New Labeling Requirements for Food Allergens

Congress recognized that food allergies are a significant problem, and it determined that allergic consumers or caregivers have to make appropriate food selections based on accurate labeling of food products. In 2001, as part of the Food and Drug Administration’s (FDA; Rockville, MD) public health mission to keep food safe, the agency increased its activity on food allergen awareness. The initiative was to provide guidance for industry and regulators on how to manage food allergens through appropriate labeling and manufacturing practices. Soon after, Congress passed the Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA), which represented the most recent of several amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act). FALCPA became effective January 1, 2006.

FALCPA requires that the label on a food product that is or contains an ingredient that includes a “major food allergen” declares the presence of the allergen as specified in the Act (Public Law 108-282). The law also requires FDA to issue a regulation to define and permit use of the term gluten-free. Further, the law includes a provision that directs the secretary of Health and Human Services (Washington, DC), or FDA by delegation, to consult with appropriate experts and stakeholders to define and permit the use of the term gluten-free in food labeling. A proposed ruling is anticipated by August 2006, while the final rule that defines the term gluten-free and identifies the criteria that would enable the food industry to use that term voluntarily for labeling their products, is due two years later.

FALCPA’s requirements apply to all packaged foods sold in the United States, including conventional foods, dietary supplements, infant formula, and medical foods, all of which are “food” within the FD&C Act’s definition. Raw agricultural commodities, such as fresh fruits and vegetables in their natural state, are not affected by FALCPA. Enforcement in the form of civil and/or criminal penalties applies to any company and its management if one of its packaged food products does not comply with the FALCPA labeling requirements. FDA may also request seizure of food products if the label of the product does not conform to FALCPA’s requirements. In addition, FDA is likely to request that a food product containing an undeclared allergen be recalled by the manufacturer or distributor. According to FALCPA, ingredients subject to the new allergen labeling law are:

• Eight major food allergens (milk, egg, fish, crustacean shellfish, tree nuts, wheat, peanuts, and soybeans).

• Any food ingredient that contains protein derived from a major food allergen.

• Incidental additives and flavors derived from major food allergens.

FALCPA allows for only two exceptions, and those are:

• Any highly refined oil derived from a major food allergen.

• Any food ingredient exempt from labeling under a petition or notification process specified in the law.

Under the petition process (21 USC 343(w)(6)), an ingredient might be exempt from FALCPA labeling if the petitioner demonstrates that the ingredient “does not cause an allergic reaction that poses a risk to human health.” The notification process is described in 21 USC 343(w)(7). FALCPA establishes a process by which any person may file a notification containing scientific evidence demonstrating that an ingredient “does not contain allergenic protein.” The scientific evidence must include the analytical method used, and the ingredient must be derived by the specified method. FDA has 90 days to object to a notification. Absent an objection, the food ingredient is exempt from FALCPA’s labeling requirements for major food allergens. FDA is required to post to a public site notifications received under 21 USC 343(w)(7) within 14 days of receipt of a notification. Four notifications for labeling exemption have been submitted to FDA. To date, the agency has not responded to any of the four notifications.

• Mead Johnson Nutritionals (Evansville, IN) for extensively hydrolyzed casein (from milk).

• Ross Products Division, Abbott Laboratories (Abbott Park, IL) for extensively hydrolyzed casein (from milk).

• F&A Dairy (Dresser, WI) and International Media and Cultures Inc. (Denver) for starter growth media (from soy).

• Purity Foods Inc. (Okemos, MI) for spelt (from wheat).

On October 5, 2005, in anticipation of the impending deadline for implementation of FALCPA, FDA issued the first edition of the guidance document for industry (Guidance for Industry: Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling and Consumer Protection Act of 2004) that contained questions and answers relating to food allergens and the new law. As numerous other issues were raised by industry about FALCPA since that time, a second edition of Guidance for Industry: Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 2) was published in the Federal Register on December 27, 2005 [Docket No. 2005D-0490]. Given the nature of the revisions to the initial document, FDA is issuing the guidance as Level 1 (21 CFR 10.115(c)(1)).

