australia and new zealand nutrient reference...

AustralianandNewZealandNutrientReferenceValuesforFluoride

AreportpreparedfortheAustralianGovernment

DepartmentofHealth

By

ExpertWorkingGroupforFluoride

JanisBaines,MichaelFoley,AndrewJohnSpencer,MarcoPeresandUtzMuellerwithResearchAssistancefrom

JudyCunningham,EmmanuelGnanamanickam,NajithAmarasenaJULY2015

ii

TableofContents

1. Introduction..............................................................................................7

1.1Fundingsource.........................................................................................7

1.2UseofNutrientReferenceValues............................................................7

1.3Summaryof2006NRVsforFluoride......................................................10

1.4Triggersandrationaleforreview...........................................................11

1.5Backgroundinformation-fluoride.........................................................11

2. ScopeandPurpose..................................................................................13

3. EvidenceReview.....................................................................................14

3.1Fluorideintakeestimatesininfantsandyoungchildren.......................14

3.1.1 AustraliaandNewZealand.......................................................14

3.1.2 International.............................................................................15

3.2Selectionofbiomarkersforfluoride......................................................17

3.2.1 Dentalcaries.............................................................................17

3.2.2 Fluorosis....................................................................................21

3.3Selectionofevidence.............................................................................25

3.3.1 Reviewofmajorreports...........................................................26

3.3.2 Systematicreviewofnewliterature.........................................31

3.3.3 SystematicLiteratureReviewResults.......................................34

3.4Assumptionsandlimitations..................................................................39

3.5Reviewofevidence-DerivationofULandAI........................................40

3.5.1 DoseresponseassessmenttoestablishaUL...........................40

3.5.2 DietaryFluorideIntakeestimatesfortheDeanstudy..............44

3.5.3 UpperLevelofIntake(UL)........................................................46

3.5.4 AdequateIntake(AI).................................................................48

3.5.5 CurrentfluorideintakeinAustraliaandNewZealand.............49

4 Guidelinerecommendations...................................................................52

4.1DraftNRVs..............................................................................................52

4.1.2 UpperLevelofIntake(UL)........................................................52

4.1.3 AdequateIntake(AI).................................................................52

4.2ValidityofRecommendations................................................................53

4.3Furtherresearch.....................................................................................54

5 Membershipofgroupsandcommitteesinvolvedinthedevelopmentprocess....................................................................................................55

6 Glossary..................................................................................................57

7 Listofabbreviations................................................................................59

8 ReferenceList..........................................................................................63

9 Listoftables............................................................................................74

10 Listoffigures...........................................................................................75

11 Listofboxes............................................................................................76

12 Appendix1.Summaryoffindings–GRADEassessment...........................77

13 Attachments...........................................................................................84

1 AustralianandNewZealandNutrientReferenceValuesforFluoride

ExecutiveSummary

TheNutrientReferenceValues(NRVs)areasetofrecommendednutrientintakesusedtoassessdietaryrequirementsofindividualsandpopulationgroups.ThecurrentNRVsforAustraliaandNewZealandwerepublishedin2006(NHMRC&MOH2006)afteracomprehensivereviewprocesscommissionedbytheDepartmentofHealthandAgeing(DOHA)andtheNewZealandMinistryofHealth(MoH).TheNationalHealthandMedicalResearchCouncil(NHMRC),whichcarriedoutthereview,recommendedthattheserecommendationsbereviewedeveryfiveyears.In2011DOHA,nowtheDepartmentofHealth(DoH),inconsultationwiththeNZMoHcommissionedascopingstudyforundertakingareviewoftheNRVs.ThisresultedinthedevelopmentofaMethodologicalFrameworkforthereviewbyNousandaconsortiumofexperts(NousGroup2013).Thepurposeofthepresentreviewistotestthisframeworkonthreenutrients,onebeingfluoride.

Fluorideisnaturallypresentinthefoodanddrinkweconsumeandisconsideredanormalconstituentofthehumanbody.Thefluorideconcentrationinbonesandteethisabout10,000timesthatinbodyfluidsandsofttissues(Bergmann&Bergmann1991;1995).Nearly99%ofthebody’sfluorideisboundstronglytocalcifiedtissues.Fluorideinboneappearstoexistinbothrapidly-andslowly-exchangeablepools.

Fluorideavailablesystemicallyduringtoothdevelopmentisincorporatedintoteethasfluorapatiteintoothenamel.Fluorapatiteintoothenamelaltersitscrystallinestructure,reducingthesolubilityofenameltoaciddissolution,ordemineralization.Athigherfluorideintakesthecrystallinestructuremaybedisruptedduringtoothdevelopmentperiods,formingporositieswhicharethebasisofdentalfluorosis.However,outcomessuchasskeletalfluorosisandbonefracturesoccuronlyafterprolongedexposuretoveryhighfluorideintakes.Fluorideatthesurfaceofenamelcanalsoformcalciumfluoride,amorerapidly-exchangeablepooloffluoridetoalterthedemineralization-remineralizationbalance,whichisthedynamicprocessunderlyingdentalcaries.DentalcariesisalargelypreventablebuthighlyprevalentchronicdiseaseinAustralianandNewZealandchildrenandadults.

AustraliaandNewZealandhavepursuedpublichealthpolicytoadjustfluorideintakeatthepopulationlevelwiththeaimofpreventingdentalcarieswithoutcausingmoderateorseveredentalfluorosisandotheradverseeffects.Itisconsidereddesirabletohaveafluorideintakethatissufficienttopreventdentalcaries(anAdequateIntake)withoutexceedingintakesthatareassociatedwithmoderateorseveredentalfluorosis(anUpperLevelofIntake).However,thereisevidencethatfluorideintakesmayexceedrecommendedlevelsorestablishedupperlevelsofintakeforchildrenevenwhenwaterfluoridationlevelsfollowthecurrenttargetdrinkingwaterlevelsinAustralia(0.6-1.1mgF/L)(NHMRC2007)andNewZealand(0.7to1.0mgF/L)(MoH2005)and/orwhenindividualsareexposedtofluoride


fromothersources1.Yetneithercountryexperiencesmorethantherareoccurrenceofmoderateorseveredentalfluorosis.ThisapparentexceedanceofrecommendedfluorideintakelevelswithouttheoccurrenceofmoderateorseveredentalfluorosiscreatedtheconundrumaroundNRVsforfluoridetowhichthisreportresponds.

ThecurrentNRVsforfluorideforallagegroupswerenotabletobereviewedinthetimeallocatedforthispilotreview.TheExpertWorkingGroup(EWG)narrowedthescopeofitsreviewtoanAdequateIntake(AI)andUpperLevelofIntake(UL)forfluorideforinfantsandyoungchildren,asthecriticalagegroupstoconsiderfordentalcariesandfluorosis.TheEWGnotedtheterm‘TolerableUpperLevelofIntake’wasanappropriatewaytodescribetheULforfluoridethathasbeenusedinternationally,however,tomaintainconsistencywiththeestablishmentofNRVsforothernutrientsinAustraliaandNewZealand,theterm‘UpperLevelofIntake’wasretainedforfluoride.

TheEWGconductedseveralliteraturereviews.First,eightformalreportsincludingthelandmarkUSInstituteofMedicineonfluoride,publishedin1997,andsevenotherspublishedinthe17yearssincetheIOMreport,werereviewed(IOM1997,McDonaghetal..2000,NRC2006,EPA2010a,b,SCHER2011,EFSA2005,2013).ThefocusofthisreviewofreportswasthedataavailableuponwhichtobuildNRVsandthemethodologyadopted.ThereviewofreportsrevealedthecentralrolethatDean’sdataofthelate1930s-40s(Deanetal.1941,1942;Dean1942,1946)hadinalltheseevaluationsinestimationofdose-responserelationshipsbetweencriticalfluorideconcentrationsinthewatersupplyandthepreventionofdentalcariesandadversedentalfluorosis.

Theend-pointfordentalcariesintheDeanstudieswasthecariesexperiencemeasuredbytheDecayed,Missing,andFilledTeethscoreamong12–14yearoldchildrenwhiletheendpointfordentalfluorosiswastheDean’sIndexscoresortheCommunityFluorosisIndex.Themostseveredentalfluorosisobservedhadpittingorlossofdentalenamel,interpretedasaDean’sIndexscoreof4(Dean1942).

ApproachestothederivationoffluorideintakesatcriticalfluorideconcentrationsinthewatersupplywereassessedsoastoguidetheEWG’ssubsequentdeterminations.

Literaturepublishedin2005andonwardswassearchedandrelevantliteratureidentified.NoalternativedatawereidentifiedthatcouldbesubstitutedforDean’sdatafromthe1930s(Deanetal.1941,1942;Dean1942,1946)forcriticalfluorideconcentrationsinrelationtothepreventionofdentalcariesandminimisationofmoderateandseveredentalfluorosis.Thebulkoftherelevantliteratureaddressedfluorideintakesincontemporarycommunitiesandthepreventionofcariesorriskofdentalfluorosis.

