handbook of food allergen detection and control || food allergen risk assessment and management

Handbook of Food Allergen Detection and Control. http://dx.doi.org/10.1533/9781782420217.1.41Copyright © 2015 Elsevier Ltd. All rights reserved.

Food allergen risk assessment and management R. W. R. Crevel Unilever , Sharnbrook, UK

3

3.1 Introduction

Clinical recognition of food allergy dates back to the beginning of the 20 th century (Prausnitz and Küstner, 1921 ; Loveless, 1950 ). However, while it was known that patients could suffer extremely severe and sometimes fatal reactions following ingestion of minute amounts of the offending food, acknowledgement of food allergy as an important public health problem only occurred in the last decade of the 20 th century. Important milestones refl ecting this process include the FAO–WHO Consultation (FAO, 1995 ), which defi ned the major allergenic foods of public health importance, and the revision of the Codex general standard for labelling (Codex Alimentarius, 1999 ), which incorporated those foods and declared that they must always be labelled whenever present as ingredients. A major factor in the increased concern about food allergy is probably the rise in the prevalence of atopic disease (Lewis et al ., 1996 ), of which IgE-mediated food allergy can be considered a manifestation. The prevalence and incidence of food allergy and the number of severe reactions (Chafen et al ., 2010 ; Venter and Arshad, 2011 ) appears be increasing, although the lack of sound baseline epidemiological data precludes fi rm conclusions. The new perception of food allergy has been accompanied by the recognition that the solution to the problem lies with collaboration between all the stakeholders, including those with a food allergy and those who look after them, clinicians, public authorities and the food industry.

Many factors infl uence the development of allergy to common foods. However, these are outside the scope of this chapter, which is concerned with assessing the risk of eliciting reactions in people who already have an allergy. In this context, the ultimate aim for all stakeholders is to prevent people with food allergy reacting to the allergens to which they are sensitised. This can be achieved in two complementary ways. One is to ensure accurate allergen declaration through labelling, so that sufferers can avoid the relevant foods. The other is to ensure that the unintended presence of specifi c allergens is rigorously managed to ensure that any risk posed is limited and well understood. Both these requirements can be fulfi lled only by detailed knowledge of the composition of products. The process of food manufacture is extremely complex. This complexity derives from several factors, including material sourcing, processing, effi cient use of equipment and other resources, product formulation and food safety requirements. Managing allergen risks requires an integrated approach, which takes into account all these factors throughout the supply chain, from ingredient suppliers through to retailers, and ultimately the consumer.

42 Handbook of Food Allergen Detection and Control

Total avoidance of cross-contact and therefore of the unintentional presence of specifi c allergens is often not practicable. Managing allergen risks therefore requires an analysis of the risk arising from residual allergen and, where appropriate, a full quantitative risk assessment. However, until fairly recently considerable doubt reigned about the feasibility of such an assessment. Data regarding how much was needed to trigger a reaction were extremely scarce, as well as being of poor quality. Anecdotal reports suggested that extremely small amounts could result in severe, indeed occasionally fatal, reactions. This lack of knowledge and resulting uncertainty engendered considerable fear and anxiety both in those with food allergies and those tasked with managing them. Although knowledge of minimum eliciting doses for many allergens remains sub-optimal, it is now generally recognised that quantitative risk assessment is practicable. Knowing how much allergen is present in a product is a key element in this assessment, and in the subsequent management of the allergen risk. This chapter will focus on the derivation of safe reference doses from available data and how to translate the requirement for safe products into practical allergen management.

3.2 Food allergy as a public health issue

3.2.1 Food allergy and food intolerance

Food allergy forms part of a wide spectrum of adverse reactions to foods, which also includes microbial and chemical toxicity, pharmacological effects and those due to errors of metabolism, as well as idiosyncratic reactions (EAACI classifi cation) (Figure 3.1 ) (Bruijnzeel-Koomen et al ., 1995 ). Reactions which are attributable to neither toxic mechanisms nor allergy are often referred to as food intolerance, but are also frequently confused, possibly because the symptoms can often be the same.

Food allergy refers to an immune response to a food, where encounter with that food results in an adverse (allergic) reaction. Foods can produce many different types of immune and allergic responses. However, the public health concern lies largely with those in which formation of IgE antibodies to proteins in the food occurs, which

Figure 3.1 Classifi cation of adverse reactions to foods according to the European Academy of Allergy and Clinical Immunology (Bruijnzeel-Coomen et al ., 1995 ).

Adverse reactions to foods

Non-toxic

Immune-mediated(food allergy)

Non-IgE-mediated IgE-mediated Enzymatic Pharmacological Undefined

Non-immune-mediated(food intolerance)

Toxic

Food allergen risk assessment and management 43

are then implicated in immediate-type reactions on subsequent exposure. Allergic reactions mediated by IgE can vary from very slight, indeed barely perceptible, to severe and occasionally fatal, depending on the dose, the individual and other factors. Food allergy affects a higher proportion of children than adults (Sicherer and Sampson, 2010 ), and reactivity to some allergenic foods, such as milk and egg, tends to be largely outgrown, while allergy to others, such as peanuts, generally persists (Venter and Arshad, 2011 ). Little is known about why allergy to certain foods develops, although exposure and its pattern, the characteristics of the implicated proteins, but also those of the affected individual, such as atopy, all play a role. The range of minimum doses (minimum eliciting doses–MEDs, thresholds) required to elicit a reaction in allergic people spans at least six orders of magnitude, based on data from controlled food challenges. Until recently, the distribution of these doses among the allergic population remained largely uncharacterised, making risk assessments arduous and fraught with considerable uncertainty (EFSA, 2004 ; Crevel et al ., 2008 ; Threshold Working Group, 2008 ). However, recent work analysing results from double-blind placebo-controlled food challenges (DBPCFC) conducted under well-defi ned conditions demonstrates that suffi cient data are available to characterise the response to many regulated allergenic foods on the EU list (Taylor et al ., 2009, 2010, 2014 ; Allen et al ., 2014 ).

