1
Radiation Effects Research Foundation News and Views
Hiroshima and Nagasaki, Japan

Volume 16, 2005

Table of Contents
From the Editors ............................................................................................................................................... 1
RERF NewsThe 31st Scientific Council Meeting ........................................................................................................ 1
The 39th Board of Directors Meeting ..................................................................................................... 2
Staff News ................................................................................................................................................... 4
Report on Conferences and Workshops
International Conference on Radiation Health Effects:
Biology, Risk Estimation, and Protection, by Dale L. Preston ........................................................ 4
International Workshop on New Horizons in Radiation Biology of
Fetal and Childhood Exposure, by Nori Nakamura ......................................................................... 6
Science Articles
Fetal Exposure to Ionizing Radiation: Chromosome Aberrations Do Not Persist
in Lymphocytes and Bone Marrow Cells of Mice Irradiated In Utero or
Soon after Birth, by Nori Nakamura et al. ................................................................................. 7
Radiation Dose-response Relationships for Thyroid Diseases of Atomic Bomb Survivors
in Hiroshima and Nagasaki, by Misa Imaizumi et al. ................................................................. 13
Human Interest Notes
Memories of My Father, Paul Henshaw, by Robert E. Henshaw ......................................................... 18
Thanks for RERF Home Page, by Gorden K. Livingston ...................................................................... 20
Facts and Figures ............................................................................................................................................ 21
Research Protocols and Publications
Research Protocols .................................................................................................................................... 22
Recent Publications ................................................................................................................................... 24

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

1

From the Editors, RERF News

Sumimasen
This volume of the RERF Update has been a longtime in coming to press. For one reason or another,time got away from us and we failed to produce a
volume during the last calendar year. For this we doindeed apologize to our readers.
We plan on atoning for our lapses, and for thetime lost in reporting of RERF’s ongoing scientificprograms and events, by publishing three volumes
over the next twelve months. This volume, No. 16,
will be devoted largely to RERF’s activities of fiscal
year 2004; whereas volumes 17 and 18 will focus
on activities of fiscal years 2005 and 2006,
respectively. Although the basic format of the RERF
Update will remain the same, several new sections
have been added in order to enhance the quality of

The 31st Scientific Council meeting was held on
March 17-19, 2004 at the Hiroshima Laboratory, cochaired by Drs. Yasuhito Sasaki and Theodore L.
Phillips, with the aims of reviewing the research programs of the Radiation Effects Research Foundationand of looking closely into the Statistics
Department’s research activities as well as its dose
estimation program. On the first day, there were presentations regarding departmental activities and future plans by the Departments of Genetics, Radiobiology/Molecular Epidemiology, Clinical Studies,
Epidemiology, and Information Technology as well
as a report from the Chief of Research. Following
these presentations, the Scientific Councilors madean inspection of a recently renovated blood sample
storage facility; they were then divided into small
groups to visit specific departments, and received
reports directly from research scientists on recent
research achievements and current problems. On thesecond day, the Statistics Department made an indepth report on its research programs including its
dose estimation program. Each presentation was followed by valuable, lively discussions.
The 31st Scientific Council made 12 general recommendations, of which six were the same as thoseof last year’s Scientific Council, and detailed recommendations to each department. The following
are responses to the general recommendations:
1. We again appreciate the Scientific Council’s
recommendation that the recruiting of replaceReturn to Table of Contents

the publication and to increase the pleasure of its
reading. Most notably a “Human Interest Notes” section has been added, along with an expanded “Science Articles” section, including newest researchfindings.
Sincerely,

Thomas M. Seed
Editor-in-Chief

Yuko Ikawa
Technical Editor

ments for senior people who are leaving within
this year, especially from the Department of
Statistics, should be considered as the highest
possible priority. We will make more efforts to
identify top candidates for the statistician positions.
2. We concur that the publication rate of many of
the scientists at RERF should be higher. The
chief of each department should have many
opportunities to discuss plans for publicationof research projects as well as to make highlevel research protocols.
3. The Council again recommended that every
effort be made to limit our internal review process for publications to no longer than one
month. We will make greater efforts to shorten
the time of this internal review process to within
one month.
4. We agree with the Scientific Council that weshould develop a data sharing policy and should
allow RERF researchers and selected external
collaborators to have more ready access.
5. As recommended by the Council, we will makeefforts to have high-quality on-line access tomore journals as well as ready access to journals not available on line.
6. Regarding the new dose estimation system,
RERF Update Volume 16, 2005

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RERF News
DS02, as recommended by the Scientific Council, we will continue refinement of the dose assignments based on the DS02 system.
7. We also feel that there was insufficient time
available for in-depth study of the department
being reviewed, even though informal department meetings attended by Scientific Councilors were held. We will reconsider possible improvement to provide enough time for in-depth
review of the department.
8. Regarding the number of participants in the F1study, it was advised that another search be donein the catchment area to find additional persons
whose parents received significant doses above
1 Sv. There are about such 2,000 people, and it
is estimated that about 35% of these individuals reside within the catchment area. In cooperation with the Department of Statistics, wewill estimate statistical power to be obtained
from the addition of these individuals, and carefully consider balancing this with matters of personal data protection.
9. We agree whole-heartedly that the review of
new research protocols (RPs) and pilot studies
should be speeded up. We will make more efforts to expedite the review process of theseprojects as soon as possible.
10. The Council again recommended that a statistician should be in principle included in every
research protocol, including pilot studies. However, all of RERF’s RPs and pilot studies lastyear involved a statistician as a co-investigator
while the study was being designed and conducted.
11. Regarding the recommendation that guidelines

The 39th Board of Directors meeting was heldon June 23 and 24, 2004 in the auditorium of theHiroshima Laboratory with 23 participants including directors, supervisors, and observers. Active discussion was held on the operations of RERF.
At the beginning of the meeting, Dr. Burton G.
Bennett, in his opening remarks, paid a tribute to Abomb survivors cooperating in RERF’s research activities, emphasized the significance of the Adult
Health Study and the F1 health effects study, and referred to the efforts of RERF to call on entities concerned for cooperation in obtaining support needed
Return to Table of Contents

for outside grant applications be established, we
do not think that they are necessary because all
grant applications approved so far in the outside grant application process are directly or
indirectly related to the mission of RERF.
12. We concur that further steps should be taken tofund and attract young scientists to RERF at
the postdoctoral level. We will make more efforts at recruiting such scientists.
RERF Scientific Councilors
Dr. Yasuhito Sasaki, President, National Institute ofRadiological Sciences
Dr. Ohtsura Niwa, Professor, Radiation Biology
Center, Kyoto University
Dr. Toshitada Takahashi, Director, Aichi Cancer
Center Research Institute
Dr. Shinkan Tokudome, Professor, Health Promotion and Preventive Medicine, Nagoya City University Graduate School of Medical Sciences
Dr. Teruhiko Yoshida, Chief, Genetics Division, National Cancer Center Research Institute
Dr. Theodore L. Phillips, Professor, Radiation Oncology, Cancer Center, School of Medicine, University of California, San Francisco
Dr. Gloria M. Petersen, Professor of Epidemiology,
Mayo College of Medicine
Dr. Clarice Ring Weinberg, Chief, Biostatistics
Branch, Environmental Diseases and Medicine
Program, National Institute of Environmental
Health Sciences
Dr. Joel S. Bedford, Professor, Department of Environmental and Radiological Health Sciences, and
the Graduate Faculty of Cellular and Molecular
Biology, Colorado State University
Dr. Roy E. Shore, Professor, Department of Environmental Medicine, New York University
School of Medicine

for continuing RERF projects and pursuing thefoundation’s mission.
Subsequently, the minutes of the previous board
meeting (38th, Hiroshima) were approved. The meeting agenda then proceeded to reporting on the items
for information.
The session “Items for Information” was opened
by Dr. Bennett presenting a status report of RERF
including progress of the research projects. Subsequently, Dr. Senjun Taira reported on progress in theclinical study of survivors’ children and on international collaboration work, and then Dr. Eiichi Tahara
RERF Update Volume 16, 2005

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RERF News
outlined the status of current external grants. Mr.
Masaharu Yoshikawa gave reports on the present
personnel status, FY2003 salary revision, and Labor Union FY2004 negotiations.
In the session “Discussion of Issues Proposed by
the Members of the Board,” Dr. Bennett explained
the current budgetary situation, referring to support
from U.S. Ambassador Howard Baker in an attempt
to prevent reduction of FY2005 U.S. funding as proposed by the Department of Energy (DOE), Dr.
Bennett’s efforts to approach U.S. lawmakers andothers and actions to be taken in future. The directors had a lively exchange of views about how tosecure funding for the RERF operations, and theboard as a whole decided to prepare a statement opposing the U.S. planned budget cut. The board also
discussed the auditing process and remuneration andsalaries for directors and staff.
With respect to the “Items for Deliberation andAction,” Scientific Councilor Ohtsura Niwa gave asummary report on the recommendations of the 31st
meeting of the Scientific Council, and Dr. Tahara
expressed his gratitude for those recommendations
and presented responses. Consequently, discussion
was held on such items as the FY2003 research activities report and audit, the FY2004 research activities plans, the FY2003 settlement of accounts andaudit, the FY2004 working budget, and the FY2005
provisional budget plan, all of which were approvedby the Board of Directors.
In the session “Election and Appointment of Directors and Others,” Dr. Tomio Hirohata, who continued to fulfill his duties even after completion of
his term at the end of June 2003, was unanimously
reappointed as supervisor. As for the scientific councilors, Dr. Niwa, Professor of the Kyoto University
Radiation Biology Center, was reappointed. Dr.
Theodore L. DeWeese (Professor and Chairman,
Department of Radiation Oncology and MolecularRadiation Sciences, The Johns Hopkins University
School of Medicine) was elected and appointed as
successor to Dr. Theodore L. Phillips. Furthermore,
Mr. Eiji Akimoto (Director of the Matsuyama Finance Office, Shikoku Local Finance Bureau, Ministry of Finance) was recommended for the positionof Chief of Secretariat, succeeding Mr. Yoshikawa
who will leave RERF at the end of June, and theappointment of Mr. Akimoto was approved by theboard. Each of them will assume his post on July 1.
(As for the directors, Dr. James D. Cox [Professor,
University of Texas M.D. Anderson Cancer Center]
was appointed by mail ballot as successor to Dr.
Samuel H. Wilson, who resigned effective June 1.)