Under FALCPA, Congress designated protein in or derived from any of the following eight foods or food groups as major food allergens: milk, egg, fish, crustacean shellfish, tree nuts, wheat, peanuts, and soybeans. The eight foods or food groups account for 90% of all documented IgE-mediated food allergies (the most severe type) worldwide. This action is welcomed, because approximately 6 million to 7 million individuals are affected by food allergies in the United States (2–2.5% of the population). According to the August 2005 issue of the Journal of Allergy and Clinical Immunology, in a study conducted by the National Institutes of Health (Bethesda, MD), the highest allergic test response (27.5%) was to dust mites, while the lowest (8.6%) was to peanuts. Although a lower response to peanuts, the 8.6% positive response still translates into an estimated 3 million Americans allergic to peanuts or tree nuts. Further, allergic reactions to peanuts tend to be significantly more severe than those to dust mites and, in certain individuals, such reactions can be life threatening. The number of children afflicted with food allergies is also considerable. According to the Louisiana State University Pediatric Allergy/Immunology Department, 6% of children suffer from food allergies, of which 2 million are of school age.

Some of FALCPA’s new food labeling requirements are unprecedented, as the law demands declaration of the specific type of tree nut (e.g., almonds, pecans, or walnuts), the species of fish (e.g., bass, flounder, or cod), and the kind of crustacean shellfish (e.g., crab, lobster, or shrimp). Under the new law, there are two ways to label products: within a statement of ingredients or in a separate statement, but either one must include the common or usual name of the allergen. For example:

• Ingredient listing: Milk-listed with other ingredients casein (milk) or whey (milk)-adding the food source in parentheses where the technical term is used in the ingredient list.

• A statement immediately following the ingredient list: Allergen Information: Contains milk-immediately following or next to the ingredient list; or contains milk-at the end of the ingredient list.

Food allergies have a considerable impact on modern society, as there is no known cure. Serious or life-threatening allergic reactions have been reported when certain sensitized consumers are exposed to allergens in food. Avoidance of the offending foods is the only successful approach, together with pharmacological agents for symptomatic treatment, including self-administered epinephrine. Accidental exposure is not uncommon. Food allergy is the leading cause of anaphylaxis, a severe type of allergic reaction requiring hospitalization. According to FALCPA, each year, approximately 30,000 individuals require emergency room treatment, 2000 are hospitalized, and 150 die because of allergic reactions to food.

Not all adverse reactions to food are allergies, however, and establishing the exact cause of a reaction to food may not be an easy task. Adverse reactions may result from microbial or chemical food poisoning or from a nonspecific nonallergic response. Although consumers use the terms food intolerance and food allergy interchangeably, the terms stand for very different conditions based on diverse mechanisms of action. For example, food intolerance (also known as nonallergic food hypersensitivity reaction) is an adverse food-induced reaction that does not involve the immune system (e.g., lactose intolerance). Food allergy occurs when the immune system reacts to a certain food and includes those that involve immunoglobulin E (IgE)-mediated reactions (e.g., peanut allergy). The reactions of IgE antibodies with specific proteins (allergens) found in food cause the release of mediators (e.g., histamine) into the bloodstream and reach certain target organs, such as the skin (causing hives, swelling of the lips, tongue, and face), the respiratory system (causing shortness of breath or wheezing), and the gastrointestinal tract (causing abdominal pain or vomiting). Allergic reactions can develop within minutes, and if left untreated may become fatal in certain individuals. Food allergy is less common than food intolerance.

One major point of contention in implementing FALCPA has to do with threshold levels and the existence of levels below which it is unlikely that a food-allergic individual would experience an adverse effect. Interestingly, FALCPA does not require FDA to establish a threshold level for any food allergen. Nevertheless, FDA is placed in the position where it has to consider a threshold level for one or more food allergens in the context of reviewing a petition or a notification submitted to request that an ingredient be exempt from FALCPA’s labeling requirements. FDA charged the Threshold Working Group (TWG) with this task.

The working group’s draft report, published in June 2005, summarizes the current state of scientific knowledge regarding food allergy and celiac disease, including information on dose-response relationships for major food allergens and for gluten, respectively. The report presents data needed to evaluate various approaches to establishing thresholds that would be scientifically sound and efficacious in relation to protection of public health. The TWG identified four general approaches that could be used to establish thresholds for allergens and glutens: analytical methods–based, safety assessment–based, risk assessment–based, and statutorily derived. Each of the four approaches has advantages and limitations. The Draft Report describes several important findings by the TWG.

• Finding 1. As new scientific and clinical findings emerge, a review of the initial approach selected to establish thresholds for major food allergens, the threshold values, and any uncertainty factors used in establishing the threshold values should be undertaken.

• Finding 2. The analytical methods–based approach is an option to establishing thresholds for major food allergens for which validated analytical methods are available. However, these thresholds should be replaced quickly by other thresholds established using one of the other approaches.

