Management of Food Allergens

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Management of Food Allergens

Management of Food Allergens Edited by

Jacqueline Coutts and Richard Fielder Gen-Probe Life Sciences PLC, BIOKITS Products, Deeside, Flintshire, UK

A John Wiley & Sons, Ltd., Publication

This edition first published 2009 C 2009 Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell. Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom Editorial offices 9600 Garsington Road, Oxford, OX4 2DQ, United Kingdom 2121 State Avenue, Ames, Iowa 50014-8300, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell. The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Library of Congress Cataloging-in-Publication Data Management of food allergens / edited by Jacqueline Coutts and Richard Fielder. p. cm. Includes bibliographical references and index. ISBN 978-1-4051-6758-1 (hardback : alk. paper) 1. Food allergy. 2. Food industry and trade. Jacqueline. II. Fielder, Richard. RC596.M36 2009 616.97’5–dc22 2009013261 A catalogue record for this book is available from the British Library. R Set in 10/12 pt Times by Aptara Inc., New Delhi, India Printed in Singapore

1

2009

I. Coutts,

Contents

Contributors Preface

xi xiii

PART I RISK ASSESSMENT 1

2

The reality of food allergy: the patients’ perspective David Reading 1.1 Background 1.2 Consumer reaction 1.3 Supporting consumers 1.4 Allergy services 1.5 Teenagers and young adults 1.6 Food labelling 1.7 Allergen thresholds 1.8 Food alerts 1.9 Our work with industry 1.10 The work of the FSA 1.11 Schools 1.12 Eating out 1.13 Daily life with a food allergy 1.14 Hopes for the future References

3 4 6 7 10 10 14 15 16 17 18 20 21 22 24

Clinical incidence of food allergy Zsolt Szépfalusi and Thomas Eiwegger

26

2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 3

3

Introduction Case 1 – Severe anaphylaxis to an unknown food product Case 2 – Idiopathic anaphylaxis Case 3 – Cross-reactivity or contamination? Case 4 – To vaccinate or not in egg allergy Case 5 – Adrenalin auto-injector for all egg-allergic patients? Case 6 – Immunotherapy for oral allergy syndrome? Conclusion References

Identification and characterisation of food allergens E.N. Clare Mills, Philip Johnson, Yuri Alexeev, and Heimo Breiteneder 3.1

Introduction

26 29 30 31 33 34 36 37 37 42 42

vi

Contents

3.2 3.3 3.4 3.5

4

Classification of food allergens Plant food allergens Animal food allergens Conclusions References

52 53 57 59 60

Coeliac disease: allergy or intolerance? Norma McGough

70

4.1 Introduction 4.2 About Coeliac disease 4.3 Prevalence and diagnosis 4.4 What is gluten? 4.5 The gluten-free diet 4.6 Gluten-free foods 4.7 Prescriptions 4.8 Allergen labelling 4.9 Food production 4.10 The Codex standard 4.11 Gluten testing 4.12 Gluten-free catering 4.13 Cross-contamination 4.14 Nutritional adequacy 4.15 Lactose intolerance 4.16 Coeliac UK References

70 70 70 71 71 72 72 72 74 74 75 75 76 76 77 77 77

PART II RISK MANAGEMENT 5

Risk management – the principles René Crevel 5.1 5.2 5.3 5.4 5.5 5.6

6

Introduction Allergen management: the issues Development of allergen management plans: principles and considerations Objectives Application Concluding remarks References

Risk management – operational implications Anton J. Alldrick 6.1 6.2 6.3 6.4

Introduction Identifying the hazard Managing the hazard Conclusion References

83 83 84 85 87 93 98 99 102 102 103 104 113 113

Contents

7 Choices for cleaning and cross-contact Steve Bagshaw 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14

Allergen management and cleaning The cleaning process Principles of cleaning Open plant cleaning Dry cleaning Manual cleaning Foam and gel cleaning Cross-contamination Floor cleaning Tray and rack washing machines Cleaning-in-place Management of allergen cross-contamination Cleaning management The cleaning programme References

8 Validation of cleaning and cross-contact Helen M. Brown 8.1 8.2 8.3 8.4 8.5

Introduction Validation of a cleaning regime Sampling to validate cleaning What to measure to validate cleaning Summary References

9 Validation, standardisation and harmonisation of allergen activities in Europe and worldwide Bert Popping 9.1 9.2 9.3 9.4

10

Analytical methods Method validation Standardisation of methods Harmonisation References

Standardisation of analytical methodology with special reference to gluten analysis Ingrid Malmheden Yman 10.1 10.2 10.3 10.4

Introduction Methods and standards Gluten analysis Gluten determination References

vii

114 114 115 117 119 119 121 122 123 125 125 127 131 131 132 137 138 138 139 141 145 148 148

150 150 150 151 152 153

154 154 154 157 160 164

viii

11

12

Contents

Analytical choices Marie-Claude Robert

166

11.1 11.2 11.3 11.4 11.5

166 166 168 172 182 182

Development of allergen testing Test formats Commercial test kits Analytical issues specific to immunoassays Conclusions References

Food allergen method development programme at Health Canada: support to standard setting and consumer protection Samuel Benrejeb Godefroy, Michael Abbott, Terry Koerner, Dorcas Weber, and Theresa Paolisini 12.1 12.2 12.3

Rationale to ACT on preventing food allergy incidents in Canada Health Canada’s food allergen methodology programme Conclusion References

184

184 185 191 193

PART III RISK COMMUNICATION 13

Finished product labelling and legislation Sue Hattersley 13.1 13.2 13.3 13.4 13.5 13.6

14

Introduction Legislation on allergen labelling – European Directive 2003/89/EC and subsequent amendments Allergen cross-contamination and advisory labelling (Such as ‘May Contain’ statements) Provision of allergy information for foods that are not pre-packed ‘Free from’ foods Conclusions References

197 197 197 203 208 210 210 211

Guidelines for manufacturing and certification programmes Neil Griffiths

212

14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 14.9 14.10 14.11

212 212 213 214 217 218 220 221 222 224 225

Preface Introduction The law Voluntary information Guidelines Certification schemes Training The use of risk assessment Management The environment Labelling and communication

Contents

14.12 14.13 14.14

15

Thresholds Testing Conclusions References

Risk communication – a manufacturer’s perspective Clive Beecham 15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8

Background The process of going ‘nut free’ The factory changes People disciplines Verification Retailer reaction What is nut free? – the problem of evolving science The need for thresholds

Appendix: Useful web links Index The colour plate section follows page 146

ix

226 228 229 231 233 233 234 237 238 241 243 244 245 248 253

Contributors

Michael Abbott Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada

Samuel Benrejeb Godefroy Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada

Yuri Alexeev Institute of Food Research, Norwich, UK

Neil Griffiths Neil Griffiths Consultants, Portslade, Brighton, UK

Anton J. Alldrick Campden BRI, Chipping Campden, Gloucestershire, UK Steve Bagshaw Holchem Laboratories Ltd, Haslingden, Rossendale, Lancashire, UK Clive Beecham Kinnerton (Confectionery) Company Ltd, London, UK Heimo Breiteneder Department of Pathophysiology, Medical University of Vienna, Alsergrund, Vienna, Austria Helen M. Brown Campden BRI, Chipping Campden, Gloucestershire, UK René Crevel Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedford, UK Thomas Eiwegger Department of Pediatrics, Medical University of Vienna, Alsergrund, Vienna, Austria

Sue Hattersley Food Standards Agency, Aviation House, Kingsway, London, UK Philip Johnson Institute of Food Research, Norwich, UK Terry Koerner Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada Norma McGough Coeliac UK, High Wycombe, Buckinghamshire, UK E. N. Clare Mills Institute of Food Research, Norwich, UK Theresa Paolisini Bureau of Food Regulatory and International Affairs, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada Bert Popping Eurofins, Pocklington, Yorkshire, UK David Reading The Anaphylaxis Campaign, Farnborough, Hampshire, UK

xii

Contributors

Marie-Claude Robert Nestlé Corporate Allergen Management, Nestlé Research Centre, Lausanne, Switzerland Zsolt Szépfalusi Department of Pediatrics, Medical University of Vienna, Alsergrund, Vienna, Austria

Dorcas Weber Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada Ingrid Malmheden Yman Livsmedelsverket (National Food Administration), Uppsala, Sweden

Preface

This book is about one of the greatest challenges facing the food industry: providing food to an ever-increasing number of allergic consumers through a global supply chain. The subject is complex and in its infancy. Keeping up to date with the rapid advances from the fragmented knowledge base is a challenge for the reader, especially when it is drawn from such diverse sources. Any investigation into food allergens and their management inevitably produces many more questions than answers, and it is this challenge that the book seeks to address with author contributions from recognised specialists active in the field. A risk analysis perspective has been taken in order to discuss information relevant to evolving best-practice approaches for managing food allergens in the process environment. The topic is treated as a food safety issue rather than a product labelling one. It aims towards helping all those with a vested interest in understanding how to protect consumer health through good manufacturing practice and providing clear labelling advice. Discussion excludes the catering sector, where foods consumed are perceived to pose a greater risk to the allergic consumer than packaged foods. The need for this book has been driven by the wider public awareness of food allergies and intolerances and the growth in the number of people who follow a restricted diet, at least for a period in their lives. Regardless of whether those individuals have been clinically diagnosed, the number of family members, friends and colleagues affected is appreciable. In the USA, more than ten million people are affected, with a similar number in Europe. The choice of foods available is important to sustain a restricted diet and a healthy lifestyle. Not surprisingly, the market for ‘free from’ foods has grown dramatically in recent years. The market for such gluten-free and dairy-free foods shows no signs of abating in the foreseeable future. The trend for healthier foods has led to the inclusion of diverse natural ingredients in the diet (such as nuts, seeds and grains), many of which are potentially allergenic. Whilst such ingredients can help to prevent and counteract ill health in some, to others their presence can prove fatal. The global economy means that such ingredients are sourced worldwide and can simply be selected from countries where costs are the lowest. Ingredient specifications, including any possible contaminants, must be declared by suppliers. Avoiding contamination in food production can be as much about control during supply as during manufacture and distribution. Without the means to control every stage, the risks for the food producer and consumer alike can never be reduced to zero – in spite of the ‘free from’ claim. ‘Hidden’ allergens (i.e. where contaminants are not declared, for whatever reason) continue to be the largest single cause of global product recalls. Most recalls could be averted by stricter supplier and factory controls (both prerequisite and HACCP). This is indicative of the early developmental stage of best-practice approaches to validate and verify the effectiveness of manufacturers’ risk management systems. The role of testing is deemed to be an integral element in any approach, and much work is needed to develop effective programmes of routine testing, particularly at a time when

xiv

Preface

there are intense external pressures to do so. Such pressures come from a number of directions: r Increased labelling legislation: e.g. European Directive 2007/68/EC added lupin and molluscs to the list of allergenic foods requiring labelling as an ingredient, whilst some non-allergenic ingredients gained permanent exemption from labelling. In Japan, lobster and crab are proposed to be added by 2010. r Guidance documents: on allergen management have been provided in many countries, e.g. in the UK and in Australia and New Zealand. r Codes of practice: to make food retailers’ advice more explicit for their suppliers. r Manufacturing standards: consumer groups continue to liaise with the industry to develop criteria which should be met when producing ‘allergen-free’ foods. r Thresholds: in reality, how much is too much for the allergic consumer and how does this relate to statutory levels for enforcement and management levels for process control? Different specialists’ perspectives are offered in this book to address the huge challenge that undeclared food allergens pose to the industry. An extremely important part of allergen control practices is the documentation of every aspect of the process, activities and operations of food manufacture. Documentation serves the need for traceability in the event of future problems and product recalls from the market. However, it cannot be relied upon alone without audits, inspection and testing to demonstrate that the control systems are working. The need for validation of previously agreed specifications is another key message of the book, and this has to include manufacturing, cleaning and analytical testing. Until such times that new techniques (e.g. clinical interventions, genetic modification) bring an end to food allergy and intolerance, allergic consumers are reliant on manufacturers’ systems of allergen control. However, minimising sufferers’ exposure will undoubtedly help to enhance their quality of life. Richard Fielder Jacqueline Coutts

Part I

Risk Assessment

1

The reality of food allergy: the patients’ perspective

David Reading

1.1 BACKGROUND Most of us take our food for granted. We know where the next meal is coming from and we can be fairly confident that it is going to be safe to eat. But people who deal every day with a life-threatening food allergy do not have that confidence. They can find mealtimes a source of enormous stress. For what is nutritious to the majority can be an extreme danger to a minority. Anyone who has been rushed to casualty suffering a life-threatening allergic reaction to a food, or has seen that happen to his or her child, knows how life changing that experience is. One mother wrote to us saying: ‘My seven-year-old daughter is allergic to nuts, milk, eggs and fish. Our lives are pretty much ruled around food. I worry terribly about the future.’ That is typical of the messages we receive from families dealing with this problem every day of their lives. The fact that food allergy can be deadly serious has been well known for decades to the medical profession, but it was not until the early 1990s that the public at large, the media and the food industry began to understand that it can kill a small but significant number of people. And for many, food allergy can be lifelong. Before the 1990s, allergy was generally regarded as a minor inconvenience, if it existed at all. It was out there on the fringes of medicine, affecting (so it was thought) people who let their imaginations run riot. At the most, it was generally considered that food allergy amounted to no more than a bit of indigestion or an itchy rash. Then in late 1993, the UK media reported that four people had died suddenly in a short space of time from allergic reactions to nuts. They included my 17-year-old daughter, Sarah, who died after eating a dessert-containing peanut in a town centre restaurant. She had an inkling that she was allergic to peanuts but had no idea how serious it could be. The condition from which she died is called anaphylaxis. Her throat swelled and closed up, she suffered a severe asthma attack and her blood pressure plummeted. The resulting media publicity spread alarm throughout the food industry and placed immense pressure on the government to take action. For if people’s lives were at risk from a common, everyday food that was nutritious for the majority, what were the implications for food production and labelling? The author is shown with his daughter, Sarah, who died from her allergy, in Figure 1.1. As a result of those four tragic deaths, and others that came to light, the Anaphylaxis Campaign was formed in January 1994 with me as its co-founder and chairman. A small core group of a dozen of us (people with food allergy and the parents of children with food allergy) met in a flat near Baker Street, London, in January of that year. We had never met

4


Fig. 1.1 David Reading with his 17-year-old daughter, Sarah, who died in 1993 from an allergic reaction to peanuts.

before, but made contact as a result of the huge wave of media coverage that occurred. That informal London get together was the inaugural meeting of the Anaphylaxis Campaign, which began its life as a small pressure group run from people’s homes. Our clear objective was to save lives, and in those early months we set out to be a focal point for the spread of information. This proved to be more straightforward than we had dared to hope. After the Campaign’s launch, and the resulting media publicity, I was receiving 60–70 letters a day through my letterbox, many of them telling heart-rending stories of children who had been rushed to casualty suffering from extreme allergic reactions to food. Along with the information provided to us by medical professionals, this influx of case histories from people with allergies provided a comprehensive file from which to develop guidance for patients and the industry alike. We met the Food Minister, Nicholas Soames, in February of 1994, a few of the major retailers and manufacturers in March and the Department of Health in April. We told Soames that more than 1000 people had contacted the Campaign in less than 2 months; 700 had signed up, and more were joining daily; 85% of those were allergic to peanuts; 80% of the total were the parents of allergic children younger than 15 years. Soames said that he was ‘staggered’ by the scale of the food allergy problem. He said that the food labelling issue had to be fought in Europe, but agreed to launch an awareness drive throughout the UK food industry. The Ministry of Agriculture, Fisheries and Food (MAFF) began that year to commission allergy-related research, and this has grown into a formidable programme in the hands of the Food Standards Agency (FSA). See Tables 1.1 and 1.2 for a breakdown of the current membership profile of the Anaphylaxis Campaign.

1.2 CONSUMER REACTION Several facts became apparent from that flood of letters to the Campaign: nut allergy was far more common than had been recognised; it was causing terrible anxiety and disruption to


5

Table 1.1 Anaphylaxis Campaign membership profile by age (March 2008). Number Number Number Number Number

of of of of of

members members members members members

with recorded allergies aged 0–11 aged 12–20 aged 21–30 aged 31 and older

7566 2738 2995 660 1173

people’s lives; and many had been labouring under the mistaken impression that they were among only a handful of families affected. One mother of a nut-allergic 13-year-old boy said: ‘Until we found your organisation, we were forced to cope on our own. We felt we were playing Russian roulette every mealtime. The future looked very bleak.’ We learned that teenagers and young adults seemed to be those most vulnerable to potentially fatal reactions; a range of foods seemed to be implicated (not just nuts); and people were reacting to tiny amounts of the offending allergen. On the face of it, it was a nightmare scenario for the food industry. Since that time, the Campaign has remained in the forefront of efforts to raise the level of debate. With our membership of almost 8000 people (Spring 2008), we have been able to comprehend quite clearly what people with food allergies want. Primarily, they want to be understood. Many believe their needs have been bypassed. Those who are allergic to foods other than peanuts, for example, will often complain that industry (and indeed the Campaign itself) is fixated on peanut allergy and that other foods are played down. It is important to understand that any food that contains protein could potentially cause anaphylaxis for someone, somewhere. To the outsider, the degree of anxiety expressed by families who care for a food-allergic child can appear out of all proportion. The level of apprehension becomes understandable when you realise that there is a frightening unpredictability to severe food allergy and very often inadequate medical guidance. Many of those affected have experienced sudden life-threatening episodes requiring an emergency dash to hospital. One parent of an

Table 1.2 Anaphylaxis Campaign membership profile by allergens (March 2008). Peanuts and tree nuts Egg Sesame Milk Fish Shellfish Wheat/gluten Kiwi Soya Lupin Mollusc Mustard Celery

6680 1554 905 845 546 508 195 427 192 22 21 19 14

6


allergic child answered one of our surveys with a bullet point list of food allergy’s ‘side effects’:

r r r r r r r r

Holidays are limited to within 10 miles of a large hospital that can speak English. None of the family likes my son being out of our direct care. We can’t go anywhere without medicine of some sort being administered, i.e. antihistamine daily. We pay for private education in a small school that is nut free and allows no packed lunches. Many parents will not have my son for tea let alone sleepovers. Pub food or restaurant visits involve a long and embarrassing plough through lists of food sheets to be told my son can have pasta – without sauce. That’s if they have a food list. Many leisure facilities are not keen to let me leave him in their care. Schoolwork is sporadic at best for my son, and he suffered hair loss from a virus recently. His self-confidence is low.

Although the proportion of the population at risk of anaphylaxis is relatively small, the impact is felt much wider. If it is a child who has the allergy, the burden is carried by parents, siblings, grandparents, aunts and uncles, friends and their parents (particularly if a party is planned) and the local school.

1.3 SUPPORTING CONSUMERS Over the years, it has become apparent that most food allergy problems are manageable – both for the patient and for the industry. But both parties need comprehensive, reliable information, and sometimes that is lacking. Furthermore, there are many allergy myths that have to be dispelled. The most destructive of these myths relates to levels of risk. From the early days, it has been common to hear the comment that ‘even the smell of a peanut will kill my child’ or ‘my child is unlikely to reach adulthood’. This is an understandable fear, because the media will always focus on the worst-case scenario of death. Many of the headlines were sensational from the start: ‘The deadly allergy we should all fear’ was how one magazine put it. Others were equally alarmist – with peanuts described as ‘the hidden killer’ and another announcing that ‘allergies can kill in seconds’. Instead of playing up the risks to gain attention, the Campaign found itself having to keep a cool head and dampen down the hysteria (see Figure 1.2). In order to address this alarm and despondency, the Campaign instigated a programme of support and education to help both those affected by life-threatening allergies and the food industry. Thanks to a National Lottery grant, we opened an office in Farnborough, Hampshire; we developed information tools including fact sheets and training videos; we set up a helpline; we began a series of interactive workshops for allergic teenagers; and we continued to inform and encourage industry. The picture emerging from calls to our helpline showed that many people were receiving woefully inadequate medical guidance, and therefore they were unable to cope with what is fundamentally a manageable condition. Patients need an accurate diagnosis, they need to understand exactly what foods to avoid and where they might encounter those foods, and


Fig. 1.2

7

Newspaper cuttings related to food allergies.

they need to know how to treat themselves when things go wrong. But it was common to hear it reported that a general physician (GP) faced with a young allergic patient had told the child’s parents: ‘If you think he’s allergic to nuts, the solution is simple – don’t give them to him.’ This is easier said than done, and frequent close calls and occasional deaths occur. Crucially, those at risk need to carry their own medication for self-treatment, should they inadvertently encounter an allergen that causes them harm. The front-line treatment is an injection of adrenaline, to be administered as soon as a serious reaction is suspected. People at risk are prescribed their own self-treatment kits (e.g. EpiPen or Anapen), and these must be carried at all times, with no exceptions.

1.4

ALLERGY SERVICES

But first the patient needs a good diagnosis, and as several influential reports have pointed out, allergy services in most parts of the United Kingdom are poor and many patients are unable to obtain the advice they need. In the early days, there were promising developments. During the Campaign’s first few months, the Chief Medical Officer gave the nation’s GPs some clear guidance in one of his regular bulletins (CMO’s Update, May 1994). He told doctors never to advise a peanutallergic patient to test his or her reaction by eating peanuts, stressed the importance of prescribing adrenaline, and asked them to note that repeat injections were often needed. But although we attended several meetings with ministers and civil servants at the Department of Health, allergy services have been painfully slow to improve. A report by the

8


Royal College of Physicians (2003) declared that 18 million people suffered from allergy at some time in their lives, but there were only six full-time allergy clinics run by an allergy specialist. Other clinics existed, the report said, but most of these were run by specialists in other fields (such as ear, nose and throat) and were a part-time ‘add-on’. People told us frequently that their GP was unable to help. They were floundering with food labelling that confused them, restaurant staff who were reluctant to serve them and (in the case of children) school staff who had received little or no guidance on how to manage what is sometimes a life-threatening condition. The Royal College report said that hospital admissions due to anaphylaxis had increased sevenfold from 1993 to 2003 and doubled from 1999 to 2003. Comments we received during a 2005 survey of our members included the following: The wait to see a specialist is two years. We have known about our son’s allergy since he was nine months and have never been seen. The GP said he had no training in allergies and a slow reintroduction of nut traces may be the way to go. Without the Anaphylaxis Campaign our lives would be much poorer. We would have many more hospital visits. After she suffered a reaction after eating banana, we took her to A&E. We were told it couldn’t have been the banana. We gave it to her again, and she had another reaction. Our son spent months visiting skin and eye specialists, who failed to diagnose his allergy. Figure 1.3 shows a graph of survey results.

Thinking about your experiences, how do you feel the NHS is equipped to manage the needs of people with severe allergy? 500 Series1

450 400 350 300 250 200 150 100 50 0 Very well

Fairly well

Not particularly well

Not at all well

Fig. 1.3 Results of a 2005 Anaphylaxis Campaign Survey looking at people’s perception of allergy services. (Reproduced with permission.)


9

In 2005, the House of Commons Select Committee on Health reported categorically that Britain is in the grip of an allergy epidemic and the present NHS services cannot cope (House of Commons Health Committee, 2004). The committee’s report said that 1 in 50 children in England is now allergic to nuts – almost a quarter of a million children – and there has also been an alarming rise in other allergies, including sesame and latex. The committee documented a huge amount of evidence of unmet need. In 2007, the House of Lords Science and Technology Select Committee again emphasised the scale of the problem after it carried out its own inquiry into allergy (House of Lords Science and Technology Committee, 2007). The committee’s recommendations included the following:

r r r r

At least one allergy centre should be established in each Strategic Heath Authority. This should be run by a full-time allergy specialist. These allergy centres should encourage and coordinate the training of local GPs and other health care workers in allergy. The allergy centre should act as a lead in providing public information and advice. The lead allergist in each allergy centre should be responsible for maintaining a patient database to support clinical research.

We are still waiting for a firm commitment to allergy from the Department of Health. Government reports and statements have proved deeply disappointing. A campaign for change is being led by the National Allergy Strategy Group, a partnership of medical professionals and allergy charities. Early in 2008, a hopeful sign emerged when it was revealed that an All Party Parliamentary Working Group had been formed to ensure allergy maintains a high profile. Deep concern over the lack of activity displayed by the Department of Health is demonstrated by a letter that appeared in The Times on 31 January 2008. Signed by some of the leading allergy experts of the United Kingdom, the letter stated:

We are in the midst of an allergy epidemic with about 20 million children and adult allergy sufferers in the UK. Indeed, we have one of the highest prevalences of allergic diseases worldwide – diseases such as asthma, anaphylaxis, drug and food allergy, eczema, rhinitis and insect-sting allergy. There is an enormous burden on patients and their families, and costs to the NHS are rising.

The letter stated that many problems could be eased or prevented by expert diagnosis and management. The Department of Health had acknowledged the need for improvement, but nothing had been done to implement the key requirements. Instead, responsibility had been passed to local agencies, which could not solve the problem because it required a national solution. The letter ended by urging the Health Minister to adopt the Lords’ recommendations without further delay.

10


1.5 TEENAGERS AND YOUNG ADULTS Although people of all ages have food allergy, teenagers and young adults are at most risk from fatal reactions. This has been demonstrated by published studies (Pumphrey, 2000; Pumphrey and Gowland, 2007) and our own experience. Many in this age group find it hard to cope. Time and time again, we hear reports of problems faced by teenagers and so this age group became a particular focal point. The experience gained from our 1-day workshops for allergic teenagers is that the participants are often poorly informed and lack confidence in managing their allergies. Many admit they take risks. They know they should carry their adrenaline, but choose to leave it at home, particularly if they do not anticipate that they are going to eat anything. And they are so fed up with defensive labelling (e.g. ‘may contain nuts’) that they just choose to ignore it. The first of our workshops for teenagers took place in London in 1999 and since then we have held almost 100 across the United Kingdom. We found early on that teenagers respond well to the interactive format, in which they share ideas, discuss best practice and act out challenging situations (such as confrontations with difficult restaurant staff). Reporting on one of our early workshops, a young participant wrote in the Campaign’s newsletter: We gained a lot of useful information from each other during the day. We shared experiences and shared ways of dealing with situations and how to tell people about our allergies. We used role play to help devise ways of telling people we have allergies. For example, how do you ask someone you’re going to kiss whether they’ve been eating peanuts? And how do you tell someone who thinks allergies are a joke that it’s a very serious condition. Another wrote: It was a great feeling to know I’m not on my own out there and there are many other people just the same as me. Also I think people should be more aware of other allergies such as dairy products, eggs, fruit and non-food causes of allergy, as most publicity seems to be given to nut allergy.

1.6

FOOD LABELLING

From the early days, it became clear that one of the burning issues for the consumer was food labelling – in particular, the use of ‘may contain’ warning statements. These warning labels are believed to have originated in the confectionery industry in 1994 when it became clear that production methods carried a risk that small quantities of nut could potentially be picked up in the factory by products that were not intended to contain nut. To warn the allergic consumer, food companies began to adopt advisory statements on their packaging. This practice spread like wildfire, and within a few years customers were complaining that ‘just about everything carries a warning these days’. In 2005 and 2006, the Campaign organised two surveys of people with food allergy with the objective of providing evidence to the Department of Health on people’s concerns and needs. One question asked online was: ‘How well or badly does the current system of food labelling work for people with severe allergy?’


11

The results were:

r r r r r

Very well 0.8% Fairly well 32.5% Fairly badly 39.1% Very badly 26.3% Don’t know 1.3%

This online survey, and another survey in which we wrote to every one of our 7695 members, drew many comments about food labelling. Allergic consumers rely on the accuracy of labelling and one respondent expressed the views of many others when she said: ‘A weekly shop takes ages as checking all ingredients is a must.’ The most frequent complaint focused on the increasing use of ‘may contain’ statements: ‘We were looking for a birthday cake in (supermarket X) and all cakes said “may contain traces of nuts”. In a sponge cake with buttercream and jam filling, where would the nuts be? What do I do, take a chance or trail around until I find one that’s OK?’ ‘So many products sold by (supermarket Y) “cannot guarantee nut free” – nearly all the products I once used now say this. What am I supposed to do?’ ‘What’s the difference between “may contain nuts” and “made in a factory that handles nuts”?’ ‘I went through every item in (an in-store) bakery and did not find one which I could eat.’ ‘Recently I saw a bag of peanuts labelled “may contain traces of nuts” – what were they trying to convey?’ ‘At the end of the day the “may contain” label is all down to cleanliness of production lines. (Manufacturer X) have got it sorted, they are fantastic.’ Many respondents had formed the view that ‘may contain’ was simply a defensive device with no substance and some said they disregarded the warnings believing the risk was not genuine. One person wrote: ‘We ignore all “may contain traces of nuts” warnings since we found one of these warnings on a cabbage.’ And another wrote: ‘(My son) eats many things that are made in factories where nuts are handled and a couple of times has had a reaction. But he has to eat!’ Sometimes, labelling proves to be confusing, inaccurate and even dangerous. Respondents ranged from having an understanding attitude, even though life was difficult, to displaying anger. There was a strong feeling that information should be more consistent.

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Accuracy of information proved to be a serious concern. Some respondents reported mistakes and discrepancies that they believed to be extremely hazardous. People said they were constantly telephoning manufacturers and retailers to obtain clarity. A few became aware that manufacturers sometimes moved production to different sites, where there were different allergen issues. They had become used to eating a ‘safe’ product only to find that it was now out of bounds. People offered criticism or praise of specific food outlets, depending on their experiences. There were those who felt neglected, such as the respondent who wrote: ‘Some supermarkets are very helpful, but a lot are terrible. The attitude seems to be that “we have enough customers so why bother to improve product safety or choice of food for a minority”.’ Industry has pointed out that ‘may contain’ warnings are usually adopted for good reason – and only after all possible measures have been taken to minimise or eliminated crosscontamination. In our experience, many members of the public are sceptical, especially when they encounter nut warnings in the most unlikely places, such as a bag of mixed salad or even on a packet of nuts. In the two examples given, there may be good reason why the warnings appear, but the average shopper is baffled. The Campaign’s view is that ‘may contain’ warnings are a necessary short-term solution to a difficult problem, but we hope that eventually they will become unnecessary. One possible solution – the Campaign’s certification programme – will be explored later. A study we carried out for the FSA on ‘may contain labelling’ (FSA, 2002) indicated that it takes 39% longer to shop for a nut-allergic person and costs 11% more than for someone without food allergy in the family. Alarmingly, the study also revealed that one in ten ‘may contain’ labels was missed by shoppers reading food packets. Frustration over advisory labelling is just one of many issues that consumers raise with our helpline staff. We are often the first port of call when a reaction occurs. If you can imagine what it can be like for you, or your child, to be rushed to casualty suffering from anaphylaxis, you will probably understand that there is confusion as well as distress. What was it that caused the reaction? People will often jump to conclusions, and these may be the wrong ones. They may blame allergen contamination or – if they are fish allergic – they make think the company has added omega-3 without declaring it. A whole range of scenarios are presented to our helpline. As a first step, if a particular product is believed to be responsible for the reaction, we encourage the consumer to have a full and open dialogue with the manufacturer or retailer, and try to get to the bottom of the problem. We may also contact the company ourselves and explore whether there was indeed allergen contamination or a mistake during production. Or has the consumer become newly sensitised to an allergen? We urge food companies to be honest and open, and consumers not to play the blame game. But if a serious mistake appears to have been made, we will expect local enforcement officers to become involved. Occasionally, a sample of a suspect product is sent off for analysis. Reactions sometimes occur when a food product contains an ingredient that is properly declared but unexpected. We urge people to read the label every time they shop, but people lead busy lives and want short cuts. Consumers have failed to notice egg present in Edam cheese, kiwi extract in an Easter egg moulding kit and casein in a wide variety of pre-packed goods where you might not expect to find milk. Often consumers make mistakes, but on occasions they can be forgiven for being confused. The average person has never been inside a food factory and will have no concept about risk levels. Does ‘made in a factory that handles nuts’ signify a real risk or can the statement be disregarded? Sometimes the packaging tells a contradictory story. The consumer may expect different-sized but similar products to carry the same allergen risk but it may be wrong to


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make this assumption. In other cases, you find an allergen statement on the outer wrapper but not on the inner wrapper, or vice versa. Confusion may also occur where one brand of pesto sauce contains pine nuts but another is made with cashews. Some Bakewell tarts may be made with almonds, others with apricot kernel. All of this serves to make life difficult for the consumer. Some people’s demands are unrealistic. They expect to see a ‘contains nuts’ warning if coconut is present (when in fact coconut is not strictly speaking a nut); they want frontof-pack allergen information that will save them the trouble of going to the ingredient list (we advise people to read the list of ingredients every time); in extreme cases, they may want an allergen banned from the environment, such as in schools. This last point may sound unreasonable if you are not affected by allergy – and the Campaign itself has serious reservations about allergen bans – but such demands demonstrate the understandable anxiety that people feel. Other consumer demands are more reasonable. If a new allergen has been introduced into a product, they are right to expect to see some indication on pack (such as a ‘new recipe’ flash). A company’s information should be consistent. For example, people should see the same information on pack that appears on the company’s website, which does not always happen. And food companies should be as scrupulous with their ‘free from’ lists as they are with their product labelling. There are occasions when someone makes a mistake for which the manufacturer is partially responsible. This happened with tragic consequences in the case of a 20-year-old mother. She died from an allergic reaction to peanuts following a terrible mistake that involved a ‘may contain’ label. The young woman regularly ate products that carried ‘may contain’ warnings because she had never reacted to them and believed she was fine with them. In October 2003, she prepared a pack of vegetarian sausages for herself and her son. She saw that the pack carried a warning, ‘may contain traces of nuts’, and looked no further. Had she gone next to the ingredient list, she would have seen peanuts listed as an intentional ingredient. As she ate her meal, the young woman immediately realised she was having an allergic reaction. She was treated with adrenaline at her local surgery but by then too much time had elapsed. An inquest recorded a verdict of misadventure. At the time of her death, the young woman had not renewed her EpiPens. It was suggested at the inquest that she might have been frightened of having them. The Campaign’s food adviser, Hazel Gowland, who was an expert witness at the inquest, commented at the time: This was a shocking example of what can happen out there in the real world. We all hope that people with food allergy will always read food labels thoroughly and have adrenaline to hand at all times, but life in the real world is often different. It’s a fact that some people will eat a product carrying a warning label, find they don’t react and believe this means they can eat other similar products. In this young woman’s case, there was an additional factor that led her to making a mistake: the vegetarian sausages carried a ‘may contain’ warning plus the word ‘peanuts’ among the ingredients. She made a wrong assumption that ‘may contain traces of nuts’ was the only reference to nuts. However, it is important to strike a positive note, as well as to list the problems. Industry has made huge strides since 1994. There is a genuine concern for people with food allergies

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and even if this is only partially altruistic, it is a fact that you can walk into a shop and see comprehensive allergen labelling that would have been unheard of just over a decade ago. Some companies have acknowledged the needs of the allergic public by developing products ‘free from’ certain allergenic ingredients and although this has sometimes brought its own problems (there have been recalls of products in ‘free from’ ranges), nevertheless this is one more sign that food allergy is well and truly on the industry’s agenda.

