Table of Contents
From the Editors ......................................................................................................................................... 1
Letter to the Editors .................................................................................................................................... 2
RERF News
45th Board of Directors Meeting........................................................................................................... 2
First Public Lecture for Citizens ........................................................................................................... 5
IAEA Director General Visits RERF..................................................................................................... 5
U.S. Consul General Visits RERF ......................................................................................................... 6
Staff News ............................................................................................................................................. 6
Visiting Scientists .................................................................................................................................. 7
Visiting Student Researchers ................................................................................................................. 7
Awards Received by RERF Scientists ................................................................................................... 8
Employee Training on Ethics and Protection of Study Participants in Medical Research,
by Takanobu Teramoto .................................................................................................................... 10
Conference and Workshop Reports
First Meeting of the Scientific and Ethics Committee for the Study of the F1 Offspring of
A-bomb Survivors, by Saeko Fujiwara............................................................................................ 11
Epidemiological Training Workshop for Biologists, by Nori Nakamura ............................................ 13
RERF Studies and Results Highlighted in Presentations at Two Annual Scientific Meetings,
by Evan B. Douple .......................................................................................................................... 14
Science Articles
Interaction Effects of Radiation and Smoking on Lung Cancer Incidence in the Life Span
Study, by Kyoji Furukawa ............................................................................................................... 15
Associations of Radiation Exposure and Circulatory Disease Mortality Risk Based on
Hiroshima and Nagasaki A-bomb Survivor Data, 1950–2003, by Yukiko Shimizu ....................... 23
Human Interest Notes
Recollections of Japan, by William J. Schull ...................................................................................... 31
In Memoriam: Dr. Yutaka Hosoda, by Saeko Fujiwara ....................................................................... 32
Dr. Elaine Ron, by Evan B. Douple ............................................................................ 32
Facts and Figures
Open Houses in Hiroshima and Nagasaki ........................................................................................... 34
Research Protocols and Publications
Research Protocols approved in April–October 2010 ......................................................................... 35
Recent Publications ............................................................................................................................. 37

This newsletter is published by the Radiation Effects Research Foundation (formerly the Atomic
Bomb Casualty Commission), established in April 1975 as a private, nonprofit Japanese foundation.
It is supported by the government of Japan through its Ministry of Health, Labour and Welfare andthat of the United States through the National Academy of Sciences under contract with the
Department of Energy.
RERF conducts research and studies—for peaceful purposes—on the medical effects of radiation on humans with a view toward contributing to the maintenance of the health and welfare of
atomic-bomb survivors and to the enhancement of the health of all mankind.
Editor-in-Chief: Evan B. Douple, Associate Chief of ResearchTechnical Editor: Yuko Ikawa, Public Relations & Publications Office
Editorial Policy
Contributions to Update receive editorial review only and do not receive scientific peer review.
The opinions expressed herein are those of the authors only and do not reflect RERF policies orpositions.
Contact: Mailing address: RERF Public Relations & Publications Office, 5-2 Hijiyama Park,
Minami-ku, Hiroshima 732-0815 Japan
Telephone: 81-82-261-3131; Facsimile: 81-82-263-7279
Internet: www.rerf.jp

1

From the Editors

From the Editors
Welcomeback!
Thebeautyofthekōyō(theJapanesewordfor“autumnleaves”),especiallythemomiji(Japanesemaple)signalscomfortabledaysandevenings—like“Indian summer” in New England—and a special
relief from the record-breaking heat of this year’sJapansummer.ButRERFstaffmembershavebeen
workinghardandhavehadlittletimeformomijigari(Japanesemaplehunting).We’repleasedtobeabletoreportsomeoftheresultsofourstaff’sefforts.
SeveralneweventsforRERFwereinitiatedduringthesecondhalfof2010andarereportedinthisissue. For example, read about Dr. Truong-Minh
Pham,thefirstrecipientofanewlyestablishedRERF
postdoctoralprogram.ThefirstmeetingoftheScientificandEthicsCommitteefortheStudyoftheF1
Offspring ofA-bomb Survivors was held, and an
Epidemiological TrainingWorkshop for BiologistswasheldforradiationbiologiststhroughoutJapanasameansofachievingcommunicatingacrossdifferent
fields.AnemployeetrainingsessiononEthicsand
ProtectionofStudyParticipantsinMedicalResearchwasinaugurated,andRERFscientistsparticipatedinthreespecialpanelsessionsheldtopublicizethe
scientificcontributionsofRERF,thefirsttwoatthe56th Meeting of the Radiation Effects ResearchSocietyandthethirdatthe52ndAnnualMeetingoftheAmericanSocietyforRadiationOncology.The
RERFOpenHouseinHiroshimaincludedarecordbreakingattendanceaswellasanOpenHousePreview for RERF employees.A series of lectures on
topicsrequestedbyemployeeswasbeguntoprovidea better understanding of ongoing RERF research
amongallemployees,notjustscientists.Finally,the
firstinwhatRERFplanstobeacontinuingseriesof
Public Lectures to inform the public—includingA-bombsurvivorsandtheirfamilies,cityofficials,
andotherinterestedattendees—abouttheresearchandfindingsofRERFwasheldattheInternationalConferenceCenterHiroshimalocatedinthePeace
MemorialParktoafullaudienceof230.ThePublic
Lecturesevent(seecoverphoto)wasjudgedtobea

successandresultedinsomegoodpresscoverageas
partofRERF’seffortstoimprovepublicunderstandingandrelations.
Pleasereadotherarticles,includingareportofthe45thBoardofDirectorsMeetingheldinNagasaki,
andcondensationsoftwoimportantscientificpapers
publishedrecentlyinprominentjournals.WewerepleasedtoreceiveavisitinMaybylong-timeABCCRERFsupporterandformerDirectorWilliam“Jack”
SchullwhodeliveredanentertainingandinformativelecturetoRERFstaffabouthisrecollectionsofthe
earlydaysofABCC.JackhaspromisedacondensationofthatlectureinthenextissueofUpdateand
inthemeantimehasprovidedashortandhumorous
HumanInterestNoteinthisissue.
And yes—for those who have inquired—theworld’s economic situation, including the reduced
JapaneseyentoU.S.dollarratio,hascontinuedto
impact adversely on the budget of RERF.As anakama(“team”)effort,our“beltshavebeentightened”andRERFstaffhaveworkedhardtoreduce
expenditures.Forexample,thereplacementofthe
fallen-down,dilapidatedgateatHijiyamaHall(seethebeforeandafterphotos)wastheworkof“Sunday
carpenters” Chairman Toshiteru Okubo and yours
truly(EBD).
WereceivedaniceletterfromMr.KenjiJoji.As
always,weappreciateyourfeedbackandanysuggestionsyoumighthaveastohowwecanimprovethereportingofRERF’simportantwork.SountilthenextissueofUpdate—Mataoidekudasai(goodbyeandpleasecomeagain)!

Hijiyama Hall gate before renovation (Winter 2009)

After renovation by “Sunday carpenters” (Autumn 2010)

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EvanB.Douple,Editor-in-Chief

YukoIkawa,TechnicalEditor

RERF Update Volume 21, Issue 2, 2010

2

Letter to the Editors, RERF News

Letter to the Editors
Itisalwaysapleasureandjoytoreceiveacopy
ofyourRERFUpdate.
Yourreportofthe52ndAnnualMeetingoftheJapanRadiationResearchSocietywhichwashosted
for the first time by Radiation Effects Research
Foundation in Hiroshima was read with renewed
interest.ThedevotedeffortofChairmanToshiteruOkubo who made this possible should be highly
commended.Thismeeting,nodoubt,hasservedto
bringaboutarenewedrecognitionofthelong-term
longitudinalstudiesconductedbyABCC-RERFin
HiroshimaandNagasakiontheradiationeffectson
humans.
Being a faithful subscriber of National GeographicandanadmireroftheirDVDsonthewonders
ofourworld,yournewsthataNationalGeographicTelevisionfilmcrewvisitedRERFinpreparationofadocumentaryfilmoftheA-bombingofHiroshima

andtheresearchactivitiesofRERFwasarealdelighttome.
Today’s Chugoku Shimbun presented a very
favorablereportoftheopenhouseprogramatHijiyamaRERFwhereevenonthefirstdaytherewereathousandvisitorstotheresearchfacilitiestolearnmoreabouttheradiationeffectsonhumans.
These to me are valuable avenues of favorable
publicity of RERF and of dissemination of its
researchactivitiesandresults.
Gratefullyyours,
KenjiJoji
Hiroshima,Japan
August6,2010,65thanniversaryoftheA-bomb

45th Meeting of RERF’s Board of Directors Convened in Nagasaki
Discussions Centered on Transition to a Juridical Person with
New Management System
The45thmeetingoftheBoardofDirectorswas
heldintheConferenceRoomatNagasakiRERFon
June21and22,2010.Atthemeeting,theparticipants
engagedinactivediscussionsonRERF’stransitiontoapublic-interestincorporatedfoundation,inaddition to such regular items as the activities report,
activityplans,settlementofaccounts,andworkingbudget.
OnbehalfoftheJapaneseandU.S.governments,
Mr.YasunoriWada,Director,A-bombSurvivorSupportOffice,GeneralAffairsDivision,HealthService
Bureau, Ministry of Health, Labour and Welfare
(MHLW),andDr.JosephF.Weiss,JapanProgram
Manager, Office of International Health Studies,
OfficeofHealth,SafetyandSecurity,U.S.DepartmentofEnergy(DOE),deliveredopeningremarks,
theyexpressedtheirintentionstocontinueprovidingsupporttoRERF,andwiththatthemeeting’sagenda
wasbegun.
Dr.Toshiteru Okubo, RERF Chairman, opened
withhisstatusreportforRERF,explainingtheScientificCouncil’sreviewthisyearofthefoundation’s
studyprogramwithafocusontheDepartmentof
Clinical Studies. He then referred to personnel
actionsamongresearchscientists,reportingthat,withthe recent hiring of two research scientists in theDepartment of Statistics, the current number of
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researchscientistsreached46,anincreaseofthreecomparedwiththenumberatthetimeoflastyear’sBoardofDirectorsmeeting.
As one of RERF’s ongoing research projects,
dosimetry,Dr.OkuboreportedthattheDosimetry
Committee,establishedinApril2009,hadcompleted
datasetcoordinateadjustmentworkandpreparationstostarttheworkofcorrectingtheU.S.Armymap
distortionwithuseoforthophotographsandreconfirmingcoordinatesofproximallyexposedsurvivors
throughtheuseofneighborhoodmapswithshielding
historyinformation.
RegardingtheresponsetotherecommendationsfromtheSeniorReviewPanelonFuturePlanningforRERF,Dr.OkuboreportedthatRERFwascontinuing discussions with the U.S. and Japanesegovernments concerning the foundation’s future
directionandtheHiroshimaLaboratory’srelocation.
Intermsofthestatusofpreparationsfortransitionto a public-interest incorporated foundation, Dr.Okuboreportedthefollowing:thatMHLWandthe
MinistryofForeignAffairshaveauthorizedestablishment of the Committee for Selection of First
Councilors; and that the Hiroshima Laboratory
hostedtheinitialmeetingoftheCommitteeforSelectionofFirstCouncilorsinMarch2010.
Dr.OkuboalsoexplainedthattheemployeetrainRERF Update Volume 21, Issue 2, 2010

3

RERF Newsingprogram,whichcontinuedfor18months,concluded on April 21. The Executive Committee
reviewedreportssubmittedbythreepolicy-review
groups,andbasedonthereports,establishedworkinggroupstoresolvetheissuesthathadbeenraised,
startingwiththemostpractical.
Following the status report, Dr. Roy E. Shore,Vice Chairman and Chief of Research, reportedthat RERF received 39 external grants totaling¥121,160,574, including the MHLW Scientific
Research Grants. He also reported that last year
RERFenteredintoanewresearchagreementwith
theU.S.NationalInstituteofAllergyandInfectious
Diseases(NIAID).
Regarding international collaboration and PR
activities,Mr.TakanobuTeramoto,PermanentDirector,reportedthatatotalof15RERFDirectorsand
staffmembersparticipatedinfiveinternationalcollaborativeactivities,includinganactivityrelatedtothe United Nations Scientific Committee on theEffects ofAtomic Radiation (UNSCEAR). RERF
accepted,forobservationandtraining,atotalof173
visitorsfromoverseas,includingthoseconnectedtotheHiroshimaInternationalCouncilforHealthCareoftheRadiation-exposed(HICARE)andtheNagasaki
AssociationforHibakushas’MedicalCare(NASHIM).
Relatedtotheitemsfordeliberationandaction,
theBoardofDirectorsapproved,aspresented,the
FY2009researchactivitiesreport,thesettlementofaccountsandauditreport,theFY2010researchactivityplansoftheF1clinicalstudy,dosimetryrevisions,
andacirculatorydiseasestudy,aswellastheFY2010
workingbudget.
InresponsetotheSeniorReviewPanel’srecommendations, comprehensive explanations wereprovidedregardingsuchaspectsofRERFoperationsasresearchthemes,five-yearresearchplans,project
prioritization,andprogressinexpansionofinternational collaborative research, with the Directors
expressing many valuable comments about these
explanations.
Onthesecondday,priortoproceedingwiththe
meeting,Dr.PatriciaR.Worthington,Director,OfficeofHealthandSafety,OfficeofHealth,Safetyand
Security, U.S. DOE, who arrived in Nagasaki thepreviousnight,deliveredanaddressstatingthatthe
U.S.andJapanesegovernmentswouldcontinueto
join forces in supporting the RERF project.After
that,Mr.MarkS.Dieker,ConsulforPoliticaland
EconomicAffairs,U.S.ConsulateinFukuoka,who
traveledtoNagasakifromFukuoka,statedthattheoccasionrepresentedhisfirstparticipationinaBoardofDirectorsmeetingandthathewantedtolearnas
much as possible about the foundation’s research
activities.
In terms of status change to a public-interest
incorporatedfoundation(PIIF),themostsignificantissueforRERFsincelastyear,theBoardofDirectors
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lastyearapprovedatwo-stageapproach,asfollows:
anapplicationforchangestotheActofEndowment
would be submitted to the competent government
agencies,andthenanapplicationforPIIFauthorization would be submitted to the Cabinet Office in
Japan.Thisyear,therewasdiscussiononthechanges
totheActofEndowment,whichconstitutethefirst
stageofthetransitionprocess.BasedonthediscussionatthelatestBoardofDirectorsmeeting,several
modifications were made and, as soon as relevant
preparationsarecompleted,anapplicationforauthorizationasajuridicalpersonwithanewmanagementsystem(specialincorporatedCivilLawActfoundationwithcouncilors)willbesubmittedtothecompetent government agencies based on a Board of
Directorsmailballot.
Inaddition,therewasacommentrequestingplanning of an effective approach for recruitment of
young talented researchers in connection with theongoingpolicyofreducingpersonnelnumber.Itwas
alsoreportedthatinternalregulationswereprepared
regardingappointmentofpostdoctoralscientists,and
that one research scientist was hired based on thefundingreceivedfromNIAID.
Lastly, the Board discussed appointments
involving two Scientific Councilors, whose terms
concluded at the end of June.As a result of such
discussions,theappointmentofDr.KazuoTajima,
Director,AichiCancerCenterResearchInstitute,to
replaceScientificCouncilorYoshiharuYonekurawas
approved. In the case of Scientific Councilor
MarianneBerwick,however,sincehersuccessor’s
recommendationhadnotbeenforthcoming,itwas
approved in accordance with regulations that Dr.Berwickwouldcontinuetoserveinherpositionuntil
hersuccessor’sappointment.
Thetwo-daymeetingwasconcludedwithadecisionthatthenextmeetingwouldbeheldinHiroshima
over the two days of June 21 (Tuesday) and 22
(Wednesday),2011,andthatthetwodayswouldbe
reserved for the Board of Councilors meeting, if
approval of the newArticles of Incorporation is
obtainedinApril2011.
List of Participants
Directors:
Dr. Toshiteru Okubo,Chairman
Dr. Roy E. Shore,Vice Chairman and Chief of
Research
Mr. Takanobu Teramoto,PermanentDirector
Mr. Masaaki Kuniyasu, Former Ambassador
ExtraordinaryandPlenipotentiarytotheRepublic
ofPortugal
Dr. Yasuhito Sasaki, Executive Director, Japan
RadioisotopeAssociation
Dr. Senjun Taira, President, Japan University of
HealthSciences
RERF Update Volume 21, Issue 2, 2010

4

RERF NewsMr. James W. Ziglar,FormerSergeantatArmsoftheUnitedStatesSenate
Dr. James D. Cox,ProfessorandHead,Divisionof
Radiation Oncology, The University of Texas
M.D.AndersonCancerCenter(Attendanceby
attorney)Dr. Shelley A. Hearne, Managing Director, Pew
Health Group, The Pew Charitable Trusts,
Washington,DC
Supervisors:
Mr. Takashi Kohno,CPA/licencedTaxAccountant,
HiroshimaGeneralLaw/AccountingOffice
Mr. David Williams, Senior FinancialAdvisor,
NationalAcademyofSciences
Co-chairman Scientific Council:
Dr. Takashi Yanagawa,Professor,TheBiostatistics
Center,KurumeUniversity
Representatives of Supporting Agencies:
Mr. Yasunori Wada, Director,A-bomb Survivor
SupportOffice,GeneralAffairsDivision,Health
ServiceBureau,MinistryofHealth,Labourand
Welfare(MHLW)
Dr. Kiwamu Nagoshi, Deputy Director,A-bombSurvivorSupportOffice,GeneralAffairsDivision,HealthServiceBureau,MHLW
Mr. Kazuhiro Kanayama,DeputyDirector,A-bombSurvivorSupportOffice,GeneralAffairsDivision,HealthServiceBureau,MHLW
Dr.Yukiko Shinya,GroupLeader,A-bombSurvivor
SupportOffice,GeneralAffairsDivision,Health
ServiceBureau,MHLW
Dr. Patricia R. Worthington, Director, Office of
HealthandSafety,OfficeofHealth,Safetyand
Security,U.S.DepartmentofEnergy(DOE)
Dr. Joseph F. Weiss,JapanProgramManager,OfficeofInternationalHealthStudies,OfficeofHealth,
SafetyandSecurity,DOE
Mr. Mark S. Dieker,ConsulforPoliticalandEconomicAffairs,U.S.ConsulateFukuoka
Dr. Warren R. Muir,ExecutiveDirector,Division
on Earth and Life Studies, National ResearchCouncil(NRC),NationalAcademyofSciences
(NAS)
Dr. Kevin D. Crowley,Director,NuclearandRadiationStudiesBoard,DivisiononEarthandLife
Studies,NRC,NAS
RERF:
Mr. Eiji Akimoto,ChiefofSecretariat
Dr. Evan B. Douple,AssociateChiefofResearch
Dr. Nori Nakamura,ChiefScientist
Dr. Kazunori Kodama,ChiefScientist
Mr. Douglas C. Solvie,Associate Chief of Secretariat

Participants of the 45th Board of Directors meeting (in front of lunch venue in Nagasaki)

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RERF Update Volume 21, Issue 2, 2010

5

RERF NewsRERF Held Its First Public Lecture for Citizens
On November 17 (Wednesday), RERF held its
firstPublicLectureforCitizensattheInternationalConferenceCenterHiroshimalocatedinthePeace
MemorialParkfrom18:00to20:00.Theobjectives
ofthelectureweretoexplaintothegeneralpublic,
includingA-bomb survivors, RERF’s long-term
researchfindingsonhealtheffectsfromatomic-bomb
radiation in a straightforward manner, as well as
provideanopportunityforthepublictocommunicatewithRERF.About230citizensfilledtheauditoriumandparticipatedinthelecture.
FollowingopeningremarksbyRERFChairman
ToshiteruOkubo,thepubliclecturecomprisedtwo
talks.Thefirst,titled“RadiationandCancerRisk,”
wasgivenbyDr.KazunoriKodama,ChiefScientist,
whoexplainedonthebasisofresultsfromlong-term
healtheffectsresearchthedegreeofincreasedrisk
of cancer including leukemia caused by radiation
exposure.Healsoreportedthatabouthalfofleukemia cases and roughly 10% of solid cancer cases
amongA-bombsurvivorswereattributabletoradia-tion according to results from RERF’s Life SpanStudy.Thesecondtalk,titled“StudiesonChildren
ofA-bomb Survivors Conducted Thus Far,” was
givenbyDr.NoriNakamura,ChiefScientist,who
introducedresultsfromstudiesofbirthabnormalities, sexratio,chromosomeaberrations,mortality,
andcancerincidenceamongthechildrenofA-bomb
survivors. He explained that genetic effects from
parentalexposuretoradiationhavenotbeenobserved
thusfar.
Thosetwotalkswerefollowedbyaquestion-andanswersession,duringwhichanumberofinquiries
were made by the audience including anA-bomb
survivor regarding associations between radiation
and disease. The lecture concluded with closing
remarksbyViceChairmanandChiefofResearchRoy E. Shore, and several audience members
remainedeagerlyaskingquestions,whichindicated
thatcitizenshaveahighinterestinRERF’sresearchfindings.

