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Scientific Concepts of Functional Foods in EuropeConsensus Document

PREFACE

ILSI Europe’s role

The European Commission Concerted Action on FunctionalFood Science in Europe (FUFOSE), which is co-ordinatedby The International Life Sciences Institute – ILSI Europe,aims to establish a science-based approach for concepts infunctional food science. The goal of this Concerted Actionhas been to set up a multidisciplinary European network:

1. to assess critically the science base required to provideevidence that specific nutrients and food componentspositively affect target functions in the body;

2. to examine the available science from a function-drivenperspective rather than a product-driven one; and

3. to reach consensus on targeted modifications of food andfood constituents, and options for their application.

This approach led to identifying key partners from Europe’sfood and agricultural industry, governmental and inter-governmental bodies and the scientific community. Thisproject provided them with an opportunity to exchangeideas and to interact on a neutral platform.

Theme groups for physiological functions

The First Plenary Meeting on Functional Food Science inEurope: State of the Art was held in Nice, France, in April1996. Based on the results of this meeting, six majorareas in human physiology were selected and correspondingIndividual Theme Groups (ITG) were set up and chargedwith producing theme papers to review critically the sciencebase of the concepts in their respective areas:

X Growth, development and differentiation: a functionalfood science approach.

X Functional food science and substrate metabolism.X Functional food science and defence against reactive

oxidative species.X Functional food science and the cardiovascular system.X Functional food science and gastrointestinal physiology

and function.X Functional food science and behaviour and psychological

functions.

Each ITG reviewed the published literature to: define thestate of the art with respect to specific body systems; assesscritically methodologies to characterize and quantifyspecific related functions; identify and review nutritionaloptions modulating these functions; evaluate potentialsafety implications related to these nutritional options;identify the role of food technology on nutritional andsafety aspects; assess critically the science-base requiredfor providing evidence that specific nutrients positively

affect functions; identify areas where further research isrequired.

The resulting documents were scrutinized in a SecondPlenary Meeting held in July 1997 in Helsinki, Finland, andrevised by the ITG chairs to include the comments madeduring that consultation. The final reports of the six ITGswere published in theBritish Journal of Nutrition(Bellisleet al. 1998).

Theme group for technology

An Expert Group on Food Technology was also establishedto examine the impact and feasibility of food technologyon functional food development. Bearing in mind that afunction-driven approach rather than a product-drivenapproach should be adopted, the group considered examplesof technologies that are applied to raw materials to improvetheir quality, the identification of new materials and newprocesses, and the interactions between processing andfunctionality.

The group reviewed the impact of food processing onthemes such as technological processes to optimize anti-oxidants, minerals, micro-organisms, carbohydrates andpeptides.

The Technology Theme Group was asked to addresstopics such as the state of the art (impact of processing);source of materials; processing options modulating func-tionality, including post-harvest technology, unit operationsand storage and distribution/packaging; safety implicationsof materials and processes; process monitoring forfunctions; and further development and research needs.

These five technology theme papers have been publishedin Trends in Food Science and Technology(Knorr et al.1998).

Concept of the Consensus Document

The six ITG reviews and that of the Technology Groupprovided the foundation for this Consensus Document onScientific Concepts of Functional Foods in Europe. Theoutline for the document was reviewed by participants at theSecond Plenary Meeting in Helsinki, Finland.

The draft document was reviewed by the SteeringCommittee set up to monitor this project, as well as theILSI Europe Functional Food Task Force, and by theparticipants in the Third Plenary Meeting, which was heldin Madrid in October 1998. Their comments have allbeen taken into consideration in this final ConsensusDocument.

The text of the document, which follows, will makeconstant reference to the six ITG papers as well as thosefrom the Technology Group. Readers who require further

British Journal of Nutrition(1999),81, S1–S27S1

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details and full references are advised to consult the originaldocuments in theBritish Journal of Nutrition(Bellisleet al.1998) and inTrends in Food Science and Technology(Knorret al. 1998).It should be emphasized that the intention of thisConsensus Document was to select specific examples to high-light some aspects of the subjects covered. It was not theintention for it to be a comprehensive and exhaustive account.

It also must be borne in mind that the subjects of theITGs were identified on the basis that they representedmost, but not all, of the important physiological functionsrelated to this field. The exclusion of subjects in thesepapers should not be taken to indicate that they areunimportant. Because scientific knowledge is continuallyadvancing, the Consensus Document cannot pretend to betotally up to date. Nevertheless, it has been based on themost recent data available at the time of writing (publishedup to the end of 1997).

Structure of the Consensus Document

After the introductory Section 1 of this Consensus Docu-ment, Section 2 will outline the aims of functional foodscience and will introduce some important considerationsabout classification and criteria for markers of targetfunctions, which play a major role in health.

Section 3 will consider each of the areas of physiologicalfunction reviewed in the six ITG papers and will highlightsome of the key target functions with examples of relevantmarkers wherever possible. Also included in the considera-tion are the options for application (i.e. how the target

functions could be modulated positively by componentswithin functional foods), as well as proposals for researchopportunities.

Section 4 of this document will consider how foodtechnology can play an important role in the developmentof functional foods and will draw on examples ofkey technological challenges from the five areas coveredin the technology theme papers. Research opportunities thatcould help to meet the challenges will be indicated.

Finally, Section 5 of this Consensus Document dealswith the communication of health benefits to the public andthe principles, definitions, use and scientific basis of claims.Although this area is primarily a regulatory concern and notwithin the mandate of ILSI as a scientific organization, werecognize that communication of health benefits is an essentialelement in improving public health in which science plays avital role. This section offers a brief overview, using examplesof types of claims and of local regulatory philosophies andapproaches. The aim is to explain/highlight the differences inclaims and approaches based on nutritional, physiological orpathophysiological scientific knowledge. This EU ConcertedAction has allowed the development of ideas that suggest aninnovative way in which to link the science of functionalfoods with the communication about their possible benefits toconsumers.

The Executive Summary, which includes the Recommenda-tions of the Consensus Document, is found in Section 6, andthe Key Messages are summarized in Section 7.

The following scientists reviewed and agreed on the textof this Consensus Document:

S2 Consensus Document

Prof. P. J. Aggett University of Central Lancashire UKProf. J. Alexander National Institute of Public Health NMrs M. Alles Borculo Whey Products NLDr P. A. Anderson ILSI North America USADr J.-M. Antoine Groupe Danone FDr M. Ashwell Ashwell Associates UKProf. N.-G. Asp University of Lund SProf. C. A. Barth German Institute for Human Nutrition DProf. B. Beaufre`re University of Auvergne FDr F. Bellisle INSERM FProf. P. A. Biacs KEKI – Central Food Research Institute HDr J. G. Bindels Numico Research NLDr N. M. Binns Coca-Cola Greater Europe UKProf. J. E. Blundell University of Leeds UKMrs J. Booth St Ivel UKDr F. Bornet Eridania Be´ghin-Say BProf. A. Bruce National Food Administration SDr L. Contor ILSI Europe BDr B. Danse ILSI Europe BProf. A. T. Diplock International Antioxidant Research Centre UKMrs S. Doyran FAO – Food and Agriculture Organization IProf. I. Elmadfa University of Vienna ADr E. Fern Nestle´ CHMr R. J. Fletcher Kellogg UKDr A. Franck Raffinerie Tirlemontoise BDr F. Guarner General Hospital Vall d’Hebron EDr F. Guillon INRA FMrs C. Guittard Monsanto F

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Acknowledgements

We wish especially to thank all of the individual contribu-tors to this project and Consensus Document for devotingtheir time and efforts within the required timeframe. Theircontinuous willingness to ensure the success of this Con-certed Action has been sincerely appreciated and ILSIEurope, as co-ordinator of this Concerted Action, is extremelygrateful to all of them.

Co-ordinators

Co-ordinator:Dr Berry Danse, ILSI Europe, 83 Avenue E. Mounier, Box 6,B-1200 Brussels, Belgium.

Scientific co-ordinator:Prof. Marcel Roberfroid, Catholic University of Louvain,Ecole de Pharmacie, Tour Van Helmont, 73 Avenue E.Mounier, B-1200 Brussels, Belgium.

EC responsible:Dr Liam Breslin, Agro-industrial Research, Food, Commis-sion of the European Communities, Directorate-GeneralXII, Science, Research and Development, 200 Rue de laLoi, B-1049 Brussels, Belgium.

Project manager:Dr Laura Contor (for further information), ILSI Europe,83 Avenue E. Mounier, Box 6, B-1200 Brussels, Belgium.Tel. þ32-2 771.00.14 Faxþ32-2 762.00.44

S3Scientific Concepts of Functional Foods in Europe

Dr W. Haehnlein BASF DDr B. Hanley CSL – Food Science Laboratory UKProf. J. Hautvast Wageningen Agricultural University NLDr T. Hirahara ILSI Japan JMr J. R. Hislop Procter & Gamble DProf. G. Hornstra Maastricht University NLDr J. Howlett Cultor Food Science UKProf. J. Huis in’t Veld Yakult Europe NLProf. D. Knorr Berlin University of Technology DProf. F. J. Kok Wageningen Agricultural University NLProf. B. Koletzko Ludwig-Maximilian University Munich DProf. H. Korhonen Food Research Institute SFMrs R. Korpela Valio SFDr J. Kruseman Nestle´ CHDr J. Lambert Mars UKDr M. G. Lindley University of Reading UKDr J. Lucas European Commission – DG XII BDr G. Malgarini Ferrero Group BDr M. N. Meah MAFF UKMs A. Michel-Drees German Food Office DDr D. J. G. Muller Procter & Gamble DMs B. Nielsen F. Hoffman-La Roche CHDr H. Nordmann Monsanto CHDr L. Ovesen Danish Veterinary and Food Administration DKDr G. Pascal CNERNA FDr A. L. J. Peters Cosun/Sensus NLProf. G. Riccardi University of Naples IProf. M. Roberfroid Catholic University of Louvain (UCL) BProf. S. Salminen University of Turku SFProf. W. H. M. Saris Maastricht University NLDr A. M. Stephen University of Saskatchewan CDNDr O. Tello-Anchuela National Centre for Epidemiology EIr. E. Timmermans Borculo Whey Products NLMr R. Top Ministry Public Health, Well-being and Sport NLDr H. van den Berg TNO NLDrs P. M. Verschuren Unilever Research Vlaardingen NLDr S. Videla General Hospital Vall d’Hebron EDr V. Viechtbauer Red Bull AProf. B. Viell BgVV DDr M. Vogel Sudzucker DProf. A. G. J. Voragen Wageningen Agricultural University NLProf. P. Walter University of Basel CHDr D. A. Whitmore Novartis UKMr D. Wils Roquette Fre`res FDr M. J. Wiseman Department of Health UK

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About ILSI

The International Life Sciences Institute (ILSI) is a non-profit, world-wide foundation established in 1978 toadvance the understanding of scientific issues related tonutrition, food safety, toxicology and the environment. Bybringing together scientists from academia, government,industry and the public sector, ILSI seeks a balancedapproach to solving problems with broad implications forthe benefit of the general public. ILSI is affiliated withthe World Health Organization as a non-governmentalorganization and has specialized consultative status withthe Food and Agriculture Organization of the UnitedNations. Headquartered in Washington, DC, USA, ILSIhas branches in Argentina, Australasia, Brazil, Europe,India, Japan, Korea, Mexico, North Africa and the GulfRegion, North America, South Africa, the South Andeanregion, Southeast Asia and Thailand, and a Focal Point inChina. Today, ILSI enjoys the support of around 300companies and a network of scientists throughout theworld.

About ILSI Europe

In 1986, ILSI Europe was created to focus on the specificneeds defined by the Institute’s European partners.

The main goals of ILSI Europe are to:

X foster scientific advances by promoting collaborationamong scientific experts in industry, academia, andnational and international regulatory bodies;

X provide coherent scientific answers to scientific issues

of common concern for the well-being of the generalpublic;

X support an active publication programme for thedissemination of scientific information to the broadestpossible audience including the scientific community,international organizations and regulatory agencies.

To address these issues, ILSI Europe’s members initiateprojects, which are managed by specific task forces. Taskforces accomplish their goals through activities such asresearch, workshops, conferences and publications.

About the European CommissionFAIR RTD programme

This concerted action ‘Functional Food Science in Europe’(FUFOSE) has been funded within the FAIR RTDprogramme, which is part of the Commission’s FourthFramework Programme for research and technologicaldevelopment.

This programme aims at promoting trans-Europeanresearch in the primary production sectors of agriculture,horticulture, forestry, fisheries and aquaculture, linkingthese with the input and processing industries, particularlyfood processing and renewable biomaterials.

The food area is important within this programme and iscovered by the theme ‘Generic Science and AdvancedTechnologies for Nutritious Foods’.

There is growing interest in Europe in the concept of‘Functional Foods’ and this Concerted Action, bringingtogether Europe’s scientists and industry, is fundamentalto establishing a science-based approach to such foods.


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1. INTRODUCTION

1.1 From traditional to new concepts in nutrition

The primary role of diet is to provide sufficient nutrients tomeet the metabolic requirements of an individual and togive the consumer a feeling of satisfaction and well-beingthrough hedonistic attributes such as taste. However, inaddition to this there is evidence to support the hypothesisthat, by modulating specific target functions in the body,diet can have beneficial physiological and psychologicaleffects beyond the widely accepted nutritional effects. Infact, diet can not only help to achieve optimal health anddevelopment, but it might also play an important role inreducing the risk of disease.

We are at a new frontier in nutrition science because,at least in the industrialized world, concepts in nutritionare changing significantly. We are progressing from aconcept of ‘adequate nutrition’ to one of ‘optimal nutrition’.We have moved from a former emphasis on survival,through one of hunger satisfaction and of food safety,to our present emphasis on the potential for foods topromote health, in terms of both improving well-being(mental and physical conditioning) and reducing the riskof diseases.

