Table of Contents
From the Editors ......................................................................................................................................... 1
RERF NewsThe 34th Scientific Council Meeting .................................................................................................... 1
The 42nd Board of Directors Meeting .................................................................................................. 3
The 6th Annual Gilbert W. Beebe Symposium—Sixty Years of ABCC-RERF:
Major Contributions and Future Studies ........................................................................................... 5
RERF Chairman Meets with the U.S. Secretary of Energy ................................................................ 16
Staff News ........................................................................................................................................... 17
Student Researchers ............................................................................................................................ 17
Gilbert W. Beebe Fellows ................................................................................................................... 18
2008 Distinguished Lecture Series ..................................................................................................... 18
Honors and Awards Received by RERF Scientists ............................................................................. 18
Conference and Workshop Report
Radiation and Age-associated Immunosenescence, by Yoichiro Kusunoki ....................................... 20
Science Article
Ophthalmologic Studies in Atomic-bomb Survivors, by Kazuo Neriishi et al. .................................. 22
Human Interest Notes
In Remembrance of Dr. Howard Hamilton, by Akio Awa .................................................................. 26
In Memory of Dr. Koji Takeshima, by Hideya Tamagaki ................................................................... 28
It’s a Small World—With a Strong Link Between Hiroshima and Texas ........................................... 30
Research Protocols and Publications
Research Protocols .............................................................................................................................. 32
Recent Publications ............................................................................................................................. 33

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, RERF News

Haikei!
We are once again trying to catch up on ourreporting of RERF’s various research activities. The
Editor in Chief of last year’s Update Volume 18, 2007
helped set a high standard by making what we believe
to be significant improvements in the quality andinterest-level of the articles and reporting. However,
Tom Seed has retired to his home in the United States.
Only half of our editorial team (nakama) is new but,
as we worked on preparing Volume 19, we realizedthat Tom left big footsteps to fill!
The year 2007 was a very special year for theFoundation since it marked the 60th anniversary of
the founding of the Atomic Bomb Casualty Commission (ABCC). So it should not be surprising thatin this issue we have highlighted the National
Academy of Sciences’ symposium that was held
December 12, 2007 to commemorate this historic
landmark. We have also included a very interesting

and timely science article.
We hope that you enjoy this volume and don’t
hesitate to drop us a line and let us know how wemight improve our reporting of RERF’s many
activities.
Sincerely,

Evan B. Douple
Editor in Chief

Yuko Ikawa
Technical Editor

Report on the 34th Scientific Council Meeting
The 34th Scientific Council meeting, co-chaired
by Dr. Ohtsura Niwa (Kyoto University and National
Institute of Radiological Sciences) and Dr. Joel
Bedford (Colorado State University) was convenedon March 5–7, 2007 in Hiroshima to review the scientific program of RERF. Besides the annual review
of departmental research activities and short-range
plans, the Scientific Council’s charge was broadened
this year to review two additional issues, the longterm Future Plans of RERF, and the results and future
directions of the F1 Clinical Study, so extended presentations were made of these.
Summary of General Recommendations by the
Scientific Council:
The Scientific Council emphasized the importantrole that RERF plays world-wide in radiation risk
research through its exemplary design and conductof studies of the health effects of radiation in A-bomb
survivors. They also recognized the generous support by the Japanese and U.S. governments, the U.S.
National Academy of Sciences (NAS), and especiallythe benevolent collaboration of the survivors andtheir families. The principal general recommendations were:• There is a vital need to fill key vacancies createdby the recent and impending loss of leading
scientists at RERF through mandatory retirement. This is made more difficult by the reduction in personnel mandated by the Japanese
government.
Return to Table of Contents• RERF should strive to maintain its strength andfocused mission, since there is still much to bedone even after 60 years of research. One reason for this is that nearly half of the A-bomb
survivors’ lifetime, radiation-associated cancer
and non-cancer disease is projected to occur inthe future. RERF’s existence and continuation
at current levels of support are crucial, not only
to both nations supporting it, but to the entire
world.
• The role of NAS in this research should be continued and strengthened, as it has lent additional
credibility and scientific expertise to the efforts.
• With additional support over and above current levels, RERF can be expanded in two
directions: the globalization of RERF’s mission
and the augmentation of its role in educationand training.
• Consideration of more direct partnering withother international organizations would enhance
the profile of RERF and showcase its mission
and expertise. The new “Partnership” between
RERF and the University of Washington and
Kurume University is a good example of thebenefits of such partnering.
• Every effort should be made to exploit theexpertise and resources accumulated in RERF
to obtain more and better knowledge about themechanisms and extent of radiation healtheffects. To achieve maximum potential from thestored blood and other archival samples, an
RERF Update Volume 19, Issue 1, 2008

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RERF News
expert panel should be assembled to recommend appropriate approaches and technologies.
Introduction of high-end technologies will require collaborations with other groups outside
RERF and additional sources of funding.
• Possibilities should be carefully evaluated forgarnering additional outside funding to support
expansion of activities while fully maintaining
the efforts of our current mission. Any increased
funding should be used for hiring staff and postdoctoral fellows.
• In order for RERF to continue its research mission at the highest level, including introductionof contemporary research tools, an updating andrenovation of current facilities or a move to a
new campus may be required.
Recommendations regarding the F1 epidemiological and clinical studies:• The only current opportunity to evaluate thehuman health effects upon offspring of radiation-exposed parents, in a dose range wheresome effects might be seen, lies in studies basedon the children of atomic-bomb survivors. This
opportunity should not be missed and the study
should be pursued.
• The Scientific Council sees great merit in transforming the current cross-sectional F1 clinicalstudy into a longitudinal investigation. It would
be a unique biomedical research resource.
Recommendations regarding RERF’s long-term
future plans:• The Scientific Council is pleased to see extensive future plans which are crucial to the continuation and further extension of RERF’s
service to risk research communities and to thewelfare of mankind. The plans describe thedetail of projects which current research staff
would like to conduct in the future. The Council would like to see a further reevaluationof scientific strengths and accomplishments,
accumulated resources and administrative
structures, as these factors should bear on theways future contributions are planned andimplemented.
Highlights of a few of the numerous recommendations to departments:• The Scientific Council was impressed by thedose-response curves for non-cancer disease
deaths in the Life Span Study (LSS). Basicstudies to clarify the mechanisms of radiation
effects on non-cancer diseases are encouraging, and should be further developed in order
to better understand those effects, the impact
of covariates, and the biological mechanisms.
This work will require continued collaboration
Return to Table of Contents

among departments and with other institutions
that have sufficient infrastructure and expertise.
• The efforts to mount a new mail survey of LSS
participants are commendable. The collectionof biological samples from LSS participants canalso be an important adjunct.
• The efforts should be continued to expand the
Adult Health Study (AHS) cohort and to increase the number of younger survivors. This
increase is particularly important for non-cancer risk estimation with higher precision andalso for the collection of biospecimens forfurther basic analyses.
• The large number of paired samples collectedfrom survivors and their progeny is an important resource which merits careful protection
and also the development of collaborative
projects between RERF staff and the scientificcommunity in general.
• The efforts in immunophenotyping are an
important line of research. We believe increased
work is appropriate on the relationships ofinflammation, cancer and altered immune function.
• We encourage continued work on the relationship between infection and cancer and how suchrisk is modified by radiation exposure, including additional cancer sites that have a known
infectious component.
• Worldwide efforts to delineate the genetic
determinants of adult diseases need to be followed closely in order to help interpret findings and differentiate disease endpoints.
• The development of methods for quantitativerisk estimation and clinical data analysis,
augmented by new collaborations with outside
universities, should be continued. Causal modeling is a promising new direction for radiation risk assessment of cancer and non-cancer
outcomes in the AHS.
• The biological dosimetry should be applied ina pilot study to evaluate the likelihood of thesetechniques making a relevant change to physical dose estimates and their statistical uncertainties.
RERF Scientific Councilors
Dr. Ohtsura Niwa, Professor, Radiation Biology
Center, Kyoto University, Co-chairperson
Dr. Joel S. Bedford, Professor, Department ofRadiological Health Sciences, Graduate Facultyof Cellular and Molecular Biology, Colorado
State University, Co-chairperson
Dr. Teruhiko Yoshida, Chief, Genetics Division,
National Cancer Center Research InstituteDr. Yoshiharu Yonekura, President, National
Institute of Radiological Sciences
RERF Update Volume 19, Issue 1, 2008

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RERF News
Dr. Katsushi Tokunaga, Professor, Department of
Human Genetics, Graduate School of Medicine,
The University of Tokyo (Absent)
Dr. Takashi Yanagawa, Professor, The Biostatistics
Center, Kurume University
Dr. Theodore L. DeWeese, Professor and Chair,
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine
Dr. Marianne Berwick, Professor and Chief, Divi-sion of Epidemiology, Head, Epidemiology andCancer Prevention, University of New Mexico
Dr. John J. Mulvihill, Director, Program of Human
Genetics and Professor of Biostatistics and Epidemiology, College of Public Health, Universityof Oklahoma Health Sciences Center
Dr. David G. Hoel, Distinguished University Professor, Department of Biostatistics, Bioinformatics
and Epidemiology, Medical University of South
Carolina

The 42nd Board of Directors Meeting in Nagasaki
The 42nd meeting of the Board of Directors washeld at the Nagasaki RERF on June 20 and 21, 2007.
This was the first Board meeting held in Nagasaki
in eight years, since 1999.
In their opening remarks, representatives of the
U.S. and Japanese governments highly commended
the scientific program of RERF and assured theircontinued active commitment to the program. Then,in his status report for RERF, Dr. Toshiteru Okubo,
RERF Chairman, reported on the steady progress ofthe Foundation’s studies over the past one year. Dr.
Okubo reported that the health effects study of thechildren of A-bomb survivors, initiated in 2000, wascompleted with final reviews made at the end of
February 2007, and that the chairs of the Scientificand Ethics Committees submitted a study report in
April. He also reported on publication of a DS02based, cancer incidence study report as part of theLife Span Study (LSS). Dr. Okubo thus emphasized
the solid achievements of research at RERF. His
report also touched on the Senior Review Panel on
Future Planning for RERF. Dr. Okubo stated that thepanel met in December 2006 and May 2007 and that
it would submit a final report to the U.S. and Japanese governments in 2008.
In conjunction with the Senior Review Panel’sdeliberations, the current Board meeting had inattendance the U.S. and Japanese chairs of the panel,
who explained the panel’s roles and presented a
progress report on its deliberations and solicited the
directors’ opinions regarding RERF’s future plans.
Reports were also made on the Agreement on Cooperation in Education and Research, concluded with
Hiroshima University and Nagasaki University forenhancing comprehensive cooperation in research,
as well as on the updated RERF promotional video.
In the course of the meeting’s discussions, after
reports on the background, study details and resultsof the health effects study of the children of A-bomb
survivors, it was confirmed that the Senior Review
Panel would be asked to provide opinions regarding
possible involvement of the U.S. side in the study
and that this matter would be dealt with in a conReturn to Table of Contents

structive way through negotiations with those concerned. As for the government’s plan for personnel
reduction, it was suggested by the directors that theuniqueness of RERF as a research institution should
be considered because reduction in the numbers of
research scientists and general employees would
bring about serious problems for RERF in terms of
securing young and talented research scientists. In
response, it was reported that new systems have been
introduced at RERF in terms of recruitment andcontract renewal for research scientists.
Additionally, research activities reports and settlement of accounts for FY2006, as well as research
activities plans and working budget for FY2007,
were discussed and approved. Of the four directors,
one supervisor and two scientific councilors whoseterms of office were due to expire, three directors,
one supervisor and one scientific councilor werereappointed. Appointment of Mr. James W. Ziglar
as successor to Dr. Paul L. Ziemer, who acted as
director for four years, and Dr. Michael N. Cornforth
as successor to Dr. Joel S. Bedford, who acted as
scientific councilor for five years, was approved.
At the last Board meeting, it was agreed that thehealth effects study of the children of A-bomb
survivors, which ended in February 2007, should becontinued for follow-up of study results, as recommended by the Scientific Council. Continuation of
the study is an important decision that could greatly
impact RERF’s future. While we will continue ourcoordination efforts with the authorities concernedin terms of budget, we have to wait for the final
recommendations of the Senior Review Panel.
It was decided that the next Board meeting would
be held in Washington, D.C., U.S., for three days
beginning June 18, 2008.
List of Participants
Directors:
Dr. Toshiteru Okubo, Chairman
Dr. Roy E. Shore, Vice Chairman and Chief of Research
RERF Update Volume 19, Issue 1, 2008

RERF NewsMr. Takanobu Teramoto, Permanent Director
Mr. Masaaki Kuniyasu, Former Ambassador Extraordinary and Plenipotentiary to the Republicof Portugal
Dr. Yasuhito Sasaki, Director General, Radiology
Center, International University of Health andWelfareDr. Senjun Taira, Permanent Director, Japanese
Association of Quarantine Inspection Hygiene
Dr. Paul L. Ziemer, Professor Emeritus, Purdue
University
Dr. James D. Cox, Professor and Head, Division ofRadiation Oncology, University of Texas M.D.
Anderson Cancer Center
Supervisor:
Dr. Tomio Hirohata, Professor Emeritus, Faculty of
Medicine, Kyushu University
Co-chairmen Senior Review Panel on Future
Planning for RERF:
Dr. Sadayoshi Kitagawa, Director General, Japan
Public Health Association
Dr. Paul Gilman, Director, Oak Ridge Center for
Advanced Studies
Co-chairman Scientific Council:
Dr. Ohtsura Niwa, Deputy Director, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences
Representatives of Supporting Agencies:
Mr. Osamu Okabe, Director, General Affairs Division, Health Bureau, Ministry of Health, Labourand Welfare (MHLW)
Dr. Takeshi Sasaki, Deputy Director, General
Affairs Division, Health Bureau, MHLW

Return to Table of Contents

4
Mr. Kazuhiro Kanayama, Deputy Director, General
Affairs Division, Health Bureau, MHLW
Mr. Glenn S. Podonsky, Chief Health, Safety andSecurity Officer, Office of the Secretary of Energy, U.S. Department of Energy (DOE)
Mr. Michael A. Kilpatrick, Deputy Chief for Operations, Office of Health, Safety and Security,
DOE
Mr. Dean C. Hickman, Project Manager, Office of
Health, Safety and Security, DOE
Dr. Joseph F. Weiss, Japan Program Manager, Office of International Health Studies, Office of
Health, Safety and Security, DOE
Mr. Thomas W. Wolf, Science and Technology and
Health Affairs Officer, Environment, Science andTechnology Affairs, Embassy of the UnitedStates of America
Dr. Kevin D. Crowley, Director, Nuclear and Radiation Studies Board, Division on Earth and Life
Studies, National Research Council (NRC),
National Academy of Sciences (NAS)
Dr. Evan B. Douple, Scholar, Nuclear and Radiation Studies Board, Division on Earth and Life
Studies, NRC, NAS
Ms. Laura Llanos, Financial and Administrative
Associate, Nuclear and Radiation Studies Board/
RERF Program, Division on Earth and Life Studies, NRC, NAS
RERF:
Mr. Eiji Akimoto, Chief of Secretariat
Dr. Thomas M. Seed, Associate Chief of Research
Dr. Nori Nakamura, Chief Scientist
Dr. Kazunori Kodama, Chief Scientist
Mr. Douglas C. Solvie, Associate Chief of Secretariat

