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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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7

Management of Packaged Foods

Consumers with a food allergy, like the general population, rely on packaged foods as a key component of their diet. Therefore, the packaged foods industry is an essential stakeholder if consumers with food allergies are to succeed in their prevention approaches and be safe. For this reason, the labeling of allergenic foods is an important public health intervention that assists consumers in avoiding potentially allergenic foods.

The food supply chain from production to consumption is complex (see Figure 7-1). Packaged foods are made and assembled primarily in commercial food processing facilities but also in restaurants, retail grocery stores, and other retail outlets. Commercial food processing facilities range from very large companies that may make dozens of different products within a single facility to very small companies that tend to make a narrower range of products but also often use shared facilities. In addition, food processing equipment is frequently shared to make different products. Furthermore, a packaged food may contain several dozen ingredients that may be obtained from a range of suppliers who likewise may have upstream suppliers. Finally, the farms and other suppliers that are sources of these ingredients (e.g., oceans, mines) are also often diversified and often share harvesting equipment, transportation vehicles, and storage facilities.

Allergens, then, can enter foods from many sources along the food chain, intentionally or unintentionally, through cross-contact1 in farms,

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1 Cross-contact is the inadvertent introduction of allergenic food residues into a product. It is generally the result of environmental exposure during processing or handling, which may occur when multiple foods are produced in the same facility, when the same processing line

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Image
FIGURE 7-1 Conceptual model of a food supply chain. Elements or actors in this supply chain in one area (e.g., region or country) also have interactions (e.g., international trade) with actors in other areas.
SOURCE: IOM and NRC, 2015.

storage, distribution and manufacturing facilities, food service establishments, or the home. The food industry, of course, wishes to prevent the possibility that a consumer with a food allergy will experience an adverse reaction after consuming a packaged food product. In reality, achieving this goal at all times is challenging. From the food industry perspective, three general approaches can be used to minimize the risk of a reaction from an allergenic food: (1) eliminate potential allergens or specific allergens from products; (2) list the allergen on the product label as an ingredient, when it is intentionally added as such; and (3) implement strict allergen control plans (ACPs) to minimize allergen contamination and use advisory labels (precautionary allergen labeling, or PAL) to inform the consumer about the risk when necessary. The Food and Drug Administration (FDA) Food Safety

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is used to produce allergenic and nonallergenic food as the result of ineffective cleaning, the generation of dust or aerosols containing an allergen, or other causes (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm106890.htm#q19 [accessed January 5, 2017]).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Modernization Act2 (FSMA) identifies allergens as a hazard that is reasonably likely to occur in food manufacturing operations and requires that food manufacturing develop ACPs, In so doing, the FSMA acknowledges the importance of food allergy as a public health priority for the packaged food industry. This chapter includes a brief description of ACPs in Box 7-1 but does not attempt to review them in depth even though the development of effective ACPs has an impact on both labeling and PAL.

Likewise, although the committee recognizes that processing can affect the allergenicity of foods either by reducing the amount of the allergenic protein or by altering the protein in some manner, the chapter does not examine the effects of processing in depth. The main focus of this chapter is on labeling and PAL because of the obvious importance of these approaches to the consumer.

Although this chapter focuses on the food manufacturing industry, it is important to note that in addition to packaged foods, foods are consumed in many other forms and venues (e.g., homes, restaurants, other retail food establishments, places of worship, camps, recreational facilities). A few of these situations are addressed in Chapter 8. Following a review of the current labeling practices in packaged foods, the chapter describes a labeling approach based on risk and makes recommendations to that effect. Research needs are also included. The Annex to this chapter delves into data inputs needed for a risk-based approach and their limitations.

ELIMINATING ALLERGENS FROM PACKAGED FOODS

As noted above, one approach to managing food allergen hazards within food manufacturing operations is to eliminate one or more allergens from the group of products being manufactured in shared facilities. Within the product development groups in some major food companies, a so-called allergen-gating process has been implemented as a best practice. This process is intended to question and, if desirable or possible, eliminate specific allergenic foods (or ingredients derived from those foods) from a new food product under development. Allergen-gating can take several forms. For example, a food company might question the development of a new product containing a peanut butter component because the manufacturing of that new product might introduce peanut into a manufacturing facility that presently does not include peanuts. In another example, a milk ingredient might be considered as a relatively minor part of a new product formulation. The decision to include the milk ingredient could be questioned and the product might be formulated without the milk ingredient if that change has no impact on product quality. Finally, in a third varia-

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2 Public Law 353, 111th Cong., 2d sess. (January 4, 2011).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

tion of this approach, a food company might decide to harmonize certain ingredients across all products made on shared equipment. For example, if a food company made 30 different cake mixes on shared equipment and 27 of those cake mixes contained milk ingredients, they could decide to add milk to the other three formulations. Consumers have been known to protest harmonization efforts because this decision can eliminate popular food products from the diets of consumers with specific food allergies. Each of these “allergen-gating” decisions would be advantageous to the company because it would avoid additional costs and reduce the complexity of the company’s ACP.

With the enhanced awareness of food allergies among consumers,

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

marketing interest has grown in the development of “free-from” foods. Dairy-free3 and gluten-free products have been marketed for years, but their availability and popularity with consumers has increased greatly recently. Now, some foods are marketed as peanut-free, peanut- and tree nut–free (nut-free), and allergen-free, which typically means the absence of all of the eight most allergenic foods and food groups (milk, egg, peanut, tree nuts, wheat, soybean, fish, and crustacean shellfish).

Of course, producing allergen-free food precludes the need to develop and implement ACPs if done in a facility dedicated to allergen-free food

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3 It should be noted that dairy-free and nondairy foods may contain caseins, the major allergenic proteins in cow milk.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

manufacturing. However, the chief reason for the expanding commercial interest in “free-from” foods is the opportunity to exploit a profitable niche market. In such cases, the involved food companies must exercise extreme vigilance to assure that their suppliers do not have the allergens of interest in any of the ingredients and perhaps even in their facilities. Although some companies do make “free-from” products in facilities where the allergens of interest are also present in other formulations, great care must be taken to assure that no cross-contact occurs under those circumstances.

LABELING OF FOOD ALLERGENS

As described above, the label on a food package is a tool that ideally should alert consumers of the presence of specific allergens so they can make informed decisions about the level of risk they are willing to take. Two types of labeling exist and they serve two distinct purposes: (1) mandatory labeling, used when the allergen is intentionally added as an ingredient; and (2) voluntary labeling, used when the allergen may inadvertently be in the food as a result of cross-contact. Even when ACPs (see Box 7-1) are strictly followed, errors occur that might result in the presence of low levels of the allergen in the formulated food (i.e., residue). This is shown in part by the number of food recalls that are due to undeclared allergens in food products (see Box 7-2). Such unintentional allergens, when the possible cross-contact is predictable, can be identified on the labels of packaged foods using PAL statements, such as “May Contain X.” Although PAL statements on packaged food are voluntary, the FDA has indicated that they should be truthful and not misleading.

The food industry, however, lacks the ability to conduct allergen risk assessments to determine threshold doses and safe levels. As a result of the uncertainties regarding limits necessary to avoid cross-contact as well as unacceptable risks that could result in litigation, PAL statements have proliferated. They are now applied to a wide range of products, including products that likely pose little risk to consumers with a food allergy. Another result of this uncertainty is that the majority of food recalls in the United States are now due to undeclared food allergens (see Box 7-2). Recalls, however, can happen for numerous reasons and are not limited to cross-contact. Important lessons can be learned from product recalls if information is shared about root causes, preventive and corrective actions that are implemented to prevent recurrences, and consumer complaints.

The mandatory ingredient labeling of packaged foods is a government regulatory issue. Despite the fact that PAL is voluntary, its widespread use invites regulatory limitations. If government chooses to move forward, it would have to answer several questions, such as: What allergens should be labeled? What criteria to identify allergens should appear on a label?

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Although the discussion below is centered on the United States, policies in other countries are also described to illustrate the global diversity in the criteria used and lists of major allergens. For the packaged food industry, labeling is a matter of compliance with regulatory requirements, including the variable requirements of different countries. As more allergens are added to the priority lists, the complexity of ACPs increases for the food industry.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Which Allergens Need to Be Labeled?

A Historical Perspective

Many countries have implemented laws, regulations, or standards specifically governing food allergen labeling for a list of priority allergenic foods. The foods on such lists vary around the world due to several factors, including differing eating habits and differing criteria to select the priority allergenic foods (see Table 7-1). Likewise, the regulatory framework for the labeling of allergenic foods differs from country to country (Gendel, 2012), which can affect individuals as they travel between countries.

Increased attention to the labeling of allergenic foods emerged within the Codex Alimentarius Commission (CAC)4 in 1993, when a working paper on food allergens was developed by the Nordic countries. This working paper led to the creation of a Food and Agricultural Organization of the United Nations (FAO) Technical Consultation in 1995 that was charged with developing a list of priority foods that cause food allergies and sensitivities. Ultimately, the priority foods list promulgated by the FAO Technical Consultation was adopted by CAC in 1999 and continues to serve as guidance to all countries (individual countries have the option to adopt this list or to modify the list as they might choose).

Part of the background discussion that occurred within the 1995 FAO Technical Consultation has been reported by Taylor and Baumert (2015). They reported that, in 1995, the amount of published information available to the FAO Technical Consultation concerning the comparative prevalence of allergies to specific foods was limited largely to pediatric populations, with virtually no information on the prevalence of food allergy among adults. Comparative prevalence was the main criterion of the FAO Technical Consultation, although the differential severity of certain allergenic foods also was recognized as a criterion. In 1999, a revised CAC priority was released. As a consequence of data gaps, expert judgment was used, in part, to develop this list. The 1999 CAC priority list included milk, egg, fish, crustacean shellfish, peanut, soybean, tree nuts, cereal grain sources of gluten, and sulfites. Several of these items were added because the FAO Technical Consultation also considered celiac disease, intolerances, and sensitivity reactions in addition to immunoglobulin E (IgE)-mediated food allergies in its deliberations. For example, gluten was included because of its association with celiac disease. Sulfites were added because of the documented severity of sulfite-induced asthma.