Return to Table of Contents

It was agreed that the next meeting of the Board of
Directors be held on June 22–24, 2005.
Lastly, the board closed its annual meeting by
approving the board’s statement opposing the budget curtailment proposed by the U.S. government.
List of Participants
Permanent Directors:
Dr. Burton G. Bennett, Chairman
Dr. Senjun Taira, Vice Chairman
Dr. Eiichi Tahara, Permanent Director and Chief ofResearch
Visiting Directors:
Mr. Masaaki Kuniyasu, Former Ambassador Extraordinary and Plenipotentiary
Dr. Hiromichi Matsudaira, Consultant, Radiation
Effects Association
Dr. Takefumi Kondo, Guest Professor, Keio University School of Medicine
Dr. Paul L. Ziemer, Professor Emeritus, Purdue University
Dr. James D. Cox, Professor, University of Texas
M.D. Anderson Cancer Center
Dr. John E. Burris, President, Beloit College
Supervisors:
Dr. Tomio Hirohata, Professor Emeritus, Kyushu
University Faculty of Medicine
Mr. David Williams, Senior Financial Advisor, National Academy of Sciences
Scientific Councilor:
Dr. Ohtsura Niwa, Professor, Kyoto University Radiation Biology Center
Representatives of Supporting Agencies:
Mr. Shuichi Oshige, Ministry of Health, Labour andWelfareMr. Takaaki Kikuta, Ministry of Health, Labour andWelfareMr. Kevin K. Maher, Embassy of the United Statesof America
Ms. Nicole Nelson-Jean, Embassy of the UnitedStates of America
Dr. Evan B. Douple, National Academy of Sciences
Ms. Catherine S. Berkley, National Academy of Sciences
RERF Secretariat:
Mr. Masaharu Yoshikawa, Chief of Secretariat
Dr. Charles A. Waldren, Chief Scientist
Dr. Gen Suzuki, Chief Scientist
Dr. Kazunori Kodama, Chief Scientist
Dr. Nori Nakamura, Chief Scientist

RERF Update Volume 16, 2005

RERF News, Conference and Workshop Report

The period from April 2004 to March 2005, wasa busy one in terms of personnel turnover here at
RERF. The “revolving-door” was moving briskly,
indeed, bringing new people into the organization,
and at the same time, losing its share of well-known
individuals.
Coming into the Foundation, the Department ofClinical Studies, Hiroshima hired two new researchscientists (1 April 2004): Dr. Waka Ohishi, currently
serves as the Chief of the Division of Clinical Laboratories, while Dr. Yoshimi Tatsukawa is serving asa clinical researcher at the Division of Health Examinations. Four additional staff researchers were
hired as well, including: Dr. Yasunari Satoh (1 April
2004), a research scientist in the Laboratory of Biochemical Genetics, within the Department of Genetics; Dr. Reiko Ito (1 April 2004), a research scientist, in the Laboratory of Cell Biology, within the
Department of Radiobiology/Molecular Epidemiology; Dr. Nobuo Nishi (1 April 2004) who is serving
as the Chief of the Tumor and Tissue Registry Office within the Department of Epidemiology
Hiroshima; and Dr. Kyoji Furukawa (1 October2004) a research scientist within the Department of
Statistics.
Going out, the Foundation lost several of its mostprominent, senior investigators: Drs. Dale L. Preston

4and Donald A. Pierce of the Statistics Department
resigned their posts on 31 July and 31 December
2004, respectively. Dr. Preston currently is working
in California, USA, at HiroSoft International Co.,
while Dr. Pierce is retired and enjoying the “goodlife.” It’s good to report that both of these gentlemen
are still very much engaged in RERF science andtry to assist the Foundation whenever and wherever
they can. In addition, Statistics lost (via resignation,
31 December 2004) the very talented, Dr. Shizue
Izumi, who moved on to a university position in
Engineering at Oita University, Oita, Japan. The
Department of Clinical Studies was hard hit as wellwith the resignations of the outstanding Chief Scientist Dr. Gen Suzuki who moved on to a management position within the Department of Environmental Health, National Institute of Public Health inSaitama, and Dr. Masayuki Hakoda, the hard working Chief of the Clinical Laboratories, who assumeda faculty post in the Department of Human Ecology
at Yasuda Women’s University here in Hiroshima.
In addition, Dr. Donald G. MacPhee, the former headof the Department of Radiobiology, and latter Research Advisor, resigned (30 September 2004), returned to his native Australia, and assumed a new
post within the Department of Microbiology at La
Trobe University, Melbourne, AU.

Dale L. Preston, Former Chief
Department of Statistics
On June 21st and 22nd 2004 RERF in collaboration with the Kyoto University Radiation Biology
Center sponsored an international conference on
Radiation Health Effects: Biology, Risk Estimation,
and Protection. The conference was organized byProfessor Niwa of Kyoto University and Dr. Prestonof the RERF Department of Statistics. The meeting,which was held in Hiroshima at the Aster Plaza, wasattended by more than 100 people. The conference
highlighted the current status and future directionsof radiation research. It succeeded in achieving thesegoals and in illustrating the continuing vitality andimportance of RERF research.
The speakers included leading RERF scientists
and renowned Japanese and international experts.
The first half-day session focused on the current stateof understanding of the biological basis for the long
Return to Table of Contents

term effects of radiation on human health. The topics discussed included: a description of evolving
ideas about the mechanisms by which radiation
causes cancer and the importance of animal experiments (Prof. R. Ullrich); the importance of improved
understanding of the physical interactions involved
in radiation energy deposition at the cellular levelfor understanding these mechanisms (Dr. D.
Goodhead); the need to develop a biological basis
for radiation protection (Prof. O. Niwa); descriptionof a biologically-based hypothesis that can explain
the nature of the temporal patterns in radiation risks
seen in the Life Span Study (LSS) leukemia risks(Dr. N. Nakamura); and an overview of current workon using animal data to understand the relative biological effectiveness of different types of radiation(Prof. M. Sasaki).

RERF Update Volume 16, 2005

Conference and Workshop Report
The second session focused on issues in risk estimation with talks on current challenges in conducting radiation health effect studies in human populations (Dr. K. Kopecky); an overview of current analyses of solid cancer incidence in the LSS (Dr. D.
Preston); a discussion of important new approaches
to describing the uncertainties in radiation risk estimates more completely (Dr. C. Land); a look at how
the methods used in RERF risk estimates have
evolved in recent years with some ideas for future
directions (Dr. D. Pierce); and an example illustrating the application of biologically-based mathematical models to data on leukemia risks in mice exposed
to radiation (Prof. M. Kai).
The second day began with a session on how datafrom RERF and other radiation studies are used to
inform and develop radiation protection standards.
The topics considered included: an overview of
emerging evidence from the RERF and other populations for radiation effects on non-cancer disease(Dr. K. Mabuchi); new concepts for radiation protection being developed in Japan (Dr. T. Kosako); a
description of how RERF results are used in the formulation of U.S. radiation protection standards (Dr.
J. Puskin); and the current status and future direction of international radiation protection guidelines
with an emphasis on the continued relevance of
RERF results (Dr. A. Gonzalez).
The meeting concluded with a lively panel discussion in which the panelists and conference participants described outstanding issues while highlighting the ongoing importance of the RERF studies. The comments stressed the importance of collaboration between RERF scientists and other researchers in Japan and other countries. It was clearthat many of the non-RERF participants would beinterested in such collaborations.
Comments from the speakers and conference participants echoed my own view that this conference
was a great success. The presentations were interesting and generated a considerable amount of discussion. A number of people noted that it would begood if RERF could host similar conferences in the
future. The success of the conference owes a lot to
the generous financial support provided by RERF
and Kyoto University and the excellent organizational support provided by RERF staff, particularly
Ms. R. Shibukawa, Ms. S. Funamoto, and Ms. S.
Teranishi of the Department of Statistics.
The conference highlighted the historical importance of RERF research and demonstrated that there

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5
is much important work yet to be done by RERF. I
hope that RERF researchers and staff will take pridein their contributions to our important work and bechallenged to continue our research in order to realize the full potential of these studies.
Participants[Speakers]
Dr. Abel Gonzalez, Director, Division of Radiationand Waste Safety, International Atomic Energy
Agency, Austria
Dr. Dudley Goodhead, Former Director, Radiation
and Genome Stability Unit, MRC Harwell,
United Kingdom
Prof. Kenneth Kopecky, Fred Hutchinson Cancer
Research Center Public Health Sciences Division
Prof. Robert Ullrich, Department of Environmental
and Radiological Health Sciences, Colorado
State University, USA
Dr. Charles Land, Senior Investigator, Radiation
Epidemiology Branch, National Cancer Institute,
USA
Dr. Kiyohiko Mabuchi, Expert, Radiation Epidemiology Branch, National Cancer Institute, USA
Dr. Jerome Puskin, Office of Radiation and Indoor
Air, Environmental Protection Agency (EPA),
USA
Prof. Michiaki Kai, Laboratory of Environmental
Health Science, Oita University of Nursing and
Health Sciences
Dr. Toshiso Kosako, Associate Professor, ResearchCenter for Nuclear Science and Technology, University of Tokyo
Dr. Nori Nakamura, Chief, Department of Genetics, Radiation Effects Research Foundation
Prof. Ohtsura Niwa, Department of Late Effect Studies, Kyoto University Radiation Biology Center
Dr. Donald Pierce, Research Advisor, Radiation
Effects Research Foundation
Dr. Dale Preston, Chief, Department of Statistics,
Radiation Effects Research Foundation
Prof. Masao Sasaki, Professor Emeritus, Kyoto
University[Observer/Panelists]
Prof. Tomio Hirohata, Professor Emeritus, Kyushu
University Faculty of Medicine
Dr. Jiro Inaba, Chief, Department of Radioecology,
Institute for Environmental Sciences
Dr. Yasuhito Sasaki, President, National Institute ofRadiological Sciences
Prof. Yoshisada Shibata, Department of Radiation
Epidemiology, Atomic Bomb Disease Institute,
Nagasaki University Graduate School of Biomedical Sciences

RERF Update Volume 16, 2005

Conference and Workshop Report

6

Nori Nakamura, Chief Scientist andChief, Department of Genetics
The above workshop was held at the RERF Auditorium on February 3, 2005. The reason for selecting fetal exposure as a topic for discussion for theworkshop is that there have recently been interesting discoveries in this field.
Epidemiological studies conducted since the1950s have shown that a fetus is highly sensitive toradiation. In general, if a pregnant woman is exposed
to X rays for a pelvic examination, the mortality ofher child due to leukemia (or cancer) increases by
50%. It is estimated that diagnostic X rays during
the 1950s caused exposure to some 10 mGy (equivalent to several years of exposure to natural radiation), corresponding to a relative risk per Gy of 50(mean cancer risk per Gy for all A-bomb survivors
is only 2). On the other hand, most animal experiments have not demonstrated a high risk for fetuses(i.e., cancer hardly increases in exposed fetuses).
Few aberrations were identified in RERF’s studyof chromosome aberrations among about 300 individuals exposed in utero (study conducted 40 years
after the bombings). Those exposed in utero to highlevels of radiation are highly susceptible to mental
retardation. It was thus considered that few chromosome aberrations were identified because it was
not possible to examine such heavily exposed individuals. A study of the mothers of those exposed inutero was therefore conducted. This study resulted
in a new finding that despite a high frequency ofchromosome aberrations in the mother’s lymphocytes, very few chromosome aberrations were observed in those exposed in utero.
It is known that various types of chromosometranslocations are involved in the development ofleukemia in humans. Recently, it has become clearthat most translocations related to infantile leukemia are already present in the fetus. About 1% of
newborns (umbilical cord blood) have cells withtranslocations specific to infantile leukemia (pre-leukemia cells, which do not directly bring about leukemia). This frequency is 100 times higher than thefrequency of infantile leukemia (0.01%). These translocation cells can be found at a rate of one in 1,000
in the immune cells that are the origin of leukemia.
Although radiation actually does increase the risk of
infantile leukemia, it cannot produce translocations
in a large number of cells simultaneously (in prinReturn to Table of Contents

ciple, radiation-induced chromosome aberrations
occur at random). According to the above results,
rather than assuming that radiation induces cells tohave various types of translocations and that one ofsuch cells is unfortunately affected by leukemia, it
seems more reasonable to consider that there are asmall number of individuals in which such translocations were already present before exposure to radiation and that radiation brings about an increaseof leukemia in these individuals.
After my introductory presentation as mentioned
above, in Session (1), Dr. M. Linet (U.S. National
Cancer Institute) talked about leukemogenic factors
and Dr. D. Preston (formerly of RERF) on cancer riskin those exposed in utero. Session (2) focused onmouse-experiment issues: First, Dr. Masao Sasaki(Kyoto University) reported that skin cells in a mouse
fetus are not susceptible to chromosome aberrations,but with in vitro cultivation, their sensitivity reaches
a level similar with that of an adult mouse. Dr. Mimako
Nakano (RERF) reported that a mouse exposed to X
rays in its fetal period does not have a memory ofchromosome damage after reaching adulthood (as is
the case with A-bomb survivors). Dr. Tetsuya Ono(Tohoku University) explained that mice deficient in
a DNA repair gene (Mlh1) exhibit an accumulationof mutations especially during their fetal period. Session (3) covered abnormal chromosome numbers andtheir development: First, Dr. J. Chun (University ofCalifornia) reported that about 30% of brain cells inmouse fetuses show abnormalities in the number ofchromosomes, but that such cells are rare in adult mice.
Dr. D. Kalousek (formerly of the University of British Columbia) reported that most fetuses are normal
even if diagnosis prior to birth shows abnormalities
in the number of chromosomes in the placenta. Dr.
Shinya Matsuura (Hiroshima University) reported onhereditary diseases showing abnormal chromosome
segregation, a topic recently drawing much attention.
Lastly, it should be noted that we owe much to
Dr. S. Rockwell (Yale University), Dr. Toshiaki Ogiu
(National Institute of Radiological Sciences), Dr.
Koichi Tatsumi (Radiation Effects Association), Dr.
Gen Suzuki (RERF) and Dr. C. Waldren (RERF) for
their contribution to the workshop as chairpersons. I
would like to express my heartfelt appreciation tothese scientists, as well as to those who supported
the event behind the scenes.
RERF Update Volume 16, 2005