3.2.2 Mechanisms of IgE-mediated food allergy

All allergic responses are characterised by two phases: sensitisation and elicitation. During the sensitisation phase, the immune system recognises a harmless component of the allergenic food (almost invariably a protein) as foreign, resulting in a series of events culminating in the production of circulating IgE antibodies and their distribution around the body. These IgE antibodies do not all remain in the blood and lymph, but attach themselves via a specialised receptor (denoted Fc ε R1) to specifi c types of cell, in particular mast cells. During the elicitation phase, allergenic protein cross-links IgE antibodies bound to mast cells, resulting in the release of chemical mediators which then cause the symptoms of an allergic reaction (Figure 3.2 ).

Coeliac disease is grouped with food allergy for purposes of allergen management although clinically it is classed as an auto-immune disease rather than an allergy. People with coeliac disease are unable to tolerate in their diet the proteins known as gluten found in wheat and related cereals. In susceptible individuals, exposure to gluten results in the formation of auto-antibodies against certain endogenous proteins, and the ensuing reaction ultimately leads to atrophy of the lining of the small intestine (villus atrophy) which greatly reduces its ability to absorb nutrients.

3.2.3 Symptoms of food allergy

The symptoms of an IgE-mediated reaction refl ect directly the infl ammatory response to the chemicals released from cells such as mast cells. They can affect one or more organ systems, including the skin, the gastrointestinal tract, the respiratory and cardiovascular system, with skin reactions being among the most frequently


implicated. Symptoms range from pruritis or tingling in the mouth, which would not be perceptible other than to the allergic person, through eczema and rashes, angioedema, shortness of breath to the drop in blood pressure and cardiovascular collapse characteristic of anaphylactic shock. Gastrointestinal symptoms include stomach cramps, nausea, vomiting and diarrhoea.

While coeliac disease may mimic some of the symptoms of food allergy, the underlying mechanisms are very different, as is the timing of reactions after consumption of gluten. Symptoms thus include diarrhoea, bloating, abdominal pain, weight loss, failure to grow at the expected rate and malnutrition. In adults, fatigue is common. The speed with which symptoms occur after ingestion depends to some extent on the dose, but reactions are never of the rapid and catastrophic type like anaphylaxis that is associated with IgE-mediated allergies.

3.2.4 Prevalence of food allergy

One reason why food allergens need to be managed is that they constitute a threat to public health. One aspect of this threat is the potential severity of reactions and consequences for the quality of life of sufferers, but another is its prevalence in populations (Figure 3.3 ). Until recently, estimates of the prevalence of food allergy as a whole and allergy to individual foods were scarce and provided an inadequate

Figure 3.2 Mechanism of allergic sensitisation and elicitation.

Initial contact with anallergen, e.g. pollen,‘sensitises’ the immunesystem leading toproduction of specificantibodies (IgE) whichrecognise the allergen

Upon re-exposure,allergen cross-links IgEon the surface of mastcells which then releasehistamine and othermediators which causethe symptoms of allergy

Allergen

Allergen-specific allergic antibody (IgE)

Allergen cross-linking two IgEantibodies on the surface of a mastcell which contains histamine

Mediator release

Antigen-presenting cell

T cell

B cell

Y YYY

YY

Food allergen risk assessment and m

anagement

45

Figure 3.3 Prevalence of food allergy across the world.

USA (children 0−18) 3.9 %(Branum et al., 2008)

Australia (infants 0−1) 10 %(Osborne et al., 2011)

China (infants 0−2) 7.7 %(Hu et al., 2010)

China (infants) 3.8 %(Chen et al., 2011)

South Korea(infants 0−1) 5.3 %(Kim et al., 2011)

Germany (adults) 2.6 %(Zuberier et al., 2004)

Denmark (children) 2.6 %(Osterballe et al., 2005)

France (adults) 3.24 %(Kanny et al., 2001)

UK (children) 3.2 %(Venter et al., 2006)USA (children 0−18) 3.8 %

(Gupta et al., 2011)


basis for risk assessment and management (Rona et al ., 2007 ). One particular problem was the considerable over-estimate arising from self-reporting compared to formal diagnosis by food challenge. However, recent studies in several regions and continents, including Europe, the USA and Australia, have provided high-quality data. Thus a cross-sectional study in over 40,000 children (up to 18 years) by Gupta and colleagues (Gupta et al ., 2011 ) in the USA indicated an overall prevalence of 8 %, of which about 40 % reported having experienced a severe reaction. A recent meta-analysis (Chafen et al ., 2010 ) estimated prevalence of food allergy in the USA as not less than 1–2 % and not more than 10 %, thus potentially affecting anywhere between three and 30 million people. Peanut, milk and shellfi sh were the foods implicated most frequently. Osborne and colleagues (Osborne et al ., 2011 ) demonstrated that over 10 % of infants up to 1 year old in Australia suffered from a challenge-verifi ed food allergy.

Countries with emerging economies also show similar trends. Kim et al . (2013) estimated that 5.3 % of a birth cohort of Korean infants suffered from a food allergy, while Hu et al . (2010) reported a rise from 3.5 % to 7.7 % in challenge-verifi ed food allergy from 1999 to 2009 in cross-sectional studies of infants up to 2 years old in Chongqing (China). Thus, as the social and environmental changes seen in Europe and the USA spread to other parts of the world, they will likely start to experience similar increases in the prevalence of food allergies, as seen for instance in Hong Kong and Singapore. Despite the recent promising news about specifi c immunotherapy for food allergens, avoidance remains the primary means whereby allergic consumers protect themselves. This requires either that they know that the allergen is present (labelling) or that its presence must be reduced to the point where it poses a negligible risk, hence the importance of defi ning MEDs and their distribution in populations.

Coeliac disease was long thought to be rather rare, but recent studies indicate that it may affect over 1 % of the population (Bingley et al ., 2004 ; Hu et al ., 2010 ; Lamireau and Clouzeau, 2013 ), but much of it is undiagnosed.

3.3 Risk assessment for food allergens: background and issues

Allergy was long thought to be an area where the conventional risk assessment paradigm could not be applied. Indeed, a publication on the Threshold of Toxicological Concern (Kroes and Kozianowski, 2002 ) acknowledges that

a particular challenge is the evaluation of food allergens and components causing other forms of intolerances, and how to determine the levels present and actual intakes vs the limited knowledge of amounts needed for induction or elicitation of a response.

