Office of Workers' Compensation Programs v. Greenwich Collieries, 512 U.S. 267, 272-80 (1994) (discussing the Administrative Procedure Act's allocation of the burden of proof in agency proceedings).

n149. See United States v. An Article of Food * * * Coco Rico, Inc., 752 F.2d 11, 15 (1st Cir. 1985) (upholding FDA seizure of product that manufacturer had thought was GRAS: "The burden of proving general recognition of safe use is placed on the proponent of the food substance in question."); Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,939 (1997) ("The proponent of the exemption has the burden of proving that the use of the substance is [GRAS]."); General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. at 53,604 ("The burden of proof is always on the manufacturer to demonstrate that the ingredient he is using is GRAS."); GAO, New Food Technologies, supra note 9, at 29 ("When challenged, a manufacturer must prove that its food substance is, in fact, GRAS."); cf. United States v. Vital Health Prods., Ltd., 786 F. Supp. 761, 774 (E.D. Wis. 1992) ("[In applying the GRAS exception for drugs], the moving party bears the burden of proof as to each element. Moreover, because the clause is an exception to a comprehensive regulatory scheme which protects public safety, it must be strictly construed.").

n150. See infra Part III.B (discussing GRAS affirmation procedures); see also Status of Review of GRAS and Prior Sanctioned Direct Human Food Ingredients: Notice of Availability of Information, 38 Fed. Reg. 20,054, 20,056 (1973) ("All future [advisory] opinions relating to GRAS or prior-sanctioned status will be issued in the form of Federal Register notices proposing appropriate new regulations.").

n151. See Degnan, supra note 89, at 572 (adding that food processors may be willing to use a substance in their products on this basis); Heckman, supra note 57, at 45 (explaining that, because the "FDA's acceptance of the petition amounts to a prima facie finding that GRAS status is probable, the substance may be marketed while the petition is pending").

n152. See Hutt, supra note 1, at 126 ("For new food substances, the GRAS exclusion has turned out to be the single most important statutory provision.").

n153. Food Additives Amendment of 1958, Pub. L. No. 85-929, 2, 72 Stat. 1784, 1784 (codified at 21 U.S.C. 321(s)(4) (1994)); see also Poliquin, supra note 15, at 122-35, 153 & n.170. The Poultry Products Inspection Act (PPIA) was enacted in 1957. See Pub. L. No. 85-172, 71 Stat. 441 (1957) (codified as amended at 21 U.S.C. 451-470 (1994)). The Federal Meat Inspection Act (FMIA) was originally enacted in 1907. See Meat Inspection Act, ch. 2907, tit. I, 34 Stat. 1256, 1260 (1907) (codified as amended at 21 U.S.C. 601-680).

n154. See 21 C.F.R. 170.30(a) (1997).

n155. See id. 170.3(l), 181.5(a).

n156. See, e.g., Caffeine in Nonalcoholic Beverages, 52 Fed. Reg. 18,923, 18,923 (1987); Lead-Soldered Food Cans, 58 Fed. Reg. 33,860, 33,861 (1993); see also Merrill, supra note 10, at 215 ("Though a continuing source of controversy, the kind of documentation needed to establish a "prior sanction' is principally a matter of interest for archivists....").

n157. See United States v. An Article of Food * * * Coco Rico, Inc., 752 F.2d 11, 16 (1st Cir. 1985) ("The sanction permitting very limited use of potassium nitrate in meats cannot be construed to sanction use of the same substance for an altogether different purpose in beverages."); United States v. Articles of Food * * * Buffalo Jerky, 456 F. Supp. 207, 209-10 (D. Neb. 1978) (holding that prior sanctions for use of sodium nitrate and sodium nitrite with other meats did not apply to their use with bison meat), aff'd, 594 F.2d 869 (8th Cir. 1979) (per curiam). But cf. Public Citizen v. Foreman, 631 F.2d 969, 975-77 (D.C. Cir. 1980) (rejecting request for a declaratory judgment that nitrites used as preservatives in cured meats were unsafe food additives, finding that a prior sanction from the USDA was not limited to their use as a color-fixative).

n158. See 21 C.F.R. 181.33-.34 (1997); see also Use of Sodium Nitrite, Sodium Nitrate, Potassium Nitrite, and Potassium Nitrate: Withdrawal of Proposed Rule and Proposed Declaration that No Prior Sanction Exists, 48 Fed. Reg. 9299, 9299-300 (1983) (summarizing the convoluted regulatory history of nitrites, including subsequently withdrawn proposals to restrict nonessential uses and to find no prior sanction for use in poultry, reflecting Agency concerns about the formation of carcinogenic nitrosamines); supra note 157 (collecting cases). The USDA gradually has increased restrictions on the use of nitrites. See, e.g., Immersion Cured and Dry Cured Bacon, 54 Fed. Reg. 43,041, 43,045 (1989) (codified at 9 C.F.R. 318.7(b) (1997)) (regulating the use of nitrite ascorbate in bacon).

n159. See 21 C.F.R. 181.22-.32 (1997). The original list appeared in 1960. See Substances Employed in the Manufacture of Food Packaging Materials, 25 Fed. Reg. 866 (1960); see also 1957 Hearings, supra note 22, at 461-62 (statement of George P. Larrick, Comm'r, FDA) (submitting a partial list of chemicals previously accepted by the FDA or the USDA for use in foods).

n160. See Proposal Regarding Regulation of Prior-Sanctioned Food Ingredients, 37 Fed. Reg. 16,407, 16,407 (1972) ("Not all of these sanctions and approvals can be ascertained because of the destruction of old records and the retirement of personnel involved in these matters."); Food Additive Status Opinion Letters; Statement of Policy, 35 Fed. Reg. 5810, 5810-11 (1970) (codified as amended at 21 C.F.R. 170.6 (1997)) (revoking certain informal opinions and requesting the submission of opinion letters for possible reissuance); Merrill, supra note 10, at 215 n.169 ("Because of the diverse evidence of approval accepted by the FDA, estimates of the number of [prior sanctioned] ingredients... are mere speculation, but persons familiar with the matter doubt the number exceeds 200.").

n161. See 21 C.F.R. 181.5(d); see also id. 170.35(c)(6) (advising that a notice proposing affirmation of GRAS status will call for the submission of any applicable prior sanctions); id. 170.38(d) (explaining same in the case of a determination of food additive status). In response to objections, the FDA explained that fairness among processors, efficient enforcement, and opportunities for the full airing of safety questions justified this disclosure requirement. See General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,603 (1976).

n162. Compare Caffeine in Nonalcoholic Carbonated Beverages, 52 Fed. Reg. 18,923, 18,923 (1987) (proposing to recognize a prior sanction for caffeine in nonalcoholic carbonated beverages), with Soda Water; Amendment to Standard, 45 Fed. Reg. 69,816, 69,830-31 (1980) (proposing to revoke caffeine's GRAS status and to require additional safety studies pursuant to an interim food additive regulation). Both proposals are still pending, and caffeine remains on the GRAS list, see 21 C.F.R. 182.1180, in part because of continuing ambiguity in the safety data, see, e.g., Jane E. Brody, The Latest on Coffee? Don't Worry. Drink Up, N.Y. Times, Sept. 13, 1995, at C1 ("A substantial amount of research, including several large studies done in the last few years, has turned up very little solid scientific evidence to indict a moderate intake of coffee or caffeine as a serious or even minor health threat."); see also Caffeine; Deletion of GRAS Status, Proposed Declaration that No Prior Sanction Exists, and Use on an Interim Basis Pending Additional Study; Availability of Information, 46 Fed. Reg. 32,453 (1981) (reviewing available teratogenicity studies).

n163. See Merrill, supra note 10, at 216 ("The FDA has historically assumed that a prior sanctioned ingredient is permanently grandfathered, i.e., that it may never become a food additive so long as it is used for its sanctioned purpose, even if new evidence casts doubt on its safety."); id. at 244 (commenting that the prior sanction exception "provides apparently indefinite protection for ingredients once approved, however casually, by the FDA or the USDA"); Gary A. Sunshine, Regulatory Aspects of Food Additives - Yesterday, Today and Tomorrow, 31 Food Drug Cosm. L.J. 264, 269 (1976) ("It would seem logical that, if Congress said a substance was not a food additive if a particular act had occurred prior to the enactment of the Food Additives Amendment, nothing could be done 15 years later to change the previously occurring exempting act.").

n164. The FDA has, however, previously suggested that it could revoke a prior sanction. See, e.g., 1957 Hearings, supra note 22, at 35 (HEW memorandum) ("This, of course, would not prevent rescission of such a sanction or approval, and consequent inclusion of the additive under the bill, if the particular use of the additive is subsequently found to be toxic or of doubtful safety."); Poliquin, supra note 15, at 130 (describing the discussion of this issue during congressional consideration of the Color Additive Amendments of 1960).

n165. For instance, the FDA rescinded its pre-1958 sanctions for glycine in human food and for nitrites and nitrates to the extent that they were being used in curing premixes containing secondary or tertiary amines, see 21 C.F.R. 170.50, 170.60, but, notwithstanding the associated calls for food additive petitions, these actions should only render the sanctions inoperative as to the statute's adulteration provisions.

n166. 21 U.S.C. 342(a)(1) (1994) (providing that a food containing such a poisonous or deleterious substance shall be deemed to be adulterated). A prior sanction only provides an exception to the statutory controls specifically applicable to "food additives."

n167. See 21 C.F.R. 181.1(b)-(c), 181.5(b)-(c); Food Additives; Prior Sanctioned Food Ingredients, 38 Fed. Reg. 12,737, 12,737 (1973) ("There is no merit to the argument that prior-sanctioned food ingredients are exempt from safety evaluation under the adulteration provisions of the act."); see also Lead-Soldered Food Cans, 60 Fed. Reg. 33,106, 33,109 (1995) ("FDA finds that a prior sanction exists for the use of lead solder in food cans. However, the available toxicological and exposure data on lead demonstrate that this use of lead solder may be injurious...."); Lead-Soldered Food Cans, 58 Fed. Reg. 33,860, 33,865 (1993) (Because of its prior sanction, "lead solder used in food containers is not a food additive... [but it] may be subject to regulation as an added poisonous or deleterious substance...."). A list of such prohibited substances identified by the FDA appears in 21 C.F.R. pt. 189.

n168. Lead-Soldered Food Cans, 60 Fed. Reg. at 33,107.
 
One comment stated that a prior sanction for the use of a food ingredient is based solely on its recognized use prior to enactment of the Food Additives Amendment of 1958... FDA considers the comment to be making a semantic point that ultimately has no effect on the agency's action... If the agency prohibits use of a prior-sanctioned food ingredient [under the basic adulteration provision], this action has the effect of revoking the prior sanction for that use of the ingredient.
 
 Id.

n169. See Michael R. Taylor, Food Safety Regulation, in Food and Drug Law 182, 196 (Richard M. Cooper ed., 1991) (stating that there exists a "kind of hierarchy of food substances, ranging from foods to "food additives,' with various subcategories of GRAS and prior-sanctioned substances in between. This hierarchy has great practical importance because a substance's place in it determines the basis upon which the substance may enter and remain on the market.").

n170. 21 U.S.C. 342(a)(2)(C), as amended by Food Quality Protection Act of 1996, Pub. L. No. 104-170, 404, 110 Stat. 1514.

n171. See 21 U.S.C. 348(a). If a food contains an approved food additive, then it may not be regarded as adulterated under the statute's broader prohibition against bearing or containing any added poisonous or deleterious substance which may render it injurious to health. See id. (cross-referencing 21 U.S.C. 342(a)(1)).

n172. See, e.g., GAO, Need For More Effective Regulation of Direct Additives to Food, No. HRD-80-90 (1980), at v (recommending the elimination of the GRAS and prior sanction exceptions); see also GAO, New Food Technologies, supra note 9, at 10 ("Because new food products may incorporate GRAS substances - such as oat fiber, beta carotene, or egg white - in previously untested quantities, concentrations, or forms, some... have questioned whether the laws leaving GRAS determinations up to industry adequately protect public health.").

n173. See, e.g., Degnan, supra note 89, at 553, 580-82. Mr. Degnan suggested, for instance, that new uses of previously approved and widely used food additives could be treated as falling within the GRAS exception rather than requiring the submission of a new food additive petition. See id. at 581. Although the FDA once dismissed this possibility, see Substances Generally Recognized as Safe, 48 Fed. Reg. 48,457, 48,458 (1983), its recent insistence that only uses (and not substances) may be considered GRAS, see Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,939, 18,945 (1997), seems to permit such a reform.

n174. See 21 U.S.C. 348(c). The Agency also may issue a food additive regulation on its own initiative. See id. 348(d); 21 C.F.R. 170.15 (1997). In addition, if significant new data become available after an additive has been approved, the FDA may, on its own initiative or in response to a citizen petition, issue a proposal to amend or repeal a food additive regulation. See id. 171.130. The amendment or repeal of regulations must abide by the same procedures required for initial promulgation. See 21 U.S.C.A. 348(i) (West Supp. 1998).

n175. See 21 U.S.C. 348(b)(2). In addition, upon the FDA's request, the petitioner must provide descriptions of production methods and facilities as well as samples of the additive for testing. See id. 348(b)(3)-(4); 21 C.F.R. 171.1(j). The FDA's implementing regulations describe in greater detail the required format and content of a petition. See id. 171.1.

n176. See, e.g., 21 U.S.C. 331(j) (prohibiting the disclosure of trade secret information acquired under, inter alia, the provision governing food additive petitions); 21 C.F.R. 171.1(h)(2) (prohibiting, except in a few circumstances, the disclosure of manufacturing methods, sales data, and quantitative formulas).

n177. The FDA promulgated these regulations one year after enactment of the Food Additives Amendment. See Food Additives; Definitions and Procedural and Interpretive Regulations, 24 Fed. Reg. 2434 (1959) (originally codified at 21 C.F.R. pt. 121 (1965)); Proposed Definitions and Procedural and Interpretive Regulations, 23 Fed. Reg. 9511 (1958). The EPA also implements this provision of the FD&C Act insofar as it must set finished food tolerances for pesticides used on raw agricultural commodities. See Procedure to Establish, Modify, or Revoke Food Additive Regulations, 55 Fed. Reg. 50,282 (1990) (codified at 40 C.F.R. pt. 180 (1997)); Food Additive Regulations Concerning Pesticide Residues: Procedural Regulations, 53 Fed. Reg. 41,126 (1988). The EPA's procedures for revocation parallel those used for the establishment of food additive regulations. See 40 C.F.R. pts. 177-178 (1997).

n178. See 21 C.F.R. 171.1(i)(1). If a petition is not accepted for filing, the Agency will notify the petitioner in what respects the petition is incomplete. See id. 171.1(d),(i)(1); see also id. 171.1(g) ("A petition shall be retained but shall not be filed if any of the data prescribed by... the Act are lacking or are not set forth so as to be readily understood."). If the food additive petition is not accepted for filing, the petitioner may either supplement it to address any identified deficiencies or demand that it be filed as originally submitted. See id. 171.1(i)(1).

n179. See 21 U.S.C. 348(b)(5); 21 C.F.R. 171.1(i)(2). At any time before the Agency issues an order approving or denying the petition, the petitioner may, upon its own initiative or at the FDA's suggestion, withdraw the food additive petition without prejudice to refiling it in the future. See id. 171.7. Even after the rejection of a food additive petition, nothing prevents a resubmission based on additional safety data. See, e.g., Calorie Control Council and Abbott Laboratories; Filing of Food Additive Petition, 47 Fed. Reg. 51,227 (1982) (announcing the filing of a second food additive petition for cyclamate more than six years after the FDA originally rejected the first petition).

n180. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 61 Fed. Reg. 33,654, 33,655 (1996) ("Although public notice of a petition is required, the act is silent with respect to public comment on a petition."). This contrasts with the procedure used for GRAS affirmation petitions, described infra Part III.B, which expressly provides for a 60-day public comment period. See 21 C.F.R. 170.35(c)(3). The statute does, however, require that at least 30 days elapse before the Agency finalizes a food additive regulation proposed on its own initiative. See 21 U.S.C. 348(d).

n181. See S. Rep. No. 85-2422, at 7-9 (1958) (describing the exhaustive consideration of the judicial review question). In court, the Agency's findings "with respect to questions of fact shall be sustained if based upon a fair evaluation of the entire record at such [public] hearing." 21 U.S.C. 348(g)(2).

n182. HEW did object to an industry suggestion that some sort of hearing procedure be available prior to the issuance of a final order. See 1957 Hearings, supra note 22, at 459-60 (HEW memorandum) (concluding that such an added procedure "would complicate materially the efficient administration of the act without giving any genuine benefit either to the Government or the petitioner"). The statutory procedure for action on food additive petitions contrasts with the two-stage process contained in Section 701(e) of the Act, which involves a notice-and-comment period followed by a formal rulemaking hearing if necessary. See 21 U.S.C. 371(e); Pharmaceutical Mfrs. Ass'n v. Gardner, 381 F.2d 271, 278 (D.C. Cir. 1967) (explaining that this procedure was designed to eliminate formal hearings unless necessary). The drafters of Section 409 of the FD&C Act were aware of this more formal procedure and could have easily covered food additive petitions through a cross-reference in that section, but instead they chose a procedure which only contemplates public objections after a food additive order is published. The FDA's general procedures for notice-and-comment rulemaking specifically exempt food additive petitions from the regulation. See 21 C.F.R. 10.40(e)(2).

n183. See Merrill, supra note 10, at 248.
 
[The FDA] ordinarily approves food additives simply by publishing in the Federal Register a regulation specifying the terms of the approval and reciting that the additive has been found safe. The supporting safety data are evaluated privately, except on those rare occasions when a member of the public comes to the agency to evaluate the petition.
 
 Id. Of the hundreds of notices of filing published by the FDA in the Federal Register since 1965, none has invited public comment. Indeed, until fairly recently, the Agency's decisions on food additive petitions have never alluded to, much less responded to, comments submitted by third parties (the boilerplate language used in these orders simply refers to "data in the petition and other relevant information"). This suggests that such comments were rarely filed in response to a petition.

n184. The procedures used by the EPA for pesticide residue petitions under Section 409 of the FD&C Act are similar in tacitly allowing prepublication comment. See Food Additive Regulations Concerning Pesticide Residues: Procedural Regulations, 53 Fed. Reg. 41,126, 41,128 (1988) (observing that, because "section 409(b) does not require publication of a proposed version of a food additive regulation for notice and comment by the public, the section 409(b)(5) notice of filing may be the only opportunity for members of the public to submit any comments they wish to make"). The EPA regulations differ from the FDA's in one important respect, however: the Administrator may respond to a petition by "publishing a proposed food additive regulation and requesting public comment thereon." 40 C.F.R. 177.125(b) (1997). "This could occur because of the complexity or controversiality of the issues raised by a petition or because of a need to gather information from members of the public." Food Additive Regulations Concerning Pesticide Residues: Procedural Regulations, 53 Fed. Reg. at 41,128.

n185. See Food Additives Permitted for Direct Addition to Food for Human Consumption, 60 Fed. Reg. 57,586, 57,587 (1995) (conceding that the FD&C Act "is silent with respect to public comment on a [food additive] petition," but viewing this as a difficulty only in choosing a proper deadline). Indeed, the Agency went to some lengths in justifying its decision to impose any deadline on comments in this case, see id., even though the food additive petition under review had been filed more than eight years earlier and been the subject of a week-long advisory committee meeting, see infra Part V.C.

n186. See Administrative Practices and Procedures; Notice of Proposed Rule Making, 40 Fed. Reg. 40,682, 40,699 (1975) ("The Commissioner will make available for public disclosure all safety and functionality data relating to any color additive or food additive at the time of filing of the petition, so that public comment can be prepared meaningfully and submitted prior to publication of the final regulations.").

n187. See 21 C.F.R. 171.1(h). Certain confidential information and protected trade secrets are exempt. See, e.g., id. 171.1(h)(1)(iii) (exempting from public disclosure any identifying information in adverse reaction reports and consumer complaints); id. 171.1(h)(2) (exempting from public disclosure manufacturing methods, sales data and quantitative formulas).

n188. See Lars Noah, Sham Petitioning as a Threat to the Integrity of the Regulatory Process, 74 N.C. L. Rev. 1, 3 (1995) (explaining that "real opportunities exist for sham petitioning in administrative proceedings, especially when market entry requires some sort of agency licensing as in the pharmaceutical, transportation, communications, and energy industries").

n189. See H.R. Rep. No. 104-436, at 5, 9 (1995) (noting that FDA officials have conceded that this may represent a problem); 1995 Hearings, supra note 1, at 78 (statement of Robert C. Gelardi, Exec. Vice President, Calorie Control Council) (noting that "the careful timing of their submissions can hold up a review numerous times just short of approval"); id. at 90-91 (describing anonymous submissions as a method of delaying FDA approval of a food additive petition for competitive reasons); FDA Delay in Sucralose Approval Gets "Golden Grinch" Award from Sen. Mathews, Food Chem. News, Aug. 29, 1994, at 46 (quoting Sen. Harlan Mathews as complaining that ""any third party could indefinitely delay approval of [a food] additive simply by repeatedly submitting their interpretation of data'"); Formal Comment Period on Food Additive Petitions Requested, Food Chem. News, July 6, 1992, at 36-37 (suggesting that the tardy submission by the Center for Science in the Public Interest of old data about sucralose, data which purportedly was received from an anonymous source, may have reflected bad faith intervention by a company seeking to retain its competitive advantage in the market for non-nutritive sweeteners). But see 1995 Hearings, supra note 1, at 181 (statement of Michael F. Jacobson, Exec. Director, CSPI) (responding that CSPI "has not been used by anti-competitive forces to delay decisions on pending petitions").

n190. A 60-day prepublication comment period for food additive petitions would provide a reasonable time frame without blatantly ignoring the statutory deadlines. For instance, the FDA's Center for Veterinary Medicine, acting pursuant to identical statutory and regulatory authority, often includes an explicit 60-day comment period in the notice of filing. See, e.g., Purina Mills, Inc.; Filing of Food Additive Petition, 57 Fed. Reg. 11,325 (1992). GRAS affirmation petitions allow 60 days for public comment, see 21 C.F.R 170.35(c)(3), and this is also the amount of time provided in the FDA's general procedures for rulemaking, see id. 10.40(b)(2); see also Glen Scott; Filing of Food Additive Petition and Citizen Petition to Prohibit Uses of Butylhydrated Hydroxyanisole (BHA), 55 Fed. Reg. 49,576 (1990).

n191. See 21 U.S.C. 348(c)(1)-(2) (1994); 21 C.F.R. 171.100. Apparently, an order denying a petition need only be made available to the petitioner. See 21 C.F.R. 171.100(a) (calling for publication in the Federal Register only in the case of approvals).

n192. See Alan M. Rulis & Laura M. Tarantino, The Food Additive Petition Process: Recent Data, 48 Food & Drug L.J. 137, 138, 145 (1993) (illustrating how experts in chemistry, toxicology, and environmental science all simultaneously review the food additive petition).

n193. The Agency's implementing regulations make provision for "tolling" the statutory clock in certain instances where the petitioner submits further information. See 21 C.F.R. 171.1(j) ("The date used for computing the 90-day limit... shall be moved forward 1 day for each day after the mailing date of the [FDA] request taken by the petitioner to submit the sample."); id. 171.6 ("If the Commissioner determines that the additional information or data amount to a substantive amendment, the petition as amended will be given a new filing date, and the time limitation will begin to run anew."); id. 171.7 (If a petition is withdrawn and then refiled, "the time limitation will begin to run anew.").
 
