Downloaded from https://journals.lww.com/nuclearmed by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD36i5Q5e8D5BtvQoBw0bi++97mYT1DgmHK9U4aDJO1JU2Djf0SawCyHA== on 05/22/2019 ACriticalAssessmentoftheLinearNo-ThresholdHypothesis ItsValidityandApplicabilityforUseinRiskAssessmentandRadiationProtection JeffryA.Siegel,PhD,*AntoneL.Brooks,PhD,† DarrellR.Fisher,PhD,‡ PatB.Zanzonico,PhD,§ MohanDoss,PhD,||MichaelK.O'Connor,PhD,¶EdwardB.Silberstein,MA,MD,** JamesS.Welsh,MS,MD,†† andBennettS.Greenspan,MD,MS‡‡ Abstract: TheSocietyofNuclearMedicineandMolecularImagingconvenedataskgrouptoexaminetheevidencefortheriskofcarcinogenesis fromlow-doseradiationexposureandtoassessevidenceinthescientific literaturerelatedtotheoverallvalidityofthelinearno-threshold(LNT) hypothesisanditsapplicabilityforuseinriskassessmentandradiation protection.Inthelow-doseanddose-rateregion,thegroupconcludedthat theLNThypothesisisinvalidasitisnotsupportedbytheavailablescientific evidenceand,instead,isactuallyrefutedbypublishedepidemiologyand radiationbiology.Thetaskgroupconcludedthattheevidencedoesnot supporttheuseofLNTeitherforriskassessmentorradiationprotection inthelow-doseanddose-rateregion. KeyWords: linearno-threshold,ALARA,radiationcarcinogenesis, riskassessment,radiationprotection,radiophobia (ClinNuclMed 2019;00:00 00) T heSocietyofNuclearMedicineandMolecularImagingconvenedataskgrouptoevaluatethedose-responserelationship forradiationcarcinogenesisatlowdosesanddataintherelevantliteratureaddressingthevalidityofthelinearno-threshold(LNT) dose-responserelationshipforregulatingradiationsafety. Althoughbasedonathoroughandcriticalreviewoftheavailablescientificevidence,thisarticleispurposelysuccincttocapture andmaintaintheattentionofourreadership.Thetaskgroupcomprisedpersonsrepresentingnuclearmedicine,radiationoncology, radiationbiology,medicalphysics,andhealthphysics.
ThefirstassignmentofthetaskgroupwastoassessthevalidityoftheLNThypothesis.Thefollowingquestionwasposed: “Do thescientificdatasupportorrefutethelinearno-thresholddose-
responsehypothesis?” Thetaskgroupconcludedafterexamining theavailableevidencethat,inthelow-doseanddose-rateregion, theLNThypothesisisnotsupportedand,instead,isactuallyrefuted bypublishedepidemiologyandradiationbiology. Next,thetaskgroupassessedwhethertheLNThypothesis wasappropriatelyapplicableforuseinriskassessmentandasa modelforradiationprotection.Theimportanceofthisassessment isparamount,becausetheInternationalCommissiononRadiologicalProtection(ICRP)onpage43ofitsPublication1031 unequivocallydeclaredtheLNThypothesistobe “thebestpracticalapproach tomanagingriskfromradiationexposure” commensuratewiththe “precautionaryprinciple.”2 Andfurther,despiteevidencetothecontrary,theCommissionconsideredthattheLNThypothesis “remains aprudentbasisforradiationprotectionatlowdosesandlowdose rates.”3 ThetaskgroupmembersconcludedthattheLNTmodelis notapracticalbasisforformulatingradiationprotectionstandards, anditdoesnotprovide “reliable” riskfactorsinthelow-dose,doserateregion;itisempiricallyfalse.Nocredibleevidenceshowsthat low-doseradiationexposurerepresentsasignificanttoxin.Radiation atrelativelyhighdosesisaweakcarcinogen,butthisisnottrueatlow doses.Credibleevidenceoflow-dose(<100mGy)carcinogenicrisk isnonexistent;itisahypotheticalpredictionderivedfromtheLNT hypothesis.Further,thebenefitsofdiagnosticimaging,usingsuch lowdoses,faroutweighitsclaimedrisksbasedontheLNTmodel. THELNTHYPOTHESISISNOTSUPPORTEDBY EMPIRICALEVIDENCE:ITSHOULDNOTBE USEDFORRISKASSESSMENT