7

Science Articles: Fetal Exposure to Ionizing Radiation

Fetal Exposure to Ionizing Radiation: Chromosome
Aberrations Do Not Persist in Lymphocytes andBone Marrow Cells of Mice IrradiatedIn Utero or Soon after Birth
Nori Nakamura,1 Mimako Nakano,1 Yoshiaki Kodama,1 Kazuo Ohtaki,1 Ohtsura Niwa,2Megumi Toyoshima2
1

Department of Genetics, Radiation Effects Research Foundation; 2Kyoto University
Radiation Biology Center

Methods
Male and female B6C3F1 mice (10-12 weeks old)
were mated and the progeny at various ages (including 15.5-day fetuses) were exposed to 1 or 2 Gy of
X rays (220 kVp, with a 0.5 mm Al and 0.3 mm Cu
filter; 1.0 Gy/min). When the mice reached about 20
weeks of age, blood lymphocytes, spleen cells, andbone marrow cells were examined with fluorescencein situ hybridization (FISH) method using probes forchromosomes 1 and 3.3 The observed translocation
frequency was used to estimate genomic translocation frequency as described,3 which is about fourtimes the observed frequency under the conditions
used.2 Metaphase spreads were prepared by conventional air-drying method.4 Generally, 800 cells werescored with FISH for each tissue sample from eachanimal (no less than 500 cells).
Results
In the case of fetal irradiation, the observed translocation frequencies were generally very low (genome-equivalent frequency of <3%). Similar lowtranslocation yields were also observed in mice irradiated as newborns (3 days old). However, with time
following birth and with subsequent irradiations,these translocation frequencies gradually increased
and reached a plateau of 10 to 20%. This frequency
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plateau occurred when the mice were irradiated at
approximately 6 weeks following birth or beyond(Figure 1).

Translocation frequency (%)

Introduction
We have recently reported that atomic-bomb (Abomb) survivors exposed in utero did not show translocation dose response (about 300 survivors were
examined when they were about 40 years of age).
Since 13 mothers did show a clear dose response as
we usually observe in A-bomb survivors, we interpreted the results as indicating that the lack of a dose
response is a biological response, rather than possible overestimations of individual doses assigned
to the in utero-exposed survivors that we examined.1
Because we found no relevant studies in animals,
we conducted a mouse study to confirm the results.2

Age at the time of exposure (weeks)

Figure 1. Translocation frequency of mice irradiatedwith 2 Gy of X rays at various ages andexamined with FISH when the animals
reached about 20 weeks of age. ■ Blood
lymphocytes,  spleen cells, and  bonemarrow cells (ref. 2). Each point represents
a mean of 2 to 12 animals except for the
points at 12–13 weeks which represent theresults of mothers (single animal per point).
The y-axis represents the genome-equivalent frequency.

The results seemed to indicate that damaged cells
in fetuses and in neonates were actively eliminated.
To test for the possibility, we used mutant mice bearing a knocked-out allele of the p53 gene. Following
X irradiation (2 Gy) of a pregnant dam [p53(–/–)]
which was mated with a p53(+/–) sire, we found thatthe mean translocation frequency in blood lymphocytes and bone marrow cells in mice irradiated inutero was about 7% in p53(–/–) offspring and 6% in
p53(+/–) littermates (examinations were done at 6
to 11 weeks of age, earlier than 20 weeks, before
RERF Update Volume 16, 2005

Science Articles: Fetal Exposure to Ionizing Radiation
onset of lymphoma in the homozygous mutant mice),and the difference was not statistically significant.
In addition, these frequencies were considerably
lower than 30% in the p53(–/–) mother (p <0.001
when compared to the frequency in either heterozygous or homozygous offspring). Therefore, the data
did not seem to support the idea the radiation-damaged cells were being eliminated by a p53-dependent apoptotic process. Although it remained possible that the damaged cells were eliminated throughother apoptotic pathways, we felt that fetal irradiation probably induced chromosome damage to fetal
lymphohematopoietic cells (not necessarily stem
cells per se) but that these aberrant cells simply did
not persist. To test for the possibility, we carried out
another set of experiments to see if chromosome
aberrations are observable in situ or not (i.e., without use of cell cultures in vitro) within spleen cells
and liver cells soon after irradiation of neonates. As
expected, various kinds of chromatid- and chromosome-type aberrations (both stable- and unstable-typeones) were observed, and was strikingly similar tothe observations in bone marrow cells of irradiatedadults (also spontaneously cycling cells). The results
indicated that most of the spleen cells and liver cellsof neonates (and probably fetal cells as well) enteredmitosis irrespective of bearing chromosome aberrations or not. Further, the frequency of unstable aberrations rapidly declined with the increase of postirradiation time, and approached nearly zero at 48 h
after irradiation (i.e., passive elimination of cells
bearing unstable-type aberrations). By contrast,
translocation frequency remained at 10% at 48 h inboth neonatal splenocytes and in adult bone marrowcells. However, the neonates and adults differed in alonger time scale; namely, the frequency in splenocytes
following neonatal irradiation declined andapproached nearly zero after 20 weeks whereas thefrequency in bone marrow cells following adult exposure remained relatively stable over the same period.

8

Discussion
Irradiation of fetuses and neonates
The present study seems to indicate that fetal
blood cells in general (excepting perhaps stem cells
and primitive precursors) are sensitive for inductionof various kinds of chromosome aberrations, including translocations. However, fetal cells bearing thesechromosomal lesions are efficiently cleared with time
following irradiation, and as such the translocation
frequency declines to close to control levels as theirradiated animal grows postnatally. This is probably
because hematopoietic stem cells (and the precursors
as well) in fetuses are equipped with a system thatmakes the cells refractory to yield exchange-type
aberrations. As such the progeny derived from suchstem cells (blood lymphocytes, spleen cells, and bonemarrow cells) are aberration-free as well, and that
ultimately serve to dilute the preexisting cells thatcarry radiation-induced aberrations. Figure 2 showsa schematic representation of the hypothesis.
Irradiation of adults
By contrast to fetal irradiation, in the case of irradiating adult mice one fully expects to find dosedependent frequencies of chromosome aberrations
within bone marrow cells (a mixed cell populationof different lineages at various levels of differentiation), and with subpopulations of persisting cells
bearing translocations. For example, Xiao et al. reported that after irradiation of 6-week old mice, thetranslocation frequency remained relatively stable for
100 days, although there was a small decline in a
first few days following the 3-Gy exposure (Figure
3, ref. 5). The initial decline was probably due topartial inclusion of unstable-type aberrations within
the translocation-bearing cells soon after irradiation(the FISH method used here paints only a few, select sets of chromosomes, and is effective in detecting translocations between the painted and unpainted
chromosomes; whereas the method used cannot

Figure 2. A schematic presentation to explain why chromosome aberrations are unlikely to remain in blood cells
or bone marrow cells following fetal irradiation.

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Science Articles: Fetal Exposure to Ionizing Radiation
readily detect unstable-type aberrations among theunpainted chromosomes). During the 100-day postirradiation period, substantial numbers and kinds ofbone marrow cells would be produced from bonemarrow stem cells, and hence the overall translocation frequency would surely decline if the stem cellsof the adult mouse were refractory to translocationinduction at the time of irradiation. This is not thecase, however.
Another example to support that exchange-typeof aberrations are induced in bone marrow stem cells
comes from our observation that identical translocations exist in multiple lineages of blood cells from
A-bomb survivors (clonal translocation).6

9of blood cells originating from bone marrow stem
cells in A-bomb survivors.6
The apparent contradiction may be explained byassuming a tissue repair system in adult bone marrow; namely, the stem cell death, and replacementof the stem cell niche by the daughter cell. This idea
was presented by Cairns8 to explain the results of amutation study at Dlb locus in mouse intestine.9 In
this study, Dlb-1a/b heterozygous mice were repeatedly treated with ethylnitrosourea (ENU) and mutant cells as a result of inactivation of Dlb-1b allele
were detected by tissue staining. Contrary to the expectation of one-hit dose response, the results showeda curvilinear response (Figure 4). Cairns interpreted
the results as indicating that depletion of stem cells
in the niche by cell death was the first event, andreplacement by a mutant daughter (undergoes exponential growth, has to be discarded after differentiation) was the second event.8 These daughter cells are
not prohibited to acquire mutations and therefore it
appears as if mutation occurred in the stem cells. It
seems that the induction of clonal translocations
originating from bone marrow stem cells in A-bomb
survivors may also be explained by this two-hit
mechanisms, although it would be difficult to distinguish from the possibility of its direct induction
in stem cells.

Figure 3. Translocation frequency in bone marrowcells of mice exposed to 1 or 3 Gy at 6
weeks of age (ref. 5).

Evaluation of Cairns’ hypothesis and its expansion
Our data suggest that exchange-type chromosomal aberrations are not induced within fetally irradiated lymphohematopoietic stem cells whereas
they are readily induced in bone marrow stem cellsof adults. Is this really so?
After the hypothesis proposed by Cairns, tissue
stem cells (defined functionally by its self-renewing, proliferative, and differentiative capacities, andoperationally by its reproductive pattern in which
one daughter cell remains as the stem cell, while theother daughter cell starts to differentiate) have amechanism to maintain master strands of DNA (solidline within a tissue stem cell, Figure 2).7 There areseveral reports to support the hypothesis. If the system is properly operating, both sister chromatid exchanges (SCE) and chromosomal rearrangements
resulting from misrepair of DNA double strand
breaks are not expected to occur. Our results here on
the low frequency of translocations following fetal
irradiation are compatible with Cairn’s hypothesis.
It does not however explain the noted constancy of
the translocation frequency in bone marrow cells ofirradiated adult mice for periods as long as 100 days.5
Further, it does not explain the occasional observation of clonal translocations within various lineages
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Figure 4. Dose response for induction of Dlb mutation in mouse intestine by daily exposure
to ethylnitrosourea (ENU, 3 mg/kg bodyweight) (ref. 9).