1.7

ALLERGEN THRESHOLDS

In the tragic case outlined above, peanut was an intentional ingredient that was present as a significant amount. But a question frequently asked by industry and consumers alike is: When do unintentional traces of an allergen constitute a real risk? Is there a limit below which people won’t react? Scientists around the world are working to develop an understanding of threshold doses for food allergens – the lowest amount that can trigger an allergic reaction. The big questions are: How much is too much? Is there a measurable level below which people wouldn’t react? If so, this would offer much-needed reassurance. Industry could make efforts to reduce cross-contamination to below these levels and consumers might feel safer. However, not everyone is happy with this approach. Some consumers tell our helpline that they want to see every possibility of cross-contamination removed. They know that minuscule traces can trigger reactions and want zero risk. The perception that microscopic traces can kill may be founded largely on scare stories and extreme cases, but it is true that reactions can be triggered by small quantities of allergen. They may not be life threatening but any symptoms requiring treatment are unpleasant and alarming. Furthermore, an allergic person’s own threshold can vary from day to day. How much they react to at any given time may depend on factors such as their general state of health, how well their asthma is controlled, whether they have been exercising strenuously or drinking alcohol, and other factors. Even if industry works to agreed thresholds, would these limits be misleading if a person can react to lower amounts at certain times? People question whether any industry action based on agreed thresholds will protect 100% of the allergic population all of the time. The answer is that there may be a very small minority who are so susceptible that they could react to an amount below the threshold. It is highly unlikely that this would be a life-threatening reaction – but do we know that for sure? Establishing thresholds will not totally remove uncertainty. On the other hand, many consumers agree that establishing thresholds would hold benefits both for them and for the food industry. Total elimination of risk is impossible in any area of life, but risk minimisation is achievable. The most severe allergic reactions are normally caused not by traces, but by significant quantities of allergen, intentionally added to the food. In such cases, there is usually a major error made somewhere along the way, either by the person supplying the food or the person eating it, or both. Food industry action based on agreed thresholds could lead to a reduction in ‘may contain’ labels. We suspect that many of these warnings are applied when a food company is hampered by a lack of knowledge about what constitutes a significant risk. Knowledge of thresholds will make industry’s job easier and have a positive knock-on effect for the allergic consumer. The Anaphylaxis Campaign leans towards the pro-threshold argument. We sympathise with those who want zero risk. They want to see separate factories, or at least segregated


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production lines, to eliminate cross-contamination altogether, and this is something the Campaign supports wholeheartedly. But this will take some time to achieve and meanwhile risk minimisation is the goal. In our experience, most life-threatening reactions are caused by significant quantities of an allergen. Anxiety is fuelled by the myth that even touching or smelling a peanut is likely to cause death. There is no doubt that unpleasant reactions do occur when an allergen such as peanut or milk gets on to the hands of an allergic person. However, these are more likely to be localised reactions where the contact occurred. The myth that a trace is likely to kill needs to be dispelled. In an attempt to offer practical advice to people, we point out that they can lower their own personal risk by managing their asthma and eczema, taking special care with food when they feel unwell, run down or stressed and ensuring they do not take any risks with food if they have been drinking alcohol, which can increase the severity of allergic reactions.

1.8

FOOD ALERTS

In order to protect its members, the Campaign operates an early alert system that warns people when a mistake has been made by industry and products are on sale that pose a risk. After investigating the circumstances, and becoming sure of the facts, we target our allergic members by first class mail. Our database of members can tell us specifically who we need to target. For example, if necessary, we could pull out all members aged 0–7 years in Bolton with milk allergy. Our first alerts occurred in the late 1990s and the number rose steeply when the European Union’s regulations governing the mandatory labelling of allergens took effect. The Campaign sent out 36 product alerts to allergic members during 2006, compared with 17 in 2004. In 2007, the figure rose to 58. The following incidents are examples of those that have occurred over the years. A company specialising in food for babies and infants announced the recall of four batches of cheese and tomato bake for infants from 4 months. These batches contained milk ingredients but had been incorrectly labelled as milk and lactose free. Table 1.3 shows food alerts during 2007. Due to a packaging error, a batch of children’s ham snacks was recalled because they contained the hot dog variety. The affected packs did not show the correct ingredients or allergy advisory statement and there was a risk of contamination with nuts, milk, soya,

Table 1.3 Anaphylaxis Campaign food alerts by allergen during 2007. Milk Peanuts/nuts Wheat/gluten Soya Sulphites Egg Seafood Celery Mustard Sesame

26 7 7 7 6 5 2 1 1 1

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poppy, sesame and sunflower seeds. The error was said to be due to an isolated manufacturing incident at a factory on the Continent. Muesli products marketed by two separate companies were found to contain undeclared nuts – in one case pecan, hazelnut and flaked almond and in the other case whole hazelnuts and Brazils. A retailer’s chicken product containing couscous was labelled ‘gluten free’, but couscous is derived from wheat. Bags of yoghurt-coated raisins were found to contain a number of yoghurt-coated peanuts. The packaging carried a warning statement: ‘This product may contain traces of nuts.’ In a separate incident, the mother of a peanut-allergic child found 13 chocolate-covered peanuts in a bag of chocolate raisins. The product was withdrawn after the company was contacted by environmental health officers. And there was yet another case involving a different company’s yoghurt raisins. These were withdrawn from the shops after a customer found ten containing peanuts in the packet. A major retailer withdrew stocks of fresh shortcrust pastry because, although butter was clearly listed among the ingredients, the words ‘contains milk’ were inadvertently omitted from the allergen box. The product contained a small quantity of milk protein. The message here is that if an allergen advice box is used, it should be comprehensive. In the vast majority of cases, the company with the problem agrees to pay for the mail alert to our members. In a small number of cases, the Campaign has to pay for the alert out of its own funds. The FSA also runs an alert system, based on SMS text messages sent to subscribers. The Campaign welcomes this scheme but decided to remain with its own system after a postal survey among members came out overwhelmingly in favour of alerts by post.

1.9 OUR WORK WITH INDUSTRY Industry faces significant challenges in ensuring that food is safe and properly labelled for people with allergies. What food companies require is information and guidance based on good science. In March 2003, we set up a membership scheme for the food industry in which we offer our subscribers regular, high-quality news bulletins and the opportunity to attend seminars, where problems can be discussed and analysed. Eighty companies had joined this scheme by the end of 2007. Bulletins contain important information on subjects such as peanut allergy research, the need for thresholds, allergy to individual foods such as lupin, poppy seeds and pine nuts, and European legislation. However, we concluded early on in the Campaign’s history that fundamentally what consumers really need is the knowledge that there are consistent, high-quality standards in place for the control of food allergens. Primarily people want to know that they can eat safely and they wish to see a significant reduction in ‘may contain’ warnings. Progress was made in 2007 when the Campaign became the first organisation in the United Kingdom to develop a standard that specifically aims to promote good allergen management and labelling (Anaphylaxis Campaign, 2007). The standard had been developed thanks to a grant from the FSA in 2006. The work was done by recognised experts from within the industry and a rigorous consultation exercise was launched in the autumn of that year. Pilot audits were held and the standard was revised in line with the findings and with the comments that emerged during the consultation. The United Kingdom Accreditation Service (UKAS) completed a technical review of the standard in August 2007 and it became available for sale


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Fig. 1.4 The logo that food companies will be invited to use on products that have been certified against the Anaphylaxis Campaign Standard. The logo denotes good allergen control during the food production process. (Reproduced with permission.)

in November of that year. In developing the scheme, the Campaign had always intended that companies adopting the standard would have the option of participating in a certification scheme to show compliance with the requirements of the standard. With that in mind, a logo was designed for use on food packets to show the product had been independently certified. The Campaign is working with Doncaster-based Highfield.co.uk Ltd. to seek to ensure that the standard is widely adopted, thus bringing a high quality of allergen control to food production. Highfield was given the task of marketing and selling the standard, and also took on the crucial role of training those people who are required to carry out audits against the standard as well as the staff of food companies that participate in the scheme. Highfield have now launched the Anaphylaxis Campaign allergen training courses for manufacturers, retailers, auditors and trainers (see Figure 1.4). However, it would be completely wrong to infer that all of the good news relating to food allergy has been generated by consumer groups. Specific food companies, trade bodies and the FSA have been in the forefront of numerous positive developments. For example, the British Retail Consortium and Food and Drink Federation have both written realistic and constructive guidance documents for their members on issues such as the handling of nuts and the practical requirements of European allergen legislation. Both organisations have also provided positive input into important FSA initiatives relating to food allergens.

1.10 THE WORK OF THE FSA Since our 1994 meeting with Nicholas Soames, a succession of government ministers and civil servants have shown a strong commitment to food allergy.

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In 1997, the Ministry of Agriculture, Fisheries and Foods (MAFF) instigated a poster and leaflet campaign aimed at the catering industry. This was re-branded by the FSA and became the popular ‘Be Allergy Aware’ pack. The FSA produced web guidance for caterers and for newly diagnosed patients, commissioned work on catering, shopping and consumer attitudes, and worked with the Anaphylaxis Campaign to produce a poster aimed at allergic students and leaflets translated into Asian languages. The FSA also published a guidance document for retailers and manufacturers on allergen management, focusing largely on the ‘may contain’ issue (FSA, 2006). At the same time, the FSA developed training for enforcement officers and added food allergy to the curriculum for caterers. In early 2007, the FSA published its allergen guidance for caterers and businesses that sell food loose (FSA, 2008). Furthermore, the FSA’s allergy research programme now funds projects to the tune of more than one million pounds a year.

1.11 SCHOOLS Food allergy has a disconcerting effect on schools and playgroups. Saying goodbye to your severely allergic child at the school gate can be a stressful experience. Parents may be accused of being overprotective, but anyone who has first-hand knowledge of anaphylaxis will understand why a high degree of anxiety exists. Our surveys have found many examples of good practice in schools. As one head teacher stated, it is possible to have excellent policies: All children have to be registered with the school as having an allergy. We have to hold two EpiPens (the expiry dates are noted and parents reminded). The ‘pens’ are held in the office in a secure cupboard with easy access. Each child has the box clearly marked with photos on the box, also consent forms with medication to be given by school from parent, plus a pencil and checklist in each box. The teachers/staff are encouraged to attend annual courses for anaphylaxis training. But there have been many other cases where understanding and awareness were poor. ‘At playgroup, I had to organise the EpiPen training myself, and had to sit in the car outside the school in case of emergency as staff were not confident.’ ‘Our daughter with severe nut allergy was excluded from playgroup for 2 weeks until they could investigate their insurance cover.’ Our surveys showed up inconsistencies with regard to training of school and preschool staff in the procedures necessary to care for allergic children. Where teachers have not been trained, or have forgotten the training, there can be serious issues to deal with: ‘He cannot have school dinners because they feel unable to take the risk . . . this has been hard for a 4-year-old to understand.’ ‘My son was rejected by his nursery school when he was prescribed an EpiPen, which now has a “no EpiPen” policy.’


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We ask schools to be aware of the dangers of bullying, as everyone who is different is a potential target. The parent of a nut-allergic boy told us: ‘One pupil even tried to make him eat something containing nuts.’ Most schools have at least one child who carries adrenaline, and most will have several. School staff cannot be compelled to administer a child’s injection in the event of a reaction occurring, but in most cases there are enough volunteers to give reassurance to the parents and their child. Educating the school staff is crucial. To meet this need, the Anaphylaxis Campaign has launched a major programme of training. Thanks to the receipt of several grants, including substantial amounts from the American Peanut Council and several food companies, the Campaign devised a comprehensive training package for school nurses. The project was piloted in five areas of the United Kingdom in 2006 and was so successful that a countrywide launch began in 2007 and will continue at least until 2009. The aim is to train all school nurses in the country so that they are able to pass down their knowledge to school staff. Subjects covered in the training packs and seminars include avoidance of allergens, symptom recognition and treatment of reactions, as well as a wide expanse of background knowledge. Even within the first few months, 12 newly trained nurses had led 44 training sessions in schools and reached no fewer than 630 members of school staff. In a separate programme, the Campaign has launched an awareness drive to provide information and guidance for allergic students and for caterers in colleges and universities. This high-risk group forms an important part of the Campaign’s work. The attempt to improve safety in schools and other educational settings may have been hampered by government guidance that actively encourages the sale of nuts and seeds in school tuck shops and vending machines. Under 2007 rules formulated by the School Food Trust, snacks such as chocolate and crisps are banned from sale in schools, and instead they are being told to sell products that are considered healthy. Government guidelines promote nuts and seeds as healthy options. We believe this could lead to an increase in risk for allergic children. Good food labelling will help, but primarily the major risks are likely to be through cross-contamination. Nut proteins tend to become transferred easily from children’s sticky hands to desks, chairs, computer keyboards and other surfaces. The danger is that through ‘casual contact’ with these allergens, susceptible children may suffer reactions. Whilst these reactions may not necessarily be severe, they will certainly be unpleasant and disruptive. The potential risk was demonstrated in a paper published by a German medical team (Lepp et al., 2002). They reported the case of a 32-year-old man with peanut allergy who suffered a serious allergic reaction during a card game. His friends were eating peanuts and peanut protein from their fingers found its way on to the playing cards. As the cards often stuck together, the player with the allergy licked his thumb to separate them. It was this that caused his serious reaction. In an attempt to assess whether our fears are founded, we launched an online survey in which we encouraged families to report whether there was an increase in nuts and seeds in individual schools around the country and whether they perceived the risks to have risen. We are encouraged by the initial findings. Although these are early days, results suggest that there has not been the expected rush by schools to introduce nut products. However, the exercise will have to be repeated to establish whether snack trends in schools will change to the advantage or disadvantage of children with allergies.

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1.12 EATING OUT Our more general online survey in 2006 asked respondents about the degree to which they were affected by everyday situations. A high level of concern was given to eating out as a family, with 78% mentioning this as having a great effect on them. In our experience, supported by published studies, people with serious food allergies face significant risks when they eat out. Clearly because this is, in part, due to the fact that the usual food labelling rules do not apply and people are relying on menu statements and verbal assurances by staff. Pumphrey (2000) and Pumphrey and Gowland (2007) have shown that a significant proportion of the reported deaths occurred when food was bought in catering establishments, such as restaurants, hotels and takeaways. Peanuts or tree nuts were frequently implicated. In some cases where the victim had asked for a meal without nuts, the person serving (and in several cases even the caterer) had not been aware that the food contained nuts. In other cases, the request for nut-free food had either been misunderstood or forgotten. This shows that some highly allergic patients know that they need to be extremely vigilant at mealtimes, but mistakes still occur. In our view, most documented cases highlight the importance of prescribing adrenaline for ‘at risk’ allergy patients and educating them about their use. Our surveys showed that eating out ranges from difficult to impossible for people with severe food allergies and their families. People complained about a lack of understanding and said catering staff were frequently unable to offer accurate advice. One person told us: ‘Most waiters just say, “You should be OK.” One waitress said to me: “Please don’t die here.” ’ Respondents noted that some national chains had put in place good systems of allergen control and communication with allergic customers. Implicit in these comments was the idea that if it could be done by one or two companies, why could not others do it? People complained of a lack of consistency among restaurants, hotels and takeaways: ‘Some chefs are brilliant, making special meals, but otherwise you get a lethargic response.’ ‘Restaurants and cafes refuse to serve you.’ ‘We get very embarrassed. People think we are just being fussy if we ask for the ingredients.’ Respondents reported widespread lack of understanding and a need for training and education: ‘Restaurants have no understanding of how life threatening it is to eat a food with nuts.’ ‘(My daughter) had a reaction due to nut-containing foods in a restaurant where two different waiters had assured us there were no nuts.’ ‘There is a widespread belief that only peanuts cause allergies. One restaurant owner guaranteed there were no allergy-causing nuts in a dish, but it arrived with cashew nuts.’


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‘In a café, I bought chocolate chip cookies labelled “may contain traces of nuts” but found white bits in them which turned out to be peanuts.’ Deaths are rare, but when they occur they generate dramatic media publicity which has a demoralising effect on people affected. My own daughter’s death in 1993 is one of many that have been well publicised. A 13-year-old girl died after eating a small amount of curry sauce made with peanut butter. There was some mention in her doctor’s notes about peanut allergy, but there had been no proper diagnosis and no prescribing of adrenaline. Her family had no idea that she was at risk of a fatal reaction. Another teenage girl collapsed and died during a formal dinner at university after she ate a dessert that – unknown to her – contained nuts. She knew she had nut allergy and had asked her GP for help. Her GP had led her to believe that nothing could be done. There had been no proper allergy diagnosis or advice and no prescribing of adrenaline. Fatalities are thankfully rare but near misses are probably more common than most people realise. A young woman reported a severe reaction requiring hospitalisation following a meal in a cafe. The dessert menu had nut logos on some dishes and she asked about the tiramisu, which did not have a logo. The staff checked and checked again and she was served the tiramisu. She began to have a reaction, which became severe, and was taken to hospital. The restaurant double checked the box and found that the tiramisu she had eaten contained hazelnut crumb. A young London man reported a severe reaction from a meal in his local curry house, where he ate regularly. He said that the staff had told him twice that his menu choice did not contain nuts. He was taken by ambulance to hospital, spent the weekend there and then a week recovering. One must never forget that the onus is on each allergic diner to be clear with catering staff about what he or she cannot eat. This is an important message for people with food allergy. Despite the problems outlined above, many catering businesses now have excellent allergen management systems and effective controls in place. Furthermore, the FSA’s guidance (2008) offers caterers a useful reference point if they wish to take allergy seriously. People with food allergy can be assured that things are improving. But here, as ever, we return to the problem of inadequate allergy advice under the NHS. How can people protect themselves adequately if they do not have an expert diagnosis and high-quality guidance in the first place?

1.13 DAILY LIFE WITH A FOOD ALLERGY People’s lives are affected in many other ways, some of which are demonstrated by these comments that arose from our surveys: ‘No woodland walks, house plants, or fresh flowers, no holding my grandchildren’s cuddly toys.’ ‘I am smell-sensitive to nuts. This makes it impossible for me to go to the cinema.’ ‘I can’t spontaneously embrace my husband in case he has eaten anything I’m allergic to.’ ‘My husband has had to give up his job to look after my daughter during school holidays.’

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‘We had problems booking flights with one airline. They wanted a form completed by the doctor before letting our son fly, so we booked with another airline which just asked for a doctor’s letter.’ ‘If airlines provide nut-free meals, this is usually reliable on the outbound journey but frequently forgotten on the inbound.’ ‘I was made to feel like a second-class citizen. Why should I be denied the social pleasures everyone else enjoys because of ignorance?’ ‘When my son leaves home for university, he is likely to eat out more. Because of the years that have passed without an anaphylactic reaction, he may become less inclined to carry his EpiPen and less careful about reading ingredients labels.’ However, there are positive experiences among the negatives: ‘Whilst on holiday with (travel company A) recently, it was fantastic to hear the captain announce the need for all passengers to avoid all nuts as there were two passengers on board with severe nut allergies.’

1.14 HOPES FOR THE FUTURE What does the future hold for people with food allergy? There is some cause for concern. Pumphrey and Gowland (2007) showed that almost a third of the people who die from food allergy are not actively avoiding the particular food allergen. Some may have had minor symptoms in the past, but they were not expecting symptoms to become so severe so quickly. This presents a challenge to GPs, specialists and all those who diagnose allergy. It is also the job of researchers to devise ways of identifying the patients who are most at risk: something that cannot be done with any certainty yet. The quality of life of people with food allergy is also a burning issue. One study (Avery et al., 2003) showed that quality of life was more severely impaired in peanut allergy than insulin-dependent diabetes. The great challenge for the future is to improve the lives of allergic people by developing the clinical services and information systems, but also by better food manufacturing procedures and labelling to allow people to make accurate and appropriate risk assessments. Clearly there is the chance, too, that further allergens will be identified as causing problems. When the Campaign first began its work, just a few food allergens were considered worthy of attention. Then kiwi fruit appeared on the radar. And others, such as lupin flour, began to emerge as potential problems. A young man with peanut allergy suffered a severe allergic reaction in 2002 after eating a chicken and ham pie in his office canteen. He suspected there were peanuts in the meal, but laboratory tests proved negative. Then it was pointed out that the pastry – imported from France – contained lupin flour. He saw an allergist and skin prick tests showed him to be extremely allergic to lupin. Until these emerging allergens are better understood, GPs cannot be expected to know about them, let alone know how to offer advice. There is some cause for unease. However, there is also much cause for optimism. The Campaign’s standard promoting consistent allergen control provides a real opportunity for food companies to get to grips with allergens for the benefit of the allergic public. We hope


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to see more and more companies opting for certification, but even without it, the standard will improve life considerably for industry and consumers alike. On the schools front, the Campaign’s national training programme will inevitably lower risks for allergic pupils. The present commitment by the FSA to allergy is to be applauded and we hope the good work will continue. The campaign to achieve an improvement in allergy services will continue, despite the lack of attention given to allergy so far by the Department of Health. The National Allergy Strategy Group will continue campaigning until the point is reached where everyone with an allergy gets optimum diagnosis, treatment and guidance. But what people really want for the future is a cure. Can the effects of a severe allergic reaction be reduced by drugs, and can allergy even be switched off altogether? Many parents who face the grim prospect of their allergic child remaining severely allergic for life – with the fear of death never far away – ask us passionately about the likelihood of medical science finding the elusive cure. Only this will end their anxiety. The answer is that there is good work going on worldwide with this objective in mind. Oral immunotherapy offers the possibility that people with food allergy can become desensitised by eating increasing amounts of the culprit food over a long period. Their immune systems would eventually become tolerant to the food. There are several research teams, in the United Kingdom and elsewhere, hoping to demonstrate that this can be done. The US researchers have had success with egg (Buchanan et al., 2007) and are trying to do the same with peanut. Children in their study had reduced symptoms to egg when the team increased the amount they ate over a 2-year period. After the 2 years of desensitisation, all the children tolerated a higher dose of egg than at the outset of the study, and this was more than would typically be encountered in an accidental exposure. Most of the children could tolerate two scrambled eggs with no adverse reaction by the end of the study. In those who did react, the reactions were less severe. Eventually, the study team hopes to induce lasting tolerance to egg. Anti-IgE therapy is intended to block the action of IgE, the antibody responsible for triggering the cascade of symptoms in patients with allergies. The drug could be delivered by injection once or twice a month indefinitely to people at risk of severe allergic reactions. People might still react, but the severity of reactions would be diminished. People would still be advised to avoid eating peanuts, but they might not have to worry about having a life-threatening reaction if they eat a small amount by mistake. Researchers in the United States are experimenting with a vaccine based on Escherichia coli bacteria (Li et al., 2003). These are killed and then used as a carrier for modified peanut proteins. These would be administered to the allergic person by suppository. The treatment seems to activate the immune system to turn off the IgE response. Canadian researchers believe a protective enzyme found in the blood decreases the severity of allergic reactions (Vadas et al., 2008). The enzyme acetylhydrolase breaks down PAF (platelet-activating factor), a chemical produced by the body as part of a severe allergic response. People with low levels of acetylhydrolase appear to have more severe reactions than those with higher levels of the enzyme. If the findings are verified, drugs might be developed that would treat life-threatening allergic reactions when they occur and possibly even protect people from experiencing severe responses in the first place. Furthermore, scientists are also working on the question of what makes people allergic in the first place – and can this trend be reversed? Since 1994, the government has wrestled with the problem of why peanut and other food allergies are on the increase. The famous Isle of

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Wight studies showed initially that 1 in 200 children was peanut allergic and a decade later that the figure had risen to 1 in 70 (Grundy et al., 2002). Parents of a peanut-allergic child have their own theory about how their child became sensitised. Many mothers become convinced it was because they ate peanuts while pregnant or breastfeeding, and are consumed by guilt. Although such anecdotal evidence is unreliable, the Department of Health gave credence to this hypothesis in 1998. Drawing on evidence provided by the Committee on Toxicity, the Department of Health issued guidelines to women suggesting that they ‘may wish’ to avoid nuts and peanuts during pregnancy and while breastfeeding if there is allergy in the immediate family (i.e. if they or their partners are allergic, or if they have an allergic child, e.g. with asthma, eczema, hay fever or food allergy). The guidelines also state that peanuts and tree nuts should not be introduced to children until after 3 years of age (Committee on Toxicity, 1998). Recently, serious doubts have been expressed about this advice. A team of London-based researchers believe that they may demonstrate that introducing peanut-containing foods early into children’s diets will actually prevent peanut allergy from developing. The team has been recruiting infants (aged 4–10 months) with severe eczema and/or egg allergy from the London area. Half the children are receiving peanut-containing snacks and the other half are advised on the avoidance of peanuts (as per the Department of Health recommendations). When the children have reached 5 years of age, a determination of the relative rates of peanut allergy will be made. It is a case of ‘watch this space’. There are many experts who believe this study offers hope that the apparent rise in food allergy can be reversed. In this chapter, I have tried to demonstrate that whilst there is much good work taking place to improve life for people with food allergy, the level of anxiety that some experience is unbearable. That is summed up poignantly in this final quotation: Our daughter suffered from an allergy to peanuts. There was no specialist support system in place to help her. In particular, we had no knowledge of the fact that peanut allergy sufferers may also be allergic to lupin flour – an ingredient in high grade pastry. At the age of 15 she had this potentially fatal anaphylactic reaction to lupin flour following the consumption of school food. The paramedic responded well but the local hospital was lamentable following the first attack. The doctor dealing with our daughter had never before seen an EpiPen. He succeeded in squirting it up a wall and suggested we find a pharmacy to replace it since the hospital did not have any. We have no doubt that the cavalier treatment Alice received affected her psychologically. She took her own life on the eve of starting at university and having just completed her Duke of Edinburgh Award Gold.

REFERENCES Anaphylaxis Campaign (2007) The Anaphylaxis Campaign Standard to Increase Trust in Information about Allergens in Food. The Anaphylaxis Campaign, Farnborough, Hampshire. Avery N., King R., Knight S. and Hourihane J. (2003) Assessment of quality of life in children with peanut allergy. Pediatric Allergy and Immunology, 14(5), 378. Buchanan A., Green, T., Jones, S. et al. (2007) Egg oral immunotherapy in non-anaphylactic children with egg allergy. The Journal of Allergy and Clinical Immunology, 119(1), 199–205. Committee on Toxicity (1998) Report on Peanut Allergy. Department of Health (Government report), London. Available at http://cot.food.gov.uk/cotreports/cotwgreports/cotpeanutallergy, accessed 25 January 2008.


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FSA (Food Standards Agency) (2002) ‘May Contain’ Labelling – The Consumer’s Perspective. Food Standards Agency, London. Available at http://www.food.gov.uk/foodlabelling/researchandreports/ maycontainsummary, accessed 25 January 2008. FSA (Food Standards Agency) (2006) Guidance on Allergen Management and Consumer Information. Food Standards Agency, London. Available at www.food.gov.uk/multimedia/pdfs/maycontainguide.pdf, accessed 25 January 2008. FSA (Food Standards Agency) (2008) The Provision of Allergen Information for Foods that Are Not Prepacked. Food Standards Agency, London. Available at http://www.food.gov.uk/foodindustry/ guidancenotes/labelregsguidance/nonprepacked, accessed 25 January 2008. Grundy J., Matthews S., Bateman B. et al. (2002) Rising prevalence of allergy to peanut in children: data from two sequential cohorts. Journal of Allergy and Clinical Immunology, 110(5), 784–789. House of Commons Health Committee (2004) The Provision of Allergy Services. Sixth Report of Session 2003–2004, Vol. 1. Parliamentary Publication (UK Government), London. Available at http://www. publications.parliament.uk/pa/cm200304/cmselect/cmhealth/696/69602.htm, accessed 25 January 2008. House of Lords Science and Technology Committee (2007) Allergy. Sixth Report of Session 2006–2007. Parliamentary Publication (UK Government), London. Available at http://www.publications.parliament. uk/pa/ld200607/ldselect/ldsctech/ldsctech.htm, accessed 25 January 2008. Lepp U., Zabel P. and Schocker F. (2002) Playing cards as a carrier for peanut allergens. Allergy, 57(9), 864. Li X., Srivastava K., Grishin A. et al. (2003) Persistent protective effect of heat-killed Escherichia coli producing engineered, recombinant peanut proteins in a murine model of peanut allergy. Journal of Allergy and Clinical Immunology, 112(1), 159–167. Pumphrey, R.S.H. (2000) Lessons for the management of anaphylaxis from a study of fatal reactions. Journal of Clinical and Experimental Allergy, 30, 1144–1150. Pumphrey R.S.H. and Gowland M.H. (2007) Further fatal reactions to food in the United Kingdom 1999–2006. The Journal of allergy and clinical immunology, 119, 1018–1019. Royal College of Physicians (2003) Allergy the Unmet Need: A Blueprint for Better Patient Care. Royal College of Physicians, London. Available at www.rcplondon.ac.uk/pubs/books/allergy/allergy.pdf, accessed 25 January 2008. Vadas P., Gold M., Perelman B. et al. (2008) Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. New England Journal of Medicine, 358(1), 28–35.

2

Clinical incidence of food allergy

Zsolt Szépfalusi and Thomas Eiwegger

2.1 INTRODUCTION The understanding of food allergy and hypersensitivity has progressed substantially since 1950, when Loveless first suggested using masked food challenges to objectively determine the veracity of patients’ histories of food allergy. May (1976) codified this approach and established the double-blind, placebo-controlled food challenge (DBPCFC) as the gold standard for the investigation and accurate diagnosis of adverse reactions to food. The definition of the term allergy has been replete with misunderstanding when applied to foods. This chapter restricts the use of the term allergy to those adverse food reactions that have been shown to have an immunologic basis of strong immunologic association. A series of crucial clinical case histories detailed below will lead the reader through the areas of diagnosis and management of anaphylaxis due to food allergy:

r r r r

making a diagnosis, deciding who needs a special diet with particular restrictions, deciding who needs a self-injectable adrenaline device, and for how long and considering new allergens causing food allergy.

Anaphylaxis is a common paediatric emergency with less frequent incidences in adulthood (see Figure 5 in Poulos et al., 2007) (Figure 2.1). There is no current consensus about the specific criteria for diagnosis of anaphylaxis, as reflected in very different incidence assessments among countries. A widely accepted definition would be a ‘severe, life-threatening generalised or systemic hypersensitivity reaction’ (Johansson et al., 2004) or a ‘serious allergic reaction that is rapid in onset and may cause death’ (Sampson et al., 2006). In allergic anaphylaxis, there is an IgE-mediated systemic release of mediators from mast cells and basophils. This leads to the development of the cutaneous, respiratory and/or cardiovascular symptoms and/or signs that are seen in anaphylaxis (Sheikh and Walker, 2005). The development of such IgE-mediated symptoms is shown in Figures 2.2a–2.2d. These photographs show before and after food challenge with microgram amounts of peanut in a small child. Figures 2.3a and 2.3b show the development of urticaria and eczema in a baby challenged with food material containing milk. The incidence of anaphylaxis is unclear, but probably ranges from 1 to 20 per 100,000 person-years (Yocum et al., 1999; Macdougall et al., 2002; Braganza et al., 2006). Routine UK hospital admission data suggest an increase of 250% in severe anaphylaxis between 1995 and 1999 (Sheikh and Alves, 2000) (see Figure 2.4). Among the causes of anaphylaxis in infants and children, foods are the most frequent, with peanuts, tree nuts, milk, egg and


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Image not available in this electronic edition.

Fig. 2.1 Australian hospital admissions for anaphylaxis caused by food by broad age group, 1994–1995 to 2004–2005. (Reprinted from Poulos et al . (2007), with permission from Elsevier.)

(a)

(b)

(c)

(d)

Fig. 2.2 (a) Child prior to challenge. (b) Child showing cutaneous and respiratory distress shortly after consumption of small amount of peanut material. (c) Further progression of the Ig-E-mediated allergic response-producing urticaria. (d) Urticaria on hand.

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(a)

(b)

Fig. 2.3 (a) Baby showing signs of urticaria and discomfort when challenged with small amount of milk protein. (b) Progression of the allergic response causing itching and spread of urticaria.

fish being the most common precipitants (Pumphrey, 2000; Bock et al., 2001; Mehl et al., 2005; Bock et al., 2007; Pumphrey and Gowland, 2007). While the majority of children outgrow their allergy to milk, egg, wheat and soya, allergies to peanut, tree nuts, fish and shellfish are often lifelong. Although any food can cause anaphylaxis, the most commonly implicated foods for severe allergic reactions are peanuts, tree nuts, fish and shellfish (Burks et al., 1999).

Image not available in this electronic edition.

Fig. 2.4 Number of hospital discharges with the primary diagnosis of anaphylaxis per 100,000 episodes of hospital discharge and cause of anaphylaxis (in England). (Reprinted from Sheikh and Alves (2000), with permission from BMJ Publishing Group Ltd.)


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2.2 CASE 1 – SEVERE ANAPHYLAXIS TO AN UNKNOWN FOOD PRODUCT A 7-year-old boy complains of an itchy mouth at a birthday party. Ten minutes later, he starts to develop an itchy rash on his face. Within minutes his lips become swollen and he indicates to his friend’s parents that he is experiencing difficulties in breathing. The parents of his friend give him some cetirizine syrup and call the ambulance. He is treated in the emergency department with oxygen, subcutaneous adrenaline, nebulised salbutamol and intravenous prednisolone. He recovers after a couple of hours without developing any other symptoms. The dietary history reveals that he consumes all the common food sources without any problem but he avoids peanuts since a school friend had experienced an anaphylactic attack in the classroom while eating peanut chips. Due to this event, the child attended a consultation at an outpatient allergy clinic in a university hospital. The central question was whether or not the boy had true peanut allergy. In his history, the boy had eczema assigned as ‘atopic’ by his paediatrician. The examination is unremarkable. Skin prick testing (SPT) with peanut, a selection of tree nuts (walnut, cashew, almond) and a panel of common food allergens (milk, egg, wheat, soy, fish) revealed a positive reaction only to peanuts (6-mm wheal). The histamine control gave a 4-mm wheal; the saline control was negative. Specific IgE levels to peanuts were elevated with 12 kU/L (Roberts, 2007). The questions arising from this case can be summarised as follows:

r r r r

Is the child allergic to peanuts? Is the anaphylaxis-inducing food peanut? Should a diet be recommended? Is a self-injectable adrenaline to be prescribed?