Thetaskgroup'sexaminationoftheavailablescientific evidenceidentifiedsubstantialdeficienciesintheunderlying foundationsoftheLNThypothesis: 1.TheLNThypothesisofradiationcarcinogenesispostulatesthat allacuteionizingradiationexposuredowntozeroisproportionatelydetrimentalwithdose.Althoughcancerriskisunderstood athigherradiationdoselevelsdeliveredacutely,wefindnounequivocalevidenceofproportionateriskatlowerdoses(less than100mGy).4 11 Low-doseriskoverbackgroundincidence ofcancerduetoothercausescanonlybeinferredandcannot beknownwithstatisticalconfidencebylinearextrapolationof theriskathighdoses. 2.Whetherornotlow-dosedamageislinearlyproportionateto dose,thebody'sdefensiveresponsesarenonlinear,leavingthe netresultnonlinear.12 14 Thebodydealswithinitialradiation damagethroughasetofwell-knownprotectivemechanismsat thecellularandsuborganlevels,collectivelycalledtheadaptive protectiveresponses,whichprovidecancerprotectionthrough DNArepairinvolvingmorethan150genes,antioxidantproduction,apoptosisatthecellularlevel,bystandereffectsatthemulticellularlevel,andimmunesystemresponseinvolvingremoval ofsurvivingbutdamagedcellsontheorganismallevel.15,16 Thesemechanismsdefendtheorganismagainstbothexogenous andendogenousDNAdamageandenhancebothsurvivaland maintenanceofgenomicstability.17 3.DNArepairmechanismsmayhaveevolvedinamuchhigher backgroundlevelofradiationandmayhavebecomequiteefficientatrepairingdamagefromlow-doseexposure.Athigh ReceivedforpublicationFebruary20,2019;revisionacceptedMarch27,2019. Fromthe*NuclearPhysicsEnterprises,Marlton,NJ; †WashingtonStateUniversity, Kennewick; ‡VersantMedicalPhysicsandRadiationSafety,Richland,WA; §DepartmentofMedicalPhysics,MemorialSloanKetteringCancerCenter, NewYork,NY;||DiagnosticImaging,FoxChaseCancerCenter,Philadelphia, PA;¶DepartmentofRadiology,MayoClinic,Rochester,MN;**Departments ofRadiologyandMedicine(emeritus),UniversityofCincinnatiMedicalCenter, Cincinnati,OH; ††DepartmentofRadiationOncology,StritchSchoolofMedicineLoyolaUniversity-Chicago,Maywood,IL;and ‡‡NorthAugusta,SC. Conflictsofinterestandsourcesoffunding:nonedeclared. Correspondenceto:BennettS.Greenspan,MD,MS,150RiverClubLane,North Augusta,SC29841.E-mail:bengreenspan0708@gmail.com. Copyright©2019WoltersKluwerHealth,Inc.Allrightsreserved. ISSN:0363-9762/19/0000 0000 DOI:10.1097/RLU.0000000000002613 ORIGINAL ARTICLE ClinicalNuclearMedicine • Volume00,Number00,Month2019www.nuclearmed.com 1 Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
Animportantdistinctionmaybemadebetweenuseofthe LNTmodelforradiationprotection,asconcludedbytheNCRP Commentary,forformulatingpolicy,andasascientificallydefensiblehypothesis.Thisdistinctionisreferredtoasriskmanagement versusriskassessment.Evenregulatoryagencies,aswellasthe NCRP,ICRP,andotheradvisorybodies,drawattentiontothisdistinctionandexplicitlycallfortheLNThypothesistonotbeused forriskassessment,1,42 butinstead,onlyasafoundationalassumptionguidingradiationprotectionandregulationunderthe “AsLow AsReasonablyAchievable” (ALARA)concept. 139that “theepidemiologicdatadonotjustifyusingtheLNTmodel andcollectivedosestoestimatethenumbersofexcesscancersin somelargepopulationwhoreceivedsmallindividualdoses.”
Suchclaims,hesaid,are “
In1980,LauristonTaylor(pastpresidentoftheNCRP)observedthatLNT-basedpredictivecalculations,whichcontinueto bemisused,werebasedonaliteralapplicationofthehypothesis, treatingitasfactevenwithoutstatisticalorotherscientificverification.43 deeplyimmoralusesofour scientificknowledge. tionbybothNCRPandICRP,and(2)beingunabletofindany alternativemodel.