IAEA Director General Yukiya Amano Visits RERF
InthemorningofAugust6,Mr.YukiyaAmano,DirectorGeneraloftheInternationalAtomicEnergy
Agency(IAEA),paidavisittoRERF’sHiroshima
Laboratory.ArrivingattheRERFfrontentrance,Mr.
AmanowaswelcomedbyChairmanToshiteruOkubo
andViceChairmanandChiefofResearchRoyE.
Shore.SinceRERF’sOpenHouseeventwasongoing,Mr.Amanowasfirstguidedtotheevent’sdisplay
panelsandwasprovidedwithexplanationsaboutthe
historyofABCC-RERFandthefoundation’sactivities, including contributions the organization has
madetoIAEAaspartofitsinternationalcollaborativeactivities.Mr.Amanotouredtheresearchdepartments,andthenintheChairman’sOffice,Dr.Shore
providedhimanexplanationaboutthefoundation’s
recentresearchachievements.Mr.Amanoexpressed
appreciationforRERF’sscientificcontributionsto
IAEA’s development of protection standards for
nuclearpowerworkers.
Intheafternoonofthesameday,atHiroshima
RedCrossHospitalandA-bombSurvivorsHospital(whosedirectorisDr.HirooDohy,Chairmanofthe
HiroshimaInternationalCouncilforHealthCareofthe Radiation-exposed [HICARE]), IAEA and
HICAREexchangedamemorandumofunderstand-

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ingforcollaborativeactivitiesintheareaofmedicalcareofthoseexposedtoradiation,withtheaimofutilizing the expertise and experience regardingA-bomb survivor medical care accumulated in
Hiroshima for support of the radiation exposed
worldwide.Thejointactivitiesaretoincludepersonnel training, collaborative research, educational
activities,andinformationexchange,withtheexpectationthatRERFwillcontributetotheproject.

IAEA Director General Yukiya Amano (second from right)
touring RERF with guidance from Chairman Toshiteru
Okubo (right)

RERF Update Volume 21, Issue 2, 2010

6

RERF News

Public Affairs Officer at the U.S. Consulate General
Osaka-Kobe Visits RERF
OnOctober1,2010,Mr.GregoryW.Kay,PublicAffairsOfficer,andMr.KeizoSanukiandMs.Mari
Matsumura,fromthePublicAffairsSectionatthe
U.S.ConsulateGeneralOsaka-Kobe,visitedRERF
inHiroshima.Duringthevisit,Mr.Kayaskedseveralquestions while listening intently to explanations
about RERF’s history, overview, and research
activitiesprovidedbyPermanentDirectorTakanobu
Teramoto,Associate Chief of Secretariat Douglas
Solvie,andChiefofStatisticsHarryCullings.Mr.
Kayandthetwomembersofhisstaffwerethentaken
onatourofRERF’sfacilities.
Mr. Gregory W. Kay, Public Affairs Officer at the U.S. Consulate
General Osaka-Kobe (center), touring RERF with guidancefrom Chief of Statistics Department Harry Cullings (right)

Staff NewsWearepleasedtoreportthatTomonori Hayashi,ChiefoftheImmunologyLaboratoryintheDepartment of Radiobiology/Molecular Epidemiology
(RME)since2005,hasbeenpromotedtoAssistantDepartment Chief of RME as of 1 July 2010. Dr.HayashihasbeenaresearchscientistatRERFsince
1990,hasbeenrecentlyleadingresearchonimmunogenomics,andisaprincipalinvestigatorontwo
projectsintheRERFradiationimmunosenescencestudy supported by the U.S. National Institute ofAllergyandInfectiousDiseases.
WearealsopleasedtoreportthatTruong-Minh
Phamwasappointedasthefirstrecipientofanew
postdoctoral scientist fellowship program recently
initiatedandadvertisedbyRERF.WehaveaskedDr.
Phamtowriteabriefintroductionabouthimself.
Truong-Minh Pham, MD, PhD
Ispentmychildhoodina
smallvillageinthecountrysideinVietnam.Myearliest
memoriesareofthesmellofthesoilofthericefields.Inthe harvest season, I followed farmers reaping riceinthefieldandusedagrapefruitasasoccerball.Iplayedwith other boys on the rice Truong-Minh Pham,fields.Itwasapeacefuland Postdoctoral Scientist

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enjoyabletimeofmylife.
WhenIwashighschoolstudent,Ididnotwantto be a doctor like my parents had hoped. I first
thoughtaboutenteringanaturalsciencestudyprogram. But finally I entered a medical college and
receivedanMD.Afterwards,Ispentyearstrainingto become an ear-nose-throat specialist, includingonetrainingyearinaclinicalresidencyintheDepartment of Otorhinolaryngology, at the University
Hospital,LilleCity,France.Ithenservedthreeyears
asaclinicianandlecturerinThaiNguyenMedical
CollegefromwhereIhadreceivedmyMD.
MylifecertainlychangedwhenIcametoJapan
tolearnepidemiology.IstartedepidemiologicalworkbybeinginvolvedintheJapanCollaborativeCohortStudy.AfterfinishingmydoctoratefromtheUniversity of Occupational and Environmental Health, Iwas awarded a postdoctoral fellowship from theJapanSocietyforthePromotionofSciencetocontinuemyresearchworkinepidemiology.
RERFhastraditionallyagoodreputationinstatisticsandepidemiology.Thus,Iamverygratefulandfortunatetobeacceptedasapostdoctoralscientistintheinstitute.Itisaspecialopportunitytomeet
RERFstaff,andtolearnmanyresearchideasfrom
them.IjustmovedintotheRERFDepartmentof
EpidemiologyatthebeginningofSeptember,2010.
I hope that I can contribute significantly to theresearchworkoftheinstitute.

RERF Update Volume 21, Issue 2, 2010

7

RERF News

Visiting Scientsts
RERFwasveryfortunatetohaveseveralABCC
andRERFformeremployeesandconsultantsvisitforvarioustimesduringthepastsixmonthsinorder
to provide consultation and to engage in somecollaborationswithRERFscientists.ThosevisitingscientistsincludedformeremployeesDr.William
Schull (President, The Schull Institute), Dr. Dale
Preston (Chief Scientist, HiroSoft InternationalCorporation),Dr.Donald Pierce(ProfessorEmeritus,
OregonUniversity),andDr.Robert Delongchamp(ProfessorofEpidemiology,UniversityofArkansas
forMedicalSciences),andcurrentmemberofthe
partnership between RERF and the University ofWashingtonDr.C. Y. Wang(FullMember,Program
inBiostatisticsandBiomathematics,FredHutchinson
CancerResearchCenter).

Visiting Student ResearchersWe are from Latvia. It is the one of the Baltic
States(Estonia,Latvia,andLithuania)andislocatedin Northeastern Europe on the east coast of theBalticSea.Wehadthewonderfulopportunitytovisit
RERF,tobecomeacquaintedwiththemethodsofradiationresearchusedhere,andtoacquirenewskills
inthisareaofresearch.ThenewknowledgewillhelpusinourdailyworkwiththeChernobylclean-up
workers. We spent two months (30/09/2010–04/12/2010)intheRERFDepartmentofRadiobiology/MolecularEpidemiology.
Inese Martinsone
AftergraduatingfromtheUniversityofLatviawithaMScinchemistryIstartedworkinginRigaStradins
University (RSU) (previous MedicalAcademy of
Latvia) in 1997 as a researcher in the Institute of
OccupationalandEnvironmentalHealth’sLaboratory
of Hygiene and Occupational Diseases. My work
dutiesfocusedonanalyzingdifferentchemicalsubstancesinhumantissues(i.e.,changesinmetallevels
inChernobylclean-upworkers’bloodandhairsamples)andwork-placeairsamples.Iwasinvolvedininterestingresearchrelatedtomychemicalbackgroundand I added knowledge in biochemistry, hygiene,
occupational medicine, and toxicology. In this year(2010) I wrote my PhD thesis in my speciality of
occupationalandenvironmentalmedicine.Researchisonepartofmyduties;theotherpartiseducational
work.IamworkingasalecturerinRSUandteachpublichealthstudentsandpostgraduatestudents.
Jolanta CiruleIamworkingasanoccupationalphysicianinan
out-patientdepartmentoftheCenterofOccupationaland Radiological Medicine of P. Stradins Clinical
UniversityHospitalinRigaandasalecturerinRiga
StradinsUniversity.TheCenterofOccupationaland

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Radiological Medicine conducts follow-up of theChernobylclean-upworkersofLatviaandcollects
thedataabouttheChernobylclean-upworkersinthe
LatvianStateRegisterforpersonswhohavereceived
ionizing radiation exposure in Chernobyl and for
patientswithoccupationaldiseases.
We both want to express our gratitude to theHiroshimaInternationalCouncilforHealthCareoftheRadiation-exposed(HICARE)andRERFforthe
opportunity to take a part in the RERF TrainingProgram,toallstaffofRERFforacceptingandhostingus,andtothestaffoftheDepartmentofRadiobiology/MolecularEpidemiologyfortheircollegial
collaboration,especiallytoDr.TomonoriHayashi,
whowasourteacherandsupervisor.

Dr. Jolanta Cirule (front) and Dr. Inese Martinsone

RERF Update Volume 21, Issue 2, 2010

8

RERF NewsAwards Received by RERF Scientists
Upon Receiving the New Investigator Award
Munechika Misumi, Research Scientist
Department of Statistics

IrecentlyreceivedtheNewInvestigatorAwardat
theAmericanStatisticalAssociation(ASA)ConferenceonRadiationandHealth,heldonJune13–16,
2010,inAnnapolis,Maryland.Imadeapresentation
titled“RadiationRiskofSkinCanceramongMembersoftheRERFLifeSpanStudy(LSS)CohortofAtomicBombSurvivors,”speakingmainlyaboutthe
statistical analysis collaboratively conducted
betweentheRERFDepartmentofEpidemiologyand
theU.S.NationalCancerInstitute(NCI).
Ihadheardthatmanyexpertsinradiationepidemiologythroughouttheworldwouldparticipateinthe conference, and I was therefore expecting to
discussstatisticalaspectsofradiationriskanalysis
withthem,especiallybecausetheeventwassponsoredbytheASA.However,theconferenceturned
outtoincludescientistsfromawidevarietyofdisciplinesengagedinradiationresearch.Inadditionto
radiationepidemiologists,therewereradiobiologistsandbiostatisticiansfromtheNCIandotherradiationresearchorganizationsintheU.S.,Germany,England,
andothercountries,techniciansfromradiotherapy
devicemanufacturers,andphysicians.Agreatvarietyof sessions were held including such themes as
medicalradiationeffectsoncancerandnon-cancerdiseases,radiationexposureamongmedicalradiation
workers, the latest technologies in radiotherapy
devices, low-dose radiation exposure, and genetic
susceptibilitytoradiation.
Since it has been reported that radiation dose
response for skin cancer in the LSS cohort has athreshold,manyscientistsaskedmeaboutthistopic.
ScientistsfromAmericaandEuropeweresurprisedtofindouthowsmallthenumberofcasesofskin
cancerisintheRERFstudycohorts,andhowrela-

Dr. Dale Preston (left) and Munechika Misumi in front of his
presentation poster
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tivelyrarethediseaseisintheJapanesepopulation.
IfeltgreatprideinbeingamemberofRERFwhenIrealizedthateveryoneknewaboutRERFwhenI
introducedmyself,whenDr.HarryCullingsandDr.
DalePrestonspokeaboutRERFanditsresearchat
thewrap-upsessionandthereceptionparty,respectively, and when it became apparent how widely
RERFisacknowledgedthroughouttheworldasthecenterofradiationhealthresearch.
Inconclusion,thiswasthefirstprojectforwhichIhaveactuallyanalyzeddataatRERFsinceIstepped
into the field of radiation health effects two years
ago. In dealing with unique statistical models ofradiationriskanalysisforthefirsttime,Ireceivedmuch advice from Dr. Hiromi Sugiyama, Dr.FumiyoshiKasagi,andothersfromtheDepartment
ofEpidemiology,myseniorsattheDepartmentof
StatisticsincludingDr.Preston,Dr.KyojiFurukawaandDr.JohnCologne,andfromDr.RoyShore,as
wellasfromDr.KiyohikoMabuchiandDr.ElaineRonattheNCI.Iwasabletomanagethepresentation
thankstosuchindividuals.WhatIdidforthestudy
isconductstatisticalanalysisanddiscussitsinterpretationswithotherresearchers,butIhavecometo
realizethatsomanypeopleareinvolvedinastudy,
includingthepathologistswhocollectdata.SinceIjusthappenedtobeanewcomertotheassociation
thatorganizestheASAbiennialmeetingsandwas
thuseligiblefortheNewInvestigatorAward,Iwas
originallyreluctanttoemphasizethefactthatIwon
the award. However, I decided to contribute thisarticletoexpressmygratitudetoeveryonewhohas
guidedmeandassistedmeinthisstudy.Iwouldliketoconcludebyrequestingeveryone’scontinuedsupportandguidance.

Upon Receiving the Poster Award by theInternational Association of Cancer Registries
Midori Soda, Assistant Chief
Department of Epidemiology, NagasakiWith the main theme of “Society and Cancer
Registration:TowardsHarmonization,”athree-day
meetingoftheInternationalAssociationofCancer
Registries(IACR)washeldOctober12–15,2010,
inYokohama,KanagawaPrefecture.Thismarkedthe
32ndsuchscientificmeeting,whichisheldannuallyindifferentcountriesonfivecontinentsinrotation.
Itwasdecidedatthe2007meetinginSloveniathatthe venue for the 2010 meeting would be Japan.
Subsequently,anorganizingcommitteewasestablishedundertheleadershipofDr.TomotakaSobue,
from Japan’s National Cancer Center, and I was
RERF Update Volume 21, Issue 2, 2010

RERF News
engagedinpreparationsforthemeetingasacommitteemember.
Even though I was concerned that participants
fromabroadwouldhesitatetoattendthemeetingdueto the recent appreciation of the yen, the meetinggatheredmorethan250peopleandwasconcluded
successfully.Thisyear’smeetingwasattendedbyanunusuallylargenumberofparticipantsfromAsiancountries,inadditiontomanyfromthecontinents
ofEurope,Africa,andAmerica.
Oneofthefeaturesofsuchmeetingsisthepresentationofposterawards.Almosteveryyear,Dr.
HansStormfromDenmarkservesaspresenterand
introducesawardeesinalightandhumorousmanner,makingmelaugheventhoughIamnotverygoodat
English.Sinceattendingthe1998meetinginAtlanta
forthefirsttime,Ihavebeencaptivatedbyhispresentations.Therefore, I have prepared posters and
attendedthemeetingeverysingleyearinthehopes
ofreceivingtheposterawardjustonce.
PosterspreparedbyJapaneseresearchersinthepastwerelampoonedaspatchwork.SincealargescaleprinterwasintroducedatRERFsixtoseven
yearsago,however,followedbyassignmenttothe
EpidemiologyDepartmentinNagasakiofMr.Mikio
Soejima,whowouldputprofessionalgraphicdesignerstoshame,ourpostershavebeenimprovedvisually. I then worked on the poster content. From
amongatotalof147posterssubmittedtotheassociationforthisyear’smeeting,myposter,thepreparationofwhichMr.Soejimadevotedhimselftoonmybehalf,wasremarkableevenfromanobjectivestandpoint.Evenso,Ineverdreamedofreceivingtheposteraward,becausetheselectioncommittee,
comprisedofatleast10members,wastoevaluate

Midori Soda (right) with Dr. Adriano Laudico of Philippines
in front of her presentation poster
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9eachoftheposterpresentationsonthebasisofsix
pointsforcontentandfourpointsforvisualpresentation.
Atthecloseofthemeetingonthethirdday,Dr.
Storm was announcing awardees.When he called
outthename“MidoriSoda,”Icouldnotimmediately
believethatIhadreceivedtheaward.IfeltuncomfortableatfirstbecauseaJapaneseresearcherhad
beengrantedtheposterawardatthemeetingheldinJapan.When Dr. Brenda Edwards (U.S. National
CancerInstitute;NCI),PresidentofIACR’sExecutive Board, presented a certificate of merit to me,however, I felt genuinely delighted. This was my
11thattempt.Thetitleofmyaward-winningposterwas “Decreased mortality from prostate cancer
observedinSaseboCity,NagasakiPrefecture,with
introductionofPSAscreening.”

Upon Receiving the Shichijo Prize from theJapan Thyroid Association
Misa Imaizumi, Chief, Division of Radiology
Department of Clinical Studies, Nagasaki

OnNovember12,2010,Iwasawardedthe39th
Shichijo Prize at the 53rdAnnual Meeting of theJapan ThyroidAssociation. This prize was established to encourage young scientists to actively
pursuetheirresearchandisawardedtoaresearcher
oflessthan45yearsofagewhohaspublishedtop
papers concerning thyroid disease over the years.
I am both pleased and humbled to win such aprestigiousprize,whichhadalsobeenawardedto
Dr.ShigenobuNagataki,formerRERFchairman(5th
recipient,1976).
I have studied thyroid disease since I was agraduate student at Nagasaki University. I was
engagedinbasicresearchusinganimalmodelsasa
postgraduateresearcheratNagasakiUniversityand
duringmyoverseasstudyintheUnitedStatesatMt.
Sinai School of Medicine. Thereafter, I had theopportunitytoconductresearchinthefieldofclinicalepidemiologyatRERF.Mymainareaofinterest
isthyroiddiseaseinA-bombsurvivors.Iampursuing my research thanks to the cooperation of theAdultHealthStudy(AHS)participantsandwiththeassistanceofmanypeople,includingmembersofthe
DepartmentsofClinicalStudiesinHiroshimaand
Nagasaki,aswellastheDepartmentsofStatistics,
Epidemiology, and Information Technology. Our
studies during 2000–2003 showed that effects of
A-bombradiationarestillobservedintheformof
malignant and benign thyroid nodules inA-bomb
survivorsalivemorethan50yearsafterthebombings.Wealsoshowedthattheriskofischemicheart
diseasemayincreaseintheAHSparticipantsdiagnosedashavingsubclinical(minor)hypothyroidism.
RERF Update Volume 21, Issue 2, 2010

10

RERF NewsApaperreportingthosefindingsrecentlyprovided
mewiththeopportunitytoparticipateinacollaborative study of 11 cohorts comprising a total of
55,000subjectsthroughouttheworld.Thecollaborativestudydemonstratedincreasedincidenceand
mortality rates of cardiovascular disease amongpatientswithsubclinicalhypothyroidism(Rodondi
N,…ImaizumiM,et al.Subclinicalhypothyroidism
andtheriskofcoronaryheartdiseaseandmortality.
JAMA2010;304[12]:1365–74).
Iwouldliketoexpressmysincereappreciation
tothemanypeoplewhosesupportenabledmetobe
awardedtheprize.Iwillcontinuetoworkhardwithafocusonthyroiddisease.Yourkindguidancewould
bemuchappreciated.