In practice, ... the FDA allows this clock to run only when it has in its possession adequate information to review. Should it be determined that additional information must be submitted, a letter is issued to the petitioner and the clock stops. When a substantial supplement is received by the FDA, the clock is restarted again, but it may be reset to zero. Thus, the evaluation periods for petitions may extend beyond the nominal 180 days allotted by the statute.
 
 Alan M. Rulis, The Food and Drug Administration's Food Additive Petition Review Process, 45 Food Drug Cosm. L.J. 533, 535 (1990). The FDA uses a similar 180-day review clock for new drug applications. See 21 C.F.R. 314.60, 314.100-.101; see also In re Barr Lab., Inc., 930 F.2d 72, 74 (D.C. Cir. 1991) (describing the FDA's practice of tolling the statutory clock for reviews of generic drug applications); cf. Republic of Texas Corp. v. Board of Governors of Fed. Reserve Sys., 649 F.2d 1026, 1037 (5th Cir. 1981) (discussing ambiguities that arise in the operation of statutory deadlines for the review of applications submitted by bank holding companies).

n194. See infra Part VI.A (explaining that, although some delays result from the tardy submission of supplemental information by petitioners, the FDA generally does not meet the statutory deadlines even as modified by these tolling rules).

n195. A final order granting or denying a food additive petition becomes effective immediately unless the FDA elects to stay its effect pending action on objections that are filed following publication of the order. See 21 U.S.C. 348(e); see also 21 C.F.R. 171.102. In contrast, the filing of objections and requests for an evidentiary hearing automatically stays a final FDA order terminating the listing of a color additive. See 21 U.S.C. 371(e)(2).

n196. See 21 U.S.C. 348(f)(1); 21 C.F.R. 171.110 (cross-referencing 21 C.F.R. pt. 12). The statute provides:
 
The Secretary shall, after due notice, as promptly as possible hold such public hearing for the purpose of receiving evidence relevant and material to the issues raised by such objections. As soon as practicable after completion of the hearing, the Secretary shall by order act upon such objections and make such order public. Such order shall be based upon a fair evaluation of the entire record at such hearing, and shall include a statement setting forth in detail the findings and conclusions upon which the order is based.
 
 21 U.S.C. 348(f)(1)-(2).

n197. See 21 C.F.R. 12.24(b); see also Community Nutrition Inst. v. Young, 773 F.2d 1356, 1363 (D.C. Cir. 1985) [hereinafter CNI]; Marshall Minerals, Inc. v. FDA, 661 F.2d 409, 417, 425 (5th Cir. 1981). The FDA's order in response to objections may not take effect until 90 days after publication, to allow any person who will be adversely affected an opportunity to seek judicial review. See 21 U.S.C. 348(f)(3), (g). A petition for review may be filed in a U.S. Court of Appeals within 60 days after entry of an order responding to objections. See id. 348(g)(1); see also CNI 773 F.2d at 1360-62 (holding that the federal district court lacked jurisdiction). Judicial review is not available unless timely objections were filed to the FDA's initial order on a food additive petition. See, e.g., Nader v. EPA, 859 F.2d 747, 751 (9th Cir. 1988) ("If a party seeks to invoke judicial review under 348(g),... objection under 348(f) is a prerequisite.").

n198. See Merrill, supra note 10, at 209 & n.139 (describing hearings on the denial of a food additive petition for cyclamates and the approval of one for aspartame). Since 1980, the FDA consistently has denied hearing requests. See, e.g., Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 57 Fed. Reg. 6667 (1992); Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 49 Fed. Reg. 6672 (1984). The Agency has held formal hearings on decisions concerning other food-use substances. See, e.g., FD&C Red No. 4; Denial of Petition for Permanent Listing; Availability of Commissioner's Decision, 48 Fed. Reg. 48,533 (1983); Acrylonitrile Copolymer Used to Fabricate Beverage Containers, 42 Fed. Reg. 17,529 (1977); Denial of Petition for Permanent Listing of FD&C Red No. 2, 41 Fed. Reg. 29,896 (1976). The statute imposes no deadlines for responding to objections and hearing requests. See 1957 Hearings, supra note 22, at 211 (statement of H.T. Austern, appearing on behalf of the Nat'l Canners Ass'n) (noting the risk of delays at this stage because the bill failed to specify any deadlines). An earlier bill would have established a deadline of 120 days for final action on objections. See H.R. 7606, 84th Cong. 5 (409(d)) (1955). The Agency sometimes has been slow to make a final decision. See, e.g., Abbott Lab. v. Harris, Food Drug Cosm. L. Rep. (CCH) P 38,046 (N.D. Ill. June 12, 1980) (refusing to compel final agency action in response to the manufacturer's objections to the FDA's denial of a food additive petition for cyclamate, though noting that "over six-and-one-half years is just not, by any view, compatible with the prompt determination intended by Congress"); cf. CNI, 773 F.2d at 1361-62 (noting that a five month delay in ruling on objections to the approval of aspartame in carbonated beverages was not excessive).

n199. See 1995 Hearings, supra note 1, at 88 (testimony of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n) ("The average cost for a food additive application typically ranges between $ 15 million and $ 25 million. However, there have been applications whose total costs have exceeded $ 200 million."); see also Proposal for a Coordinated Framework for Regulation of Biotechnology, 49 Fed. Reg. 50,856, 50,859 (1984) (estimating that it takes five to seven years from the time that safety testing on a direct food additive starts to FDA approval); cf. Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. 36,582, 36,593 (1995) (estimating that an indirect food additive petition "can require on average 2,600 hours to prepare and cost anywhere from $ 85,000 to $ 100,000").

n200. See GAO, New Food Technologies, supra note 9, at 27; Rulis, supra note 193, at 534; 1957 Hearings, supra note 22, at 67 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.) (explaining that the food additive bill "radically differs from the new drug law of the FD&C Act, because its administrative regulation has a general industry force; whereas an effective application under the latter law is an individual one"). In the case of unpatented products or processes, the FDA's confidential treatment of "trade secrets" such as manufacturing methods and formulas, see 21 C.F.R. 171.1(h)(2) (1997), may provide a limited substitute for market exclusivity, but only if such information could not be discovered independently by a competitor; see, e.g., David D. Friedman et al., Some Economics of Trade Secret Law, 5 J. Econ. Persp. 61 (1991).

n201. See 21 C.F.R. pt. 330; see also 21 U.S.C. 357 (providing that antibiotics be approved through published regulations rather than private licenses).

n202. See 21 C.F.R. pt. 60; Determination of Regulatory Review Period for Purposes of Patent Extension; Anionic Polyurethane, 54 Fed. Reg. 38,289, 38,290 (1989) (determining that the FDA's regulatory review period for an indirect food additive exceeded 11 years for purposes of possibly granting patent term restoration of up to five years). To date, the FDA has advised the Patent and Trademark Office (PTO) of the regulatory review times for only three direct food additives in response to requests for patent term extensions. See Determination of Regulatory Review Period for Purposes of Patent Extension; Olean, 62 Fed. Reg. 763 (1997) (olestra); Determination of Regulatory Review Period for Purposes of Patent Extension; Kelcogel, 56 Fed. Reg. 3110 (1991) (gellan gum); Determination of Regulatory Review Period for Purposes of Patent Extension; Acesulfame Potassium, 53 Fed. Reg. 48,727 (1988).

n203. See 21 U.S.C. 355(j)(4)(D); Suzan Kucukarslan & Jacqueline Cole, Patent Extension Under the Drug Price Competition and Patent Term Restoration Act of 1984, 49 Food & Drug L.J. 511 (1994) (explaining the patent extension process available for pharmaceuticals).

n204. See Hutt, supra note 1, at 125-26.

n205. 21 U.S.C. 348(i).

n206. 21 C.F.R. 170.17(a) (The label must include the following language: "Caution. Contains a new food additive for investigational use only in laboratory research animals or for tests in vitro. Not for use in humans."). If a study involves food-producing animals, more stringent restrictions apply. See id. 170.17(b)-(c). Nonetheless, investigational substances may be utilized in clinical trials, perhaps under an investigational new drug (IND) exemption, see id. pt. 312, and any results from such trials included in a food additive petition must be accompanied by a statement concerning compliance with institutional review requirements, see id. 171.1(m); see also GAO, New Food Technologies, supra note 9, at 59-61 (noting that the FDA has the authority and has considered promulgating regulations to govern human clinical trials of novel food additives); infra note 378 (discussing the use of an IND for clinical trials of olestra).

n207. See Stephen H. McNamara, Can You Taste It Without FDA Approval? What to Do When You Need to Taste-Test a New Food Additive Before FDA Approval, 46 Food Drug Cosm. L.J. 869, 870-75 (1991) (describing the limited scope of the investigational use exemption and possible alternative bases for lawful testing of an unapproved additive in humans).

n208. See Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,958 (1997) ("Manufacturers of these foods and retail establishments buying these foods for subsequent resale to consumers may be reluctant to offer them for sale in the absence of assurance that FDA will not subsequently conclude that ingredients independently determined to be GRAS are unapproved food additives.").

n209. See id. at 18,939; cf. 21 C.F.R. 170.6(d) (revoking informal opinions issued in the decade after enactment of the Food Additives Amendment concerning the GRAS or other status of substances added to food).

n210. See GRAS and Food Additive Procedures, 37 Fed. Reg. 25,705, 25,706 (1972) (originally codified at 21 C.F.R.121.40 (1975)); GRAS and Food Additive Status: Proposed Procedures for Affirmation and Determination, 37 Fed. Reg. 6207 (1972); see also Degnan, supra note 89, at 571-72 (discussing the GRAS affirmation petition process).

n211. Congress did not adopt an explicit GRAS affirmation procedure, though it had been recommended by some industry representatives. See, e.g., 1957 Hearings, supra note 22, at 64 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.).

n212. See 21 C.F.R. 170.35(c)(1)(i)-(iv). Though it respects the confidentiality of trade secrets contained in food additive petitions, the FDA will not recognize any assertion of trade secret status for information contained in a GRAS affirmation petition. See id. 170.35(c)(1)(i)(h) (permitting the exclusion of any trade secrets concerning manufacturing processes); General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,604 (1976); GRAS and Food Additive Procedures, 37 Fed. Reg. at 25,705. The FDA takes the same position with regard to its recently proposed GRAS notification procedure. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,952.

n213. See 21 C.F.R. 170.35(c)(1)(iv). The petition must also include any adverse information or consumer complaints about the substance. See id. As described below, "functionality" refers only to a substance's effectiveness in accomplishing an intended physical or other technical effect, not to the utility of that effect. See infra notes 281-86 and accompanying text.

n214. See 21 C.F.R. 170.35(c)(2)-(3). If the Agency proposes GRAS affirmation on its own initiative, it also must provide an opportunity for public comment. See id. 170.35(b).

n215. See id. 170.35(c)(4)-(5); see also id. 170.38(a) (authorizing the FDA to publish a notice that a substance is not GRAS). Even if not the product of an unsuccessful GRAS affirmation petition, the FDA may, either on its own initiative or at the prompting of a citizen petition, propose to determine that a substance is not GRAS and invite public comment before issuing any final notice to that effect. See id. 170.38(b); see also Heterochemical Corp. v. FDA, 741 F. Supp. 382, 384-85 (E.D.N.Y. 1990) (discussing the application of parallel procedures for food additives intended for consumption by animals).

n216. In the preamble to the final regulation, the FDA rejected suggestions of a self-imposed deadline for final action on GRAS affirmation petitions, though it did promise to "make every effort to act upon such petitions within 90 days." GRAS and Food Additive Procedures, 37 Fed. Reg. at 25,706 ("[A] specific time period should not be included in the regulation because it is entirely possible that extraneous circumstances [such as the need to consult with outside experts or the volume of petitions] will preclude meeting any time limit established.").

n217. See, e.g., Direct Food Substances Affirmed as Generally Recognized as Safe; High Fructose Corn Syrup, 61 Fed. Reg. 43,447, 43,450 (1996) (affirming the GRAS status of this sweetener more than 22 years after the first petition was filed and more than 13 years after the substance was listed as GRAS); Direct Food Substances Affirmed as Generally Recognized as Safe; Microparticulated Protein Products, 55 Fed. Reg. 6384, 6384 (1990) (affirming the GRAS status of this fat-substitute in frozen desserts, more than 15 months after receiving the petition); see also GAO, supra note 172, at iii ("As of October 1979, FDA had received 39 petitions for GRAS substances... and had completed its review of 18. Only 4 of the 18 contained sufficient scientific evidence to support a GRAS affirmation."); Hutt, supra note 1, at 124 ("[The] FDA has become simply a dumping ground for GRAS affirmation petitions. The current backlog is more than 50 GRAS affirmation petitions for direct human food substances, in various stages of consideration, and it has been growing every year.").

n218. See infra note 437 and accompanying text.

n219. See infra Part VI.A (comparing delays in FDA action on food additive and GRAS affirmation petitions). As one FDA officially presciently warned at the outset: "I shudder to think of the difficulty in securing general agreement on each specification and each usage... We may be so hopelessly tied up with trying to figure out what is not subject to the amendment that we won't be able to deal effectively with that which is." Arthur A. Checchi, Food-Additives Procedures and Policies, 14 Food Drug Cosm. L.J. 591, 592 (1959).

n220. See Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,945 (1997); Hutt, supra note 1, at 124 ("Nonetheless, the program is still a resounding success... precisely because FDA involvement is not needed to make it work. Self-determination of GRAS permits immediate marketing, whether or not a GRAS affirmation petition is filed, and whether or not FDA ever acts on it.").

n221. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,960-61 (proposed 21 C.F.R. 170.36). The Agency would retain its GRAS lists and procedures for GRAS affirmations on its own initiative. See id.at 18,952. The notification procedure may be utilized even before finalization of the proposed regulation. See id. at 18,954-55. Still pending GRAS affirmation petitions would be converted to GRAS notifications. See id.at 18,953-54.

n222. See id. at 18,946 ("In order for the agency to meet this [90 day] time frame, the information in the notice needs to be presented in an orderly and consistent fashion."). Because GRAS notification does not involve notice-and-comment rulemaking, the FDA proposed to make all such correspondence available to the public through mechanisms other than publication in the Federal Register. See id. at 18,952-53.

n223. Id. at 18,941; see also id. at 18,956 ("A response that does not advise that the agency has identified a problem with the notice would not be equivalent to an affirmation of GRAS status by the agency."); id. at 18,951 ("This narrow evaluation would facilitate FDA's rapid response to the notifier... This response, however, would not be equivalent to an agency affirmation of GRAS status...."); id. at 18,947 ("FDA intends to conduct random audits of data and information maintained by the notifier.").

n224. Id. at 18,947; see also id. at 18,951 (explaining that, even if it does not initially object to a GRAS notification, if questions or concerns subsequently arise the Agency could advise the notifier by a follow-up letter, publish a notice in the Federal Register calling for a food additive petition, or even immediately seize the substance or enjoin its continued sale); id. at 18,958 (recognizing that the proposal "reduces the options available to industry for obtaining FDA feedback on independent GRAS determinations at a level of authoritativeness comparable to that currently offered"); id. at 18,955 (recognizing that it will have less weight with regulatory authorities in other countries).

n225. See id. at 18,941-42.

n226. See id. at 18,951. Even if it decides to provide a letter in every case, nothing guarantees that the FDA will abide by its commitment to issue such responses within 90 days of receipt. See id. (basing this timetable on the assumption that it would receive 50 notifications each year, and inviting comments on the possibility of specifying a longer review period).

n227. See id. at 18,941 (asserting that the "resource-intensive [rulemaking] process deters many persons from petitioning the agency to affirm their independent GRAS determinations"); id. ("In addition, the proposed notice is simpler than a GRAS affirmation petition and therefore conceivably would provide an incentive for manufacturers to inform FDA of their GRAS determinations.").

n228. See id. at 18,958. Indeed, it could require more effort insofar as the notifier must certify that there is evidence of general recognition at the time of submission. See id. at 18,946 (emphasizing that the proposal "would distinguish the notification procedure, in which the notifier explicitly accepts responsibility for the GRAS determination, from the GRAS petition process, in which the notifier is requesting that the agency affirm the GRAS status of use of a substance"); id. at 18,953 (explaining that "under the notification procedure a notifier explicitly accepts full responsibility for the GRAS determination by signing a GRAS exemption claim").

n229. See id. at 18,946 ("FDA anticipates that at least two agency scientists with food safety expertise relating to identity, dietary exposure and health effects, will evaluate most notices."); id. at 18,958 ("In some cases, the GRAS petition process involves a number of iterative steps in which FDA asks for and receives additional supporting information. Under the notification procedure, FDA will base its response on the notifier's initial submission.").

n230. See id. at 18,951. Unlike the issuance of such a notice, which a petitioner could challenge in court, an objection letter would leave the sponsor with an unclear series of options. The FDA suggested utilizing internal appeal mechanisms. See id. at 18,952. Instead, the sponsor presumably could resubmit the notification with some additional information. Although the Agency proposed to eliminate the existing GRAS affirmation petition process, the sponsor also could file a citizen petition consistent with the FDA's general administrative procedures requesting that the Commissioner amend the GRAS list to include the substance. Finally, the sponsor could convert the notification into a food additive petition. Interestingly, the FDA suggested that firms could commence marketing on the basis of a GRAS self-determination even though a food additive petition is pending. See id. at 18,959.

n231. See GRAS and Food Additive Status Procedures, 37 Fed. Reg. 25,705 (1972) (codified as amended at 21 C.F.R. pt. 180 (1997)).
 
The Commissioner recognizes that, with the vast increase in the quantity of scientific testing and in the sophistication of test methodology, there is virtually not [sic] natural or synthetic food substance that cannot be questioned on some technical ground. It would be impossible to require elimination from the food supply of every food substance for which such scientific questions have been or will be raised.
 
