Radiation Effects Research Foundation News and Views
Hiroshima and Nagasaki, Japan
Volume 15, Issue 1, Spring 2004

Table of Contents
RERF NewsThe 38th Board of Directors Meeting ........................................................................... 1
The 30th Scientific Council Meeting ............................................................................ 2
International Workshop: Immunological Homeostasis in Inflammatory
Response and Disease Development .................................................................... 4
Staff News .......................................................................................................................... 5
Current Status of Dosimetry Revision ......................................................................... 5

ArticlesLong-term Effects of A-bomb Radiation on the Immune System:
Beyond a Half Century, by Yoichiro Kusunoki, Tomonori Hayashi,
Masayuki Hakoda, Gen Suzuki, Kei Nakachi, and Seishi Kyoizumi ............. 7
Ethics Issues in Human Health Research, by Senjun Taira ................................. 19
Facts and Figures .................................................................................................................... 25
Hiroshima Memorial to Norman Cousins ....................................................................... 26
Research Protocol and Publications
Research Protocol ............................................................................................................. 28
Recent Publications ......................................................................................................... 28

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 equally by the government of Japan through its Ministry of Health, Labour andWelfare and that 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 atomicbomb survivors and to the enhancement of the health of all mankind.
Editor: Donald Pierce, Department of Statistics
Technical Editor: Yuko Ikawa, Editorial & Publications Section
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 Editorial & Publications Section, 5-2 Hijiyama Park,
Minami-ku, Hiroshima 732-0815 Japan
Telephone: 81-82-261-3131; Facsimile: 81-82-263-7279
Internet: update@rerf.jp

1

RERF NewsThe 38th Board of Directors Meeting
The annual meeting of the Board of Directors washeld on June 18–19, 2003 in the auditorium of theHiroshima Laboratory with 23 participants including directors, supervisors, a scientific councilor, andobservers. Current issues of RERF management andbudget were discussed.
In opening remarks, RERF Chairman Dr. Burton
G. Bennett cited the on-going mission and the highlevel of research activities of RERF, paid a tribute toand expressed his resolve to support A-bomb survivors, and requested the directors and sponsors tocontinue their active involvement and support of theimportant work.
Subsequently, the minutes of the previous Boardof Directors meeting (37th, Washington, DC) wereapproved. The meeting proceeded to a status report
and to items for information on the agenda.
In the status report of RERF, Dr. Bennett summarized recent research accomplishments and pointed
out several issues to be addressed in the future, suchas data accessibility, further development of futureplans, and establishment of a consortium in cooperation with universities in the US and Japan. He also
explained the points of difference between the DS86
and the new dosimetry system DS02, and said thatthe final report of the US-Japan Working Groups on
the new dosimetry evaluation would be published by
RERF within the year.
Dr. Senjun Taira, RERF Vice Chairman, reported
on the progress in the clinical study of survivors’
children and on activities of RERF involving international collaboration. Dr. Eiichi Tahara, Chief ofResearch, gave an overview of the external research
grants that had been granted to RERF researchers.
RERF Chief of Secretariat, Mr. Masaharu
Yoshikawa, reported on the present personnel status,
the FY2002 salary revision, and the FY2003 Labor
Union negotiations.
Along with the scheduled agenda items, Drs.
Bennett and Taira reported on the issues of journal
subscriptions and travel reimbursements. After sudden bankruptcy of its journal subscription agent,
RERF faced a considerable loss on payments alreadymade. Fortunately, however, many publishers agreed
to honor these subscriptions without further payment.
It was further reported that measures were being taken
to revise the RERF travel regulations to avoid excessive, although authorized, travel reimbursements andReturn to Table of Contents

to base payments on actual, often low-cost fares now
widely available.
Concerning the issues proposed by the membersof the Board, a lively discussion was held on the
management system for external research grants andwhether or not an internal audit of these ought to be
conducted by the supervisor. As a result of the discussion, it was unanimously agreed that a centralized
management system would be established; however,it was decided to continue to examine whether or not
an internal audit of external grants ought to be conducted.
Discussions were also held on the policy on theuse of biological materials, recruitment of young research scientists and statisticians, and the futureplanning.
For the items for deliberation and action, Scientific Councilor Ohtsura Niwa gave a summary reporton the recommendations of the 30th meeting of the
Scientific Council, and Dr. Tahara presented the responses to these recommendations.
Subsequently, discussions were held on the
FY2002 research activities report and audit, theFY2003 research activities plans, the FY2002 settlement of accounts and audit, the FY2003 working
budget, and the FY2004 provisional budget plan, allof which were approved by the Board of Directors.
Lastly, election of the directors and others were
held. As for the directors, Dr. Takefumi Kondo wasreappointed. Dr. Samuel H. Wilson (Deputy Director, National Institute of Environmental Health
Sciences, National Institute of Health) was elected
as a successor to Dr. Richard B. Setlow. It was reported that Mr. Masaaki Kuniyasu (former officer ofthe Ministry of Foreign Affairs) and Dr. Paul L.
Ziemer (Professor Emeritus of Purdue University)
were elected directors in the preceding month via amail ballot effective 1 June 2003 as successors to
Mr. Kazuaki Arichi and Dr. Jonathan M. Samet, who
had continued to serve as directors after the expiration of their terms on 30 June 2002. With regard to
the supervisors, while Mr. David Williams was reappointed, it was agreed to have Dr. Tomio Hirohata
continue to fulfill his duties even after completion of
his term until his successor assumes his/her post.
As for the scientific councilors, Dr. Teruhiko
Yoshida (Chief, Genetics Division, National Cancer
Center Research Institute) and Dr. Roy E. Shore (ProRERF Update Volume 15, Issue 1, Spring 2004

2

RERF News
fessor, Department of Environmental Medicine, NewYork University School of Medicine) were elected
as successors to Dr. Yusuke Nakamura and Dr. J.
Martin Brown, respectively. Also, Dr. Shinkan
Tokudome (Professor in Health Promotion and Preventive Medicine, Nagoya City University Graduate
School of Medical Sciences) was elected as a successor to Dr. Hiroyuki Shimizu, who had expressed
his intention to resign, effective 1 July 2003. Each ofthem will assume his post as scientific councilor on
July 1, 2003.
It was agreed that the next meeting of the Boardof Directors would be held on June 23–25, 2004 at
the Hiroshima Laboratory.
List of Participants
Permanent Directors:
Burton G. Bennett, Chairman
Senjun Taira, Vice Chairman
Eiichi Tahara, Permanent Director and Chief of Research
Visiting Directors:
Hiromichi Matsudaira, Consultant, Radiation Effects
Association
Takefumi Kondo, Member, Pollution-related Health
Damage Compensation Grievance Board, Ministry of the Environment, Guest Professor, Keio
University School of Medicine
Masaaki Kuniyasu, Former Ambassador Extraordinary and Plenipotentiary to the Republic of
Portugal
Richard B. Setlow, Senior Biophysicist, Biology Department, Brookhaven National Laboratory,
Adjunct Professor, Biochemistry and Cell Biology Department, State University of New Yorkat Stony Brook
John E. Burris, President, Beloit College
Paul L. Ziemer, Professor Emeritus, Purdue University
Supervisors:
Tomio Hirohata, Professor Emeritus, Department of
Public Health, Faculty of Medicine, Kyushu University

David Williams, Senior Financial Advisor, National
Academy of Sciences (NAS)
Scientific Councilor:
Ohtsura Niwa, Professor, Kyoto University Radiation Biology Center
Representatives of Supporting Agencies:
Masami Kato, Deputy Director, General Affairs Division, Health Service Bureau, Ministry of Health,Labour and Welfare
Steven V. Cary, Deputy Assistant Secretary for HealthStudies, Department of Energy (DOE)
Kevin Maher, Minister-Counselor for Environment,
Science and Technology, Embassy of the UnitedStates of America
Steve M. Dyokas, Scientific and Technical Affairs
Officer, Environment, Science and Technology
Office, Embassy of the United States of America
Nicole Nelson-Jean, Energy Attaché, Director, DOE
Asia Office, Embassy of the United States ofAmerica
Yoshimi Tamada, Assistant, DOE Tokyo Office, Embassy of the United States of America
Warren R. Muir, Executive Director, Division on
Earth and Life Studies, National Research Council, NAS
Evan B. Douple, Director, Board on Radiation Effects Research, Division on Earth and Life
Studies, National Research Council, NAS
Secretariat:
Charles A. Waldren, Chief Scientist
Masaharu Yoshikawa, Chief of Secretariat
Richard D. Sperry, Administrative Advisor, Secretariat
Observers:
Gen Suzuki, Chief, Department of Clinical Studies,
Hiroshima
Kei Nakachi, Chief, Department of Radiobiology/
Molecular Epidemiology
Kazunori Kodama, Chief, Department of Epidemiology, Hiroshima
Hiroaki Katayama, Chief, Department of Information Technology

The 30th Meeting of RERF Scientific Council
The 30th meeting of the Scientific Council washeld on March 10–12, 2003, in Hiroshima. The meeting was co-chaired by Drs. Martin Brown and Yusuke
Nakamura. In addition to reviewing as usual the scientific program of the RERF, a specific aim was an
in-depth review of the Department of Radiobiology/
Molecular Epidemiology. After RERF Chairman Dr.
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Burton Bennett extended greetings and introductory
remarks, Chief of Research Dr. Eiichi Tahara presented a general report of RERF research. Dr. Taharaemphasized the need for RERF to move into newareas of research focused on, but not limited to, radiation-related research. He pointed out that the peakof cancer mortality in the Life Span Study (LSS) will
RERF Update Volume 15, Issue 1, Spring 2004

RERF Newsnot occur until around 2015, thereby emphasizing
the importance of continuing to follow the survivors.
He also presented a new comprehensive strategy formolecular analysis of all newly diagnosed cancers
and for obtaining archival tissue samples from thesurvivors.
Presentations were then made by all departments.
In addition to overviews given by department chiefs,
the following more specific presentations were made:• Hepatocellular carcinoma risk, hepatitis and radiation exposure (Saeko Fujiwara, ClinicalStudies)• Ophthalmologic study of atomic-bomb survivors(Kazuo Neriishi, Clinical Studies)• Thyroid autoantibodies (Misa Imaizumi, ClinicalStudies, Nagasaki)• Sjogren’s syndrome (Ayumi Hida, Clinical Studies, Nagasaki)• Does A-bomb exposure increase oxidative stressafter 55 years? (Gen Suzuki, Clinical Studies)• Genetic effects of radiation in mice by 2D-DNA(Junichi Asakawa, Genetics)• Progress of array CGH (Norio Takahashi, Genetics)• Search for genetic instability in lymphocytes(Kazuo Ohtaki, Genetics)• Why does in utero exposure not induce chromosome aberrations (Nori Nakamura, Genetics)• Study of breast cancer using stored serum samples(Gerald Sharp, Epidemiology)• Fruit-vegetable intake and cancer mortality in LSS(Catherine Sauvaget, Epidemiology)• Data cleaning of mail survey information(Fumiyoshi Kasagi, Epidemiology)• Age-period-cohort model for Hiroshima Tumor
Registry data (Kojiro Koyama, Epidemiology)• Progress report on F 1 mail survey (AkihikoSuyama, Epidemiology, Nagasaki)• Implementation of DS02 (Shoichiro Fujita andHarry Cullings, Statistics)• Issues of bias due to selection by survival in LSS(Donald Pierce, Statistics)• Estimating radiation risk from dose-matched studies (John Cologne, Statistics)• Design of stratified case-control studies of diabetes and genetic polymorphisms (Eiji Nakashima,
Statistics)• Overview of immunological studies on radiation
effects (Seishi Kyoizumi, Radiobiology/Molecular Epidemiology)• Immunogenetic background in development ofdiabetes among A-bomb survivors (Tomonori
Hayashi, Radiobiology/Molecular Epidemiology)• Overview of molecular studies of breast and thyroid cancers (Yuko Hirai, Radiobiology/Molecular
Epidemiology)

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3
There was then a two-hour round-table discussion on future plans of the Radiobiology/Molecular
Epidemiology Department. Topic 1 was the immunogenome, and Topic 2 was molecular analyses of solidcancers among atomic-bomb survivors.
The Scientific Council continues to support thecore mission of RERF to study effects of radiation
exposure on atomic-bomb survivors. They also support expansion of the core mission, but suggest thatthe nature of this expansion be based on thoroughevaluation of research priorities in relation to its contribution to the mission of RERF, funding bases, andresources. The Council’s general recommendations
were as follows:• Recruiting of replacements for senior people leaving in the next 1–2 years, especially from theStatistics Department, needs to be given highest
possible priority.
• The publication rate of many RERF scientists
should be higher. It is recommended that at least
once per year the chief of each department review
with each professional staff plans for publicationof their research.
• RERF investigators are encouraged to apply foroutside funding, one of the items to be discussed
in the annual review of each scientist.
• The Council is concerned that in some cases anoverly long internal review process for publications
discourages scientists from writing up their work.
It recommends that every effort be made to restrict
this review process to no longer than one month.
• The Council is concerned about potential conflictof interest when a director of RERF is also a principal investigator of a research project thatinvolves significant use of RERF resources (morethan two Ph.D. level staff). It recommends thatany such arrangement require the director in question to recuse himself from the process of approvalof the research protocol (RP), and that final approval of the RP by the Board of Directors of
RERF should be required.
• All RPs other than pilot projects should be subject to external review by at least one past/present
member of the Scientific Council, as a supplement
to the normal review process.
• With rare exceptions, every RP should have a statistician as a co-investigator. The intent is that thestatistician would be included as a full partner inthe research, and be actively involved in formulating the study design as well as in analyzing andinterpreting the findings.
• The Council feels that there was insufficient time
for in-depth study of departments being reviewed
under the aegis of Multinational Peer Reviews. It
recommends that a different process be developedthat will allow more time for review and interaction with the scientists.
RERF Update Volume 15, Issue 1, Spring 2004

4

RERF News• The Council remains concerned about the num-

ber of participants in the F1 Study, particularly the
low anticipated numbers of those with one parent
having exposure above 1 Sv. Experience to datesuggests that only 77% of the expected participants in clinical examinations are attending, which
would result in a total of 10,000 or fewer participants. Greater effort is needed to attract
participants and to include participants from outside of the catchment area.
Extensive evaluations and recommendations werealso made for each research department.
Members of the Scientific Council
Yusuke Nakamura, Director, Human Genome Center, Institute of Medical Science, University ofTokyo
Yasuhito Sasaki, President, National Institute of Radiological Sciences
Ohtsura Niwa, Director, Radiation Biology Center,
Kyoto University

Hiroyuki Shimizu, Professor, Department of Public
Health, Gifu University School of Medicine
Toshitada Takahashi, Director, Aichi Cancer Center
Research Institute
J. Martin Brown, Professor and Division Chairman,
Division of Radiation Biology, Department ofRadiation Oncology, Stanford University Schoolof Medicine
Theodore L. Phillips, Professor and Chairman, Department of Radiation Oncology, Cancer Center,
School of Medicine, University of California, San
Francisco
Gloria M. Petersen, Professor of Clinical Epidemiology, Mayo Medical School
Clarice R. Weinberg, Chief, Biostatistics Branch,
Environmental Diseases and Medicine Program,
National Institute of Environmental Health Sciences
Joel S. Bedford, Professor, Department of Radiological Health Sciences, Graduate Faculty of Cellular
and Molecular Biology, Colorado State University

International Workshop: Immunological Homeostasis in Inflammatory
Response and Disease Development
On January 16 and 17, 2004, RERF hosted at its
Hiroshima Laboratory a workshop on the subject of
immunological homeostasis. This is the mechanism
by which the immune system responds to invasive
foreign substances, such as infectious germs, thenreturns to its original state except for its memory of
the foreign substance. Without this mechanism, theimmune system would also target the body’s own
normal tissue and result in a state of continuous inflammation. Discussions at the workshop focused on
how immunological homeostasis deteriorates due toaging and how radiation exposure is associated withdisease occurrence in atomic-bomb survivors. Key
research questions involve how immunological homeostasis is maintained and how the genetic
determinants of immunity are related to disease development.
The first day featured a special lecture by Professor Abul K. Abbas of the University of California,
San Francisco. He described T-cell regulation of immune functions—from the T cells’ initial response to
their complex regulatory mechanism involving a large
number of molecules and cells. Following that lecture there was a topical session, “T- and B-cell
homeostasis and disease development,” at which presentations were made by Drs. Toshiaki Ohteki (Akita
University), Hajime Karasuyama (Tokyo Metropolitan Institute of Medical Science), Paul J. Martin (Fred

Return to Table of Contents

Hutchinson Cancer Research Center, Seattle), andYoichiro Kusunoki and Seishi Kyoizumi (RERF Radiobiology/Molecular Epidemiology Department).
The second day began with another special lecture, given by Professor Tadatsugu Taniguchi of the
University of Tokyo. He spoke on regulation of immune response by interferon. After that, the second
topical session, “Innate immunity, inflammation anddisease,” featured presentations by Drs. Shigeo
Koyasu (Keio University) and Gen Suzuki (RERF
Clinical Studies Department). The third topical session, “Genetic approaches to human inflammatory
diseases,” included presentations by Drs. Eric G.
Wright (Dundee University, UK), Katsushi Tokunaga(University of Tokyo), and Kei Nakachi andTomonori Hayashi (RERF Radiobiology/Molecular
Epidemiology Department). The workshop concluded with a general overview and closing remarksby Dr. Charles A. Waldren, RERF Chief Scientist.
Dr. Yoichiro Kusunoki, Chief of the Immunology
Laboratory of RERF’s Department of Radiobiology/
Molecular Epidemiology, said a number of suggestions beneficial to RERF’s future immunologicalresearch activities arose out of the talks and discussions. He also expressed his appreciation to the RERF
directors, especially Chief of Research Dr. Eiichi
Tahara, for their support of the workshop.