If the child has experienced his first adverse reaction to a specific food (i.e. peanut), the positive predictive value for correctly identifying the allergen is 50% (Sampson and Ho, 1997). If the adverse reaction to the same food has already occurred three times, the positive predictive value for that food to be the allergen is around 100% (Eggesbo et al., 2001). When the history is not diagnostic, testing by skin prick or serum-specific IgE levels is required. SPT is less expensive and the result is immediately available. Serum-specific IgE may be used when a greater range of allergens needs to be tested and, in contrast to prick testing, concomitant medication (e.g. antihistamines, steroids) does not affect the result. It has been recognised that the greater the wheal response on SPT or the higher the serum-specific IgE level, the more likely a positive result will indicate clinical allergy. Many different groups have generated cut-off levels for different populations (Sampson and Ho, 1997; Sporik et al., 2000; Boyano Martinez et al., 2001; Garcia-Ara et al., 2001; Sampson, 2001; Rance et al., 2002; Bernard et al., 2003; Perry et al., 2004). The use of these cut-off levels may reduce the need for food challenges (Table 2.1). An SPT result of 2 years 7 15 15 15 20

Infants 95% (Sporik et al., 2000; Sampson, 2001). However, quantitative SPT and specific IgE levels are not particularly predictive of the severity of a clinical reaction. In the described case, the doctor asked particularly whether or not to prescribe an adrenaline self-injector, and this question is more related to the severity than to the presence of any reaction to egg consumption or exposure. Some additional factors may help in that decision (Kemp, 2003). Aggravating factors are shown in Table 2.3, these being: age over 5, since most deaths have been observed in school-age children or teenagers; a history of asthma requiring controlling medication (inhaled steroids); peanut or tree nut sensitivity; reactions induced by traces or small amounts of allergen; and a strongly positive SPT. The presence of asthma in general is considered to increase the risk of death (Bock et al., 2001; Macdougall et al., 2002) or

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a severe reaction (Sicherer et al., 2001). This conclusion is derived predominantly from older individuals with peanut and tree nut allergy. It remains to be clarified whether this also applies for younger children and infants with egg allergy. In the present case, asthma was not reported, but at that age involvement of the respiratory tract might represent the first manifestation of wheezy bronchitis, which might later be assigned as bronchial asthma. Thus respiratory symptoms as reported with cough would support the prescription of an adrenaline self-injector. Consequently, the answer to the doctors’ question would be yes. Importantly, prescription is not enough to prevent a severe reaction upon unexpected egg exposure. Without parental and individual teaching how to use an auto-injector, the likelihood to be applied correctly is very low. Some surveys on that issue highlight that only around 30% of adrenaline auto-injectors were used appropriately in a subsequent anaphylactic reaction (Gold and Sainsbury, 2000; Mehl et al., 2005). Instructions on auto-injector administration and provision of a clear and simple anaphylaxis action plan are just as important as the provision of the devise itself (Hu et al., 2007).

2.7 CASE 6 – IMMUNOTHERAPY FOR ORAL ALLERGY SYNDROME? A 35-year-old man has been suffering from tree pollen allergy for 3 years and approaches his doctor because of tingling in his mouth and throat while eating his favourite apple variety. His allergies during birch pollen season are well controlled. He regularly takes antihistamines and topical nasal steroids to treat his blocked nose. He has heard from friends and read in newspapers that immunotherapy might also help to relieve his symptoms associated with ingestion/contact with apples. Birch pollen sensitisation has been proven by SPT (wheal of 13 mm) and specific IgE-antibodies of 25 kU/L. Prick-to-prick test with different apple varieties induced wheals in the range of 10 mm. The patient clearly asks for immunotherapy as treatment of his oral allergy syndrome to apple associated with his birch pollen allergy affecting the upper airways. The following questions shall be answered:

r r

Shall an immunotherapy be recommended? Is the sublingual route as effective as the subcutaneous route?

Allergen-specific immunotherapy in birch pollen allergies is recommended as a first-line treatment. Short-term and long-term efficacy, as well as safety data, strongly support such a treatment in birch pollen-allergic individuals (Bousquet et al., 1998). In addition, successful allergen-specific immunotherapy (in particular the subcutaneous route) has been associated with an increase in allergen-specific IgG4-antibodies, reduced proliferative and cytokine responses in allergen-stimulated peripheral blood cells in vitro and a shift from a diseaseeliciting TH2 cells towards a more non-pathogenic TH0/1-like phenotype (Secrist et al., 1993; Jutel et al., 1995; Ebner et al., 1997). The balance between allergen-specific IL-10producing Treg and TH2 cells has also been proposed to be pivotal for a physiological immune response to allergens (Akdis et al., 2004). As an alternative of the subcutaneous route, the sublingual route is regarded as a validated option, particularly in adults (Wilson et al., 2005). Thus, an allergen-specific immunotherapy in either form (subcutaneous or sublingual) is


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recommended. However, the patient asked for the allergen-specific immunotherapy in order to control his oral allergy syndrome caused by apples. Recent data support the view that current strategies applying allergen-specific immunotherapy in birch pollen allergies have limited effects on concomitant food allergy to apple (Hansen et al., 2004; Mari et al., 2005; Kinaciyan et al., 2007), although beneficial effects, including partial long-lasting effects, have been reported in a non-randomised study (Asero, 1998, 2003). Another randomised study revealed significant statistically calculated improvements, but the treatment did not result in symptom-free consumption of apples (Bucher et al., 2004). In addition to missing clinical efficacy, immunological changes observed in Bet v1-specific responses in vitro did not affect the Bet v1-homolog in apple Mal d1 (Bohle et al., 2007; Kinaciyan et al., 2007). One study has, however, described the successful benefits of tree pollen immunotherapy on fennel, cucumber and melon allergy (Asero, 2000). Thus, despite improvements in the understanding of how pollen-associated food allergies develop, manifest and affect patients, treatment with a tree pollen targeted immunotherapy is currently not recommended for tree pollen-allergic individuals.

2.8 CONCLUSION The evaluation of food allergy should follow an orderly approach. The history may not allow the physician to accurately make the diagnosis, but it can be used to formulate a plan that will include skin testing, determination of food-specific serum IgE, diagnostic laboratory (or endoscopic studies), the use of limited or oligoallergenic food elimination diets and ultimately the decision to perform food challenges. The rigour of challenge is dictated by the nature of the problem and the setting in which the challenges are to be performed, recognising that families can be greatly aided without having to involve a tertiary medical centre. It has become one of the more straightforward areas of allergy diagnosis and treatment provided that the steps outlined and discussed above are followed.

REFERENCES Aickin R., Hill D. and Kemp A. (1994) Measles immunisation in children with allergy to egg. BMJ, 309, 223–225. Akdis M., Verhagen J., Taylor A. et al. (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. Journal of Experimental Medicine, 199, 1–10. Allen C.W., Campbell D.E. and Kemp A.S. (2007) Egg allergy: are all childhood food allergies the same? Journal of Paediatrics and Child Health, 43, 214–218. Asero R. (1998) Effects of birch pollen-specific immunotherapy on apple allergy in birch pollenhypersensitive patients. Clinical and Experimental Allergy, 28, 1368–1373. Asero R. (2000) Fennel, cucumber, and melon allergy successfully treated with pollen-specific injection immunotherapy. Annals of Allergy, Asthma, and Immunology, 84, 460–462. Asero R. (2003) How long does the effect of birch pollen injection SIT on apple allergy last? Allergy, 58, 435–438. Asero R. (2007) Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses. Clinical and Experimental Dermatology, 32, 34–38. Bernard H., Paty E., Mondoulet L. et al. (2003) Serological characteristics of peanut allergy in children. Allergy, 58, 1285–1292.

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Besler M., Steinhart H. and Paschke A. (2001) Stability of food allergens and allergenicity of processed foods. Journal of Chromatography. B, Biomedical Sciences and Applications, 756, 207–228. Bierman C.W., Shapiro G.G., Pierson W.E. et al. (1977) Safety of influenza vaccination in allergic children. Journal of Infectious Diseases, 136(Suppl), S652–S655. Bindslev-Jensen C. and Poulsen L.K. (1998) Accuracy of in vivo and in vitro tests. Allergy, 53, 72–74. Bock S.A., Munoz-Furlong A and Sampson H.A. (2001) Fatalities due to anaphylactic reactions to foods. Journal of Allergy and Clinical Immunology, 107, 191–193. Bock S.A., Munoz-Furlong A. and Sampson H.A. (2007) Further fatalities caused by anaphylactic reactions to food, 2001–2006. Journal of Allergy and Clinical Immunology, 119, 1016–1018. Bohle B., Kinaciyan T., Gerstmayr M. et al. (2007) Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. Journal of Allergy and Clinical Immunology, 120, 707–713. Bonnelykke K., Pipper C.B. and Bisgaard H. (2008) Sensitization does not develop in utero. Journal of Allergy and Clinical Immunology, 121, 646–651. Bousquet J., Lockey R. and Malling H.J. (1998) Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. Journal of Allergy and Clinical Immunology, 102, 558–562. Boyano Martinez T., Garcia-Ara C., Diaz-Pena J.M. et al. (2001) Validity of specific IgE antibodies in children with egg allergy. Clinical and Experimental Allergy, 31, 1464–1469. Braganza S.C., Acworth J.P., McKinnon D.R. et al. (2006) Paediatric emergency department anaphylaxis: different patterns from adults. Archives of Disease in Childhood, 91, 159–163. Bucher X., Pichler W.J., Dahinden C.A. and Helbling A. (2004) Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy, 59, 1272–1276. Burks W., Bannon G.A., Sicherer S. and Sampson H.A. (1999) Peanut-induced anaphylactic reactions. International Archives of Allergy and Immunology, 119, 165–172. Clark A.T. and Ewan P.W. (2003) Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clinical and Experimental Allergy, 33, 1041–1045. David T.J., Waddington E. and Stanton R.H. (1984) Nutritional hazards of elimination diets in children with atopic eczema. Archives of Disease in Childhood, 59, 323–325. De Boissieu D. and Dupont C. (2006) Natural course of sensitization to hen’s egg in children not previously exposed to egg ingestion. European Annals of Allergy and Clinical Immunology, 38, 113–117. Dean T., Venter C., Pereira B. et al. (2007) Patterns of sensitization to food and aeroallergens in the first 3 years of life. Journal of Allergy and Clinical Immunology, 120, 1166–1171. Ebner C., Siemann U., Bohle B. et al. (1997) Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clinical and Experimental Allergy, 27, 1007–1015. Eggesbo M., Botten G., Halvorsen R. and Magnus P. (2001) The prevalence of allergy to egg: a populationbased study in young children. Allergy, 56, 403–411. Eigenmann P.A., Burks A.W., Bannon G.A. and Sampson H.A. (1996) Identification of unique peanut and soy allergens in sera adsorbed with cross-reacting antibodies. Journal of Allergy and Clinical Immunology, 98, 969–978. Eigenmann P.A. and Sampson H.A. (1998) Interpreting skin prick tests in the evaluation of food allergy in children. Pediatric Allergy and Immunology, 9, 186–191. Falth-Magnusson K. and Kjellman N.I. (1992) Allergy prevention by maternal elimination diet during late pregnancy – a 5-year follow-up of a randomized study. Journal of Allergy and Clinical Immunology, 89, 709–713. Foucard T. and Malmheden Yman I. (1999) A study on severe food reactions in Sweden – is soy protein an underestimated cause of food anaphylaxis? Allergy, 54, 261–265. Garcia-Ara C., Boyano-Martinez T., Diaz-Pena J.M. et al. (2001) Specific IgE levels in the diagnosis of immediate hypersensitivity to cows’ milk protein in the infant. Journal of Allergy and Clinical Immunology, 107, 185–190. Gold M.S. and Sainsbury R. (2000) First aid anaphylaxis management in children who were prescribed an epinephrine autoinjector device (EpiPen). Journal of Allergy and Clinical Immunology, 106, 171– 176.


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Hansen K.S., Khinchi M.S., Skov P.S. et al. (2004) Food allergy to apple and specific immunotherapy with birch pollen. Molecular Nutrition and Food Research, 48, 441–448. Hattevig G., Kjellman B., Johansson S.G. and Bjorksten B. (1984) Clinical symptoms and IgE responses to common food proteins in atopic and healthy children. Clinical Allergy, 14, 551–559. Holloway J.A., Warner J.O., Vance G.H. et al. (2000) Detection of house-dust-mite allergen in amniotic fluid and umbilical-cord blood. Lancet, 356, 1900–1902. Hu W., Grbich C. and Kemp A. (2007) Parental food allergy information needs: a qualitative study. Archives of Disease in Childhood, 92, 771–775. James J.M., Zeiger R.S., Lester M.R. et al. (1998) Safe administration of influenza vaccine to patients with egg allergy. Journal of Pediatrics, 133, 624–628. Johansson S.G., Bieber T., Dahl R. et al. (2004) Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. Journal of Allergy and Clinical Immunology, 113, 832–836. Jutel M., Pichler W.J., Skrbic D. et al. (1995) Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. Journal of Immunology, 154, 4187–4194. Kemp A.S. (2003) EpiPen epidemic: suggestions for rational prescribing in childhood food allergy. Journal of Paediatrics and Child Health, 39, 372–375. Kemp A.S. (2007) Egg allergy. Pediatric Allergy and Immunology, 18, 696–702. Kinaciyan T., Jahn-Schmid B., Radakovics A. et al. (2007) Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d 1. Journal of Allergy and Clinical Immunology, 119, 937–943. Kleine-Tebbe J., Vogel L., Crowell D.N. et al. (2002) Severe oral allergy syndrome and anaphylactic reactions caused by a Bet v 1- related PR-10 protein in soybean, SAM22. Journal of Allergy and Clinical Immunology, 110, 797–804. Lack G. (2008) Clinical practice. Food allergy. New England Journal of Medicine, 359, 1252–1260. Liu T., Howard R.M., Mancini A.J. et al. (2001) Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance. Archives of Dermatology, 137, 630–636. Lloyd-Still J.D. (1979) Chronic diarrhea of childhood and the misuse of elimination diets. Journal of Pediatrics, 95, 10–13. Loveless M. (1950) Milk allergy: a survey of its incidence. Journal of Allergy, 21, 489–499. Macdougall C.F., Cant A.J. and Colver A.F. (2002) How dangerous is food allergy in childhood? The incidence of severe and fatal allergic reactions across the UK and Ireland. Archives of Disease in Childhood, 86, 236–239. Mari A., Ballmer-Weber B.K. and Vieths S. (2005) The oral allergy syndrome: improved diagnostic and treatment methods. Current Opinion in Allergy and Clinical Immunology, 5, 267–273. May C.D. (1976) Objective clinical and laboratory studies of immediate hypersensitivity reactions to food in asthmatic children. Journal of Allergy and Clinical Immunology, 58, 500–515. Mehl A., Wahn U. and Niggemann B. (2005) Anaphylactic reactions in children – a questionnaire-based survey in Germany. Allergy, 60, 1440–1445. Monti G., Muratore M.C., Peltran A. et al. (2002) High incidence of adverse reactions to egg challenge on first known exposure in young atopic dermatitis children: predictive value of skin prick test and radioallergosorbent test to egg proteins. Clinical and Experimental Allergy, 32, 1515– 1519. Ostblom E., Lilja G., Ahlstedt S. et al. (2008) Patterns of quantitative food-specific IgE-antibodies and reported food hypersensitivity in 4-year-old children. Allergy, 63, 418–424. Osterballe M., Hansen T.K., Mortz C.G. et al. (2005) The prevalence of food hypersensitivity in an unselected population of children and adults. Pediatric Allergy and Immunology, 16, 567–573. Palmer D.J., Gold M.S. and Makrides M. (2005) Effect of cooked and raw egg consumption on ovalbumin content of human milk: a randomized, double-blind, cross-over trial. Clinical and Experimental Allergy, 35, 173–178. Pereira B., Venter C., Grundy J. et al. (2005) Prevalence of sensitization to food allergens, reported adverse reaction to foods, food avoidance, and food hypersensitivity among teenagers. Journal of Allergy and Clinical Immunology, 116, 884–892.

40


Perry T.T., Matsui E.C., Kay Conover-Walker M. and Wood R.A. (2004) The relationship of allergen-specific IgE levels and oral food challenge outcome. Journal of Allergy and Clinical Immunology, 114, 144–149. Pfefferle P.I., Sel S., Ege M.J. et al. (2008) Cord blood allergen-specific IgE is associated with reduced IFN-gamma production by cord blood cells: the Protection against Allergy-Study in Rural Environments (PASTURE) Study. Journal of Allergy and Clinical Immunology, 122, 711–716. Poulos L.M., Waters A.M., Correll P.K. et al. (2007) Trends in hospitalizations for anaphylaxis, angioedema, and urticaria in Australia, 1993–1994 to 2004–2005. Journal of Allergy and Clinical Immunology, 120, 878–884. Pumphrey R. (2000) Lessons for management of anaphylaxis from a study of fatal reactions. Clinical and Experimental Allergy, 30, 1144–1150. Pumphrey R. and Gowland M. (2007) Further fatal allergic reactions to food in the United Kingdom, 1999–2006. Journal of Allergy and Clinical Immunology, 119, 1018–1019. Rance F., Abbal M. and Lauwers-Cances V. (2002) Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays. Journal of Allergy and Clinical Immunology, 109, 1027–1033. Retailliau H.F., Curtis A.C., Storr G. et al. (1980) Illness after influenza vaccination reported through a nationwide surveillance system, 1976–1977. American Journal of Epidemiology, 111, 270–278. Ring J., Brockow K. and Behrendt H. (2004) History and classification of anaphylaxis. Novartis Foundation Symposium, 257, 6–16. Roberts G. (2007) Anaphylaxis to foods. Pediatric Allergy and Immunology, 18, 543–548. Roberts G. and Lack G. (2005) Diagnosing peanut allergy with skin prick and specific IgE testing. Journal of Allergy and Clinical Immunology, 115, 1291–1296. Roehr C.C., Edenharter G., Reimann S. et al. (2004) Food allergy and non-allergic food hypersensitivity in children and adolescents. Clinical and Experimental Allergy, 34, 1534–1541. Sampson H.A. (2001) Utility of food-specific IgE concentrations in predicting symptomatic food allergy. Journal of Allergy and Clinical Immunology, 107, 891–896. Sampson H.A. and Ho D.G. (1997) Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. Journal of Allergy and Clinical Immunology, 100, 444–451. Sampson H.A., Munoz-Furlong A., Campbell R.L. et al. (2006) Second symposium on the definition and management of anaphylaxis: summary report – second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Annals of Emergency Medicine, 47, 373– 380. Secrist H., Chelen C.J., Wen Y. et al. (1993) Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. Journal of Experimental Medicine, 178, 2123–2130. Sheikh A. and Alves B. (2000) Hospital admissions for acute anaphylaxis: time trend study. BMJ, 320, 1441. Sheikh A. and Walker S. (2005) Anaphylaxis. BMJ, 331, 330. Sicherer S.H. (1999) Food allergy: when and how to perform oral food challenges. Pediatric Allergy and Immunology, 10, 226–234. Sicherer S.H., Furlong T.J., Munoz-Furlong A. et al. (2001) A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants. Journal of Allergy and Clinical Immunology, 108, 128–132. Sicherer S.H., Sampson H.A. and Burks A.W. (2000) Peanut and soy allergy: a clinical and therapeutic dilemma. Allergy, 55, 515–521. Sicherer S.H. and Simons F.E. (2007) Self-injectable epinephrine for first-aid management of anaphylaxis. Pediatrics, 119, 638–646. Sporik R., Hill D.J. and Hosking C.S. (2000) Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clinical and Experimental Allergy, 30, 1540–1546. Steinke M., Fiocchi A., Kirchlechner V. et al. (2007) Perceived food allergy in children in 10 European nations. A randomised telephone survey. International Archives of Allergy and Immunology, 143, 290–295. Sugai K., Shiga A., Okada K. et al. (2007) Dermal testing of vaccines for children at high risk of allergies. Vaccine, 25, 3454–3463. Szépfalusi Z., Loibichler C., Pichler J. et al. (2000) Direct evidence for transplacental allergen transfer. Pediatric Research, 48, 404–407. Taramarcaz P., Hauser C. and Eigenmann P.A. (2001) Soy anaphylaxis. Allergy, 56, 792.


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3

Identification and characterisation of food allergens

E. N. Clare Mills, Philip Johnson, Yuri Alexeev, and Heimo Breiteneder

3.1 INTRODUCTION As part of its normal humoral immune responses, in a process generally known as sensitisation, the body produces various different types of molecules called immunoglobulins (Igs or antibodies) which are designated as IgA, IgG, IgM and IgE. These molecules comprise a binding domain which is capable of recognising, usually with high affinity and specificity, ‘non-self’ molecules which include those found in microbes, parasites, environmental agents such as pollen and dust, as well as dietary proteins. In one type of allergic disease known as type I hypersensitivity, the repertoire of antibodies is altered, the body producing larger quantities of IgE, the antibody class normally produced in response to parasitic infections. These IgE responses are directed towards a variety of environmental agents, the target molecules recognised by IgE being termed allergens. It is these molecules that are responsible for triggering an allergic reaction, a process also known as elicitation. IgE works by becoming associated with cells, such as mast cells, which are packed full of inflammatory mediators like histamine. On binding multivalent allergen, the surface bound IgE becomes ‘cross-linked’, triggering release of the mediators, such as histamine, which actually cause the symptoms associated with allergic reactions. Allergens are usually proteinaceous in nature, the sites recognised by the IgE being known as epitopes. These epitopes can comprise either linear sequences of amino acids (also termed continuous) or disparate portions of a protein’s amino acid sequence which are brought together by the folding of the polypeptide chain to form a discontinuous, or conformational, epitope. It is thought that the majority of epitopes are conformational in nature (Van Regenmortel, 1992) and consequently can be difficult to define in relation to food allergens where processing may either disrupt conformational epitopes found in the native, unprocessed protein, or even introduce new epitopes. In the absence of any treatment, the only option for food allergic individuals is to avoid the food they are allergic to, and, if appropriate, rescue medication is given in case of an accidental consumption of a problem food. Such food avoidance strategies can be difficult to implement. As a consequence, legislation has been brought in around the world which makes it mandatory to label certain foods and derived ingredients, irrespective of the level to which they are added to a foodstuff (Mills et al., 2004c). The list of ingredients which must be labelled does vary across the world and in the European Union it has already been updated to include molluscs and lupin. Table 3.1 shows the major foods that have to be labelled under this legislation, together with the allergens that have been isolated and characterised from them. In addition to these foods, there are many fresh fruits and vegetables that trigger food allergies and are associated with allergies to other substance such as pollen.

Peanut (Arachis hypogaea)

P34

Vacuolar thiol protease

Protein family

2S albumin Conglutin, 2S albumin n Arachin, 7S seed storage globulin Actin-binding proteins

Ara h 2

Ara h 6

Ara h 3,4

Ara h 5

Gly m Bd 28 k

None Conarachin, vicillin, 7S seed storage globulin

Gly m Bd 30 k

None

Ara h 1

11S seed storage globulin, Glycine Glycinin, individual gene products known as G1, G2, G3, G4 and G5.

None

Profilin

Cupin

Prolamin; 2S albumin


Cupin

C-protease (unconfirmed)

C-protease

Cupin

Profilin Bet v 1

SAM22, PR-10 protein

Gly m 3

Gly m 4

Not known

Gly m 1

Soybean (Glycine max )

Other names

Gly m 2

IUIS allergen name

AF059616

(Continued )

Kleber-Janke et al . (1999)

Restani et al . (2005)

Koppelman et al . (2005) AAL37561, 1W2Q A, AAD56337 AAC63045, AAD47382, AAM46958, AAM93157, ABI17154

Clarke et al . (1998)

Koppelman et al . (2004)

Ogawa et al . (1991), Hiemori et al . (2004)

Bando et al . (1996)

Nielsen et al . (1989)

Crowell et al . (1992)

Rihs et al . (1999)

Codina et al . (2002)

Gonzalez et al . (1995)

Reference

AAM78596, AAN77576, CAC41202

P43237, AAT00596, AAT00595, P43238

BAB21619, P22895, AAB09252

P22895, AAB09252, BAA25899

CAA26723, CAA 332154895 (G1), CAA33216 (G2), CAA33217 (G3), CAA37044, CAA26478, CAA60533 (G4), AA33964, AAA33965, CAA55977 (G5)

CAA42646

O65809, CAA11755

A57106 (partial sequence only)

AAB34755, ABA7, ABA54898

Sequence accessions

The major foods that have to be labelled under EU labelling legislation, together with the allergens that have been isolated and characterised from them.

Food

Table 3.1

Identification and characterisation of food allergens 43

Cashew nut (Anacardium occidentale)

Almond (Prunus dulcis)

Tree nuts

Legumin-like, 11S seed storage globulin 2S albumin

Ana o 3

60S acidic ribosomal protein

Pru du 5

Ana o 2

Major almond protein, Amandin, 11S seed storage globulin

None

Vicilin-like, 7S seed storage globulin

Prunus Seed allergenic protein 2, Conglutin-γ

None

Ana o 1


2S, Prunus Seed allergenic protein 1

None

Prolamin

Cupin

Cupin

Ribosomal 60S superfamily

Cupin


Profilin

Cupin

Pru du 4

Congluten-β

Oleosin-like

Lup an 1

Bet v 1 Oleosin

Protein family

None

Other names

Ara h 8

IUIS allergen name

(Continued )

Lupin (Lupinus luterus)

Food

Table 3.1

AAL91665

AAN76862

AAM73729, AAM73730

DQ836316

S51942, CAA55009

Robotham et al. (2005)

Wang et al. (2003)

Wang et al. (2002)

Abolhassani and Roux (2007)

Garcia-Mas et al. (1995), Sathe et al. (2002)

Poltronieri et al. (2002)


P82944 1, P82944 2 (partial sequences only) P82952 (partial sequences only)

Scheurer et al. (2001)

Peeters et al. (2007)

Pons et al. (2002)

Mittag et al . (2004b)

Reference

AAL91662, AAD29411, CAD37201

EU352876

Q6J1J8

AAQ91847

Sequence accessions

44 Management of Food Allergens

Soybean (Glycine max )

Hazelnut (Corylus avellana)

C-protease (unconfirmed)

Cysteine protease

Gly m Bd 30k, P34 Gly m Bd 28 k

Cupin

11S seed storage globulin, Glycine Glycinin, individual gene products known as G1, G2, G3, G4 and G5.

None

None

Profilin BetV1 family

SAM22, PR-10 protein

Not known

Gly m 4

Defensin

Gly m 2

Vacuolar thiol protease

Cupin

Gly m 3

P34, Hydrophobic protein


Cor a 11

Gly m 1

Legumin-like, 11S seed storage globulin

Cor a 9

Cupin

Profilin Prolamin; LTP family

Non-specific lipid transfer protein (nsLTP)

Cor a 2

Cor a 8

Bet v 1

Cor a 1

BAB21619, P22895, AAB09252

P22895, AAB09252, BAA25899

CAA26723, CAA33215 (G1); CAA33216 (G2); CAA33217 (G3); CAA37044, CAA26478, CAA60533 (G4); AAA33964, AAA33965, CAA55977 (G5).

CAA42646

O65809, CAA11755

A57106 (partial sequence only)

AAB34755, ABA54897, ABA54898

AAL86739

AAL73404

AAK28533

Q9AXH5

CAA50325, CAA50326, CAA50328, Q08407, CAA96548, CAA96549, AAD48405, AAG40329, AAG40330, AAG40331

(Continued )

Ogawa et al. (1991), Hiemori et al. (2004)

Bando et al. (1996)

Nielsen et al. (1989)

Crowell et al. (1992)

Rihs et al., 1999

Codina et al. (2002)

Gonzalez et al. (1995)

Lauer et al. (2004)

Beyer et al. (2002a)

Schocker et al. (2004)

Flinterman et al. (2008a)

Lüttkopf et al. (2002)


Almond (Prunus dulcis)

Tree nuts

Lupin (Lupinus luterus)

Prolamin

2S albumin, Prunus Seed allergenic protein 1 2S albumin, Prunus Seed allergenic protein 2, Conglutin gamma Amandin, Pru du amandin, 11S globulin 60S acidic ribosomal prot. P2

None

None

None

Pru du 5

Ribosomal 60S superfamily

Cupin

Prolamin

Profilin

Cupin

Oleosin-like

Bet v 1 family

Profilin

Cupin

Prolamin

Prolamin

Cupin

Protein family

Pru du 4

Conglutin beta

Oleosin

None

Lup an 1

Actin-binding protein

Arachin, 7S seed storage globulin

Ara h 3,4

PR-10 protein

Conglutin, 2S albumin

Ara h 6

Ara h 5

2S albumin

Ara h 2

Ara h 8

Conarachin, vicillin, 7S seed storage globulin

Ara h 1

Peanut (Arachis hypogaea)

Other names

IUIS allergen name

(Continued )

Food

Table 3.1

DQ836316

S51942, CAA55009

Abolhassani and Roux (2007)

Garcia-Mas et al. (1995), Sathe et al. (2002)


Poltronieri et al. (2002) P82944 1, P82944 2 (partial sequences only) P82952 (partial sequences only)

Scheurer et al. (2001), Tawde et al. (2006)

Peeters et al. (2007)

Pons et al. (2002)

Mittag et al. (2004aa, 2004bb)

Kleber-Janke et al. (1999)

Restani et al. (2005)

Koppelman et al. (2005)

Clarke et al. (1998)

Koppelman et al. (2004)

Reference

AAL91662, AAD29411, CAD37201

EU352876

Q6J1J8

AAQ91847

AF059616

AAC63045, AAD47382, AAM46958, AAM93157, ABI17154

AAL37561, 1W2Q A, AAD56337

AAM78596, AAN77576, CAC41202

P43237, AAT00596, AAT00595, P43238

Sequence accessions


2S albumin

Ana o 3

Oleosin (14–16 kDa)

Cor a 13

2S albumin

Oleosin (17 kDa)

Cor a 12

Jug r 1


Cor a 11

Walnut (Juglans regia)


Cor a 9

No allergens characterised, clinically relevant type-1 hypersensitivity observed

Prolamin

Non-specific lipid transfer protein (nsLTP)

Cor a 8

Prolamin

Oleosin-like

Oleosin-like

Cupin

Cupin

Profilin

Bet v 1 family

Prolamin

Cupin

Cupin

Cor a 2

PR-10 protein


Ana o 2

Cor a 1


Ana o 1

Macadamia nut (Macadamia integrifolia, Macadamia tetraphylla)

Hazelnut (Corylus avellana)

Cashew nut (Anacardium occidentale)

AAB41308

AY224599

AY224679

AAL86739

AAL73404

AAK28533

Q9AXH5

CAA50325, CAA50326, CAA50328, Q08407, CAA96548, CAA96549, AAD48405, AAG40329, AAG40330, AAG40331

AAL91665

AAN76862

AAM73729, AAM73730

(Continued )

Teuber et al. (1998)

Pallares (2000)

Akkerdaas et al. (2006)

Akkerdaas et al. (2006)

Lauer et al. (2004)

Beyer et al. (2002b)

Schocker et al. (2004)

Flinterman et al. (2008b)

Lüttkopf et al. (2002)

Robotham et al. (2005)

Wang et al. (2003)

Wang et al. (2002)


Wheat (Triticum aestivum)

Celery (Apium graveolens)

Sesame (Sesamum indicum)

Black Mustard (Brassica nigra)

Unknown

Api g 5

Prolamin

Profilin

Api g 4

Alpha gliadins

Bet v 1 family

Api g 1

FAD binding oxidase homologue

Beta-globulin Cupin

7S globulin

Prolamin

Glucose and ribitol dehydrogenases

Prolamin

Ses i 2

2S albumin

Seed maturation protein

2S albumin

Cupin

Prolamin

Cupin

Cupin

Protein family

Ses i 3

Ses i 1

Bra j 1

11S-type or legumin-like globulin

Sin a 2


Jug r 4

2S albumin


Jug r 2

Sin a 1

Other names

IUIS allergen name

(Continued )

White mustard (Sinapis alba)

Mustard

Food

Table 3.1

Q41545, Q41509, P04721, P04723, P04725, P18573, Q9M4M1, Q9M4L7, Q9M4M6

P81943

Q9XF37

P49372, P92918

Q9AUD0

Q9XHP1

AF240005, AF091841

AF449242

P80207

AAX77383, AAX77384

CAA62909, CAA62910, CAA62911, CAA62912, CAA62908, P15322

AAW29810

AAF18269

Sequence accessions

Sandiford et al. (1997)

Ganglberger et al. (2000)

Scheurer et al. (2000), Scheurer et al. (2001)

Breiteneder et al. (1995)

Beyer et al. (2002b)

Tai et al. (2001)

Tai et al. (1999), Pastorello et al. (2001b)

Beyer et al. (2002a)

Palomares et al. (2005)

Palomares et al. (2007)

Monsalve et al. (1993)

Wallowitz et al. (2006)

Teuber et al. (1999)

Reference


Cows milk (Bos Taurus)

Prolamin Serine protease inhibitor family

Omega-5-gliadin Serine protease inhibitor

Tri a 19

Beta-Lactoglobulin Immunoglobulin

Bovine Serum Albumin Lactoferrin

Bos d 5

Bos d 7

Bos d 6

None

Beta-Casein Alpha-Lactalbumin

Bos d 4

Kappa-Casein

Bos d 8

Casein

Alpha S2-Casein

Bos d 8

Bos d 8

Transferrin

Serum albumin family

Immunoglobulin family

lipocalin

lysozyme/alpha-lactalbumin

Casein

Casein

Casein

Alpha S1-Casein

Bos d 8

Thoredoxin-fold family

Thioredoxin glutenin

Tri a 25

Tri a 26

Prolamin

Lipid Transfer Protein (LTP1)

Tri a 14

Profilin

Profilin-1 Isolectin A, WGA1

Tri a 12

Trypsin/alpha-amylase inhibitor

CM3

Tri a 18

Trypsin/alpha-amylase inhibitor

Alpha-amylase inhibitor 0.53

P24627

P02769

(Continued )

Pierce et al. (1991)

Restani et al. (2004)

Kontopidis et al. (2004) Bernhisel-Broadbent et al. (1991)

P02754

Hurley and Schuler (1987), Neyestani et al. (2003).

Jimenez-Flores et al. (1987)

Chatchatee et al. (2001)

Busse et al. (2002)

Mercier et al. (1971), Bernard et al. (1998)

Battais et al. (2003)

Weichel et al. (2006)

Constantin et al. (2008)

DuPont et al. (2000), Lehto et al. (20030

Asero et al. (2000)

Sutton et al. (1984)

Rihs et al. (1994)

Salcedo et al. (2004)

Carbonero and Garcia-Olmedo (1999)

XP 593266, AAB37381.2, AAB37380.1, XP 587538.1, AAC18409.1

P00711

P02666

P02668

P02663

P02662 (minor variants)

X12928

AJ404845

EU051824

Q40215

P24296

P49232

P17314

P01084


Lysozyme α-livetin

Gal d 4

Gal d 5

Calcium-binding EF-hand


Calcium-binding EF-hand Calcium-binding EF-hand Collagen

Cyp c 1, β-parvalbumin

Sco j 1, β-parvalbumin

β-parvalbumin Thu o 1, β-parvalbumin Gelatine (denatured collagen aggregate)

Carp (Cyprinus carpi)

Mackerel (Scomber japonicus)

Salmon (Salmo salar )

Tuna (Thunnus tonngol )

Sal s 1


β-parvalbumin

Cod (Gadus morhua)


Transferrin

Serpin

The c 1, β-parvalbumin

Gad c 1

Serum albumin family

Ovotransferrin

Gal d 3

Fish Alaska pollack (Theragra chalcogramma)

C-type lysozyme

Ovalbumin

Gal d 2

Kazal-type srine protease inhibitor

Ovomucoid

Gal d 1

Protein family

Hen’s egg

Other names

IUIS allergen name

(Continued )

Food

Table 3.1

U23822 (red seabream), O93484 (rainbow trout)

n.d.