Following this, a Task Force of the International Life Sciences Institute-

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4 Codex Alimentarius Commission is an organization formed jointly by the Food and Agricultural Organization (FAO) and the World Health Organization (WHO) to develop food standards and guidelines that would be recognized worldwide.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

TABLE 7-1 Priority Allergenic Food Lists

Food Codex Alimentarius Commission USA European Union Australia/New Zealand Canada Japan
Milk X X X X X X
Egg X X X X X X
Fish X X X X X
Crustacea X X X X X Xa
Tree nutsb X X X X X
Peanut X X X X X X
Wheat X X X X X Xa
Soybean X X X X X
Gluten X X X X
Sesame seed X X X
Molluscs X X
Mustard X X
Celery X
Lupine X
Buckwheat X
Other Xa

a Japan: Shrimp and crab are the only crustacea on the list. Grains include wheat and buckwheat but not other cereal sources of gluten. Other includes foods that are not required, but are on a recommended labeling list include salmon, salmon roe, mackerel, abalone, squid, beef, pork, chicken, soybean, walnut, orange, kiwi, banana, peach, apple, yam, matsutake mushroom, and gelatin.

b See Box 7-3.

SOURCE: Taylor and Baumert, 2015.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Europe (ILSI-EU) conducted a more thorough assessment of foods that warranted placement on a list of priority allergenic foods (Bousquet et al., 1998). The criteria used by the ILSI-EU group included published evidence of severe or fatal anaphylactic reactions. The ILSI-EU Task Force recommended a priority food allergens list that included milk, egg, fish, crustacean shellfish, peanut, soy, tree nuts, wheat, and sesame seed. Other groups within ILSI-EU have continued to develop criteria for the selection of allergenic foods of public health importance and have recently recommended that the criteria should encompass consideration of prevalence, severity and potency5 (Bjorksten et al., 2008; Houben et al., 2016; van Bilsen et al., 2011).

In the United States, the priority list of allergenic foods was established by the Congress with the passage of the Food Allergen Labeling and Consumer Protection Act6,7 (FALCPA) of 2004. The FALCPA list mirrored the 1999 CAC list except that the FALCPA list did not address celiac disease and therefore did not recognize cereal sources of gluten as major allergenic foods.

In the European Union (EU), the first priority list of allergenic foods was established by EC Directive 2003/898 as a result of deliberations within the EU Parliament. The initial EU list included the eight foods or food groups from the CAC list, but also included sesame seed, mustard, and celery.9 In addition to allergenic foods, the EU list also includes cereal sources of gluten and sulfites. Subsequently, the EU priority list of allergenic foods was updated by EC Directive 2007/6810 and included the addition of molluscan shellfish and lupine to the EU list based on the opinion of the European Food Safety Authority (EFSA) Panel Scientific Panel on Dietetic Products, Nutrition, and Allergies (EFSA, 2005, 2006). The decision to include lupine appeared to be based on the recognition that some peanut-allergic individuals will experience allergic reactions on ingestion of lupine due to the presence of cross-reacting allergens in these two legumes.

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5 Prevalence is defined as the percentage of the general population who have a clinically confirmed allergic reaction to a specific food. Severity is defined as the frequency of occurrence of fatal or life-threatening allergic reactions to a specific food. Potency is defined as the minimal eliciting dose or threshold dose needed to provoke objective symptoms among individuals allergic to a specific food.

6 For an analysis on Food Allergen Labeling and Consumer Protection Act see Derr, 2006.

7 Public Law 282, 108th Cong., 2d sess. (August 2, 2004).

8 See http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32003L0089 (accessed July 3, 2016).

9 “Celery” in the EU priority list of food allergens refers to “celery root.” Celery root and celery stalk are marketed as foods derived from different varieties of Apium graveolens. Allergy to celery root is frequent in some European countries but not in the United States.

10 See http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1467581123948&uri=CELEX:32007L0068 (accessed July 3, 2016).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

In Canada, the priority allergen list includes the eight foods and food groups on the 1999 CAC list plus molluscan shellfish, sesame seeds, and mustard. Australia and New Zealand were the first countries to develop a priority list of allergenic foods that includes sesame seeds in addition to the 1999 CAC list.

Japan uses a unique approach, with a short mandatory labeling list and a longer recommended labeling list. The mandatory priority list includes wheat, milk, egg, peanut, buckwheat, and crustacean shellfish. Among the crustacean shellfish, only crab and shrimp are identified on the Japanese list. Japan and Korea are the only countries to include buckwheat on their priority allergen lists. Buckwheat can cause frequent and occasionally severe allergies in countries where buckwheat (soba) noodles are frequently consumed (Akiyama et al., 2011). The recommended priority list in Japan is lengthy, including several molluscan shellfish (abalone, squid), several fish (mackerel, salmon, and salmon roe), several fruits (orange, kiwi, peach, apple, banana), one tree nut (walnut), several meats (pork, chicken, beef), soybean, matsutake mushroom, yam, and gelatin. A survey of Japanese allergy clinics on the causative foods in more than 1,500 cases of food allergy was used as the basis for the priority list in Japan (Ebisawa, 2003).

As previously noted, many countries simply refer to the 1999 CAC list in their food labeling regulations. A few countries (Argentina, Switzerland, Ukraine) have adopted the EU regulatory framework instead (Gendel, 2012).

How Should Foods Be Selected for Priority Allergen Lists?

Initially, the CAC sought expert opinion and attempted to use the available scientific information in establishing the 1999 list of priority allergenic foods. Although the list of eight priority allergenic foods or food groups established by the CAC remains valid in general, the list has not been reviewed since 1999 and it should be reconsidered now and periodically thereafter. As mentioned, scientific and clinical data regarding the prevalence of allergies to specific foods were insufficient. In particular, data were missing on the prevalence of specific food allergies in adults and the variability in the prevalence of specific food allergies between countries. Allergies to some foods that are common in young children are much less prevalent among adults (e.g., milk, egg, wheat, soy) (Boyce et al., 2010) (see Chapter 3). Based on self-report, soybean allergy appears to be relatively frequent among young infants in the United States (Gupta et al., 2011), but they tend to outgrow this allergy within a few years (Savage et al., 2010). A systematic review (Nwaru et al., 2014) showed soy allergy to be generally lower than previously thought in the general population when oral food

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

challenge was used as the method of assesment, but none of the data was collected in the United States (see Chapter 3).

In general, data are lacking on the comparative prevalence of allergies to specific foods among adults. This knowledge gap should be addressed and prevalence data on the overall population also should be considered so that priority allergenic foods for regulatory purposes can be identified.

A logical next question is whether any foods should be added to this global priority list. Certain foods and food groups are considered major allergens in some countries but not others (e.g., sesame seed, molluscan shellfish, mustard, buckwheat, lupine). The decisions about the placement (or removal) of additional allergenic foods on global priority lists should be based on scientific evidence regarding the prevalence, severity, and potency of allergies to those specific foods. Individual countries may have justifiable reasons for expanding this list due to cultural dietary habits but such decisions also should be made on the basis of scientific and clinical evidence. For example, in the United States, the priority list of allergenic foods established by Congress is currently undergoing a legislative review, and the addition of sesame seeds is being considered. This decision should be based on scientific and clinical evidence of the prevalence, severity, and potency of sesame seed allergy compared to allergies to the existing eight foods or food groups. The prevalence of sesame seed allergy in the United States appears to be equivalent to the existing eight priority foods or food groups recognized in the United States among children (Gupta et al., 2013).

Insufficient evidence exists on the prevalence and severity of allergies to other foods on the lists of priority allergenic foods in other countries, including molluscan shellfish, mustard, celery root, and buckwheat, to warrant their addition to the priority list in the United States. However, alterations in consumer eating habits could increase the prevalence of allergies to these or perhaps other foods. So, the list of priority allergenic foods should remain dynamic and subject to change as new data on prevalence and severity might dictate (see Box 7-3).

Ingredient Labeling of Allergens

Ingredient labels on packaged food products are particularly critical to consumers with food allergies who are attempting to follow an allergen avoidance diet. In most countries, the ingredient statement on packaged food products must include the names of all foods (e.g., milk) and ingredients (e.g., caseinate) that are added deliberately and that have a technical or functional effect in the finished food product. However, the allergenic source of the ingredient (e.g., milk) cannot always be readily discerned from its common or usual name appearing on ingredient lists (e.g., caseinate). To help U.S. consumers with this information, FALCPA requires that the

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

source should be clearly indicated if the ingredient was derived from a food on the priority allergenic foods list. Examples include labeling caseinate as “caseinate (milk),” whey as “whey (milk),” gluten as “gluten (usually wheat),” glucose syrup as “glucose syrup (occasionally wheat),” semolina as “semolina (wheat),” and lecithin as “lecithin (often soy).” Similar legislation does not exist in many countries.

Exemptions

Flavors, spices, or processing aid Artificial or natural flavors, spices, colors, or processing aids (i.e., minor ingredients that have no technical or

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

functional effect in the finished product) are often exempt from labeling requirements, which could affect consumers with food allergies. Flavors can occasionally contain allergenic proteins, although at a rather low level, so they have caused only a few documented episodes (Taylor and Dormedy, 1998). Spices are not commonly allergenic, with possible exception of mustard and sesame seed. In addition, some colors, such as carmine and annatto, contain proteins that have caused allergic reactions (Lucas et al., 2001). In the United States, certain ingredients can be grouped as “spices,” “flavors,” “natural flavors,” “artificial flavors,” and “artificial colors.” In the United States, to circumvent the possibility of a hidden allergen in such ingredients, the priority allergenic foods must be declared if they are contained in flavors, spices, colors, or processing aids.

Ingredients with low levels of allergenic protein Ingredients derived from allergenic sources contain widely different levels of allergenic protein (Taylor and Hefle, 2000). Some ingredients, such as casein, whey, and gluten, contain substantial amounts of specific allergenic proteins from the allergenic source. In contrast, a few examples of ingredients, such as fish gelatin, contain substantial protein from the allergenic source but the protein fraction in the ingredient does not include much of the major allergen from the source (Koppelman et al., 2012). Other ingredients from priority allergenic sources contain low to moderate levels of protein. Food-grade lactose may contain as much as 1 percent milk protein, although the amount of protein in lactose will depend upon the method of manufacture of this ingredient. Lactose with 1 percent milk protein likely has sufficient milk allergens to provoke allergic reactions, so its clear identification as a milk-derived ingredient on food labels is prudent. However, some ingredients from priority allergenic sources contain no detectable protein or very low levels of detectable proteins. Examples include highly refined oils from soybeans and peanuts, soy lecithin, wheat starch, and several milk-derived flavors (butter oil, butter ester, butter acid, starter distillate).

Due to this variation in levels of allergen content, in a few countries, selected ingredients are exempted from source labeling. In the United States, highly refined oils were exempted by Congress when it passed FALCPA. Congress also established a regulatory process under FALCPA where food ingredient manufacturers could petition for source labeling exemptions. Under that process, only one successful petition to the FDA has occurred for a source labeling exemption and that was for the use of specific soy lecithin ingredients when used as a processing aid as a stick-release agent in bakeries.