RERF Update Volume 19, Issue 1, 2008

5

RERF NewsThe Sixth Annual Gilbert W. Beebe Symposium
Sixty Years of ABCC-RERF: Major Contributions and Future Studies
As the theme of its Sixth Annual Gilbert W. Beebe
Symposium, the National Academies elected to commemorate the 60th anniversary of the founding of
the Atomic Bomb Casualty Commission (ABCC)
that became the Radiation Effects Research Foundation in 1975. The site of the special symposium—
named after the distinguished epidemiologist who
helped to establish ABCC and who was instrumental in the design of the ABCC’s most important research studies—was the National Academy of Sciences Auditorium on Constitution Avenue in Washington, DC, and the date was December 12, 2007.
An RERF delegation consisting of current directors,
former chairman Dr. Itsuzo Shigematsu, and current
RERF scientists, joined a number of former ABCCRERF employees who gathered for the symposiumfrom across the U.S. and renewed old friendships.
Opening Ceremony
The program began with an opening ceremonythat included a koto concert played by Mrs. VeraLand who learned to play the koto when her husband, Dr. Charles Land, worked with Dr. Beebe at
ABCC. Dr. Ralph Cicerone, President of the
National Academy of Sciences (NAS), welcomed theparticipants on behalf of NAS and commented on
the historical role and long-term commitment of NAS
to this important scientific and humanitarian project.
Mr. Michael Kilpatrick, Deputy Chief for Operations in the Department of Energy (DOE) Office of
Health, Safety, and Security, gave greetings andcongratulations on behalf of the U.S. government.
He reminded the audience that the U.S. and the DOE
Return to Table of Contents

have had a long-term interest in, and have provided
extensive support for, the important studies of healtheffects in the A-bomb survivors. He thanked themany current and past employees of ABCC-RERF
for their dedicated service and extended a special
thank you and appreciation to the many thousandsof A-bomb survivors. Without the support of bothgroups, RERF’s valuable scientific accomplishments
would not have been possible.
Mr. Kilpatrick was followed by Mr. MasahiroMori, First Secretary for Health and Welfare of the
Embassy of Japan, who represented the governmentof Japan. He honored all current and former employees for their devoted service to ABCC-RERF andfor “their remarkable track record in leading theworld in radiation research.” He also expressed
appreciation to all A-bomb survivors for their participation and cooperation in the radiation research
for more than 60 years. He emphasized that “Without their understanding and contribution, the world’s
scientists could not understand what happened in
Hiroshima and Nagasaki and could not pass on thisvaluable information to future generations.” Heconfirmed that the government of Japan will continue
to support the research by RERF and to improve thequality of life for A-bomb survivors. He also pointed
out that the U.S.-Japan partnership and cooperationin this project is symbolic evidence of the history
that the U.S. and Japan experienced as they overcame a tragedy six decades ago.
Since the “Honorary Chair” for this year’s Beebe
Symposium was a dedication to all former employees of ABCC and RERF and to all A-bomb surviRERF Update Volume 19, Issue 1, 2008

RERF News

6

A standing ovation in response to Mr. Sunao Tsuboi’s message from the perspective of an A-bomb survivor

vors who have participated in the ABCC-RERF studies, Dr. Itsuzo Shigematsu accepted congratulations
on behalf of all former ABCC-RERF employees. But
it was particularly noteworthy that the final speakerof this opening ceremony was Mr. Sunao Tsuboi,
representative of the Japan Confederation of A-bomb
Sufferers Organizations, who was invited by NAS.
Most participants probably would agree that his
address commemorating RERF’s achievements fromthe perspective of a survivor was a highlight of thesymposium. Mr. Tsuboi told his own story of exposure to the A-bomb radiations and referred to his
ardent wish for the abolition of nuclear weapons. He
expressed confidence that RERF would continue tocontribute to the future survival of all humanity
through its research activities. His concluding remark“Never give up!” won the sympathy of the audienceand elicited a spontaneous standing ovation. Despite
being over 80 years of age and suffering from several ailments, it was Mr. Tsuboi’s energetic, thoughtful, and motivational message that produced an
outpouring of emotion which was shared by the Japanese and U.S. participants in the audience.
The History
Following the opening ceremony, the special day’s
program was introduced by the Vice Chairman of
the National Academies’ Nuclear and Radiation
Studies Board (NRSB), Dr. James Adelstein. The
program included three sessions regarding ABCCRERF’s history, major scientific contributions, andfuture. Dr. Adelstein introduced Dr. William “Jack”
Schull, a former ABCC department head and aformer RERF director, who served as moderator of
the historical session and presented a keynote lecture: “Hajimeru—ABCC and the early years.” Dr.
Robert Henshaw then showed some of the earlyphotographs taken by his father, Dr. Paul Henshaw,
during his early visits to Hiroshima and Nagasaki asa member of the group that was responsible for someof the earliest assessments of the effects of the Abombs in 1946. The Henshaw family has donatedthe photos to the archival collections of the ABCCReturn to Table of Contents

RERF. Dr. Carl Tessmer, the first director of ABCC
(1948–1951) gave his greetings and congratulations
in a recorded message. A film followed, in which
two of ABCC’s first and longest-term employees,
Mr. Michael Rappaport and Mr. Shizuo Inoue,
reminisced about their experiences. Mr. Rappaporthelped to direct the construction of the ABCC buildings on Hijiyama beginning in 1946 and later held
the position of Business Administrator until his
retirement in 1988. Mr. Inoue was recruited as an
ABCC Motor Pool Dispatcher in 1949 and eventually assisted Chairman Shigematsu until he retiredin 1997. You may recall reading more about these
two employees in RERF Update Volume 18, 2007.
A panel joined Dr. Schull on stage that included
four of the early U.S. physicians who spoke about
their recollections as NAS employees assigned to
ABCC. Dr. James Yamazaki arrived in 1949 andwas in charge of the Nagasaki Laboratory between
1949–1951. Dr. Niel Wald was the Senior Hematologist at ABCC from 1954–1957. Dr. Bertrand(Randy) Brill arrived in Hiroshima as a Public
Health Service Officer in July 1957, at a time whenDrs. George Darling and Beebe arrived at ABCC.
He spent more than two years, mostly in Nagasaki,
as a member of the ABCC Statistics and Medicine
Departments. Dr. Stuart Finch spent a total of nineand half years as either Chief of Medicine at ABCC
or Chief of Research at RERF while on leave ofabsence from his medical school positions. He
pointed out the relatively large numbers of visiting
scientists to RERF from both Dartmouth College(from which he and Dr. Beebe graduated) and Yale
Medical School (where Dr. Finch served as head of
the Division of Hematology for 24 years). Following the panel discussions, Dr. James Norman, aVisiting Statistician at RERF during 1975–1977,
gave a brief account of Dr. Beebe’s founding of theNAS’ Medical Follow-up Agency that provided
management and oversight of the RERF. Dr. James
Liverman, formerly affiliated with the ABCC-RERF
through the U.S. Department of Energy, gave a firsthand account of the transition of ABCC to RERF in
RERF Update Volume 19, Issue 1, 2008

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RERF News
1975. The historical session concluded with Dr.
Itsuzo Shigematsu reflecting on the major highlights
and contributions of ABCC-RERF during his earlier years as an epidemiology advisor to ABCC andhis 16 years as the longest-term Chairman of RERF,
beginning in 1981.
Major Scientific Contributions
Attention turned to the major scientific contributions of ABCC-RERF in the next session that wasmoderated by the former Chairman of RERF (2001–
2005), Dr. Burton Bennett, who served as the only
U.S. Chairman of RERF. The first speaker, Dr. Dale
Preston, served more than 20 years as a biostatistician at RERF and most of that time he was Chief ofthe Department of Statistics. He began his presentation “Radiation effects on cancer risks in the
ABCC-RERF Life Span Study and in utero
cohorts” by describing the important role that Dr.
Beebe played in developing ideas for the ABCC
cohort-based studies of cancer and other outcomes.
He also described the impact of the NAS committee
chaired by Dr. Thomas Francis that was formed toassess the early stages of ABCC research and thatrecommended a unified study plan and the need forsound dose estimates. He then focused on the estimates of radiation effects on cancer risks derived
from the Life Span Study (LSS) that was formed in
1958 and contains 121,320 persons and the cohortsthat include 3,638 persons who were exposed inutero.
The major questions addressed by the LSS
included: “Does cancer risk increase with dose, andif so, what is the shape of the dose-response curve?”and “How does the increase in risk depend on nondose factors such as gender, age at exposure, age atdeath or diagnosis (attained age or age), time since
exposure, and other factors such as nutrition, smok-

ing, reproductive history, genotype, phenotype, etc.?”
He described the results of the analyses with respect
to relative risk (RR, ratio to what is expected in acomparable unexposed population), excess absolute
rate (EAR, difference from what is expected in acomparable unexposed population or baseline), andexcess relative risk (ERR, ratio of EAR to what is
expected in a comparable unexposed population or
proportional increase). The number of subjects invarious dose categories and their attendant cases ofsolid cancers are shown in Table 1, with the resultthat women appear to be more sensitive than men
when ERR% and EAR are taken into account. The
dose response is illustrated in Figure 1 in which thelinear model (red line) describes the data well with alinear dose response on 0–0.15 Gy, and no indication of a threshold. The non-parametric model(dashed and bolded blue line) suggests some upwardcurvature on the 0–2 Gy range (P = 0.09).
The age-time patterns for A-bomb survivor solidcancers are shown in Figure 2 which illustrates:• ERR higher for younger exposure ages anddecreases with increasing age at diagnosis• EAR higher for younger exposure ages and increases throughout life following exposure toradiation
Cancer incidence has also been characterized forsite-specific risks as shown in Table 2 where the largest proportion of radiation-attributable cases are forbreast, thyroid, and non-melanoma skin cancers.
An increase in leukemias was observed relatively
soon after the A-bombs and LSS leukemia mortality
is shown in Table 3, including the observations that
despite smaller numbers of excess cases, a considerably larger proportion of the cases are radiation-associated than for solid cancer and the dose response
appears non-linear over the low-to-moderate dose
range.

Table 1. Solid cancer risks among A-bomb survivors (1958–1998)
Dose category(Gy)

Subjects

Person years

Cases

RadiationassociatedAttributablefraction (%)<0.0050.005–0.1
0.1–0.2
0.2–0.5
0.5–1
1–2
2+

60,792
27,789
5,527
5,935
3,173
1,647
564

1,598,944
729,603145,925
153,886
81,25141,412
13,711

9,597
4,406
968
1,144
688
460
185

3
81
75
179
206
196
111

0%
2%
8%
16%
30%
43%
60%

2,764,732

17,448

853

11%

Total
ERR%*
EAR**

105,427
women
58% per Gy
60 per Gy

men
35% per Gy
43 per Gy*ERR/Gy at age 70 following exposure at age 30**Excess cases per 10,000 PY Gy at age 70 following exposure at age 30

Return to Table of Contents

RERF Update Volume 19, Issue 1, 2008

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RERF News

Figure 1. LSS solid cancer incidence (1958–1998) dose response.

Figure 2. A-bomb survivor solid cancer age-time patterns.

Table 2. Solid cancer incidence and site-specific risks
Excess Attributable
cases
risk*

Site

Cases

StomachFemale breast
Remainder
Lung
Colon
Thyroid
Liver
Non-melanoma skin
BladderBrain, CNS
RectumUterus

4,730
1,073
3,325
1,759
1,516
471
1,494
330
469
281
838
1,162

151
147
126
117
78
63
54
40
35
19
14
10

7%
27%
8%
15%
11%
25%
8%
23%
16%
13%
4%
2%

All solid

17,448853

11%*Percentage of excess cases among those with dose
>5 mGyReturn to Table of Contents

Dr. Preston summarized by pointing out that theresults of the LSS analyses provide:• unequivocal evidence of life-long dose-related
increase in cancer rates following exposure at
any age;• a linear solid-cancer dose response even into a
relatively low dose range;• temporal patterns and gender differences thatprovide general insight into carcinogenesis;• characterization of site-specific solid cancer
incidence rates; and• information that serves as a primary source forquantifying risk estimates for radiation protection and risk projections which are utilized bymany countries throughout the world.
The results of the leukemia risks from the in utero
cohort studies do not show a dose response which issurprising given the striking dose-related increase
following early-childhood exposure and the highchildhood leukemia and other childhood cancer risks
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Table 3. LSS leukemia mortality (1950–2000)
Marrow dose

Subjects

Person years

Cases

Estimated excess

AR%<0.0050.005–0.1
0.1–0.2
0.2–0.5
0.5–1.0
1.0+

36,50230,898
6,006
6,993
3,512
2,700

1,342,168
1,135,582
223,701
256,584
129,053
97,267

89
69
17
31
27
63

0
4
4
13
18
55

0%
6%
25%
41%
68%
87%

Total

86,611

3,184,355

296

94

46%*

*Attributable risk % among survivors with marrow dose >0.005 Gy

reported in case-control studies of effects following
pre-natal x-ray exposures.
Dr. Preston concluded by acknowledging the important contributions made by the A-bomb survivors
and several ABCC-RERF scientists and staff who
have been “standing on the shoulders of giants such
as Gilbert Beebe, Seymour Jablon, Jim Neel, andJack Schull.” He pointed out that with more than
40% of the A-bomb survivors still alive, and most of
those alive having been exposed to the radiation as
children, potentially more than 40% of the LSS
excess solid cancers are yet to occur and there is muchto be done in the next 20 years.
After a lunch break, a film “RERF Today” wasshown followed by a violin solo performed by Mrs.
Mayumi Pawel and accompanied by pianist Dr.
Alejandro Hernandez-Valdez. Mrs. Pawel lived in
Hiroshima from 1992–1994 when her husband,
David, was a statistician at RERF.
The scientific session continued with a presentation by Dr. Saeko Fujiwara, Chief of the RERF
Department of Clinical Studies, titled “The Adult
Health Study: Clinical health assessments,
biospecimens, and medical support for A-bomb
survivors.” Dr. Fujiwara, who has been conducting
clinical studies at RERF for more than 20 years, de-scribed the Adult Health Study (AHS), a subcohortof the LSS that was begun in 1958 with 20,000 study
subjects. Some 17,000 individuals in the AHS, whocurrently number about 4,000, have had clinicalexaminations every two years. The participation ratein the first exam cycle in 1958–1960 was about 90%
and for 50 years has remained amazingly high (85%have participated in more than 20 examinations and
60% have participated in all 24 examinations) and
4,000 (about 70%) underwent examinations in the
24th cycle in 2004–2006 when the average age ofthe cohort was 72 years. Blood samples obtained
from the AHS participants are used for basic researchand stored for future studies. Storage of serum
samples began in 1969 and samples have beenobtained from about 16,000 AHS subjects. Storageof blood cells began in 1990 and blood cells fromabout 7,000 persons have been stored.
An important finding of the AHS study has been
associations between certain non-cancer healtheffects and radiation exposure. For example, a significant linear dose response was found for uterine
myoma, thyroid diseases, and chronic liver disease.
A significant quadratic dose response was found for
hypertension and myocardial infarction as illustrated
in Figure 3.