X97824

P59747

CAC83658

P02622

Q90YK7

P19121

P00698

P02789

P01012

P01005

Sequence accessions

Hansen et al. (2004)

Bugajska-Schretter et al. (1998)

Lindstrøm et al. (1996)

Hamada et al. (2003)



Van Do et al. (2005)

de Blay et al. (1994)

Mohan et al. (2003)

Awade et al. (1994)

Honma et al. (1996)

Besler et al. (1997)

Reference


Cha f 1

Crab

He as 1

Hal m 1

Cra g 1

Snail (Helix aspersa)

Abalone (Haliotis midae)

Oyster (Crassostrea gigas)

n.d., not determined.

Tod p 1

Squid (Todarodes Pacificus)

Molluscs

Pan s 1

Spiny lobster (Panulirus stimpsoni)

Tropomyosin

Unknown

Tropomyosin

Tropomyosin

Tropomyosin

Tropomyosin

Tropomyosin

Arginine kinase

Pen m 2

Hom a 1

Tropomyosin

Pen m 1, Pen a 1, Met e1

American lobster (Homarus americanus)

Shrimp

Crustacea


Unknown






Phosphagen kinase


Q95WYO

n.d.

Y14855

n.d.

Q9N2R3

Q61379

O44119

Q819P7

AAZ76743, Q25456

Ishikawa et al. (1998)

Lopata et al. (1997)

Asturias et al. (2002)

Miyazawa et al. (1996)

Leung et al. (1998b)

Leung et al. (1998a)

Leung et al. (1998a)

France et al. (1997), Binder et al. (2001)

Daul et al. (1994)


52


The World Health Organization and the International Union of Immunological Societies (IUIS) produce an official list of allergens, which is designated by the Allergen Nomenclature Sub-Committee (Hoffman et al., 1994). Allergens included in this listing must induce IgEmediated (atopic) allergy in humans with a prevalence of IgE reactivity above 5%. An allergen is termed major if it is recognised by IgE from at least 50% of a cohort of allergic individuals but does not carry any connotation of allergenic potency; allergens are otherwise termed ‘minor’. The allergen designation is then based on the Latin name of the species from which it originates and is composed of the first three letters of the genus, followed by the first letter of the species finishing with an Arabic number, for example Ara h 1 relates to an allergen from Arachis hypogea (peanuts). The numbers are determined by the order in which allergens are identified and are common to all homologous allergens (also known as isoallergens) in a given species. Isoallergens are defined on the basis of having a similar molecular mass, an identical biological function, if known, for example enzymatic action and >67% identity of amino acid sequences. For those species where the first three letters of a genus and the first letter of a species are identical, the second letter of the species is also used. The IUIS designations for those allergens in foods for which labelling is mandatory are also given in Table 3.1.

3.2 CLASSIFICATION OF FOOD ALLERGENS It is generally held that the vast majority of food allergies are caused by a limited number of foods (Bush and Hefle, 1996), but a large number of foods have been documented as causing food allergies, reflecting the diversity of species that humans consume. Over the past 20 years, there has been an explosion in the number of allergens that have been identified and characterised and subsequently there have been efforts to classify them in order to identify common properties and motifs which may be predictive of allergenicity. Observations have been made that food allergens are restricted to certain protein families (Mills et al., 2004a), and subsequently a classification of plant food allergens based on the membership of allergens to certain protein families and superfamilies has been proposed (Breiteneder and Radauer, 2004). Using post-genomic bioinformatic tools such as Pfam (Bateman et al., 2004), an analysis of plant food allergen families showed that they belonged to only 27 of the then identified 8183 Pfam families, indicating that conserved structures and biological activities play a role in determining or promoting allergenic properties of proteins (Jenkins et al., 2005). Three plant food allergen protein families/superfamilies were found to predominate: the prolamin superfamily, the cupin superfamily and the Bet v 1 family, which together with the profilins accounted for more than 65% of all plant food allergens. A similar situation was found for pollen allergens which were classified into 29 Pfam families representing a 0.35% section of today’s classified protein universe (Radauer and Breiteneder, 2006). A similar distribution was found for food allergens of animal origin (Jenkins et al., 2007) with three protein families: the tropomyosins, parvalbumins and caseins dominating. Thus, the repertoire of allergenic proteins identified is small compared to the vast array of different proteins found in biology. The explanations for this are lacking but may in part result from conservation of surface structures in certain families, such as the Bet v 1 and parvalbumin superfamilies, which promotes IgE cross-reactivity (Jenkins et al., 2005, 2007).


53

3.3 PLANT FOOD ALLERGENS 3.3.1

Fresh fruits and vegetables

Allergy to fresh fruits and vegetables is frequently associated with inhalant allergies to agents such as birch and grass pollen and latex. It is thought that individuals initially become sensitised to the inhalant allergens in pollen and latex and subsequently go on to develop allergies to foods because of IgE cross-reactivity to closely related homologues of the pollen and latex allergens. Symptoms are often mild and confined to the oral cavity, which has given rise to the term oral allergy syndrome (OAS) and frequently (although not always) processing removes allergenicity. Thus, many individuals with the fruit/vegetable-pollen or fruit/vegetable-latex allergies can safely consume cooked fruits and vegetables but not fresh produce. The pollen-related fruit and vegetable allergies tend to have a geographic distribution related to pollen distribution. Allergens involved include those homologous to the major birch pollen allergen, Bet v 1, whose role in plants has yet to be defined, although it does belongs to family 10 of the pathogenesis-related proteins (Breiteneder et al., 1989; Hoffmann-Sommergruber, 2002). As it can bind plant steroids in a central tunnel, one suggestion is that it functions as a steroid carrier in plants (Markovic-Housley et al., 2003) (see Plate 3.1). Homologues involved in pollen-fruit cross-reactive allergies have been identified in a very large number of fruits and vegetables, some of the most important include the Rosaceae fruits such as apple (Mal d 1; Vanek-Krebitz et al., 1995), cherry (Pru av 1; Neudecker et al., 2001) and peach (Pru p 1; Gaier et al., 2008). Homologues have also been identified in fruits such as kiwi fruit which are emerging as important allergenic foods in Europe (Act d 8; Oberhuber et al., 2008) and exotic fruits not generally consumed in Europe which may pose a risk such as Sharon fruit (Bolhaar et al., 2005) and jackfruit (Bolhaar et al., 2004). In addition, allergenic Bet v 1 homologues have also been identified in vegetables notably celery (Api g 1; Breiteneder et al., 1995) and carrot (Dau c 1; Hoffmann-Sommergruber et al., 1999). In general, the IgE-binding sites on Bet v 1 are conformational in nature (Gajhede et al., 1996; Neudecker et al., 2001) and consequently IgE reactivity is lost following processing that causes unfolding of the protein. They are also labile to gastrointestinal digestion. A second group of widespread IgE cross-reactive allergens involved in pollen-fruit cross-reactive allergies are the profilins, which were originally identified as the birch pollen allergen Bet v 2 (Valenta et al., 1991). Profilins have a key role in biological systems promoting the polymerisation of actin, but whilst being widespread in nature only those found in plants have been described as allergens. Whilst some studies have cast doubt about the clinical relevance of IgE to profilins (Wensing et al., 2002), others have demonstrated that profilins play an important role in eliciting symptoms in certain patients (Radauer et al., 2006). There is second type of fruit and vegetable allergy which is generally found in the Mediterranean area which is not associated with pollen allergy and tends to be expressed with much more severe, even life-threatening allergic reactions. It involves a distinctly different group of allergens, the non-specific lipid transfer proteins (LTPs) (Fernandez-Rivas et al., 2006). These proteins have been characterised as allergens in fruits such as apple (Mal d 3; Sanchez-Monge et al., 1999b), peach (Pru p 3; Pastorello et al., 1999) and grape (Vit v 1; Pastorello et al., 2003), and vegetables such as asparagus (Diaz-Perales et al., 2002) and cabbage (Bra o 3; Palac´ın et al., 2006). Whilst originally identified in plants through their ability to transfer lipids in an in vitro system, their function in vivo is probably quite different and they appear to have some role in plant protection as they belong to PR group 14 (Breiteneder and Mills, 2005). The observation that those LTPs involved in food

54


allergies are located in epidermal tissues (Douliez et al., 2000) along with their lipid-binding characteristics has led to suggestions that they play a role in transporting cutin and suberin monomers to the outer layers where they are polymerised to form the outer waxy layers. Like many other members of the prolamin superfamily, they are highly resistant to gastric and duodenal digestion (Asero et al., 2000), with major IgE-binding sites remaining intact as indicated by the fact that simulated gastrointestinal digestion does not alter their ability to elicit skin reactions in vivo as observed for grape LTP (Vassilopoulou et al., 2006). A third group of relevant fruit allergens are those involved in the latex-fruit cross-reactive allergy syndrome which include the class-I chitinases. A group of carbohydrases with a role in protecting plants from pathogens, these proteins are found widely in plants they have been termed panallergens (Salcedo et al., 2001). A number of allergens have been described including ones from avocado (Pers a 1, Sowka et al., 1998), banana (Mus p 1.2 SanchezMonge et al., 1999a) and chestnut (Cas s 1, Diaz-Perales et al., 1998). Other allergens involved in IgE cross-reactive allergies between foods and latex include patatin; a storage protein from potato has also been shown to be cross-reactive with the latex allergen Hev b 7 along with other proteins from avocado and banana (Sowka et al., 1999). Other minor fruit allergens include the highly disulphide-bonded proteins known as thaumatin-like proteins (TLPs), C-proteases (Pastorello et al., 1998a) and a variety of lectins and Kunitz inhibitors identified in potato (Seppala et al., 2001). Many have anti-fungal and/or anti-bacterial activity and therefore may have a role in plant protection. One example of an important emerging allergenic fruit which contains several of these is kiwi fruit in which is found both a TLP (Act d 2; Gavrovic-Jankulovic et al., 2002) and a thiol-protease actinidin (Act c 1; Pastorello et al., 1998a). The eight disulphide bonds in TLP are probably reponsible for their stability to proteolysis (Smole et al., 2008) and the fact that grape TLP retains its allergenicity even after fermentation during wine production (Flamini and De Rosso, 2006). Other less widely found allergens include the flavin adenine dinucleotide (FAD)-containing oxidase allergen of celery, Api g 5, an M r 53-57-kDa protein which is extensively glycosylated and posesses cross-reactive glycans (Bublin et al., 2003) and a germin-like protein which has been identified in bell pepper (Leitner et al., 1998) and orange (Cit s 1, Crespo et al., 2006) for which the N-linked glycans have been found to be important for IgE binding (Pöltl et al., 2007).

3.3.2

Nuts and seeds

In addition to the pollen-fruit cross-reactive allergy syndromes, it is emerging that Bet v 1 homologues in various nuts and seeds can cause similar allergies. These have been especially well documented for hazelnut where an isoform, Cor a 1.04, has been identified in the nut which resembles Bet v 1 more closely than the allergenic Bet v 1 homologue from hazelnut pollen Cor a 1.01 (Lüttkopf et al., 2002). There are also reports of LTPs found in nuts and seeds triggering allergies similar to those observed in fruits such as peach, including LTP allergens from walnut (Jug r 3; Pastorello et al., 2004) and hazelnut (Cor a 8; Pastorello et al., 2002) the latter having been shown to be an allergen in a population from Northern Europe (Flinterman et al., 2008a). However, the major allergens in these foods include other members of the prolamin superfamily, the 2S albumins and the cupin seed globulins, both of which often function as a protein store in the seed (Jenkins et al., 2005) (see Plate 3.2). The 2S albumins are usually synthesised in the seed as single chains of M r 10,000–15,000 which maybe post-translationally processed to give small and large subunits which usually


55

remain joined by disulfide bonds. The type of this processing depends on the plant species with those in sunflower being single chain albumins, whilst those in Brazil nut are two-chain albumins (Shewry and Pandya, 1999). They have been identified as important allergens in nuts including walnut allergen Jug r 1 (Teuber et al., 1998), almond (Poltronieri et al., 2002) and Ber e 1 from Brazil nut (Pastorello et al., 1998b), and in seeds such as oriental and yellow mustard allergens Bra j 1 and Sin a 1 (Monsalve et al., 1993; Menendez-Arias et al., 1988), Ses i 1 and 2 from sesame (Pastorello et al., 2001b; Beyer et al., 2002b; Wolf et al., 2004) and the 2S albumin from sunflower seeds SFA-8 (Kelly et al., 2000). In addition to the 2S albumins, a major group of allergens found in nuts and seeds are the 11S and 7S seed storage globulins which belong to the cupin superfamily. The 11S globulins, sometimes termed legumins because they are particularly found in legume seeds, are hexameric proteins of M r ∼300,000–450,000. Each subunit is synthesised in the seed as a single chain of M r about 60,000, which is post-translationally processed to give rise to acidic (M r about 40,000) and basic (M r about 20,000) chains, linked by a single disulfide bond and are rarely, if ever, glycosylated (Mills et al., 2004b). The 7/8S globulins, also termed vicilins, are somewhat simpler, comprising three subunits of M r ∼40,000–80,000, but typically about 50,000. Seed storage protein allergens have been described in a variety of nuts and seeds with both 11S and 7S proteins having been reported as allergens in hazelnut (Cor a 11 (7S globulin) and Cor a 9 (11S globulin); Pastorello et al., 2002; Beyer et al., 2002a, b), cashew nut (Ana c 1 and Ana c 2; Wang et al., 2002, 2003), whilst only the 7S globulins of walnut (Jug r 2; Teuber et al., 1999), sesame seed (Ses i; Beyer et al., 2002b) and mustard seed (Palomares et al., 2005, 2007) having been identified. The 11S globulins have also been shown to be allergens in almond, also known as almond major protein (AMP) (Roux et al., 2003). Another group of potentially important allergens that has been identified in the last few years is the oleosins, a group of proteins associated with oil bodies where they play an important role in packaging and stabilising the oil droplet surface, having a portion of the protein structure buried in the oil phase with a second domain on the aqueous facing surface. These have been identified as allergens in sesame (Leduc et al., 2006) and hazelnut (Akkerdaas et al., 2006). They may be important if they find their way into crudely refined oil which, unlike highly refined oils, has sufficient protein to trigger allergic reactions (Crevel et al., 2000).

3.3.3

Legumes

Many of the types of allergens found in other plant foods have also been identified in allergenic legumes. Thus, allergens involved in the cross-reactive pollen syndromes have been identified in several legumes including the Bet v 1 homologues in soybean (KleineTebbe et al., 2002; Mittag et al., 2004a), peanut (Ara h 8; Mittag et al., 2004b) and mung bean (Mittag et al., 2005) and peanut profilin (Kleber-Janke et al., 1999). In addition, the 7S (β-congrlcinin) and 11S (glycinin) seed storage globulins have been described as allergens in soybean (Ogawa et al., 1995; Burks et al., 1988; Beardslee et al., 2000) (see Plate 3.3). There is also some evidence that the 2S albumins of soy (Shibasaki et al., 1980) and chickpea (Vioque et al., 1999) are allergenic. In addition, the 7S (Ara h 1; Burks et al., 1991) and 11S (Ara h 3; Rabjohn et al., 1999; Beardslee et al., 2000) seed storage globulins as well as the prolamin superfamily albumin, Ara h 2, 6 and 7 (Burks et al., 1992; Kleber-Janke et al., 1999), are important allergens in peanut. In contrast to the 2S albumins which are relatively resistant to simulated gastrointestinal proteolysis (Suhr et al., 2004), the 7S globulins are

56


highly susceptible to pepsinolysis. A number of lower molecular weight polypeptides appear to persist following digestion of the peanut Ara h 1, although they retain their IgE-binding capacity following proteolysis (Shin et al., 1998) and simulated gastrointestinal digestion (Eiwegger et al., 2006). Seed storage globulin allergens have also been identified as allergens in lentil (Len c 1; Lopez-Torrejon et al., 2003) and pea (Pis s 1; Sanchez-Monge et al., 2004) which can be cross-reactive with peanut (Wensing et al., 2003). Such cross-reactivity is particularly problematic with lupin (Moneret-Vautrin et al., 1999) with proteins such as conglutin-β having been identified as a major allergen, Lup an 1 (Goggin et al., 2008). Lup an 1 is a 7S seed storage globulin with significant homology to the peanut allergen Ara h 1 and hence may be responsible for the clinical cross-reactivity observed between these two legumes. Other allergens identified in peanut include an oleosin (Pons et al., 2002) and a lectin, peanut agglutinin (Burks et al., 1994), whilst in soybean a Kunitz trypsin inhibitor (Moroz and Yang, 1980; Burks et al., 1994) and a member of the cysteine protease family, the 34 kDa so-called oil body-associated protein, known as Gly m 1, and Glym Bd 30 k (Ogawa et al., 1993), have been identified as allergens in soybean. Another soybean allergen which is of relevance in countries such as Japan is the M r 23 kDa protein known as Gly m 28 k which is glycosylated and contains important IgE-reactive glycans also found in a derived 23 kDa peptide (Hiemori et al., 2004). Found in the protein storage vacuoles, the protein has an as yet unknown function in the plant.

3.3.4

Cereals

Cereals have been found to trigger two types of IgE-mediated allergic disease: the occupational allergy known as Baker’s asthma, which results from inhalation of flour particles in dusty working environments such as bakeries, and food allergies resulting from ingestion of cereal containing foods. There also appear to be some individuals who react to wheat proteins as a result of prior sensitisation to grass pollen, who are serologically distinct from those who are exposed to flour in a work environment (Sander et al., 1997). However, IgE-mediated allergy to wheat products does not appear to be as widespread as allergies to foods such as egg and peanut, despite a public perception that wheat allergy is prominent. Diagnosis of wheat allergy is further complicated by the low solubility of cereal seed storage prolamins in the dilute salt solutions routinely used in clinical diagnosis, which may mean that cereal allergy may remain undiagnosed. The seed storage prolamins of cereals, also known more commonly as gluten, are usually associated with causing the food intolerance syndrome, coeliac disease, but can also trigger allergies to cereals, both by ingestion and through inhalation (Sandiford et al., 1997) including conditions such as atopic dermatitis (Varjonen et al., 1995, 1997) and exercise-induced anaphylaxis (EIA) (Varjonen et al., 2000). The latter is a severe allergic reaction that certain patients experience only if they exercise after eating a problem food; two allergens have been described as triggering such reactions, including γ -, α- and ω-5 gliadins (Palosuo et al., 1999, 2001; Matsuo et al., 2004). Other prolamin storage proteins have been identified as major cereal allergens, including both the polymeric HMW and LMW subunits of glutenin as well as the monomeric γ and an α-gliadins (Watanabe et al., 1995; Tanabe et al., 1996; Maruyama et al., 1998; Simonato et al., 2001a). Cooking appears to affect allergenicity, and one study suggested baking may be essential for allergenicity of cereal prolamins (Simonato et al., 2001b).


57

In addition to the gluten protein fraction, other wheat proteins have been implicated as food allergens including a single M r ∼15,000 subunit corresponding to an trypsin/αamylase inhibitor identified as an allergen (James et al., 1997), whilst another trypsin/αamylase inhibitor, termed CM3, has been identified as an allergen triggering atopic dermatitis (Kusaba-Nakayama et al., 2000). α-Amylase inhibitors have also been implicated in allergies to other cereal-based foods, including an Mr 16,000 beer allergen which originates from barley (Curioni et al., 1999) and an Mr 16,000 protein which is a major allergen in maize (Pastorello et al., 2000). A number of α-amylase inhibitors with M r of about 14,000–16,000 including one M r ∼16,000 subunit, termed RA 17, have been described as allergens in rice (Nakase et al., 1994). Another group of proteins which have been described as cereal allergens is the type 1 non-specific lipid transfer proteins (LTPs), including ones from maize (Pastorello et al., 2000), spelt (Pastorello et al., 2001a) and wheat (Tri a 14; Pastorello et al., 2007). Species differences in response to processing are emerging, since cooking wheat did not modify the IgE-binding capacity of the α-amylase inhibitors but some patients lost their IgE-binding capacity towards the LTP, in contrast to maize (Pastorello et al., 2007). In addition, barley LTP has been found to trigger allergic reactions in beer (Curioni et al., 1999; Asero et al., 2001; Garcia-Casado et al., 2001).

3.4 ANIMAL FOOD ALLERGENS 3.4.1

Cow’s milk

The major allergens in cow’s milk are the caseins, a group of structurally mobile proteins which bind calcium through clusters of phosphoserine and/or phosphothreonine residues. Caseins are a heterogeneous mixture of proteins, the product of expression of a polymorphic multigene family which undergoes post-translational proteolysis and phosphorylation. They show a heterogeneity of IgE-binding properties. Thus, IgE cross-reactivity studies in a group of cow’s milk allergic infants showed that whilst all but 10% had serum IgE against α S2 casein, only around half recognised α S1 -casein and only a small proportion (15%) had IgE against β-casein (Natale et al., 2004). The high level of homology between caseins form different mammalian species explains their IgE cross-reactivity. Extensive cross-reactivity has been observed between the milks of cow, sheep and goat (Spuergin et al., 1997) and between the milks of cow, ewe, goat and buffalo, but not of camel (Restani et al., 1999). Thus individuals with cows’ milk allergy generally reacting when undergoing oral challenge with goat’s milk (Bellioni-Businco et al., 1999) whose caseins have sequence identities of over 90% with bovine caseins. Lower sequence identities of 22–66% may be associated with reduced IgE cross-reactivity, which may explain why some individuals with cow’s milk allergy can tolerate mare’s milk (Businco et al., 2000) and do not show IgE cross-reactivity to milk proteins from species such as camel (Restani et al., 1999). In addition, it has also been suggested that mare’s milk and donkey’s milk might be used in selected cases of cow’s milk allergy after appropriate modification to make them suitable for human infants (Businco et al., 2000; Muraro et al., 2002). More recently, allergies to goats’ or sheep’s milk have been emerging, although the IgE reactivity appears to be confined to the casein fraction (Ah-Leung et al., 2006). The other important allergens in cows’ milk are the whey proteins β-lactoglobulin, the only lipocalin which acts as a food allergen (Virtanen, 2001), and α-lactalbumin, which like the egg allergen lysozyme belongs to the glycoside hydrolase family 22 clan of the

58


O-glycosyl hydrolase superfamily (Wal, 2002). Lastly, one minor allergen identified in milk is the iron-binding protein, lactoferrin (Wal, 2002).

3.4.2 Egg A number of allergens have been described in egg, in particular the Kazal inhibitor known as ovomucoid, the dominant hen’s egg white allergen Gal d 3 (Bernhisel-Broadbent et al., 1994), which is extensively glycosylated and may act to stabilise the protein against proteolysis (Cooke and Sampson, 1997). Another egg allergen is also a protease inhibitor, the serpin serine protease inhibitor namely ovalbumin Gal d 1 (Bernhisel-Broadbent et al., 1994). A third type of hydrolase, this time a glycosidase belonging to the glycoside hydrolase family 22 clan of the O-glycosyl hydrolase superfamily, namely lysozyme has been described as a minor hen’s egg allergen, known as Gal d 4 (Nitta and Sugai, 1989). It probably acts as a muramidase, hydrolysing peptidoglycans found in bacterial cell wall. Lastly, the sulphur-rich iron-binding glycoprotein ovotransferrin has also been identified as minor allergens in hen egg white (Holen and Elsayed, 1990; Aabin et al., 1996).

3.4.3

Fish

The major allergen identified so far in fish is the white muscle protein known as parvalbumin, a protein which contains a calcium-binding domain known as an EF-hand which is widely found throughout living systems (Lewit-Bentley and Rety, 2000). Loss of calcium results in a major change in conformation which also results in a loss of IgE binding capacity (Bugajska-Schretter et al., 1998, 2000). The parvalbumins family comprises two distinct subtypes, known as α- and the β-parvalbumins, and whilst their three-dimensional structures are very similar, with only one exception all food allergens belong to the β-parvalbumin family (Jenkins et al., 2007) (see Plate 3.4). The only α-parvalbumin reported to be an allergen is that of frog (Hilger et al., 2002). The codfish allergen, Gad c 1, was the first allergenic fish parvalbumin to be described (Aas and Jebsen, 1967; Elsayed and Bennich, 1975) but a number have now been identified in many different fish species and can therefore be considered to be the pan-allergens in fish (Bernhisel-Broadbent, 1992). Clinical crossreactivity to multiple fish in individuals with fish allergy based on the major fish allergen parvalbumin is a common observation (Sicherer, 2001).

3.4.4

Shellfish and Crustacea

A family of closely related proteins present in muscle and non-muscle cells, tropomyosins are major allergens in the two invertebrate groups, Crustacea and Mollusca, which are generally known as shellfish and are generally assumed to be responsible for seafood allergies. The first to be characterised were those identified in shrimp, and are now acknowledged to be invertebrate pan-allergens by several laboratories (Shanti et al., 1993; Daul et al., 1994; Leung et al., 1994; Reese et al., 1999). The first two residues of the IgE binding region (epitope) in the C-terminal portion of the protein appear to be crucial for IgE binding and is not found in vertebrate tropomyosin. As a consequence of the lack of homology in the IgE epitopes, there is no reported cross-reactivity between IgE from shellfish allergic individuals, and animal muscle tropomyosins. As a result of their extensive homology, tropomyosins exhibit IgE cross-reactivity between various crustacean and mollusc species


59

(Motoyama et al., 2006), but whilst clinical reactions to multiple crustacean species seem to be fairly common, this is less clear regarding mollusc reactivity which may be restricted to cross-sensitisation (Sicherer, 2001). The proteins appear to be generally heat stable, their allergenicity being unaltered by boiling (Naqpal et al., 1989), with tropomyosins being detected in the cooking water (Lehrer et al., 1990). A minor group of allergens identified in shrimp is the arginine kinases (Yu et al., 2003) which have also been identified as crossreactive allergens in the Indian meal moth, king prawn, lobster and mussel (Binder et al., 2001).

3.5 CONCLUSIONS The last 20 years have seen a great expansion in our knowledge of food allergens, particularly with regard to their identification and characterisation with most of the allergens identified in the major allergenic foods. This knowledge is facilitating development of novel diagnostic approaches, in particular component resolved diagnosis using individual purified and highly characterised allergens to relate specific symptoms with the profile of allergens recognised. Such approaches, should they prove effective, have many benefits, as currently the most effective way to diagnose a food allergy is to undertake a food challenge with all its attendant risks to the patient their with time-consuming nature. Novel diagnostic platforms, such as protein arrays, have the potential to deliver improved diagnostic capability whilst utilising only small quantities of serum (Asero et al., 2007). This knowledge of allergens is also leading to the development of new approaches regarding the development of therapeutics, in particular allergens engineered to lose their IgE epitopes, yet retain sufficient immunological activity to allow them to be used to desensitise allergic individuals. Such approaches appear promising, based on studies in animal models using fish parvalbumins (Swoboda et al., 2007). This large body of knowledge is also allowing us to begin to study what makes one protein become an allergen, but not another. There are indications that the food processing and the matrix itself may modulate any intrinsic allergenic potential of an allergen per se. For example, the potency of peanut allergens in a chocolate matrix to elicit an allergic reaction was shown some years ago to be modulated by addition of vegetable fat, the higher fat content masking early oral reactions, resulting in greater consumption of the food and subsequently more severe reactions (Grimshaw et al., 2003). Our extensive knowledge of the allergens responsible for food allergies will make it possible to begin tackling such issues, despite the lack of adequate animal models for food allergy. This will be important for managing the risks associated with food allergies, whether it be predicting the allergenic potential of a novel protein or food, or managing allergens in foods within existing factory environments. Certainly, new methods for detecting allergens on foods based on the revolution in protein mass spectroscopy that has taken place in the past 10 years will need to draw on this body of knowledge in the future.

Acknowledgements This work was supported by the competitive strategic grant from BBSRC to IFR.

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4

Coeliac disease: allergy or intolerance?

Norma McGough

4.1 INTRODUCTION Coeliac disease (CD) is not an allergy or simple food intolerance. It is a life-long disease which affects the immune system, i.e. it is an autoimmune disease, and although it mainly affects the gut, it also affects other parts of the body. It is caused by an intolerance to gluten and is therefore triggered by eating gluten, a sequence of amino acids (protein) in the cereals wheat, rye and barley. Some people with CD are also sensitive to oats, one study reported this sensitivity in 1 in 20 people with CD (Lundin et al., 2003). Gluten causes inflammation of the gut in people with CD and the finger-like projections become flattened. This is known as villous atrophy (see Plates 4.1 and 4.2). This results in a variety of symptoms including stomach pain, bloating, sickness, diarrhoea and constipation. This damage affects the absorption of nutrients and can result in a range of nutritional deficiencies and other clinical manifestations. There is no cure for CD, but the gluten-free diet provides a complete treatment.

4.2 ABOUT COELIAC DISEASE Screening studies indicate that CD affects 1% of the population (West et al., 2003; Bingley et al., 2004), making CD one of the most common chronic autoimmune disorders and the most common cause of malabsorption in the United Kingdom. Complications associated with CD include gut cancer (Collin et al., 1994), osteoporosis (Kemppainen et al., 1999) and infertility (Sanders, 2003). CD is more common in those with other autoimmune diseases such as type 1 diabetes (Holmes, 2001) and autoimmune thyroid disease (Cuoco et al., 1999).

4.3 PREVALENCE AND DIAGNOSIS CD can present and be diagnosed at any age, from weaning onto gluten-containing cereals through to late old age. However, it is more commonly diagnosed later in life and is therefore more common in adults than children. Most people are diagnosed between 40 and 50 years of age and more women are diagnosed than men. Underdiagnosis of CD is significant; evidence suggests that only 1 in 8 cases are currently diagnosed (van Heel and West, 2006). CD is diagnosed by antibody blood tests and a small intestinal biopsy. It is important that gluten is not taken out of the diet until all the tests for CD are complete. Following


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a gluten-free diet prior to testing can result in false negative results (BSG, 2002; CREST, 2006).

4.4

WHAT IS GLUTEN?

‘Gluten’ is a general term used to cover the alcohol-soluble proteins; gliadins in wheat, hordeins in barley and secalins in rye; these proteins are toxic to people with CD. The glutenfree diet involves avoidance of wheat, rye and barley and ingredients derived from these cereals, e.g. wheat starch and barley malt. Some individuals with CD are also sensitive to oats (Lundin et al., 2003; Silano et al., 2007). A significant problem with most oat products is contamination from wheat, rye or barley (Thompson, 2005). The allergen labelling directive currently lists oats as a gluten-containing cereal (EC, 2007). The Draft Revised Codex Standard for Foods for Special Dietary Use for Persons Intolerant to Gluten makes a special reference to oats (CAC, 2007).

4.5

THE GLUTEN-FREE DIET

Dietary management provides a complete treatment for the disease, resulting in gut healing which in turn improves absorption of nutrients. Since the elimination of gluten-containing cereals from the diet results in elimination of the staples in the diet, substitute staple foods including gluten-free bread, gluten-free pasta, gluten-free flour, gluten-free crackers, glutenfree biscuits and gluten-free breakfast cereals are produced by a range of manufacturers including specialist gluten-free manufacturers and retailers. The gluten-free diet is made up of a combination of gluten-free substitute foods to replace the gluten-containing staples of a normal diet; naturally, gluten-free foods such as rice, corn, meat, fish, cheese, eggs, milk, fruit, pulses and vegetables, and mainstream processed foods that also happen to be gluten free. Although the gluten-free diet may sound ‘black and white’, this is not the case and the tolerance to gluten varies amongst people with CD. Over the years, different ranges of substitute products have been developed, which contain acceptably low levels of gluten, known as Codex wheat starch, to replace staple foods on a gluten-free diet. The standard for labelling of these products has been governed by a WHO/FAO body under the auspices of the Codex Committee on Nutrition for Special Dietary Uses (FAO/WHO, 2008).

4.5.1 Oats Historically, oats have been considered unsafe for people with CD and it is only recently that it has become accepted practice for people to include pure uncontaminated oats as part of a balanced gluten-free diet. Although most people with CD may be able to tolerate uncontaminated oats without a problem, research has suggested that some people who have CD may still react (Lundin et al., 2003; CAC, 2007). However, two systematic literature review have shown that pure uncontaminated oats may be incorporated safely into the gluten-free diet (Thompson, 2003; Haboubi et al., 2006), suitability has to be decided on an individual basis Oats are a good source of soluble fibre, which can help to lower cholesterol as well as adding variety to the diet. However, as oats are included in the Directive 2003/89/EC of

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allergens, even uncontaminated oats cannot be used in a product or recipe advertised as gluten-free (see Section 4.8; Haboubi et al., 2006). In addition, acceptance of oats differs on the gluten-free diet varies from one country to another with countries like Canada, the USA, Australia and Italy avoiding the use of oats completely.

4.6

GLUTEN-FREE FOODS

The gluten-free checklist provides a guide to what products generally contain gluten (see Table 4.1). There are different ranges of specialist gluten-free foods, e.g. bread and pasta, to replace standard wheat-containing varieties. Some of these foods are available on prescription, from health-food shops, mail order, pharmacies, the internet and supermarkets, with some retailers producing their own ranges of gluten-free substitute products as part of a ‘free from’ range. Bulk catering supplies are also available from suppliers, distributors and the company directly. For more information refer to Appendix 1 of the Coeliac UK Food and Drink Directory.

4.7 PRESCRIPTIONS Gluten-free foods available on prescription tend to be staples such as bread, flour, bread mixes, pizzas, crackers and pasta. It is advantageous for people with CD to be able to obtain samples of products from manufacturers in order to help choose products that they want to obtain on prescription. Coeliac UK provides information via their helpline (Tel: 0870 4448804), website (www.coeliac.org.uk), publications and events. Registered dietitians working in the NHS also provide advice on prescriptions for gluten-free products. The gluten-free foods available on prescription are listed in the National Health Service Drug Tariff for England and Wales (NHS, 2007), following successful submission to the Advisory Committee on Borderline Substances (ACBS). People with CD in England and Scotland are currently still required to pay for prescriptions, unless they meet the criteria for exemption, i.e. children, those in full-time education, those older than 60 years or those individuals on income support or other benefits. Prescriptions in Wales are free of charge. There are voluntary guidelines available on reasonable quantities of gluten-free foods for individuals, based on nutritional requirements, which have been incorporated into PCSG guidance for CD management (PCSG, 2006).