” IntheUnitedStates,regulatorshavefrequentlyacknowledged deficienciesintheLNThypothesis,buthavecontinuedtoaccept itandtouseitforregulatorylanguagedueto(1)ongoingadvoca-
RISKMANAGEMENTVERSUSRISKASSESSMENT
Riskassessmentisthescientificprocessofcharacterizing thenatureandmagnitudeofradiationeffects,butthescientificevidencedoesnotsupporttheuseoftheLNThypothesistoaccurately assessorestablishthelevelofassociatedriskatlowdoses.Thus, LNTuseisrestrictedto,andduetoitsmathematicalsimplicity assumedtobeaprudentmodelfor,r adiationprotection,thatis, themanagementofrisksfromlow-doseradiationexposure.The authorsofNCRPCommentaryNo.27alsoagreed,statingonpage
THENULLHYPOTHESISANDBURDENOFPROOF AttemptingtodisproveanullhypothesismayconfoundcorrectdatainterpretationtosupportorrefutetheLNThypothesis. Thismaybeillustratedintherecentepidemiologicalupdateofsolid cancerincidenceamongtheLSScohortofJapaneseatomicbomb survivorsasreportedbyGrantetal39 in2017.Inthatanalysis,the LNThypothesiswasselectedasthenullhypothesis.Grantetal foundthattheatomicbombsurvivordatadidnotpermitrejection ofthenullhypothesis(thatestimatesforthresholdsderivedfrom theLSSdatacannotbedistinguishedstatisticallyfromzero).However,wemaintainthatfailuretorejectanullhypothesisisnotthe sameasconfirmingitsvalidity,44 becausefailuretorejectmayonly resultfrominsufficientconfirmatorydataratherthanfromthevalidityofthenullhypothesis.InthecaseoftheLSS,thedatawere insufficienttorejectthenullhypothesisduetolargeuncertainties. Siegeletal ClinicalNuclearMedicine • Volume00,Number00,Month2019 2 www.nuclearmed.com ©2019WoltersKluwerHealth,Inc.Allrightsreserved. Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
doses,repairmechanismsareoverwhelmed.TheLNThypothesisignorespotentialevolutionaryfactors.18 4.TheLNTmodelassumesthatradiationdamageandassociated cancerriskarecumulative.Thisassumptionincorrectlyimplies theabsenceofDNAdamagerepairandcellularturnoverand elimination.Tothecontrary,thepublishedscientificliterature confirmsthebody'sabilitytorespondtoradiation-induced damageatlowdosesanddoserates. 16 5.TheLNTmodelassumesthatradiation-inducedriskisindependentofdoserate.Althoughvariousscientificgroupshaveproposedadoseanddose-rateeffectivenessfactorontheorderof 1.5to2asaresponsemodifier,19 thisfactorfailstoadequately considerthewell-knowndose-rateeffect,9,20 suchasdemonstrated bythepracticeoffractionationofhigh-doseradiationtherapy, whichdemonstratesthatnormaltissuerecoveryoccursbetween treatments.Inadditiontobiologicalchangesinducedbylowdoses ofacuteradiation,itisimportanttorecognizethatdose-rateand dosedistributionareveryimportantinriskassessment;thesame dosedeliveredatalow-doserateortoonlyapartofthebodyis muchlessdamagingthanacuteexposuretothissamelevel.21,22 Doseratephenomenahavebeenprovenatalllevelsofbiological organizationfromthemolecular,cellular,tissue,organ,towhole organismsincludinghumans.12 6.TheLNThypothesisassumesthatanymutationmayleadtoa potentiallylethalcancer.However,majorparadigmshiftsbetter explainrecentdata.23 AlthoughDNAdamageintheformofinitialgeneticmutationsmaybeanecessaryprequel,singlemutationsareinsufficientascausativefactorsincancerinduction.24 Theoutdated “onemutationequalsonecancer” theoryhasbeen replacedbythealternativeconceptsinvolvingfailureofmultiple defensemechanisms,DNAmisrepair,failuresofcellularelimination,andlossofimmunesystemfunction.Functionalfailures relatedtodoseanddoseratehavebeendemonstratedforthekey eventsincriticalcarcinogenesispathways.25 7.TheaverageannualnaturalbackgroundradiationdoseonEarth rangesfrom1to260mSv.Irrespectiveofthelevelofbackgroundexposuretoagivenpopulation,noassociatedadverse healtheffectsproportionaltobackgrounddosehavebeendocumentedanywhereintheworld.26 IncontrasttoLNT-based predictions,severalhigh-backgroundradiationareas(suchas