 Id. at 25,706; see also GRAS and Food Additive Status: Proposed Procedures for Affirmation and Determination, 37 Fed. Reg. 6207, 6208 (1972) ("The conclusion that an interim food additive order is or is not justified will depend upon the nature of the question raised, the reliability of the other scientific data pertinent to the additive, the purpose for which the additive is used, and the availability of alternative ingredients."). In contrast to its silence with regard to food additives whose safety is later brought into question, Congress created a transitional category for existing color additives. See supra note 94 (noting that Congress authorized the FDA to include color additives in use in 1960 on a provisional list pending further safety testing).

n232. See Brominated Vegetable Oil, 35 Fed. Reg. 12,062 (1970), aff'd, Jacobson v. Edwards, Food Drug Cosm. L. Rep. (CCH) P40,817 (D.D.C. July 6, 1971) ("I think it is, within the letter and the spirit of the Statute, permissible for the agency to issue interim orders of this kind."), aff'd mem., No. 71-2046 (D.C. Cir. Dec. 15, 1972); see also Federation of Homemakers, Inc. v. Harris, Food Drug Cosm. L. Rep. (CCH) P38,100 (D.D.C. Mar. 25, 1981) (refusing to compel the FDA to remove caffeine from the GRAS list, and instead recognizing the Agency's authority to propose an interim food additive regulation). Because the preliminary data from the additional studies on BVO did not suggest any safety concerns, the FDA concluded in 1974 that the ongoing studies could continue. See Brominated Vegetable Oil, 39 Fed. Reg. 36,113 (1974); see also Merrill, supra note 10, at 213 n.155 ("The Act makes no provision for the transition between the loss of GRAS status and the approval as a food additive. To bridge this gap, the FDA has established procedures for the issuance of interim food additive regulations."); Richard A. Merrill & Michael R. Taylor, Saccharin: A Case Study of Government Regulation of Environmental Carcinogens, 5 Va. J. Nat. Resource L. 1, 23-24 (1985) (suggesting that the procedure grew out of the Agency's experience with cyclamate).

n233. 21 C.F.R. 180.1(a) (1997). "No interim food additive regulation may be promulgated if the new information is conclusive with respect to the question raised or if there is a reasonable likelihood that the substance is harmful or that continued use of the substance will result in harm to the public health." Id. 180.1(b); see also GRAS and Food Additive Status Procedures, 37 Fed. Reg. 25,705, 25,705 (1972) ("The purpose of an interim food additive regulation is not to permit the continued use of a substance in food for which there is no reasonable certainty of safety....").

n234. See 21 C.F.R. 180.1(c) (cross-referencing the procedures specified in 21 C.F.R. pt. 10); see also id. 10.50(c)(5) (providing for an opportunity for a formal evidentiary public hearing to the extent required for the issuance, amendment or repeal of food additive regulations under the statute); GRAS and Food Additive Status Procedures, 37 Fed. Reg. at 25,706 (explaining that 121.74, the regulation governing the procedures for amending or repealing a food additive regulation or exemption but not GRAS status (now codified at 170.38), was revised to state that it is "applicable to a petition for determination of food additive status and for an interim food additive regulation").

n235. 21 C.F.R. 180.1(c)(1).

n236. See GRAS and Food Additive Status Procedures, 37 Fed. Reg. at 25,706 (explaining that "these regulations will encourage additional testing").

n237. See 21 C.F.R. 180.1(c)(2). In its preamble, the FDA emphasized that the purpose of declaring a substance an interim food additive "is to assure that prompt action is taken to resolve the issue." GRAS and Food Additive Status Procedures, 37 Fed. Reg. at 25,706 (adding that "this requires that studies be instituted as rapidly as possible"); see also Caffeine; Deletion of GRAS Status, Proposed Declaration that No Prior Sanction Exists, and Use on an Interim Basis Pending Additional Study, 45 Fed. Reg. 69,817, 69,830 (1980) ("A primary advantage of interim regulation is that it permits FDA to require the sponsor of a substance about which questions have been raised to perform the studies necessary to resolve the questions."). Presumably, the suspension or revocation of a food additive regulation would encourage even prompter action, assuming sufficient commercial demand exists for the additive - if demand were too weak to justify an investment in additional safety studies, interim food additive status will delay abandonment of the additive but not create any greater incentives to undertake testing. By issuing an interim food additive regulation, the FDA arguably shifts the burden of proof concerning safety back to itself. See Merrill & Taylor, supra note 232, at 36 ("In postponing action, however, the Agency was in effect assuming the burden of proof on the ultimate issue of safety.").

n238. See 21 C.F.R. 180.1(c)(3) ("If the progress report is inadequate or if the Commissioner concludes that the studies are not being pursued promptly and diligently or if interim results indicate a reasonable likelihood that a health hazard exists, [a revocation] order will promptly be published....").

n239. Id. 180.1(d). The procedures governing interim food additive regulations parallel those applicable to provisionally listed color additives. See Color Additive Amendments of 1960, Pub. L. No. 86-618, 203, 74 Stat. 397, 404-07 (describing provisional listing of commercially established colors); Termination of Provisional Listing and Certification of FD&C Red No. 4 for Use in Maraschino Cherries and Ingested Drugs, 41 Fed. Reg. 41,852, 41,853 (1976) (summarily terminating provisional listing for Red No. 4 because the manufacturers had failed to undertake the toxicological studies necessary to resolve safety questions); Certified Color Mfrs. Ass'n v. Mathews, 543 F.2d 284, 296-98 (D.C. Cir. 1976) (upholding summary termination of provisional listing of Red No. 2).

n240. See 21 C.F.R. 180.22-.37. Two other interim food additive regulations were proposed but not finalized. See Caffeine; Deletion of GRAS Status, Proposed Declaration that No Prior Sanction Exists, and Use on an Interim Basis Pending Additional Study, 45 Fed. Reg. at 69,817; Butylated Hydroxytoluene: Use Restrictions, 42 Fed. Reg. 27,603 (1977).

n241. In the case of saccharin, the FDA awaited conclusion of ongoing studies in Canada. See 21 C.F.R. 180.37(c). The original interim food additive regulation for saccharin contained a seventeen month sunset provision, see Saccharin and Its Salts, 37 Fed. Reg. 2437 (1972) (to be codified at 21 C.F.R. 121.4001(c)), but the FDA subsequently revised the regulation to delete any expiration date, see Saccharin and its Salts, 38 Fed. Reg. 13,733, 13,734 (1973); see also Merrill & Taylor, supra note 232, at 84 ("Despite the Agency's efforts to create a legal middle ground... , this territory could only be occupied temporarily."). In the case of mannitol, the FDA simply demanded "timely and adequate progress reports" of feeding studies. See 21 C.F.R. 180.25(f). Although it did not explicitly require progress reports in the case of acrylonitrile, the Agency enumerated six elements necessary for the toxicity review and called for the prior submission of study protocols. See id. 180.22(e).

n242. See Nitrites and/or Nitrates Combined with Spices in Curing Premixes, 38 Fed. Reg. 19,218 (1973) (to be codified at 21 C.F.R. 121.4002), revoked, Nitrites and/or Nitrates Combined with Spices in Curing Premixes, 38 Fed. Reg. 31,679, 31,680 (1973) (noting that preliminary studies detected nitrosamines even in buffered curing premixes).

n243. See Food Additives Permitted in Food on an Interim Basis or in Contact with Food Pending Additional Study; Mannitol, 61 Fed. Reg. 7990, 7991 (1996). The 1994 notice of filing did explain that the Agency was still reviewing a 1986 FASEB report which had found that mannitol and other sugar alcohols caused a statistically significant increased incidence of adrenal medullary hyperplasia and pheochromocytoma at high doses in rats. See Roquette America, Inc.'s Filing of Food Additive Petition, 59 Fed. Reg. 64,207, 64,208 (1994).

n244. See Saccharin Study and Labeling Act, Pub. L. No. 95-203, 91 Stat. 1451 (1977) (codified at 21 U.S.C. 343(o)(1) (1994)). The Act prohibits the Agency from revoking or amending any interim food additive regulations applicable to saccharin. See id. 3 (prohibiting such actions for 18 months); see also Pub. L. No. 104-180, 602, 110 Stat. 1569, 1594 (1996) (extending moratorium until May 1, 2002); Sheryl Gay Stolberg, Panel of Experts Rebuffs Effort to Absolve Saccharin, N.Y. Times, Nov. 1, 1997, at A13 (reporting that an expert panel voted 4-3 against removing saccharin from the list of suspected carcinogens).

n245. See Heterochemical Corp. v. FDA, 741 F. Supp. 382, 385-86 (E.D.N.Y. 1990) (holding that, pursuant to its regulations, the FDA could not find a lack of evidence to support GRAS status without demanding a food additive petition or taking some other appropriate action). For example, the litigation concerning the use of acrylonitrile copolymers in beverage containers concluded in 1979. See Acrylonitrile Copolymers Used to Fabricate Beverage Containers; Final Decision, 42 Fed. Reg. 48,528, 48,543 (1977) (staying food additive regulations pending the completion of further safety studies pursuant to an interim food additive order), rev'd, Monsanto Co. v. Kennedy, 613 F.2d 947, 954-56 (D.C. Cir. 1979) (remanding final order so that the FDA could determine whether any migration actually was detectable and, if so, whether the Agency would regard it as de minimis). The Agency has amended the applicable food additive regulations to allow certain uses in beverage containers, see, e.g., Indirect Food Additives: Polymers; Acrylonitrile/Styrene Copolymers, 49 Fed. Reg. 36,635 (1984) (codified at 21 C.F.R. 177.1040 (1997)), but its interim food additive regulation for acrylonitrile copolymers remains in effect, see Acrylonitrile Copolymers Intended for Use in Contact with Food, 41 Fed. Reg. 23,940, 23,946 (1976) (codified as amended at 21 C.F.R. 180.22 (1997)).

n246. At least one court has invalidated a similar "holding category" designed by the Agency to authorize the continued use of an OTC drug product while awaiting the results from further studies of an active ingredient. See Cutler v. Kennedy, 475 F. Supp. 838, 853-55 (D.D.C. 1979) (invalidating the FDA's original scheme for the review of OTC drugs which allowed for the continued marketing of products designated as Category III in a final monograph on the condition that additional testing be undertaken); cf. Cutler v. Hayes, 818 F.2d 879, 899-901 (D.C. Cir. 1987) (upholding the FDA's revised Category III regulations because they only authorized continued marketing during testing before the completion of a final monograph); McIlwain v. Hayes, 690 F.2d 1041, 1046 (D.C. Cir. 1982) (upholding the FDA's authority to continue postponing final action on provisionally listed color additives, noting that the statute "sets no time limit on provisional listings, a fact that is particularly significant since Congress has set such time limits in analogous statutes").

n247. See 21 U.S.C. 348(c)(3)(A) (1994). The statute provides:
 
In determining, for purposes of this section, whether a proposed use of a food additive is safe, the Secretary shall consider among other relevant factors -

 
 (A) the probable consumption of the additive and of any substance formed in or on food because of the use of the additive;

 
 (B) the cumulative effect of such additive in the diet of man or animals, taking into account any chemically or pharmacologically related substance or substances in such diet; and

 
 (C) safety factors which in the opinion of experts qualified by scientific training and experience to evaluate the safety of food additives are generally recognized as appropriate for the use of animal experimentation data.
 
 Id. 348(c)(5). Lack of effectiveness alone would not justify the denial of a food additive petition. See Marshall Minerals, Inc. v. FDA, 661 F.2d 409, 423 (5th Cir. 1981). Lack of effectiveness may, however, still be relevant insofar as such an additive may promote consumer deception or otherwise result in a misbranding violation. See id. at 423 n.18; see also 21 U.S.C. 348(c)(3)(B) (providing that a food additive shall not be approved if "the proposed use of the additive would promote deception of the consumer in violation of this chapter"). A discussion of the special proviso in this subsection which governs potential carcinogens is reserved for Part IV.B.

n248. Another obvious reason is that most potent or risky medical products are used by, or under the supervision of, a physician. See 21 U.S.C. 353(b)(1)(B) (requiring a prescription for drugs which are "not safe for use except under the supervision of a practitioner licensed by law to administer such drugs"); 21 C.F.R. 330.10(a)(4)(vi) (1997) (allowing over-the-counter sale unless licensed supervision is necessary for safety).

n249. H.R. Rep. No. 85-2284, at 4-5 (1958) (emphasis added); accord S. Rep. No. 85-2422, at 6 (1958); see also Food Quality Protection Act of 1996, Pub. L. No. 104-170, 405, 110 Stat. 1489, 1516 (to be codified at 21 U.S.C. 346a(b)(2)(A)(ii)) ("The term "safe,' with respect to a tolerance for a pesticide chemical residue, means that the Administrator has determined that there is a reasonable certainty that no harm will result....").

n250. See S. Rep. No. 85-2422, at 2 (explaining that the test is reasonable certainty that the food additive is safe).

n251. See 21 C.F.R. 170.30(b), (c)(1); Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,942 (1997) (explaining that "a GRAS substance is neither more safe nor less safe than an approved food additive"). A GAO review concluded that the FDA initially did not strictly abide by this rule. See GAO, supra note 172, at v ("GAO reviewed 15 of these [GRAS affirmed] substances and found that only 2 had been subjected to the same type of scientific tests FDA considers necessary for a food additive.").

n252. See supra notes 12-22 and accompanying text; see also David D. Doniger, Federal Regulation of Vinyl Chloride: A Short Course in the Law and Policy of Toxic Substances Control, 7 Ecology L.Q. 497, 593 (1978) (arguing that the safety standards are identical).

n253. See 1957 Hearings, supra note 22, at 456 (HEW memorandum) (preferring a more stringent "without hazard" standard, even while conceding an inability to be "absolutely sure"). The initial version of the bill that Congress ultimately enacted included a separate definition of the term "safe" as meaning "without hazard," see H.R. 13,254, 85th Cong. 2 (201(t)) (1958), but this did not appear in the final version.

n254. 104 Cong. Rec. 17,418 (1958). Although "harm" is not separately defined, Congress evidently understood the term to mean a capacity to injure or otherwise cause disease. See H.R. Rep. No. 85-2284, at 4 ("The concept of safety used in this legislation involves the question of whether a substance is hazardous to the health of man or animal."); S. Rep. No. 85-2422, at 11 (explaining that the intent of the bill was "to assure our people that nothing shall be added to the foods they eat which can reasonably be expected to produce any type of illness"). This would exclude undesirable side effects that posed no risk of adverse health consequences.

n255. 21 C.F.R. 121.1(i) (1970) (emphasis added); see also 1957 Hearings, supra note 22, at 456 (HEW memorandum) ("We do not want to feed chemically treated food to our children if the only assurance we have is that it is reasonably probable that the added chemicals will not cause harm. We want to know that it has been established convincingly....").

n256. Eligibility of Substances for Classification as Generally Recognized as Safe in Food, 36 Fed. Reg. 12,093, 12,093 (1971) (codified at 21 C.F.R. 121.1(i) (1972)).

n257. See General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,604 (1976) (codified at 21 C.F.R. 170.3(i) (1997)); see also Marshall Minerals, Inc. v. FDA, 661 F.2d 409, 419 (5th Cir. 1981) (noting that the FDA "asserted that this later definition is taken from the legislative history of the Act," but resolving the dispute concerning gentian violet without regard to which of the two standards applied); Cyclamate (Cyclamate Acid, Calcium Cyclamate, and Sodium Cyclamate), Commissioner's Decision, 45 Fed. Reg. 61,474, 61,477 (1980) (discussing the general safety standard in the course of affirming the decision to reject the food additive petition for cyclamate).

n258. 21 C.F.R. 170.3(i) (1997) ("It is impossible in the present state of scientific knowledge to establish with complete certainty the absolute harmlessness of the use of any substance."). The color additive regulations still demand "convincing evidence that establishes with reasonable certainty that no harm will result." Id. 70.3(i).

n259. Courts accord heightened deference to contemporaneous agency interpretations of a statute and require that any subsequent modifications in the original interpretation be well explained. See, e.g., General Elec. Co. v. Gilbert, 429 U.S. 125, 142-43 (1976) ("We have declined to follow administrative guidelines in the past where they conflicted with earlier pronouncements of the agency."); NLRB v. Bell Aerospace Co., 416 U.S. 267, 274-75 (1974) ("[A] court may accord great weight to the longstanding interpretation placed on a statute by an agency charged with its administration."); Les v. Reilly, 968 F.2d 985, 989-90 (9th Cir. 1992) ("As a contemporaneous agency construction of the statute, this interpretation is entitled to great weight."); Rhodia, Inc. v. FDA, 608 F.2d 1376, 1379 (D.C. Cir. 1979) ("The agency should follow [the] course [of its interpretation] consistently or articulate reasons for its departure.").

n260. See Community Nutrition Inst. v. Young, 773 F.2d 1356, 1363 (D.C. Cir. 1985) (aspartame); cf. Simpson v. Young, 854 F.2d 1429, 1431 (D.C. Cir. 1988) (FD&C Blue No. 2); Scott v. FDA, 728 F.2d 322, 324 (6th Cir. 1984) (D&C Green No. 5); Daryl M. Freedman, Reasonable Certainty of No Harm: Reviving the Safety Standard for Food Additives, Color Additives, and Animal Drugs, 7 Ecology L.Q. 245, 255-73 (1978) (concluding that FDA and judicial interpretations of the food additive safety standard are overly permissive).

n261. See 21 C.F.R. 170.3(i); see also id. 170.20(a) ("The Commissioner will give due weight to the anticipated levels and patterns of consumption of the additive specified or reasonably inferrable."). This interpretation of the safety standard comports with the legislative history. See H.R. Rep. No. 85-2284, at 5 (1958) ("In determining the "safety' of an additive, scientists must take into consideration the cumulative effect of such additive in the diet of man or animals over their respective life spans together with any chemically or pharmacologically related substances in such diet.").

n262. 21 C.F.R. 170.20(a).

n263. See id. 170.22 (explaining that "a food additive for use by man will not be granted a tolerance that will exceed 1/100th of the maximum amount demonstrated to be without harm to experimental animals").

n264. See Rulis, supra note 193, at 537; see also Food Additives, Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. 36,582, 36,583 n.1 (1995). Efforts have been made to disaggregate the different uncertainty factors imbedded in this margin of safety. See WHO, Principles for the Safety Assessment of Food Additives and Contaminants in Food, Envtl. Health Criteria No. 70 (1987) (suggesting 10-fold uncertainty factors for both interspecies differences and interindividual variations); A.G. Renwick, Data-Derived Safety Factors for the Evaluation of Food Additives and Environmental Contaminants, 10 Food Additives & Contaminants 275 (1993) (suggesting further subdivision of each 10-fold uncertainty factor to account for individual differences in sensitivity and pharmacokinetic differences).

n265. The FDA typically uses the estimated 90th percentile chronic intake as the proper measure of consumption. See, e.g., Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 53 Fed. Reg. 6595, 6597-98 (1988) (explaining why the FDA usually estimated consumption based on the 90th percentile).

n266. See Rulis, supra note 193, at 537 ("Normally an additive whose EDI does not exceed its ADI for the proposed use can be considered to be safe within the meaning of theAct.").

n267. See 1957 Hearings, supra note 22, at 459 (HEW memorandum) ("The [FDA] agrees that a fixed set of uniform test procedures which are prescribed and obligatory would serve effectively to slow down progress in the development of more effective procedures and methods."); cf. id. at 67 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.) (urging that the statute specify the appropriate testing procedures).

n268. See 21 C.F.R. 170.20(a) ("A petition will not be denied... [if] the procedures used give results as reliable as, or more reliable than, those reasonably to be expected from the use of the outlined procedures.").

n269. Id. 170.20(b); see also id. 10.90(b)(1)(i) (stating that, although persons are free to use procedures other than those identified as acceptable in guidelines, the FDA encourages such persons to "discuss the matter in advance with FDA to prevent the expenditure of money and effort on activity that may later be determined to be unacceptable").

n270. See Food Additives: Competitive, Regulatory, and Safety Problems: Hearings Before the Senate Select Comm. on Small Business, 95th Cong. 57-60 (1977) (statement of Sherwin Gardner, Acting Comm'r, FDA); see also Howard R. Roberts, Food Additives - A Study in the Evolution of Safety, 31 Food Drug Cosm. L.J. 404, 409 (1976) (describing direct additive review program); Alan M. Rulis & Richard J. Ronk, Cyclic Review - Looking Backward or Looking Forward?, 36 Food Drug Cosm. L.J. 156, 157-59 (1981) (describing the goals of the cyclic review).

n271. See Hutt, supra note 1, at 122 (explaining that the process "died a natural death by the mid-1980s" because the Agency's goal "was clearly unachievable").

n272. See Availability of Toxicological Standards for Food and Color Additive Safety Evaluation, 47 Fed. Reg. 46,141 (1982). The notice explains that the principles will not apply to the review of indirect additives. See id. at 46,142; see also Edward F. Bouchard, The Food and Drug Administration's Redbook: The Practical Implications for Business Practices, 39 Food Drug Cosm. L.J. 211 (1984) (discussing the Redbook's impact); Hutt, supra note 1, at 124 (criticizing the evolution of the Redbook into a "rigid compendium of required tests designed more to protect an FDA reviewer from criticism than to protect the consuming public"). For a description of international efforts on this subject, see International Harmonization; Policy on Standards, 60 Fed. Reg. 53,078, 53,083-84 (1995) (announcing the FDA's policy on harmonization efforts and explaining that Redbook II will take into account existing OECD guidelines); Charles Feldberg, The Food and Drug Administration's Redbook: Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food - International Implications, 38 Food Drug Cosm. L.J. 368 (1983).

n273. Draft Revised "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food;" Availability, 58 Fed. Reg. 16,536, 16,536 (1993). Some of the important changes include recommendations for routine neurotoxicity and immunotoxicity screening assays. The inclusion of GRAS reviews expanded the scope of the guidelines beyond the review of food and color additive petitions. See Food Additive Approvals to Halt if Redbook II Adopted, Food Chem. News, Jan. 3, 1994, at 41. The notice of availability of the original Redbook, see Availability of Toxicological Standards for Food and Color Additive Safety Evaluation, 47 Fed. Reg. at 46,141-42, nowhere suggested that the FDA would apply its guidelines to GRAS determinations.

n274. See 21 C.F.R. 10.90(b) (1997); see also United States v. Bioclinical Sys., Inc., 666 F. Supp. 82, 83-84 (D. Md. 1987) (rebuffing the FDA's effort to impose new requirements announced in a guideline rather than a duly promulgated regulation).

n275. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 57 Fed. Reg. 6667, 6669 & n.2 (1992); see also Simpson v. Young, 854 F.2d 1429, 1435 (D.C. Cir. 1988) (holding that the FDA need not demand adherence to the guidelines set out in the Redbook given the "permissive language in the manual").

n276. The FDA has proposed to revise its administrative regulations so that Agency personnel would not be bound to adhere to formally announced opinions and guidelines. See Administrative Practices and Procedures; Advisory Opinions and Guidelines, 57 Fed. Reg. 47,314 (1992). Although it has not yet finalized this proposal, the FDA recently published a guidance document on the subject. See The Food and Drug Administration's Development, Issuance, and Use of Guidance Documents, 62 Fed. Reg. 8961, 8963 (1997) (reiterating its view that guidelines do not bind the Agency, and explaining that the proposal would soon be finalized). Such a change in the FDA's procedures would reduce the utility of the new Redbook. It would impede new product development if sponsors could no longer be assured that toxicological studies, performed in accordance with the Redbook's guidelines, would be acceptable to Agency reviewers. See Lars Noah, The FDA's New Policy on Guidelines: Having Your Cake and Eating It Too, 47 Cath. U. L. Rev. 113, 124 (1997).

