Opportunities and Barriers to Global Harmonization of Food Allergen Risk Management

Opportunities and Barriers to Global Harmonization of Food Allergen Risk Management Steve L. Taylor, Ph.D. Food Allergy Research & Resource Program University of Nebraska 2017 FAMS Meeting Sydney NSW, Australia May 22, 2017

Finding a Path to Safety in Food Allergy Highlights of the Consensus Report

Global Harmonization The Impossible Dream Advantageous to global trade If done properly, consumers should get very safe food Codex Alimentarius Commission has set the minimum guidance for global harmonization with respect to issues such as food safety and labeling Yet, many countries enact regulations that vary from Codex guidance Countries can be more flexible and nimble

Global Harmonization on Food Allergens The Barriers - Priority allergen lists - The zero threshold approach/mentality - Ingredient labeling regulations - Precautionary labeling - Analytical approaches - Regulatory enforcement

Global Harmonization on Food Allergens The Opportunity - Science-based priority allergen lists - Statistically sound threshold approach with establishment of Reference Doses - Food consumption surveys by country - Validated analytical methods - Quantitative risk assessment (QRA) - QRA-based regulatory decision-making Sound science as the guiding principle

The Opportunity Science-based priority allergen lists Statistically sound threshold approach with establishment of Reference Doses Food consumption surveys by country Validated analytical methods Quantitative risk assessment (QRA) QRA-based regulatory decision-making

History of Priority Allergen Lists 1992: Nordic countries develop a paper on Consideration of Potential Allergens in Food 1993: That paper is submitted to and discussed by Codex Committee of Food Labeling (CCFL) which recommends an expert consultation 1995: The Food & Agricultural Organization of the United Nations (FAO) assemble an expert panel and convene a Technical Consultation on Food Allergens (Nov. 1995)

History of Priority Allergen Lists Charge to FAO Expert Panel Recommend criteria for establishment of a list of priority foods that should always be labeled due to food allergies or intolerances Consider prevalence and severity; potency not considered Develop a list of priority foods So the list included foods causing IgE-mediated food allergies, celiac disease, and food intolerances/sensitivities

1995 FAO Recommended List The list of ingredients that should always be declared: Cereals containing gluten, i.e. wheat, rye, barley, oats, spelt or their hybridized strains and products of these. Crustaceans, and products of these Eggs and egg products Fish and fish products Peanuts, soybeans and products of these Milk and milk products (lactose included) Sulfite in concentrations of 10mg/kg or more Tree nuts and products of these

The Big 8 Most Common Causes of Food Allergy (IgE-Mediated) Cows milk Egg Crustacea Fish Peanut Soybean Tree nuts Cereal sources of gluten

A Great Start!! Observations on Codex List Expert panel had remarkably limited information on prevalence especially in adults; severity data even more limited; no information on potency Judgment based partly on clinical experience Included allergies + sensitivities and intolerances What was intended by products of these?

Worldwide Response to Codex List Various countries responded to Codex guidance by creating their own priority lists Australia/New Zealand was first; added sesame seeds, royal jelly, and bee pollen/propolis to list EU now has Big 14 with sesame seed, molluscan shellfish, celery, mustard, and lupine Canada has Big 12 with sesame seed, molluscan shellfish and mustard Japan and Korea have unique lists but added buckwheat

Recommendation on Priority Allergen List The Codex list should be revisited Prevalence data do not exist in most countries but very expensive to obtain EuroPrevall established prevalence of food allergies across EU countries variable by geography and eating habits; soybeans may not belong on list but this likely requires further confirmation How many of the other foods belong? My opinion sesame seeds; molluscan shellfish, buckwheat SE Asia

POLICIES REGARDING LABELING OF PACKAGED FOODS The committee recommends that the Codex Alimentarius Commission and public health authorities in individual countries decide on a periodic basis about which allergenic foods should be included in their priority lists based on scientific and clinical evidence of regional prevalence and severity of food allergies as well as allergen potency 14

The committee recommends that The Centers for Disease Control and Prevention obtain prevalence estimates on food allergy in a systematic and statistically sound manner in: o a sufficiently large population o both children and adults o groups defined by race, ethnicity, and socioeconomic status to determine differences in diagnosis and prevalence within these groups 15