Denver,CO;Kerala,India;Yangjiang,China;Guarapari,Brazil; Ramsar,Iran)havethesameorlowercancerratescomparedwith nearbyareaswithlowerbackgroundrates.27,28 8.Variousepidemiologicstudiesofpopulationsexposedtolow levelsofradiationhavedocumentedbenefit(reducedcancer incidenceandincreasedlongevity),andnotjustabsenceof harm,fromradiationexposures.4,8,14,29 Uponcarefulcriticalreview,manyrecentepidemiologicstudiesclaimingtosupporttheLNThypothesisfactuallydonot.30 34 Theirconclusionsseemoverreachingbasedonthedatapresented andanalysesperformed.35 38 In2018,theNationalCouncilonRadiationProtectionand Measurements(NCRP)publishedCommentaryNo.27,ImplicationsofRecentEpidemiologicStudiesfortheLinear-Nonthreshold ModelandRadiationProtection,whichwasintendedtoprovidea criticalreviewof29epidemiologicstudiesofpopulationsexposed toradiationinthelow-doseandlow-doseraterange,mostlypublishedwithinthelast10years.CommentaryNo.27concludedthat themorerecentepidemiologicstudiessupportedtheideaofcontinuedrelianceontheLNTmodelforradiationprotectionpurposes. AccordingtoNCRPCommentaryNo.27,only5ofthe29studies providestrongsupportfortheLNTmodel,includingtheLife Span39 andInternationalNuclearWorkers33,34 studies.Several criticalreviewsbyothers,however,showedthatthecitedstudies insteadofstrongsupport providelittleifanyfoundationalsupport for(andactuallyprovidedrefutingevidenceagainst)theLNThypothesis.11,38,40,41 Unfortunately,NCRPCommentaryNo.27chose toignorethesecontradictoryandinconclusivefindings.Further,the Commentary'sassessmentthattheupdatedanalysisoftheJapanese LifeSpanStudy(LSS)data,asreportedbyGrantetal,39 provided strongsupportfortheLNTmodelforradiationprotectionwas contradictedbythisstudy'smajorconclusion: “Atthistime,uncertaintiesintheshapeofthedose responseprecludedefinitiveconclusionstoconfidentlyguideradiationprotectionpolicies.”
”
InabilitytorejecttheLNTmodel(basedoninsufficientdata)should not,asasserted, “precludedefinitiveconclusionstoconfidently guideradiationprotectionpolicies.
Thedoserateanddosedistribution frominternallydepositedradioactivematerialsaremuchlesseffective inproducingeitherlife-shorteningorincreasingcancerfrequency comparedwiththesameacutewhole-bodydose.47
Applicationoftheprecautionaryprincipleexcludesempiric low-doseradiationresearch.Effectiveriskmanagementandrisk communicationmaythusbecompromisedinlow-dosescenarios unlessitisrecognizedthatuseofLNT,anditscorollary,ALARA, maynoterronthesideofcaution,butratherresultinsignificant collateralnegativeconsequences,asdetailedbelow.
Currentregulatoryopinionneedstobemodifiedandupdated becauseregulatorscontinuetoi gnoreordismissthescientific literatureondose-response,existenceofthresholds,andadaptive hormeticeffects.Suchconsiderationsmayrevealthatalternative dose-responserelationshipsaremoreplausibleandconsistentwith thelow-dosedatathanistheLNThypothesis.Becausemanyepidemiologicstudies5,6,8,29 andvariousanalysesoftheLSSdata40,41 haveactuallydocumentedbenefitatlowdoses,andnotjustabsence ofharm,theburdenofproofmayneedtobeshiftedtothoseasserting thattheLNThypothesisiscorrect.
1.Thenumberofdisaster-relateddeathsresultingfromthemisguided LNT-basedevacuationpolicyfornearbyresidentsafterthe 2011FukushimaDaiichinuclearaccidentreachedalmost 2000,asof2016.Thisnumberexceedsthenumberof Fukushimaresidentswhowerekilleddirectlybytheearthquake distribution,subjectageandsex,andvarioustissueradiosensitivitiesandresponses.However,suchthinkingdiscountsthesubstantialvolumeofscientificevidenceshowingthenumerous mechanismsbywhichnaturalbiologicalprocessesprotectliving organismsagainstlow-doseanddose-rateradiation.Fromamechanisticmolecularandcellularperspective,linearextrapolationfrom high-dosecancerdatatopredictthecancerfrequencyinthelow-dose rangecannotbesupportedasavalidbiologicalmechanism,and therefore,isnotavalidassessmentofriskofradiationcarcinogenesis.