n277. See Rulis & Tarantino, supra note 192, at 138 (describing the FDA's review of a food additive petition); Rulis, supra note 193, at 536-38. Dr. Rulis, then the Chief of the FDA's Regulatory Food Chemistry Branch and the manager of the food additives program, concluded that the "inquiry must not be so stringent as to make it impossible for additives to be approved; it must be finite in scope. Yet, it must be rigorous enough to ensure with reasonable certainty that additives are safe for consumption by the consumers." Id. at 544; see also id. at 536 ("If the FDA's scientists approached this problem as some of their counterparts in academia might, they would be prepared to ask an infinite range of questions....").

n278. Taylor, supra note 169, at 204.

n279. See infra note 433 (providing examples of industry complaints).

n280. See Rulis & Tarantino, supra note 192, at 138; see also 1995 Hearings, supra note 1, at 184 (statement of Michael F. Jacobson, Exec. Dir., CSPI) ("Efforts to accelerate the review process must take into account the complexity of this post-filing review, and must acknowledge that clearing up unresolved issues can take years."); Rulis, supra note 193, at 536 ("The scientific aspects of the evaluation are conducted simultaneously within several separate scientific disciplines... This parallel review procedure decentralizes petition review and makes it possible for scientific questions to be resolved under a type of consensus system....").

n281. See, e.g., H.R. 6747, 85th Cong. 5 (409(c)(3)) (1957); see also 1957 Hearings, supra note 22, at 22 (HEW memorandum) ("The law should make certain that no active poison be allowed in the food supply in any case where its use, or the particular level of use, is not clearly shown to result in a definite benefit to the producer or consumer."); id. at 257 (statement of Hon. John D. Dingell) (suggesting that "for many centuries the human race has gotten along without these things, and if these things serve no useful purpose, there is no reason for adding them"); id. at 448-53 (statement of George P. Larrick, Comm'r, FDA) (asserting that "functional value... is a vital safety factor").

n282. See, e.g., 1957 Hearings, supra note 22, at 68-69 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.); id. at 117 (statement of Lawrence A. Coleman, appearing on behalf of the Mfg. Chemists' Ass'n) (joining "the overwhelming consensus of food manufacturers" in opposition of any consideration of functional value); 1956 Hearings, supra note 16, at 74 (statement of Glenn G. Paxton, appearing as counsel for various food industry associations) ("It would be a mistake to inject into legislation dealing with questions of safety or toxicity of foods questions as to the functional value of a given ingredient.").

n283. See Food Additives Amendment of 1958, Pub. L. No. 85-929, 4, 72 Stat. 1784, 1786 (codified at 21 U.S.C. 348(c)(4) (1994)); H.R. Rep. No. 85-2284, at 6 (1958) (This standard "does not involve any judgment on the part of the Secretary of whether such effect results in any added "value' to the consumer of such food or enhances the marketability from a merchandising point of view."); 1957 Hearings, supra note 22, at 503 (statement of Charles W. Dunn, counsel for the Grocery Mfrs. of Am.); Bernard L. Oser, The Functional Value of Food Additives, 13 Food Drug Cosm. L.J. 131 (1958); see also H.R. Rep. No. 92-1338, at 6 (1972) (emphasizing that the FDA should not evaluate the "value" of nitrites and nitrates as food additives).

n284. By comparison, such a requirement is typical in other industrialized countries. See, e.g., Council Directive 89/107, 1989 O.J. (L40) 27, annex II(2) (explaining that in the European Union "it is necessary to establish the case for what is commonly referred to as "need'"); C.R.C. ch. 870, B.16.100 (1995) (same in Canada); John Abraham & Erik Millstone, Food Additive Controls: Some International Comparisons, 14 Food Pol'y 43, 47 (1989) (explaining that in the United Kingdom and other European countries utility must be shown because, "no matter how safe an additive might be, it is policy to prohibit compounds unless they are, in some sense, needed").

n285. See General Recognition of Safety and Prior Sanctions for Food Ingredients, 41 Fed. Reg. 53,600, 53,601 (1976) ("The ordinary understanding of the term "safe' would require some benefit-to-risk analysis in such circumstances."). The Agency suggested that it might tolerate chronic risks posed by a major food source but not the same risk if posed by a minor additive. See id. Nonetheless, the FDA deleted from the regulations a separate reference to benefits because they will only occasionally be relevant and are sufficiently subsumed within the safety determination. See id.; see also Merrill, supra note 10, at 246 (noting that the statute "does not state whether other considerations may enter into [the FDA's] judgment"). Similarly, the EPA "has interpreted the general safety clause in section 409 as allowing the balancing of risks and benefits," Section 409 Tolerances; Response to Petition Requesting Revocation of Food Additive Regulations, 55 Fed. Reg. 17,560, 17,561 (1990), though it previously had noted that the FDA applies a risk-only interpretation, see Food Additive Regulations Concerning Pesticide Residues: Procedural Regulations, 53 Fed. Reg. 41,126, 41,127 (1988).

n286. See Diethylstilbestrol; Withdrawal of Approval of New Animal Drug Applications; Commissioner's Decision, 44 Fed. Reg. 54,852, 54,882 (1979) ("This language... has never been the basis for an agency decision... There is no justification for such a statement either in the statute itself or in its legislative history."). The controversy over saccharin had peaked two years earlier.

n287. The statute provides that, in approving an additive, the FDA may prescribe conditions for safe use
 
including, but not limited to, specifications as to the particular food or classes of food in or on which such additive may be used, the maximum quantity which may be used or permitted to remain in or on such food, the manner in which such additive may be added to or used in or on such food, and any directions or other labeling or packaging requirements for such additive deemed necessary by [the Secretary] to assure the safety of such use.
 
 21 U.S.C. 348(c)(1)(A) (1994). Another subsection authorizes the FDA to fix tolerances if necessary to assure safe use at a level no higher than reasonably required to achieve the additive's effect. See id. 348(c)(4); 21 C.F.R. 170.18 (1997). The Agency may include similar limitations in GRAS affirmation regulations, see id. 170.30(j), 184.1(b)(1), but it has done so only infrequently.

n288. See Lars Noah, The Imperative to Warn: Disentangling the "Right to Know" from the "Need to Know" About Consumer Product Hazards, 11 Yale J. on Reg. 293, 315-20 (1994) (discussing the FDA's warning requirements for foods and food additives).

n289. See Merrill, supra note 10, at 206 (suggesting that the statute only covers the labeling of bulk quantities of an additive sold to food processors and other commercial users). The possibility of deception represents a legitimate basis for denying a food additive petition but is not obviously an appropriate ground under the statute for conditioning approval on compliance with specific labeling requirements. Compare 21 U.S.C. 348(c)(3)(B) (1994) (listing grounds for denial), with id. 348(c)(1) (listing conditions "under which such additive may be safely used").

n290. 21 U.S.C. 348(c)(3)(A). Substantially similar clauses appear in provisions governing animal drugs and color additives. See id. 360b(d)(1)(H), 379e(b)(5)(B).

n291. See Merrill, supra note 10, at 178 (reviewing the history and impact of the Delaney clause); see also Frederick H. Degnan & W. Gary Flamm, Living with and Reforming the Delaney Clause, 50 Food & Drug L.J. 235, 244-56 (1995). Most of the commentary on this subject has been critical. See, e.g., Charles H. Blank, The Delaney Clause: Technical Na<um i>vete and Scientific Advocacy in the Formulation of Public Health Policies, 62 Cal. L. Rev. 1084, 1116-20 (1974); Margaret Gilhooley, Plain Meaning, Absurd Results and the Legislative Purpose: The Interpretation of the Delaney Clause, 40 Admin. L. Rev. 267, 296-301 (1988); Richard A. Merrill, FDA's Implementation of the Delaney Clause: Repudiation of Congressional Choice or Reasoned Adaptation to Scientific Progress?, 5 Yale J. on Reg. 1, 74-88 (1988).

n292. Lay press coverage incorrectly suggested that the Food Quality Protection Act of 1996 had repealed the Delaney clause. See, e.g., Timothy Noah, Congress Eases Rules for Pesticides in Processed Foods, Wall St. J., July 25, 1996, at A22 ("Ending two decades of fighting between consumer groups and the food industry, Congress voted to eliminate the Delaney Clause, a 1958 law that prohibits even minute traces of carcinogens in processed foods."). Instead, Congress simply had exempted pesticide residues from regulation as food additives. See Food Quality Protection Act of 1996, Pub. L. No. 104-170, 404, 405, 110 Stat. 1489, 1514; see also Scott Douglas Bauer, Note, The Food Quality Protection Act of 1996: Replacing Old Impracticalities with New Uncertainties in Pesticide Regulation, 75 N.C. L. Rev. 1369 (1997).

n293. Technically, the Delaney clause does not apply to GRAS substances (or prior sanctioned ingredients), though the FDA initially took the position that evidence of carcinogenicity would undermine GRAS status. See, e.g., Acrylonitrile Copolymers Used to Fabricate Beverage Containers; Final Decision, 42 Fed. Reg. 48,528, 48,543 (1977) (explaining that "a carcinogenic substance per se cannot be considered [GRAS]," and also that a "substance that is the subject of testing whose preliminary results strongly indicate that it will be shown to be carcinogenic cannot be considered [GRAS]"); Cyclamic Acid and Its Salts, 34 Fed. Reg. 17,063 (1969) (deleting cyclamate from the GRAS list because of evidence of carcinogenicity in laboratory animals); cf. Public Citizen v. Young, 831 F.2d 1108, 1119-20 (D.C. Cir. 1987) (noting in dicta that the GRAS exception "may permit a de minimis exception at a stage that logically precedes the FDA's ever reaching the food additive Delaney Clause").

n294. See 104 Cong. Rec. 17,414 (1958) (statement of Hon. Oren Harris); 104 Cong. Rec. 17,420 (1958) (statement of Hon. James J. Delaney). The subject was, however, discussed at some length during the Subcommittee's earlier hearings. See, e.g., 1957 Hearings, supra note 22, at 168-69 (statement of Hon. James J. Delaney) (explaining his introduction of a new bill revised only to add the anti-cancer clause); id. at 383 (letter from James S. Adams, American Cancer Society) (recommending the inclusion of such a clause).

n295. See S. Rep. No. 85-2422, at 11 (1958) ("In short, we believe the bill reads and means the same with or without the inclusion of the clause referred to. This is also the view of the [FDA]."); 104 Cong. Rec. 17,414 (1958) (statement of Hon. Oren Harris) ("While the Committee felt that the bill as reported by the committee includes the matter covered by the Delaney amendment in the general language contained in the bill, there was no objection to the addition of the amendment suggested by Mr. Delaney."); id. at 17,415 (letter from Elliot L. Richardson, Asst. Secretary, HEW).
 
To single out one class of diseases for special mention would be anomalous and could be misinterpreted... At the same time, if it would serve to allay any lingering apprehension on the part of those who desire an explicit statutory mandate on this point, the Department would interpose no objection to appropriate mention of cancer in food additives legislation.
 
 Id.; cf. H.R. Rep. No. 85-2284, at 5 (1958) ("Since the scientific investigation and the other relevant data to be taken into consideration by the Secretary include information with respect to possible cancer causing characteristics of a proposed additive, the public will be protected from possible harm on this count."). The Delaney clause prompted some minor debate on the floor of the House. See 104 Cong. Rec. 17,421-22 (1958).

n296. See 1957 Hearings, supra note 22, at 170 (statement of Dr. William E. Smith); see also Color Additives: Hearings Before the House Comm. on Interstate and Foreign Commerce, 86th Cong. 501 (1960) (statement of Arthur S. Flemming, Secretary, HEW) ("The opposition to the inclusion of an anticancer clause arises largely out of a misunderstanding of how this provision works. It allows the Department and its scientific people full discretion and judgment in deciding whether a substance has been shown to cause cancer...."); Merrill, supra note 10, at 182 ("Scientific judgment has played, and apparently was intended to play, an important role in the policy's application.").

n297. FDA scientists were leading participants in the Interagency Regulatory Liaison Group (IRLG). See Scientific Bases for Identification of Potential Carcinogens and Estimation of Risks; Request for Comments on Report, 44 Fed. Reg. 39,858 (1979). The Report explained that:
 
Determination that a causal relationship exists between a test treatment and the responses observed in a bioassay is a complex judgmental activity that includes evaluation of the identity of the test agent and the biologic test system, the conditions of exposure, the methods of observation, and the qualitative and quantitative nature of the pathologic response. The assessment of carcinogenicity therefore relies upon the judgment and expertise of professionals.
 
 Id. at 39,862-63. The FDA also participated in the Interagency Staff Group on Carcinogens of the Office of Science and Technology Policy (OSTP). See Chemical Carcinogens; A Review of the Science and Its Associated Principles, 50 Fed. Reg. 10,372 (1985). The OSTP digest of principles for evaluating chemical carcinogens makes many of the same points as the IRLG report. See id. at 10,414-19; cf. Proposed Guidelines for Carcinogen Risk Assessment, 61 Fed. Reg. 17,960 (1996) (proposing revisions to the EPA's cancer assessment guidelines). The FDA has on a number of occasions explicitly endorsed the OSTP guidelines. See, e.g., Sponsored Compounds in Food-Producing Animals; Criteria and Procedures for Evaluating the Safety of Carcinogenic Residues; Animal Drug Safety Policy, 52 Fed. Reg. 49,572, 49,577-78 (1987).

n298. Sponsored Compounds in Food-Producing Animals; Criteria and Procedures for Evaluating the Safety of Carcinogenic Residues; Animal Drug Safety Policy, 52 Fed. Reg. at 49,577 (quoting with approval from a report of the Interdisciplinary Panel on Carcinogenicity entitled Criteria for Evidence of Chemical Carcinogenicity, 225 Science 682, 683 (1984)); see also Chemical Carcinogens; A Review of the Science and Its Associated Principles, 50 Fed. Reg. at 10,415; Cyclamate (Cyclamate Acid, Calcium Cyclamate, and Sodium Cyclamate), Commissioner's Decision, 45 Fed. Reg. 61,474, 61,478 (1980) (The Commissioner's final decision denying the food additive petition for cyclamate explained that "there is an interrelationship between statistical significance and biological significance. Scientists view the statistical and the biological data together to determine what, if any, conclusions can be drawn from the results of the study.").

n299. See, e.g., Permanent Listing of FD&C Yellow No. 6, 51 Fed. Reg. 41,765, 41,767-71 (1986); FD&C Blue No. 2, 48 Fed. Reg. 5252, 5254-57 (1983); D&C Green No. 5, 47 Fed. Reg. 24,278, 24,281-83 (1982).

n300. FD&C Blue No. 2, 48 Fed. Reg. at 5257.

n301. See D&C Green No. 5, 47 Fed. Reg. at 24,283. The FDA identified the following evidence as support for its conclusion that the color additive did not induce cancer:
 
(1) the fact that the incidence in the high dose group is within the normal range of background spontaneous incidence; (2) the absence of evidence of progressiveness that would be expected from a carcinogen; (3) the absence of observable non-neoplastic disease in the mouse liver; (4) the negative findings on testing D&C Green No. 5 for mutagenic activity; and (5) the atypical form of the apparent dose-response data.
 
 Id. "Thus, in acceptable carcinogenicity bioassays in two species where numerous tissues were examined in both sexes, a slightly higher [though by some measures statistically significant] number of neoplasms was observed in only one site (the liver), one dose group of one sex and in one species." Id. (adding that "all other evidence indicates that the effect was unlikely to be related to treatment with D&C Green No. 5"). On the basis of this weight-of-the-evidence analysis, the Agency found, and later reiterated, that the color additive was noncarcinogenic and nontumorigenic. See D&C Green No. 5; Listing as a Color Additive in Drugs and Cosmetics; Termination of Stay and Confirmation of Effective Date, 47 Fed. Reg. 49,628 (1982).

n302. Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 57 Fed. Reg. 6667, 6675 (1992). "The evidence can reasonably include a dose response or a lack of a dose response, consideration of historical controls, associated pathological data, the time to induction [of] tumors, and the multiplicity of tumors." Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 53 Fed. Reg. 28,379, 28,381 (1988).

n303. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 57 Fed. Reg. at 6674-75; see also Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. 3118, 3128-30 (1996) (disregarding various effects observed in chronic rodent studies in the course of approving the new food additive olestra).

n304. Selenium in Animal Feed: Proposed Food Additive Regulation, 38 Fed. Reg. 10,458, 10,460 (1973).
 
Even some human nutrients - such as selenium, chromium, and nickel - when isolated and administered to laboratory animals in the enormous quantities represented by the maximum tolerated dose, have been found to be carcinogenic. In short, without interposing an evaluation of genuine risk of causing cancer, a regulatory assumption that any chemical that has a carcinogenic effect of any kind is unsafe could require that a significant portion of the food supply be banned.
 
 Correction of Listing of D&C Orange No. 17 for Use in Externally Applied Drugs and Cosmetics, 52 Fed. Reg. 5081, 5083 (1987); see also Regulation of Dietary Supplements, 58 Fed. Reg. 33,690, 33,694 (1993) ("Certain vitamins and minerals are safe when consumed at low levels but may have adverse effects when consumed daily at higher levels."); Richard A. Merrill et al., The FDA's Authority Under the Delaney Clause to Consider Mechanisms of Action in Determining Whether Additives "Induce Cancer," 47 Food & Drug L.J. 77 (1992) (defending the FDA's use of scientific judgment in evaluating the carcinogenicity and safety of food additives); Bruce N. Ames et al., Ranking Possible Carcinogenic Hazards, 236 Science 271, 277 (1987) (arguing that animal cancer tests cannot be used to predict absolute human risks).

n305. See Selenium in Animal Feed, 39 Fed. Reg. 1355 (1974); Selenium in Animal Feed: Proposed Food Additive Regulation, 38 Fed. Reg. at 10,458. In addition to selenium, the Agency has permitted the continuing use of suspected secondary carcinogens such as the antioxidant butylated hydroxyanisole (BHA), see 21 C.F.R. 172.110 (1997), and the indirect food additive melamine, see id. 175.105; Cyromazine; Proposed Tolerance, 49 Fed. Reg. 18,120, 18,121 (1984).

n306. See, e.g., Indirect Mechanisms of Carcinogenesis Discussed at FDA Workshop, Food Chem. News, Mar. 11, 1996, at 24 (acknowledging that the issue of indirect mechanisms of carcinogenesis is a "highly volatile" one for FDA regulators).

n307. As the FDA explained in support of its policy:
 
Each chemical in the complex mixture that constitutes a food additive could itself be considered to be a food additive. Each of these chemicals in some sense becomes a component of the Food... The Delaney Clause does not apply to a carcinogenic chemical in a food additive absent a finding, after appropriate tests, that the additive as a whole induces cancer.
 