Misa Imaizumi with her award

Employee Training on Ethics and Protection of Study
Participants in Medical Research
Takanobu Teramoto, Permanent DirectorIt is probably common knowledge among
researchersthatanethicalreviewisrequiredbefore
initiationofmedicalresearch.Thiscannotbeunderestimated,sinceanyscientificprojectinvolvingthe
study of humans may not start without an ethics
committee’sapproval.Ontheotherhand,wemightnothavehadtheopportunitytothinkdeeplyofthisissue’shistoricalandphilosophicalbackground.In
addition,eventhoughsomeadministrativeandtechnicalstaffmembersdailymeetstudyparticipantsorhandletheirclinicalorotherepidemiologicaldata,orbloodandotherbiospecimens,theymayhavehad
littleopportunitytobedirectlyinvolvedinethical
reviewofresearch.Irecentlyservedaslecturerfor
theemployeetrainingonethicalissuesinvolvedin
medicalresearch—possiblythefirstofsuchtrainingatRERF.
TheideaofhavingthistrainingwasbornwhentheU.S.DepartmentofEnergy(DOE)Panel,consistingofsixhighly-qualifiedexpertsfromtheU.S.and
Japan,reviewedthestatusofhumansubjectprotection at RERF in June 2009.Although the Review
Panel concluded that “RERF demonstrates an
extremely high level of commitment to protectingtherightsandwelfareofitsuniqueresearchparticipantpopulation,”italsopointedoutafewitemsfor
improvement,inparticularemployeetraining.
First,itwasnecessarytofindtrainingmaterials.
SinceRERF’sresearchprogramisregulatedbythe
U.S. and Japanese laws/guidelines, it means thatthe training needs to satisfy both the U.S. and
Japanese requirements. For this reason, I beganReturn to Table of Contents

collecting, studying, and
editing work of relevantmaterialsobtainedinboththe U.S. and Japan. Fortunately, Ms. Elizabeth
White of DOE encouragedmetoparticipateina national convention of
thoseinvolvedinmedical
researchethicsintheU.S.
Takanobu Teramoto,inNovember2009,andIPermanent Director
took the opportunity to
attendandtocollectU.S.materials.Usingasaguidethe DOE’s Human Subjects Protection ResourceBook,Idecidedonthetrainingoutline,whichconsistedofthefollowingfivetopics:1)Introduction,2) History, 3) Philosophy, 4) Regulation, and
5)RERF’spolicyandprocedures.
ThenextstepwaspreparationofJapanesematerials.Thankstoanonlinesearch,Ifound“RecNet
Fukuoka,”whichpostedexcellentreferencematerialsonline.Thiswebsitewaswritteninaclearstyle,andincludeddetailedexplanationsaboutsomeofthefivetrainingitemsmentionedabove.Italsoincluded
substantial overseas materials translated into
Japaneseinanexcellentway.ThewebsitewasreportedlydevelopedbyprofessorsatKyushuUniversity
with support of a Ministry of Health, Labour and
Welfare(MHLW)researchgrant.
ThefirsttrainingsessionsinJapanesewereheld
inNagasakionMarch23,trainingtimewasoneand
ahalfhours,andinHiroshimaonApril20and23.
RERF Update Volume 21, Issue 2, 2010

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Conference and Workshop Reports
AlectureinEnglishwasgiveninHiroshimaonJuly
9.There was quite a large turnout for each of thethreetrainingsessions,andalmostallemployees—
bothfulltimeandtemporarystaff—haveparticipatedinoneofthesessions.Thevideo-recordedlectureshavebeenmadeavailableforviewingontheRERF’sinternalwebsiteforemployeeswhocouldnotattendthelectures.Ihopethat,fortheircontinuedstudy,
employees will use the training material and thereferencesourcesonresearchethicsavailableonthe
RERFinternalwebsitethatwasalsodevelopedon
thisoccasion.
For each session, I conducted a questionnaire
surveyamongthetrainingparticipantsandmanyofthemresponded.Thequestionnaireconsistedofthefollowing simple questions: 1)What did you find
difficulttounderstand?;2)Whatdidyoufindinstructive?;3)Whatdidyoufindnotinstructive?;4)What
wouldyoulikefuturesessionstoinclude?;and5)
Anyothercomments?Thefree-entryquestionnaireon an anonymous basis served to provide frank
opinionsfrommanyparticipantsandIusedthemto
improvethenextsession.
Inaddition,tomakethebestuseofthefeedback

providedinthequestionnairesurveysforthenext
year’s training, I plan to divide the training into
coursesunderspecificthemeslikeethicalreviewof
researchprotocols,informedconsent,andprotection
ofpersonalinformation,sothatemployeeswillbe
abletoparticipateinoneormorecoursesdependingon their individual needs.Also, many employeeshaverequestedthatspecificexamplesbeshownin
thetrainingsession.Ithereforewouldliketodesign
futuretrainingcourseswithsomecasestudiesunder
specificthemestobediscussedbythelecturersand
trainees.
Iwouldliketotakethisopportunitytoexpress
my sincere thanks to all RERF employees who
participatedinthetraining,andallmycolleagues,
whohelpedprepareforthetraining.AndIwouldliketo express my deepest gratitude to Dr. David
Thomassen,Ms.White,Dr.PeterKirchnerandother
officialsinDOE,whogavemeguidancetoconductthetrainingandtheopportunitytoattendworkshops
onthesubjectofethicalresearchintheU.S.Iam
alsogratefultomyNationalAcademyofSciencescolleagues, whose long-time support of research
ethicsiscriticaltoRERF’ssuccess.

First Meeting of the Scientific and Ethics Committee for theClinical Study of the F1 Offspring of A-bomb Survivors
Saeko Fujiwara, Chief
Department of Clinical Studies, Hiroshima
The first meeting of the Scientific and Ethics
CommitteefortheClinicalStudyoftheF1OffspringofA-bombSurvivorswasheldintheAuditoriumat
HiroshimaRERFonJuly7,2010,duringwhichthecommitteediscussedtheproposedF1clinicalstudy
(longitudinalstudy).Asinthecaseoftheprevious
Health Effects Study of the Children ofA-bombSurvivors (cross-sectional study), which was conducted between 2000 and 2006, the committee
consistingofoutsidespecialistswasestablishedto
verify in advance the scientific and ethical appropriatenessofthestudyplanandensurethestudy’stransparency.Basedontheoriginalstudy,thelongitudinalF1clinicalstudyaimstoconductalongterm study on whether parentalA-bomb radiation
exposure affects development of disease in offspring.Thestudywillconducthealthexaminations,
inwhichabout12,000A-bombsurvivors’childrenaretoparticipateeveryfouryears.
In the original cross-sectional study, 24,673
persons,primarilytheA-bombsurvivors’childrenin Hiroshima and Nagasaki, were contacted to
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requesttheirparticipationinthestudy,with11,951
actually participating. The study results wereannounced in March 2007 as the “Report on theHealth Effects Study of the Children ofA-bombSurvivors”bytheJointScientificandEthicsCommitteefortheHealthEffectsStudyoftheChildren
ofA-bomb Survivors. The report concluded that,
“Inanalysisofthedatafromthecurrentstudy,whenlifestyle diseases in children were combined, no
evidencesuggestingincreasedriskassociatedwith
parental radiation exposure was observed.”At thesametime,however,therewasaproposalfromthe
jointcommitteeregardingthenecessityofalongitudinal study. In addition, the RERF Scientific
Council and the Senior Review Panel on FuturePlanningforRERF,twoadvisorybodiesconsisting
ofU.S.andJapanesethird-partymembers,recommendedthattheF1clinicalstudybecontinued.TheRERF’sF1ClinicalStudyWorkingGroupthenhad
repeated discussions on planning a longitudinal
study,resultingintheholdingofthisfirstmeetingof the Scientific and Ethics Committee for theRERF Update Volume 21, Issue 2, 2010

12

Conference and Workshop Reports
ClinicalStudyoftheF1OffspringofA-bombSurvivors.
The agenda started with greetings from
CommitteeChairmanTadaoShimao.I,asChiefoftheDepartmentofClinicalStudies,thenpresented
the outline and results of the original F1 clinical
study,whichwasfollowedbySeniorScientistWaka
Ohishi’spresentationontheoutlineoftheproposed
longitudinal F 1  clinical study. Moderated by
Chairman Shimao, there was a lively Q andA
session on scientific aspects of the long-termfollow-upstudy,includingthestudy’ssignificance,
statistical power, hypothesis, subjects, schedule,health examination’s contents, diagnostic criteria,and storage of biological samples. Moderated by
Committee Vice Chairman Hiraku Takebe, thecommittee next discussed such ethical issues as
RERF’sapproachtoethics,contentsoftheinformed
consent form, and obtaining of informed consent
forpotentialepigenomeresearchinthefuture.The
committee ultimately approved initiation of thestudy, on the condition that the explanatory notes
in the informed consent form would be partiallyrevisedonthebasisofethicalconsiderations.The
study started in October, and we are receiving
substantial support from the Department ofInformation Technology, the Department of
Epidemiology, and others. With the additional F1
participants, the number of health examinationsconductedperyearisexpectedtoroughlydouble.

Members of the Scientific and Ethics Committee
for the Clinical Study of the F1 Offspring of
A-bomb Survivors
Tadao Shimao (Chairman),Consultant,JapanAntiTuberculosisAssociation
Hiraku Takebe (Vice Chairman), Fellow, Kinki
UniversityAtomicEnergyResearchInstitute
Hirotsugu Ueshima, Special Contract Professor,
Lifestyle-related Disease Prevention Center,ShigaUniversityofMedicalScience
Takashi Kawamoto,Professor,GraduateSchoolof
Education,TheUniversityofTokyo
Shinsuke Kimura,Attorney,KimuraShinsukeLaw
OfficeSteve Wing,Associate Professor, Department of
Epidemiology,SchoolofPublicHealth,UniversityofNorthCarolina
Kazuo Tajima, Director, Aichi Cancer Center
ResearchInstitute
Masao Tomonaga, Director, Japanese Red Cross
NagasakiAtomicBombHospital
Hiroo Dohy,Director,HiroshimaRedCrossHospitalandAtomic-bombSurvivorsHospital
Ohtsura Niwa,ProfessorEmeritus,KyotoUniversity
Taisei Nomura,ProfessorEmeritus,OsakaUniversity
Norihiko Hayakawa, Professor Emeritus, HiroshimaUniversity
Katsumi Furitsu,VisitingLecturer,HyogoCollege
ofMedicine
Eiji Maruyama,Professor,GraduateSchoolofLaw,
KobeUniversity

First Meeting of the Scientific and Ethics Committee for the Clinical Study of the F1
Offspring of A-bomb Survivors

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RERF Update Volume 21, Issue 2, 2010

13

Conference and Workshop Reports

Epidemiological Training Workshop for Biologists
Nori Nakamura, Chief Scientist
The training workshop, held at the Radiation
EffectsResearchFoundation(RERF)onSeptember
2–3,2010,turnedouttobealivelygathering,with
participationby32outsideresearchersandmorethan
20RERFresearchers.Theeventwasorganizedas
part of the activities of the Council of Radiation
Effects Research Organizations, consisting of
HiroshimaUniversity,KyotoUniversityRadiation
BiologyCenter,NagasakiUniversity,theNational
Institute of Radiological Sciences (NIRS), and
RERF,establishedtofacilitatemutualunderstandingandcollaborationamongradiationeffectsresearch
organizations.Theevent’sobjectivesweretoallow
biologists and epidemiologists an opportunity to
becomeacquaintedwitheachotherandengagein
conversation on their common theme of radiationrisk.
Startingat1p.m.onthefirstday,RERFChairman
Toshiteru Okubo gave opening remarks and theworkshop participants introduced themselves. Dr.KotaroOzasa,ChiefoftheDepartmentofEpidemiology at RERF, then delivered two lectures titled
“Methods of epidemiological study” and “A briefoutlineofthestudyresultsofatomic-bombsurvivors:riskofleukemia,solidcancers,andnon-cancerdiseases,” each followed by a question-and-answer
session. Subsequently, a reception was held at
RERF’sHijiyamaHall.ThisprovidedbiologistswithagoodopportunitytofeelclosertoRERFepidemiologists and statisticians with whom many of thebiologiststypicallyhavefewinteractions.
Ontheseconddayoftheworkshop,theepidemiologists,statisticians,andbiologistsparticipatedinadiscussionsession.Questionshadbeensolicited
from expected workshop participants beforehand,
andarespondentforeachquestionwasidentified,eitheronavoluntarybasisorbyrecruitment.The
trialarrangementturnedouttobeasuccess.Thefirst
pre-submittedquestionfromthebiologists,“Does
age-dependenceinbreastcancerriskamongA-bomb
survivorsexist?,”wasrespondedtobyDr.Yukiko
Shimizu(RERF)inanexplanationthatreferredto
twopapers—Landet al.’s2003paperreportingthe
presence of dependence of age at exposure and

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Prestonet al.’s2007paperreportingnosuchdependence—totheeffectthatthestudiesuseddifferent
observationperiodsandcaseascertainmentmethods,
andthusdifferentnumbersofcases,whichresulted
inapartialdiscrepancyintheconclusionstheydrew.
Asforthenextquestion,“Canusefulinformationbe
derivedfromcensoredanimalexperimentswithoutobserving animals throughout their lives?,” Dr.MichiakiKai(OitaUniversityofNursingandHealth
Sciences)offeredhiscommentary.Astothequestion
“Howshouldcompetingcausesofdeathbeassessedinanimalexperiments?,”Dr.KazutakaDoi(NIRS)
offeredanexplanationtitled“Survival-timeanalysis
andcompetingrisks.”Iwasremindedagainofhow
difficultcross-fieldcommunicationisandalsofelt
thatRERFbiologistsprobablyarenotfullytakingadvantage of their fortunate work environment,
whichallowsthemtoconsultwithstatisticiansanytimetheywant.Thefinalquestiontheme,“Radiobiological interpretation regarding site-specific
radiationrisk,shapeofdose-responserelationships,
andeffectsbyagingandageatthetimeofexposuretoradiation,”theultimatequeryposedbytheepidemiologists,wasaddressedbyDr.YoshiyaShimada(NIRS)andmyself.
Althoughtherewassomeroomforimprovement
intermsofoperationoftheevent,awidevarietyofpeople—from graduate students to retired scientists—participatedintheworkshop,andItherefore
believethatourinitialobjectiveswereachieved.Both
fieldsofradiationbiologyandradiationepidemiology have, to this point in time, addressed similar
themeswithouthavingmanyopportunitiestocommunicate with each other. The workshop made it
clearthatthegapbetweenthetwofieldsofresearchis wider than originally many thought. I felt that
RERFshouldtaketheinitiativeincreatingopportunitiestoenhance“cross-fieldcommunication”onan
ongoingbasis,notonlyoutsideRERF,butalsowithin
toensurethatresearchersindifferentfieldscancommunicateeffectively.
Inconclusion,Iwouldliketoexpressmydeepest
appreciationtoboththoseinsideandoutsideRERF
whohelpedorganizetheworkshop.

RERF Update Volume 21, Issue 2, 2010

14

Conference and Workshop Reports

RERF Studies and Results Highlighted in Presentations
at Two Annual Scientific Meetings
Evan B. Douple, Associate Chief of ResearchInanefforttoencouragemoreparticipationby
epidemiologists in the annual meetings of theRadiationResearchSocietyandtoincreasedialogue
betweenradiationbiologistsorotherradiationscientistsandepidemiologists,Dr.ShoreandIworked
withthemeetingorganizersofthe56th Meeting of
the Radiation ResearchSocietytoplanandrecruit
speakersfortwosymposiaforthemeetingheldin
Maui,Hawaii,September25–29.Thefirstsymposium,titled“StudiesofRadiationSusceptibilityto
Cancer:WhereDoWeStand?,”focusedongenotyping,statistical,phenotypic,andfunctionalassaysas
meanstodetermineradiationsusceptibilitytocancer.
The opening speaker was RERF’s Tomonori
Hayashiwhopresentedapaper“Molecularepidemiologyofradiationsusceptibilitytocanceramong
atomic-bomb survivors.” His presentation focusedon RERF’s progress in analyses of: 1) radiationeffects on immunological and somatic mutability
markers (phenotypic effects); 2) genetic polymorphismsresponsibleforinter-individualvariationofthebiomarkers(genotype-phenotypeassociations);
and3)riskestimationofcancersonthebasisofgene/radiationinteractions(genotypiceffects).Thesecond
symposium, titled “Risk from In Utero Radiation
Exposure” focused on recent epidemiology and
radiobiologystudiesfollowing in uteroexposureto
theA-bombsinJapan,the 131Iemissionsfromthe
Chernobyl accident, and to occupational sources.
Thefirstspeaker,RERF’sViceChairmanandChief
ofResearchRoy Shore,summarizedtheRERFfindingsinapapertitled“Arethoseexposedin uterothemostsensitivepopulation?—theJapaneseA-bomb
experience.”Thefourthandfinalspeaker,RERF’s
ChiefScientistNori Nakamura,describedresults
of RERF’s radiobiology studies in animals and
humansrelatedtoin uteroexposuresin“Fetusesare
notlittlechildren:Justasktheirhematopoieticstem
cells.”ASTRO is a society of approximately 10,000
NorthAmerican and international members composed of radiation oncologists, nurses, therapists,
medicalphysicists,andbiologists.The 52nd Meeting of ASTRO (American Society of Radiation

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Oncology)washeldin
SanDiego,California,
October31–November
4. Early in the year, amember of the meeting’sSteeringCommittee,formerRERFScientific Councilor, Dr.Theodore DeWeese(Johns Hopkins UniEvan B. Douple, AssociateversitySchoolofMedChief of Researchicine) encouraged Dr.Shoreandmetoplanapaneltopresentatthe2010
ASTROmeetingthatwouldhighlightthescientific
contributions ofABCC-RERF to the long-term
radiationeffectsissuesrelatedtoradiationexposures
inthetreatmentofcancerpatients.Suchapanelwas
organizedandwastitled:“HiroshimaandNagasaki
65YearsLater—LessonsLearnedbytheRadiation
EffectsResearchFoundationThatAreHelpingScience,Physicians,Patients,andtheA-bombSurvivors
Today.”Afteranintroductoryoverviewoftheformation, mission, and major cohorts and studies of
ABCC-RERF,Roy Shore discussedtheepidemiologicalassessmentofcancerrisksin“Whatlightdo
thecancerstudiesofA-bombsurvivorsshedonlate
effects from radiation therapy?” Chief ScientistKazunori Kodama followedwithareviewofnoncancerriskassessmentin“Whatandhowimportant
arethelatenon-cancerrisksfromradiationtherapy
(withspecialreferencetoheartdiseaserisksamongA-bombsurvivors)?”IconcludedthepanelwithareviewofthelaboratorysciencestudieswithemphasisontheworkintheDepartmentsofGeneticsand
Radiobiology/MolecularEpidemiologyin“Genetic
and molecular research contributions, challenges,and opportunities.”We were pleased to learn that
despiteseveralongoingparallelpanelsatthesametimeandalate-afternoontimeslot,severalhundred
meetingparticipantsfilledthelargelecturehalland
showed an interest in hearing the latest scientific
resultsfromRERF’sstudiesofahistoricanduniquecohort.CurrentVisitingDirectorDr.James Cox wasinthefrontrowlendinghissupport!