Figure 3. Dose responses for incidence of hypertension and myocardial infarction, 1958–1998.
(Yamada M et al. Radiat Res 161:622, 2004)

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Figure 4. Radiation dose responses for thyroid nodules and effects of age at the time of bombing.
(Imaizumi M et al. JAMA 295:1011-22, 2006)

A recent comprehensive thyroid evaluation study
demonstrated a significant linear dose-response
relationship for solid nodules, malignant tumors, andbenign nodules (see Figure 4), with younger survivors having a higher risk than older survivors, while
no significant dose response was observed for positive anti-thyroid antibodies, hypothyroidism, andGraves’ Disease.
There is, so far, little or no evidence of radiation
effects on risks for chronic infectious diseases, suchas tuberculosis, autoimmune diseases such as rheumatoid arthritis, or common diseases associated withaging such as dementia, osteoporosis, and prostate
hyperplasia. In terms of sub-clinical conditions,markers related to inflammation increased withradiation dose. Since chronic inflammatory conditions can lead to various diseases, RERF has studies

underway examining inflammation as an intermediate factor in the pathways by which radiation induces
non-cancer disease.
One of the early ABCC findings was that radiation-induced cataracts developed relatively early
after the A-bomb exposures. RERF studies showedthat cortical and posterior subcapsular opacities
increased with radiation doses, whereas there was
no evidence for increases for nuclear opacities.
Recent studies demonstrate that clinically significant
cataracts that were removed surgically increased withradiation dose compatible with a no-thresholdresponse. Those results are illustrated in Figure 5.
The survivors who were exposed in utero have
now reached the age of 62 years. Recent studies wereconducted to examine the effects of prenatal exposure on non-cancer disease and, thus far, no increased

Figure 5. Dose responses for postoperative cataract. Prevalence study in 2000–2002.
(Neriishi K et al. Radiat Res 168:404, 2007)

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Figure 6. Age-adjusted incidence of stroke and coronary heart disease
by radiation dose (AHS, 1958–1978, Hiroshima females).

risk of prenatal radiation exposure was observed forthyroid nodules, hypertension, hypercholesterolemia,
or myocardial infarction and stroke.
Dr. Fujiwara acknowledged the important contributions that the A-bomb survivors have made to the
AHS and pointed out that participants are informedof the examination results with health guidance, andif necessary, are referred to local physicians for further examinations and treatment. She concluded bysummarizing that in addition to providing importantdata regarding the health effects of radiation, the AHS
has contributed important biospecimens used forbasic research and provides a number of beneficial
services to the participants including disease prevention through early disease detection, medical consultation, health guidance, and welfare services.
Dr. Kazunori Kodama, currently a Chief Scientist at RERF, was introduced to discuss “ABCCRERF epidemiology: Non-cancer diseases in the
LSS population, and cancer and multifactorialdisease in the F1 population.” Dr. Kodama firstjoined the Department of Medicine of ABCC in 1974
and has served as the Chief of both the RERF Department of Clinical Studies and later the Department of Epidemiology. In his presentation, Dr.
Kodama showed the early data from 16,000 AHS
subjects that suggested a dose-related increase in bothstroke and coronary heart disease, especially in
Hiroshima females, and most markedly in survivors
who were under the age of 30 at the time of the bombing (Figure 6).
Later LSS mortality studies revealed a causespecific dose response for non-cancer deaths fromheart disease, stroke, respiratory disease, and digestive diseases as illustrated in Figure 7. Current studies continue to explore the apparent increases in noncancer mortality associated with radiation dose, especially ischemic, hypertension, and rheumatic heartdiseases, since the survivors who are alive today are
entering the decades of life when these diseases beReturn to Table of Contents

come predominant causes of death.
Dr. Kodama concluded his presentation by describing the results of studies of the second-generation (offspring born to one or both parents who were
A-bomb survivors). Risk estimates for multi-factorial disease in relation to parental radiation doseamong the offspring in those F1 Clinical Studies
showed no evidence of an increased risk of adultonset multi-factorial disease with parental radiation
exposure. Furthermore, a series of genetic studies at
ABCC-RERF over many years did not detect radiation effects for malformations, stillbirths, perinatal
death, sex ratios, growth and development, chromosome aberrations, protein analyses, mortality, andcancer incidence in the F1 generation.
The final RERF scientist speaking in this session,
Dr. Nori Nakamura, summarized the many basic
science and laboratory studies conducted over theyears as “ABCC-RERF laboratory studies: Past
and future.” Dr. Nakamura joined RERF in 1984
and was Chief of the Genetics Department from1998–2006. He is currently an RERF Chief Scientist and his presentation focused on five topics thathe chose to highlight.
1. Individual radiation sensitivity. While the resultsof early studies demonstrated that normal skinfibroblasts showed a wide variation in radiation
sensitivity, studies using blood lymphocytes
generally did not.
2. Mutant cell frequencies in vivo. Glycophorin A(GPA) mutations were studied in red blood cells
but clearly were not a suitable biomarker forradiation dose (biodosimetry). HPRT (hypoxanthine-guanine phosphoribosyl transferase)
mutations showed only a weak correlation withradiation dose and T-cell receptor (TCR) mutants did not persist and disappeared with time
as did dicentrics. The somatic mutation studies
concluded: (a) that while bone marrow stem cells
provide red blood cells for decades and can
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Figure 7. Cause-specific dose-response functions for non-cancer deaths, LSS, 1950–1997(Preston DL et al. Radiat Res 160:381-407, 2003).

record mutations, the number of stem cells is
not large; (b) some mutations in lymphocytes
are negatively selected and cannot be sustainedin vivo; and (c) although they require tediouswork to score, chromosome aberrations remain
one of the best biomarkers and biodosimeters
for radiation exposure.
3. Genomic instability in vivo. Clonal cell populations marked by stable-type aberrations (translocations) were examined using techniques suchas G-banding and multicolor fluorescence in situ
hybridization (M-FISH). There appeared to be
no indication that there was an increased frequency of spontaneous translocations amongclonally-derived cells, and it is unlikely that theoverall translocation frequency includes a large
contribution from genomic instability.
4. In utero exposures. While it is generally believedthat the fetus is hypersensitive to radiation,
A-bomb survivors exposed in utero did notindicate a radiation dose response for translocations when examined at 40 years of age. However, when mothers who received >0.5 Gy doses
were studied they did show a dose response for
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translocations. Therefore, the lack of a responsein the in utero cohort is due to a biological effect.
Subsequent studies in mice confirmed that irradiated fetuses do not sustain the cytogenetic
damage in hemato-lymphoid cells (Figure 8)
and these results appear to be related to theunexpectedly low excess risk of cancer in thesurvivors who were exposed in utero.
5. Germline mutations. Dr. Nakamura concluded
by describing some of the ongoing studies thatare using two-dimensional DNA gel electrophoresis (2DE) to visualize about 1,000 DNA
fragments that are visualized in an autoradiogram. In mice, the mean mutation induction rate
at 1,000 loci appears to be much lower than thehistoric mouse genetic “Russell Studies” at 7
loci. Studies using new microarray technologies(a 2,500 BAC-array) are also being used tosearch for alterations in DNA in the offspring of
A-bomb survivors.
So despite many avenues of research that are being explored, chromosome aberrations appear to remain an important biomarker and biodosimeter.
RERF scientists are attempting to further calibrate
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Figure 8. The frequency of translocations detected in blood lymphocytes (closed
square), spleen cells (open square), and bone marrow cells (triangle),in mice exposed to 2 Gy of X rays at different ages indicated on the xaxis but were all examined at 20 weeks of the age.
(Nakano M et al. Radiat Res 167:693-702, 2007)individual doses in survivors using the technique ofelectron spin resonance (ESR) in tooth enamel tomeasure radiation dose in teeth donated by survivors. The results of this biodosimeter are being compared to calibration curves using chromosome aberrations in the same survivors.
Dr. Martha Linet, Chief of the Radiation Epidemiology Branch of the National Cancer Institute(NCI), spoke about the many contributions that
RERF has made as a result of several long-standing
collaborations between the NCI and RERF scientists, especially with respect to site-specific cancer
risk assessments following exposure to radiation.
Several NCI scientists, such as Dr. Beebe, hadworked at ABCC and RERF over the years. Dr.
Burton Bennett concluded this session by summarizing the impact of ABCC-RERF on radiation risk
assessment through the contributions to bodies suchas the NAS’ BEIR committees, and to the work of
NCRP, ICRP, and UNSCEAR. He was especiallyfamiliar with the contributions to the latter body,having served 12 years as director of the UNSCEAR
secretariat in Vienna, Austria.
The Future
The final session of the symposium focused on
the future of RERF and was moderated by Dr.
Charles Waldren who served as the RERF Chief
Scientist and then became the former Vice Chairman and Chief of Research. Dr. Waldren pointed outthat one of the valuable resources at RERF is thelarge number of biospecimens that have been collected and stored. In order to exploit the potential
for these samples to contribute knowledge regarding mechanisms of radiation-induced adverse health
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effects, RERF is challenged to employ the latest technologies of molecular biology and perhaps establish
collaborations with investigators from laboratories
around the world who are refining new methodologies and investigations. He introduced the final keynote speaker of the symposium, Dr. Joe Gray, currently the Associate Laboratory Director for Life andEnvironmental Sciences and Life Sciences Division
Director at the Lawrence Berkeley National Laboratory whose lecture was titled “The ‘omic’ revolution and epidemiology.”
Dr. Gray outlined the goal of his lecture which
was to review the “omics” landscape and provide
some of the technological advances that have beenmade. He also promised to illustrate some applications of the methodologies to epidemiological research and to summarize some of the lessons learned
from those applications. He defined the scope of omic
analyses at levels of DNA, RNA, proteins, and pathophysiology, and indicated that omic analyses at alllevels may eventually reveal molecular events that
influence disease susceptibility.
Dr. Gray first reviewed the use of various microarrays for scanning genomes for disease-associatedpolymorphisms and the identification of cancer
susceptibility loci. He predicted that the use ofnumerous low penetrance, high prevalence single
nucleotide polymorphisms (SNPs) are likely to contribute to a better understanding of the risks of breast
cancer. He then proceeded to take the audience on a“journey” through various examples of this dynamic
field of molecular biological and technologicaldevelopments. Some major approaches included:• Integration of mouse and human studies to validate functional polymorphisms;
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• The use of large-scale copy number polymorphisms (CNPs) in the human genome whereallele-specific copy number analyses of tumors
may suggest candidate polymorphisms to betested in epidemiological searches for susceptibility genes;• Next-generation array technologies (such as
molecular inversion probes [MIPs]) and candidate disease-associated SNPs and mutations
are emerging from genome-wide sequencing
efforts;• The Cancer Genome Atlas (TCGA) Project
should accelerate studies given the large number of participants at numerous institutions
across the U.S.;• Genome-scale DNA and epigenome sequencing will generate a candidate disease gene “partslist” to guide future epidemiological studies;• Advances have been rapid as illustrated by going from 454 sequencer 100 million bases with
250 bp reads to Helicos 1 billion bases in 25–
35 bp reads;• The next generation of sequencing and highthroughput sequencing of affinity-enrichedsequences will enable one to capture “all”
human exons on arrays;• Epigenomic events may be important; functional proteomics could employ reverse-phase
protein lysate arrays and use protein profilingto predict mutational status; and• Proteomic platforms should become potentiallypowerful tools for detection of pathway-associated molecular aberrations that may be especially suitable for detection of blood-borne
disease indicators.
Dr. Gray emphasized that the manipulation of invitro systems can identify molecular events associated with response phenotypes. The large collectionof well-characterized lymphoblastoid cell lines at
RERF might be used to facilitate discovery of a rangeof biomolecular associations.
Dr. Gray concluded his lecture with three observations:• Powerful analysis tools are permitting discovery of candidate disease variants in all parts of
the “ome”;• Robust technologies support analyses of variants in archival materials; and• Well-studied RERF populations and RERF’s
biosample archives constitute a unique resource
for a broad range of molecular epidemiologic
studies.
Two relatively new initiatives were the focus of
the next part of this session. Dr. Scott Davis is Chairman of the Department of Epidemiology at the University of Washington and he served as a Research
Associate in Epidemiology at RERF from 1983–
1985. Dr. Davis, along with his biostatistician
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14colleague Dr. Kenneth Kopecky, developed aPartnership in March of 2005, with RERF, the University of Washington (UW), the Fred Hutchinson
Cancer Research Center (FHCRC), and Kurume
University (KU) in Japan. Supported with funds
provided by DOE through the NAS, the Partnership’s
goals are to:• encourage and facilitate scientific exchange andcollaborations in epidemiology and biostatistics;• provide expertise and advice to RERF fromscientists at UW, FHCRC, and KU;• augment RERF staff with students and faculty;• assist NAS in recruiting a new generation ofqualified investigators to RERF;• develop and provide training opportunities toattract talented young investigators to careers
in radiation science; and to• provide RERF scientists with access to expertise and opportunities for training in developing areas of epidemiology and biostatistics.
Dr. Davis reviewed the current research projectsof the three graduate students and the three faculty
members affiliated with the UW and FHCRC component of the Partnership.
Dr. Tatsuyuki Kakuma, Professor of Biostatistics
and Director of the Biostatistical Center in Kurume
University, completed the presentation by describing the role of his university in the Partnership.
Kurume University’s School of Medicine is 80 years
old and the only medical school in Japan with a federally-supported graduate program in biostatistics.
A second initiative was represented by the presentation by Dr. David Pawel, a statistician in the
U.S. Environmental Protection Agency. Dr. Pawel
was the second scientist sponsored by a Gilbert W.
Beebe Fellowship, a research program administeredby NAS through funding provided by DOE. The
purpose of the Beebe Fellowship is to provide scientists the opportunity to spend some time working
at RERF in order to become more familiar with the
RERF research and to learn more about the radiation sciences while contributing to the RERF research
activities. The goal is to attract new scientists into
radiation statistics and epidemiology with the hopethat some might even become interested in working
as an NAS/RERF employee in the future or, at thevery least, might develop future scientific collaborations. Dr. Pawel presented results of his studies
which tested methods for sharing information among
data for specific cancer types to improve site-specific radiogenic risk estimates such as improved
estimates of ERR: “Improved estimates of cancer
site-specific risks for A-bomb survivors.”
The DOE’s support of the RERF program resides
in the Office of Health and Safety (HS) within DOE’s
Office of Health, Safety, and Security (HSS). The
Director of HS, Dr. Patricia Worthington, described
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RERF News
the activities of a Senior Review Panel on Future
Planning for RERF as “The future of RERF: Viewof a funding agency.” That panel is charged withmaking recommendations regarding the future of
RERF and to provide a vision of what RERF shouldlook like at various time points during the next 20
years and beyond. Chaired by Dr. Paul Gilman (OakRidge Center for Advanced Studies) and Dr.
Sadayoshi Kitagawa (Japan Public Health Association), the panel consists of a total of four U.S. scientists and four Japanese scientists and is expecting todeliver its report to DOE and the Japanese Ministryof Health, Labour and Welfare in 2008.
Dr. Toshiteru Okubo, the current Chairman of
RERF, presented his “Personal perspectives
regarding RERF’s future.” He began by reviewing the key characteristics of the ABCC-RERF studies which have contributed to the important RERF
achievements, namely the large-scale cohorts consisting of both genders and all age groups, the longterm dedicated institutional follow-up, and thedevelopment of a dosimetry system for determining
individual doses that spanned a relatively large dose
range. Most importantly, he emphasized the sacrifices and the commitment to participation made by
the A-bomb survivors and whose contributions
inspire the resolve to never give up on the Foundation which is a symbol of the eternal desire of theJapanese and U.S. peoples for world peace and theabolition of nuclear weapons. He pointed out that
RERF’s future is important because the exposed
population includes a large percentage with relatively
low doses in the 0.005–0.1 Gy range which is anarea of interest to the world’s radiation protection
community. Also, more than 40% of the LSS cohort
members are alive today and most of them were <10years of age at the time of the bombing. As thosesurvivors enter their cancer-prone years, more
cancers (perhaps as many as have occurred during
the first 60 years of this study) are projected tooccur. Furthermore, the survivors have contributed
biospecimens which have the potential to contribute
important information related to the processes leading to adverse health effects, such as cancer and heartdisease. And finally, new technologies of modern science may provide more sensitive assessments ofwhether there are radiation-induced health effects in
the F1 generation. He concluded by pointing out that
the RERF future should be bright provided RERF
continues to: (a) build strong collaborations withinternational scientists; (b) accumulate reliable data;(c) contribute to world peace and the health of mankind; (d) maintain high standards and is a “Center of
Excellence” for research and education; and (e) build
affiliations with international organizations.
The final presentation was made by the current
Vice Chairman and Chief of Research at RERF, Dr.
Roy Shore, whose talk was titled “Future RERF
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15
research directions: Continuity and change.” Hebegan by pointing out how RERF’s cancer mortality
and incidence data are used in many ways, including:• establishing exposure standards and risk estimations for radiation workers and the public;• developing probability of causation assessments for workers and for compensation;• assessing the impacts of radiation accidents;• estimating the effects that radiation has had on
special groups, such as fetuses and young children; and• estimating potential affects of medical radiation exposures.
Dr. Shore then focused on a number of issues andchallenges that remain to be resolved in RERF’s
future including:• what we expect to learn about radiation andcancer in the next 20 years;• cancer and non-cancer research in the clinicalAHS;• studies of the relationship between radiation andcirculatory disorders;• radiation and heritable diseases in the F1 generation; and• basic research on radiation such as susceptibility to disease and to radiogenic cancers, including genetic, immunological, and phenotypic
aspects of radiation and aging, and transgenerational effects.
He concluded by emphasizing that the AHS
provides a rich biospecimen resource permitting
innovative studies of radiation and disease and thepotential for strategic collaborations for ideas,
expertise, and access to new techniques and methodologies. RERF has a unique opportunity tocontinue to provide essential new information onradiation risks that is vital given the world’s widespread and increasing use of radiation.
Dr. Evan Douple, Scholar in the National Academies’ NRSB and the Responsible Staff Officer for
NAS’ support role in RERF for more than 10 years,
closed the symposium by thanking the speakers, theattendees, and the sponsors, including the Presidents
Committee of the National Academies, the Environmental Protection Agency, and the Department ofEnergy—and recognized Dr. Joseph Weiss in theaudience who has been the DOE’s Project Manager
for RERF for more than 10 years. He reminded theaudience that the symposium was dedicated to all of
the current and past employees of ABCC-RERF and
the A-bomb survivors—such as Mr. Tsuboi—whose
contributions and participation in the studies were
essential to the success of ABCC-RERF. And heacknowledged the presence in the audience of Mrs.
Cathie Berkley and Mr. David Williams, who havebeen intimately associated with the National Academy of Sciences support of the ABCC-RERF project,
each for more than 40 years. Finally, he turned to
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16