RERF Update Volume 15, Issue 1, Spring 2004

5

RERF News

Staff News
Dr. Frederic Lagarde joined the Statistics Department in June 2003. He was previously in Biostatistics
at the Karolinska Institute, Stockholm, where he received his Ph.D. and was subsequently involvedin studies of residential exposures to radon. Mr.
Douglas Solvie joined RERF in January 2004 as Assistant to Chief of Secretariat, replacing Mr. Richard
Sperry as liaison for the National Academy of Sciences (NAS) in regard to their financial interests at
RERF. A substantial number of new scientific staff
joined RERF in April 2004, and details will be provided in the next issue of Update.

Mr. Sperry retired in June 2003 following 45 yearsof service at ABCC, NAS, and RERF. As noted, his
primary function is being taken over by Mr. Solvie.
Ms. Margaret Irwin resigned in July 2003, following
several years of work organizing the ABCC-RERF
archives. Dr. Gerald Sharp resigned in November
2003 to take a position at the US National Instituteof Allergy and Infectious Diseases to carry out research in their HIV/AIDS projects. Dr. Shoichiro
Fujita retired in December 2002 and was re-employedon a temporary basis to continue his work.

Current Status of Dosimetry Revision
The dosimetry system revision from DS86 to
DS02 was completed in March 2004. The last threeissues of RERF Update have contained columns summarizing the developing status of the revision, andthe Spring 2003 issue carried a full article by Cullings
and Fujita explaining much of the background anddevelopment. An RERF paper1 is in press at Radiation Research describing how the revision affects
radiation risk estimates for solid cancer and leukemia. Datasets for various RERF cohorts including
the new dose estimates are available to RERF workers through the database access system EasyClick.
Several years of intensifying concerns about theneed for revision culminated in a 2001 National Research Council Report recommending that therevisions be undertaken, directed as for DS86 by a
Bi-National Dosimetry Committee largely external
to RERF. A group of about 30 physicists from Japan,
the U.S. and Germany, assisted by RERF statisticians,
contributed enormous and varied efforts leading to
the basic DS02 system that was approved in March
2003. For the next year RERF scientists, research
assistants, and Master File Section staff carried out
the extensive work necessary to implement the new
system. Documentation of DS02, prepared by those
who developed the system, will be in a forthcoming
volume published by RERF.
The primary impetus for the revision was indications from activation measurements in exposedmaterials that DS86 Hiroshima neutron estimates at
distances greater than 1.5 km might be much too low.
However, after a thorough reconsideration of bomb
source terms, radiation transport calculations, experimental errors in the activation measurements, andadditional samples using refined or new methods, there
was agreement that this was not the case. Thus DS02

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came to be a progressive refinement of DS86, improving on it in many details but largely confirmatory innature. In addition to many improvements in shielding calculations, source term adjustments and improved
radiation transport calculations resulted in changes indose estimates summarized by the figure here. Gammaray estimates are increased by about 8–10% in distance
ranges relevant to risk estimation, and neutron estimates are decreased. This means that the ratio of
neutron to gamma-ray dose estimates is smaller thanin the past. Thus adjusting for the higher biologicaleffect of neutrons to estimate gamma-ray risks has become less of an issue than before, and estimation ofneutron risks has become even less feasible.
The RERF paper1 in press concludes that cancer
risk estimates are decreased by about 8% due to thedosimetry change, with negligible change in the apparent shape of the dose response or the age-time
patterns of risk. Work is underway to update the methods to allow for random errors in dose estimates. Thisis far enough along to indicate that such changes will
not appreciably affect the conclusions of that paper.
Although there had been some promise that DS02
would substantially reduce problems with dose estimates for Nagasaki factory workers, which can beseen from both chromosome aberration and cancer
data to be too large, this improvement did not materialize.
A feature of the DS02 implementation is that dose
estimates have newly been assigned to a large number of persons related to RERF cohorts. Some details
on this are given in the Facts & Figures section ofthis Update issue. Although most of these new dose
estimates are zero, the improvement will provide for
substantially improved analysis of data on the F1 andin utero cohorts.

RERF Update Volume 15, Issue 1, Spring 2004

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RERF News

Summary of gamma-ray and neutron survivor colon dose estimates, and their relativechanges with dosimetry revision, for each city
Nagasaki

Hiroshima
1000

100

100

10

10

1

1

0.1

0.1

Colon dose (mGy)

1000

0.01

1000

1500

2000

Gamma

10
% Change from DS86

2500

0.01

0

-10

-10
Neutron-30-40

Neutron
DS02
DS86

1000

1500

2000

2500

1000

1500

2000

2500

10

0

-20

Gamma

-20
-30

1000

1500

2000

2500

-40

Distance to hypocenter (m)Reference
1. Preston DL, Pierce DA, Shimizu Y, Cullings HM, Fujita S, Funamoto S, Kodama K: Effect of recent atomic bomb
survivor dosimetry changes on cancer mortality risk estimates. (Radiat Res, in press)

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RERF Update Volume 15, Issue 1, Spring 2004

7

Long-term Radiation Effects on Immune System

Long-term Effects of A-bomb Radiation on
the Immune System: Beyond a Half Century
Yoichiro Kusunoki, Chief, Immunology Laboratory, Department of Radiobiology/Molecular Epidemiology, Tomonori Hayashi, Senior Scientist, Department of Radiobiology/Molecular Epidemiology, Masayuki Hakoda, Chief, Division of Clinical Laboratories, Department of Clinical Studies, Gen Suzuki, Chief, Department of Clinical Studies,
Kei Nakachi, Chief, Department of Radiobiology/Molecular Epidemiology, and Seishi
Kyoizumi, Assistant Chief, Department of Radiobiology/Molecular Epidemiology

IntroductionMore than 50 years after exposure, we still haveno clear answers as to how A-bomb radiation has
caused biological effects in humans and how theseeffects seem to lead to many different diseases including noncancer diseases as well as cancer.
Radiation-related cancer has been observed for a very
long time, but recently there have emerged clear associations among A-bomb survivors between
radiation dose and the death rate of most major
noncancer diseases.1,2 Mechanisms for radiation-related cancer, although not totally understood, aremuch clearer than those for radiation-related
noncancer diseases, where in fact almost nothing is
known. An interesting hypothesis is that radiation
effects on the immune system may be in part involvedin these radiation-related diseases, especially fornoncancer diseases. Recent developments in immunological science have paved the way to explain many
human diseases as abnormalities in the immune system. Therefore, to gain further insights into themechanisms of radiation-induced diseases, it is necessary to study the possible origin of theseradiation-associated disorders from the immunological point of view (Figure1). Exposure to radiation isthought to affect host immune surveillance, but little
is known about the direct relationship between radiation effect on the immune system and disease

A-bombradiation

Mechanisms?

development. Immunological studies at RERF are
aimed at obtaining better understanding of the possible relationships between the damaging effects ofradiation on the immune system and the subsequentdevelopment of radiation-induced diseases.
Does acute radiation-induced damage of theimmune system lead to disease development?
The immune system was dose-dependently damaged in A-bomb survivors at the time of exposure,mainly due to radiation-induced cell death. Several
months after radiation exposure, following cell
repopulation, the hematopoietic system had nearly recovered from the damage in the survivors.3,4 However,even 50 years after radiation exposure there still remain lymphocyte and hematopoietic stem cell
populations that bear radiation-induced DNA damage,such as somatic mutations and chromosome aberrations, in the survivors’ hematolymphoid systems.5–15
In addition, we can still observe significant effects ofthe previous radiation exposure on lymphoid cell composition and function in the immune system of thesurvivors (Figure 2).16–25 Since most of these effects
appear as small, few percent changes per 1 Gy of exposure (Table 1), one can not easily draw the scenariothat such changes in the immune system may lead to
succumbing to any particular diseases. Nevertheless,it may be possible that even immunological changes(if the alterations last for more than several decades)
may have led to increased risks of diseases that we

Increased riskof selected diseases

Late effects
Alterations of composition
and functions

Helper T cells

A-bombradiation

Involvement of any possible
immunological abnormalities in diseasedevelopment?
Effects of immunogenetic backgroundon disease development?

Acuteeffects> 50 years

Persistent
inflammation

ThymusT cell function

Cytokines

Cell killing

Mutations

B cells

Stem cells
MutationsFigure 1. Immunological approaches to investigationof the mechanisms on the development ofradiation-related diseases.
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Figure 2. Acute and late effects of A-bomb radiationon the human immune system.
RERF Update Volume 15, Issue 1, Spring 2004

8

Long-term Radiation Effects on Immune System

Immunological alterations observed in A-bomb
survivors
Immunological alterations that we have observedin A-bomb survivors are listed in Tables 1 and 2. Tcell functions, such as responses to mitogens(phytohemagglutinin-dependent proliferation, 16
interleukin (IL)-2-producing cell frequency19), alloantigens,17 and superantigen staphylococcal enterotoxin23
appear to be consistently lower in the survivors, due
to reduction in the number of T cells as a consequenceof insufficient supply of new T cells. These functional
alterations agree well with observations of lymphocyte composition (Table 1), that is, a decrease in the
CD4 helper T-cell population, especially naïve CD4 T
cells.22–25 A similar decrease in the number of naïve
CD4 T-cell population was also observed in other studies such as follow-up studies of radiotherapy patients.26
A proportion of memory CD4 T cells did not show
significant changes with radiation exposure.22,24,25 In
contrast to the CD4 T-cell population, CD8 T-cell population of A-bomb survivors showed significant

Disease risk

Immune function

frequently observe in the A-bomb survivor population. We suppose that the more compromised theimmune competence becomes in an individual fromconsequences of aging and/or radiation exposure, thehigher the disease risk will likely be for the individual(Figure 3).

Low

High

A factor that can affect the immune system(age, radiation dose, etc.)

Figure 3. A schematic model explaining how a slight
immunological change may have caused
an increased risk of disease. Each blue
circle represents each individual value forany given immunological parameter, andthe orange line indicates the regression line
between value for the immunological parameter and an appropriate environmental
factor such as radiation dose. The lower
value for the immunological parameter anindividual has become to possess as consequences of aging and/or radiation exposure, the higher disease risk the individualis likely to have.

Table 1. Comparing effects of sex, age, radiation dose on the percentages of lymphocyte subsets inperipheral blood lymphocyte fractions of A-bomb survivors
Effects

Lymphocyte
subsets

Sex

Age (10 years)

Radiation (Gy)

T cells
CD4 total

F > M (5.3%)a

Decrease (5.0%)

Decrease (2.0%)

naïveF > M (3.3%)

Decrease (7.5%)

Decrease (4.5%)

memoryF > M (8.2%)

NSb

NS

NS

NS

NS

naïve

F > M (18.5%)

Decrease (42.3%)

Decrease (7.7%)

memoryNS

Increase(7.3%)

Increase (5.6%)c

CD8 total

B cells

F > M (5.3%)

Decrease (7.3%)

Increase (8.5%)

NK cells

M > F (20.3%)

Increase (20.7%)NSa(% change), bnot significant, csuggestive

Table 2. Late effects of A-bomb radiation on immune functions
Cell type

Function

Radiation effect

Reference

T cells

PHA response

Decrease

Radiat Res 93:572 (1983)

MLR

Decrease

Radiat Res 117:26 (1989)

IL-2 production

Decrease

Radiat Res 155:81 (2001)

SAg response

Decrease

Radiat Res 158:715 (2002)

Ab production (serum levels)

Increase

Radiat Res 137:89 (1994)

RF

Increase

K562 cell lysis

Not significant

B cells

NK cells

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Radiat Res 116:343 (1988)

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Long-term Radiation Effects on Immune System
reductions in the proportion of naïve cells but also asignificant increase in that of memory T cells.25 As
for B-cell population, the number of B cells, as wellas B-cell functions such as serum IgM, IgG, and IgAlevels (ref. 21 and Hayashi et al, submitted), anti-EB
virus antibody,20 and prevalence of rheumatoid factor21 are significantly higher in the exposed persons.
The reason why B-cell immune responses are enhanced in the survivors is unclear. It may be that
increased inflammatory reactions due to deficit ofhelper T cells are involved in the enhanced B-cell
responses of the survivors. With regard to innate
immunity, however, the proportion and cytotoxic
activity of natural killer (NK) cells showed no significant effect of A-bomb radiation.27
Possible alterations in lymphocyte function of
A-bomb survivors
RERF’s immunologists have proposed the hypothesis that A-bomb radiation acted as a trigger to reduce
cellular immune responses controlled by Th1 cells
but to augment humoral immune responses controlled
by Th2 cells.28 That the ratio Th1/Th2 is fundamental is a well-known paradigm in immunology. The
above hypothesis has been tested by measuring thelevels of plasma cytokines that are related to either
Th1- or Th2-dominant status and by enumerating thenumbers of Th1 and Th2 cells in the peripheral bloodusing a chemokine receptor (CXCR3) and a prostaglandin D receptor (CRTH2) as their cell surface
markers, respectively.29 Results obtained in recent
years provided indications that radiation-dose dependent elevations of cytokine levels are apparent not
only for a Th2-related cytokine, IL-6, but also for
Th1-related cytokines, IFN-γ and TNF-α (Hayashi
et al, submitted), indicating enhanced production of
inflammatory cytokines irrelevant to Th1/Th2 imbalance in A-bomb survivors. Furthermore, there has
been no significant effect of A-bomb radiation on theratio between Th1 and Th2 cells (Kusunoki, unpublished observation). It is therefore unlikely that
A-bomb radiation has induced a long-lasting alteration in the host immunity controlled by Th1 and Th2
cells even though a possible impairment of the ability of T cells to produce IL-2 has been suggested in
A-bomb survivors.19 Recent studies have indicatedthat CD4+CD25+ regulatory T cells play crucial roles
in suppression of the host immune responses, especially of those to self-antigents.30 NKT cells are alsosuggested to play pivotal roles in the interplay between innate and acquired immune responses inwhich the direction of T-cell function polarization isdetermined.31 It remains to be determined whether
radiation exposure affects these important lymphocyte subsets.
Possible perturbation of T-cell homeostasis in Abomb survivors
In the T-cell system, a constant supply and diverse
repertoire of lymphocytes are maintained, despite theemergence of new lymphocytes and tremendous exReturn to Table of Contents