The authors in fact decided to exclude consideration of this issue from their paper. Work which started in the late 1990s challenged this perception and demonstrated

that quantitative assessment of the risk from allergens was possible. Consideration


of the risk assessment paradigm revealed that the most striking gap was in the characterisation of the relationship between the dose of allergen, the proportion of the allergic population that reacted to that amount and the nature of those reactions. The feasibility of statistical modelling of dose distributions using data on MEDs from food challenges was demonstrated by Bindslev-Jensen and collaborators (Bindslev-Jensen et al ., 2002 ) and its interpretation further elaborated by Crevel and colleagues (Crevel et al ., 2007 ). This approach, with its further refi nements (Taylor et al ., 2009, 2010 ) has analogies with the benchmark dose (BMD) approach used in other areas of toxicology (Madsen et al ., 2009 ) and has proved very successful in characterising the hazard posed by several allergens of public health importance, while avoiding the diffi culties of defi ning an absolute [population] threshold or no observed adverse effect level (NOAEL) experimentally.

3.4 Development of risk assessment for food allergens

As previously mentioned, the concept of assessing the risk posed by food allergens is relatively recent, but its evolution can be traced back through the activities of various offi cial and scientifi c organisations. This evolution matches the acquisition of the various types of information required to undertake a risk assessment, based on the conventional risk assessment paradigm.

3.4.1 Evolution of food allergen risk assessment

The evolution of risk assessment for allergens can be divided into three broad, but overlapping phases. The fi rst phase from about 1990 to 1999 basically identifi ed the hazard and those foods which were most signifi cant in this respect. The second phase, hazard characterisation, stretched from 1997 onwards and continues to this day as new allergens are investigated (Bindslev-Jensen et al ., 2002 ; Crevel et al ., 2007 ). Risk characterisation is the third phase, starting in the mid-2000s with the acceptance of established risk assessment approaches as valid for food allergens (Madsen et al ., 2009 ) .

Initially, specifi c allergenic foods were identifi ed as a hazard through the FAO–WHO consultation of 1995 (FAO, 1995 ), using the very limited information available at the time to designate those foods and food groups considered to pose the greatest threat to public health at a global level. This hazard identifi cation step was further given offi cial recognition with the incorporation of those foods into the Codex Alimentarius global standard for labelling as ‘known to cause hypersensitivity’ and therefore required ‘always to be declared when present as ingredients’. However, once a hazard has been recognised, assessing and managing the resulting risk requires that it be characterised. Here, food allergens differ from most other substances that may be present in food insofar as characterisation is based on human data rather than animal studies. Very early evidence pointed to the importance of dose, with the studies on the allergenicity of various vegetable oils (Taylor et al ., 1981 ; Bush et al ., 1985 ;


Hourihane et al ., 1997 ) indicating both that there existed levels of allergenic protein below which reactions did not occur in appropriately sensitive allergic individuals and that those individuals differed in their sensitivity, as expressed by their MEDs. Another milestone was the compilation by Taylor and colleagues (Taylor et al ., 2002 ) of data on MEDs (thresholds) for a range of foods (principally those identifi ed by the FAO–WHO consultation) that had been collated by clinicians through the use of the DBPCFC for diagnosis.

Review of these and other data led regulatory authorities to acknowledge the existence of thresholds, although they deemed the data inadequate at the time to defi ne them for regulatory purposes (EFSA, 2004 ; Threshold Working Group, 2008 ). However, a critical development was the demonstration that challenge data, provided they were obtained from a suffi ciently large population, could be described by dose distributions fi tted by well-understood statistical models (Bindslev-Jensen et al ., 2002 ). While the use of such dose distributions to characterise food allergen hazards needed careful application to avoid erroneous conclusions (Crevel et al ., 2007 ), the US FDA was one regulatory authority to acknowledge that such approaches promised to be the most robust in addressing the issue of the development of regulatory thresholds (Threshold Working Group, 2008 ). Having identifi ed a way of characterising the hazard, the totality of risk assessment could be considered through incorporation of the exposure dimension. In line with this, several groups have investigated probabilistic approaches, which take into account not only the maximum exposure value (e.g. assuming all of a product run contains unintended allergen at the maximum level), but also the distribution of unintended allergen presence across a product population (Spanjersberg et al ., 2007 ; Kruizinga et al ., 2008 ; Rimbaud et al ., 2010 ; Remington et al ., 2013a ).

3.4.2 Identifying the hazard

Hazard identifi cation in the case of food allergens is relatively simple. As mentioned above, food allergens somewhat uniquely are both identifi ed and characterised on the basis of human data rather than animal studies. These data include clinical reports from a range of sources including, but not limited to, allergy clinics, people who experience reactions, etc. Two principal issues need to be considered in relation to these data: correct attribution, which can be diffi cult if the allergenic food is consumed with or as part of other foods, which makes it diffi cult to identify the actual causative food and, subsequently, deciding whether the number, type and pattern of reactions constitutes a public health issue. The recently completed Europrevall project illustrates the point that not all common allergenic foods are currently considered of suffi cient public health interest to warrant the ultimate recognition of being subject to mandatory labelling. Thus many reactions in clinics across Europe relate to fruits and some of those are even quite severe (e.g. kiwi), yet because they are used in such a way that they can be readily avoided, they are not up to now considered appropriate for mandatory labelling. In contrast, molluscs are subject to mandatory labelling, but appear to provoke a comparatively small number of reactions.


3.4.3 Characterising the hazard

Since around the turn of the century, much progress has been made in both generating data on individual thresholds and understanding the nature of the risk posed by allergens. In parallel, tools to analyse these data and apply them in a public health context have been developed. As detailed earlier, allergic reactions can differ considerably in the symptoms they provoke. Clearly, from the perspective of risk management, more severe reactions occasion considerably more concern and the tolerable frequency of such reactions will be much lower than for milder reactions (Madsen et al ., 2010, 2012 ). Thus characterisation of allergen risk must take into account both the probability that a reaction could occur to a defi ned dose of allergen and the probability that such a reaction would constitute a threat to health. As discussed earlier, initial belief, largely based on well-publicised case reports of severe reactions to low doses, was that allergens were not amenable to classical dose–response relationships, in particular because the responses of allergic individuals appeared to vary considerably and without obvious cause from one exposure to the next. However, such a conclusion is unwarranted, since these observations do not take into account other variables affecting the reaction, including dose. Inability to characterise the hazard from allergens was thus a critical initial data gap, which thwarted early attempts at quantitative risk assessment. However, lack of appropriate methodology to analyse responses to allergens was of equal importance, particularly since it was very apparent that the range of doses to which allergic people could respond was very wide and that a true level (NOAEL) would be both unlikely to be determined experimentally and too low to serve as a basis for operational management.

