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.

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.

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.

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.

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.

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.

Development and evolution of risk assessment for food allergens.

The need to assess the risk from food allergens derives directly from the need to manage effectively this food safety hazard. Work spanning the last two decades dispelled the initial thinking that food allergens were so unique that the risk they posed was not amenable to established risk assessment approaches and methodologies. Food allergens possess some unique characteristics, which make a simple safety assessment approach based on the establishment of absolute population thresholds inadequate. Dose distribution modelling of MEDs permitted the quantification of the risk of reaction at the population level and has been readily integrated with consumption and contamination data through probabilistic risk assessment approaches to generate quantitative risk predictions. This paper discusses the strengths and limitations of this approach and identifies important data gaps, which affect the outcomes of these predictions. These include consumption patterns among allergic individuals, analytical techniques and their application, severity-dose relationships, and the impact of extraneous factors which alter an individual's physiology, such as infection or exercise. Nevertheless, application of these models has provided valuable insights, leading to further refinements and generating testable hypotheses. Their application to estimate the risk posed by the concurrent consumption of two potentially contaminated foods illustrates their power.

Application of the threshold of toxicological concern (TTC) concept to the safety assessment of chemically complex food matrices.

The toxicological assessment of chemically complex food matrices (CCFM) usually is very time consuming, expensive and uses many animal studies. Improvements to obtain a more efficient assessment process remain limited as long as we retain traditional approaches to toxicological risk assessment. New concepts would be needed to achieve real innovations in risk assessment. The threshold of toxicological concern (TTC) potentially is such a concept that has existed for many years and recently has been further developed. The safety of CCFM is difficult to assess as there are numerous unknown substances present (often referred to as 'Forest-of-Peaks' in chromatographic analysis). Usually, for the evaluation of CCFM, a full safety assessment approach involving animal studies is needed, but the exposure to most substances is low and TTC might be applicable. However, to apply TTC efficiently to CCFM, a strategy is needed to deal with large numbers of unknowns (substances of which structural information is lacking). Therefore, we have drafted a framework for application of TTC in safety assessment of CCFM. This paper describes the criteria and development of the framework proposing a stepwise approach for the application of TTC in safety assessment of CCFM and future developments required.