9pansion of individual clones that may occur during
responses to antigens. This homeostasis in the T-cellsystem is achieved by the balance between renewal
and death among naïve and memory T cells, and thesizes of these T-cell populations are maintained independently (Figure 4a).30 Maintenance of both naïve
and memory T-cell pools is important for the body toprotect against intrusions by pathogens. However, theability to maintain both pools is believed to declinewith age. In older persons, the size of the naïve Tcell pool becomes smaller due to reduced productionof new T cells in the thymus, and responses to antigens are subsequently impaired as compared withyounger individuals (Figure 4b).33–35 Although theentrance of naïve cells into the memory T-cell poolbecomes rare, the size of memory T-cell pool is kept
constant regardless of age. However, some fractionsof cells preferentially proliferate, and clonally expanded populations frequently arise in the memory
T-cell pool of older individuals. The existence of
clonal populations that make up a large portion of
the memory T-cell pool may result in deviation of
immune responses to antigens.
Both naïve CD4 and CD8 T-cell pools of A-bomb
survivors are not likely to be appropriately maintained
because of lower numbers of naïve CD4 and CD8 T
cells than in unexposed controls of the same age,25
even 50 years after the bombing. This may indicatethat the naïve T-cell pool has insufficiently recovered after radiation-induced damage of the T-cellsystem and has not reached the normal level in size
(Figure 4c). In contrast, memory T-cell pools of Abomb survivors appeared to be almost normal (CD4)or larger (CD8) in size.25 However, we have recently
demonstrated that the extent of T-cell receptor repertoire deviation in memory CD4 T cells significantly
increased with radiation doses to which the survivors were exposed (Figure 5). 24 Because therepertoire deviation in memory CD4 T cells was frequently associated with the presence of a large sizeof clonal populations, we speculate that A-bomb radiation may have resulted in preferential expansionof memory CD4 T-cell clones that might have existed at the time of the bombing (Figure 4c). Thus,
our current interpretation of the long-lasting abnormality in the T-cell systems of survivors is that theprevious radiation exposures have 1) reduced theability to produce new T cells and 2) impaired themaintenance of helper T-cell memory. The reductionin the size of naïve T-cell populations may compromise the ability of the host to defend against an
intrusion by pathogens to which the host has not previously been exposed. The impaired maintenance ofmemory T-cell populations may lead to reduced abilities to prevent recurrent infection by pathogens andto control latently infected microbes.
Disease development in A-bomb survivors
through inflammatory responses
It has been already reported that there are statistically significant associations between inflammatory
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Long-term Radiation Effects on Immune System

10

Figure 4. T-cell homeostasis is likely to be perturbed by aging or radiation exposure.
a)
Peripheral T-cell pool
Naive

MemoryEducation
ThymusStem cells
Response to pathogen A(secondary response)
Response to pathogen A(primary response)b)a) T-cell homeostasis involves the maintenance of abalance between renewal and death among the naïve
and memory T-cell populations. The naïve T-cell poolis primarily maintained by the inflow of T-cell populations that acquired diverse receptors for recognitionof various kinds of peptides associated with self MHC
molecules in the thymus (education). Once the immune system encounters an antigen, a populationof T cells in the naïve T-cell pool will recognize theantigen and proliferate, but most of the cells that proliferate will die and only a few of them will enter the
memory T-cell pool after the immune response has
run its course (primary response). T cells in thememory pool can be recalled by antigens that havepreviously been encountered by the immune system(secondary response). A secondary response is usually more rapid and vigorous than a primary response.
Only a few memory T cells return to the memory pool
after the secondary immune response has run its
course. The renewal rate of a memory T-cell population is believed to be much higher than that of thenaïve T-cell population.

Peripheral T-cell pool
Naive

MemoryClonal populations

ThymusStem cells

Response to pathogen B
Response to pathogen A

c)Peripheral T-cell pool
A-bomb radiation

Naive

MemoryStem cells

Thymus

Inefficient

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Expansion of clonal
populationsb) Our ability to maintain both naïve and memory Tcell pools is believed to decline with aging. In older
people, the naïve T-cell pool becomes reduced insize as a result of diminishing rates of production of
new T cells in the thymus; their responses to antigens begins to be impaired in comparison with thoseof younger individuals. Although fewer naïve T cells
move into the memory T-cell pool, the size of thememory T-cell pool is nonetheless maintained in aging individuals. However, some cells proliferate preferentially, and clonally expanded populations frequently appear to arise in the memory T-cell pools ofolder individuals. Thus clonal populations often cometo represent a considerable percentage of thememory T-cell pool, and this may lead to a distorted
array of immune responses to antigens.
c) Perturbation of T-cell homeostasis in A-bomb survivors could be considered as accelerated aging. Abomb radiation exposure may have damaged theability of thymus to produce naïve T cells and subsequently resulted in reduced size of the naïve T-cellpool, which may be associated with increased risk ofinfection-associated diseases such as myocardial infarction. The maintenance of memory T-cell pool may
have been also perturbed by A-bomb radiation exposure. Although the size of memory T-cell pool was
not reduced by A-bomb radiation exposure, emergence of clonal expansions of a part of memory Tcell population has been frequently observed in thememory T-cell populations of A-bomb survivors.

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11

Long-term Radiation Effects on Immune System

Extent of deviation per Vβ family (%)

1.5
ATB = 30

n = 710

ATB = 20
1.0
ATB = 10
ATB > 20 (P < 0.05)
0.5

0.0
0

1

2

3

4

Dose(Gy)

Figure 5. Evaluation of T-cell repertoire of memory CD4 T-cell population by determining to what extent any
individual’s value for the percentages of T cells expressing specific TCR Vβ families deviated from theaverage value for all subjects. The T-cell receptor repertoire in the memory CD4 T-cell populations
diverged significantly from the population average for counterpart families especially in individuals
who had been exposed to higher doses and were at least 20 years of age at the time of the bombing(ATB).

biomarkers (leukocyte count, erythrocyte sedimentation rate, alpha 1 globulins, alpha 2 globulins, andsialic acid) and radiation dose in A-bomb survivors.36
To test whether defects in CD4 helper T-cell activities in A-bomb survivors are related to inflammatory
responses, we recently measured the levels of inflammatory cytokines and C-reactive proteins (CRP) in
plasma samples from a large group of survivors.37
There was a strong correlation between IL-6 and CRP
levels. Interestingly, the plasma IL-6 level appeared
to correlate negatively with the percentages of peripheral blood CD4 T cells. We found that both IL-6
and CRP levels appeared to have increased with increased radiation dose. These results may indicatethat pre-clinical inflammatory status is linked in some
way to the decrease in CD4 T-cell count, suggestingthat immunological changes may have caused somediseases through inflammatory responses. To investigate this possibility, we examined whether any
immunological changes were associated with thepathogenesis of cardiovascular diseases including
myocardial infarction (MI), since recent studies provide evidence that inflammation plays a role in thistype of cardiovascular disease and since a dose-dependent increase in relative risk of MI has been
observed in the Adult Health Study (AHS) cohort.
Adjusting for dose, the prevalence of MI was significantly higher in individuals who had reduced CD4
T-cell percentages (Figure 6).38 Furthermore, the IL6 levels appeared to be significantly higher insurvivors with a history of MI than in those without
such a history. A similar result was also found in levels of CRP (Figure 7). 37 These results indicate that
MI in A-bomb survivors may be at least in part due
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to their having reduced numbers of CD4 helper T
cells, and hence to their having a diminished ability
to mount an immune defense against infections of a
type which may be implicated in the etiology of atherosclerosis (Figure 8).
Could genetic background be involved indisease risks of A-bomb survivors?
It is quite apparent that there are large individual
variations in the levels of immunological and inflammatory markers (e.g., Figures 6 and 7) and that only
a part of individuals who show reduced immune functions and/or elevated inflammatory biomarkers
develop particular diseases. Both immune and inflammatory responses are controlled by a series of genesthat are genetically polymorphic. Thus, one can hypothesize that individual immunogenetic backgroundmay determine individual susceptibility to diseases.
A careful analysis of the data obtained from a previous study of AHS subjects suggested that there was asignificant positive correlation between prevalenceof type 2 diabetes and radiation dose in individuals
who were less than 20 years of age at the time of
exposure to the A-bomb in Hiroshima.37 One especially important genetic factor that can affect hostimmune responses appears to be the major histocompatibility complex (MHC) locus, which in humans isreferred to as the HLA (for Human Leukocyte Antigens) locus. We used HLA class II typing dataobtained from a subset of the same survivors to determine whether there was any evidence of a
relationship between the development of diabetes andHLA class II type that might also be associated withthe estimated doses of A-bomb radiation that they
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12

Long-term Radiation Effects on Immune System
Male
80

a

70

70

60

60

%CD4

%CD4

80

50
40

b

50
40

30

30

20

20
0.0

0.5

1.0

1.5

2.0

2.5

3.0

50

Dose (Gy)

60

70

80

90

Age ATE (year)

Female
80

c

70

70

60

60

%CD4

%CD4

80

50
40

d

50
40

30

30

20

20
0.0

0.5

1.0

1.5

2.0

2.5

3.0

50

Dose (Gy)

60

70

80

90

Age ATE (year)

Figure 6. Proportion of peripheral blood CD4 T cells in A-bomb survivors with histories of myocardial infarction (MI, closed squares) and those without such histories (open circles). Lines denote regression
lines between CD4 T-cell proportion and radiation dose (a and c) or age (b and d), after adjusting
the proportion for 66-year-old male (a) and female (c) survivors or unexposed males (b) andfemales (d), respectively. CD4 T-cell proportion is significantly (P < 0.01) higher in females thanmales and decreased with age (P < 0.01) and dose (P < 0.01). Proportion of CD4 T cells issignificantly (P = 0.02) lower in survivors with myocardial infarction than those without.

IL-6 (pg/mL)

Myocardial infarction (MI)
10

10

1

1

CRP (mg/dL)

0

2

4

50

10

10

1

1

0.1

0.1

0.01

0.01

0
1E-3

60

70

80

90

100

60

70

80

90

100

1E-3
0
0

2

Dose (Gy)450

Age at measurment (yrs)

Figure 7. Plasma IL-6 (upper panels) and CRP (lower panels) levels in A-bomb survivors with histories of MI(closed squares) and those without such histories (open circles). Lines denote regression lines
between IL-6 level and radiation dose or age and, between CRP level and radiation dose or age.
Inflammatory markers, IL-6 and CRP, increased with radiation dose (P < 0.01) or age (P < 0.01).
Adjusting for dose, history of MI was associated with higher IL-6 and CRP (P < 0.05).

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RERF Update Volume 15, Issue 1, Spring 2004

13

Long-term Radiation Effects on Immune System
A-bomb radiation
Perturbation of T-cell
homeostasis:
Helper T-cell counts
Immune functions

Inflammatory cytokines:
IL-6 level

Environmental
factors

Infection

CRP level

Persistent inflammation

Diseases(e.g., cardiovascular disease)

Figure 8. A hypothesis of the immunological mechanism on the disease development in Abomb survivors. A-bomb radiation may haveperturbed T-cell homeostasis and resulted
in deficits of helper T-cell counts that areassociated with reduced immune functions.
Such abnormalities in the T-cell system maycause long-lasting inflammation that may
lead to the development of diseases suchas cardiovascular diseases. Infections andother environmental factors such as
lifestyles may certainly interact with the process of disease development.

0.5

DQA1*0301-DRB1*09 or
DQA1*0401-DRB1*08(n = 236)

received.34 We found that there appear to be significant differences in diabetes prevalence between
exposed and low-dose or non-exposed survivors withdifferent HLA DQA1 and DRB1 alleles. Thus, forexample, the odds ratios (ORs) for the most heavily
exposed (>1.5 Gy) group of survivors who had either DQA1*0401 and DRB1*08 alleles or
DQA1*0301 and DRB1*09 alleles were significantly
higher than the ORs observed for either unexposed
controls or survivors in the low dose group, whereas
there were no comparable dose-dependent increases
in diabetes incidence among equivalently exposed
survivors who were not carrying either DQA1*0401
and DRB1*08 or DQA1*0301 and DRB1*09 (Figure 9). These findings suggest that certain HLA class
II genes (or possibly even certain closely-linked geneor genes) regulate one or more components of theimmune system that are an important influence on
the likelihood of diabetes development among theyounger (<20 year-old) and more heavily exposed
A-bomb survivors. We believe this is the first reportof differences in apparent radiation risk for somedisease, according to individual genetic backgrounds.
Such an immunogenetic approach may provide us
a new clue to determine the mechanisms by which radiation exposures cause diseases. A finding based on
genetic differences in individuals should be more defi-

Other haplotypes(n = 236)

0.4

Prevalence

P = 0.0003
0.3

0.2

P = 0.1421

0.1

0.0
0

1

2

3

4
0
1
Radiation Dose (Gy)

2

3

4

Figure 9. Cumulative prevalence rates of diabetes by HLA haplotyping in radiation dose categories. Prevalence of diabetes increased with higher radiation dose categories among individuals who have
either the DQA1*0301-DRB1*09 or DQA1*0401-DRB1*08 haplotype (trend P = 0.0003). No significant association was found between radiation and diabetes among individuals who have neither
the DQA1*0301-DRB1*09 alleles nor the DQA1*0401-DRB1*08 haplotype (trend P = 0.14). The
prevalence of diabetes among individuals with these haplotypes was significantly higher than thatamong individuals without these haplotypes (P = 0.03).

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Long-term Radiation Effects on Immune System
nite than that based on conventional phenotypical observations. In other words, if a genetic difference inindividual immunogenome can explain a difference
in individual susceptibility to a disease, one can argue
that there is a possible immunological mechanism inthe development of this particular disease.
Future directions in RERF’s immunology
studies
To address the questions of how A-bomb radiation
has caused biological effects in humans and many different diseases, the immunologists at RERF have madethree hypotheses (Figure 10). The first hypothesis is that
A-bomb radiation may have accelerated immunological aging by perturbing T-cell homeostasis. To test thishypothesis, we have begun determining the number ofT cells that contain T-cell receptor-rearrangement excision circles (TRECs), and also measuring the lengthsof telomere repeats in blood leukocytes (see RP 4-0241).
To gain a better understanding of the mechanisms involved in radiation-induced perturbation of T-cell
homeostasis, we also plan to investigate the processesof T-cell reconstitution following radiation-induced
damage, using a number of potentially valuable animalmodels.

2. Inflammation
A-bomb Accelerateradiation

Immunologicalaging

1. Perturbation ofT-cell homeostasis

Diseasedevelopment

3. Immunogenetic
background

Prospective cohort study
Retrospective case control study using preserved samples
Animal model

Figure 10. Strategies of RERF’s immunology study.

14

The second hypothesis is that A-bomb radiation
may have induced long-lasting inflammation that may
lead to disease development. We believe that RERF’s
multidimensional research environment will make itpossible to carry out a comprehensive investigationof the immunological mechanisms underlying diseasedevelopment in A-bomb survivors. Data obtained
from comparative measurements of serum cytokine
levels as well as of surface markers for lymphocyte
subsets in the survivors will be referred to onsets ofvarious diseases in the survivors, both prospectively
and retrospectively. Inflammatory response, mediatedby immune cells, is thought to be a key mechanismin the development of various lifestyle-associateddiseases, such as diabetes, coronary heart disease,and several cancers. We will investigate whether there
are any interactions between immune inflammatory
mediators (such as pro-inflammatory cytokines, IL1, IL-6, TNF-α, etc.) and lifestyle factors in thedevelopment of these diseases among A-bomb survivors.
We also hypothesize that individual immunogenetic
background may determine individual susceptibility
to succumbing to diseases. To test this hypothesis, wewould like to utilize the results that have been achievedin the human genome project and in the current
progress of molecular immunology. RERF’s studies
provide immunological data as well as clinical andepidemiological data on the health status and mortality in a fixed A-bomb survivor cohort. In addition,
blood lymphocytes of approximately 7,000 survivors
have been preserved, and these samples are quite useful for genome analyses. Thus, we will examine thegenotypes of a series of genes that are closely involvedin host immune and inflammatory responses among
A-bomb survivors using preserved blood samples, andcomprehensively analyze their associations with diseases and radiation exposure.

