The 50th percentile of the general population single eating occasion intake of food is optimal for the calculation of action levels for precautionary allergen labelling.

Lack of guidance regarding selection of food intake values for allergen risk assessment can lead to different outcomes for similar levels of allergens in food products. Several food consumption survey databases (United States, North-West Europe, and Netherlands) were analyzed to identify optimal food intake percentiles using a sensitivity analysis. Deterministic risk assessment scenarios using the 50th percentile up to the maximum intake per food group were compared with probabilistic risk assessment outcomes. The optimal intake percentile is the lowest percentile that results in a deterministic risk assessment outcome compliant with the predefined safety objective, i.e., the predefined risk of an objective allergic reaction at ED01, ED2.5, ED05 or ED10 doses of 14 allergenic foods. The P50 intake met these criteria in more than 99.9% of all 28,784 scenarios tested. The P50 is therefore recommended for deterministic allergen risk assessment and calculation of action levels for precautionary allergen labelling. In case a P50 value is not available, the mean is a good alternative, as analyses of the intake data showed that the mean generally is between the P50 and P65.

Accidental allergic reactions to food in adolescents and adults: An overview of the factors involved and implications for prevention.

Accidental allergic reactions to food are one of the major problems in adult patients diagnosed with food allergy. Such reactions occur frequently, are often severe and are associated with higher medical and non-medical costs. The aim of this Perspective is to provide insight into the different factors involved in the occurrence of accidental allergic reactions and to present an overview of practical implications for effective preventive measures. Several factors affect the occurrence of accidental reactions. These factors are related to the patient, health care, or food. The most important patient-related factors are age, social barriers to disclosing their allergy and non-adherence to the elimination diet. With regards to healthcare, the degree to which clinical practice is tailored to the individual patient is an important factor. The major food-related factor is the absence of adequate precautionary allergen labeling (PAL) guidelines. Since many factors are involved in accidental allergic reactions, different preventive strategies are needed. It is highly recommended that health care be tailored to the individual patient, with regard to education about the elimination diet, support on behavioral and psychosocial aspects, usage of shared decision-making and taking into account health literacy. In addition, it is crucial that steps are taken to improve policies and guidelines for PAL.

Updated full range of Eliciting Dose values for Cow's milk for use in food allergen risk assessment.

Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow's milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally.

Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis.

BACKGROUND: Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds. OBJECTIVE: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. METHODS: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. RESULTS: Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. CONCLUSIONS: About 5% of CM-allergic individuals reacting to ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

Low dietary adherence after a positive food challenge in food allergic adults.

BACKGROUND: After a positive food challenge (FC), patients receive dietary advice regarding avoidance of the culprit food. We examined the frequency and variables associated with dietary adherence after a positive FC in adults. METHODS: In this prospective daily practice study, adults with a positive FC were included. After every FC, dietary advice was given consisting of three options: (1) strict avoidance, (2) avoidance but products with precautionary allergen labelling (PAL) allowed and (3) (small) amounts allowed. Questionnaires about dietary adherence and associated variables were completed prior to and 6 months after the FC(s). RESULTS: 41 patients (with 58 positive FCs) were included. Overall, patients adhered to the advised diet after 31% of the FCs. After 33 FCs, the advice was strict avoidance, whereof 82% followed a less strict diet. After 16 FCs, the advice was avoidance but products with PAL allowed, whereof 19% followed a less strict and 25% a stricter diet. In 9 FCs with the least strict advice, "(small) amounts allowed'', 67% followed a stricter diet. Three variables were associated with adherence: misremembering dietary advice, impaired health-related quality of life (HRQL) on domain "Emotional impact'' and the need for dietary change after the FC. CONCLUSION: After one third of the positive FCs, patients adhered to the dietary advice. Variables associated with adherence were misremembering dietary advice, impaired HRQL on domain "Emotional impact'' and the need for dietary change after the FC. It seems important that healthcare professionals should more frequently apply adherence-enhancing strategies to improve dietary adherence.

Peanut Can Be Used as a Reference Allergen for Hazard Characterization in Food Allergen Risk Management: A Rapid Evidence Assessment and Meta-Analysis.

Regional and national legislation mandates the disclosure of "priority" allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen ("may contain") labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed "reference doses," below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure.

Poor understanding of allergen labelling by allergic and non-allergic consumers.