In the EU, the initial directive provided a means for companies to petition for source labeling exemptions for specific ingredients derived from the priority allergens. In this process, petitions were evaluated by the EFSA

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Panel of Dietetic Products, Nutrition and Allergies and several ingredients were exempted from source labeling requirements but often only for specific purposes (see Box 7-4). Although the EU appears to have the highest number of source labeling exemptions, it does not appear to have established a permanent process to seek further exemptions in a manner similar to the United States.

Australia and New Zealand have considered the necessity of labeling the fish origin of isinglass, an ingredient used in the clarification of alcoholic beverages, including wines. Isinglass, which is comprised of collagen derived from fish swim bladders, contains little detectable parvalbumin, the major fish allergen and is exempt from source labeling in the EU (Weber et al., 2009). Currently, Australia and New Zealand are also not requiring the declaration of isinglass or its fish origin on labels of alcoholic beverages. Very recently, Food Standards Australia and New Zealand exempted the source labeling of fully refined soybean oil, glucose syrup from wheat, tocopherols (including vitamin E), and phytosterols from soybeans, and distilled alcohol11 from wheat or whey (Food Standards Australia New Zealand, 2015).

Voluntary Precautionary Allergen Labeling

The existing regulations in most countries focus on intentionally added ingredients as described above. However, greater public health concerns exist regarding the potential that residues of allergenic foods may occur inadvertenly as the result of cross-contact due to common food industry practices such as the use of shared equipment. Such practices can result in the presence of detectable levels of allergen residues in various foods. As mentioned above, to avoid risks due to cross-contact contamination of food allergens, the food industry has made a concerted effort by implementing voluntary ACPs (see Box 7-1) in their manufacturing processes. For the most part, these plans rely on segregation and cleaning procedures to remove allergens, but errors do occur occasionally. In addition, for products regulated by the FDA, preventive control plans were not required until FSMA rules were final in 2015 and therefore ACPs were not developed across all food manufacturing companies.

Therefore, even with strict allergen control plans, it is not possible to ensure that a product will be free of allergens (unless the product is designed to be allergen-free). One approach to inform consumers about the risk of food allergens in a food product is through the use of an advisory label on

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11 Alcoholic beverages in the United States are mostly regulated by TTB (Tax & Trade Bureau), and allergen labeling is not clearly mandated. TTB does generally follow the FDA approaches but is not required to do so. Isinglass is not typically labeled in the United States.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

the packages. Increasingly, food companies in many countries are providing consumers with voluntary PAL statements to alert them to products that are at risk of inadvertent allergen contamination. PAL is not required in any country; instead, many countries (United States, EU-member nations,

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Canada, Australia, and New Zealand) have allowed its voluntary use on packaged foods and, if a company decides to display PAL, some countries do mandate certain forms of PAL. Partly because it is not regulated, different forms of PAL are employed by various food companies worldwide (Taylor and Baumert, 2010). For example, Canada uses “may contain X,” while the United Kingdom uses “not suitable for X allergy sufferers.” In the United States, which has no standard form for PAL, three formats predominate: (a) “may contain X,” (b) “manufactured on shared equipment with X” and (c) “manufactured in shared facility with X,” (Hefle et al., 2007; Pieretti et al., 2009).

Many problems are acknowledged with the current voluntary PAL approach (Allen et al., 2014b; DunnGalvin et al., 2015). First, food companies do not have the capability to determine which allergen levels in foods might be hazardous and, therefore, PAL, as currently implemented, does not correlate with risk. This is shown by analytical surveys of products both with and without PAL indicating that many products having PAL do not contain detectable allergen levels while some products without PAL do contain detectable allergen levels (Crotty and Taylor, 2010; Ford et al., 2010; Hefle et al., 2007; Pele et al., 2007; Remington et al., 2013a, 2015; Robertson et al., 2013; Zurzolo et al., 2013). Thus, evidence suggests that food companies are both overusing and underusing PAL (DunnGalvin et al., 2015). Second, various stakeholders, including consumers, food industry management professionals, health care professionals, psychologists, food industry auditors, analysts, and regulatory professionals, agree that PAL has lost its credibility due to its inconsistent application and lack of association with actual risk (DunnGalvin et al., 2015). Stakeholders agree that PAL should bear a relationship to actual risk and that the decision-making criteria for application of such labeling should be transparent to all stakeholders (DunnGalvin et al., 2015). Additionally, if PAL is applied in some risk-based coordinated manner, then some mechanism should be provided on the food label to indicate that the food has been evaluated for PAL but that no PAL statement is needed. Otherwise, consumers with a food allergy will never know whether the packaged food lacks a PAL statement because it does not need one or because the food manufacturing company did not apply the risk assessment process.

A NEW PARADIGM:
AVOIDING FOOD ALLERGENS AT LEVELS THAT PRESENT RISKS

Avoiding Allergens Is Important

There is no question that avoidance diets remain essential to prevent adverse reactions among individuals with a food allergy (de Silva et al.,

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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2014; Sampson et al., 2014). However, as Chapter 6 reflects, there are special situations where, under medical consultation, non-strict allergen avoidance is also an option. Whether an individual needs to avoid the food strictly or not, foods that pose a meaningful risk to those with food allergies should be adequately labeled. As already explained in Chapters 1 and 6, consumers are not adequately informed about food allergies in general and about the risks of packaged foods in particular. Partly because of the absence of a labeling approach that informs about food allergy risks, all individuals with food allergy are given the same advice, namely that they should completely avoid the offending food(s). This situation has consequences for the food industry (e.g., foods that are made in shared facilities that pose almost no risk to consumers with a food allergy still carry a PAL) and for individuals with food allergy (e.g., some individuals who are currently following a strict avoidance diet could in reality safely ingest low levels of the allergen). However, a more meaningful, evidence-based approach is possible. In reality, individuals with one or more food allergies should avoid only the specific food(s) that have allergen levels sufficient to trigger their conditions. A risk assessment approach would lead to a decrease in the occurrence of allergic reactions while maximizing the quality of life of individuals with a food allergy.

However, Low Doses of Allergenic Foods May Not Always Pose a Problem

The first evidence that individuals with food allergy could safely be exposed to low doses of allergens perhaps occurred with the development of hypoallergenic infant formulas for infants with milk allergy. With some exceptions, oral food challenges (OFCs) with hypoallergenic infant formulas derived from cow milk in infants with cow milk allergy do not generally lead to adverse reactions to the formula under study (AAP, 2000). Similar findings were published for highly refined peanut oil (Hourihane et al., 1997b) and codfish oil (Hansen et al., 2004). Evidence now clearly demonstrates that individuals with a food allergy have threshold doses below which they will not experience adverse reactions (Buchanan et al., 2007; Hourihane et al., 1997a; Jones et al., 2009; Taylor et al., 2010). It also is known that considerable individual variability occurs in the minimal amounts of the offending food that are needed to provoke allergic reactions, ranging from 0.1 mg up to as much as 10 g for peanut (Taylor et al., 2010).

Furthermore, the dose of the food allergen directly affects the likelihood and the severity of an allergic reaction. Different individuals with the same food allergy (e.g., peanut) have different minimal reactive doses (known as threshold doses) for the allergenic food (Bindslev-Jensen et al., 2002; Taylor et al., 2009). However, no evidence indicates that sensitiv-

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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ity and severity are related, that is, the most sensitive individuals are not always the ones who experience more frequent severe reactions. In fact, small (sometimes very small) doses have a lesser impact. For cow milk and egg, low milligram (mg) doses can provoke severe reactions in some children with allergy but the percentage of children experiencing severe reactions increases as the challenge dose increases (Rolinck-Werninghaus et al., 2012). The dose-severity relationship may vary among allergenic foods, as wheat and soy challenges are unlikely to provoke severe reactions at initial low challenge doses (Rolinck-Werninghaus et al., 2012).

A NEW APPROACH TO CREATING A SAFE ENVIRONMENT: THE RISK ASSESSMENT CONCEPT

Risk analysis is the overall process for controlling situations in which an organism, system, or given population could be exposed to a hazard. The risk analysis process has three components: risk assessment, risk management, and risk communication (IPCS, 2004). Risk assessment, developed by the National Research Council (NRC, 1980), is the process that serves to estimate the risk to a given target organism, system, or population, including the identification of attendant uncertainties following exposure to a particular agent. Risk assessment also takes into account the inherent characteristics of the agent of concern as well as the characteristics of the specific target (e.g., a given population) (IPCS, 2004). For allergenic foods, risk assessment would estimate the level of risk to a population of individuals with a specific food allergy based on exposure to that food and would allow risk managers throughout the food chain, including public health authorities, to define an acceptable levels of risk (e.g., that 1 percent of individuals with food allergy will have mild reactions). If the risk needs to be mitigated (i.e., when the risk is higher than an established acceptable level of risk), appropriate interventions will follow (i.e., risk management), together with communication of that risk to affected individuals (i.e., risk communication).

Public health authorities have generally applied the risk assessment concept to determine the public health risk from chemical or microbiological contaminants on a population basis (e.g., aflatoxin levels in oilseeds and grains; arsenic levels in infant rice cereals; mercury levels in seafoods). The FDA has used risk assessment principles of increasing sophistication for many years. Although the appropriateness of using these concepts in the setting of allergenic foods was questionable in the past, improved understanding of the mechanism for allergic reactions to food, together with emerging data from individuals with food allergy has led to the realization that the classical principles, terminology, and methodologies of chemical toxicology risk assessment can be applied to food allergens. A common,

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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in-depth understanding of the risk assessment terminology and concept is essential to achieve consensus about conducting the assessment itself and to define and implement risk management approaches (e.g., labeling) and risk communication approaches.

Risk assessment incorporates a number of features, which are defined in Box 7-5, and encompasses four steps: hazard identification, hazard characterization, exposure assessment, and risk characterization, which are defined in Box 7-6.

Application of Risk Assessment to Allergenic Foods

As noted, the risk assessment process can be applied to allergenic foods. Although its general features are similar to those used for chemical hazards, a few unique differences exist and are highlighted in this section. Further details about the data inputs, their characteristics and limitations can be found in the Annex to this chapter.