RERF Newsthe symbol that was chosen forthe banners on the stage and thesymposium program cover andposters—the 380 year-old bonsai that had survived the A-bombin Hiroshima. A delegation from
RERF, including scientists, directors, and Mr. Tsuboi visited
the U.S. National Arboretum in
Washington the day before thesymposium to view the actual
tree. It stands at the entrance to
the Arboretum and is a dignified
testament to Japan-U.S. cooperation and to peace, beauty, andsurvival.

With the “Yamaki’s Pine” at the U.S. National Arboretum in Washington, DC,(from left) Dr. Kazunori Kodama, Dr. & Mrs. Itsuzo Shigematsu, Mr. Sunao
Tsuboi, Dr. Toshiteru Okubo, Mr. Takanobu Teramoto, and Dr. Saeko Fujiwara

RERF Chairman Meets with the U.S. Secretary of Energy
Dr. Toshiteru Okubo, RERF Chairman, paid acourtesy visit to Dr. Samuel Wright Bodman, the 11th
U.S. Secretary of Energy, on December 13, 2007,

Dr. Toshiteru Okubo (at left) presenting Dr. SamuelBodman with an aerial photo of RERF Hiroshima
Laboratory

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the day following the Beebe Symposium. Dr. Bodman,
who received a bachelor’s degree in chemical engineering from Cornell University and a doctor ofscience degree from the Massachusetts Institute ofTechnology, has had a long and sincere interest in
RERF’s research, and dialogue between the twocontinued for more than ten minutes.
Arrangements for the courtesy visit were madeby Mr. Glenn Podonsky, Chief Health, Safety andSecurity Officer, Dr. Patricia Worthington, Director
for Health and Safety, and Dr. Joseph Weiss, Japan
Program Manager, Office of International HealthStudies, Department of Energy (DOE). This was thefirst visit with the DOE Secretary by an RERF chairman since the inauguration of RERF in 1975. Chairman Okubo presented Dr. Bodman with an aerial
photo of RERF’s Hiroshima Laboratory as a memoryof the occasion, which Dr. Bodman unwrapped on
the spot and hung on the wall of his office.

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RERF NewsThe RERF scientific staff continues to evolve withnew recruitments, retirements, and visiting scientists.
During the period of April 2007 to March 2008 there
have been three new additions to the scientific staff,
along with three departures. In addition, two longterm employees retired but were rehired under new
contracts of employment.
Dr. Nobuko Sera joined the Division of Internal
Medicine, Department of Clinical Studies, inNagasaki, in April 2007, as a fixed-term researchscientist. She came from the Nagasaki University
Graduate School of Biomedical Sciences and
Mitsubishi Hospital. Dr. Susan M. Geyer joined theDepartment of Statistics in June 2007 as an Associate Senior Scientist. She had been working at theMayo Clinic in Rochester, Minnesota and brings
valuable expertise in analyzing biological data,
including high-dimensional data analyses andbioinformatics. Her advice and participation in RERF
research will be very important as RERF enters the‘omic revolution of bioresearch and she was instrumental in working with the Chief of Statistics, Dr.
Phil Ross, and the RERF department chiefs in planning a Bioinformatics Symposium held March 24–
25, 2008.
Dr. Thomas M. Seed resigned as Associate Chiefof Research in December 2007 and he returned tohis home in Bethesda, Maryland. Dr. Seed has had avery positive impact on RERF through his oversightof the Genetics and Radiobiology/Molecular Epidemiology Departments and chairing of the Scientific
Reports Review Committee and the Biological
Samples Committee (BSC). Before he left RERF he
was instrumental in working with Dr. Kei Nakachi
to organize a major symposium held at RERF in
November 2007 in a collaboration between RERF
and the U.S. National Institute of Allergies andInfectious Diseases (NIAID) on the subject ofRadiation and Age-associated Immunosenescence(see meeting report on page 20). He also prepared a

BSC report that summarizes the status of RERF
biosamples and makes important recommendations
regarding this precious RERF resource.
Dr. Seed was replaced in January 2008 by Dr.
Evan B. Douple. Dr. Douple had been directly
involved in the RERF for more than 10 years, withresponsibility for the National Academy of Sciences(NAS) role in supporting RERF, most recently as a
Scholar in the National Academies, and prior to that,as director of the Board on Radiation Effects
Research with involvement in the most recent BEIR
studies. While he had visited RERF several times
and was quite familiar with RERF research andscientists, he is now pleased to be able to help provide support as an RERF employee living here in
Japan. Prior to joining NAS in 1992, Dr. Douple had
been a radiobiologist and Professor of Medicine at
Dartmouth Medical School for more than 20 years.
During this past year long-term RERF employee
Dr. Kazunori Kodama retired as Chief of the
Department of Epidemiology to focus on his role as
Chief Scientist. Dr. Fumiyoshi Kasagi was
appointed Acting Chief. In addition, Dr. Jun-ichi
Asakawa was appointed Acting Chief of the Genetics Department in December 2007, replacing Dr.
Norio Takahashi who faced mandatory retirementin June 2007 but who was reemployed.
Other departures included Dr. Frederic A. A.
Lagarde who had been employed in the Departmentof Statistics since June 2003 and who resigned in
October 2007 and returned to his native country ofFrance. Dr. Hidetaka Eguchi resigned from the
Department of Radiobiology/Molecular Epidemiology in September 2007 where he had been contributing important work in the area of molecularbiological studies since July 2001 (see his excellent
review article on the molecular features of colorectal
cancer in the Update Volume 18). Dr. Eguchi has
joined the faculty of Saitama Medical University.

Student Researchers
While RERF scientists have been involved every
year with training students and short-term visitors,
two students have spent several weeks in 2008 in
the RERF Department of Statistics working on their
Ph.D. dissertations. Carmen D. Tekwe is from the
Department of Biostatistics in the School of Public
Health and Health Professions at the State University of New York at Buffalo. She is working with
her advisor, Professor Randy L. Carter (a former

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RERF scientist in the 1980s) on the application ofgeneralized multiple indicators multiple causes measurement error (G-MIMIC ME) models to dose uncertainties in RERF data. Guangquan “Philip” Li
is from the Department of Epidemiology and Public
Health, at the Imperial College London Faculty of
Medicine, St. Mary’s Campus. He is working withhis advisor Dr. Mark P. Little on a Bayesian approach
to modeling of measurement error using RERF data.

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Gilbert W. Beebe Fellows
The Gilbert W. Beebe Fellowships were established in order to provide an opportunity for scientists to work at RERF in order to become morefamiliar with RERF’s research and to explore thefields of radiation epidemiology and statistics. The
Fellowships are supported by the National Academyof Sciences in collaboration with the U.S. National
Cancer Institute’s Radiation Epidemiology Branchusing funds provided by the U.S. Department ofEnergy. During the past year, two Beebe Fellows
were supported and conducted research at RERF. Dr.
Dino Samartzis, from Chicago, Illinois, used theLife Span Study (LSS) cohort to estimate the excess

relative risk per gray of ionizing radiation exposurein the development of bone sarcomas. Dr. Byron S.
Kennedy continued a long tradition of scientists fromYale University working at RERF since he hadreceived an M.P.H. and Ph.D. in Chronic Disease
Epidemiology and an M.D. from Yale. He came to
RERF after completing a Postdoctoral Fellowshipin Cardiovascular Epidemiology at Stanford University and an Internship in Family Medicine at
Georgetown University’s Providence Hospital. At
RERF he is working on the patterns and predictorsof risk of esophageal and gastric cancers in the RERF
LSS cohort.

2008 Distinguished Lecture Series
RERF initiated a new Distinguished Lecture
Series and was fortunate to have its first two lecturers in 2008. In addition to delivering lectures, thedistinguished scientists spend time visiting with
RERF scientists and they receive briefings regarding the latest results of RERF research. Dr. Andre
Bouville, Senior Radiation Physicist, Chornobyl
Research Unit, Division of Cancer Epidemiology andGenetics, U.S. National Cancer Institute, visited
January 21, 2008. He delivered a lecture “Radiation
dosimetry for use in epidemiologic studies: Current

research program at the U.S. National Cancer Institute.”
On February 12, Dr. John D. Boice, Jr. visited
RERF and delivered a lecture entitled “Genetic consequences of cancer treatments: An international
study of the children of cancer survivors.” Dr. Boiceis from the International Epidemiology Institute andis also a Professor of Medicine at Vanderbilt University Medical Center and the Vanderbilt-Ingram
Cancer Center.

Honors and Awards Received by RERF Scientists
Poster Prize at the Fifth International
Congress on Vascular Dementia
Michiko Yamada, Assistant Chief
Department of Clinical Studies, Hiroshima

The Fifth International Congress on Vascular
Dementia was held in Budapest, Hungary, November 8-11, 2007. I participated in this congress to makea presentation titled “Incidence and risks of dementia in Japanese women: Adult Health Study,” which
was awarded second prize for posters. Modern society is populated with increased numbers of elderly,
which has made them important subjects in terms of
public-health research into the possibilities of early
diagnosis, treatment/care, and prevention of dementia. The congress is held biennially, and with eachmeeting, the number of participants increases. At thislatest congress, there were increased numbers of participants from China, South Korea, and Thailand,presenting a good opportunity to learn about relevant
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studies in the Asian region. Japanese participants,
however, represented a minority, at about 20 individuals in total.
My presentation at the above congress can besummarized as follows: “Analytical result of risk
factors for dementia supports usefulness of bloodpressure control and physical strength improvementin preventing dementia.” We have been studying
dementia within the RERF’s Adult Health Study
based on Research Protocol 5-92 since 1992. In
RERF’s study on dementia, we examine cognitive
abilities like memory and orientation (ability to understand time and place), and for persons suspectedof declining cognitive abilities, neurologists provide
a more detailed examination for determining status
of dementia incidence. Diagnosing dementia requires
many data based on cognitive ability examinations,interviews with caregivers, neurologists’ diagnoses,
CT/MRI data, and so on. This study has been madepossible with support from physicians of Hiroshima
University’s Third Department of Internal Medicine
RERF Update Volume 19, Issue 1, 2008

RERF Newsand other researchers at other medical organizations,in addition to support from RERF employees. I would
like to take this opportunity to express my sincere
thanks to my co-presenter Yasuyo Mimori of
Hiroshima University, in particular, and other related
individuals.
Finally, I think the layout and coloring of the presentation materials were important factors in theposter prize evaluation. Please let me conclude thisarticle by adding that support from Ms. Hiromi Tsuji,
a staff member of the Department of Clinical Studies, was indispensable in our receiving the prize.

