Action Levels and Allergen Thresholds What they will mean for the Food Industry

Dr. Rachel WARD

r.ward consultancy limited

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Allergenic Foods Are Unique!

• More than 160 foods are known to provoke allergic reactions in sensitive individuals

• Allergenic foods are generally safe for most people

BUT…

• Food allergens pose a serious health risk to individuals who may become sensitised or who are already sensitised to them

• Adverse reactions to food allergens • Can occur at very low levels of food allergens • Can be lethal from a single exposure

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Food Allergen Risk Management

Consumers health protection lies with AVOIDANCE of products containing food to which they are allergic

• Clear, consistent and reliable risk communication • Appropriate and accurate vs.

level of food allergen presence

• Common simple descriptors for allergenic foods

• Common approaches across brands and between countries

• Available on-line, on-pack and in retail/catering

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Food Allergen Risk Management Labelling

• Where food allergens intentionally present in foodstuffs…

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Labelling declaration mandated for allergenic foods For specified allergenic foods and derivatives

(Also must label all deliberately added ingredients and additives)

Some exemptions for a few allergenic derivatives

Gluten free claim when product <20ppm

Food Allergen Risk Management Labelling

• Where food allergens intentionally present in foodstuffs…

Labelling declaration mandated for allergenic foods

BUT… • Ingredients labelling mismatch with “free from” claims for gluten

• Gluten derivatives must be labelled, even when product overall is <20ppm gluten = confusing for consumers

• Labelling required irrespective of level of food allergenic protein

• Highly refined peanut oil contains no protein, but must be labelled

• Analytical methods limit of detection used to qualify safety

• Not clinically relevant or based on scientific risk assessment

• Different methods have different LOD – which one to choose?

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Food Allergen Risk Management Labelling

• Where food allergens unintentionally present through cross-contact in foodstuffs…

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Risk communication expected, but not mandatory Precautionary warnings

Introduced in the 1990s “May contain” Voluntary in most countries

Food Allergen Risk Management Labelling

• Where food allergens unintentionally present through cross-contact in foodstuffs… Risk communication expected, but not mandatory

BUT…

• Most apply “fail-safe” approaches • Any potential presence triggers use of warnings

• Analytical non-detect also used as trigger • Not clinically relevant or based on scientific risk assessment

• Inconsistency in interpretations of supply chain risk • No quantitative guidance from regulators or clinicians

• Negative perception by consumers and health care practitioners • Basis for use of warnings unclear and variable • Different wordings / styles used across brands/retailers

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Food Allergen Risk Management Risk Communication

• Effective avoidance requires….

• Appropriate clinical guidance

• Proven allergic individual → avoid foods labelled as containing allergens

• Exercise affected sensitivity → avoid allergens especially after exercise

• Highly sensitive allergic individual → only consume ‘free from’ foods

• Reliable food information relevant to allergen status

• Label matches the content!

• ‘Free from’ allergen claim = choose preferentially, even if unwell

• No allergen label or warnings = consume with confidence

• Allergen precautionary warning = avoid if unwell or highly sensitive

• Allergen ingredient label = avoid completely, always

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Food Allergen Risk Management Risk Communication

• How would Action Levels help? • Quantitative targets for use in consistent decision-making

• Based on clinically relevant (and globally agreed) values

• Accurate, reliable food information vs. allergen risk status

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‘Free from <allergen>’ claim

when < ‘Free from’ action level

Allergen warning

when > ‘May contain’ action level

Allergen ingredient label

when Allergenic protein present

Food Allergen Risk Management

• Hazard-based approach • Qualitative basis for risk management

• Some exemptions but not across all allergenic foods on basis of protein present

• Risk communication voluntary • Analytical non-detect default action level

• Can have mismatch with degree of risk

• Applied inconsistently • Consistent industry best practice guidance

• No common quantitative targets

• Lack of confidence & confusion!