Glossary
Adapted, with permission from Elsevier, from pp. 468–99 of Cellular and Molecular Immunology,
4th Ed., Abbas A, Lichtman AH, Pober J (eds), W.B. Saunders, Philadelphia, 2000.
Acquired immunity. The form of immunity by lymphocytes that is stimulated by exposure to infectious
agents. In contrast to innate immunity, acquired immunity is characterized by exquisite specificity for
distinct macromolecules and “memory” which is theability to respond more vigorously to repeated exposure to the same microbe.
Alloantigen. A cell or tissue antigen that is present
in some members of a species and not others, that isrecognized as foreign on an allograft. Alloantigens
are usually products of polymorphic genes.
B cell. The only cell type capable of producing antibody molecules. B cells develop in the bone marrow,and mature B cells are found mainly in lymphoid
Return to Table of Contents

follicles in secondary lymphoid tissues such as lymph
nodes and spleen, in bone marrow, and in low numbers in the circulation.
CD4 T cell (helper T cell). The functional subset of
T cells whose main effector functions are to activate
macrophages in cell-mediated immune responses andpromote B-cell antibody production in humoral immune responses. These effector functions are
mediated by secreted cytokines and by T-cell binding to macrophages or B cells.
CD8 T cell (cytotoxic T cell). A type of T cell whose
major effector function is to recognize and kill hostcells infected with viruses or other intracellular microbes.
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Long-term Radiation Effects on Immune System
Chemokines. A large family of structurally homologous, low molecular weight cytokines that stimulate
leukocyte movement and regulate the migration ofleukocytes from blood to tissues.
CRP (C-reactive protein). A member of thepentraxin family of plasma proteins involved in innate immune responses to bacterial infections. CRP
in an acute phase reactant, and it binds to the capsuleof pneumococcal bacteria. CRP also binds to C1q
and may thereby activate complement or act as anopsonin by interacting with phagocyte C1q receptors.
Cytokines. Proteins produced by many different cell
types that mediate inflammatory and immune reactions. Cytokines are principal mediators ofcommunications between cells of the immune system.
Haplotype. The set of alleles inherited from one
parent and therefore on one chromosome.
HLA (human leukocyte antigens). Major histocompatibility complex (MHC) molecules (see below)
expressed on the surface of human cells.
Immune system. The molecules, cells, tissues, andorgans that collectively function to provide immunity, or protection against foreign organisms.
Innate immunity. Protection against infections that
relies on mechanisms that exist before infection, arecapable of rapid responses to microbes, and react inessentially the same way to repeated infections. The
innate immune system includes epithelial barriers;
phagocytic cells (neutrophils, macrophages); natural killer cells; the complement system; and cytokines,
largely made by mononuclear phagocytes, that regulate and coordinate many of the activities of the cellsof innate immunity.
IFN-γγ (interferon-γγ). A cytokine produced by T cells
and NK cells whose principal function is to activate
macrophages in both innate immune responses andcell-mediated immune responses.
IL-1 (interleukin-1). A cytokine produced mainly
by activated mononuclear phagocytes whose principal function is to mediate host inflammatory
responses in innate immunity (e.g., induction of endothelial cell adhesion molecules, stimulation ofchemokine production by endothelial cells and macrophages, stimulation of the synthesis of acute phasereactants by the liver, induction of fever).
IL-2 (interleukin-2). A cytokine produced by antigen-activated T cells that acts to stimulate T-cellproliferation and also potentiates the apoptotic cell
death of antigen-activated cells. Thus IL-2 is requiredfor both the induction and self-regulation of T-cellmediated immune responses. IL-2 also stimulates theproliferation and effector functions of NK and B cells.
IL-4 (interleukin-4). A cytokine produced by the Th2
subset of CD4 helper T cells whose functions include
induction of differentiation of Th2 cells from naïve
CD4 T cells, stimulation of IgE production by B cells,
and suppression of IFN-γ-dependent macrophagefunctions.
IL-5 (interleukin-5). A cytokine produced by the Th2
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15

cells and activated by mast cells. IL-5 stimulates IgA
production by B cells and activates eosinophils that
contribute to many of pathogenic processes in allergic diseases.
IL-6 (interleukin-6). A cytokine produced by manycell types and functions in both innate and acquired(T- and B-cell mediated) immunity. IL-6 stimulates
the synthesis of acute phase proteins (such as CRP)
by hepatocytes, as well as the growth of antibodyproducing B cells.
Memory T cells. T cells that mediate rapid and enhanced (i.e., memory or recall) responses to secondand subsequent exposure to antigens. Memory T cells
are produced by antigen stimulation of naïve T cells
and survive in a functionally quiescent state for many
years after the antigen is eliminated.
MHC (major histocompatibility complex). A large
genetic locus that includes the highly polymorphic
genes encoding the peptide-binding molecules recognized by T cells. Two structurally distinct types of
MHC molecules exist. Class I MHC (HLA-A, B, andC in human) molecules are present on most nucleated cells, bind peptides derived from cytosolic
proteins, and are recognized by CD8 T cells. Class II
MHC (HLA-DR, DQ, and DP in human) molecules
are restricted largely to professional antigen-presenting cells (macrophages, dendritic cells, B cells), bind
peptides derived from endocytosed proteins, and arerecognized by CD4 T cells.
MLR (mixed lymphocyte reaction). An in vitro
reaction of alloreactive T cells from one individual
against MHC antigens on blood cells from anotherindividual. The MLR involves proliferation of andcytokine secretion by both CD4 and CD8 T cells andis used as a screening test to assess the compatibilityof a potential graft recipient with a potential donor.
Naïve T cell. A mature T cell that has not previously
encountered an antigen, nor is the progeny of an antigen-stimulated mature T cell. When naïve T cells
are stimulated by antigen, they differentiate into effector cells. Naïve T cells have surface markers andrecirculation patterns that are distinct from those ofpreviously activated T cells.
NK (natural killer) cells. A subset of bone marrowderived lymphocytes, distinct from B or T cells, thatfunction in innate immune responses to kill microbeinfected cells by direct lytic mechanisms and by
secreting IFN-γ. NK cells do not express clonally
distributed antigen receptors like Ig receptors or
TCRs, and their activation is regulated by a combination of cell surface stimulatory and inhibitory
receptors, the latter recognizing self-MHC molecules.
PHA (phytohemagglutinin). A carbohydrate-binding protein, or lectin, produced by plants thatcross-links human T-cell surface molecules, including the T-cell receptor, thereby inducing polyclonal
activation of T cells. PHA is frequently used in experimental immunology to study T-cell activation. In
clinical medicine, PHA is used to assess whether aperson’s T cells are functional or to induce T-cellmitosis for the purpose of generating karyotypic data.
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Long-term Radiation Effects on Immune System
Superantigen (SAg). Proteins that bind to and activate all the T cells in an individual that express aparticular set or family of T-cell receptor (TCR)
genes. Several staphylococcal enterotoxins aresuperantigens. Their importance lies in their ability
to activate many T cells, which results in large
amounts of cytokine production and a clinical syndrome that is similar to septic shock.
T cell. The cell type that mediates cell-mediated immune responses in the acquired immune system. T cells
mature in the thymus, circulate in the blood, populatesecondary lymphoid tissues, and are recruited to peripheral sites of antigen exposure. They express antigen
receptors (TCRs) that recognize peptide fragments offoreign proteins bound to self-major histocompatibility complex (MHC) molecules. Functional subsets ofT cells include CD4 helper and CD8 cytotoxic T cells.
Th1 cells. A functional subset of helper T cells that
secretes a particular set of cytokines, including IFNγ, and whose principal function is to stimulate
phagocyte-mediated defense against infections, especially with intracellular microbes.
Th2 cells. A functional subset of helper T cells that16

secretes a particular set of cytokines, including IL-4
and IL-5, and whose principal functions are to stimulate IgE and IgA productions by B cells andeosinophil/mast cell-mediated immune reactions andto downregulate Th1 responses.
Thymus. A bilobed organ situated in the anterior mediastinum, which is the site of maturation of T cells
from bone marrow-derived precursors. Thymic tissue
is divided into an outer cortex and an inner medulla
and contains stromal thymic epithelial cells, macrophages, dendritic cells, and numerous T-cell precursors(thymocytes) at various stages of maturation.
α (tumor necrosis factor-αα). A cytokine proTNF-α
duced mainly by activated mononuclear phagocytesthat functions to stimulate the recruitment of neutrophils and monocytes to sites of infection and toactivate these cells to eradicate microbes. TNF-α produced in large amounts has systemic effects, including
induction of fever, synthesis of acute phase proteinsby the liver, and cachexia. TNF-β is a closely related
cytokine with identical biologic effects to TNF-α but
is produced by T cells.

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mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors using a single beam flow sorter.
Cancer Res 49: 581–8, 1989
9. Hakoda M, Hirai Y, Shimba H, Kusunoki Y, Kyoizumi S, Kodama Y, Akiyama M: Cloning of phenotypicallydifferent human lymphocytes originating from a single stem cell. J Exp Med 169:1265–76, 1989
10. Nakamura N, Umeki S, Hirai Y, Kyoizumi S, Kushiro J, Kusunoki Y, Akiyama M: Evaluation of four somatic
mutation assays for biological dosimetry of radiation-exposed people including atomic-bomb survivors. In:
Gledhill BL, Mauro F, eds. New Horizons in Biological Dosimetry. Progress in Clinical and Biological Research. Vol. 372. New York, NW, Wiley-Liss Inc, 1991, pp 341–50.
11. Kyoizumi S, Umeki S, Akiyama M, Hirai Y, Kusunoki Y, Nakamura N, Endoh K, Konishi J, Sasaki MS, Mori T,
Fujita S, Cologne JB: Frequency of mutant T lymphocytes defective in the expression of the T-cell antigen
receptor gene among radiation-exposed people. Mutat Res 265:173–80, 1992
12. Kusunoki Y, Kodama Y, Hirai Y, Kyoizumi S, Nakamura N, Akiyama M: Cytogenetic and immunologic identification of clonal expansion of stem cells into T and B lymphocytes in one atomic-bomb survivor. Blood 86:2106–
12, 1995
13. Awa AA, Honda T, Sofuni T, Neriishi S, Yoshida MC, Matsui T: Chromosome-aberration frequency in cultured

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Long-term Radiation Effects on Immune System

17

blood-cells in relation to radiation dose of A-bomb survivors. Lancet ii:903–5, 1971
14. Hirai Y, Kusunoki Y, Kyoizumi S, Awa AA, Pawel DJ, Nakamura N, Akiyama M: Mutant frequency at the HPRT
locus in peripheral blood T-lymphocytes of atomic bomb survivors. Mutat Res 329:183–96, 1995
15. Nakano M, Kodama Y, Ohtaki K, Itoh M, Awa AA, Cologne JB, Kusunoki Y, Nakamura N: Estimating thenumber of hematopoietic or lymphoid stem cells giving rise to clonal chromosome aberrations in blood T lymphocytes. Radiat Res 161:273–81, 2004
16. Akiyama M, Yamakido M, Kobuke K, Dock DS, Hamilton HB, Awa AA, Kato H: Peripheral lymphocyte response to PHA and T cell population among atomic bomb survivors. Radiat Res 93:572–80, 1983
17. Akiyama M, Zhou O-L, Kusunoki Y, Kyoizumi S, Kohno N, Akiba S, Delongchamp RR: Age- and dose-related
alteration of in vitro mixed lymphocyte culture response of blood lymphocytes from A-bomb survivors. Radiat
Res 117:26–34, 1989
18. Kusunoki Y, Akiyama M, Kyoizumi S, Bloom ET, Makinodan T: Age-related alteration in the composition of
immunocompetent blood cells in atomic bomb survivors. Int J Radiat Biol 53:189–98, 1988
19. Kusunoki Y, Hayashi T, Morishita Y, Yamaoka M, Maki M, Hakoda M, Kodama K, Bean MA, Kyoizumi S: Tcell responses to mitogens in atomic bomb survivors: A decreased capacity to produce interleukin 2 characterizes the T cells of heavily irradiated individuals. Radiat Res 155:81–8, 2001
20. Akiyama M, Kusunoki Y, Kyoizumi S, Ozaki K, Mizuno S, Cologne JB: Study of the titers of anti-Epstein-Barrvirus antibodies in the sera of atomic bomb survivors. Radiat Res 133:297–302, 1993
21. Fujiwara S, Carter RL, Akiyama M, Akahoshi M, Kodama K, Shimaoka K, Yamakido M: Autoantibodies andimmunoglobulins among atomic bomb survivors. Radiat Res 137:89–95, 1994
22. Kusunoki Y, Kyoizumi S, Hirai Y, Suzuki T, Nakashima E, Kodama K, Seyama T: Flow cytometry measurements of subsets of T, B and NK cells in peripheral blood lymphocytes of atomic bomb survivors. Radiat Res
150:227–36, 1998
23. Kusunoki Y, Yamaoka M, Kasagi F, Hayashi T, Koyama K, Kodama K, MacPhee DG, Kyoizumi S: T cells of
atomic bomb survivors respond poorly to stimulation by Staphylococcus aureus toxins in vitro: Does this stemfrom their peripheral lymphocyte populations having a diminished naive CD4 T-cell content? Radiat Res 158:715–
24, 2002
24. Kusunoki Y, Yamaoka M, Kasagi F, Hayashi T, MacPhee DG, Kyoizumi S: Long-lasting changes in the T-cell
receptor V beta repertoires of CD4 memory T-cell populations in the peripheral blood of radiation-exposed
people. Br J Haematol 122:975–84, 2003
25. Yamaoka M, Kusunoki Y, Kasagi F, Hayashi T, Nakachi K, Kyoizumi S: Decreases in percentages of naïve CD4
and CD8 T cells and increases in percentages of memory CD8 T cell subsets in the peripheral blood lymphocyte
populations of A-bomb survivors. Radiat Res 161:290–8, 2004
26. Watanabe N, De Rosa SC, Cmelak A, Hoppe R, Herzenberg LA, Roederer M: Long-term depletion of naïve T
cells in patients treated for Hodgkin’s disease. Blood 90:3662–72, 1997
27. Bloom ET, Akiyama M, Korn EL, Kusunoki Y, Makinodan T: Immunological responses of aging Japanese Abomb survivors. Radiat Res 116:343–55, 1988
28. Kusunoki Y, Hayashi T, Kyoizumi S: Immunity polarization in atomic-bomb survivors: From the viewpoint of
the Th1/Th2 paradigm. RERF Update 9(2):10–11, 1998
29. Cosmi L, Annunziato F, Galli MIG, Maggi RME, Nagata K, Romagnani S: CRTH2 is the most reliable marker
for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J
Immunol 30:2972–9, 2000
30. von Herrath MG, Harrison LC: Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3:223–
32, 2003
31. Taniguchi M, Nakayama T: Recognition and function of Valpha14 NKT cells. Semin Immunol 12:543–50, 2000
32. Goldrath AW, Bevan MJ: Selecting and maintaining a diverse T-cell repertoire. Nature 402:255–62, 1999
33. Miller RA: The aging immune system: Primer and prospectus. Science 273:70–4, 1996
34. Mackall CL, Gress RE: Thymic aging and T-cell regeneration. Immunol Rev 160:91–102, 1997
35. Rufer N, Helg C, Chapuis B, Roosnek E: Human memory T cells: Lessons from stem cell transplantation.
Trends Immunol 22:136–41, 2001
36. Neriishi K, Nakashima E, Delongchamp RR: Persistent subclinical inflammation among A-bomb survivors. Int
J Radiat Biol 77:475–82, 2001
37. Hayashi T, Kusunoki Y, Hakoda M, Morishita Y, Kubo Y, Maki M, Kasagi F, Kodama K, MacPhee DG, Kyoizumi
S: Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors. Int J Radiat Biol

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Long-term Radiation Effects on Immune System18