Young Investigator Award from theJapan Epidemiological Association
Nobuo Nishi, Assistant Chief
Department of Epidemiology, Hiroshima

I had the honor of receiving the Young Investigator Award at the 18th annual scientific meeting of
the Japan Epidemiological Association, held inTokyo on January 25 and 26, for a study titled“Regional differences in stroke mortality using
multilevel modeling.” The award is intended toencourage continued work by promising young andmiddle-aged researchers who conduct excellent
research in epidemiology, but awardees must be
under the age of 45 at the time of the application
deadline (June 30). I consider myself very fortunatethat I did not miss my last chance to win this award,

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19since I will turn 45 this coming May.
At the awards ceremony, a professor at Nagoya
University, another winner of the award, and I each
received a certificate and a commemorative gift fromDr. Kazunori Kodama, trustee head of the association. In fact, as chief of secretariat of the association, I was responsible for choosing the new commemorative gift last year, when the secretariat office was relocated to RERF. I eventually became thefirst winner of this gift, an acrylic plaque of very
sophisticated design, although that might sound as
if I am blowing my own horn.
The research for which I received the award elucidated regional differences in stroke mortality by
population size using multilevel modeling based on
the study NIPPON DATA (participants of which are
aged 30 years or older and selected from 300 regions
throughout Japan, both of which were randomly
selected). I hope that younger research scientists win
this award in the future for research based on RERF’s
Life Span Study, Adult Health Study, and other study
cohorts.
I reported in the last issue of the RERF Update
published in 2007 that I was awarded a poster prizeat the 28th annual meeting of the International
Association of Cancer Registries held in November
2006. Now that I have received prizes from bothinternational and national associations, I guess mynext goal is to win a Hiroshima local prize. I would
like to conclude this report by asking for your continuous support and guidance.

RERF Update Volume 19, Issue 1, 2008

20

Conference and Workshop Report

RERF-NIAID Workshop: Radiation and Age-associatedImmunosenescence
27–29 November 2007, Hiroshima Laboratory
Yoichiro Kusunoki, Assistant Chief
Department of Radiobiology/Molecular Epidemiology
Various changes in the immune system become
apparent with aging, and many of these changes are
related to predisposition of aged people to a wide
variety of diseases. For example, reduction in thenumber and function of T lymphocytes with aging
causes decrease in resistance to pathogenic microbes
and exacerbation of infectious diseases and chronic
inflammation. One of the impending issues in medical care of aged people is how immunological function reduced in the aging process can be recovered
and how such recovery can lead to prevention andtreatment of infectious diseases. Currently, there areconcerns about emerging infectious diseases, suchas new types of influenza, and infection frommultidrug-resistant pathogenic bacteria, and therefore strong demand exists for studies on mechanismsof immunological aging and ways to recover immune
function so that effective measures can be establishedto protect the elderly from such disease. Thesestudies are also expected to help reduce the risk ofinfectious diseases among patients whose immune
systems have been compromised due to radiotherapy
and chemotherapy.
In view of the above, the U.S. National Instituteof Allergy and Infectious Diseases (NIAID) has been
inviting research institutes throughout the world toparticipate in collaborative studies to promoteresearch on immunological aging. On the other hand,
RERF studies have shown reduction in function andnumber of blood T lymphocytes and increase ininflammatory protein levels with increase of A-bombradiation dose, suggesting the possibility that immunological aging in A-bomb survivors has been
accelerated by radiation exposure. Dr. Thomas Seed,
former Associate Chief of Research, who resigned
from RERF in December 2007, planned this workshop to gauge the possibility of promoting RERF
studies on immunological aging through collaborative studies with other research institutes. RERF
invited to the workshop three researchers from
NIAID, five researchers from other U.S. research
institutes, and two researchers from within Japan.
Following presentations of RERF’s overall
research by RERF directors, the associate chief of
research, chief scientists, and department chiefs,
outlines of ongoing collaborative studies at NIAID,
and prospects for studies on immunological aging
were presented by Drs. Richard Hatchett, Joseph
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Kaminski, and Francesca Macchiarini (all from
NIAID). Our honest reaction at that point of theworkshop was to wonder what would be expectedof RERF’s researchers, who have promoted immunological studies on A-bomb survivors on their own,
if RERF were to embark on such international collaborative studies. Presentations were then made byDrs. Nancy Manley (University of Georgia), Yoko
Hirabayashi (Japanese National Institute of Health
Sciences), and Koji Yasutomo (Tokushima University) on “hematopoiesis and T-cell development,”Drs. Nan-ping Weng (U.S. National Institute on
Aging), Janko Nikolich-Zügich (Oregon Health andScience University), and Yoichiro Kusunoki (RERF)
on “breakdown and reconstitution of the immune
system,” and Drs. Gregory Sempowski (Duke University) and Marcel van den Brink (Sloan-Kettering
Cancer Center) on “molecular approaches to enhancing immune response,” which were followed by discussion. Vigorous debate continued thereafter onmechanisms of immunological aging and reconstitution, indicating great interest in this topic. The
discussion mainly focused on factors involved in
reduction of T-cell mediated immune competencewith aging and medical procedures for enhancementof this competence. We believe that the discussion
prompted participants to understand and support ourstudies that have been carried out based on theassumption of immunological aging in A-bomb
survivors.
This was followed by a proposal put forth by the
Department of Radiobiology/Molecular Epidemiology regarding collaborative studies on the issue ofradiation and immunological aging, the main focusof this workshop. First, Department Chief Kei
Nakachi explained the research framework of thatdepartment. Next, Assistant Department Chief
Kusunoki proposed research studying hematopoietic
stem cells and dendritic cells. Because it has beensuggested that genetic instability is involved in agerelated reduction in function of hematopoietic stem
cells, the producers of various kinds of immune cells,
genetic instability of hematopoietic stem cells
induced by radiation is considered to be one of thepossible factors in immunological aging among
A-bomb survivors. Thus, it was considered necessary to conduct studies on this possibility. Dendritic
cells are known to play important roles at the beginRERF Update Volume 19, Issue 1, 2008

Conference and Workshop Reportning of T-cell mediated immune response and in themechanism of controlling this response. Therefore,
the importance of studying the relationship between
these cells and aging of T-cell immunity in A-bomb
survivors was emphasized. Further, Dr. Tomonori
Hayashi, Chief of the Immunology Laboratory,
proposed development of a comprehensive scoring
system for immune competence. His proposal
represents an attempt at risk estimation of infectious
and inflammatory diseases on an individual basis.
Such risk estimation would be possible by collecting data on various immunological parameters basedon results of cross-sectional and longitudinalstudies of RERF Adult Health Study (AHS) subjects
and stored biological samples and by conducting
comprehensive evaluation of changes in immune
response on the basis of radiation exposure status
and aging. We obtained agreement from the workshop participants that the three research projects
proposed at this workshop would be studies incorporating the newest information on immunobiology
and genomic science based on the AHS results andimmunological studies conducted at RERF.
Following the proposals by the Department ofRadiobiology/Molecular Epidemiology, Dr. Seed
explained RERF’s stored biological specimens, andDrs. Yoshiaki Kodama, Jun-ichi Asakawa, and Norio
Takahashi from the Department of Genetics introduced the molecular genetic techniques used at
RERF. In addition, workshop participants were

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briefed on research projects at each department andtaken on a tour of the facilities to ensure that theywould have a better understanding of RERF’s overall research activities. Lastly, the participants weredivided into groups for discussion of details relating
to the three research projects proposed for collaborative studies on radiation and immunological aging(“hematopoietic stem cells,” “dendritic cells,” and“comprehensive scoring system for immune competence”). Results of these group discussions werethen summarized at a general session. Through these
discussions, opinions based on specialized fields
were exchanged vigorously concerning technicalproblems and possible directions for the respective
research projects, and ideas for the development ofplans aiming at collaborative studies were strongly
supported. In addition to these research projects,
several researchers proposed a new project toassess immune response to flu vaccinations in AHS
participants. For any of these research projects, thecooperation and support of both RERF directors andmany RERF researchers will be necessary. We hope
to conduct further discussion in the future.
Lastly, we would like to express appreciation to
the RERF directors who provided the opportunity
for holding this workshop, the researchers who madesuch valuable research presentations and participatedin the workshop discussion, and the staff members
who cooperated in organizing this workshop.

RERF Update Volume 19, Issue 1, 2008

22

Science Article: Ophthalmologic Studies in Atomic-bomb Survivors

Ophthalmologic Studies in Atomic-bomb
Survivors
Kazuo Neriishi,a Tomoko Yokoyama,b Michiya Takamatsu,b Takeshi Kumagami,cMasafumi Uematsu,c Eiko Tsuiki,c Atsushi Minamoto,d Yoshiaki Kiuchi,b Takashi
Kitaoka,c Eiji Nakashima,e Ayumi Hida,f Saeko Fujiwara,a Masazumi Akahosh,f Roy
ShoregDepartments of aClinical Studies (Hiroshima), eStatistics, and fClinical Studies (Nagasaki),and gVice Chairman, Radiation Effects Research Foundation; bDepartment of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima
University; cDepartment of Ophthalmology and Visual Sciences, Graduate School of
Biomedical Sciences, Nagasaki University; dMinamoto Eye Clinic

Synopsis: Until now, the radiation protection
community has assumed that only high doses of 2
Gy or more cause cataracts, but new data from theatomic-bomb (A-bomb) survivors suggest that thedose threshold for both minor opacities and visionlimiting cataracts may be below 1 Gy. That important finding is causing major risk assessment groups
to consider re-evaluating their guidelines for permissible occupational and medical exposures to the eye.
A well-known deterministic effect of ionizing
radiation exposure to the eye is the formation of
opacities of the lens, cataracts. At the Atomic Bomb
Casualty Commission (ABCC), and later at theRadiation Effects Research Foundation (RERF),
three major cataract studies based on ophthalmoscopic and slit-lamp examinations were conducted.
During 1963–1964, Nefzger and colleagues found asignificant radiation dose response for posterior
subcapsular cataracts,1 as did Choshi and colleagues
in a later study in 1978–1980.2 Otake and Schullreported evidence for a dose threshold,3 based on the
Nefzger study.1 In 2000–2002, Minamoto and colleagues found a statistically significant radiation dose
response for posterior subcapsular and cortical
cataracts with no clear evidence of a dose threshold.4 This article describes the recent reanalysis of
the ABCC-RERF data with a focus on the issue of
whether there is evidence for a dose-effect thresh-

old and, if so, the estimated threshold dose.5
Slit-lamp examinations were performed on
A-bomb survivors based upon an RERF ResearchProtocol (RP 3-00).6 Results from the examinationof 837 A-bomb survivors during 2000–2002 revealed
a significant radiation dose response for posterior
subcapsular cataract, cortical cataract, and retinal
arteriosclerosis.4 Furthermore, in the reanalysis of
730 A-bomb survivors, threshold estimates were 0.6
Sv (90% confidence interval [CI], <0.0 Sv–1.2 Sv)
and 0.7 Sv (90% CI, <0.0 Sv–2.8 Sv) for cortical
cataract and posterior subcapsular opacity, respectively, which are not significantly different from 0
Sv (p > 0.30) but were also compatible with a dosethreshold of >1 Gy (Table 1). Detailed analyses
applying a no-threshold model showed no dose
responses (p > 0.40) for nuclear color and nuclear
opacity. Cortical cataract showed a significant dose
effect (p = 0.002) with an odds ratio (OR) at 1 Sv of
1.30 (95% CI, 1.10–1.53) with no dose-effect modifiers. Posterior subcapsular opacity showed asignificant dose effect (p < 0.001), with an OR at 1
Sv of 1.44 for an age at exposure of 10 years (95%CI, 1.19–1.73). That dose effect decreased significantly with increasing age at exposure (p = 0.02).
The results of re-analysis in this study are quite
similar to that of the original study.4 No dose response
was observed for survivors exposed in utero (p >0.20), though this study had quite limited statistical

Table 1. Thresholds in studies in A-bomb survivors
Type of study

Threshold dose (Gy)

90% CI

Slit-lamp examination

0.6
for cortical cataract<0.0–1.2

0.7
for posterior subcapsular cataract<0.0–2.8

0.1<0–0.8

Postoperative cataract cases

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RERF Update Volume 19, Issue 1, 2008

Science Article: Ophthalmologic Studies in Atomic-bomb Survivors
power because of the small number of study members with high doses.
Similar evidence has been reported from studies
of cohorts other than A-bomb survivors. A study ofchildren living in the vicinity of the Chernobyl
accident reported a subsequent excess of cataracts.7
A Swedish follow-up study of infants treated withradium plaques for hemangiomas, reported an OR
at 1 Gy of 1.49 (95% CI, 1.07–2.08).8 A study of 295
astronauts participating in NASA’s longitudinal studyof astronaut health reported that relatively low dosesof space radiation might predispose crew to anincreased incidence and early appearance of cataracts.9 A recent study of Chernobyl clean-up workers reported significant risk estimates very similar
to the one in the present study (OR at 1 Gy of 1.42
for Stage 1 posterior subcapsular cataracts and 1.51
for Stage 1 cortical cataracts), and also foundestimates of the dose threshold that were statisticallyinconsistent with values over 0.7 Gy.10 The 2007
ICRP publication numbered 10311 summarizes that“… the lens of the eye may be more radiosensitive
than previously considered. In particular, among bothA-bomb survivors (Minamoto et al., 2004) and agroup of children treated for skin hemangioma (Hallet al., 1999), there is evidence of excesses of both
cortical and posterior subcapsular cataract at doses
somewhat lower than expected.”11
However, none of the above studies reported
evidence of radiation effects on vision-impairing
cataracts, because they were based on slit-lamp
microscope examinations and they excluded manyof the cataract cases of greatest interest, namely, themost severe cases in whom lenses had been removed.
Therefore, we evaluated evidence regarding theradiation dose response for clinically significant cataracts, namely, those that were surgically removed,on the assumption that the lensectomies in most cases
represent vision-impairing cataracts.12 We conducteda logistic regression analysis to estimate the dose
response and used a likelihood profile procedure to
determine the best-fitting threshold model among
3,761 A-bomb survivors who underwent medical
examinations during 2000–2002, for whom radiation dose estimates were available. These data
included 479 operative cataract cases. The analyses
indicated a statistically significant dose-response
increase in the prevalence of operative cataracts (OR,1.39; CI, 1.24–1.55) at 1 Gy, with no indication of
upward curvature in the dose response. (Please see
Figure 5 of Dr. Saeko Fujiwara’s presentation on the
Adult Health Study in the article of the Sixth
Annual Gilbert W. Beebe Symposium, page 10 inthis issue of Update.) The dose response was suggestive when the restricted dose range of 0 to 1 Gy
was examined. A non-significant dose threshold of
0.1 Gy (95% CI, <0–0.8) was found (Table 1). The
prevalence of postoperative cataracts in A-bomb
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23

survivors increased significantly with A-bombradiation dose. The best estimate (0.1 Gy) and upperbound (0.8 Gy) of the dose threshold for operative
cataract prevalence was much lower than the threshold of 2–5 Gy usually assumed by the radiation
protection community and was statistically compatible with no threshold at all.
Why did we observe results different from previous ones? Otake and Schull3 had conducted analyses of A-bomb cataract data that have often been cited
as showing a dose threshold. They reported that doselinearity provided an inadequate fit to their data,
while a model incorporating separate dose thresholds for gamma and neutron doses provided a goodfit. Specifically, the estimates of the dose thresholds
were 0.73 (95% CI, 0–1.39) Gy for gamma and 0.06
(95% CI, 0–0.16) Gy for neutrons. There are a few
possible explanations for the apparent dose response
and threshold differences between the current study
and theirs. Their analyses were based on datacollected in the early 1960s,1 about 20 years after
the bombings, and used the older DS86 dosimetry
system that was available in 1990. Conceivably, thetypes of early cataract observed in the 1960s differedfrom those observed in this study. Although it is notpossible to determine which types of cataract were
present then, visual impairment in the elderly iscaused mainly by posterior subcapsular or cortical
cataracts, and these showed significant dose
responses in our recent study.5
Another possibility is that age at exposure may
relate to the magnitude of a dose threshold; thepersons developing cataracts in the 1960s study weremainly those who were relatively old at the time of
the bombing (ATB), whereas the present study subjects are primarily those who were young ATB since
the older cohort members have died. Other possible
differences include improvements over time in thedosimetry13 and statistical methodology. On the other
hand, the Otake estimates of dose thresholds werealso compatible with no threshold (i.e., the CI included zero dose). Although Otake’s interpretationof a threshold for cataracts in A-bomb survivors has
been widely accepted, 14 the evidence in the
Minamoto study, which used an ophthalmologic slitlamp examination with adequate pupil dilation andthe more sophisticated LOCS II diagnostic classification system,15 is more consistent with the results
generated in the study of more severe (postoperative) cataracts.
However, there are many unanswered questions.
Some examples of questions to be addressed include:(1) Is the dose response in the LOCS II classification identical with that in a radiation-specific classification? (2) Does the association of cataract formation with radiation dose progress with time? (3) Isthere any predictive and mechanistic factor(s) in
the radiation-associated cataract formation? (4) DoesRERF Update Volume 19, Issue 1, 2008