 Policy for Regulating Carcinogenic Chemicals in Food and Color Additives; Advance Notice of Proposed Rulemaking, 47 Fed. Reg. 14,464, 14,466-68 (1982); see also Agriculture, Rural Development and Related Agencies Appropriations for 1984 (Part 4): Hearing Before a Subcomm. of the House Comm. on Appropriations, 98th Cong. 472-77 (1983) (testimony of Arthur H. Hayes, Comm'r, FDA) (describing and defending the FDA's constituents policy). Thus, the FDA approved D&C Green No. 5 even though it contained D&C Green No. 6, which was manufactured with and contained trace levels of p-toluidine, a suspect carcinogen. See D&C Green No. 5, 47 Fed. Reg. 24,278 (1978); see also Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. 36,582, 36,589 (1995) (clarifying that references to carcinogenicity in the "threshold of regulation" policy referred only to the food-contact substance and not to any of its impurities); Proposed Uses of Vinyl Chloride Polymers, 51 Fed. Reg. 4177, 4180 (1986) (applying constituents policy to vinyl chloride polymers, an indirect food additive); Indirect Food Additives: Polymers; Acrylonitrile/Styrene Copolymers, 49 Fed. Reg. 36,635, 36,636-37 (1984) (same, for acrylonitrile copolymers). The legality of this so-called constituents policy has been upheld. See Scott v. FDA, 728 F.2d 322, 325 (6th Cir. 1984) (holding that the Delaney clause is satisfied if the color additive as a whole did not cause cancer in animals, irrespective of whether constituents or impurities present in the additive may be carcinogenic).

n308. See 21 C.F.R. 173.255(c) (1997) (authorizing the use of methylene chloride for extracting caffeine from green coffee beans).

n309. Cosmetics; Proposed Ban on the Use of Methylene Chloride as an Ingredient of Aerosol Cosmetic Products, 50 Fed. Reg. 51,551, 51,557 (1985). With improvements in analytical methods and more sensitive animal studies for identifying the potential to cause cancer, such problems will arise even more frequently in the future. See Policy for Regulating Carcinogenic Chemicals in Food and Color Additives; Advance Notice of Proposed Rulemaking, 47 Fed. Reg. at 14,466; Chemical Compounds in Food Producing Animals: Criteria and Procedures for Evaluating Assays for Carcinogenic Residues, 44 Fed. Reg. 17,070, 17,075 (1979) (noting that detection limits have improved by several orders of magnitude); 1995 Hearings, supra note 1, at 41 (statement of Richard L. Hall, Chair, NAS Food Forum) ("Due partly to the progress of toxicology, but even more to the phenomenal advances in analytical chemistry, we are now aware of possible hazards, often remote or simply theoretical, of which, 20 or 40 years ago, we were blissfully unaware.").

n310. See Rulis, supra note 193, at 540-41 (discussing the impact that "macro" food ingredients, those food additives with the potential for significant human consumption, would have on the FDA's policies); Taylor, supra note 169, at 210 (pointing out that dramatic advances in science and food technology will result in new issues that require regulatory attention).

n311. See G.D. Searle & Co.: Notice of Filing of Petition for Food Additive, 38 Fed. Reg. 5921 (1973).

n312. See Aspartame, 39 Fed. Reg. 27,317, 27,320 (1974) (codified as amended at 21 C.F.R. 172.804(c) (1997)) (approving the use of aspartame as a tabletop sweetener and in cold breakfast cereals, powdered beverages, desserts, dessert toppings, and chewing gum). Technically, aspartame is a nutritive rather than non-nutritive sweetener, but its caloric contribution is trivial because this substance is almost 200 times sweeter than an equal quantity of sugar. See Aspartame: Commissioner's Final Decision, 46 Fed. Reg. 38,284, 38,285 (1981).

n313. See Aspartame, 39 Fed. Reg. at 27,320 (codified at 21 C.F.R. 172.804(e)(2) (1997)). In addition, labeling of tabletop sweeteners containing aspartame must advise consumers not to use it in cooking or baking. See id. (codified at 21 C.F.R. 172.804(e)(3) (1997))). This latter requirement exists for functional rather than safety reasons. See id. at 27,318 (explaining that, under prolonged heating, aspartame breaks down to diketopiperazine (DKP) and loses sweetness, adding that the safety of DKP remains under investigation).

n314. See Aspartame; Stay of Effectiveness of Additive Regulation, 40 Fed. Reg. 56,907 (1975); see also GAO, Regulation of the Food Additive Aspartame, No. MWD-76-111 (1976). An independent audit eventually validated the study results. See Aspartame; Ruling on Objections and Notice of Hearing Before a Public Board of Inquiry, 44 Fed. Reg. 31,716, 31,717 (1979).

n315. See Aspartame; Time and Place of Hearing, 45 Fed. Reg. 2908 (1980). Normally, an administrative law judge (ALJ) would conduct such a hearing, but the objectors agreed to the modified procedure and submitted a slate of names from which board members would be selected. See Aspartame; Ruling on Objections and Notice of Hearing Before a Public Board of Inquiry, 44 Fed. Reg. at 31,717.

n316. See In re Aspartame, Food Drug Cosm. L. Rep. (CCH) P 38,072, at 38,346-49 (Sept. 30, 1980); see also Aspartame; Availability of Board of Inquiry Decision, 45 Fed. Reg. 69,558 (1980); Sidney A. Shapiro, Scientific Issues and the Function of Hearing Procedures: Evaluating the FDA's Public Board of Inquiry, 1986 Duke L.J. 288, 307-13 (outlining the aspartame approval process); Todd R. Smyth, Note, The FDA's Public Board of Inquiry and the Aspartame Decision, 58 Ind. L.J. 627 (1983).

n317. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Reinstatement of Regulation for Aspartame, 46 Fed. Reg. 50,947 (1981); Aspartame: Commissioner's Final Decision, 46 Fed. Reg. at 38,287-89 (commenting that "few compounds have withstood such detailed testing and repeated, close scrutiny"). One year later, Congress extended aspartame's patent term to restore a portion of the time Searle lost during the lengthy delays in the FDA's decisionmaking process. See Pub. L. No. 97-414, 11, 96 Stat. 2049, 2065 (1983) (codified at 35 U.S.C. 155 (1994)). The patent term extension represented a floor amendment to a bill amending the Orphan Drug Act and triggered little debate. See 128 Cong. Rec. 26,979 (1982) (amendment introduced by Sen. Byrd); 128 Cong. Rec. 30,451 (1982) (statement by Hon. Henry Waxman) (explaining only that the "amendment extends the patent for a food additive").

n318. Aspartame: Commissioner's Final Decision, 46 Fed. Reg. at 38,303. The FDA did not require the submission of additional safety information.

n319. See G.D. Searle & Co.; Filing of Food Additive Petition, 47 Fed. Reg. 46,140 (1982).

n320. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 48 Fed. Reg. 31,376, 31,382 (1983) (codified at 21 C.F.R. 172.804(c)(6) (1997)). In the preamble, the Agency reiterated its previous conclusions concerning the safety of aspartame, and it reviewed new information including studies on DKP and other degradation/reaction products. See id. at 31,378-81.

n321. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 49 Fed. Reg. 6672 (1984); see also Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 48 Fed. Reg. 52,899 (1983) (rejecting requests for a stay).

n322. See Community Nutrition Inst. v. Young, 773 F.2d 1356, 1362 (D.C. Cir. 1985).

n323. See id. at 1362-63. The court specifically agreed with the FDA's finding that there were no material issues warranting a hearing on the objections concerning the risks of brain damage from changes in neurotransmitter production, nitrosamine formation, carcinogenicity, embryotoxicity of degradation products, increased levels of consumption, or more rapid decomposition associated with its use in carbonated beverages. See id. at 1364-67 (deferring to the FDA's expert judgment on these matters). The court also found no basis for arguments urging revised labeling requirements. See id. at 1366.

n324. See 21 C.F.R. 172.804(c)(7)-(23) (1996); see also id. 172.800(c) (acesulfame potassium). The citations to the numerous Federal Register notices announcing amendments for new uses appear at the end of these sections in the regulations.

n325. See, e.g., Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 53 Fed. Reg. 6595, 6600 (1988).

n326. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Aspartame, 61 Fed. Reg. 33,654, 33,656 (1996) (codified at 21 C.F.R. 172.804 (1997)).

n327. See, e.g., "NutraSweet" - Health and Safety Concerns: Hearing Before the Senate Comm. on Labor and Human Resources, 100th Cong. 1-3 (1987) [hereinafter NutraSweet Hearing] (statement of Sen. Metzenbaum); GAO, Food and Drug Administration: Food Additive Approval Process Followed for Aspartame, No. HRD-87-46 (1987) (investigating allegations that the FDA had mischaracterized the available safety data); GAO, Food and Drug Administration: Six Former HHS Employees' Involvement in Aspartame's Approval, No. HRD-86-109BR (1986) (investigating allegations of a conflict of interest by several former FDA officials involved in the review of aspartame who later took positions in the private sector); Robert Frank, Aspartame Critic Urges More Study of the Sweetener, Wall St. J., Nov. 8, 1996, at B5B.

n328. See NutraSweet Hearing, supra note 327, at 209-12 (statement of Frank E. Young, Comm'r, FDA) (describing the adverse experience monitoring system established by the FDA in light of consumer complaints about aspartame); see also id. at 222 (noting that the "FDA does not require the petitioner of an approved food additive to provide safety studies after the additive has been approved unless questions of safety arise"); id. at 293-95 (estimating that the FDA already had expended several millions of dollars on aspartame). The FDA created the Adverse Reaction Monitoring System (ARMS) in 1985. See Linda Tollefson, Monitoring Adverse Reactions to Food Additives in the U.S. Food and Drug Administration, 8 Reg. Toxicology & Pharmacology 438, 441-44 (1988) (noting that the majority of initial reports concerned aspartame and sulfiting agents).

n329. See, e.g., Food Additives Permitted for Direct Addition to Food for Human Consumption; Acesulfame Potassium, 57 Fed. Reg. 6667 (1992) (rejecting objections to the approval of acesulfame potassium); Robert Frank, Sweetener Ace K Faces Challenge Before Approval, Wall St. J., July 30, 1996, at B14 (describing CSPI's plans to protest the anticipated approval of acesulfame potassium for wet use); CSPI Steps Up Pressure on FDA to Deny Artificial Sweetener Petition, Food Chem. News, Aug. 5, 1996, at 7.

n330. See Calgene, Inc.; Availability of Letter Concluding Consultation, 59 Fed. Reg. 26,647 (1994).

n331. See Secondary Direct Food Additives Permitted in Food for Human Consumption; Food Additives Permitted in Feed and Drinking Water of Animals; Aminoglycoside 3'-Phosphotransferase II, 59 Fed. Reg. 26,700, 26,702 (1994).

n332. See Interpretive Ruling on Calgene, Inc.; Petition for Determination of Regulatory Status of FLAVR SAVR[su'TM'] Tomato, 57 Fed. Reg. 47,608 (1992) (ruling that Calgene's tomato would no longer be considered a regulated article under the Federal Plant Pest Act). Calgene subsequently received similar rulings on several other tomato lines. See, e.g., Addition of Two Genetically Engineered Tomato Lines to Determination of Nonregulated Status for Calgene, Inc., 60 Fed. Reg. 38,788 (1995). The USDA's regulatory requirements governing agricultural biotechnology, which are implemented by the Animal and Plant Health Inspection Service (APHIS) and appear at 7 C.F.R. pt. 340 (1997), are beyond the scope of this Article.

n333. See Calgene, Inc.; Request for Advisory Opinion, 56 Fed. Reg. 20,004 (1991).

n334. See Calgene, Inc.; Request for Advisory Opinion, 57 Fed. Reg. 22,772, 22,773 (1992) (noting that Calgene's primary interest in the choice of regulatory classification was whether the company would have to prepare an environmental assessment).

n335. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. 22,984 (1992). This policy is discussed more fully below.

n336. See Calgene, Inc.; Filing of Food Additive Petition, 58 Fed. Reg. 38,429 (1993).

n337. Calgene, Inc.; Availability of Letter Concluding Consultation, 59 Fed. Reg. 26,647, 26,648 (1994).

n338. See id. at 26,648 (citing 21 C.F.R. 170.30(f)(2), the provision in the regulations which provides that substances of natural biological origin widely consumed prior to 1958 but then significantly altered through selective breeding will be reviewed for possible GRAS affirmation). Of course, as previously explained in Part II, the tomato itself would not be subject to regulation as a "food additive" when sold as produce, even if not GRAS.

n339. See Direct Food Substances Affirmed as Generally Recognized as Safe; Chymosin Enzyme Preparation Derived from Escherichia Coli D-12, 55 Fed. Reg. 10,932, 10,935 (1990) (codified at 21 C.F.R. 184.1685 (1997)); see also Enzyme Bio-Systems, Ltd.; Filing of Petition for Affirmation of GRAS Status, 53 Fed. Reg. 16,191 (1988) (notice of filing of GRAS affirmation petition for rDNA alpha-amylase enzyme); CPC International, Inc.; Filing of Petition for Affirmation of GRAS Status, 51 Fed. Reg. 10,571 (1986) (same); GAO, New Food Technologies, supra note 9, at 42 (noting that the FDA's review of the GRAS affirmation petition for chymosin took 2.5 years and represented "a learning experience for the agency"); Degnan, supra note 89, at 580-81 (urging greater reliance on the GRAS exception for bioengineered foods); cf. Enzyme Preparations from Animal and Plant Sources; Affirmation of GRAS Status as Direct Food Ingredients, 60 Fed. Reg. 32,904 (1995) (affirming GRAS status of several enzyme preparations from animal and plant sources).

n340. See Secondary Direct Food Additives Permitted in Food for Human Consumption; Food Additives Permitted in Food and Drinking Water of Animals; Aminoglycoside 3'-Phosphotransferase II, 59 Fed. Reg. 26,700, 26,711 (codified at 21 C.F.R. 173.170, 573.130 (1997)) (approving APH(3')II encoded by the kan[su'r'] gene for use in the development of genetically modified cotton, oilseed rape and tomatoes). In the preamble, the FDA emphasized that "only the translation product of the kan[su'r'] gene, APH(3')II, and not the gene itself, is being regulated as a food additive." Id. at 26,701 ("The DNA that makes up the kan[su'r'] gene does not differ from any other DNA and does not itself pose a safety concern as a component of food.").

n341. See id. at 26,702-03.

n342. See id. at 26,703-04.

n343. See id. at 26,704-06.

n344. In fact, DNA Plant Technology and Monsanto have both developed tomatoes with even longer shelf lives by modifying the gene that controls ethylene production, and other more elaborate bioengineered food products are on the horizon. See, e.g., CFSAN, Bioengineered Foods Derived from New Plant Varieties Derived Through Recombinant DNA Technology (last modified Feb. 24, 1998) <http://vm.cfsan.fda.gov/lrd/biocon.html> (listing 33 final consultations conducted with various companies since the 1994 Calgene approval); Biotechnology and Food Ingredients (Israel Goldberg & Richard Williams eds., 1991) (compiling articles on bioengineered foods); Alan Goldhammer, The Regulation of Agricultural Biotechnology: An Industrial Perspective, 48 Food & Drug L.J. 501, 509-10 (1993) (listing prospective bioengineered food products); Scott Kilman, Green Genes: If Fat-Free Pork Is Your Idea of Savory, It's a Bright Future, Wall St. J., Jan. 29, 1998, at A1.

n345. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. 22,984 (1992); see also GAO, New Food Technologies, supra note 9, at 9-10, 31-56 (describing the FDA's approach to the regulation of biotechnology as applied to food, and framing the terms of the debate over the proper regulatory approach); Robert A. Bohrer, Food Products Affected by Biotechnology, 55 U. Pitt. L. Rev. 653, 659-66 (1994) (summarizing the FDA's 1992 policy statement). A rudimentary framework previously had been described in the mid-1980s. See Statement of Policy for Regulating Biotechnology Products, 51 Fed. Reg. 23,309, 23,312-13 (1986) (discussing the GRAS or food additive status of bioengineered food substances); Statement of Policy for Regulating Biotechnology Products, 49 Fed. Reg. 50,878, 50,878 (1984) (same); see also Jeffrey N. Gibbs & Jonathan S. Kahan, Federal Regulation of Food and Food Additive Biotechnology, 38 Admin. L. Rev. 1, 16-26 (1986); Stephen H. McNamara, FDA Regulation of Food Substances Produced by New Techniques of Biotechnology, 42 Food Drug Cosm. L.J. 50 (1987); Michele J. Brace, Comment, Regulation of Genetically Engineered Foods Under the Federal Food, Drug, and Cosmetic Act, 33 Am. U. L. Rev. 899 (1984).

n346. See Alternative and Traditional Models for Safety Evaluation of Food Ingredients; Announcement of Study; Request for Scientific Data and Information; Announcement of Open Meeting, 61 Fed. Reg. 8291 (1996) (announcing that FASEB will undertake a comprehensive review of the appropriate scientific criteria and principles for the assessment of the safety of food ingredients, noting that recent innovations such as bioengineering may "present new situations for which an alternative approach to safety assessment may be needed"). The 1992 policy statement suggested that "many of the scientific considerations for evaluating the safety and nutritional aspects of food from new plant varieties... are similar regardless of the [traditional or new] technology used." Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,991.

n347. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,984. The Agency recognized that "most, if not all, cultivated food crops have been genetically modified" by traditional breeding techniques. Id. at 22,984 n.3; see also id. at 22,985 ("The genetic modification techniques used to develop new plant varieties constitute a continuum."). The policy statement does not address food uses of biotechnology other than in the development of new plant varieties. See id. at 22,985; cf. Steven W. Frank, Food Additive Models for the Regulation of Recombinant DNA Technology Under the Federal Food, Drug, and Cosmetic Act, 45 Food Drug Cosm. L.J. 169, 173-79 (1990) (describing the range of potential food uses of biotechnology).

n348. Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,986. In discussing genetic modification techniques to achieve desirable traits, the Agency distinguishes between agronomic characteristics of the plant (e.g., yield and resistance to pests or disease) and quality characteristics of the food (e.g., preservation, nutrition, and flavor). See id. at 22,985.

n349. See id. at 22,986-88 (adding that some of these concerns are magnified with regard to plants used in animal feed because of animals' different consumption patterns); see also Ron Winslow, Allergen is Inadvertently Transferred to Soybean in Bioengineering Test, Wall St. J., Mar. 14, 1996, at B6 (reporting that "the findings provide fuel to critics who contend that altering the genes of plants... raises the possibility of unintended... health consequences"). In its earlier statements, the FDA called for a food additive petition in every case where a substance added to animal feed was produced with recombinant DNA technology. See Coordinated Framework for Regulation of Biotechnology, 51 Fed. Reg. 23,302, 23,311 (1986).

n350. Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,984-85.
 
The method by which food is produced or developed may in some cases help to understand the safety or nutritional characteristics of the finished food. However, the key factors in reviewing safety concerns should be the characteristics of the food product, rather than the fact that the new methods are used.
 
 Id.; see also Organization for Economic Co-operation and Development, Safety Evaluation of Foods Derived by Modern Biotechnology (1993); David A. Kessler et al., The Safety of Foods Developed by Biotechnology, 256 Science 1747 (1992); International Food Biotechnology Council, Biotechnologies and Food: Assuring the Safety of Foods Produced by Genetic Modification, 12 Reg. Toxicology & Pharmacology S1 (1990).

n351. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,990 (explaining that it will "require food additive petitions in cases where safety questions exist sufficient to warrant formal premarket review by FDA to ensure public health protection").

n352. See id. Because nucleic acids appear in the genetic material of all foods and have posed no safety problems in the past, the "FDA does not expect that there will be any serious question about the GRAS status of transferred genetic material." Id.

n353. Id. ("For example, if a food derived from a new plant variety contains a novel protein sweetener as a result of the genetic modification of the plant, that sweetener would likely require submission of a food additive petition...."). The policy does not further define what might constitute a significant modification, though similar language appears in the GRAS regulations. See 21 C.F.R. 170.30(f)(2) (1997); see also Frank, supra note 347, at 193 ("What the agency considers significant could well hinge on any interests in restraining rDNA processes...."); Gibbs & Kahan, supra note 345, at 16 n.80 (noting that, "at one point, FDA had proposed that a "significant alteration' would be a 10% or greater increase in a toxicant or a 20% or greater reduction in a nutrient... [but] these numerical criteria were not adopted"). The accompanying flow charts make reference to "macroconstituents" as necessitating possible review, but again the Agency failed to define the term. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,998-23,004.

n354. Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,990.

n355. See id. at 22,991-23,004 (including several flow charts but emphasizing that they do not impose any new regulatory requirements). "This guidance section provides a basis for determining whether new plant varieties are as safe and nutritious as their parental varieties." Id. at 22,992. This sounds like the test of "substantial equivalence" for medical devices under Section 510(k) of the FD&C Act to determine the need for premarket review. See 21 U.S.C. 360(k), 360c(i)(1) (1994). Indeed, the Agency cited international organizations that have proposed a "substantial equivalence" test for new foods. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,992. The FDA subsequently explained that it had
 
used the term "substantial similarity" rather than "substantial equivalence," to avoid possible confusion with the agency's use of the concept... for medical devices. For consistency with current thinking from international expert groups such as the FAO/WHO and OECD consultation groups, FDA is now using the term "substantial equivalence" with respect to food products.
 
 Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,945 n.2 (1997).

n356. See Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,985. As a consequence, a petitioner may avoid the need to submit an environmental assessment, a potentially significant matter for biotechnology products even though an assessment may have been submitted at an earlier stage to the USDA or the EPA. Food additive and GRAS affirmation petitions must either include an environmental assessment or claim a categorical exclusion. See 21 C.F.R. 25.22(a)(10), (12), 25.24(b); see also Foundation on Econ. Trends v. Heckler, 756 F.2d 143, 153-55 (D.C. Cir. 1985) (enjoining deliberate release experiment of genetically engineered organism until the National Institutes of Health completes an environmental assessment). The FDA recently proposed expanding the list of categorical exclusions. See National Environmental Policy Act; Proposed Revision of Policies and Procedures, 61 Fed. Reg. 14,922, 14,927-29 (1996).

n357. See Background Material, FDA Joint CFSAN/CVM Advisory Committee Meeting, Procedures for Industry-FDA Interaction Prior to Commercial Distribution of Foods Derived from New Plant Varieties Developed Using Recombinant DNA Techniques (last modified Nov. 1994) <http://vm.cfsan.fda.gov/lrd/biopro.txt>. Previously, FDA officials had expressed concerns that it lacked the statutory authority to create such a premarket notification system. See GAO, New Food Technologies, supra note 9, at 12 (explaining the misgivings of certain FDA officials regarding the authority to enact, and the effect of, a premarket notification system).

n358. See, e.g., CFSAN, Bioengineered Foods Derived from New Plant Varieties Derived Through Recombinant DNA Technology (last modified Feb. 24, 1998) <http://vm.cfsan.fda.gov/lrd/biocon.html> (listing 33 final consultations conducted with various companies since the 1994 Calgene approval). For the latest guidance, see CFSAN, Bioengineered Foods Derived from New Plant Varieties: Consultation Procedures (last modified Oct. 15, 1996) <http://vm.cfsan.fda.gov/lrd/consulpr.html>. Although it encouraged use of the recently proposed GRAS notification procedure, the FDA recognized that the procedure could not fully replace its existing consultation policy for bioengineered foods. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,946 & n.3.

n359. See Food Labeling; Foods Derived from New Plant Varieties, 58 Fed. Reg. 25,837, 25,840 (1993); Statement of Policy: Foods Derived from New Plant Varieties, 57 Fed. Reg. at 22,991.
 
If a tomato has had a peanut protein introduced into it and there is insufficient information to demonstrate that the introduced protein could not cause an allergic reaction in a susceptible population, a label declaration would be required to alert consumers who are allergic to peanuts so they could avoid that tomato...
 