79:129–36, 2003
38. Kusunoki Y, Kyoizumi S, Yamaoka M, Kasagi F, Kodama K, Seyama T: Decreased proportion of CD4 T cells inthe blood of atomic bomb survivors with myocardial infarction. Radiat Res 152:539–43, 1999
39. Fujiwara S, Nakashima E, Kodama K: Diabetes mellitus among atomic bomb survivors. Radiation Research.
Volume 1: Congress Abstracts. Ed by Moriarty M, Mothersill C, Seymour C. Lawrence, Kansas, Allen Press,
1999, p 142. (Proceedings of the Eleventh International Congress of Radiation Research, Dublin, Ireland, 18–
23 July 1999)
40. Hayashi T, Fujiwara S, Morishita Y, Kusunoki Y, Nakashima E, Nakanishi S, Suzuki G, Nakachi K, Kyoizumi S:
HLA haplotype is associated with diabetes among atomic bomb survivors. Hum Immunol 64:910–6, 2003
41. Kusunoki Y, Kyoizumi S, Hayashi T, Hakoda M, Suzuki G, Kasagi F, Fujita S, Kodama Y, MacPhee DG:
Perturbation of T-cell homeostasis in atomic-bomb survivors. RERF Research Protocol 4-02, 2002

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RERF Update Volume 15, Issue 1, Spring 2004

19

Ethics Issues in Human Health Research

Ethics Issues in Human Health Research
Senjun Taira, Vice Chairman
Translated and revised with permission from the Journal of theJapan Association for Bioethics, Vol. 14 (2003)

Introduction
At present, ethical issues figure very prominently
in research studies involving human subjects. Although informal discussions on bioethical issues
between doctors and patients have always taken place,full-scale, organizational discussions on ethical issues involved in medical care began about 20 years
ago in Japan. Ethical committees began to be established to discuss ethical issues from an objective
viewpoint after the issue of in vitro fertilization aroseat the Tokushima University School of Medicine in
1982. These committees were first established in aneffort to create bodies comparable to institutional
review boards (IRB) in the United States. On theagenda in those days were mainly ethical issues arising from clinical situations, such as in vitro
fertilization and organ transplantation.
When did the debate on ethical issues in scientific research begin? It is no exaggeration to say that
until quite recently there were virtually no ethicalregulations or requirements for "studies on humanbeings" funded by the research grants offered by the
Ministry of Education, Culture, Sports, Science andTechnology (MEXT) or the Ministry of Health,Labour and Welfare (MHLW). Only very recently
did discussions on the ethical issues involved in studies on genes begin in Japan, with guidelines issued
jointly by three ministries and review procedures
adopted by research institutes that included the establishment of ethics committees based on theguidelines. Guidelines for epidemiological studies
have also been published recently.
I am involved in research and studies conductedat the Radiation Effects Research Foundation(RERF). I gave a keynote lecture at the 14th annual
meeting of the Japan Association for Bioethics (November 2002), focusing on examples from RERF andtaking heed of social trends, including invasion ofprivacy and enhancement of researcher awareness of
ethical issues, partly in order to present problems fromthe viewpoint of someone involved in ethical issues,
with the intent of raising this issue at the meeting.
This paper is based on that lecture.
Before discussing the main subject, I will describe
the research conducted at RERF on the effects ofatomic-bomb radiation on human beings.

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I. Establishment of ABCC-RERF
In 1945, atomic bombs were used in warfare forthe first time in human history, and Hiroshima andNagasaki became the targets. About 114,000 individuals were killed directly by the bomb in Hiroshima,
and about 70,000 in Nagasaki. Those who survived
the bombings have suffered from various late effects
on health from their exposure to radiation from thebombs.
The bomb dropped on Hiroshima was a uranium
bomb called "Little Boy." This type of bomb is nolonger produced. The one dropped on Nagasaki wasa plutonium bomb called "Fat Man." This is the typeof bomb that is still currently produced. I do not know
why different types of bombs were dropped on
Hiroshima and Nagasaki. Some people say it was totest two types of atomic bombs developed in the
United States and to investigate the destructive powereach had on human beings and materials by dropping them on different places. What is certain is thatdifferent types of atomic bombs release different
amounts of gamma rays and neutrons, exerting different effects on humans.
On August 6 and 9, atomic bombs were dropped
on Hiroshima and Nagasaki, respectively. The bombs
exploded, producing a mushroom cloud, and the blasts
and heat rays generated by the roughly 7,000°C fireballs burned out everything near by, including humans
and buildings.
Shortly after the bombings, the United States senta group of experts to Hiroshima and Nagasaki to investigate the damage caused by the bombs. Some
Japanese experts joined the group, forming the socalled "US-Japan Joint Commission." It was Dr.
Masao Tsuzuki of the School of Medicine, the University of Tokyo, who served as a coordinator of as
many as 90 Japanese and American scientists who
participated in the investigation.
The investigation began on September 8, 1945, andits report was submitted to then US president Harry
Truman. President Truman, in response, directed the
US National Academy of Sciences-National ResearchCouncil (NAS-NRC) to conduct studies of the lateeffects of atomic-bomb radiation, and the Atomic
Bomb Casualty Commission (ABCC), RERF's
predecessor, was established in March 1947.
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Ethics Issues in Human Health Research
II. Research at ABCC–RERF
Epidemiological research was the core research
activity at ABCC. The study cohorts for the epidemiological studies were first selected from among
the atomic-bomb survivors based on information
obtained from the supplementary questionnaire foratomic-bomb survivors conducted as part of the 1950
national census to survey their actual conditions atthat time. Of the 284,000 individuals from whom
information was obtained, 120,000 were selected toform a cohort for the Life Span Study (LSS). The
mortality study of that cohort has been continued up
to the present time. About 60,000 individuals havealready died, and epidemiological studies are being
carried out to investigate the relationship of radiation dose to their causes of death and other issues.
In addition to the LSS, ABCC-RERF has conducted the Adult Health Study (AHS) throughbiennial health examinations of about 20,000 individuals extracted from the LSS cohort. Other study
cohorts include a cohort of about 3,600 in utero
atomic-bomb survivors and a cohort of about 88,000
second-generation atomic-bomb survivors.
These studies show that the incidence of leukemia and other types of cancer is higher among
atomic-bomb survivors than among unexposed individuals. Studies on the relationship between radiationdose and development of diseases have also been
conducted, and RERF's study results have been used
as important data in establishing radiation protection
standards.
The relative risk for radiation-induced cancer
death has been shown to be highest for leukemia, and
it is higher for breast cancer in those exposed at young
age compared with other solid cancers. Quantitativerisk estimates and dose and age-related relationships
for leukemia and solid cancers following radiation
exposure have been derived from the ABCC-RERF
data.
ABCC, which had conducted these studies, wasreorganized into the Radiation Effects Research
Foundation in 1975 as a private nonprofit organization authorized by the former Ministry of Health andWelfare and the Ministry of Foreign Affairs, allowing the studies of atomic-bomb survivors to continue
for a long period of time. The US and Japanese governments agreed to equally fund RERF, enabling
RERF to take over ABCC's programs.
Rarely have I heard that previously in Japan, there
was a practice of having review committees review
research protocols (RPs) before studies were initiated. RERF, however, has adopted an Americansystem, under which an RP that researchers havedeveloped is reviewed for its quality before the research project in question can be initiated. During
the days of ABCC, 316 RPs were approved after reReturn to Table of Contents

20view, and 218 RPs since ABCC was reorganized into
RERF.
RERF, which succeeded ABCC, has continued the
RP review system and has had RPs reviewed by the
Research Protocol Review Committee before initiation of research projects. However, only the scientificaspects were reviewed and no ethical aspects wereconsidered. In 1972, the Tuskegee incident came tolight, and this triggered the movement at RERF toreview studies from the viewpoint of protection ofhuman rights.
III. Tuskegee study and IRB
The Tuskegee incident was, so to speak, a humanexperiment conducted in Macon County, Alabama,
beginning in 1932, in which 399 African-American
males who had syphilis were left purposely untreated
so that the natural course of untreated syphilis could
be observed.
In 1929, venereal diseases, including syphilis,
were quite prevalent in the United States. The Julius
Rosenwald Fund, a Chicago-based charity, initiateda project to eradicate venereal diseases with the support of the United States Public Health Service(USPHS). They chose Macon, Alabama, one of thecounties where syphilis was most prevalent in the
United States, and carried out a survey of syphilis on
African-American males in this county, where 82%
of its population was African-American. In the county
was a famous university called Tuskegee University,
after which the study was named. It was found out
through this survey that the incidence of syphilis in
Macon County was 36%, the highest in the UnitedStates. The Fund began treating 3,694 syphilis patients with Neosalvarsan.
In the same year, the Great Depression began. The
Fund ran short of funds, and was left with no otherchoice but to withdraw its financial support from thecharity project before completion. Then, the USPHS
took over and scaled the project down from medical
treatment to a study.
In this survey, 399 African-American males who
had never been treated for syphilis were identified.
Although penicillin was developed and made widely
available in the 1940's, those subjects of the Tuskegee
study were never administered penicillin in the 1940's,
50's, or even 60's. The objective of this study was
clearly to observe the natural course of untreatedsyphilis. Physicians wanted to know how untreatedsyphilis would progress. This is quite conceivable,considering the tide of medical science of those days.
I would like to emphasize, however, that serious ethical problems were involved here.
Around 1966, Peter Buxton, a young physician
newly employed at the USPHS, became suspicious
about the Tuskegee study and, after investigation,
RERF Update Volume 15, Issue 1, Spring 2004

Ethics Issues in Human Health Researchbegan criticizing the officials who had been carrying
it out. In July 1972, an Associated Press reporter,
Jean Heller, a friend of Buxton's, wrote an article
about the Tuskegee study. The article was publishedon the front page of newspapers throughout the country, bringing the incident to light. Finally, in
November of the same year, the Secretary of Health,
Education, and Welfare, Casper Weinberger issued
an official command to terminate the study.
The Tuskegee incident can be summarized once
more from an ethical viewpoint as follows:
1) The study was conducted in total disregard of obtaining informed consent;
2) The physicians left the patients untreated and observed the natural course of untreated syphilis
regardless of their duty to cure diseases, and;
3) The medical society helped the study.
These are some of the ethical problems that cameto light. Before this incident was disclosed, no ethical regulation had been enforced in the fields ofresearch even in the United States. In those days, there
were movements to establish ethics committees only
for such issues as organ transplantation and in vitro
fertilization, and Senator Edward Kennedy held public hearings to arouse public opinion. However, there
was a deep-rooted belief that medical care should beleft in the hands of physicians, since they are experts,
and lawyers or representatives of citizens could not
be accepted as ethics committee members. The
Tuskegee incident changed public opinion in the
United States dramatically and the arrangements havebeen changed, requiring inclusion of representativesof study subjects, such as lawyers and citizens, inethics committees.

21
which it is recorded that the HIC members were appointed in August 1976. However, there is no clear
description as to whether the first HIC discussion washeld in the form of an actual meeting or by means of
exchanging written communications; what remains
is only a copy of the letter sent to NAS saying thatthe HIC discussed the "Assurance of protection ofhuman rights for the Nagasaki tumor registry plan."At that time, the HIC was composed of a permanent director who served as its chairman, seven RERF
employees, and one non-RERF lawyer. Figure 1 isan RERF official document, "Draft Action Form,"
drawn up to convene an HIC meeting in April 1977.
It is clear that the HIC was established in August 1976
and met in April 1977. This probably is the first committee established in Japan to protect human rights
in "studies involving human subjects." For some reason, however, this fact is not well known. A book on
ethics issues says that the first ethics committee inJapan is the one established at Tokushima University in December 1982. I believe that the RERF HIC
must be the first ethics committee in Japan, as it wasestablished five years earlier.
RERF's "Operational Procedures of RERF Human Investigation Committee" stipulates in the"Range of work" that the HIC shall review matters

As a result of the incident, a law, which requires
the establishment of IRBs that consist not only ofphysicians but also experts in other fields for all studies involving human subjects, was established andenforced in the United States in 1974.
IV. Establishment of RERF Human Investigation Committee and its activities
Thus the US government legislated an act requiring research institutes to establish IRBs and have them
review all federally funded projects involving humansubjects before those projects are initiated. Since
RERF receives one-half of its funds from the US
government, it has been requested by NAS to establish a committee to review the ethical aspects ofstudies and protect human rights. In response, thenChief of Research Dr. Stuart Finch and Permanent
Director Dr. Masuo Takabe began preparations forestablishment of the RERF Human Investigation
Committee (HIC) in July 1976. With this in the background, RERF has continued to submit reports of the
HIC's reviews of research protocols to NAS.
There is a document in the RERF archives, in
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Figure 1. Draft Action Form to approve the Human
Investigation Committee at RERF on April
15, 1977, the first documented ethicalcommittee meeting in Japan.
RERF Update Volume 15, Issue 1, Spring 2004

22

Ethics Issues in Human Health Research

V. Ethical problems RERF has faced
While RERF has mainly studied and examinedatomic-bomb survivors, genetic studies of secondgeneration atomic-bomb survivors have also been
conducted, such as studies of chromosome aberrations and abnormal development. No genetic effectsof radiation have been found in these studies so far.

pertaining to protection of human rights 1) as seenfrom the ethical points of view and from the universally accepted concept, 2) in the handling of
biological materials including blood and biopsy sections, and 3) in the handling of investigation records.
Presently the HIC includes two non-RERF experts,
because the IRBs are obligated to include experts
other than physicians when ethical issues are dealt
with, as mentioned earlier. Participation of individuals outside RERF as its members carries a high degreeof significance in many senses.

However, the average age of second-generation
atomic-bomb survivors reached 42 years in or around
1996, the age at which they are prone to develop
lifestyle diseases. Therefore, the RERF ScientificCouncil recommended that RERF study the relationship between lifestyle diseases (i.e., multifactorialdiseases such as hypertension, diabetes, and heartdiseases) among these individuals and genetic effects,
if any. In response, RERF initiated the study.

The followings are some of the noteworthy examples of actual cases discussed by the RERF HIC.
One case concerns consent for storage of blood
samples; that is, what course of action should we taketo use the blood samples of deceased donors in theabsence of their informed consent. Another example
concerns the amount of blood to be drawn. The
present regulations stipulate that blood cannot be
drawn in an amount of more than 30 ml. Anotherissue that the HIC has addressed involved non-RERF
researchers' use of RERF stored research samples bytaking the samples out of RERF for collaborative
studies.

A study plan was developed to select second-generation atomic-bomb survivors living either in
Hiroshima or Nagasaki City or their surrounding areas from the full second-generation survivor (F1)cohort of about 88,000 second-generation atomicbomb survivors, carry out a mail survey on about
24,000 individuals, conduct health examinations of
those who wish to undergo health examinations, store
blood and urine samples for future genetic studies,and to study the relationship between lifestyle diseases and radiation effects (Figure 2).

As mentioned above, RERF has well organizedregulations concerning review of ethical issues involved in research projects. Dr. Kazumasa Hoshino
wrote in his book that the percentage of universities
that have ethics committees had increased from 35%
in 1985, nine years after the RERF HIC was established, to 94% in 1988. However, most of these ethics
committees mainly address issues involved in organtransplantation, in vitro fertilization, and other issuesof clinical medicine. Only recently were ethical guidelines developed for genome and epidemiologicalresearch.