andtsunami.48 2.Fearofradiationatlowdoses(radiophobia)14,49 causedmany Japanesetoavoidimportantradiologicmedicalexaminations neededtodiagnoseatraumaticinjuryorotherdiseases,such ascancer.50,51 Withoutradiologicalexaminationsoriftheexaminationswereperformedusingaradiationexposurethatwastoo low,patientsmayhavebeenundiagnosedormisdiagnosed.52,53 Usingalternativemethods(eg,longer-durationmagneticresonanceimaginginplaceofcomputedtomography)54 maybeless accurate,andmayexposepatientstogreaterrisks,suchasuse ofanesthesiafortheexamination.51 3.Focusingonpotentialrisksofdiagnosticimagingwhileignoringbenefitsisimproperandcouldevenbeharmfulsincethehypotheticallyprojectedrisksoflow-doseradiationexposureare farlowerthanitsactualbenefits.14,55 Suchbenefitsmayinclude thevaluableinformationprovided(enablingmoreaccurateand rapiddiagnoses,evaluationofextentofdisease,orpatients'peace ofmindfornegativeexaminations),livessaved,improvedquality oflife,avoidanceofunnecessarysurgeries,reducedhospital stays,andreducedcosts.56 58 4.Theapplicationofhighlyconservativeradiationdoselimits requiredtoachieveadequateremediationorcleanupintheaftermathofcontaminationoranuclearaccidentprovide questionablebenefit.Excessiveamountsofshieldingthat mayberequiredareexpensiveandincurunnecessaryinjuries anddeathsfrommininglead. Thus,effectiveriskmanagementandcommunicationwithrespecttodiagnosticmedicalimagingandotherlow-doseusesand scenariosarenotpossibleuntilLNTanditscorollary,ALARA, areuniversallyviewedasbeingscientificallyindefensible. CONCLUSIONS ConventionalthinkingamongnationalandinternationalscientificcommitteesandregulatorsholdsthattheLNTdose-response hypothesiscannotbeprovenordisprovenduetolargestatistical uncertainties,competingcausesofcancer,andnumerousother confoundingfactors,suchasradiationquality,doserate,dose
Consequently,sinceLNThasbeendisproven,itshouldnot beusedforriskassessmentandinradiationprotectionsimplybecauseitiserroneouslythoughttoerronthesideofcaution.Focusingonpotentialrisksofdiagnosticimagingwhileignoringitsfar greateractualbenefitsisimproperandcouldevenbeharmful.In lightoftheuncertaintiesandotherconsiderations,theLNThypothesisandriskfactorsderivedtherefromshouldnotbeusedtoestimatecancerrisksforindividualpatientsorpatientpopulations undergoingdiagnosticimagingproceduresandshouldnotbeused
ClinicalNuclearMedicine • Volume00,Number00,Month2019 TheLNTHypothesisIsNotValid ©2019WoltersKluwerHealth,Inc.Allrightsreserved. www.nuclearmed.com 3 Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
AccordingtotheICRP,theLNTmodelprovidesaprudent basisforpracticalapplicationofradiologicalprotectionguidelines, meaningpropermanagementofpotentialriskfromlow-doseradiationexposure.3 Riskmanagement,thekeydriverforpolicysetting, involvesuseoftheLNTmodelaswellassubjectivevaluejudgments.1 Valuejudgmentsmayconsiderpracticality,publicsentiment,andeconomicandpoliticalconsiderations.Butaregulatory themostcurrentderiveddose-responserelationshipreportedby Grantetal39 essentiallyprecludeduseoftheLNTmodeltoconfidentlyguideradiationprotectionpolicies;earlieranalyseshavealso notsupportedtheLNTmodel.8,9
THELNTMODELANDRISKMANAGEMENT
TheLSSdata-generatedradiationcancerriskestimateshave unfortunatelybeenassumedtoapplytochronicradiationexposures aswellasinstantaneousexposures.Thetotaldosefromnuclear medicineprocedures,forexample,isprotracted;low-doserateswith chronicexposureareknowntoreduceriskcomparedwithacuteexposureofthesametotaldose.21
protectionpolicycanonlybelegitimatewhenbasedoncorrectscience.Toproperlymanageriskatlowradiationdoses,thecomplete spectrumofpossiblehealthoutcomesmustbeacknowledged,includingthepotentialforbeneficialeffectsanddose-and-dose-rate thresholdsbelowwhichthebiologicaleffectcannotbedetected. UseoftheLNTmodeleffectivelyexcludestheseconsiderationsin policyandrulemaking. CurrentradiationprotectionpolicyacceptstheLNTparadigm (basedmainlyontheJapaneseatomicbombsurvivorcohort,apopulationexposedinstantaneouslytotheblast).Individualabsorbed dosesforsurvivorsintheLSScohortcanonlybeestimatedfrom survivor-providedinformationpertainingtotheirlocationatthe timeofthebombingandterrainshieldingdata.39 Thesepotentially impreciseandinaccuratebombsurvivordosesmayhavealsobeen underestimatedbecausetheywerebasedsolelyontheinitialblast radiation;falloutradioactivitywasnotaccountedforinsurvivordosimetrycalculations.45 Thisomissionlikelyimpactedtheexcess relativeriskestimates,leadingtoanoverestimatedcancerriskin thecohort particularlyatlowdoses.Accordingtoa2012analysis oftheLSSdatareportedbyOzasaetal,46 thereis “insufficientinformationaboutfalloutorresidualradiationtocompletelyrule outthispossibility.” Giventhemanyuncertaintiesandincomplete information,theLSSdataarenotconsistentwith,andtherefore donotsupport,theLNTmodel.Aspreviouslynoted,theshapeof
41.FurukawaK,MisumiM,CologneJB,etal.ABayesiansemiparametric modelforradiationdose-responseestimation. RiskAnal.2016;36:1211 1223. 42.BoiceJDJr.LNT101. HealthPhysNews.2015;XLIII:25 26.