 Id.; cf. H.R. 5401, 102d Cong. (1992) (proposing to require disclosures of origin in labeling).

n360. See Animal Drugs, Feeds, and Related Products; Sterile Sometribove Zinc Suspension, 58 Fed. Reg. 59,946, 59,947 (1993) (codified at 21 C.F.R. 522.2112 (1997)).

n361. See Interim Guidance on the Voluntary Labeling of Milk and Milk Products from Cows that Have Not Been Treated with Recombinant Bovine Somatotropin, 59 Fed. Reg. 6279 (1994).

n362. See id.; see also Stauber v. Shalala, 895 F. Supp. 1178, 1192-93 (W.D. Wis. 1995) (rejecting challenge to the FDA's decision against mandating rBST disclosure in labeling); Terence J. Centner & Kyle W. Lathrop, Labeling rBST-Derived Milk Products: State Responses to Federal Law, 45 U. Kan. L. Rev. 511 (1997). Producers recently challenged Vermont's rBST disclosure requirement as an abridgement of their First Amendment rights, and the court granted them a preliminary injunction. See International Dairy Foods Ass'n v. Amestoy, 92 F.3d 67 (2d Cir. 1996).

n363. See First Biotech Tomato Marketed, FDA Consumer, Sept. 1994, at 3, 4. The tomato has not been a commercial success, however, thanks in part to problems with distribution. See Terzah Ewing, Monsanto Buys Rest of Calgene for $ 240 Million, Wall St. J., Apr. 2, 1997, at B5 ("Calgene had problems transporting the tomatoes from Florida, where they are grown, to its packing center in Chicago....").

n364. See, e.g., GAO, New Food Technologies, supra note 9, at 45-48. In its report, the GAO elaborated on the premarket notification suggestion:
 
In principle, such a system would bridge the gap between the absence of a requirement for premarket approval of whole foods and of substances that manufacturers and others have determined are GRAS and the requirement for extensive premarket review of new food additives. Several premarket notification systems have been proposed that range in formality and complexity from relatively simple letters from food companies to notify FDA about the introduction of a new product to mandatory FDA premarket reviews of data submitted by manufacturers to support the safety and/or GRAS status of their food product.
 
 Id. at 50 (adding that the FDA's policy statement "did not require premarket notification of food developed through new biotechnology"); see also id. at 51-52 (canvassing competing arguments and noting uncertainty about the FDA's power to impose a premarket notification system under its existing statutory authority).

n365. Id. at 48.

n366. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. 3118, 3172 (1996) (codified at 21 C.F.R. 172.867(c) (1997)) (approving the use of olestra in "savory snacks," which are defined as "snacks that are salty or piquant but not sweet"); see also Determination of Regulatory Review Period for Purposes of Patent Extension; Olean, 62 Fed. Reg. 763, 763 (1997) (calculating, for purposes of patent term restoration, the approval phase of the regulatory review period as 3,227 days).

n367. See Marian Burros, Intensifying Debate on a Fat Substitute, N.Y. Times, Jan. 17, 1996, at C1. This investment rivals the average R&D costs for new drugs. See Joseph A. DiMasi et al., Cost of Innovation in the Pharmaceutical Industry, 10 J. Health Econ. 107, 124-26 (1991) (estimating that, on average, drug research and development costs $ 231 million and requires twelve years before a new chemical may be introduced in the United States); F-D-C Rep. ("The Pink Sheet"), Dec. 18, 1995, at 11 (quoting the latest estimate as approaching $ 400 million).

n368. The term "macroingredient" usually encompasses substances that make up a significant portion of the diet, such as carbohydrates, proteins, and fats, while "micronutrients" generally refer to vitamins and minerals, and "microingredients" might further encompass direct additives such as emulsifiers and preservatives. Other fat-substitutes, though less versatile, were already on the market. See, e.g., 21 C.F.R. 184.1498 (1997) (affirming the GRAS status of a microparticulated egg white and milk protein product as a fat-replacer in frozen desserts).

n369. See 21 C.F.R. 172.867(d)-(f) (specifying conditions for the use of olestra).

n370. See Procter & Gamble Co.; Filing of Food Additive Petition, 52 Fed. Reg. 23,606 (1987).

n371. See H.R. 2805, 102d Cong. 1 (1991) (requesting a ten year extension to start running after FDA approval); S. 1506, 102d Cong. 1 (1991). One patent already had expired (and three others were likely to expire prior to FDA approval), so the bills technically would revive rather than extend expired patents. Once the patents expired, patent term restoration would not be available, and food additives do not benefit from the market exclusivity alternative available to drugs irrespective of patent status. See supra note 203. Because Congress failed to enact the proposed legislation, though both Houses had acted favorably on the bills, a new bill was introduced in the next session. See S. 409, 103d Cong. (1993). Ultimately, Congress enacted a provision authorizing interim patent term extensions when the regulatory review period continues beyond the original patent term. See Pub. L. No. 103-179, 5, 107 Stat. 2040 (1993) (codified at 35 U.S.C. 156(d)(5) (1994)). The FDA approved olestra just one day before the expiration of this interim extension, thereby allowing the company to seek a further two year patent term extension. See Sally Squires, FDA Decision Nears on Fat Substitute, Wash. Post, Jan. 23, 1996, at Z8; see also Determination of Regulatory Review Period for Purposes of Patent Extension; Olean, 62 Fed. Reg. at 763.

n372. See Interim Patent Extensions: Hearing Before the Subcomm. on Intellectual Property and Judicial Administration of the House Comm. on the Judiciary, 103d Cong. 19 (1993) (statement of Walker J. Wallace, Vice President, P&G) (summarizing olestra's regulatory history); Patent Term Extension Legislation: Hearing Before the Subcomm. on Intellectual Property and Judicial Administration of the House Comm. on the Judiciary, 102d Cong. 369-74 (1991) [hereinafter House Patent Extension Hearing] (P&G's regulatory chronology); Patent Extension Hearing: Hearing Before the Subcomm. on Patents, Copyrights and Trademarks of the Senate Comm. on the Judiciary, 102d Cong. (1991) [hereinafter Senate Patent Extension Hearing]; see also Richard M. Cooper, Legislative Patent Extensions, 48 Food & Drug L.J. 59 (1993).

n373. See 21 C.F.R. 172.867(a) (describing olestra). The original patent term extension legislation would have defined "olestra" as "sucrose esterified with four or more fatty acid groups." H.R. 2805, 102d Cong. 3(a) (1991).

n374. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. 3118, 3119 (1996).

n375. See id. at 3152.

n376. See id. at 3130-52 (reviewing drug and nutrient absorption studies).

n377. See id. at 3152-59 (reviewing gastrointestinal tract studies, concluding that diarrhea-like symptoms reflect a disruption in the fecal matrix and did not cause any adverse health effects such as dehydration or an electrolyte imbalance).

n378. Evidently, P&G was told that, under then existing FDA policy, a food could make no claims about fatty acid or cholesterol content. See Senate Patent Extension Hearing, supra note 372, at 455-56, 459 (written responses from Edwin L. Artzt, Chairman and CEO, P&G); GAO, FDA Premarket Approval: Process of Approving Olestra as a Food Additive, No. HRD-92-86 (1992), at 5. Also, the investigational exemption for food additives could not be utilized for purposes of undertaking clinical (as opposed to animal) testing. See 138 Cong. Rec. E2371 (daily ed. Aug. 4, 1992) (memorandum from Richard M. Cooper, counsel for Unilever) (explaining the use of the investigational new drug exemption for this purpose); supra notes 205-06 and accompanying text (discussing regulations governing the testing of food additives).

n379. See S. Rep. No. 103-64, at 5 & n.16 (1993) (faulting both P&G and the FDA for the inordinate amount of time spent obtaining regulatory approval for olestra); H.R. Rep. No. 102-775, at 6, 15-17 (1992); id. at 23 (dissenting views of Hon. George E. Sangmeister and Hon. Romano L. Mazzoli) ("In fact, that ambiguities persist - despite the GAO's report - only contributes to the case against these patent extensions."); Jennifer Lawrence, Whatever Happened to Olestra? How P&G's Hopes for Food Division's Future Got Mired in FDA Quicksand, Adver. Age, May 2, 1994, at 16. Competitors testified at the hearings in opposition to patent term extension, arguing that any delays in approval resulted from P&G's poor business decisions rather than regulatory tardiness. See, e.g., House Patent Extension Hearing, supra note 372, at 224-51 (statement of Richard A. Goldstein, President and CEO, Unilever United States, Inc.); see also 138 Cong. Rec. E2369 (daily ed. Aug. 4, 1992) (remarks by Hon. Terry L. Bruce).

n380. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3121.
 
First, the volume of available safety evidence for olestra is enormous, all of which FDA was obligated to review, evaluate, and synthesize. Second, as a macro-ingredient, olestra is intended to replace a sizeable portion of the diet, and thus, will likely be consumed in relatively large amounts; this alone sets olestra apart from almost all food additives previously reviewed by FDA. Third, olestra presents a number of questions regarding nutritional effects, most of which have not been presented previously to FDA... Because of the challenge presented by olestra, the agency used an expanded approach to its evaluation...
 
 Id.; see also id. at 3169 (adding that olestra is "a macro-ingredient that is not metabolized, one of the first of its type to be subject to FDA review").

n381. See Senate Patent Extension Hearing, supra note 372, at 302 (statement of Edwin L. Artzt, Chairman and CEO, P&G); Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3119. In response to comments fearing that the use of olestra would spread to other fatty foods, the FDA explained that its approval was limited and that other uses would require the filing and review of additional food additive petitions. See id. at 3166, 3168.

n382. See Advisory Committee; Notice of Meeting, 60 Fed. Reg. 53,790 (1995).

n383. See Food Advisory Committee Meeting: Working Group on Olestra, Nov. 14-17, 1995; Vitamin Addition, Labeling for Olestra Foods Recommended by Advisory Group, Food Chem. News, Nov. 20, 1995, at 31 (summarizing what transpired at the meeting); see also Henry Blackburn, Olestra and the FDA, 334 New Eng. J. Med. 984, 985 (1996) (criticizing, as a member of the olestra working group, the FDA's consultation process).

n384. See Food Additives Permitted for Direct Addition to Food for Human Consumption, 60 Fed. Reg. 57,586 (1995) (announcing a deadline of December 1, later extended to December 21, 1995). The FDA then responded to criticisms that it provided insufficient time for comment. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3163; see also CSPI Charges P&G with Deceptively Publicizing Olestra Study, Food Chem. News, Mar. 4, 1996, at 11 (describing letter filed one month after the close of the comment period and one day before approval).

n385. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3162 (noting that it had received approximately 2,300 comments, though roughly 2,000 of those were part of a CSPI letter writing campaign urging rejection of the petition).

n386. See CSPI Files Objections to Olestra Decision; P&G Responds to Charges, Food Chem. News, Mar. 11, 1996, at 15; see also Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3162-64 (recounting CSPI's aggressive participation during and after the working group meeting to express its opposition); Marian Burros, Consumer Group Cites Illnesses in Urging Ban of Fat Substitute, N.Y. Times, July 2, 1996, at C8; Henry I. Miller, The Naderites' Big Fat Problem, Wall St. J., July 11, 1996, at A14; Raju Narisetti, Anatomy of a Food Fight: The Olestra Debate, Wall St. J., July 31, 1996, at B1.

n387. See Marian Burros, Question at Olestra's Debut: Is the "Fake Fat" Truly Safe?, N.Y. Times, May 20, 1996, at A1; Glenn Collins, Crunch Time for a Fake Fat: Will America Take the Bait?, N.Y. Times, Aug. 24, 1997, at C1; see also Dana Canedy, Fat-Free Fanfare as Procter Starts Shipping out Olestra, N.Y. Times, Feb. 11, 1998, at D2 (describing subsequent nationwide roll out).

n388. See Alternative and Traditional Models for Safety Evaluation of Food Ingredients; Announcement of Study; Request for Scientific Data and Information; Announcement of Open Meeting, 61 Fed. Reg. 8291, 8291 (1996) (announcing that FASEB will undertake a comprehensive review of the appropriate scientific criteria and principles for the assessment of the safety of food ingredients, especially novel foods); see also Draft Revised "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food;" Availability, 58 Fed. Reg. 16,536 (1993) (announcing the availability of a revised draft of the Redbook, which now addresses some of these issues). Scientists in and out of the FDA have begun to consider the subject more closely. See, e.g., Proceedings of the Workshop on Safety and Regulatory Aspects of Macronutrient Substitutes, 23 Reg. Toxicology & Pharmacology S1-S62 (1996); Joseph F. Borzelleca, Macronutrient Substitutes: Safety Evaluation, 16 Reg. Toxicology & Pharmacology 253 (1992).

n389. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3120 ("The fact that olestra is not absorbed also means... the safety issues for olestra are focused on effects in the intestine, including potential interference with absorption of nutrients.").

n390. See id. at 3120; Ian C. Munro et al., Alternative Approaches to the Safety Assessment of Macronutrient Substitutes, 23 Reg. Toxicology & Pharmacology S6, S7 (1996) (noting that traditional approaches to safety and toxicity testing yield spurious results when used for macroingredients).

n391. See Joseph F. Borzelleca, A Proposed Model for Safety Assessment of Macronutrient Substitutes, 23 Reg. Toxicology & Pharmacology S15, S17-S18 (1996); Margaret Cheney, Postmarket Surveillance to Determine Nutritional Impact of Macronutrient Substitutes, 23 Reg. Toxicology & Pharmacology S22, S23-S24 (1996). In announcing FASEB's review of safety criteria, the FDA posed this question: "Can postmarketing surveillance (such as monitoring of use or monitoring of adverse reaction reports by consumers and physicians) be used to ensure safety?" Alternative and Traditional Models for Safety Evaluation of Food Ingredients; Announcement of Study; Request for Scientific Data and Information; Announcement of Open Meeting, 61 Fed. Reg. at 8292 ("For example, can such surveillance be used without compromising safety to verify exposure estimates or to eliminate the need for specific data prior to marketing...?").

n392. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3120-21, 3125-59. All told, the Agency reviewed more than 150,000 pages of data submitted by P&G in the original food additive petition and its subsequent amendments. See Olestra Approved with Special Labeling, FDA Consumer, Apr. 1996, at 11. According to the GAO investigator who studied the olestra approval, the "FDA feels that they really learned a lot by going through this process." H.R. Rep. No. 102-775, at 16 (1992); see also GAO, New Food Technologies, supra note 9, at 11 ("New food technologies such as functional foods, that incorporate specific food components to lower the risk of disease may not fit the existing categories for food and food ingredients... These products may blur, if not erase, the legal boundary line between foods and drugs.").

n393. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3119-20. Several comments supporting approval emphasized problems with obesity and "that the health benefits from lower fat intake far outweigh the perceived adverse side effects," id. at 3163, but the Agency again noted that such health benefits were not relevant to its decision, see id. at 3166.

n394. See 21 C.F.R. 172.867(d) (1997) (specifying the amounts of each vitamin to be added); see also Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3162 ("The agency has not previously approved an additive which interferes with the absorption of vitamins to a degree that necessitates requiring that foods containing the additive be compensated with such vitamins to mitigate the effect of olestra."). In addition, data indicated that olestra would reduce serum levels of carotenoids, substances from fruits and vegetables believed to prevent certain diseases (such as macular degeneration and prostate cancer), but the FDA dismissed these supposed protective effects as unsupported. See id. at 3147-49.

n395. 21 C.F.R. 172.867(e) (specifying the precise placement and format of this disclosure statement).

n396. See Policies Concerning Uses of Sulfiting Agents, 58 Fed. Reg. 24,314, 24,314 (1993) ("The agency's primary tool for handling a situation where population subgroups may be at increased risk from a food ingredient that is safe for most people is to use [ingredient] labeling to inform those persons who need or want to avoid the ingredient."); Food Labeling; Declaration of Ingredients, 56 Fed. Reg. 28,592, 28,615 (1991) ("The information present in the ingredient list is adequate to enable the consumer to avoid ingredients of concern.").

n397. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3160 n.83. On only a few other occasions has the FDA required the disclosure of similar information about possible non-serious side effects. See, e.g., 21 C.F.R. 172.841(e) ("The label and labeling of food a single serving of which would be expected to exceed 15 grams of [polydextrose] shall bear the statement: "Sensitive individuals may experience a laxative effect from excessive consumption of this product.'"); id. 180.25(e) (imposing a similar requirement for mannitol); id. 184.1835(e) ("The label and labeling of food whose reasonably foreseeable consumption may result in a daily ingestion of 50 grams of sorbitol shall bear the statement: "Excess consumption may have a laxative effect.'").

n398. See 21 U.S.C. 343(a)(1) (1994) (providing that a food shall be deemed to be misbranded if "its labeling is false or misleading in any particular"); id. 321(n) ("In determining whether the labeling or advertising is misleading there shall be taken into account (among other things)... the extent to which the labeling or advertising fails to reveal facts material in the light of such representations or material with respect to consequences which may result from the use....").

n399. See id. 348(c)(3)(B) ("No such regulation shall issue if a fair evaluation of the data... shows that the proposed use of the additive would promote deception of the consumer in violation of this chapter or would otherwise result in adulteration or in misbranding of food within the meaning of this chapter.").

n400. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3160-62. To justify requiring the gastrointestinal side effect information, the FDA explained that these facts are material with respect to the consequences of use even though not a safety concern. See id. at 3161 ("Providing this information to consumers would preclude unnecessary concerns about the origin of GI effects, were they to be observed, and also may prevent unnecessary or inappropriate medical treatment of those symptoms."). In regard to the vitamin fortification aspect of the required statement, the Agency explained that ingredient disclosure elsewhere on the label amounts to a representation that could mislead consumers if it omitted the material facts concerning the need for vitamin replacement. See id.

n401. See id. at 3160 (providing a 30-day comment period). P&G filed comments urging a less explicit labeling requirement, while CSPI sought a more conspicuous warning. See Raju Narisetti, P&G Seeks Less-Explicit Labeling Rules from FDA for Products with Olestra, Wall St. J., Apr. 9, 1996, at A2; CSPI Protests Olestra Labeling; NFPA and GMA Also Object, Food Chem. News, Apr. 8, 1996, at 34.

n402. 21 C.F.R. 172.867(f) (adding that the FDA "will present such data, information, and evaluation to the agency's Food Advisory Committee within 30 months of the effective date of this regulation," and then "will initiate any appropriate regulatory proceedings"). The FDA recently scheduled another advisory committee meeting in order to conduct this review. See Food Advisory Committee; Notice of Meeting, 63 Fed. Reg. 26,194 (1998).

n403. Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3168 (stating that Procter and Gamble notified FDA that it would conduct additional studies of olestra consumption (both amounts and patterns) and its effects because "only with data from the broader marketing of olestra can the agency be in the position to evaluate in the future whether there continues to be reasonable certainty of no harm from the use of olestra"); see also GAO, New Food Technologies, supra note 9, at 61 (noting that, according to one official, the "FDA may try to negotiate requirements for firms to conduct postmarket surveillance, including the collection and reporting of data on dietary use and on any adverse effects, as a condition for approving novel macro ingredients as food additives").

n404. Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3169.

n405. Cf. supra note 200 and accompanying text (explaining that approval of a food additive petition results in the promulgation of a regulation rather than the issuance of a private license). The FDA's threat also seemingly ignores the procedures imposed by Congress for withdrawing an approval. See 21 U.S.C. 348(h) (1994); 21 C.F.R. 171.130. For a criticism of the Agency's reliance on "voluntary" concessions of this sort from regulated entities, see Lars Noah, Administrative Arm-Twisting in the Shadow of Congressional Delegations of Authority, 1997 Wis. L. Rev. 873.

n406. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3169; cf. GAO, New Food Technologies, supra note 9, at 61 (noting that the FDA obtained voluntary postmarket surveillance for aspartame, as part of the approval process for this substance, but that the FDA does not have statutory authority to require surveillance for food products, as it does for human drugs); see supra note 318 (discussing condition in aspartame approval).

n407. Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra, 61 Fed. Reg. at 3169; see also supra Part III.C (discussing the data collection requirements for interim food additives). The FDA did not, of course, purport to approve olestra as an interim food additive.

n408. See Olestra Gets Fewer Gripes Than Expected, P&G Says, Wall St. J., July 25, 1996, at B10 (noting that P&G reported to the FDA an adverse health effect rate of one per 3,000 bags of potato chips sold); see also Lawrence J. Cheskin et al., Gastrointestinal Symptoms Following Consumption of Olestra or Regular Triglyceride Potato Chips, 279 JAMA 150 (1998) (reporting the results of a double-blind study finding no increases in the incidence or severity of GI side effects from olestra). This contrasts with CSPI's claim that 20% of consumers experienced GI problems (3% of them severe). See Burros, supra note 386, at C8.

n409. See 1995 Hearings, supra note 1, at 35 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("For the last two decades, the Center has suffered from substantial reductions in personnel... This occurred at a time when not only the process of safety evaluation had become more complex but the Center, by legislative mandate, had received several new responsibilities."); id. at 54 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) (noting that "CFSAN staffing has remained essentially constant for the last 12 years (ranging from about 800 to 900 [FTEs]) while that for drugs and biologics increased steadily").

n410. See supra notes 191-93 and accompanying text.

n411. See Rulis & Tarantino, supra note 192, at 140; supra notes 216-17 and accompanying text (discussing delays in the GRAS affirmation process). As the manager of the FDA's food additive program has written, the Agency "is aware that an evaluation delayed can be an evaluation denied because of the competitive pressure of the marketplace." Rulis, supra note 193, at 538. Smaller companies may be especially susceptible because they lack the resources to endure lengthy regulatory delays. See 1995 Hearings, supra note 1, at 88 (statement of Hon. Edolphus Towns); id. at 101 (statement of C. Wayne Callaway, George Washington Univ. Med. Ctr.) ("Delays influence the costs and financial risks involved in developing [additives], dampen further innovation, [and] place smaller companies at a competitive disadvantage.").