4.8

ALLERGEN LABELLING

Clear use of allergen labelling including management of allergens is essential. The advent of allergen labelling guidance in November 2005, which included gluten as one of the 12 named allergens (currently 14 allergens), makes it possible to select suitable gluten-free food by checking the label. The guidance which makes it necessary for all food pre-packaged and sold in countries belonging to the European Union (EU) to list all deliberate ingredients and clearly identify any food allergen included in a food as a deliberate ingredient (EC, 2007). The presence of gluten must appear on the ingredients list as the grain itself, e.g. wheat, barley, rye, oats, triticale, kamut and spelt. The use of allergen advice boxes is recommended, but not

Coeliac disease: allergy or intolerance? Table 4.1

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Gluten-free ingredients checklist.

Gluten free

May contain gluten

Cereals and flour Corn, corn flour, rice, rice flour, Flavoured savoury rice arrowroot, amaranth, buckwheat, products, cereal bars, corn and millet, teff, quinoa, sorghum, soya rice-based breakfast cereals flour, potato starch, modified starch, potato flour, gram flour,

Gluten containing Wheat, bulgar wheat, durum wheat, wheat bran, wheat germ, wheat starch, semolina, couscous, barley, malt, malted barley, rye, triticale, kamut, spelt Bread, crackers, pasta, oats, cereals, muesli

Meat, poultry, fish, cheese, eggs All fresh meats, poultry, fish, Meat and fish pastes, pates, shellfish, smoked meats and fish, sausages, burgers, fish in cured pure meats, smoked, fish in sauce, oil/brine, cheese, eggs

Meat, poultry, fish cooked in batter or breadcrumbs, faggots, rissoles, haggis, breaded ham

Milk and milk products Fresh, UHT, dried, condensed, evaporated, goat’s, sheep’s milk, fresh and soured cream, buttermilk, crème frˆ aiche

Milk with added fibre, artificial cream, yogurt and fromage frais containing muesli or cereals

Coffee and tea whiteners, oat milk, flavoured yoghurt and fromage frais

Fats and oils Butter, margarine, lard, cooking oils, ghee, low-fat spread Fruits and vegetables All fresh, frozen, canned and dried pure fruits and vegetables Savoury snacks Plain potato crisps, homemade popcorn Soups, sauces and pickles Tomato and garlic puree, individual herbs and spices, vinegars, mixed herbs and spices, ground pepper,

Suet

Oven, microwave and frozen chips, instant mash, fruit pie fillings, waffles

Vegetables and potatoes in batter, breadcrumbs or flour, potato croquettes

Flavoured crisps

Snacks made from wheat, rye, barley and oats, pretzels

Gravy, stock cubes, soups, Shoyu (Chinese soy sauce), sauces, mixes, tamari, mustard, stuffing mix mayonnaise, salad cream, dressings, pickles, chutney, blended seasoning, curry powder

Preserves and spreads Jam, conserves, honey, golden Mincemeat, lemon curd syrup, treacle, marmalade, peanut and other nut butters Drinks Tea, coffee, fruit juice, squash, clear fizzy drinks, cocoa, wine, spirits, cider, sherry, port Miscellaneous Gelatine, bicarbonate of soda, cream of tartar, yeast, artificial sweeteners,

Drinking chocolate, cloudy drinks

Malted milk drinks, barley waters/squash, beer, lager, ales, stouts

Tofu, cake decorations, marzipan, baking powder, ready to use icings

Ice cream cones and wafers

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compulsory, and is used to highlight the presence of gluten, i.e. contains ‘wheat gluten’. The guidance and legislation regarding identification of allergens in food products is explained in more detail in Chapter 13. The following provides a basic list of those ingredients that are gluten free, and those that are not. The source of gluten-free ingredients in food production is critical. Flours are high-risk ingredients regarding contaminants.

4.8.1

r r r r r r r r

Maize starch Modified starch Modified maize starch Maltodextrin Glucose syrup Dextrose Monosodium glutamate Fructose syrup

4.8.2

r r r r r r r r r r r r

Gluten-free ingredients

Not gluten-free ingredients

Wheat starch Modified wheat starch Wheat flour Wheat rusk/wheat bran Barley flour Barley malt Rye flour Oat bran Bulgar wheat Couscous Spelt Semolina

4.9 FOOD PRODUCTION In all food production, it is necessary to apply a system of quality control with Hazard Analysis and Critical Control Point (HACCP). The FSA has produced guidance on allergen management and awareness of gluten-containing ingredients. This incorporates a set of principles to pre-empt and apply control measures to potential hazards throughout production, processing, manufacture and distribution (FSA, 2006).

4.10 THE CODEX STANDARD The first development regarding a standard for gluten-free food was in 1981 when the WHO, FAO, Codex Alimentarius set a standard for foods labelled gluten free of 0.05 g nitrogen


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per 100 g of dry food (Codex Alimentarius Commission, 1981). This was interpreted as 200 parts per million (ppm) for ‘gluten-free’ labelling purposes. This standard has enabled manufacturers to produce gluten-free substitute products that contain a specially washed ingredient derived from wheat starch (Codex wheat starch) which improves the texture and palatability of the products. However, there has never been universal acceptance of this standard and in some countries, such as the USA, Canada, Australia and some countries in Southern Europe, products containing Codex wheat starch were not adopted. In these countries, only naturally gluten-free ingredients have been permitted in gluten-free substitute products and a standard of less than 20 ppm has been applied. Recent debate has produced a new draft dual standard known as the Codex standard for Foods for Special Dietary Use for Persons Intolerant to Gluten (WHO/FAO) which lowers the standard for gluten-free labelling purposes to less than 20 ppm. This development has occurred in the light of new research showing gut damage at very low levels of gluten ingestion and the knowledge that there is a greater risk of exceeding the safe level of intake the higher the standard, due to an additive effect of consuming gluten-free substitute products (Catassi et al., 2007). People with CD eat different amounts of substitute products, like gluten-free bread and gluten-free flour, so the suitability of products containing Codex wheat starch or those that are naturally gluten free is managed on an individual basis (Gubert et al., 2006). According to the proposed standard, substitute staple products containing Codex wheat starch may be considered suitable for people with CD if they have a level of gluten between 20 and 100 ppm. However, these products cannot be labelled gluten free and precise terminology for labelling purposes is still to be decided at this point in time at European Union level and implemented at a national level.

4.11

GLUTEN TESTING

Another important development associated with the standard for gluten-free labelling purposes has been in the science behind the methods of detection of gluten in foods below the standard of 200 ppm. The Codex Committee on Methods of Analysis and Sampling (CCMAS) approved the enzyme-linked immunoassay (ELISA) R5 Mendez method as a type I method in 2006. This method detects gluten reliably at a level as low as 5 ppm. It is considered to be the most accurate method currently available. As a type 1 method, it is the recommended method to be used in sampling and detection of gluten in foods (CAC, 2006).

4.12

GLUTEN-FREE CATERING

Careful checking of ingredients is essential. It is also important to make sure that all prepackaged ingredient information is retained. Gluten-free options or choices can be incorporated into menus with some additional care in menu planning and preparation (see Table 4.1). Soy sauce, mustard, sauces, spice mixes, curry powder, mayonnaise and stock cubes may all contain gluten. Table 4.2 provides a useful guide to gluten-free catering alternatives.

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Table 4.2

Guide to gluten-free catering alternatives.

Food

Alternative

Soup containing barley, pasta or wheat Sauces containing wheat flour Chips fried in oil with wheat battered products Stock cubes containing wheat

Use potato or other root vegetables to thicken Use cornflour Use a separate fryer just for chips Make stock from fresh meat, poultry or vegetable products or select those which happen to be gluten free

4.13 CROSS-CONTAMINATION Complete avoidance of gluten can be a challenge for individuals with CD trying to ‘eat out’. Dry gluten-containing ingredients like flour and breadcrumbs are high-risk ingredients for contamination and cross-contamination when you are producing gluten-free meals. Therefore, careful sourcing of gluten-free flours and substitute products is necessary if you intend to use them. Since flour can easily travel from one surface to another, it is essential to consider best practice guidance to ensure that gluten is not passed between surfaces or utensils. Steps to avoid contamination include:

r r r r r r

Cleaning surfaces immediately before their use (because flour can take hours to settle and can subsequently contaminate surfaces and utensils). Use clean frying oil for chips and gluten-free foods – DO NOT reuse oil that has cooked breaded or battered products. Keep all pans, utensils and colanders separate during preparation and cooking and wash in-between use. Using a clean grill, separate toaster or toaster bags to make gluten-free toast. Use separate butter or spreads to prevent contamination between gluten-free and glutencontaining foods. Use squeezing bottles to avoid contamination through the dipping of spoons or knives.

4.14 NUTRITIONAL ADEQUACY CD is a disease of malabsorption and therefore optimal nutrition is imperative. There may even be a case for increasing recommendations for specific nutrients in appropriate foods. There are reports of deficiencies in iron, fibre, folate, thiamine, riboflavin and niacin compared to standard diets. In addition, there are particular circumstances whereby people with CD may be more at risk of nutritional deficiencies, as symptoms of intestinal damage or noncompliance are often unrecognised, resulting in associated anaemias, including iron, folate and B12 vitamin deficiency (Thompson, 2005; Silano et al., 2007). As diagnosis commonly occurs later in life and is associated with the concomitant diagnosis of osteoporosis, an increased calcium intake is recommended (BSG, 2007). Staple gluten-free substitute products are classed as ‘foods for particular nutritional uses’ and they are also included in allergen labelling (FSA, 2006). However, in legislative terms, there is no equal guidance on fortification for gluten-free flours compared to wheat flour. This means that gluten-free substitute products do not have an equivalent nutritional composition to standard wheat-containing products. In the absence of legislation, gluten-free


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product ranges may vary in nutritional composition with only a few products having added calcium, iron and B vitamins. Therefore, consideration of current fortification policies on the nutritional status of gluten-free substitute products is required.

4.15 LACTOSE INTOLERANCE Lactose is a sugar found in mammalian milk (human, cows, sheep and goats), not in soya or rice milk. The enzyme lactase, which breaks down lactose, is found in the lining of the villi. When people are first diagnosed with CD, the lining of the gut is damaged, which can mean that not enough lactase is produced or that the enzyme does not work effectively. Once established on a gluten-free diet, the gut is able to heal and lactose digestion returns to normal. Lactose intolerance is therefore usually temporary (Murphy et al., 2002; Ojetti et al., 2005). However, although in reality levels of tolerance to lactose vary, catering for a lactose-free diet means avoiding all mammalian milks and their products (e.g. cow’s, goat’s and sheep’s milk, cream, ice cream, whey and evaporated milk).

4.16 COELIAC UK Coeliac UK is the leading charity in the UK working to improve the lives of people with CD and dermatitis herpetiformis (DH). Our mission is to improve the lives of people living with the condition through support, campaigning and research. Our vision is that the needs of people with CD and DH are universally recognised and met. We work to achieve this vision by:

r r r r

providing expert and independent information to help people manage their health, campaigning on their behalf to improve access to fast diagnosis, good subsequent, improving health care and safe foods – in the home and out and researching new treatments and the possibilities of a cure.

Each year, we raise awareness and campaign for change. This year, we had an awareness week in May to ensure eating out, whether through need or pleasure, is freed from restrictions. Our Awareness Week campaign, ‘Food Without Fear’ aims to raise awareness and understanding of a gluten-free diet amongst chefs and caterers, health care professionals and hospital ward staff, parliamentarians and the general public to ensure that eating out, through pleasure or need, is freed from restrictions. We provide a wide range of services including a dedicated helpline for members, health care professionals, manufacturers, suppliers and caterers, Crossed Grain magazine, annual Food and Drink Directory, which is updated monthly online at www.coeliac.org.uk. For more information, please contact the Coeliac UK helpline on 0870 4448804 or customer services on 01494 437278.

REFERENCES Bingley P.J., Williams A.J. and Norcross A.J. et al. (2004) Longitudinal studies of parents and children study team. British Medical Journal, 328, 322–323.

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BSG (British Society of Gastroenterology) (2002) Guidelines for the Management of Patients with Coeliac Disease. BSG, London. Available online at www.bsg.org.uk, accessed 20 January 2008. BSG (British Society of Gastroenterology) (2007) Guidelines for Osteoporosis in Inflammatory Bowel Disease and Coeliac Disease. BSG, London. Catassi C., Fabiani E., Iacono G. et al. (2007) A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with coeliac disease. American Journal of Clinical Nutrition, 85, 160– 166. CREST (Clinical Resource Efficiency Support Team) (2006) Guidelines for the Diagnosis and Management of Coeliac Disease in Adults. CREST, Belfast. Available online at www.crestni.org.uk, accessed 20 January 2008. Codex Alimentarius Commission (1981) Standard for Gluten-Free Foods. Codex Standard 118 – 1981. Rome, CAC. Available online at http://www.codexalimentarius.net/web/standard list.jsp, accessed 12 January 2008. Codex Alimentarius Commission (2006) Report of the Twenty Seventh Session of the Codex Committee on Methods of Analysis and Sampling. CAC, Budapest. Codex Alimentarius Commission (CAC) (2007) Report of the 29th Session of the Codex Committee on Nutrition and Food for Special Dietary Uses (ALINORM 08/31/26). CAC, Rome. Collin P., Reunala T., Pukkala E. et al. (1994) Coeliac disease – associated disorders and survival. Gut, 35(9), 1215–1218. Cuoco L., Certo M., Jorizzo R.A. et al. (1999) Prevalence and early diagnosis of celiac disease in autoimmune thyroid disorders. Italian Journal of Gastroenterology and Hepatology, 31(4), 283–287. European Commission (EC) (2007) COMMISSION DIRECTIVE 2003/89/EC of the European Parliament and of the Council 10 November 2003 amending Directive 2000/13/EC. Official Journal of the European Union, L308, 15–18. European Commission (EC) (2007) COMMISSION DIRECTIVE 2005/26/EC of 21 March 2005 establishing a list of food ingredients or substances provisionally excluded from Annex IIIa of Directive 2000/13/EC of the European Parliament of the Council. Official Journal of the European Union, L75, 33–34. European Commission (EC) (2007) COMMISSION DIRECTIVE 2007/68/EC of 27 November 2007 amending Annex IIIa to Directive 2000/13/EC of the European Parliament and of the Council as regards certain food ingredients. Official Journal of the European Union, L310, 11–14. FAO/WHO (Food and Agricultural Organisation/World Health Organisation) (2008) Codex Alimentarius. FAO/WHO, Italy. Available online at http://www.codexalimentarius.net/, accessed 20 March 2008. FSA (Food Standards Agency) (2006) Guidance on Allergen Management and Consumer Information. Best Practice Guidance on Managing Food Allergens with Particular Reference to Avoiding CrossContamination and Using Appropriate Advisory Labelling (e.g. ‘May Contain’ Labelling). FSA, London. Gubert A., Espadlaler M., Angel Canela M. et al. (2006) Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 ppm. European Journal of Gastroenterology and Hepatology, 18(11), 1187–1195. Haboubi N.Y., Taylor S. and Jones S. (2006) Coeliac disease and oats: a systematic review. Postgraduate Medical Journal, 82(972), 672–678. Holmes G. (2001) Coeliac disease and Type 1 DM – the case for screening. Diabetic Medicine, 18, 169– 177. Kemppainen T., Kroger H., Janatuinen E. et al. (1999) Osteoporosis in adult patients with celiac disease. Bone, 24, 249–255. Lundin K.E.A., Nilsen E.M., Scott H.G. et al. (2003) Oats induced villous atrophy in coeliac disease. Gut, 52, 1649–1652. Murphy M.S., Sood M. and Johnson T. (2002) Use of the lactose H2 breath test to monitor mucosal healing in coeliac disease. Acta Paediatrica, 91(2), 141–144. NHS (National Health Service) (2007) The Electronic Drug Tariff. NHS, London. Available online at http://www.ppa.org.uk/ppa/edt intro.htm">http://www.ppa.org.uk/ppa/edt intro.htm, accessed 4 March 2008. Ojetti V., Nucera G., Migneco A., Mauricio G., Lauritano C., Silvio D., Zocco M.A., Nista E.C., Cammarota G. and De Lorenzo A. (2005) High prevalence of celiac disease in patients with lactose intolerance. Digestion, 71(2), 106–110.


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PCSG (Primary Care Society for Gastroenterology) (2006) The Management of Adults with Coeliac Disease in Primary Care. PCSG, Rickmansworth. Sanders D.S. (2003) Coeliac disease and subfertility: association is often neglected. British Medical Journal, 327(7425), 226–227. Silano M., Dessi M., De Vincenzi M. et al. (2007) In vitro tests indicate that certain varieties of oats may be harmful to patients with celiac disease. Journal of Gastroenterology and Hepatology, 22(4), 528–531. Thompson T. (2003) Oats and the gluten-free diet. Journal of the American Dietetic Association, 103(3), 376–379. Thompson T. (2005) Contaminated oats and other gluten-free foods in the United States. Journal of American Dietetic Association, 105, 348. van Heel D. and West J., Logan R.F., Hill P.G. (2006) Recent advances in coeliac disease. Gut, 55, 1037–1046. West J., Logan R.F., Hill P.G. et al. (2003) Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut, 52, 960–965.

Part II

Risk Management

5

Risk management – the principles

René Crevel

5.1 INTRODUCTION Food allergy has been long recognised as a clinical phenomenon, with numerous reports in the twentieth-century medical literature (Prausnitz and Küstner, 1921; Tuft and Blumstein, 1942; Loveless, 1950). Epidemiological studies published in the last 10–15 years indicate that significant proportions of the population of most countries surveyed suffer from food allergy. Early studies by Young et al. (1994) in the United Kingdom estimated a population prevalence of 1.4–1.9%, while more recent studies suggest figures of the order of 3.5–4% in the industrialised world (Young et al., 1994; Bruijnzeel-Koomen et al., 1995; Kanny et al., 2001; Sicherer et al., 2004; Pereira et al., 2005; Venter et al., 2006; Rona et al., 2007). The prevalence among children is generally accepted to be higher, of the order of up to 8% (Sampson, 2005). Such figures equate to upwards of 10 million people with the condition in regions such as the EU or USA, and therefore a significant burden of ill health and reduced quality of life. Avoidance of the offending allergen is currently the only treatment for food allergy and an immediate consequence is that having a member with food allergy affects the whole family and, to a lesser extent, the social circle of the allergic individual. Over the last two decades, food allergy has thus evolved from a problem for the food-allergic individual to one of significant public health importance. This recognition has led to initiatives by public authorities and subsequently legislators. Stages in this development include the proposal by the Nordic countries in the early 1990s to amend the Codex Alimentarius’s 25% rule, leading to the FAO–WHO consultation in 1995 which identified eight major foods or food groups as important causes of food allergy (FAO/WHO, 1997). These early stages were followed in the early years of the twenty-first century by legislation in many countries and regions, including Australia, New Zealand, Japan, the European Union (Directive 2003/89/EC), the USA (FALCPA, 2004) and Canada, while proposals have been formulated in South Africa. In parallel, many food-manufacturing companies recognised the importance of food allergy and their responsibilities to their foodallergic consumers. Experience in the food industry, now going back a decade or longer, has demonstrated that allergen management shares many of the principles underlying management of other risks, such as toxicological or microbiological ones. In particular, safety cannot be ensured through end product batch testing, but must be built upon the careful analysis of the hazards at each stage of the product cycle. A key principle is therefore the development of an integrated approach that considers each stage of manufacturing, from the raw materials to the product that is delivered to the consumer, and involves all levels within a food company from the shop floor to the boardroom, as reflected in recently published guidelines (DG

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Table 5.1

Sources of allergen management issues (from FDA–CFSAN 2004).

Issue

Details

Raw materials Manufacturing processes and procedures Labelling or packaging Equipment design Training

Adventitious presence of allergen, rework Lack of cleaning, physical separation, carryover Lack of labelling review process Old equipment, difficult to clean and inspect Insufficient and not including appropriate people

Sanco HACCP guidance 2005; ISO 22000:2005). However, responsibility for ensuring the food safety of allergic consumers does not (and cannot) rest solely with the food industry, but is a responsibility shared by other stakeholders, including health professionals, regulators and the allergic patients or their carers themselves. This chapter considers the main issues associated with, the principles underlying allergen management, its objectives, and how these have been applied in a large food-manufacturing company.

5.2

ALLERGEN MANAGEMENT: THE ISSUES

The increasing number of recalls triggered by regulatory inspections (Vierk et al., 2002), by consumer complaints (Hefle and Lambrecht, 2004) or by system failures, which result in the presence of undeclared allergen at hazardous levels, indicate that unresolved issues exist with allergen management systems. A report commissioned by the US FDA as part of a review of good manufacturing practices (GMPs) in the food industry summarised issues arising from the operation of allergen management systems (FDA–CFSAN, 2004). These issues spanned the whole manufacturing supply chain (see Table 5.1).

5.2.1 Raw materials Adventitious presence of allergen was a problem, with incomplete knowledge of the formulation of ingredients used as raw materials, and the use of reconditioned ingredients and raw materials. Suggestions for overcoming these issues included developing a close working relationship with suppliers and performing regular audits. Training for the supplier could also be considered to improve understanding of the issues. Rework, which could be classed as a raw material, should be handled according to a defined and documented plan.

5.2.2 Manufacturing processes and procedures The presence of undeclared allergen in a product was found to result from a multiplicity of sources during manufacture, including inadequate cleaning, lack of physical separation at crossover points in production lines, lack of separation between production runs, carryover of allergen from shared storage equipment or from maintenance tools. The report recommended that allergens should be included in an overall hazard analysis, using a system such as the hazard analysis critical control point (HACCP) approach or equivalent. Specific recommendations included cleaning to an appropriate degree of thoroughness, recognising that this may exceed what is required to assure microbiological safety. If appropriate, cleaning


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should include disassembly of the equipment. Cleaning protocols may need to be validated analytically. Other measures included production scheduling, building in physical barriers to prevent allergen ingress at crossover points and providing dedicated storage facilities and maintenance equipment for specific allergenic materials.

5.2.3

Labelling or packaging

The report found that many companies failed to review their labelling, as a result of which ingredient declaration could be inaccurate. Recommendations included regular label reviews, together with policy to ensure old labels cannot be reused.

5.2.4

Equipment design

The report identified old equipment as an important issue, either because it is difficult to clean, for instance because it cannot be dismantled, or because it lends itself to allergen accumulation which cannot be readily detected by inspection. Hygienic design should overcome much of this problem as old plant is renewed.

5.2.5 Effective training of employees The report identified training as one of the areas where effectiveness was perceived to be lowest. Issues included training of the wrong people, not training enough people and not providing enough training. A key point made was that training should be delivered by people familiar with the plant rather than by consultants.

5.3

DEVELOPMENT OF ALLERGEN MANAGEMENT PLANS: PRINCIPLES AND CONSIDERATIONS

Allergen management systems form part of a family of food safety management systems, which include general toxicological and microbiological food safety. The requirements of allergen management may sometimes be at variance with those needed to control other food safety hazards. For instance, wet cleaning of dry mix lines would be a very effective way of removing allergenic residues, but at the risk of subsequent microbiological contamination, if water could not be adequately removed. Allergen management therefore needs to be integrated into the overall food safety management system, a fact now explicitly recognised in new international guidance documents such as ISO 22000:2005. Allergen management systems must meet both minimum statutory requirements and those that the company itself may have defined, after considering its objectives in this area of safety. These company requirements will arise from its own understanding of its operations and of the needs of its allergic consumers. Development of an allergen management system could proceed through the following series of steps:

r

Definition of objectives. Defining objectives forms a key stage and merits careful consideration. Without clear objectives, an allergen management plan will be difficult both to communicate to those who must apply it operationally and to other stakeholders. It will

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also make it difficult to evaluate success and compliance. Absence of explicit objectives does not mean that no objectives exist, only that they are implicit. Such a situation poses a risk that objectives could be externally imposed without consideration for their achievability. Clear objectives also provide a company with a defensible position in the event of challenge. Setting out a policy. Once objectives have been defined, these can be set out in a policy which will be a statement of what the company aims are and an outline of how they are to be achieved. It can also set out broad responsibilities for ensuring that these aims are achieved. The policy enunciates the commitment of the company through its senior management. It also provides the basis for defining subsidiary objectives and mechanisms which will ensure compliance. Drawing up guidelines. As indicated above, the policy document is not a day-to-day working document. Guidelines fulfil this purpose by detailing mechanisms and procedures to implement the broad objectives at a practical level. Guidelines will therefore cover detailed operations at all levels of the organisation. They will be adapted to cover the diversity of the company’s operations, including raw material types and sourcing, types of operation, etc.

An allergen management system must also balance a number of other requirements, the main one being to ensure a high degree of food safety with respect to allergens without impairing other aspects of food safety, but also without putting at risk the economic viability of the manufacturer. Such systems will therefore need to take into account a number of factors, as detailed below.

5.3.1 Nature of food manufacturing operations Food manufacturing is typically a complex operation, which, for purposes of allergen management, may be divided into several stages. These include the following:

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Raw material selection and specification: depending on the operation, raw materials range from primary, minimally processed ingredients, e.g. wheat flour, to complex formulated ingredients. The specification of these raw materials will limit what can be achieved in terms of residual allergen content. For instance, Codex Standards for wheat allow up to 3% other grains, while the Codex Standard for maize (corn) allows up to 2% (Codex Alimentarius Commission, 1995a,b). Manufacturing operations: these vary considerably in complexity, depending on the type of products that are made at the facility. However, in almost all operations, many different products with different formulations are made on the same lines, with a constant risk of inadvertent transfer of residues from the previous formulations onto the following ones. An added complexity is that some equipment can be extremely difficult to clean down between production runs because of its design or the characteristics of the product made. Thus allergen management in dry mix plants, where water or aqueous solvents cannot usually be used, poses challenges which differ from those in wet process lines. Similarly, thermal treatments of the product often alter the ease with which allergenic residues can be removed by sanitation procedures. Delivery to the consumer: most food manufacturers will deliver through retail or other outlets. In terms of allergen management, the manufacturer will need to consider how


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relevant information will be conveyed to the final consumer in such a way that it retains its integrity. In addition, food safety needs to be integrated into product development and innovation such that new products do not degrade inadvertently the safety of existing operations when they are introduced. This can occur, for instance, if a new product brings in an allergen which is new to a facility without consideration of additional control measures.

5.3.2

Biological and clinical characteristics of food allergens and food allergy

As with other toxicological hazards, food allergens may arise at any point in the food chain. However, they differ from most other chemical hazards as they pose a risk only to a limited and reasonably well-defined proportion of the population and are harmless to the vast majority at almost any level of intake. Known food allergens are exclusively proteins or polypeptides in foods, which provoke an immune response mediated by IgE antibodies in susceptible individuals. Allergenic proteins from foods belong to a relatively small number of protein families (Breiteneder and Mills, 2005) and tend to share certain molecular characteristics (e.g. thermal stability, resistance to pepsinolysis, possession of intramolecular disulphide bonds), although there is no single set of features which can discriminate between an allergenic and a non-allergenic protein. Food allergy, because of its nature, affects the wider household and community, modifying their food-buying habits and generally decreasing their quality of life (Gudgeon et al., 2005; Hefle et al., 2007). Allergic reactions to foods can be life threatening and can occur in some individuals in response to exposure to milligram quantities of the relevant food (Taylor et al., 2002). Avoidance of the offending allergenic food, together with the use of rescue medication, is the only therapy. Typically, the range of minimum doses which elicit reactions in foodallergic individuals varies over many orders of magnitude. For peanut, for instance, this may be at least four to five orders of magnitude among patients which have been challenged. Furthermore, the reactivity of patients varies over time, depending on extraneous factors such as environment, concurrent physical activity, etc. Although reliable information is beginning to emerge on the distribution of minimum eliciting doses within selected population groups, little information is available on how symptoms in any one individual vary with the amount of allergen to which they are exposed. Thus it is difficult to define the safety margin between the dose provoking a slight reaction, which does not pose a threat to health and a dose which provokes a severe reaction. Protection of the food-allergic consumer can thus pose difficult problems for food businesses. ILSI Europe has recently published an excellent overview of the scientific and clinical aspects of food allergy and the issues involved in its management in the form of a concise monograph (Jackson, 2003).

5.4

OBJECTIVES

Risk management of food allergens, as of other hazards, requires a clear definition of objectives. These need to recognise and balance sometimes the divergent interests of different stakeholders, a process which is often difficult to make explicit in the absence of formal

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mechanisms. In this context, the concept of food safety objectives, analogous to those proposed by the ICMSF for microbiological hazards and as elaborated by the Codex Alimentarius Commission (2003), could form a useful basis for eliciting a consensus. The primary objective behind allergen risk management must be to prevent adverse reactions in food-allergic individuals while not limiting their food choices unnecessarily. However, the apparent simplicity of this statement hides a number of complex issues. Firstly, in a matter of public health such as allergen management, the interests and needs of different stakeholders, which may diverge, must be balanced. These stakeholders include not only the allergic population but also the general population, as well as the food industry and health professionals. Most common food allergens play an important nutritional role in the diet of the population as a whole, and it is not practicable, let alone desirable to eliminate them from products. Furthermore, the majority of the population is not exposed to any risk from food allergens, irrespective of the amounts to which they may be exposed. This situation differentiates food allergens from other food hazards, such as chemical or microbiological contaminants, from which no individual derives any benefit, and where the whole population is potentially at risk. This has two implications: firstly, the general population derives no direct benefit from allergen control measures, and indeed must indirectly bear their cost; secondly, because most product lines are shared, the presence of adventitious specific residual allergens will be inevitable in many products. As discussed above, the threshold of reactivity to allergenic foods ranges over many orders of magnitude, while allergic reactions to foods span a considerable range of severity, from the barely noticeable to life-threatening anaphylaxis. There is thus a small and poorly defined fraction of the allergic population who react severely to very small amounts of allergenic food. Procedures to reduce unintentional presence of allergens may not be sufficient to protect such people, and other allergen management measures will be required to protect them. These observations underline the importance of setting clear objectives for allergen risk management, and ensuring that they are clearly communicated to stakeholders. These objectives should define who the risk management activities aim to protect and against what. They can then serve to evaluate the effectiveness of measures taken to achieve them.

5.4.1

Who are we trying to protect and against what? – the concept of tolerable risk

Because of the characteristics of food allergens and food allergy discussed earlier, particularly the difficulties in defining the proportion of the population which reacts severely to small amounts of allergen, the concept of protecting the whole allergic population against all reactions, however mild, is unrealistic. Design of food allergen management plans must therefore consider what level of protection they purport to provide, or in other words what can be considered a tolerable risk. Defining the tolerable risk level involves considering the probability of an adverse event, as well as its consequences in terms of severity. The two aspects are clearly related, inasmuch as the tolerable frequency for severe adverse events will be much lower than the tolerable frequency of all adverse events, among which events of low severity will predominate. Establishing the tolerable level is a societal issue, but little explicit guidance exists in the area of food allergy itself. One approach would be to consider the disease burden attributable to the less common food allergens, which are not subject to statutory regulation. This burden of disease could be considered to be that tolerated


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implicitly by society. In practice, however, information is still lacking on the disease burden attributable to common, regulated allergens, let alone the less common ones, making this approach impracticable. Another approach might be to look to other situations analogous to food safety. Assuring the safety of drinking water shares characteristics with the protection of food-allergic people. In particular, any risk posed by drinking water is imposed on those who consume it and, for practical purposes, is usually impossible to avoid. The World Health Organization has debated drinking water standards and proposed draft guidelines for drinking water quality, which translate to a probability of disease for any one individual of 10−3 per year or approximately one in ten over a lifetime (WHO, 2003). This figure, of course, refers to all disease, irrespective of severity, so cannot be applied without qualification to allergic reactions to food. However, it could provide a basis for discussion among stakeholders.

5.4.2

Hazard versus risk-based approaches

The simplest way to protect allergic consumers would be to ensure that the allergenic constituents to which they are reactive are either declared on the product label in all circumstances or totally excluded. This hazard-based approach is broadly appropriate to deliberately added ingredients, and indeed has been adopted in several pieces of legislation regulating food allergens (e.g. Directive 2003/89/EC). However, food-allergic individuals are also at risk from small amounts of residual allergen inadvertently carried over from other products because of the sharing of manufacturing lines, or because of admixture into raw materials such as grains during storage and transport. The hazard-based approach focuses on the presence of the allergen and does not recognise the existence of any amount of allergenic protein below which there is virtually no risk. As a result, it provides no mechanism to decide on the magnitude of the danger that the presence of residual allergen constitutes. It is arguably therefore not the most effective way to protect the vast majority of food-allergic people while balancing the interests of different stakeholders. At the limit, it leads to declaration of the presence of allergen in amounts which present little or no risk to health. Application of such an approach thus decreases the food choices of the allergic population and increases the likelihood that they will suffer nutritional deficiencies as well as reducing their quality of life (Avery et al., 2003). When applied to cross-contact allergens, it is reflected in excessive use of precautionary (‘may contain’) labelling. While such a label on an individual product may well add to the protection of allergic individuals who might otherwise eat that product, the uncontrolled proliferation of such labels is likely to decrease it as trust in the label reduces and it is ignored (Hefle et al., 2007). The possibility also exists that some allergic people will misinterpret such a label, if they consume the product and fail to react, wrongly concluding that they are no longer allergic. The theoretical diagram (see Figure 5.1) attempts to illustrate these observations. Maximising public health outcomes thus ineluctably leads to a risk-based approach to allergen management. Risk can be defined as the probability that a hazard will become manifest, and is often expressed as a function of the intrinsic hazard and the exposure to that hazard. This definition is sometimes expanded to include severity of the resulting adverse effect. Thus, risk is defined in ISO/IEC Guide 51 as the combination of the probability of occurrence of harm and the severity of that harm (ISO 22000:2005). The key concept is therefore that of probability. In line with that concept, risk management does not seek to eliminate the risk, which is generally regarded as impossible unless there is no exposure, but to reduce the probability of harm to a level which is considered tolerable.

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Probability of adverse event Frequency of labelling associated with minimum risk 0 Frequency of precautionary labelling Fig. 5.1 Relationship between the extent of precautionary labelling and risk to allergic consumers. (Reprinted from Crevel, R. (2006) Allergen management in the food industry. In: Managing Allergens in Food (eds C. Mills, H. Wichers and K. Hoffmann-Sommergruber). With permission from Woodhead Publishing Ltd, UK.)

5.4.3

Risk assessment principles for allergens in food manufacturing: do we have the tools needed, can the available data be used with those tools?

Kroes et al. (2000) acknowledge in their paper on the application of the ‘threshold of toxicological concern’ 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. However, food allergens make a significant impact on public health, and allergen management is mandated under general food law. Management of the risk they pose is thus imperative. Before a risk can be managed, it must first be assessed. Both risk assessment and risk management form part of the process of risk analysis which the Codex Alimentarius Commission (2003) defines as being composed of three components:

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Risk assessment: a scientifically based process consisting of hazard identification, hazard characterisation, exposure assessment and risk characterisation. Risk management: the process, distinct from risk assessment, of putting in place measures which minimise the risk, taking into account the interests of all those affected by it. Risk communication: the interactive exchange of information and opinions throughout the risk analysis process concerning hazards and risks, risk-related factors and risk perceptions, among risk assessors, risk managers, consumers, industry, the academic community and other interested parties, including the explanation of risk assessment findings and the basis of risk management decisions.