RERF Update Volume 21, Issue 2, 2010

15

Science Articles

Interaction Effects of Radiation and Smoking on
Lung Cancer Incidence in the Life Span Study*
KyojiFurukawa
DepartmentofStatistics,RadiationEffectsResearchFoundation*ThisarticleisbasedonthefollowingpublicationthatcanbereadinitsentiretyattheRERF
websitewww.rerf.jp:
FurukawaK,PrestonDL,LönnS,FunamotoS,YoneharaS,MatsuoT,EgawaH,TokuokaS,
OzasaK,KasagiF,KodamaK,MabuchiK.Radiationandsmokingeffectsonlungcancerincidenceamongatomicbombsurvivors.Radiat Res 174:72–82,2010.

Introduction
Lungcanceristhemostcommoncancerworldwide.1Whilelungcancerratesarelargelydeterminedby smoking patterns, medical, occupational, and
environmental radiation exposures have also been
shown to increase risks of lung cancer.2 There is
considerableinterest,frombiologicalandpractical
perspectives,inthejointeffectofradiationandsmokingonlungcancer.LungcanceristhesecondmostcommoncancerintheLifeSpanStudy(LSS)cohort,
andlungcancerincidenceratesintheLSShavebeen
knowntobestronglyassociatedwithradiation,with
anestimatedexcessrelativerisk(ERR)perGyof
0.81andexcessabsoluterisk(EAR)of7.5per10,000
person-yearGy.3Thoseestimatesdonottakeinto
accountapossiblemodifyingeffectofsmokingonthe radiation risk.While earlier analyses 4,5 of the
LSS data were unable to describe sufficiently thenature of the interaction between radiation and
smokingforlungcancerrisk,duemostlytolimited
numbersofcases,thelatestanalysisbyPierceet al.6
suggestedthattheinteractionwassub-multiplicativeandconsistentwithadditivity.
Thepresentstudywasbasedonlungcancerincidence data from a special pathology review thatprovideddiagnosticconfirmationoncasesdiagnosed
between1958and1999.Areassessmentofsmoking
historydataassembledfrommultiplesourcesprovidedenoughdetailedinformationneededtoconsider models in which the effect of cumulative
amountsmokedcouldbemodifiedbysmokingdurationandintensityandtoconsidervarioustypesofgeneralizedinteractionmodelsusedinmanyother
analysesofthejointeffectsofcarcinogenicagents.
Inthisstudy,wepresenttheresultsfromtheeffort
toevaluatealltypesoflungcancerasagroup.
Materials and Methods
Study population and case ascertainment
The LSS cohort includes 120,321 residents of
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HiroshimaandNagasakiwhowerebornpriortothe
atomicbombingsinAugust1945andwerestillalive
on October 1, 1950. For the present analyses, we
excludedcohortmemberswhocouldnotbetraced,
haddied,orwereknowntohavehadcancerpriorto
January 1, 1958 (8,396 subjects) or those with
radiation dose estimates not available (6,521 subjects),resultinginatotalof105,404eligiblesubjects.
Aspecialpathologyreviewprovideddiagnostic
confirmation for lung cancer cases. The primarysourcesusedtoidentifypotentialcasesforthepathologyreviewweretheHiroshimaandNagasakitumorandtissueregistries.Additionalsourcesincludedthe
RERF autopsy program and death certificate dataroutinely obtained for LSS follow-up.The review
consideredcasesdiagnosedthroughtheendof1999,
resultinginthefollowed-upagesrangingfromabout
12tomorethan100andtheagesatdiagnosisfrom27to104.Aninitialscreeningidentified5,711LSS
cohortmemberswhowerecodedashavingtumors
ofthelungorrelatedregions.Threestudypathologistsindependentlyreviewedthosecasesanddevelopedaconsensusdiagnosisforeachpotentialcase.
Thereviewswerebasedonallavailableinformation
includingtumortissueslidespathologyandclinical
records, and death certificates. Lung tumors werediagnosedusingthelatestWHOdiagnosticcriteria.7
Thereviewidentified2,446lungtumorsincluding2,368 cancers. Second primary or non-malignanttumors were excluded. The primary analyses
described herein considered 1,803 primary lung
cancercasesdiagnosedamong105,404cohortmembers,including40,980subjects(677cases)withno
informationonsmokingstatuspriortothediagnosis
date.
Radiation dose and smoking information
Radiation dose estimates to the lung from an
improveddosimetrysystem(DS02),8computedasthe sum of the gamma-ray dose and 10 times theRERF Update Volume 21, Issue 2, 2010

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Science Articles
neutron dose, were used for these analyses. Most
of the data on smoking habits of LSS cohort
members came from a series of mail surveys
conductedbetween1965and1991.Informationon
smokinghabitsincludedamountsmoked,duration
of smoking, and, for past-smokers, when he/she
stopped. Smoking history was summarized by
indicators of smoking status (never-smoker, pastsmoker,orcurrent-smoker)atthetimeofthelatest
information, age started smoking, age stopped
smoking,theaveragenumberofcigarettessmokedper day, and the year in which data on smoking
werefirstobtained.Valueswereimputedforthose
subjects as the gender and birth cohort-specific
mean values among smokers with complete
information. Smoking information was availablefor 62% of the eligible cohort members. Theamountsmokedwasimputedfor4%ofthosewho
indicatedthattheyhadeversmokedwhiletheage
at the start of smoking was imputed for 9.5% of
thisgroup.
Data organization for analysesTheriskanalyseswerebasedonincidencerates
computed from a table of person-years and lung
cancercasesstratifiedbyage,sex,city,smoking,and
radiation dose categories.The smoking categories
were time-dependent.All cohort members wereclassified as unknown smoking status prior to thedate at which they first provided information on
smokinghabitsinordertoavoidbiasingriskestimates by overcounting person-years in known
smoking-statuscategories.
AsinallrecentanalysesoftheLSScancerincidencedata,theanalyseswerelimitedtocasesdiagnosedamongresidentsofthetumor-registrycatchmentareas.Becauseindividualresidencehistorydata
were not available for all cohort members, city,
gender,age,andtime-dependentresidenceprobabilitiesestimatedfromtheAdultHealthStudy(AHS)
clinicalcontactdatawereusedtocomputemigrationadjustedperson-years.9
Statistical analysis
Smoking and radiation joint effects

These analyses focused on the joint effects ofradiationandsmokingintermsofrisksrelativeto
attained age (a), gender (g), and birth cohort (b)specific baseline rates for non-smokers with no
radiation exposure. That model can be written as
l0 (a, g, b) RR(C , D) whereRR isarelativeriskfunctionthatdependsonsmoking-relatedvariables(C)
andradiation-dose-relatedvariables(D).Thesmoking-related variables included years smoked (y),
cigarettessmokedperday(c),andyearssincelast
knownquitting(q)forpastsmokers,andotherfactorssuchasgenderandbirthcohort.Theradiationrelatedvariablesincludeddose(d)andeffectmodiReturn to Table of Contents

fiers such as age at exposure (e), gender, and
attainedage.
Thesimplestjointeffectsmodelistheadditive
ERRmodel:
RR(C , D) = 1 + φ (C ) + ρ ( D), [Additive]

wherefandρarefunctionsthatdescribetheERR’sfor smoking- and radiation-related variables,
respectively.Underthismodel,smokingandradiation have independent effects on the baseline rate
fornon-smokers.ThemostcommonlyusedalternativetotheadditiveERRmodelisthemultiplicative
ERRmodel:

RR(C , D) = [1 + φ (C )][1 + ρ ( D)]= 1 + φ (C ) + ρ ( D) + φ (C ) ρ ( D).
[Multiplicative]

With this model, a given radiation exposure (or a
givensmokinghistory)increasestheriskbythesame
proportion for any smoking history (or radiation
exposure).
Thesetwomodelsarespecialcasesofmoregeneralizedjointeffectmodels,whichwecallthegeneralized additiveandmultiplicativeERRinteraction
models:RR(C , D) = 1 + φ (C ) + ρ ( D)ω (C ),[Generalizedadditive]
RR(C , D) = [1 + φ (C )][1 + ρ ( D)ω (C )],[Generalizedmultiplicative]

whereωisafunctionofsmokingvariableswith
ω(C)= 1forlifelongnon-smokers.Inthesemodels,
theeffectofsmokingontheradiationdoseresponseisneitherindependentofdose(asinthesimpleadditivemodel)norconstrainedtobeproportionaltothemaineffectofsmoking,f (C)(asinthesimplemultiplicativemodel).
Additional models utilized in the statistical
analyses are described in the manuscript and
include a Baseline rate (zero-dose, non-smokers)model, a Smoking effect model,andaRadiation effectmodel.As in most recent work on risk modelingin the LSS,3,10 radiation main effects, ρ(d), weremodeledasaproductofadose-responseshapefunction, η (d), and an effect-modification function
ε (a, g, e) = δ g a β exp(γ e).
Poissonregressionmaximumlikelihoodmethods
wereusedforparameterestimation,hypothesistesting,andthecomputationofconfidenceintervals(CI)
forspecificparameters.ModelfittingwascarriedoutusingEpicure11andthegeneralizednon-linearmodel
package (gnm) in R.12 We also used theAkaike
InformationCriteria(AIC)13forcomparisonofnonnestedmodelsinvolvingdifferentnumbersofparameters.

RERF Update Volume 21, Issue 2, 2010

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Results
Dataonsmokingwereavailableforabout60%
ofmenand64%ofwomen.Roughly85%ofthemen
and18%ofthewomenwhoprovidedinformation
on smoking habits indicated that they had eversmoked.Theproportionofever-smokersamongmenwas similar over birth-cohort and radiation-dose
categories.Womenwhowereover20atthetimeofthe bombs were somewhat more likely to have
smokedthanyoungerwomen,andtheproportionof
ever-smokers increased slightly with decreasing
distance from the hypocenters (and, hence, with
increasingdose).Menreportedsmokingabouttwiceasmanycigarettesperday(mean19.6)aswomen(mean 10.6) and tended to start smoking younger(mean starting ages of 21 and 31.6, respectively).
About one-third of ever-smokers reported having
stoppedsmokingpriortothelastsurveytowhich

theyresponded.Bytheendoffollow-up,thosewho
reportedhavingstoppedhadsmokedforroughly20
yearslessthanthosewhodidnot.Incidencerates
werehigherforcurrentsmokersthanfornever-or
past-smokers.Cruderatesforagivensmokingcategory were about twice as high for men than for
womenandincreasedwithincreasingageatexposure(ordecreasingcalendaryearofbirth)aswellaswith
radiationdose.
Non-smoker baseline rates and smoking effects
SmokingeffectsweremodeledusingERRmodelsandexpressedrelativetogender-specificbaseline
ratesfornon-smokerswithallowanceforradiationeffects.Thenon-smokerbaselineratesformenand
womenincreasedmarkedlywithattainedage.There
was a statistically significant gender difference in
theattained-agetrend(P=0.05).Theincreasewas

Table 1. Parameter estimates for smoking effects (Panel A) and radiation effects (Panel B) and modifying effects with 95%(likelihood-based) confidence intervals
A. Smoking effect
EffectSimple additive

Generalized multiplicative

ERR per 50 pack-years (born in 1915)
5.32 (4.10,6.70)
3.48 (2.40,5.00)
7.16 (5.20,9.70)
2.15 (1.30,3.40)

Gender-average
Male
FemaleFemale:Male ratio

4.69 (3.65,5.94)
3.60 (2.60,5.10)
5.77 (4.10,7.90)
1.61 (1.00,2.50)

Birth-cohort effect (% change per decade decrease in birth year)% per decade decrease in birth year
0.38 (18%,61%)Log(duration/50)
Log(duration/50) squaredPower of years since quitting plus 1

0.33 (15%,54%)

Smoking-duration effect (log-linear)-0.30 (-1.26, 0.60)-2.58 (-5.30,-0.63)-0.24 (-1.20, 0.69)-2.51 (-5.20,-0.56)

Years since quitting effect-0.50 (-0.90,-0.29)-0.47 (-0.77,-0.27)

B. Radiation effect
EffectRadiation only

Simpleadditive

Simplemultiplicative

Generalized
additive

Generalized
multiplicative

Gender-averaged
Male
FemaleFemale:Male ratio

ERR per Gy (age 70, age-at-exposure 30, never-smoker)
0.98 (0.59,1.50)
0.68 (0.43,1.00)
0.65 (0.31,1.10)
0.83 (0.55,1.20)
0.34 (0.15,0.60)
0.69 (0.26,1.30)
0.31 (0.13,0.56)
0.30 (0.01,0.56)
1.31 (0.83,1.90)
1.27 (0.73,2.00)
1.06 (0.64,1.60)
1.00 (0.77,2.30)
3.82 (2.00,9.00)
1.85 (0.84,5.10)
3.44 (1.70,9.00)
3.38 (1.40,11.0)

0.59 (0.31,1.00)
0.29 (0.10,0.62)
0.90 (0.47,1.50)
3.13 (1.60,7.00)

Attained age-2.00 (-4.0,-0.03)

Attained-age effect (power)-2.70 (-4.7,-0.6)-2.50 (-4.5,-0.4)-3.05 (-5.2,-0.9)-2.78(-4.9,-0.7)

Age at exposure

Age-at-exposure effect (% change per decade increase)31% (-2%,77%)
26% (-5%,69%)
50% (9%,111%)
21% (-6%,55%)

30% (-3%,77%)

Smoking-intensity effect (effect modification)––
10.20 (4.6,17.0)––-15.30 (-30.0,5.4)

9.20 (3.8,15.0)-16.6 (-30.0,-6.6)

Packs per day
Packs per day squared
Deviance
Parameters
AIC

Return to Table of Contents

––9815.5149843.5Model and fit summary information
9428.79425.126
269480.79477.19415.728
9471.79410.3
28
9466.3

RERF Update Volume 21, Issue 2, 2010

Science Articles
well-described using a simpleArmitage-Doll-like
model in which the rates were proportional to
attained age to the power 5.6 (95% confidenceinterval [CI]: 5.2, 6.1) with age-specific rates for
womenbeing61%ofthoseformen(95%CI:48%,
80%).Age-specific rates exhibited a statistically
significant (P < 0.001) increase of 17% (95% CI:10%, 25%) per decade in year of birth. The final
baselineratemodelallowedamorerapidincreasein the risk at younger ages, which resulted in astatisticallysignificantimprovementinthefit(P<
0.001).
Table 1A presents smoking-effect parameters
estimatedusingthegeneralizedmultiplicativeand
simpleadditiveradiation-smokinginteractionmodels,togetherwithmodifyingeffectsofbirthyearand
smokingduration.Assumptionsaboutthenatureoftheinteractionhadlittleeffectonthesmokingrisk
estimates.Withthegeneralizedmultiplicativemodel,thegender-averagedERRassociatedwithsmoking20cigarettesperdayfor50years(i.e.,50pack-years)
foranunexposedindividualbornin1915wasestimatedtobe4.7(95%CI:3.6,5.9).Thiswasonly
slightlylowerthanthatof5.3basedontheadditivemodel.TheERRassociatedwithsmokingwasstatisticallysignificantlyhigherforwomenthanformen
(P=0.02),withthegenderdifferencebeinggreater
with the additive model estimates.Age-specific
ERRsforagivensmokinghistoryexhibitedastatisticallysignificantincrease(P<0.001)withdecreasing birth year without an indication of a gender

18
difference(P=0.4,datanotshown).
InourmodelingofthesmokingERR,thepackyeareffectwasallowedtovarydependingonsmokingduration(P=0.001).Whilethepack-yeareffectwashighlystatisticallysignificant,thenegativecoefficientsforthedurationeffectsimplythattheincreaseinratesisnotlinearinyearssmokedandthatthisdeparture from linearity becomes more marked at
longerdurations.Underthisduration-modifiedpackyearmodel,smokinghadlittleimpactonlungcancer
ratesforthefirst20yearsofsmoking,afterwhichthe effect of smoking increases dramatically.This
modelimpliesareducedpotencyathighersmokingintensitieslikethepatternsuggestedinRefs.14and
15,wherethedeparturesfromalinearpack-years
effectwereattributedtomodifyingeffectsofintensityandnotduration.
Therewasastatisticallysignificanttime-dependentreduction(P<0.006)intheERRforthosewho
reportedthattheyhadstoppedsmoking.Theestimateddeclineforpastsmokers(relativetothatfor
non-smokers of the same age) was approximately
proportionaltooneoverthesquarerootoftimesince
quitting.WhilethesmokingERRdeclinesfollowingsmokingcessation(Figure1A),lungcancerratesfor
past smokers never return to the level for nonsmokers(Figure1B).Although,forthosesmoking
patterns, women have larger ERRs than men, theabsoluterateestimatesformaleandfemalesmokers
aresimilar(Figure1B).

Figure 1. Gender-specific smoking effects on the excess relative risk (Panel A) and absolute rate (Panel B) as a functionof age. The darker curves are for men and the lighter ones for women. The solid curves illustrate the modeledlung cancer risks for a person who smokes 20 cigarettes (one pack) per day from age 20. The long-dashedlines indicate the risk for an individual who stopped smoking at age 50. The short-dashed lines in Panel B
indicate the risk for non-smokers. The curves correspond to risk for an unexposed person born in 1915.
Return to Table of Contents

RERF Update Volume 21, Issue 2, 2010

Science Articles
Radiation effects and radiation by smoking interactions
Table1Bpresentsparameterestimatesforradiationeffectsandtheirmodifyingeffects,togetherwith
95%CIsandinformationaboutthefit,fromtheERR
interactionmodelsdescribedearlier.Thetablealso
includesresultsfromamodelinwhichtheradiationeffectparameterswereestimatedwithoutallowance
forsmokingeffects(radiation-only)asinmostLSS
reports.3,16
Both the deviance andAIC values suggest thatthegeneralized-interactionmodelsfitbetterthanthe
simpleinteractionmodelsandthatthegeneralized
multiplicativemodeldescribedthedatasomewhat
betterthanthegeneralizedadditivemodel.Modelsin which the generalized interaction was modeledintermsofpack-yearsoryearssmokedwerealso
considered,butdidnotdescribethedataanybetter
than the smoking-intensity models given in Table
1B.
Sincemostmensmokeandmostwomendonot,
withoutallowanceforsmokingtheestimatedERR/
Gyformenwassimilartothatforasimplemultiplicativemodelwhilethatforwomensimilartothatforasimpleadditivemodel.Inallofthemodelsexcept
thesimpleadditivemodel,theERR/Gywassignificantlylargerforwomenthanformen.TheradiationassociatedERRsdeclinedwithincreasingattained
age while rising with increasing age at exposure(Figure2).
There was no indication of statistically-significantcurvatureintheradiationdoseresponse(P>

190.5)overthefulldoserangeorwhenthedatawererestricted to the 0–2 Gy range (P = 0.3). Furthermore,thegender-averageddose-responseslopefor
therestrictedrange(0.67perGy)wassimilartothat
forthefullrange(0.59).Therewerenoindicationsof gender-dependence in effect modification by
attainedage(P>0.5)orageatexposure(P>0.5).
Nor was there evidence of non-linearity for thoseeffects(P=0.3forattainedageandP=0.5forage
atexposure).
Figure3illustrateshowtheERRchangeswithsmokingintensityanddoseunderthreeinteraction
models.Thepointsinthisfigurearecategory-specific
estimatesfromageneralizedmultiplicativemodelin
which smoking-intensity categories replaced thelinear-quadratic function of log intensity in theradiationmodel.Theleftpaneldescribesthejoint
effectofradiationandsmokingrelativetotherates
for non-smokers with no radiation exposure. Therightpaneldescribestheradiationeffectintermsofthe ERR/Gy relative to the risk for an unexposed
individualwiththesamesmokinghistory.Thegeneralized interaction model suggests that at lowersmoking intensities (10 cigarettes per day) theradiationeffecttendstobegreaterthanpredictedbyeitherthesimpleadditiveormultiplicativemodels,
butthatthereislittleornoapparentradiationeffectfor heavy-smokers (20 cigarettes per day). Therewasnoindicationthattheriskpatterninthegeneralized interaction models depended on gender (P >
0.5).

