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individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens.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.

Evidence-based approaches to the application of precautionary allergen labelling: Report from two iFAAM workshops.

Food allergy is a major public health concern with avoidance of the trigger food(s) being central to management by the patient. Food information legislation mandates the declaration of allergenic ingredients; however, the labelling of the unintentional presence of allergens is less defined. Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the risk of reaction from the unintended presence of allergens in foods. In its current form, PAL is counterproductive for consumers with food allergies as there is no standardized approach to applying PAL. Foods with a PAL often do not contain the identified food allergen while some products without a PAL contain quantities of common food allergens that are capable of inducing an allergic reaction. Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM) was an EU-funded project that aimed to improve the management of food allergens by the food industry for the benefit of people with food allergies. Within iFAAM, a clinically validated tiered risk assessment approach for food allergens was developed. Two cross-stakeholder iFAAM workshops were held on 13-14 December 2016 and 19-20 April 2018. One of the objectives of these workshops was to develop a proposal to make PAL effective for consumers. This paper describes the outcomes from these workshops. This provides the basis for the development of more informative and transparent labelling that will ultimately improve management and well-being in consumers with food allergy.

Accidental food allergy reactions: Products and undeclared ingredients.

BACKGROUND: Accidental allergic reactions to food are frequent and can be severe and even fatal. OBJECTIVE: We sought to analyze the culprit food products and levels of unexpected allergens in accidental reactions. METHODS: A prospective cohort study was conducted in adults (n = 157) with a physician-confirmed diagnosis of food allergy. During a 1-year follow-up, 73 patients reported accidental allergic reactions and the culprit food products. Food samples received (n = 51) were analyzed for a wide range of suspected noningredient allergens, and risk was quantified. RESULTS: A very diverse range of food products was responsible for the unexpected allergic reactions. Thirty-seven percent (19/51) of products analyzed had 1 to 4 culprit allergens identified that were not supposed to be present according to the ingredient declaration. Concentrations varied from 1 to 5000 mg of protein of the allergenic food per kilogram of food product and were greatest for peanut, milk, and sesame. Milk proteins posed the highest estimated risk for objective allergic reactions. The intake of culprit allergens by patients varied considerably. For those cases in which culprit allergens were detected, the intake of at least 1 allergen exceeded the reference dose or a culprit allergen with a yet unknown reference dose was present. Both patient neglect of precautionary allergen labeling statements and omission of using a precautionary allergen labeling statement by food manufacturers seem to contribute to accidental reactions. CONCLUSION: A wide range of food products are causing accidental reactions in patients with food allergy. Eight different allergens not declared on the ingredient lists were detected in the culprit food products, all of which were representative of allergens regulated in the European Union.

Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.

BACKGROUND: There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in a significant reduction in choice of potentially safe foods for allergic consumers. OBJECTIVES: We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data. METHODS: Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used. RESULTS: The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.03 mg for egg, and 0.1 mg for hazelnut. CONCLUSIONS: These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety.

Threshold dose distributions for 5 major allergenic foods in children.

BACKGROUND: For most allergenic foods, insufficient threshold dose information within the population restricts the advice on levels of unintended allergenic foods which should trigger precautionary labeling on prepackaged foods. OBJECTIVE: We wanted to derive threshold dose distributions for major allergenic foods and to elaborate the protein doses at which a proportion of the allergic population is likely to respond. METHODS: For 7 allergenic foods double-blind, placebo-controlled food challenges (DBPCFCs) with a positive outcome for allergic reactions were selected from the clinical database of children routinely tested to diagnose food allergy at the University Medical Center Groningen. For each allergen 2 population threshold distributions were determined with the individual minimal eliciting dose and the preceding dose of each DBPCFC for objective symptoms and any symptom (either subjective or objective). RESULTS: Individual positive DBPCFCs were available for peanut (n = 135), cow's milk (n = 93), hen's egg (n = 53), hazelnut (n = 28), and cashew nut (n = 31). Fewer children were challenged with soy (n = 10) or walnut (n = 13). Threshold dose distributions showed a good statistical and visual fit. The protein dose at which 5% of the allergic population is likely to respond with objective reactions was 1.6 mg for peanut, 1.1 mg for cow's milk, 1.5 mg for hen's egg, 7.4 mg for cashew nut, and 0.29 mg for hazelnut. Thresholds for any symptom were on average 2 to 6 times lower than for objective symptoms. The 95% upper and lower confidence intervals of the threshold distributions were overlapping. The peanut threshold distribution on objective symptoms was similar to the distribution of another European center. CONCLUSIONS: Threshold distribution curves and eliciting doses are a powerful tool to compare different allergenic foods and for informing policy on precautionary labeling.

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.

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.

Frequentist and Bayesian approaches for food allergen risk assessment: risk outcome and uncertainty comparisons.

Peer-reviewed probabilistic methods already predict the probability of an allergic reaction resulting from an accidental exposure to food allergens, however, the methods calculate it in different ways. The available methods utilize the same three major input parameters in the risk model: the risk is estimated from the amount of food consumed, the concentration of allergen in the contaminated product and the distribution of thresholds among allergic persons. However, consensus is lacking about the optimal method to estimate the risk of allergic reaction and the associated uncertainty. This study aims to compare estimation of the risk of allergic reaction and associated uncertainty using different methods and suggest improvements. Four cases were developed based on the previous publications and the risk estimations were compared. The risk estimation was found to agree within 0.5% with the different simulation cases. Finally, an uncertainty analysis method is also presented in order to evaluate the uncertainty propagation from the input parameters to the risk.

Sensitivity analysis to derive a food consumption point estimate for deterministic food allergy risk assessment.