Risk assessment as a process thus begins with hazard identification, followed by hazard characterisation, exposure assessment and risk characterisation to scope the overall risk to the population (FAO/WHO, 1995, 1997). Translating this process to food allergens, the hazard itself is already defined as their intrinsic allergenicity, in this context their ability to provoke an allergic reaction. Beyond this, risk assessors require information about the characteristics of the hazard, which in this context can mean the response characteristics of the population


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at risk (distribution of minimum eliciting doses – thresholds, dose–response), the size of the population at risk and the extent of exposure. In ideal circumstances, risk assessors could calculate the number of reactions that would occur for any given level of residual allergen in a food product if people allergic to that food consumed it. In practice, information on all the elements required for a risk assessment remains extremely limited. Indeed, important reports from both the EFSA (2004) and the US FDA (Threshold Working Group, 2008) have questioned whether adequate data currently exist to establish thresholds, one of the key measures characterising the risk from food allergens. Studies to describe the reactivity of the allergic population in terms of minimum eliciting doses (thresholds) are still largely limited to selected populations, such as clinic patients, and further work is needed to map their reactivity onto the general allergic population. It is also limited to certain allergenic foods. Most available information is still based on studies undertaken for other purposes, further limiting their value for establishing minimum eliciting doses because of the type of data generated. Only anecdotal information is available on the relationship between the dose of allergen to which an individual is exposed and the severity of the reaction experienced, as obtaining that information systematically presents considerable ethical difficulties. Further complexities arise from differences in the extent to which allergenic proteins are released from different food matrices, and become available to be recognised by the immune system. Uncertainty also exists over the size of the population at risk, given that epidemiological data are scarce for most regions. In most countries, there is also a surprising lack of detailed information about the incidence of reactions, even severe and fatal ones. Minimum eliciting doses (thresholds) clearly form a key piece of information for risk assessors. A recent report by FDA–CFSAN (Threshold Working Group, 2008) identified four ways in which they might be determined: analytically based, statutorily derived, using a safety assessment approach and using a risk assessment approach. They indicated a preference for the risk assessment approach on the grounds that it was the most scientifically robust, as well as transparent, an important consideration in communicating with other stakeholders. Of those four approaches, only the safety and risk assessment ones use biological data on the reactivity of allergic patients, generated under controlled conditions. The safety assessment approach applies an uncertainty factor either to the highest dose of allergenic protein observed not to provoke a reaction or to the lowest one which does provoke a reaction (depending on what is available). In recent years, well-designed clinical studies have begun to define the distribution of the minimum doses of allergen that elicit responses in members of the allergic population. These new data have stimulated the development of new approaches (Bindslev-Jensen et al., 2002; Crevel et al., 2007) to overcome this problem. These approaches use statistical modelling of the population distribution of minimum eliciting doses (thresholds) to characterise the allergenic hazard. Coupled with estimates of exposure to the relevant allergen and knowledge of prevalence, these dose-distribution models can generate quantitative estimates of risk, helping to prioritise allergen management measures (Spanjersberg et al., 2007; Kruizinga et al., 2008). Recently, we described in detail how such an approach might be used as well as its limitations (Crevel et al., 2007). The approach is illustrated conceptually in Figure 5.2 and takes the following steps: 1. Good quality data from well-controlled challenge studies constitute the foundation of the approach. Such studies should be conducted using the agreed protocol proposed by Taylor et al. (2004) or the EuroPrevall partnership (Crevel et al., 2008). 2. A tolerable limit for the proportion (p) of allergic individuals who might react is established for the allergens of interest. The level p is defined in consultation with other stakeholders

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(regulators, patients, industry, clinicians). This part of the process requires other factors to be accounted for such as the prevalence of allergy to the allergen of interest, the actual rate of reported reactions and their severity. 3. Data from challenge studies are analysed and a statistical distribution is fitted to the data. The model is used to predict the EDp and the lower confidence interval on the EDp for the p defined in step 2. Precedents from other areas of food safety support this approach, although there are distinct differences, related to the type of data that are available or can be generated in each case. Thus Buchanan et al. (1997) estimated a conservative dose–response relationship for listeriosis using surveillance data on the number of cases, together with food sampling data on Listeria contamination of a food responsible for most such cases. In our approach, we use statistical distributions to describe data from clinical challenge studies performed under carefully controlled conditions. In microbiological terms, such data are more akin to controlled feeding studies with defined numbers of microorganisms in human volunteers. Inevitably, the populations tested in these studies contain an element of bias. Firstly, they will tend to exclude individuals who have suffered life-threatening reactions, as these may be less willing to participate and the clinicians more reluctant to accept them in a study on account of the risks. Perhaps more significantly, the process of selecting for challenge studies will result in a bias towards the more severely affected of the allergic population, other than the category previously mentioned. This arises because volunteers are chosen from the population which attends tertiary referral clinics, and who are therefore sufficiently motivated by the impact of their condition to visit a clinical expert. Publication bias will also occur in the case of analyses based on the published literature, which will tend to focus on the more interesting challenge responses. Limitations also exist when using such data as a basis for risk management, because they do not take into account some of the factors which modulate the allergic response, such as alcohol intake, exercise, etc. However, it can be argued that compared to other areas of toxicology, these data present the major advantage of being generated in the species of interest. Currently, available data do not permit a direct Proportion of reactions (in clinical study)

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Illustration of the characterisation of food allergen risks using the population dose distribution.


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application of the methods proposed in Buchanan et al. (1997). Specifically, data on the incidence of even severe allergic reactions to foods are not reliable, and usable published data on the distribution of undeclared allergen in food are very limited and do not anyway purport to provide a statistically representative picture of the extent of residual allergens in foods (Hefle and Lambrecht, 2004; Pele et al., 2007). Nevertheless, the next step in the development of this approach is to validate the predictions by comparing the number of predicted reactions with their actual incidence. Risk assessment could provide a sound scientific basis to deal with unintentional allergenic ‘cross-contact’ through the definition of an appropriate upper limit for non-ingredient allergenic food components. For example, Switzerland requires the declaration of specified allergenic constituents whenever present in concentrations greater than 0.1% (1000 mg/kg), whether as ingredients or otherwise (Conseil fédéral suisse, 2002). However, a threshold of 0.1% would almost certainly not be considered sufficiently protective of public health, since less than 1 mg of peanut protein has been shown to elicit adverse reactions in allergic subjects (reviewed in Taylor et al., 2002; Threshold Working Group, 2008). Obviously, an upper limit for non-ingredient allergenic food components also needs to consider the No Observed Adverse Effect Level (NOAEL) reported for each of the important allergenic foods. Thus, while allergic consumers are protected against undeclared allergenic ingredients, they remain at risk from non-ingredient allergenic components, while the food industry lacks clear guidance from regulatory authorities. This absence of a regulatory threshold also has other consequences, which may reduce the protection afforded the allergic consumer. Allergenic ingredients present in insignificant quantities must be declared. For example, an ingredient containing refined peanut oil, with almost undetectable protein, could be a component of another ingredient used in very small amounts, such as a flavour. Yet products containing this ingredient must be labelled as containing peanut and allergic consumers who eat them could erroneously conclude that their allergy had resolved when in fact the amounts were too small to trigger a reaction.

5.5

APPLICATION

5.5.1 From policy to guidelines: the need for an integrated approach Allergen management policies establish principally intent, but guidelines are required to set out the detailed mechanisms whereby this intent is made operational. As already mentioned, allergen management requires consideration of all the elements of the life cycle and production of a product from its design, through selection of raw materials to production processes and finally delivery to the consumer. This marks out allergen management as an activity which requires commitment throughout a company from senior management all the way to those working on production lines. Procedures that are put in place for allergen management may also impinge on other aspects of food safety. Effective delivery of such commitment therefore requires that allergen management be integrated into overall food safety management and encompass all stages of the life cycle of the product from the raw materials to the end product which the consumer buys. This has recently been recognised in external standards for food safety management systems such as ISO 22000:2005 and the EU’s DG Sanco HACCP guidance 2005. As already discussed, this integrated approach starts with the development of policies, which provide the framework for the operation of the allergen

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management plans. Typically, such policies will specify the aims of the plan, indicate what will be done to achieve those aims, and define major responsibilities for their fulfilment. Policies thus enshrine the corporate commitment to the plan. However, implementation requires more detailed guidance documents, which can be tailored to specific operational requirements and provide practical advice to individual manufacturing units. Guidelines will therefore differentiate between different types of food processing, such as dry mix lines and wet lines, but will also cover elements such as the cleaning of specific pieces of equipment within a factory. This approach ensures that a high minimum standard exists for the handling of allergens throughout the company. Existing food safety management systems can be helpful in applying these principles operationally.

5.5.2

Food safety management systems and food allergens

A number of formal systems have been developed to deal with food safety hazards, of which the best known are GMPs and HACCP systems. More recently, the International Standards Organization (ISO) has published ISO22000:2005, which describes a fully integrated approach to food safety management.

5.5.3 Good manufacturing practice GMP regulations (CFR 21 Pt 110, 1999) are probably the earliest food safety management systems. These evolved originally to counter chemical contamination, adulteration and misrepresentation of products to the consumer. The current content of these regulations reflect these origins, as well as the later focus on microbiological safety. Many aspects of the current GMPs relating to human food production contain elements with application to allergen management. They thus cover provisions for personnel, including health, education and training and supervision arrangements, provisions for buildings and facilities, including construction, layout, maintenance, sanitary operations and facilities, provisions for equipment design, construction and maintenance, in particular with regard to sanitation. The GMPs also cover production and process controls, including raw materials as well as manufacturing operations. Main requirements are as follows:

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Personnel: Personnel working in food handling or processing facilities are required to be free of disease, to maintain adequate cleanliness to avoid contamination of the food, to take other necessary precautions to avoid contamination. If they are responsible for identifying food contamination, they must have an adequate level of education and training. Furthermore, responsibility for compliance must be assigned to suitably competent supervisory personnel. Buildings and facilities: Plant buildings and structures must be of sufficient size, and adequate construction, and design to facilitate maintenance and sanitary operations for food-manufacturing purposes. The guidelines lay particular emphasis on sufficient size to ensure adequate separation of operations to avoid contamination. Facilities must also have adequate arrangements for cleaning of equipment as well as for employees to clean their hands. Equipment: Equipment must be designed to be cleaned adequately and must be properly maintained.


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Production and process controls: All operations from the raw material selection and handling to the final product must be conducted in accordance with adequate sanitation principles. Again, stress is laid on the requirement for adequate supervision. The regulations require that ‘All reasonable precautions shall be taken to ensure that production procedures do not contribute contamination from any source’.

Even a cursory consideration of the requirements of current GMPs shows that although they are heavily focused on microbiological control, their principles should constitute a good starting point for allergen management. The original US regulations date from 1986, when food allergy was not deemed a significant public health problem. A report commissioned by the FDA into modernisation of the GMPs recommended revision to incorporate, among other elements, guidance on allergen control (FDA–CFSAN, 2004). This recommendation was endorsed by many of those who offered comments during the consultation phase on the report.

5.5.4 Hazard analysis and critical control points HACCP, unlike GMP, is not a system of regulations which specify what must be done. Instead, it is a set of principles which can be applied as part of an approach to food safety management. It was originally proposed by the Codex Alimentarius Commission and is now considered by various regulatory authorities (e.g. EFSA) to be an appropriate tool to control hazards in food businesses. In contrast to GMP, HACCP is process-specific, and indeed can be considered complementary to GMP. The structure of HACCP means that it can be applied to almost any hazard. HACCP consists of the following seven stages: 1. hazard analysis: identify any hazards that must be prevented, eliminated or reduced to tolerable levels, 2. identify the critical control points, 3. establish critical limits at critical control points, 4. establish and implement effective monitoring procedures at critical control points, 5. establish corrective actions when monitoring indicates that a critical control point is not under control, 6. establish procedures to verify that the measures outlined in paragraphs 1 to 5 are working effectively, 7. establish documents and records commensurate with the nature and size of the food business to demonstrate the effective application of the measures outlined in steps 1 to 6. Some regulatory authorities, rather than defining GMPs, have mandated the use of HACCP principles as part of food safety management. Thus, EU Regulation 852/2004 on the hygiene of foodstuffs requires the application of HACCP principles. However, the guidance document (EU, 2006) also stresses the flexible application of the concept, commensurate with the complexity of the business.

5.5.5 ISO 22000:2005: food safety management systems ISO 22000:2005 starts from the premise that the most effective food safety systems are established, operated and updated within the framework of a structured management system and

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Management of Food Allergens Table 5.2 Key elements of food safety management systems according to ISO22000:2005. Element Role of management Communication Resources Documentation Procedures to deal with non-conformity Evaluation

incorporated into the overall management activities of the organisation (ISO 22000:2005). The standard aims to provide the structure for a comprehensive food safety management system, integrated into other management systems (e.g. quality management systems, such as ISO 9001:2000). Key elements (Table 5.2), which it highlights, include:

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Role of management: the standard recognises the essential role of senior management commitment, demonstrated by definition of the food safety policy, its documentation and its communication within and beyond the company. It also details a requirement for operation of the policy to be reviewed periodically by senior management, and for attribution of key responsibilities. Communication: the standard lays considerable stress on communication, both within the company to promote its effective application, but also beyond to suppliers, retailers and consumers. Resources: compliance with the standard can only be achieved if adequate resources both in equipment and trained personnel are available. Documentation: the safety management system must be documented, both in terms of its different elements (e.g. HACCP plans) and evidence that it is being adhered to (e.g. audit results). Non-conformity: plans to deal with breaches of the policy (e.g. product non-conformity) need to be documented, including a system for managing recalls. Evaluation: the food safety management system must be evaluated periodically to ascertain whether it continues to cover the company’s requirements and takes into account the most recent information on the food safety hazards subject to control.

The principles of HACCP, as enunciated by the Codex Alimentarius Commission and outlined in the previous section, form an integral part of ISO 22000:2005. The standard differs from the GMP regulations inasmuch as it provides a framework for companies who do not have a food safety management system to develop and implement one. It also permits those who have already implemented such a system to review it against the standard and, if appropriate, update or add elements to it. It does not provide detailed guidance, for instance, on how to design and operate a factory to minimise the risk of allergen cross-contact. It links to GMPs through the requirement that prerequisite programmes, covering for instance hygiene, are in place prior to implementation of the system.

Risk management – the principles Table 5.3

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Key factors covered by Unilever’s allergen guidelines.

Factor Innovation and product development Supply chain Manufacturing protocols Packaging, promotion and advertising Training Retailers Food professionals

5.5.6 Food allergen management in Unilever Unilever, in parallel with other large food companies, identified food allergy as public health issue long before it was addressed in international and regulatory documents dealing with food safety. Although its approach thus evolved separately, it contains many of the elements which have now been identified as key to food safety management. Unilever thus has a policy for dealing with allergens, which states that it shall declare the presence in its products of any allergen which is a common cause of allergic reactions. At a minimum, any allergen required by local regulations will be declared. However, beyond that, the allergenic risk from foods not considered commonly allergenic may be assessed if clinical or epidemiological data indicate the need. If classed as a common cause of allergic reactions in accordance with the company’s criteria, this food component would then be declared on labels and included in allergen management plans. Unilever also undertakes to inform any consumer on request about the presence of uncommon allergens in specific products. The custodian of this policy, as of all Unilever policies, is the Executive Committee, thereby demonstrating senior management commitment. This approach enables the company to react more rapidly to emerging allergens than if it relied solely on reacting to external regulation. The policy, however, is made operational through specific guidelines, which exist for dry mix plants, wet savoury plants, ice cream factories and other operations. Allergen management guidelines (Table 5.3) need to ensure that allergens are correctly and intelligibly declared in products, but also to make sure that allergen is not present inadvertently at levels likely to cause adverse health effects. Such guidelines need to address all stages in the product life cycle, from its design, through the sourcing of ingredients to manufacture, labelling and distribution. Specifically, they need to deal with the following:

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Innovation: the product developer needs to consider whether the allergenic ingredient plays a functional role in the product or whether an equivalent non-allergenic ingredient could serve as well. Similarly, could an ingredient already present in the product replace an allergenic one; for instance, could wheat flour be used as a carrier for a flavour in a product already containing wheat? A further question that needs consideration is whether the use of the allergenic ingredient in a product would alter the risks arising from existing operations, for instance by bringing a new allergenic ingredient into a plant. Supply chain: control of allergens in the supply chain requires a close relationship with suppliers, so that they understand the needs of the manufacturer and can meet its requirements. Typically, within Unilever, the starting point of the supplier assessment will be a questionnaire about allergens handled and precautions in place to avoid cross-contact, including the existence of a HACCP plan. This is backed up by periodic audits of the

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suppliers’ facilities. Taking together, the resulting information will permit an assessment of the risk that an allergen is present inadvertently through the raw materials, and will form the basis for risk management measures, which might include a change of supplier. Additionally, where applicable, suppliers are required to seek agreement to any change in the formulation of the ingredient they supply. Manufacturing protocols: the main considerations are the inclusion of common allergens in HACCP plans, production scheduling to minimise cross-contact, validated cleaning procedures and clear labelling and separation of specific allergenic ingredients within the factory. Procedures need to cover rework, where sound product is not packaged but ‘recycled’. Finally, the same degree of attention is needed whether the company’s own manufacturing facility is concerned or that of co-packers. Packaging, promotion and advertising: packaging carries the label and therefore the allergen information. Care is required to ensure that information remains with the product until it reaches the consumer; the allergen management plan needs to assess the probability that packs containing multiple individually packed items will be split, and the outer packaging separated from the product. Other considerations include the use of warnings if the formulation has changed to include an allergenic ingredient previously not present. Training: staff at all levels need to understand the importance of allergen control procedures and their own role in ensuring compliance. Training is thus vital and improves support for what could otherwise be perceived as irksome restrictions. Retailers: generally, the manufacturer’s allergen information will be sufficient. However, situations such as in-store promotions require care to ensure that the consumer is fully informed. Sound product, which fails to meet all standards for general sale, may be repackaged and sold on in specialised outlets or even in a different market. The manufacturer needs to ensure that appropriate allergen information is retained and available to the ultimate consumer. Food professionals: most allergic reactions to foods occur outside the home, in conditions where the product is often not labelled and even when asked, food professionals fail to provide correct information. Where pre-prepared food is provided to that sector, the manufacturer has a responsibility to ensure that accurate allergen information is provided and conveyed to the consumer.

This brief summary of the elements of allergen management in Unilever illustrates the close parallels between the evolution of thinking within the company and the emerging consensus in the food safety management community. Although implementation in Unilever has characteristics specific to the company, with the key elements of a system integrated with other safety management systems, and the ultimate responsibility lying with the senior leadership of the company, it is more striking by its similarities to that consensus than by its differences from it.

5.6 CONCLUDING REMARKS Food allergy has emerged over the last two decades as a fully fledged public health issue, which it became imperative for food manufacturers to address. Food allergens possess some very distinct characteristics compared to other food safety risks, not least that they affect a small but significant proportion of the population, that many are used in


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a multitude of applications and that small amounts can sometimes provoke severe reactions. However, experience and research have shown that the risks posed by food allergens could be handled using methodologies developed in the context of other hazards. Considerable progress has been made in assessing the risks from food allergens, but confidence in the reliability of such risk assessments among a significant proportion of stakeholders continues to be limited by the scarcity of data, as well as by difficulties in evaluating its quality and interpreting it. Notwithstanding these limitations, the food industry has faced the need to protect its allergic consumers, which has led to the development of allergen management systems. A key observation arising from this experience is that optimal outcomes require consideration of the whole life cycle of a product, which can best be achieved through full integration of allergen risk management with management of other food safety risks. Newly developed standards, such as ISO 22000:2005, build on this crucial observation. Development of allergen management policies and procedures by food manufacturers contributes significantly to protection of allergic consumers by ensuring that the inadvertent presence of allergenic ingredients in products is minimised.

REFERENCES Avery N.J., King R.M., Knight S. and Hourihane J.O. (2003) Assessment of quality of life in children with peanut allergy. Pediatric Allergy and Immunology, 14, 378–382. Bindslev-Jensen C., Briggs D. and Osterballe M. (2002) Can we determine a threshold level for allergenic foods by statistical analysis of published data in the literature? Allergy, 57, 741–746. Breiteneder H. and Mills E.N. (2005) Molecular properties of food allergens. Journal of Allergy and Clinical Immunology, 115(1), 14–23. Bruijnzeel-Koomen C., Ortolani C., Aas K. et al. (1995) Adverse reactions to food. European academy of allergology and clinical immunology subcommittee. Allergy, 50, 623–635. Buchanan R.L., Damert W.G., Whiting R.C. and Van Schothorst M. (1997) Use of epidemiologic and food survey data to estimate a purposefully conservative dose–response relationship for Listeria monocytogenes levels and incidence of listeriosis. Journal of Food Protection, 60(8), 918–922. Codex Alimentarius Commission (1995a) Codex Standard For Maize (Corn). Codex Stan 153 – 1985 (Rev. 1 - 1995). Codex Alimentarius Commission (1995b) Codex Standard For Wheat And Durum Wheat. Codex Stan 199 – 1995. Codex Alimentarius Commission (2003) Draft Principles for the Risk Analysis of Foods Derived from Modern Biotechnology, at Step 8 of the Elaboration Procedure. ALINORM 03/34, Appendix II. Codex Alimentarius Commission, Joint FAO/WHO Food Standards Programme, Food and Agriculture Organisation, Rome. Available at ftp://ftp.fao.org/codex/alinorm01/al0134ae.pdf, accessed 21 April 2009. Conseil fédéral suisse (2002) Ordonnance sur les denrées alimentaires. RO, 573. Crevel R.W., Ballmer-Weber B.K., Holzhauser T. et al. (2008) Thresholds for food allergens and their value to different stakeholders. Allergy, 63(5), 597–609. Crevel R.W.R., Briggs D., Hefle S.L. et al. (2007) Hazard characterisation in food allergen risk assessment: the application of statistical approaches and the use of clinical data. Food and Chemical Toxicology, 45(5), 691–701. Directive 2003/89/EC of the European Parliament and Council (2003) Official Journal of European Union L308/15, 25.11.2003. Available at http://eur-lex.europa.eu/LexUriServ/LexUriServ .do?uri=OJ:L:2003:308:0015:0018:EN:PDF, accessed 21 April 2009. EFSA (European Food Safety Authority) (2004) Opinion of the scientific panel on dietitic products, nutrition and allergies on a request from the commission relating to the evaluation of allergenic foods for labelling purposes. EFSA Journal, 32, 1–197.

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EU (European Union) (2006) Guidance Document. Key questions related to import requirements and the new rules on food hygiene and official food controls. Available at http://ec.europa.eu/food/ international/trade/interpretation imports.pdf, accessed 21 April 2009. FAO/WHO (1995) Application of Risk Analysis to Food Standards Issues, Report of the Joint FAO/WHO Expert Consultation, Geneva, Switzerland, 13–17 March 1995, WHO/FNU/FOS/95.3. World Health Organization, Geneva. Available at http://www.who.int/fsf/Documents/applira.pdf, accessed 21 April 2009. FAO/WHO (1997) Risk Management and Food Safety, Report of a Joint FAO/WHO Consultation, Rome, Italy, 27–31 January 1997, FAO Food and Nutrition Paper 65. Food and Agriculture Organisation of the United Nations, Rome. Available at http://www.fao.org/docrep/W4982E/W4982E00.htm, accessed 21 April 2009. FDA–CFSAN (2004) Good Manufacturing Practices (GMPs) for the 21st Century – Food Processing. Available at http://www.cfsan.fda.gov/˜dms/gmp-toc.html, accessed 21 April 2009. FALCPA (Food Allergen Labeling and Consumer Protection Act) (2004) (Title II of Public Law 108–282) s.741–15-21. Available at http://www.cfsan.fda.gov/ãcrobat/alrgact.pdf, accessed 21 April 2009. Gudgeon L.A., Trewin J.B., Grimshaw K.E.C. and Hourihane J.O.B. (2005) Patients find low dose threshold challenges useful in the management of their peanut allergy. American Academy of Allergy, Asthma and Immunology, San Antonio. Hefle S.L., Furlong T.J., Niemann L. et al. (2007) Consumer attitudes and risks associated with packaged foods having advisory labeling regarding the presence of peanuts. Journal of Allergy and Clinical Immunology, 120, 171–176. Hefle S.L. and Lambrecht D.M. (2004) Validated sandwich enzyme-linked immunosorbent assay for casein and its application to retail and milk-allergic complaint foods. Journal of Food Protection, 67(9), 1933–1938. International Standard 22000 (2005) Food safety management systems – requirements for any organization in the food chain. First Edition 1 September 2005. International Standards Organization, Geneva, Switzerland. Jackson W.F. (2003) Food Allergy. ILSI Europe Concise Monograph Series. International Life Sciences Institute (ILSI), Brussels, Belgium. ISBN 1–57881-160–0. Kanny G., Moneret-Vautrin D.A., Flabbee J. et al. (2001) Population study of food allergy in France. Journal of Allergy and Clinical Immunology, 108(1), 133–140. Kroes R., Galli C., Munro I. et al. (2000) Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. Food and Chemical Toxicology, 38, 255–312. Kruizinga A.G., Briggs D., Crevel R.W.R. et al. (2008) Probabilistic risk assessment model for allergens in food: sensitivity analysis of the minimum eliciting dose and food consumption. Food and Chemical Toxicology, 46(5), 1437–1443. Loveless M.H. (1950) Milk allergy: a survey of its incidence; experience with masked ingestion test. Journal of Allergy, 21, 489. Pele M., Brohée M., Anklam E. and Van Hengel A.J. (2007) Peanut and hazelnut traces in cookies and chocolates: relationship between analytical results and declaration of food allergens on product labels. Food Additives & Contaminants, 24, 1334–1344. Pereira P., Venter C., Grundy J. et al. (2005) Prevalence of sensitization to food allergens, reported adverse reaction to foods, food avoidance, and food hypersensitivity among teenagers. Journal of Allergy and Clinical Immunology, 116, 884–892. Prausnitz C. and Küstner H. (1921) Studien u¨ ber die Ueberempfindlichkeit. Zentralbl Bakteriol Abt Orig, 86, 160–169. Rona R.J., Keil T., Summers C. et al. (2007) The prevalence of food allergy: a meta-analysis. Journal of Allergy and Clinical Immunology, 120(3), 638–646. Sampson H.A. (2005) Food allergy – accurately identifying clinical reactivity. Allergy, 60(Suppl 79), 19–24. Sicherer S.H., Munoz-Furlong A. and Sampson H.A. (2004) Prevalence of seafood allergy in the United States determined by a random telephone survey. Journal of Allergy and Clinical Immunology, 114(1), 127–130. Spanjersberg M.Q., Kruizinga A.G., Rennen M.A. and Houben G.F. (2007) Risk assessment and food allergy: the probabilistic model applied to allergens. Food and Chemical Toxicology, 45(1), 49–54.


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Taylor S.L., Hefle S.L., Bindslev-Jensen C. et al. (2004) A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much? Clinical and Experimental Allergy, 34(5), 689–695. Taylor S.L., Hefle S.L., Bindslev-Jensen C. et al. (2002) Factors affecting the determination of threshold doses for allergenic foods: how much is too much? Journal of Allergy and Clinical Immunology, 109, 24–30. Threshold Working Group (2008) Approaches to establish thresholds for major food allergens and for gluten in food. Journal of Food Protection, 71(46), 1043–1088. Tuft L. and Blumstein G.I. (1942) Studies in food allergy. Sensitization to fresh fruits: clinical and experimental observations. Journal of Allergy, 13, 574–581. Venter C., Pereira B., Grundy J. et al. (2006) Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study. Pediatric Allergy and Immunology, 17, 356–363. Vierk K., Falci K., Wolyniak C. and Klontz K.C. (2002) Recalls of foods containing undeclared allergens reported to the US Food and Drug Administration, fiscal year 1999. Journal of Allergy and Clinical Immunology, 109(6), 920–922. WHO (2003) Guidelines for Drinking-Water Quality, 3rd edn. World Health Organization, Geneva. Young E., Stoneham M.D., Petruckevitch A. et al. (1994) A population study of food intolerance. Lancet, 343(8906), 1127–1130.

6

Risk management – operational implications

Anton J. Alldrick

6.1 INTRODUCTION Modern approaches to food safety management are often based on some form of risk evaluation and the institution of appropriate management systems to ensure that the risk (probability) of an adverse event occurring is reduced to an acceptable level. Such a process involves a number of steps. These are:

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Hazard identification Estimation of risk Management of risk

Most experienced food-safety practitioners have the intellectual ability to deal with these concepts; however, experience has shown that in the case of food allergens the subject can be challenging. To get some idea of the scope of the problem in a 12-month period beginning March 2007, 78 allergen product recalls/withdrawals were notified to the UK Food Standard Agency; this compares with 26 alerts for foreign-body contamination (Food Standards Agency, www.food.gov.uk/safereating/allergyintol/alerts/, www.food.gov.uk/enforcement/alerts). Arguably, one of the reasons for this is that as a class of contaminants, food-allergens often provoke challenges to existing patterns of thinking in terms of food-safety management. Fundamentally, these arise out of the following dichotomy. On the one hand (generally in the case of most food-safety hazards):

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most hazards represent some form of threat to the entire population; any adverse reaction can, in many cases, be related to a minimum eliciting dose.

On the other hand (as discussed in a recent paper published by the European Food Safety Authority (2004), in terms of food allergens):

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the eliciting agent is usually an integral component of the food or ingredient; generally speaking food allergy only affects a small proportion of the consumer base; sometimes inevitable levels of cross-contamination within a production system, while low enough not to compromise product quality, are sufficiently large enough to induce adverse reactions in susceptible individuals; there is no ‘rule of thumb’ as to what amount of a particular allergen in a particular food matrix will not induce an adverse reaction in a particular individual (in other words, there is no preset threshold value).


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As discussed in this chapter, while managing food allergens may require a rigorous intellectual approach, the operational techniques used are no different from those required normally to achieve ‘good manufacturing practice (GMP)’.

6.2 IDENTIFYING THE HAZARD It can be argued that the underlying principles of modern food-safety management philosophy are twofold:

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The correct definition of the hazard faced by the consumer. The subsequent identification and implementation of those steps necessary to remove the hazard completely or to reduce the risk of it occurring within a food business to an acceptable level.

Thus the first step in any sensible food-safety management system is to identify the hazard which has to be managed. Given the subject matter covered in this chapter and for convenience, in the case of food-allergy within a food-processing business, the hazard might be defined as ‘The inadvertent consumption of a food allergen by a sensitive individual’. Fundamentally, therefore the risk of the hazard occurring revolves around two factors:

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The use (or lack thereof) of appropriate communication mechanisms whereby the foodallergic consumer can be informed of the presence of allergenic materials within a particular food. Minimising the inadvertent inclusion of food allergens in products where they would not be expected to be present.

Allergenic materials can be present in the food by virtue of the fact that either they are an ingredient or they are present as the result of cross-contamination consequential to other activities within the food business providing the food in question. In the latter case, it is reemphasised that a level of cross-contamination insufficient to provoke a consumer complaint in terms of overall product acceptability (e.g. taste or appearance) will often be high enough to provoke a response in an allergic individual. Potentially most foods can act as an allergen to at least one individual. In 1996, Hefle et al. published a list of over 150 foods demonstrated to have caused an allergic response on at least one occasion. Thus, in terms of identifying which food allergens to focus on, those responsible for food-safety management are faced with performing a triage exercise to identify those allergens which present the most significant threat to the food business’s consumer base. In the European Union, this exercise has to a large degree been achieved through labelling legislation. At the time of writing (2008), food labelling requirements (including how food ingredients may be declared) are governed by Directive 2000/13/EC as amended. A key amendment to this legislation relates to the communication of foodallergen-related information; this has progressed through various forms and is currently encapsulated in Commission Directive 2007/68/EC. This document not only details how food-allergen-related information should be transmitted but also supplies a list of allergenic foods (Annex IIIa) covered by the regulation. The British Retail Consortium (2008) in version 5 of its ‘global food standard’ identified the same list. Within the European Union, therefore,

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food-safety practitioners have a basic list of food allergens which forms the basis of their hazard risk assessments. It is important to note that this list acts as a starting point. Depending on the product and consumer base other potentially allergenic foods might have to be considered. It should be remembered that a number of food businesses were considering food allergens such as lupins and molluscs within their food-safety management systems, before their subsequent inclusion within Annex IIIa. Furthermore, in order to reflect local susceptibilities, national food-safety authorities often include other foods in addition to those listed on the Annex IIIa list, when giving advice to consumers. For example, on its ‘eat well be well’ website, the UK Food Standards Agency (www.eatwell.gov.uk) lists a further nine foods or food types, which include rice and kiwi fruit. Thus in arriving at a list of allergenic foods to be managed attention needs to be paid not only to those allergens considered significant by legislation but also those that the consumer segment at which the food is targeted might be considered vulnerable to. This principle forms not only part of good food-safety management but is, in a number of jurisdictions, also underpinned by law. For example, within the European Union, Article 14 of Regulation 178/2002 (the basic food law) requires that food to be sold shall be safe (i.e. not injurious to health, nor unfit for human consumption). The article goes on to require that decisions concerning the safety of food take into account (amongst other things) the processes used to produce the food, information provided to the consumer and ‘the particular health sensitivities of a specific category of consumers where that food is intended for that category of consumers’ (Article 14.4c). A reasonable interpretation of this part of the legislation would be that unless a food was specifically labelled as being unsuitable for a person allergic to a food listed in Annex IIIa, it should be considered suitable unless appropriate precautionary labelling (e.g. ‘may contain’) was applied.

6.3 MANAGING THE HAZARD 6.3.1

Management principles

Having identified the hazard and the likely causes, the next step is to reconcile the food production process with the information that the sensitive consumer will be provided with at the point of sale. In general terms, the consumer relies on three principal aspects of the label: the product description, the ingredients declaration, and any allergen advice (this may highlight the presence of a particular allergen and/or contain precautionary (e.g. ‘may contain’) labelling discussing the circumstances under which the product was made. The first point to be made is that given their nature, food allergens can rarely, if ever, be processed out of the product. Application of modern GMP philosophy, as proposed by Codex Alimentarius (2003) would therefore indicate that successful management of the food-allergen hazard is through appropriate validated prerequisite programmes which take into account the appropriate food allergens and are verified on an appropriate basis. Another challenge to the food safety manager of any particular manufacturing facility is that while he/she can exercise some degree of management control on that facility that level of control cannot be exercised either on the suppliers of raw materials or on the distribution of the finished product. Furthermore, given the normal dynamics of business – activities from other functions within the organisation have the potential of aggravating the risk of a food-allergen-related hazard occurring. Such functions would include those responsible for raw materials procurement, new product development, sales and marketing.