Figure 2. Effects of attained age (Panel A) and age at exposure (Panel B) on the excess relative risk (ERR) per Gy.
The plots compare the gender-averaged risk estimates for three joint effect models. The generalized multiplicative model for non-smokers is indicated by the dark solid line while the additive model is indicated by
the long-dashed line. For both of these models the ERR is relative to the risk for non-smokers. The shortdashed line is for a model with no adjustment for smoking. In this model the ERR is relative to the risk for an
unexposed cohort member without regard to smoking status.
Return to Table of Contents

RERF Update Volume 21, Issue 2, 2010

Science Articles

20

Figure 3. Variation of the excess relative risk (ERR) with smoking intensity. The gender-averaged risk estimates at age 70
following radiation exposure at age 30. Smoking was assumed to start at age 20 so that smoking duration was
fixed at 50 years in this figure. Panel A describes the joint effect of radiation and smoking relative to the baseline
rate for a non-exposed non-smoker. The thin long dashed line is the fitted ERR for a person with no radiation exposure. The solid line is the fitted ERR following exposure to 1 Gy under the generalized multiplicative model, thethick dashed line is the fitted risk under a simple multiplicative model, and the short-dashed line is the fitted ERR
under a simple additive joint effect model. The points are based on a generalized multiplicative model in whichsmoking intensity categories replaced the linear-quadratic function of log intensity used in the generalized multiplicative model. Panel B presents radiation-associated excess risks for an exposure of 1 Gy relative to the risk ofan unexposed person with the same smoking history.

Discussion
Questionsaboutthejointeffectofradiationand
smokingaregenerallyframedintermsofachoice
betweensimpleadditiveandmultiplicativemodels.
With additional follow-up, data from more cohort
members,andmoreparsimoniousdescriptionofthe
departures from simple models, we were able to
reject both the simple additive and multiplicativemodels.Underourfittedgeneralizedmultiplicativemodelthejointeffectappearstobesuper-multiplicativeforlight-tomoderate-smokers(smokingless
thanapackofcigarettesperday)butadditiveoreven
sub-additiveforheavy-smokers(smokingapackormoreperday).
Adjustmentforsmokingcanimpactthemodifyingeffectsofgenderandagefactorsontheradiationrelatedlungcancerrisk.OurestimateoftheERR/
Gyof0.59wassmallerthanthatof0.89fromthepreviousanalysisbyPierceet al.6andthatof0.81
fromtherecentanalysisofLSSlungcancerincidencewithnoadjustmentforsmoking.3Thepresentestimateofthefemale:maleratioofERR/Gyof3.1was
smallerthanthatof4.8fromtheunadjustedanalysis3
butlargerthansmoking-adjustedestimateof1.6by
Pierceet al.6Formanytypesofsolidcancers,the
ERR/Gy decreases with increasing age at exposure,3,16buttheunadjustedERR/Gyforlungcancerhas been found to increase with increasing age at
exposure.AlthoughitwassuggestedbyPrestonetal.3thatthispatternmightbeaconsequenceofthe
failuretoadjustfortheeffectofsmoking,thecurrent
analysesindicatethatthismaynotbethecase.Itmay
bethatthereisacertainpoolofpeoplegenetically
Return to Table of Contents

susceptible to lung cancer and that high levels of
smoking have saturated that pool so that there is
littleroomforanadditionalradiationeffect.Anotherpossibleexplanationisthatradiationexposurepriorto the start of smoking may be less harmful thanradiation exposure after smoking initiation. In theLSS, age at exposure is highly correlated with
whetherornotradiationexposureoccurredbefore
or after smoking initiation, making it difficult to
address this question. However, in an analysis in
whichtheradiationeffectwasallowedtodependon
whetherornotonereportedsmokingbeforeexposure,wefoundthatradiationriskswerenotsignificantlyhigherforthosewhosmokedbeforeexposureandthattheage-at-exposureeffectbecameevenmore
pronounced.
Weestimatedthatsmokingrelatedrelativeriskswere4.6formalesand6.8forfemaleswhosmoked
apackadayfor50years.Ifthesmokingduration
andintensitywereaveragedoverthegeneralpopulation,thosevalueswouldbeclosetotheriskestimates
of4.5and4.2formaleandfemalesmokers,respectively,fromanotherJapanesecohortstudy.17Thesevalues are much smaller than those reported fromwestern populations,18,19 which may in part reflectthehigherlungcancerratesamongnon-smokersinJapanandotherAsiancountriesthaninthewest.A
recentstudy20suggestedthatlungcancerratesmight
behigheramongJapanesenon-smokersandrelativerisksloweramongJapanesesmokers,comparedwith
theU.S.whitecounterparts.Ourestimatesoflung
cancerratesfornon-smokersweresimilartothosefound for Japanese and Korean populations in an
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internationalcomparisonoflungcancerrisksamongnon-smokers.21
Despite limitations which are discussed in themanuscript,webelievethatthisstudyprovidesthemost comprehensive characterization of the joint
effectsoflow-doseradiationandsmokingonlung
cancer in any radiation-exposed population. The
resultssuggestthatsimpleadditiveormultiplicativemodels may not adequately describe the complex
interactionbetweensmokingintensityandradiation
andthatasimilarcomprehensiveanalyticalapproachmaybeneededinriskestimationforsmokerswith
medical or occupational radiation exposures. We
thinkthatfurthereffortsshouldbemadetodevelop
methodsforusinggeneralizedinteractionmodelsin
radiationriskassessment.Thisstudyalsoisoneofthemostdetailedquantitativeanalysesofsmoking

effectsonlungcancerratesinaJapanesepopulation,
andwhetherornotthepresentfindingsareduplicatedinotherJapanesecohortswouldbeofinterestasthey
haveanimportantpublichealthimplicationforone
ofthemajorcancerproblemsinJapan.
Insummary,thegender-averagedERRperGyoflungcancer(atage70afterradiationexposureat30)
wasestimatedas0.59(95%CI:0.31–1.00)fornonsmokerswithafemale:maleratioof3.1.Aboutone
third of the lung cancer cases in this cohort wereestimatedtobeattributabletosmokingwhileabout
7%wereassociatedwithradiation.Thejointeffect
ofsmokingandradiationonlungcancerintheLSS
is dependent on smoking intensity and is bestdescribedbythegeneralizedinteractionmodelrather
thanasimpleadditiveormultiplicativemodel.

References 1. ParkinDM,BrayF,FerlayJ,PisaniP.Globalcancerstatistics,2002.CA Cancer J Clin55:74-108,2005.
 2. United Nations Scientific Committee on the Effects ofAtomic Radiation. Effects of Ionizing Radiation—
UNSCEAR 2006 Report to the General Assembly with Scientific Annexes. Volume I. UnitedNations,NewYork,
2008.
 3. PrestonDL,RonE,TokuokaS,FunamotoS,NishiN,SodaM,MabuchiK,KodamaK.Solidcancerincidenceinatomicbombsurvivors:1958–1998.Radiat Res168:1-64,2007.
 4. KopeckyKJ,NakashimaE,YamamotoT,KatoH.Lungcancer,radiation,andsmokingamongA-bombsurvivors,
HiroshimaandNagasaki.RERF Technical Report 11-86.RadiationEffectsResearchFoundation,Hiroshima,
Japan,1986.
 5. PrenticeRL,YoshimotoY,MasonMW.RelationshipofcigarettesmokingandradiationexposuretocancermortalityinHiroshimaandNagasaki.J Natl Cancer Inst70:611-22,1983.
 6. PierceDA,SharpGB,MabuchiK.Jointeffectsofradiationandsmokingonlungcancerriskamongatomic
bombsurvivors.Radiat Res159:511-20,2003.
 7. TravisWD,ColbyTV,CorrinB,ShimosatoY,BrambillaE,SobbinLH.Histological Typing of Lung and PleuralTumours,3rded.WHO,SpringerVerlag,Berlin,Heidelberg,NewYork,1999.
 8. CullingsHM,FujitaS,FunamotoS,GrantEJ,KerrGD,PrestonDL.Doseestimationforatomicbombsurvivor
studies:Itsevolutionandpresentstatus.Radiat Res166:219-54,2006.
 9. SpostoR,PrestonDL.Correctingforcatchmentareanonresidencyinstudiesbasedontumorregistrydata.
RERF Commentary and Review Series 1-92. RadiationEffectsResearchFoundation,Hiroshima,Japan,1992.
10. PrestonDL,PierceDA,ShimizuY,CullingsHM,FujitaS,FunamotoS,KodamaK.Effectofrecentchanges
inatomicbombsurvivordosimetryoncancermortalityriskestimates.Radiat Res162:377-89,2004.
11. PrestonDL,LubinJH,PierceDA,McConneyME.Epicure Users Guide. HirosoftInternationalCorporation,
Seattle,Washington,1993.
12. TurnerH,FirthD.gnm:Apackageforgeneralizednonlinearmodels.R News 7:8-12,2007.
13. AkaikeH.Anewlookatthestatisticalmodelidentification.IEEE Transactions on Automatic Control6:716-23,
1974.
14. LubinJH,CaporasoN,WichmannHE,Schaffrath-RosarioA,AlavanjaMC.Cigarettesmokingandlungcancer:
Modelingeffectmodificationoftotalexposureandintensity.Epidemiology18:639-48,2007.
15. LubinJH,CaporasoNE.Cigarettesmokingandlungcancer:Modelingtotalexposureandintensity.Cancer
Epidemiol Biomarkers Prev15:517-23,2006.
16. PrestonDL,ShimizuY,PierceDA,SuyamaA,MabuchiK.Studiesofmortalityofatomicbombsurvivors.
Return to Table of Contents

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Report13:Solidcancerandnoncancerdiseasemortality:1950–1997.Radiat Res160:381-407,2003.

17. SobueT,YamamotoS,HaraM,SasazukiS,SasakiS,TsuganeS.Cigarettesmokingandsubsequentriskoflungcancerbyhistologictypeinmiddle-agedJapanesemenandwomen:TheJPHCstudy.Int J Cancer99:24551,2002.
18. StellmanSD,TakezakiT,WangL,ChenY,CitronML,DjordjevicMV,HarlapS,MuscatJE,NeugutAI,etal.
SmokingandlungcancerriskinAmericanandJapanesemen:Aninternationalcase-controlstudy.Cancer
Epidemiol Biomarkers Prev10:1193-9,2001.
19. CrispoA,BrennanP,JockelKH,Schaffrath-RosarioA,WichmannHE,NybergF,SimonatoL,MerlettiF,
ForastiereF,etal.Thecumulativeriskoflungcanceramongcurrent,ex-andnever-smokersinEuropeanmen.
Br J Cancer91:1280-6,2004.
20. HaimanCA,StramDO,WilkensLR,PikeMC,KolonelLN,HendersonBE,LeMarchandL.Ethnicandracial
differencesinthesmoking-relatedriskoflungcancer.N Engl J Med354:333-42,2006.
21. Thun MJ, Hannan LM,Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, FlandersWD, Jee SH,KatanodaK,etal.Lungcanceroccurrenceinnever-smokers:Ananalysisof13cohortsand22cancerregistry
studies.PLoS Med5:e185,2008.

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Associations of Radiation Exposure and Circulatory
Disease Mortality Risk Based on Hiroshima andNagasaki A-bomb Survivor Data, 1950–2003*
YukikoShimizu
DepartmentofEpidemiology,RadiationEffectsResearchFoundation*Thisarticleisasummaryofthefollowingpublication:
ShimizuY,KodamaK,NishiN,KasagiF,SuyamaA,SodaM,GrantEJ,SugiyamaH,Sakata
R,MoriwakiH,HayashiM,KondaM,ShoreRE.Radiationexposureandcirculatorydisease
risk:HiroshimaandNagasakiatomicbombsurvivordata,1950–2003.BMJ 340:b5349,2010.
(doi:10.1136/bmj.b5349)

Introduction
Radiationeffectsoncirculatorydiseaseincidenceor mortality have implications for public health,
especiallyifthereareeffectsatdosesunder1Gy.Given
thatthefrequencyofmultiplecomputedtomography(CT)scansoftheheadorchestandofinterventional
radiographicproceduresisincreasingrapidly,informationonwhetherthesemayconferriskforsubsequentstrokeorheartdiseaseisimportant.
Anumberofstudies,includingrandomizedcontrolled trials, have documented that high doses ofradiationtotheheartfromradiotherapyforHodgkin
disease or breast cancer cause an excess of heart
diseasedeathsinlateryears,1–4andseveralstudies
havesuggestedthatradiotherapyforHodgkindisease,5,6 childhood leukemia or brain tumors,7 and
headandneckcancer8increasestheriskofstroke.
Therearealsoseveralsuggestionsthatlowerdoses
from occupational, medical, and environmental
exposuresmaybeassociatedwithexcesscirculatorydiseasemortality,9–14althoughotherstudiesdonot
findsuchlow-doseeffects.15–19Informationondoses
andpotentialconfoundinglifestylefactorsislimitedinmanyofthelow-dosestudies.InthispaperpublishedintheBritish Medical Journal,weexaminedthedose-responseinformationontheriskofheart
diseaseandstrokeinthelargeLifeSpanStudy(LSS)
cohortofA-bombsurvivorsinHiroshimaandNagasakiwhohavebeenfollowedupfor53years,from1950to2003.
Methods and Procedures
Study population
The LSS cohort defined on the basis of theJapanesenationalcensusin1950consistsof86,611
A-bomb survivors with estimated radiation doses.
TheLSSincludesalargeproportionofthesurvivors
whowerewithin2.5kmofthehypocentersatthe
Return to Table of ContentstimeofthebombingsandstillresidedinHiroshima
orNagasakiin1950,plusarandomage-andsexmatched sample of people 2.5 to 10 km from thehypocenterwhosustainedsmalltonegligibleradiationdoses.20Thestudypopulationwasofallages
andbothgendersatthetimeofthebombings.
Individual doses have been carefully estimated
usingtherecentimprovedDS02dosimetrysystem,basedprimarilyontheirlocationandshieldingatthetimeoftheA-bomb.21,22Riskswereestimatedusing
weightedcolondosesingray(Gy)forallanalyses.
Thefollow-upofvitalstatuswasconductedfrom1October1950totheendof2003andwasbasedon the nationwide obligatory family registration
system (koseki) that documents mortality and is
virtually 100% complete. Causes of death wereobtained from the officialVital Statistics DeathSchedulesbasedonthedeathcertificates.Underlyingand contributing causes of death were classifiedaccordingtotheInternationalClassificationofDiseases(ICD)version7(fordeathsin1950–1968),8
(in 1969–1978), 9 (in 1979–1997), and 10 (in
1998–2003).However,forpurposesofouranalyses
codeswereconvertedtoICD9codes.Onlyunderlyingcauseswereusedintheprimaryanalyses.
Collection of covariate data and data from autopsy
and tumor registryA defined sub-cohort of 51,965 LSS memberswas sent a mail survey in 1978. Information was
obtained from 36,468 (response rate of 70%) on
sociodemographic(education,typeofoccupation),
lifestyle(smoking,alcoholintake),andhealthvariables(obesity,diabetesmellitus),whichenabledtheevaluationofpossibleconfoundingbythesevariables.
Between1950and1985,autopsydatawerealsoavailableonover1,900deathsthathadanunderlyingcause
ofcirculatorydiseaseonthedeathcertificate,which
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usingmodelscorrespondingtothoseinPrestonetal.20,25Bothdoseanddose-squaredtermswereexaminedinordertoevaluatethedegreeoflinearityor
curvature in the dose-response forms.A linearthreshold model was also tested. Differences in
maximum likelihood or theAkaike Information
Criterion (AIC)26 were used to compare nested or
non-nestedmodels,respectively.Alinear-thresholdmodelwasevaluatedrepeatedlyforawiderangeof
possiblevaluesofathresholddose(d0)modelingtheriskfunctionERRondosesdasβ(d–d0)ford>d0
ord=0ford≤d0.Thevaluesyieldingthemaximum
likelihoodand95%confidenceboundswereempiricallydetermined.
Theimpactofthepossibleconfoundingfactors
of smoking (never, past, present <20/day, present
20+/day), alcohol intake (regular, seldom/never),
education(primaryorless,secondary,college/university), occupation for household (professional/
technical,clerical/sales,farmer/craftsman,transportation/service),obesity(bodymassindex[BMI]<20,20–25,25+),anddiabetes(yes/no)ontheradiationriskestimateswereexamined,includingcodes
formissinginformation.Cox-typeregressionmodels
fitted to the individual data were included, where
radiation dose was modeled as a linear ERR, and
indicatorvariablesforthepotentialconfounderswereincludedjointlyinthemodelsasconventionalexponential relative risk terms by using the Peanuts
programinEpicure.24

permitted evaluation of diagnostic accuracy. To
identify pre-existing cancer cases we used theHiroshimaandNagasakitumorregistries(available
since1958)andtissueregistries(since1974).
Statistical analysis
The analyses were based on a summary of thenumberofdeathsandperson-yearsstratifiedbydose,
city,sex,andfive-yearintervalsofageatexposure,
attainedage,andfollow-upperiod.Studysubjects
weredividedintocategoriesreflectingthenumber
ofstudysubjectsatvariousweightedcolondose(in
Gy=gdoseplus10timesneutrondose).
Poissonregressionmethodsforgroupedsurvival
data23wereusedtodescribethedependenceofrisk
onradiationdoseandtoevaluatethevariationofthedoseresponsewithrespecttocity,sex,ageatexposure,timesinceexposure,andattainedage,essentially identical to the methods used previously to
examinecancermortalityinthiscohort.20Parameter
estimationandtestswerecarriedoutwithEpicure
software,24andsignificancetestsand95%confidenceintervals(CI)werebasedonlikelihoodprofiles.
Theprimarymodelsusedhereareexcessrelativerisk(ERR)modelsoftheform

λ 0 (c, s, a, b) [ 1 + ERR(d , e, s, a )]wherel0(·)isthebaseline,orbackgrounddeathrate(i.e., the rate for people with zero dose) whichdependedoncity(c),sex(s),attainedage(a),and
birthyear(b).ThefunctionERR(d,e,s,a)describes
therelativechangeinratesassociatedwithdosed,allowingfortheeffectsofsex,ageatexposure(e)
and attained age. Effect modifiers were examined

Results
There were 19,054 circulatory disease deaths
amongthe86,611LSSmemberswithDS02dose.

