Food Safety

Mild symptoms, clear science: time to implement allergens Reference Doses

April 21, 2025

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The time has come for the immediate implementation of scientifically established Reference Doses for food allergens. Pivotal research, particularly a recent study by Blom et al. (2025) published in Food and Chemical Toxicology, provides compelling evidence that allergic reactions occurring at low exposure levels (at or below the Eliciting Dose ED05 threshold) are consistently mild to moderate.

This comprehensive analysis provides the scientific basis for adopting a risk-based approach to allergen management. We contend that implementing Reference Doses is essential to address the current chaos in precautionary allergen labelling (PAL), provide clarity for both consumers and the food industry, and ensure an evidence-based approach to managing potential allergen cross-contamination and associated product recalls.

Table of Contents

Understanding food allergen thresholds

For individuals with food allergies, complete avoidance of trigger foods remains the primary management strategy. However, the inconsistent use of precautionary allergen labelling has created significant challenges for allergic consumers, leading to uncertainty, anxiety, and reduced quality of life. The absence of standardized approaches to PAL has resulted in a proliferation of warnings that may not reflect actual risk, undermining consumer confidence and unnecessarily restricting food choices.

The recently published research by Blom and colleagues (2025) offers a detailed analysis of symptoms that occur at low levels of exposure to food allergens. Their study meticulously examines the nature and severity of allergic reactions at doses below or equal to the eliciting dose for 10% of the allergic population (ED10), with particular focus on the ED05 threshold – the dose predicted to elicit objective allergic symptoms in 5% of the allergic population.

Study methodology: a comprehensive approach

The researchers conducted an extensive analysis of data from the TNO-FARRP (The Netherlands Organisation for Applied Scientific Research – Food Allergy Research and Resource Program) threshold database, which contains over 3,400 individual threshold data points from double-blind placebo-controlled food challenge studies conducted in clinical settings worldwide. This database represents the most comprehensive collection of food allergen threshold data currently available.

From this extensive collection, the researchers extracted detailed symptom descriptions for 1,102 food challenges involving 11 priority food allergens where patients received at least one dose at or below the ED10. These challenges spanned participants from 13 countries and 15 clinical centers throughout Europe, with ages ranging from 0.3 to 72.5 years. The dataset included detailed information for cashew (n=244), celery (n=41), egg (n=99), fish (n=26), hazelnut (n=165), milk (n=131), peanut (n=308), shrimp (n=27), soy (n=14), walnut (n=41), and wheat (n=6).

The researchers standardized the reported symptoms according to a previously established classification system developed in cooperation with international clinicians and scientists, resulting in 46 unique classified symptoms. They then categorized all reported symptoms into three different Eliciting Doses ranges: ≤ED01 (affecting 1% of allergic individuals), ED01 to ≤ED05 (affecting 1-5% of allergic individuals), and ED05 to ≤ED10 (affecting 5-10% of allergic individuals). This approach allowed for a detailed analysis of the progression of symptom severity across increasing doses.

Key findings: symptom profiles at low doses

The study revealed that at doses ≤ED10, patients typically experienced only 1-2 symptoms per positive challenge (average 1.8 ± 1.2, range 1-8). The majority (68%) of these symptoms were subjective rather than objective, with most objective symptoms affecting the skin (60-71%), such as flushing and erythema. This was followed by symptoms in the eyes/nose and oral cavity regions, including rhinorrhea, red eyes, and lip swelling.

Notably, all symptoms occurring at doses ≤ED05 were classified as mild to moderate. Only two cases of severe symptoms (wheeze and laryngeal edema) were recorded in the entire dataset, both occurring at doses above the ED05 (approximately at the ED08 level). These findings suggest that exposure to doses at or below the ED05 of priority food allergens results only in mild to moderate symptoms in the small proportion of the allergic population that reacts at such low doses.

In the dose range ≤ED01, most reported symptoms were mild subjective or mild objective symptoms, primarily (82.6%) affecting the oral cavity, eyes and nose, or skin. Most frequently reported were oral allergy syndrome (37.6%), flush (13.8%), and pruritus of the skin (11%). In the ED01-≤ED05 range, a similar pattern was observed, with the majority (76%) of symptoms present in the oral cavity, eyes and nose, or skin.

Gastrointestinal symptoms such as nausea or abdominal pain occurred in approximately 5% of cases, while respiratory symptoms were even less common (5.6% of all symptoms in the ED01-≤ED05 range), including cough (1.0%), throat tightness (3.3%), and dyspnea (0.8%).