Science Article: Ophthalmologic Studies in Atomic-bomb Survivors
radiation have transgenerational effects on the lens?
(5) Is there any relationship with other ophthalmologic findings such as arteriolosclerosis and macular degeneration?
As for radiation-specific cataract classification,
we are using the Merriam-Focht method, which isbelieved to be radiation specific,16 and stored lensimages, to re-evaluate RERF data. Stored lensimages of A-bomb survivors have great potential incataract research, not only for the above-mentioned
re-evaluation and/or follow-up of the cases, but also
for standardization of analyses in training new ophthalmologic researchers. As for possible progressionof the cataracts, Klein et al. have shown that small
posterior subcapsular cataracts observed in middle
age dramatically increase the need for lens implants
at later ages.17 We tried to analyze the impact ofradiation exposure on cataract latency using incident
cases of cataract surgery. However, information on
cataract incidence was available only for 1988–2000.
The results indicated a 0.18-year acceleration of cataract surgery per Gy which was non-significant (p =0.30). A longer observation period and additional
aging of the potentially most sensitive population(the youngest survivors were only 55 years old in
2000, while the average age of cataract surgery was72.9) may provide more meaningful data on cataract acceleration by radiation.
In addition, we have a plan to conduct a followup study on cases who were examined with a slitlamp microscope during 2000–2002 by comparing
those stored lens digital images with new ones weobtain. This study would also provide information
on several risk factors indicative of predictive andmechanistic factor(s). As for genetic predisposition,a study on ATM mutations, in which differential

24radiosensitivity has been observed in mice,18,19 isunder way in A-bomb survivors. Furthermore, weare starting a project to collect and store lens tissues
removed from A-bomb survivors for future use,
because postoperative cases among A-bomb survivors showed a strong association with A-bombradiation,12 and the removed cataract tissues are likely
to have important information on molecular biological change in radiation cataractogenesis.20 We werevery fortunate to obtain generous cooperation from
ophthalmologist groups in universities and ophthalmologist associations in Hiroshima and Nagasaki,
respectively. As for possible transgenerational effectsof radiation on the lens, cataract studies on childrenof the A-bomb survivors (RP 8-02)21 conductedduring 2002–2006 also are being analyzed.
As for other ophthalmologic findings, retinal
arteriolosclerosis has been recognized to have anassociation with radiation dose in A-bomb survivors4
as well as in other radiation-exposed populations.22,23
Quantitative analysis of retinal arteriolosclerosis andmacular degeneration is being planned becauseradiation-associated arteriosclerosis has great potential influence on retinal function, including the optic
nerve24 and macula.25 A glaucoma prevalence study(RP 1-05)26 started in 2006 will finish examinations
by September 2008 and will then be analyzed.
In conclusion, recent cataract studies in A-bomb
survivors have revealed new findings, such as a dose
response in cortical cataract and, perhaps more
importantly, results suggesting a possibility for alower threshold, both in cortical and posterior subcapsular cataract, compared to previous estimates.
We also expect more mechanistic and predictive
findings in new studies in the near future.

References
1. Nefzger MD, Miller RJ, Fujino T. Eye findings in atomic bomb survivors of Hiroshima and Nagasaki: 1963–
1964. Am J Epidemiol 89:129-38, 1969.
2. Choshi K, Takaku I, Mishima HK, Takase T, Neriishi S, Finch SC, Otake M. Ophthalmologic changes related
to radiation exposure and age in the Adult Health Study sample, Hiroshima and Nagasaki. Radiat Res 96:56079, 1983.
3. Otake M, Schull WJ. Radiation-related posterior lenticular opacities in Hiroshima and Nagasaki atomic bomb
survivors based on the DS86 dosimetry system. Radiat Res 121:3-13, 1990.
4. Minamoto A, Taniguchi H, Yoshitani N, Mukai S, Yokoyama T, Kumagami T, Tsuda Y, Mishima HK, Amemiya
T, Nakashima E, Neriishi K, Hida A, Fujiwara S, Suzuki G, Akahoshi M. Cataract in atomic bomb survivors.
Int J Radiat Biol 80:339-45, 2004.
5. Minamoto A, Taniguchi H, Mishima HK, Amemiya T, Nakashima E, Neriishi K, Hida A, Fujiwara S, Suzuki G,
Akahoshi M. Ophthalmologic study of atomic bomb survivors. RERF Research Protocol 3-00, Radiation
Effects Research Foundation, 2000.
6. Nakashima E, Neriishi K, Minamoto A. A reanalysis of atomic-bomb cataract data, 2000–2002: A thresholdanalysis. Health Phys 90:154-60, 2006.
7. Day R, Gorin MB, Eller AW. Prevalence of lens changes in Ukrainian children residing around Chernobyl.
Health Phys 68:632-42, 1995.

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RERF Update Volume 19, Issue 1, 2008

Science Article: Ophthalmologic Studies in Atomic-bomb Survivors

25

8. Hall P, Granath F, Lundell M, Olsson K, Holm LE. Lenticular opacities in individuals exposed to ionizing
radiation in infancy. Radiat Res 152:190-5, 1999.
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Kyrychenko OY, Musijachenko NV, Shylo SA, Vitte OP, Xu S, Xue X, Shore RE. Cataracts among Chernobyl
clean-up workers: Implications regarding permissible eye exposures. Radiat Res 167:233-43, 2007.
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12. Neriishi K, Nakashima E, Minamoto A, Fujiwara S, Akahoshi M, Mishima HK, Kitaoka T, Shore RE. Postoperative cataract cases among atomic bomb survivors: Radiation dose response and threshold. Radiat Res 168:4048, 2007.
13. Young RW, Kerr GD, ed. Reassessment of the Atomic Bomb Radiation Dosimetry for Hiroshima and Nagasaki—
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16. Worgul BV, Merriam GR Jr, Medvedovsky C. Cortical cataract development—An expression of primary damage to the lens epithelium. Lens Eye Toxic Res 6:559-71, 1989.
17. Klein BE, Klein R, Linton KL. Prevalence of age-related lens opacities in a population. The Beaver Dam Eye
Study. Ophthalmology 99:546-52, 1992.
18. Worgul BV, Smilenov L, Brenner DJ, Junk A, Zhou W, Hall EJ. Atm heterozygous mice are more sensitive toradiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci USA 99(15):9836-9, 2002.
19. Kleiman NJ, David J, Elliston CD, Hopkins KM, Smilenov LB, Brenner DJ, Worgul BV, Hall EJ, Lieberman
HB. Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice.
Radiat Res 168(5):567-73, 2007.
20. Chang PY, Bjornstad KA, Rosen CJ, Lin S, Blakely EA. Particle radiation alters expression of matrix
metalloproteases resulting in ECM remodeling in human lens cells. Radiat Environ Biophys 46(2):187-94,
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21. Minamoto A, Kumagami T, Yoshitani N, Mishima HK, Amemiya T, Nakashima E, Neriishi K, Hida A, Fujiwara
S, Suzuki G, Akahoshi M. Ophthalmologic study of children of atomic bomb survivors (Addendum to RP 102). RERF Research Protocol 8-02, Radiation Effects Research Foundation, 2002.
22. Peiretti E, Slakter JS, Wu S, Iranmanesh R, Yannuzzi LA. Late effect of external eye irradiation on choroidal
circulation. Eur J Ophthalmol 16(4):637-40, 2006.
23. Robertson DM, Buettner H, Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, EarleJD, Forbes GS, Kline RW, Bergstralh EJ, Offord KP, Rademacher DM, Stanley NM, Bartley GB. Retinal
microvascular abnormalities in patients treated with external radiation for graves ophthalmopathy. Arch
Ophthalmol 121(5):652-7, 2003.
24. Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, Renard JP, Stefansson E. The impact ofocular blood flow in glaucoma. Prog Retin Eye Res 21(4):359-93, 2002.
25. Metelitsina TI, Grunwald JE, DuPont JC, Ying GS, Brucker AJ, Dunaief JL. Foveolar choroidal circulation andchoroidal neovascularization in age-related macular degeneration. Invest Ophthalmol Vis Sci 49(1):358-63,
2008.
26. Minamoto A, Tsukamoto H, Yokoyama T, Tsuiki E, Uematsu M, Ogawa T, Mishima HK, Kitaoka T, Nakashima
E, Neriishi K, Hida A, Fujiwara S, Akahoshi M. Glaucoma study in atomic bomb survivors. RERF ResearchProtocol 1-05, Radiation Effects Research Foundation, 2005.

Return to Table of Contents

RERF Update Volume 19, Issue 1, 2008

26

Human Interest Notes

In Remembrance of Dr. Howard Hamilton(1918–2007)
Akio Awa, Former Associate Chief of Research

On the afternoon of April 30, 2007, Dr. Dale
Preston, who lives in California, left a message forme at my office at the Oak Ridge Associated Universities (ORAU). I called him back and found thatDr. Howard Hamilton had passed away on April 27
in Falls Church, Virginia, where he had lived sinceleaving Japan in 1986.
Dr. Hamilton joined ABCC in 1956 and worked
at ABCC and RERF until 1983 when a mandatory
retirement age was introduced for RERF researchers. Following his formal retirement he worked as afull time consultant to RERF until leaving Hiroshima
and returning to Falls Church, a suburb of Washington, DC.
For most of his 30 years in Hiroshima, Dr.
Hamilton served as chief of the Department of Clinical Laboratories and devoted considerable attention
to improving the accuracy and maintaining the quality of hematological tests for Adult Health Study
participants. He paid particularly close attention to
insuring the consistency of the measurements fromthe Hiroshima and Nagasaki laboratories.
In addition to his managerial activites, Dr.
Hamilton was an active researcher with an interest
in molecular structural alterations in blood hemoglobin. He detected many molecular variants in study
participants and published the findings in several
international scientific journals. Dr. Hamilton
also made substantive contributions to many otherimportant ABCC-RERF research projects.
From Hokkaido University, I joined the Cytogenetics Laboratory, which was newly established at
ABCC, in January 1967, more than 10 years after
Dr. Hamilton had first begun to live in Hiroshima. I
worked for him from the beginning, and collaborated
closely with him for almost 20 years. I am still grateful for his presence in Hiroshima over that period.
Most of the department chiefs at ABCC came toHiroshima from the U.S. on two-year contracts. One
disadvantage of that arrangement was that, every timea new department chief came, a new managerial
system was introduced. On the other hand, since Dr.
Hamilton lived in Japan permanently, researchers
who worked under him were able to develop longterm perspectives, which was a great merit. I wasfortunate to be able to engage in research under suchcircumstances. Dr. Hamilton contributed to thedevelopment of not only the Cytogenetics Laboratory but also the Biochemical Genetics Laboratory,
Return to Table of Contents

Dr. Howard Hamilton receiving the Hiroshima
Governor’s Cup after winning the 26th Hiroshima
Tennis Competition (May 3, 1972)

which was jointly managed by Professor James Neel,
who came from the University of Michigan. Dr.
Hamilton’s contribution to the Biochemical Genetics Laboratory should be given high marks as one of
his unheralded achievements.
Dr. Hamilton’s hobbies were varied (some say
they were his main occupation). Many already haveheard about them, so I will not cover his activities indetail here, but his performance of Kita-style Nohdrama is widely known. I have heard that he once
fell from the stage because he was so focused on his
dancing. His collection of “Kumadori” (Kabuki
actors’ makeup printed on silk), which he obtained
immediately after performances, was wonderful.
That collection was only possible because he had
been a friend of the performers for many years andthus had free entry to their dressing rooms. He alsoamassed an impressive collection of hand-carved
noh-masks, many of which were created by living
national treasures. I was really pleased that he published a book on Noh and Kabuki after he returnedto the U.S. Dr. Hamilton was not only well versed incultural arts but was also an excellent tennis player.
After he returned to the U.S., I visited him at his
home many times in Falls Church, and sometimes
stayed overnight. Until recently, I had been communicating with him by the Internet, but our communication stopped in the fall of 2006. In the meantime,
Dr. Preston told me that Dr. Hamilton was sick.
I am in deep mourning since receiving the news
RERF Update Volume 19, Issue 1, 2008

Human Interest Notesof the death of Howard, my supervisor and friend,
who was a master of cultural arts and sports. I close
this memorial note with hands clasped in prayer forthe repose of his soul.

27

Editor’s note: Dr. Dale L. Preston, former chief of
RERF Department of Statistics, who knew Dr.
Howard Hamilton well, conveyed his sincere condolences to us on the occasion of Dr. Hamilton’s
death. We would like to introduce below a part ofhis condolence message since it clearly reveals Dr.
Hamilton’s personality and his deep affection forJapanese traditional culture.

scanned these slides and developed a computer database that contains information on the play, actors,roles, theater, and performance date for each of thesephotos.
Until the end of his life, Howard maintained astrong interest in science in general and RERF research in particular while carrying on a lively correspondence with his many friends in the worlds ofscience and art around the world. I feel privileged
and honored to have known Howard as a colleague
and a friend for more than 20 of his remarkable 89
years. Even now, more than one year after his death,
I often recall his impish grin and curmudgeonly wit.