How does the Cairns’ hypothesis fit the results
following fetal irradiation? Since hematopoietic stem
cells move from fetal liver to spleen and to bonemarrow along with development of animals, it seems
reasonable to assume that lymphohematopoietic stem
cell niche is not yet established in fetuses. This meansthat fetal hematopoietic stem cells are not yet established to maintain the master strand DNA, which inturn indicates that mutation induction is not prohibited in these cells. Nevertheless, translocations are
not readily induced in fetal stem cells (although on
occasion stem cell-derived clonal translocations have
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Science Articles: Fetal Exposure to Ionizing Radiation
been observed). The discrepancy may be explainedby the possibility that stem cell precursors that are
still undergoing exponential growth also do not generally repair DNA breaks (thus, exchange-type aberrations are difficult to be induced). Such a system
might have been evolutionarily acquired in order toavoid an accumulation of somatic mutations during
fetal growth, and subsequently significant pathology
later in life (e.g., cancer). Alternatively, it might simply be a matter of saving time and energy by leaving
the broken DNA unrepaired so that fetal development can proceed since fetuses contain a large number of stem cells (or at least cells with the potential).
If this were the case, one would expect it to bedifficult to induce translocations in stem cell precursors. While no relevant studies were found in theliterature, there are studies indicating that exchangetype aberrations are inducible in mouse embryonicstem (ES) cells.10 If ES cells and multipotent embryonic stem cells (inner cell mass of an embryo) sharethe same characteristics (which is still to be confirmed), then, translocations might be induced by irradiation in fetuses younger than 15.5 days. We think
this probability is rather low, however, because wehave no evidence to suggest that gestational age affected the low yield of translocations in A-bomb survivors exposed in utero.1
Similar kinds of observations, i.e., proneness ofmutagen-exposed fetal cells to die and to be cleared
from tissues rather than to repair and survive withspecific genomic lesions, have been made repeatedly. One such observation relates to significantly
lower (~50% lower) yields of mutation in male germ
cells of fetuses or newborns as compared to the yields
found in adults.11-13 A similar observation was madefor the induction of translocations.14 Likewise, infemale gametes, the mutation induction rate wasshown to be lower if irradiated perinatally.15,16 Fetuses are also generally less sensitive to radiation interms of tumor induction when compared to young
animals (for example, ref. 17).
Fetal exposure, cell death, and cancer risk
Last, we would like to address a possible relation
between the low yield of translocations and the low
yield of cancer induction following irradiation ofmouse fetuses. Studies on radiation sensitivity ofhuman fetuses have been interesting to say the least.
Epidemiologic studies in the 1950s (the first one was
the famous Oxford Survey of Childhood Leukemia
conducted by A. Stewart) indicated that offspring ofpregnant mothers who were exposed to diagnostic,
low-dose X rays (estimated dose of about 10 mSv)
had an increased relative risk (RR) of dying fromchildhood leukemia or cancer by ~50% above thebackground level (ref. 18 for a good review). This
corresponds to an excess RR value of 50 per Sv if alinear dose response is assumed, which might look
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10very large but is not in fact unrealistic because leukemia risk of the survivors exposed below 10 yearsof age showed similar large RR values.19 Regarding
the lack of excess leukemia cases among the survivors exposed in utero, there had been hot arguments
between Dr. Stewart and epidemiologists at theAtomic Bomb Casualty Commission (ABCC). Now
we know that individual dose estimates by the Dosimetry System in 1965 (T65D) were on average
nearly twice as large as the current estimates (DS86
or DS02), and gave rise to too many expected number of cases of leukemia. Further, there are only 3,600
survivors in the in utero cohort; a number too small
to derive any firm conclusion.19
A puzzle still remained however; in none of thecomparable in utero animal irradiation studies conducted were large RR values generated as one might
have expected from the human epidemiologic studies at low doses. We think that the apparent contradiction might be resolved by assuming that the cancer dose response is non-linear; namely, the increased
risk of childhood cancers occur only at low doses,
and the lack of dose effect in animal studies occurs
because the doses were too high (e.g., 1 Gy or larger)
and killed excessive numbers of the target cells at
risk. A non-linear (i.e., a humped shaped) dose response curve is often observed in many studies using young or adult mice (e.g., induction of cancer orgermline mutation). However, the dose required togive the peak response is usually in the range of 5
Gy, whereas in fetuses, it might well be much smaller,e.g., less than 0.5 Gy. A humped dose response at<0.1 Sv was suggested in translocation dose responsein blood lymphocytes from A-bomb survivors (Figure 5, ref. 1) and a similar humped response at <0.5
Gy of X rays was also reported for induction of liver
tumors after irradiation of mouse fetuses (Figure 6,
left panel, ref. 20). The results after irradiation offission neutrons gave a very similar response with apeak effect at around 0.5 Gy (Figure 6, right panel),Figure 5. Fitted dose response curve for inductionof translocations in blood lymphocytes ofA-bomb survivors exposed in utero and examined at about 40 years of age (ref. 1).

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Science Articles: Fetal Exposure to Ionizing Radiation

11

Figure 6. Dose response for induction of liver tumors in mice exposed to X rays or fission neutrons at various
ages (ref. 20).

Figure 7. Comparison of age at the time of irradiation for induction of various types of tumors (single exposure to
3.8-Gy gamma rays, ref. 17).

thus strengthening the possibility of a humped shaped
dose-response curve. It needs to be pointed out, however, that since the dose range that gave the peak
response is a rather narrow one, low dose experiments, with its appropriate selection of doses, would
be difficult. Further, it remains to be determined why
fetuses (e.g., 17 days p.c.) are more sensitive than
young animals to radiation for induction of certain
types of tumors (e.g., pituitary and lung), while being less sensitive for others (e.g., ovarian tumors,liver tumors, malignant lymphoma, and myeloid leukemia) (Figure 7, ref. 17). We suspect that these differences might be related to differences in modes ofdeath within stem cell pools within these different

tissues. Further studies are required to test the hypothesis however.
Conclusion
Ironically, the one clear conclusion that we draw
from the present study is that we need to know more
about biology of fetuses and associated effects ofionizing radiation. Preconceived notions on this subject probably should be set aside, because our concepts are often based on biological responses of adultmammals and not on fetal responses. A prime example of this is that fetuses that had undergone heart
surgery and returned to uterus have no scar on theskin when born at full term.

References
1. Ohtaki K, Kodama Y, Nakano M, Itoh M, Awa AA, Cologne JB, Nakamura N. Human fetuses do not register
chromosome damage inflicted by radiation exposure in lymphoid precursor cells except for a small but significant effect at low doses. Radiat Res 161: 373-9, 2004.
2. Nakano M, Kodama Y, Ohtaki K, Niwa O, Toyoshima M, Nakamura N. Chromosome aberrations do not persist
in the lymphocytes or bone marrow cells of mice irradiated in utero or soon after birth (submitted for publication).
3. Lucas JN, Awa AA, Straume T, Poggensee M, Kodama Y, Nakano M, Ohtaki K, Weier H-U, Pinkel D, Gray J,
Littlefield G. Rapid translocation frequency analysis in humans decades after exposure to ionizing radiation.
Int J Radiat Biol 62: 53-63, 1992.

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RERF Update Volume 16, 2005

12

Science Articles: Fetal Exposure to Ionizing Radiation

4. Awa AA, Sofuni T, Honda T, Itoh M, Neriishi S, Otake M. Relationship between the radiation dose and chromosome aberrations in atomic bomb survivors of Hiroshima and Nagasaki. J Radiat Res 19: 126-40, 1978.
5. Xiao Y, Darroudi F, Grigorova M, Natarajan AT. Induction and persistence of chromosome exchanges in mousebone marrow cells following whole-body exposure to X-rays. Int J Radiat Biol 75:1119-28, 1999.
6. 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.
7. Cairns J. Mutation selection and the natural history of cancer. Nature 255:197-200, 1975.
8. Cairns J. Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci USA
99:10567-70, 2002.
9. Shaver-Walker PM, Urlando C, Tao KS, Zhang XB, Heddle JA. Enhanced somatic mutation rates induced instem cells of mice by low chronic exposure to ethylnitrosourea. Proc Natl Acad Sci USA 92:11470-4, 1995.
10. Griffin C, de Waard H, Deans B, Thacker J. The involvement of key DNA repair pathways in the formation ofchromosome rearrangements in embryonic stem cells. DNA Repair 4: 1019-27, 2005.
11. Carter TC, Lyon MF, Phillips RJS. The genetic sensitivity to X-rays of mouse foetal gonads. Genet Res 1:3515, 1960.
12. Selby PB. X-ray-induced specific locus mutation rate in newborn male mice. Mutat Res 18:63-75, 1973.
13. Selby PB. X-ray-induced specific locus mutation rate in young male mice. Mutat Res 18:77-88, 1973.
14. Sankaranarayanan K. Genetic Effects of Ionizing Radiation in Multicellular Eukaryotes and the Assessment of
Genetic Radiation Hazard in Man. Elsevier Biomedical Press, Amsterdam, 1982.
15. Selby PB. The X-ray induction of specific locus mutations in newborn female mice. ORNL 4740, Biology
Division Annual Report, 1971. p. 92.
16. Selby PB, Kelly EM, Lee SS. Possible dose-rate effect for the induction of specific locus mutations in oocytesof mice irradiated shortly before birth. ORNL 5685, Biology Division Progress Report (Oct. 1, 1978 to May 31,1980), 1980. p. 64.
17. Sasaki S. Influence of the age of mice at exposure to radiation on life-shortening and carcinogenesis. J Radiat
Res 2(Suppl):73-85, 1991.
18. Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol 70:130, 1997.
19. Delongchamp RR, Mabuchi K, Yoshimoto Y, Preston DL. Canecr mortality among atomic bomb survivors
exposed in utero or as young children, October 1950–May 1992. Radiat Res 147:385-95, 1997.
20. Di Majo V, Coppola M, Rebessi S, Covelli V. Age-related susceptibility of mouse liver to induction of tumors
by neutrons. Radiat Res 124:227-34, 1990.

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Science Articles: Radiation Dose-response Relationships for Thyroid Diseases

13

Radiation Dose-response Relationships for
Thyroid Diseases of Atomic Bomb Survivors
in Hiroshima and Nagasaki
Misa Imaizumi,1 Toshiro Usa,2 Tan Tominaga,3 Kazuo Neriishi,4 Masazumi Akahoshi,1Eiji Nakashima,5 Kiyoto Ashizawa,1 Ayumi Hida,1 Midori Soda,1 Saeko Fujiwara,4Michiko Yamada,4 Eri Ejima,2 Naokata Yokoyama,6 Masamichi Okubo,7 Keizo Sugino,8
Gen Suzuki,4 Renju Maeda,1 Shigenobu Nagataki,9 Katsumi Eguchi2
1

Departments of Clinical Studies (Nagasaki), 4Clinical Studies (Hiroshima), and 5Statistics, Radiation Effects Research Foundation; 2Graduate School of Biochemical Sciences,
Nagasaki University; 3Sasebo Chuo Hospital; 6Nagasaki Saiseikai Hospital; 7Hisayasu
Clinic; 8Tsuchiya General Hospital; 9Japan Radioisotope Association
Introduction
A number of RERF studies evaluated thyroid abnormalities among atomic-bomb survivors by using
the Life Span Study cohorts and Adult Health Study(AHS) cohorts at different times after bombing.1-7
Most studies suggested a positive radiation effect on
thyroid cancer confirmed by tumor registry and autopsy information.1,3-7 This is consistent with the results of studies conducted in other irradiated populations.8-10 The RERF studies, however, were limited by their inability to identify various thyroid diseases such as benign nodule and autoimmune thyroid diseases; therefore, dose responses for these thyroid diseases other than cancer were not fully evaluated. From 1984 through 1987, the thyroid study
evaluated dose responses for thyroid nodules and autoimmune thyroid diseases in the ASH cohort.11 However, this study was conducted only in Nagasaki but
not in Hiroshima.
In this article, we describe the results of the firstcomprehensive thyroid disease survey using advanced methods to detect thyroid nodules (malignant and benign) and autoimmune thyroid diseases.
This clinical survey was conducted in both Hiroshima
and Nagasaki AHS cohort members between 2000
and 2003.
Participants and Methods
A total of 4,552 AHS cohort members visited
RERF for biennial health examinations between
March 2000 and February 2003. We asked them toparticipate in the thyroid disease study at the time ofthe examinations, and 4,091 subjects (89.9%) agreed
and completed the thyroid examination.
A trained nurse recorded information on current
and past thyroid disease and thyroid medication byusing a questionnaire. A blood sample was drawn tomeasure free thyroxine, thyrotropin levels, antithyReturn to Table of Contents

roid peroxidase antibody (TPOAb), andantithyroglobulin antibody (TgAb). All participants
underwent thyroid ultrasonography. Ultrasoundguided fine needle aspiration biopsy was performedin participants with solid nodules 1 cm or larger indiameter. Aspirates were examined microscopicallyand assessed for pathology. Analyses were performed
in 3,185 participants specifically excluding individuals who were in utero at the time of atomic bombings, or not in city, or had unknown radiation doses(mean age: 71 years, 1,023 men and 2,162 women,mean and median radiation doses of 0.449 Sv and
0.087 Sv, respectively). A dose response for eachthyroid disease was analyzed by using linear excess
odds ratio (EOR) models.12
Results
In the 3,185 participants, the prevalence of allsolid nodule, malignant tumor, benign nodule andcyst was 14.6%, 2.2%, 4.9%, and 7.7%, respectively.
The prevalence of positive thyroid antibodies, antithyroid antibody-positive hypothyroidism, andGraves’ disease was 28.2%, 3.2%, and 1.2%, respectively.
Significant linear dose-response relationships
were observed for the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts(P < 0.001, Figure 1). We estimate that about 28%
of all solid nodules, 37% of malignant tumors, 31%of benign nodules, and 25% of cysts were associated with the radiation exposure. The interaction ofage at exposure with dose was significant for theprevalence of all solid nodules (P < 0.001, Figure 2)
and benign nodules (P = 0.002, Figure 2) showingthat the dose effects were significantly higher in those
exposed when young. It was not, however, statistically significant for the prevalence of malignant tumors (P = 0.10, Figure 2). For malignant tumors,
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Science Articles: Radiation Dose-response Relationships for Thyroid Diseases

14

Figure 1. Dose response for thyroid diseases. The red straight line displays the odds ratio from the best-fitting
linear excess odds ratio model at 10 years of age at exposure. The points are dose category-specificodds ratio with 95% confidence intervals. P-values are calculated by likelihood ratio test.