An early insight was the concept of building cumulative population dose distributions using data on MEDs from controlled diagnostic food challenges (Bindslev-Jensen et al ., 2002 ) and modelling them statistically. This approach has proved very successful in fi lling this gap for several allergens, while avoiding the diffi culties of defi ning an absolute [population] threshold or NOAEL experimentally, and is now widely accepted. This concept resembles the BMD approach applied to more conventional toxicological endpoints and can thus generate data which can be used to help risk management. Like the BMD approach and unlike the classical safety assessment approach, it makes use of all the data available on the population of interest and thus provides more robust characterisation of the hazard. The principle of this approach consists of plotting the individual MEDs from controlled food challenges against the proportion of the allergic (test) population reacting in order to derive a cumulative population dose distribution which can then be fi tted to different statistical models (Crevel et al ., 2007 ; Taylor et al ., 2009 ). This method helped to defi ne eliciting doses corresponding to amounts of allergenic protein predicted to cause reactions in small proportions of the allergic population (usually 5 % or less). These analyses confi rm that while the range of reactivity spans amounts from micrograms to grams, as revealed by the actual challenge data, the proportion reacting to very low amounts is actually quite small. For peanut, the most extensively studied allergenic food, data on 450 patients were modelled (Figure 3.4 ). These indicated that 10 % of peanut-allergic patients from clinics react to a dose of between 2.5 and 4 mg


of total peanut protein, and 5 % to a dose of around 1.25 mg (Taylor et al ., 2009, 2010 ). These fi ndings have been extended to a larger population and range of allergenic foods as part of the VITAL 2.0 work (Allen et al ., 2014 ).

3.4.4 Voluntary Incidental Trace Allergen Labelling (VITAL) and the elaboration of reference doses

The Voluntary Incidental Trace Allergen Labelling (VITAL) scheme, developed by the Allergen Bureau of Australia and New Zealand (Allergen Bureau), holds a unique place in the progress towards harmonised limits for unintended allergen presence. In its fi rst iteration (2007), it proposed a series of allergen action levels (concentrations), based on the compilation of LOAELs published by Taylor et al. (2002) and cited by the US FDA (Threshold Working Group, 2008 ), deriving the said action levels using a classical safety assessment approach and applying a 10-fold uncertainty factor to those LOAELs. Given the both the quality and quantity of data then available, this was probably the only realistic approach.

The basis of the VITAL action levels was revised by a Scientifi c Expert Panel (VSEP), commissioned by the Allergen Bureau, which integrated the considerable amount of new, high-quality data that had become available since the original formulation of VITAL. The use of the VSEP also aimed to provide a more robust appraisal of these data, based on the most advanced methodologies and thereby place any recommendations on a sounder scientifi c footing, helping to foster their acceptance

Figure 3.4 Example of dose distribution (peanut) with illustration of ED01 (from Taylor et al . 2009 ).

100%

90%

80%

70%

60%

50%

40%

30%

ED 01

20%Cum

ulat

ive

perc

enta

ge o

f res

pons

es

10%

0%0.01 0.1 1 10

Discrete CumulativeLog-normal dose of protein (mg)

100 1000 10,000 100,000


by other stakeholders. The Panel undertook a thorough review of the challenge data available for allergenic foods on the EU list in order to assure wide international relevance. Data inclusion and exclusion criteria were carefully defi ned and care was taken to ensure that consistent criteria were applied across studies to the defi nition of subjective and objective reactions for the purpose of identifying the MEDs to be used in the analyses. Three different statistical curve-fi tting models (lognormal, log-logistic and Weibull) were considered, with the fi nal recommended reference dose for each allergen based on the values predicted by each of the curve-fi ts, but also using expert judgement to take into account goodness of fi t at the low-dose end of the curve, which is of most relevance to the selection of a protective benchmark (reference doses). The statistical technique called Interval Censoring Survival Analysis (Taylor et al ., 2009 ) was applied to the curve fi tting. This allows for the reality that MEDs fall within an interval between the recorded dose at which a reaction was observed and the immediately preceding dose. It also permits use of data where actual individual thresholds are not known (for instance where someone reacted at the fi rst dose or failed to react at the highest dose, despite being demonstrably allergic) and thus reduces the potential biases from excluded data, making for a more robust analysis.

Reference doses themselves were based where possible on a level protecting 99 % of the allergic population against any reaction, i.e. the value corresponding to the population ED01. However, this was only possible for four allergenic foods (peanut, egg, milk and hazelnut), because of the amount of data required to avoid extrapolation beyond the experimental data with its attendant issues for the robustness of any calculations (Crevel et al ., 2007 ). For the remaining foods, the lower boundary of the 95 % confi dence interval (LCI) of the population ED05 was used instead. This made it possible to defi ne reference doses for all but three allergenic foods on the EU list (Table 3.1 ) (Allen et al ., 2014 ; Taylor et al ., 2014 ).

Of course, any choice of reference doses or similar benchmarks contains an arbitrary component since it represents a judgement about what risk is accepted (Madsen et al ., 2010 ) and a critical element will be to accurately communicate this risk to other stakeholders in order to ascertain its wider acceptability. It is useful therefore to consider how the VITAL 2.0 reference doses compare to other low doses and their clinical effects. The Reference dose for peanut (0.2 mg) is 25 times lower than the lowest dose which Wainstein et al . (2010) reported as leading to anaphylaxis. Another study, in which 869 infants were challenged with milk, egg, wheat or soy, is informative (Rolinck-Werninghaus et al ., 2012 ). The authors used a low-dose challenge protocol, but started at 3–5 mg of protein for egg and milk. While they observed approximately 10 % of fi rst dose reactions, reassuringly, only one twentieth to one tenth of those (i.e. 0.5–1 % of the total) were classed as severe. To put the VITAL 2.0 reference doses in perspective, they were between 33 and 166 times lower than those starting doses.