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CURRENT

STATUS FUTURE

Food Allergen Risk Management

• Hazard-based approach • Qualitative basis for risk management • Some exemptions but not across all

allergenic foods on basis of protein present

• Risk communication voluntary • Analytical non-detect default action level • Can have mismatch with degree of risk

• Applied inconsistently • Consistent industry best practice

guidance • No common quantitative targets

• Lack of confidence & confusion!

• Risk-based approach • Quantitative basis for risk management • Quantitative action levels based on risk

assessment and clinical thresholds

• Risk communication mandatory • Quantitative basis matching degree of

risk present • Exemptions on basis of level of

allergenic protein present

• Applied consistently • Common agreed quantitative action

levels

• Confident avoidance of risky foods

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CURRENT

STATUS FUTURE

VISION

Risk Assessment vs. Risk Management

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Define Risk

• Hazard - Inherent property of an agent or situation having the potential to cause adverse effects, when an organism, system, or (sub)population is exposed to that agent. (International Programme on Chemical Safety (IPCS), 2009)

• Exposure - a measurement of the level at which one encounters any

substance, usually through inhalation (breathing), dermal (skin) or oral (mouth, eating).

• Risk - Probability of an adverse effect in an organisms, system or (sub)population caused under specific circumstances by exposure to an agent. (IPCS, 2009)

So, …Food allergens pose a risk due to their inherent properties (hazard) when consumed (acute oral exposure) by the sensitive allergic consumer

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Definitions

• Threshold (biological): a dose level below which no (allergic) reactions occur. Each individual has a personal threshold, and population thresholds can be mathematically determined.

• Eliciting dose (ED) : a dose or amount which provokes an adverse allergic reaction in a sensitive allergic individual. A minimal eliciting dose (MED) is the minimal amount of allergen at which an allergic reaction occurs in a sensitive individual = threshold

• Reference Dose: estimate of the oral exposure dose (amount) that is likely to be without appreciable risk of deleterious effects (adverse allergic reaction) in a given % of the sensitive test population. Uses a dataset which combines multiple challenge studies and defines the degree of risk that an adverse reaction would occur from a specific amount of allergen

• Point of departure: Dose point on the dose-response curve near the lower end of the observed range, which can be directly estimated without significant extrapolation to lower doses.

• Action level (or Management (action) level): level of allergen in a food, below which the risk of a reaction is deemed insignificant. Calculated from the Reference Dose multiplied by the likely amount exposed to the sensitive consumer, (i.e. amount of food to be consumed per eating occasion).

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Food Allergen Risk Assessment Scientific Developments

• Food allergens do show dose-response relationships • Confirmed that individuals can have a threshold below which they do not have

adverse reactions

• More/better quality clinical thresholds data available

• EAACI standard procedure for double blind placebo controlled food challenge (DBPCFC) allows comparison of studies

• Europrevall studies generated large food allergen datasets

• Models reviewed to best estimate population thresholds • Margin of Exposure and Probabilistic Modelling both have merit • Do not rely on low-dose extrapolation and make use of the whole dataset • Combining data from studies with comparable protocols provides large enough

datasets to estimate population threshold levels

• Quantitative risk assessment approach found to provide the strongest and most transparent scientific approach to establish management or regulatory action levels for allergenic foods.

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Food Allergen Risk Assessment ...still not easy to determine safe dose

• Hazard Assessment • Sufficient good quality clinical data not available for some food

allergens, e.g. celery, fish, tree nuts other than hazelnut, molluscs

• Range of reactivity to allergens in the sensitive population is extremely wide (µg to g) and poorly characterised

• Severity of adverse reactions not only related to dose - also influenced by extraneous factors (exercise, stress, illness...)

• Difficult to derive a definitive population no-adverse effect level • Paediatric <3.5 years; Young children; Older children and adults

• Exposure Assessment • Data for dietary intake usually focuses on daily or weekly intake

• Food allergen exposure needs single consumption occasion exposure data

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Food Allergen Risk Management

• ILSI-Europe Food Allergy Task Force Expert Group “Thresholds to Action Levels” workshop, September 2012

• Agreed transparent set of reference doses (as a basis for action levels) would be a desirable outcome, in principle.