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Science Articles: Radiation Dose-response Relationships for Thyroid Diseases

15

however, there was a model with better fit in termsof AIC (Akaike Information Criterion) than the linear EOR model; i.e., a nonlinear model in which thesquare root of dose replaced dose in the linear EOR
model equation. With this model, EOR at 1 Sv at 10
years of age at exposure was 3.96 (95% CI: 1.31,
12.86, P < 0.001), with significant effect modification by age at exposure (P = 0.04) and 36 (52%)
cases associated with radiation exposure. However,in terms of the prevalence of cysts, there appeared
to be no interaction of age at exposure with dose (P= 0.49). Further, there was no interaction of sex orcity with dose in the prevalence of any thyroid nodules (P > 0.30).
The prevalence of positive cases for antithyroid
antibodies was not associated with thyroid radiationdose (P = 0.20, Figure 1). The separate analyses for
TPOAb and TgAb showed that neither the prevalence of TPOAb-positivity (P = 0.91) nor TgAb-positivity were associated with dose (P = 0.52). Neither
antithyroid antibody-positive hypothyroidism nor-negative hypothyroidism were associated with dose
(P = 0.92 and P = 0.31, respectively, Figure 1). An
association between the prevalence of Graves’ disease and radiation dose was suggested but did notreach the level of statistical significance (P = 0.10,
Figure 1).

Figure 2. Trend for age at exposure in radiation dose
response for thyroid diseases. The curve
displays the trend for age at exposure inexcess odds ratio per Sv based on the best
fitting model. The points are excess odds
ratio per Sv in each age at exposure category with 95% confidence intervals. P-values are calculated by likelihood ratio test.

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Discussion
It is well substantiated that thyroid cancer increases with radiation exposure8-10; our results here
are consistent with those of the reports. There havebeen several previous studies that have reported on
the association between benign thyroid nodule formation and thyroid radiation dose,10,13 but this relationship has not been well documented in atomicbomb survivors.5 Our results clearly demonstrated
that benign nodule formation increased with radiation dose. While it is well known that sufficient dosesof ionizing radiation can induce DNA strand breaks,
along with a host of other types of genomic lesions,the mechanisms by which those molecular lesions
evolve into thyroid neoplasms are at best ill-defined.
Recent studies have suggested that rearrangementsof the ret proto-oncogene are in someway associated with post-Chernobyl thyroid cancer.14 However,in contrast to earlier suggestions that specific rearrangements of the ret proto-oncogene are directly
associated with radiation exposure have not been substantiated.15
The present study indicated that individuals who
were exposed when young were at higher risk ofdeveloping thyroid nodules. This result is consistent
with previous studies on children in the Chernobyl
accident,16 medical irradiation,10 and atomic-bomb
survivors.7,11 The reason why radiation elicits this
response at younger ages is unknown. The fact that
not only solid thyroid nodules but also other solid
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Science Articles: Radiation Dose-response Relationships for Thyroid Diseases
cancers in various organs were observed more frequently in subjects exposed at younger ages6 indicates that organs in children may be more radiation
sensitive to the carcinogenic effects of radiation thanthose in adults.
Reports on effects of radiation on autoimmune
thyroid diseases have been inconsistent; largely because of methodological differences of sample selection, and the varied diagnostic techniques and criteria used in these studies.5,11,17 Eheman et al. pointed
out that some studies had limitations due to small
subject number, absence of thyroid radiation dose,or uncertain diagnostic methods.18 Therefore, we diagnosed autoimmune thyroid diseases using technologically advanced methods and clear diagnostic
criteria in a large cohort with known radiation doses.
In the dose-response analyses, we did not observe
significant radiation dose-response relationships between either antithyroid antibody positivity or antithyroid antibody-positive hypothyroidism. This isconsistent with the results of a recent publication
evaluating people exposed as young children to iodine 131 from the Hanford Nuclear Site19 and previous epidemiological studies on atomic-bomb survivors.5,20,21 However, the study conducted in Nagasaki
AHS subjects from 1984 through 1987 demonstrated
a convex dose-response relationship in antithyroid
antibody-positive hypothyroidism, with maximum
prevalence at a dose of 0.7 Sv.11 This discrepancy
may be the result of (1) the present study’s increased
study population, which includes both Hiroshima andNagasaki atomic-bomb survivors, (2) the different
diagnostic techniques used for measurements of thyroid antibodies and thyroid stimulating hormone(TSH), and (3) change of dose distribution of thecohort members over time because mortality andcancer risks are partially dependent on radiation

16

dose.22 Furthermore, we made diagnoses on the basis of serum tests at one point in time in both studies, but the results of serum tests sometimes varyover time.
There are some limitations in this study. First,
people with previously diagnosed nodular thyroid
diseases might have been motivated in agreeing toparticipate by their preexisting medical condition,
thus creating a specific study bias. Second, a survival bias clearly exists in this study: median life
expectancy decreases with increasing radiation doseat rate of about 1.3 years per Gy,23 thus reducing the
proportion of high-dose atomic-bomb survivors in
the present study, relative to the larger proportion of
the original 1958 cohort. Furthermore, not only ismortality risk radiation dose dependent, but cancer
risks are radiation dose dependent as well. Severe
thyroid cancer patients may have been excluded fromthis study due to early death. Therefore, we realizethat a survival bias exists in the present population,
especially in the high-dose exposed atomic-bomb
survivors. Third, we were not able to clarify the earlier effects of radiation and how long the effects ofradiation on thyroid nodule formation persisted after exposure, because the present cross-sectional
study was conducted 55-58 years after the atomic
bombings.
In conclusion, the present study revealed that 5558 years after radiation exposure, a significant linear dose-response relationship exists not only formalignant thyroid tumors but also for benign thyroid nodule formation as well. This relationship was
significantly higher, i.e., the unit effectiveness ofradiation was greater, in those exposed at younger
ages. Autoimmune thyroid diseases, by contrast, were
not found to be significantly associated with radiation exposure.

References
1. Socolow EL, Hashizume A, Neriishi S, Niitani R. Thyroid carcinoma in man after exposure to ionizing radiation. A summary of the findings in Hiroshima and Nagasaki. N Engl J Med 268:406-10, 1963.
2. Hollingworth DR, Hamilton HB, Tamagaki H, Beebe GW. Thyroid disease in the ABCC-JNIH Adult HealthStudy sample, Hiroshima, 1958-59. ABCC Technical Report 4-62, 1962.
3. Wood JW, Tamagaki H, Neriishi S, et al. Thyroid carcinoma in atomic bomb survivors Hiroshima and Nagasaki.
Am J Epidemiol 89(1):4-14, 1964.
4. Parker LN, Belsky JL, Yamamoto T, Kawamoto S, Keehn RJ. Thyroid carcinoma after exposure to atomic
radiation. A continuing survey of a fixed population, Hiroshima and Nagasaki, 1958-1971. Ann Intern Med
80(5):600-4, 1974.
5. Yoshimoto Y, Ezaki H, Etoh R, Hiraoka T, Akiba S. Prevalence rate of thyroid diseases among autopsy cases of
the atomic bomb survivors in Hiroshima, 1951-1985. Radiat Res 141(3):278-86, 1995.
6. Thompson DE, Mabuchi K, Ron E, et al. Cancer incidence in atomic bomb survivors. Part II: Solid tumors,
1958-1987. Radiat Res 137(2 Suppl):S17-67, 1994.
7. Akiba S, Lubin J, Ezaki H, et al. Thyroid cancer incidence among atomic bomb survivors, 1958-79. RERF
Technical Report 5-91, 1991.

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Science Articles: Radiation Dose-response Relationships for Thyroid Diseases

17

8. Ron E, Lubin JH, Shore RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis ofseven studies. Radiat Res 141(3):259-77, 1995.
9. Shore RE, Hildreth N, Dvoretsky P, Andresen E, Moseson M, Pasternack B. Thyroid cancer among persons
given X-ray treatment in infancy for an enlarged thymus gland. Am J Epidemiol 137(10):1068-80, 1993.
10. Schneider AB, Ron E, Lubin J, Stovall M, Gierlowski TC. Dose-response relationships for radiation-induced
thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid. J Clin
Endocrinol Metab 77(2):362-9, 1993.
11. Nagataki S, Shibata Y, Inoue S, Yokoyama N, Izumi M, Shimaoka K. Thyroid diseases among atomic bomb
survivors in Nagasaki. JAMA 272(5):364-70, 1994.
12. Imaizumi M, Usa T, Tominaga T, et al. Radiation dose-response relationships for thyroid nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors 55-58 years after radiation exposure.
JAMA 295(9):1011-22, 2006.
13. Shore RE, Moseson M, Harley N, Pasternack BS. Tumors and other diseases following childhood x-ray treatment for ringworm of the scalp (Tinea capitis). Health Phys 85(4):404-8, 2003.
14. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57(9):1690-4, 1997.
15. Expert Group Health. Health Effects of the Chernobyl Accident and Special Health Care Programes, Working
Draft. World Health Organization, August 31, 2005.
16. Demidchik E, Mrochek A, Demidchik Y, et al. Thyroid cancer promoted by radiation in young people of Belarus(Clinical and epidemiological features). Paper presented at: Radiation and thyroid cancer, Cambridge, 1998.
17. Pacini F, Vorontsova T, Molinaro E, et al. Prevalence of thyroid autoantibodies in children and adolescents from
Belarus exposed to the Chernobyl radioactive fallout. Lancet 352(9130):763-6, 1998.
18. Eheman CR, Garbe P, Tuttle RM. Autoimmune thyroid disease associated with environmental thyroidal irradiation. Thyroid 13(5):453-64, 2003.
19. Davis S, Kopecky KJ, Hamilton TE, Onstad L. Thyroid neoplasia, autoimmune thyroiditis, and hypothyroidism in persons exposed to iodine 131 from the Hanford Nuclear Site. JAMA 292(21):2600-13, 2004.
20. Fujiwara S, Carter RL, Akiyama M, et al. Autoantibodies and immunoglobulins among atomic bomb survivors.
Radiat Res 137(1):89-95, 1994.
21. Morimoto I, Yoshimoto Y, Sato K, et al. Serum TSH, thyroglobulin, and thyroidal disorders in atomic bomb
survivors exposed in youth: 30-year follow-up study. J Nucl Med 28(7):1115-22, 1987.
22. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K. Studies of mortality of atomic bomb survivors.
Report 13: Solid cancer and noncancer disease mortality: 1950-1997. Radiat Res 160(4):381-407, 2003.
23. Cologne JB, Preston DL. Longevity of atomic-bomb survivors. Lancet 356(9226):303-7, 2000.