Hazard Identification

The allergen (hazard) is identified through case reports of adverse reactions in humans and can be confirmed with clinical diagnosis (e.g., with clinical OFCs or food-specific IgE antibodies in the serum or tissues of affected individuals). Unlike the risk assessment process for chemicals, typical experimental animals do not serve as good predictive models for identifying food allergens to humans (Kimber et al., 2003). Hazard identification also may include data on the prevalence and severity of the reactions. However, numerous foods, such as peanut, cow milk, and egg, are already widely recognized as allergenic foods based on prevalence (Gendel, 2012). Several foods, notably peanut and tree nuts, are recognized as frequent causative factors of severe allergic reactions in children and adults (Bock et al., 2007). Hazard identification can include a demonstration that residues of that allergenic food are present in some food product, especially for allergenic foods known to be more prevalent and/or severe than other foods. If the allergenic food residues are not declared on the label of a packaged food, then the potential hazard is particularly acute. Thus, for packaged foods, an undeclared allergenic food is considered the identified hazard.

Hazard Characterization

In the hazard characterization step of food allergy, safe levels of exposure (Reference Doses estimated as protein from the allergenic food) can be derived from OFC data. Oral food challenges have been used in the clinical practice of food allergy for several decades as a diagnosis method

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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(see also Chapter 4). In addition to their use in diagnosis, low-dose OFCs are becoming more widely used to identify the most sensitive individuals and to identify the starting dose for oral immunotherapy trials. The more widespread use of low-dose OFCs in clinical practice has confirmed the fact that individuals with food allergy have a threshold dose below which they ordinarily will not experience an adverse reaction upon ingesting the allergenic food (Hourihane et al., 1997a; Taylor et al., 2002). Thus, food

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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challenge trials in clinical settings provide human data that can be used for risk assessment purposes, specifically to establish adverse effects associated with specific levels of allergenic foods and to derive Reference Doses (Taylor et al., 2014). Although for each individual, the response is likely related to the dose of exposure, the full spectrum of adverse responses over a range of doses cannot be determined due to the ethical concerns about administering high doses. However, unlike for other hazards, the individual minimal eliciting dose (MED) for sensitive individuals or lowest-observed-adverse-effect level (LOAEL) can be determined. In addition, the individual threshold, or no-observed-adverse-effect level (NOAEL) can be determined with OFCs. Determining the true threshold dose for an individual has some caveats. First, as noted in Chapter 6 and in the Annex to this chapter, multiple factors can influence the threshold dose for individuals with food allergy. Although evidence indicates that concurrent viral infections, exercise, and consumption of alcohol affect an individual’s threshold dose (Crevel et al., 2014), additional factors could contribute to the variation. Researchers and clinicians should take these factors into account by performning OFCs to determine thresholds in controlled settings and counseling patients on exacerbating factors. Second, because OFCs are conducted using interval (versus continuous) dosing of the food, the true threshold dose cannot be exactly determined but lies somewhere between the NOAEL and the LOAEL for that individual. For example, if the first objective response occurs at 100 mg but no response occurs at the prior dose of 10 mg, then for that individual the NOAEL is 10 mg and the LOAEL is 100 mg. However, the patient’s true threshold dose is somewhere between 10 and 100 mg. Taylor et al. pioneered the use of interval censoring survival analysis (ICSA) in the dose-distribution modeling of OFC data (Taylor et al., 2009). ICSA assigns individual thresholds to an interval range rather than a fixed value by assigning equal probability to the likelihood that the true threshold dose could lie anywhere along that continuum. ICSA allows the use of first-dose reactors (i.e., their true threshold dose is between zero and the first dose administered in the challenge trial) and those individuals who fail to react to any of the challenge doses (i.e., they have a true threshold dose between the highest dose administered in the trial and infinity) in the dose-distribution analysis. Questions still remain among stakeholders about the extent of individual variability despite the lack of evidence supporting it. Still, in performing the risk assessment, regulators need to take into account that an individual’s threshold may be lower depending on various factors, such as use of alcohol, use of nonsteroidal anti-inflammatory drugs, or exercising.

The NOAELs also can be estimated on a population basis, as the largest amount of the allergenic food that will not result in an allergic reaction when tested experimentally in a defined population individuals with a food

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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allergy. With probabilistic modeling, the degree of risk posed by a specific dose of the allergenic food can be predicted based on the distribution of individual threshold doses. In this manner, although zero risk cannot be predicted, acceptable risk levels can be defined by choosing a Reference Dose (see the following discussion).

Although the data demonstrate the usability of clinical OFCs to estimate Reference Doses for food allergens, methodological considerations, potential biases, and uncertainty factors should be recognized and are described in the Annex.

Determining population thresholds for a risk assessment: Dose distribution and probabilistic modeling The use of probabilistic modeling12 in risk assessment of food allergens requires the use of individual NOAELs and LOAELs.

Increasing amounts of quality NOAEL and LOAEL data from clinical low-dose OFCs from a number of different allergenic foods continue to become available (Ballmer-Weber et al., 2015; Blom et al., 2013; Dano et al., 2015). Taylor et al. provide a summary of the data available in 2014 (Taylor et al., 2014).

When estimating the population-based NOAEL, defining the population of study is a key aspect because the dose distribution will vary according to the population definition and characteristics. For example, the dose distribution (and the NOAEL) could be affected if patients with a history of severe reactions are excluded from OFC studies, as happens in some clinics. However, findings from one study suggest that the predicted eliciting dose (ED) is similar for individuals with severe reactions and for those with less severe reactions (Taylor et al., 2010) (see the Annex to this chapter).

From the published clinical literature, individual LOAEL data can be found from three different types of studies: diagnostic series, threshold studies, and immunotherapy trials (Allen et al., 2014a; Clark et al., 2009; Skripak et al., 2008; Taylor et al., 2009). Published studies often report only the LOAEL but they also report the dosage progression scheme so that the NOAEL can be discerned as well (Taylor et al., 2009). With fewer individuals, more uncertainty exists in population threshold estimates. The greatest improvement in the accuracy of the estimates is achieved by increasing the number of individuals from 20 up to 60 (Klein Entink et al., 2014). A large quantity of data (>200 patients) are available for peanut, milk, egg, and hazelnut (Klein Entink et al., 2014). Data are less available but still sufficient to support probabilistic modeling approaches for shrimp (crustacean shellfish), fish, soybean, wheat, cashew, walnut, sesame seed,

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12 Probabalistic modeling is a statistical analysis tool that estimates, on the basis of past (historical) data, the probability of an event occurring again.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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lupine, celery root, and mustard (Ballmer-Weber et al., 2015; Blom et al., 2013; Dano et al., 2015; Taylor et al., 2014). The range of individual NOAELs and LOAELs for individuals with a food allergy can be quite broad. For example, in the examination of individual thresholds among 450 individuals with a peanut allergy, the range of individual LOAELs spanned five orders of magnitude from 0.1 mg up to 2.5 g of peanut protein or 0.4 mg to 10 g of whole peanut (Taylor et al., 2010).

Probabilistic risk assessment (see Figure 7-2) has been performed with the log-normal, log-logistic and Weibull modeling approaches, as are commonly used in other risk assessments. No biological reason exists to favor one of these models over another. Figure 7-3 presents the three probabilistic approaches to the dose–response for peanut. The probabilistic models allow the derivation of an ED, where EDp refers to the dose of total protein from the allergenic food that is predicted to produce an objective response in

Image
FIGURE 7-2 Figure prepresenting the concept of probabilistic risk assessment. The area in green represents those individuals who would react because their intake is above the Reference Dose.
SOURCE: Spanjersberg et al., 2007. Reprinted with permission from Elsevier.
Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×
Image
FIGURE 7-3 Dose distribution modeling of peanut protein minimum eliciting doses using log-normal, log-logistic, and Weibull probabilistic models.
SOURCE: Taylor et al., 2014. Reprinted with permission from Elsevier.

p percent of the allergic population (Crevel et al., 2007). However, these approaches do not identify a dose below which no allergic individual would react (zero risk). The ED estimate can be used to describe the population threshold or establish Reference Doses; the value of p, however, defines the acceptable risk, which is a risk management decision. These statistical models also allow estimation of the 95 percent confidence intervals (CIs) around any EDp value. The lower 95 percent CI also could be selected as a population threshold or Reference Dose as another risk management choice.

Exposure Assessment

Risk is a function of hazard and exposure to the hazard. Thus, exposure assessment is another component of the overall risk assessment. Because allergenic foods are required to carry labels whenever they are used as intentional ingredients, the risk to the consumer is only actually imposed from exposure to any unintended presence of allergens (e.g., contamination due to cross-contact). Exposure assessment has two components: the level of contamination in the food (concentration and frequency) and the intake (amount and frequency) of the particular food. These two components of

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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contamination and intake can be used as inputs in quantitative risk assessment to generate an allergen intake distribution. Because the threshold dose distribution is given in terms of doses of protein from the allergenic food, the intake distribution also should be calculated in terms of protein from the allergenic food. The challenges and considerations in collecting data to develop an accurate exposure assessment, including validated methods of detection in food and lack of intake data for consumers with food allergies are described in the Annex.

Risk Characterization

Risk characterization involves combining the hazard assessment and exposure assessment approaches to determine the level of risk posed to consumers with food allergy using selected scenarios. Risk characterization involves three key input distributions: the dose-distribution of individual threshold doses, the intake distribution, and the contamination distribution. Highlighted below are two approaches to conduct a risk characterization: examining the individual threshold dose-distribution to arrive at acceptable Reference Doses or using probabilistic modeling.

Using the individual threshold dose-distribution A comparatively simple strategy can be used by examining the individual threshold dose distribution to arrive at acceptable Reference Doses. For example, the dose calculated to elicit an allergic reaction in p percent of allergic individuals (EDp) can be selected as the Reference Dose. If more caution is desirable, the dose can be selected to be at the 95 percent lower CI of the EDp. The selection of the appropriate EDp value is a risk management decision. Establishing acceptable Reference Doses (or action levels) is a simple approach to risk characterization. Action levels can easily be calculated by the following formula:

[EDp (in mg) / intake (in kg)] = action level (in mg/kg or ppm)]

If a contamination level is found to be above the action level, then an appropriate action would be taken. For example, a precautionary label would be placed on the product or a product recall would be initiated if the product is already in the market with an undeclared allergen.