The ethical problem that RERF faced erupted
when RERF began obtaining family register (koseki)
attachments from local governments before initiation of the study in 1997 to locate 24,000
second-generation atomic-bomb survivors so thatquestionnaires could be mailed. The mass media(Asahi Newspaper) created a commotion by exaggerated reporting, claiming that it would be a
violation of those survivors' privacy. It came as a

Number of study subjects: 88,000 (Full F1 cohort)

Number of study subjects: 38,600 (Basic mail survey cohort)

Number of study subjects: 17,000(Mail survey Hiroshima/Nagasaki resident cohort)
Addition of 7,000 individuals
Number of study subjects: 24,000
Figure 2. Number of subjects in health effects study of the children of atomicbomb survivors. Of 88,000 persons in the full F1 cohort, about
24,000 were selected for a mail questionnaire survey.
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RERF Update Volume 15, Issue 1, Spring 2004

Ethics Issues in Human Health Research
surprise to us, because RERF had followed the required legal procedures to obtain koseki attachments.
In response, RERF held the first meeting with theHiroshima Prefecture Second Generation A-bomb
Victims Liaison Council in November of the same
year to explain to them the objectives of the study.
The Council's arguments can be summarized asfollows:
1) It is a gross invasion of privacy for RERF to obtain koseki attachments without the knowledge
or consent of second-generation atomic-bomb survivors themselves.
2) This study could create discrimination.
3) RERF, which has been criticized for examining
atomic-bomb survivors without giving medicalcare (since the days of ABCC, its predecessor),
hiding unfavorable data, and giving data only to
America, is utterly untrustworthy.
4) RERF must apologize.
The mass media at that time published articles inconcert, as if RERF were a devil. Listening to thearguments of study subjects, I became keenly awarethat studies, depending on approaches, could create
problems such as discrimination and invasion of privacy. Thus, RERF actively began to hold as manytalks with those groups as possible.
At one of the talks with them, we told them that
there would be no point in having discussions, if they
were against the study itself, and we asked if they
were absolutely against the study. They replied thatthey were not against it per se and that they wanted
RERF to fully explain the objectives and listen tothem in good faith. Therefore, RERF made the following proposals:
1) RERF will formulate a third party "scientific committee" consisting of non-RERF experts toincorporate opinions of learned and experienced
persons outside RERF in deciding the nature anddesign of the study.
2) RERF will establish a third party "ethics committee," aside from the HIC, to review ethicalissues, such as discrimination and privacy, involved in the study of second-generation
atomic-bomb survivors.
3) The koseki attachments obtained will be storedsafely and carefully in a safe installed in a room
accessible to only those concerned until the issue
is settled.
4) RERF will study the relationship between radiation exposure and lifestyle diseases strictly
scientifically.
As mentioned above, RERF reviewed and discussed the study plans while deepening mutual
understanding with the groups concerned. All these
efforts were made because the study of second-generation atomic-bomb survivors would be the firststudy of this kind in the world, an important study
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23
that could be done only by RERF. It took us as manyas four years to initiate the study, as we waited forsecond-generation atomic-bomb survivors to understand the importance of the study.
As we made progress in the preparation of thestudy, the following four ethical problems were identified and became the focus of discussions:
1) What considerations should be given to the feelings that recipients of the questionnaire might
have when they receive it by mail?
2) Recipients of the questionnaire might wonder why
and how they were selected.
3) Many prospective study subjects do not know that
their parents are LSS cohort members.
4) Questionnaires could cause family problems tothose who have been hiding the fact that theirparents were atomic-bomb survivors.
The Ethics Committee for the Health Effects Studyof the Children of Atomic-bomb Survivors discussed
other issues in addition from various angles. The Ethics Committee also reviewed the design and otherdetails of this study carefully. One example of thesuggestions we incorporated in the study plan was to
add such a note as "The following questions are asked
to obtain information on health and living habits. We
have no intention to meddle in your private life. Pleaseanswer them up to the point you don't mind." to thedelicate questions that could invade privacy, such as
the questions about "Present marital status, occupation and education," and "Pregnancy, childbirth andchild rearing (ladies only)."
Another issue the Committee discussed was thename of the sender for the purpose of minimizing thediscomfort the recipients might experience when theyreceive the questionnaires. In response, we formulated
several proposals for our return address, including or
excluding the name of RERF and the Second-Generation Secretariat. It was decided that use of the RERF
address only would be most appropriate. The study isgoing smoothly, although it requires attention to thesmallest detail by the staff in the front line.
The pilot study was followed by the first full-scale
mail survey, the results of which are shown in Table
1. The initial mailing of questionnaires was sent to a
total of 4,355 individuals in Hiroshima and Nagasaki,of whom 3,118 replied. Of these respondents, 2,213
expressed their willingness at varying degrees to undergo health examinations. This allowed the initiationof the first study.
VI. Mutual trust underlying ethical issues
The genetic studies conducted at RERF have notshown genetic effects of radiation. Some individuals
wondered what RERF wanted to study after so many
years had passed since the atomic bombing. There
were others who were afraid that genetic effects orabnormalities, if any, could lead to discrimination.
RERF Update Volume 15, Issue 1, Spring 2004

24

Ethics Issues in Human Health Research
Table 1. The first full-scale mail survey: Summary of responses (as of 16 November 2001)
Results

Both cities

Hiroshima

Nagasaki1

Responded and willing to participate in health examinations

1,840

1,219

621

2

Responded but refused to participate in health examinations

467

342

125

3

Responded but not decided to participate in healthexaminations

346

244

102

4

Responded but wrote reasons for refusing to participate inhealth examinations

1

0

1

5

Refused (No response, etc.)

21

19

2

6

Address unknown

399

251

148

7

Deceased

5

5

0

8

Participation not possible

12

6

0

9

Responded but left blank the question about participation in
health examinations

27

16

11

3,118

2,102

1,016

Total

We have learned through the course of the healtheffects study of the children of atomic-bomb survivors that possible problems, such as violation ofprivacy and disadvantages to study subjects, can beprevented by showing some consideration.
However, there is concern that the study, if itshows the involvement of genetic effects of radiation in diseases among the second-generation
atomic-bomb survivors, would create discrimination
against the study participants or bring disadvantages
to them when the results are published.
Yet we must accept the results obtained from a scientific study and publish them without distortion. Of
course, the data must be objectively presented and interpreted with some sensitivity to alleviate any individual
or group concerns. Depending on the results obtained,
the study could cause a serious social problem. What
judgment should the Ethics Committee make?
I have never heard of ethics committees, either inJapan or abroad, going so far as to discuss how study
results should be handled. Of course, there have beenstudies that were judged to generate results unfavor-

able to study subjects and thus were called off before
their initiation at RERF, and I believe other research
institutes and universities have experienced similar cases.
Many geneticists "predict" that "no effects will befound" from the study of second-generation atomicbomb survivors. If we can say that no effects are foundfrom the study, it will be a relief to them and eliminate discrimination, if any, making the study
worthwhile. However, what should we do if someeffects are found? It is a matter of grave importance,
and it will probably be settled through discussions
with the parties concerned.
The term "ethical issues" is used casually; however,
I keenly feel that there are many important problems
that need to be discussed and resolved. The studies
involving human subjects would be impossible without coordination of efforts and mutual trust between
the party being studied and the party conducting thestudy. In other words, it is probably correct to say that
we must not conduct studies if mutual trust has notbeen established. How to proceed with the building of
mutual trust between these two parties seems to be thestarting point of resolving ethical issues.

References
1. Gregory E. Pence (translated and edited by Michio Miyasaka and Shigeo Nagaoka): Medical Ethics 2. Case
Analysis for Better Dicision. Misuzu Shobo, 2001
2. Committee on Questions and Answers about Medical Ethics Publication (edited): Questions and Answers about
Medical Ethics. Taiyo Shuppan, 1998
3. Advisory Committee for the President of the United States (translated and edited by the Medical Professions
Division, Health Policy Bureau, Ministry of Health and Welfare): Comprehensive Report of Bioethics. Shinohara
Shuppan, 1984
4. Medical Professions Division, Health Policy Bureau, Ministry of Health and Welfare (edited): Thoughts on Lifeand Ethics. Report of Discussions on Life and Ethics. Igaku Shoin, 1985
5. Chiaki Kagawa: Historical Development of Bioethics: Human Experiment, Organ Transplant, and Termination of
Medical Treatment. Keiso Shobo, 2000
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RERF Update Volume 15, Issue 1, Spring 2004

25

Facts and Figures

Facts and Figures
New Dosimetry Roster
The current status of the new dosimetry system
DS02 is presented elsewhere in this issue of Update.
In the process of RERF implementation of DS02
substantial improvements have been made in addition to the changes in the basic system itself. These
efforts resulted in the creation of dosimetry roster of
250,000 people, whose doses are of interest to RERF,
containing the best available information on exposure status and shielding established from a review
of all relevant data sources. A large number of persons have newly-assigned dose estimates, mainly
zero, which will lead to improved analyses.
The roster includes not only the Life Span Study(LSS) cohort members, but (a) mothers of the in utero
cohort, (b) parents of those included in the F1 mortality and laboratory study cohorts, and (c) parentsof F1 members of the early ABCC study (GE-3) ofpregnancy outcomes. Because of the previous lackof a comprehensive roster, dose estimates were often treated as unknown for some members of cohorts(a)–(c) even though RERF records contained sufficient information to assign doses. Also, in some cases
different sources were used in dose computations forvarious studies, leading to inconsistencies. The development of the more complete roster has no affect

In Cityon estimates for the LSS. The table below summarizes the current dose estimation status for theoverlapping groups mentioned above. Most of the113,000 people added to the roster were unexposedor received doses of less than 1 mGy. As with DS02,
doses are not assigned to proximal survivors unlessthey are known to have been exposed in a standard
house or have detailed shielding information of a type
handled by the dosimetry system.
There is an important distinction between the InCity Unknown Dose and No Information groups. The
Unknown Dose group includes survivors who wereclose enough to the hypocenters to have received
doses in excess of 10 mGy but for whom doses cannot be computed because of the complexity or lackof information regarding their shielding conditions.
The mean distance from the hypocenter for survivors in this group is about 1.6 km, where the mean
survivor dose is about 0.17 Sv. The No Informationgroup comprises people for whom there is no information on shielding or location. Most of this groupare F1 parents where the other parent has been assigned a dose. These were largely unexposed persons,and can sometimes be used as such in analyses eventhough a dose has not been officially assigned to them.

Not in City
No Info

Total

Change00120,321

0

727

524

699

4,367

1,525

−27

42,71436,393

10,153

99,404

48,645

3,557

1,260

72,42867,583760

109,038

80,300

8,342

973

363

2,133

2,133

17

16,087

10,85520,757

10,5201,568

106,70280,122

10,996

253,617

113,443

Known

ChangeUnknown

ChangeZero Dose

ChangeLSS

86,671

39

7,070

−39

26,580In Utero Mother

2,693

344

248

−42

F1 Parent

42,832

2,126

3,705

F1 GE-3 Parent

32,293

10,697

Other Groups

12,964All Groups

125,399

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RERF Update Volume 15, Issue 1, Spring 2004

26

Hiroshima Memorial to Norman Cousins

Hiroshima Memorial to Norman Cousins–The common language of humanity–
On August 2, 2003, a memorial to the late Norman
Cousins was dedicated in the Peace Memorial Parkin Hiroshima. Mr. Cousins (1915–1990), as editorof the Saturday Review, involved himself in the peace
movement of the post-World War II world. He
showed particular compassion for the survivors of
the atomic bombings, arranging adoptions of orphans,scholarships and the medical treatment in New Yorkfor 25 young women who had facial keloids (or severe skin burns), who became known as theHiroshima Maidens. Staff members of ABCC wereable to help Mr. Cousins in this humanitarian work,
especially Hatsuko Yokoyama, ABCC clinical staff
member and Japanese American (second generation),
who served as chaperone for the group in New Yorkin 1955. Perhaps because of this connection, RERF
was part of the memorial dedication ceremony. RERF
staff members made a financial contribution to themonument.
Those who made short remarks or greetings at the
memorial ceremony included the Presidents of theHiroshima Medical Associations, Dr. Shizuteru Usui(city) and Dr. Koso Sanada (prefecture), the Governor of Hiroshima Prefecture, Yuzan Fujita, Hiroshima
Mayor, Tadatoshi Akiba, Chairman of the Prefecture
Assembly, Atsumi Nitta, Chairman of the Hiroshima
City Council, Tadamasa Asao, and RERF Chairman,
Burton Bennett.
A special part of the ceremony was made by family members of Mr. Cousins, who had come fromthe US and Israel: Andrea Cousins, daughter, Sarah
Cousins Shapiro, daughter, and Shigeko Sasamori,
adopted daughter and one of the Hiroshima Maidens. They eloquently expressed the strong feelingsof common humanity that unites us all.
In order to inform a wider audience of this event,
the statements by the RERF Chairman and by Sarah
Cousins Shapiro are included below. We are allpleased that the deeds of Norman Cousins will be
remembered and the ideals that found life in
Hiroshima will be permanently honored.
Statement by Burton Bennett, Chairman of RERF:
The atomic bombings of Hiroshima and Nagasaki
caused indescribable death and destruction and left
the survivors with lives forever changed by trauma
and injuries. If ever care and compassion were required in this world, it was needed in the aftermathof those events.

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Fortunately there were individuals who did demonstrate compassion and who provided support forcare and recovery. Norman Cousins was one of those
who responded to the desperate needs. To remember
those deeds and to keep alive the spirit of compassion that he demonstrated, this monument isdedicated.
Former colleagues of mine at the Radiation Effects Research Foundation and its predecessor,
ABCC, were able to assist Mr. Cousins in his humanitarian work. We have the greatest respect forthe survivors and their families and have always
wished to contribute to their welfare and well-being.
I am grateful for this opportunity to acknowledge in the presence of family members of Norman
Cousins, who have come to Hiroshima for this ceremony, our gratitude for the deeds of Mr. Cousins
and for the ideals that he upheld.
On behalf of my colleagues at RERF, I wish to
express to all of the survivors of the atomic bombings our determination to maintain the spirit of careand compassion that is enshrined in this monument.
We will bear this in heart and mind as we in continue
our scientific studies in Hiroshima and Nagasaki. We
would like to contribute to the good health of all of
you and promote an enduring peace throughout theworld.
Statement of Sarah Cousins Shapiro:
A few years before he died, my father wrote hisdaughters a letter.
He asked us not to think anything was pending orthat he was having premonitions, but something had
come up, he said, in the course of attending to his
will, and he didn’t wish to make such a decision without discussing it with us beforehand. Upon his death,the letter informed us, he would like his ashes to be
scattered over Hiroshima.
This announcement presented me with adaughter’s most profound dilemma. First of all, it
was unbearable to hear my father speak of his own
death. I was a mother already myself at that point,
but the childhood belief that my parents had to live
forever had never left me, and I was ashamed toadmit the possibility that one day this thing would
come to be.

RERF Update Volume 15, Issue 1, Spring 2004

Hiroshima Memorial to Norman Cousins
Secondly, I didn’t want his ashes to be scattered
here. When the unthinkable day would arrive that hewouldn’t be with us anymore, I wanted to be able tovisit his grave, and wanted my children to visit his
grave. As a little girl, I had said goodbye to him andmy mother many times when they traveled to Japan,
yet as an adult I found myself unwilling to consider
letting go of him in this way forever.
Thirdly, and most importantly, cremation contradicts Jewish tradition. According to the Torah, therelationship between body and soul is a mystery ultimately known only to God, and Judaism teaches us
to return the soul to its Creator by returning the body,dust to dust, to the earth from whence it came.
With anguish and apology, I wrote back to my father all of these things. He answered at once that heaccepted my reasons, and that I should please put
my mind at rest, he would do as I asked.
Last week my family and I visited my father’s
grave, and the significance for us of that privilege isbeyond my ability to convey. Yet it was not in thatcemetery in America, where he and my mother are
buried, that I can best feel his spirit but here, today,with you. For it is in Hiroshima that my father saw
the ideals and values he cherished come alive; that
our lives on this small planet are a constant miracle,
and our capacity for regeneration far beyond what
we imagine; that it is every human being’s responsibility to justify that gift; that it is possible to reachout across all the differences of culture which seemto divide us, and recognize the vastness of all that weshare.
One morning here in Hiroshima thirteen years ago,
my mother and I stepped into the hotel elevator, exchanging small nods of acknowledgement with theJapanese woman who was standing inside. In the fouror five seconds down to the lobby, we were feelingthe customary awkwardness strangers usually feel
when facing each other in an elevator, whereupon

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27
she turned and with a little smile bowed to us in thecustomary manner, and we bowed back. Then we got
off and never saw her again.
It was an unremarkable event but the image ofthat woman’s face has stayed with me until today, as
has the memory of the way that traditional gesture ofrespect restored for us our inherent human dignity.
We couldn’t say anything, because we didn’t share alanguage, but her gesture instantly gave back to us
that which in Hebrew is called tzelem Elokim, thedivine image in which each human being is created.
The divine image is not anything having to do withthe physical body, but is, rather, the godliness within
all of us which only becomes visible when we strive
to emulate the infinite kindness of our Creator.
A few minutes away from our home in Jerusalem,
my sons-in-law learn at a yeshiva, a school of Jewish
learning, all of whose students were saved in WorldWar II by Chiune Sugihara. As you surely know,
Sugihara issued visas to this large group of Jews toescape Germany, thereby putting himself in extreme
danger. He served as a lifeline to people who could
not have been more different from himself culturally, saving the lives of hundreds of people whosechildren and grandchildren and great-grandchildren
are alive today, thanks to him. He, like my father,had eyes to perceive the humanity of people who
seemed to be so foreign. In Israel today, Sugihara issomeone to whom we are eternally grateful. Gratitude is a common language. Suffering is a common
language. Joy is a common language.
I stand before you now knowing how happy it
would make my mother and father to see us todaywith you in Hiroshima they loved. I don’t know how
to thank you for the opportunity you have given me
to honor them in this way. It is a joy to be here together with my sisters Andrea and Shigeko, and on
behalf of my sisters Amy and Candis, who could not
be here, to remember the deeds of my father and perpetuate the ideals which found life in this place.