BACKGROUND: Understanding consumers' interpretation of allergy information is crucial for effective food safety policies. We evaluated consumer understanding of allergy information on foods in controlled, experimental studies. METHOD: Using 18 packaged foods, we evaluated consumer understanding of information about allergens in two experiments: First, a comparison of foods with no stated allergen versus allergen as a stated ingredient versus a precautionary allergen label (PAL); second, a comparison of three common variants of PAL. In each experiment, consumers with and without self-reported food allergy were asked to estimate the risk of allergic reaction and to rate the comprehensibility of the allergen information. In the second experiment, consumers were also asked which form of PAL they preferred. RESULTS: Risk of reaction was assessed as high and low for foods with the allergen stated as ingredient, or without any mention of allergen. However, risk assessment for PAL varied and was judged as higher by non-allergic than allergic participants (82% vs. 58%, p < .001). Understanding of risk associated with PAL also varied by health literacy (p < .001). Both allergic and non-allergic consumers judged all forms of allergy information to be unclear, especially products with no allergy information for non-allergic consumers. Products with a 'Produced in a Factory' PAL were perceived as less risky than 'May contain' or 'Traces of' PALs (p < .001), less than 40% of participants judged PAL information to be comprehensible, and participants preferred 'May contain' over the other PALs. CONCLUSION: Both allergic and non-allergic consumers find allergen information difficult to interpret on packaged foods and misunderstand PAL, incorrectly distinguishing different risk levels for different PAL wording. Clearer allergy information guidelines are called for, and the use of only one PAL wording is recommended.

Allergen labelling: Current practice and improvement from a communication perspective.

BACKGROUND: Allergen information on product labels is crucial in food allergy management, though inadequacy in current labelling practices is one of the major causes for accidental reactions upon consuming prepacked food products. OBJECTIVE: This study analyses current status of communicating allergen information on food labels and provides practical recommendations for improving the label format based on communication theory. METHODS: Product labels (N 288) of seven food categories from private label products and brands were obtained at three retailers in the Netherlands. Information regarding the 14 EU-regulated allergens was evaluated by the frequency of emphasizing allergens in the ingredient list, use of precautionary allergen labelling (PAL), icons and an allergen information section. Effectiveness of communication was assessed evaluating readability and findability of information on allergens using principles of Gestalt and Cognitive Load theories. RESULTS: As requested by EU regulation 1169/2011, emphasizing allergens in the ingredient list was almost 100%, all other presentations of information on allergens on labels was highly diverse. A separate allergen information section was present on most private label products. This section could, but not necessarily did, repeat allergens from the ingredient list and/or give a PAL. Brands often provided a PAL at the end of the ingredient list. Part of the products displayed an icon at different locations of the label. Label background, a lack of cohesion and variation in location of topics hamper the identification of relevant information on allergens by (allergic) consumers. Recommendations include a standardized order for mandatory and voluntary topics on the label and a separate allergen information section. CONCLUSION AND CLINICAL RELEVANCE: Overall, consumers encounter a wide and inconsistent range in ways of presentation of allergen information on labels. Standardization according to basic design principles can improve usability and support safe food purchases for allergic consumers.

A systematic comparison of food intake data of the United States and the Netherlands for food allergen risk assessment.

National population-based food consumption surveys are used in food allergen risk assessment. It would be beneficial if food intake data is interchangeable between countries to bridge potential gaps present in national survey data, which is only possible when risk assessment outcomes for comparable food product groups between countries are fairly similar. Additionally, merged food intake data would enable risk assessments that cover scenarios for various countries, if based on the most critical situation. Therefore, we systematically compared risk assessment outcomes for a broad range of food groups based on United States and Dutch population food consumption survey data. We calculated risks for 14 allergenic foods for 9 concentrations (1-10,000 ppm) to assess comparability. Depending on the assumed allergen concentration, risk assessment outcomes for 20% (10 out of 49) food groups differed considerably. We consider the number of potentially relevant risk differences too high to conclude that food intake data from the US and The Netherlands can be used interchangeably. To allow risk assessments that cover scenarios for several countries, we recommend development and use of a food intake dataset based on the highest intake levels for each food group of the involved countries to facilitate risk management efforts and harmonization.

Full range of population Eliciting Dose values for 14 priority allergenic foods and recommendations for use in risk characterization.

Previously, we published selected Eliciting Dose (ED) values (i.e. ED01 and ED05 values) for 14 allergenic foods, predicted to elicit objective allergic symptoms in 1% and 5%, respectively, of the allergic population (Remington et al., 2020). These ED01 and ED05 values were specifically presented and discussed in the context of establishing Reference Doses for allergen management and the calculation of Action Levels for Precautionary Allergen Labeling (PAL). In the current paper, we publish the full range of ED values for these allergenic foods and provide recommendations for their use, specifically in the context of characterizing risks of concentrations of (unintended) allergenic proteins in food products. The data provided in this publication give risk assessors access to full population ED distribution information for 14 priority allergenic foods, based on the largest threshold database worldwide. The ED distributions were established using broad international consensus regarding suitable datapoints and methods for establishing individual patient's NOAELs and LOAELs and state of the art statistical modelling. Access to these ED data enables risk assessors to use this information for state-of-the-art food allergen risk assessment. This paper contributes to a harmonization of food allergen risk assessment and risk management and PAL practices.

Allergen risk assessment: Food intake levels of the general population represent those of food allergic patients.