• Data from food challenge studies can provide the appropriate foundation from which action levels can be derived

• Agreed sufficient data now exist to move forward and better estimate the risk to the allergic population for the allergens specified in the report

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Food Allergen Risk Management

• Hazard-based approach • Qualitative basis for risk management • Some exemptions but not across all

allergenic foods on basis of protein present

• Risk communication voluntary • Analytical non-detect default action level • Can have mismatch with degree of risk

• Applied inconsistently • Consistent industry best practice

guidance • No common quantitative targets

• Lack of confidence & confusion!

• Risk-based approach • Quantitative basis for risk management • Quantitative action levels based on risk

assessment and clinical thresholds

• Risk communication mandatory • Quantitative basis matching degree of

risk present • Exemptions on basis of level of

allergenic protein present

• Applied consistently • Common agreed quantitative action

levels

• Confident avoidance of risky foods

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CURRENT

STATUS

FUTURE

VISION

Food Allergen Risk Assessment Voluntary Incidental Trace Allergen Labelling (VITAL) 2.0

• Action levels for whether to apply a ‘May Contain’ warning

• Combined data from published and unpublished clinical data; for DBPCFC, NOAEL and/or LOAEL determinations, from individual patients and large studies

• Chosen points of departure were ED01 (dose where 1% of test population had an objective adverse reaction in DBPCFC) or Lower 95% confidence interval of ED05 where data insufficient

• Estimated reference doses using dose-distribution models using interval-censoring survival analysis

• Created a calculator to translate Reference Dose into Action Level for individual foodstuffs

• Note: Considerations of homogeneity and production run variability need to be over-laid, and quantitative action levels not appropriate for discrete pieces e.g. nuts / whole seeds

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VITAL Scientific Expert Panel Review Peanut Dose Distribution: Adults and Children combined

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10%

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Log-Normal Dose of Protein (mg)

0.01 0.1 1 10 100 1000 10000 100000

Discrete Cumulative

ED 01

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ED01 = eliciting dose where 1% of the test population of human subjects responded with an adverse allergic reaction

In this combined dataset, ED 01 = 0.2mg peanut protein

Food Allergen Risk Assessment Management of food allergens: from thresholds doses to analysis in foods (FSA research project T07062)

• Allergen threshold research to identify allergen presence of sufficient concern to warrant consumer precautionary warnings • Estimated reference doses using two different approaches to dose-distribution

modelling – LOAELs and interval-censoring survival analysis • Using DBPCFC data generated in EuroPrevall • Only objective symptoms should be used for dose distribution modelling due to

uncertainty in symptom recording • Chosen point of departure as ED10 (eliciting dose where 10% of test population

had an objective adverse reaction in DBPCFC) at 95% confidence intervals

• With the exception of shrimp, there is little difference between the

ED10’s of the various foods. • All plant-derived foods ED10 1.6-10.1 mg protein; • Fish ED10 25.8-32.6mg protein; • Shrimp ED10 3.1-3.4 g protein

• If included subjective symptoms, lowers ED10 to µg range of protein

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Food Allergen Risk Assessment EFSA 2014

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• “The Food Safety Authority of Ireland requests that EFSA provides a scientific opinion on: • The prevalence of each allergy in the European Union.

• Recommendations for threshold concentrations of each allergen in food that would provide an acceptable level of protection for at-risk consumers

• The suitability, or otherwise, of qualitative and quantitative DNA-based tests (PCR) for the detection and quantification of food allergens in comparison with immunological (e.g. ELISA) or other methods.”

• Requested May 2011

• Draft Opinion May 2014

• Final Opinion October 2014

Food Allergen Risk Assessment Expected EFSA to provide quantitative estimates of risk to public health (with appropriate uncertainty) for different scenarios

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• The Draft Opinion states that ….“Current clinical, epidemiological and experimental data do not allow determining safe allergen threshold levels that would not trigger adverse reactions in a sensitised consumer”. • This appears to answer the question “can a level of allergen be defined below

which no allergic person would react?”