RERF Update Volume 15, Issue 1, Spring 2004

28

Research Protocol, Recent Publications
Research Protocol Approved 2003

Recent Publications

RP 1-03 A Study of Gene Polymorphisms andTheir Possible Role in the Development of Diabetes in the Adult Health Study Population
Hayashi T, Fujiwara S, Kusunoki Y, Kyoizumi S,
Hakoda M, Nakanishi S, Nakashima E, Takahashi
N, Akahoshi M, Suzuki G, MacPhee DG, Nakachi K
The purpose of this study is to analyze the relationships between a certain genotype-related diabetes
prevalence and dose in all the cases and controls
available for study and determine whether differencesin the frequency of any particular genotypes between
Hiroshima and Nagasaki survivors may be the reason why a significant association between diabetes
prevalence and radiation dose is observed in the
Hiroshima but not Nagasaki survivors. In this study,
it is focused on the major histocompatibility complex (MHC) locus, as an especially important genetic
factor, which in humans is referred to as the humanleukocyte antigen (HLA) locus and the tumor necrosis factor A (TNFA) gene, which includes polymorphic
genes that map in the HLA gene cluster and appears
to involve with the expression of TNF-a and with thedevelopment of diabetes. We therefore plan to analyze HLA (DQA1, DQB1, and DRB1) genotypes and
TNFA gene polymorphisms of total 3,226 Adult
Health Study (AHS) subjects composed of diabetic
cases (Hiroshima 627 and Nagasaki 269 subjects)
and controls (Hiroshima 1,254 and Nagasaki 1,076
subjects). We will also begin by measuring autoantibodies against glutamic acid decarboxylase (GAD),
tyrosine phosphatase IA-2, and insulin as many as
possible of survivors who develop diabetes in orderto determine the clinical characteristics of those diabetes. From the results of the newly-typed Hiroshima
and Nagasaki subjects in this study, we should be ina very good position to specify the clinical feature of
an HLA-linked diabetes subtype, of which prevalence
has been influenced by radiation exposure.

(Japanese): the original article is in Japanese.
(Bilingual): the original article is in both English
and Japanese.
(JTr): a Japanese translation is available.
Abdel-Rahman MS, Preston DL, Suzuki G. Fact andfigures. Effect of AHS participation on cancer
survival. Hiroshima Igaku [Journal of theHiroshima Medical Association] 2003 (August);
56(8):515–6. (Japanese)
Akahoshi M, Amasaki Y, Soda M, Hida A, Imaizumi
M, Nakashima E, Maeda R, Seto S, Yano K. Effects of radiation on fatty liver and metabolic coronary risk factors among atomic bomb survivors in
Nagasaki. Hypertension Research 2003;
26(12):965–70. (RERF Report 22-02)
Arita K, Kurisu K, Tominaga A, Eguchi K, Iida K,
Uozumi T, Kasagi F. Mortality in 154 surgicallytreated patients with acromegaly—A 10-year follow-up survey. Endocrine Journal 2003 (April);50(2):163–72.
Bennett BG. Overview of the RERF scientific research program. Cooper R, Dickie G, Hill D, Lavin
M, Martin R, Whittaker A, Mather D, eds. 12th
International Congress of Radiation ResearchBook of Abstracts. Brisbane: Australian Instituteof Nuclear Science and Engineering; 2003 (August), p 109. (Abstract) (Proceedings of the 12th
International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Bennett BG. The new Dosimetly System DS02.
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2003 (June); 56(6):386. (Japanese)
Cologne JB, Izumi S, Shimizu Y, Preston DL. Effectof comparison group on inference about effectmodification by demographic factors in cohort risk
regression. Japanese Journal of Biometrics 2002;
23(2):49–66. (RERF Report 9-02)
Cologne JB, Langholz B. Selecting controls for assessing interaction in nested case-control studies.
Journal of Epidemiology 2003 (July); 13(4):193–
202. (RERF Report 3-98)
Fujita S, Cullings HM, Preston DL. The implementation of DS02 at RERF and resulting survivor
doses. Cooper R, Dickie G, Hill D, Lavin M,
Martin R, Whittaker A, Mather D, eds. 12th International Congress of Radiation Research Book of
Abstracts. Brisbane: Australian Institute of

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RERF Update Volume 15, Issue 1, Spring 2004

Recent Publications
Nuclear Science and Engineering; 2003 (August),
p 50. (Abstract) (Proceedings of the 12th International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Fujiwara S, Cologne JB, Hattori N, Suzuki G. Hepatocellular carcinoma risk in relation to atomicbomb radiation and hepatitis virus infections.
Cooper R, Dickie G, Hill D, Lavin M, Martin R,
Whittaker A, Mather D, eds. 12th International
Congress of Radiation Research Book of Abstracts. Brisbane: Australian Institute of Nuclear
Science and Engineering; 2003 (August), p 186.
(Abstract) (Proceedings of the 12th International
Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Fujiwara S, Kasagi F, Masunari N, Naito K, Suzuki
G, Fukunaga M. Fracture prediction from bonemineral density in Japanese men and women.
Journal of Bone and Mineral Research 2003 (August); 18(8):1547–53. (RERF Report 18-02)
Fujiwara S, Sharp GB, Cologne JB, Kusumi S,
Akahoshi M, Kodama K, Suzuki G, Yoshizawa
H. Prevalence of hepatitis B virus infection
among atomic bomb survivors. Radiation Research 2003 (June); 159(6):780–6. (RERF Report 10-02)
Hayashi T. Do genetic backgrounds affect radiationand immune-related disease development among
A-bomb survivors? RERF, ed. RERF International Workshop: Regulation of Immunological
Homeostasis in Inflammatory Response and Disease Development. Hiroshima: RERF; 2004
(January), pp 26–7. (Abstract) (Proceedings of
RERF International Workshop, Hiroshima, 16–
17 January 2004).
Hayashi T, Fujiwara S, Morishita Y, Kusunoki Y,
Nakashima E, Nakanishi S, Suzuki G, Nakachi
K, Kyoizumi S. HLA haplotype is associated withdiabetes among atomic bomb survivors. Human
Immunology 2003 (September); 64(9):910–6.
(RERF Report 10-03)
Hirai Y, Taga M, Cao J, Tokuoka S, MacPhee DG,
Nakachi K. BRCA1 gene expression and promoter
methylation patterns in early-onset breast cancers
among A-bomb survivors. Cooper R, Dickie G, Hill
D, Lavin M, Martin R, Whittaker A, Mather D,
eds. 12th International Congress of Radiation Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering; 2003
(August), p 381. (Abstract) (Proceedings of the
12th International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).

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29
Imaizumi M, Neriishi K, Akahoshi M, Suzuki G,
Nakashima E, Nagataki S, Eguchi K. Thyroid
disorders in atomic-bomb survivors. Cooper R,
Dickie G, Hill D, Lavin M, Martin R, Whittaker
A, Mather D, eds. 12th International Congress ofRadiation Research Book of Abstracts. Brisbane:
Australian Institute of Nuclear Science and Engineering; 2003 (August), p 110. (Abstract) (Proceedings of the 12th International Congress ofRadiation Research, Brisbane, Australia, 17–22
August 2003).
Inoue M, Hasegawa S, Suyama A, Meshitsuka S.
Automated graphic image generation system foreffective representation of infectious disease surveillance data. Computer Methods and Programsin Biomedicine 2003 (November); 72(3):251–6.
Inoue M, Suyama A, Kato T, Urakami K, Nakashima
K, Meshitsuka S. Development of computerized
Kana Pick-out Test for the neuropsychologicalexamination. Computer Methods and Programsin Biomedicine 2003 (March); 70(3):271–6.
Izumi S, Koyama K, Soda M, Suyama A. Cancer
incidence in children and young adults did notincrease relative to parental exposure to atomic
bombs. British Journal of Cancer 2003 (November); 89(9):1709–13. (RERF Report 7-03)
Izumi S, Suyama A, Koyama K. Radiation-related
mortality among offspring of atomic bomb survivors: A half-century of follow-up. International
Journal of Cancer 2003 (November);107(2):292–7. (RERF Report 13-02)
Kasagi F, Kodama K. Risk appraisal chart for coronary heart disease death—Lessons from NIPPON
DATA. Igaku no Ayumi [Journal of Clinical andExperimental Medicine] 2003 (November);
207(7):463–7. (Japanese)
Katayama H. Construction of the epidemiological
database—Double structure of the database. Journal of Epidemiology 2004 (January); 14(Supplement)(1):207. (Abstract) (Abrstracts of the 14th
Annual Meeting of the Japan Epidemiological
Association, Yamagata, 22–23 January 2004).
(Japanese)
Katayama H. The present situation and problems of
the international collaboration in the radiation
research. Japanese Journal of Computer Science
2003 (December); 8(1):52–5. (Japanese)
Kodaira M, Sasaki K, Tagawa H, Omine H, Kushiro
J, Takahashi N, Katayama H. Analysis of human
HPRT-deletion mutants by the microarray-CGH
RERF Update Volume 15, Issue 1, Spring 2004

Recent Publications(comparative genomic hybridization). Cooper R,
Dickie G, Hill D, Lavin M, Martin R, Whittaker
A, Mather D, eds. 12th International Congress ofRadiation Research Book of Abstracts. Brisbane:
Australian Institute of Nuclear Science and Engineering; 2003 (August), p 196. (Abstract) (Proceedings of the 12th International Congress ofRadiation Research, Brisbane, Australia, 17–22
August 2003).
Kodama Y, Nakano M, Itoh M, Ohtaki K, Kusunoki
Y, Nakamura N. Evidence for a single stem cell toreconstitute nearly one half of the total blood T
cells in two A-bomb survivors. Cooper R, Dickie
G, Hill D, Lavin M, Martin R, Whittaker A, Mather
D, eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 368. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Kusunoki Y. Possible perturbation of T-cell homeostasis among A-bomb survivors. RERF, ed. RERF
International Workshop: Regulation of Immunological Homeostasis in Inflammatory Response
and Disease Development. Hiroshima: RERF;
2004 (January), pp 12–3. (Abstract) (Proceedingsof RERF International Workshop, Hiroshima, 16–
17 January 2004).
Kusunoki Y, Yamaoka M, Kasagi F, Hayashi T,
MacPhee DG, Kyoizumi S. Long-lasting changes
in the T-cell receptor V beta repertoires of CD4
memory T-cell populations in the peripheral bloodof radiation-exposed people. British Journal of
Haematology 2003 (September); 122(6):975–84.
(RERF Report 21-02)
Kyoizumi S. Human CD4+ memory T cell subsetswith distinct memory functions and death proneness. RERF, ed. RERF International Workshop:
Regulation of Immunological Homeostasis in Inflammatory Response and Disease Development.
Hiroshima: RERF; 2004 (January), pp 14–5. (Abstract) (Proceedings of RERF International Workshop, Hiroshima, 16–17 January 2004).
Kyoizumi S, Suzuki G. Study of late effects of atomic
bomb radiation on maintenance of T-cell homeostasis. Study on Atomic Bomb Diseases Entrusted
by the Japan Public Health Association. FY2002
Reports Comprehensive and Specific Studies.
Tokyo: Japan Public Health Association; 2003
(March), pp 81–6. (Japanese)Land CE, Tokunaga M, Koyama K, Soda M, Preston
DL, Nishimori I, Tokuoka S. Incidence of female

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30
breast cancer among atomic bomb survivors,
Hiroshima and Nagasaki, 1950–1990. Radiation
Research 2003 (December); 160(6):707–17.
(RERF Report 4-03)
MacPhee DG. Mutagenic and epigenetic events inradiation induced cancer. Cooper R, Dickie G, Hill
D, Lavin M, Martin R, Whittaker A, Mather D,
eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 103. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Masunari N. Study on Legal Protection of Personal
Medical Information. Tokyo: Seibundoh; 2004
(January 10), 239 p. (Japanese)
Matsuo K, Akahoshi M, Seto S, Yano K. Disappearance of the Brugada-type electrocardiogram after
surgical castration: A role for testosterone and an
explanation for the male preponderance? Pacing
and Clinical Electrophysiology 2003 (July);
26(7):1551–3. (RERF Report 7-02)
Miller RW. Historical vignette 1955: Hiroshima Diary and the Hiroshima Maidens. Hiroshima Igaku[Journal of the Hiroshima Medical Association]
2003 (July); 56(7):453–4. (RERF Section) (Japanese)
Nagasaka T, Sharp GB, Notohara K, Kambara T,
Sasamoto H, Isozaki H, MacPhee DG, Jass JR,
Tanaka N, Matsubara N. Hypermethylation of O6methylguanine-DNA methyltransferase promoter
may predict nonrecurrence after chemotherapy incolorectal cancer cases. Clinical Cancer Research
2003 (November 1); 9(14):5306–12.
Nakachi K. Individual variations in innate immune
response. RERF, ed. RERF International Workshop: Regulation of Immunological Homeostasis
in Inflammatory Response and Disease Development. Hiroshima: RERF; 2004 (January), pp 30–
1. (Abstract) (Proceedings of RERF International
Workshop, Hiroshima, 16–17 January 2004).
Nakamura N, Nakano M, Kodama Y, Ohtaki K,
Cologne JB, Awa AA. Prediction of clonal chromosome aberration frequency in human blood
lymphocytes. Radiation Research 2004 (March);161(3):282–9. (RERF Report 15-03)
Nakamura N, Ohtaki K, Kodama Y, Nakano M, Itoh
M, Awa AA, Cologne JB. Human fetuses do notregister chromosome damage inflicted by radiation exposure in lymphoid precursor cells.
RERF Update Volume 15, Issue 1, Spring 2004

Recent Publications
Cooper R, Dickie G, Hill D, Lavin M, Martin R,
Whittaker A, Mather D, eds. 12th International
Congress of Radiation Research Book of Abstracts. Brisbane: Australian Institute of Nuclear
Science and Engineering; 2003 (August), p 109.
(Abstract) (Proceedings of the 12th International
Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno
N. Relationship between development of diabetes and family history by gender in JapaneseAmericans. Diabetes Research and Clinical Practice 2003 (August); 61(2):109–15.
Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno
N. Elevated C-reactive protein is a risk factor forthe development of type 2 diabetes in JapaneseAmericans. Diabetes Care 2003 (October);26(10):2754–7.
Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno
N. The effect of polymorphism in the intestinal
fatty acid-binding protein 2 gene on fat metabolism is associated with gender and obesity amongst
non-diabetic Japanese-Americans. Diabetes, Obesity and Metabolism 2004 (January); 6(1):45–9.
Nakano M, Kodama Y, Ohtaki K, Itoh M, Awa AA,
Cologne JB, Kusunoki Y, Nakamura N. Estimating the number of hematopoietic or lymphoid stem
cells giving rise to clonal chromosome aberrations
in blood T lymphocytes. Radiation Research 2004
(March); 161(3):273–81. (RERF Report 1-02)
Nakano M, Kodama Y, Ohtaki K, Itoh M, Awa AA,
Cologne JB, Nakamura N. Prediction for the occurrence of clonal chromosome aberrations inhuman blood lymphocytes. Cooper R, Dickie G,
Hill D, Lavin M, Martin R, Whittaker A, Mather
D, eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 368. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Nakashima E, Tsuji S, Fukuoka H, Ohtaki M, Ito K.
Estimating the stenosis probabilities in arteriosclerosis obliterans using generalized estimating equations. Statistics in Medicine 2003 (July 15);22(13):2149–60.
Neriishi K, Nakashima E, Hida A, Minamoto A,
Mishima HK, Mukai S, Taniguchi H, Amemiya
T, Fujiwara S, Suzuki G, Akahoshi M. Ophthalmologic study in atomic bomb survivors. Cooper
R, Dickie G, Hill D, Lavin M, Martin R, Whittaker