When elaborating action levels using this combination of a chosen food intake level and an EDp value, the choice of the intake level is critical. Crevel et al. provide an example of bread consumption (Crevel et al., 2014). For this example, Crevel et al. assume that the EDp has been selected as the ED1, that peanut is the allergenic food of concern, and that the Reference Dose is 0.2 mg peanut protein, based on the individual threshold dose

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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distribution (Taylor et al., 2014). The portion size for the single serving of sliced brown wheat bread is given as 35 g but the mean consumption per meal is 140 g (4 slices) and the 95 percent intake level is 210 g (6 slices). In calculating the action level using the single serving size, then the action level would be 5.7 ppm (parts per million) peanut protein. However, if the mean meal intake level was used, the action level would be 1.4 ppm peanut protein. If the 95 percent intake level of 210 g was used, the action level would be 1.0 ppm peanut protein. The selection of the appropriate consumption level complicates the use of this simplistic risk assessment approach. An underestimate of consumption amount results in selection of a higher action level and carries an associated higher level of risk. Action levels allow risk characterization to be conducted in a very straightforward manner that allows a definitive risk management decision.

Probabilistic modeling Risk characterization also can be conducted in a more complex manner using probabilistic modeling as depicted in Figure 7-2 (Crevel et al., 2014; Spanjersberg et al., 2007). In this approach, in addition to data inputs for allergen thresholds, the consumption patterns and allergen contamination test results can be fitted to statistical distributions for use in a Monte Carlo simulation.13 The allergen intake distribution of a particular product can be determined based on the allergen distribution in the product (based on analytical testing) and the consumption distribution (based on surveys). The results can predict objective allergic reactions in an estimated fraction of the population with food allergy. The frequency of consumption of a particular type of food can be further incorporated into the model to obtain an estimate of the allergic population’s risk. The prevalence of the specific food allergy within the general population can additionally be incorporated into the model to obtain an estimate of the overall population risk. This probabilistic modeling approach is generally considered to be the most thorough way to characterize allergic risks (Kruizinga et al., 2008; Madsen et al., 2009; Spanjersberg et al., 2007, 2010). Quantitative probabilistic risk assessment has been applied to characterize the allergic risks in several practical examples (Remington et al., 2013a,b, 2015; Robertson et al., 2013; Spanjersberg et al., 2007, 2010).

Probabilistic modeling inherently accounts for some of the uncertainties associated with the input variables and reflects those in the probability distribution for the output (Crevel et al., 2014). However, probabilistic modeling does not account for factors, such as systematic bias in the selection of the challenge population, unless these systematic factors can be quantified.

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13 In a Monte Carlo simulation, the program repeatedly samples the three input distributions, picking a value from each at random and building a distribution representing the probability of an allergic reaction given the values and distributions of the specified variables.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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DEVELOPING POPULATION THRESHOLDS: MOVING FORWARD

Bindslev-Jensen et al. were the first to attempt the use of dose-distribution modeling for allergenic foods (Bindslev-Bindslev-Jensen et al., 2002). The authors used data on four commonly allergenic foods using individual threshold doses from the peer-reviewed clinical literature to merely illustrate their model. Crevel et al. expanded upon the value of statistical dose-distribution modeling to estimate population thresholds for allergenic foods and also pointed out the data limitations to use of that approach (Crevel et al., 2007). In 2006, the FDA, through an ad hoc internal Threshold Working Group (TWG), evaluated various approaches to establishing population thresholds for allergenic foods and produced a report with recommendations (Gendel et al., 2008). The TWG recommended the use of statistical dose-distribution modeling as the preferred ideal approach for establishing this threshold. As mentioned, the use of statistical dose-distribution modeling relies upon the availability of sufficient quantities of food challenge data from low-dose clinical OFC studies. The TWG concluded that insufficient data existed to use this preferred approach. Gendel et al. cited several concerns with the data that existed before 2005: (1) the general paucity of data on low-dose challenges for many allergenic foods; (2) the representativeness of the populations of individuals with food allergy in those studies; (3) potential exclusion of individuals with histories of severe reactions; and (4) lack of comparative data to establish the optimal parametric dose-distribution relationship to use for modeling purposes (Gendel et al., 2008). The following section describes the progress made over the ensuing 10 years to address those concerns.

Do Sufficient Data Exist?

Since 2005, numerous low-dose challenge studies have been performed by multiple clinical investigators so that extensive data now exist for modeling purposes (Taylor et al., 2014; Zhu et al., 2015). Table 1 in Taylor et al. provides a list of the number of data points for each of the priority allergenic foods used to establish Reference Doses as of 2014 (Taylor et al., 2014). More individual threshold data points exist for peanut, milk, egg, and hazelnut than for other allergenic foods. Using statistical analysis, Klein Entink et al. determined that the largest gain in reliability of population threshold estimates occurs as the number of data points increases from N=20 to N=60 (Klein Entink et al., 2014). However, population threshold estimates can be made from small numbers of subjects provided that the statistical confidence intervals are included (Taylor et al., 2014). Appropriately, the FDA TWG recommended that population threshold estimates should be adjusted as more individual threshold data are acquired (Gendel et al., 2008).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Do Subjects with Histories of Severe Reactions Have Lower Thresholds?

Several studies have demonstrated that no relationship exists between reaction severity by challenge or history and threshold dose (Blumchen et al., 2014; Eller et al., 2012; Taylor et al., 2010; Turner et al., 2016; Zhu et al., 2015). Symptom severity increases, however, with increasing challenge doses for milk and egg (Rolinck-Werninghaus et al., 2012). Several studies have documented that severe reactions occur on the initial challenge dose (Perry et al., 2004; Sicherer et al., 2000) but these observations stem from challenges that were initiated at doses above 100 mg of the allergenic foods (much higher than the low doses now used in low-dose OFCs). A recent single-dose study administering the predicted log-normal ED05 dose of peanut to 375 unselected peanut-allergic individuals documented that 8 of 375 subjects (2.1%) experienced objective responses to this dose and that none experienced severe reactions (Hourihane et al., In press). Although peanut is recognized among the allergenic foods as most likely to provoke severe reactions (Blumchen et al., 2014; Zhu et al., 2015), the ED05 dose of peanut (6 mg whole peanut or 1.5 mg peanut protein) is unlikely to provoke severe reactions (Hourihane et al., In press).

Do Sufficient Data Exist from a Wide and Varied Enough Population?

Although most low-dose challenge studies have been conducted in Europe, the United States, or Australia, evidence suggests that thresholds do not differ on the basis of age or geography (Allen et al., 2014a). Patient selection bias can affect threshold distributions (Allen et al., 2014a), but the comparisons show that patients involved in immunotherapy trials tend to be more highly sensitive, which favors the establishment of conservative population thresholds. Differences in dosing ranges can affect threshold distributions (Allen et al., 2014a) but these effects can be lessened by normalizing the data on the basis of protein content (Taylor et al., 2009) and focusing on data from low-dose studies with initial doses in the low mg range.

How Much Inter-Individual Variability in Thresholds Exists?

The persistence of individual threshold doses has not been thoroughly investigated. However, it is well known that infants and children with milk, egg, soy, and wheat allergies will frequently outgrow their condition (Keet et al., 2009; Savage et al., 2007, 2010; Skripak et al., 2007). Presumably their individual threshold doses increase over time until tolerance is achieved although this has not been specifically investigated. Peanut allergy is more persistent, although about 20 percent of peanut-allergic individu-

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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als also outgrow their condition (Skolnick et al., 2001). Individual peanut thresholds were found to be relatively stable over a period of years and multiple OFCs with the exception of 6 percent of patients whose peanut allergy resolved (Crevel et al., 2010). Little scientific evidence exists to suggest that individuals become more sensitive over time, although this is a point of frequent conjecture.

Which Statistical Models Are Optimal for Estimating Population Thresholds?

As mentioned above, several parametric models (log-normal, log-logistic, and Weibull) have been compared (Taylor et al., 2009, 2014). For peanut, the Weibull model offers the most conservative predicted population threshold (Taylor et al., 2014), but recent data suggest that the log-normal and log-logistic models are optimal (Hourihane et al., In press). In this study, the predicted log-normal ED05 dose for peanut was administered as a single dose to 375 unselected peanut-allergic individuals. Only 2.1 percent of these individuals experienced objective reactions (none severe) indicating that even the log-normal prediction was overly conservative and indicating that the extra conservatism predicted by the Weibull model is unnecessary (Hourihane et al., In press).

With the generation of additional clinical data on individual threshold doses from low-dose clinical challenges, the feasibility of statistical dose-distribution modeling has improved. Following on from this, other groups in Europe (Crevel et al., 2014; Madsen et al., 2009) and Australia (Taylor et al., 2014) also have recommended the use of statistical dose-distribution modeling as the ideal approach to estimating population thresholds for various allergenic foods.

The VITAL Program

The Allergen Bureau of Australia and New Zealand (an industry consortium) has recommended establishing Reference Doses based on statistical dose-distribution modeling and the use of the Reference Doses to support their VITAL® (Voluntary Incidental Trace Allergen Labeling) program. VITAL is a voluntary program aimed at the food industry that aims to provide a scientific basis for precautionary labeling decisions. The Allergen Bureau has established an entire risk management program using these Reference Doses as the basis.14

The Allergen Bureau of Australia and New Zealand established an

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14 The VITAL program can be found at http://allergenbureau.net/vital (accessed July 8, 2016).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

expert panel to examine existing individual threshold dose distributions and apply statistical modeling approaches (log-normal, log-logistic, and Weibull) to those distributions. The expert panel recommended using ED1 estimates for peanut, milk, egg, and hazelnut because sufficient data (from >200 individuals) were available. The panel selected the 95 percent lower CI of the ED5 for other foods when data from fewer individuals were available (Taylor et al., 2014). Subsequently, the Task Force on Thresholds to Action Levels of the ILSI-EU endorsed the same EDp levels and the same Reference Doses (Crevel et al., 2014). The Reference Doses for 11 allergenic foods taken from priority lists in Australia and New Zealand and the EU are provided in Table 7-2. Attempts were made to examine individual threshold dose distributions for celery and fish as well, but the existing data did not fit any of the probabilistic models. The Allergen Bureau did establish a Reference Dose for fish but it was not established on the basis of the existing clinical evidence. The EDp value used by the Allergen Bureau is rather conservative by comparison to the approaches used to define hypoallergenic infant formula (the ED10) and similar to EDp values used for chemical toxicants. As subsequent data become available from low-dose clinical food challenges and single-dose validation studies, the selection of the optimal EDp value should be re-examined.

Although this risk assessment approach has achieved acknowledgement from expert groups in the United States, European Union, and Australia and New Zealand (Crevel et al., 2014; Taylor et al., 2014), its adoption by governmental public health agencies remains unfulfilled as it has not been incorporated into public health policy regulation.