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RERF Update Volume 16, 2005

18

Human Interest Notes

Memories of My Father, Paul Henshaw
Robert E. Henshaw, Ph.D.
My father began his career with a post-doctoral
program with Gioacchino Failla at the Biophysics
Laboratory, Memorial Hospital, New York City.
Their pioneering studies on the effects of radiation
on cell functions, and on use of radiation to bothcause and cure cancer were classics and were cited
for many years afterward. He moved on to the National Institute of Health (NIH) and continued his
studies of the effects of radiation on cells. When the
war started he joined the Manhattan Project, first in
Chicago in 1942 for five months, then at the Oak
Ridge National Laboratory in Tennessee as a staff
biophysicist. His wartime attempts to predict thepossible effects of the bomb’s radiation led to his
later work at the Atomic Bomb Casualty Commission (ABCC).
Like nearly all the scientists involved in the Manhattan Project early on, he surely was initially convinced of the need for such a weapon, though his
particular work was not in production, but in analysis of effects. I am convinced that he, like many—
perhaps most—of the Manhattan Project scientists,
developed increasing unease with the certainty ofthe potential for devastation and for causing futureworld arms races.
I know that he became convinced by at least springof 1945 that the bomb should not be dropped on a
population center because he hosted a meeting of
his fellow Oak Ridge scientists in our living room
seeking a way to head off the expected carnage. In
the course of their deliberations, the assembled scientists decided to send two emissaries to the WhiteHouse to appeal directly to President Truman not todrop the bomb on a population center. On 17 July
1945 two scientists did go to the White House, andwere shown into a front room where they sat for about
two hours. Finally Secretary of War Stimson entered
to inform them that the President was detained andthat he (Mr. Stimson) would relay the scientists’message to the President. Within weeks the bomb
was indeed dropped on Hiroshima and Nagasaki.
Only years later when official records were declassified was it divulged that President Truman had notbeen informed of the scientists’ plea, and in fact that
Mr. Stimson did not even mention the Manhattan
Project while meeting with the military Joint Chiefsof Staff on the day following the scientists’ visit.
I sat on the floor in the corner of our living room
watching. I, at age eleven, did not appreciate the sigReturn to Table of Contentsnificance of the meeting, nor even the actual topic
discussed since my father and other scientists did
not share details of their work at home. I rememberthat there was no levity and there was great consternation. I understood only that the meeting was very
important. Shortly after the bomb was dropped, myfather divulged to me the topic of the meeting in our
living room, and the story about their delegation
having gone to the White House. My father and I
discussed that meeting many times in the 1950s and1960s—years before other accounts were publishedof Dr. Leo Szilard appealing to Mr. Truman on behalf of Manhattan Project scientists. I have recently
reviewed many accounts of the “Decision to Drop
the Atomic Bomb” published on the web. I have reviewed the documents produced by the Manhattan
Project scientists that were delivered to the WhiteHouse. My father’s name is not among the signatories. I wish he were alive to discuss the reasons forhis absence.
My father’s attempt to influence the President’s
decision, together with his scientific interest in theactual effects of the bomb, might have been contributing factors in his decision to be a part of the ABCC
at its inception. He was assigned by the National
Academy of Sciences (NAS) as a head of the fieldsurvey team for the establishment of ABCC and cameto Japan in 1946 with Austin Brues, another civilian
consultant selected by NAS. My father was shaken
by the devastation he saw in Japan. He also came torespect and to love the people of Japan while there,
and following ABCC, he took a position with theSupreme Commander for the Allied Powers (SCAP)
in 1947 so that he could bring his family to Japan for

At the meeting held in Tokyo in 1946. (First row fromleft) Dr. Nakahara, Dr. Henshaw, Dr. Sasaki, Dr. Brues,(second row from left) Dr. Neel, Dr. Murachi, Dr.
Tsuzuki, Dr. Higashi, Dr. Ulrich (photo courtesy of Dr.
James Neel)

RERF Update Volume 16, 2005

Human Interest Notesa year. That year with ABCC and the subsequent two
and half years with SCAP living in Tokyo changed
my father in fundamental ways, I believe. He became a life-long anti-war activist, always voting andcampaigning for a peaceful solution to all conflicts.
I am certain that he felt complicity in the tragedy
and that he had been betrayed, but he went on withhis career. While he retained life-long interest in thework of ABCC and kept close ties with Austin Brues
and Jim Neel throughout his life, his later work did
not stay close to his earlier interests. In the 1950s heworked at the Atomic Energy Commission in the
Medical and Biological Division handing out research grants to others, and then turned to world
population growth studies. By the l950s he was talking of world peace, and by the 1970s of the futilityof war. Late in his life he would support nearly anyorganization thinking of running a peace candidate
for president of the United States. Two years before
his death, he prepared a talk and slide show which
he entitled “Holocaust,” clearly demonstrating his
beliefs late in life. His last slide was labeled “Monument in the Hiroshima Peace Park: ‘Rest in Peace,
These Errors Shall Not Be Repeated.’”My father’s professional interests in cell function
surely influenced my own decision to go into animal physiology. Being old enough to remember lifein the Manhattan Project, I have always felt some
sort of complicity-by-extension. I early-on adopted
my father’s desires for peace and his view of the
futility of war. These surely explain why I will attend the 60th anniversary Peace Ceremony on 6
August 2005. My father and I had planned to attend
the 50th anniversary, but he died in 1992. They may

The A-bomb Dome around 1946-1948. The devastated town seems to be undergoing reconstruction.
(photographed by Dr. Paul Henshaw and donated by
Dr. Robert Henshaw)

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19
also explain why I have related to the story of Sadako
Sasaki and the 1,000 paper crane to such an extent
that I am bringing about a thousand paper cranes
which I will hang at the Peace Shrine. In July I sent
the above story of my father’s work in the Manhattan Project and in the ABCC to many persons on myemail list. The letter took on wings of its own. I havereceived paper cranes folded by dozens of people,
many of whom are not known to me, but who wish
to be represented at the Peace Shrine this year. My
sister, who was just young enough to not remember
the meeting of scientists nor even the bombing, nevertheless was heavily influenced by my father’s evolution into a peace activist. She indulged in many
discussions with my father through the years, andtoday reads voraciously on related topics. My daughter knew her grandfather before he died, and greatly
valued his wisdom and values.
I would very much appreciate the opportunity tovisit the Radiation Effects Research Foundation(RERF) and see some of the work that has taken placesince the ABCC days. I plan to donate to RERF theseslides taken by my father while he was in Japan,
believing that they belong to history rather than to
our family personally. I do hope that people in Japan
will see these photographs and share with my father
what he thought about world peace and futility ofwar.
(Written in July 2005)(Editor’s note: The comments and views expressed aresolely those of the author and do not necessarily reflect
the views or opinions of RERF and its supporting U.S.
and Japanese agencies.)

Dr. and Mrs. Robert Henshaw donating the photographs
to RERF Chairman Okubo on August 5, 2005. (Fromleft to right) Dr. Katayama, Mrs. Henshaw, Dr. Okubo,
Dr. Waldren, Dr. Henshaw, and Dr. Cologne

RERF Update Volume 16, 2005

20

Human Interest Notes

Thanks for RERF Home Page
Conventional Giemsa Staining and AutomatedKaryotyping to Detect Chromosome Aberrations
Gordon K. Livingston, Ph.D.
Cincinnati, Ohio, U.S.A.
We now consider it commonplace, even a daily
practice to communicate with individuals in distantlands whom we have never met, do not know (except through the literature), likely will never meetand yet are still able to achieve worthwhile scientific goals by utilizing the internet and working as ateam. I am a cytogeneticist and briefly describe inthis article a fruitful collaboration with Drs. Akio
Awa and Nori Nakamura at RERF in Hiroshima,
Japan that culminated in obtaining research grantsupport within one year, which was quite unexpected.
This support now makes it possible to conduct further cytogenetic evaluations of former U.S. nuclear
workers with known intakes of plutonium in lung,bone and liver and known individual external andinternal doses of radiation.
This rewarding collaboration can be traced to the
RERF publication authored by Dr. Nakano and coworkers (Int. J. Radiat. Biol. 77:971-977, 2001) thatcompared cytogenetic data based on solid Giemsa
staining with FISH-based staining for a large cohortof 230 A-bomb survivors. I found that this paper provided the RERF website and also a link to Dr. Awa’s
manual entitled, “Biodosimetry of Human Exposure
to Radiation: A Manual for Detecting Stable Chromosome Aberrations by the Conventional Giemsa
Staining Method.”
My initial attempts to contact Dr. Awa by e-mailwere handled by Dr. Nakamura but I eventually
gained direct access to Dr. Awa, which led to a productive exchange devoted to radiation cytogenetics.
When I read Dr. Awa’s manual on the RERF website,
my waning enthusiasm (associated with lack of gainful employment) received a much needed boost, andit renewed hope that my plutonium research material (which cannot be duplicated) was still a valuable resource. I felt it a privilege to be able to talkwith him about a subject of mutual interest over theinternet.
The method, based on conventional Giemsa staining of chromosomes and subsequent karyotyping,has merit for the reasons enumerated by Dr. Awa:
1) simplicity and low cost (no expensive DNA probes
or fluorescence microscopy are necessary), 2) complete coverage of all chromosome pairs, 3) ability todetect upwards of 70% of stable aberrations, and4) that archived slides have value as long as the staining quality is not affected. The most difficult chalReturn to Table of Contents

lenge using this approach, however, is the daunting
task of screening the karyotypes of at least 100
metaphase cells per examinee. The task, however,has been largely solved with the advent of computers, digital cameras and specialized software capableof counting and recognizing distinctive morphologic
features of chromosomes and arranging standardized
karyotypes in less than five minutes. This technology allows the chromosomes to be arranged automatically then manually edited as the karyotype isscrutinized on the computer monitor. The method
links the microscope and computer as research tools
and helps to reduce the fatigue of working on the
microscope. Cells are screened for chromosome aberrations using the International System for Chromosome Nomenclature (ISCN, 2005), which assigns
the chromosome pairs into the standard seven groups(A-G) of autosomes and the XY sex chromosomes.
Although the method cannot detect all chromosome
aberrations (i.e., translocations involving equivalentsegments) it can detect a reasonable fraction of stable
aberrations as shown by RERF scientists.
Following communication with Dr. Awa, I was
invited to present a seminar at the Health-Related
Energy Research Branch (HERB) at the National Institute for Occupational Safety and Health in Cincinnati, Ohio, U.S.A. The seminar title was “FISHbased Chromosome Aberrations: A Dose-related
Biomarker of Historical Radiation Exposure” presented in March of 2004. Shortly afterwards, I was
encouraged to submit a grant application to the National Research Council. The application was prepared, evaluated, and ultimately selected for funding. Dr. Awa kindly submitted one of the letters ofrecommendation in behalf of the application, which
no doubt carried considerable weight given his reputation.
I am pleased that the research study is now underway with the involvement, assistance and encouragement of many individuals and organizations. I
would especially like to take this opportunity to thankindividuals for the effort to present Dr. Awa’s manualon the RERF home page, and Dr. Awa for his encouragement and support to my research investigation.
(Editor’s note: This article was originally written for the
July 2005 issue of the in-house RERF Newsletter. A sequel will follow in the next issue of the RERF Update.)

RERF Update Volume 16, 2005

21

Facts and Figures

Facts and Figures
When treasures are mentioned, our first thought
generally turns toward the treasures of the Realmthe crown jewels of the empire and all of that. However, here at RERF we speak in terms of anothertype of “crown jewels”—the vast Biosample Archive
derived from the various study cohorts. Much likethe Emperor’s jewels, RERF’s carefully collected,
preserved, and archived biosamples have incalculable wealth; not monetary value per se, but rather
extraordinary value in terms of the research and development resource for long-term health effects
analyses associated with radiation exposure, aging,and general life-style issues.
There are few biosample repositories that canmatch the size, scope and shear potential of RERF’s
collection. As one can glean from the table, the collection is sizable one, with large numbers of individuals donating various types of biosamples (blood,urine, tissues, etc.) over extended periods.
The archived materials have been extensively
used to date, and have added nicely not only to ourbasic understanding of late arising health consequences of prior acute radiation exposures, but also
in helping establish risk assessment standards forradiation hygiene programs throughout the world,
as well as allowing researchers to address a numberof very basic radiobiological questions.
With evolving analytic technologies, thesesamples will gain appreciable value in the coming
years. Therefore, full and proper additions, maintenance, safeguarding, and research use of RERF’s
Biosample Archives become critically importantmissions in their own right. In this regard, RERF
welcomes any and all constructive input from theoutside scientific community on the nature and useof this unique biosample repository.