• However, the request from FSAI was for “threshold concentrations

of each allergen in food that would provide an acceptable level of protection for at-risk consumers • EFSA do not define acceptable level(s) of protection for at risk consumers • EFSA do not estimate of the variety and range of clinical adverse effects, and

their different public health impact provided

• Rationale for EFSA conclusions are not clear • EFSA’s comments seem to go against current scientific developments

in allergen risk assessment approach

Food Allergen Risk Management

• Hazard-based approach • Qualitative basis for risk management • Analytical non-detect default action level

• Risk communication voluntary • Some exemptions but not across all

allergenic foods on basis of protein present

• Can have mismatch with degree of risk

• Applied inconsistently • Consistent industry best practice

guidance • No common quantitative targets

• Lack of confidence & confusion!

• Risk-based approach • Quantitative basis for risk management • Quantitative action levels based on risk

assessment and clinical thresholds

• Risk communication mandatory • Quantitative basis matching degree of

risk present • Exemptions on basis of allergenic

protein present

• Applied consistently • Common agreed quantitative action

levels

• Confident avoidance of risky foods

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CURRENT

STATUS

FUTURE

VISION

Food Allergen Risk Management Food Categories Defined By Allergen Presence

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(Ward et al Trends in Food Science & Technology 2010)

Food Allergen Risk Management Food Categories Defined By Allergen Presence

• ‘Free-from’ foods • Specifically developed and marketed for the food allergic consumer

• ‘Free-from’ claimed allergen ‘absent’ i.e. < ‘free-from’ action level

• Should be safe to eat by allergic consumers under any circumstances

• ‘Mainstream’ foods • Unintentional allergen cross-contamination < ‘may contain’ warning

action level

• Should be safe to eat by most allergic consumers as part of varied diet

• Might need to be avoided by exquisitely sensitive allergic consumers, or when the allergic individual is unwell

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Food Allergen Risk Management Food Categories Defined By Allergen Presence

• ‘Foods with precautionary warning labels’ • Unintentional allergen cross-contamination > ‘may contain’

warning action level

• Should carry an allergen precautionary warning label

• Should not be chosen for consumption by allergic consumers

• ‘Allergen-containing’ food products • Allergenic food is intentionally used as an ingredient

• Product clearly and correctly labelled

• Should not be chosen for consumption by allergic consumers

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Food Allergen Risk Management Challenges…

• Lack of quantitative risk assessment • Awaiting EFSA response to comments on Draft Opinion • Regulator-approved action levels are dependent on the risk assessment outcomes • Until action levels available, hazard-based approach will continue

• Over-labelling in absence of allergenic protein • Highly refined allergenic derivatives without exemptions must be labelled • Exemption basis varies globally • Many gluten derivatives must be labelled even if gluten <20ppm • Exempting all gluten derivatives <20ppm from labelling would rationalise risk communication

• Analytical methods capability

• Currently protein detection methods not available for all allergenic foods mandated for labelling in EU

• Analytical methods report in different units of measure • No common calibrants to simplify interpretation • Analytical methods limit of detection ≠ action levels proposed to date • Lack of certified reference materials to permit comparison between analytical methods

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Food Allergen Risk Management Next Steps…

• Risk Assessment • 2014 EFSA derived thresholds for food allergens

• ???? FDA risk assessment to establish regulatory thresholds

• Risk Management Model • Common agreement across regulatory jurisdictions for

application of action levels and appropriate risk communication

• Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM) EU funded program

• € 9,000,000, Consortium of 38 partners from 18 countries

• 1 Mar 2013 – 28 Feb 2017

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Thank You for Your Attention!

Any questions?

Dr. Rachel WARD PhD CSci FIFST

r.ward consultancy limited

Email. rachel@rwardconsultancy.com

Tel. +44 7879 646358

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