The Science of Thresholds

Food Allergen Thresholds Clinical data exist on individual threshold doses for various allergenic foods from oral challenges conducted for diagnosis, threshold trials, and immunotherapy trials published and unpublished FARRP and TNO collaborate to develop a continuously updated dataset of individual thresholds Dose-distribution modeling can be performed to determine population thresholds which could be used as basis for Reference Doses

Log-Normal Population Distribution (expressed as whole peanut)

FARRP-TNO Food Allergen Threshold Database Allergenic Source Included in 2012 New Published or Clinic Threshold Total VITAL Analysis Data Peanut 750 452 1202 Milk 351 100 451 Egg 206 176 382 Hazelnut 202 209 411 Soy Flour 51 3 54 Soy Milk 29 4 33 Wheat 40 57 97 Cashew 31 214 245 Mustard 33 0 33 Lupine 24 1 25 Sesame 21 19 40 Shrimp 48 27 75 Celeriac* 39 43 82 Fish* 19 29 48 Buckwheat** 26 26 Walnut** 74 74 Total 1844 1434 3278

VITAL Scientific Expert Panel Recommendations - 2012 Allergen mg Protein Level Peanut 0.2 Milk 0.1 Egg 0.03 Hazelnut 0.1 Soy 1.0 Wheat 1.0 Cashew 2.0 Mustard 0.05 Lupin 4.0 Sesame 0.2 Shrimp 10.0 Celery n/a Fish n/a

Current Status of Reference Doses Instituted by VITAL in 2012 Endorsed by ILSI-Europe in 2014 and ifaam in 2017 Approach endorsed by U.S. FDA (2006) and EuroPrevall (2009) Unofficially used by several public health agencies in several countries in recent years But no official endorsement by public health agencies Continuing questions about population modeling including choice of models, protection of severe reactors, uncertainty factors, etc.

Thresholds and Reference Doses We have human data from the sensitive segment of the population and lots of it!! The single-dose peanut study (JACI, 2017) has validated the log-normal model for peanut Model averaging approach being investigated by TNO, FARRP and statistical experts Patients with severe reactions are represented in the data set Patients with severe reactions do have lower population thresholds than others with same allergy

Thresholds and Reference Doses Patients experiencing severe reactions tend to make big mistakes in their avoidance diets (Reactions in Community study ifaam) Do uncertainty factors really matter that much? (PPI study ifaam) Processing likely makes a difference but physicians have tended to use the most potent forms of the food for baseline threshold measurements, e.g. raw eggs

POLICIES REGARDING LABELING OF PACKAGED FOODS the food manufacturing industry, the Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) work cooperatively to replace the Precautionary Allergen Labeling system for low-level allergen contaminants with a new risk-based labeling approach, such as the VITAL program used in Australia and New Zealand 25

POLICIES REGARDING LABELING OF PACKAGED FOODS A Risk-Based Labeling Approach FDA and USDA should establish Reference Doses (thresholds) for allergenic foods, where possible Sufficient clinical data on thresholds exist for peanut, milk, egg, certain tree nuts (hazelnut, cashew), soybean, wheat, fish and crustacean shellfish (shrimp) to establish Reference Doses With Reference Doses, foods should have PAL only when exposure would result in doses above the Reference Dose level FDA should restrict allowable PAL statements to one phrase FDA and USDA should educate consumers and health care providers on the meaning of PAL statements

Precautionary Allergen Labeling (PAL) Voluntary, NOT required Must be truthful and not misleading Cannot be used as a substitute for GMP Many different statement formats

Precautionary Labeling for Allergenic Foods: Use and interpretation by various stakeholders?

Precautionary Labeling for Allergenic Foods (PAL) Personal Observations PAL is quite candidly a mess PAL does not serve allergic consumers well Because PAL is not truly risk-based PAL is confusing to consumers PAL serves the food industry better than consumers because it allows them to identify potential risks without really having to assess the risk PAL serves public health authorities very well because they can avoid difficult risk management decisions

Precautionary Labeling for Allergenic Foods FARRP Criteria Use May Contain or other similar labeling strategies judiciously and ONLY in situations where contamination is: 1. Documented 2. Sporadic 3. Uncontrollable AND 4. Potentially Hazardous

The VITAL Approach Is Best Practice With Reference Doses, foods should have PAL only when exposure would result in doses above the Reference Dose level - from NAS report

POLICIES REGARDING LABELING OF PACKAGED FOODS The committee recommends that: the Food and Drug Administration makes its decisions about labeling exemptions for ingredients derived from priority allergenic sources based on a quantitative risk assessment framework 33