3.4.5 Risk assessment, including probabilistic approaches

Risk assessment brings together hazard characterisation and exposure to the hazard to determine the likelihood of an adverse effect and the nature of that effect. Risk


Allergen Reference dose (mg protein)

Basis of reference dose

50 g serving size: action level (ppm)

250 g serving size: action level (ppm)

Peanut 0.20 ED 01 4.0 0.80

Milk 0.10 ED 01 2.0 0.40

Egg 0.03 ED 01 0.6 0.12

Hazelnut 0.10 ED 01 2.0 0.40

Soy 1.00 ED 05 (95 % LCI) 20.0 4.00

Wheat 1.00 ED 05 (95 % LCI) 20.0 4.00

Cashew 2.00 ED 05 (95 % LCI) 40.0 8.00

Mustard 0.05 ED 05 (95 % LCI) 1.0 0.20

Lupin 4.00 ED 05 (95 % LCI) 80.0 16.00

Sesame 0.20 ED 05 (95 % LCI) 4.0 0.80

Shrimp 10.00 ED 05 (95 % LCI) 200.0 40.00

Celery Insuffi cient data

Fish Insuffi cient data

Molluscs No data

Table 3.1 VITAL reference doses

Sources: after Allen et al . (2014) , Taylor et al . (2014) .

assessment for food allergens has been extensively discussed in recent years as part of the Europrevall project (Madsen et al ., 2009 ), as well as in an Expert Group set up by the European Branch of the International Life Sciences Institute (ILSI-Europe) (Hattersley et al ., 2014 , Crevel et al, 2014a, b ). Three main approaches were identifi ed: safety assessment, establishment of a BMD and full probabilistic modelling. While the approaches span a range of complexity and data requirements and vary in the extent to which they produce quantitative risk estimates, each has a place in food allergy risk assessment.

3.4.5.1 Safety assessment

The safety assessment approach corresponds to the classical toxicological evaluation of chemicals. It requires data that defi ne a NOAEL, or at least a lowest observed adverse effect level (LOAEL). This value is then divided by uncertainty factors that refl ect the expected variability within the human allergic population to derive an intake that would be safe when consumed on any one eating occasion (e.g. in a portion


of a food product). Application of such an approach was illustrated by the FDA Threshold Working Group (Threshold Working Group, 2008 ). In that example, a ‘safe’ dose of peanut protein was estimated as 0.3 μ g of peanut protein per person per eating occasion. The original VITAL scheme was also a variant of this approach, although without the same degree of conservatism in its assumptions about uncertainties, with the result that the derived benchmarks were more realistic and achievable. This approach benefi ts from its long and successful application to the world of chemical risk assessment, as well as its simplicity and inherent conservatism and its relatively frugal data requirements. However, it also fails to make best use of data and, more signifi cantly, could result in such low benchmarks that they would neither be verifi able with current analytical techniques nor, more importantly, usable for practical management of unintended allergen presence in most circumstances. However, it retains value as a fi rst pass, since it reveals whether a more elaborate and detailed risk assessment is necessary.

3.4.5.2 Benchmark dose

The Benchmark dose, together with calculation of a margin of exposure (MoE), involves the construction of a dose-distribution curve which is fi tted to an appropriate curve-fi t, enabling the derivation of a point of departure (PoD) as the basis for the calculation of the MoE (Crump, 1984 ). As indicated, it makes use of the complete available dataset and therefore requires more and higher quality data than the safety assessment approach. Uncertainty arising from the data and its quality are readily incorporated as confi dence intervals around the estimate of the BMD, and indeed the lower boundary of that interval (BMDL) is commonly used as the PoD in preference to the BMD itself. As discussed previously in relation to the use of statistical dose distributions, it is important that the BMD lies within (or very close to) the experimental data points, so that it is less sensitive to the choice of mathematical model. Risk assessment using the BMD or BMDL involves estimating the exposure as a point value and dividing it by the BMD or BMDL to derive a MoE, which can be used to make a decision on safety.

Like the safety assessment approach, the BMD approach does not generate a quantitative estimate of risk. Use of dose-distribution modelling represents a variant of a BMD approach, but it has not generally been used to derive MoEs, but rather to characterise the population response to an allergen. While the amount and quality of food challenge data are critical in deriving a sound and robust BMD, the quality and selection of the exposure data will clearly strongly infl uence the MoE and therefore any conclusions that are drawn from it.

The strengths of the BMD approach lie in the full use of data which it makes, thereby rewarding good study design. Similarly to the safety assessment approach, it is easy to understand and apply once a BMD has been calculated. On the other hand, the method depends heavily on the quality of the data and an understanding of the population used to build the dose distributions, since this will determine how valid any BMD or other parameter is when evaluating the extent to which they protect health. In addition, if MOEs are used, then good-quality exposure data are critical to the validity of any conclusions. In common with the safety assessment approach, it


also does not generate true quantitative risk estimates. However, the MoE can clearly inform the requirements for a further, more elaborate and quantitative risk assessment or, alternatively, risk management measures to increase the MoE.

3.4.5.3 Probabilistic risk assessment

Probabilistic risk assessment for allergenic foods, fi rst described conceptually by Spanjersberg et al . (2007) , has become feasible with the growth in the amount and quality of challenge data and the development of techniques to combine input variables as distributions and generate from them the probability that a defi ned number of reactions will occur. At their most basic, such models use the distribution of MEDs in the allergic population, the distribution of unintended allergen among the affected products and the distribution of the amounts of the relevant food(s) consumed on a single eating occasion to generate, using a Monte Carlo simulation, a distribution from which can be calculated the likely number of allergic reactions to the unintended allergen. More elaborate models can include the probability that the product in question is consumed, as well as the prevalence of reactivity to the allergen of interest. Thus the output can be tailored to specifi c requirements, ranging from a risk assessment for a specifi c product to decide whether a recall is necessary to a full public health impact of choosing a specifi c benchmark for application of precautionary labelling, for instance. Recent developments have incorporated Bayesian approaches to refi ne the input probabilities, such as the prevalence of allergy and whether or not a product is consumed, and provide better estimates of those variables (Rimbaud et al ., 2010 ; Remington et al ., 2013b ). The model thus calculates the most likely number of allergic reactions that might result from the unintended presence of an allergenic constituent in a food product.