Although there are still many people who know littlenutrition science, consumer awareness of the subject and itsrelationship to health is, nevertheless, growing appreciably.Almost everyone today is more conscious of and betterinformed about the subject than they were in the past. As aresult, their expectations of obtaining health benefits fromthe food they consume is increasing. In a recent survey of14 331 people interviewed in all 15 Member States of theEuropean Union, 9 % chose ‘eating healthily’ as the mostimportant influence in selecting food and 32 % said thatthis had some influence of their food choice (Institute ofEuropean Food Studies, 1996).

1.2 From the importance of improving life expectancy tothe importance of quality of life

The changing concepts in nutrition are of particular import-ance in view of some significant trends in our present society.They are:

1. The increasing cost of health care and of days lost fromwork.

2. The continuing increase in life expectancy.3. The increase in the numbers of elderly people.4. The desire of people for an improved quality of life.

The rising cost of health care is of primary concern in manyparts of the world. The cost of health care in Europeancountries in 1995 was estimated to be, on average, around8 % of the gross domestic product, approximately onepercentage point higher than it was a decade ago.

Life expectancy in virtually every country of the world ishigher today than it has ever been for all age groups – frombirth as well as at later ages. Expectation of life from birthfor both men and women is highest in Japan, but is followedclosely by a number of European countries. Furthermore,the rate of increase in life expectancy appears to show nosign of declining.

Associated with this increase in life expectancy isthe growth in the size of the population above the age of65 years. In Europe the relative proportion is currentlybetween 14–17 % of the total population and several Euro-pean countries have the highest population of elderly peoplein the world. This figure is expected to rise to between 20–24 % in the next 30 years.

An improved quality of life must accompany thisimproved life expectancy and increase in the elderlypopulation if relative health care costs can ever be bettercontrolled and managed.

1.3 From new concepts in nutrition to functional foods

The wide range of food products available to today’sconsumer offers a wide variety of complex food compo-nents, both nutritive and non-nutritive. These have thepotential to improve the health and well-being of indivi-duals and, maybe, to reduce the risk from, or delay thedevelopment of, major diseases such as cardiovasculardisease (CVD), cancer and osteoporosis.

Advances in food science and technology are now pro-viding the food industry with increasingly sophisticatedmethods to control and alter the physical structure and thechemical composition of food products. There is now agrowing realization of the market potential for functionalfoods, based on the principle of added value linked to healthbenefit.

1.4 International developments relating tofunctional foods

The new concepts in nutrition outlined in Section 1.1 have,over the last 10–12 years, justified the efforts of healthauthorities in many countries, especially in Japan and in theUnited States of America, to stimulate and support researchon physiological effects of food components and their healthbenefits. They have also been a major factor in the recon-sideration of their regulatory policy on foods and healthclaims.

In Japan, research on functional foods began in the early1980s, when 86 specified programmes on ‘Systematicanalysis and development of food functions’ were fundedby the government. Later, the Ministry of Educationsponsored additional focal point studies on ‘Analysis ofphysiological regulation function of food’ and ‘Analysis offunctional foods and molecular design’. Then, in 1991, theconcept of Foods for Specified Health Use (FOSHU) wasestablished. These foods are included as one of the fourcategories of foods, described in the ‘Nutrition Improve-ment Law’ as ‘Foods for special dietary use’ (i.e. ‘foods thatare used to improve people’s health and for which specifichealth effects are allowed to be displayed’). Upon satisfac-tory submission of comprehensive data documenting thescientific evidence in support of a proposed health claim, theMinister of Health and Welfare is able to approve aclaim, and grant permission, to use a ‘symbol’ on labelling,to indicate to the consumer that the health claim hasgovernment approval.

Foods identified as FOSHU are required to provideevidence that the final food product is expected to exert a


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health or physiological effect; data on the effects of isolatedindividual components are not sufficient. FOSHU productsshould be in the form of ordinary foods (i.e. not as pills orcapsules) and are assumed to be consumed as part of anordinary diet (i.e. not as very occasional items linked tospecific symptoms). Most FOSHU products currentlyapproved contain either oligosaccharides or lactic acidbacteria for promoting intestinal health.

In the United States of America, ‘reduction of diseaserisk’ claims have been allowed since 1993 on certain foods.These contain components where the Food and DrugAdministration (FDA) has accepted there is objective evi-dence for a correlation between nutrients or foods in the dietand certain diseases on the basis of ‘the totality of publiclyavailable scientific evidence, and where there is substantialagreement amongst qualified experts that the claims weresupported by the evidence’. By 1998 there were elevenFDA-approved correlations between foods, or components,and diseases. These are claims for the relationship betweenfoods that are high in calcium and the reduced risk ofosteoporosis; claims for foods that are low in saturatedfats, low in cholesterol and low in fat and the reduced riskof coronary heart disease; and the claim for sugar alcoholsin relation to reduced risk of dental caries. The claimrelating diets containing soluble fibre with the reducedrisk of coronary heart disease has been amended twice toallow claims for the soluble fibre from whole oats and frompsyllium seed husk. Very recently, the FDA has announcedthat claims can also be based on ‘authoritative statements’of a Federal Scientific Body, such as the National Instituteof Health and Center for Disease Control, as well as fromthe National Academy of Sciences, as allowed by the FDAModernization Act of 1997.

In the European Union, there is no harmonized legislationon health claims, which means that they are dealt with at anational level. However, it is well recognized that thecompetitive position of the European food and drink indus-try should be reinforced through a better understanding ofthe scientific basis for the functionality of food.

A self-regulating programme on health claims was intro-duced in Sweden in 1990 and revised in 1996. It permitsclaims with two parts: information on one of eight approveddiet–health relationships, followed by information onthe composition of the product (function-based claims).The accepted conditions are obesity (energy), bloodcholesterol (fat quality), blood pressure (sodium), athero-sclerosis (blood pressure, serum cholesterol, long-chain n-3polyunsaturated fatty acids (PUFA) in fish), constipation(dietary fibre), osteoporosis (calcium), dental caries (easilyfermentable carbohydrates) and iron deficiency (iron). Thefood industry and retail organizations behind the pro-gramme have recently suggested an extension to coverproduct-specific physiological claims, characteristic offunctional foods.

1.5 From functional foods to functional food science

Up to now, the approaches used for functional food science,both in Japan and to a lesser extent in the USA, to matchthese new concepts in nutrition have mostly been ‘productor food component-driven’, and they are likely to be very

much influenced by local, traditional or cultural character-istics. A science-based, ‘function-driven’ approach is pre-ferable, because the functions and their modulation areuniversal. Functional food science, therefore, refers to thenew concepts in the science of nutrition that lead to thestimulation of research and to the development of functionalfoods.

1.5.1 Working definitions

No universally accepted definition for functional foodsexists. In fact, because functional foods are more of aconcept than a well-defined group of food products, aworking definition rather than a firm definition is preferredfor the purposes of this Consensus Document.

A food can be regarded as ‘functional’ if it is satis-factorily demonstrated to affect beneficially one or moretarget functions in the body, beyond adequate nutritionaleffects, in a way that is relevant to either an improved stateof health and well-being and/or reduction of risk of disease.Functional foods must remain foods and they must demon-strate their effects in amounts that can normally be expectedto be consumed in the diet: they are not pills or capsules, butpart of a normal food pattern.

A functional food can be a natural food, a food to which acomponent has been added, or a food from which acomponent has been removed by technological or biotech-nological means. It can also be a food where the nature ofone or more components has been modified, or a food inwhich the bioavailability of one or more components hasbeen modified, or any combination of these possibilities. Afunctional food might be functional for all members of apopulation or for particular groups of the population, whichmight be defined, for example, by age or by geneticconstitution.

1.5.2 The functional food science approach for Europe

The design and development of functional foods is a keyissue, as well as a scientific challenge, which should rely onbasic scientific knowledge relevant to target functions andtheir possible modulation by food components. Functionalfoods themselves are not universal, and a food-basedapproach would have to be influenced by local considera-tions. In contrast, a science-based approach to functionalfood is universal and, because of this, is very suitable for apan-European approach. The function-driven approach hasthe science base as its foundation – in order to gain abroader understanding of the interactions between diet andhealth. Emphasis is then put on the importance of the effectsof food components on well-identified and well-characterizedtarget functions in the body that are relevant to health issues,rather than solely on reduction of disease risk.

2. THE SCIENTIFIC BASIS OFFUNCTIONAL FOODS

2.1 The aims of functional food science

Knowledge of the mechanism(s) by which functionalfood(s) can modulate the target function(s) and their


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relevance to the state of well-being and health and/orreduction of a disease will originate from basic knowledgein the biological sciences. It might also be supported byepidemiological data that could demonstrate a statisticallyvalidated and relevant relationship between the intake ofindividually specified food components (better still, aserum, faecal, urinary or tissue marker of intake of thecomponents under study) and the specific benefit. Further-more, it will be of particular value to have good prospectiveevidence that links the habitual intake of specified foodcomponents with the reduction of the risk of disease, whichmight develop some time later.

The aims of functional food science are, therefore, asfollows:

X To identify beneficial interaction(s) between a functionalcomponent within a food and one or more target func-tions in the body and to obtain evidence for the mechan-ism(s) of these interactions. (Results from studies carriedout in vitro, in cells in culture, the use ofin vitro/ex vivomodels and animal models, as well as results from humanstudies, should be included.)

X To identify and validate markers relevant to these functionsand their modulation by food components (see below).

X To assess the safety of the amount of food or itscomponent(s) needed for functionality. This will requireevidence that is equally applicable to all major groups inthe population, including those who are indulging inbehaviour that might be expected to compromise theanticipated benefits of the functional food. It mightinvolve post-marketing monitoring, including the effectson the whole diet.

X To formulate hypotheses to be tested in human interven-tion trials that aim to show that the relevant intake ofspecified food components is associated with improve-ment in one or more target functions, either directly, or interms of a valid marker of an improved state of health andwell-being and/or a reduced risk of a disease.

2.2 Target functions for health outcomes

This Consensus Document on ‘functional food science’does not intend to summarize the science and thetechnology theme papers. Rather, its aim is to illustrate

the concepts presented above, by selecting from each themepaper a few topics based on the identification of key targetfunctions:

X that play a major role in maintaining an improved state ofhealth and well-being and/or reduction of risk of disease;

X for which appropriate markers are available and/orfeasible;

X for which potential opportunities exist for modulation bycandidate food components.

2.3 Markers – a proposal for classification

One key, but difficult, approach to the development offunctional foods is the identification and validation ofrelevant markers that can predict potential benefits or risksrelating to a target function in the body.

If markers represent an eventdirectly (i.e. causally)involved in the process they should be considered asfactors, whereas if they represent correlated events theyshould be considered asindicators.

Markers relevant to functional foods (see Fig. 1) can alsobe classified according to whether they:

X relate to the exposure to the food componentunder study,such as a serum, faecal, urinary or tissue marker. Forinstance, the increased level of red-blood-cell folate is amarker of exposure to folate in food and the increasedlevel of blood tryptophan is a marker of exposure totryptophan in food. Markers relating to exposure to thefunctional food component can give some indication, butnot absolute proof, of the bioavailability of the foodcomponent.

X relate to the target function or biological response, suchas changes in body fluid levels of a metabolite, protein orenzyme (e.g. the reduction in levels of plasma homo-cysteine as a possible response to dietary folate, and theincreased levels of brain serotonin as a possible responseto dietary tryptophan).

X relate to an appropriate intermediate endpointof animproved state of health and well-being and/or reductionof risk of disease, such as the measurement of a bio-logical process that relates directly to the endpoint(e.g. the extent of narrowing of the carotid artery asevidence of cardiovascular disease, or functional imaging


Consumptionof

functionalfood

component

Markers of Markersof target

function/biological

response

exposureto foodcomponent

Markers ofintermediate

endpoint

Improvedstate of

health andwell-being

or

Reducedrisk of

disease

Fig. 1. Classification of markers relevant to the effects of functional foods. This is adiagrammatic representation to show how different types of markers would be expectedto lie within a logical progression from the food component to the health outcome. Thetypes of markers are completely independent of each other. Markers can be eitherindicators or, if they can be proven to be causal, factors (see Section 2).

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of the brain by magnetic resonance imaging as anintermediate endpoint marker for the amelioration ofdepression).

Markers of exposure and markers of biological response caneither be factors that are causally related to the endpoint, orindicators that are indirectly related. Markers of an inter-mediate endpoint are likely to be factors, rather thanindicators.

Markers become less specific and more attenuated andsubject to confounding variables as they become moreremote from the endpoint. Conversely, they become morespecific and quantitatively related the closer they are to theendpoint in question. The elucidation of the mechanismsleading to health outcomes would refine the identification ofmarkers and their appreciation.

This differential classification is considered to be of realimportance in the development of new markers for use inhuman studies. The results from such studies can also form ascientific basis for formulating and controlling claims (seeSection 5).

2.4 Criteria for markers

In general, all markers, whether they are biochemical,physiological or behavioural in nature, should befeasible,valid, reproducible, sensitiveand specific. The followingcriteria should apply equally well, for example, to measure-ments of particular blood components as they do tomeasurements of subjective experience and behaviour.

X Markers should represent relatively immediate outcomes,which can be used to assess interventions in a reasonabletimescale; they could, therefore, wherever possible,replace later and more remote outcomes as have beenused in some epidemiological studies.

X Markers must be rigorously validated and amenable tostandard quality-control procedures.

X Markers must be clearly linked to the phenomenainvolved in the biological process being studied. It isimportant to prevent the pursuit of increasingly accurateand precise measurements, which have limited biologicalsignificance.

X Markers should undergo single-centre studies to establishtheir sensitivity (i.e. the frequency of a negative test whenthe process is present) and their specificity (i.e. the fre-quency of a positive test when the process is absent). Theymust also be shown to be reproducible in different centres.

X Markers must be measurable in easily accessiblematerial, or obtainable using methodology that must beboth ethical and minimally invasive.

X Dynamic responses might be as useful as, or more usefulthan, static measurements. For example, changes inmarkers during clearance studies and in postprandialsituations and studies of enzyme function, inductionand suppression should be considered.