1DrinkingwaterGuidelinesinAustraliaandNewZealandarebasedonhealthconsiderationsandstatethe

concentrationoffluorideindrinkingwatershouldbeintherangeof0.7to1.0mgF/Lbutshouldnotexceed1.5mgF/L(NHMRC2013,MoH2005).However,intheNHMRC2007statementonthesafetyandefficacyoffluoridation,itisrecommendedthatwaterinAustraliabefluoridatedintherange0.6-1.1mg/L,dependingonclimate,tobalancethereductionofdentalcariesandoccurrenceofdentalfluorosis(NHMRC2007).


TheEWGidentifiedthecriticalfluorideconcentrationsinthewatersupplyfromDean’sdataforthenearmaximalpreventionofdentalcaries(theAI)andforpreventionofmoderateorseveredentalfluorosis(theUL).Nearmaximalcariespreventionwasassociatedwithafluorideconcentrationof1.0mgF/L,whilethecriticalconcentrationforpreventionofseverefluorosis(<0.5%prevalenceofseverefluorosis)was1.9mgF/L.

Dietaryfluorideintakeforchildrenatthecriticalfluorideconcentrationswasestimatedusingthreesetsofdataonfluidandfoodconsumptionamongchildren:McClure’smodeldiet,theUS1977–78NationwideFoodConsumptionSurveyandtheAustralian1995NationalNutritionSurvey(McClure1943,EPA2010a,FSANZ2014).Therewasahighlevelofagreementbetweenthedailyfluorideintakeestimates.Theyrangedfromapproximately0.04mgF/kgbw/dayatthemeanto0.20mgF/kgbw/dayatthe95thpercentileofintake.

Thedistributionoffluorideintakesforarangeofchildagesandtheirassociatedbodyweightsatthecriticalfluorideconcentrationof1.9mg/Lwaterwasdeterminedandthe95thpercentileoffluorideintakesusedtoestablishanUpperLevelofIntakeoffluoride.TheUpperLevelofIntakeoffluoridewasestablishedat0.20mgF/kgbw/dayforchildrentoavoidseveredentalfluorosis.ThisestimateishigherthantheexistingUpperLevelofIntakeoffluorideof0.1mgF/kgbw/daypreviouslyestablishedbytheNHMRCin2006,whichwasbasedontheIOM1997report(NHMRC2006).TheEWGwassatisfiedthattherewasaninconsistencyintheestimationoftheUpperIntakeLevelintheIOMreport.TheEWGnotedthattherevisedULishigherthanthefluorideReferenceDoseof0.08mgF/kgbw/dayestablishedbytheEPAin2010(EPA2010a).TheEWGconsideredtheEPA’suseofthemeandietaryfluorideintake,ratherthanahighpercentilefluorideintake,at1.9mgF/LindrinkingwatertointerpretfluorideintakesatthecriticalfluorideconcentrationdidnotprovidearobustbasistoderiveanUpperLevelofIntakeforfluoride.

Theaveragefluorideintakewascalculatedforarangeofchildren’sagesandtheirassociatedbodyweightsatafluorideconcentrationof1.0mgF/Lindrinkingwater.ThecurrentAdequateIntakeof0.05mgF/kgbw/daywasreaffirmedtobeanintakelikelytobeassociatedwithappreciablyreducedratesofdentalcaries.AnAIwasnotestablishedforinfantslessthan6monthsofage,asfluidsforthemajorityoftheseinfantswereassumedtobebreastmilk.

TheUpperLevelofIntakeoffluoridewascomparedwithestimatedtotaldailyfluorideintakes(fluid,foodandingestedtoothpaste)forAustralianandNewZealandchildrenlivinginareaswith1.0mgF/Linthewatersupply.Theupperrangeofthetotaldailyfluorideintakeestimateswas0.10to0.14mgF/kgbw/dayacrossdifferentagegroupsconsidered,whichisconsiderablylowerthantheestablishedUpperLevelofIntakeoffluorideof0.2mgF/kgbw/day.

ThenewreferencebodyweightdataforAustralianandNewZealandpopulationswasusedtoderivetherecommendationsonaperdaybasisfromtheUpperLevelofIntakeoffluorideof0.2mgF/kgbw/dayforchildrenaged4-8years.ThemostrecentUSreferencebodyweightdatawereusedforinfantsandchildrenaged1-3yearsasnosuitableAustralianandNewZealanddatawereavailablefortheseagegroups(NRC2005,AppendixB).


UpperLevelofIntake

Age Meanbw(kg) UL

Infants0–6months 6 1.2mg/day

7–12months 9 1.8mg/day

Children1–3years 12 2.4mg/day

4–8years 22 4.4mg/day

TheAdequateIntakeoffluorideforchildrenupto8yearsoldof0.05mgF/kgbw/dayisequivalenttothefollowingintakesexpressedasmgF/day,usingthesamereferencebodyweightdataasfortheUL.

AdequateIntake Age Meanbw(kg) AI

Infants0–6months 6 Notapplicable

7–12months 9 0.45mg/day

Children1–3years 12 0.6mg/day

4–8years 22 1.1mg/day

TheEWGconsidersthereisaModeratedegreeofcertaintyintheestimatesoftheAIandUL,usingtheGRADEsystem.StrengthsoftheevidenceincludethelargenumberofchildrenincludedintheDeanobservationalstudies,thewiderangeofdrinkingwaterfluorideconcentrationsreported,thecleardoseresponserelationshipsfoundbetweenthewaterfluorideconcentrationsanddentalcariesorfluorosisandtheabsenceofpotentialconfoundingfactorsthatarepresentinlaterstudiesfromtheuseoffluoridatedwatersupplies,andtoothpaste,supplementsanddentaltreatmentscontainingfluoride.TheseissuessupportincreasingtheratingbasedonthestrengthoftheevidencefromtheusualLowforevidencefromobservationalstudiestoModerate.AlthoughdataforfoodandfluidconsumptionandbodyweightswerenotdirectlyavailablefromtheDeanstudiesandhadtobedrawnfromothersources,thethreesourcesofinformationusedforthispurposeprovidedconsistentresultsandhadgoodprecision.

TheseestimateshavenoimplicationsforcurrentdrinkingwaterstandardsinAustraliaandNewZealandorforactiononfluorideintakefromtheingestionoftoothpaste.

FutureworkincludesthereviewofexistingULsandAIsforolderchildrenandadults,includingpregnantandlactatingwomen.


SummaryofRecommendations

Fluorideiswidespreadinnatureandanormalpartofthehumanbody.Itisparticularlyconcentratedinteethandboneandhelpsformtoothenamel.Fluorideisingestedfromseveralsourcesincludingfoods,fluoridatedandunfluoridatedwater,fluoridatedtoothpastesandsomedietarysupplements.Bothinadequateandexcessivefluorideintakescanaffectdentalhealth.Inadequateintakesareassociatedwithincreasedtoothdecay(dentalcaries)andexcessiveintakeswithdamagetotoothenamel(dentalfluorosis).

NutrientreferencevalueswereestablishedforfluoridebyNHMRC/MoHin2006followingareview,whichdrewonanearlierreviewbytheUSInstituteofMedicinein1997.Nutrientreferencevaluesareguidestodietaryintakesthathelptoprotectpopulationsandindividualsagainstdeficiencydiseaseand,insomecases,againstexcessivenutrientintakes.Inthe2006review,bothAdequateIntakes(AI)andUpperLevelsofIntake(UL)wereestablishedforfluorideintakefordifferentagegroups.

RecentestimatesofdietaryfluorideintakeinAustraliaandNewZealandhavesuggestedthatthefluorideintakeofasubstantialproportionofinfantsandyoungchildrenmayexceedtheUL.Atthesametime,thereisnoevidenceofwidespreadoccurrenceofmoderateorseveredentalfluorosis.ThissuggeststhattheexistingULneedsreconsideration.

Thisreportexaminesevidencefromthe1997InstituteofMedicinereviewandsevenothermajorreviewsoffluoridereleasedsincethe1997reviewandfromasystematicreviewofpost-2005scientificliteratureonfluorideintakesandoralhealth.Fromthisexaminationofrelevantevidence,aULandanAIforfluorideweredeterminedforchildrenupto8yearsofage.

AsthisreportwasapilotforfutureNRVreviews,itwaslimitedtoconsideringchildrenupto8yearsofage,thecriticalagegrouptoconsiderfordentalcariesandfluorosis.

Dentalfluorosiswaschosenasthekeymeasureofexcessfluorideintakeanddentalcariesasthemeasureoffluorideadequacy.Thesemeasuresareconsistentwiththoseusedinothermajorreviews.ThesereviewsshowedthecentralroleofobservationaldatacollectedintheUSinthelate1930s-40sforestimatingdose-responserelationshipsbetweenthepresenceofdentalcariesordentalfluorosisandtheconcentrationoffluorideinthewatersupply.Thesystematicliteraturereviewdidnotfindanymorerecentdata,observationalorexperimental,thatcouldreplaceit.

BasedontheseUSdata,thereportidentifiesthecriticalfluorideconcentrationsinthewatersupplyforoptimisingpreventionofdentalcariesandforminimisingseveredentalfluorosis:1.0mgfluoride/litreand1.9mgfluoride/Lrespectively.Fromthesevalues,togetherwithnationallyrepresentativedataonwaterandfoodconsumptionandbodyweightdataforAustralianandNewZealandpopulations,theUpperLevelofIntakeoffluorideforinfantsandchildrenupto8yearsoldwasestimatedtobe0.2mgfluoride/kgbodyweight/day.TheAdequateIntakewasreaffirmedtobe0.05mgF/kgbodyweight/day.NewreferencebodyweightdataforAustralianandNewZealandchildrenaged4yearsandabovewereusedtodeterminenewvaluesfortheAIandULexpressedinmgF/day;themostrecentUS


referencebodyweightdatawereusedforinfantsandchildrenaged1-3yearsasnoAustralianandNewZealanddatawereavailablefortheseagegroups.

TheEWGconsidersthereisaModeratedegreeofcertaintyintheestimatesoftheAIandUL,usingtheGRADEsystem(seeAppendix1).StrengthsoftheevidenceincludethelargenumberofchildrenincludedintheUSobservationalstudy,thewiderangeofdrinkingwaterfluorideconcentrationsreported,thecleardoseresponserelationshipsfoundandtheabsenceofpotentialconfoundingfactorsthatarepresentinlaterstudiesfromtheuseoffluoridatedwatersupplies,andtoothpaste,supplementsanddentaltreatmentscontainingfluoride.TheseissuessupporttheratingupthestrengthoftheevidencefromtheusualLow,forevidencefromobservationalstudies,toModerate.AlthoughdataforfoodandfluidconsumptionandbodyweightswerenotdirectlyavailablefromtheUSstudyandhadtobedrawnfromothersources,thethreesourcesofinformationusedforthispurposeprovidedconsistentresultsandhadgoodprecision.

TheEWGstronglyrecommendstheadoptionofthesevaluesfortheULandAIforAustralianandNewZealandchildrenagedupto8years.

TheseestimateshavenoimplicationsforcurrentdrinkingwaterstandardsinAustraliaandNewZealandorforactiononfluorideintakefromingestionoftoothpaste.

RecommendedfutureworkincludesthereviewofexistingULsandAIsforolderchildrenandadults,includingpregnantandlactatingwomen.


1. Introduction

1.1 Fundingsource

ThisreviewhasbeenfundedbytheAustralianDepartmentofHealthandtheNewZealandMinistryofHealth.

1.2 UseofNutrientReferenceValues

NutrientReferenceValues(NRVs)areasetofrecommendednutrientintakesdesignedtoassistnutritionandhealthprofessionalsassessthedietaryrequirementsofindividualsandgroups.Publichealthnutritionists,foodlegislatorsandthefoodindustryalsousetheNRVsfordietarymodellingand/orfoodlabellingandfoodformulation.

ThecurrentNRVsforAustraliaandNewZealandwerepublishedin2006afteracomprehensivereviewprocessoftheRecommendedDietaryIntakes(theonlytypeofnutrientreferencevaluethathadbeenproducedatthetime),commissionedbytheDepartmentofHealth(Health)inconjunctionwiththeNewZealandMinistryofHealth(NZMoH).

ThereviewresultedinanewsetofrecommendationsknownastheNutrientReferenceValuesforAustraliaandNewZealand(2006).TheNationalHealthandMedicalResearchCouncil(NHMRC)carriedoutthe2006reviewandrecommendedthattheseguidelinesbereviewedeveryfiveyearstoensurevaluesremainrelevant,appropriateanduseful.

In2011Health,inconsultationwiththeNZMoH,commissionedascopingstudytodeterminetheneedandscopeforareviewofNRVs.Thescopingstudyconsidereddevelopmentsincomparablecountries,expertopinions,stakeholderconsultationandpublicsubmissions.Thescopingstudyconcludedtherewassufficientjustificationforconductingareviewandasaresult,HealthandtheNZMoHengagedNousGroupandatechnicalteamledbyBakerIDI,todevelopaMethodologicalFrameworktoguidefutureNRVreviews.

ASteeringGroupisoverseeingthereviewprocessandisresponsibleforallstrategic,fundingandtechnicaldecisionsofthereview.Itconsistsofrepresentativesfrombothfundingagencies,HealthandtheNZMoH,withtheNHMRCasanobserver.TheSteeringGroupisalsoresponsiblefortheongoingmonitoringoftriggersforanewreview,andensuringnutrientreviewsareconductedinatimelymanner.

ReviewsarebeingconductedonarollingbasistoensureNRVsremainrelevantandappropriate.Theprocesscomplieswiththe2011NHMRCProceduresandrequirementsformeetingthe2011NHMRCstandardforclinicalpracticeguidelines.

TheDOHappointedanAdvisoryCommitteeasanexpertreferenceandadvisorygroupwhichalsoactsasanindependentmoderatorofnutrientrecommendations.


TheAdvisoryCommitteecomprisesmemberswithabroadrangeofexpertise,includingexpertsintheareasofmicronutrients,toxicology,publichealth,enduserneeds,research,chronicdisease,nutritionandmacronutrientsfromAustraliaandNewZealand.

ThescopingstudyalsoidentifiedtherationaleandtriggersforreviewingspecificnutrientsincludingchangesordevelopmentstoNRVsincomparableOECDcountries,emergenceofnewevidence,impactonpublichealthprioritiesand/orconcernsregardingthestrengthoftheunderlyingmethodologyorevidence.FluoridewasidentifiedasaprioritynutrientforreviewandthishasbeenfundedbyHealthandNZMoH.

TheHealth(withtheadvicefromNZMoHandtheAdvisoryCommittee),establishedagroupofexpertstoconductthisfluoridereview.TheExpertWorkingGroupwasprimarilyresponsibleforexaminingscientificevidenceandestablishingnutrientvalues.

MembershipofthegroupsinvolvedinthedevelopmentoftheNRVguidelinescanbefoundinSection5.

ThesuiteofNRVtermsoutlinedinthe2006document(NHMRC2006),adaptedfromtheUS/CanadianDietaryReferenceIntakes(DRIs),wereconsideredtoremainapplicablefortheNRVreviewswithnochangeofnametothereferenceindicators(NHMRC2006,NousGroup2013).


NRVtermsEAR EstimatedAverageRequirementAdailynutrientlevelestimatedtomeettherequirementsofhalfthehealthyindividualsinaparticularlifestageandgendergroup.

RDI RecommendedDietaryIntakeThedailyintakelevelthatissufficienttomeettherequirementsofnearlyall(97–98%)healthyindividualsinaparticularlifestageandgendergroup.

AI AdequateIntakeTheaveragedailynutrientintakelevelbasedonobservedorexperimentallydeterminedapproximationsorestimatesofnutrientintakebyagroup(orgroups)ofapparentlyhealthypeoplethatareassumedtobeadequate.

EER EstimatedEnergyRequirement

Theaveragedietaryenergyintakethatispredictedtomaintainenergybalanceinahealthyadultofdefinedage,gender,weight,heightandlevelofphysicalactivity,consistentwithgoodhealth.Inchildrenandpregnantandlactatingwomen,theEERistakentoincludetheneedsassociatedwiththedepositionoftissuesorthesecretionofmilkatratesconsistentwithgoodhealth.

UL UpperLevelofIntake

Thehighestlevelofnutrientintakelevellikelytoposenoadversehealtheffectstoalmostallindividualsinthegeneralpopulation.AsintakeincreasesabovetheUL,thepotentialriskeffectincreases.

AMDR AcceptableMacronutrientDistributionRange

Anestimateoftherangeofintakeforeachmacronutrientforindividuals(expressedaspercentcontributiontoenergy),whichwouldallowforanadequateintakeofalltheothernutrientswhilstmaximisinggeneralhealthoutcome.

SDT SuggestedDietaryTarget

Adailyaverageintakefromfoodandbeveragesforcertainnutrientsthatwillhelpinpreventionofchronicdisease.


1.3 Summaryof2006NRVsforFluoride

The2006NHMRCAustralianandNewZealandrecommendationsforfluoridewereforAIsandULsforallagegroups,andwerebasedonthevaluesfromthe1997InstituteofMedicine(IOM)Report.TheAIof0.05mg/kgbw/dayandULof0.1mg/kgbw/daywereextrapolatedtodifferentagegroups(exceptinfants≤6monthsofage)usingbodyweightsfortheUSpopulationusedinthe1997IOMreport(IOM1997).ThecurrentNRVsaresummarisedinTable1.