One particular advantage of this approach is that it can quantitatively link information on allergen concentrations in food products to the risk of a reaction. This addresses one of the main disadvantages of the deterministic approaches. Often a worst case scenario (e.g. most reactive individual together with highest intake) is described and leads to a conclusion that an allergic reaction cannot be excluded. However, such a conclusion is of limited value to risk managers, since it neither indicates the likely number of reactions, nor specifi es their nature and therefore their public health impact, limiting their value in deciding on mitigating measures. From a technical point of view, probabilistic approaches make optimal use of all available information, but the counterpart is that they also require most data to function effectively. Because they integrate uncertainty into their outputs, specifi c safety factors are not needed as they are inherent in the outputs. The quality of the outputs, and therefore of the conclusions that can be drawn, depend even more heavily on a good understanding of the data and their quality, while application of the methodology requires the highest degree of technical expertise of the three approaches.

A current issue is that probabilistic models predict vastly more reactions than apparently occur, or at least come to the knowledge of public health organisations. Two possible reasons exist for this; the fi rst is that the dose-distribution inputs predict the total number of reactions, irrespective of their nature, while those which are likely


to be noted and give rise to public health concern represent a subset of more severe reactions. The other reason may lie with the extent to which the allergic populations which have been used to model the dose distributions are truly representative of the overall allergic population. This is illustrated in Table 3.2 using the results of Rimbaud et al . (2010) .

3.5 Practical aspects of risk assessment

The protein component of allergenic ingredients is the determinant of allergenic risk and, as discussed above, allergic individuals react to the amount consumed on any one eating occasion (i.e. meal, snack, etc.). For any given allergenic ingredient, therefore, the starting point of the risk assessment is the protein content and the amount that will be present in a portion (or amount eaten on any one occasion). The protein content of different types of ingredient should be available from the general specifi cation provided by the supplier, both for intended and unintended allergens. However, in the event that the supplier cannot readily provide this information, generic information is available from a variety of sources on food composition. Taylor and colleagues summarised generally available data on several allergenic foods some

Variable Value ( P 2.5 , P 97.5 ) Units

Peanut exposure Adults 0.2 (0.0024, 1.10) mg/occasion/wkChildren 0.2 (0.0028, 1.14)

Prevalence of peanut allergy Adults 0.33 %Children 0.59

Risk of reaction Adults 0.57 (0, 3.61) %/weekChildren 0.61 (0, 3.85)

Predicted number of reactions Adults 19 (15, 23) /10 6 /wkChildren 36 (28, 48)Total for France (popn 60 million) 66 518 /year

Actual number of reactions All food allergies 15 000–30 000 /yearPeanut alone 1 230–2 460

Table 3.2 Probabilistic modelling of peanut contamination in chocolate: calculated yearly incidence of reactions

Sources: after Rimbaud et al . (2010) , prevalence based on Rancé et al . (2005) .


years ago (Taylor et al ., 2002 ) and the values have also been used by the US FDA Threshold Working Group (Threshold Working Group, 2008 ). Values are also available for derived ingredients such as oils derived from allergenic sources (Crevel et al ., 2000 ).

Where allergenic constituents are used as ingredients in foods (i.e. deliberately added), they are required by law to be declared irrespective of the amount present. The focus of risk assessment is therefore on unintended allergens present by cross-contact or otherwise. Thus the next step is to consider how much can be present by cross-contact, usually in a worst case scenario. A typical worst case scenario would be a product without the allergen being made on the same equipment immediately after one with a high concentration of allergen, with any already established cleaning protocol between products being used. As previously discussed, the worst case carryover may be subject to other constraints than allergens, such as taste, colour, etc. Depending on the process and equipment, the proportion of the previous product carried over may be measured by collecting and weighing residual product in the equipment, or the allergen itself can be assayed in the following product. In some cases, the proportion carried over will have been previously established or it may be suffi cient initially to make a reasonable assumption based on other factors such as those already mentioned.

Once a value is available for the proportion carried over, the allergenic protein concentration in the following product can be calculated, as can be the amount in a portion of the product. The amount of allergenic protein can then be compared to the amounts reported to cause reactions and a conclusion drawn about the risk posed by cross-contact, starting with a simple deterministic approach. Although, at the time of writing, no generally agreed reference amounts have been published, dose-distribution data can also be used to derive the likely proportion of allergic consumers reacting to any particular amount of allergenic protein to decide whether the residual risk can be considered low enough. This decision can be based on any one of the approaches, described earlier in this section. For example, soy lecithin is widely used as an emulsifi er in which role it is used at fairly low concentrations in the fi nal product, typically 0.3 %. Soy lecithin used in food must comply with the Codex Standard which stipulates that the concentration of non-hexane extractable matter should not exceed 3000 ppm (3 g/kg). Therefore, a product with a 0.3 % lecithin will contain a maximum of [(3000 × 3000)/1 000 000] i.e. 9 mg/kg of soy protein, assuming that all non-hexane extractable matter is protein. If such a product is produced immediately before a product which does not contain soy, assuming for the purposes of cross-contact risk assessment a carry-over of 1 %, the amount of unintended soy protein will be at most 0.09 mg/kg for the following product. The VITAL reference dose for soy protein is 1 mg, so will be met by any reasonable portion size in this example.

The website of the European Trade Association for Edible Oils and Fats (FEDIOL) also shows a publicly available example of a risk assessment which led to the conclusion that precautionary labelling of edible oils because of the possible presence of peanut proteins from highly refi ned peanut oil was unwarranted ( http://www.fediol.be/data/133916470409COD017Final%20CoP%20on%20allergens%20june%202012.pdf ).


3.6 Risk management

Risk assessment is a critical component of risk management, without which it cannot proceed. That allergens pose a threat to public health and must therefore be managed is now beyond argument. Clearly, it is important that new risks, which may affect even more people, are not created in addressing the risks arising from allergens. Thus a key aspect of allergen management is the need to integrate it into general food safety management. An integrated system is likely to be inherently more effi cient, but it is also absolutely required because the measures required to deal with one safety hazard, e.g. microbiological, may confl ict with those needed to mitigate another, e.g. allergens. Thus wet cleaning is generally extremely effective in reducing allergen contamination, but can lead to severe microbiological problems in dry mix systems. However, more fundamentally, allergens differ from other contaminants with consequences for their management. Unlike those contaminants, allergens can generally be consumed safely by the vast majority of the population in any reasonable quantity and many are also important sources of nutrients, and may also have important functional attributes.