Table 1. Number of subjects and deaths from circulatory disease
Number of
persons

Number of
circulatory
disease deaths

Number of
stroke deaths

Number ofheart disease
deathsNumber of othercirculatory
disease deaths

86,611

19,054

9,622

8,463

969

Male
Female35,68750,924

7,607
11,447

3,958
5,664

3,261
5,202

388
581

Age at A-bomb exposure (years)
0–9
10–19
20–29
30–49
50+

17,833
17,563
10,891
25,774
14,550

428
951
1,551
9,712
6,412

176
404
652
4,735
3,655

238
508
831
4,575
2,311

14
39
68
402
446

Weighted colon dose (mGy)
<5
5–
50–
200–
500–
1000–
2000+

38,50923,427
12,508
6,356
3,424
1,763
624

8,440
5,089
2,838
1,485
745
341
116

4,247
2,637
1,405
735
363
176
59

3,723
2,205
1,305
680
342
158
50

470
247
128
70
40
7
7

Total
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Table1showsthenumbersofsubjectsandcirculatory disease deaths by age, gender, and radiation
dose. The table shows that the cohort has a wide
range of doses but is weighted toward low doses,
whichindicatesthatithasconsiderablecapabilityto
examinelow-doserisksandtoexaminetheshapeofthe dose-response curve. There were 9,622 strokedeaths, 8,463 heart disease deaths, and 969 other
circulatorydiseasedeaths.ThepercentERRperGy(ERR/Gy) for all circulatory disease based on thelinearmodeloverthefulldoserangewas11%(95%
CI:5to17%;p<0.001).Thatrepresentsabout210
excesscasesofcirculatorydiseasemortalityassociatedwiththeradiationexposure.
Stroke
TheERR/Gyforstrokebasedonthelinearmodel
overthefulldoserangewas9%(CI:1to17%,p=
0.02)(Table2).Figure1showsestimatesoftheshape

of the dose-response for all stroke, including thefitted linear, pure quadratic, and linear-quadratic
models.Thetestfornon-linearitybasedonacomparisonoflinearandlinear-quadraticdose-response
modelswasnotstatisticallysignificant(p=0.17),
butthepurequadraticmodel,whichsuggeststhere
is relatively little risk at lower doses, nominally
providedaslightlybetterfitthandidthelinearmodel(differenceinAICstatisticsof1.87).Thiswasconfirmedbyanalysesoflowerdoseranges,0–1Gyand
0–0.5Gy,whichshowedERR/Gyof3%(CI:–10to16%)and–7%(CI:–28to16%),respectively.Figure1alsoshowsthattherewasnoapparentriskforthelowerpartofthedoserange.Theremaybeanonnegligiblethresholdbelowwhichthereisnoexcess.
Thebestestimateofathresholddose was0.5Gy
withanupper95%confidenceboundofabout2Gy.
However,thelower95%confidenceboundwasnot
greaterthan0,sotheremaybenothresholddose.

Table 2. Summary excess relative risks (ERR)1 per Gy and excess additive risks 2(EAR per 104 person-year Gy) for types of circulatory disease mortality 1
Underlying or contributing
cause of death

Indicated as underlying cause of death
Deathsp-value% ERR/Gy(95% CI)

EAR/104 PY-Gy(95% CI) 2

Deaths% ERR/Gy(95% CI)

Total circulatory diseases

19,054<0.001

11 (5 to 17)

5.5 (2.7 to 8.4)

25,11315 (10 to 20)

Stroke

9,622

0.02

9 (1 to 17)

2.3 (0.4 to 4.4)

12,13912 ( 5 to 19)

Heart disease

8,463<0.00114 (6 to 23)

3.2 (1.3 to 5.2)

14,01818 (11 to 25)

969

>0.5

2 (–18 to 29)

0.1 (–0.4 to 0.7)

5,846

58 (45 to 72)

Other circulatory disease
1
2

Estimates are based on a linear model, adjusting for city, gender, age at exposure, and attained age.
The average EARs are calculated directly from the fitted ERR models.

Figure 1. Radiation dose-response (ERR) for stroke mortality, showing thelinear and linear-quadratic functions. The shaded area is the 95%
confidence region for the fitted linear line. The vertical lines are 95%
confidence intervals for specific dose-category risks. Point estimatesof the risk for each dose-category are indicated by circles.
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Ananalysisofeffectmodificationofstrokerisk
bygender,attainedage,andageatexposureshowed
astatisticallysignificantdifferenceforattainedage(p = 0.04); the radiation ERR/Gy for stroke was
higher before age 60 than after, especially amongmen.Therealsowasanonsignificantindication(p=0.23)thattheradiationriskofstrokemaybehighestafterexposureatyoungages.
Heart diseaseTheriskestimateforallheartdiseasebasedonthelinearmodelinthefulldoserangewas14%ERR/
Gy(CI:6to23%,p<0.001)(Table2).Resultsfor
thelinear,linear-quadraticandpurequadraticmodelsareshowninFigure2.Thetestfornon-linearity
basedonacomparisonoflinearandlinear-quadratic
dose-responsemodelswasnotstatisticallysignificant(p>0.5).Apurelinearmodelfitsthedatanominally
betterthanapuredose-squaredmodel(differencein
AICstatisticsof2.47).TheERRsforheartdisease
overrestricteddoserangesweresimilartothatfor
thefulldoserange.Specifically,theERRs/Gybased
onthelinearmodelforthedoserangesunder2,1,
and0.5Gywere14%(CI:4to25),18%(CI:3to33),and20%(CI:–5to45),respectively.InFigure2theslopeoverthelowerpartofthedoserangewas
almostidenticaltotheonefortheentiredoserange.
Thebestestimateofthresholddosewas0Gywithan upper 95% confidence bound of about 0.5 Gy.There was no significant effect modification by
gender,ageatexposure,orageatrisk.
Confounding factors and misdiagnosis
Theimpactofthepossibleconfoundingfactors
ontheradiationriskestimateswasexaminedamongthe51,965LSSsubjectsinthe1978mailsurveyand
wefoundthattheassociationbetweenradiationand
circulatorydiseasewasunlikelytobeanartifactof
confounding(seemanuscript).
We also examined the diagnostic accuracy of
deathcertificatesbycomparingthemwithautopsy
reportsamongthe1,963death-certificatedesignated
circulatorydiseasecasesforwhomautopsieswereavailablefromourautopsyprogrambetween1950
and 1985.27The accuracy of the diagnoses on thedeathcertificate(DC)isfairlygoodforstrokeand
heart disease, though the accuracy of the DC was
decreasedforfinersub-categories(seemanuscript).
Circulatory disease deaths based on death certificatesmayincludemisdiagnosedcancerdeathsorcasesarisingfromcardiotoxicityduetocancerchemotherapyorradiotherapy.Toremovetheeffectsofcancer misdiagnosis, risks were estimated after
excludingpersonswhohadpreviouscancerdiagnoses, based on our tumor registry data. The ERRs
excluding pre-existing cancer diagnoses were
reduced,butthedoseresponsesremainedsgnificant(seemanuscript).
Although the designated underlying cause was
usedinthemortalityanalyses,itisdifficulttoselectasinglecauseofdeathwhenseveralcorrelateddiseasesorconditionsarecontributingtodeath.Therefore,theriskswereexaminedbasedonbothunderlyingandcontributingcausesofdeath(Table2).The
radiation-doseresponseswerenominallyhigherthan
thosebasedonunderlyingcauseofdeathalone(12%
vs.9%ERR/Gyforstroke,respectively,and18%vs.
14%forheartdisease),whichlendsadditionalsupporttothehypothesisofradiationrisk.

Figure 2. Radiation dose-response (ERR) for heart disease mortality, showing
the linear and linear-quadratic functions. The shaded area is the 95%
confidence region for the fitted linear line. The vertical lines are 95%
confidence intervals for specific dose-category risks. Point estimatesof the risk for each dose-category are indicated by circles.
Return to Table of Contents

RERF Update Volume 21, Issue 2, 2010

Science Articles

Discussion
Thepresentstudyreportsdose-responseevidenceforheartdiseaseandstrokeamongA-bombsurvivors
overthedoserange0–4Gy(mostly0–2Gy)based
on well-characterized individual doses and essentially complete mortality ascertainment over theperiodof5to58yearsafterradiationexposure.This
reportupdatesearlierbriefreportsofadose-related
circulatory disease excess amongA-bomb survivors.20,28,29Thepresentresults,basedon~25%more
deaths than the previous paper, are substantiallystronger,andmoreelaborationoftheassociationsis
nowprovided.
As shown in Table 1, at the youngest ages of
exposure(morerecentbirthcohorts)theheartdisease
deathsoutnumberthoseduetostroke,whereasthe
opposite is true of the earlier birth cohorts; thisreflects the general secular trends in the Japanese
population.Thetablealsoshowsthatthecohorthasawiderangeofdosesbutisweightedtowardlow
doses,whichindicatesthatithassubstantialcapability to examine low-dose risks and to examine theshapeofthedose-responsecurve.
Thoughthepresentdatawerestatisticallyconsistent with linearity over the full dose range in thisstudy, there is considerable uncertainty about theshapeofthedoseresponseinthelow-doserange.
Theextentofcurvatureseemedtobelargerforstrokethanforheartdisease;apuredose-squaredmodelfitsthestrokedataslightlybetterthanapurelinearmodel,whereasthelinearmodelprovidedabetterfitforheartdisease.However,thedoseresponsewas
notstatisticallysignificantforeitherendpointwhenthecalculationwaslimitedtothedoserange0to0.5
Gy, implying that evidence regarding risk below
about 0.5 Gy is limited. For stroke, the estimated
thresholddosewas0.5Gywithanupper95%confidenceboundofabout2Gy.Forheartdisease,the
estimated threshold dose was 0 Gy with an upper
95%confidenceboundofabout0.5Gy.
Additionalanalysessupportedtheassociationofradiationwithstrokeandheartdisease.Adjustment
ofthedataforotherpotentialriskfactorsforcirculatory disease—obesity, diabetes, smoking, alcohol
consumption, education, and occupation—had
almostnoimpactontheradiationassociations,whileananalysisforpossiblemisdiagnosisofcanceras
circulatory disease showed a small diminution ofradiationrisk.Becauseunderlyingcauseofdeathis
oftenuncertain,analysesofstrokeandheartdiseaseaseitheranunderlyingorcontributingcausewerealsoperformedandshowedevennominallystronger
associations with radiation than the analyses ofunderlyingcausealone.
Thefindingsoftheepidemiologicstudyofcirculatory disease amongA-bomb survivors are confirmed and extended by ourAdult Health Study
(AHS),whichconsistsofbiennialclinicalandlaboReturn to Table of Contents

27
ratoryexaminationssince1958ofabout15%ofthe
LSS cohort members. TheAHS has found doserelated increases in the incidence of stroke and
myocardial infarction,30,31 and in the incidence or
prevalence of hypertension,30,32,33 elevated serumcholesterol levels,34 and aortic arch calcification.35
Lateradiationeffectsalsohavebeenfoundforpotential biomarker precursors of circulatory disease,
includingbiomarkersforinflammation,36–38deficient
immunological responses, 39 and alterations in
immune cell repertoire.40,41 Despite the limitationsof our studies (discussed in the manuscript), thefindings present a reasonably coherent picture of
preclinical and clinical risk of circulatory disease
associated with radiation exposure. However, thisneedstobecomplementedbylow-doseriskassessmentbasedonmechanisticandanimalmodels.
Althoughepidemiologicalandexperimentaldataarelimited,anumberofstudiessuggestthepossibilityofradiationeffectsoncirculatorydisease.Among
medically exposed cohorts, excess heart diseasemortalityhasbeendemonstratedamongpatientswho
received radiotherapy for Hodgkin lymphoma or
breastcancer(e.g.,Refs.1–4,42).Atsomewhatlower
doses, an increase in coronary heart disease wasobservedamongpatientswhoreceivedradiotherapy
forpepticulcer.9Anassociationwasalsoseenamong
scoliosispatientswhoreceivedmultiplefluoroscopic
examinations,43 but not among tuberculosis (TB)
patients who received multiple chest fluoroscopic
examinations16 nor among patients who received
X-raytreatmentforbenigngynecologicdisease.44,45
Studiesofcohortswithoccupationalorenvironmentalradiationexposurehavenotprovidedclear
evidence for or against a radiation-associated
increaseincirculatorydiseasemortality.
Mostofthosestudieswerenotabletoadjustfor
potentiallifestyleorotherconfoundingfactors,and
someofthestudieshadnooronlycrudeindividualdose estimates. Most of the low-dose studies had
limited statistical power and some potential for
biases; consequently the potential for both falsepositiveandfalse-negativeresultsmaybehigh.The
UnitedNationsScientificCommitteeontheEffects
ofAtomicBombRadiation(UNSCEAR)concluded
thereislittleevidence,otherthantheatomicbomb
studies,tosupportanassociationbetweencirculatorydiseaseandradiationinthedoserangelessthan1–2
Gy.46

Conclusions and Implications
Theeffectofradiationoncirculatorydiseaserisk
ispotentiallyaveryimportantpublichealthissue.
GiventhewidespreaduseofmultipleCTscans47,48
and other relatively high-dose diagnostic medical
procedures,aswellasradiotherapythatexposestheheart,theimplicationsaresubstantialinsofarasthereareeffectsatdosesunder1Gy.ThepotentialmagRERF Update Volume 21, Issue 2, 2010

Science Articles
nitudeoftheriskisshownbythefactthat,inthe
LSS cohort who received whole-body irradiation,
the radiation-related excess of circulatory disease
deaths(~210)isaboutonethirdaslargeasthetotal
excessnumberofcancerdeaths(~625).
Thestudyprovidesthestrongestevidenceavailabletodatethatradiationmayincreasetheratesof
stroke and heart disease at moderate dose levels(mainly 0.5–2 Gy), but there is a need for robust
confirmatoryevidencefromotherstudies.Whilethe
present results below 0.5 Gy are not statistically

28
significant,theadditionalcasesoccurringwithfurther follow-up time should provide more precise
estimatesoftheriskatlowdoses.
[Theauthorswouldliketothankthemembersofthe RERF Master File Section for their diligenteffortstoprovideaccuratedataonmortalityinthe
LSS,andHiroshimaandNagasakitumorandtissue
registriesfortheirapprovalfortheuseofthedata.
WealsothankYoshisukeNonakaforhisstatistical
advice.]References 1. SwerdlowAJ,HigginsCD,SmithP,CunninghamD,HancockBW,HorwichA,etal.Myocardialinfarctionmortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst
99(3):206-14,2007.
 2. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after
radiotherapyforearlybreastcancer:prospectivecohortstudyofabout300,000womeninUSSEERcancer
registries.Lancet Oncol6(8):557-65,2005.
 3. DarbyS,McGaleP,PetoR,GranathF,HallP,EkbomA.Mortalityfromcardiovasculardiseasemorethan10
yearsafterradiotherapyforbreastcancer:nationwidecohortstudyof90,000Swedishwomen.BMJ326:25657,2003.
 4. EarlyBreastCancerTrialistsCollaborativeGroup(EBCTCG).Effectsofradiotherapyandofdifferencesinthe
extentofsurgeryforearlybreastcanceronlocalrecurrenceand15-yearsurvival:anoverviewoftherandomized
trials.lan366:2087-106,2005.
 5. BowersDC,McNeilDE,LiuY,YasuiY,StovallM,GurneyJG,etal.StrokeasalatetreatmenteffectofHodgkin’s
Disease:areportfromtheChildhoodCancerSurvivorStudy.J Clin Oncol23(27):6508-15,2005.
 6. DeBruinML,DorresteijnLD,van’tVeerMB,KrolAD,vanderPalHJ,KappelleAC,etal.Increasedriskof
strokeandtransientischemicattackin5-yearsurvivorsofHodgkinlymphoma.J Natl Cancer Inst101(13):92837,2009.
 7. BowersDC,LiuY,LeisenringW,McNeilE,StovallM,GurneyJG,etal.Late-occurringstrokeamonglongtermsurvivorsofchildhoodleukemiaandbraintumors:areportfromtheChildhoodCancerSurvivorStudy.J
Clin Oncol24(33):5277-82,2006.
 8. SmithGL,SmithBD,BuchholzTA,GiordanoSH,GardenAS,WoodwardWA,etal.Cerebrovasculardisease
riskinolderheadandneckcancerpatientsafterradiotherapy.J Clin Oncol26(31):5119-25,2008.
 9. CarrZA,LandCE,KleinermanRA,WeinstockRW,StovallM,GriemML,etal.Coronaryheartdiseaseafter
radiotherapyforpepticulcerdisease.Int J Radiat Oncol Biol Phys61(3):842-50,2005.
10. HauptmannM,MohanAK,DoodyMM,LinetMS,MabuchiK.Mortalityfromdiseasesofthecirculatory
systeminradiologictechnologistsintheUnitedStates.Am J Epidemiol157(3):239-48,2003.
11. HoweGR,ZablotskaLB,FixJJ,EgelJ,BuchananJ.AnalysisofthemortalityexperienceamongstU.S.nuclear
powerindustryworkersafterchroniclow-doseexposuretoionizingradiation.Radiat Res162(5):517-26,2004.
12. IvanovVK.LatecancerandnoncancerrisksamongChernobylemergencyworkersofRussia.Health Phys
93(5):470-9,2007.
13. McGeogheganD,BinksK,GilliesM,JonesS,WhaleyS.Thenon-cancermortalityexperienceofmaleworkers
atBritishNuclearFuelsplc,1946-2005.Int J Epidemiol37(3):506-18,2008.
14. MuirheadCR,O’HaganJA,HaylockRG,PhillipsonMA,WillcockT,BerridgeGL,etal.Mortalityandcancer
incidence following occupational radiation exposure: third analysis of the National Registry for Radiation
Workers.Br J Cancer100(1):206-12,2009.
15. VrijheidM,CardisE,AshmoreP,AuvinenA,BaeJM,EngelsH,etal.Mortalityfromdiseasesotherthancancer
followinglowdosesofionizingradiation:resultsfromthe15-CountryStudyofnuclearindustryworkers.Int
J Epidemiol36(5):1126-35,2007.

