GECropFoodSafetyDataPackageandHarmonizationContentsHarmonizationofdata:why?AnintroductiontotheCodexPlantGuideline(CAC/GL45-2003)TheCodexframeworkforfoodsafetyassessmentofgeneticallyengineered(GE)cropsFurtherdataharmonizationchallengesWhyDataHarmonization?Agriculturalbiotechnologyproductstypicallyneedregulatoryapprovalstoenteramarket.Dataneedsfordecision-makingdifferindifferentjurisdictions,leadingtoapprovalinconsistencies.Globally,dataharmonizationbenefitseveryone(byassistingregulationstoidentifysafeproducts).RegulatorsProductdevelopersFarmersFoodchainworkersConsumersTheCodexGuideline(CAC/GL45-2003)Fortunately,anauthoritativeinternationalguidelineisavailable.ThisGuidelinereflectswideinternationalconsensusonwhatconstitutesafoodsafetyassessmentforfoodderivedfromaGEplant.WhatisCodex?TheCodexAlimentarius(Latin)means“foodcode”.Itwasestablishedin1963bytheFoodandAgricultureOrganizationoftheUnitedNations(FAO)andtheWorldHealthOrganization(WHO).ThepurposeofestablishingtheCodexAlimentariusis“todevelopharmonisedinternationalfoodstandards,whichprotectconsumerhealthandpromotefairpracticesinfoodtrade”.TheoperatingbodyistheCodexAlimentariusCommission(CAC),anintergovernmentalbodywhereeverymembercountryhasavote.TheCodexPlantGuidelineACodexAdHocIntergovernmentalTaskForceonfoodsderivedfrombiotechnologywasformedin1999andhelditsfirstmeetingin2000.TheTaskForcewasformedbecausemembercountriesagreedthatharmonizationwasnecessarytofacilitatetradeandassurancesofhumanhealth.TheTaskForcefacedaspecialchallenge,sincefoodsafetywastraditionallyconcernedwithindividualfoodadditivesormicrobialandchemicalcontaminants.Butthepurposeoftheireffortwastoensurethesafetyofwholefoods,aneffortthatdidnotreallyexistpriortodiscussionsattheOECDinthe1980sand1990s.TheGeneralRiskAssessmentConsiderationsaccordingtotheCodexPlantGuidelineComparativeanalysisapproachwasproposedforassessingsafetyofcropsandfoodsderivedfromGEcrops.Wholefoodanimalstudiesshouldonlybeusedincertaincircumstances:“Animalstudiescannotreadilybeappliedtotestingtherisksassociatedwithwholefoods....If…theavailabledataareinsufficientforathoroughsafetyassessment,properlydesignedanimalstudiescouldberequestedonthewholefoods…”Bothintendedandunintendedeffectsshouldbeaddressed:Theassessmentforunintendedeffectstakesintoaccounttheagronomic/phenotypiccharacteristicsoftheplant.Unintendedeffectsisaninherentandgeneralphenomenonthatcanalsooccurinconventionalbreeding.TheCodexFrameworkforFoodSafetyAssessmentofGECropsA)Descriptionoftherecombinant-DNAplant;B)Descriptionofthehostplantanditsuseasfood;C)Descriptionofthedonororganism(s);D)Descriptionofthegeneticmodification(s);E)Characterizationofthegeneticmodification(s);F)Safetyassessment:expressedsubstances(non-nucleicacidsubstances);compositionalanalysesofkeycomponents;evaluationofmetabolites;foodprocessing;nutritionalmodification;andotherconsiderations.TheCodexFrameworkforFoodSafetyAssessmentofGECropsThemajorpurposeofSectionsA)toE)istoidentifytheplantunderstudy.A)Descriptionoftherecombinant-DNAplant;B)Descriptionofthehostplantanditsuseasfood;C)Descriptionofthedonororganism(s);D)Descriptionofthegeneticmodification(s);E)Characterizationofthegeneticmodification(s);TheCodexFrameworkforFoodSafetyAssessmentofGECropsSectionF)istheaspectsthatshouldbeconsideredforriskassessment.F)Safetyassessment:expressedsubstances(non-nucleicacidsubstances);compositionalanalysesofkeycomponents;evaluationofmetabolites;foodprocessing;nutritionalmodification;andotherconsiderations.a)ExpressedSubstances(Non-nucleicAcidSubstances)(1)Assessmentofpossibletoxicityfromunintendedsources–newmetabolites,knowntoxins,andanti-nutrientsForexample,iftherearenewmetabolitesresultedfromtheactivityofenzymesgeneratedbytheexpressionoftheintroducedDNA,thefollowingshouldbeexamined:Thechemicalnatureandfunctionofthenewlyexpressedsubstance,TheconcentrationofthesubstanceintheediblepartsoftheGEplantThecurrentdietaryexposureandpossibleeffectsonpopulationsubgroupsGenescodingforknowntoxinsoranti-nutrientspresentinthedonororganismsshouldnotbetransferredtoGEplantsthatdonotnormallyexpressthosetoxinsoranti-nutrients.ThisisparticularlyimportantifaGEplantisprocesseddifferentlyfromadonorplant.a)ExpressedSubstances(Non-nucleicAcidSubstances)(2)AssessmentofpossibletoxicityofintentionallyintroducedsubstancesConventionaltoxicologystudiesmaynotbenecessarywherethesubstanceoracloselyrelatedsubstancehasbeenconsumedsafelyinfoodatlevelsthatareexpectednottochangewiththegeneticmodification(s).Whendeemednecessary,theassessmentofpotentialtoxicityforproteinsshouldrelyonbioinformatics,stabilityoftheproteinstoheat,processing,anddigestion.Oraltoxicitystudiesarenecessaryifaproteinisdifferentfromthosethathavepreviouslybeenconsumedsafely,takingintoaccountitsbiologicalfunctionintheplant.Potentialtoxicityofnon-proteinsubstancesthathavenotbeensafelyconsumedinfoodshouldbeassessedonacase-by-casebasis.a)ExpressedSubstances(Non-nucleicAcidSubstances)(3)Assessmentofpossibleallergenicity(proteins)Anintegrated,stepwise,case-by-caseapproachwasproposed.GlutensensitivitytestingshouldberequiredforGEwheat,rye,barley,oats,orrelatedcerealgrains.b)CompositionalAnalysesofkeyComponentsOncedataareobtained,concentrationsofkeycomponentsofaGEplantshouldbecomparedwithaconventionalcounterpartgrownandharvestedunderthesameconditions.Differencesshouldbeassessedforbiologicalrelevanceagainstthenaturalvariationsforthoseparameters.Ideally,acomparatorusedinthisassessmentshouldbethenear-isogenicparentalline.Inpractice,however,thismaynotalwaysbefeasibleandthereforetheclosestlineischosen.Anexposureassessmentshouldbeconductedwhennecessary.c)EvaluationofMetabolitesSomeGEplantscouldhaveneworalteredlevelsofvariousmetabolites.Ifthemetabolitesaccumulate,residueandmetabolitelevelsinthefoodshouldbemeasured,andanyalterationsinnutrientprofileshouldbeassessed.Wherealteredlevelsofresiduesormetabolitesareidentified,thepotentialimpactsonhumanhealthshouldbeexaminedusingconventionalprocedures,whicharetypicallyusedforassessingthesafetyofchemicals.d)FoodProcessingInformationshouldbeprovidedabouttheprocessingconditions(includinghomepreparations)usedintheproductionofafoodingredientfromtheplant.e)NutritionalModification

AdditionalnutritionalassessmentisneededforfoodsderivedfromGEplantsthathavebeenintentionallymodifiedforimprovednutritionalorfunctionality.Exposureassessmentwithconsiderationsforsub-populationsisimportant.AlthoughGEplantcomponentsmaybeindividuallyassessedassafe,thechangeontheoverallnutrientprofilecouldhavepotentialsafetyissuesandsoshouldbeexamined.AnimalfeedingstudiesmaybewarrantedforfoodsderivedfromGEplantswithexpectedchangesinthebioavailabilityofnutrientsorwithchangesinthecomposition,makingthemnon-comparablewithconventionalfoods.MoredetailscanbefoundinAnnexIItoGuidelineCAC/GL45-2003.f)OtherConsiderationsPotentialaccumulationofsubstancessignificanttohumanhealth(suchasherbicides)UseofantibioticresistancemarkergenesPossibilityisverylowforgenetransferfromplantsortheirfoodproductstogutmicro-organismsorhumancells.Nevertheless,thepossibilityofsucheventscannotbecompletelydiscounted.ReviewofsafetyassessmentsWhennewscientificinformationbecomesavailable,thesafetyassessmentshouldbereviewedtoseeiftheoriginalconclusionsarestillvalid.FurtherHarmonizationChallengesTheconsensusintheCodexGuidelineisamilestone,butitisnotthedestinationinthejourneytoharmonization.NoguidelinecanaddresseverydetailofananalysisthatmustbeputintopracticeSomechallengesforharmonizedimplementationofCodexGuideline:InterpretationsofcomparativeanalysesWhenisadifference“significant?”HarmonizationofanimalstudydesignWhenareanimaltestswarranted,andhowshouldtheybedesigned?SomeCo