Now that statistical dose-distribution modeling for the hazard characterization step of the risk assessment process is available, it can be integrated with exposure assessment inputs to make risk characterization feasible. The first demonstrations of the use of this approach came from the Netherlands Organization for Applied Scientific Research (Kruizinga et al., 2008; Spanjersberg et al., 2007, 2010). This approach was later adopted and used by groups in France (Rimbaud et al., 2010), the United States (Remington et al., 2013a,b), and Ireland (Robertson et al., 2013). Improvements on the risk assessment approach for allergenic foods continue to be developed, together with the recognition that this approach provides the best way to quantitatively assess the magnitude of the risk of any given scenario to appropriate segments of the populationwith food allergies.

OVERALL CONCLUSIONS

The labeling of allergenic packaged foods is an important public health measure assisting consumers with a food allergy to avoid potentially aller-

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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TABLE 7-2 Reference Doses Established by Allergen Bureau of Australia and New Zealanda

Allergen N with Objective Symptoms Right Censoredb Left Censoredc Population Basis of RD RD (mg total protein)
Peanut 750 132 30 Children and Adults ED01 0.2 mg
Milk 351 19 59 Children and Adults ED01 0.1 mg
Egg 206 33 24 Children and Adults ED01 0.03 mg
Hazelnut 202 67 4 Children and Adults ED01 0.1 mg
Soybean 80 28 6 Children and Adults LCI ED05 1.0 mg
Wheat 40 1 5 Children and Adults LCI ED05 1.0 mg
Cashew 31 16 1 Children Hazelnut 0.1 mg
Mustard 33 10 2 Children and Adults LCI ED05 0.05 mg
Lupin 24 7 2 Children and Adults LCI ED05 4.0 mg
Sesame 21 1 2 Children and Adults LCI ED05 0.2 mg
Shrimp 48 26 0 Adults LCI ED05 10 mg
Celery 39 4 15 Children and Adults NR
Fish 19 2 6 Children and Adults LCI ED05 0.1 mg (provisional)

NOTE: ED = eliciting dose, LCI = lower confidence interval, LOAEL = lowest-observed-adverse-effect level, mg =milligram, NOAEL = no-observed-adverse-effect level, NR = no recommendation, RD = Reference Dose.

a The Allergen Bureau of Australia and New Zealand adopted the RD recommendations of the VITAL Scientific Expert Panel (Taylor et al., 2014) except for cashew, fish, and celery. For cashew, due to lack of clinical data on adults, the RD dose was based on that of hazelnut. Fish had insufficient clinical data and, therefore, an arbitrary RD was selected. Likewise, celery had insufficient clinical data; however, celery is not included in the food allergen priority list of Australia and New Zealand, and therefore, a recommendation for celery was not needed.

b Number of right-censored subjects (NOAEL = highest challenge dose; LOAEL set to infinity).

c Number of left-censored subjects (NOAEL set at zero; LOAEL = lowest challenge dose).

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

genic foods. The current precautionary labeling system for allergenic foods is not effective in informing consumers about the risks from food allergens in the food for various reasons.

First, although all proteins can be allergenic, it is critical for public health authorities to select the list of major allergens to be included in food packaging labels. Although a panel of experts recommended prevalence, potency, and severity as criteria to select the major allergens (Houben et al., 2016; van Bilsen et al., 2011), the 1999 CAC list, which forms the basis for priority lists of allergens in different countries, was developed when data on the prevalence, potency, and severity for most allergenic foods were just beginning to emerge. Since then, various countries have added other allergenic foods based on a variety of reasons, including their regional diets and other criteria. Consequently, although the eight basic major allergenic foods are common in the priority lists of all countries, the lists also have substantial differences. The committee concludes that prevalence, severity, and potency should be used as scientific criteria for addition of foods to the U.S. priority list in the future. Methods for collecting data on prevalence and severity are outlined in Chapter 3. The probabilistic modeling of individual threshold dose-distributions is advocated as an approach to measure allergenic potency. At the same time, the committee recognizes that such an approach will be difficult in the case of novel foods due to the absence of data to support the criteria, potency in particular.

Second, the PAL system for warning consumers about the presence of low levels of allergens in food is not effective. Initially, preventive approaches related to packaged foods centered on mandatory labeling of intentionally added allergenic foods or ingredients. However, potential risks associated with unintentional residues of allergenic foods also exist. Manufacturing companies develop ACPs to minimize the possibility of allergen residues in foods due to shared processing equipment or manufacturing facilities (i.e., cross-contact). However, low-level residues might still be present. Few analytical surveys have been conducted to determine the frequency of packaged foods containing undeclared allergens in the marketplace, but the frequency of product recalls in the United States and Canada suggests that foods with undeclared allergens are on the market in both countries. Concerns about potential risks to consumers with a food allergy due to shared processing equipment or facilities prompted the packaged foods industry to use PAL statements. PAL statements are voluntary, but regulatory authorities indicate that statements must be truthful and not misleading. Because the food industry has no capability to conduct allergen risk assessments to determine threshold doses and safe levels, the food industry has clearly struggled to make prudent and effective use of PAL. Therefore, PAL statements are applied to a wide range of products, including products that likely pose little risk to consumers with a food

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

allergy. The use of PAL also is driven by the potential legal consequences associated with manufacturing a packaged food that can provoke allergic reactions, and the desire to avoid litigation is thus an additional motivator. The result is a labeling system for unintentional allergen residues that bears almost no relationship to actual risk. For the consumer, the degree of risk posed by a particular food bearing a PAL is unknown. The implementation of a complete avoidance diet poses burdensome restrictions on individuals and adversely affects their quality of life (Soller et al., 2014). In addition, evidence suggests that consumers with a food allergy attempt to apply a risk matrix to the various forms of PAL statements and that they ignore PAL in some situations (Hefle et al., 2007; Sheth et al., 2010). Meanwhile, the limited analytical surveys indicate that packaged food products with PAL statements often do not contain detectable food allergen residues (Crotty and Taylor, 2010; Ford et al., 2010; Hefle et al., 2007; Remington et al., 2013a, 2015; Robertson et al., 2013; Zurzolo et al., 2013). Many different stakeholders are critical of the current usage of PAL on packaged foods and agree that the lack of Reference Doses has contributed to the inconsistent application of PAL by the food industry (DunnGalvin et al., 2015).

The ineffectiveness of PAL statements and the lack of consistency and transparency in the implementation of voluntary PAL statements to protect the consumer with food allergies call for public health authorities to use a risk-based approach predicated upon risk assessment principles. Quantitative risk assessments can be conducted to assess the level of risk to consumers from exposure to residue levels of allergenic foods in specific food products (Crevel et al., 2007; Remington et al., 2013a, 2015; Spanjersberg et al., 2007). In this manner, the estimated level of risk to consumers with a food allergy can be communicated to consumers through more consistent application of PAL strategies. Public health authorities in various countries could use the information on individual thresholds to reach consensus about population thresholds for specific allergenic foods and, ideally, these population thresholds would be used to guide regulatory and food industry labeling practices with the goal to match labeling to risk in a more meaningful way. Ultimately, knowledge of population and individual thresholds for specific allergenic foods could be helpful to allergic individuals, their physicians, the food industry, and governmental regulatory agencies in protecting the health of these consumers.

The approach described in this chapter is not currently used except in Australia and New Zealand. The Allergen Bureau of Australia and New Zealand, formed voluntarily by the food industry in an attempt to curtail the widespread use of PAL, has developed the VITAL program. VITAL has established Reference Doses for allergenic foods based on clinical data on the distribution of individual threshold doses for individuals with spe-

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

cific food allergies (Allen et al., 2014a; Taylor et al., 2014). In the VITAL approach, the use of PAL in food packaging is based on risk.

Although the voluntary establishment of Reference Doses by organizations such as the Allergen Bureau is laudable and a sign of progress, the endorsement of Reference Doses by public health authorities would enhance the impact of such approaches. Moreover, while the VITAL program has emerged as a noteworthy, benchmark approach, it will be important to critically assess its overall effectiveness.

In closing, it is important to emphasize that the largest share of the responsibility for the implementation of safe and effective avoidance diets falls onto consumers with a food allergy or their caregivers. However, individuals often lack much of the critical information that is needed (see Chapters 6 and 8). As mentioned in those chapters, all relevant stakeholders, including health care professionals, public health authorities, and food allergy advocacy groups, should be trained to offer consistent, evidence-based advice on allergen risks and allergen avoidance diets. which should also be consistent with regulations and food industry labeling practices. Risk assessment based on the best available scientific and clinical evidence offers the best approach to achieve the desired consensus.

RECOMMENDATIONS

The committee recommends that the Codex Alimentarius Commission and public health authorities in individual countries decide on a periodic basis about which allergenic foods should be included in their priority lists based on scientific and clinical evidence of regional prevalence and severity of food allergies as well as allergen potency.

For example, in the United States, some foods listed by the FDA as tree nuts (i.e., beech nut, butternut, chestnut, chinquapin, coconut, gingko nut, hickory nut, lichee nut, pili nut, shea nut) could be removed from the current priority list based on the paucity of data or low frequency of allergic reactions. In addition, evidence of the allergy prevalence and reaction severity to sesame seeds may warrant their inclusion on the priority allergen list in the United States.

The committee recommends that the Food and Drug Administration makes its decisions about labeling exemptions for ingredients derived from priority allergenic sources based on a quantitative risk assessment framework.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

A quantitative risk assessment is based on knowledge of the detectable level of protein, its presence in the ingredient, exposure levels to the ingredient, and threshold dose-distributions for individuals allergic to the food.

The committee recommends that the food manufacturing industry, the Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) work cooperatively to replace the Precautionary Allergen Labeling system for low-level allergen contaminants with a new risk-based labeling approach, such as the VITAL program used in Australia and New Zealand.

To meet this risk-based approach, the following three steps are recommended:

  1. The FDA and the USDA should establish Reference Doses (thresholds) for allergenic foods, where possible. The committee concludes that at this time, sufficient data exist on milk, egg, peanut, certain tree nuts (i.e., cashew, walnut, hazelnut), wheat, soybean, fish, and crustacean shellfish (shrimp) to establish Reference Doses. The FDA and the USDA should review the Reference Doses periodically, with particular attention to the remaining tree nuts for which data to establish Reference Doses are not currently available (i.e., almond, Brazil nut, macadamia nut, and pine nut).
  2. Once Reference Doses are established, a food product would carry an advisory label (e.g., “peanut may be present”) only in situations when ingesting the product would expose the individual to a level above the Reference Dose for that allergen. The FDA should restrict the number of allowable advisory labels to one phrase. Because this labeling is voluntary, the product should clearly inform the consumer, through labeling as appropriate, as to whether a risk-based approach (such as VITAL) has been followed for each specific product. The FDA and the USDA should educate health care providers and consumers about the meaning of such a food allergy advisory statement.
  3. The FDA and the USDA, together with the food industry and the analytical testing industry, should develop and validate detection methods and sampling plans for the various food allergens for which Reference Doses are established. A common unit of reporting also should be established, such
Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

as parts per million of protein from the allergenic source, so that comparisons can be made between methods and between levels in the food and clinical threshold values.