One of the input parameters in food allergy risk assessment is the amount of a given food consumed at an eating occasion. There is no consensus on how to use food consumption data when assessing the risk from unintended allergen presence in food products. A sensitivity analysis was performed to establish the optimal food consumption estimate for a deterministic food allergy risk assessment. Exposure was calculated for consumption percentiles (50th percentile, P50 to maximum) using the iFAAM consumption database in conjunction with an allergen concentration range from 1 to 1000 ppm. The resulting allergen intakes were compared to the allergic population reference doses proposed by Taylor et al. (2014) for 10 major allergenic foods. Optimal consumption percentiles were defined as those which predicted an intake below the relevant reference dose and met the defined acceptable risk level confirmed by probabilistic risk assessments. Analysis showed that, for 99% of the food groups, the P50 consumption met our criteria, while the P75 did so for 100% of the food groups. We suggest that the P75 is the optimal point estimate for use in deterministic food allergy risk assessment. It meets the safety objective and is adequately conservative for a public health context.

Food groups for allergen risk assessment: Combining food consumption data from different countries in Europe.

To prevent allergic reactions, food producers have to be able to make a knowledge based decision on whether to label their products with precautionary labelling. As many manufactured food products are sold in different countries across Europe, the allergen risk assessment should be estimated at the European levels. As currently, there are no pan-European food data suitable for food allergy risk assessment. The aim of this paper is to investigate if consumption data, at a meal level, from National Food Consumption Surveys, can be combined to form a common Food Consumption database. In this first attempt we developed a procedure to investigate, if national food consumption data can be combined and grouped using data from Netherlands, France and Denmark. The homogeneity of consumption patterns and the relevance of difference in risk of allergic reaction were compared, using a fixed framework of allergen concentration levels and threshold distribution. Thus, the relevance of using common consumption data across countries was verified. The food groups formed were subsequently evaluated and adjusted based on practical considerations. It resulted in designing 61 food groups that can be used for allergen risk assessment. The summary statistics and descriptive names for each food group are included.

Assessing food allergy risks from residual peanut protein in highly refined vegetable oil.

Refined vegetable oils including refined peanut oil are widely used in foods. Due to shared production processes, refined non-peanut vegetable oils can contain residual peanut proteins. We estimated the predicted number of allergic reactions to residual peanut proteins using probabilistic risk assessment applied to several scenarios involving food products made with vegetable oils. Variables considered were: a) the estimated production scale of refined peanut oil, b) estimated cross-contact between refined vegetable oils during production, c) the proportion of fat in representative food products and d) the peanut protein concentration in refined peanut oil. For all products examined the predicted risk of objective allergic reactions in peanut-allergic users of the food products was extremely low. The number of predicted reactions ranged depending on the model from a high of 3 per 1000 eating occasions (Weibull) to no reactions (LogNormal). Significantly, all reactions were predicted for allergen intakes well below the amounts reported for the most sensitive individual described in the clinical literature. We conclude that the health risk from cross-contact between vegetable oils and refined peanut oil is negligible. None of the food products would warrant precautionary labelling for peanut according to the VITAL® programme of the Allergen Bureau.

Cofactors in allergic reactions to food: physical exercise and alcohol are the most important.

INTRODUCTION: Involvement of cofactors, like physical exercise, alcohol consumption and use of several types of medication, are associated with more severe food allergic symptoms. However, there is limited evidence on how often cofactors play a role in food allergic reactions. The study aimed to get more insight into the frequency of exposure to cofactors and how often cofactors are associated with more severe symptoms in food allergic patients. METHODS: A questionnaire was completed by patients visiting the Allergology outpatient clinic. Patients with food allergy were included. Outcome measures were the frequency of medication use of medication groups that might act as cofactor and the frequency that physical exercise, alcohol consumption and use of analgesics are associated with more severe food allergic symptoms. RESULTS: Four hundred ninety-six patients were included in the study. The frequency with which patients used one or more types of medication that might act as cofactors was 7.7%: antacids/acid neutralizing medication (5%), NSAIDs (2%), beta blockers (0.6%), angiotensin-converting enzyme inhibitors (0.6%), and angiotensin receptor blockers (0.2%). Of all patients, 13% reported more severe symptoms to food after involvement of one or more of the cofactors: physical exercise (10%), alcohol consumption (5%), and use of analgesics (0.6%). Sixty-five percent did not know if these cofactors caused more severe symptoms; 22% reported that these cofactors had no effect. CONCLUSIONS: Only a small percentage of patients (7.7%) used medication that might aggravate food allergic reactions. Physical exercise and alcohol consumption were the most frequently reported cofactors, but occurring still in only 10% or less.

Establishment of Reference Doses for residues of allergenic foods: report of the VITAL Expert Panel.

In 2011, an expert panel was assembled to establish appropriate Reference Doses for allergenic food residues as a part of the VITAL (Voluntary Incidental Trace Allergen Labeling) program of The Allergen Bureau of Australia & New Zealand (ABA). These Reference Doses would guide advisory labeling decisions for use on food labels. Individual NOAELs and LOAELs were obtained from clinical challenges of food-allergic subjects. Statistical dose-distribution models (log-normal, log-logistic, Weibull) were applied to the individual NOAELs and LOAELs for each allergenic food. The Reference Doses, in terms of mg of total protein from the allergenic food, were based upon either the ED01 (for peanut, cow's milk), the 95% lower confidence interval of the ED05 (for wheat, soybean, cashew, shrimp, sesame seed, mustard, and lupine), or both (egg, hazelnut) using all appropriate statistical dose-distribution models. Reference Doses were established for 11 allergenic foods ranging from 0.03 mg for egg protein to 10mg for shrimp protein. Reference Doses were not established for fish or celery due to poor model fits with existing data. Reference Doses were not established for other tree nuts beyond hazelnut and cashew because of the absence of data on NOAELs and LOAELs from individual subjects.