3.6.1 The practice of allergen management

Allergen management implies actively dealing with allergens when making food products so that allergic consumers can make safe choices. This goes well beyond just avoiding the use of allergens or telling the consumer that a product may contain a particular allergen or allergens. Rather, it is about knowing where and what allergens are present throughout the food manufacturing process, whether deliberately or, perhaps even more importantly, unintentionally. It is also about assessing the residual risk if an unintended allergen cannot be completely removed from a product and communicating clearly and accurately that risk to consumers, neither exaggerating it nor playing it down, or requiring them to assess the risk themselves. Allergen management thus concerns the whole supply chain from the farm to the fi nal consumer and requires accurate and comprehensive information about allergens from all those stages. Implementation of allergen management demands signifi cant resources and therefore requires engagement of senior management within companies, as recognised by the Food Safety Management Standard (ISO, 2005 ).

Underlying allergen management, as well as food safety generally, are prerequisite programmes which describe the basic conditions considered necessary to assure safe food production. These include considerations of premises design, hygiene, etc. and will not be described here as they are discussed extensively elsewhere.

Allergen management requires fi rstly identifi cation of all sources of the allergen risks, then assessment of those risks and subsequently their management. This will be an iterative process since, having identifi ed a risk and determined that it is signifi cant, the fi rst step will be to look at ways of reducing it. Allergen risks can occur at all phases of the food manufacturing process, which can be summarised as design, sourcing, manufacture and delivery.


3.6.1.1 Design

At the Design stage, key considerations include product composition and ingredient specifi cation. Typically the allergen ’ s contribution to product functionality should be critically assessed and the feasibility of substitution considered. For instance, if an allergen is present as a fl avour carrier, does an alternative exist which does not use that allergen or uses an allergen already present in the formulation? Ingredient specifi cations are also critical, particularly in respect of unintentional presence of allergens, since risks which are not known about cannot be managed. For instance, a ‘gluten-free’ claim would require assurance from suppliers of absence of gluten, supported by evidence that their ingredients meet appropriate specifi cations, which enable the fi nal product to comply with its description. Another consideration during development is what measures will be needed to manufacture the product so that no additional allergen risks are created in products made in the same factory. This requires consideration of whether a particular manufacturing site already handles a specifi c allergen, or at the limit, even whether the product should be made at all, since the measures needed to control allergen risks could easily make a low-volume product economically unviable.

3.6.1.2 Sourcing

At the Sourcing stage, the critical consideration is obtaining comprehensive, accurate and reliable information about the ingredients, ensuring previously defi ned specifi cations are appropriate. Supplier questionnaires should provide information about their allergen management, including the extent to which they understand and apply processes such as hazard analysis critical control point (HACCP). Absence of management thresholds for allergens has led many suppliers to use disclaimers or ‘may contain’ assertions about possible allergen presence by cross-contact. Such disclaimers and statements need to be critically scrutinised to understand the resulting risk and, where appropriate, quantitative information should be sought to permit a quantitative risk assessment. Periodic audits, either by the company ’ s own auditors or by auditors accredited under the major standards (e.g. BRC, IFS, GFSI), should support this process. Suppliers must also understand that they cannot change a formulation or specifi cation without agreement. Inclusion of provision of appropriate (i.e. suitable for use in risk assessment) allergen information in contractual terms is strongly recommended.

3.6.1.3 Manufacturing

The Manufacturing stage is the one over which the manufacturer has the greatest control, but possibly also the most complex. Detailed knowledge of the design and operation of the plant are imperative to successful management of allergens, particularly where it was designed before allergens were considered a food safety issue. Critical elements include identifying where the risk of allergen cross-contact arises and devising systems to minimise it. Risk matrices can be a very useful tool in systematically evaluating the allergen status of different unit operations and thereby


identifying those which give rise to the greatest risk. Typically, one dimension scores the likelihood of allergen presence, while the other scores the likelihood that it would remain undetected (Table 3.3 ).

Parts of the manufacturing system through which the ingredients do not obviously fl ow can seriously challenge attempts to manage allergens as well as validation studies. The fi lters used to protect the machinery in vacuum/pneumatic material transport systems are a good example. Product residues will build up on them and, unless they are replaced or cleaned at appropriate intervals, they can act as reservoirs which will release material, including allergenic ingredients, at random intervals into product which should not contain it. As a result, the quantitative risk assessment based on validation studies can be totally negated. Measures to minimise cross-contact include allergen segregation in both space and time, including careful design of storage areas to minimise potential contamination in the event of spills, dedicated equipment and, occasionally, whole lines or facilities. Production scheduling effects separation in time and is a powerful measure in allergen management. However, the complexity involved should not be under-estimated, since allergens are not the only variable that needs to be taken into account, with fl avour and colour among two other important considerations. Of course each allergen needs to be considered individually too.

Cleaning also separates allergens from other components and each other, both in time and space. Indeed cleaning can also be considered as a critical control point in a HACCP plan and subject to validation and verifi cation. Validation usually involves analytical measurements, but can also be a check that the equipment is visually clean.

3.6.2 Allergen control plans

Allergen control plans summarise all the necessary elements that must be checked in order to determine the allergen status of a specifi c facility and defi ne the control measures that may be needed. It can thus be developed as part of the more general HACCP plan, considering the fl ow of materials through the factory. The allergen control plan can therefore follow the schema outlined above and should cover questions such as:

• Raw material sourcing: • Is the specifi cation of raw materials and semi-fi nished ingredients accurate and

comprehensive with regard to allergens? • Does the specifi cation provide enough information to assess the allergen risks accurately,

given the use of the raw material? • Have all allergenic materials that are used at the facility been categorised?

• Raw material receipt and storage: • Do procedures exist to assure integrity of the separation between raw materials during

transport (i.e. no cross-contact during this stage)? • Do procedures exist to ensure that raw materials are correctly assigned for storage

location? • Is storage designed to ensure segregation of allergens from other raw materials and each

other and maintain it in case of failure to contain them (e.g. damage to containers)?


Allergen ranking matrix

Det

ecta

bilit

y

5 [25] [50] [75] [100] [125]

4 [20] [40] [60] [80] [100]

3 [15] [30] [45] [50] [75]

2 [10] [20] [30] [40] [50]

1 [5] [10] [15] [20] [25]

1 2 3 4 5

Probability

Severity × probability × detectability = RPN

Probability scale

Score Probability of failure

5 Extremely likely

4 Very likely

3 Somewhat likely

2 Very unlikely

1 Remote

Detectability scale

5 Extremely likely NOT to detect failure with current controls

4 Very likely NOT to detect failure with current controls

3 Somewhat likely NOT to detect failure with current controls

2 Unlikely NOT to detect failure with current controls

1 Remotely possible NOT to detect failure with current controls

Table 3.3 Example of risk matrix scoring

Note: In this example, a severity score of 5 was given due to the potential consequences of allergen ingestion.