X Appropriate static and dynamic markers might also bebased on objective assessments of psychological andphysical performance and subjective assessments ofquality of life or other similar outcomes.

These criteria for markers should be taken into accountbefore human intervention studies are carried out. In many

cases a ‘battery’ of markers might be needed in order tocreate a ‘decision tree’ from multiple tests. A new genera-tion of human intervention studies using markers that accordwith these criteria will generate readily interpretable,valid and reliable data, which can form the basis forfuture development of functional foods in the Europeanpopulation. Markers, arising from new techniques such asmolecular biology, might be expected to identify targetgroups who could benefit from functional foods.

2.5 Safety considerations

Functional foods must be safe according to all standards ofassessing food risk. However, the concept of risk versusbenefit cannot be applied in such a straightforward manneras it is for drugs; new concepts and new procedures willneed to be elaborated and validated.

For example, the safety evaluation of micronutrientsmust take into account potential adverse effects of lowintakes (clinical deficiency) as well as effects from intakesthat are too high (clinical toxicity). Furthermore, a moretraditional toxicology testing approach might be suitableto assess the safety of (phyto)chemicals, the daily intakeof which remains low, but it is not necessarily ideal fornew functional food components, which might account fora relatively larger percentage of the total food intake.The classical ‘dose–effect relationship’ might lead to con-siderations of physiological/nutritional disturbances thatare irrelevant to standard safety assessment. If a functionalfood is considered in the framework of novel foods, thedecision tree leading to a relevant package of toxicity testingwill be driven by the principle of substantial equivalenceof the tested food compared with traditional counterparts(see Jonaset al. 1996).

Protocols for human nutrition studies need to be devel-oped including, in some cases, post-marketing surveillance.Even though the design of clinical studies as used in drugdevelopment can serve as a reference point, specific proto-cols and specific criteria relevant to functional foods mightbe needed. It might also be necessary to identify specifictarget groups of individuals who might present higher/lowersusceptibilities to potential adverse effects and to considerthat the effects of functional foods might be positive in sometarget groups and negative in others. Finally, the long-termconsequences of the interaction(s) between functional foodcomponents and function(s) in the body and the interactionsbetween components must be carefully monitored. This EUConcerted Action proposes that markers as described inSections 2.3 and 2.4 should, if possible, be used andintegrated in the safety assessment.

3. TARGET FUNCTIONS AND RESEARCHOPPORTUNITIES IN RELATION TO HEALTH

OUTCOMES (see Bellisleet al. 1998, S5–S45)

3.1 Growth, development and differentiation

3.1.1 Introduction

Food supply, and the metabolism of food components,during both pregnancy and lactation have important im-plications on intra-uterine and postnatal development of


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children. Early nutrition might modulate growth anddevelopment of the organism, which is thought to affectneural function and behaviour. Equally important, theeffects of early nutrition also appear to influence the overallquality of life by exerting life-long programming effects onmodulating health, disease and mortality risks in adulthood.

3.1.2 Key target functions

3.1.2.1 Maternal adaptations during pregnancy andlactation. The energy cost of development of the placentaand fetus is only about 6 % of the mother’s normalrequirements. This value is relatively low and is probablydue to adaptations during pregnancy, which enable themother to increase the absorption and use of nutrients fromher diet, and also the mother’s ability to use stored nutrientsfor fetal growth. Some of these adaptations occur very earlyin pregnancy; others, such as those involving the increasedabsorption of iron in the gut, take place in the later stages.Some adaptations seem to target specific nutrients such asiron, towards the placenta for transfer to the fetus, but thesetransport processes have not been well characterized.

It is important to ensure that mothers are adequatelynourished during lactation and between pregnancies withevery nutrient, so as to ‘re-stock’ any nutrient storage depotsthat might have been depleted during pregnancy.

3.1.2.2 Fetal development. Fetal development is undergenetic control, which can be disturbed by severe depriva-tions or excesses of nutrients. The critical periods of fetalorgan formation often occur before the fetus has a placentalsupply of nutrients from the mother. The best documentedexample of this is the spectrum of iodine deficiency disease.Poor iodine status is associated with an increased risk ofmiscarriage in early gestation and preterm delivery, as wellas abnormal mental development of the infant. However, themechanisms and regulation of supplying nutrients to theearly embryo and their susceptibility to diet are not clear.

Another more recent example is the critical period for theeffect of additional dietary intakes of folate on the optimaldevelopment of the neural tube – a very early component ofthe nervous system. Intervention at this critical stage canresult in a reduction in incidence of a number of neural tubedefects, one of which is spina bifida.

3.1.2.3 Infant and child growth and development. Post-natal growth and development of the infant is a continuationof the in utero events and processes. Although the natureand means of delivering nutrients has changed significantly,the functional and structural integrity of organs and tissuessuch as the gut, liver, skeleton, brain, adipose tissue, muscle,blood cells and the immune system continue to mature andremain potentially susceptible to dietary factors.

The newborn infant has an intermittent nutrient supplyfrom breast milk or infant formula, both of which are rich inlipids. Absorption of nutrients takes place through theintestine, and delivery to the tissues is initially via theportal circulation. At the transition between suckling andweaning, there is a switch to a more solid diet with a lowerfat and higher carbohydrate content.

The adaptation of infants to these changes requiresimportant modifications of substrate and energy metabolism

through the induction of metabolic pathways. The program-ming of metabolic responses at the cellular level, theprogramming of stem cells and the control of programmedcell death are not well understood. Postnatal developmentand differentiation also creates distinctive requirements fornutrients such as amino acids and long-chain fatty acids.Some of these, although not regarded as essential in adults,are considered to be ‘conditionally’ essential in the infant.

There is now epidemiological evidence that early diet,and presumably related metabolic eventsin utero and ininfancy, manifest themselves by inappropriate intra-uterineand postnatal growth. This is now thought to predispose thechild to obesity, diabetes mellitus, and risk factors for CVDin adult life. These later consequences might arise fromalterations in critical stages in metabolic programming ofseveral nutrients and might be analogous to the earlyconsequences of deficiency of iodine and folate.

Breast milk contains some constituents derived directlyfrom the maternal diet that might not only have an obviousrole to play in determining the baby’s perception of smelland taste (which is well developedin utero) but also in thedevelopment of immunotolerance. Thus it is possible thatearly diet might condition the development of taste prefer-ences, which, in turn, could affect the diversification of thediet in later infancy.

3.1.3 Examples of options for modulation

Human breast milk is an example of a food with functionalproperties. The precise roles and essentiality of many of thediverse components of breast milk are not certain andfurther clarification of their role might be informative forthe development of functional foods. Bioactive componentsin human milk include the specific nature of the protein andlipid composition, digestive enzymes, growth factors,peptide and steroid hormones, free amino acids (taurine,arginine, glutamine), choline, polyamines, nucleotides, non-protein nitrogen sources such as urea, immunoglobulins andoligosaccharides.

These components in breast milk might be presentadventitiously or they might be present for specific pur-poses, which have been developed under evolutionarypressure. In any case, study of their function can possiblyinform the development of infant formulae and might havewider implications.

3.1.4 Research opportunities

3.1.4.1 Basic science.X The development of the interaction between food com-

ponents and gene expression needs to be better elucid-ated. Targeting of genes affected by, and the nature ofinteraction with, specific nutrients such as glucose,cholesterol, fatty acids and amino acids needs to becharacterized.

X To what extent is metabolic maturation intrinsicallycontrolled? How much is it responsive and determinedby external stimuli such as the pattern of feeding andchanges in the nature of the diet?

X The bioactive compounds in breast milk should be char-acterized in further detail. There might be opportunities


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to isolate and include them as functional components ininfant formulae or other foods.

X Research is required on the interactions of differentdietary components on the development and long-termfunction and integrity of intestinal function (substrate trans-porters, mucosal immunity and xenobiotic metabolizingsystems), intestinal growth and microflora.

X Oral immunotolerance and dietary factors modulatingthe development of food protein allergy need bettercharacterization.

3.1.4.2 Cross-sectional and prospective epidemiologicalevidence.X What is the interaction between the ingestion of human

breast milk and the programming and development ofinfant metabolism during the subsequent introduction ofdiversified diet?

X Possible mechanisms must be identified to explain theepidemiological associations between impaired intra-uterine and postnatal growth and the prevalence, inadulthood, of obesity, diabetes mellitus, hypertension,hypercholesterolaemia, cardiovascular disease, obesityand other diseases. Well-structured prospective studies,using appropriate markers, are needed.

3.1.4.3 Markers.X There is a general need to apply many of the markers

developed for the study of intermediary metabolism andwell-being (see later in this Section) to the prospectivestudy of the long-term impact of feeding in early childhood.

3.1.4.4 Human intervention studies.X The nutritional and metabolic basis of the benefits of breast

feeding and of human milk need better understanding.What are the maternal dietary factors that influence thecomposition of human milk? The early differences insubstrate metabolism, body composition, the efficiency ofgrowth and functional development between breast-fedbabies and those fed infant formula might be important.

3.1.4.5 Evidence of safety.X We need the scientific basis to be more specific about

nutritional needs during weaning and childhood to be ableto address the potential risks of infants and children beinggiven an adult diet too early or too late. Weaning and theadaptation to an adult diet is assumed to be a gradualprocess, but this has not been systematically established.

X Although all of childhood involves growth and develop-ment, the most critical periods are probably thosein uteroand during early infancy, as well as the growth spurtsduring pre-school age and during puberty. The develop-ment of functional foods for pregnant women and lactatingmothers will need special consideration of the possibleadverse effects of these foods on the fetus and child.

3.2 Substrate metabolism(Bellisle et al. 1998, S47–S75)

3.2.1 Introduction

A number of chronic diseases such as obesity, non-insulin-dependent diabetes mellitus (NIDDM) and osteoporosis are


Table 1. Examples of opportunities for modulation of target functions related to growth, development and differentiation by candidate foodcomponents with possible markers*

Target functions Possible markers Candidate food components

Maternal adaptation during maternal weight micronutrientspregnancy and lactation body fat n-3 and n-6 PUFA

infant birth weight energymilk volume and quality

Skeletal development ultrasound measures calciumanthropometric measures vitamin Dbone mineral density (e.g. DEXA) vitamin C

Neural tube development ultrasound measurements folic acid

Growth and body composition anthropometry growth factorsbody fat mass essential amino acidstotal body water unsaturated fatty acidsprocollagen propeptide excretionurinary creatinine excretion

Immune function cellular and non-cellular immune markers vitamin Avitamin Dantioxidant vitaminsn-3 and n-6 PUFAtrace elementsargininenucleotides and nucleosidesprobiotics

Psychomotor and cognitive tests of development, behaviour, cognitive function and visual acuity n- and n-6 PUFAdevelopment (electro-) physiological measurements iron

zinciodine

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S5–S45), where, if not given in this Consensus Document, further detailsof options for modulations, markers and safety issues can be found.

n-3 PUFA ¼n-3 series long-chain polyunsaturated fatty acids.n-6 PUFA ¼ n-6 series long-chain polyunsaturated fatty acids.DEXA ¼ dual-energy X-ray absorptiometry.

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partly related to changes in total food intake, levels ofphysical activity and a poorly balanced diet.

The balance of the diet can determine substrate metabol-ism and the optimally balanced diet is usually expressed interms of its macronutrient content. The carbohydrates aresubdivided chemically into monosaccharides, disacchar-ides, oligosaccharides, starches, and non-starch polysac-charides, polyols and alcohol. Nutritionally, a mostimportant distinction is between carbohydrates that aredigested and absorbed in the small intestine and those thatare not. The lipids are defined according to their fatty acidcomposition, particularly the relative contents of saturatedfatty acids (SFA), monounsaturated fatty acids (MUFA)(cis and trans) and the polyunsaturated fatty acids (PUFA),which can be further sub-divided into the PUFA of the n-6series and the PUFA of the n-3 series.

A number of adverse metabolic changes and other cardio-vascular risk factors tend to ‘cluster’ within individuals. Theseinclude high blood pressure, high plasma levels of insulin and/or glucose, high plasma levels of triacylglycerols (TAG) in thefasting state and after a meal, a preponderance of small, denselow-density lipoprotein (LDL) particles and low levels of high-density lipoprotein cholesterol (HDL). The terms ‘SyndromeX’, ‘metabolic syndrome’ or ‘insulin-resistance syndrome’have been used to describe the whole cluster of cardiovas-cular risk factors since the underlying change appears to bean increase in insulin resistance (or a decrease in insulinsensitivity) of the tissues. The characteristic changes in thelipid profile have been called the Atherogenic LipoproteinPhenotype (ALP). Each of these factors has been shownto relate independently to the risk of CVD, and insulinresistance is a strong marker of the risk development ofNIDDM.

During physical stress such as exercise, the substratedemands are enormous and a balanced diet with a carefullyplanned mix of food components can play a crucial role inimproving the level of performance.


3.2.2.1 Maintenance of appropriate body weight, bodycomposition and body fat distribution. Obesity developswhen the energy intake is consistently greater than energyexpenditure. The excess energy is stored in the form ofadipose tissue and results in a body weight and total body fatcontent that is excessive for height.

Obesity, particularly a tendency to store fat in internal,visceral depots (‘central obesity’), is associated with anincreased risk of developing high blood pressure, insulinresistance, diabetes and CVD. Since obesity and relative fatdistribution are themselves, in part, genetically determined,there might be a considerable genetic component to theinsulin resistance syndrome. Nevertheless, they must also bestrongly influenced by environmental factors including dietand physical activity level. There has been a shift towardsthe consideration of markers that can distinguish ‘centralobesity’ as well as the more traditional body markers fortotal body fat in the determination of the health risks of obesity.

3.2.2.2 Control of macronutrient oxidation. Achievementof macronutrient balance requires that the net oxidation of

each macronutrient equals the amount of that nutrient in thediet. Oxidation of carbohydrates and proteins tend to vary inresponse to the recent intake of each fuel and thus these twofuels appear to regulate their own oxidation. In contrast,when carbohydrate content of the diet is constant, fat intake,particularly in the short term, does not always directlypromote its own oxidation.