Biosample Archive
Class
Blood

Urine

Tissues

Subclass
1

Type

NumberCohort source description

Whole

Freeze-dried

5,700

Cell1

Cryo-mnc fractions

6,900

AHS 1990 to present (4-5 vials per blood subject-sample)

Cell1

Cryo-mnc fractions

11,000F1 subjects 2002 to present (4-5 vials per subject-sample)

Cell2

Cryo-ebv lymphs

2,603

AHS 1987 to present (~2-4 vials per sample/9,504 vials in total)

Cell3

Cryo-ebv lymphs

3,310

F1/AHS 1985 to present (1,403/1,928 child/parent cells)

Cell

Blood smears

nd6

LSS/AHS 1952 to present (Nagasaki); 1961 to present (Hiroshima)

Sera/plasma1

Cryo/freeze-dried

15,000

AHS 1969-present (1-8 vials per subject-sample; multiple samplings)

11,000F1 2002-2006 (1-8 vials per subject-sample; single samplings)

Whole1

Surgery4

Autopsy4

Dental5

AHS 1997 to present (20-53 discs per blood subject-sample)

Cryopreserve

4,600

AHS 1999 to present (4-1 ml vials per urine subject-sample)

Cryopreserve

11,000F1 2002 to 2006 (4-1 ml vials per urine subject-sample)

Cases

130,000

LSS/AHS and others

Embedded tissues

173,000

LSS/AHS and others

Stained slides

308,000

LSS/AHS and others

Cases

13,000LSS/AHS and others

Embedded tissues

472,000

LSS/AHS and others

Stained slides

633,000

Teeth

1,394

LSS/AHS and others
AHS 1987-present (1,387/7 Hiroshima/Nagasaki AHS subjects)

Notes
Yamada, M. Personal communication to RERF Archives Unit and to Update editors, 2006
2
Hayashi et al. X-ray radiosensitivity of lymphocytes in vitro from A-bomb survivors. Part 3: Transformation of B-cell by Epstein Barr virus
and their cryopreservation (RP 7-87, Addendum to RP 3-86) In: Program-Project Report, 1 April 2005-31 March 2006, pp 219, Radiation
Effects Research Foundation, Hiroshima, Japan, 2006.
3
Takahashi et al. Culture of lymphoblastoid cell lines as sources of biological samples for investigation of genetic effects of radiation on
children of atomic bomb survivors (RP 5-85). In: Program-Project Report, 1 April 2005-31 March 2006, pp 142, Radiation Effects
Research Foundation, Hiroshima, Japan, 2006.
4
Submitted from the Department of Epidemiology, October 31, 2005.
5
Nakamura et al. Radiation dose estimates of A-bomb exposed people by using teeth. Part 1. Collection of teeth from A-bomb exposed
people in Hiroshima and Nagasaki (RP 10-86). In: Program-Project Report, 1 April 2005-31 March 2006, pp 147, Radiation Effects
Research Foundation, Hiroshima, Japan, 2006.
6
nd = not determined
1

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RERF Update Volume 16, 2005

Research Protocols and Publications

Research Protocols Approved 2004
RP 1-04 A Nested Case-Control Study ofHepatocellular Carcinoma among Atomicbomb Survivors Using Stored Sera
Fujiwara S, Ohishi W, Suzuki G, Cologne JB,
Akahoshi M, Hakoda M, Chayama K
Hepatitis C virus (HCV) or hepatitis B virus(HBV) infections are a major cause of hepatocellular carcinoma (HCC). Increased liver cancer and cirrhosis among atomic-bomb survivors have been reported based on mortality studies or tumor registries,
but virus infection status was not taken account in
the analyses. The previous studies at RERF demonstrated no increase in prevalence of anti-HCV antibody with radiation dose, but reported
supermultiplicative effects between radiation exposure and chronic HCV infection in the etiology of
HCC without concurrent cirrhosis. However, theprecise mechanism of the synergy has not been elucidated.
The determinants of a progressive course forchronic HCV infection are likely to include both viral factors and aspects of host immune function. To
epidemiologically test a hypothesis that radiation
exposure accelerated HCC occurrence among
atomic-bomb survivors in the early stage of liver fibrosis after HCV infection, in this research protocol
we will plan a nested case-control study of HCC
using stored serum.
The proposed study will examine sero-positivityof HBV and HCV, serum levels of the two viruses,
viral genotype and subtype of HBV and HCV in core,
E2-HVR-1, and NS5A of HCV, hyaluronic acid, andtype IV collagen using stored serum in the HCC patients and their controls in the Adult Health Study.
Presently, stored serum is available for 207 HCC
patients. We will select three age- and sex-matchedat-risk controls for each HCC case. We will analyze
the relationship between HCC and these variables
in serum, after taking account of potential predictors of progression toward HCC, such as body massindex, platelet counts, smoking, alcohol drinking,diabetes mellitus and others.
In 10 selected subjects who are positive for HCVRNA, viral genotype and subtype of HCV will be
examined in three samples that were serially collected, and the natural history of virus mutation after infection will be analyzed by a phylogenetic tree
analysis with divergence time in collaboration with
Dr. Kazuaki Chayama’s laboratory at Hiroshima
University.

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22
RP 2-04 A Case-Control Study of Atrophic
Gastritis and Gastric Cancer Using Frozen Seraand Genomic DNA: Identification of New
Biomarkers for Chronic Gastritis Associatedwith Gastric Cancer
Suzuki G, Hattori N, Hakoda M, Fujiwara S,
Akahoshi M, Kodama K, Hayashi T, Nakachi K,
Cullings HM, Ito M, Hatakeyama M, Tahara E
The risk for development of atrophic gastritis andgastric cancer is known to vary depending on a hostfactor (Helicobacter pylori [H. pylori] infection) andgenetic factors that regulate inflammatory-response.
Bacterial toxicity is dependent on binding sites for
SHP-2 in the CagA sequences of H. pylori, which
would be evaluated by antibody titer in sera specificfor sequences containing the SHP-2 binding site. The
IL1B allele and the LTA/NFKBIL1/BAT1 haplotype
are thought to direct the magnitude and nature of
inflammatory response to H. pylori. Since radiation
exposure has an additive effect on the multi-step process of human stomach carcinogenesis, we will include “dose” as a potential variable in the analyses.
The main purpose is to determine whether serum antibody against the binding site for SHP-2 of the H.
pylori CagA sequences and genetic factors, namely
the IL1B allele and the LTA/NFKBIL1/BAT1 haplotype, would provide new biomarkers for chronic
gastritis associated with gastric cancer.
A nested case-control study will be conductedusing the stored sera of about 500 Adult Health Study(AHS) participants who developed gastric cancer
with histological diagnosis between 1970 and 2001.
Of these, only one serum sample collected 2 to 4
years before diagnosis is available in 160 cases, while
two serum samples collected 2 to 4 and 8 to 12 years
before diagnosis are available in 340 cases. The primary endpoint of the study is to examine the relationship between infection with virulent strains of
H. pylori and the development of gastric cancer. The
secondary endpoint is to analyze the association between infection with virulent strains of H. pylori andthe development of chronic atrophic gastritis among
the portion of the controls for the cancer study who
are free of gastritis at the beginning of the study period. The cancer registries and tissue registries in
Hiroshima and Nagasaki will be used for the determination of gastric cancer cases. To evaluate atrophic gastritis, pepsinogen I and II will be measured
using sera collected 2 to 4 years and 8 to 12 years
before diagnosis of cancer, and diagnosis will be
carried out based on Miki’s criteria for atrophic gastritis. Two control cases (about 1,000), matched forsex, age, city, and year of blood drawing, per casewill be selected from among the AHS participants.
Using serum samples collected 8 to 12 years before
cancer diagnosis, IgG antibodies against H. pylori
will be measured via a conventional method, while
antibodies against the binding sites for SHP-2 of the
RERF Update Volume 16, 2005

Research Protocols and Publications
CagA sequences of H. pylori in sera of the patients
will be measured using a new ELISA (enzyme linked
immunosorbent assay) kit now being developed. The
incidence of atrophic gastritis increased at the rateof 8%/5 years in H. pylori-infected individuals. Thus,
it is expected that about 10% of the study subjects(16% of infected subjects [60%]) are incident casesof atrophic gastritis. We suspect that the risk for atrophic gastritis and gastric cancer varies depending on
the presence or absence of CagA, and the type of
CagA sequences, i.e., European/American or East
Asian.
H. pylori induces a chronic inflammatory reaction that causes intestinal metaplasia, which plays
an important role in the multi-step process of humangastric carcinogenesis. Therefore, it is of interest tonote whether A-bomb exposure is implicated in thedevelopment of chronic gastritis associated with gastric cancer.
For genetic factors, in addition to the IL1B genetic polymorphism, which has already been reported
as a risk factor for hypochlorhydria and gastric cancer, haplotype polymorphisms of the LTA-NFKBIL1BAT1 genome region will be studied. The latter is in
the spotlight as a gene locus that regulates the expression of many pro-inflammatory cytokines andinflammatory cytokines.
This is a novel study for several reasons; the casecontrol epidemiological study’s observation period
is over 10 years; the study will be conducted withspecial reference to CagA toxicity; and it will investigate the polymorphisms of the IL1B and LTANFKBIL1-BAT1 genome region as a genetic factor.

RP 3-04 ESR Measurements of Tooth Samples
from Nagasaki Survivors (Addendum to RP 192)
Nakamura N, Kodama Y, Tomonaga M, Iijima Y,
Mine M, Okumura Y, Kodama K, Cullings HM,
Akahoshi M
The purpose of the study is to measure tooth
enamel from Nagasaki survivors by means of electron spin resonance (ESR) technique to evaluate radiation dose under the same conditions specified for
tooth enamel obtained from Hiroshima survivors.
Frequency of chromosome aberrations will also be
examined in blood lymphocytes from the tooth donors if they are Adult Health Study (AHS) members.
The present study is a collaborative work between
RERF and a group at Nagasaki University who collected the tooth samples. After the measurements,
the enamel samples are returned to Nagasaki University in due time.

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23
RP 4-04 Relationship between Cancer Development and Genetic Polymorphisms among Abomb Survivors, Focusing on Immune-related
Genes
Hayashi T, Kusunoki Y, Kyoizumi S, Imai K, Hakoda
M, Eguchi H, Cologne JB, Tsugane S, Yoshida T,
Tahara E, Fujiwara S, Suzuki G, Akahoshi M,
Nakachi K
This research project will study the A-bomb survivor cohort to assess whether individual genetic
background affects individual susceptibility to cancer development. This study focuses on polymorphisms of genes encoding molecules that are possibly involved in immunological defense against cancer development. The immune system can distinguishbetween self and non-self, and cancer development
can be immunologically prevented when cancer (orpre-cancerous) cells themselves, or cancer-associatedmolecules, are recognized by the system as non-self,
a process referred as cancer immune surveillance.
In innate immunity, self and non-self recognition ismediated by natural-killer (NK) and toll-like receptors, and in acquired immunity, by the interaction
between T-cell receptor and major histocompatibility complex (MHC: human leukocyte antigen [HLA]in humans) molecules. Persistent inflammation occurs as a consequence of immunological host response to xenobiotics, which involves activation of
a number of genes including relevant cytokines,
chemokines and their receptors. Reactive oxygen
species (ROS) generated by persistent inflammation
are thought to cause cancer in some cases by damaging DNA. The major defence mechanism for DNA
damage is the DNA repair system, and polymorphisms of DNA repair genes may be important inanalyzing genetic susceptibility to cancer. Drugmetabolizing enzymes, a counterpart of DNA repair
enzymes, are involved in generating certain types of
DNA damage — specifically, DNA-adducts — andpolymorphisms of these genes may also be important. In this study, we will use stored biological materials (lymphocytes and paper discs) that have beencollected from about 2,900 individuals including
1,444 cancer cases, a subcohort of the Adult HealthStudy (AHS) cohort. Genome analyses of immunerelated genes, inflammation-related genes, and othercancer-associated genes, such as DNA repair genes
and drug-metabolizing enzyme genes, will be conducted to identify individuals at high risk of cancer,
and to determine whether the risk is related to radiation exposure or not, based on polymorphisms ofthese genes.