• Manufacturing operations: • Are material fl ows comprehensively described and understood, so that all possibilities

for cross-contact have been identifi ed? This should include possible reservoirs where materials can be held up and subsequently released, as well as shared pipework, etc.


• Have all operations where cross-contact can take place been identifi ed? • Have the opportunities for scheduling (e.g. non-allergen before allergen) been explored

and implemented? • Do positive measures exist to ensure that formulations are correctly made up, in

particular to avoid an allergen being added by mistake? • Is work in progress properly labelled? • Are procedures in place to ensure that rework of products containing allergens is

controlled? • Do procedures exist to avoid mispackaging, with resulting incorrect allergen declaration? • Do protocols exist for all cleaning operations and have they been validated? • What measures exist to verify cleaning operations? • Has a study to validate allergen management at the facility been conducted and

documented? • Are there procedures to avoid inadvertent introduction of allergens into manufacturing

areas (e.g. on clothing, tools, etc.)? • Personnel and training:

• Have all personnel, including part-time and temporary staff, undergone training in aspects of allergen management to a level appropriate to their role?

• Is basic allergen training included in staff induction procedures appropriate to each role?

Finally, measures which can only be implemented as part of a longer term plan include equipment and factory design.

3.6.2.1 Delivery

The Delivery stage is the one at which the product is brought to the consumer. It is diffi cult to minimise the importance of allergen considerations at this stage and failures at this point account for a signifi cant proportion of allergen alerts (for example UK Food Standards Agency reports). Critical attention to artwork is needed to ensure that the correct packaging has been used and that all allergens are listed and clear to the consumer or purchaser. The packaging should be checked for incompatible elements, such as a ‘dairy-free’ logo, but with milk in the ingredients. The packaging is also the vehicle for any precautionary labelling that a risk assessment has shown to be required for the product. It is critical to remember in this regard that precautionary labelling can never be a substitute for good allergen management measures and does not, of itself, exonerate the manufacturer from any legal liability.

3.6.3 Precautionary labelling

Precautionary labelling is a somewhat unique feature of allergen labelling. Its use arguably has refl ected the uncertainties over the ability to assess the risk and the fear over the severe nature of the consequences of exposure to unintended allergen. However, its rapid spread and often extensive use have simultaneously imposed severe limitations on the food choices of allergic consumers, and thereby their quality of life, and reduced its credibility and thereby its effectiveness as a risk management measure, leading to risk taking (Madsen et al ., 2010 ; Cochrane et al ., 2013 ). Thus a current challenge in allergen risk assessment is to identify a dose or range of doses


where the balance between the level of protection afforded by defi ned management thresholds and the extent of precautionary labelling minimises the number of reactions and thus maximises protection for the allergic consumer (Figure 3.5 ).

Precautionary labelling is voluntary and generally lacks clear status in law. European food law states that ‘ Food shall not be placed on the market if it is unsafe ’ and explains how ‘unsafe’ can be determined:

‘regard shall be had: (b) to the information provided to the consumer, including information on the label, or other information generally available to the consumer concerning the avoidance of specifi c adverse health effects from a particular food or category of foods’.

However, Recital 16 in the preamble to the Regulation states:

Measures adopted by the Member States and the Community governing food and feed should generally be based on risk analysis except where this is not appropriate to the circumstances or the nature of the measure

which implies that they should be based on a risk assessment, which is a necessary component of risk analysis. Precautionary labelling used without an appropriate risk assessment arguably falls foul of the law ’ s requirement that labelling is not misleading. Thus precautionary labelling based on a thorough risk assessment also aligns much better with European food law.

When using precautionary labelling, the wording should be carefully considered. Recent studies show that allergic consumers can readily misinterpret labels (Barnett et al ., 2011 ). A simple phrase such as ‘may contain’ or ‘may be present’ (VITAL Allergen Management guide) is to be preferred to those which may imply a lesser degree of risk, such as ‘may contain traces of’ or which require food-allergic consumers to try to evaluate the risk associated with a particular production facility or process, such as ‘made in a factory which also produces’ and ‘made on a line which also makes’.

Figure 3.5 Risk profi le in relation to reference doses and precautionary labelling.

100

75

50

100

75

Obs

erva

nce

of p

reca

utio

nary

labe

lling

(%

)

Pro

port

ion

of p

rodu

cts

affe

cted

(%

)

Risk profile

5025

0 0.1 1Reference dose (arbitrary units)

10 100


3.7 Conclusions

Food allergy is a relative newcomer to the ranks of food safety issues. Although as a medical phenomenon it was described as far back as the early 20 th century, only in the last decade of that century did the fi rst attempts to mitigate its effects through food safety regulation occur. While allergenic foods obviously pose a risk when they are used as ingredients, a major concern and one more diffi cult to address arises from their unintended and therefore potentially undeclared presence, to which all stages of the food supply chain may contribute. The nature and observed severity of reactions to foods before the risk could be adequately characterised gave rise to the somewhat unique approach of precautionary labelling. However, its increasing prevalence brought about the unintended effect of reducing its credibility and thereby its effectiveness in protecting allergic consumers. It thus highlighted ever more strongly the acute need for robust and trustworthy assessment of the risk.

For many years, risk assessment remained severely constrained by a lack of data and doubts about the applicability of established risk assessment approaches. However, work started in the last years of the 20 th century is beginning to bear fruit and indeed to highlight the strengths of food allergen risk assessments, based as they are on sophisticated modelling approaches and human data. Although knowledge gaps inevitably remain, initiatives such as the development of the VITAL 2.0 reference doses demonstrate that the risk from food allergens can now indeed be assessed quantitatively. Thus, precautionary labelling can now be informed by an evidence-based perspective, which can be shared with other stakeholders. Coming years will undoubtedly see ever better estimations of the risk as well as the fi lling of data gaps such as the relationship between doses and severity of reaction and a better understanding of the food choices of allergic consumers and how they are governed.

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handbook of food allergen detection and control || food allergen risk assessment and management

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