3.2.2.3 Regulation of thermogenesis. The increased energyexpenditure after a meal (diet-induced thermogenesis) ismediated by a prolonged activation of the sympatheticnervous system leading to an increased catecholaminerelease.

3.2.2.4 Control of insulin sensitivity and blood glucosecontrol. Insulin sensitivity is usually measured as theability of insulin to stimulate glucose disposal, usually bymeans of the ‘clamp’ technique. The measurement of thefasting plasma insulin and glucose concentrations can beused as simple markers, suitable for large-scale epidemio-logical studies. Fasting blood glucose values in the upperpart of the normal range, which become mildly elevatedafter a meal (impaired glucose tolerance), might representa cardiovascular risk factor. Values that exceed the upperlimit of the normal range might become the primary causeof the long-term microvascular complications of diabetes(such as those that affect the retina, the kidneys and thenervous system).

3.2.2.5 Control of plasma triacylglycerols. The com-bination of elevated plasma TAG concentrations andlow HDL-cholesterol concentrations is a particularlystrong risk marker for CVD. This is the characteristicdisturbed lipid profile associated with insulin resistance.The magnitude and duration of elevated TAG concentra-tions after a meal (postprandial lipidaemia) is a strongmarker of CVD risk, even in the presence of normal fastingTAG concentrations.

3.2.2.6 Optimal performance during physical activity.Training and competition will increase the daily energyexpenditure by between 500 and 1000 kcal per hour ofexercise, depending on its intensity. Large sweat lossesmight pose a risk to health by inducing severe dehydration,impaired blood circulation and heat transfer. This willultimately lead to heat exhaustion and collapse. Insufficientreplacement of carbohydrates might lead to low bloodglucose levels, fatigue and exhaustion.

The requirements for specific nutrients and water dependson the type, intensity and duration of the physical effort.Specific nutritional measures and dietary interventions canbe devised that are particularly appropriate for the distinctphases of preparation, competition and recuperation.


X Foods with reduced energy and/or fat content can help tocontrol body weight and to improve glucose toleranceand insulin sensitivity. Further developments will includethe use of new fat replacers and fat substitutes and thesearch for food components that can specifically mod-ulate ‘central obesity’. Saturated fatty acids could impairinsulin sensitivity thus increasing the risk of developing


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NIDDM. In contrast, n-6 PUFA (but not n-3 PUFA)might decrease this risk, but this needs to be confirmed byintervention trials.

X The glycaemic index (GI) can be used to categorize foodsand is defined as the incremental blood glucose area afterthe test product has been ingested. It is expressed as apercentage of the corresponding area after ingesting aglucose load or a carbohydrate equivalent amount ofwhite bread – both of which have high GIs. An increasein foods with a lower GI in the diet, such as pasta orlegumes, might improve postprandial blood glucoselevels and might help to improve insulin sensitivity inthose prediposed to NIDDM.

X Non-digestible, fermentable carbohydrates in the diet(resistant starch, non-starch polysaccharides and oligosac-charides and polyols), and, possibly, some of their fer-mentation products, could also lower blood glucose levelsby a decrease in liver glucose production. Cell wall poly-saccharides are able to ‘encapsulate’ dietary carbohydratesand, in so doing, slow their accessibility and thus theirdigestibility. Soluble viscous fibres consumed in largeamounts have the most effect on postprandial glucoseand insulin response. The effect is related to viscosity,which inhibits mixing and diffusion in the intestinal tractand possibly delays gastric emptying.

X Caffeine is a potent thermogenic agent of the group ofmethylxanthines, but other pungent components fromspices, such as ginger, chilli and mustard, are alsopotential thermogenic agents.


3.2.4.1 Basic science.X Further research is necessary to understand mechanisms

responsible for insulin resistance, in particular in relationto the role of intermediary carbohydrate and fat metabol-ism in the development of ‘central’ obesity.

X What is the effect of different types of carbohydrate in theregulation of carbohydrate balance? What are the mech-anisms behind the impact of the ratio of PUFA to SFA inthe diet on fat oxidation? We need to know the impact ofthe different short-chain fatty acids (SCFA), such asacetic and propionic acids, on metabolism in general.

X Are there mechanisms, apart from the activation of thesympathetic nervous system, that can account for theelevation of diet-induced thermogenesis?

X Nutrient mechanisms that have an impact on geneticexpression or immunological function should be examined.Modern methods of molecular biology and immunologymust be used with a focus on post-translational modifica-tions related to various proteins, diets or indispensablesubstrates. Interactions between different nutrients are anessential focus of future studies because of alterationscaused by the ageing process.

3.2.4.2 Cross-sectional and prospective epidemiologicalevidence.X Is it possible to make a distinction between the genetic

and the environmental components of the ALP? ALPappears to be a secondary consequence of insulin resistance


Table 2. Examples of opportunities for modulation of target functions related to substrate metabolism by candidate food components withpossible markers*


Maintenance of desirable body BMI, body fat content anthropometric indices and imaging energy density (↓)weight techniques as indirect and direct measures of ‘central obesity’ fat replacers

respiratory quotient carbohydrate : fat ratioresting metabolic rate food with low glycaemic index

fibre

Control of blood glucose levels fasting glucose as for body weight control, plus:and insulin sensitivity postprandial glucose food with low glycaemic index

glucose tolerance test soluble viscous fibreglycosylated haemoglobin saturated fatty acids (↓)measures of insulin dynamicsfasting plasma insulin

Control of TAG metabolism fasting plasma TAG as for body weight control, plus:postprandial plasma TAG n-3 PUFA

n-6 PUFAmonounsaturated fatty acids

Optimal performance during body temperature water/electrolytesphysical activity performance testing energy

muscle mass high and low glycaemic indexmuscle protein synthesis carbohydrates

ergogenic substances such ascreatine

protein/specific amino acids

Fluid homeostasis water balance isotonic carbohydrateselectrolyte balance electrolyte fluids

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S47–S75), where, if not given in this Consensus Document, furtherdetails of options for modulations, markers and safety issues can be found.

(↓) ¼ reduced intake of candidate food component.TAG ¼ triacylglyceroln-3 PUFA ¼ n-3 series long-chain polyunsaturated fatty acids.n-6 PUFA ¼ n-6 series long-chain polyunsaturated fatty acids.

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but is often regarded as a genetic condition. How pre-valent is ALP in non-obese, non-diabetic subjects?

X Is it reasonable to base our understanding of the effectsof dietary manipulation within individuals on evidencefrom epidemiological studies? An elevated plasma TAGconcentration, for example, might be a risk factor forCHD in epidemiological terms, but does it then followthat elevation of plasma TAG by dietary means confersan equivalent risk?

3.2.4.3 Markers.X Achievement of the above goals requires the develop-

ment of analytical methods (bioassay), the identificationof markers and a more precise knowledge of nutrientrequirements.

3.2.4.4 Human intervention studies.X What are the long-term effects of macronutrient repla-

cers, in particular fat replacers, on energy and fat balanceand on body weight control? Is the consumption of fat-reduced or energy-reduced foods eventually compensatedfor by an increased total food intake?

X Long-term intervention studies are required to investigatewhether insulin resistance can be ameliorated by themanipulation of the carbohydrate : fat ratio in the dietand by the composition of the dietary fatty acids. Shorter-term mechanistic studies should also be carried outwithin these long-term studies to investigate the regula-tion and rate of adaptation of carbohydrate and fat balancewithin the body. Potential gene/nutrient interactions mustbe considered.

X Low GI foods are a useful tool for dietary management ofpeople with NIDDM, and some can help to reduce plasmacholesterol concentrations and insulin resistance. Theirfurther potential should be explored, particularly in relationto the prevention of NIDDM and cardiovascular diseases.

X It is critically important that long-term (at least 6 months)studies of the effects of low-fat, high-carbohydratediets on plasma lipid constituents are carried out. Isthe elevation of plasma TAG concentration on a high-carbohydrate diet transient or longer lasting? What is thenature of the elevation of plasma TAG concentrations,i.e. what are the size and density of lipoprotein particlescontaining TAG? What is the impact of the elevation ofTAG on other lipid constituents (e.g. the density distri-bution of LDL particles) and on postprandial lipidaemia?

X It is important to know the effects of different types offatty acids and available carbohydrates, as well as theeffects of the carbohydrate : fat ratio, on long-term energyand substrate balance.

3.2.4.5 Evidence of safety.X The safety of substances that modulate energy and

glucose metabolism should be evaluated in short- andlong-term studies because of the risk of disturbances inthe lipid and glucose metabolism.

3.3 Defence against reactive oxidative species(Bellisle et al. 1998, S77–S112)

3.3.1 Introduction

The normal development and functioning of any aerobic

organism is associated with the generation of reactiveoxidative species (ROS), referred to as oxidants or pro-oxidants. ROS are responsible for oxidative damage tobiological macromolecules such as DNA, lipids or proteins,which might be involved in the initiation or progression ofdiseases, such as some forms of cancer and cataract,cardiovascular disease, age-related macular degeneration,rheumatoid arthritis and a number of neurodegenerativeconditions such as Parkinson’s disease or Alzheimer’sdisease. Gene regulation and the immune system mightalso be affected. It is also possible that ROS are involvedin intracellular signal transduction.

ROS can arise endogenously as secondary products fromnormal metabolic reactions, or they can be primarily formedas part of the body’s defence against foreign organisms. Thebody is also exposed to ROS from external sources; manyprooxidants are present in the diet and are inhaled incigarette smoke and in other forms of air pollution. Themost relevant ROS are peroxyl radicals (ROO⋅), the nitricoxide radical (NO⋅), the superoxide anion radical (O2⋅−), thehydroxyl radical (OH⋅), singlet oxygen (1O2), peroxynitrite(ONOO−), and hydrogen peroxide (H2O2).

To counteract the oxidant load, a diversity of defencemechanisms operate in biological systems, which includeboth enzymic and non-enzymic antioxidant systems. Anantioxidant has been defined as ‘any substance that, whenpresent in low concentrations compared to that of anoxidizable substrate, significantly delays or inhibits theoxidation of that substrate’.


3.3.2.1 Preservation of structural and functional activity ofDNA. Oxidative damage to DNA can lead to strand breaksand/or the modification of DNA bases, which might result inpoint mutations, deletions, or gene amplification. TheCOMET assay can measure distortion of morphology dueto damaged DNA. High-performance liquid chromatogra-phy (HPLC) and gas chromatography–mass spectrophoto-metry (GC–MS) methods can be used to measure damagedDNA bases such as 8-hydroxy-deoxyguanine; antibodytechniques are currently also being developed for thispurpose. However, measurement of gross damage to DNAmight give little information about oxidative damage tospecific genes whose expression has a key cellular function.

3.3.2.2 Preservation of structural and functional activityof circulating lipoproteins and of polyunsaturated fattyacids in cell membranes. Oxidation of the PUFAs in LDLwithin the arterial wall plays a major role in thepathogenesis of fatty streak formation in arteries, which,in turn, leads to atherosclerosis. Oxidative modification ofboth the lipid and protein part of the lipoprotein contributeto the atherogenic properties of oxidized LDL (LDLOX).The products of lipid oxidation are best measured in plasmaas lipid hydroperoxides or their derivatives such asmalondialdehyde, or as isoprostanes. Development ofisoprostane measurement will advance specificity andprecision and is expected to provide a marker for wholebody lipid peroxidation. Direct measurements of oxidizedLDL are also now possible.


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Oxidative stress might play a role in the development ofneuronal degeneration, since ROS can cause peroxidation ofthe PUFA in all cell membranes including nerve cells withsubsequent membrane disruption.

3.3.2.3 Preservation of structural and functional activity ofproteins. Proteins in the lens of the eye are extremelylong-lived and often show oxidative damage by ROSthrough chronic exposure to light and oxygen. Damagedproteins can aggregate and precipitate, giving rise tocataracts and to macular degeneration in elderly people.The methodology for the measurement of oxidative damageto the protein part of lipoproteins and other proteins has not,as yet, been sufficiently developed and evaluated.


X The human diet contains an array of different compoundsthat possess either antioxidant activities or the apparentability to scavenge ROS. Epidemiological studies sup-port the hypothesis that the major antioxidant nutrientsvitamin E and vitamin C (as well asb-carotene, whichmight or might not be acting as an antioxidantin vivo)play a beneficial role in the maintenance of health andin the reduction of chronic disorders. LDL oxidation isefficiently inhibited by lipophilic antioxidants, of whicha-tocopherol is the most important inin vitro systems;b-carotene is, however, ineffective. Carotenoids andpolyphenolic compounds such as flavonoids are alsopotent antioxidants in otherin vitro systems, but thereis no evidence that they function this wayin vivo.Vitamin C has been demonstrated to be the mostimportant antioxidant in the human eye.

X The food industry has a long experience in the controlof oxidative damage in foods and this expertise can beused to advantage for the protection of antioxidantsspecifically used as food components to be beneficial tohealth.


3.3.4.1 Basic science.X More studies are needed on the uptake, distribution,

metabolism and elimination of vitamin E and vitamin C.X Can flavonoids and carotenoids be taken up by human

subjects and distributed to the tissues in quantities suffi-cient to confer a biological effect, and what is the natureof that effect if it occurs?

X Are there combined effects of synergy or antagonismboth with respect to the antioxidants themselves or toother food components?

X Is it the antioxidant role of the substance that is import-ant, or is it some other function, such as some aspects ofthe modulation of gene expression?

X Further work is needed on the chemical analysis of theantioxidant content of foods so that more realistic foodcomposition tables can be compiled. Ideally this shouldtake account of agricultural practices, industrial proces-sing and food preparation.

3.3.4.2 Cross-sectional and prospective epidemiologicalevidence.X Better food composition data and better markers of

disease could enable re-analysis of existing epidemiolo-gical data in some cases and will improve study design infurther investigations. Further knowledge of basicscience will also allow consideration of confoundinginfluences in epidemiological studies.

3.3.4.3 Markers.X Because direct measurementin vivo of the prooxidants

that are detrimental to human health is difficult orimpossible, it is essential to develop and validate anumber of markers of oxidative damage to key bodystructures that are non-invasive and can be used ethicallyand acceptably in human volunteers.

X Existing methods for measurement of oxidative damagein human subjects in a non-invasive manner must be


Table 3. Examples of opportunities for modulation of target function by candidate food components and possible markers related to defenceagainst reactive oxidative species*


Preservation of structural and functional measurement of damaged DNA components vitamin Eactivity of DNA vitamin C

carotenoidspolyphenols including flavonoids

Preservation of structural and functional measurement of lipid hydroperoxides or vitamin Eactivity of polyunsaturated fatty acids derivatives vitamin C


Preservation of structural and functional measurement of lipid hydroperoxides and vitamin Eactivity of lipoproteins oxidized apoproteins vitamin C


Preservation of structural and functional measurement of damaged proteins or components vitamin Eactivity of proteins vitamin C

seleniumcarotenoidspolyphenols including flavonoids

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S77–S112), where, if not given in this Consensus Document, furtherdetails of options for modulations, markers and safety issues can be found.

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refined and validated. Results obtained in the samelaboratory on identical material using different, butcomplementary, methodology should be compared. Forthe purposes of quality assurance, results from severaldifferent participating laboratories of oxidative damagein identical samples must be compared.

X In the case of reduction of disease risk, it is important toshow that markers are clearly linked to those phenomenathat give rise to a specific human disease since itsdevelopment is the ultimate paradigm by which therelevance of a marker is judged. For example, which ofthe multiple oxidative modifications of DNA are thosethat lead to carcinogenesis? What is the comparativerelevance of modification of the protein and lipid inLDL particles or of changes in thickening of the carotidartery wall, all of which contribute to the process ofatherogenesis?

3.3.4.4 Human intervention studies.X A new generation of intervention trials using validated

and accepted markers as intermediate endpoints might beused to test the efficacy of antioxidants; these willprovide results in a shorter time than old-style interven-tion studies where development of disease was the onlymarker. Bioavailability studies and dose-response stu-dies, in combination with the development and applica-tion of biomarkers, are required for a successful researchstrategy.

X These new studies will enable quantitation of the optimallevels of intake of antioxidants. Care must be taken toensure that the importance of the antioxidant contributionof the whole diet, as distinct from that of each individualantioxidant, is evaluated.

3.3.4.5 Evidence of safety.X The mechanism for the apparent exacerbation of the

incidence of lung cancer in heavy smokers given supple-ments ofb-carotene needs urgent clarification. Furtherwork is also needed on the safety of other carotenoids,flavonoids and other phenolic compounds that have beenshown to have bioactivity in human subjects.

X Developments in food technology will include the pre-servation, enhancement, and perhaps additionde novotofoods, of the particular forms of antioxidants that havebeen shown to have functional capacity.

3.4 Cardiovascular system(Bellisle et al. 1998,S113–S146)

3.4.1 Introduction

CVD is essentially caused by the narrowing of the arteries,which can lead to a reduced supply of oxygen to organs suchas the heart, skeletal muscle, brain, intestine and kidneys.Key elements involve changes in the constituents of theblood and in the walls of the blood vessels. The main targetfunctions in this process are those involved with the integ-rity of the blood vessels (e.g. control of cellular immuno-logy and hypertension); in lipoprotein homeostasis (e.g.insulin resistance) and the control of the thrombogenicbalance (the likelihood of blood clot formation). The inter-dependence of these factors has not been fully character-ized, and since only 50 % of the incidence of CVD can be

explained by the known risk factors, there are possibly otherunexplored contributory and interactive factors, such asgenetic polymorphisms.


3.4.2.1 Lipoprotein homeostasis. A raised plasma con-centration of LDL cholesterol is a risk factor for CVD. Highlevels of lipoprotein(a), very low-density lipoprotein(VLDL), TAG concentrations and low levels of HDLcholesterol are strong risk indicators, rather than riskfactors, for CVD.

It is important to consider the lipoprotein profile after ameal (the postprandial response), as well as under fastingconditions, in relation to CVD. For example, the athero-genicity of lipoprotein remnants is more pronounced onhigh-fat diets, which induce higher postprandial TAG levels,even if fasting TAG levels are low. Long-chain n-3 PUFAfrom fish oil might reduce the postprandial TAG response.

The efficacy of dietary manipulations to alter lipoproteinprofiles depends on an individual’s genetic constitution. Forexample, there is a genetic polymorphism for one of theapolipoproteins, apolipoprotein E (apoE). People with theapoE2 isoform have a delayed clearance of lipid-richparticles after a meal that is rich in fat, because this typeof apolipoprotein has a lower affinity for the receptors onliver cells, resulting in slower removal from the plasma.

3.4.2.2 Endothelial and arterial integrity. Damage to, oractivation of, the endothelial cells that line the arteries, aswell as more general structural damage at susceptible pointsin the arteries (such as bifurcations), might increase the riskof atheromatous plaque formation. Endothelial activationincreases production, release or exposure of various reactivemolecules such as cytokines, adhesion molecules andmarkers of platelet activation and it causes decreasedsynthesis of some prostaglandins and transforming growthfactors. The consequences might be inflammatory changesand fibrosis of the vascular wall with an increased risk ofsmall blood clot formation. These consequences are allthought to be involved in fibrous plaque formation.

3.4.2.3 Control of thrombogenic potential. The control ofthrombogenic potential is likely to be an important elementin the reduction of CVD. However, available measures ofplatelet functionin vitro and plasma concentration of factorsinvolved in coagulation and in fibrinolysis are not reliableindicators of any pro-thrombotic state or risk in humans.Similarly, the particular influence of endothelial cells on thisprocess, as indicated by relevant markers, has not beensufficiently elucidated.

3.4.2.4 Control of homocysteine levels. Epidemiologicaldata suggest that high plasma levels of homocysteine areassociated with increased risk of CVD and several proposedmechanisms for the effects of homocysteine on atherogenesisand thrombosis have been suggested.

3.4.2.5 Control of hypertension. CVD is directly related tosystolic and diastolic blood pressure, and antihypertensivemeasures reduce the risk of coronary disease. Evidencesuggests that, in addition to certain food components(e.g. sodium, calcium, certain fatty acids), many other factors


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are involved in the aetiology of hypertension (e.g. geneticpredisposition, obesity, etc.).


X Dietary SFA (chain length up to 16 carbon atoms)increase plasma LDL cholesterol concentrations morethan they increase plasma HDL concentrations. Stearicacid (C18 : 0) has less effect on plasma LDL and HDL.Dietary trans-unsaturated fatty acids increase plasmaLDL and reduce HDL cholesterol concentrations. More-over, they increase the plasma lipoprotein(a) concentra-tion. Foods low in SFA andtrans fatty acids could,therefore, reduce the risk of CVD.

X The cis-unsaturated fatty acids oleic, linoleic and alphalinolenic acids reduce plasma concentrations of LDLcholesterol without significantly affecting plasma HDLcholesterol and lipoprotein(a) concentrations. Foodsenriched in these unsaturated fatty acids, therefore,could also be used to reduce the risk of CVD.

X Soluble fibre, certain phytosterols and phytostanols andother food components can reduce LDL cholesterolconcentrations, particularly in hyperlipidaemic subjects.Similar effects have been shown for ethanol and for garlic.

X The long-chain n-3 PUFA found in fish oils can promotemechanisms that improve endothelial and arterial integrity,particularly those dependent on the balance of prosta-glandins. They also reduce plasma TAG and may alsohave suppressive effects on the cellular immune system.

X Diets rich in antioxidants can influence the activities ofimmune-competent cells and can inhibit the expressionof genes coding for the cell–cell adhesion factors.

X There is scope for the modulation of factors such as highplasma homocysteine concentrations and high bloodpressure to protect vascular integrity.


3.4.4.1 Basic science.X Modifications to certain fatty acids, cholesterol and other

lipids should be developed in order to influence theirabsorption and/or systemic handling.

X What is the mechanism of LDL uptake by monocytes andmacrophages and what are the factors influencing theaccess of these cells to the vascular sub-endothelialspace?

X The underlying short- and long-term mechanisms, fast-cell signalling-pathway factors involved in cell–cellinteractions, thrombogenic and inflammatory reactionsshould be studied in detail at the level of gene activationand transcription. These could help to explain the linksbetween certain food components and the developmentand possible regression of vascular lesions.

3.4.4.2 Cross-sectional and prospective epidemiologicalevidence.X Because cardiovascular disease is a multifactorial condi-

tion, we need to know, in the context of nutrition and


Table 4. Examples of opportunities for modulation of target functions related to the cardiovascular system by candidate foodcomponents with possible markers*


Lipoprotein homeostasis lipoprotein profile, including: #SFA (↓)plasma LDL-cholesterol MUFAplasma HDL-cholesterol PUFAplasma TAG (fasting and postprandial response) certain phytosterolslipoprotein particle size certain phytostanols

soluble fibretrans-fatty acids (↓)soy proteinstocotrienolsfat replacers

Arterial integrity #growth factors certain antioxidantsadhesion molecules n-3 PUFA from fishcytokines

Control of thrombogenic potential platelet function n-PUFA from fishactivated clotting factors and activation peptides certain antioxidants

linoleic acid

Control of hypertension systolic and diastolic blood pressure total energy (↓)sodium chloride (↓)n-3 PUFA from fish

Control of homocysteine levels plasma homocysteine levels folic acidvitamin B6vitamin B12

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S113–S146), where, if not given in this ConsensusDocument, further details of options for modulations, markers and safety issues can be found.

(↓) ¼ reduced intake of candidate food component.# ¼ see text.n-3 PUFA ¼ n-3 series long-chain polyunsaturated fatty acids.SFA ¼ saturated fatty acids.MUFA ¼ monounsaturated fatty acids.TAG ¼ triacylglycerol.LDL ¼ low-density lipoprotein.HDL ¼ high-density lipoprotein.

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public health policy, who is likely to benefit fromparticular dietary/ingredient modifications.

X There is also a need to characterize prospectively, andestablish relationships between, population groups andpossible risk indicators/factors, such as high bloodpressure, high levels of homocysteine in the blood,abnormal lipid profiles, and CVD.

3.4.4.3 Markers.X Prospective validation studies should be performed to

establish to what extent the presently available indicatorsactually reflect the risk of arterial thrombosis. The currentavailable indicators of arterial thrombosis tendencyinclude platelet aggregationin vitro, urinary excretionof thromboxane- and prostacyclin metabolites and ofspecific platelet proteins, plasma concentrations ofsoluble forms of cell adhesion molecules, activationfragments of clotting factors, and fibrin degradationproducts.

X It might be necessary to develop and validate newmethods to measurein vivo arterial thrombosis tendencyin humans and to look for, and prospectively validate,more specificin vivo activation markers for platelets,endothelial cells, leukocytes, clotting factors and thefibrinolytic process.

X Markers of cellular and immune activation are needed.Measurements of soluble adhesion molecules in plasmaand, possibly, of cleavage products in urine, mightimprove the diagnosis of CVD and the evaluation of itsprognosis. In addition these markers may help to estab-lish and monitor the impact of nutrient supplementation.

3.4.4.4 Human intervention studies.X Interactions and relative amounts of fatty acids (e.g. the

n-3 PUFA : n-6 PUFA ratio, palmitate) and the effect ofdietary cholesterol on lipid metabolism (particularly onpostprandial hyperlipidaemia), should be studied in well-controlled dietary trials. These investigations shouldexamine systemic trafficking of the fatty acids and thelipoproteins. Effects on other lipid parameters, such asthe key enzyme activities in TAG metabolism andlipoprotein particle sizes, should also be studied inorder to understand the dietary effects on lipoproteinmetabolism.

X The effect of selected dietary components (e.g. individualn-3 and n-6 fatty acids and combinations of them,antioxidants, fibre) on the processes involved in arterialthrombus formation should also be established andcharacterized.

X The effect of dietary constituents, e.g. fatty acids andbioactive amines, on nitric oxide (NO) metabolism, freeradicals and other local endothelial mediators of vasculartone should be explored.

X Particular attention ought to be paid to study design andto characterization of experimental subjects. Geneticpolymorphisms and diet–gene interactions, life-styleeffects and endocrine factors must all be considered.

3.4.4.5 Evidence of safety.X The potential toxicity of very high intakes of long-chain

PUFA and antioxidants should be investigated.

3.5 Intestinal physiology(Bellisle et al. 1998,S147–S170)

3.5.1 Introduction

The gut is an obvious target for the development of functionalfoods since it acts as an interface between the diet and theevents that sustain life. The target functions relating to thephysiology of the gut can be subdivided according to thosethat determine transit time and stool characteristics, those thatinvolve the colonic microflora, those that are associated withthe gut-associated lymphoid tissue (GALT), and those thatdepend on the products of nutrient fermentation.

The development of intestinal and mucosal microfloraprovides the basis for the gut barrier that prevents patho-genic bacteria from invading the gastrointestinal tract. Thebalance of intestinal microflora together with the gutimmune system allows the resident bacteria to have aprotective function.

The principal role of the intestinal flora, apart from theirbarrier function against infection, is to salvage energy fromcarbohydrates not digested in the upper gut, through fer-mentation. The main substrates for fermentation are endo-genous (e.g. mucus) and dietary carbohydrates that haveescaped digestion in the upper gastrointestinal tract. Theseinclude starch that enters the colon (resistant starch), as wellas non-starch polysaccharides, e.g. celluloses, hemi-celluloses, pectins and gums. Other carbohydrate sourcesavailable for fermentation include non-digestible oligo-saccharides, and sugar alcohols. In addition, proteins andamino acids can be effective as growth substrates forcolonic bacteria. Total substrate availability in the humanadult colon is 20–60 g of carbohydrate and 5–20 g ofprotein per day.


3.5.2.1 Optimal intestinal function and stool formation.Both large bowel integrity and the colonic microflora areimportant in determining the characteristics of the stool.Such characteristics include stool weight and consistency,stool frequency and total intestinal transit time. Theseare possibly the most reliable markers of general colonicfunction.

3.5.2.2 Colonic flora composition. Bacterial numbers andcomposition vary considerably along the human gastro-intestinal tract but the large intestine is by far the mostintensively populated microbial ecosystem with severalhundred species accounting for a total of between 1011–1012

bacteria per gram of contents. Quantitatively, the mostimportant genera of intestinal bacteria in man arethe bacteroides and the bifidobacteria, which can accountfor 35 % and 25 % of the known species, respectively. Themicroflora of the large intestine is acquired at birth andreflects the breast-milk-based diet of infants. Subsequently,however, differences in the species composition develop,largely as a result of differences in adult-type diets.

The colonic microflora is a complex interactive commu-nity of organisms and its functions are a consequence of thecombined activities of the microbial components. The groupof potentially health-promoting bacteria are thought toinclude principally the bifidobacteria and lactobacilli. The


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major diseases in which changes in the composition of thegastrointestinal microflora might possibly play a role aregastrointestinal infections, constipation, irritable bowel syn-drome, inflammatory bowel diseases and colorectal cancer.

The composition and activities of the colonic microflorahave to be considered both as a risk indicator and a riskfactor for large bowel functions (see Section 2). Thecomposition and activity of the faecal flora, when analysedcorrectly, are also good indicators of the residual colonicflora. Traditional gut microbiological methodologies arebased on morphological and biochemical properties of theorganisms. However, recent advances in molecular geneticsfor quantitative and qualitative monitoring of the nucleicacids of human colonic microflora have revolutionized theircharacterization and their identification. This approach alsoallows extensive (including multiple centre) bacteriologicalinvestigations.

3.5.2.3 Control of gut-associated lymphoid tissue (GALT)function. The human intestine GALT represents the largestmass of lymphoid tissue in the body, and about 60 % of thetotal immunoglobulin produced daily is secreted into thegastrointestinal tract. The colonic microflora is the majorantigenic stimulus for specific immune responses at localand systemic levels. Abnormal intestinal response to a foreignantigen, as well as local immunoinflammatory reactions,might, as a secondary event, induce impairment of theintestine’s function because of breakdown of the intestinalbarrier.

3.5.2.4 Control of fermentation products. The importanceof fermentation products in the form of SCFA (namelybutyrate, acetate and propionate) for colonic health has beenincreasingly documented. Butyrate is the most interesting ofthe SCFA since, in addition to its trophic effect on themucosa, it is an important energy source for the colonicepithelium and regulates cell growth and differentiation.


X Probiotics, prebiotics and possibly synbiotics are inter-esting concepts to support the development of functional

foods that are targeted towards gut functions. A probioticis defined as ‘A live microbial food ingredient that isbeneficial to health’. Prebiotics, in contrast, are ‘non-digestible food components that beneficially affect thehost by selectively stimulating the growth and/or activityof one or a limited number of bacteria in the colon, thathave the potential to improve host health’. Synbiotics arebest described as ‘a mixture of probiotics and prebioticsthat beneficially affects the host by improving thesurvival and implantation of live microbial dietarysupplements in the gastrointestinal tract’.

X Probiotics have been shown to stimulate the activity ofsome compounds of the GALT, e.g. immunoglobulin A(IgA) antibody response, production of cytokines andreduction of the risk of rotavirus infections.

X Prebiotics (as well as probiotics) help the colonic micro-flora to reach/maintain a composition in which bifido-bacteria and/or lactobacilli become predominant innumber. This is considered optimal for health promotion.

X Non-digestible carbohydrates increase faecal mass bothdirectly by increasing non-fermented material and/orindirectly by increasing bacterial biomass; they alsoimprove stool consistency and stool frequency.

X Promising food components for functional foods will bethose, such as specific non-digestible carbohydrates, thatcan provide optimal amounts and proportions of fermenta-tion products at relevant sites in the colon, particularlythe distal colon, if they are to help reduce the risk of coloncancer.


3.5.4.1 Basic science.X More methods need to be developed to characterize

intestinal microflora, including the non-culturable spe-cies. Molecular approaches based on the separation andidentification of genetic material, such as 16S ribosomalRNA, are promising.

X We need to understand the role of the human diet in thegeneral modulation of immune functions, particularly theexact role of GALT.


Table 5. Examples of opportunities for modulation of target functions related to intestinal physiologyby candidate food components with possible markers*


Optimal intestinal function stool consistency non-digestible carbohydratesand stool formation stool weight probiotics

stool frequency prebioticstransit time synbiotics

Colonic flora composition composition probioticsenzyme/metabolic activities prebiotics

synbiotics

Control of GALT function IgA secretion probioticscytokines prebiotics

synbiotics

Control of fermentation short-chain fatty acids prebioticsproducts synbiotics

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S147–S171),where, if not given in this Consensus Document, further details of options for modulations, markers and safetyissues can be found.

GALT ¼ gut-associated lyphoid tissue.IgA ¼ immunoglobin A.

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3.5.4.2 Cross-sectional and prospective epidemiologicalevidence.X Further work is needed to characterize the composition

and activities of human colonic microflora to investigatethe effects of age and race, and to explore the influence ofdifferent dietary habits. Of particular interest would belarge-scale studies of different European populations,using molecular approaches.

3.5.4.3 Markers.X Markers related to immune functions associated specific-

ally with GALT need to be developed and validated.X Improved characterization and validation are needed of

the composition of bacterial genera and strains and theactivities of the colonic microflora (e.g. specific enzymes,carcinogen formation). Only then can these be regardedas markers of important target functions.

X Early markers of carcinogenesis (e.g. recurrence of largeadenomas or gut mucosal changes such as DNA damage,DNA repair and apoptosis) need to be validated as aprerequisite to investigating the effect of functional foodson the risk of colon cancer.

3.5.4.4 Human intervention studies.X What factors determine the intra-individual variation in

response to probiotics and prebiotics?X Well-designed placebo controlled human studies are

required to examine the effects of different probioticand prebiotic components.

3.5.4.5 Evidence of safety.X The long-term effects of permanent changes in the

composition of the colonic microflora need to bemonitored.

3.6 Behavioural and psychological functions(Bellisle et al. 1998, S173–S193)

3.6.1 Introduction

Functional foods might lead to an improved state of healthand well-being and/or reduction of risk of disease. However,there are some foods or food components that are not directlyrelated to disease or to health in the traditional sense but,nevertheless, provide an important function in terms of chan-ging mood or mental state. These foods, therefore, areinvolved in creating more a sense of ‘feeling well’ than of‘being well’. Effects on behaviour, on emotional state, and oncognitive performance fall within this category.

Behaviour is probably the most varied and complex of allhuman responses. The complexity and variability arisesfrom the fact that behaviour is the cumulative outcome oftwo distinct influences – biological factors (encompassinggenetics, gender, age, body mass, etc.) and socio-culturalaspects (including tradition, education, religion, economicstatus).


The effects of foods on behavioural and psychologicalfunctions are conspicuously varied, typically subtle andfrequently interdependent. For the purpose of simplicity,however, they can be grouped into four areas of targetfunctions.

3.6.2.1 Appetite, satiation and satiety. Food intake can beaffected by sensory, gastrointestinal and metabolic factors,as well as by social cues, all of which influence appetite,either in terms of meal size (satiation) or eating frequency(satiety) or in changes in food preferences and dietaryselection.

The most widely used markers for assessing parametersof appetite and satiety are visual analogue scales. These aresubjective measurements of sensations such as hunger,desire to eat and fullness.

Objective assessment of energy and/or nutrient intakeof individuals is made either directly, by duplicate mealanalyses, or indirectly, with diaries of dietary consumption.

Modulation of food intake is most often considered interms of reducing food intake (to normalize body weight ofoverweight and obese individuals), but it is also important toconsider it in terms of increasing food intake to increasebody weight in persons at risk of malnutrition (such aselderly people, people suffering from eating disorders orthose recovering from illness). See Section 3 for considera-tion of markers for body weight control.

3.6.2.2 Cognitive performance. There are several perfor-mance markers that are used to assess cognitive function.These range from reactions to single stimulus tests to thoseinvolving complex interactive inputs. They can be based onrecognition of either numbers (to test vigilance, rapidinformation processing and/or continuous performance) orwords (to monitor immediate recall, word recognition and/or memory span). They can also be based on visual orauditory stimuli (to examine ‘simple’ or ‘choice’ reactiontimes) and on reactions to dynamic stimuli (to analysepsycho-motor performance).

3.6.2.3 Mood and vitality. Target functions relating tomood and vitality have focused generally on behaviourssuch as sleep and activity (including hyperactivity), as wellas feelings of tension, calmness, drowsiness and alertness.These psychological or behavioural states can be assessedeither subjectively (with questionnaires and visual analoguescales) or objectively (with electrophysiological, heart rateor blood pressure monitoring systems). Because of theexpense and sophistication of electrophysiological instru-ments, the data gathered on these markers are inevitablyrestricted to laboratory investigations. Portable continuousmonitoring systems for heart rate and blood pressure areideal for field work.

Changes in mood and vitality as a result of shifts in circadianrhythm (jet lag) are also an important target function.

3.6.2.4 Stress (distress) management. Certain foods orindividual nutrients have been implicated in causing oralleviating behavioural stress (or distress). The mostappropriate markers for stress states are heart rate, bloodpressure, blood catecholamines and skin electrical imped-ance. With regard to pain, data on blood opioid levels canprovide additional useful information.


X Fat, protein and carbohydrates have independent anddiffering effects on appetite and satiety; protein hasbeen shown to be the most effective, and fat the least


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effective, at suppressing energy intake. Macronutrientsubstitutes (e.g. fat substitutes and high-intensity sweet-eners), because they improve palatability of diets, might,in certain circumstances, also help to control body weightthrough a reduction in total energy intake.

X There are general beneficial effects of glucose on variousaspects of mental performance, including an improve-ment in working memory, improved decision time, fasterinformation processing and better word recall. Caffeinecan also lead to an improvement in most measures ofcognitive performance (reaction time, vigilance, memoryand psychomotor performance), particularly during themorning.

X High carbohydrate meals help to produce feelings ofdrowsiness, sleepiness and calmness. In addition, theamino acid tryptophan reduces sleep latency and promotesfeelings of drowsiness and fatigue in both adults andchildren. Tyrosine and tryptophan might help with jet lagbut there is only scant scientific evidence for this effect.

X Alcohol, whose intake is both traditional and widespreadin Europe, is one of the very few substances to affect allmajor areas of psychological and behavioural function(appetite, cognitive performance, mood and stress) andthe effects are conspicuously dependent on the dose.

X Sweet foods, such as sucrose, might relieve distress inyoung infants, as might activation of endogenous opioids(b-endorphins) reduce pain perception in the generalpopulation.


3.6.4.1 Basic science.X It is crucial to improve the reliability of food intake data.

The current methods of measurement, both indirect anddirect, are either inaccurate (both under- and over-estimations), tedious or expensive. A more accurate andprecise method is required, which is not only relatively

inexpensive and user/operator friendly but also can be usedfor large field trials. The use of digital cameras, and theassociated computer technology needed for image analysis,might make it possible to measure food intake morereliably under realistic free-living conditions. Patterns ofdietary intakes of food components throughout Europe canthen be obtained to reflect the cultural diversity.

X Is the ability of alcohol to correct depressive episodeslinked, qualitatively and quantitatively, to central neuro-chemical activity, such as that of serotonin?

3.6.4.2 Cross-sectional and prospective epidemiologicalevidence.X The large population of Europe, and the ethnic and

cultural diversity within it, offer important opportunitiesto test the validity of laboratory investigations and tostudy regional differences in psychotropic effects offoods.

3.6.4.3 Markers.X Better measures of cognitive function (memory, reaction

time, alertness) are needed. Testing of multiple, ratherthan independent, responses to nutritional stimuli isnecessary to understand the interaction between cogni-tive processes. This requires development, elaborationand evaluation of methods that can assess operationalperformance in complex conditions. Driving or flyingsimulators, and interactive electronic games, are exam-ples of such methods.

X It cannot be assumed that identical foods will exertsimilar effects in every individual. Methods are neededto identify vulnerable or sensitive individuals. Is itpossible to develop genetic markers?

3.6.4.4 Human intervention studies.X Behavioural animal studies are no substitute for human

investigations. Data derived from animal studies give, atbest, only an insight into the possibility that similar


Table 6. Examples of opportunities for modulation of target functions related to behaviour and psychologicalfunctions by candidate food components with possible markers*

Target function Possible markers Candidate food components

Appetite, satiety and satiation reliable direct measure of food intake proteinindirect measures of food intake fat replacerssubjective ratings of appetite and hunger fat substitutes

sugar substitutesstructured fatsspecific fatty acids

Cognitive performance objective performance tests glucosestandardized mental function tests caffeineinteractive games B vitaminsmultifunction tests choline

Mood and vitality quality and length of sleep alcoholattitudes (questionnaires) carbohydratesstandardized mental function tests carbohydrate : protein ratioratings of subjective states tyrosine and tryptophan

Stress (distress) management blood pressure alcoholblood catecholamines carbohydratesblood opioids sucroseskin electrical impedanceheart rate continuous monitoring

* The information given in this table is derived from the Theme Paper (see Bellisle et al. 1998, S173–S193), where, if not given inthis Consensus Document, further details of options for modulations, markers and safety issues can be found.

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phenomena occur in man. Even when a potential effecthas been demonstrated in man in the laboratory, it is veryimportant to proceed with appropriate human trials in afree-living situation.

X Most research into behaviour and psychological func-tions is short term. Extended observations, beyond theimmediate effect, are required to see if there is long-termadaptation to the intake of specific food components. Instudies on satiety, for example, there are indications thatshort-term effects of food might weaken with repeatedadministration.

3.6.4.5 Evidence of safety.X Evidence of safety of food components is particularly

important in the study of behaviour since this encom-passes intrinsic and extrinsic aspects – the classicalbiochemical and histopathological changes related toingestion of specific food components and the changesarising from modification of the person’s behaviour ormood. The safety issue of alcohol is a good example ofthese two aspects.

X In some cases the influence of dietary substances onbehaviour and psychological functions involves eitherdoses above those normally consumed in food, or dosescausing some degree of nutritional imbalance. The effectof melatonin on circadian rhythms, or of L-tryptophan onsleep, fall within this area.

X Long-term consequences are as important as thoseobserved in the short or medium term. For example, themodulation of eating behaviour through the modificationof appetite or satiety should never lead to a deteriorationin the general nutrition status of individuals.

4. TECHNOLOGY ASPECTS OF FUNCTIONALFOOD SCIENCE (Knorr et al. 1998)

4.1 Introduction

The traditional aim of food processing is to convert rawmaterials into edible, safe, wholesome, nutritious foodproducts with desirable physico-chemical properties,extended shelf life and optimal features for palatabilityand convenience of eating. The development of functionalfoods, however, requires an additional aim – namely, thatthe functional component (as defined in this document) iseither created or optimized (see below). This will require anincreased level of complexity and monitoring of foodprocessing.

New raw materials will have to be considered, includingthose produced by genetic modification and emergingthermal and non-thermal technologies. Safety issues thenbecome increasingly important (e.g. inhibiting transfer ofsecondary genetic material in genetic modification andeffective inactivation of specific components such astoxins, anti-nutrients, micro-organisms, allergens orenzymes by gentle processing techniques).

Integration throughout the entire food chain will also berequired to ensure product safety and quality, as well aspreservation and/or enhancement of functional components.Sharing of knowledge with scientists in related areas, suchas nutrition, is essential to change the traditional pattern ofthinking in food science and technology.

The three key areasfor technological challenges thathave been identified are:

1. The creation of new functional food components intraditional and new raw materials and byde novosynthesis.

2. Theoptimizationof functional food components in rawmaterials and in foods (e.g. maximal preservation orretention of components, modification of their functionand their increased bioavailability).

3. Theeffective monitoringof the amount and efficacy offunctional food components in raw materials and infoods.

Examples will be drawn from the five technology areascovered in the Technology Theme Group papers (i.e. anti-oxidants, minerals, micro-organisms, carbohydrates andproteins). Some examples of research opportunities (posedas questions in italics) to meet the technological challengeswill also be selected from these areas.

4.2 Examples of technological challenges and researchopportunities for the creation of new functional food

components

X To identify viable technologies for the use of new rawmaterials as sources.

– Can genetic modification be used to increase theantioxidant content of plant foods?– Can under-utilized and unconventional sources,such as algae and seaweeds, be used as raw materialsfor the extraction of carbohydrates?

X To produce new classes of functional food components,which can be incorporated into foods and used as sub-strates for beneficial micro-organisms.

– Can we find a wider spectrum of sources forproduction of non-digestible oligosaccharides or othercarbohydrates? Can we use ‘tailored’ degradation andtransglycolysation of suitable oligosaccharides?

X To generate new functional carbohydrates (e.g. resistantstarches and non-digestible carbohydrates) by upgradingraw materials and by-products, which are rich in carbo-hydrates, using extraction, fractionation and chemical orphysical treatments.

– Can the cell wall matrix of the raw plant materialsbe modified to alter the binding of water, cations andbile salts to polysaccharides? Can new fat replacersbe produced in this way?

X To develop the large-scale isolation and enrichmentof bioactive peptides and proteins from various rawmaterials, such as milk and plants, using enzymatic andbacterial hydrolysis using separation and chromato-graphic techniques.

– Can bioreactors based on immobilized proteolyticenzymes or live micro-organisms be developed?

4.3 Examples of technological challenges and researchopportunities to optimize the amount and efficacy of

functional food components

X To develop economic membrane-processing techniquesand to overcome problems of membrane fouling and


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efficiency to obtain maximum recovery of functionalfood components,

– Is it possible to develop membrane-processingtechniques, such as membrane purification for fatsand oils to reduce energy consumption, minimizedegradation and to maximize stability and antioxidantpotential?– Can we use membrane technologies on food processwastes to recover absorbable mineral complexes withfood grade ligands?

X To understand the relationships between packagingenvironments and antioxidant retention to maximize thefunctionality of antioxidants in processed foods.

– Can we obtain better data on the antioxidant contentof raw materials and of minimally processed foods toensure their maximal retention?– What is the impact of controlled and modified atmos-phere packaging environments on antioxidant retention?

X To use separation technology to provide specific frac-tions from raw materials, each with predeterminedmineral content and bioavailability.

– Can the controlled separation of skimmed milk frombutter preferentially retain important minerals in theskimmed milk?

X To ensure that new minimal processing technologies notonly improve the stability of the product, but also retainor improve, mineral availability and allow the release of‘absorbable’ minerals.

– Can mineral content, yield, speciation, solubility andbioavailability be improved using gentle physical pro-cesses, such as high hydrostatic pressure treatment,ultrasound treatment, high-intensity electric field pulsetechnology, membrane techniques, fractionation tech-nologies (such as liquid–liquid phase separation forpartitioned foods) and enzymic processes (such asmalting, fermentation and enzyme addition)?

X To modify fermentation processes for micro-organismsto retain their viability during food processing, storage orpreparation and thus provide optimal probiotic function.

– Can non-thermal technologies (e.g. high hydrostaticpressure, supercritical carbon dioxide treatment orhigh-intensity electric field pulses) be developed toachieve adequate safety, quality, retention andfunctionality of products containing probiotics?

X To develop probiotics with increased resistance to theenvironment within the human intestinal tract.

– Is it possible to control fermentation rate in the colonby selecting and developing suitable non-digestibleoligosaccharides? Is the fermentability rate due to theirdegree of polymerization, the type of sugar and glyco-sidic linkage, the degree of branching or other factors?– Can genetic modification be used to develop highlyselective and specific probiotics in terms of theirbinding properties to intestinal receptors? Canstrain selection, fermentation techniques or ‘protec-tion’ techniques (e.g. by acid-resistant, encapsulatedimmobilization systems) be used to retain high initialmicrobial viability and productivity in the intestine?– Can emerging technologies, such as pressure-assisted freezing in conjunction with antifreeze pro-teins and cryo-protectants, be used as alternativesto conventional freeze-drying of microbial startercultures for increased viability?

X To optimize the beneficial effects of new carbohydrates(e.g. non-digestible carbohydrates, fat replacers, resistantstarch, soluble/insoluble fibre).

– How can the glycaemic index and the resistant starchcontent be optimized by the careful selection of rawmaterials and processing conditions?

X To optimize the processing conditions for retaining theactivity of bioactive proteins and peptides so that inter-actions with other food components do not affect thestructural/textural quality of food products duringprocessing and subsequent storage.

– What are the effects of conventional versus emerg-ing processing technologies on the bioactivity/reactivity of proteins and peptides? Can differentdelivery systems such as liposomes, microencapsulation


Table 7. Examples of technological challenges, with possible solutions and examples of applications, to optimize functional food components*

Technological challenges Possible technological solutions Examples of applications

Creation of functional components from raw materials and immobilized enzyme systems bioactive peptidesfrom de novo synthesis membrane processes antioxidants

minerals

Optimization of functional food components by increasing fermentation, enzyme technologies mineralstheir concentrations in raw materials non-thermal processes (e.g. high pressure) antioxidants

Optimization of functional food components through tailored enzymatic processes oligosaccharides (fat replacers)their modification

Optimization of functional food components through fermentation technologies micro-organismsincreased bioavailability membrane permeabilization processes minerals

(e.g. enzymes, electric field pulses)

Optimization of functional components in raw materials encapsulation processes micro-organismsand in foods through maximal retention sphere packaging technologies bioactive peptides

antioxidantsminerals

Monitoring the production of functional foods and sensors/markers micro-organismsfunctional components minerals

carbohydrates

* The information given in this table is derived from the Technology Theme papers (see Knorr et al. 1998), where, if not given in this Consensus Document, furtherdetails of technological challenges, possible technological solutions and examples of applications can be found.

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systems and emulsion systems optimize their physio-logical functions?

X To develop alternative production methods for bioactivepeptides and proteins from raw materials to avoid prob-lems such as non-availability, which can occur withconventional processing technology.

– What are the functional properties and interactionsof bioactive proteins and peptides in different foodsystems, e.g. liquid or solid products (i.e. productswith high or low water activity)?

4.4 Examples of technological challenges and researchopportunities to monitor the effective production of

functional food components

X To develop efficient technologies to monitor specificfunctional effects of foods and food components through-out the food chain.

– Is it possible to monitor microbial viability andproductivity for optimal probiotic function?

X To improve analytical assays to monitor the availabilityof functional food components at all stages of processing.

– Can encapsulated minerals and vitamins retainstability in foods during processing as well asbeing available for absorption in the intestinaltract?– Can highly specific and sensitive markers be devel-oped that record speciation changes and interactionswith food components during processing?

X To develop methods to monitor controlled release and tocontrol bioconversion processes.

– Is it possible to monitor the extent of conversion ofindividual oligosaccharides and the relevant aspectsof the fermentation process?

5. COMMUNICATION OF THE HEALTH BENEFITSOF FUNCTIONAL FOODS

5.1 Introduction

As the relationship between nutrition and health gainspublic acceptance and as the market for functional foodsgrows, the question of how to communicate the specificadvantages of such foods becomes increasingly important.Communication of health benefits to the public, throughintermediaries such as health professionals, educators, themedia and the food industry, is an essential element inimproving public health and in the development of func-tional foods. Its importance also lies in avoiding problemsassociated with consumer confusion about health messages.Of all the different forms of communication, those concern-ing the use of ‘claims’ – made either directly as a statementon the label or package of food products, or indirectlythrough secondary supporting information – remain anarea of extensive discussion. It is therefore essential thatclaims, which are an inherent part of functional foods, mustbe based on, and driven by, scientific information.

5.2 General principles of claims

The fundamental principle that any claim must be true andnot misleading should apply equally to those related to

health benefits. All such claims, therefore, should be scien-tifically valid, unambiguous, and be clear to the consumer.The key issue, however, is how this basic principle shouldbe safeguarded without becoming a disincentive either forthe industrial development and production of functionalfoods (an important determinant in trying to achieve thegoal of improved public health) or the acceptance of thesefoods by consumers (the ultimate target for the functionalbenefit).

5.3 Current definitions of claims

One of the difficulties in the communication of the benefitsof functional foods is that the term ‘health claim’ is defineddifferently in different countries. The meaning of the word‘claim’ itself (as opposed to ‘health claim’) is, however,generally well understood. A widely accepted definition of a‘claim’ is that of Codex Alimentarius (1991). It is defined as‘Any representation, which states, suggests or implies thata food has certain characteristics relating to its origin,nutritional properties, nature, production, processing,composition, or any other quality.’

With the term ‘health claim’, however, there are someappreciable differences in interpretation. The Food AdvisoryCommittee (of the UK Ministry of Agriculture, Fisheriesand Food – MAFF), for example, has defined health claimas ‘any statement, suggestion or implication in food labellingand advertising (including brand names and pictures) that afood is in some way beneficial to health, and lying in thespectrum between, but not including, nutrient claims andmedicinal claims’. In contrast, in the USA, a health claimrefers to any statement ‘that expressly or by implicationcharacterizes the relationship of any substance to a diseaseor health-related condition’. In the UK, therefore, a claimrelated to a disease would be considered as a medicinal claimwhereas in the USA it would be regarded as a ‘health claim’.

5.4 Current classification of types of claims

The principal difficulty (implied in the above UK definition)in dealing with statements about health benefits is thatthere are a number of distinct types of claims concerningthe association between nutrition and health, and that thedefinition of them is not the same in all countries.

Codex Alimentarius (1997) has very recently classifiedand defined some of the different forms of claims. Forease of reference we have called these Types 1–4 andthey are:

Type 1. Claims related to dietary guidelines or healthy diets.These relate to the pattern of eating in dietary guidelinesofficially recognized by the appropriate national authority.

Examples: Diets low in saturated fats are recommendedby … ; The advice of… is to choose a diethigh in fibre.

Type 2. Nutrient content claims (subsection of nutritionclaims).These are nutrition claims that refer to the level of a nutrientcontained in a food.

Examples: Source of calcium; High in fibre; Low infat.


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Type 3. Comparative claims (subsection of nutrition claims).These make a comparison of the nutrient level of two ormore foods.

Examples: Reduced; Less than; Fewer; Increased; Morethan.

Type 4. Nutrient function claims (subsection of nutritionclaims).This is a form of claim that refers to the physiological role ofa nutrient in its relationship to growth, development andnormal functions of the body. Claims in this categoryare similar to ‘structure/function’ claims in the USA.They make no reference whatsoever to a specific disease,pathological state or abnormal condition.

Examples: Calcium might help the development of strongbones and teeth; Contains folic acid; folic acidcontributes to the normal development of thefetus.

The above four categories of claims refer to known nutrientsand their role in growth development and normal functionsof the body. They are, therefore, factual in that they arebased on established knowledge that is widely acceptedwithin the scientific nutrition community and make noreference to a particular consequence over and above thatexpected from the consumption of a balanced diet. Althoughthere is need for research to continue in the areas coveredby these claims (to enlarge on the detail of the processes)there is little further necessity to substantiate the conceptsthemselves.

5.5 Claims relevant to functional foods

This EU Concerted Action supports the development of twofurther types of claims, which are not covered by the aboveCodex classification and which differ significantly fromthem. They embrace, but are not restricted to, claims forfunctional foods. They are based on the scientific classifica-tion of markers for target functions that have been devel-oped in this Consensus Document (see Fig. 1 in Section 2).Claims must always be valid in the context of the whole dietand must relate to the amounts of foods normally consumed.This applies to specific effects of foods and food compo-nents, both nutrients and non-nutrients.

Type A. ‘Enhanced function’ claims.These claims concern specific beneficial effects of nutrientsand non-nutrients on physiological, psychological functionsor biological activitiesbeyond their established roleingrowth, development and other normal functions of thebody.

This type of claim is also similar to a ‘structure/function’claim in the USA and, again, makes no reference to aparticular disease or pathological state. However, referenceto a mild abnormal condition, as for example indigestion orinsomnia, could possibly be permitted.

Examples: Certain non-digestible oligosaccharidesimprove the growth of a specific bacterialflora in the gut.Caffeine can improve cognitive performance.Folate can help reduce plasma homocysteinelevels.

Type B. ‘Reduction of disease-risk’ claims.Claims for reduction of disease risk relate to the consump-tion of a food or food component that might help reduce therisk of a specific disease or condition because of specificnutrients or non-nutrients contained within it. These claimscorrespond to those referred to as ‘health claims’ in theUSA.

Examples: Folate can reduce a women’s risk of having achild with neural tube defects.Sufficient calcium intake may help to reducethe risk of osteoporosis in later life.

It is frequently suggested that there should be an additionaland specific claim for an improved state of health andwell-being. However, since an improved state of healthand well-being results from either an enhanced function(physiological or psychological) or from the reduction ofrisk of disease, it is sufficiently covered by the above twocategories.

Satisfactory control procedures are required to ensurethat claims are used to their best effect, both for thepromotion of public health and protection of the consumeragainst false and misleading information. Currently Type 1,2 and 3 claims are generally allowed in most countries. Toa much lesser extent, this is also true for Type 4 andType A claims whilst, in contrast, Type B claims arecurrently almost universally disallowed (see Section 1).

5.6 Scientific basis for claims relevant to functional foods

Perhaps the most pertinent aspect in communication ofhealth benefits is that any claim, or statement, must bebased on sound scientific evidence that is both objective andappropriate. However, it is not always clear what constitutesobjective and appropriate evidence. One of the major issuesto be resolved, therefore, concerns the biological level atwhich evidence can be accepted as demonstrating functionalefficacy.

Data, obtained at several levels of biological organization(molecular, sub-cellular, cellular, tissue, organ, whole bodyand population level) can be grouped into three types ofexperimental evidence – biological (biochemical) observa-tions, epidemiological data and intervention trials. All threetypes of evidence are based on markers. For any givenspecific food or food component, supporting evidence forfunctional efficacy might not be available from all threeareas. The effectiveness of certain antioxidants in thereduction of risk for cancer, for example, is adequatelysupported by biological data (at the molecular, sub-cellularand cellular levels), less well supported by epidemiologicalevidence (at the population level) and hardly at all byclinical intervention trials (whole-body level). In contrast,the effects of dietary fibre are better documented andunderstood in terms of epidemiology and intervention thanthey are at the biochemical level.

Whatever judgement or decision is made for establishingproof of functional efficacy, it is important that the requiredsupporting evidence should:

X be consistent in itself;X be able to meet accepted scientific standards of statistical

and biological significance;


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X be plausible in terms of the relationship between inter-vention and results;

X be provided from a number of sources, including humanstudies.

Clearly, the use of different types of markers can play a veryimportant role in justifying claims. This EU ConcertedAction proposes that the classification of markers on thebasis of their relationship to the target function or diseaseendpoint (see Section 2) now offers a scientific approach forthe basis of Type A and Type B claims:

If evidence for the effects of a functional food or afunctional food component is based on a marker of targetfunction or biological response (functional markers), then aType A claim (enhanced function claim) might be justified.

A Type B claim (reduced risk of disease claim), however,would only be justified if the evidence for the effect of a

functional food or a functional food component is based onan intermediate endpoint marker of disease. This markerwould have to be shown to be significantly and consistentlymodulated by the functional food component for theevidence to be acceptable.

5.7 Linking the scientific basis of functional foods withthe communication about their benefits to the public

The development of functional foods, with their accom-panying claims, will proceed hand in hand with progress infood regulation which is the means to guarantee the validity ofthe claims as well as the safety of the food. Science in itselfcannot be regulated and functional food science provides onlythe scientific basis for these regulations. At the present time, inseveral European countries, different initiatives have beentaken, based on the dialogue between the food industry,


Consumptionof

functionalfood

component

Markers of Markersof target

function/biological

response

exposureto foodcomponent

Markers ofintermediate

endpoint

Reducedrisk of

diseaseEnhancedtarget

function

TYPE A CLAIMS(enhanced function)

TYPE B CLAIMS(reduced risk of disease)

Fig. 2. From scientific evidence based on markers for functional foods to types ofclaims relevant to them.

SCIENTIFIC BASIS

For determining

Markers

Effects

To establish

To justify

To establish

To justify

Claims

COMMUNICATIONWITH THE PUBLIC

MODULATION OFTARGET FUNCTIONS

MODULATION OF DISEASEPROCESS

ENHANCED FUNCTIONS REDUCED RISK OF DISEASE

TYPE A CLAIMS TYPE B CLAIMS

Fig. 3. From the scientific basis for functional foods to communication with the public.

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retailers, regulatory authorities with consumer organizations.A self-regulating programme for ‘health claims’, which is notindependent of existing legislation or the requirements ofrelevant authorities but would complement both, has beenintroduced in Sweden and more recently in The Netherlands.It is also being actively considered in the UK and Belgium.

This EU Concerted Action has proposed a schemewhereby the scientific basis of functional food developmentcan be linked to the communication of the benefits offunctional foods to the public. This scheme is summarizedin Fig. 3. Improved communication with consumers shouldfollow if the principles in this scheme are adopted.

6. EXECUTIVE SUMMARY

1. The Functional Food Science in Europe (FUFOSE)project was introduced, evaluated and accepted by theEU DG XII FAIR Programme as a Concerted Action.Its aim was to develop and establish a science-basedapproach for the emerging concepts in functional fooddevelopment. Over the last three years of this EUConcerted Action co-ordinated by ILSI Europe,scientific data have been evaluated and new conceptshave been elaborated.This Consensus Document is theculmination of the EU Concerted Action and its keypoints and recommendations are summarized here.Itis by no means the end of the process, but, rather, animportant starting point and the stimulus for functionalfood development.

2. Considerable progress has been made in scientificknowledge leading to the identification of functionalfood components which might eventually lead to animproved state of health and well-being and/or reduc-tion of risk of disease. Consumers are becoming moreaware of this development as they seek a better-quality, as well as a longer, life.The food industryhas an opportunity to provide products that are notonly safe and tasty, but also functional. The originalityof the approach in this EU Concerted Action is thatit is function-based, rather than product-based. Thelatter approach would have to be influenced by localconsiderations of different cultural as well as dietarytraditions, whereas the function-based approach startsfrom the biologically based science that is universal.Furthermore, and most importantly, the function-based approach in this EU Concerted Action hasallowed the development of ideas that suggest aunique way in which to link this scientific basis offunctional foods with the communication about theirpossible benefits to consumers.

3. This EU Concerted Action has adopted the followingworking definition, rather than a firm definition, forfunctional foods:

A food can be regarded as ‘functional’ if itis satisfactorily demonstrated to affectbeneficially one or more target functionsin the body, beyond adequate nutritionaleffects in a way that is relevant to either animproved state of health and well-beingand/or reduction of risk of disease.

4. Functional foods must remain foods and they mustdemonstrate their effects in amounts that can normallybe expected to be consumed in the diet. They are notpills or capsules, but part of a normal food pattern. Afunctional food can be a natural food, a food to whicha component has been added, or a food from which acomponent has been removed by technological orbiotechnological means. It can also be a food wherethe nature of one or more components has been modi-fied, or a food in which the bioavailability of one ormore components has been modified; or any combina-tion of these possibilities. A functional food might befunctional for all members of a population or for parti-cular groups of the population, which might be defined,for example, by age or by genetic constitution.

5. The development of functional foods must rely onbasic scientific knowledge of target functions in thebody that are relevant to an improved state of healthand well-being and/or the reduction of risk of diseases,the identification of validated markers for these targetfunctions and the evaluation of sound scientific datafrom human studies for their possible modulation byfoods and food components.This EU Concerted Actionhas proposed that markers can be classified accordingto whether they are markers of exposure to the func-tional food component, whether they are markers thatrelate to target function or biological response orwhether they are intermediate markers of the actualdisease endpoint or health outcome (see Fig. 1).

6. Consumers must be made aware of the scientificbenefits of functional foods and this requires clearand informative communication through messages(claims) on products and in accompanying materials.This EU Concerted Action has identified two types ofclaims that are vital to functional food developmentand has provided a scientific basis for them to helpthose who have to formulate and regulate the claims(see Fig. 2).

Claims for ‘Enhanced Function Claims’ (Type A)should require that evidence for the effects of thefunctional food is based on establishment and accept-ance of validated markers of Improved TargetFunction or Biological Response, while claims forthe Reduced Risk Of A Disease (Type B) shouldrequire that evidence is based on the establishmentand acceptance of Markers of Intermediate Endpointsof Disease. These markers must be shown to besignificantly and consistently modulated by the func-tional food or the functional food component for eithertype of claim to be made.This EU Concerted Actionhas therefore proposed a scheme whereby the scien-tific basis of functional food development can be linkedto the communication of their benefits to the public(Fig. 3). If the principles of such a scheme can beuniversally adopted, then this should ultimatelyimprove communication to consumers and minimizetheir confusion.

7. Functional foods must be safe according to allstandards of assessing food risk and new approachesto safety might need to be established.This EU Con-certed Action proposes that the development of validated


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markers as described above should, if possible, be usedand integrated in the safety assessmentwith particularattention being paid to long-term consequences andinteractions between components.

8. The development of functional foods, with theiraccompanying claims, will proceed hand in handwith progress in food regulation, which is the meansto guarantee the validity of the claims as well asthe safety of the food. Science in itself cannot beregulated and functional food science provides onlythe scientific basis for these regulations.

9. The Individual Theme Group papers, which are thescience base for this Concerted Action, represent thecritical assessment of the literature by Europeanexperts (see Bellisleet al. 1998 and Knorret al.1998). The health outcomes that have been coveredare those related to growth, development and differen-tiation, substrate metabolism, defence against reactivespecies, cardiovascular system, intestinal physiologyand behavioural and psychological functions.

10. This Consensus Document has selected some examplesfrom each theme paper to illustrate the key targetfunctions for each health outcome with their possiblemarkers and candidate functional food components andhas also indicated some research opportunities, tech-nological challenges and safety considerations.Amongthe technological challenges are issues relating to thecreation of new functional food components, theiroptimization within foods and the continual monitor-ing of their efficacy throughout food processing.

11. The collaboration between the many disciplinesinvolved in food and nutrition science, such as thatwhich has existed throughout this EU ConcertedAction, is essential for successful innovation in func-tional food development leading to an improved stateof health and well-being and/or reduction of risk ofdisease for consumers.

12. The European Union must play a leading role in thedevelopment of, and communication about, functionalfood science and the European Food industry shouldshare the lead and work in partnership with thescientific community.Support must be given to inte-grated research programmes aimed at solving the keyscientific and technological challenges that have beenidentified in this Consensus Document.

7. KEY MESSAGES

X The food industry has unique opportunities to developproducts that are not only nutritional in the traditionalsense, but which have additional activity that can leadto an improved state of health and well-being and/orreduction in risk of disease (functional foods).

X Foods can be regarded as functional if they can besatisfactorily demonstrated to affect beneficially one ormore target functions in the body, beyond adequatenutritional effects in a way that is relevant to either animproved state of health and well-being and/or reductionof risk of disease. Functional foods must remain foods

and they must achieve their effects in amounts that couldnormally be expected to be consumed in a diet. They arenot pills.

X A function-based, rather than a product-based, approachhas been proposed whereby the scientific basis of func-tional foods can be linked to the communication of theirbenefits to the public. The ability to communicate thesebenefits is essential for the successful development offunctional foods and their role in improving publichealth.

X Scientific understanding of the way in which componentsaffect body processes involved in health and well-beingenables the development of markers that could registerthe impact of the new food products and could also beused in their safety assessment.

X Evidence from human studies based on markersrelating to biological response or on intermediate end-point markers of disease could thus provide a soundscientific basis for messages and claims about the func-tional food products. Two types of claims are proposedthat would relate directly to these two categories ofmarkers: enhanced function claims, and reduced risk ofdisease claims.

X Support is needed for integrated research programmes,with interdisciplinary activity, to solve the key scientificand technological challenges and to exploit the scientificconcepts in functional food science.

8. SOURCES OF INFORMATION

Theme papersBellisle F, Diplock AT, Hornstra G, Koletzko B, Roberfroid M,

Salminen S and Saris WHM (1998) Functional Food Sciencein Europe. British Journal of Nutrition 80 (Suppl. 1), S1–S193.

Knorr D et al. (1998) Functional Food Science in Europe.Trendsin Food Science and Technology9, 293–344.

Other references and sourcesClydesdale FM, Ha Chan S (1996)Proceedings of the First

International Conference on East-West Perspectives on Func-tional Foods. Nutrition Reviews54, S1–S202.

Clydesdale FM (1997) A proposal for the Establishment ofScientific Criteria for Health claims for functional foods.Nutrition Reviews55, 413–422.

Codex Alimentarius(1991) Second Edition. Codex General Guide-lines on Claims. (CAC/GL 1–1979, rev 1–1991). Geneva,WHO.

Codex Alimentarius(1997)Guideline for Use of Nutrition Claims(CAC/GL 23–1997, Volume 1A, revised). Geneva, WHO.

Food Advisory Committee (1991)Report on its review of foodlabelling and advertising. Report FDAC/REP/10. HMSO,London.

ILSI Europe (1998) Addition of Nutrients to Foods: Nutritionaland Safety Considerations. InILSI Europe Report Series.Brussels, ILSI Europe.

Institute of European Food Studies (1996)A pan-European Surveyof Consumer Attitudes to Food, Nutrition and Health. Dublin,Institute of European Food Studies.

Jonas DAet al. (1996) The Safety Assessment of Novel Foods. InFood & Chemical Toxicology, Vol. 34, No. 10, pp. 931–940.

q Nutrition Society 1999


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