n412. See Tertiary Butylhydroquinone, 37 Fed. Reg. 25,356 (1972) (codified as amended at 21 C.F.R. 172.185 (1997)). The food additive petition had been filed one year earlier. See Eastman Chemical Products, Inc.; Notice of Filing of Petition for Food Additive, 36 Fed. Reg. 22,617 (1971). An earlier petition had been withdrawn the previous year. See Eastman Chemical Products, Inc.; Notice of Withdrawal of Petition for Food Additive, 35 Fed. Reg. 440 (1970).

n413. See Polydextrose; Food Additives Permitted for Direct Addition to Food for Human Consumption, 46 Fed. Reg. 30,080, 30,081 (1981) (codified as amended at 21 C.F.R. 172.841 (1997)). The food additive petition had been filed more than two years earlier. See Pfizer, Inc.; Filing of Food Additive Petition, 44 Fed. Reg. 22,816 (1979).

n414. See Food Additives Permitted for Direct Addition to Food for Human Consumption, 53 Fed. Reg. 28,379 (1988) (codified at 21 C.F.R. 172.800 (1997)). The food additive petition had been filed almost six years earlier. See American Hoechst Corp.; Filing of Food Additive Petition, 47 Fed. Reg. 46,139 (1982); see also Determination of Regulatory Review Period for Purposes of Patent Extension; Acesulfame Potassium, 53 Fed. Reg. 48,727, 48,728 (1988) (calculating the approval phase of the regulatory review period as 2,172 days, in response to a patent term extension request by the manufacturer). In 1998, the FDA approved sucralose, almost 11 years after the food additive petition had been filed for this artificial sweetener. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Sucralose, 63 Fed. Reg. 16,417 (1998) (to be codified at 21 C.F.R. 172.831).

n415. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Gellan Gum, 55 Fed. Reg. 39,613 (1990) (codified at 21 C.F.R. 172.665 (1997)). The original food additive petition had been filed more than four years earlier. See Kelco Division of Merck & Co., Inc.; Filing of Food Additive Petition, 51 Fed. Reg. 687 (1986); see also Determination of Regulatory Review Period for Purposes of Patent Extension; Kelcogel, 56 Fed. Reg. 3110 (1991) (calculating the approval phase of the regulatory review period as 1,795 days, in response to a patent term extension request by the manufacturer). Other less significant direct additive approvals include: (1) glyceryl tristearate as primarily a formulation aid, see Food Additives Permitted for Direct Addition to Food for Human Consumption; Glycerol Tristearate, 53 Fed. Reg. 21,631 (1988); (2) dimethyl dicarbonate as a yeast inhibitor in wine, see Direct Food Additives; Food Additives Permitted for Direct Addition to Food for Human Consumption; Dimethyl Dicarbonate, 53 Fed. Reg. 41,325 (1988); (3) DL-alanine as a sweetener in pickling mixtures, see Food Additives Permitted for Direct Addition to Food for Human Consumption; Flavoring Agents and Related Substances, 56 Fed. Reg. 6968 (1991); (4) cocoa butter substitute, see Food Additives Permitted for Direct Addition to Food for Human Consumption; Cocoa Butter Substitute, 56 Fed. Reg. 66,969 (1991); (5) certain esters of fatty acids used to dehydrate grapes, see Food Additives Permitted for Direct Addition to Food for Human Consumption; Ethyl Esters of Fatty Acids and Sulfated Butyl Oleate, 57 Fed. Reg. 12,709 (1992); and (6) curdlan, see Food Additives Permitted for Direct Addition to Food for Human Consumption; Curdlan, 61 Fed. Reg. 65,941 (1996); cf. 1995 Hearings, supra note 1, at 31 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) (asserting that the FDA approved 42 direct food additives since July 1988, of which at least eight "were of significance").

n416. See 1995 Hearings, supra note 1, at 31 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) (noting that "almost 150 of the approximately 290 pending petitions are for indirect food additives"); Hutt, supra note 1, at 122 ("It is easy to be misled about the efficiency of FDA regulation of food additives by counting the Federal Register food additive notices... More than 80% of these notices relate to obscure indirect food additives that have no possible bearing on the public health."); Rulis & Tarantino, supra note 192, at 140 (estimating that fifty to sixty of the approximately eighty food additive petitions filed each year are for indirect food additives).

n417. See Hutt, supra note 1, at 122 (describing the "large number of follow-on amendments" which create "an extraordinary amount of sheer busywork").

n418. See Food Additives Permitted for Direct Addition to Food for Human Consumption; Polydextrose, 59 Fed. Reg. 37,419 (1994) (codified at 21 C.F.R. 172.841 (1997)).

n419. See Rulis & Tarantino, supra note 192, at 137, 139-41 (discussing findings from these studies).

n420. See id. at 140. Only three of the ninety petitions approved during this period required less than six months to review and six of the petitions required more than six years. See id. at 148 fig.7.

n421. See id. at 148 fig.8. Evidently these included both direct and indirect additives.

n422. See H.R. Rep. No. 104-436, at 2 (1995). Earlier oversight hearings had focused on different aspects of the subject. See, e.g., Oversight of Food Safety, 1983: Hearings Before the Senate Comm. on Labor and Human Resources, 98th Cong. (1983) (considering advances in detection methods); Food Additives: Competitive, Regulatory, and Safety Problems, 1977: Hearings Before the Senate Select Comm. on Small Business, 95th Cong. (1977) (reviewing concerns about the carcinogenicity of nitrites used for curing beef).

n423. H.R. Rep. No. 104-436, at 5-6 (adding that in no year since 1970 had the average review time for approved direct additives been less than 20 months). Two years later, the FDA reported that it still had approximately 60 pending GRAS affirmation petitions. See Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,953 (1997).

n424. See 1995 Hearings, supra note 1, at 35 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("The time required for the Center to reach a conclusion on those petitions for which orders were finally issued had increased from 20 months to 40 months. For pending petitions, the time for consideration increased from about 30 months in 1983 to over 60 months in 1994."); see also id. at 42 (statement of Richard L. Hall, Chairman, NAS Food Forum) ("Approvals often are badly delayed even when they simply involve new uses for an already approved additive. When they involve something entirely new the pace becomes glacial.").

n425. See id. at 10, 14 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) (outlining measures designed to reduce the numbers of pending petitions and ensure their timely review). These initiatives are discussed more fully in Part VI.B infra.

n426. See id. at 25-26 (testimony of Margaret J. Porter, Chief Counsel, FDA) (adding that even a "goal of 360 days... may not be possible"). Certain members of the Subcommittee expressed dismay with the Agency's position, recognizing that the deadline may be too short but disagreeing that the FDA could, therefore, simply choose to ignore it. See id. at 2 (statement of Hon. Christopher Shays, Subcomm. Chairman) (observing that "the statutory deadline has been interpreted out of existence by the FDA"); id. at 27 ("What I get a sense of is, from the lack of having a fixed deadline, all other problems follow. And it gives you extraordinary opportunity to do whatever the hell you want."); see also id. at 84-85 (expressing surprise at the industry's apparent patience with the Agency and reluctance to seek judicial relief). After the hearings, FDA officials met with the Subcommittee staff and requested that the statutory deadline be set at 360 days but promised to complete reviews for 90% of all petitions within 180 days. See H.R. Rep. No. 104-436, at 3.

n427. See 1995 Hearings, supra note 1, at 10 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("Presently, many petitions, when submitted, have shortcomings in the data needed to support a decision to approve the additive. Similarly, during FDA's review, the data in a petition too often are found to be of poor quality or inadequate."); id. at 18 (testimony of Alan M. Rulis, Acting Director of CFSAN's Office of Premarket Review) (observing that FDA scientists must evaluate thousands of submitted toxicological studies and that "it is almost always the case that there are substantive questions... for example, that the tables don't make sense or the columns don't add up"); id. at 176 (statement of Michael F. Jacobson, Exec. Dir., CSPI) (pointing out that the criticized delays in the approval process for acesulfame potassium arose because the "FDA spent several years working with the Company to salvage very poor test data").

n428. See id. at 10 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("The industry has been reluctant to have the Agency formally deny product petitions. Consistent with industry's preference, FDA's traditional policy for food additives has been to work very closely with each petitioner to develop data... instead of simply denying those petitions that lack adequate supporting data."); id. at 23 (testimony of Alan M. Rulis, Acting Dir. of CFSAN's Office of Premarket Review) ("We'vee kept the petitions on the books in order to eventually reach closure with them in a favorable way with the petitioner.").

n429. See id. at 84-86 (testimony of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n) (explaining that companies have attempted to work within the existing system rather than seek judicial or legislative intervention); id. at 106 (testimony of D. Stephen Saunders, Frito-Lay, Inc.) (suggesting that, "if you push for an answer, the answer is likely to be a no"). Apart from the unfavorable (and somewhat misleading) impact of this policy on average review times, one witness objected to what he regarded as the FDA's goal of eventually approving all additives unless patently unsafe. See id. at 176-77 (statement of Michael F. Jacobson, Exec. Dir., CSPI); see also id. at 184 ("Perhaps the best way for FDA to get out its message that cooperation with the agency in the pre-filing stage is imperative would be for FDA to implement a policy of quick rejections, without prejudice, of petitions filed with inadequate safety data.").

n430. See Shank: More Emphasis to Be Placed on Food Additive Deadlines, Food Chem. News, Apr. 22, 1996, at 38 (""Because FDA is under the gun to get reviews completed as quickly as possible, the agency will no longer spend time working with petitions to bring them up to par,' [according to CFSAN Chief Fred Shank].").

n431. See, e.g., 1995 Hearings, supra note 1, at 2 (statement of Hon. Christopher Shays, Subcomm. Chairman). Officials from a couple of companies did testify or provide written statements. See, e.g., supra note 429 (quoting the testimony of a witness from Frito-Lay, Inc.).

n432. See 1995 Hearings, supra note 1, at 70, 86 (statement and testimony of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n); see also Allegations of FDA Abuses of Authority: Hearings Before the Subcomm. on Oversight and Investigations of the House Comm. on Commerce, 104th Cong. (1995).

n433. See 1995 Hearings, supra note 1, at 54, 62 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) ("This caution is frequently exhibited in requests that reviewers make for more studies and data that have little, if any, relevance to the determination of safety for a food ingredient."); id. at 70-71 (statement of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n); id. at 35 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("[CFSAN] clearly has difficulty in reaching decisions and in particular those decisions that require judgment. It is never possible to have all the data we believe we need to make safety evaluations."); id. at 43 (statement of Richard L. Hall, Chairman, NAS Food Forum) ("The most important thing to do is not to make a mistake. It is far safer to delay, usually by asking more questions, than to make a decision."); id. at 101 (statement of C. Wayne Callaway, George Washington Univ. Med. Ctr.) ("The current system is too costly, too lengthy, and too much influenced by emotionally-charged issues, promoted by self-appointed "consumer advocates,' resulting in delays.").

n434. See id. at 20-21 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("When you have an outlier - for example, if we approve something that we'vee had in-house for 20 years, then it skews your average. That's why, sometimes, average is not in fact the best."). No effort has been made to update the statistics for petitions that remain pending. In any event, old petitions may remain pending long after a sponsor has given up, simply because the sponsor has not withdrawn the inactive petition. See id. at 177 (statement of Michael F. Jacobson, Exec. Director, CSPI) (suggesting that the FDA should periodically inquire whether a petition remains active).

n435. This survey does not include amendments to tables listing approved flavors and amino acids.

n436. If one excludes the 25 supplemental use petitions for acesulfame potassium and aspartame (on the theory that each supplemental use should become progressively easier to review, though possibly offset because of delays triggered by pending objections to earlier approvals), the average review time increases to 39.7 months (n=8).

n437. This survey consolidates approvals of petitions for closely related substances that were filed and approved together (even if ultimately reflected in separate regulations), such as the GRAS affirmations of various citrates, enzymes, and iron substances. (Note, however, that such consolidated counting actually understates the length of review periods for GRAS affirmation petitions by almost one year when compared to the average if each substance were counted separately.) This survey excludes the few supplemental petitions approved by the FDA to revise an existing GRAS affirmation regulation.

n438. See 1995 Hearings, supra note 1, at 23-24 (testimony of Alan M. Rulis, Acting Dir. of CFSAN's Office of Premarket Review) (explaining that only 77 of the 295 pending petitions were under active Agency review for more than 180 days). In calculating the approval phase of the regulatory review period for patent extension requests, however, the FDA does not attempt to subtract any time spent waiting for further information from a food additive petitioner. See, e.g., Determination of Regulatory Review Period for Purposes of Patent Extension; Olean, 62 Fed. Reg. 763 (1997); Determination of Regulatory Review Period for Purposes of Patent Extension; Kelcogel, 56 Fed. Reg. 3110 (1991).

n439. See 1995 Hearings, supra note 1, at 139 (statement of Jerome H. Heckman, on behalf of the Soc'y of the Plastics Indus.) ("Typically, a petition will have been pending for at least several months (and in some cases, a year or longer) before a filing notice is published."). The averages reported in the main text reflect the time that elapsed between the dates of publication in the Federal Register of the notice of filing and the final regulation; the sole exception was the GRAS affirmation of high fructose corn syrup where the much later date of the Agency's notice of proposed rulemaking was used.

n440. See id. at 20 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("One thing is that the review time, the trend, has been coming down since 1990. That shows progress."); id. at 21 (noting that, since 1988, there has been "a fairly stable number" of approvals and pending petitions, concluding that "the process has not completely shut down"); Rulis & Tarantino, supra note 192, at 141, 150 fig.11; Alan M. Rulis & Laura M. Tarantino, Food Ingredient Review at FDA: Recent Data and Initiatives to Improve the Process, 24 Reg. Toxicology & Pharmacology 224 (1996).

n441. See, e.g., Sam Peltzman, Regulation of Pharmaceutical Innovation (1974); GAO, FDA Drug Approval - A Lengthy Process that Delays the Availability of Important New Drugs, No. HRD-80-64 (1980).

n442. See, e.g., C. Frederick Beckner, III, Note, The FDA's War on Drugs, 82 Geo. L.J. 529, 531 (1993) (noting the social costs to patients of awaiting approval by the FDA for "superior drugs that will eventually be found efficacious"). The FDA now contends that it has substantially reduced average review times. See Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations for 1997: Hearings Before a Subcomm. of the House Comm. on Appropriations, 104th Cong. 328 (1996) (statement of David A. Kessler, Comm'r, FDA) (testifying that, "between 1987 and 1992, drug review and approval times were reduced by more than 40 percent").

n443. See 1995 Hearings, supra note 1, at 9 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA).
 
Unlike drugs which are ingested for the significant therapeutic benefit they are intended to confer on the patient, food additives are eaten by everyone and, by definition, are not supposed to produce any pharmacological effect. They do not provide direct benefits that justify exposing consumers to risk. This is true even for food additives, such as artificial sweeteners, that may have a beneficial effect on the American diet... [because] alternatives [are] available to reduce caloric intake for anyone motivated to do so.
 
 Id.; see also id. at 175 (statement of Michael F. Jacobson, Exec. Director, CSPI) ("Additives make it possible to market an increased range of processed foods, but it's unusual for additives to provide consumers with measurable health benefits.").

n444. See id. at 47 (statement of Al S. Clausi, Inst. of Food Technologists) ("Food additives are also an important component of food preservation, i.e. in inhibiting microbiological spoilage and reducing the risk of foodborne illness; preventing chemical, physical, and enzymatic deterioration; and in conserving nutritive value."); Rulis, supra note 193, at 534 ("Food scientists are aware that some additives enhance the safety of foods... [and] make possible the creation of a wider variety of foods, make some foods more palatable, and, in some cases, make it possible to produce foods that may have healthier nutritional profiles (i.e., fewer calories or less fat).").

n445. See H.R. Rep. No. 104-436, at 9 (1995) ("Several companies told the Subcommittee staff in interviews that they had abandoned research into promising food additives because of the delays in the petition review process."); 1995 Hearings, supra note 1, at 2 (statement of Hon. Christopher Shays, Subcomm. Chairman) ("The potential benefits of this technology, both in terms of public health and economic vitality, are too great to permit regulatory torpor to jeopardize food research and innovation."); id. at 35 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("The agency's inability to reach decisions on their pending petitions has resulted in nearly a complete stasis in innovation in the food industry."); id. at 54 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) ("The inherent delays resulting from this inability to make final decisions is beginning to turn off major food companies from investing in new additives and technology."); id. at 69 (statement of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n) (same).

n446. See Douglas L. Archer & Catherine M. DeRoever, CFSAN's Program Offices, 48 Food & Drug L.J. 487, 489 (1993) (describing the new Office of Pre-Market Approval). The FDA has also proposed to coordinate with the USDA any reviews of substances intended for use in meat and poultry products. See Substances Approved for Use in the Preparation of Meat and Poultry Products, 60 Fed. Reg. 67,490, 67,492 (1995). In addition, as part of the President's "Reinventing Government" initiative, the FDA published an advance notice of proposed rulemaking for its food additive regulations, though all of the suggested changes represent non-substantive revisions intended to eliminate redundancies or ambiguities in the rules governing specific additives. See Reinvention of Certain Food Additive Regulations, 61 Fed. Reg. 29,711, 29,712-14 (1996).

n447. See 1995 Hearings, supra note 1, at 10-14 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) (describing initiatives such as performance goals and outreach efforts to better educate petitioners about data requirements, and proposing to reduce environmental assessment requirements for routine petitions); see also Rulis, supra note 193, at 538-39 (arguing that the establishment of written guidelines and "points to consider" for prospective petitioners would make for a more efficient review process); Administrative Reforms Could Significantly Reduce Petition Backlog, Food Chem. News, Feb. 26, 1996, at 3 (detailing a number of administrative reforms aimed at reducing the Office of Premarket Approval's list of backlogged petitions); FDA Food Ingredient Review Reform is Ongoing, With More Planned for the Future, Food Chem. News, Dec. 25, 1995, at 33 (highlighting several administrative areas "necessary to create and maintain an effective process for ingredient review"); FDA Staff Manual Guide, Policies, Authority, and Procedures for Food and Color Additive Petitions and GRAS Affirmation Petitions (Apr. 1993). Many of these guidelines are now available through CFSAN's home page <http://vm.cfsan.fda.gov/dms/opa-toc.html>.

n448. See 1995 Hearings, supra note 1, at 78 (statement of Robert C. Gelardi, Exec. Vice President, Calorie Control Council).

n449. See Richard A. Merrill, The Architecture of Federal Regulation of Medical Products, 82 Va. L. Rev. 1753, 1848-49 (1996).

n450. See Rulis & Tarantino, supra note 192, at 141 (conceding that most "improvements in the efficiency of the process will take place at the margin, that is, improvements by factors of 10% to 20%"); OPA Contract Looks at Petition Review While Headway Seen on Backlog, Food Chem. News, Oct. 28, 1996, at 17 (reporting that the inventory of active petitions had been reduced from 295 in June 1995 to 240); see also 1995 Hearings, supra note 1, at 10-14 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) (cautioning that "the zeal to speed up the process not be allowed to override the credibility and integrity of that process"); Hutt, supra note 1, at 128 (doubting that the FDA will "reform itself from within, and restore the efficiency and effective regulatory approach taken in the early 1960s").

n451. See 1995 Hearings, supra note 1, at 72 (statement of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n) ("We have no reason to expect that new resolve by FDA to mend its ways, in response to current public concerns about its performance, will be sustained over the long term that is necessary for achievement of real action."); id. at 49 (testimony of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("I don't believe they are going to meet even their performance standards.").

n452. For petitions classified in Tiers I and II, the goal "is to issue an Agency response - that the submission is adequate, or provide a complete description of why it is not adequate - within" 90 and 180 days respectively. See 1995 Hearings, supra note 1, at 13 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA). Moreover, for most Tier III petitions, the announced goal is to provide such an initial response within 360 days, see id., double the maximum statutory time frame for final action, see id. at 25-27 (statement of Hon. Christopher Shays, Subcomm. Chairman); see also Protecting the U.S. Consumer from Food Borne Illnesses: Hearings Before the Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Government Reform and Oversight, 104th Cong. (1996) (testimony of Michael Friedman, Deputy Comm'r, FDA) (announcing hopes to complete reviews on 50% of new direct food additive petitions within 12 months during the first year after the existing backlog is cleared).

n453. Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 406(b), 111 Stat. 2296, 2369-70 (to be codified at 21 U.S.C. 393(f)(2)(E)-(F)). In addition, Congress required that the FDA annually prepare and publish in the Federal Register a report that provides, among other things, "detailed statistical information on the performance of the [Agency] under the plan." Id. (to be codified at 21 U.S.C. 393(g)(1)).

n454. See H.R. Rep. No. 104-436, at 14 (1995) (additional views of Hon. David M. McIntosh and Hon. Mark E. Souder) (concluding that the "inertia" within the FDA "cannot be eliminated without a significant enforcement hammer," and suggesting that the Agency be given a short period of time after a more realistic review period to either approve the additive or deny the petition if it "can demonstrate that an additive has not been found to be safe"); S. 1477, 104th Cong. 404 (743(c)) (1996) (providing that an additive already approved in the European Union or the United Kingdom would be deemed approved at the petitioner's request if the FDA fails to act on a petition within the statutory time frame); 1995 Hearings, supra note 1, at 71, 83 (statement of Rhona S. Applebaum, Exec. Vice President, Nat'l Food Processors Ass'n) ("Without amendments to the Act that establish an effective forcing mechanism, there can be no real prospect for substantial improvement in the food additive approval process."); id. at 87 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.).