Implications for Reference Doses: the ED05 threshold

The ED05 – the dose predicted to elicit objective allergic symptoms in 5% of the allergic population – has emerged as a critical threshold for establishing Reference Doses for allergen risk management. The findings of Blom and colleagues (2025) provide robust scientific support for this approach by demonstrating that all symptoms occurring at or below this threshold are mild to moderate in nature.

The Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens (FAO and WHO, 2022) recently recommended using the ED05 as the basis for deriving Reference Doses for precautionary allergen labelling (PAL). Based on the comprehensive analysis by Houben et al. (2020) and Remington et al. (2020), the FAO/WHO Expert Consultation endorsed specific reference doses for priority allergens:

1.1 mg protein for peanut
0.2 mg for milk
0.2 mg for egg
0.5 mg for cashew
0.8 mg for hazelnut
0.8 mg for walnut
0.6 mg for mustard
1.5 mg for soy
1.3 mg for lupin
1.0 mg for sesame
1.3 mg for shrimp
0.7 mg for wheat.

Notably, these recommended reference doses were rounded down from the population ED05 values to levels that for many allergens equate to approximately the ED03-ED04, providing an additional safety margin.

This conservative approach means that at exposures up to these reference doses (RfD):

approximately 96-97% of the allergic population will not experience objective symptoms because their individual thresholds are higher;
for those few individuals with thresholds below the reference dose, the study under examination (Blom et al., 2025) demonstrates that they would likely experience only mild to moderate symptoms, primarily subjective in nature.

Moving towards evidence-based PAL: implementation challenges and opportunities

The implementation of reference doses based on ED05 values represents a significant advancement in allergen risk analysis and management. This approach would provide, among other things, clear guidance – based on scientific evidence – on cases where precautionary allergen labelling (PAL) is justified, thus reducing not only recalls but also unnecessary warnings and ensuring that they appear only on products that represent a significant risk for allergic consumers.

The FAO/WHO Expert Consultation has outlined a framework for implementing these reference doses in risk analysis and management. The process involves comparing the estimated amount of unintended allergen that may be present in a food product with the established reference dose. If the estimated amount falls below the reference dose, PAL would not be necessary; if it exceeds, PAL would be warranted.

This approach is similar to the Voluntary Incidental Trace Allergen Labelling (VITAL) program developed by the Allergen Bureau in Australia and New Zealand, which has successfully implemented reference doses in allergen risk management. The VITAL program uses action levels based on reference doses to guide decisions on when to apply precautionary labelling, providing a practical model for global implementation.

Stakeholder organizations’ urgent call for RfD implementation

Scientific organisations and patient advocacy groups have been vocally calling for the implementation of Reference Doses (RfD) in the analysis and management of food allergen contamination risk for five years now:

the Food Allergy Research and Resource Program (FARRP) at the University of Nebraska-Lincoln (USA), which co-developed the threshold database used in this study, has been a leader advocate for evidence-based approaches to allergen management;
Food Allergy Research & Education (FARE), the reference organisation for allergic patients globally, also supports an evidence-based approach to allergen labelling;
the European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) has published various position papers asserting the need to improve allergen labelling based on scientific evidence. In its document ‘Towards Improved Food Allergen Labelling in the EU’ (2020), EFA emphasised the need for harmonised approaches to precautionary allergen labelling based on established reference doses;
the European Academy of Allergy and Clinical Immunology (EAACI) has also published position papers supporting the use of Reference Doses in allergen risk management. Already the ‘EAACI Food Allergy and Anaphylaxis Guidelines: Managing patients with food allergy in the community’ (2020) endorsed evidence-based approaches to precautionary labelling. This position was later refined in a 2024 update, which introduced more rigorous criteria for risk-based labelling;
the European Platform of Food Allergens Experts and Stakeholders has also forcefully highlighted the regulatory paralysis in a recent position paper (Smits et al., 2025), calling for the immediate development of EU-level guidelines for allergen risk assessment and management.

Interim conclusions: evidence for ED05-based Reference Doses

The study by Blom and colleagues (2025) provides critical evidence that symptoms occurring at low doses of allergenic foods (≤ED05) are mild to moderate in nature. The research meticulously analyzed symptoms from 1,102 food challenges across 11 priority allergens, finding that at doses ≤ED10, patients typically experienced only 1-2 symptoms per positive challenge. The majority (68%) of these symptoms were subjective rather than objective, with most objective symptoms affecting the skin (60-71%).

This scientific evidence strongly supports the use of ED05-based reference doses for risk analysis and management of food allergens in food products, particularly in cases of cross-contamination where unintended allergen presence may occur. The findings align perfectly with the FAO/WHO Expert Consultation’s recommendations, which endorsed specific reference doses for priority allergens based on ED05 values, often rounding down to provide additional safety margins.