15.LöbrichM,RiefN,KühneM,etal.InvivoformationandrepairofDNA doublestrandbreaksaftercomputedtomographyexaminations. ProcNatl AcadSciUSA.2005;102:8984 8989.
Siegeletal
8.DossM.Areweapproachingtheendofthelinearno-thresholdera? JNucl Med.2018;59:1786 1793.
36.KrilleL,DregerS,SchindelR,etal.Riskofcancerincidencebeforetheage
13.NeumaierT,SwensonJ,PhamC,etal.EvidenceforformationofDNArepaircentersanddose-responsenonlinearityinhumancells. PNAS.2012; 109:443 448.
16.FeinendegenLE,PollycoveM,NeumannRD.Hormesisbylowdoseradiationeffects:low-dosecancerriskmodelingmustrecognizeup-regulationof protection.In:BaumRP,ed. TherapeuticNuclearMedicine.Heidelberg: Springer;2013.
18.WelshJS.Furtherthoughtsonlow-levelradiation:anevolutionarybiologist's perspective. Radiology.2004;231:922 923.
19.NationalResearchCounciloftheNationalAcademies. HealthRisks fromExposuretoLowLevelsofIonizingRadiation:BEIRVIIPhase2 . Washington,DC:TheNationalAcademiesPress;2006. HealthPhysNews.2015;XLIII: 23 (UNSCEAR). SourcesandEffectsofIonizingRadiation:UNSCEAR1993 ReporttotheGeneralAssembly,WithScientificAnnexes.NewYork,NY: UnitedNations;1993. deathfromleukaemiaandlymphomainradiation-monitoredworkers (INWORKS):aninternationalcohortstudy. LancetHaematol e276 e281. tionalexposuretoionisingradiation:retrospectivecohortstudyofworkers BMJ fromCTscansbiasedbyindication?Elementsofanswerfromalarge-scale cohortstudyinFrance. BrJCancer.2015;112:185 193. of15yearsafterexposuretoionizingradiationfromcomputedtomography: resultsfromaGermancohortstudy. RadiatEnvironBiophys.2015;54:1 12.
.2015;2:
20.SiegelJA,SacksB,StabinMG.LNT999.
38.SacksB,MeyersonG,SiegelJA.Epidemiologywithoutbiology:falseparadigms,unfoundedassumptions,andspeciousstatisticsinradiationscience (withcommentariesbyIngeSchmitz-FeuerhakeandChristopherBusby andareplybytheauthors). BiolTheory.2016;11:69 101.
40.SasakiMS,TachibanaA,TakedaS.Cancerriskatlowdosesofionizingradiation:artificialneuralnetworksinferencefromatomicbombsurvivors. JRadiatRes.2014;55:391 406.
6.TubianaMF,FeinendegenLE,YangC,etal.Thelinearno-thresholdrelationshipisinconsistentwithradiationbiologicandexperimentaldata. Radiology 2009;251:13 22.
39.GrantEJ,BrennerA,SugiyamaH,etal.Solidcancerincidenceamongthe LifeSpanStudyofatomicbombsurvivors:1958 2009. RadiatRes.2017; 187:513 537.
14.SiegelJA,PenningtonCW,SacksB.Subjectingradiologicimagingtothe linearno-thresholdhypothesis:anonsequiturofnon-trivialproportion. JNuclMed.2017;58:1 6.
12.DauerLT,BrooksAL,HoelDG,etal.Reviewandevaluationofupdatedresearchonthehealtheffectsassociatedwithlow-doseionisingradiation. RadiatProtDosimetry.2010;140:103 136.
37.BoiceJDJr.Radiationepidemiologyandrecentpediatriccomputedtomographystudies. AnnICRP.2015;44(1suppl):236 248.
24. 21.UnitedNationsScientificCommitteeontheEffectsofAtomicRadiation
7.GonzálezAJ,AkashiM,BoiceJDJr,etal.Radiologicalprotectionissues arisingduringandaftertheFukushimanuclearreactoraccident. JRadiol Prot.2013;33:497 571.