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RERF Update Volume 21, Issue 2, 2010

29

Science Articles

16. DavisFG,BoiceJD,Jr.,HrubecZ,MonsonRR.Cancermortalityinaradiation-exposedcohortofMassachusetts
tuberculosispatients.Cancer Res49(21):6130-6,1989.
17. BerringtonA,DarbySC,WeissHA,DollR.100yearsofobservationonBritishradiologists:mortalityfromcancerandothercauses1897-1997.Br J Radiol74(882):507-19,2001.
18. BolotnikovaMG,KoshurnikovaNA,KomlevaNS,BudushchevEB,OkatenkoPV.Mortalityfromcardiovasculardiseasesamongmaleworkersattheradiochemicalplantofthe‘Mayak’complex.Sci Total Environ142(12):29-31,1994.
19. KreuzerM,KreisheimerM,KandelM,SchnelzerM,TschenseA,GroscheB.MortalityfromcardiovasculardiseasesintheGermanuraniumminerscohortstudy,1946–1998.Radiat Environ Biophys45(3):159-66,2006.
20. PrestonDL,ShimizuY,PierceDA,SuyamaA,MabuchiK.Studiesofmortalityofatomicbombsurvivors.
Report13:Solidcancerandnoncancerdiseasemortality:1950–1997.Radiat Res160(4):381-407,2003.
21. CullingsHM,FujitaS,FunamotoS,GrantEJ,KerrGD,PrestonDL.Doseestimationforatomicbombsurvivor
studies:itsevolutionandpresentstatus.Radiat Res166(1Pt2):219-54,2006.
22. PrestonDL,PierceDA,ShimizuY,CullingsHM,FujitaS,FunamotoS,etal.Effectofrecentchangesinatomic
bombsurvivordosimetryoncancermortalityriskestimates.Radiat Res162(4):377-89,2004.
23. BreslowNE,DayN.Statistical Methods in Cancer Research. Vol. II: The Design and Analysis of Cohort Studies.
NewYork,OxfordUniv.Press,1987.
24. PrestonDL,LubinJ,PierceD.EPICURE: Risk Regression and Data Analysis Software.HiroSoftInternationalCorporation,Seattle,Washington,1991.
25. PrestonDL,RonE,TokuokaS,FunamotoS,NishiN,SodaM,etal.Solidcancerincidenceinatomicbomb
survivors:1958-1998.Radiat Res168(1):1-64,2007.
26. AkaikeH.Anewlookatstatisticalmodelidentification. IEEE Trans. Automat. Control19:716-23,1974.
27. RonE,CarterR,JablonS,MabuchiK.Agreementbetweendeathcertificateandautopsydiagnosesamong
atomicbombsurvivors.Epidemiology5(1):48-56,1994.
28. ShimizuY,KatoH,SchullWJ,HoelDG.StudiesofthemortalityofA-bombsurvivors.9.Mortality,1950-1985:
Part3.Noncancermortalitybasedonthereviseddoses(DS86).Radiat Res130(2):249-66,1992.
29. ShimizuY,PierceDA,PrestonDL,MabuchiK.Studiesofthemortalityofatomicbombsurvivors.Report12,
partII.Noncancermortality:1950–1990.Radiat Res152(4):374-89,1999.
30. Yamada M,Wong FL, Fujiwara S,Akahoshi M, Suzuki G. Noncancer disease incidence in atomic bomb
survivors,1958-1998.Radiat Res161(6):622-32,2004.
31. RobertsonTL,ShimizuY,KatoH,KodamaK,FuronakaH,FukunagaY,etal.IncidenceofstrokeandcoronaryheartdiseaseinatomicbombsurvivorslivinginHiroshimaandNagasaki,1958–1974.RERF Technical Report
12-79.RadiationEffectsResearchFoundation,Hiroshima,Japan,1979.
32. SasakiH,WongFL,YamadaM,KodamaK.Theeffectsofagingandradiationexposureonbloodpressure
levelsofatomicbombsurvivors.J Clin Epidemiol55(10):974-81,2002.
33. KasagiF,KodamaK,YamadaM,SasakiH,AkahoshiM.Anassociationbetweentheprevalenceofisolated
hypertensionandradiationdoseintheAdultHealthStudy.Nagasaki Med. J.67:479-82,1992.
34. WongFL,YamadaM,SasakiH,KodamaK,HosodaY.Effectsofradiationonthelongitudinaltrendsoftotalserumcholesterollevelsintheatomicbombsurvivors.Radiat Res151(6):736-46,1999.
35. YamadaM,NaitoK,KasagiF,MasunariN,SuzukiG.Prevalenceofatherosclerosisinrelationtoatomicbomb
radiationexposure:anRERFAdultHealthStudy.Int J Radiat Biol81(11):821-6,2005.
36. NeriishiK,NakashimaE,DelongchampRR.PersistentsubclinicalinflammationamongA-bombsurvivors.Int
J Radiat Biol77(4):475-82,2001.
37. HayashiT,MorishitaY,KuboY,KusunokiY,HayashiI,KasagiF,etal.Long-termeffectsofradiationdoseon
inflammatorymarkersinatomicbombsurvivors.Am J Med118(1):83-6,2005.
38. HayashiT,KusunokiY,HakodaM,MorishitaY,KuboY,MakiM,etal.Radiationdose-dependentincreasesininflammatoryresponsemarkersinA-bombsurvivors.Int J Radiat Biol79(2):129-36,2003.
39. KusunokiY, Hayashi T. Long-lasting alterations of the immune system by ionizing radiation exposure:
implicationsfordiseasedevelopmentamongatomicbombsurvivors.Int J Radiat Biol84(1):1-14,2008.
Return to Table of Contents

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30

Science Articles

40. KusunokiY,KyoizumiS,HiraiY,SuzukiT,NakashimaE,KodamaK,etal.Flowcytometrymeasurementsof
subsetsofT,BandNKcellsinperipheralbloodlymphocytesofatomicbombsurvivors.Radiat Res150(2):22736,1998.
41. KusunokiY,KyoizumiS,YamaokaM,KasagiF,KodamaK,SeyamaT.DecreasedproportionofCD4Tcells
inthebloodofatomicbombsurvivorswithmyocardialinfarction.Radiat Res152(5):539-43,1999.
42. Hancock SL,Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of
Hodgkin’sdisease.JAMA270(16):1949-55,1993.
43. DoodyMM,LonsteinJE,StovallM,HackerDG,LuckyanovN,LandCE.Breastcancermortalityafterdiagnostic
radiography:findingsfromtheU.S.ScoliosisCohortStudy.Spine25:2052-63,2000.
44. Darby SC, Reeves G, KeyT, Doll R, Stovall M. Mortality in a cohort of women given X-ray therapy for
metropathiahaemorrhagica.Int J Cancer56(6):793-801,1994.
45. AldersonMR,JacksonSM.Longtermfollow-upofpatientswithmenorrhagiatreatedbyirradiation.Br J Radiol
44(520):295-8,1971.
46. UnitedNationsScientificCommitteeontheEffectsofAtomicRadiation.AnnexB:Epidemiologicalevaluation
ofcardiovasculardiseaseandothernon-cancerdiseases.UNSCEAR 2006 Report.UnitedNations,NewYork,
2008.pp325-83
47. HallEJ,BrennerDJ.Cancerrisksfromdiagnosticradiology.Br J Radiol81(965):362-78,2008.
48. Mettler FA, Jr.,Wiest PW, Locken JA, Kelsey CA. CT scanning: patterns of use and dose. J Radiol Prot
20(4):353-9,2000.

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RERF Update Volume 21, Issue 2, 2010

31

Human Interest Notes

Recollections of Japan
William J. Schull, Former Vice Chairmam[Editors’note:RERFstaffwerefortunatelastMay
tohaveavisitfromDr.WilliamSchullwhohasbeen
oneofourmostavidsupportersandwhohasserved
ABCC and RERF in several capacities, including
PermanentDirector.HespentafewdaysatRERF
andonMay21gavealectureentitled“ABCCinthe
OldenDays.”“Jack”haspromisedtowriteuphis
informativeandentertaininglectureforafutureissue
ofUpdate,butfornowhassubmittedashorthumaninterestnote.]Asachild,andthatwasmany,manyyearsago,I
wasrepeatedlytoldbymyparentsthattoenjoylifetoitsfullestIshouldnevertakemyselftooseriously.
Yes,Ineededtobefocussedandstudyhard,butit
wasamistaketobelievethattheworldwouldseemeasanewMessiah.TheiradvicehasbroughtmeamyriadofhappymemoriesofmylifeinJapan.But
occasionallytherewasasadmemoryoranespecially
funnyone.Itisafunny,butembarrassingoneabout
whichIwritenow.
Foryears,ABCCandsubsequentlytheRadiation
EffectsResearchFoundationhasmaintainedatravelofficetoexpediteandassistintravel.Theheadofthatoffice,untilafewyearsago,wasJimmyYorioka,
whodiedrecently.Yorioka-sanwasalsotheheadofthelibrary,andassuchwaswell-informedontravel.
ItwasthroughhimthatIlearnedthatemployeesoftheMinistryofHealth,LabourandWelfare(MHLW)
whentheytraveledcouldstayatthevariousaccommodationsmaintainedbytheMinistry.PerhapsthebestknownofthoseplacesarethenumerousKosei
NenkinKaikans.Thosehotelsorinnsarereasonably
priced, generally attractive, well maintained, and
havetheirowndiningfacilities.Asaresult,whenwe
traveled within Japan, Jimmy would try to book
roomsforusatoneoftheMHLWfacilities.
TheincidentofwhichIwriteoccurredin1986
whenmywife’syoungestsister,MaryJane,andher
husband,JamesMintner,visitedusinJapan.Atthetime I was one of the Foundation’s “permanent”
directorsandlivedinHijiyamaHall.NaturallywewereanxiousforthemtoseeasmuchofJapanas
possibleintheirbriefstay.Ihadacarwhichmeantthat we could visit any place that was reasonably
accessiblebycarfromHiroshimawithoutmuchprior
arrangement.OnesuchplacewasIzumo.Giventhe

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importance of Izumo’s
great shrine and theshrine’s beauty, we
thoughtitimportantto
arrange a trip there.
Jimmywasabletobookustwodoubleroomsat
theMinistry’sfacilityin
Izumo.Oncewelearned
that we had reservations, late on a Friday Dr. William J. Schull when heafternoon, we drove visited RERF in May 2010
acrossHonshuuntilwereachednationalhighway3whereweturnedsouthto Izumo (actually mostly west).The Kaikan was
expecting us and had set aside two comfortablerooms.Thenextday,thatwasSaturday,wetouredthe shrine and drove out to Misaki and the Japan
seaside.Idonotrecallwhereweate,butthefoodmusthavebeengoodorIwouldundoubtedlyhave
remembered otherwise. On Sunday morning, we
intendedtoleavethehotelearly,driveonwestalongthecoasttoHagi,andthenturnbackacrossHonshu
to Tsuwano and ultimately Hiroshima. I tried to
impress on everyone that this was a lot of travel,
manyplacestosee,andthatweshouldleavethehotel
promptlythenextmorning.
SinceIhadbeenasadamantasIhad,whenSundaybrokeIwasupearlyandpresentedmyselftothe
Kaikan’sfrontdesktocheckusoutandtopaythebill.After I said what I thought was intelligible
Japanese,“Kanjokudasai(pleasebringthebill),”the
clerkaskedmetopleasewaitforthehotel’snurse
hadnotyetcome.Thisseemedtometobeavery
strangerequest,butIsatdowntoawaitthearrivalofthenurse.However,asthemomentspassed,andmoreandmoreguestscheckedout,Ibecameconcerned.
Finally,IthoughtIshouldgobacktothefrontdeskandattempttounderstandwhyIseemedtobetreated
differently from other guests. This time I again
repeatedthesamerequest,orsoIthought,andwas
immediatelypresentedwiththebill.Ihappilypaid
thisbutremainedperplexed.Itwasmuchlaterthat
Ilearnedthewordforanenemaiskancho.Apparently the first clerk had thought that I wanted an
enemaandtheonlyonewhocouldadministersuchwasthehotelnurse.

RERF Update Volume 21, Issue 2, 2010

32

Human Interest Notes

In Memoriam
Yutaka Hosoda
Dr.Yutaka Hosoda,
who served as Chief ofthe Clinical Studies
Department during thefour-yearperiodstartingin1985andwasoneoftheresearchscientistsfor
whomIhadthegreatestesteem, passed away attheageof84onOctober Dr. Yutaka Hosoda in 1985
3, 2010, surrounded by
familyathisownhome.Iwasveryshockedatthissadnews,becauseIhadheardofhisbadhealthonly
twodaysbeforebychanceandintendedtovisithim
atmynextopportunitytotraveltoTokyo.
Dr. Hosoda worked for the Radiation Effects
ResearchFoundationforfiveshortyears,includinghistenureasDepartmentChief,buthetransformed
the Department of Clinical Studies from one of
conducting only health examinations to a true
researchdepartment.PriortocomingtoRERF,Dr.
HosodaservedattheJapanNationalRailwaysCentral Health Institute for many years, working on
epidemiologicalresearchactivitieswithafocuson
suchthoracicdiseasesassarcoidosisandpneumoconiosis.AttheDepartmentofClinicalStudies,Dr.
Hosoda instructed us in epidemiological research,
makinggooduseofhisworkexperience.Heintroducedustodistinguishedresearchersthroughoutthecountry and helped us increase the range of ourresearchactivities.Severalstudies,includingthefirst
longitudinal analysis of disease incidence in theAdult Health Study and non-cancer studies, commenced under Dr. Hosoda’s direction. Despite hisgentle nature, Dr. Hosoda maintained a forcefulattitudeofworkingtodevelopthestrengthsofeach
individualresearchscientistandcriticizingthefaults
thatneededtobechanged.Itseemslikejustyesterdaythat,whenImadeanexcusefornotbeingabletodosomething,Dr.Hosodaupbraidedmeinaquiet
tone. “Don’t justify why you can’t do something;
insteadfindouthowyoucan,”hesaid.Ilearnedsomuchfromhim,includingtheimportanceofaproactiveattitudeandgracioustreatmentofstaff,amongother things. I feel extraordinarily fortunate that I
metDr.Hosodawhenyoung.
Dr.Hosoda’sfuneralwasheldinlinewithhislastwillandtestament:onlyacrosswasplacedonthealtar,slightlymoreflowersthannormaldecoratedthe worship services, and funeral attendants wererequestedtoinscribetheirfarewellmessagesonhis
whitewoodencasket.Iwrote“Thankyou”onthe
casket and meant it from the bottom of my heart.
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Pleasecontinuetowatchovermenowfromheaven,
Dr.Hosoda.Iprayforthereposeofyoursoul.
(bySaekoFujiwara,Chief,DepartmentofClinicalStudies,Hiroshima)

Elaine RonItwassadnewswhenwelearnedthatlong-time
friendandsupporteroftheRERFresearchcommunity, Dr. Elaine Ron, lost her battle with cancer
Friday,November19,onedayafterher67thbirthday.
The Chief of the Radiation Epidemiology Branch
(REB)oftheU.S.NationalCancerInstitute’s(NCI)
Division of Cancer Epidemiology and Genetics
(DCEG), Dr. Martha Linet, reported that Dr. Ron
diedpeacefullyatherhomewithhersonArielholdingherhand.Dr.RonandhersonlivedinHiroshima
fromAugust30,1990untilAugust22,1991when
ElainewasaResearchAssociateintheDepartment
ofEpidemiology.ShecontinuedhercloseandlongtermrelationshipwithandsupportofRERFasanExpertAdvisortotheDepartmentofEpidemiology,andshevisitedRERFtocollaboratewithourscientists.ShewasinstrumentalinestablishingthelongtermcontractbetweentheNCI,theNationalAcademyofSciences,andRERF,whichhasresultedin
numerouspublications.Forexample,Dr.Ronplayed
akeyroleinthe2007solidcancerincidencemanuscript working closely with RERF scientists and
colleagues Dale Preston, Shoji Tokuoka, SachiyoFunamoto, Nobuo Nishi, Midori Soda, Kiyohiko
Mabuchi,andKazunoriKodama.
Dr.RonfirstjoinedtheNCIin1986andserved
asChiefoftheREBfrom1997to2002.TheDirectoroftheDCEG,Dr.JosephF.Fraumeni,Jr.,pointed
outthatDr.Ron“wasaninternationallyrenowned

Dr. Elaine Ron in 1990

RERF Update Volume 21, Issue 2, 2010

Human Interest Notes
expertinthehealtheffectsofexposuretoradiation,
includingmedical,occupational,andenvironmental
settings.Herearliestworkontheeffectsoftreatment
fortineacapitisinIsraelisconsideredagroundbreakingclassic.”Hewentontomentionthatatarecent
NCIBoardofScientificCouncilors’reviewofthe
REB,thesitevisitors“praisedElaine’sworkasbeing
ofthehighestqualityandhavingsignificantimpact
on public health and radiation policy.” They also
commentedonherexceptionalmentoring,collegiality,andseniorleadershipintheBranchandDivision.
Dr.Fraumeniaddedthat“Elainehadgreatwarmth,
humor, and forthrightness, with a passion to fight
injustice,andwillbedeeplymissed.”Dr.Ronservedonmanyexpertradiationcommittees including Committee 1 of the International
CommissiononRadiologicalProtection.AtthetimeofherdeathshewasservingontheRadiationEffects
ResearchFoundationRecruitmentCommitteeforthe

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33
NationalAcademyofSciences’NuclearandRadiationStudiesBoard.Dr.RonhasbeencommendedforherexceptionalmentoringbyrecipientsofGilbertBeebe Fellowships—a program she strongly supported—andbyRERFscientistswhohavespenttime
trainingattheNCIsuchasDrs.KyojiFurukawaand
Ritsu Sakata. RERF’s Chief of Research Dr. Roy
Shorerespondedtothesadnewsbypointingoutthat
“Dr. Ron had such vitality and humaneness.”The
RERFcommunityhaslostacolleague,astrongsupporter,andafriend.
(byEvanB.Douple,AssociateChiefofResearch)[Editors’note:AsthisissueofUpdategoestopress,
we were saddened to learn of the deaths of Dr.TsutomuSugahara,formerRERFdirectorandscientificcouncilor,andMs.LouiseCavagnaro,thefirst
directoroftheABCCnursingstaff.]

RERF Update Volume 21, Issue 2, 2010

34

Facts and Figures2010 Open House in Hiroshima and Nagasaki
August5and6andAugust8and9,RERFheld
itsannualOpenHouseinHiroshima(16thannual
event) and Nagasaki (14th annual event), respectively.The theme was “Forefront of radiation and
healthsciences,”andincludedthisyearwasaspecial
exhibitiontitled“Forefrontofhigh-precisionradiotherapy.” The Open House also featured a special
panel-basedexhibitintroducingtheactivitiesofthe
HiroshimaInternationalCouncilforHealthCareoftheRadiation-exposed(HICARE).Anartisticexhibit
titled“Kage-e(shadowpicture)exhibitionofsmall
prayersfromHiroshima”(seephoto)attractedtheattentionofvisitorsforitsuniqueconcept.
Intheevent’slectures,whichhavebecomepartoftheregularprograminHiroshima,Dr.AsaoNoda,
Chief, Cytogenetics Laboratory, Department of
Genetics,andDr.KotaroOzasa,ChiefoftheDepartmentofEpidemiology,spokeabout“Whatisradiation?”onthe5thand“Whatisradiationepidemiology?” on the 6th, respectively, with both lectures
attended by large enthusiastic audiences. TheHiroshima Laboratory’s Open House drew 1,476

visitorsforthetwodays—thelargestnumberinthe
event’shistory.Couldithavebeendueinparttothe
eye-catching “PR bus masks” on the front of
Hiroshimabuses(seephoto)?
Dr.MasatakaTagaandDr.KiyohiroHamatani,
fromRERF’sCellBiologyLaboratoryinHiroshima’s
DepartmentofRadiobiology/MolecularEpidemiology,traveledtoNagasakiandprovidedexplanationsinareadilyunderstandablemanner.Also,Dr.KotaroOzasa,ChiefoftheHiroshimaDepartmentofEpidemiology,togetherwithDrs.AkihikoSuyamaand
MidoriSodaandthestaffattheNagasakiDepartment
of Epidemiology, provided explanations regardingtheA-bomb survivors’mortalitystudy and cancer
registriestothevisitorsinNagasaki.
As in past years, the examination “corners” in
RERFNagasakifortestingarteriosclerosisandothersuch conditions presented by the Department of
Clinical Studies were very well received by adult
visitors.Thechildrencornersfeaturinganexperimentininstantaneousfreezingofflowersandmicroscopic
observation of cells collected from the mouths of
visitorsthemselvesalsoprovedtobeverypopular.
The Nagasaki Laboratory’s Open House attracted
515visitorsforthetwodays.