The implementation of harmonized reference doses based on ED05 values would provide significant benefits for all stakeholders in the food allergy domain:

food manufacturers and retailers would have clear guidelines for when PAL is necessary
regulatory authorities would have a scientific basis for enforcement
healthcare professionals would be better equipped to advise allergic patients
allergic consumers would have increased confidence in their food choices.

Future research should focus on developing educational tools for healthcare providers, food manufacturers, retailers, and allergic consumers to ensure understanding of the implications of reference doses.

Crisis management: the critical importance of Reference Dose-based approaches

The implementation of Reference Dose-based approaches is not only essential for consistent precautionary allergen labelling but also plays a fundamental role in crisis management scenarios involving potential allergen cross-contamination. Current practices in many EU Member States and beyond reveal an alarming pattern of food alerts and product withdrawals based solely on the detection – or even just the suspicion – of allergen traces, without any quantitative risk assessment to determine whether these traces pose an actual risk to allergic consumers.

As highlighted in a recent analysis (Dongo, 2022), this approach demonstrates a fundamental misunderstanding of the difference between ‘hazard’ and ‘risk’ – concepts that are clearly defined in EU legislation. According to Regulation (EU) 2017/625:

a ‘hazard‘ merely represents ‘any agent or condition with the potential to have an adverse effect on human health‘, while
‘risk‘ involves an assessment of ‘the likelihood of an adverse effect and the severity of that effect, consequential to a hazard‘ (Reg. EU 2017/625, Article 3).

The mere presence, or suspect, of an allergen (hazard) does not automatically constitute a risk if the concentration is below scientifically established thresholds that would trigger reactions in allergic individuals. Yet, regulatory authorities often trigger extensive and costly product recalls based solely on the detection or the suspect of allergen traces, regardless of concentration levels. This results in:

massive food waste
huge economic damage to all operators involved
unnecessary alarm among allergic consumers.

The adoption of Reference Dose-based risk assessment tools such as VITAL 4.0 is crucial to introduce a uniform, certain and scientifically sound approach to crisis management. When allergen traces are detected, quantitative analysis could determine whether concentrations exceed the established reference doses. Only in cases where the allergen concentration poses a genuine risk to allergic consumers would product withdrawal be warranted.

This approach would prevent scenarios where entire production batches are withdrawn based on presumptions and/or analytical results showing allergen concentrations well below levels that could trigger reactions even in highly sensitive individuals. Such incidents represent not just economic waste but also contribute to ‘alert fatigue‘ among consumers, potentially diminishing the impact of notifications about genuinely risky products.

The stakes are significant: without clear reference doses enshrined in legislation, food industry and retail face unpredictable enforcement actions, while allergic consumers continue to navigate a system that fails to differentiate between significant and negligible risks. Reference Dose-based risk assessment would bring rationality, proportionality, and scientific rigor to crisis management decisions, ensuring that regulatory interventions focus on situations that represent genuine public health concerns rather than theoretical hazards.

Call for Action: time to implement Reference Doses

The time for debate has ended – action is now imperative. Despite scientific consensus on reference doses, European authorities continue delaying while allergic consumers suffer from inconsistent labelling practices. The European Commission has failed to coordinate allergen risk management, creating a fragmented regulatory landscape that confuses both vulnerable consumers and food businesses. Without centralized guidance on evidence-based thresholds, national authorities apply inconsistent standards, undermining the single market principle.

Manufacturers and retailers face an impossible dilemma – legally obligated to prevent cross-contamination but lacking standardized methodology for PAL. Only legislated reference doses can provide necessary legal certainty.

Some member states have moved forward on their own, recognizing the urgent need for clarity. The Netherlands has implemented national guidelines for allergen labelling that embrace reference doses based on scientific evidence. Their approach provides a clear model for EU-wide action, demonstrating how evidence-based thresholds can be successfully incorporated into practical guidance for food businesses while improving protection for allergic consumers.

Despite unprecedented consensus among patient organizations, scientific bodies, and industry, regulators continue citing the need for ‘more research’ or suggesting that the EU should wait for the Codex Alimentarius Committee for Food Labelling (CCFL) to decide – a process that could take years – as justification for inaction. Such delaying tactics are not tolerable when we already have robust scientific evidence and practical examples of implementation. We urge the European Commission to follow the Dutch example and mandate EFSA to develop guidelines incorporating ED05-based reference doses and rapidly transform these into binding legislation.

For 17 million Europeans with food allergies, further delay impacts their daily lives and fundamental right to safe food choices. Concerned citizens and professionals can support this effort by contacting their national food safety authorities and elected representatives to demand the implementation of reference dose-based approaches to allergen management.

#Égalité!

Dario Dongo

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