• Finding 3. The safety assessment–based approach, based on currently available clinical data, is a feasible way to establish thresholds for the major food allergens by utilizing the lowest observed adverse effect level (LOAEL) or no observed adverse effect level (NOAEL) determinations. Effort should be placed in establishing individual thresholds for each of the major food allergens. However, if it is not possible, a single threshold based on the most potent food allergens should be established.

• Finding 4. The quantitative risk assessment–based approach provides the strongest, most transparent scientific analyses to establish thresholds for the major food allergens. A research program should be initiated to develop the necessary data to support the quantitative risk assessment–based approach. Thresholds established using this approach should be reevaluated periodically in light of new scientific data.

• Finding 5. The statutorily derived approach provides a mechanism for establishing thresholds for allergenic proteins in foods based on a statutory exemption. Conceivably, this approach could be used to set a single threshold level for proteins derived from any of the major food allergens; however, the approach might yield thresholds that are unnecessarily protective of public health as compared with thresholds established using the safety assessment-based approach. This approach should be used only on an interim basis and should be reevaluated as new data and risk assessment tools emerge.

Another possible approach to establishing thresholds for the eight major food allergens would be to establish a single threshold for all allergens, based on the most potent food allergen. Although conceivable, this is considered by many as an overly protective measure, particularly in the case of soy as compared with egg or peanut.

In the draft report, the TWG concluded that implementation of the FALCPA petition and notification provisions could present three key scientific issues, and significantly more work is necessary to address them. They are:

• Defining an allergic response.

• Determining if all allergic responses pose an equal risk to human health.

• Determining if allergens occur in a food either in a form or at a level that is too low to cause harm (i.e., either the allergen does not cause a biological response or the response is too mild to be considered hazardous).

According to the TWG, there are several factors that make it difficult to detect and measure food allergens. Sampling problems and quantifying allergenic proteins in a wide variety of foods are still challenging tasks.

Currently, the only commercial methods available for testing for the presence of allergens are few and nonspecific. These techniques use enzyme-linked immunosorbent assay (ELISA), which was initially designed for different purposes, mainly to detect representative biomarkers, and not allergenic protein. Many kits contain polyclonal antibodies that detect both allergenic and nonallergenic proteins. For example, the peanut ELISA assays that have completed Multiple Laboratory Performance Tested validation are designed to detect multiple proteins indicative of the presence of the food (e.g., peanuts), not to detect or quantify specific allergenic proteins (e.g., Ara h 1 in peanut). There are no validated detection methods or commercial kits for most food allergens or for specific allergenic proteins.

FALCPA, enacted in August 2004, became effective January 1, 2006, for all packaged foods regulated under the FD&C Act. Although industry had arduously prepared to comply with the new allergen labeling law and meet the deadline, there remain numerous fundamental and complex unresolved issues that affect both industry and consumers.

• Quantitative food allergen thresholds are not known and have not been established.

• Although there are several test kits for commercial use to test for allergenic proteins in food, kits do not exist for each allergen in the food supply.

• Food ingredients may contain little to no protein but are required to be labeled as an allergen if they are derived from allergenic food.

• Scientific evidence must be used to assert that ingredients are free of allergenic proteins and qualify for the exemption process review.

• “Problem ingredients” commonly used in foods or food processing include, but are not limited to: soy lecithin, soy sauce, wheat starch, Worcestershire sauce, starter cultures, lactoferrin, lysozyme, fish gelatin, caramel, butter, butter oil, diacetyl, tocopherol/vitamin E, xanthan gum, sorbitol, lactitol, maltitol, amino acids, enzymes, vinegars, flavors, and natural essences derived from allergenic food, such as tree nuts.

The labeling will present a challenge to consumers who have previously eaten food products without an adverse reaction and now will see many more allergen listings on packages. Because FALCPA does not contain an exemption for major allergens that may be present in small quantities thought to be inconsequential, consumers will have no way of knowing whether the food formulation has changed, the manufacturer received new information indicating that a major allergen may now be present in the food, or the manufacturer is only adding the name of the major allergen because an ingredient derived from an allergen has always been used but was not previously labeled as an allergen.

Several of these issues are complex and will require time, research, and combined effort on the part of FDA, industry, and consumers to resolve them. Meanwhile, industry has to contend with requirements set forth by FALCPA for all packaged foods sold in the United States, including conventional foods, dietary supplements, infant formula, and medical foods. More importantly, industry needs to remain vigilant to any new scientific findings that might impact the labeling requirement of their products.

Ioana G. Carabin, MD, is president and medical director of Women's Health Sciences Institute (Vero Beach, FL). Bernadene A. Magnuson, PhD, is a toxicologist at the Burdock Group (Washington, DC).

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