Unintentional intake of allergens through food products poses a daily risk for allergic patients. Models estimating the risk of reactions mostly use intake data from general population surveys. Our study evaluates the comparability of food intake levels in the general population to those in the food allergic population. Data were collected by a 24-h recall method on 2 non-consecutive days in 38 cow's milk and/or hen's egg and 35 peanut and/or tree nut allergic adult patients. All products were assigned to food groups previously developed for allergen risk assessment. Food intake distributions from the allergic populations and a matched sample from the Dutch National Food Consumption Survey were compared, and risk assessments were performed. Food intake data was obtained for 92% of the food groups. Comparison of the intake showed no statistically significant differences between either of the two allergic populations and the general population. Consequently, only small variations in estimated risks were found, that would not result in different risk management decisions. In conclusion, food intake data from the general population can be used for food allergen risk assessment and will not lead to a relevant under- or overestimation of the risk for the food allergic population.

Can we define a level of protection for allergic consumers that everyone can accept?

Substantial progress has been made in characterising the risk associated with exposure to allergens in food. However, absence of agreement on what risk is tolerable has made it difficult to set quantitative limits to manage that risk and protect allergic consumers effectively. This paper reviews scientific progress in the area and the diverse status of allergen management approaches and lack of common standards across different jurisdictions, including within the EU. This lack of regulation largely explains why allergic consumers find Precautionary Allergen Labelling confusing and cannot rely on it. We reviewed approaches to setting quantitative limits for a broad range of food safety hazards to identify the reasoning leading to their adoption. This revealed a diversity of approaches from pragmatic to risk-based, but we could not find clear evidence of the process leading to the decision on risk acceptability. We propose a framework built around the criteria suggested by Murphy and Gardoni (2008) for approaches to defining tolerable risks. Applying these criteria to food allergy, we concluded that sufficient knowledge exists to implement the framework, including sufficient expertise across the whole range of stakeholders to allow opinions to be heard and respected, and a consensus to be achieved.

Seeking Windows of Opportunity to Shape Lifelong Immune Health: A Network-Based Strategy to Predict and Prioritize Markers of Early Life Immune Modulation.

A healthy immune status is strongly conditioned during early life stages. Insights into the molecular drivers of early life immune development and function are prerequisite to identify strategies to enhance immune health. Even though several starting points for targeted immune modulation have been identified and are being developed into prophylactic or therapeutic approaches, there is no regulatory guidance on how to assess the risk and benefit balance of such interventions. Six early life immune causal networks, each compromising a different time period in early life (the 1st, 2nd, 3rd trimester of gestations, birth, newborn, and infant period), were generated. Thereto information was extracted and structured from early life literature using the automated text mining and machine learning tool: Integrated Network and Dynamical Reasoning Assembler (INDRA). The tool identified relevant entities (e.g., genes/proteins/metabolites/processes/diseases), extracted causal relationships among these entities, and assembled them into early life-immune causal networks. These causal early life immune networks were denoised using GeneMania, enriched with data from the gene-disease association database DisGeNET and Gene Ontology resource tools (GO/GO-SLIM), inferred missing relationships and added expert knowledge to generate information-dense early life immune networks. Analysis of the six early life immune networks by PageRank, not only confirmed the central role of the "commonly used immune markers" (e.g., chemokines, interleukins, IFN, TNF, TGFB, and other immune activation regulators (e.g., CD55, FOXP3, GATA3, CD79A, C4BPA), but also identified less obvious candidates (e.g., CYP1A2, FOXK2, NELFCD, RENBP). Comparison of the different early life periods resulted in the prediction of 11 key early life genes overlapping all early life periods (TNF, IL6, IL10, CD4, FOXP3, IL4, NELFCD, CD79A, IL5, RENBP, and IFNG), and also genes that were only described in certain early life period(s). Concluding, here we describe a network-based approach that provides a science-based and systematical method to explore the functional development of the early life immune system through time. This systems approach aids the generation of a testing strategy for the safety and efficacy of early life immune modulation by predicting the key candidate markers during different phases of early life immune development.

Updated population minimal eliciting dose distributions for use in risk assessment of 14 priority food allergens.

Food allergy and allergen management are important global public health issues. In 2011, the first iteration of our allergen threshold database (ATDB) was established based on individual NOAELs and LOAELs from oral food challenge in roughly 1750 allergic individuals. Population minimal eliciting dose (EDp) distributions based on this dataset were published for 11 allergenic foods in 2014. Systematic data collection has continued (2011-2018) and the dataset now contains over 3400 data points. The current study provides new and updated EDp values for 14 allergenic foods and incorporates a newly developed Stacked Model Averaging statistical method for interval-censored data. ED01 and ED05 values, the doses at which 1%, and respectively 5%, of the respective allergic population would be predicted to experience any objective allergic reaction were determined. The 14 allergenic foods were cashew, celery, egg, fish, hazelnut, lupine, milk, mustard, peanut, sesame, shrimp (for crustacean shellfish), soy, walnut, and wheat. Updated ED01 estimates ranged between 0.03 mg for walnut protein and 26.2 mg for shrimp protein. ED05 estimates ranged between 0.4 mg for mustard protein and 280 mg for shrimp protein. The ED01 and ED05 values presented here are valuable in the risk assessment and subsequent risk management of allergenic foods.

Deriving individual threshold doses from clinical food challenge data for population risk assessment of food allergens.

BACKGROUND: Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. OBJECTIVE: We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. METHODS: Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. RESULTS: In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. CONCLUSION: With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption.