! 1 CODEX!ALIMENTARIUS!COMMISSION! Joint!FAO/WHO!Food!Standards!Program! Codex!Committee!on!Nutrition!and!Foods!for!Special!Dietary!Uses!(CCNFSDU)!

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1 1 st CONSULTATIONDOCUMENTONNRV s4ncdforepaanddha CODEXALIMENTARIUSCOMMISSION JointFAO/WHOFoodStandardsProgram CodexCommitteeonNutritionandFoodsforSpecialDietaryUses(CCNFSDU) ElectronicWorkingGrouptoestablishaCodexNRVONCD fordhaandepa (CoOchairedbyTheRussianFederationandChile) FIRSTCONSULTATIONPAPER,APRIL2015 The36 th Session2014oftheCodexCommitteeonNutritionandFoodsforSpecialDietary Uses(CCNFSDU)agreedtorecommendnewworktodevelopandaddapotentialnewCodex nutrient reference value (NRV) to docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intended for the general population for labelling purposes in relation to the risk of NonNCommunicableDiseases(NCDs). The project document for the new work will be considered for approval by the Codex AlimentariusCommissioninthe38 th session,injuly2015. ThereferenceaspectsofthisworkforCCNFSDUareto: AssessthemostcurrentscientificevidenceinlinewiththeGeneralPrinciples. MakerecommendationstosetapotentialCodexNRVNNCDforthetotalofOmegaN3 fattyacidsdhaandepa,inaccordancewiththegeneralprinciplesfornrvnncdas setoutintheannextotheguidelinesonnutritionlabelling(cac/gl2n1985). The document reviews the main scientific evidence available on the beneficial effects of DHAandEPAintakeforhealth,inordertoassessitaccordingtothegeneralprinciplesto establishnrvnncd. 1

2 Whenreviewing,observingandanalyzingthedatasupportingapositiveeffectonhealthin many ways(thrombosis risk, arrhythmia risk, post heart attack, better cardiovascular rate includingsuddendeathfromarrhythmias)itmaybeconsideredthattheomega3fattyacid of 18 carbon atoms 18:3 nn3 (alphanlinolenic acid) is precursor to form EPA and DHA. Similarly, EPA 20:5 nn3 serves as precursor in DHA 22:6 nn3 formation. Nevertheless, this conversion is limited and variable. Therefore, the effects of diet or supplement contributionsrichinomega3fattyacidswilldependonhoweachindividualisabletoform moreorlessamountofactivecompounds(epaanddha).thismakesthedatacombination of diverse studies difficult, and weakens the evidence, which must be judged in a global way.forthisreason,thisreviewwillbefocusedontheevidenceavailableforhealtheffects ofepaanddhaspecifically. 2.GENERALPRINCIPLESFORESTABLISHINGNRVONCD(REP13/NFSDUAppendixIV) Potential Attachment to guidelines of Codex on Nutritional Labelling, consolidated version: general principles to establish the reference values of nutrients for general population(foradoption). 3.GENERALPRINCIPLESFORESTABLISHINGNRVs 3.1SelectionofSuitableDataSourcestoEstablishNRVs Relevant daily intake reference values provided by FAO/WHO that are based on a recent reviewofthescienceshouldbetakenintoconsiderationasprimarysourcesinestablishingnrvs Relevantdailyintakereferencevaluesthatreflectrecentindependentreviewofthescience, from recognized authoritative scientific bodies other than FAO/WHO could also be taken into consideration.higherpriorityshouldbegiventovaluesinwhichtheevidencehasbeenevaluated throughasystematicreview The daily intake reference values should reflect intake recommendations for the general population. 2

3 3.2SelectionofNutrientsandAppropriateBasisforNRVs 3.2.1SelectionofNutrientsandAppropriateBasisforNRVsOR TheNRVsNRshouldbebasedonIndividualNutrientLevel98(INL 98 ).Incaseswherethereis anabsenceofanestablishedinl98foranutrientforaspecificsubngroup(s),itmaybeappropriate toconsidertheuseofotherreferencevaluesorrangesthathavebeenestablishedbyrecognized authoritativescientificbodies.thederivationofthesevaluesshouldbereviewedonacasenbyncase basis ThegeneralpopulationNRVsNRshouldbedeterminedbycalculatingthemeanvaluesfora chosen reference population group older than 36 months. NRVsNR derived by the CCNFSDU are basedonthewidestapplicableagerangeforeachofadultmalesandfemales ForthepurposeofestablishingtheseNRVsNR,thevaluesforpregnantandlactatingwomen shouldbeexcluded SelectionofNutrientsandAppropriateBasisforNRVsONCD Thefollowingcriteriashouldbeconsideredintheselectionofnutrientsfortheestablishment ofnrvsnncd: _Relevantconvincing 3 /generallyaccepted 4 scientificevidenceorthecomparablelevelofevidence under the GRADE classification 5 for the relationship between a nutrient and noncommunicable diseaseriskrelationship,includingvalidatedbiomarkersforthediseaserisk,foratleastonemajor segmentofthepopulation(e.g.,adults). _ Public health importance of the nutrientnnoncommunicable disease risk relationship(s) among Codexmembercountries Relevant and peernreviewed scientific evidence for quantitative reference values for daily intake should be available in order to determine an NRVNNCD that is applicable to the general population Daily intake reference values from FAO/WHO or other recognized authoritative scientific bodiesthatmaybeconsideredfornrvsnncdincludevaluesexpressedinabsoluteamountsorasa percentageofenergyintake Forpracticalapplicationinnutritionlabelling,asingleNRVNNCDforthegeneralpopulation shouldbeestablishedforeachnutrientthatmeetstheprinciplesandcriteriainthisannex An NRVNNCD for the general population should be determined from the daily intake referencevalueforthegeneralpopulationoradults,orifgivenbysex,themeanofadultmalesand adultfemales. 3

4 Whereadailyintakereferencevalueisbasedonapercentageenergyintake,thesingleNRVN NCD should be expressed in grams or milligrams based on a reference intake for the general populationof8370kilojoules/2000kilocalories. Governments may use a Codex NRVNNCD based on the reference energy intake of 8370 kilojoules/2000kilocalories,ormayderivetheirownreferencevaluesfornutritionlabellingbased onanotherreferenceenergyintakethatconsidersfactorsspecifictotheircountryorregion. 3.3ConsiderationofDailyIntakeReferenceValuesforUpperLevels TheestablishmentofgeneralpopulationNRVsshouldalsotakeintoaccountdailyintakereference valuesforupperlevelsestablishedbyfao/whoorotherrecognizedauthoritativescientificbodies whereapplicable(e.g.,upperlevelofintake,acceptablemacronutrientdistributionrange). 3 At the time these guiding principles were drafted, the definition and criteria for convincing evidence from the following FAO/WHO report were used Diet, Nutrition and the Prevention of Chronic Diseases. WHO Technical Report Series 916. WHO, For these General Principles the terms convincing/generally accepted evidence are considered synonymous. 5 WHO s Guidelines Review Committee. WHO Handbook for guideline development. Geneva, World Health Organization (WHO), 2012 ( 3.REVIEWOFSCIENTIFICEVIDENCEFROMFAO/WHOANDRASB* *RASB: Recognized Authoritative Scientific Body. (REP14/CNFSDU, paragraph 31 and REP15/CNFSDU,paragraph56;80) TheCommitteeagreedwiththefollowingworkingdefinitionforRASBs.Forthepurposesof establishing Codex Nutrient Reference Values, a recognized, authoritative, scientific body otherthanfaoand/orwhoisanorganizationsupportedbyacompetentnationaland/or regionalauthority(ies)thatprovidesindependent,transparent*,authoritativeandscientific advice on daily intake reference values through primary evaluation** of the scientific evidence upon request and for which such advice is recognized through its use in the developmentofpoliciesinoneormorecountries. *Inreceivingtransparentscientificadvice,theCommitteewouldhaveaccesstowhatwas consideredbyarasbinestablishingadailyintakereferencevalueinordertounderstand thederivationofthevalue. ** Primary evaluation involves a review and interpretation of the scientific evidence to develop daily intake reference values, rather than the adoption of advice from another RASB. 4

5 TheCommitteeacceptedthesixlistedscientificbodiesasRASB EuropeanFoodSafetyAuthority(EFSA); UnitedStatesInstituteofMedicine(IOM); Australian National Health and Medical Research Council & New Zealand MinistryofHealth(NHMRC/MOH); JapaneseNationalInstituteofHealthandNutrition(NIHN); InternationalZincNutritionConsultativeGroup(IZiNCG); NordicCouncilofMinisters(Nordiccountries). 3.1 FoodandAgricultureOrganisationandWorldHealthOrganisation(FAO/WHO) World Health Organisation (2003) Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Disease (2002: Geneva, Switzerland) Technical ReportSeries916. This WHO report made recommendations for preventing cardiovascular diseases (CVDs), which are the major contributor to the global burden of disease among the nonn communicablediseases.anumberofkeypointsarosefromtheexpertconsultation,which relatedtodiet,physicalactivityanddisease,including,forexample,(a)the lagtime effect ofriskfactorsforcvdmeansthatpresentmortalityratesaretheeffectsofpreviouslongn term exposure to behavioral risk factors such as inappropriate nutrition and insufficient physical activity; and (b) provision ofa summary of the strength of evidence on lifestyle factorsandriskofdevelopingcvds. The report concludes that there are convincing associations for reduced risk of CVDs includingconsumptionoffruitsandvegetables,fishandfishoils(epaanddha),foodshigh in linoleic acid and potassium, as well as physical activity and low to moderate alcohol intake. With respect to the relationship between fats and CVD, especially coronary heart disease, the report states that there have been extensive investigations, with strong and consistent associations emerging from a wide body of evidence accrued from animal experiments, as well as from observational studies, clinical trials and metabolic studies conductedindiversehumanpopulations. 5

6 With respect to the nutritionally important fatty acids, the report states that the most importantomegan3(pufas)areepaanddhafoundinfattyfish. Thetextstates, The$biological$effects$of$Omega13$PUFAs$are$wide1ranging,$involving$lipids$ and$lipoproteins,$blood$pressure,$cardiac$function,$arterial$compliance,$endothelial$function,$ vascular$reactivity$and$cardiac$electrophysiology,$as$well$as$potent$anti1platelet1aggregation$ and$ anti1inflammatory$ effects.$ $ The$ very$ long$ chain$ Omega13$ PUFAs$ (EPA$ and$ DHA)$ powerfully$lower$serum$triglycerides$but$they$raise$serum$ldl$cholesterol.$$therefore,$their$ effect$on$chds$is$probably$mediated$through$pathways$other$than$serum$cholesterol.the same text indicates: Most$ of$ the$ epidemiological$ evidence$ related$ to$ Omega13$ PUFAs$ is$ derived$from$studies$of$fish$consumption$in$populations$or$interventions$involving$fish$diets$ in$clinical$trials. Fromtheseobservations,itwasconsideredlikelythatdietaryEPA+DHAarebeneficialfor secondaryprevention,i.e.forthosewithpreviouschd Joint FAO/WHO Expert Consultation on Fats and Fatty Acids in Human Nutrition, 10 14November2008,WHOHQ,Geneva Fromthisexpertconsultationitwasrecognisedthatindividualfattyacidsmayhaveunique biologicalpropertiesandhealtheffects,andthatforthepurposesoffoodlabelling,itwould benecessarytospecifyfullythesefattyacidsandtheiramounts. ForEPAandDHAcombined,therecommendedacceptablemacronutrientdistributionrange (AMDR)is g/day.Theintakeof2g/dayisforsecondarypreventionofCHD.The expertsagreedthecriteriatojudgethelevelsandstrengthofevidencerequiredtoconclude that the fatty acids affect major health and disease outcomes (i.e. convincing, probably, possible,insufficient).itwasconcludedthatthereis convincing evidenceofreducedrisk offatalchdeventsforepaanddhaandalevelofevidenceof possible forreductionof risk of CHD events and stroke. For adult males and nonnpregnant/nonnlactating adult females,0.250g/dayofepaplusdhaisrecommended,withinsufficientevidencetoseta specificminimumintakeofeitherepaordhaalone;bothshouldbeconsumed. 6

7 3.1.3 JointFAO/WHOExpertConsultationontherisksandbenefitsoffishconsumption, January 2010, Rome. FAO Fisheries and Aquaculture Report No FIPM/R978 (En),ISSN2070O6987. From this expert consultation the evidence was found convincing that fish consumption lowers mortality from coronary heart disease in the general population. The report recommends that Member States should emphasise the benefits of fish consumption in reducing coronary heart disease mortality(and the risks of mortality from coronary heart disease associated with not eating fish) for the general adult population. The conclusions alsostatedthatmoderateconsumptionoffattyfish(oneortwo100gservingsperweek) wouldprovidemaximumbenefit(twoservingsprovideabout250mgepa+dha),butrisks are lowered by any level of fish consumption evaluated (up to seven 100 g servings per week)unlessveryhighdioxinlevelsarepresent. Inaddition,thisexpertconsultationdidnotmakeadistinctionbetweenthestrengthofthe evidence for primary and secondary prevention, and it was concluded that the totality of theevidenceisconvincingforarisknreducingeffectofepa+dhaonchd,asisdescribedin thedocument,basedonlargenumbersofprospectivecohortstudies,itisevidentthatthere is consistent and convincing evidence for a beneficial effect of EPA and DHA for primary preventionofheartdisease. 3.2 EuropeanFoodSafetyAuthority(EFSA) Reference:EFSA$J2010;8(3):1461. EFSAconcludedthatinterventionstudieshavedemonstratedbeneficialeffectsofEPAand DHAonrecognisedcardiovascularriskfactors,suchasareductionofplasmatriacylglycerol concentrations, platelet aggregation and blood pressure. These effects were mainly observedatintakes 1g/day,wellabovelevelsthatwereassociatedwithlowerCVDriskin epidemiological studies. With respect to cardiovascular diseases, prospective epidemiological and dietary intervention studies indicate that oily fish consumption or OmegaN3 LCPUFA dietary supplements (equivalent to a range of mg of EPA plus DHAdaily)decreasetheriskofmortalityfromCHDandsuddencardiacdeath.Anintakeof 250mgperdayofEPAplusDHAappearstobesufficientforprimarypreventioninhealthy subjects. Therefore, and because available data are insufficient to derive an Average Requirement(AR),theEFSAPanelsetanAdequateIntake(AI)of250mgforEPAplusDHAin adultsconsideringcardiovascularhealth. 7

8 3.3 NorwegianScientificCommitteeforFoodSafety/NordicCouncilofMinisters Reference:Vitenskapskomiteenformattrygghet(VKM).Evaluationofnegativeandpositive health effects of OmegaN3 fatty acids as constituents of food supplements and fortified foods.opinionofthesteeringcommitteeofthenorwegianscientificcommitteeforfood Safety.Date Doc.No.08N707Nfinal.ISBN:978N82N8082N365N6. TheVKMscientificopinionmakesimportantobservationsonthepositivehealtheffectsof DHAandEPAinrelationtocardiovasculardiseases: Considerationsonadequateintakesofomega3fattyacidsshouldbespecifictoEPA anddhaonthepositivehealtheffects. FromthereviewedliteratureitisnotpossibletodistinguishthehealtheffectsofEPA anddhaconsumedastriacylglycerol(tag)orasethylesters. The strongest evidence for possible beneficial effects of supplementation with OmegaN3fattyacidinhumansisprovidedbyrandomisedcontrolledtrialsinvolving more than 43,000 study participants with cardiovascular disease (secondary prevention).inpatientsgiveneither0.8gepaanddhaor1.8gofepaasethylester daily,theriskofcardiovasculareventsandmortalitywasreduced. Primary prevention from EPA and DHA supplementation has been less studied. However,VKMendorsedEFSA srecommendationforadultsbasedonthescientific evidence indicating that oily fish consumption (1 2 servings per week or dietary supplementscontainingepaanddhaandequivalenttoarangeof0.25to0.5gof EPAandDHAdaily)decreasetheriskofmortalityfromcoronaryheartdiseaseand suddencardiacdeath. TheVKMscientificopinionalsoconsidersevaluationsofcardiovascularfunctionsofEPAand DHAmadebyWHO/FAO2008,WHO/FAO2010,EFSA2009andFDA.IntheEFSAscientific opinion in 2009, the EFSA NDA Panel concluded that a cause and effect relationship had beenestablishedbetweenconsumptionof3g/dayepaanddhaandareductioninblood pressure.thisrelatestobothhypertensiveandnormotensivepersons.similarly,thepanel concludedthatacauseandeffectrelationshiphasbeenestablishedbetweenconsumption of2 4g/dayofEPAandDHAandareductioninnormalfastingTAG.Bothmaintenanceof normalbloodpressureandareductioninfastingplasmatagsareconsideredtobepositive cardiovascularhealtheffects. 8

9 The VKM scientific opinion provides an extensive literature search, including studies with fishoilsandmarineethylestersandstudieswithplantoils.themechanismsofactionsare not fully understood and there is less evidence for primary prevention than secondary prevention, the conclusions suggest that increased consumption of OmegaN3 fatty acids fromfishorfishoilsupplementsreducetheratesofcvdnrelateddeaths,cardiacandsudden death,andpossiblystroke,andthatasufficientintakeofepaanddhaisimportantforgood health. VKM also states that the optimal dose is not known, and that the amount may vary in different populations depending on the basal dietary intakes of OmegaN3 fatty acids and OmegaN6fattyacids. In 2013 the Nordic Council of Ministers recommended that OmegaN3 fatty acids should contributeatleast1%energy.takingintoaccountgp ,1%energyequatesto1%of 2000kcal/day,whichis20kcal.Assuming9kcal/goffat,theequivalentamountofOmegaN 3fattyacidsis2.2g/day. 3.4 Australian and New Zealand Health Authorities (2006): National Health and MedicalResearchCouncilandNewZealandMinistryofHealth(NHMRC/MOH) Reference: National Health and Medical Research Council Nutrient Reference Values for Australia and New Zealand including recommended dietary intakes. Commonwealth of Australia,2006. Formenandwomen(19+years)arecommendationof160mgand90mg,respectively,of totalnomegan3(dha+epa+dpa)wasmadeforanadequateintake.thesuggesteddietary targettoreducechronicdiseaseriskwas610mgand430mg,respectively,fordha+epa+ DPAperday. TherecommendationtolowertheriskofCHDisthatalladultAustraliansshouldconsume about500mg/dayofcombineddhaandepathroughacombinationofthefollowing: 2or3servings/perweek(150gservings)ofoilyfish Fishoilcapsulesorliquid ConsumingfishatleastonceaweekisassociatedwithalowerriskoftotalstrokeandCHD mortality in the general population and in postnmyocardial infarction patients. Level of evidenceisiiin2ofnhmrc,obtainedfromcomparativestudieswithconcurrentcontrolsand nonnrandomisedallocation,cohortstudies,casencontrolstudies,orinterruptedtimeseries withacontrolgroup. 9

10 3.5 UnitedStatesInstituteofMedicine(2005) Ref.: Institute of Medicine of the National Academies. Dietary Reference Intakes of energy,carbohydrate,fiber,fat,fattyacids,cholesterol,proteinandaminoacids The United States Institute of Medicine made DHA and EPA intake recommendations for adultmenandwomen(+19yearsold)of10%oftotalomegan3intake(1.6gand1.1g/day, respectively).i.e.160mg/dayand110mg/day. 4. ADDITIONALBACKGROUNDABOUTTHESCIENTIFICEVIDENCEREVIEWREGARDING GENERALPRINCIPLESFORESTABLISHINGNRVS Attached are 4 reviews made by The Russian Federation, Chile and IADSA, of scientific evidence on the beneficial health effects of EPA and DHA(Attachment 2, 3, 4 and 5).On thesereviews,qualityoftheavailableevidenceisanalysedwiththegradeapproachand recommendationsfromrasbs. Attachment2 Document on International Alliance of Dietary/Food Supplement Associations (IADSA) ProposaltoCCNFSDUofnewworktoestablishaCodexNRVforomega3fattyacidsbased oneicosapentaenoicacid(epa)anddocosahexaenoicacid(dha).november2014. A"2"IADSA"Proposal" New"NRV"for"Omeg a7 Attachment3 ReviewofscientificandregulatoryapproachesinestablishingaCodexNRVvaluesforωN3N fattyacidsbasedoneicosapentaenoic(epa)anddocosahexaenoicacid(dha)acids.bythe RussianFederation. A"3"Review"by"the" Russian"Federation"en Attachment4 MinistryofHealthofChile.SummaryoftheavailableevidenceonthebenefitsofEPAand DHAfattyacidstodetermineareferencevaluerecommendedforintake.March

11 A"4"Review"Chile" english.pdf Attachment5 IADSA. Summary of the evidence available on the benefits of EPA and DHA fatty acids. March2015. A"5"Review"IADSA" english"march"2015.pd In addition to the recommendations from the RASBs, several global, regional and expert scientificorganisationshavesetoutrecommendationsforintakesoffish,fishoilsanddha+ EPAperday.TheserecommendationshavebeensummarisedandtabulatedbytheGlobal Organisation for EPA and DHA OmegaN3 (GOED), included on attachment 6 for additional information. Attachment6 Global Recommendations for EPA and DHA Intake. Global Organization for DHA and EPA Omega3(GOED),18March2015. A"6"Summary"GOED" For"IADSA"only"eng lish 5. POTENTIAL MECHANISMS THAT COULD CONTRIBUTE TO EFFECTS OF EPA + DHA ON REDUCEDRISKOFCARDIOVASCULARDISEASEINRELATIONTOCAC/GL2O1985 Thestudiesonriskmarkersandthepotentialunderlyingmechanismsarebeyondthescope of this review. However, in almost all the human studies investigating the biological mechanisms of the beneficial effects, the amounts of EPA + DHA have been large (i.e. intakes of 3000 mg/day). It is therefore difficult to translate the findings from these mechanisticstudiestorealisticeverydaysituationsofthegeneralpopulationwhereepa+ DHA are consumed. However, the following mechanisms that could explain the main cardiovascularbenefitshavebeenproposed: Reductionofcardiacarrhythmias Loweringofplasmatriglycerides AntiNatheroscleroticpotential Reductionsinbothsystolicanddiastolicbloodpressure Reductioninarterialstiffness Effectsonplateletaggregationandhaemostasis Effectsonendothelialfunctionandinflammation 11

12 6.PUBLICHEALTHIMPORTANCE 6.1 DietaryintakeassessmentandOmegaO3(DHAandEPA)nutritionalstatus The bulk of the scientific evidence is now pointing towards not so much optimal ratios of dietary OmegaN3 and nn6 fatty acids, but rather towards the absolute intakes of specific OmegaN3 and nn6 PUFAs that are associated with many different endpoints and health outcomes, such as CHD, mental health or immune/inflammatory responses (Deckelbaum andcalder,2010).aspreviouslyshown,theevidencerelatedtointakeamountsforomegan 3 PUFAs are best defined for CVD. What is abundantly clear is the total disconnect regarding the amounts of seafood and EPA and DHA and what is actually consumed (Griegeret$al.,2013).MostpopulationsarenotmeetingcurrentrecommendationsforDHA andepaintakes. ReliableandvaliddietaryintakeassessmentsarecrucialindeterminingDIRVs(Flocket$al., 2013). This poses a challenge for all nutrients, including EPA and DHA. The amounts, durationofintake,sourcesofepaanddha,dietaryandlifestylefactors,choiceofhealthy individuals versus patients, inconsistencies in the design, execution and interpretation of studies all contribute to the challenge of establishing DIRVs and NRVs. Much more information is needed about the endogenous production of EPA and DHA in vegans and vegetarians,interindividualvariabilityinresponsestoepaanddha,differentresponsesin relationtoage,sex,weight,race,specificgenotypesandoverallhealthstatus.upntondate foodcompositiondatabasesarealsoimportantforassessingomegan3pufaintake,andthe limitationsoffoodintakerecordshavetobetakenintoaccount. Forexample,EFSA(2012)selectedreferencesinordertoobtaindataonintakedistributions in European countries. Mean daily intakes for adults of EPA only ranged between 50 and 150 mg/day and median daily intakes were between 14 and 180 mg. For DHA, the mean amountsrangedbetween131and273mg/dayandthemediandailyintakeswerebetween 42.5and430mg/day. Forallthesereasons,reliablebiomarkersofOmegaN3PUFAstatusarenecessarytovalidate dietary intake data (Flock et$ al., 2013). Significant progress has been made over the last decadeandseveralmarkersofepaanddhaarenowavailable,includinglevelsinplasma, erythrocytesandadiposetissue.theuseofbloodmarkersoffattyacidintakehasmadeit possible to evaluate the outcomes related to disease. Plasma levels of fatty acids reflect intake over the past few days, whereas adipose tissue levels of fatty acids are more reflective of longernterm fatty acid intake. The OmegaN3 Index (SalaNVila et$ al., 2011; Schacky, 2014), i.e. the erythrocyte content of EPA and DHA is a useful biomarker. This standardised assessment method is important for assessing DHA and EPA status and the biologicaleffectsoftheirintake. 12

13 6.2 DietaryriskfactorsassociatedwithglobalburdenofNCD:cardiovasculardisease In view of the fact that current DHA and EPA intakes are low compared with the recommended levels, it is important to emphasise that substantial public health benefits wouldbeexpectedaslongasthegeneralpopulationmeettherecommendeddhaandepa intake;thereforeitisimportanttoestablishanrvforthesenutrients. As part of a systematic analysis for the Global Burden of Diseases Study 2010, Lim et$ al. (2012)wereabletoestimatedeathsanddisabilityNadjustedlifeyears(DALYs:sumofyears livedwithdisability(yld)andyearsoflifelost(yll))attributabletotheindependenteffects of67riskfactorsandclustersofriskfactorsfor21regionsin1990and2010.dietaryrisk factors and physical inactivity collectively accounted for 10.0% of global DALYs in Severaldietaryfactorsaffectischaemicheartdiseaseandstroke,includingconsumptionof fruits, vegetables, nuts and seeds, whole grain cereals, processed meat, polyunsaturated fatsandepa+dhaseafood.theresearchersupdatedearliersystematicreviewsandmetan analyses for seafood omegan3 fatty acids, which included both observational and intervention studies, and they tested whether a significant difference exists between the results of randomised clinical trials of seafood omegan3 fatty acid supplementation and observationalstudiesofseafoodomegan3fattyacidintake.theeffectofseafoodomegan3 fatty acids tended to be lower in RCTs than in observational studies; however, this difference was not statistically significant (P = 0.057). Hence, the researchers used the effect based on the combination of RCTs and observational studies. Of the individual dietaryriskfactorsassessedin2010,theglobalburdenofadietlowinseafood(richsource of EPA + DHA) was 1.1% of global DALYs (95% CI ) compared with fruits (4.2%), followedbydietshighinsodium(2.5%),lowinnutsandseeds(2.1%),lowinwholegrains (1.6%) and low in vegetables (1.5%). The proportion of ischaemic heart disease DALYs attributabletoindividualdietaryriskfactorsworldwidein2010included40%fordietslow innutsandseeds,30%fordietslowinfruits,22%fordietslowindhaandepaseafood, 17%fordietslowinwholegrains,17%fordietshighinsodiumand12%fordietslowin vegetables. InTable1fromLimet$al.$(2012),thefollowingdataforEPA+DHAincluded: Riskfactor Exposuredefinition Outcomes Subgroup Maindatasourcesforexposure DietlowinseafoodomegaO3fattyacids (DHAandEPA) DietaryintakeofEPA+DHAmeasuredin mg/day Deathcausedbyischaemicheartdisease Age 25years Foodandhealthsurveys 13

14 Theoretical minimum risk exposure 250mg/day distribution Sourceofrelativerisks Updated published review of Mozaffarianet$al.2010 Although further human intervention studies could unravel some of the inconsistencies observedbetweentheepidemiologicalevidenceandsomeresultsfromhumanintervention studies, there is already a large body of convincing evidence that supports CVD benefits related to increased intakes of EPA and DHA, and compelling reasons for establishing an NRV(KrisNEthertonet$al.,2009;Harriset$al.,2009;Flocket$al.,2013;Griegeret$al.,2013). Insummary,theavailableevidenceshowsthatEPAandDHAmayhavebeneficialeffectson health, including reduction of blood pressure, improvement of the efficiency of hypertensiondrugs,andreductionofcvdrisk. 7.SafetyofincreasedEPAandDHAintake TheprimaryconcernswithregardtothesafetyofDHAandEPAareitseffectsonglycaemic control in diabetes, reduced platelet aggregation/increased bleeding time and adverse immunological effects (EFSA, 2012). LongNterm human intervention studies that have investigateddiversehealthresultsandtheeffectsofsupplementalintakesofepaanddha, either alone or in combination, at amounts up to about 1 g/day on a variety of health outcomes (e.g. cardiovascular, neurological, immunological), have generally reported no adverseeffectsinrelationtotheconsumptionofepaordhaattheselevelsofintake. TheGISSIPrevenzionetrialin1999,theJELISstudy(Yokoyamaet$al.,2007)andtheGISSINHF Investigators (2008) study reported no clinically relevant adverse effects in over 35,000 individuals.over10yearsago,theusfoodanddrugadministration(fda)determinedthat intakesofepaanddhaofupto3g/dayaresafeforthegeneralpopulation.in2011,the NorwegianScientificCommitteeforFoodSafetyconductedasafetyreviewofEPAandDHA andfoundnoadverseeffectonbleedingtime,withlevelsashighas6.9g/day(froylandet$ al.,2011).morerecently,efsa(2012)concludedthatintakesuptoabout5g/dayofepa and DHA combined do not appear to increase the risk of bleeding complications and spontaneous bleeding episodes or affect glucose homeostasis, immune function or lipid peroxidation,providedthattheoxidativestabilityoftheepaanddhaisguaranteed.efsa alsoconcludedthatsupplementalintakesofepaaloneupto1.8g/daydonotraisesafety concernsforadults. 14

15 8.OTHERCONSIDERATIONS Consumptionoffishraisestheissueofhumanexposuretomethylmercury,atoxicformof mercury found in longnlived predators and fish at the top of the food chain, such as king mackerel, swordfish, shark, tilefish and albacore tuna. Although public health advice has been given for women who may become pregnant and for pregnant women, nursing mothersandyoungchildrentoavoidcertaintypesoffishpotentiallyhighinmercury,riskn benefitanalysesindicatethatloweringfishconsumptionwouldhaveseriouspublichealth consequences (Cohen et$ al., 2005; Mozaffarian and Rimm, 2006; Wennberget$ al, 2012; Hughneret$ al., 2012; European Food Safety Authority, 2014). The messages about fish consumption should therefore not discourage individuals from eating fish (FDAEE.UU., 2014). 15

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