Source Labeling Exemptions A source labeling process existed in EU in 2006 and EU has several source labeling exemptions e.g. highly refined soybean oil, fish gelatin for vitamin encapsulation, wheat-based glucose syrup. But process seemed to stop after 2006. U.S. Congress exempted highly refined oils or an ingredients derived from such oils U.S. also has an exemption process by petition or notification but it is based on no protein standard (zero threshold)

U.S. Situation All ingredients from an allergenic source treated as allergens for source labeling purposes Fails to recognize allergen load (protein from the allergenic source) as a determinant of ingredient risk Continuation of a zero threshold approach With Reference Doses, science-based decisions of labeling are straightforward much preferred approach

Food Ingredient Issues Milk Casein, caseinates Whey, whey protein concentrates and isolates Hydrolyzed milk protein Hydrolyzed casein /hydrolyzed whey Lactose Lactoferrin Tagatose Nisin Butter Butter oil Butter acid Butter esters Diacetyl Starter distillate Enzyme check substrates Bacterial culture check substrates

Exemptions Based on Allergen Load and Quantitative Risk Assessment Determine how much protein from the source is in the ingredient (allergen load) Assess exposure levels to the ingredient and the allergenic protein contained in the ingredient Based on population threshold distribution, determine if any allergic consumers are at risk If so, then no exemption should be allowed

Butter Ester Example No detectable protein Flavoring so low exposure dose Orders of magnitude below any dose that might provoke an allergic reaction

Food Consumption Surveys Few countries actually know what their population eats U.S. National Health & Nutrition Examination Survey (NHANES) ifaam European data exists for Netherlands, Denmark, France and U.K. Information may not be gathered in a uniform manner Do food-allergic consumers have the same consumption behaviors as other consumers?

Validated Analytical Methods Another factor that prevents adoption of Reference Doses and QRA Do we get the right answer when we do allergen analysis? ELISA methods are the most frequently used analytical approaches specific, sensitive, rugged, fast PCR methods detect DNA and not protein/allergen Mass spectrometry methods specific, sensitive, but expensive; active area of research

Allergen ELISA Methods Qualitatively excellent; quantitatively -?? remain Differing results obtained with ELISA kits from different manufacturers Users must develop ability to select the best kit that is fit for their purpose run a positive control Need to develop reference standards and then use them as basis for standards in all kits Calibration standards should be uniform and should be ppm total protein from the allergenic source Extraction issues: spike and recovery vs. naturally incurred

Quantitative Risk Assessment

QRA The Inputs Threshold dose-distributions: solid, validated especially for peanut, milk, egg, hazelnut Food consumption estimates (mean, 90%, 95%): excellent in U.S.; USDA NHANES database Analytical estimates of allergen residues: commercial ELISA methods available for many allergenic foods but not often validated with naturally incurred standards; have variable calibrators with questionable adjustment factors

QRA The Output Can predict the percentage of food-allergic consumers who would react to a given dose of a food containing allergen residues Determine the hazard associated with undeclared allergenic food in a food product or ingredient Determine if PAL is needed on a product Set corporate target levels for preventive allergen controls

Improved Allergen Risk Assessment Circa 2017 Quantitative risk assessment is emerging as an approach to guide labeling, recalls, and ACPs Not yet widely adopted But we have human threshold data from allergic consumers Reliable analytical data can be obtained with caution Reliable consumption information exists in some countries These form the elements of QRA

Improved Allergen Risk Assessment Circa 2017 Endorsed by Allergen Bureau of Australia & New Zealand for decision-making with PAL Endorsed by ifaam (Europe) for labeling decisions, preventive control assessment, etc in Tier 1 and Tier 2 risk assessment models Would be ideal to use for regulatory recall decisionmaking as many recalls in U.S. and Canada probably involve foods with no consumer complaints and minimal to non-existent risk

Summary Some allergen exposure doses are quite safe for food-allergic consumers Low doses of food allergens do NOT cause adverse reactions (and certainly not severe reactions) Stakeholders need to acknowledge these facts We need to quit chasing the elusive zero to improve the quality of life for food-allergic consumers and focus industry and regulatory attention on the truly hazardous situations

Summary The food industry should adopt VITAL Consequently, usage of PAL would become more meaningful Industry should attempt to reach consensus on a single PAL statement The allergen testing industry should improve test strategies to support the use of VITAL