RERF Update Volume 16, 2005

24

Research Protocols and Publications

RP 5-04 Identification of Cancer-related Gene
Polymorphisms and Immunological Markers(Addendum to RP 4-04)
Hayashi T, Kusunoki Y, Imai K, Cologne JB, Tahara
E, Nakachi K
This research project aims to elucidate the association between cancer-related gene polymorphisms
and immunological phenotypes, supplementing RP
4-04, which is a study of the A-bomb survivor cohort to assess whether radiation exposure affects individual susceptibility to cancer development. The
present project will examine the association between
individual genetic background and individual susceptibility to cancer development, using samples
obtained from the Saitama cohort. This study focuseson gene polymorphisms encoding molecules believed to involve immunological defense against
cancer development. With the aim of elucidating theassociation between cancer-related gene polymorphisms and immunological phenotypes, this study
will examine biological samples obtained from 2,479
individuals examined in the Saitama cohort study.
The immunogenome study includes the investigation of genetic background, which influences various immunological phenotype markers. Some immunological phenotype markers measured in the
Saitama cohort are the same as those measured in
the RERF cohort, and other markers were measured
only in the Saitama cohort. The statistical power inthe genome analysis with common phenotype markers can be increased by analyzing the Saitama cohort subjects. In addition, the results from the phenotype-genotype analyses in the Saitama cohort
study will allow genotyping-based analyses even forphenotype markers that were not measured in the
RERF cohort, including natural-killer (NK) activity.

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

Allen NE, Sauvaget C, Roddam A, Appleby PN,
Nagano J, Suzuki G, Key TJ, Koyama K. A prospective study of diet and prostate cancer in Japanese men. Cancer Causes and Control 2004 (November); 15(9):911-20.
Asakawa J, Kuick R, Kodaira M, Nakamura N,
Katayama H, Pierce DA, Funamoto S, Preston DL,
Satoh C, Neel JV, Hanash SM. A genome scanning approach to assess the genetic effects of radiation in mice and humans. Radiation Research
2004 (April); 161(4):380-90. (RERF Report 1602)
Ban S, Konomi C, Iwakawa M, Yamada S, Ohno T,
Tsuji H, Noda S, Matui Y, Harada Y, Cologne JB,
Imai T. Radiosensitivity of peripheral blood lymphocytes obtained from patients with cancers of
the breast, head and neck or cervix as determinedwith a micronucleus assay. Journal of Radiation
Research 2004 (December); 45:535-41.
Buerger H, Packeisen J, Boecker A, Tidow N,
Kersting C, Bielawski K, Isola J, Yatabe Y,
Nakachi K, Boecker W, Brandt B. Allelic lengthof a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of thissequence—first results of an inter-ethnic breast
cancer study. Journal of Pathology 2004; 203:54550.
Cologne JB, Pawel DJ, Sharp GB, Fujiwara S. Uncertainty in estimating probability of causation ina cross-sectional study: Joint effects of radiationand hepatitis-C virus on chronic liver disease. Journal of Radiological Protection 2004 (June);24(2):131-45. (RERF Report 5-03)
Cologne JB, Sharp GB, Neriishi K, Verkasalo PK,
Land CE, Nakachi K. Improving the efficiency ofnested case-control studies of interaction by selecting controls using counter matching on exposure. International Journal of Epidemiology 2004
(June); 33(3):485-92. (RERF Report 8-03)
Darby SC, Hill D, Auvinen A, Barros-Dios JM,
Baysson H, Bochicchio F, Deo H, Falk R,
Forastiere F, Hakama M, Heid I, Kreienbrock L,
Kreuzer M, Lagarde F, et al. Radon in homes andrisk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. British Medical Journal 2005 (January 29);
330(785):223-6.

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RERF Update Volume 16, 2005

Research Protocols and Publications
Eguchi H. Factors leading to endometrial cancer andindividual characteristics. Tajima K, et al., eds.
Frontiers of Cancer Prevention (Vol.2), Latest
Study Results and Preventive Strategy. Kyoto:Showado; 2005 (March 30), pp 104-10. (Japanese)
Fujiwara S. Factor affecting fragile fractures.
Horumon to Rinsho [Clinical Endocrinology]
2004; 52(4):279-83. (Japanese)
Fujiwara S. Fracture and EBM. Kotsu Soshosho
Chiryo [Journal of Osteoporotic Medicine] 2004
(July); 3(3):258-61. (Japanese)
Fujiwara S. Lumbar vertebra transformation and
QOL. Kotsu Soshosho Chiryo [Journal of Osteoporotic Medicine] 2004 (April); 3(2):128-37.
(Japanese)
Fujiwara S. Risk for spine or non-spine fracture.
Igaku no Ayumi [Journal of Clinical and Experimental Medicine] 2005 (January); 212(2):139-42.
(Japanese)
Fujiwara S. Epidemiology of osteoporosis and fracture. Medical Practice 2004 (October);21(10):1661-4. (Japanese)
Fujiwara S. Conditions of spine fracture. Seikei-Geka
Kango [Japanese Journal of Orthopedic Nursing]2004 (August); 9(8):713-5. (Japanese)
Fujiwara S. Epidemiology of osteoporosis. Seisa to
Iryo [Gender & Sex Specific Medicine] 2004 (October); 1(3):295-9. (Japanese)
Fujiwara S, Ohishi W. A nested case-control studyof factors enhancing progression into hepatocellular carcinoma. MHLW Grants: FY-2004 Reportof Third Term Comprehensive Control Research
for Cancer. 2005 (March), pp 30-3. (Japanese)
Gilbert ES, Koshurnikova ME, Sokolnikov ME,
Shilnikova NS, Preston DL, Ron E, Okatenko PV,
Khokhryakov VF, Vasilenko EK, Miller S,
Eckerman K, Romanov SA. Lung cancer in Mayakworkers. Radiation Research 2004 (November);
162:505-16.
Hakoda M, Kasagi F. Association of hyperuricemiawith cardiovascular disease; A population-based
cohort study. Konyosankessho to Tsufu [Hyperuricemia and Gout] 2004; 12(2):137-42. (Japanese)
Hakoda M, Ohiwa H, Masunari N, Yamada M,
Fujiwara S, Suzuki G, Kasagi F. Mortality risk ofrheumatoid arthritis revealed by the analysis of
atomic bomb survivors. Hiroshima Igaku [JourReturn to Table of Contents

25
nal of the Hiroshima Medical Association] 2004
(April); 57(4):334-5. (Proceedings of the 44th Late
A-bomb Effects Research Meeting, 2003) (Japanese)
Hamatani K, Yano S, Hamasaki K, Hirai Y, Hayashi
Y, Nakachi K. Application of a new cDNA amplification method to the analysis of ET rearrangements in archival paraffin-embedded thyroid
microcarcinomas. Nagasaki Igakkai Zasshi[Nagasaki Medical Journal] 2004 (September);79(Special Issue):301-3. (Proceedings of the 45th
Late A-bomb Effects Research Meeting, 2004)(Japanese)
Hayashi T. Identification of high immunological cancer risk group. MHLW Grants: FY-2004 Reportof Third Term Comprehensive Control Research
for Cancer. 2005 (March), pp 34-9. (Japanese)
Hayashi T, Hayashi I, Shinohara T, Morishita Y,
Nagamura H, Kusunoki Y, Kyoizumi S, Seyama
T, Nakachi K. Radiation-induced apoptosis ofstem/progenitor cells in human umbilical cord
blood is associated with alterations in reactive
oxygen and intracellular pH. Mutation Research
2004 (November); 556(1-2):83-91. (RERF Report
1-04)
Hayashi T, Imai K, Kusunoki Y, Hayashi I, Kyoizumi
S, Tahara E, Nakachi K. HLA genotyping is involved in inter-individual variations of NK activity. Immunology 2004. Bologna, Italy: Medimond
S.r.l; 2004, pp 21-5.
Hayashi T, Morishita Y, Kubo Y, Kusunoki Y,
Hayashi I, Kasagi F, Hakoda M, Kyoizumi S,
Nakachi K. Long-term effects of radiation doseon inflammatory markers in atomic bomb survivors. American Journal of Medicine 2005 (January); 118(1):83-6. (RERF Report 27-03)
Hirai Y, Hamasaki K, Shinohara T, Inoue T,
Takahashi K, Taga M, Hamatani K, Nii K, Mizuno
M, Tokuoka S, Nakachi K, MacPhee DG. Methylation patterns of BRCA1 promoter regions inbreast cancers among atomic-bomb survivors.
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2004 (April); 57(4):402-3. (Proceedings of the 44th Late A-bomb Effects Research
Meeting, 2003) (Japanese)
Imaizumi M, Akahoshi M, Ichimaru S, Nakashima
E, Hida A, Soda M, Usa T, Ashizawa K, Yokoyama
N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and all-cause mortality in
subclinical hypothyroidism. Journal of Clinical
Endocrinology and Metabolism 2004 (July);
RERF Update Volume 16, 2005

Research Protocols and Publications
89(7):3365-70. (RERF Report 14-02)
Ito Y, Nakachi K, Imai K, Hashimoto S, Watanabe
Y, Inaba Y, Tamakoshi A, Yoshimura T. Stabilityof frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-likegrowth factor binding protein-3, transforming
growth factor beta, soluble Fas, and superoxide
dismutase activity for the JACC study. Journal of
Epidemiology 2005 (March); 15 Suppl 1:67-73.
Izumi S, Imai K, Nakachi K. Excess concordance ofcancer incidence and lifestyles in married couples(Japan): survival analysis of paired rate data. Cancer Causes and Control 2004 (August); 15:551-8.
Izumi S, Ohtaki M. Aspects of the Armitage-Doll
gamma frailty model for cancer incidence data.
Environmetrics 2004 (May); 15(3):209-18. (RERF
Report 2-01)
Kamiya K, Kimura A, Miyagawa K, Inaba T, Suzuki
G, Kyoizumi S. Molecular biological study of thedevelopment of bone marrow/immune abnormality among A-bomb survivors—Comprehensive
report of Hiroshima group. FY-2004 Report ofAtomic Bomb Disease Research Project Entrusted
by MHLW. Tokyo: Japan Public Health Association; 2005 (March), pp 37-46. (Japanese)
Kanis J, Johnell O, De Laet C, Johansson H, Oden
A, Delmas P, Eisman J, Fujiwara S, Garnero P,
Kroger H, McCloskey EV, Mellstrom D, Melton
LJ, Pols H, Reeve J, Silman A, Tenenhouse A. A
meta-analysis of previous fracture and subsequent
fracture risk. Bone 2004 (August); 35:375-82.
Kanis J, Johnell O, Oden A, Johansson H, De LaetC, Eisman JA, Fujiwara S, Kroger H, McCloskey
EV, Mellstrom D, Melton LJ, Pols H, Reeve J,
Silman A, Tenenhouse A. Smoking and fracturerisk: a meta-analysis. Osteoporosis International
2005 (January); 16:155-62.
Kasagi F, Kodama K. Epidemiological study on primary prevention of cancers of the long-term follow-up population. MHLW Grants: FY-2004 Report of Third Term Comprehensive Control Research for Cancer. 2005 (March), pp 17-20. (Japanese)
Kodaira M, Izumi S, Takahashi N, Nakamura N. No
evidence of radiation effect on mutation rates at
hypervariable minisatellite loci in the germ cellsof atomic bomb survivors. Radiation Research
2004 (October); 162(4):350-6. (RERF Report 704)

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26
Kodaira M, Sasaki K, Sugita K, Katayama H, Tagawa
H, Omine H, Imanaka M, Kushiro J, Takahashi N.
Characterization of microarray-based comparative
genomic hybridization (array CGH) techniqueusing model analysis of radiation-induced large
deletions at the human HPRT (hypoxanthine guanine phosphoribosyl transferase) locus. Hiroshima
Igaku [Journal of the Hiroshima Medical Association] 2004 (April); 57(4):417-21. (Proceedingsof the 44th Late A-bomb Effects Research Meeting, 2003) (Japanese)
Kodama Y, Nakano M, Itoh M, Ohtaki K, Kusunoki
Y, