complementary feeding of the breastfed child the risk...

COMPLEMENTARYFEEDINGOFTHEBREASTFEDCHILD

TheriskofcarcinogeniceffectMaxMantik

Objectives

• Todiscusscomplimentarybreastfeeding• Toaddressthelinksbetweenchildhoodenvironmentsandriskonsetofcancer

• Topresentcurrentknowledgeofcausationandenvironmentalriskfactors

• Tobiologicalefects developmentoncancer

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Energyrequired(toplineandtheamountfrombreastmilk)

WHO/UNICEF,1998

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DURATIONOFEXCLUSIVEBREASTFEEDINGANDAGEOFINTRODUCTIONOFCOMPLEMENTARYFOODS

• Exclusivebreastfeedingfrombirthto6monthsofage• Complementaryfoodsat6monthsofage(180days)whilecontinuingtobreastfeed.

• Continuefrequent,on-demandbreastfeedinguntil2yearsofageorbeyond

WHO,guiding principles for complementary feeding of the breastfed child, 2003

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Responsivefeeding

Principlesofpsycho-socialcare• Sensitive• Patiently,andencourage• Combinations,tastes,textures• Minimizedistractions• Periodsoflearningandlove

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SAFEPREPARATIONANDSTORAGEOFCOMPLEMENTARYFOODS• Thepeakincidenceofdiarrhealdiseaseisduringthesecondhalfyearofinfancy,as

• Theintakeofcomplementaryfoodsincreases• Difficulttokeepclean• Feedingbottlesareaparticularlyimportantrouteoftransmissionofpathogens

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SAFEPREPARATIONANDSTORAGEOFCOMPLEMENTARYFOODS

Practicegoodhygieneandproperfoodhandling• Handhygiene• Storingfoodssafelyandservingfoodsimmediately• Cleanutensilstoprepareandservefood• Cleancupsandbowls• Avoidingtheuseoffeedingbottles,whicharedifficulttokeepclean.

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Breastfedchildrenat12-23months

• Indevelopingcountriesabout550g/d• Receive35-40%oftotalenergyneedsfrombreastmilk

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FOODCONSISTENCY

• Graduallyincreasefoodconsistencyandvarietyastheinfantgetsolder

• Pureed,mashedandsemi-solidfoodsbeginningatsixmonths• By8months"fingerfoods"(snacks)• By12months,thesametypesoffoodsasconsumedbytherestofthefamily

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NUTRIENTCONTENTOFCOMPLEMENTARYFOODS

• Varietyoffoodstoensurethatnutrientneedsaremet• Meat,poultry,fishoreggsshouldbeeatendaily,orasoftenaspossible

• VitaminA-richfruitsandvegetablesshouldbeeatendaily• Adequatefatcontent• Avoidgivingdrinkswithlownutrientvalue,suchastea,coffeeandsugarydrinkssuchassoda

• Limittheamountofjuiceofferedsoastoavoiddisplacingmorenutrient-richfoods

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USEOFVITAMIN-MINERALSUPPLEMENTSORFORTIFIEDPRODUCTSFORINFANTANDMOTHER

• Fortifiedcomplementaryfoodsorvitamin-mineralsupplementsfortheinfant,asneeded

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FEEDINGDURINGANDAFTERILLNESS

• Increasefluidintakeduringillness,includingmorefrequentbreastfeeding,andencouragethechildtoeatsoft,varied,appetizing,favoritefoods

• Afterillness,givefoodmoreoftenthanusualandencouragethechildtoeatmore

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Cancersthatdevelopinchildren

• Leukemia 30%• Brainandspinalcordtumors 26%• Neuroblastoma 6%• Wilmstumor 5%• Lymphoma

• Hodgkin 3%• NonHodgkin 5%

• Rhabdomyosarcoma 3% • Retinoblastoma 2%• Bonecancer(includingosteosarcomaandEwingsarcoma) 3%

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RiskFactorsandCausesofChildhoodCancer

• Differentcancershavedifferentriskfactors• Inadults,lifestyle-relatedriskfactors,suchas beingoverweight,eatinganunhealthydiet,notgettingenoughexercise,andhabitslikesmokinganddrinkingalcohol

• Manyyearstoinfluencecancerrisk,andtheyarenotthoughttoplaymuchofaroleinchildhoodcancers

• Radiationexposure,linkwithsometypesofchildhoodcancers• DNAchangesthatturnononcogenes orturnofftumorsuppressorgenes.

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Inheritedversusacquiredgenemutations

• MostchildhoodcancersarenotcausedbyinheritedDNAchanges.TheyaretheresultofDNAchangesthathappenearlyinthechild’slife,sometimesevenbeforebirthà acquiredmutation

• SomechildreninheritDNAchanges(mutations)fromaparentthatincreasetheirriskofcertaintypesofcancer

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Comparedwithadults,infantsandyoungchildren• Eatrelativelymorefoodperunitofbodyweightthandoadults.

• Eatlargequantitiesofsinglefoods.• Playingonthefloorandplacinghandsandobjectsintheirmouths,mayincreaseexposurestopesticides.

• Developingorgansystemssusceptibletotheeffectsofpesticidesorlessabletoclearthemetabolites.

• Uniqueexposurepathwayssuchasthroughtheplacentaandthroughbreastmilk.

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ArtificialSweetener

• CyclamatebannedasfoodadditiveinUSin1969andsaccharinein1977afterbeingassociatedwithbladdercancerinmice

• Underpublicpressure,saccharinereturnedtothemarket;itwasreviewedandtakenoffthelistofpotentialcarcinogensin2000

• Aspartame:noevidenceimplicatingitinincreasedcancerrisk

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Inconsistenciesinresultsofnutritional

• Canbeattributedtomultiplefactors• Observationalstudiesà imprecisionindietrecall• Confoundingfactorsthatinfluencetheriskofcancerandoccurdisproportionatelyamongindividualsexposedandnotexposedtothenutrientofinterest.

• Randomizedcontrolledtrialsà inaccurateresults• pooradherencetothedietaryintervention,• insufficientfollow-uptime,• wrongdoseorformofthenutrient.

• Additionally,studiestendtofocusononenutrientinisolation,when• wholefoodsorthefullcompositionofadietmaycorrelatebetterwithcancerriskthananysinglecomponent.

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Objectives

• Todiscusscomplimentarybreastfeeding• Toaddressthelinksbetweenchildhoodenvironmentsandriskonsetofcancer

• Topresentcurrentknowledgeofcausationandenvironmentalriskfactors

• Tobiologicalefects developmentoncancer

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Cancerinchildren

• Childhoodcancersmakeuplessthan1%ofallcancersdiagnosedeachyear.About10,380childrenintheUnitedStatesundertheageof15willbediagnosedwithcancerin2016.Childhoodcancerrateshavebeenrisingslightlyforthepastfewdecades.

• Becauseofmajortreatmentadvancesinrecentdecades,morethan80%ofchildrenwithcancernowsurvive5yearsormore.Overall,thisisahugeincreasesincethemid-1970s,whenthe5-yearsurvivalratewasabout58%.Still,survivalratesvarydependingonthetypeofcancerandotherfactors.Thesurvivalratesforaspecifictypeofchildhoodcancercanbefoundinourinformationforthatcancertype.

• Afteraccidents,canceristhesecondleadingcauseofdeathinchildrenages1to14.About1,250childrenyoungerthan15yearsoldareexpectedtodiefromcancerin2016.

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HRs (95% CIs) for total cancer and specific cancer types associated with a 1-point increment in WCRF/AICR score (range: 0–6 in men, 0–7 in women).

Dora Romaguera et al. Am J Clin Nutr 2012;96:150-163

©2012 by American Society for Nutrition41

Childhoodexposure

• Children,ingeneral,aremoresusceptibletotoxicants,suchasarsenic,foravarietyofreasonsincluding:moreopportunitiesforexposurefromincreasedhand-to-mouthbehaviorandbreathingclosertotheground,differencesinmetabolism,andgreatersensitivityofthedevelopingnervoussystemtotoxicinsults[101,102].Childrenarelessablethanadultstointernallydetoxifyinorganicarsenicthroughmethylation[101].

• Childrencanbecomepoisonedwitharsenicthroughaccidentalingestion,asinthecaseoftwosiblingswhodrankoutdatedarsenic-containingpesticidestoredinawaterbottle[45].Childrencanalsodeveloparsenicpoisoningfromplayingonsoilcontaminatedwitharsenicfromnearbyminingorsmeltingorinhazardouswastesites.Anotherpotentialsourceofexposureisthroughcontactwith"pressuretreatedwood"throughplayingonit,chewingit,orbeinginthevicinitywhenitisburned

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Cancerprevention

• In2008,therewereanestimated12.7millioncancercasesand7.6millioncancerdeathsworldwide,despiteoverwhelmingevidencethatmanymalignanciesarepreventable[1,2].Survivalratesareimproving,butoverhalfamillionpeoplediefromcancereachyearintheUnitedStatesalone.CanceroutrankscardiovasculardiseaseasthenumberonecauseofdeathintheUnitedStatesforthoseundertheageof85[3].

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• TheInternationalAgencyforResearchonCancer(IARC)hasidentifiedandtabulatedover100humancarcinogens[7].

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Aflatoxins Liver(hepatocellularcarcinoma)

Suppl7(1987);56(1993);82(2002)

Saltedfish,Chinesestyle Nasopharynx Stomach 56(19

Tobaccosmoking Bonemarrow(myeloidleukemia)*;cervix*;oropharynx,hypopharynx);stomach*;ureter*;urinarybladder;insmokers’children:hepatoblastoma*

Breast;insmokers’children:childhoodleukemia(particularlyacutelymphocytic)

38(1986);83(2004)

Benzene Leukemia(acutenonlymphocytic)

Leukemia(acutelymphocytic, chroniclymphocytic,multiplemyeloma,non-Hodgkinlymphoma)

7(1974);29(1982)

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Lifestylefactorshavebeenlinkedtoavarietyofmalignancies• AcomprehensivesystematicreviewwithaglobalfocusconductedbytheWorldCancerResearchFundcametosimilarconclusionsregardingdietary,weight,andactivityfactors[10].

• WorldCancerResearchFund/AmericanInstituteforCancerResearch.Food,Nutrition,PhysicalActivityandthePreventionofCancer:AGlobalPerspective.Washington,DC:AICR,2007

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CanChildhoodCancersBePrevented?

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Screeningforcancerinchildren

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selenium

• Cancer— EpidemiologicstudiessupportapossiblerelationshipbetweenSeandcancermortality[149,150].Asaresult,anumberofstudieshaveinvestigatedtheroleof selenium supplementationforpreventionofcancer.(See "Cancerprevention",sectionon'Selenium' and "Riskfactorsforprostatecancer".)

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Dietary selenium

• Dietaryreferenceintake— isavailablefromseafoods,organmeats,andplantfoods.PlantSecontentdependsuponsoilSeconcentrations.TheRDAforseleniumis20mcgdailyforyoungchildren,risingto55mcgdailyforadults(table2)[23].

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Possiblesignsandsymptomsofcancerinchildren

• Anunusuallumporswelling• Unexplainedpalenessandlossofenergy• Easybruising• Anongoingpaininoneareaofthebody• Limping• Unexplainedfeverorillnessthatdoesn’tgoaway• Frequentheadaches,oftenwithvomiting• Suddeneyeorvisionchanges• Suddenunexplainedweightloss•

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References:CancerinChildren

• AmericanCancerSociety. CancerFacts&Figures2016.Atlanta,Ga:AmericanCancerSociety;2016.

• AmericanCancerSociety. CancerFacts&Figures2014.Atlanta,Ga:AmericanCancerSociety;2014.

• AmericanCancerSociety.Cancersitedetailedguides.Accessedatwww.cancer.org onNovember7,2014.

• Cogliano VJ,BaanR,Straif K,etal.Preventableexposuresassociatedwithhumancancers. JNatlCancerInst.2011;103:1827-1839.

• NationalCancerInstitute.ASnapshotofPediatricCancers.2014.Accessedatwww.cancer.gov/researchandfunding/snapshots/pediatriconNovember7,2014.

• RossJA,SeversonRK,PollockBH,RobisonLL.ChildhoodcancerintheUnitedStates.AgeographicalanalysisofcasesfromthePediatricCooperativeClinicalTrialsgroups. Cancer.1996;77:201-207.

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RiskFactorsandCausesofChildhoodCancer

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Organicallygrownfoods

• arefoodsthataregrownorprocessedwithouttheuseofsyntheticfertilizersorpesticides[1-5].Organicfarmersattempttoprotecttheenvironmentbyusingnaturalmatter(eg,agedmanure,humus,andcompost)forfertilizerandbiologicalmethodsofpestcontrol(eg,croprotationandnaturalinsectpredatorslikeladybugs)[2,4,6].Livestockandpoultryusedforegg,dairy,andmeatproductionareraisedonorganicallygrownfeed,withoutantibioticsorhormones,andprovidedwithaccesstotheoutdoors[6]

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Thestandardsforgrowingandlabelingorganicfood• mayvarydependinguponthecertifyingorganizationoragency.TheWorldHealthOrganization(WHO)andtheFoodandAgricultureOrganization[7],aswellastheEnvironmentalProtectionAgency(EPA)oftheUnitedStateshaveadoptedorproposedguidelinesfortheproduction,processing,labeling,andmarketingoforganicfoodsinanattempttoensurethatallfoodsthatarelabeledorganicmeetthesameminimumstandards.

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Labelingrequirements

• —AsofApril,2008,foodthatislabeled"100percentorganic"or"organic"intheUnitedStatesmustmeetthestandardsoftheUnitedStatesDepartmentofAgriculture(USDA),withthefollowinglabelingrequirements[8]:

• ●Tobelabeledas"100percentorganic,"allingredientsmustbecertifiedasorganicallyproducedandprocessed(excludingwaterandsalt).

• ●Tobelabeled"organic,"foodsmustconsistofatleast95percentcertifiedorganicallyprocessedingredients(excludingwaterandsalt);theremaining5percentofingredientsmaybenon-organicallyproducedbutmustbeontheUSDA'sNationalList.

• ●Productsatleast70percentcertifiedorganicingredients(excludingwaterandsalt)canusetheclaim"madewithorganicingredients"andmaylistuptothreeindividualorganicallyproducedingredientsonthesidepanel,butmaynotclaimtobeorganiconthefrontofthepackage.

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Exposureinchildhood

• Mostevidenceindicatesthattracesofpesticideresiduesinfoodsarenotaproblemformostpeople[83].However,dataarelimitedregardingthetoxicologic consequencesofexposuretopesticideresidueduringinfancyandearlychildhood[84].

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TheFDAmonitorsnutritionalconcerns

• ,includingpesticideexposure,throughtheTotalDietStudy.Thisstudyexamines234foodsselectedtotypifytheAmericandiet.Between1985and1991,analysisofthesefoodsrevealed:

• ●Noresidueswerefoundininfantformulas• ●NoresiduesovertheEPAtoleranceorFDAactionlevelwerefoundinanyofthe"marketbasket"foods

• ●Lowlevelsof malathion werefoundinsomecereals• ●Lowlevelsofthiabendazole,apost-harvestfungicide,werefoundonsomefruitsandfruitproducts

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Factorstoconsiderwhendecidingwhethertouseorganicproductsinclude:

• •Organicfoodsarenotfreeofsyntheticpesticide residues,buttypicallycontainsmalleramountsthanarepresentonconventionallygrownfoods.Thus,organicallygrownfoodsprovideanalternative sourceoffruitsandvegetablesforindividualswhoareconcernedaboutsyntheticpesticides.(See 'Reductionofexposure' above.)

• •Infantsandchildrenmaybemoresusceptibletotheadverseeffects ofpesticidesthanareadults.(See 'Exposureinutero' aboveand 'Exposureinchildhood' above.)

• •Ingeneral,thetracesofpesticideresiduethatarefoundinfoodposelittlethreattohumanhealth. Potentialadverseeffects ofpesticideexposureonspecialpopulationsincludeneurologic,developmental,andreproductivedisorders.(See 'Exposureinutero' aboveand 'Adverseeffects' above.)

• •Populationsinvolvedinagriculturalworkhavehigherlevelsofpesticide exposure,butevidence ofadverseeffectsofsuchexposurelevels islimited.(See 'Exposureinutero' aboveand 'Exposureinchildhood' above.)

• •Pesticides helptomaintainanabundantandvariedfoodsupply.Pesticide useisregulatedbytheEPAandenforcedbytheUSDAandtheFDA.Effortsarebeingmadetoensurethattheseregulationsareappropriateforinfantsandchildren.(See 'Pesticideregulation' above.)

• •Exposuretopesticide residueineitherorganicorconventionallygrownfoodcanbereducedthroughwashing,peeling,cooking,orprocessingoffoods.(See 'Reductionofexposure' above.)

• •Organicfoodproductiondoesnoteliminate theriskoffoodborneillness,and"organic"shouldnotbeinterpretedasmeaning "safe".(See 'Microbialinfection' above.)

• •Organicfarmingistypicallyperformedbysmaller,family-ownedfarmsandmaybemoreenvironmentallyfriendly[5].

• •Because organicfarmingprohibitsnontherapeuticantibiotics, itmayreducetheriskofdiseaseattributedtoorganismsthat areresistanttomultipleantibiotics.(See 'Hormone,sex-steroid,andantibiotictreatment oflivestock' above.)

• •Ithasbeenpostulatedthat ingestedestrogeninfoodderivedfromsex-hormone-treatedanimalsmayleadtoearlierdevelopment ofpuberty,butlimitedstudieshavenotsupportedthishypothesisinhumans.(See 'Hormone,sex-steroid,andantibiotictreatment oflivestock' above.)

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reduceexposuretofoodbornepathogensandpesticides:

• •Buythefreshestfoodsavailable.Theywillhavethebesttasteandhighestnutrient (ie,vitamin)content.• •Considerusingfrozenorcannedfruitsandvegetablesasanalternativeorsupplement tofreshproduce.Thesefoodsmaintainmostoftheirnutritionalvalueandmayalsoreducepesticideexposureascomparedtofreshproduce.

• •Eatavarietyoffoods toensureabalancednutritional intakeandtolessencontaminationfromanyonesource.

• •Selectproduce thatisfreeofdirt,insectholes,mold,ordecay.(See 'Naturaltoxins' above.)• •Alwayswashfruitsandvegetablesthoroughly withadishbrush,butdonotusesoaporotherdetergents.• •Peelfruitsandvegetablesbeforeeatingandthrowawaytheouterleavesof leafyvegetables.Somenutrientsandfibermaybelostwhenproduce ispeeled.

• •Trimfatfrommeatandskinfrompoultryandfishbecausesomepesticideresiduesareconcentratedinfat.• •Makesurethatapplejuiceandciderarepasteurized, toreducetheriskoffood-borne illnesssuchasE.ColiO157.(See 'Microbialinfection' above.)

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Arsenicexposureisassociatedwithcancers

• ●Skincancer– Ingestionofinorganicarsenicincreasestheriskofdeveloping skincancers(picture1)[69].Lesionscommonlydescribedaremultiple squamouscellcarcinomas,arisingfromthearsenichyperkeratoticwarts,aswellasbasalcellcarcinomasarisingfromcellsnotassociatedwithhyperkeratinization.

• ●Bladdercancer– Therehasalsobeenconsiderableepidemiologic evidencetosupport theassociationbetweenexposuretoinorganicarsenicandbladdercancer[67].AcohortstudyfromTaiwanfound that,comparedwithpeopledrinking waterwithanarsenicconcentrationof≤10 mcg/L, theadjustedrelativerisksofbladdercancerinpeopleexposedtowellwatercontainingarsenicinconcentrationsof10.1to50,50.1to100,and>100 mcg/L were1.9,8.2,and15.3,respectively[70].(See "Epidemiology andriskfactorsofurothelial (transitionalcell)carcinomaofthebladder", sectionon'Drinkingwater'.)

• ●Lungcancer– Thereisevidencetosupport anassociationbetweenarsenicexposureandlungcancer[67,71-73].ObservationalstudiesfromChilehavefound adose-response relationship,withevidencethattheriskforlungcancermaybegintoincreasewhenarsenicconcentrationsindrinkingwaterreachapproximately60 mcg/L [71,72].Theadjustedrelativeriskfor lungcancerwas8.9fordrinking waterwitharsenicconcentrationsof200to400 mcg/L [72].Inanother study,mortalityratesfromlungcancerdeclinedfollowing theeliminationofarsenicfromdrinkingwater[74].Thereisalsoevidenceof synergybetweenarsenicandsmokingontheriskoflungcancer[72,73].(See "Cigarettesmokingandotherpossible riskfactorsforlungcancer",sectionon'Occupationalandenvironmental carcinogens'.)

• ●Liver – Arsenicexposureisbelievedtoincreasetheriskofhepaticangiosarcomas,butitdoesnotappeartobeassociatedwithhepatocellularcarcinoma[75].

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N-nitroso compounds

• N-nitroso compoundsarepotentneurocarcinogens inanimalmodels[59].Humanexposuretotheseagentsoccursfrombothendogenousandexogenoussources.

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N-nitroso compounds

• Exogenous– ThemajorexogenoussourcesofpopulationexposurestoN-nitroso compoundsincludetobaccosmoke,cosmetics,automobileinteriors,andcuredmeats[11].Othersourcesincluderubberproducts(babypacifiers,bottlenipples)andcertaindrugsincludingantihistamines,diuretics,oralhypoglycemicagents,antibiotics,tranquilizers,andopiates.N-nitrodiethanolamine,acarcinogeninanimalmodels,occursmainlyasacontaminantincosmeticproducts,soaps,shampoos,andhandlotions.

• ●Endogenous– EndogenousformationofN-nitroso compoundsisacomplexprocessthatoccursinthestomach,andisdependentuponthepresenceofNOCprecursors,gastricpH,thepresenceofbacteria,andotherphysiologicparameters[3].Thus,measurementofexposuretoendogenousNOCsisextremelydifficult.

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• Inthefourlargestcase-controlstudies,allofwhichincludedover200patientsdiagnosedwithgliomaandappropriatecontrols,andsomeassessmentofmeatintake[60-63],tworeportedasignificanttwo- tothreefoldincreasedriskofgliomaforhighconsumersofcuredmeatorbacon,ascomparedwiththosewithalowintake[61,62].However,excessriskswereonlyobservedamongmenand,inone,therelativeriskswereforhighintakeofcuredmeatincombinationwithlowfruitandvegetableintake[61].Ameta-analysisthatincludednineobservationalstudies(primarilycase-controlstudies)reportedarelativeriskof1.48(95%CI1.20-1.83)foradultgliomaamongindividualswithahighintakeofcuredmeat[64].

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• TwomorerecentpublicationsusingdatafromprospectivecohortstudiesfoundnoassociationswithmeatintakeordietaryN-nitrosocompounds[65,66].Bothstudieshadover300gliomacasesanddetaileddietaryassessmenttoexaminetheseexposuresandtheirpotentialrelationtogliomarisk.ThelackofassociationinthesetwolargeprospectivestudiescastdoubtontheN-nitroso compoundhypothesis,atleastinrelationtoadultgliomarisk.

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Antioxidants,fruits,andvegetables

• — IndirectsupportfortheNOChypothesisincludestheobservationthatcertaininhibitorsofthenitrosation process,vitaminsCandE,appeartoreducebraintumorriskinadultsandchildren[11,46,67].Dietarystudieshavedemonstratedareducedriskofbraintumorsinchildrenwhoconsumeincreasedamountsoffruitsandfruitjuices[11].Prenatalvitaminsupplementation(includingvitaminsAandCandfolate)andincreasedmaternalintakeofvegetableshavebeenassociatedwithaloweredbraintumorriskintheoffspring[67-69].

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dietarytraceminerals

• Cancer— EpidemiologicstudiessupportapossiblerelationshipbetweenSeandcancermortality[149,150].Asaresult,anumberofstudieshaveinvestigatedtheroleof selenium supplementationforpreventionofcancer.(See "Cancerprevention",sectionon'Selenium' and "Riskfactorsforprostatecancer".)

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Selenium

• — Animalstudiessuggestthat seleniumdecreasestheriskofavarietyoftumors,andsomeepidemiologicstudieshaveshownaninverserelationshipbetweenseleniumandcancer[148-150].OnestudyusingNHANESIIIdatafrom14,000adultsfoundaninverseassociationbetweenseleniumlevelsandcancermortalityatlevelsofseleniumupto130 ng/mL butanincreaseinmortalityatlevels>150 ng/mL [151].

• Aplacebo-controlledrandomizedtrialof selenium forpreventionofnonmelanoma skincancershowedasignificantmortalityreductionincancersofthelung,colon,andprostate[152].Asystematicreviewoftheeffectsofantioxidantsupplementsoncancerincludedfourrandomizedtrialsofseleniumaloneorincombinationwithothersupplementsandfoundthatseleniumreducedtheoverallriskofcancerinmen(RR0.77,95%CI0.64-0.92)butnotinwomen[153].However,alatermeta-analysisofrandomizedtrialsofantioxidanttherapyincludedfivetrialsofseleniumandfoundnosignificantcancerriskreduction(RR0.62,0.36-1.08)[154].

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Dietaryfat

• Dietaryfathasbeenextensivelystudiedasapossiblefactorexplainingthevariationininternationalcancerrates.Noclearlinkhasbeenfoundbetweentotalfatintakeandcolonorbreastcancer;thedataaresomewhatmoreconvincingforprostatecancer

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Redmeat

• —Highintakeofredmeathasbeenassociatedwithincreasedriskofcoloncancer.AworkinggroupoftheInternationalAgencyforResearchonCancer(IARC)reviewedobservationalstudiesevaluatingtheassociationofcancerwithredmeatorprocessedmeatconsumption,givingthehighestweighttoprospectivecohortstudiesandpopulation-basedcase-controlstudies[63].Thelargestbodyofevidencerelatedtoassociationswithcolorectalcancer,with7of14cohortstudiesand7of15casecontrolstudiesfindingpositiveassociationsforredmeatandcolorectalcancer,and12of18cohortstudiesand6of9case-controlstudiesfindinganassociationforprocessedmeatandcolorectalcancer.Ameta-analysisfoundadose-responserelationshipbasedon10cohortstudies,withriskincreasedby17percent(CI1.05-1.31)per100 g/day ofredmeatandincreasedby18percent(95%CI1.1-1.28)per50 g/day ofprocessedmeat.Theworkinggroupconcludedthatevidencewassufficienttoidentifycarcinogenicityforprocessedmeatbutlimitedfortheassociationofredmeatconsumptionandcancer

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Fruitsandvegetables

• — Despitesuggestionsfromcase-controlstudiesthathighintakeoffruitandvegetablesisassociatedwithasignificantreductionincancer,prospectivestudieshavefoundlessconsistentresults[66-69].DatafromtheEuropeanProspectiveInvestigationintoCancerandNutrition(EPIC)study,acohortstudyofnearly500,000Europeanmenandwomenfollowedfornineyears,foundonlyaweakassociationbetweenincreasedintakeoffruitsandvegetableswithoverallriskofcancer(HR0.97,95%CI0.96-0.99)[70].

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• Ameta-analysisfoundthatintakeofhighamountsofsoy(20 mg/day ofisoflavone)inAsianwomenwasassociatedwithadecreasedriskforbreastcancercomparedwithAsianwomenconsumingloweramounts(5 mg/day) [79].However,eventhelowestintakeofsoyisoflavones intheAsianpopulationwasmorethanfivefoldthe"high"intake(0.8 mg/day) ofwomeninWesterncountries,wherestudieshavenotshownaprotectiveeffectforsoy.Inanothermeta-analysis,Chinesewomenwhowereinthehighestquintileofsoyintakehadadecreasedriskoflungcancercomparedwiththoseinthelowestquintile[80].Increasedflavonoidsfoundintomatoes,greenpeppers,berries,andcitrusfruitshavebeenassociatedwithamodestdecreaseinbreastcancerriskinWesternpopulations[81].

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Dairy

• — Therelationshipbetweendairyintakeandovariancancerisuncertain.Twometa-analysesevaluatingtherelationshipofdairyfoodintakeandovariancancerfoundnoevidenceofasignificantassociation[82,83],whileathirdmeta-analysisof21studiesfoundnoassociationincase-controlstudies(RR0.96),butthreeprospectivecohortstudiesdiddemonstrateincreasedriskofovariancancerwithhighintakeofdairyfoods(RR1.13,95%CI1.05-1.22)[84].Inaccuracyofretrospectivedietreportsinthecase-controlstudiesmayaffecttheirreliability[85].However,asubsequentcohortstudyfoundnoincreaseinriskofovariancancerwithdietarydairyorlactoseintake[86].Thus,therelationshipofdairyintaketoovariancancerisuncertain

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Fiber

• — Fiberintakeisassociatedwithareductionintheriskofheartdisease[93,94]anddiabetes[95,96],butitseffectoncancerriskreductionislesscertain.Resultshavebeenvariableamonglargeepidemiologicstudiesandmeta-analyses,andthedegreeofprotectionfromdietaryfiber,ifany,willremainunsettleduntilprospectiveinterventionstudiesaredone.Intheabsenceofrandomizedtrials,observationaldatamaybeconfoundedbytherelationshipoffiberintakewithothermicronutrientsandwithotherchoicesrelatedtolifestyleanddiet.(See "Colorectalcancer:Epidemiology,riskfactors,andprotectivefactors",sectionon'Fiber'.)

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Fiber

• Severallargeepidemiologicstudieshavereportedasignificantinverseassociatedbetweenfiberintakeandcolorectalcancerrisk.Asanexample,alargeEuropeanstudyinvolving519,978patientsfoundthatintakeofdietaryfiberwasinverselyrelatedtocoloncancerincidence(adjustedRR0.58,95%CI0.41-0.85),comparingthehighesttolowestquintilesoffiberintake[97].However,theresultsmayhavebeenconfoundedbylackofcontrolforfolateintake,andfibermayhaveservedasaproxyforthismicronutrient.(See 'FolateandotherBvitamins' below.)

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Omega-3fattyacidsanddietaryfish

• — Asystematicreviewofprospectivestudiesevaluatingtheeffectofomega-3fattyacidconsumptionontumorincidenceconcludedthatthereisnoassociationbetweenomega-3fattyacidsandcancerriskfor11differenttypesofcancer[119].Tenstudiesevaluatedinthisreviewreportedsignificantfindings,butindividualstudiesindicatedbothincreasedanddecreasedriskwithnoconsistentpattern.Asubsequentrandomizedtrialfoundanincreaseincancerriskforwomentreatedwithomega-3fattyacids,butnotformen[120].

• Whileanassociationhasnotbeenfoundfordietarysupplementationwithomega-3fattyacidsandcancerincidence,anassociationwasfoundinasystematicreviewof41observationalstudiesforfishconsumptionandadecreasedincidenceofcolorectalcancer[121].Inthatanalysis,includingcase-controlandcohortstudies,aninverserelationshipbetweenfishintakeandrectalcancerwasdemonstrated(oddsratio[OR]0.79,95%CI0.65-0.97),whileaninversetrendwassuggestedforcoloncancer(OR0.96,95%CI0.81-1.14).

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VITAMINSANDMICRONUTRIENTS

• — Multipleobservationalandprospectivestudiesoftheuseofsupplementalvitaminsandmineralstopreventcancerhavebeendisappointing[122].Asystematicreviewof38studiesfoundthatneither vitaminC nor vitaminE supplementationwasbeneficialforpreventionofthecancersevaluated[123].A2006NationalInstitutesofHealth(NIH)consensusconferencepanelconcludedthat"presentevidenceisinsufficienttorecommendeitherfororagainsttheuseofmultivitaminsupplementsbytheAmericanpublictopreventchronicdisease"[124].Asubsequentlong-termrandomizedtrial(mean9.4yearstreatment)in8000womenfoundnoevidencethatsupplementationwithvitaminC,E,or beta-carotene (singlyorincombination)decreasedcancerincidenceorcancermortality[125].Additionally,twolong-termobservationalstudies,oneincludingover160,000womenwithfollow-upofapproximatelyeightyears[126]andanotherincludingover180,000multiethnicparticipantswith11-yearfollow-up[127],foundnoassociationbetweenmultivitaminuseandriskofcancer.(See "Vitaminsupplementationindiseaseprevention".)

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SeleniumandVit E

• Basedonpreliminaryevidencefromearliersmallertrials,theroleof selenium indecreasingtheincidenceofprostatecancerwasevaluatedinthemuchlargerSeleniumand VitaminE CancerPreventionTrial(SELECT),whichincludedover35,000men[155].ThetrialwasstoppedprematurelyforfutilityasneithervitaminEnorseleniumprotectedparticipantsfromprostatecancerandtherewasanonsignificanttrendtowardincreasedriskfordiabetesintheseleniumgroup[156].(See "Chemopreventionstrategiesinprostatecancer",sectionon'Selenium' and "Riskfactorsfortype2diabetesmellitus",sectionon'Selenium'.)

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VitaminE

• — Evidencedoesnotsupportarolefor vitaminE supplementationinthepreventionofcancer,andsomeevidencesuggeststhatvitaminEmaybeharmful.In2014,theUSPSTFmadearecommendationagainstuseofvitaminEforcancerprevention,citingadequateevidenceoflackofbenefit,butalsonotedadequateevidencethatvitaminEhasfewornosubstantialharms[132].

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• Inlong-termfollow-up(7upto12years)oftheSELECTtrial,theriskofprostatecancerwashigherinthemenwhowereassignedtotake vitaminE alonecomparedwithplacebo(HR1.17,99%CI1.004-1.36)[157].

• ●VitaminE (600internationalunitsofalpha-tocopheroleveryotherday)didnotpreventinvasivecancerina10-yearfollow-uptotheWomen'sHealthStudy,evaluatinghealthywomenage45yearsandolder(meanage55years)[158].NeithervitaminEnor vitaminC decreasedriskforprostateortotalcancerinaPhysicians'HealthStudyrandomizedtrialof14,641menaged50andolderfollowedforeightyears[159].

• ●Inameta-analysisofsixrandomizedtrials, vitaminE supplementationhadnoeffectoncancerincidenceorcancermortality[153].

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DIETPATTERNS

• —Dietarypatterns,insteadofcomponentsofthedietinisolation,havebeenthefocusofanexpandingbodyofliterature.

• TheMediterraneandietischaracterizedbyahighintakeoffruits,vegetables,nuts,legumes,wholewheatbread,fish,andoliveoil.AlargecohortstudyinGreecefoundthat,whencompliancewiththeMediterraneandietwasscoredona10-pointscale,atwo-pointincreaseinadherencetothetraditionalGreekMediterraneandietwasassociatedwitha12percentlowerriskofcancer[186].InalargeranalysisoftheEPICcohort,greateradherencetotheMediterraneandietalsowasassociatedwithadecreasedriskofcancer(foreverytwo-pointincreaseindietscore,cancerriskdecreased4percent),withasuggestionofastrongerassociationwithsmoking-relatedcancers[187].

• TheMediterraneandiethasnotconsistentlybeenassociatedwithdecreasedriskofanyspecifictumor.AdecreasedriskofcolorectalcancerwasidentifiedinonelargecohortstudyinEurope[188],butnotinalargeUnitedStatescohort[189].DataforbreastcancerissimilarlymixedwithnoassociationfoundamongSwedishandBritishcohorts[190,191],whiledatafromtheEuropeanProspectiveInvestigationintoCancerandNutrition(EPIC)cohortidentifiedanassociationforoverallbreastcancerriskandriskofpostmenopausaltumors[192].Theassociationwasmorepronouncedfor estrogen-receptor-negative/progesterone-receptor-negative (ER-/PR-) tumors.

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DIET

• — Avarietyofdietaryfactorshavebeenstudiedinrelationtocancer.Overall,dietaryfat,fruits,vegetables,andfiberhavenotconsistentlybeenshowntoaffectcancerrisk[56].Intakeofothernutrients,particularlycertainmicronutrients,mayofferadegreeofprotectionagainstcertainmalignancies

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Fruitandvegetablesandcancerrisk

• Currentadviceinrelationtodietandcancershouldincludetherecommendationtoconsumeadequateamountsoffruitandvegetables,butshouldputmostemphasisonthewell-establishedadverseeffectsofobesityandhighalcoholintakes

• KeyTJ,BrJCancer.2011

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Redmeat

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