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31
A, Mather D, eds. 12th International Congress ofRadiation Research Book of Abstracts. Brisbane:
Australian Institute of Nuclear Science and Engineering; 2003 (August), p 187. (Abstract) (Proceedings of the 12th International Congress ofRadiation Research, Brisbane, Australia, 17–22
August 2003).
Neriishi K, Nakashima E, Suzuki G. Monoclonal
gammopathy of undetermined significance inatomic bomb survivors: Incidence and transformation to multiple myeloma. British Journal of
Haematology 2003 (May); 121(3):405–10.
(RERF Report 12-02)
Nishimura M, Kakinuma S, Yamamoto D, Sado T,
Shimada Y, Suzuki G. Elevated interleukin-9 receptor expression and response to interleukins-9
and -7 in thymocytes during radiation-induced Tcell lymphomagenesis in B6C3F1 mice. Cooper
R, Dickie G, Hill D, Lavin M, Martin R, Whittaker
A, Mather D, eds. 12th International Congress ofRadiation Research Book of Abstracts. Brisbane:
Australian Institute of Nuclear Science and Engineering; 2003 (August), p 347. (Abstract) (Proceedings of the 12th International Congress ofRadiation Research, Brisbane, Australia, 17–22
August 2003).
Ohtaki K, Kodama Y, Nakano M, Nakamura N. No
evidence for the elevated frequency of spontaneous chromosome aberrations in vivo in lymphocytes of A-bomb survivors. Cooper R, Dickie G,
Hill D, Lavin M, Martin R, Whittaker A, Mather
D, eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 323. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Ohtaki M, Satoh K, Izumi S, Niwa O. A mathematical multistage model for radiation carcinogenesis
accounting for induced genomic instability andcell death. Cooper R, Dickie G, Hill D, Lavin M,
Martin R, Whittaker A, Mather D, eds. 12th International Congress of Radiation Research Book of
Abstracts. Brisbane: Australian Institute of
Nuclear Science and Engineering; 2003 (August),
p 82. (Abstract) (Proceedings of the 12th International Congress of Radiation Research, Brisbane,
Australia, 17–22 August 2003).
Pierce DA. Mechanistic models for radiation carcinogenesis and the atomic bomb survivor data. Radiation Research 2003 (December); 160(6):718–
23.

RERF Update Volume 15, Issue 1, Spring 2004

Recent Publications
Pierce DA, Preston DL, Vaeth M. Mutations, radiation, and cancer: basic stochastic aspects. Cooper
R, Dickie G, Hill D, Lavin M, Martin R, Whittaker
A, Mather D, eds. 12th International Congress ofRadiation Research Book of Abstracts. Brisbane:
Australian Institute of Nuclear Science and Engineering; 2003 (August), p 82. (Abstract) (Proceedings of the 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August2003).
Pierce DA, Vaeth M. Age-time patterns of cancer tobe anticipated from exposure to general mutagens.
Biostatistics 2003 (April); 4(2):231–48. (RERF
Report 7-01)
Preston DL, Pierce DA, Shimizu Y, Ron E, Mabuchi
K. Dose response and temporal patterns of radiation-associated solid cancer risks. Health Physics
2003 (July); 85(1):43–6.
Preston DL, Shimizu Y, Pierce DA, Fujita S, Cullings
HM, Kodama K. The impact of the change in dosimetry on atomic bomb survivor cancer risk estimates. Cooper R, Dickie G, Hill D, Lavin M,
Martin R, Whittaker A, Mather D, eds. 12th International Congress of Radiation Research Book of
Abstracts. Brisbane: Australian Institute of
Nuclear Science and Engineering; 2003 (August),
p 51. (Abstract) (Proceedings of the 12th International Congress of Radiation Research, Brisbane,
Australia, 17–22 August 2003).
Preston DL, Shimizu Y, Pierce DA, Suyama A,
Mabuchi K. Studies of mortality of atomic bomb
survivors. Report 13: Solid cancer and noncancer
disease mortality: 1950–1997. Radiation Research
2003 (October); 160(4):381–407. (RERF Report24-02) (JTr)
RERF. Comments and recommendations of the 30th
RERF Scientific Councilors Meeting (Abstract).
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2003 (September); 56(9):570–6.
(Japanese)
RERF. RERF directors, supervisors, senior scientist,and scientific councilors (as of September 2002).
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2003 (January); 56(1):93. (Japanese)
RERF. RERF directors, supervisors, senior scientist,and scientific councilors (as of September 2003).
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2003 (November); 56(11):715.
(Japanese)

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32
RERF. RERF bibliography of published papers, April
2002–March 2003. Hiroshima Igaku [Journal of
the Hiroshima Medical Association] 2003 (October); 56(10):651–5. (Japanese)
Sauvaget C. Time series of healthy life expectancies:
Is a compression of morbidity observed? Geriatrics and Gerontology International 2003 (November); 3(Supplement 1):S20. (Abstract) (Proceedings of the 7th Asia/Oceania Regional Congressof Gerontology, Tokyo, 24–28 November 2003).
Sauvaget C, Nagano J, Allen N, Grant EJ, Beral V.
Intake of animal products and stroke mortality in
the Hiroshima/Nagasaki Life Span Study. International Journal of Epidemiology 2003 (August);
32(4):536–43. (RERF Report 11-01)
Sauvaget C, Nagano J, Allen NE, Kodama K. Vegetable and fruit intake and stroke mortality in the
Hiroshima/Nagasaki Life Span Study. Stroke 2003
(October); 34:2355–60. (RERF Report 25-02)
Sauvaget C, Nagano J, Hayashi M, Spencer E,
Shimizu Y, Allen N. Vegetables and fruit intake
and cancer mortality in the Hiroshima/Nagasaki
Life Span Study. British Journal of Cancer 2003
(March 10); 88(5):689–94. (RERF Report 20-02)
Sauvaget C, Nagano J, Yamada M. Animal protein
and animal fat intake and the risk of stroke mortality. Gaceta Sanitaria 2003 (October);
17(Supplement 2):159. (Abstract) (Proceedings of
the Joint Scientific Meeting of the International
Epidemiological Association European Epidemiology Federation and the Spanish Society of Epidemiology, Toledo, 1–4 October 2003).
Sauvaget C, Soda M, Koyama K, Nagano J. Dietaryfactors and risk of stomach cancer. Journal of
Epidemiology 2004 (January); 14(Supplement)(1):107. (Abstract) (Abrstracts of the 14th
Annual Meeting of the Japan Epidemiological
Association, Yamagata, 22–23 January 2004).
Sharp GB, Cologne JB, Pierce DA, Tokuoka S. The
impact on radiation risk estimates of effect modifiers and confounders. Cooper R, Dickie G, Hill
D, Lavin M, Martin R, Whittaker A, Mather D,
eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 110. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Sharp GB, Mizuno T, Cologne JB, Fukuhara T,
Fujiwara S, Tokuoka S, Mabuchi K. HepatocelRERF Update Volume 15, Issue 1, Spring 2004

Recent Publications
lular carcinoma among atomic bomb survivors:
Significant interaction of radiation with hepatitis
C virus infections. International Journal of Cancer 2003 (February); 103(4):531–7. (RERF Report 12-00)
Shigematsu I. Introduction to epidemiology (III).
Role epidemiology has played in the Chernobyl
accident. Life & Radiation 2003 (March); No.
12:2–10. (Japanese)
Shilnikova NS, Preston DL, Ron E, Gilbert ES,
Vassilenko EK, Romanov SA, Kuznetsova IS,
Sokolnikov ME, Okatenko PV, Kreslov VV,
Koshurnikova NA. Cancer mortality risk among
workers at the Mayak nuclear complex. Radiation Research 2003 (June); 159(6):787–98.
(RERF Report 5-02)
Shimizu Y, Preston DL, Pierce DA, Suyama A,
Kodama K, Mabuchi K. Cancer and non-cancer
mortality risks in atomic bomb survivors, 1950–
1997: LSS report 13. Cooper R, Dickie G, Hill D,
Lavin M, Martin R, Whittaker A, Mather D, eds.
12th International Congress of Radiation ResearchBook of Abstracts. Brisbane: Australian Instituteof Nuclear Science and Engineering; 2003 (August), p 188. (Abstract) (Proceedings of the 12th
International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Sudo H, Sagara M, Ban S, Noda S, Iwakawa M,
Harada Y, Imai T, Cologne JB. Radiation induced
chromosomal instability in lymphocytes of cancer patients. Cooper R, Dickie G, Hill D, Lavin
M, Martin R, Whittaker A, Mather D, eds. 12th
International Congress of Radiation ResearchBook of Abstracts. Brisbane: Australian Instituteof Nuclear Science and Engineering; 2003 (August), p 326. (Abstract) (Proceedings of the 12th
International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Suyama A. Cancer screening and privacy protection.
Japanese Journal of Urological Surgery 2003
(September); 16(9):908–21. (Japanese)
Suyama A, et al. Privacy protection and informed
consent in the screening of prostate cancer. Japanese Journal of Urological Surgery 2003 (September); 16(9):925–58. (Japanese)
Suyama A, Ichimaru S. Statistical method for epidemiological study, part (1). Hoshasen Kagaku [Radiological Sciences] 2003 (September);46(9):282–7. (Japanese)
Suyama A, Soda M. Surveillance and registration—
Population-based cancer registry and cohort study
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33
of RERF. Hoshasen Kagaku [Radiological Sciences] 2003 (July); 46(7):210–5. (Japanese)
Suzuki G. Some comments on the mechanisms of anincrease in noncancer diseases among A-bomb
survivors. RERF, ed. RERF International Workshop: Regulation of Immunological Homeostasis
in Inflammatory Response and Disease Development. Hiroshima: RERF; 2004 (January), pp 22–
3. (Abstract) (Proceedings of RERF International
Workshop, Hiroshima, 16–17 January 2004).
Suzuki G, Kusunoki Y, Kyoizumi S, Akashi M,
Hirama T, Shimada Y. Irradiation increased oxidative stress levels in thymocytes in B6 mice.
Cooper R, Dickie G, Hill D, Lavin M, Martin R,
Whittaker A, Mather D, eds. 12th International
Congress of Radiation Research Book of Abstracts. Brisbane: Australian Institute of Nuclear
Science and Engineering; 2003 (August), p 110.
(Abstract) (Proceedings of the 12th International
Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Tahara E. Clinical application of molecular diagnosis—Focusing on stomach cancer. Japanese Journal of Cancer Clinics 2003 (March); 49(3):237–
45. (Japanese)
Tahara E. Study on atomic bomb diseases. Report ofcomprehensive study. Study on Atomic Bomb
Diseases Entrusted by the Japan Public Health
Association. FY2002 Reports of Comprehensive
and Specific Studies. Tokyo: Japan Public Health
Association; 2003 (March), pp 3–16. (Japanese)
Takahashi N, Sasaki K, Kodaira M, Sugita K,
Katayama H, Tsuyama N. Study for genetic effects of atomic-bomb radiation by using of a DNA
microarray-based comparative genomic hybridization (array-CGH) method. Cooper R, Dickie G,
Hill D, Lavin M, Martin R, Whittaker A, Mather
D, eds. 12th International Congress of Radiation
Research Book of Abstracts. Brisbane: AustralianInstitute of Nuclear Science and Engineering;
2003 (August), p 196. (Abstract) (Proceedings ofthe 12th International Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Vannais DB, Hirai Y, Cologne JB, Waldren CA, Ueno
AM. Molecular analysis of the distribution of chromosomal breakpoints: Characterization of a ‘hot’
region for breaks in human chromosome 11.
Cooper R, Dickie G, Hill D, Lavin M, Martin R,
Whittaker A, Mather D, eds. 12th International
Congress of Radiation Research Book of Abstracts. Brisbane: Australian Institute of Nuclear
Science and Engineering; 2003 (August), p 413.
RERF Update Volume 15, Issue 1, Spring 2004

34

Recent Publications(Abstract) (Proceedings of the 12th International
Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Vannais DB, Hirai Y, Waldren CA, Ueno AM. Vitamin C (Vit C) added after irradiation reduces thenumber and alters the spectrum of CD59– mutants
in human/CHO AL cells exposed to high LET
carbon ions. Cooper R, Dickie G, Hill D, Lavin
M, Martin R, Whittaker A, Mather D, eds. 12th
International Congress of Radiation ResearchBook of Abstracts. Brisbane: Australian Instituteof Nuclear Science and Engineering; 2003 (August), p 361. (Abstract) (Proceedings of the 12th
International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Weiss JF, Bennett BG. Establishment of a new dosimetry system for atomic-bomb survivors.
Cooper R, Dickie G, Hill D, Lavin M, Martin R,
Whittaker A, Mather D, eds. 12th International
Congress of Radiation Research Book of Abstracts. Brisbane: Australian Institute of Nuclear
Science and Engineering; 2003 (August), p 49.
(Abstract) (Proceedings of the 12th International
Congress of Radiation Research, Brisbane, Australia, 17–22 August 2003).
Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori
Y, Suzuki G. Association between dementia andmidlife risk factors: The Radiation Effects Research Foundation Adult Health Study. Journal of
the American Geriatrics Society 2003 (March);
51(3):410–4. (RERF Report 5-01) (JTr)
Yamada M, Kasagi F, Sasaki H, Mimori Y, Suzuki G.
Effects of dementia on mortality in the Radiation
Effects Research Foundation Adult Health Study.
Gerontology 2004 (March–April); 50(2):110–2.
(RERF Report 23-02)

A-bomb survivors. Radiation Research 2004
(March); 161(3):290–8. (RERF Report 22-03)
Yanagida J, Kambe M, Hakoda M, Koyama K,
Fujimoto M, Ishida S, Tani H, Kunita T, Hyoudou
M, Samura O, Murakami H, Sumitani D,
Ogasawara Y, Watanabe T, Mukai M, Soramoto
E, Okibe M, Harada T, Shukuwa T, Toriyama F,
Sanada K. Report on the results of the fourteenth
medical examination of atomic bomb survivors
resident in North America. Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2004
(January); 57(1):4–26. (Bilingual)

Publications Using RERF Data
The following publications represent research done
by non-RERF scientists based on the data publicly
available from RERF.
Little MP. Risks associated with ionizing radiation.
British Medical Bulletin 2003; 68:259–75.
Little MP, Boice JD. Analysis of breast cancer in the
Massachusetts TB fluoroscopy cohort and in theJapanese A-bomb survivors, taking account of
dosimetric error and curvature in the A-bomb dose
response: Absence of evidence of reduction of risk
following fractionated irradiation. International
Journal of Low Radiaton 2003; 1(1):88–101.
Little MP, Muirhead CR. Absence of evidence forthreshold departures from linear-quadratic curvature in the Japanese A-bomb cancer incidence andmortality data. International Journal of Low Radiation 2004; 1(2):242–55.
Little MP, Wright EG. A stochastic carcinogenesis
model incorporating genomic instability fitted tocolon cancer data. Mathematical Biosciences
2003; 183:111–34.

Yamada M, Suzuki G, Masunari N, Kasagi F. The
relationship between aortic calcification on chest
radiography and ionizing radiation in RERF’s
Adult Health Study. Cooper R, Dickie G, Hill D,
Lavin M, Martin R, Whittaker A, Mather D, eds.
12th International Congress of Radiation ResearchBook of Abstracts. Brisbane: Australian Instituteof Nuclear Science and Engineering; 2003 (August), p 189. (Abstract) (Proceedings of the 12th
International Congress of Radiation Research,
Brisbane, Australia, 17–22 August 2003).
Yamaoka M, Kusunoki Y, Kasagi F, Hayashi T,
Nakachi K, Kyoizumi S. Decreases in percentages of naïve CD4 and CD8 T cells and increases
in percentages of memory CD8 T-cell subsets inthe peripheral blood lymphocyte populations ofReturn to Table of Contents

RERF Update Volume 15, Issue 1, Spring 2004