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Potential sources of risk aggravation Procurement, new product development, external contractors, sales and marketing

Dispatch

Packaging

Production

Receipt and store

Raw materials

Rework

Supplier quality assurance, sanitation, maintenance, production control Supporting prerequisite programmes Fig. 6.1 Schematic showing production flow through an idealised manufacturing facility (shaded area) and influence of associated management functions.

A simple schema showing the dynamics of food production and the associated management systems relating for food production is shown in Figure 6.1. This shows not only the idealised production flow within a manufacturing facility, but also the various other major activities with potential to influence the risk of the hazard occurring. Alldrick (2006) coined the acronym ‘PIPE’ (people ingredients process enforcement) to describe the underpinning approach to the successful management of the hazard presented by food allergens. In essence, PIPE requires that:

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People within a food business should understand how their own activities can impact on the risk of food-allergen-linked incidents occurring and how they can minimise that risk. This responsibility extends from the chief executive officer to the temporary menial worker and everyone else within the food business. Ingredients (raw materials) should be sourced from suppliers who can demonstrate competence in providing materials of defined food-allergen risk. Once delivered on site, systems have to be in place that ensure the integrity of the packing of high-risk materials and that these are handled and stored appropriately. This also applies to rework. Processes and supporting systems used must ensure that the risk of inadvertent foodallergen consumption is minimised. This is achieved through a number of routes including segregation of production lines, scheduling of production where segregation is infeasible and application of appropriate sanitation regimes. Enforcement mechanisms are in place. These should be designed to not only ensure compliance but also verify on a continuing basis that the food-allergen management systems in place remain fit for purpose.

To one degree or another, these principles apply throughout the process flow. The challenge faced by the food-safety practitioner is to ensure that the information presented to the

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consumer on the wrapper matches the food within the wrapper. How this can be achieved is discussed in the following sections using the schematic in Figure 6.1 as a template.

6.3.2 Raw materials In some respects, the supply and sourcing of raw materials represents that part of the process over which the food-safety practitioner has least control. This is certainly the case until raw materials have been delivered to the manufacturing facility. In order to have confidence in any raw material’s integrity, there must be appropriate prerequisite programmes in place. These revolve around the concept of supplier quality assurance (SQA). In essence, SQA requires that suppliers are evaluated on a regular basis as to their competence to supply raw materials that consistently comply with specifications. The initial steps with regard to SQA often rely on a self-assessment questionnaire, depending on the overall risk presented by the raw material. This is usually followed up either by an audit of the raw material production facility by the purchaser (second party audit) or by a requirement that the facility concerned is accredited to a food-manufacturing standard (e.g. BRC Global Standard for Food Manufacture – referred to above), the so-called third party audit option. In terms of the self-assessment questionnaire, it is now usual for it to include a section concerning whether or not the raw material supplied contains a particular allergen. Two major problems with such a questionnaire lie in how the question is posed and the format it is delivered in. Frequently, the question is (apparently) simply put as: ‘Is the material free from?’ followed by a list of allergenic materials against which are placed two check boxes (either yes or no). Such an approach suffers from problems of linguistics and psychology. Dealing with the linguistics question first. In terms of the consumer to state that a product is ‘free from’, something would imply that the supplier had taken all reasonable steps to both ensure and confirm the absence of the something. However, in terms of allergen control and when used in terms of specification, a more commonly held interpretation is an application of the ‘free from’ definition used in the British Retail Consortium ‘guidelines for the handling of nuts’ British Retail Consortium (2004), viz. Free from nuts means no nuts . . . must be used in a product as any of the following: (i) An ingredient; (ii) A compound ingredient; (iii) A ‘processing aid’. It should be noted that strict application of the definition means that a raw material cross-contaminated in some way by an allergen could still be declared as being ‘free from’. Furthermore, use of this definition does not require a very high level of verification (e.g. positive release after analysis). The situation is further complicated if the English civil law ‘man on the Clapham omnibus’ principle (Greer, 1933) is applied. Thus, while a precedent has been set at a technical level (specifications), it would be unreasonable for such a definition to be inferred from a ‘free from’ endorsement placed on packaging of any raw material or food. In these cases, the inference would be that active steps had been taken to ensure the absence of the allergen in any raw material or food whose wrapper/label bore such an endorsement. A second problem relates to the psychology of completing such questionnaires. Simple reliance on tick boxes


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usually means that once a person has begun entering down one column they will continue to do so even if the answer is incorrect, with the probability of error increasing in proportion to the length of the questionnaire. There are, however, routes to circumvent these challenges. The first is to refine the nature of the questions asked. Thus in addition to asking whether a product is ‘free from’ a particular allergen, questions along the lines of:

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Is this ingredient suitable for use in foods intended for persons with an allergy to a particular food? Is there a risk of this ingredient being contaminated with a particular allergen as a consequence of other activities undertaken by the supplier?

In order to overcome some of the psychological problems associated with simply checking boxes, questionnaires can be designed to require the respondent to answer either ‘yes’ or ‘no’ and to justify those answers. In any event, best practice in food-safety management requires that information obtained from suppliers be verified on a periodic basis. Verification can take a number of forms. In the case of food allergens, the two principal ones are chemical analysis and audit. It should be emphasised that any verification process reflects a sampling process and gives only a snapshot of what is probably happening at a defined point in time. The frequency of verification will depend on the food concerned, the extent of any precautionary labelling and the target consumer. Essentially, the frequency of verification progressively increases, as products are sold which do not have recourse to precautionary labelling and further increases for those products targeted at persons with particular food allergies. The need for ongoing verification at this stage of the food manufacturing cannot be overemphasised. Within any food business, it can be possible for other elements within the business to act unilaterally and without reference to those responsible for food-safety management. One consequence could be for other elements within the business to identify and source raw materials without first determining the competence of the supplier to meet food-allergen requirements. This is not as unlikely as it might sound, since even in the most heavily managed businesses there are often contingency arrangements to purchase materials from ‘non-approved’ suppliers albeit on ‘concession.’ Thus, depending on the nature of the product and the information given to the consumer, management systems have to be in place to reduce the probability of such events happening.

6.3.3

Goods receipt and storage

Once raw materials have been received, they must be checked to ensure that they (at least visually) meet specification and stored appropriately prior to dispense into the production facility. Numerous texts have been written concerning what steps should be taken to minimise cross-contamination of different potentially allergenic ingredients (e.g. Food Standards Agency (2006). It is not the purpose of this chapter to rehearse them in detail; however, the basic principles will be discussed here. These relate to how such materials should be stored and what steps need to be taken in the event of a spillage. Most of the precautions necessary therefore relate to the physical characteristics of the material rather than their biological properties.

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In all cases, the emphasis is on segregation to both minimise and contain the effects of any spill. Storage in segregated areas (when possible) minimises the risk of crosscontamination in the event of a spill. Storage of high-risk material at low level and – particularly in the case of liquid materials storage – in bounded areas will assist in containing the spread of such material, if a spill occurs. Any facility must also have in place systems to deal with spills which occur and which minimise the risk of allergen crosscontamination. The three elements needed in such a system are documented procedures, suitable equipment and appropriately trained personnel. The lower the complexity of such systems – the better; a case in point relates to particulate allergenic materials. Food businesses operating to modern GMP standards (e.g. BRC Global Food Standard) already have systems in place to deal with glass and hard plastic breakages. Such systems include the provision for:

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Speedy notification of management and implementation of containment and control measures (see below). Areas where spills have been detected to be quarantined pending satisfactory clean-up procedures. Dedicated cleaning equipment, and protective clothing (all of which are used only once and then safely discarded) for use by trained staff. Appropriate decontamination procedures. Audit facilities to verify the efficacy of cleaning to determine whether or not the quarantine should be lifted.

Depending on the nature of the food business, such systems can be developed to include the possibility of allergen spills. Another area within the raw materials handling activities of a business and key to successful food-allergen management concerns rework. Within many food businesses, rework is a fact of life either because of its technological contribution to the recipe or the cost of raw materials. In food businesses which manufacture a range of products, it is essential that those businesses ensure that rework containing a particular allergenic material is not included in a food where that allergen is supposed to be absent. In order to achieve this, it is important that rework is considered to be an ingredient in its own right and managed in the same way as any other ingredient. In other words, stock control systems should be suitably rigorous to differentiate between different types of rework and ensure that the rework is correctly used (usually through the application of a rework matrix). In certain industries, allergen cross-contamination due to rework may probably exhibit an ‘iceberg’ effect (i.e. a large number of cases are currently going undetected). A case in point relates to the use of chocolate as an ingredient. A recent paper by Pele et al. (2007) performed a survey of chocolate products sold in a number of member states within the European Union together with (then) candidate countries. They found that over 50% of chocolate products with no ingredients declaration or precautionary labelling relating to tree nuts contained detectable amounts of hazelnut protein as measured by ELISA. In the case of peanuts, the figure was 25%. These figures may, in part, reflect poor rework management systems but also cross-contamination due to either poor in-line sanitation or other activities within the factory.

Risk management – operational implications Raw material 1%

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‘Allergen free’ claim 5%

Manufacture 46%

Label details 48% Fig. 6.2 Broad analysis of 78 UK Food Standards Agency food-allergen-related alerts notified in the period March 2007 to March 2008 inclusive.

6.3.4 Production An analysis of allergen-food-related alerts issued by the UK Food Standards Agency for the period March 2007 to March 2008 inclusive (Food Standards Agency, www.food.gov.uk/safereating/allergyintol/alerts/) indicates that a little under half of them reflected failures within the manufacturing environment (see Figure 6.2). Out of 78 alerts, 36 related to events taking place within the food-manufacturing environment. Of these, 14 related to cross-contamination events and the rest to human error. Further analysis of ‘human-error’ related alerts indicated that 16 represented products being placed into incorrect packaging. These statistics highlight the need to ensure that prerequisite programmes are in place, operatives are suitably trained and that appropriate mechanisms are in place to enforce and ensure compliance. In terms of prerequisite programmes, the obvious point to consider is the risk of crosscontamination. The risk of cross-contamination can be reduced by effective segregation of production as identified in a number of codes of practice and standards (e.g. Food Standards Agency, 2006; British Retail Consortium, 2008). As already discussed above, segregation begins at the ingredients dispense stage where the handing of allergenic ingredients should be kept separate from other ingredients and moves through to the use of dedicated production facilities. Complete segregation of production through the use of dedicated production facilities is frequently not possible for valid commercial reasons. In such cases, for raw materials, consideration should be given to the use of dedicated utensils, the use of appropriate personal protective equipment and the appropriate management systems in place to not only train all relevant personnel in their use but also the enforcement of their application. In terms of the production line itself, the use of dedicated lines is desirable; however, not always practical. Where dedicated lines are used, care must be taken in ensuring that activities on one line do not compromise those on another (non-allergenic) line. Of particular concern is the transfer of allergenic materials either through the air by means of fine particulates or through aerosols or as a consequence of plant design; for example, where one conveyor system carries an allergen-containing product over another which carries product free from that allergen. In this case, care must be taken that residues accumulating on belts and bearings of one conveyor are not ‘snowing’ on the other. Where dedicated production lines are infeasible, care must be taken to minimise allergen transfer to non-allergen-containing products. This can be achieved by scheduling of production and appropriate sanitation programmes between production runs. Given that the hazard

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to be managed is ‘the inadvertent consumption of a food allergen by a sensitive individual’ (see above), producing allergen and non-allergen-containing foods on the same line arguably provides the food-safety practitioner with the greatest challenge. It is the efficacy of the prerequisite programmes (in particular sanitation), which will determine the need or otherwise for precautionary labelling (‘may contain’ allergen X). It must also be remembered that the commercial desirability of precautionary labelling for any particular brand or product will be determined to a large degree by other elements within the food business (in particular marketing and sales). The content of a food label is not something usually within the control of those immediately responsible for local food-safety management. Care must be taken therefore, not only in scheduling manufacture of different products along a particular line but also in adopting the appropriate sanitation practices which can effectively decontaminate the line to minimise the risk of cross-contamination. As discussed earlier, the primary source of manufacturing-related alerts reflected human error. The single largest cause was using incorrect packaging (16 alerts out of a total of 76), the remainder involved factors such as incorrect ingredient addition and in one case the finding of peanuts in a manufacturing zone designated as ‘nut (and peanut)-free)’. All the points highlight the need for prerequisite programmes to be extended to account the significance of food allergy and also for constant vigilance. Higher levels of vigilance are required for products which carry a claim that they are ‘free from’ a particular allergen, of the 78 alerts reported 4 (5.1%), were attributable to some form of contamination with other ingredients containing a particular allergen (either milk or gluten); the presence of which was found only on analysis after the product had been released for sale. Products containing ‘allergen-free’ claims merit particular care in the food safety management systems employed. By placing such a claim on the product, the manufacturer is actively selecting for consumers sensitive to that particular allergen and therefore has a higher duty of care. This not only means having appropriate prerequisite programmes in place but also far more rigorous verification systems to ensure that they are functioning effectively. These would probably involve some sort of positive-release system on the basis of laboratory analysis of an appropriate sample demonstrating levels of the allergen concerned being below a particular limit (usually set by the sensitivity of the assay).

6.3.5 Packaging As already discussed, packaging and the information carried on it play a significant role in managing the risk of inadvertent allergen consumption by a sensitive individual. In dealing with packaging issues, it has already been shown that one route by which transmission of the correct information can be corrupted is through the use of inappropriate practices within the process environment. At their most extreme level, these can result in product declared as being free of an actual allergen, actually containing it (4 out of 78 alerts). A more frequent process error associated with packaging was use of incorrect packaging (16 alerts). However, a more fundamental error relates to the information provided on the label either in the form of an ingredients’ declaration or allergen advice panel. Examination of Figure 6.2 reveals that 37 (49%) of all food-allergen-related alerts issued by the UK Food Standard Agency were associated with label design problems. Of these, 29 were related to ingredients declarations and 8 to allergen information panels. The three main routes by which this occurred were: a failure to make a correct ingredients’ declaration (in a number of cases this involved more than one significant food-allergen);


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defective allergen advice panels; and using the wrong packaging for the product concerned. The first two cases might be described as the ‘correct product – faulty label’ syndrome, while the third might be described as the ‘wrong product – correct label’. The ‘wrong product – correct label’ syndrome has been discussed in the Production section above. The ‘correct product – faulty label’ syndrome alone was the largest reason for the recalls (approximately 50%). Although the supporting information published was limited, it is possible to categorise the causes of failures in label design under one of three broad categories:

r r r

Human error: In some cases, the recipe had simply not been completely copied over to the wrapper in accordance with legislation. Compound ingredients: This might reflect human error but also ‘hidden allergen’ syndrome. In this case, it is subsequently discovered that a compound ingredient contains a food allergen hitherto not declared. Given some of the products concerned, this might also be a reflection of rework practices (discussed further below). Incorrect description: In a number of cases, recalls took place because although an appropriate ingredient description was made the terminology used could not be readily understood by the consumer. As in the case of errors relating to compound ingredients, a large number of these referred to milk-derived ingredients (in particular, the use of the words ‘whey’ and ‘casein’). Other alerts related to derivatives of other Annex IIIa listed allergens that were not subject to an exemption under the provisions of Commission Directive 2007/68/EC. One such example involved the declaration of lecithin prepared from soya simply as ‘lecithin’, rather than including its origin.

6.3.6

Prerequisite programmes and the roles of other functions within the food business

No food-processing activity operates in isolation. Figure 6.1 describes some of the other functions that impact on the activity; reference has already been to elements of prerequisite programmes such as supplier quality assurance and sanitation. Within many foodmanufacturing processes, there is rarely going to be a particular process step within it, ‘at which control can be applied and is essential to prevent or eliminate a food safety hazard or reduce it to an acceptable level’, in other words, a ‘critical control point’ (as defined by Codex Alimentarius, 2003). Prerequisite programmes are thus the first line of defence in protecting the food allergic individual. Reference has already been made to supplier quality assurance and sanitation. However, going back to the principles of PIPE, arguably the key aspect of any prerequisite programme that includes food allergy within its mandate is training. It is axiomatic, but nevertheless worth re-emphasising that the efficiency of any food-safety management system is a reflection of the quality of training given to all elements of the business. It is important to note that training must be inclusive of all functions, including those who either have intermittent access to the production or whose activities are peripheral to the production process. In terms of functions ancillary to food manufacture itself, two key functions which can, if improperly managed, compromise the allergen status of a production line are sanitation and maintenance. A failure to have validated and reliable cleaning systems can rapidly lead to the risk of cross-contamination. A similar point applies to maintenance activities; appropriate clean down has to be undertaken, for both the area under maintenance and the equipment used. In the case of production areas dedicated to make products for which an allergen

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absence (‘free from’) claim is made, similar practices to those adopted for microbiological high care units should be implemented including the use of dedicated tools and protective clothing. Other functions that can impact and potentially compromise allergen management practices are invariably physically dislocated from the production line and can, in extreme circumstances, be located in an entirely separate country. Marketing, new product development (NPD) and purchasing functions activities fall within this category. Examples of events (potentially) compromising the food-allergen safety management of food-manufacturing facilities dealt with by the author as over a number of years include the following:

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Proposals to manufacture a product containing an allergen not previously used in the production plant and without consideration of the implications for cross-contamination and relevant precautionary labelling for the other products manufactured there. On a similar theme, proposals by new product development (NPD) functions to run production trials for a new product containing a food allergen not previously used and without consideration for the consequences of potential cross-contamination for existing products. Changes in the suppliers of raw materials without sufficient application of SQA procedures, leading to the sourcing of allergen compromised materials.

Thus, irrespective of their function within the food businesses, everyone needs to have appropriate training in food-allergen awareness – a point recently reinforced in the Anaphylaxis Campaign’s food manufacturing standard (Anaphylaxis Campaign, 2008).

6.3.7

Ensuring compliance (enforcement)

The acronym PIPE discussed earlier includes the word, ‘enforcement’. In this context, the term refers to not only making sure that management systems put in place to control the hazards presented by food allergens are functioning but also that their effectiveness is assessed and improvements made as required. Enforcement therefore involves elements of supervision, verification and management review. Some aspects of verification can be regarded as effectively forms of supervision, for example, personnel being asked to demonstrate their knowledge and practice of the allergen management practices put in place either by line managers or during audit. Verification itself can take the form of determining compliance on a historical basis through examination of appropriate records including those concerned with operation and sanitation of the facilities. It can also measure the current efficacy of any system operating through periodic analysis of both material (ingredients and finished product) and the environment (e.g. analysis of swabs and/or rinse waters). In commissioning such laboratory analyses, it is important that there is a full understanding of the limitations of such analyses. These include the nature of the analyte (protein versus DNA), in the case of ELISA-based assays the antibody used and, for both types of analyses, limits of detection/quantification (discussed in further detail elsewhere in this book). Information gathered from these exercises should be collated and assessed with other quality-management information and the continuing developments taking place in our understanding of food allergy to determine the ongoing efficacy of the food-allergen management system.


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6.4 CONCLUSION At first sight, the broad attributes of food allergy (wide range of allergenic foods, low eliciting dose, diverse range of symptoms and the (relatively) small size of the affected populations) seemingly present food processors with an insurmountable challenge in terms of food-safety management. A more considered analysis shows that this is not the case. Application of the basic principles of food-safety management based on an understanding of food allergy and the processes within the food business can lead to systems which can support the manufacture of foods both with and without particular allergens under conditions where the risk to the food-allergic consumer is minimal. Achieving this state of affairs requires high levels of commitment from each and every person within the food business from the chief executive down. This can be achieved only by appropriate staff education and management.

REFERENCES Alldrick A.J. (2006) Managing allergy issues. The World of Food Ingredients (October/November), 64–65. Anaphylaxis Campaign (2008) The Anaphylaxis Campaign Standard to Increase Trust in Information about Allergens in Food. The Anaphylaxis Campaign, Farnborough. British Retail Consortium (2004) BRC guidelines for the handling of nuts. Available at www.brc.org.uk/showDoc04.asp?id=2402&moid=2553, accessed 21 April 2009. British Retail Consortium (2008) Global Standard for Food Safety. The Stationery Office, London. Codex Alimentarius Commission (2003) Recommended International Code of Practice General Principles of Food Hygiene, CAC/RCP 1-1969, Rev. 4–2003, pp. 31. Available at www.codexalimentarius.net/ download/standards/23/cxp 001e.pdf, accessed 21 April 2009. Commission Directive 2007/68/EC of 27 November 2007 amending Annex IIIa to Directive 2000/13/EC of the European Parliament and of the Council as regards certain food ingredients. Official Journal of the European Union, L310, 1–4. Directive 2000/13/EC of the European Parliament and of the Council of 20 March 2000 on the approximation of the laws of the member states relating to the labelling, presentation and advertising of foodstuffs. Official Journal of the European Communities, L109, 29–42. European Food Safety Authority (2004) Opinion of the Scientific panel on dietetic products, nutrition and allergies on a request from the commission relating to the evaluation of allergenic foods for labelling purposes. EFSA Journal, 32, 1–197. Food Standards Agency (2006) Guidance on Allergen Management and Consumer Information. Available at www.food.gov.uk/multimedia/pdfs/maycontainguide.pdf, accessed 21 April 2009. Greer L.J. (1933) in Hall v. Brooklands Auto Racing Club (1933) 1 KB 205. Hefle S.L., Nordlee J.A. and Taylor S. (1996) Allergenic foods. Critical Reviews in Food Science and Nutrition, 36(S), S69–S89. Pele M., Brohée M., Anklam E. and van Hengel A.J. (2007) Peanut and hazelnut traces in cookies and chocolates: relationship between analytical results and declaration of food allergens on product labels Food Additives and Contaminants, 24, 1334–1344.

7

Choices for cleaning and cross-contact

Steve Bagshaw

7.1

ALLERGEN MANAGEMENT AND CLEANING

With the ever increasing awareness and importance of producing foods that clearly label if a product contains known allergens, either as a deliberate ingredient or as a possible contaminant, allergen risk assessments and management must be introduced to the food process. Allergens should be managed to avoid their unintentional presence in products. This management involves evaluation of the likelihood of allergen cross-contamination associated with every step of the food production process, from sourcing raw materials through to marketing of a finished product. Existing good manufacturing practice (GMP) controls will assist with allergen management, for example avoiding cross-contamination by segregation, cleaning, using separate utensils, etc. The introduction of allergen management into a food business can be seen as an extension of existing food safety management rather than a completely new system. Cleaning for allergen control is required only where that allergen is not an intentional ingredient of the food being produced. Allergenic material is generally a protein. Very small amounts of some allergens, such as peanut, can cause adverse reactions; the severity will vary but for certain individuals this may be a fatal anaphylactic shock. Existing legislation relating to allergens exists The Food Labelling (No 2) (Amendment) Regulations 2005; however, this covers only the labelling aspects of the issue. The Anaphylaxis Campaign standard has set standards relating to the level of cleanliness required. All equipment, surfaces, utensils identified by risk assessment as subject to contamination by allergens shall be cleaned to a demonstrably visually and physically clean standard, or equivalent validated standard to remove any potential cross-contamination residues. Where design of equipment prevents achievement of the above standard of cleanliness the use of “may contain’ labelling shall be considered. The company must be able to demonstrate why cleaning to the above standard is not possible and this can only happen where the decision is the result of the allergen management review process. (Anaphylaxis Campaign Standard, 2007) Cleaning practices that are satisfactory for hygiene purposes may not be sufficient for the removal of allergens from surfaces and equipment. Any cleaning process developed for allergen removal must be validated to ensure allergens are removed from the target surface and that no risk of cross-contamination to other food contact surfaces occurs. It


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must be remembered that, unlike microbial contamination, allergenic material is generally unaffected by heat (Taylor and Lehrer, 1996) or chemicals. Cleaning is used to remove contamination but it can in itself be a source of contamination. Potential sources of cross-contamination from cleaning include overspray from wash-down guns, aerosols, cleaning tools, personnel and recovered cleaning solutions. The time of cleaning, methodology of clean and cross-contamination controls must be carefully considered to avoid cleaning causing allergen cross-contamination. The cleaning regime can be tested and compared with other regimes by checking for levels of contamination after the clean. The assessment could look at residual soil level which can be tested by looking at ATP or protein, though specific allergen tests are more widely recognised as offering a better means for control after the cleaning and rinsing stages.

7.2

THE CLEANING PROCESS

With all food production processes, both equipment and surfaces become contaminated with food residues, foreign bodies and microbial contamination. The removal of these contaminants, soil, is the process of cleaning. Cleaning should always be considered an essential and integral part of the production process for many reasons. Namely:

r r r r r r r r

Legislation – The Food Safety Act 1990, UK and EU regulations require that effective hygiene standards are implemented for anyone who handles, manufactures or serves food For microbial control – reducing bacterial numbers to an acceptable level for the product being produced Removing physical or chemical contamination Foreign body control Performance of the plant (for example removal of build-up on heat exchangers) Safety of the plant and operatives Discourage pests A pleasant and clean work environment to create the right impression for all

Cleaning needs to be carried out in such a manner that is both effective and efficient. This means without causing damage to personnel, equipment or surfaces; and without causing cross or re-contamination. The timing and frequency of clean needs to be set by risk assessment of the product and process. During the production process, product contact surfaces will become contaminated with soil and microorganisms. This contamination may lead to deterioration in product quality and eventually an unacceptable product. By assessing product quality against production running time, a frequency of clean can be determined that ensures that product quality always remains acceptable. Potential cross-contamination risks from the cleaning process must also be identified and risk assessed. Production planning should ensure that free from allergen products are produced on a line at the start of the day following a hygiene clean. When equipment is used to process both foods containing allergens and those free from allergens, then by maximising production runs the number of changes where thorough cleaning is required can be reduced.

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Fig. 7.1

Effect of periodic cleaning.

7.2.1 Inter-product cleans An inter-product clean is used when a production line is changing product. This removes physical contamination such that the subsequent product does not contain components of the previous production run. For example a vegetarian-labelled sandwich should not contain chicken from the previous production. Inter-product cleans, typically seen in food manufacturing, control physical and microbial contamination to an acceptable level where allergen cross-contamination is not an issue. With most fixed open plant food production equipment, an inter-product clean does not involve a full strip down and therefore there exists a potential for product residue to be left on the equipment. With equipment that can be taken offline or where the equipment item is naturally remote from a production area thorough cleaning can be achieved. For example on semi automated conveyor lines depositors can be taken away after a given period and replaced by a clean unit. The dirty depositor is then cleaned in a dedicated washroom where a full strip down and hygiene clean can be carried out.

7.2.2

Break cleans

Break cleans are carried out at natural breaks in production and are used for tidying/clean as you go.

7.2.3

Timed clean

Cleaning after a defined time period is appropriate for certain equipment. With continuous production, a potential for increasing soil and microbial loading on food contact surfaces exists; this can be controlled by suitable periodic cleaning (Figure 7.1).

7.2.4

Hygiene clean

A hygiene clean, or an end of production clean, refers to a thorough strip down of equipment to allow full access to all surfaces and routine entrapment areas. This is usually carried out


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when no other production is taking place nearby and when all work in progress or finished product has been cleared away from the vicinity.

7.2.5 Deep clean Certain areas or parts of equipment such as electrical control cabinets may not be accessed during the hygiene clean. These areas of the equipment are not deemed to pose a day-to-day contamination risk and are cleaned for instance every 3 months; these are often referred to as deep cleans.

7.2.6

Good cleaning practices

Cleaning a food production environment requires considerable coordination by the cleaning crew to ensure that it is effectively and efficiently cleaned without introducing crosscontamination risks. Some of the considerations are

7.2.6.1 Preparation of the area and equipment

r r r

Remove all product from area before starting Cover electrical components Ensure all cleaning equipment is clean and disinfected – brushes, cloths, pads, etc.

7.2.6.2 Cleaning

r r r r r r r r r r

Adhere to the agreed method; paying attention to detail Follow correct procedure and sequence of clean Carry out checks on cleaning process including level of strip of equipment, chemical strengths, temperatures and contact times with detergents and disinfectants Run hosepipes underneath machinery and equipment Don’t place dirty items onto clean or vice versa Work in a top to bottom manner Clean in a safe manner – don’t take risks, wear personal protection equipment Don’t clean machinery parts or equipment on the floor Keep clean and dirty items separate Wash hands regularly, particularly after handling dirty items

7.2.6.3 Reassembly

r r

Inspect all surfaces before reassembly and re-clean, if necessary Disinfect surfaces before and during reassembly using only hygiene trained personnel

7.3

PRINCIPLES OF CLEANING

Cleaning involves detaching soil from a surface and the removal of it to waste. In wet cleaning, this means the detergent has to detach the soil and then suspend it in the cleaning solution

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ic

al

en

er gy

Fig. 7.2

Thermal energy

Ph ys

al

y rg e n

e

ic

em

Ch

Cleaning energies.

until it reaches a water treatment plant. With dry cleaning, it general involves removing to a waste bin via a brush and dustpan or via a vacuum cleaner.

7.3.1

Cleaning energies

With wet cleaning, thermal, chemical and physical energy are used in combination to remove the soil from a surface (Figure 7.2). The balance of energies depends on the physical process and the detergent type; some involve low chemical energy (such as neutral detergents) combined with high physical energy (scrubbing) and others high chemical energy (acidic descaler) with little physical energy. The greater the attachment of the soil, to a surface, the greater the combined energy required for cleaning. Contact time with a detergent is necessary to maximise its performance; generally, the longer the contact time with a detergent, the less physical energy will be needed to remove the soil from the surface. Temperature is important since it increases chemical reaction speeds between detergent and soil and is also essential for the effective emulsification of fats where present.

7.3.2

Choice of detergent

The role of the detergent is to assist in the removal of soil from a surface. The choice of detergent has to be made when a number of factors have been considered. These include soil type, method of application, materials of construction of the surfaces being cleaned, water hardness, health and safety and many others. Most detergents combine emulsification properties with some type of chemical reaction. There is no evidence to suggest that any chemical reaction occurring between the detergent (or disinfectant) and allergenic protein has any effect on its allergenicity. Therefore, the effective removal of soil by the cleaning process is essential to achieve the removal of allergenic material.


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Although there are thousands of detergent products available in the professional and domestic market, they break down, broadly speaking, into the following:

r r r

r r

General purpose neutral or mildly alkaline detergents are used for hand cleaning by spraying or for soak cleaning (sinks). They rely largely on emulsification and suspension of soiling and are particularly effective on fats and oils. Sanitisers are neutral, mildly acidic or mildly alkaline detergent disinfectants that combine the cleaning properties of a neutral detergent with a degree of disinfection. Highly alkaline detergents are used where heavier soiling is encountered. They rely partly on chemical reaction to hydrolyse proteins or saponify fats. They can be applied in a number of formats including gels or foams for long contact times with open surfaces or as low foam products for recirculation cleaning such as dishwashing, tray washing and cleaning-in-place (CIP). They are effective on highly carbonised or polymerised soils. Highly alkaline chlorinated detergents, either as foams or low foam products for recirculation, are used because of their excellent removal of the fats and also proteins. Acidic detergents can be used for mineral scale removal and protein removal.

7.4

OPEN PLANT CLEANING

Open plant cleaning can be carried out either as a wet or dry process depending on the nature of the soiling present, the product, the process and type of production equipment. Dry cleaning is used mainly for processes where dry or particulate products are handled. Wet cleaning is employed wherever possible due to the higher efficacy of the wet cleaning process (better soil removal from surfaces).

7.5

DRY CLEANING

Dry cleaning (Figure 7.3) refers correctly to cleaning where no liquid detergents or disinfectants are used; however, it is also commonly used to refer to cleaning where disposable impregnated wet wipes or damp disposable cloths are used. In the food industry, it is usually found in processes where the presence of water could affect the quality and consistency of the product such as bread, pastry, biscuits, cereals and so on or create conditions that enhance microbial growth. Dry cleaning is a purely mechanical process that relies on the soil being physically removed (brush, vacuum). The nature of brushes and vacuums mean that 100% soil removal of soils will not be achieved (Holah et al., 2004). Consideration must be given to following brushing or vacuuming with wiping with detergent/disinfectant dampened cloths to increase overall soil removal.

7.5.1 Cross-contamination by dry cleaning Tools used for cleaning can become a major route of cross-contamination. Cloths and scourers should be disposed of after use. Brushes, scrapers and other tools must be cleaned, disinfected

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Fig. 7.3

Dry cleaning.

and stored hygienically for later use. Tools should be clearly defined for area of use, for example floor use only or food contact use only. In addition, specific tools need to be kept for cleaning of surfaces that have allergenic material on them. A colour code system can be used (Figure 7.4) for this. It is vitally important that the system is clearly defined and managed.

Fig. 7.4

Colour coding. (Reproduced with permission from Vikan Professional Cleaning Solutions.)


Fig. 7.5

121

Atomisation.

Vacuum cleaners tools such as nozzles and hoses will become contaminated and will need thorough cleaning. In addition, thought should be given to specific hose and nozzle sets for times when allergenic material is being handled. The vacuum cleaner, if mobile, rather than a fixed central installation will exhaust air locally. Regular cleaning and replacement of filters to ensure no particulate materials are blown out of the unit is critical. Air lines are sometimes used to dislodge soil from difficult to access areas; essentially moving it to an area that can be accessed by a dustpan and brush or vacuum. Unfortunately, air lines will impart energy to fine particulate matter making it airborne and allowing it to spread over large areas (Figure 7.5).

7.6 MANUAL CLEANING Manual cleaning refers to the cleaning process where the detergent is applied via a cleaning tool such as cleaning cloth, scourer or brush (Figure 7.6). It also refers to cleaning of parts that are put to soak in detergent solution before physical action. Manual cleaning of machinery, equipment and surfaces is the most common method employed throughout the food-manufacturing industry. Manual cleaning provides a flexible method of cleaning for a variety of equipment and surfaces and has little risk of crosscontamination caused by aerosols or overspray; however, the control and cleaning of cleaning tools is vital to ensure no cross-contamination. With manual cleaning, there is a substantial contact between the operative and the chemical being used to clean; therefore, the type of detergent used must be carefully considered. It will usually involve a 1–2% v/v solution, at typically 40–45◦ C, of either a neutral detergent, a quaternary ammonium compound (QAC)-based detergent or a light/medium duty alkaline detergent. These light duty detergents will not perform as well as the higher alkalinity products on fat or protein soils.

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Fig. 7.6

Manual cleaning.

7.7 FOAM AND GEL CLEANING Foam cleaning refers to the cleaning process where the main detergent is applied as foam, and gel cleaning where the main detergent is applied as a gel (Figure 7.7). Gels can also be aerated during application; this is called a mousse.

Fig. 7.7

Foam cleaning.