“Kage-e exhibition of small prayers from Hiroshima”

A city bus with a mask for Open House advertisement

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RERF Update Volume 21, Issue 2, 2010

Research Protocols

Research Protocols Approved in
April–September 2010
RP 4-10 Longitudinal Clinical Study of the F1
Offspring of A-bomb Survivors
Ohishi W, Fujiwara S,Akahoshi M, SuyamaA,
KasagiF,FurukawaK,HsuWL,TakahashiN,Satoh
Y,KusunokiY,YamadaM,NeriishiK,TatsukawaY,
TakahashiI,HidaA,ImaizumiM,SeraN,GrantEJ,
Ozasa K, Cologne JB, Cullings HM, KodamaY,
KatayamaH,WatanabeT,NakamuraN
Rationale:Theheritableeffectsofexposuretoionizingradiationhavelongbeenapublichealthconcern. However, there are no human data on thepotentialriskofadult-onsetmultifactorialdiseases
intheoffspringofexposedpersons.Thislongitudinal
clinicalstudyoftheF1offspringofA-bombsurvivors
willprovidethefirstinformationonthisimportantissue.
Objectives: The objectives of the Longitudinal
ClinicalStudyoftheF1OffspringofA-bombSurvivors(F1ClinicalStudy)are(1)toelucidatetheeffects
of parental exposure toA-bomb radiation on thedevelopment of multifactorial diseases and subclinicalconditionsamongtheF1offspringofA-bomb
survivors,(2)toincreasetheprecisionandreliability
ofriskassessments,(3)topreservebiologicalsamplesforfutureresearchstudies,and(4)tocontributeto the health and welfare of the F1 population via
healthexaminationsandhealthguidance.
Methods:Thisprospectivestudywillconductperiodic health examinations of a fixed cohort of F1
offspringborntoA-bombsurvivorsbetween1946
and1984.IntheinitialF1healtheffectsstudy,14,175
people indicated they were potentially willing to
undergo health examinations among the 16,789
subjectsofmailsurveyswhorespondedtoquestionnairesconcerninghealthandlivinghabitbymailor
telephonebetweenMay2000andNovember2008.
Of those, 11,984 actually attended the Radiation
EffectsResearchFoundation(RERF)clinicforan
examination by the end of November 2008.After
excluding397ofthe14,175becauseofsubsequentdeath or contact refusal and 1,320 with currently
unknownaddresses,atotalof12,458arepotentially
eligible.
TheF1ClinicalStudywithhealthexaminationswillbecarriedouteveryfouryears.First,brochures
ofthehealthexaminationwillbesenttoallsubjects,
andsecondly,participationinaclinicalstudywillbe
requestedbytelephone.Aletterexplainingthehealth
examinationandsamplesofinformedconsentforms
willbesentinadvancetothosewhoexpressadesireto participate in the health examination. In the F1
Clinical Study, upon obtaining informed consentfrom the participant, the health examination will
includeasociodemographic,lifestyleandmedicalReturn to Table of Contents

35
historyinterview,physicalexamination,anthropometricmeasurements,bloodpressuremeasurements,
electrocardiogram (ECG), urinalysis, blood/biochemical tests, stool occult blood test, abdominal
ultrasonography, chest X-ray examination, and soon. Multifactorial diseases such as hypertension,
hyperlipidemia, diabetes mellitus, ischemic heart
disease,andstrokedetectedviatheseexaminationswillbeanalyzedinrelationtoradiationexposureoftheparentsoftheF1,takingintoconsiderationconfoundingfactors.Bloodandurinetakenfromthosewhogavetheirconsentwillbepreservedforfuture
researchstudies.
TheF1ClinicalStudywillcontributetothehealth
management and welfare of the F1 offspring of
A-bombsurvivorsbyfeedingbacktheresultsofthe
health examination, providing appropriate health
guidance,andprovidinganoutsidemedicalreferral
ifnecessary.
Theproceduresandcontentsofthehealthexamination,theethicalissues,datamanagement,andsoonaregenerallysimilartothepreviousF1Clinical
Study(FOCS).Futureresearchstudiesusingstored
biologicalsampleswillbeconductedafteraseparatedetailedresearchprotocolispreparedandapproved
bytheusualRERFprocedures.

RP 5-10 Analyses of Molecular Characteristics
of Colorectal Cancer among Atomic-bomb
Survivors
ItoR,HamataniK,TagaM,ImaiK,KasagiF,Ozasa
K,KatayamaH,CologneJB,MisumiM,IzumiS,
OueN,YasuiW,NakachiK,KusunokiY
Certainsolidcancersshowasignificantandrelativelyhighexcessrelativerisk(ERR)fromradiation
exposureintheLifeSpanStudy(LSS)ofatomicbomb(A-bomb)survivors.Thosevictimswhohad
A-bombexposureatayoungage(0–19yearsold)
showahigherERRofsolidcancers,even60years
afterexposure,thandothoseexposedatover20years
ofage.Pathologicalstudieshaveinthepastprovided
significantinformationaboutthehistologicalcharacteristics of various solid cancers that developed
amongA-bombsurvivors,someofwhichseemto
differfromthoseinthenon-exposedpopulation.
AlthoughlittlehasbeenprovedaboutthemolecularcharacteristicsofsolidcancersamongA-bomb
survivors,preliminaryresultsobtainedfromourpilot
studyoncolonandrectalcancersamongA-bomb
survivorsimpliedthatprioratomicradiationexposuremightinfluencemicrosatelliteinstability(MSI)
status and result in an increase in the relative frequencyofMSI-high(MSI-H)coloncancer.Inaddition,MSI-relatedmolecularevents,typicallygenetic
and epigenetic alterations of the MLH1 and Rassignalingrelatedgenes,mightalsobeinfluencedbyradiation exposure. Determination of colon and
rectalcancerswithMSIorchromosomalinstability
RERF Update Volume 21, Issue 2, 2010

Research Protocols(CIN)isanimportantissuethatformsthebasisof
this study. MSI status will be examined by DNAfragmentanalysisusingsixdifferentmicrosatellite
markers.Inaddition,CINstatuswillbeexamined
byanalysisofgainorlossofCIN-relatedchromosomelociwithreal-timepolymerasechainreaction
(PCR)orthePCR-restrictionfragmentlengthpolymorphism (PCR-RFLP) method using single
nucleotidepolymorphism(SNP)loci,respectively.
Basedonfindingsobtainedfromthepilotstudy,
weproposethefollowinghypothesis:ThecarcinogenicpathwaywithMSImaypreferentiallyoccurin
coloncancer,butnotinrectalcancer,amongA-bomb
survivors.Totestthishypothesis,thefollowingquestionswillbeclarifiedbyexaminationofabout140
caseswithcolonorrectalcancersincluding20subjects exposed to high radiation dose: 1) WhetherradiationexposurehasastrongerrelationshipwithMSI-Hcoloncancerthanwithmicrosatellitestable/
MSI-low (MSS/MSI-L) colon cancer or overallrectalcancer;2)Ifthisisthecase,isradiationexposureassociatedwiththeoccurrenceofgeneticand
epigenetic alterations, specifically methylation of
MSI-relatedgenes(DNArepairgenes,Ras-signaling-relatedgenes,CpGislandmethylatorphenotype
[CIMP]-relatedgenes)incoloncancer?;3)WhetherradiationexposureisassociatedwithCIN-positive
colonandrectalcancers;4)Ifanswertoquestion3)
is yes, whether radiation exposure influences themostimportantinitialevent(i.e.,adenomatous polyposis coli [APC] gene alteration) or subsequent
events; and 5)Are there any differences in pathological parameters (e.g., differentiation, development, progression, and host immune reaction to
cancer)betweennon-exposedandexposedMSI-or
CIN-positivecolonandrectalcancers?
Inthisstudy,wewillexaminethosequestionsintheorderofdescendingprioritiesindicatedbythe
itemnumbers1)to5).

RP 6-10 Intrinsic Subtypes of Breast Cancer
among Atomic-bomb Survivors (Addendum to
RP 5-08)
YoneharaS,NishisakaT,NakashimaM,SekineI,
TokuokaS,SodaM,SuyamaA,FurukawaK,Hirai
Y,NakamuraN,YangR,MabuchiK,OzasaK‘Intrinsic’subtypesofbreastcancerdefinedbygeneexpressionprofilingstudiesarethoughttobe
associated with pathogenesis and prognosis (biologicalproperties)ofbreastcancer,andseemtobe
related to some etiologic factors. This molecularclassificationcanbeapproximatedbyimmunohistochemical(IHC)stainingofkeymarkers.Aspartofthespecialcancerincidencestudy(RERFRP5-08:
BreastCancerIncidenceamongAtomic-bombSurvivors, 1950–2005), we propose to investigate theIHC subtypes of breast cancer cases to add new
insightsintobiologicalpropertiesofbreastcancer
Return to Table of Contents

36
inrelationtoatomic-bombradiationexposure.Collaborating with pathologists and hospitals in
HiroshimaandNagasaki,wewillcollectparaffinembeddedtissuesofbreastcancersthatoccurredinthemembersoftheLifeSpanStudy(LSS)population,andperformIHCstainingoftargetedreceptor
markers to study associations of specific subtypes
andradiationexposurewithconsiderationofpatient’s
ageandcalendaryearatdiagnosis,birthcohortofthesubjects,ageatexposuretoradiation,andalso
anthropometricindices,reproductivehistories,and
other individual factors. The results will provide
insights into biological mechanisms of radiationinducedbreastcarcinogenesisandprovideimportantinformationforfuturemolecularstudiesofradiationrelated subgroups to elucidate possible molecularchanges associated with radiation-induced breast
cancer.

RP 7-10 Study of Body Composition of theHiroshima Adult Health Study Population
TatsukawaY, Fujiwara S, Harris TB, Misumi M,
OhishiW,MasunariN,YamadaM,OyamaH,Kasagi
F
Background:Somerecentresultsfromstudiesof
atomic-bomb (A-bomb) survivors have shown apositive association between radiation dose and
incidenceofarterioscleroticdiseasessuchashypertensionandmyocardialinfarction(MI).Theunderlyingmechanismsofradiationdoseeffectsonarteriosclerotic diseases, however, remain elusive. In
addition,therearelimitednumbersofreportsonthe
presenceorabsenceofracialdifferencesinthehealth
effectsofbodycomposition.
Objectives:Theobjectivesofthisprospectivestudy
include: 1) testing whether radiation exposure is
related to increased incidence of arteriosclerotic
diseasesandtheirriskfactorsthroughmodificationsinbodycomposition;2)examiningeffectsofbody
compositionmodifications,particularlyaging-related
lossofmusclemass(sarcopenia),onthehealthofthe Japanese people, such as the prevalence and
incidenceofarterioscleroticdiseases,andassociated
risk factors and mortality; and 3) comparing
HiroshimaAdultHealthStudy(AHS)participants
and U.S. Health,Aging, and Body Composition
(ABC)studyparticipants,withrespecttopotential
racial differences in health effects associated with
bodycomposition(internationalcollaborativestudy).
Methods: Study subjects will total approximately
2,200HiroshimaAHSparticipantswhounderwentwhole-bodycompositionexaminationbydualenergy
X-ray absorptiometry (DEXA) during the period
1994–1996.IntheHiroshimaAHS,measurements
ofwhole-body/regional(trunk,limb,etc.)fatmass,leanmass,andbonemineralcontent(BMC)wereconductedbyDEXAstartingin1994.Thosedataare
alreadystoredinadatabaseandavailableforuse.In
RERF Update Volume 21, Issue 2, 2010

37

Recent Publications
thisprospectivestudy,wewillexaminerelationships
betweenDEXA-basedbodycompositionandradiationdose,andtheprevalenceandincidenceofarterioscleroticdiseasesplusassociatedriskfactorsand
mortality.Mortalityendpointswillincludeallcauses,
ischemic heart disease, stroke, and possibly other
cardiovasculardiseases,iffeasible.
Thisstudymaybeusefultoelucidatemechanisms
oftherelationshipofradiationdosetoarteriosclerotic
diseases and their risk factors. Furthermore, theinternationalcollaborativestudyshouldbemeaningfulforboththeA-bombsurvivorsandthegeneral
Japanesepopulation.

Recent Publications(Japanese): the original article is in Japanese.

AsakawaJ,KodairaM,KatayamaH,CullingsHM,
NakamuraN.Ageneticriskestimateofradiation
inmicebasedonwholegenomescanningbytwodimensionalDNAgel.SkopekJ,ed.37thAnnualMeeting of the European Radiation ResearchSociety.Bologna:Medimonds.r.l.;2009,pp41-3.
(Proceedingsofthe37thAnnualMeetingoftheEuropean Radiation Research Society, Prague,
CzechRepublic,26-29August2009)
AshizawaK,ImaizumiM,UsaT,TominagaT,Sera
N,HidaA,EjimaE,NeriishiK,SodaM,Ichimaru
S,NakashimaE,FujiwaraS,MaedaR,Nagataki
S,EguchiK,AkahoshiM.Metaboliccardiovascular disease risk factors and their clustering in
subclinicalhypothyroidism.ClinicalEndocrinology 2010 (May); 72(5):689-95. (RERF Report
15-08)
Boice JD, Hendry JH, Nakamura N, Niwa O,
NakamuraS,YoshidaK.Low-dose-rateepidemiologyofhighbackgroundradiationareas.RadiationResearch2010(June);173(6):849-54.
CologneJB,CullingsHM,FurukawaK,RossNP.
Attributableriskforradiationinthepresenceofotherriskfactors.HealthPhysics2010(November);99(5):603-12.(RERFReport11-09)
Furukawa K, Preston DL, Lönn S, Funamoto S,
Yonehara S, Matsuo T, Egawa H, Tokuoka S,
Ozasa K, Kasagi F, Kodama K, Mabuchi K.
Radiation and smoking effects on lung cancer
incidenceamongatomicbombsurvivors.RadiationResearch2010(July);174(1):72-82.(RERF
Report8-09)
HayashiT,KusunokiY.Moleculargenetics/epidemiology of cancer. Koshu Eisei [Public Health]
2010(September);74(9):738-43.(Japanese)
HeidenreichWF,CullingsHM.Useoftheindividualdataofthea-bombsurvivorsforbiologicallybased
cancer models. Radiation and Environmental
Biophysics2010(March);49(1):39-46.
Hsu WL, TatsukawaY, Neriishi K,Yamada M,
Cologne JB, Fujiwara S. Longitudinal trends of
totalwhitebloodcellanddifferentialwhitebloodcellcountsofatomicbombsurvivors.Journalof
Radiation Research 2010 (July); 51(4):431-9.
(RERFReport5-09)
KogaY,IwanagaM,SodaM,InokuchiN,SasakiD,

Return to Table of Contents

RERF Update Volume 21, Issue 2, 2010

38

Recent Publications
Hasegawa H,Yanagihara K,Yamaguchi K,
KamihiraS,YamadaY.TrendsinHTLV-1prevalence and incidence of adult T-cell leukemia/
lymphomainNagasaki,Japan.JournalofMedical
Virology2010(April);82(4):668-74.
Kumamoto K, Nakamura T, Suzuki T, Gorai I,
FujinawaO,OhtaH,ShirakiM,YohK,Fujiwara
S, Endo N, Matsumoto T. Validation of theJapaneseosteoporosisqualityoflifequestionnaire.
Journal of Bone and Mineral Metabolism 2010
(January);28(1):1-7.
Li CI, Nishi N, McDougall J, Semmens OE,Sugiyama H, Soda M, Sakata R, Hayashi M,
KasagiF,SuyamaA,MabuchiK,DavisS,Kodama
K, Kopecky KJ. Relationship between radiation
exposure and risk of second primary cancers
amongatomicbombsurvivors.CancerResearch2010(September);70(18):7187-98.(RERFReport
1-10)
McDougallJ,SakataR,SugiyamaH,GrantEJ,Davis
S, Nishi N, Soda M, ShimizuY, TatsukawaY,
KasagiF,SuyamaA,RossPD,KopeckyKJ,Li
CI.Timingofmenarcheandfirstbirthinrelation
toriskofbreastcancerinA-bombsurvivors.Cancer Epidemiology, Biomarkers and Prevention
2010(July);19(7):1746-54.(RERFReport2-10)
Miles EF, TatsukawaY, Funamoto S, Kamada N,
NakashimaE,KodamaY,SeedTM,KusunokiY,
NakachiK,FujiwaraS,AkahoshiM,NeriishiK.
BiomarkersofradiosensitivityinA-bombsurvivorspregnantatthetimeofbombingsinHiroshima
andNagasaki.ISRNObstetricsandGynecology
2010 (September); 2011(264978):1-11.
doi:10.5402/2011/264978.(RERFReport5-08)
OhishiW,ChayamaK.HepatitisCvirusRNAand
nucleic acid testing. Nippon Rinsho [JapaneseJournal of Clinical Medicine] 2010 (June);
68(Suppl6):450-3.(Japanese)
OkuboT(Edit).MHLWGrants.FY2009ReportofAtomic Bomb Disease Research Project. 2010(September),89p.(Japanese)
RodondiN,denElzenWPJ,BauerDC,CappolaAR,
RazviS,WalshJP,ÅsvoldBO,IervasiG,Imaizumi
M,etal.Subclinicalhypothyroidismandtherisk
ofcoronaryheartdiseaseandmortality.JournaloftheAmericanMedicalAssociation2010(September);304(12):1365-74.

G.41Caintoothenamel.PartII:Ameansforretrospectivebiologicalneutrondosimetryinatomic
bombsurvivors.RadiationResearch2010(August);
174(2):146-54.(RERFReport13-09)
TabaraY,KoharaK,KitaY,HirawaN,KatsuyaT,
OhkuboT,HiuraY,TajimaA,MorisakiT,Miyata
T, Nakayama T, Takashima N, et al. Common
variantsintheATP2B1geneareassociatedwith
susceptibilitytohypertension.TheJapanesemillennium genome project. Hypertension 2010
(November);56(5):973-80.
Takahashi N, SatohY, Kodaira M, Katayama H.
Large-scale copy number variants (CNVs)
detected in different ethnic human populations.
CytogeneticandGenomeResearch2008;123(14):224-33.
TsunetoA,HidaA,SeraN,ImaizumiM,Ichimaru
S,NakashimaE,SetoS,MaemuraK,Akahoshi
M.Fattyliverincidenceandpredictivevariables.
HypertensionResearch2010(April);33(4):63843.(CommentaryandReviewSeries4-09)
UsuiS,MatsumuraM,YanagidaJ,ShimazutsuS,
OzasaK,OhishiW,TakiyamaW,TokumoH,Kira
S,WatanabeC,YoshimotoM,UekiT,YamamotoY,SuedaY,WatanabeT,OdaT,SoramotoE,Mukai
M,HadaT,TanimotoT,KumagaiF,NakamuraM.
Reportontheresultsoftheseventeenthmedical
examinationofatomicbombsurvivorsresidentinNorthAmerica.HiroshimaIgaku[Journalofthe
HiroshimaMedicalAssociation]2010(August);
63(8):567-92.
WallnerA,RühmW,RugelG,NakamuraN,Arazi
A,FaestermannT,KnieK,MaierHJ,Korschinek
G. 41Caintoothenamel.PartI:Abiologicalsignatureofneutronexposureinatomicbombsurvivors. Radiation Research 2010 (August);
174(2):137-45.(RERFReport1-07)

Publication Using RERF Data
The following publication represents research done by
non-RERF scientists based on the data publicly available
from RERF.

Richardson DB, Hamra G. Ionizing radiation and
kidneycanceramongJapaneseatomicbombsurvivors.RadiationResearch2010(June);173(6):
837-42.

Rühm W, WallnerA, Cullings HM, Egbert SD,El-FaramawyN,FaestermannT,KaulDC,Knie
K,KorschinekG,NakamuraN,RobertsJA,RugelReturn to Table of Contents

RERF Update Volume 21, Issue 2, 2010