After his retirement and return to the U.S.,
Howard maintained a strong interest in Japanese culture. His home was filled with stunning traditionaland contemporary Japanese arts and crafts, and hecreated a living space that captured the essence ofthe traditional Japanese culture he loved so much: atatami room with hand-painted byobu, a soothing
tokonoma, and exquisite shoji that opened to reveal
a beautiful small garden that echoed some ofHoward’s beloved Kyoto gardens.
Howard’s collections of Kumadori and Nohmasks reflected his passion for and involvement in
the world of Japanese traditional theater and dance.
Howard’s passion for these Japanese arts grew outof his earlier interest in opera and dance. Prior tocoming to Japan, Howard had studied modern dancewith Martha Graham and was a member of a choirorganized by the renowned 20th century composer
Paul Hindemith. In the late 1950s and throughout
much of the 1960s, Howard traveled to Tokyo andKyoto almost every month to see the latest Kabuki
and Noh programs. He developed close ties to theleading actors and was allowed to photograph theperformances. He amassed a collection of more than
10,000 carefully cataloged slides and carefully preserved all of the programs. In recent years Howard

Dr. Howard Hamilton performing a Noh dance at the
RERF 10th Anniversary in April 1985

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RERF Update Volume 19, Issue 1, 2008

28

Human Interest Notes

In Memory of Dr. Koji Takeshima(1917–2007)
Hideya Tamagaki, M.D.
Former ABCC Department of Medicine
When the Atomic Bomb Casualty Commission(ABCC) came into existence in 1947, the firstdepartment to be established was the Department of
Genetics. The latter, like the Commission itself,began in borrowed space in the Hiroshima Red
Cross Hospital in Senda-machi, where the damage
from the atomic bombing still remained. However,as soon thereafter as possible the majority of theCommission’s staff and activities moved to theGaisenkan and a newly constructed clinic in Ujina,although the genetics program continued at the Red
Cross Hospital. The genetics study to examine
every newborn baby in Hiroshima and Nagasaki, thefirst major project by ABCC, was initiated in 1948.
Direction of this program fell to a number of American scientists, the first being Dr. James V. Neel, who
was followed by Dr. Ray C. Anderson, then Dr.
William J. Schull, and finally Dr. Duncan McDonald.
However, from the work perspective, the unifying
force was not the American supervisors but Dr. Koji
Takeshima, who had been engaged in this work fromits beginning. He was fluent in Japanese and English
and as a consequence he served as an intermediary
between the American and Japanese staffs and as agood consultant for us, the young physicians, nurses,
and secretaries involved in the examination of
newborn babies.
His experience and career were ideal for that role.
His parents, Hosui and Toyo Takeshima, migrated
to Hawaii in 1909 at the urging of the Japanese Buddhists living in Olaa, a small community in the Punadistrict of the “big island.” Koji, the third child, wasborn in Hawaii in 1917, and so were his two sisters,
Kasumi (1911) and Ayame (1914). (His younger
brother died in the A-bombing of Hiroshima.) He
received his early education through the publicschools in Hawaii and at the “terakoya” where hisfather and mother taught. Koji and his family
returned to Saijo in Hiroshima Prefecture, his parents’ancestral home, when he was 13 years old. He
received his medical education at Kyoto Prefectural
Medical School from which he graduated in 1942.
As a physician he was drafted into military service
during the latter conflict, but he was not sent abroad.
After the war, his affiliation with the Department ofSurgery at the Hiroshima Red Cross Hospital was
perhaps the start of his relationship with ABCC’s
Department of Genetics.
Collaborative relationships with outside individuReturn to Table of Contents

als and organizations were essential if the aim of
examining all of
the newborns in
Hiroshima andNagasaki was tosucceed. The cooperation of the
midwives was especially important in this regard
since, at that time
Dr. Koji Takeshima in 1990
in Japan, a midwife took care of an expectant mother for the duration of her pregnancy, and thus full-scale collaboration with the midwives’ association was mandatory
if this project, aimed at examination of 100% of newborn babies, was to succeed. The success the project
achieved owed much to the warm personality andgentle demeanor of Dr. Takeshima, who often participated in general meetings with the several hundred midwives then practicing in Hiroshima. Moreoften still he was a central figure in discussions withthe officers of the association, particularly their diminutive president, Mrs. Setsuko Yamamoto, regarding issues that arose in the day-to-day interactionsof the midwives with the genetics doctors. Sometimes, he had to translate English into Japanese, andwhen this occurred his Japanese more than met thestandards of the most demanding linguist. It wasneither lacking in appropriate honorifics nor overly
deferential and unquestionably helped to establish
relationships of trust. His skill as a mediator was not
limited to the relationship with the midwives association; he was familiar with Japanese medical practices and could act as a facilitator in negotiations withthe local medical and paramedical organizations. Hisability was shown in the discussions seeking cooperation from the city government, the city andprefectural medical associations, and especially fromobstetricians, with the goal of obtaining necessary
information to be registered in mother-child handbooks and recorded in notifications of child delivery.
Our initial health examinations were performedin the home, at which time we presented each family with a bar of “Lux” soap and a towel, which were
well received and thus helpful in performing ourwork. These gifts were the warm-hearted idea of the
RERF Update Volume 19, Issue 1, 2008

Human Interest Notes
department chief and Dr. Takeshima, who appreciated the difficulties mothers were experiencing inchild rearing in those times of scarcity.
I joined the department in 1949. I was pleased tofind that the atmosphere of the workplace into which
I was enrolled was very positive and the environment very lively. There were always about 20 young
physicians, nurses, and secretaries, engaged in the
study, and working there was truly enjoyable. Dr.
Takeshima was our supervisor, and was in charge ofreviewing our reports and providing us with guidance and instruction. He was a phenomenal mentor—simultaneously demanding but sensitive andunderstanding, which I suppose was one of the
major reasons I enjoyed working there.
When the clinical study of pregnancy terminations in Hiroshima and Nagasaki ended in the Springof 1954, Dr. Takeshima moved to ABCC’s Department of Medicine, and I moved to the same department soon after. Shortly thereafter, it was decided
that members of ABCC’s Department of Medicine
should join the U.S. survey team examining thecrewmembers of a fishing vessel, the Lucky Dragon
5 (Daigo Fukuryu Maru), exposed to radiation froma hydrogen bomb test at Bikini Atoll. After the firstsurvey team was dispatched, Dr. Takeshima and I
were chosen to be members of the second team. I
remember vividly flying in the cargo compartmentof a military airplane, a DC-3, from Iwakuni to
Haneda with him.
Subsequently, Dr. Takeshima studied at Duke
University for three years for training in anesthesiology. He returned to Hiroshima to start his own
medical and surgical practice in Saijo, had a hospital constructed, and later served as chairman of thenursing home for the elderly that was established on
the property of his hospital. All of this was accomplished while he continued to maintain his father’s
temple until a suitable priest could be found.

Dr. Koji Takeshima receiving the ABCC Medallion
presented to those who provided essential services
to ABCC. (from left) ABCC Associate Director Hiroshi
Maki, Dr. Howard Hamilton, Dr. Joseph Belsky, Dr.
Koji Takeshima, ABCC Director George Darling, andDr. Yasuyoshi Nishimaru (July 8, 1969)

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29
Several years ago, I visited Dr. Takeshima in Saijowith Dr. Schull, a former chief of the Department of
Genetics, who had been invited to be a speaker atthe event commemorating the 30th anniversary of
the establishment of RERF, ABCC’s successor
organization. It was a heart-warming occasion; thefirst time in several decades the three of us were
together. We found Dr. Takeshima frail, but he wasvery alert, still spoke English easily, and was wellinformed on Buddhism, U.S.-Japan issues, and theeconomic and personnel problems private hospitals
in Japan are currently obliged to address. I still
remember him waving to us with tears in his eyes
when we left his house. In November last year, hesuddenly toppled over due to a heart attack as heworked, and passed away several days later at theage of 91.
In retrospect, it is clear that Dr. Takeshima was
not only responsible for the clinical activities of the
Department of Genetics but he was also extremely
helpful in establishing an environment conducive tothe success of the department’s various projects. He
never made much of this achievement; indeed hegenerally sought to keep it in the background andnot clearly visible, but actually I feel that his efforts
helped to establish an important framework for allof ABCC’s programs, not merely those in genetics.
He also contributed to the establishment of cooperative relationships with outside organizations, which
was one of ABCC’s most important goals in its earlydays. In my view, his contributions made possible
many if not all of the research programs RERF would
inherit almost thirty years after his employment.
He is survived by his wife, Reiko, two daughters,
Yoshimi and Akemi, and two sons, Yuji and Yasuji.
The family is engaged in the management andoperation of their hospital and nursing home. His
older sister, Ayame, who also worked at ABCC, returned to America and is in good health at present.
Editor’s note: Dr. Hideya Tamagaki, who is 85 years
old, was a physician in the Departments of Genetics
and Medicine at the Atomic Bomb Casualty Commission (ABCC), the predecessor of the Radiation
Effects Research Foundation (RERF), for 16 years
starting in 1949. His mother died and his younger
sister was seriously injured by the atomic bombingof Hiroshima. He survived only because as a medical student he had been evacuated to Tsuruoka City,
Yamagata Prefecture in the northern part of Japan.
His father, who ran a medical clinic near his house
located 1.3 km from the hypocenter, worked desperately to provide medical care to the A-bomb survivors, despite suffering from broken bones and acuteradiation symptoms. Dr. Tamagaki with Dr.
Takeshima contributed to ABCC’s studies in theorganization’s early days.

RERF Update Volume 19, Issue 1, 2008

30

Human Interest Notes

It’s a Small World—With a Strong Link
Between Hiroshima and Texas
When the National Academy of Sciences recruited
Dr. James Cox as a nominee for a Member of theBoard of Directors of the Radiation Effects Research
Foundation, it was clear that a qualified and distinguished physician recognized world-wide as a leader
in the radiation oncology community had been
selected. But nearly six decades ago, a young Japanese woman would not yet know about Dr. Cox who
had not yet begun his distinguished career or earned
his impressive credentials.
Ritsuko Komaki was born in Amagasaki City,
Hyogo Prefecture and moved with her family to
Hiroshima City at the age of four after World War II.
When she was ten years old and a fifth-grade student, she transferred to Nobori-machi Elementary
School, becoming a classmate of Sadako Sasaki.
Ritsuko still remembers how impressed she had been
by Sadako’s speed after seeing her run at a school
athletic meet. But ten years after the atomic bombing, just prior to her graduation from elementary
school, Sadako developed leukemia. That fall, at theage of 12, Sadako died. She had made many paper
cranes in her bed at the hospital in the belief that she
would recover from her disease when she finished athousand origami cranes. The following year,
Ritsuko, who was then a second-year middle-school
student working as the student council president,
discussed at the student council the wish to preserve
Sadako’s memory. She worked with Sadako’s older
brother and classmates to create “The Sadako
Memorial Statue” and joined them in collecting
donations on Hiroshima’s streets for funding amemorial statue honoring the children who werevictims of the atomic bombings.
The idea of building a monument to mourn thedeaths of children due to the atomic bombings
quickly gathered momentum, with donations
arriving from throughout Japan. In 1958, three years
after Sadako’s death, the “Children’s Peace Monument” was erected in the Peace Memorial Park in
Hiroshima. On May 5 of that year, children from allover Japan attended the new monument’s unveiling
ceremony. This year marks the 50th anniversary of
the monument’s establishment. Every year, many
millions of origami cranes are sent from all over theworld in honor of Sadako’s legacy.
The death of Sadako had a profound effect on
Ritsuko who vowed to dedicate her life to helping
people who suffered from cancer like her friend, andshe would become a cancer researcher and physician in the years to follow. Ritsuko went on to graduReturn to Table of Contents

ate from Hiroshima University School of Medicine,spent a year working at ABCC, and came to theUnited States for further medical training, thanks toa mother and father who valued education highly.
She chose the Medical College of Wisconsin for residency and fellowship training in radiation oncology.
And she credits her excellent teachers at the Medical College of Wisconsin for developing her skills
and knowledge. Over the course of her professional
career, Dr. Komaki would receive numerous awards,
including the Marie Sklodowska-Curie Award in2005 from the American Association for WomenRadiologists, the Business Professional Women of
Texas Award in 2005, and the 2006 Alumna of theYear Award from the Medical College of Wisconsin/Marquette Medical Alumni Association.
Today, Ritsuko is Doctor and Professor Komaki
and the Gloria Lupton Tennison Distinguished
Endowed Professor for Lung Cancer Research at oneof America’s largest cancer hospitals, the M.D.
Anderson Cancer Center at the University of Texas,in Houston. In 2006, Dr. Komaki was instrumental
in helping introduce a new era in cancer care at theChildren’s Peace Monument at the Peace Memorial
Park in Hiroshima City

RERF Update Volume 19, Issue 1, 2008

Human Interest Notes
M.D. Anderson Cancer Center when she wasinvolved in the planning of the Proton Therapy
Center. The Center is one of only three institutionsin the United States offering proton therapy to patients. Dr. Komaki helped M.D. Anderson navigate
the complex logistics associated with importing theproton-generating radiation equipment to Houston,which ironically was manufactured in Japan and by
a company whose CEO just happened to attend thesame high school in Hiroshima as Dr. Komaki.
Oh—and Dr. James D. Cox? He just happened tocoincidently be a faculty member at the Medical

Return to Table of Contents

31College of Wisconsin who Dr. Komaki met when
she arrived in the United States and with whom shewould form a relationship that, beginning in 1980,
grew into a 28-year marriage. They would eventually move to Houston together where Dr. Cox isProfessor and Head of Radiation Oncology. Now
serving as an RERF Visiting Director, he will beattending his third RERF Board of Directors Meeting in Washington this June.
(Evan B. Douple, RERF Associate Chiefof Research)

RERF Update Volume 19, Issue 1, 2008

Research Protocols and Publications

Research Protocols Approved in 2007
RP 1-07 Estimation of Genetic Risk of Radiation on Immature Oocytes of Rats by Using
Two-dimensional DNA Analysis: An Animal
Model for Human Female Exposure
Asakawa J, Kamiguchi Y, Nakamura N, Katayama
H, Cullings HM
It is well recognized that mouse immature oocytes
are extremely sensitive to radiation exposure andmore than 90% are killed following exposure to 0.5
Gy of X rays. Therefore, mouse mutagenesis study
using several Gy of X or γ rays have not beenpossible. In contrast, it has been recognized that rat
immature oocytes are not as radiosensitive as thosein mice, and we confirmed it on our own. We thencame to think that the analysis of rat DNA by twodimensional electrophoresis should be a uniqueanimal model for the risk estimation of human
female exposure. In the present research proposal,
we will measure the mutation induction rate byexamining F1 rats derived from immature oocytes
irradiated with 2.5 Gy of γ rays. We will use 750 F1
animals each for the exposed and the control groups.
Since we found from preliminary experiments thatapproximately 1,500 loci per animal could bescreened, the study plan makes it possible to searchfor germline mutations at 1,125,000 loci in total ineach group. Based on our previous data on the spontaneous mutation rate in female mice obtained by
two-dimensional DNA analysis technique, we think
it unlikely that the spontaneous mutation rate infemale rats exceeds 0.5–1.0 × 10–5/locus/generation.
In addition, also based on our own data in male mice,it seems unlikely that the mutation induction rate ishigher than 0.5–1.0 × 10–5/locus/Gy. Under these
conditions, it is expected that we will detect 5–11
mutations or less in the control group and 19–39
mutations or less in the exposed group. The molecular characterization of the detected mutations willfurther reveal the spectrum of radiation-induced
mutations occurring in immature oocytes. The
results to be obtained by this proposal will be thefirst data in the world on the estimation of genetic
risk of radiation in immature oocytes.
RP 2-07 Study on Genetic Effects of Radiation
by Array Comparative Genome Hybridization(Array CGH) Method—Validation of Ability of
the Methodology for the Genetic Study
Takahashi N, Satoh Y, Kodaira M, Katayama H,
Kodama Y, Cologne JB
The microarray-based comparative genome
hybridization (array CGH) method was introduced
to effectively identify “radiation-induced de novo
large deletion type mutations” to the Biochemical
Genetics Laboratory. The results of the pilot study
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32
revealed that our array CGH system could detect the
copy number changed variation. In this proposal, byarray CGH method using slide glasses with about
2,500 Bac clones, we will examine genomic DNA
of 225 offspring born to parents exposed to relatively
high radiation doses. From this research protocol(RP), we anticipate the following two outcomes.
First, we will try to assess whether the frequency oflarge deletion type mutations observed in gametes
from the exposed parents is higher than that in thosefrom unexposed parents. Even if we do not obtainany significant results, we will be able to estimate
an upper confidence bound for the induction rate inhumans. Next, with the information from this RP,
some assessment should be possible as to whether
using denser array CGH systems in the future is likely
to yield useful information for studies on the genetic
effects of atomic-bomb radiation.