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With increasing commercial and technical pressure placed on the food manufacturing industry, the time window and manpower required for cleaning have been squeezed and decreased. Foam cleaning has proven to be a very effective, efficient and popular method for cleaning of rooms and equipment. The improvement in foam technology, such as long cling foams, and the introduction of different types of foam detergents have made it a process that can be used, with benefit, in many situations. Foam is created by mixing water, detergent and air together and applying it via a hose with a special nozzle or lance onto the surfaces and equipment. The foam detergent will typically be applied at 3–5% v/v, depending on the soil to be removed and water hardness. The main advantages of foam and gel cleaning in comparison to manual cleaning are as follows:

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The detergent solution can be applied to large and difficult to reach areas in a short period of time An extended detergent contact time between the soil and the detergent A reduction in the time of clean Less manpower required Control of detergent use Safer application of hazardous detergents

A common misconception of foam and gel cleaning is that it negates the need for any type of physical action (such as scrubbing with a brush or scourer). Physical energy must be applied after suitable detergent contact time. The physical energy can be applied by either scrubbing or by energy from a water jet typically either high or medium pressure.

7.8 CROSS-CONTAMINATION 7.8.1

By wet cleaning

A wash-down system provides the hygiene operative with an efficient tool for rinsing away soil and detergent (Figure 7.8). The water jet provides a degree of physical energy to a surface that assists in the removal of the soil – the higher the pressure of the system, the higher the impact energies available. Medium pressure systems operate at typically 20 bar with a flow rate at the nozzle of 30 L/min. This gives very similar cleaning energies to a high pressure systems operating at 70 bar and with a flow rate at the nozzle of 15 L/min. Low pressure systems operate at typically 5 bar with a nozzle flow rate of 40–50 L/min. Both medium- and high-pressure systems provide sufficient cleaning energy to remove most soiling if the correct foam or gel detergent has been used. With low pressure rinsing, however, this is not the case and it is essential that surfaces are scrubbed prior to rinsing. All wash-down systems whether low, medium or high pressure will cause overspray which can lead to cross-contamination if no controls are put in place; however, high pressure systems also create aerosols which add another vector of cross-contamination. As discussed in the Section 7.5, tools are a major source of contamination. Cleaning tools and their management generally receive low priority; this was aptly demonstrated in a food industry wide survey by Campden BRI which showed that of all cleaning tools tested 35% were Listeria positive. The correct choice of tools, the management of cleaning of tools and the designation of specific tools for different purposes (usually identified by a colour coding system) is essential.

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Fig. 7.8

Wet cleaning.

7.8.2

By personnel

Cross-contamination by personnel can cause major issues with the end result of the clean. The vehicles of contamination include the following:

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Hands/gloves Protective wear – mainly overalls, aprons or wet suits Footwear

Transfer of personnel from low risk to high care and an allergen area to a non-allergen area should be avoided, if possible. If not, then hand washing and changing procedures should be adopted where all protective wear including overalls, hairnet, hat, gloves and footwear are changed. The use of specific overalls for allergen areas should be considered. The laundering of overalls used in allergen areas needs to be managed by the site and the laundry. Checks on laundered items should be carried out to establish the removal of allergens by laundering. Footwear should remain, where possible, captive to an allergen area. If this is not possible, consideration must be given to footwear washing to avoid cross-contamination on floors. Production personnel involved in cleaning (typically on an inter-product clean) must adopt very strict apron and glove changing and hand washing after cleaning and prior to production. Hand washing is important for both microbial control and allergen control. A proper hand-wash procedure including the use of a soft nail brush should be trained and monitored. Hand-washing compliance can be poor but increases when the hand-wash facilities are good, the water temperature is comfortable, the hand soap mild and most importantly personnel understand the reason for hand washing.


Fig. 7.9

7.9

125

Floor cleaning.

FLOOR CLEANING

Floor cleaning can be carried out using manual methods such as a mop/brush and bucket, by utilising the wash-down system or by a dedicated floor-cleaning machine (Figure 7.9). The most appropriate method will depend on the access to the floor area, time of cleaning and the size of the floor area. With manual and wash-down methods, the detergents used are generally the main detergent used for the equipment and wall cleaning, since the type of soil encountered will be the same. With floor cleaning machines, the detergent is usually a low foam alkaline detergent. All methods create overspray which can travel vertically onto food contact surfaces. Work by Campden BRI showed that the potential for cross-contamination of food contact surfaces from floors was real and measurable. The distance of vertical and horizontal travel by floor cleaning solutions varies depending on the method of clean (Holah et al., 1993). The greatest vertical and horizontal travel of cleaning solutions occurs when using a high pressure wash-down gun, followed by medium pressure wash-down gun, low pressure wash-down gun, floor cleaning machine with mopping and brushing creating the least travel.

7.10 TRAY AND RACK WASHING MACHINES Washing machines are used to automatically or semi-automatically clean trays, racks, utensils and in the case of dishwashers, crockery and cutlery (Figure 7.10). Because of the high volume of trays, baskets, tubs, containers, etc., required by many modern food businesses, it has become unrealistic and uneconomic to clean manually. A large bakery, for example, may require 2500 baskets an hour to keep a continuous production flow. Washing machines

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Fig. 7.10

Tray washing.

come in many shapes and sizes and are generally built for the cleaning of a specific size and type of item. Washing machines should only be used for the original purpose they were intended. The short contact time with detergent and the relatively low impact energies of the wash nozzles means that to clean effectively high chemical energies are required. In most situations, a high alkaline low foam detergent at 0.25–1% v/v is used at 55–75◦ C. The washing machines must be managed correctly with regular cleaning of the machine and filters, regular changing of wash solutions, inspection of wash and rinse nozzles and control/monitoring of detergent temperatures and strengths. Washing machines are either tunnel-type machines or single tank machines. With tunnel machines (Figure 7.11), items are placed on a conveyor which transports them through a number of stages of the washing process. Each stage occurs in a different section of the washer: pre-rinse, wash with detergent, rinse, disinfect chemically or by temperature and

Fig. 7.11

Tunnel traywash.


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then dry. With single tank machines, the item is placed in a cabinet and the wash process takes place in the cabinet by sequencing the cleaning stages (pre-rinse, wash, rinse, disinfect). The efficacy of a clean is dependent on correct original design of the machine for the items being cleaned and correct operation and maintenance.

7.10.1

Cross-contamination by washing machines

With all modern washing machines, certain cleaning solutions are reused, for instance the detergent solution. The detergent solution will become contaminated with soil from the washed items and therefore provide a transfer mechanism for allergens. The potential for this cross-contamination can be controlled by having specific dedicated washing machines for items that have allergen contamination, by washing such items separately (for instance, in a three sink system) or by validating the operation of the washing machine and then putting management controls in place to ensure its correct operation.

7.11

CLEANING-IN-PLACE

CIP is the cleaning of pipework or vessels (tanks) by passing cleaning fluids through the pipework or spraying inside the vessel (Figure 7.12). The flow rate and volume of cleaning fluids required can be very high and it is most common practice to recirculate and sometimes recover these fluids to make most use of them. The principles of cleaning are always the same, whether it is manual cleaning of a utensil in a sink or in a dishwasher or the CIP of a vessel. Energy in the form of chemical energy, thermal energy and physical energy are all required to remove the soil from the surface.

Fig. 7.12

Cleaning-in-place.

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It is important to note that for equipment to be effectively cleaned by CIP, it must be designed to do so. For instance, an automatic depositor head designed for CIP will incorporate a mode where all of the depositor head seals become exposed to cleaning solutions. With a normal depositor, the head will require full dismantling for manual cleaning and it is not possible to effectively clean this type of depositor by recirculation or CIP.

7.11.1

Chemical choice

A wide range of CIP detergents and disinfectants are available. One common feature to all is that the products are low foaming and in some circumstances act as defoamers. This is particularly important where caustic detergents are used to remove fatty deposits. The reaction between the caustic and fats produces soap which will naturally foam in recirculation situations. The choice of detergent and disinfectant are based, as in open plant cleaning, on a number of factors including soil type, materials of construction of the surfaces being cleaned, water hardness and many others. In many CIP situations, a caustic-based, low foam detergent is used at typically 0.25–1% w/v (NaOH) at 65–75◦ C. With CIP, the physical energy comes from the movement or impact of the fluid.

r r

With vessel cleaning, the physical energy comes from the impact or flow of the cleaning fluid over the internal vessel surface. In the case of pipework, the turbulence of the fluid flowing creates a physical scouring action on the internal wall of the pipe. Turbulent flow is achieved at flow velocities of greater than 1.5 m/s.

A CIP set delivers cleaning fluids (water, detergent and disinfectant) to vessels or pipework that need to be cleaned. The cleaning solutions are routed to the relevant vessel or pipework route by either a flow plate (manual connection panel) or via an automatic valve bank.

7.11.2

Vessel cleaning

Production vessels come in vast range of sizes. A large brewery or dairy vessel could hold 100,000 L (for instance a bright beer tank), while a small cooking vessel in a food factory may hold 500 L. Both can be cleaned by CIP as long as all the vessel internals can be exposed to the cleaning fluids. With any vessel, it is wise to seek advice from a spray-head manufacturer to ensure the correct spray-head(s) is used to give complete coverage (computer-aided design will be used to ensure theoretical coverage). When vessels have internal structures (e.g. scraped surface paddles in a cooker), it is vital that the spray-head design and position also ensures coverage of these internals as well as the vessel surface.

r r r

Spray devices should be regularly removed for inspection and cleaning. Internal pipework, vessels, welded joints, unions and valves should all be of a hygienic cleanable standard (Curiel et al., 1993). Ensure no pooling of liquids in the bottom of the vessel occurs; if feed rate is higher than scavenge rate, then consider burst rinsing.


Fig. 7.13

Total loss CIP set.

7.11.3

Pipework routes

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CIP feed pump and circuit design should ensure a minimum flow rate of 1.5 m/s; this ensures that the fluid flow in the pipework is turbulent.

r r r r

Pipework routes should be of consistent diameter. A change in diameter will lead to lower cleaning velocities in the larger diameter pipework and therefore potentially poor cleaning. CIP flow rates should not be too high otherwise pipe hammer can occur. Pipe hammer is caused by rapid changes in liquid velocity and can lead to seal and pipework damage. Internal pipework welded joints, unions and valves should all be of a hygienic cleanable standard. Dead-legs should be avoided.

7.11.4

Types of CIP set

7.11.4.1 Total loss CIP sets A total loss CIP set recirculates the cleaning fluids through the vessel or pipework to be cleaned. After the end of the detergent recirculation stage, the fluid is discharged to drain and not recovered to a storage tank (Figure 7.13). The buffer tank is generally small (200 L) and is used to maintain a feed to the CIP feed pump. A typical cleaning cycle will be (times will vary depending on cleaning circuit) as shown in Table 7.1.

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Table 7.1 circuit).

A typical cleaning cycle for a total loss CIP set (times will vary depending on cleaning

Cleaning stage

Description of stage

1. 2.

Pre-rinse Detergent

Feed clean water, to circuit, and return to drain. Feed for 5 min. Feed clean water, until circuit made, and return to buffer tank; while recirculating run caustic dosing pump. A plate heat exchanger is used to heat the solution to the required temperature. Allow to recirculate for 20 min.

3. 4.

Rinse Disinfect

Feed clean water, to circuit, and return to drain. Feed for 5 min. Feed clean water, to circuit, and return to buffer tank; while feeding water, run disinfectant dosing pump. Allow to recirculate for 3 min.

5.

Drain

Drain system and buffer tank

7.11.4.2 Recovery CIP sets A recovery CIP set recirculates the cleaning fluids through the vessel or pipework to be cleaned (Figure 7.14). During and after the detergent recirculation stage, the fluid is recovered to a storage tank and is then available for use on a subsequent clean. There are different degrees of recovery with some sets recovering water in a rinse recovery tank, detergent in the detergent tank and disinfectant in a disinfectant tank. The set illustrated (Figure 7.14) has two large recovery tanks; one is used to hold the detergent and the other recovered final

Fig. 7.14

Recovery CIP set.

Choices for cleaning and cross-contact Table 7.2

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A typical cleaning cycle of a recovery CIP set (times will vary depending on cleaning circuit).

Cleaning stage

Description of stage

1.

Pre-rinse

Feed water, to circuit, from rinse recovery tank and return to drain. Feed for 5 min.

2.

Detergent

Feed detergent, to circuit, from detergent tank and return to detergent tank. A plate heat exchanger is used to heat the solution to the required temperature. Allow to recirculate for 20 min.

3. 4.

Rinse Disinfect

Feed clean water, to circuit, and return to rinse recovery. Feed for 5 min. Feed clean water, to circuit, and return to rinse recovery tank; while feeding water, run disinfectant dosing pump. Disinfectant dosing for typically 3 min.

5.

Drain

Drain system returning all solutions to the rinse recovery tank

rinse water. A typical cleaning cycle will be (times will vary depending on cleaning circuit) as shown in Table 7.2

7.11.5 Cross-contamination by CIP As with an open plant surface, the best method of reducing cross-contamination by allergens in closed equipment such as vessels and pipework is to have separate process plant for allergenic and non-allergenic food products. If this is not feasible then the vessels or pipework must be capable of being cleaned free from allergens, the method validated and then verified on an on-going basis. An additional cross-contamination route exists with cleaning in place because of the commonality of the CIP set which is often used for cleaning many vessels and pipework routes. Any deposits in the CIP set, including filters, may be transferred between cleans. With recovery CIP sets, the recovered solutions are a potential for cross-contamination; but with total loss CIP sets, the potential for cross-contamination is reduced because no solutions are recovered or reused on subsequent cleans.

7.12

MANAGEMENT OF ALLERGEN CROSS-CONTAMINATION

See Table 7.3.

7.13 CLEANING MANAGEMENT All food manufacturers should have a company hygiene policy and included within this should be provisions for an effective approach to the hygiene management system. The policy should make the following provisions:

r r

A statement of commitment, at the highest level, that cleaning is essential for product integrity State the responsibilities of directors, management and operatives

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Table 7.3

Management of allergen cross-contamination.

Cross-contamination

Controls

Dry airborne particles

• • • •

Aerosols from wash-down guns Overspray from wash-down guns

• •

Cleaning tools

• • • •

Cleaning personnel

• •

Use of disposable gloves and aprons Tray and rack washers

CIP sets

r r r r r

• •

Limit the use of air lines Ensure vacuum cleaners are regularly maintained and filters changed Use local extraction from processes where allergens may be released Use positive pressure in rooms where non-allergen foods are being handled Use low or medium pressure wash-down systems; in which case aerosols are not created Maximise physical separation of equipment used for allergen and non-allergen production Use barrier screens/curtains to control overspray Consider sequence of cleaning Consider timing of cleaning Have specific tools for specific allergen containing foods. Use colour coding and training to assist with compliance Cleaning programme for the cleaning of tools Correct hand-washing procedures. Ensure compliance through training and education Effective cleaning/laundering of overalls Effective footwear washing and storage

• Wash allergen containing utensils separately from the washer where possible • If using washer, then ensure final rinse is clean and not recycled water and validate clean achieved • Carry out checks for allergen presence after the washer • Use dedicated vessels, pipework and CIP sets where possible • Use total loss CIP sets where possible • Manage cleaning of CIP sets including filter cleaning • With recovery CIP sets, manage periodic cleaning of recovery vessels • With all sets, validate CIP clean for no cross-contamination and put in place controls to ensure CIP clean follows validated procedure • Carry out routine end of clean checks for allergen presence

State the standards required by the manufacturer, customers, third party auditors and legislation Identify the resources that will be made available such as labour, equipment, chemicals, water and so on Systems for monitoring, controlling, improving the hygiene system, including documentation Training of management and operatives A system of review

7.14 THE CLEANING PROGRAMME The cleaning methodology and management controls must be appropriate to the process and the risks to the food. The flow chart shows the process required to set up and review the cleaning programme (Figure 7.15).


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Setting the standard Agree standards required

Developing cleaning methodology Methodology developed to meet standard required and then validated

Risk assessment Assessment based on risks from both process and cleaning

Create cleaning schedule documentation Scheduling is a record of the validated methodology

Training Training is carried out against schedule and detailed instructions

Control and audit of cleaning Controls put in place to ensure methodology followed

Review Periodic review and review on change

Fig. 7.15

The flow chart showing the process required to set up and review the cleaning programme.

7.14.1 Setting the standard The first step for implementing a successful hygiene management system is to ensure that the standards required by the manufacturer, customers, third party auditors and legislation are clearly identified, recorded and communicated to all employees.

7.14.1.1 Example only Standard required prior to start of production in low-risk salad preparation area:

r r r

Visually clean Free from allergenic material (if relevant) Food contact surfaces – total viable count (TVC) < 102 CFU/cm2

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Table 7.4

Example only: cleaning program for sandwich assembly area.

Frequency

Time

Type

Team

Daily Prior to product change Production breaks

14:00 to 18:00 10 min between products 22:00 to 22:30 02:00 to 02:30 06:00 to 06:30 10:00 to 10:30 18:00 to 14:00

Hygiene clean Inter-product clean Inter-product clean

Hygiene team Production Hygiene team

Clean and tidy of floor and waste

Hygiene team

On-going

Standard required during production in low-risk salad preparation area:

r r r

Visually tidy Free from allergenic material (if relevant) Food contact surfaces – TVC < 104 CFU/cm2

7.14.2

Developing cleaning methodology

The cleaning methods need to be developed and trialled to see if they meet the standards required. Competent and trained hygiene management together with third party consultants, such as reputable chemical suppliers, using the risk assessment approach should define the frequency and devise the methodology of cleaning for each area of the process. The cleaning process then needs to be risk assessed to see if any direct or cross-contamination issues occur by utilising the methodology. It is useful at this stage to summarise the cleaning programme (see Table 7.4). The cleaning programme should be validated to ensure that it meets the standards set. Once validated, the methodology can then be recorded as the cleaning schedule.

7.14.3

Design of verification programme

The verification process is part of the design and review of cleaning methodology. The process is used to validate a proposed cleaning methodology and then as part of management review to monitor performance against standards. This then enables development of the process in the drive for continuous improvement. Microbiological testing, ATP monitoring, protein testing or specific allergen tests can be used for a number of purposes; however, we are specifically considering their use for the verification of cleaning. Samples can be taken (sampled) from environmental surfaces; this includes food contact surfaces such as the cutting blade on a slicer, indirect food contact surfaces such as the control panel for a slicer and non-food contact surfaces such as the framework of a slicer. Any sample taken will as name suggests only be a sample and cannot reflect all surfaces that the food will come into contact with in production. As such the sample sites need to be chosen to best reflect the effectiveness of the clean. Process samples can be taken from the equipment as another measure of the cleanliness of the equipment and therefore the effectiveness of the clean. These can be:

r

Product samples taken as first off product from a line. As such this first off product will have contacted all food contact surfaces.


r

r

135

Rinse water samples. These are usually taken in closed plant cleaning systems and involve collecting the last rinse water from a CIP system. Great care needs to be exercised in the ‘clean’ sampling of this rinse water. In addition, any fault in the CIP such as a failure of a section of pipe to be routed during the clean will lead to an unsuccessful clean but may also give a clean rinse water sample (because the last rinse would also not have flowed through the unrouted section). A synthetic process sample can be used as a medium for sampling closed plant. For instance, a buffered saline solution can be passed through a process, such as cooking, cooling and filling. This can then be sampled and used as a measure of the cleanliness of the plant.

7.14.4

Create cleaning schedule documentation

It is the responsibility of the food manufacturer to document the cleaning procedures; however, the chemical supplier may assist with the process. The purpose of the documentation is:

r r r

For training of hygiene/production operatives As a reference for hygiene/production operatives To enable auditing of the process

The documentation can be very extensive since it needs to cover a number of different types of clean, the detail of cleaning and any controls required as defined by the risk assessment process. A typical structure of cleaning programme is illustrated in Figure 7.16.

7.14.5 Training Training of management and operatives is important to ensure that staff carry out their duties correctly and fulfil their potential by understanding:

r r

Their responsibilities within the team The standards required

With good training, confidence is promoted, job satisfaction increased, team spirit developed, performance improved and the amount of supervision required is reduced. Those companies that invest in the time and resources for training tend to reap the rewards of increased profitability. Training should be tested and recorded.

7.14.6

Control of cleaning

It is important to monitor the energies that are used for cleaning to ensure that they are in line with those established when the methodology was validated. A record of the factors should be kept and if any is out of specification corrective action must be followed to restore to that defined in the methodology.

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Cleaning plan Plan itemising all cleaning in a process area, including break, inter-product, hygiene and deep cleaning

Sequence of clean Summary of the stages of cleaning within an area

Walk-away standard The condition that the process area should be left in by production prior to the clean

Cleaning method card Detailed instructions on cleaning method for surfaces and equipment within the area

Cleaning record A signed document as proof of cleaning against method

Inspection record Signed documents of inspection

Fig. 7.16

Cleaning standard The condition that the process area should be left in after cleaning

A typical structure of a cleaning programme.

For open plant cleaning this would involve:

r r r r

Checking that the physical strip down of equipment meets that defined on the schedule. Checking the chemical strengths of detergent and disinfectant as applied to surfaces. This will generally involve a simple test kit. Checking the strength of disinfectants on surfaces after application to ensure that no dilution or inactivation is occurring. This can be carried out using disinfectant specific test strips. Checking the water temperature and pressure of any wash-down system. Water temperature and pressure are often critical to achieving a successful clean. For CIP this would involve:

r

Checking the physical set-up of the cleaning route and the correct functioning of sprayheads.


r r

137

Checking the chemical strengths of detergent and disinfectant. Modern cleaning systems will generally monitor and record return flow conductivity (relates directly to chemical strength), return flow temperature and return flow rate. Unless the CIP system automatically ensures the cleaning process parameters are met, the cleaning record should be analysed to verify that all parameters meet or exceed those achieved during validation.

7.14.7

Audit of cleaning

Visual inspections after the cleaning process are important to ensure that the required visual standards are achieved and maintained. The inspection should be thorough and all areas should be covered including those outside the daily cleaning programme. Inspections after the cleaning process should make provisions for pass, caution or re-cleans. The results of any inspection (positive or negative) should be firmly communicated to relevant members of staff with a corrective action loop in place. Where specific testing, such as microbiological or allergen, testing of product and the environment is required. It is important to have a sampling plan in place so that clear trends can be built up and any problems identified and actioned.

7.14.8

Review

As with any system, it is important to build in a review procedure. The hygiene system should be reviewed on a regular, continuous basis but no less than annually. In addition, a review must be carried out if there is a change in the process or products.

REFERENCES Anaphylaxis Campaign Standard (2007) The Anaphylaxis Campaign Standard to Increase Trust in Information about Food Allergens in Food. The Anaphylaxis Campaign, Farnborough, Hampshire. Curiel G.J., Hauser G., Peschel P. et al. (1993) Hygienic Design of Closed Equipment for the Processing of Liquid Food, EHEDG Report. Campden and Chorleywood Food Research Association, Gloucestershire. Holah J.T., Middleton K.E., Smith D.L. et al. (2004) Cleaning Issues in Dry Production Environment, R&D Report 192. Campden and Chorleywood Food Research Association, Gloucestershire. Holah J.T., Taylor J.H., Holder J.S. et al. (1993) The Spread of Listeria by Cleaning Systems, Part II. Technical Memorandum 673. Campden and Chorleywood Food Research Association, Gloucestershire. Taylor S. and Lehrer S.B. (1996) Principles and characteristics of food allergens. Critical Reviews in Food Science and Nutrition, 36(S), S91–S118.

8

Validation of cleaning and cross-contact

Helen M. Brown

8.1 INTRODUCTION Most food-manufacturing sites produce more than one product using common manufacturing facilities (storage, personnel, manufacturing line, packaging) so there is the potential for an ingredient or product to come into contact with another product to which it is not intentionally added. If cross-contact results in adventitious cross-contamination of a nonallergen-containing food with an allergen, or with a new undeclared allergen, there may be significant implications for both the allergic consumer and the manufacturer. The risk of cross-contact must therefore be controlled carefully, or the consumer be informed through product labelling. In the USA, it is estimated that 8% of product recall actions that took place between 1999 and 2003 were attributed to ineffective use of sanitation principles (Vierk et al., 2002; FDA, 2004). To avoid allergen cross-contamination, the whole operation of a manufacturing site needs to be reviewed to determine how and where allergens may be introduced (including workers lunch boxes as well as the more obvious routes), what route the allergens will take through the site and how they will be handled and by whom. The process of generating an allergencontrol plan is covered in more detail in other chapters of this book. An allergen-control plan will identify potential points of cross-contact and assess the risk of cross-contamination (i.e. that the residue will be transferred). It will also identify prerequisite programmes in the manufacturing process that may provide relevant control measures. Prerequisite programmes are basic operations within food manufacturing that are necessary to ensure good manufacturing practice. Examples of prerequisite programmes relevant to food safety are staff training, supplier quality assurance, pest control and sanitation. Cleaning is a prerequisite that is frequently identified as a process that may reduce or prevent allergen cross-contact. Where this is the case, evidence is needed to show that the cleaning process is effective in reducing or removing the allergen to an acceptable level, i.e. it has to be validated, and it has to be verified on an on-going basis. Validation is required for established cleaning regimes if the allergen-control plan identifies them as critical, but most validation studies will be for new products and processes in which case validation of cleaning regimes should take place prior to commercial manufacture of the product. No one validation study fits all cleaning processes and changes made to the manufacturing process need to be assessed for their possible impact on the efficacy of cleaning. This includes changes in product reformulation, re-configuration of equipment, or changes to the cleaning regime such as cleaning fluids and the time lapse between processes. If such changes are considered likely to affect the efficacy of cleaning, a new validation study of the changed process is required. Even if no changes are made, the cleaning process requires re-assessment


139

at defined intervals, at least annually. Manual cleaning methods are likely to be more variable than clean-in-place (CIP) systems, so should be re-assessed at more frequent intervals.

8.2 VALIDATION OF A CLEANING REGIME Validation of a cleaning regime entails generating data to show that the cleaning process is effective in removing allergens to a pre-defined acceptable level. These data may also inform risk assessments, and will certainly be required for audits of the allergen-control plan where cleaning has been identified as a critical process in preventing cross-contamination. In the pharmaceutical industry, where similar issues exist concerning the safety of products manufactured using shared equipment, there is a requirement to scientifically demonstrate that equipment cleaning processes can remove a given contaminant to below a pre-determined acceptance level (FDA, 1993, 1998). An effective validation study requires careful planning, protocols and documentation. It is best done in the context of an overall allergen-control plan, and after all possible measures to reduce and prevent cross-contact have been implemented. This pre-validation work also helps to support claims about the consistency of the cleaning process. Where limited resources are available, the pre-validation study is crucial to the effectiveness of the validation programme. Clear simple protocols for cleaning validation studies include the aim of the study, the scope of the study, what to measure (the analytical procedure to use), what to sample (the sample type), where and when to sample, how many samples to take and the criteria that define cleaning as effective. Traditionally, in the pharmaceutical industry, a minimum of three validation runs have been performed for cleaning validation, despite there being no statistical justification for this. Ultimately, it is for the manufacturer to decide on the required number of runs of the cleaning process to demonstrate validity. The scope of the cleaning validation study outlines the ingredients and products, equipment (production line, utensils, protective clothing), cleaning regimes and processes that are covered by the study. Validation may not be necessary for every product or piece of equipment and it may be possible to use groupings of similar products and select the worst case. For example, in a validation of the cleaning of equipment used to prepare slurries as an intermediate stage in the preparation of food flavourings, recipes with the highest concentration of celery and peanut were used (Stephan et al., 2004). Grouping on the basis of product and process may enable validation to focus on products that are known to be the most difficult to clean, for example, the most sticky product or the heat process that dries on residues. A standard operating procedure for the cleaning process will cover the details of the equipment to be cleaned, the cleaning procedure including cleaning materials to be used, and any temperature and time holds. It should also make clear the training requirements for staff performing the procedure. Documentation of validation studies depends on the complexity of the system and cleaning procedures. A checklist for the validation protocol (see Table 8.1) is also suitable as a checklist for documentation required. A final validation report outlining the results should be produced and approved by management. In the absence of thresholds or legally permitted levels for allergens in foods (except sulphur dioxide), the manufacturer or retailer is responsible for defining the criteria to establish whether cleaning is effective. The rationale for selecting the allowable residue

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Table 8.1

Checklist for a cleaning validation protocol.

The aim of the validation study Responsibilities For performing the validation study For approving the validation study Scope of the validation study Description of equipment to be used. Other equipment that it may apply to with rationale. The product for which the cleaning regime is to be used. Other products that it may apply to with rationale. The cleaning process Standard operating procedure for the cleaning process The interval between the end of production and the beginning of cleaning The amount of product that could be produced before the clean is carried out. General rules of the validation Choose the worst case, e.g. the process temperature likely to cause residues to stick to the surface; the clean to be after products containing the highest concentration of allergen Sampling and analytical testing The type of samples to be taken Sampling locations The analytical method(s) to be used Rationale for why these are to be used Validation requirements for sampling and analytical methods The number of samples to be taken for testing How many cleaning runs to be done to validate the cleaning Acceptance criteria State acceptance criteria with rationale The number of cleans needed to give consistent results to demonstrate efficacy Verification procedures What they will be and the frequency required Re-validation Interval and frequency

limits should be logical, based on the allergen or allergens involved and use current up-todate information. The limits need to be practical, achievable and verifiable, so need to be defined with knowledge of sampling and analytical methods. Very low levels of food allergens cause allergic reactions in sensitized individuals. On this basis, one criterion often applied to the cleaning process is that it removes allergen residues to below the limit of detection of the appropriate, analytical method. Regular reviews of such criteria are required to take account of new information as it becomes available. Historically, the limits of detection of analytical methods decrease as methods improve. This would place increasing demands on the cleaning process. Whether this is necessary to protect the majority of food allergy sufferers awaits further information from studies on allergen thresholds. In its guidance document, the UK Food Standards Agency states ‘Food producers for the time being can adopt “a visually and physically clean” standard for assessing the risk of possible allergen cross-contamination. This requires a thorough visual inspection of the production line (following cleaning) and the final product’. (FSA, 2006). When using such a criterion ‘no quantity of residue to be visible on the equipment after cleaning procedures are performed’, it would be advisable to back this up by performing some testing to determine the concentration of the allergen present when carry-over residues are just visible.


141

8.3 SAMPLING TO VALIDATE CLEANING Sampling must ensure recovery of allergen residues from the equipment surface or from final product, and the level of recovery and repeatability has to be sufficient to meet the criteria set to define cleaning as effective. Where samples are taken, when they are taken and how they are taken can influence the outcome of a validation study – a negative test result may be the consequence of poor sampling technique or cross-contaminants not being homogeneously dispersed throughout the sample, or due to samples being taken from a point where allergen residue is unlikely. The stage at which samples are taken during the cleaning process is significant. If the aim is to demonstrate a comparative decline in allergen residues removed during cleaning, samples need to be taken at suitable time intervals from the onset of cleaning. Samples taken at intervals throughout a clean can be used to demonstrate that allergen residues are not held up within a system and subsequently released at a later stage of the clean. Besides taking samples to show the efficacy of cleaning, samples taken before cleaning can be used to confirm that the sampling and testing methods are capable of recovering and detecting allergen residues, i.e. positive controls. Sampling points will be dependent on the equipment and cleaning process that is being validated. Sampling points are selected to challenge the efficacy of cleaning, targeting difficult to clean areas and areas that present opportunity for significant cross-contact. Selection of sampling points is best done in consultation with engineers and operatives who are familiar with the process. They will have knowledge of the movement of product through the system and points that are difficult to clean or may retain or hold up product. They will also be aware of access points, how to use them and the type of sample that it is possible to take.

8.3.1

Rinse samples – rinse waters, wash waters or purging/flushing materials

Samples of rinse water are taken when there is no other way to access the equipment, for example CIP systems or connecting pipe work. Wash water, particularly if is recycled or part of a common washing point for utensils or trays, could be a vehicle for cross-contamination and should be included in the sampling programme. In isolation, a single sample of final rinse water in which the allergen is below the predefined acceptable level is not sufficient to validate the efficacy of cleaning. It does not provide any information about whether allergen residues have been removed or the level of allergen residues remaining on the equipment. However, if a pre-wash rinse can be sampled, or rinse waters can be sampled from the onset of cleaning, then at intervals through to the final rinse water and these samples show a declining level of allergen, by implication the level remaining on the equipment has been reduced. Sampling of rinse water for subsequent verification of cleaning may then be justified. In a cleaning validation study on CIP equipment used to prepare peanut slurry for flavouring intermediates (Stephan et al., 2004), detection of the allergen in the pre-rinse water confirmed that the sampling and measurement approach were working (equivalent to a positive control). This gave confidence in the sampling and analytical method particularly when, as expected, the allergen was not detected in rinse waters following subsequent alkaline and acid washes and not in the final product (see Table 8.2).

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Table 8.2 peanut.

Analysis of rinse water samples and first final product after a clean for the presence of

Stage in cleaning process

ELISA result for peanut (µg/mL)

General protein Bradford Coomassie Plus, Pierce (µg/mL)

Result

Rinse water Pre-wash After alkaline cleaning After acidic cleaning

98.5–1379a ND ND

85.9–917.6a ND ND

Positive Negative Negative

Product Final product after clean

ND – 1.1c

NDb

Negative

Data from Stephan et al . (2004). ND, not detected. a the range from 4 cleans, 3 samples per clean. b the final product after clean was an artificial mix of water and maltodextrin, so did not contain protein. c mg/kg, peanut was detected after only one run and was traced back to an application error during the manufacturing process.

Collecting rinse water samples is not always easy or reproducible. It may involve sampling from a fast-moving stream of sometimes hot water. Once the sample has been collected, it needs to be chilled or frozen and analysed as soon as possible as the allergen may be unstable in water due to sedimentation of microbial growth and lost before it can be tested. Rinse or wash water samples known to contain cleaning fluids may affect the method of analysis, limiting the validity of such samples. In a study of a tray washer as a possible source of cross-contact, samples of wash water containing 1% alkaline foam detergent were taken for testing (Arrowsmith and Brown, 2006). Tests using a positive control sample in the presence of this concentration of detergent gave a false-negative result (see Table 8.3). Alternative sampling points were required to confirm that tray washing was not a route of cross-contamination. In dry manufacturing environments, cleaning may be by flushing or purging a system with a dry, inert material such as flour, diatomaceous earth, salt or starch. Removal of allergen residues can be followed by sampling the purging materials after known volumes have passed through the system. Data that show a decline in the level of the allergen until it reaches the pre-defined acceptable level or below demonstrate the efficacy of cleaning. Table 8.4 shows declining levels of soya when whey was used to purge the system of a soya product (Hefle, 2005). Table 8.3 An example of interference of a cleaning fluid in a wash water sample on the result of on an ELISA allergen test for prawns. Test material

ELISA result for tropomyosin (µg/mL)

Prawn extract diluted to 5 µg prawn/mL Prawn extract diluted to 5 µg prawn/mL in the presence of 1% alkaline foam cleaning fluid

0.08 ULOQ Positive

>ULOQ Positive

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