RESEARCH NEEDS

Some allergenic foods have higher potency and cause more severe reactions than do others. Likewise, evidence indicates that changes in proteins during food processing can contribute to their allergenicity, but these changes and their effects are not the same for all allergenic proteins. The relationship between specific protein characteristics (e.g., structure, sensitivity to heat, and digestibility) and specific processing conditions and potency needs to be elucidated so it can be considered when designing research studies and when prescribing prevention approaches for individuals.

In addition to age and geographical differences, circumstantial factors might modify the severity of a food allergy reaction and the level of allergen needed for a reaction in an individual. The effect of exercise on experiencing a food allergy reaction has been reported and it is well recognized. However, for other factors, such as alcohol or medication use, biological cycles, psychological factors, stress, and concomitant allergen exposures, anecdotes are the main source of information. Identifying the factors that can modify the severity of allergic reactions and defining their influence on whether an allergic reaction is experienced upon exposure to a food allergen or in changing in the specific eliciting dose are key pieces of information needed to provide advice to individual patients (see Chapters 6 and 7).

To fill gaps in knowledge in this area, studies should be conducted to accomplish the following objectives:

  • Strengthen current knowledge about food allergen risk assessment and management, including continued assessment of threshold doses for individual allergens; single dose oral challenges for confirmation of threshold doses; the development, application, and improvement of parametric dose-distribution modeling approaches for allergen risk assessment; food consumption patterns of populations with food allergy; and methods to detect allergen residues in food matrices.
  • Study the mechanisms that make some food proteins more allergenic than others and the effects of food processing methods and other ingredients on their allergenicity and thresholds.
  • Study the possible effects of augmentation factors on threshold doses (e.g., exercise, alcohol) or on modifying the severity of reactions, and the mechanisms underlying such effects.
Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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ANNEX 7: DATA INPUTS FOR RISK ASSESSMENT

Oral Food Challenges as Inputs to Determine Thresholds in Risk Assessment

General Protocol Considerations

For the purposes of hazard characterization, individuals with a food allergy should be challenged orally with the food over a range of incremental doses to determine the minimal dose needed to elicit an allergic reaction. These oral food challenges (OFCs) are most often conducted in controlled clinical settings. Consensus clinical protocols exist for such testing (Bindslev-Jensen et al., 2004; Taylor et al., 2004), including avoidance of certain medications before and during challenges, time intervals between doses, use of placebo-controlled crossover designs, use of objective symptoms (or abdominal pain in infants and young children) as the criteria for stopping challenges, and a fasting period before challenges. There are various types of OFC depending on the protocol.15 Ideally, the design would be a double-blind, placebo-control test with doses ranging wide enough to ensure reactions at some dose. Thus, the initial doses should be sufficiently low (low milligram [mg] or even sub-milligram levels) to ensure that very few individuals react at the initial dose (Cochrane et al., 2012). Many variations on that general protocol, such as dosage schemes, have been used by different investigators.

Dosing schemes The dosing schemes used in clinical OFC protocols vary, and the Interval-Censoring Survival Analysis approach has been used to adjust for the different dosing schemes. However, it is important to note that the outcomes of the probabilistic modeling can be influenced if a large proportion of the data are not interval-censored (e.g., first dose or left-censored reactors) (Taylor et al., 2009). Recently, concerns have been raised about the time interval between doses, generally 20 or 30 minutes, being too short (Blumchen et al., 2014). Clearly, an entire dose is unlikely to be fully assimilated (digested, absorbed, and presented to the immune system) in 20 to 30 minutes. However, by recording both the discrete and cumulative doses that provoke the first objective signs and comparing these two doses in the probabilistic modeling, this concern is abated due to the small

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15 There are three types of oral food challenges (OFCs) depending on the protocol. An open OFC is one where the food is in its natural form; a single-blind OFC is one where the food is masked from the patient’s perspective so less patient bias occurs because of anxiety; a double-blind, placebo-controlled OFC involves masking the tested allergen and feeding it or indistinguishable placebo randomly without the patient or observer knowing if the allergen or placebo is being tested.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

differences that occur at the lowest doses. In fact, the estimated population threshold for peanut obtained by Blumchen et al. (2014) was in agreement with earlier estimates based on shorter time intervals between doses (Taylor et al., 2010, 2014).

In addition to the dosing scheme, other variables in the clinical OFC protocol, such as the nature of the challenge materials and the matrix for blinding of challenges, also should be considered (Crevel et al., 2014). The nature of the material is important because the potency of the allergen may vary depending on the source or processing. The matrix also is a consideration because the allergen may be released more slowly from some matrices as opposed to others.

Identifying objective versus subjective reactions By definition, to determine an individual’s threshold, the level of allergen that provokes a response needs to be measured. Clinicians and others need to reach consensus about what constitutes an allergic response (see Box 7A-1). In some studies, subjective responses over three successive, increasing doses is considered a reaction (Ballmer-Weber et al., 2015; Flinterman et al., 2006). However, a new consensus has emerged that only objective responses should serve as the basis for identifying an individual’s threshold in an OFC (Crevel et al., 2014).16 In clinical settings, objective symptoms can be confirmed to occur and their reproducibility readily assessed (Taylor et al., 2014).

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16 One exception is for abdominal pain in infants and children younger than the age of 3 years, which is accepted as a response.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

Nature of the challenge material and matrix Various forms of the allergenic food can be used in OFC trials. For example, peanut could be in the form of crushed peanuts, peanut butter, or peanut flour. These forms of peanut vary in their protein and allergen content (e.g., peanuts are approximately 25 percent protein while peanut flour is approximately 50 percent protein). Thus, the challenge material doses can be normalized on the basis of protein content (Taylor et al., 2014), an appropriate approach considering that food allergens are proteins. In general, all forms of the allergenic food are assumed to have equivalent allergenicity at any given dose of protein although this is not true when comparing different fractions of a food (e.g., egg white and whole egg). Of course, processing of the food could have an effect on allergenicity. In fact, clinical studies have documented that many milk- and egg-allergic patients become tolerant of baked milk or egg before they develop a tolerance for these foods in forms that are subjected to lesser degrees of heat processing, and this is reflected in increased individual thresholds (Lemon-Mule et al., 2008; Nowak-Wegrzyn et al., 2008). For some allergenic foods, such as milk and egg, challenges should ideally use less processed forms of food, such as pasteurized, spray-dried or even raw, where possible in order to ensure an elicitation will occur at the lowest possible dose (Crevel et al., 2014; Taylor et al., 2014). However, for foods such as peanut, where the allergens are more heat-stable, the use of typical heat-processed forms of the food, such as roasted peanuts or peanut butter, is less likely to influence estimated lowest-observed-adverse-effect levels (LOAELs) and no-observed-adverse-effect levels (NOAELs) (Crevel et al., 2014). The individual threshold data used in probabilistic modelling have been obtained from mildly processed forms for many of the foods, as the challenge materials are pasteurized and/or spray-dried at most. The outcome of challenges also may depend upon the matrix or vehicle used for the OFCs, such as the level of fat (e.g., chocolate versus other vehicles) (Cochrane et al., 2012; Grimshaw et al., 2003; Mackie et al., 2012). This factor has not been thoroughly investigated but, to date, OFCs are generally administered in readily digestible matrices that mimic the food in which they would actually be eaten.

Biases

Population biases One obvious limitation for developing a dose distribution of individual minimal eliciting doses (EDs) for any population with a food allergy is the prevalence of that specific food allergy. This is because of the need to assemble a sufficient number of individuals to have a robust dose-distribution relationship. Besides that, challenge testing of individuals with a food allergy has revealed a wide variation of individual minimal EDs, ranging from 0.4 mg up to 10 g of whole peanut (Taylor et al., 2009,

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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2010). Thus, to develop a dose-distribution of individual minimal EDs for any population with a food allergy, individuals must be selected who are representative of the entire population of individuals allergic to the particular food in question. In this respect, the possibility of patient selection biases is one of the chief concerns. Dose–response data for statistical modeling to estimate population thresholds can be obtained from three types of published (and unpublished) studies: diagnostic series, threshold studies, and immunotherapy trials (Taylor et al., 2009). The possibility of patient selection biases in such studies is demonstrated by the existence of different ED517 estimates for peanut for patients from these three types of studies (Taylor et al., 2009). Individuals enrolled in diagnostic trials should ideally include all patients who are seeking confirmation of a particular food allergy. However, in some clinics, patients with histories of severe allergic reactions are excluded from OFCs. In addition, diagnostic series do not always start at low doses, as the recommended initial dose for diagnostic OFCs is 500 mg (Bock et al., 1988). When the first dosage interval between 0 and the first dose is large, these data are difficult to include in the model because of the effect of the interval width. Thus, data from diagnostic series should be sought from OFCs that start at rather low doses (low mg or less). An Australian study illustrated the effect of the choice of the dosing scheme on the ED estimate. In this study of milk, the first dose ranged from 66 to 300 mg (Allen et al., 2014). The ED05 for the Australian patients was 69.5 mg milk protein compared to 1.9 and 2.0 mg for the Netherlands and Italy, respectively. This difference was attributed to the dosing scheme (Allen et al., 2014).

In threshold studies, the intent is to determine the threshold doses for a group of patients with a specific food allergy. A clinical patient selection bias could occur due to efforts to include highly sensitive patients as documented by their patient history. The ED estimates for threshold studies tend to be lower than for diagnostic series, which may confirm the existence of patient selection bias toward the more highly sensitive (Allen et al., 2014; Taylor et al., 2009).

In immunotherapy trials, the goal is to desensitize patients with a specific food allergy by administering low, steadily increasing, doses of the allergenic food over time (see Chapter 6). The placebo arm of the immunotherapy trial is an oral, low-dose challenge that establishes the minimal ED, which then dictates the choice of the initial immunotherapy doses. This initial OFC provides the patient’s individual threshold dose. A patient selection bias might occur in such studies, as the selection of highly

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17 The subscript represents the percentage of the allergic population in whom the dose of total protein from the allergenic food is predicted to produce an objective response. In this case the predicted percentage is 5 percent.