RP 3-07 Clinical Health Study for ExpandedGroup of Younger A-bomb Survivors
Akahoshi M, Yamada M, Hida A, Ohishi W, Nishi
N, Kasagi F, Suyama A, Furukawa K, Ross NP,
Hayashi T, Nakachi K, Kodama Y, Katayama H,
Kodama K, Nakamura N, Fujiwara S
The Adult Health Study (AHS) of A-bomb survivors has been invaluable in determining the association of radiation with risk for conditions that cannot
be identified through mortality studies. Many of theolder members of the AHS cohort have died, however, and reviewers at the meeting of the International Blue Ribbon Panel (1996) and the 31st and32nd meetings of the Scientific Council (2004 and2005) recommended that we expand the AHS
cohort by adding more younger survivors (who are
considered highly sensitive to radiation) for radiation risk research purposes. Accordingly, we will
identify younger survivors willing to participate inclinical health examinations in a mail survey conducted by the Department of Epidemiology on theLife Span Study (LSS) in 2007. We hope to add to
the AHS cohort about 2,300 people who were <10years old at the time of the bombing, bringing thecohort to about 3,000. The added 2,300 subjects will
also undergo health examinations biennially.
RP 4-07 Pathology Study of Malignant Tumorsof Soft Tissue and Bone among A-bomb Survivors, 1957–2003
Yonehara S, Hayashi T, Daimaru Y, Ikeda T, Tokuoka
S, Nishi N, Soda M, Suyama A, Kodama K, Mabuchi
K, Ron E, Preston DL
The excess risk of sarcomas of the soft tissues
and bones associated with high therapeutic doses ofradiation has been known for some time but epidemiological data on the risk associated with radiation
exposure at relatively low doses are very limited.
The latest analysis of solid cancer incidence data of
RERF Update Volume 19, Issue 1, 2008

33

Research Protocols and Publications
the Life Span Study (LSS) cohort of the Radiation
Effects Research Foundation (RERF) provided, forthe first time in this cohort, evidence of a significant
dose response for broadly-classified sarcomas using
the tumor registry-based incidence data. We propose
to conduct a detailed, standardized pathology review
of sarcomas in order to investigate the association
between estimated radiation dose (DS02) and riskof sarcomas by histological types and sub-types. Softtissue and bone sarcomas occurring between 1957
and 2003 in the LSS cohort will be identified throughthe Hiroshima and Nagasaki tumor registries andsupplemented by additional information based on
autopsy and surgical pathology records at RERF andmajor medical institutions in both cities, and deathcertificates. A panel of pathologists will review
cases of soft-tissue and bone sarcomas as reported
to the tumor registries and other sources indicatedabove together with cases with diagnoses to whichsoft-tissue and bone sarcomas may have been
misclassified. The panel will provide consensus
diagnoses by histological types, which will be classified using the World Health Organization (WHO)Classification of Tumours of Soft Tissue and Bone
(2002). Analyses will be performed to assess theradiation-related risk of sarcomas using a Poisson
regression model and to evaluate modifying effects,
if any, of age, gender, and other factors.

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

Asakawa J, Nakamura N, Katayama H, Cullings HM.
Estimation of mutation induction rates in AT-richsequences using a genome scanning approachafter X irradiation of mouse spermatogonia. Radiation Research 2007 (August); 168(2):158-67.
(RERF Report 15-06)
Egbert SD, Kerr GD, Cullings HM. DS02 fluence
spectra for neutrons and gamma rays at Hiroshima
and Nagasaki with fluence-to-kerma coefficientsand transmission factors for sample measurements.
Radiation and Environmental Biophysics 2007
(November); 46(4):311-25.
Hamasaki K, Imai K, Hayashi T, Nakachi K,
Kusunoki Y. Radiation sensitivity and genomic
instability in the hematopoietic system: Frequencies of micronucleated reticulocytes in whole-body
X-irradiated BALB/c and C57BL/6 mice. Cancer
Science 2007 (December); 98(12):1840-4. (RERF
Report 8-07)
Hayashi I, Morishita Y, Imai K, Nakamura M,
Nakachi K, Hayashi T. High-throughput spectrophotometric assay of reactive oxygen species inserum. Mutation Research 2007 (July 10);631(1):55-61. (RERF Report 17-06)
Heidenreich WF, Cullings HM, Funamoto S,
Paretzke HG. Promoting action of radiation in theatomic bomb survivor carcinogenesis data? Radiation Research 2007 (December); 168(6):7506.
Izumi S, Ohtaki M. Incorporation of inter-individual
heterogeneity into the multistage carcinogenesis
model: Approach to the analysis of cancer incidence data. Biometrical Journal 2007 (September);49(4): 539-50.
Kodama K, Kasagi F, Nishi N. Cohort study at Radiation Effects Research Foundation in Hiroshima
and Nagasaki. Cardiac Practice 2007; 18(2):1516. (Japanese)
Kusunoki Y, Hayashi T. Long-lasting alterations of
the immune system by ionizing radiation exposure: Implications for disease development among
atomic bomb survivors. International Journal of
Radiation Biology 2008 (January); 84(1):1-14.
(RERF Report CR1-07)
Masunari N, Fujiwara S, Nakata Y, Nakashima E,
Nakamura T. Historical height loss, vertebral

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RERF Update Volume 19, Issue 1, 2008

Research Protocols and Publications
deformity, and health-related quality of life in
Hiroshima cohort study. Osteoporosis International
2007 (November); 18(11):1493-9. (RERF Report
13-06)
Matsumura M, Arita K, Takada Y, Suyama A, Nishi
N, Ishida K, Hirabayashi A, Kato H, Kato M,
Yoshida S, Hyoudou M, Egawa M, Taniguchi A,
Watanabe T, Ogasawara Y, Soramoto E, Mukai M,
Nishioka Y, Sakatani K, Yamaguchi Y, Tamura R,
Usui S. Report on the results of the sixteenth medical examination of atomic bomb survivors resident in North America. Hiroshima Igaku [Journalof the Hiroshima Medical Association] 2008
(March); 61(3):161-85.
Moriya M, Seto S, Yano K, Akahoshi M. Two casesof short QT interval. Pacing and Clinical Electrophysiology 2007 (December); 30(12):1522-6.
(RERF Report 4-07)
Nagano J, Mabuchi K, Yoshimoto Y, Hayashi Y,
Tsuda N, Land CE, Kodama K. A case-control
study in Hiroshima and Nagasaki examining nonradiation risk factors for thyroid cancer. Journalof Epidemiology 2007 (May); 17(3):76-85. (RERF
Report 10-05)
Nakamura N. Dose evaluation of A-bomb survivors
by means of electron spin resonance using tooth
enamel. Electron Spin Science 2007 (October);5(9):106-13. (Japanese)
Nakano M, Kodama Y, Ohtaki K, Nakashima E,
Niwa O, Toyoshima M, Nakamura N. Chromosome aberrations do not persist in the lymphocytes
or bone marrow cells of mice irradiated in utero
or soon after birth. Radiation Research 2007
(June); 167(6):693-702. (RERF Report 6-06)
Nakashima E, Akahoshi M, Neriishi K, Fujiwara S.
Systolic blood pressure and systolic hypertensionin adolescence of atomic bomb survivors exposed
in utero. Radiation Research 2007 (November);168(5): 593-9. (RERF Report 5-07)
Nakashima E, Fujii Y, Imaizumi M, Ashizawa K.
Finite mixture models in assessing anti-thyroglobulin antibody positivity as a marker of chronic
thyroiditis. Japanese Journal of Biometrics 2007
(November); 28(2):79-90. (RERF Report 9-06)
Neriishi K, Nakashima E, Minamoto A, Fujiwara S,
Akahoshi M, Mishima HK, Kitaoka T, Shore RE.
Postoperative cataract cases among atomic bomb
survivors: Radiation dose response and threshold.
Radiation Research 2007 (October); 168(4):4048. (RERF Report 1-06)
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34
Nishi N, Kodama K. Cohort studies in the Radiation
Effects Research Foundation of Hiroshima andNagasaki. Igaku no Ayumi [Journal of Clinical andExperimental Medicine] 2008 (January 12);224(2):157-61. (Japanese)
Nishi N, Sugiyama H, Kasagi F, Kodama K,
Hayakawa T, Ueda K, Okayama A, Ueshima H.
Urban-rural difference in stroke mortality from a
19-year cohort study of the Japanese general population: NIPPON DATA80. Social Science & Medicine 2007 (August); 65(4):822-32.
Nishi N, Sugiyama H, Kodama K, Ninomiya M,
Kuwabara M, Hiramatsu K, Umehara M, Okuno
H, Kishimoto A. Current situation and challengesof Hiroshima City Cancer Registry. Hiroshima
Igaku [Journal of the Hiroshima Medical Association] 2008 (March); 61(3):186-9. (Japanese)
Noda A, Kodama Y, Cullings HM, Nakamura N.
Radiation-induced genomic instability in tandem
repeat sequences is not predictive of unique sequence instability. Radiation Research 2007
(May); 167(5):526-34. (RERF Report 5-06)
Ohishi W, Chayama K. Guidelines for managementof hepatitis B. Shindan to Chiryo [Diagnosis andTreatment] 2008 (March 1); 96(3):481-7. (Japanese)
Ohishi W, Fujiwara S, Suzuki G, Chayama K. Validation of the use of freeze-dried sera for the diagnosis of hepatitis B and C virus infections in a longitudinal study cohort. Research Advances in Microbiology 7. Mohan RM (edit). Kerala: Global
Research Network 2007 (June), pp 1-9. (RERF
Report CR2-07)
Bib#3606
Okubo T(Edit). Report of Atomic Bomb Disease
Research Project, FY2006 MHLW Grants 2007
(April 1), 57 p. (Japanese)
Osaki Y, Okamoto M, Kaetsu A, Kishimoto T,
Suyama A. Retrospective cohort study of smoking and lung cancer incidence in rural prefecture,
Japan. Environmental Health and Preventive
Medicine 2007 (July); 12(4):178-82.
Pawel DJ, Preston DL, Pierce DA, Cologne JB. Improved estimates of cancer site-specific risks for
A-bomb survivors. Radiation Research 2008
(January); 169(1):87-98.(RERF Report 9-07)
Pierce DA, Vaeth M, Shimizu Y. Selection bias incancer risk estimation from A-bomb survivors.
Radiation Research 2007 (June); 167(6):735-41.
RERF Update Volume 19, Issue 1, 2008

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Research Protocols and Publications(RERF Report 9-05)
Preston DL, Cullings HM, Suyama A, Funamoto S,
Nishi N, Soda M, Mabuchi K, Kodama K, Kasagi
F, Shore RE. Solid cancer incidence in atomic
bomb survivors exposed in utero or as young children. Journal of the National Cancer Institute 2008
(March 19); 100(6):428-36.(RERF Report 15-07)

100.
Yoshida MA, Hayata I, Tateno H, Tanaka K, Sonta
S, Kodama S, Kodama Y, Sasaki MS. The chromosome network for biodosimetry in Japan.
Radiation Measurements 2007 (August); 42(67):1125-7.

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.
Radiation Research 2007 (July); 168(1):1-64.
(RERF Report 8-06)
Sasaki H, Kasagi F, Yamada M, Fujita S. Grip
strength predicts cause-specific mortality in
middle-aged and elderly persons. American Journal of Medicine 2007 (April); 120(4):337-42.
(RERF Report 17-04)
Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita
T, Noda T, Nagaya N, Suyama K, Aihara N,
Kamakura S, Inamoto N, Akahoshi M, Tomoike
H. Sex hormone and gender difference—Role of
testosterone on male predominance in Brugada
syndrome. Journal of Cardiovascular Electrophysiology 2007 (April); 18(4):415-21.
Sogon T, Masamura S, Hayashi SI, Santen RJ,
Nakachi K, Eguchi H. Demethylation of promoter
C region of estrogen receptor α gene is correlatedwith its enhanced expression in estrogen-ablation
resistant MCF-7 cells. Journal of Steroid Biochemistry & Molecular Biology: Elsevier 2007 (June);
105(1-5):106-14.
Suyama A. Introduction of IREP, US computer software for determining the probability of causation.
Gen-ankyo Dayori [Tidings of Nuclear Safety
Research Association] 2007 (June 25); 218:3-7.
(Japanese)
Suzuki G, Cullings HM, Fujiwara S, Hattori N,
Matsuura S, Hakoda M, Akahoshi M, Kodama K,
Tahara E. Low-positive antibody titer against
Helicobacter pylori cytotoxin-associated gene A(cagA) may predict future gastric cancer better
than simple seropositivity against H. pylori
cagA or against H. pylori. Cancer Epidemiology,
Biomarkers and Prevention 2007 (June);
16(6):1224-8. (RERF Report 12-06)
Yano M, Hamatani K, Eguchi H, Hirai Y, MacPhee
DG, Sugino K, Dohi K, Asahara T. Prognosis inpatients with hepatocellular carcinoma correlates
to mutations of p53 and/or hMSH2 genes. European Journal of Cancer 2007 (April); 43(6):1092Return to Table of Contents

RERF Update Volume 19, Issue 1, 2008