Table1.1:OverviewofNRVsforfluoride(NHMRC2006)

Agegroup AI*mg/day

UL#mg/day

Comments

Infants0–6months 0.01 0.7 Assumed780mLbreastmilkperdayandconcentrationof0.013mg/L(IOM1997)

Infants7–12months 0.5 0.9

Children1–3years 0.7 1.3

Children4–8years 1.0 2.2

Children9–13yearsboys,girls

2.0 10.0

Adolescents14–18yearsboys,girls

3.0 10.0

Adults19–70yearsmale 4.0 10.0

Adults19–70yearsfemale 3.0 10.0

Adults14–50yearsPregnancy 3.0 10.0 Noevidencethatrequirementsarehigherinpregnancythanthoseofnon-pregnantwomen

Adults14–50yearsLactation 3.0 10.0 Fluorideconcentrationinbreastmilklowandfairlyinsensitivetofluorideconcentrationindrinkingwater,requirementssameasfornon-pregnantwomen

*AIsforolderinfantsandchildrenbasedonAIof0.05mg.kgbw/dayandstandardbodyweightsforUSchildrenfor7–12monthinfantsof9kg;children1–3yrsold13kg;children4–8yrsold22kg;children9–13yrsold40kg;boys14–18yrsold64kg;girlsaged14–18yrsold57kg;adultmales76kg,adultfemales61kg(NHMRC2006,IOM1997).#BasedonDean’s1942studyonfluorideanddentalhealth(Dean1942);ULforolderchildrenandadultsderivedfromNOAELof10mg/day,whichwasbasedondataonrelationshipbetweenfluorideintakeandskeletalfluorosis(NHMRC2006,IOM1997).


1.4 Triggersandrationaleforreview

TheAustralianDrinkingWaterGuidelinesandNewZealandDrinkingWaterStandardsbothrecommendwaterfluoridationlevelsintherangeof0.7–1.0mgF/Lwithamaximumlevelinbothcountriesof1.5mg/L(NHMRC2013,MOH2005).However,itisnotedthatintheNHMRC2007statementonthesafetyandefficacyoffluoridation,itisrecommendedthatwaterbefluoridatedintherange0.6-1.1mg/L,dependingonclimate,tobalancethereductionofdentalcariesandoccurrenceofdentalfluorosis(NHMRC2007).

ThereisAustralian,NewZealandandinternationalevidencethatestimatedfluorideintakesforasizeableminorityofthepopulationwhoconsumedrinkingwateratoptimallevelsoffluoridation(1.0mgF/L)areabovetheULforfluoride(0.1mg/kgbw/day)(FSANZ2009).Yetneithercountryexperiencesmorethantherareoccurrenceofmoderateorseveredentalfluorosis.ThisapparentexceedanceofrecommendedfluorideintakelevelswithouttheoccurrenceofadversedentalfluorosiscreatedtheconundrumaroundNRVsforfluoridetowhichthisreportresponds.

Thissituationcallsforare-evaluationofthedatawhichunderpinsthecurrentUL.AspartofthisreviewanevaluationoftheAIwasalsoincludedforcompleteness.AsthisreportwasapilotforafutureNRVreviews,itwaslimitedtoconsideringchildrenupto8yearsofage,thecriticalagegrouptoconsiderfordentalcariesandfluorosis.

1.5 Backgroundinformation-fluoride

Fluorideisnaturallypresentinthefoodanddrinkweconsumeandisconsideredtobeanormalconstituentofthehumanbody.Thefluorideconcentrationinbonesandteethisabout10,000timesthatinbodyfluidsandsofttissues(Bergmann&Bergmann1991;1995).Nearly99%ofthebody’sfluorideisboundstronglytocalcifiedtissues.Fluorideinboneappearstoexistinbothrapidly-andslowly-exchangeablepools.

Fluorideavailablesystemicallyduringtoothdevelopmentisincorporatedintoteethasfluorapatiteintoothenamel.Fluorapatiteintoothenamelaltersitscrystallinestructure,reducingthesolubilityofenameltoaciddissolution,ordemineralization.Athigherfluorideintakesthecrystallinestructuremaybedisruptedformingporositieswhicharethebasisofdentalfluorosis.Outcomesoffluorideintakeonbonehavebeenconsidered,especiallyamongadults.However,outcomessuchasskeletalfluorosisandbonefracturesoccuronlyafterprolongedexposuretoveryhighfluorideintakes.

Fluorideatthesurfaceofenamelcanalsoformcalciumfluoride,amorerapidly-exchangeablepooloffluoridetoalterthedemineralization-remineralizationbalancewhichisthedynamicprocessunderlyingdentalcaries.DentalcariesisalargelypreventablebuthighlyprevalentchronicdiseaseinAustralianandNewZealandchildrenandadults.

AustraliaandNewZealandhavepursuedpublichealthpolicytoadjustfluorideintakeatthepopulationlevelwiththeaimofpreventingdentalcarieswithoutcausingmoderateorseveredentalfluorosiswithadverseeffects.Itisconsidereddesirabletohaveafluoride


intakethatissufficienttopreventmuchdentalcaries(anAI)withoutexceedingintakesthatareassociatedwithmoderateorseveredentalfluorosis(aUL).


2. ScopeandPurpose

ThepurposeofthisreviewwastodiscussandderiveaULandanAIforfluorideintakeforinfantsandyoungchildren,byconductingasystematicreviewofrelevantliteraturereleasedsincethe2006NHMRCreviewandbyconsideringrecentinternationalreviewsinthiscontext.

Basedonthisconsideration,thereviewdeterminedthecriticalfluorideconcentrationindrinkingwatertominimisebothdentalcariesandseveredentalfluorosis.Fromthis,usingnationallyrepresentativedataforfluidandfoodconsumptionandbodyweightdataforAustralianandNewZealandpopulations,aULandanAIforfluoride,expressedinmgF/bw/day,werederived.Finally,recommendationsforrevisedULandAIvalues,expressedinmgF/dayfordifferentagegroups,weredetermined.TheEWGnotedtheterm‘TolerableUpperLevelofIntake’wasanappropriatewaytodescribetheULforfluoridethatwasconsistentwithuseinternationallyinthatfluorideisnotanessentialnutrient,however,tomaintainconsistencywiththeestablishmentofNRVsforothernutrientsinAustraliaandNewZealand,theterm‘UpperLevelofIntake’wasretainedforfluoride.

ThisreportisrestrictedtodiscussionandderivationofrelevantNRVsforfluoride(ULandAI)forinfantsandyoungchildrenupto8yearsofage,whoweredeterminedtobethetwocriticalgroupsforreconsideration.TimeandresourcesavailableforthetaskrestrictedthescopeoftheworktobeundertakenandincludedinthisreportbytheEWG;itwasnotpossibletoassessAIsorULsforolderchildrenoradults.

TheEvidenceReviewinsection3setoutthereviewprocessandfindings,withfurtherdetailprovidedinSupportingDocuments1-4.TherecommendationsfortheULandAIforfluorideininfantsandyoungchildrenaresetoutinsection4.

NoissuesspecifictoAboriginalandTorresStraitIslanderpeopleinAustraliaortoMaoriandPacificIslanderpeopleinNewZealandhavebeenidentifiedinthisreport.


3. EvidenceReview

3.1 Fluorideintakeestimatesininfantsandyoungchildren

3.1.1 AustraliaandNewZealand

ThereisAustralian,NewZealandandinternationalevidencethatestimatedfluorideintakesforasizeableminorityofthepopulationwhoconsumedrinkingwateratoptimallevelsoffluoridation(1.0mgF/L)areabovetheULforfluorideof0.1mg/kgbw/day(FSANZ2009,NHMRC2013,MOH2005).Yetneithercountryexperiencesmorethantherareoccurrenceofmoderateorseveredentalfluorosis.ThisapparentexceedanceofrecommendedfluorideintakelevelswithouttheoccurrenceofadversedentalfluorosiscreatedtheconundrumaroundNRVsforfluoridetowhichthisEvidenceReviewresponds.

FoodStandardsAustraliaNewZealand(FSANZ),whenconsideringthevoluntaryadditionoffluoridetopackagedwaterin2009,foundthatinfantsandchildrenundertheageof8yearsconsumingfluoridatedwaterwerethegroupmostlikelytoexceedtheULforfluorideof0.1mg/kgbw/dayassetbyNHMRCin2006(FSANZ2009a,NHMRC2006).Allinfantsfedsolelywithinfantformulamadewithnon-fluoridatedorfluoridatedwaterhadestimatedfluorideintakesthatexceededtheUL.Forinfantsaged6–12monthsconsumptionoffluoridatedwaterontopofdietaryfluoridesources,includinginfantformula,increasedestimatedfluorideintakeovertheUL.Some22%of2–3yearoldAustralianchildrenand5%of4–8yearoldAustralianchildrenhadestimatedfluorideintakesthatexceededtheULwhenassumingthatallwaterconsumedwasfluoridatedatthemaximumlevelof1.0mgF/L(FSANZ2009a).