n455. See, e.g., H.R. 2245, 83d Cong. 6 (407(d)) (1953).

n456. See, e.g., Nutrition Labeling and Education Act of 1990, Pub. L. No. 101-535, 2(b), 3(b), 104 Stat. 2353, 2356-60; Safe Medical Devices Act of 1990, Pub. L. No. 101-629, 3(c)(2), 104 Stat. 4511, 4515; Hazardous and Solid Waste Amendments of 1984, Pub. L. No. 98-616, 201, 98 Stat. 3221, 3226 (codified at 42 U.S.C. 6924(c) (1994)); see also M. Elizabeth Magill, Congressional Control Over Agency Rulemaking: The Nutrition Labeling and Education Act's Hammer Provisions, 50 Food & Drug L.J. 149 (1995).

n457. See 1995 Hearings, supra note 1, at 177 (statement of Michael F. Jacobson, Exec. Dir., CSPI) ("Industry should realize that a rigid time limit for the review process could well mean that FDA would simply reject a petition that currently would be put in abeyance pending further research and analysis."); Hutt, supra note 1, at 128 ("It is all too easy for FDA simply to issue continual denials... on the ground that further testing is needed."); see also Miscellaneous Amendments, 43 Fed. Reg. 27,507, 27,509 (1978) (ACUS recommendation against the imposition of strict deadlines); Alden F. Abbott, The Case Against Federal Statutory and Judicial Deadlines: A Cost-Benefit Appraisal, 39 Admin. L. Rev. 171 (1987).

n458. See H.R. Rep. No. 104-436, at 8 ("The leveling of FDA resources for foods in recent years is in sharp contrast with the increased responsibilities CFSAN has assumed due to new legislation...."); 1995 Hearings, supra note 1, at 35-36 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) (noting that CFSAN is "under funded and overly-committed" and that "it is highly improbable" that it could get the 200-300 extra reviewers it needs for food additives); id. at 54 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) (same); cf. id. at 53 (asserting that reduced resources are "more of a symptom and not a root cause" of the breakdown in the food additive approval process, and that the "fundamental causes are lack of a clear mission, a steady decline in priority over the years, and the increasing lack of incentive and ability of the agency to make a final positive decision on a petition against the statutory criteria").

n459. See Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. 36,582 (1995); see also Jerome H. Heckman, Closing in on Zero, 45 Food Drug Cosm. L.J. 599 (1990) (discussing long-running industry efforts at trying to convince the FDA to adopt a threshold of regulation policy); Alan M. Rulis et al., FDA's Priority-Based Assessment of Food Additives, 4 Reg. Toxicology & Pharmacology 37 (1984); cf. Public Citizen, Inc. v. U.S. Nuclear Regulatory Comm'n, 940 F.2d 679, 680-85 (D.C. Cir. 1991) (declining to review a challenge to the NRC's analogous "below regulatory concern" policy).

n460. See S. Rep. No. 104-284, at 62 (1996) (stating that "this simple procedure will allow the FDA to quickly dispose of its existing inventory" of indirect food additive petitions); Rulis & Tarantino, supra note 192, at 141 (noting that this "could free up a considerable amount of person power for work on petitions of greater consequence to the food supply and public health protection"); 1995 Hearings, supra note 1, at 64 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) (stating that "under the proposed process for indirects, a notification would be submitted to FDA... [and] take effect in ninety days and use of the substance therefore allowed, unless FDA concluded that there existed substantial evidence to show" migration or lack of safety).

n461. See 21 C.F.R. 170.39 (1997) (establishing the threshold of regulation for food-contact substances). The threshold is set at a concentration of 0.5 ppb or, in the case of an approved direct food additive being used in a food-contact material, at 1% of the ADI. See id. 170.39(a)(2). The substance may not be exempted (much less approved) if it has been shown to induce cancer. See id. 170.39(a)(1). The 0.5 ppb threshold attempts to ensure an upper-bound lifetime risk of cancer of less than one-in-one million in the event that a substance later proves to be carcinogenic. See Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. at 36,583. The Agency rejected a suggestion that it extend the policy to substances added directly to foods at low levels. See id. at 36,585.

n462. See Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. at 36,589-60 (observing that "such reviews can usually be completed within 3 to 4 months," but fearing that a formal deadline would restrict the Agency's flexibility in allocating resources among competing priorities); Kessler Objects to Hammer Provisions, Shorter Review Times at Senate Hearing, Food Chem. News, Feb. 26, 1996, at 25 (warning that unrealistically short deadlines will result in either premature disapprovals or public exposure to potentially dangerous food-use chemicals). Last year, Congress directed the FDA to establish a premarket notification system for all "food contact substances," which authorizes a manufacturer or supplier to sell or use such indirect additives 120 days after they file a notification unless the Agency first objects, but this provision takes effect only if Congress appropriates specified funds in future years for the implementation of the program. See Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 309(b), 111 Stat. 2296, 2354-56 (to be codified at 21 U.S.C. 348(h)). Apparently, the FDA could retain its threshold of regulation policy by promulgating implementing rules that specified under what circumstances such premarket notifications would not be acceptable. See id.

n463. See 1995 Hearings, supra note 1, at 133-41 (statement of Jerome H. Heckman, on behalf of the Soc'y of the Plastics Indus.) (explaining that exemption petitions under the threshold of regulation policy already have become backlogged at about six months, and proposing a substantially less formal procedure for reviewing indirect food additives); Hutt, supra note 1, at 122 (supporting the threshold of regulation concept but criticizing the replacement of food additive petitions with exemption petitions).

n464. See Food Additives; Threshold of Regulation for Substances Used in Food-Contact Articles, 60 Fed. Reg. at 36,586-87, 36,589 (rejecting suggestions that companies be permitted to make their own judgment that a substance is exempt under the threshold of regulation policy, though noting that companies remain free to decide that a substance is not a "food additive" to begin with because it is not likely to migrate). Once the FDA issues a letter granting an exemption, any company wishing to utilize the substance under the same conditions of use may rely on the exemption. See id. at 36,587, 36,591-92.

n465. See Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103-417, 8, 108 Stat. 4325, 4331 (codified at 21 U.S.C. 350b(a)(2) (1994)); supra note 83 (discussing this legislation).

n466. See S. Rep. No. 101-513, at 15 (1990) ("Over 95% of the devices marketed since the passage of the [1976] Amendments have been found "substantially equivalent' to a predicate device."); GAO, Medical Devices: FDA Review Time, No. PEMD-96-2 (1995) (measuring the increasing length of FDA reviews); Robert B. Leflar, Public Accountability and Medical Device Regulation, 2 Harv. J.L. & Tech. 1, 46-58 (1989) (arguing that Section 510(k) has been used inappropriately to circumvent full approval requirements); Lawrence S. Makow, Note, Medical Device Review at the Food and Drug Administration: Lessons from Magnetic Resonance Spectroscopy and Biliary Lithotripsy, 46 Stan. L. Rev. 709, 710-11 (1994) (asserting that the review problems can be traced to the FDA's implementation of the statute rather than to the statute itself). To address growing backlogs, the Agency recently exempted numerous classes of low-risk devices from the notification requirement. See Medical Devices; Exemptions from Premarket Notification for Certain Classified Devices, 59 Fed. Reg. 63,005 (1994).

n467. See 1995 Hearings, supra note 1, at 79 (statement of Robert C. Gelardi, Exec. Vice President, Calorie Control Council) (urging that such an abbreviated review process would assist the FDA with its own goals for an effective and efficient review process); cf. id. at 13 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) (suggesting that most such petitions would fall within Tier I, for which the performance goal time frames are just 90 days for an initial response); Substances Generally Recognized as Safe, 48 Fed. Reg. 48,457, 48,458 (1983) (explaining that GRAS self-determination would be possible for an additional use of a substance affirmed as GRAS but not for one approved as a food additive). Congress recently instructed the Agency to publish "standards for the prompt review of supplemental applications submitted for approved articles." Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 403(a), 111 Stat. 2296, 2367. It also directed the Agency to issue guidance to industry that would "clarify the requirements for, and facilitate the submission of data to support, the approval of supplemental applications," including the possibility of referencing previously published information. Id. 403(b).

n468. See H.R. Rep. No. 104-436, at 8 (1995) (noting that the FDA "utilizes a "first in, first out' review system which does not devote the greatest resources to the applications with the greatest resource requirements"); 1995 Hearings, supra note 1, at 12, 19 (statement and testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("We need to get rid of the backlog so that we can start fresh in this program.").

n469. See supra notes 281-86 and accompanying text (discussing the debate within Congress and the FDA over whether an additive's benefits or social utility should play a part in the general safety standard).

n470. See GAO, New Food Technologies, supra note 9, at 63-64 (noting that the Edwards Committee "concluded that FDA must recognize that approving useful and safe new products can contribute as much to public health as preventing the marketing of harmful or ineffective products," adding that some "have proposed that FDA establish a fast track for processing petitions for food additives that provide some positive public health benefit"); The Need for FDA Reform: Hearing Before the Subcomm. on Health and Environment of the House Comm. on Commerce, 104th Cong. 100 (1996) (statement of Michael W. Pariza, Dir., Food Research Inst.) (same); 1995 Hearings, supra note 1, at 104-05 (testimony of Michael H. Davidson, Med. Dir., Chicago Ctr. for Clinical Research) (describing potential benefits of fat substitutes, and recommending that "at least priority be given to those food additives that do have health benefits, that they receive expedited approvals, or reviews").

n471. See 21 C.F.R. pt. 314(h) (1997) (establishing expedited approval procedures for new drugs indicated for the treatment of serious or life-threatening illnesses); Hutt & Merrill, supra note 147, at 529-31 (describing previous system for prioritizing new drug reviews according to therapeutic potential).

n472. See 1995 Hearings, supra note 1, at 13 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA) (arguing that the use of tiers to classify petitions will respond to the industry's concerns about the review process).

n473. See GAO, New Food Technologies, supra note 9, at 89-95.

n474. See Prescription Drug User Fee Act of 1992, Pub. L. No. 102-571, tit. I, 106 Stat. 4491 (codified at 21 U.S.C. 379h (1994), as amended by Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 103, 111 Stat. 2296, 2299); Bruce N. Kuhlik, Industry Funding of Improvements in the FDA's New Drug Approval Process: The Prescription Drug User Fee Act of 1992, 47 Food & Drug L.J. 483 (1992).

n475. See 1956 Hearings, supra note 16, at 141 (HEW memorandum) ("We cannot absorb this important new function without serious neglect of other essential responsibilities. And the cost of obtaining governmental review of scientific data to assure safety of a new chemical is a legitimate charge to the cost of doing business."). Industry representatives expressed strong opposition to the request for such authority. See, e.g., id. at 95 (statement of Glenn G. Paxton, appearing as counsel for various food industry associations).

n476. See Pub. L. No. 83-518, 3 (408(o)), 68 Stat. 511, 517 (codified at 21 U.S.C. 346a(o) (1994), repealed and replaced by Food Quality Protection Act of 1996, Pub. L. No. 104-170, 405 (408(m)), 110 Stat. 1489, 1529).

n477. See, e.g., H.R. 4014, 85th Cong. 6 (1957); see also 104 Cong. Rec. 17,424 (1958) (statement of Hon. Leonor K. Sullivan) (calling for adequate appropriations so that the FDA could execute its significant new responsibilities in reviewing food additives). An early draft of Representative Dingell's recent bill, H.R. 5952, 102d Cong. (1992), had included provisions applicable to food additive but not GRAS affirmation petitions, establishing an interim annual user fee of $ 75,000. Although a one time filing fee might make sense, an annual fee imposed after approval would unfairly tax the petitioner, and a fee imposed only during the pendency of the FDA's review might create a perverse incentive to delay approval.

n478. See National Cable Television Ass'n v. United States, 415 U.S. 336, 340-41 (1974); see also Clayton P. Gillette & Thomas D. Hopkins, Federal User Fees: A Legal and Economic Analysis, 67 B.U. L. Rev. 795, 826-45 (1987) (exploring the statutory scope of permissible user fees).

n479. See supra notes 200-04 and accompanying text (asking whether the significant costs of pursuing approval of a food additive might harm incentives to innovate in this area).

n480. See 1995 Hearings, supra note 1, at 29 (testimony of Linda A. Suydam, Interim Deputy Comm'r, FDA) ("[A] user fee program is difficult in the food additive area because a manufacturer is not given a product license as one is in the drug and devices area."); id. at 170 (testimony of Stuart M. Pape, on behalf of the Nat'l Soft Drink Ass'n) (remarking that the charging of fees with new drug applications is commensurate with the "major proprietary benefits" granted when such products are approved); cf. id. at 141 (statement of Jerome H. Heckman, on behalf of the Soc'y of the Plastics Indus.) (noting that "modest filing fees could be charged for [proposed indirect food additive premarket] notifications since they would be basically proprietary"). In fact, based on conversations held after the conclusion of the hearings, it appears that the FDA "may propose user fees to fund pre-filing consultation activities with sponsors." H.R. Rep. No. 104-436, at 3 (1995).

n481. See 1995 Hearings, supra note 1, at 186 (statement of Keith C. Triebwasser, Procter & Gamble) ("Patents alone do not provide this security, since patents are difficult to obtain in the food industry and difficult to enforce. Margins in the food industry are too low to support protracted patent battles."); Hutt, supra note 1, at 126 ("Without a statutory period of market exclusivity, American industry cannot be expected to invest in new food additives that cannot be patented, even if the regulatory process itself is reformed.").

n482. See Elizabeth C. Price, Teaching the Elephant to Dance: Privatizing the FDA Review Process, 51 Food & Drug L.J. 651 (1996); Charles J. Walsh & Alissa Pyrich, Rationalizing the Regulation of Prescription Drugs and Medical Devices: Perspectives on Private Certification and Tort Reform, 48 Rutgers L. Rev. 883, 987-1016 (1996). See generally Ronald A. Cass, Privatization: Politics, Law, and Theory, 71 Marq. L. Rev. 449 (1988); Harold J. Krent, Fragmenting the Unitary Executive: Congressional Delegations of Administrative Authority Outside the Federal Government, 85 Nw. U. L. Rev. 62 (1990); Douglas C. Michael, Federal Agency Use of Audited Self-Regulation as a Regulatory Technique, 47 Admin. L. Rev. 171 (1995).

n483. See supra notes 116-21 and accompanying text (reviewing the role of independent scientific organizations during the GRAS list review).

n484. See 1995 Hearings, supra note 1, at 12 (statement of Linda A. Suydam, Interim Deputy Comm'r, FDA). The FDA also has initiated a limited pilot program allowing third-party reviews of premarket notifications for certain medical devices. See Medical Devices; Third-Party Review of Selected Premarket Notifications; Pilot Program, 61 Fed. Reg. 14,789 (1996). Congress recently authorized such efforts by the Agency when they will improve the timeliness or quality of reviews, but it hastened to add that external reviewers would only make recommendations and that FDA officials would continue to make the final decisions on applications. See Food and Administration Modernization Act of 1997, Pub. L. No. 105-115, 415, 111 Stat. 2296, 2377-78 (to be codified at 21 U.S.C. 397). The EPA makes use of extramural reviews for pesticide data submissions. See 7 U.S.C. 136w(d) (1994); 40 C.F.R. 155.27 (1996).

n485. See, e.g., 1995 Hearings, supra note 1, at 116-17, 171 (statement and testimony of Kenneth D. Fisher, former Dir., LSRO); id. at 44-45 (statement of Richard L. Hall, Chairman, NAS Food Forum); id. at 54-55, 62-67 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.); see also id. at 36 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) (explaining that extramural reviews could provide a method of leveraging the Agency's limited resources, but emphasizing that the FDA cannot abdicate its regulatory duties and must, therefore, closely supervise external reviews); Stuart M. Pape, Food Industry Initiatives to Improve the FDA's Food Ingredient Review Processes, 51 Food & Drug L.J. 413, 417-20 (1996) (detailing reform proposals presented by the industry).

n486. See 5 U.S.C. app. 2 (1994) (establishing guidelines for the creation of advisory committees); 21 C.F.R. pt. 14 (1997) (setting forth the FDA's procedures for utilizing advisory committees); Food Chem. News v. Young, 709 F. Supp. 5, 6-9 (D.D.C. 1989) (holding that a FASEB expert panel under contract to prepare a food safety report for the FDA was subject to the provisions of the Federal Advisory Committee Act, including requirements for balanced membership and open meetings), rev'd, 900 F.2d 328 (D.C. Cir. 1990); see also Animal Legal Defense Fund, Inc. v. Shalala, 104 F.3d 424, 429-31 (D.C. Cir.) (holding that FACA applied to NAS guidance concerning the care of laboratory animals), cert. denied, 118 S. Ct. 367 (1997). See generally Steven P. Croley, Practical Guidance on the Applicability of the Federal Advisory Committee Act, 10 Admin. L.J. 111 (1996).

n487. See 1995 Hearings, supra note 1, at 84 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) ("The check can surely go through FDA's hands, provided a service charge is not excised during the process.").

n488. See H.R. Rep. No. 104-436, at 10, 12 (recommending this approach); H.R. 3200, 104th Cong. 105(c)(3) (1996) ("The recommendation of an accredited person to approve or deny a petition submitted to such person shall be deemed to be the decision of the Secretary unless the Secretary finds that there is a reasonable possibility it is not safe."); 1995 Hearings, supra note 1, at 36 (statement of Sanford A. Miller, Univ. of Texas Health Science Ctr.) ("If for example FDA does not issue a regulation or a report defending an opposing view within the prescribed time, then an assumption of approval is made."); id. at 63 (statement of Stephen A. Ziller, Vice President, Grocery Mfrs. of Am.) ("The presumption of approvability arising from a favorable report of the independent review organization would be rebuttable by FDA only if it concluded that there existed substantial evidence to demonstrate that the additive had not been shown to be safe."); Hutt, supra note 1, at 128 ("FDA would not be permitted, in its review of that recommendation, to veto marketing of the product on the ground that it still needs further testing.").

n489. See Degnan, supra note 89, at 580-82. The GRAS concept
 
provides the agency with a mechanism for concentrating its resources in these [novel food] areas - and for shifting some of its traditional food additive type of functions away from substances which do not raise safety issues that only the agency is qualified to address. As a result, the general pace of decisionmaking could quicken because the scientific and technical staffs available for the review of safety issues would be subject to less diversions and able to concentrate on matters of high priority.
 
 Id. at 582; see also 1995 Hearings, supra note 1, at 170 (testimony of Kenneth D. Fisher, former Dir., LSRO) (observing that the FDA "has made the GRAS affirmation process analogous to the food additive petition process," and applauding the Agency's recent suggestion "to separate these and make the GRAS affirmation process perhaps what it was originally meant to be: a way to separate food additives and GRAS substances").

n490. See supra notes 116-21 and accompanying text (discussing the relationship between the FDA and independent review organizations during the GRAS list review).

n491. See 1995 Hearings, supra note 1, at 80 (statement of Robert C. Gelardi, Exec. Vice President, Calorie Control Council) (suggesting several scientific bodies to which such deference could be accorded).

n492. In its recent GRAS notification proposal, however, the FDA repeatedly characterized GRAS as an "exemption." See, e.g., Substances Generally Recognized as Safe, 62 Fed. Reg. 18,938, 18,939 (1997).

n493. See supra Part II.B.3. In its latest proposals, the FDA recognized that the opinions of specially-convened expert panels and authoritative bodies can provide support for a GRAS self-determination. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,943.

n494. See, e.g., Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,951 (explaining the limited value of an FDA response to a GRAS notification); cf. Heckman, supra note 57, at 49 ("A food packaging manufacturer often files a food additive petition because he would rather be safe than sorry. But by the time he emerges from the petition ordeal, he will certainly be sorry and may not be one whit more safe.").

n495. See 21 C.F.R. 180.1(c)(3) (1997) ("If the Commissioner concludes that the studies are not being pursued promptly and diligently or if interim results indicate a reasonable likelihood that a health hazard exists, an order will promptly be published in the Federal Register revoking the interim food additive regulation effective on publication.").

n496. See Substances Generally Recognized as Safe, 62 Fed. Reg. at 18,958.
 
If there were no process for agency GRAS affirmation, firms making independent GRAS determinations may attempt to substitute for GRAS affirmations by doing additional research, contracting with third party research organizations, or taking other steps to provide adequate assurances to other firms that FDA will probably not subsequently challenge their independent GRAS determinations.
 
 Id.; see also Degnan, supra note 89, at 567 ("Because FEMA's GRAS determinations are independent, they do not bind the FDA. It is standard practice, however, for food processors to rely upon FEMA's GRAS determinations. The FDA has deferred to FEMA's practice and has only rarely taken issue with a FEMA determination.").

n497. See 1995 Hearings, supra note 1, at 88 (statement of Hon. Edolphus Towns) ("This proposal seems very similar to the system Congress abandoned with the passage of the Food Additives Amendment in 1958.").

n498. See id. at 124 (Stuart M. Pape, on behalf of the Nat'l Soft Drink Ass'n).
 
Contrary to some suggestions, this is not a radical reversal of the burden [of] proving that the additive is safe... [but the] FDA should not be able to frustrate the purpose of independent review and prevent the approval of the additive merely by identifying some question or issue that is unresolved.
 
 Id.; see also id. at 168 ("The proposal we made would require FDA to have substantial evidence, not to demonstrate that the additive is unsafe, but simply substantial evidence to demonstrate that safety hasn't been shown.").