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

sensitive patients establishes a more rigorous test of the effectiveness of immunotherapy. In several instances, the ED estimates for immunotherapy patient populations is lower than for diagnostic series (Allen et al., 2014), indicating a possible selection bias toward more highly sensitive individuals. However, in a study of anti-immunoglobulin E (IgE) immunotherapy, a comparison revealed that patient selection in that study was biased toward less sensitive subjects (Taylor et al., 2009). By including patients from all three types of studies in the statistical modeling, the effects of patient selection bias are muted to some degree (Allen et al., 2014; Taylor et al., 2009).

The possible under-representation of patients with histories of severe reactions in datasets used for probabilistic modeling has been an expressed concern because patients with histories of severe allergic reactions are excluded from OFCs in some clinics (Luccioli and Kwegyir-Afful, 2014). However, in one large diagnostic series study of patients with peanut allergy where all patients were enrolled in OFCs regardless of a history of severe reactions, no differences were found in the estimated ED05 between patients with histories of severe reactions and patients who had histories of mild or moderate reactions (Taylor et al., 2010). Additionally, these patients are not always excluded from oral immunotherapy trials, which represent one of the largest sources of data for this probabilistic modeling.

Uncertainty Factors

The data supporting the establishment of population thresholds are robust because they are derived from controlled OFCs in individuals who have reacted at low doses of the allergenic food. However, several uncertainties should be recognized.

Geographic and age differences Much of the low-dose challenge data emanate from Europe, so concerns have been raised regarding the possibility of geographic differences in population thresholds. Geographic differences in ED estimates have been noted for milk and peanut (Allen et al., 2014). However, the differences for peanut ED estimates may be attributable to patient selection biases because most data are from immunotherapy studies in the United Kingdom. Additionally, the differences for milk ED estimates are mostly likely attributable to the choice of dose progression scheme in Australia, as described above (Allen et al., 2014). The possibility of age differences also has been investigated for peanut and hazelnut, without much difference in EDp estimates (Allen et al., 2014). However, clearly for milk, egg, and several other foods, many infants and young children do outgrow their food allergy and become fully tolerant (Keet et al., 2009; Savage et al., 2010; Sicherer et al., 2014; Wood et al., 2013), which implies that their

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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individual thresholds increase over time, although this assumption has never been completely tested.

Validation of statistical models and ED estimates The use of a single dose oral challenge at a particular, predicted EDp, (e.g., ED05), could be used to validate the probabilistic model estimates of population thresholds (Zurzolo et al., 2013). A single dose peanut trial at the ED05 has recently been completed but not yet published. Such studies also will allow determination of the range of reactions experienced by patients allergic to a specific food at the ED05 dose.

Other factors Concerns have arisen about the possibility of differences between controlled clinical challenge trials and reactions occurring within the community due to additional factors that are not controlled in an OFC, such as dose of exposure, medication status, coexisting clinical conditions (e.g., influenza or other acute or chronic illness) (Crevel et al., 2014). Box 7A-1 includes several host-related factors that should be recognized and could be considered. Data on the impact of these host-related factors on the NOAELs and the LOAELs are extremely limited. Some of these sources of variability, such as certain biological cycles (e.g., circadian), psychological factors, stress, and concomitant allergen exposures (e.g., seasonal pollen) are likely already incorporated implicitly into the threshold datasets because attempts are not made to control these factors during clinical challenges. Others, such as genetic predisposition and host–environment interactions, have not been well studied. The assumption is that they would likely yield small differences in estimated population thresholds. The quantitative impact of other uncertainty factors (e.g., menstrual status, physical activity, health and medication status, and alcohol usage) on population threshold estimates, including individual NOAELs and LOAELs, has not been well investigated but is acknowledged to be potentially important. Certainly ample, mostly anecdotal, evidence exists that exercise can be a determinant of reaction occurrence, and food-dependent, exercise-induced allergy (FDEIA) is a well-documented condition (Wong and Krishna, 2013). However, the association between FDEIA and individual NOAEL and LOAEL has not been studied. Menstrual cycles seem to be a factor in oral immunotherapy trials (Varshney et al., 2009) suggesting that they might affect individual NOAEL and LOAEL as well. These factors can ideally be addressed in clinical guidance where patients are given personalized advice about behavior (Crevel et al., 2014) but currently this advice is probably not consistently given to patients. Further studies are needed on allergic reactions occurring within the community setting to determine whether exposure dose is the key determinant of reaction occurrence and severity and identify any role that these other factors might play. Despite these host-

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

related concerns, the imposition of additional uncertainty factors in the establishment of Reference Doses has not been suggested in part because the EDp values used for Reference Doses are already quite low (ED01 or 95 percent lower confidence interval of ED05 and probabilistic modeling integrates uncertainty and variability into the approach (Crevel et al., 2014; Taylor et al., 2014).

Exposure Assessment as an Input to Risk Assessment

Exposure assessment has two components: the level of contamination (concentration and frequency) and the intake (amount and frequency) of the particular food. These two components of contamination and intake or consumption can be used in quantitative risk assessment to generate an allergen intake distribution in terms of protein from the allergenic food. Probabilistic modeling can then be used to estimate the probability of an allergic reaction occurring based on the concentration of the allergen in the product, the amount of product consumed, and the probability that an allergic person with a threshold lower than dose of the allergen would consume the allergen. Several variables must be considered in developing an accurate exposure assessment.

Concentration of the Allergenic Residues in Foods

The overall food allergen distribution also requires knowledge of the concentration of allergenic food residue (or protein from the allergenic source) in the particular food in question. The concentration of the allergenic food residue can be determined either through calculation or by quantitative analysis of the ingredient or finished food product in question. Calculation can be made in instances where the allergenic food or food ingredient was inadvertently included in a formulation at a consistent level (e.g., a supplier changed the formulation of a component of the finished food to include a milk ingredient but failed to notify the manufacturer of the finished food). However, calculation cannot be used in most circumstances because the unintended allergen residues arise from the use of shared facilities or equipment at the food manufacturing site or at the site of a supplier. In those cases, quantitative analysis of the food product or ingredient is the most common approach to determining the concentration of the allergenic residue. In IgE-mediated food allergy, specific proteins from the allergenic source are involved in binding to IgE and initiating the allergic reactions. The quantitative methods used to determine the concentration of allergenic food residues should ideally detect proteins from the allergenic source either as total source protein, a certain protein fraction (e.g., casein), or a specific allergen (e.g., Ara h 1 from peanut). However, for risk assessment, it is critical to express the analytical

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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result as a concentration of total protein from the allergenic source so that it matches to the human threshold data from clinical challenges expressed as doses of protein from the allergenic source as has been explained above. Box 7A-2 describes current methods to detect allergen residues. Although immunochemical methods, such as Enzyme-Linked Immunosorbent Assays (ELISAs), are widely used and various kits are commercialized, many factors can affect the reliability of estimates of the allergenic protein residues occurring in food products. The selection of the best ELISA method is of paramount importance but that choice is often not straightforward nor well comprehended.

Probabilistic risk assessment can incorporate a distribution of concentrations for the unintended allergenic food residue into the risk assessment model. Analytical assessment of a number of samples taken from a batch or multiple batches of production can be used to establish a distribution of the concentration of allergenic residue that may be expected over time during a production cycle. Selecting a sufficient number of samples to obtain a representative distribution of the expected concentration of the allergenic residue is somewhat straightforward when the allergenic residue of concern is homogeneously distributed in the product of interest. However, sampling becomes more difficult when the source of contamination is due to particulates that can be randomly distributed throughout the product in question. In this instance, the likelihood and size distribution of the particulates, along with the dose distribution (based on the expected size distribution of the particles) can be included as input variables in the risk assessment model.

Consumption of Foods by Allergic Individuals

Food allergy reactions, especially IgE-mediated reactions, occur within minutes to hours after ingestion of the offending food. Therefore, the exposure scenario is based on intake of the specific food during a single eating occasion rather than cumulative exposures. The food intake patterns of consumers are typically obtained from national food surveys such as the National Health and Nutrition Examination Survey conducted by the Centers for Disease Control and Prevention’s National Center for Health Statistics. However, the use of national food surveys for food allergen risk assessments assumes that the food intake of people with allergies is the same as that of the general population. Ideally, for the quantitative risk assessment of allergenic foods, the focus should be placed on the risk for those who consume the foods as opposed to the overall mean intake levels of the food (Crevel et al., 2014). The food consumption patterns of individuals with food allergy require further evaluation.

Another important, and often incorrect, assumption is that consumers

Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
×

in countries where national consumption surveys do not exist behave similarly to U.S. or British consumers with respect to food consumption. Finally, the frequency of intake and the amount of food consumed by users of the particular product are also considered within quantitative risk assessment. Often the intake amounts of the 90th or 95th percentile user is taken to assure a worst-case assessment. Finally, a single meal could contain more than one source of a particular unanticipated allergen. The probability of such combined exposures is generally quite small and often ignored, but a discussion of its possible impact is available (Crevel et al., 2014).

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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Suggested Citation:"7 Management of Packaged Foods." National Academies of Sciences, Engineering, and Medicine. 2017. Finding a Path to Safety in Food Allergy: Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy. Washington, DC: The National Academies Press. doi: 10.17226/23658.
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Over the past 20 years, public concerns have grown in response to the apparent rising prevalence of food allergy and related atopic conditions, such as eczema. Although evidence on the true prevalence of food allergy is complicated by insufficient or inconsistent data and studies with variable methodologies, many health care experts who care for patients agree that a real increase in food allergy has occurred and that it is unlikely to be due simply to an increase in awareness and better tools for diagnosis. Many stakeholders are concerned about these increases, including the general public, policy makers, regulatory agencies, the food industry, scientists, clinicians, and especially families of children and young people suffering from food allergy.

At the present time, however, despite a mounting body of data on the prevalence, health consequences, and associated costs of food allergy, this chronic disease has not garnered the level of societal attention that it warrants. Moreover, for patients and families at risk, recommendations and guidelines have not been clear about preventing exposure or the onset of reactions or for managing this disease.

Finding a Path to Safety in Food Allergy examines critical issues related to food allergy, including the prevalence and severity of food allergy and its impact on affected individuals, families, and communities; and current understanding of food allergy as a disease, and in diagnostics, treatments, prevention, and public policy. This report seeks to: clarify the nature of the disease, its causes, and its current management; highlight gaps in knowledge; encourage the implementation of management tools at many levels and among many stakeholders; and delineate a roadmap to safety for those who have, or are at risk of developing, food allergy, as well as for others in society who are responsible for public health.

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