2015;351:h5359. 35.JournyN,RehelJL,DuCouLePointeH,etal.Arethestudiesoncancerrisk
Unauthorized
4 www.nuclearmed.com ©2019WoltersKluwerHealth,Inc.Allrightsreserved. Copyright © 2019
inFrance,theUnitedKingdom,andtheUnitedStates(INWORKS).
43.TaylorLS.Somenonscientificinfluencesonradiationprotectionstandards andpractice:the1980Sievertlecture. HealthPhys.1980;39:851 874.
17.PollycoveM,FeinendegenLE.Radiation-inducedversusendogenousDNA damage:possibleeffectofinducibleprotectiveresponsesinmitigatingendogenousdamage. HumExpToxicol.2003;22:290 306.
34.RichardsonDB,CardisE,DanielsRD,etal.Riskofcancerfromoccupa-
9.SiegelJA,WelshJS.Doesimagingtechnologycausecancer?Debunkingthe linearno-thresholdmodelofradiationcarcinogenesis. TechnolCancerRes Treat.2016;15:249 256.
44.SiegelJA,SacksB,SocolY.TheLSSCohortofAtomicBombSurvivors andLNT.Commentson “SolidCancerIncidenceamongtheLifeSpanStudy ofAtomicBombSurvivors:1958 2009” (RadiatRes2017;187:513 37) ClinicalNuclearMedicine • Volume00,Number00,Month2019 Wolters Kluwer Health, Inc. reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
tolimitsuchprocedurestoclinicallymanageindividualpatients.Asa corollarytothispoint,althoughitisimportanttorecordindividual patientdosestoprovidedataforfutureepidemiologicstudiesand analyses,itisinadvisabletouseapatient'sdosehistorytoassess theproprietyofaplannedimagingprocedure.Thedecisiontoperformimagingshouldbebasedsolelyonmedicalnecessity. AutomaticapplicationofLNTasamodelforradiationprotectionmayproduceotherharmsunrelatedtodose,suchasoverly conservativeclean-upstandardsandevacuationrequirementsafter anuclearaccident.Noscientificevidencesupportstheassumed probabilitiesofcancerinthelowdoseandlow-doserateregion. Therearedemonstrateddoseanddose-ratethresholdsbelowwhich noadverseeffectscanbedetected.Thecommonopinionthatany amountofradiationcanbeharmful,nomatterhowsmall,isafalse perceptionthatmustbecorrected. REFERENCES 1.InternationalCommissiononRadiologicalProtection. The2007RecommendationsoftheInternationalCommissiononRadiologicalProtection:ICRP Publication103.MarylandHeights,MO:Elsevier;2007. 2.UnitedNationsEducational,ScientificandCulturalOrganization. ThePrecautionaryPrinciple.Paris,France:UNESCO;2005. 3.ValentinJ.Low-doseextrapolationofradiation-relatedcancerrisk. AnnICRP.2005;35:1 140. 4.LuckeyTD. RadiationHormesis.BocaRaton,FL:CRCPress;1991. 5.AurengoA,AverbeckD,BonninA,etal DoseEffectRelationshipsand EstimationoftheCarcinogenicEffectsofLowDosesofIonizingRadiation .Paris,France:AcadémiedesSciences AcadémieNationalede Médecine;2005.
10.SiegelJA,GreenspanBS,MaurerAH,etal.TheBEIRVIIestimatesof low-doseradiationhealthrisksarebasedonfaultyassumptionsanddata analyses:acallforreassessment. JNuclMed.2018;59:1017 1019.