Cresseyetal.in2010updatedtheestimatesforfluorideintakeinNewZealandusinganalyticaldataforthefluoridecontentoffoodsfromtheNZTotalDietSurveyin1990/91,whichanalysedfluoridecontentoffoodsandusedasimulatedtypicaldiettoestimateintake(Cresseyetal.2010).CresseyfoundthatformanytheestimatedmeanfluorideintakewasbelowtheAIof0.05mg/kgbw/dayforoptimalcariesprotection(Cresseyetal.2010).Allgroupsexcept6–12montholdinfantslivinginfluoridatedareasandassuminguseofhighfluoridetoothpastehadestimatedfluorideintakesbelowtheUL(0.1mg/kgbw/day).Whileinfantsconsumingformulapreparedwithfluoride-freewater(deionisedwater)hadintakeswellbelowtheUL,asizableproportionofinfants,assuminguseofwaterwithfluorideconcentrationsof0.7or1.0mgF/L,hadestimatedfluorideintakesthatexceededtheUL(30%and90%respectively).

Cliffordetal.in2009studiedfluorideintakefrominfantformulaavailableinAustraliaandfoundthatinfantformulapowderscontainedloweraveragelevelsoffluoridein2006-07(0.07mg/kg)thanthatreportedbySilvain1996(0.24mg/kg),adecadeearlier(Cliffordetal.2009,Silvaetal.1996).Usingthesenewdata,revisedfluorideintakesforinfantswereestimatedbyFSANZforthisreviewfollowingrecommendedfluidintakes.Wheninfantformulawasreconstitutedwithwaterwithnofluoride,theULwasnotexceeded.However


whensomeformulaewerereconstitutedwithfluoridatedwater,theULwasexceeded,especiallyfor0-3montholdinfants(FSANZ2014).

SupportingDocument1providesmoredetailonfluorideintakeestimatesforAustralianandNewZealandinfantsandyoungchildren.

3.1.2 International

Anumberofstudieshavecomparedestimatedfluorideintakeagainstlong-standingrecommendationsoffluorideintake.TheserecommendationswerebasedonanaveragefluorideintakeestimatedbyMcClure(1943)of0.05mg/kgbw/dayforchildrenwith1.0mgF/Linthewatersupply,alsoexpressedasarangefrom0.05–0.07mg/kgbw/day.Thisisoftenreferredtoastherecommended‘optimal’doserange,terminologythatreportedlyemergedasarecommendationfromFarkasandFarkasandlaterwasacceptedbyOphaugetal.(FarkasandFarkas1974.Ophaugetal.1980).

ErdalandBuchananstudiedtheestimatedaveragedailyintakeoffluorideintheUnitedStatesofAmerica,viaallapplicableexposurepathwayscontributingtodentalfluorosisriskforinfantsandchildrenlivinginhypotheticalfluoridatedandnon-fluoridatedcommunities(ErdalandBuchanan2005).Theyalsoestimatedhazardquotientsandindicesforexposureconditionsrepresentativeofcentraltendencyexposure(CTE)andreasonablemaximumexposure(RME).Forinfants<1yearofageinareasofwaterfluoridation(1.0mgF/L),thecumulativedailyfluorideintakewasestimatedtobe0.11and0.20mg/kgbw/dayfortheCTEandRMEscenariosrespectively.Inolderchildren(3–5yearsofage)underthesameconditions,theCTEandRMEfluorideintakewasestimatedasbeing0.06and0.23mg/kgbw/day,respectively.Ininfantsthemajorsourceoffluoridewasinfantformulaandthefluoridatedwaterusedtoreconstituteit.Inolderchildrenthemainsourcewasinadvertentingestionoftoothpastefluoridatedat1000mgF/kg.

Reportingthattheirestimateswereingoodagreementwithmeasurement-basedestimates,ErdalandBuchananfoundthatCTEestimateswerewithintherecommendedrangefordentalcariesprevention,buttheRMEestimateswereabovetheTolerableUpperIntakeLimitestablishedbytheUSEnvironmentalProtectionAgencyatthattime(recommendedsafethresholdof0.06mg/kgbw/day;lowerboundvalue0.05mg/kgbw/day,upperboundvalue0.07mg/kgbw/day).Thissuggestedsomechildrenwereatriskofadversedentalfluorosis(ErdalandBuchanan2005).

TheIowaFluorideStudy(Hongetal.2006,Warrenetal.2009)examinedfluorideintakeacrossthefirst36monthsoflifeanditsassociationwithanydentalfluorosis(includingverymildchangestoonlyafractionofthesurfaceofkeyteeth).Hongetal.reportedthatfluorosisprevalencewasrelatedtoelevatedfluorideintakewhenaveragedoverthefirst3yearsoflife,butwasevenmorestronglyrelatedtofluorideintakethatwaselevatedforallofthefirst3yearsoflife.However,Warrenetal.reportedontheconsiderableoverlapinthefluorideintakeofchildrenintheIowaFluorideStudywithandwithoutdentalfluorosiswithupto20%ofchildrenwithfluorideintakesabovetherecommendedlevelof0.05mg/kgbw/day,somebyseveraltimesthislevel,whereseveredentalfluorosiswasnotobserved.


Colombianresearchreportedin2005examinedthetotalfluorideintakeofchildrenaged22–35monthsinfourColumbiancities.Francoetal.usedtheduplicateplatemethodandrecoveryoftoothpasteusedintoothbrushing.Toothpasteaccountedforapproximately70%offluorideintake,followedbyfood(24%)andbeverages(<6%)(Francoetal.2005a).Meandailyfluorideintakewashigherinchildrenfromhighsocio-economicstatusbackgroundsinseveralcities.Manychildrenhadtotalfluorideintakesabovetherecommendedrange(i.e.,above0.05–0.07mg/kgbw/day).ArelatedpaperbyFrancoetal.includedafocusonfluoridatedtablesalt.ItconcludedthatpreschoolchildrenresidinginColumbianurbanareaswereingestingamountsoffluorideabovetheupperboundoftheEPArecommendedsafethreshold(0.07mg/kgbw/day)(Francoetal.2005b).

Fluorideintakefromtoothpasteanddietin1–3yearoldBrazilianchildrenwasreportedbydeAlmeidaetal.in2007.Amonglownumbersofchildreninfluoridatedandnon-fluoridatedareas,fluorideintakewasmonitoredbydirectmeasurementoffluoridedispensedandrecoveredduringtoothbrushingandtheduplicateplatemethodforfoods.FluorideintakewasabovetheupperboundoftheEPArecommendedsafethresholdfordentalfluorosis(>0.07mg/kgbw/day).Toothpastewasresponsibleforanaverageof81.5%ofdailyfluorideintake(deAlmeidaetal.2007).

ThisresearchinBrazilwasfollowed-upbyMiziaraetal.in2009whostudiedfluorideintakeamong2–6yearoldchildreninafluoridatedcommunityusingafoodfrequencyapproachandestimatedfluorideintakefromfluoridatedtoothpaste.Amongthechildrenevaluated,31.2%wereestimatedtohaveanintakeoffluorideabovethesafethresholdfordentalfluorosis(>0.07mg/kgbw/d)(Miziaraetal.2009).

Nohnoetal.in2011studiedthefluorideintakeofJapaneseinfantsfrominfantformula.Eachinfantformulapowderwasreconstitutedwithdistilledwaterorwaterwith0.13mgF/Landfluorideintakeestimatedfrommodeldiets.Thepotentialfluorideintakeofaninfantdependedonthefluoridelevelofthewaterusedtoreconstitutetheformula.RiskoffluorosiswasdeemedtobelowasmostJapanesewatersuppliesarelowinfluoride.HowevertherewasapossibilityofexceedingtheTolerableUpperIntakeLevelreferredtointheirpaper,especiallyforinfantswithinthefirst5monthsoflife(Nohnoetal.2011).

ThesameapproachwaspursuedbySiewetal.inUSbasedresearch(Siewetal.2009).Theydeterminedtheconcentrationsoffluorideinformulaandestimatedthefluorideintakeofinfantsconsumingpredominantlyformulaagainstvariousconcentrationsoffluoridatedwater.Theybasedconsumptionvolumesonpublishedrecommendations.Theyconcludedthatsomeinfantsbetweenbirthand6monthsofage,whoconsumepowderedandliquidconcentrateformula,reconstitutedwithwatercontaining1.0mgF/L,werelikelytoexceedtheUpperLevelofIntakeforfluoride.

Sohnetal.examinedfluidintakesof1–10yearoldsintheUSAviaa24hourrecalldietsurveyaspartofthethirdNationalHealthandNutritionExaminationSurvey1988–94(Sohnetal.2009).Theamountoffluorideingestedfromfluidswasestimatedfromseveralassumptionsabouttheconcentrationoffluorideindrinkingwaterandbeverages.Theestimatedfluorideintakeatthe75thpercentile(0.05mg/kgbw/dayormore)and90thpercentile(0.07mg/kgbw/dayormore)heldacrossallagegroups.Somechildrenwereingestingsignificantlymorefluoridethanothersdependingonsocio-demographicfactors


andfluidconsumptionpatterns.Sohnetal.calledforadditionalresearchonfluorideingestionanditsimpactondentalfluorosis.

Morerecentpublishedinformationonfluorideintakeexplorestheingestionoffluoridatedtoothpasteby4-6yearoldsbyZohoorietal.(Zohoorietal.2012).Thefluorideintakeof4–6yearoldsfromfluoridatedtoothpastewasstudiedintheNewcastleareaoftheUK.Theresearchinvolvedalownumberofsubjects.Whiletheaverageamountoffluoridatedtoothpasteusedperbrushingwasmorethantwicetherecommendedamount(0.25g),onlyonechild(outof61)hadadailyfluorideintakethatexceededtheTolerableUpperLevelofIntakeof0.1mg/kgbw/dfortheiragegroup(fromtoothpastealone).

InasubsequentpublicationbyZohoorietal.(Zohoorietal.2014),fluorideintakewasestimatedforinfants1–12monthsoldlivinginfluoridatedandnon-fluoridatedareasoftheUKviaa3dayfooddiarycoupledwithanalysisofthefluoridecontentoffoodsanddrinksconsumed.Totaldailyfluorideintakewasestimatedfromdiet,plusfluoridesupplementsandfluoridatedtoothpastewhereused.Theconclusionwasthatinfantslivinginfluoridatedareasmayreceiveafluorideintakefromdietonlyofmorethantherecommendedrangeof0.05-0.07mgF/kgbw/day.

3.2 Selectionofbiomarkersforfluoride

TheWorkingGroupconsideredarangeofbiomarkersforfluoride,selectingdentalcariesandfluorosisasthebiomarkerstousefortheNRVreviewforinfantsandyoungchildren.TheevidencetosupportthisdecisionisgivenbelowandinSupportingDocument2.AsummaryofotherbiomarkersconsideredaspartofthescopingprocessbutnotusedinthisNRVreviewisgivenbelow.

3.2.1 Dentalcaries

Dentalcariesistheresultofaninteractionofbiologicalandenvironmentalprocesses(Holstetal.2001).Thebiologicalprocessisdefinedbythedemineralizationanddestructionofdentalhardtissuesbyacidicby-productsfrombacterialfermentationofdietarycarbohydrates,mainlysucrose(Selwitzetal.2007).Theenvironmentalprocessisacombinationofbehaviour,contextualandsocietalfactors(Holstetal.2001).Theaetiologyofdentalcariesiscomplexandinvolvesdifferentlevelsofdeterminantsfromsocialstructure,socalleddistaldeterminants,tointermediatedeterminantssuchasbehavioursanddentalcareutilisation,whichinturnaffectsmoreproximaldeterminants,suchasdentalbiofilm,fluorideexposure,andsalivaflowandcomposition.Cariesisadynamicprocessofdemineralizationandremineralisationofthetoothtissuesbutthemajorityofthelesions,particularlyinpermanentteeth,progressslowlythroughenameltodentine(Mejareetal.1998)andcanbeseeninthecrownoftheteethintheprimaryandpermanentdentitionandrootsurfacesofteethinthepermanentdentition.

Dentalcariesisamajorpublichealthproblemworldwide,itisoneofthemostprevalentpreventablechronicdiseases(Vosetal.2012),andthemostcommonchronicchildhooddiseaseinmostindustrializedcountries,affecting60–90%ofschoolchildren(Petersen2003).Despiteimprovementinthelastdecadesindevelopedcountries,recentstudiesshowedthat


cariesintheprimarydentitionisincreasingintheUSA,UK,Canada,Australia,NorwayandtheNetherlands(Gaoetal.2010).

Alongwithitshighprevalenceandfinancialburdenforsociety,dentalcariesisthemaincauseoftoothacheinchildren(Boeiraetal.2012)anditisthemainreasonfortoothextraction,resultingintoothloss,amongadults.Theexperienceofpain,chewingdifficulties,restrictionofsomefoodsandproblemswithsmilingandcommunicationduetodamagedteeth,haveanimportantimpactonpeople’slivesandwell-being(Petersenetal.2005).

Themeasurementofdentalcarieshaslargelyremainedunchangedsincethe1930s.WhilstDeanandcolleaguesusedslightlydifferentnomenclature,theywereessentiallyrecordingtheprevalenceofcariesinthepermanentdentition(i.e.,oneormoreteethwithcariesexperience)amongchildren12–14yearsoldandthenumberofteethwithdecay(D),missingbecauseofcaries(M),orfilled(F).ThenomenclatureoftheDMFTeethIndexhasbeensettledsincethelate1930s(Kleinetal.1938).RulesfortheobservationofdecayinatoothandtherecordingofteethmissingduetocarieshavebeenavailablefromtheWorldHealthOrganization(WHO2013).Sincethe1960sandonwardsrefinementstothesebasicmeasureswereintroduced.Thesehaveincludedvaryingtheunitofobservationincludingindividualtoothsurfacesandmorerecentlyobservingdecayatearlierthresholdsthancavitationordentineinvolvement.Thisreporthasstayedwiththedecayed,missing(duetocaries)andfilledprimary(dmft)andpermanent(DMF)teethindicesasthatprovidescontinuitywiththekeydatatoestablishadose-responserelationshipbetweenfluorideandcaries.

AsummaryoftheknownprevalenceandextentofdentalcariesintheAustralianandNewZealandchildpopulationsisgiveninTable3.1below.ThedatapresentedinTable3.1werederivedfromoralhealthsurveysallconductedinthe2000decade.ApproximatelyhalfofallchildreninAustraliaaged5–6yearsoldandinNewZealandaged5–11yearsoldhaveexperienceofcariesintheprimarydentitionandhaveonetotwoteethonaveragewithcariesexperience.Alowerproportionof12yearolds,approximately30%,haveexperienceofcariesinthepermanentdentitionandtheaveragenumberofteethwithcariesexperienceisbelowonetooth.Boththeprevalenceandexperience(dmftorDMFT)arestronglyage-relatedandshowvariationacrosssitesinAustralia,betweenthetwocountriesandbetweenareasthathavefluoridatedwaterornot.


Table3.1:SummaryofdatafordentalcariesinAustralianandNewZealandchildren

Year dmft/DMFT %Cariesfree

Region Age(years)

Fluoridation(mg/Lwater)

Study

2010-12

dmft:2.75(2.16-3.34)dmft:(4.31(3.79-4.84)DMFT:0.82(0.65-0.99)DMFT:1.51(1.31-1.71)

63.1(59.2-66.4)*52.3(48.7-55.9)*70.6(67.2-73.9)*60.7(57.8-63.5)*

Queensland 5-85-89-149-14

FareaNon-FareaFareaNon-Farea

Do&Spencer2015Doetal.2015

2009 dmft:2.13(2.08–2.18)DMFT:1.05(1.01–1.08)

53.754.9

Australia,National(excludingNSW,VIC)

5–612

NSNS

Haetal.2013

2007 dmft:1.88(1.78–1.99)DMFT0.95(0.85–1.05)

50.269.4

Australia,National(excludingVic)

5–612

NSNS

Meijaetat2012

2007 dmft:1.40(1.22–1.58)dmft:2.62(1.89–3.36)DMFT:0.71(0.63–0.79)DMFT:0.98(0.75–1.21)

63.2(60.0–66.3)45.9(35.0–56.7)63.2(63.7–69.4)45.9(48.8–64.0)

NSW 5–65–611–1211-12

FareaNon-FareaFareaNon-Farea

COHSNSW2009

2005 dmft2.27DMFT1.11

na Australia,National(excludingNSW)

612

NSNS

Meijaetat2012


Year dmft/DMFT %Cariesfree

Region Age(years)

Fluoridation(mg/Lwater)

Study

2003 dmft0.63(0.37–0.88)dmft0.95(0.57–1.32)DMFT0.33(0.13–0.54)

756179

NSW 6811

Farea Evansetal.2009

2009 dmft:0.8(0.3–1.2)dmft:1.9(1.5–2.3)DMFT:0.5(0.3–0.6)dmft+DMFT2.4(2.0–2.8)dmft+DMFT1.5(1.1–1.9)

79.7(71.7–87.7)51.0(53.2–58.8)75.0(71.4–83.5)nana

NZ,National 2–45-115-115–175-17

NSNSNSNon-FareasFareas

NZMoH2010

Notes:Farea=fluoridatedarea0.8–0.85mgF/L,NFarea=non-fluoridatedarea<0.2–0.3

mgF/L.

NS=notspecified.

Thedose-responserelationshipbetweenfluorideconcentrationinwatersuppliesanddentalcarieswasestablishedbyDeanandcolleaguesinthe21CitiesStudy(Deanetal.1941,1942)2.ThecurrentNRVsforfluorideestablishedinAustraliaandNewZealandandelsewhereforinfantsandchildrenwerebasedontheIOMrecommendations,whichwerederivedfromthispivotalstudy(IOM1997,NHMRC2006,EPA2010a,b,EFSA2013).ThevalueofDean’sstudyisthatitwasundertakenbeforewaterfluoridationprograms,fluoridatedtoothpasteanddentaltreatmentwithfluorideproductswereavailablesoitispossibletoexploretherelationshipbetweendentalcariesandthenaturalleveloffluorideintapwaterwithouttheseconfoundingfactors.FurtherresearchfollowedonfromDean’soriginalstudyondentalcariesandwaterfluoridation.ImportantreportsincludeGalagan

2Deanetal.studied26citiesinUSintotal;21citieswereselectedassuitableforthefluorideanddentalcariesresearch,aslightlydifferent

listof22citieswasselectedforthefluorideandfluorosisresearch.


andVermillian(1957),EklundandStriffler(1980),Helleretal.(1997)andtwosystematicreviews-theYorkReview(McDonaghetal.in2000andRugg-GunnandDo(2012)3.AnumberofreportsonwardfromthelandmarkIOMreportin1997alsoprovideoverviewsofthedose-responserelationship,theEPAreviewin2006and2010(EPA2006,2010a,b)andtheECScientificCommitteeonHealthandEnvironmentalRiskReviewin2011(SCHER2011),aswellasresearchspecifictoAustraliaandNewZealand.FurtherdetailsontheresearchonthelinkbetweendentalcariesandfluoridelevelsinwatersuppliesissummarisedinSupportingDocument2andfromthesereportsisalsosummarisedinSupportingDocument3.

3.2.2 Fluorosis

Thedose-responseoffluorideinwatersuppliesandoralhealthisalsoinseparablefromdentalfluorosis.Theoriginofadose-responserelationbetweenfluorideinwatersuppliesandoralhealthwasinitiallyfocussedondentalfluorosis,notdentalcaries.Dentalfluorosisisadevelopmentalconditionordefectoftheenamellayerofteeth.Itischaracterizedbywhiteflecksorwhite,wavylines(opacities)ontheenamelofteeth.Astheseverityofdentalfluorosisincreases,thewhitelinesmaycoalescetoformcloudypatchesinvolvingsteadilymoreofthetoothsurface.Atseverelevels,thewholesurfacemaybeinvolvedinopacitiesandpitting;chippingorlossofenamelstructuremayoccur.

Therearesetrulesfortheobservationofdentalfluorosisthatattempttoseparateoutenamelopacitiesthatarefluoroticinoriginfromthosethatarenon-fluorotic.ThebestknownsetofcriteriaforadifferentialdiagnosisoffluoroticopacitiesisthatofRussell(Russell1961)whichweremorewidelypromulgatedbyHorowitzin1986(Horowitz1986).Theseinvolvetheareaofatoothsurfaceaffected,theshapeofthelesions,theirdemarcationfromthesurroundingunaffectedpartsofthetoothsurface,thecolouroftheaffectedareas,andthepatternofteethaffectedinthewholemouth.Anessentialaspecttodocumentingdentalfluorosisistheapplicationofthesecriteriawhilstexaminingaperson,and/ortheapplicationofthesesortsofcriteriaviaalgorithmsusedinanalysis.Onceadifferentialdiagnosisoffluorosisismade,variousscoringsystemsareavailabletoratetheseverityofthefluoroticchanges.ThebestknownoftheseisDean’sIndex(ClassificationSystem)forDentalFluorosis(Dean1942),andthesubsequentsummarymeasurefromthis,theCommunityFluorosisIndex(Dean1946).

InmorerecenttimesnewindiceshavebecomewidelyusedincludingtheThylstrupandFejerskovIndex(ThylstrupandFejerskov1978),theToothSurfaceIndexofFluorosis(Horowitzetal.1984)andtheFluorosisRiskIndex(Pendrys1990).EachoftheseindiceshasdifferentemphaseswhichmakecomparisonbetweenthemandwiththeDean’sIndexsubtlycomplex.Forinstance,Dean’sIndexclassifiesanindividualbythesecondmostsevere

3TheEWGnoteamorerecentsystematicreviewwaspublishedin2015butcouldnotbeincludedinthereportduetotimingofits

publication(Iheozor-EjioforZ,WorthingtonHV,WalshT,O'MalleyL,ClarksonJE,MaceyR,AlamR,TugwellP,WelchV,GlennyAM2015.Waterfluoridationforthepreventionofdentalcaries.,CochraneDatabaseSystRev.2015Jun18;6:CD010856.doi:10.1002/14651858.CD010856.pub2).


observationoffluorosisatthetooth-levelinthemouth,theThylstrupandFejerskovIndexisadrytoothindexthatscoresthemostseverepresentationoffluorosis,theToothSurfaceFluorosisIndexisawettoothindexmeanttoreflectwhatonewouldseeineverydayactivity,whiletheFluorosisRiskIndexdividesthetoothsurfaceintothirdsandcancaptureveryearlystagesoffluorosisandindicationsofthetimingoftheriskexposure.AnyexaminationofdentalfluorosisrunsintothestronghistoricalbackgroundusingDean’sIndexandthemorerecentdominationoftheThylstrupandFejerskovIndex,especiallyinAustralianoralepidemiology.

AdifferentpathtoobservationsondentalfluorosisisthatoftheDevelopmentalDefectsofEnamelrecordingsystemwhichfirstlyrecordsalldefectsofenamelatanexaminationandthenseparatesoutpresumedfluoroticopacitiesfromotherenameldefectslikedemarcated,hyperplasticdefectsandcombinationsofthese,onthebasisoffluoroticdefectsbeingdiffuseonaffectedsurfacesandthedistributionofaffectedteethbeingsymmetrical,butnotalwaysofthesameseverity.TheDevelopmentalDefectsofEnamel(DDE)haditsorigininNewZealandandhasbeenwidelyusedinoralepidemiologicalsurveys(FDI,1982;Clarkson,O'Mullane1989).

Apopulation-basedstudyinthestateofNSWin2007examineddentalfluorosisinchildrenusingtheTFIndex(NSWCDHS2007).Atotalof5017childrenaged8–12yearswereexaminedforfluorosis.Theprevalenceofmoderate/severedentalfluorosis(TFscore4or5)was0.3%(14cases).Amongthose,twocaseswereconsideredashavingaTFscoreof5(severedentalfluorosis–thehealthadverseendpoint).TheprevalenceofthisadverseendpointintheNSWchildpopulationwas,therefore,0.04%.

StudiesinWesternAustraliaandSouthAustraliausingtheTFindexdidnotobserveanycasesofmoderatetoseveredentalfluorosis(Riordan2002;Do&Spencer2007)(seeTable3.2).

TheNZNationalOralHealthSurvey2009(NZMoH2010a)reportednocasesofseverefluorosisusingtheDeanIndex,whiletheprevalenceofmoderatefluorosiswas2.0%.

AstudyinNSWin2003(Baletal.2014)reporteddentalfluorosisusingDeanIndex.Some1%wasobservedtohavemoderatedentalfluorosiswhilesome0.135%(4cases)reportedlyhadseveredentalfluorosis.

Furtherinformationondentalfluorosis,itsmeasurementandreportsoftheprevalenceoffluorosisinAustralianandNewZealandpopulationsandothercountriesisgiveninSupportingDocument2.


Table3.2:Summaryofdatafortheprevalenceofanydentalfluorosis(PrevalenceTF1+orDeans’sIndex1+)inAustraliaandNewZealand

Non-Fluoridatedwaterarea

Fluoridatedwaterarea

Year Town/city Prevalence(%)

Town/city Prevalence(%)

Study

1989 Bunbury 33.0 Perth 40.2 Riordan1991Age:12years

2000 Bunbury 10.8 Perth 22.2 Riordan2002Age:10years

1994–1995

RuralSouthAustralia

30.3 Adelaide 48.7 Spencer&Do2007Age:7–15years

2003 BlueMountains,NSW

39.0+ Baletal.2004

2004/2005 MtGambier,Bordertown,Kingscote

15.0 Adelaide 29.5 Do&Spencer2007

2007 VariousareasinNSW

16.8 VariousareasinNSW

25.1 COHSNSW2009*

2009 VariousareasinNZ

20.4+ VariousareasinNZ

14.9+ NZMinistryofHealth2010Age:8–30years

+UsingDean’sIndex

*Wholepopulation-basedstudysamples

FurtherdetailsontheresearchonthelinksbetweendentalfluorosisandfluoridelevelsinwatersuppliesissummarisedinSupportingDocument2andisidentifiedinthereviewofreportsinSupportingDocument3.

3.2.3Otherpotentialbiomarkers

SeveralfurtherbiomarkersforfluorideandhealthwereassessedforrelevancetotheNRVreview,howevernonewereconsideredappropriateforuseinthederivationofULsforinfantsandyoungchildren.


Osteoporosis,osteosarcoma,pinealglandphysiology,IQanddelayedpermanenttootheruptionwereconsideredbytheEWGaspotentialbiomarkerswithoutcomessummarisedbrieflybelow.

TheEWGwasnotinapositiontoevaluateanypublisheddataonthegenotoxicpotentialoffluorideinthetimeframeforthispilotreviewastheliteratureavailabledidnotmeetthecriteriasetforconsideringhumandataonly.Itwasnotedthatthereareinternationalguidelinesfortestingchemicalsinthefoodsupply,includingtheirpotentialtodamageDNA,utilisingavarietyofwell–validatedbiomarkers,suchaschromosomalaberrationsandmicronuclei(OECD2014).TheEWGacknowledgedthereisabodyofliteraturethatmainlyrelatestoinvitrostudiesorstudiesinratsoftheimpactoffluorideoncellfunctionthatcanbededucedbyexploringstudiesthathaveinvestigatedeffectsongeneexpression.ThereisalackofinvivodataonDNAdamageindicesinhumanswithvaryingfluorideexposures,whichisaknowledgegap.

Osteoporosisandbonefractures:Thisisconsideredpotentiallyrelevantasabiomarkerforadultsbutnotforinfantsoryoungchildren.Alargenumberofstudieshaveinvestigatedpossibleassociationsbetweenthelevelsoffluorideindrinkingwaterandtheriskoffracturesofthehipandotherbones.Anassociationisbiologicallyplausible,sinceveryhighlevelsoffluorideareknowntoaffectbonedensityandstrength,butmayalsoreduceboneflexibility.However,researchindicatesthatwaterfluoridationatlevelsaimedatdentalcariespreventionhasbeenequivocalwithsmallvariationaroundthe‘noeffect’finding.Ithasbeenconcludedthatfluorideatlevelsassociatedwithwaterfluoridationhasnocleareffectonhipfractureriskinadults(McDonaghetal.2000,Nasmanetal.2013).ArecentreportfromthelongitudinalIowaFluorideStudyfoundnosignificantrelationshipbetweendailyfluorideintakeandadolescents’bonedensity(Levyetal.2014).

Osteosarcoma:Thisisnotconsideredsuitableasabiomarker.Anumberofstudieshaveinvestigatedlinksbetweentheleveloffluoridationandosteosarcoma,anoften-fatalbonecancermostcommonlydiagnosedinadolescents.Anassociationbetweenfluorideandosteosarcomaisbiologicallyplausible,sincebonesreadilytakeupmuchofthefluorideingested;children/adolescentsareoftendiagnosedaroundthetimeofthepubertalgrowthspurt,whenosteoblasticactivityisparticularlyhigh.Whiletherehasbeenonerecentreportofanassociationofosteosarcomainmaleswithearlierexposuretofluoridatedwater(Bassinetal.2006),mostavailablescientificevidencestronglysuggeststhatcommunitywaterfluoridationisnotassociatedwithosteosarcoma(Cohn1992,DouglassandJoshipura2006,Kimetal.2011,LevyetLeclerc2012,Blakeyetal.2014).

Pinealgland:Thisisnotconsideredsuitableasabiomarker.Concernshavebeenexpressedaboutpossibleharmfuleffectsoffluorideonthepinealgland(Luke1997,2001).Thepinealglandliesnearthecentreofthebrain,butoutsidethebloodbrainbarrierthatrestrictsthepassageoffluorideintothecentralnervoussystem.Lukestudiedtheaccumulationoffluorideinthepinealglandofolderadultcadavers.Fluoridedepositionwaslinkedtocalciumlevels,butwasconsideredanormalprocessofageing.Whiletherehasbeenspeculationthatsuchfluoridedepositionmayberelatedtobrainfunction,theEWGconsideredthatinsufficientevidenceexistedtodetermineanypossiblelinksbetweenthisdepositioninthepinealglandfunctionandhumanhealth.


IntelligenceQuotient(IQ):Thisisnotconsideredsuitableasabiomarker.Arecentmeta-analysisofanumberofstudiesdatingbacktothe1980s,almostallfromChina,concludedthatnaturallyoccurringfluoridelevelsindrinkingwatermainlyintherangeof2-11mg/Lmayreducechildren’sIQsbyalmost7points(Choietal.2012).However,theinterpretationofthissystematicreviewwascautionedbytheauthorsgiventhelackofindividual-levelmeasuresonexposure,neurobehaviouralperformanceandcovariatesthatwouldadjustforeducationalresourcesoffamiliesandcommunities,aswellasotherpossiblecontaminantsfromlowqualitycoal.EvenstrongercriticismhasbeenmadebyBormanandFyfe(2013).TheoutcomesoftheChinesestudieshavenotbeenconfirmedincountriespractisingcommunitywaterfluoridation.RecentlyBroadbent,usingdatafromtheDunedinBirthCohortstudy,foundnosupportfortheassertionthatfluorideexposurewasrelatedtoIQ(Broadbentetal.2015).

Delayedpermanenttootheruption:Thisisnotconsideredsuitableasabiomarker.Delayederuptionofthepermanentteethhasbeenraisedasagrowthanddevelopmentconsequenceoffluorideintake.Howeveracounterargumentisthatfluorideintakereducescariesintheprimarydentitionandtheearlylossofaffectedteeth,eithernaturallyorasaresultofdentaltreatment.Itisthereforenotsurprisingthattheliteratureisequivocalondelayederuption.Thelatestreportsdonotsupportanysignificantdelayintheeruptionofthepermanentteeth(Jolaosoetal.2014).Thereforedelayederuptionwasnotconsideredsuitableasabiomarker.

3.3 Selectionofevidence

TheNHMRCprepareditslatestreportondietaryreferencevaluesforfluorideandothernutrientsforAustraliansandNewZealandersin2005.Accordingly,thetaskoftheEWGwastoreviewanynewevidenceonfluorideanditsrelatednutritionalreferencedatasince2005.However,consideringtherangeofinformationthatcanbegatheredthroughreviewingthepertinentliteratureacrossthelasttwodecades,theEWGagreedthatthefollowingmajorpublicationsonfluoridealongsidetheirrelatedbibliographies,wouldberelevantandusefulinthecontextofthecurrentreportandshouldbereviewedindetail:

1. InstituteofMedicine-DietaryReferenceIntakes(DRI)forCa,P,Mg,VitaminDandFluoride(IOM1997)

2. TheNHSCentreforReviewsandDisseminationattheUniversityofYork-TheYorkReview:Asystematicreviewofwaterfluoridation(McDonaghetal.2000)

3. EuropeanFoodSafetyAuthority(EFSA2005):OpinionoftheScientificPanelonDieteticProducts,NutritionandAllergiesonarequestfromtheCommissionrelatedtotheTolerableUpperIntakeLevelofFluoride

4. NationalResearchCouncil(NRC2006)-Fluorideindrinkingwater:AscientificreviewofEPA’sstandards

5. USEnvironmentProtectionAgency(EPA2010aandb)-Fluoride:ExposureandRelativeSourceContribution(RSC),AnalysisandDose–responseanalysisfornon-cancereffects


6. ScientificCommitteeonHealthandEnvironmentRisk(SCHER2011)-Opiniononcriticalreviewofanynewevidenceonthehazardprofile,healtheffects,andhumanexposuretofluorideandthefluoridatingagentsofdrinkingwater

7. EuropeanFoodSafetyAuthority(EFSA2013):Scientificopinionondietaryreferencevalues(DRV)forfluoride.

3.3.1 Reviewofmajorreports

DetailedcommentsonthereportsreviewedaregiveninSupportingDocument3,includingtheoverview,methods,findings/estimatesandacommentonstrengths,weaknessesandinconsistenciesofthesereports.AsummaryoftheoutcomesofthereviewisgiveninTable3.3below.

Inbrief,theULof0.1mgF/kgbw/dayestablishedbytheIOMin1997hasbeenadoptedbymanyagencieswithoutfurtherconsideringitsderivation,inparticular,theconversionofafluorideconcentrationinreticulatedwaterintoafluorideintakeforchildren.ThisstepisessentialbecauseDean’s22citydentalfluorosisprevalencedatadidnotprovideanydetailsaboutwaterconsumptionorbodyweightsofthechildren.TheEWGnotedthatthebestavailabledose-responsedataforderivationofaULwasstilltheDean’sstudywhichwasconductedover70yearsago.

ThereareanumberofothermethodologicalissuestobeconsideredwhenestablishingaULorReferenceDose(RfD)(asestablishedbyEPA)thatareapparentfromthereviewoftheabovereports.Theseinclude:

• theselectionofanappropriateend-pointoroutcomei.e.severityofdentalfluorosisconsideredtobeadverse

• theacceptabilityofathresholdprevalenceoftheend-point

• theidentificationofsuitabledatawhichestablishesacleardose-responserelationshipbetweenfluorideintakeandtheprevalenceoftheend-point

• theapplicationofeitheradeterministicNOAELandLOAELanalysisorastatisticalBenchmarkDoseanalysistoasuitabledose-responserelationship.

TheseissuesarediscussedfurtherinSection3.5.