22.PuukilaS,ThomeC,BrooksAL,etal.Theroleofradiationinducedinjury onlungcancer. Cancer(Basel).2017;9:89 101. 23.BrooksAL.Paradigmshiftsinradiationbiology:theirimpactoninterventionforradiationinduceddisease. RadiatRes.2005;164:454 461. 24.DeGregoriJ.Challengingtheaxiom:doestheoccurrenceofoncogenic mutationstrulylimitcancerdevelopmentwithage? Oncogene.2013;32: 1869 1875. 25.BrooksAL,HoelDG,PrestonRJ.Theroleofdoserateinradiationcancer risk:evaluatingtheeffectofdoserateatthemolecular,cellularandtissue levelsusingkeyeventsincriticalpathwaysfollowingexposuretolowLET radiation. IntJRadiatBiol.2016;92:405 426. 26.DobrzyńskiL,FornalskiKW,FeinendegenLE.Cancermortalityamong peoplelivinginareaswithvariouslevelsofnaturalbackgroundradiation. DoseResponse.2015;13:1559325815592391. 27.TaoZ,ZhaY,AkibaS,etal.CancermortalityinthehighbackgroundradiationareasofYangjiang,Chinaduringtheperiodbetween1979and1995. JRadiatRes(Tokyo).2000;41(suppl):31 41. 28.NairRR,RajanB,AkibaS,etal.Backgroundradiationandcancerincidence inKerala,India-Karanagappallycohortstudy. HealthPhys.2009;96:55 66. 29.SponslerR,CameronJR.Nuclearshipyardworkerstudy(1980 1988):a largecohortexposedtolow-dose-rategammaradiation. IntJLowRadiat. 2005;1:463 478. 30.PearceMS,SalottiJ,LittleMP,etal.RadiationexposurefromCTscansin childhoodandsubsequentriskofleukaemiaandbraintumors:aretrospectivecohortstudy. Lancet.2012;380:499 505. 31.MathewsJD,ForsytheAV,BradyZ,etal.Cancerriskin680,000peopleexposedtocomputedtomographyscansinchildhoodoradolescence:datalinkagestudyof11millionAustralians. BMJ.2013;346:f2360. 32.KendallGM,LittleMP,WakefordR,etal.Arecord-basedcase-control studyofnaturalbackgroundradiationandtheincidenceofchildhoodleukaemiaandothercancersinGreatBritainduring1980 2006. Leukemia 2013;27:3 9. 33.LeuraudK,RichardsonDB,CardisE,etal.Ionisingradiationandriskof
11.UlshBA.AcriticalevaluationoftheNCRPCommentary27endorsementof thelinearno-thresholdmodelofradiationeffects. EnvironRes.2018;167: 472 487.
47.BrooksAL,EberlinePE,CouchLA,etal.Theroleofdose-rateonriskfrom internally-depositedradionuclidesandthepotentialneedtoseparatedoserateeffectivenessfactor(DREF)fromthedoseanddose-rateeffectiveness factor(DDREF). HealthPhys.2009;97:458 469.
45.SutouS.RediscoveryofanoldarticlereportingthattheareaaroundtheepicenterinHiroshimawasheavilycontaminatedwithresidualradiation,indicating thatexposuredosesofA-bombsurvivorswerelargelyunderestimated. JRadiatRes.2017;58:745 754.
46.OzasaK,ShimizuY,SuyamaA,etal.Studiesofthemortalityofatomic bombsurvivors,report14,1950 2003:anoverviewofcancerandnoncancer diseases. RadiatRes.2012;177:229 243.
and “ReplytotheCommentsbyMortazaviandDoss” (RadiatRes2017; 188:369 71). RadiatRes.2017;188:463 464.
48.HayakawaM.Increaseindisaster-relateddeaths:risksandsocialimpactsof evacuation. AnnICRP.2016;45(2suppl):123 128.
50.BoutisK,CogolloW,FischerJ,etal.Parentalknowledgeofpotential
51.BrodyAS,GuillermanRP.Don'tletradiationscaretrumppatientcare: 10waysyoucanharmyourpatientsbyfearofradiation-inducedcancer fromdiagnosticimaging. Thorax.2014;69:782 784. 52.CohenMD.CTradiationdosereduction:canwedoharmbydoinggood? PediatrRadiol.2012;42:397 398. 53.GoskeMJ,StraussKJ,CoombsLP,etal.DiagnosticreferencerangesforpediatricabdominalCT. Radiology.2013;268:208 218. 54.ParkerMW,ShahSS,HallM,etal.Computedtomographyandshiftstoalternateimagingmodalitiesinhospitalizedchildren. Pediatrics.2015;36: e573 e581. 55.BalterS,ZanzonicoP,ReissGR,etal.Radiationisnottheonlyrisk. AJRAm JRoentgenol.2011;196:762 767. 56.ZanzonicoPB.Theneglectedsideofthecoin:quantitativebenefit-riskanalysesinmedicalimaging. HealthPhys.2016;110:301 304. 57.PandharipandePV,ReisnerAT,BinderWD,etal.CTintheemergencydepartment:areal-timestudyofchangesinphysiciandecisionmaking. Radiology.2016;278:812 821. 58.MehannaH,WongW,McConkeyCC,etal.PET-CTsurveillanceversus neckdissectioninadvancedheadandneckcancer. NEnglJMed.2016; 374:1444 1454. ClinicalNuclearMedicine • Volume00,Number00,Month2019 TheLNTHypothesisIsNotValid ©2019WoltersKluwerHealth,Inc.Allrightsreserved. www.nuclearmed.com 5 Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.
49.SiegelJA,McColloughCH,OrtonCG.AdvocatingforuseoftheALARAprincipleinthecontextofmedicalimagingfailstorecognizethattheriskishypotheticalandsoservestoreinforcepatients'fearsofradiation.
MedPhys.2017;44:3 6. cancerrisksfromexposuretocomputedtomography. Pediatrics .2013; 132:305 311.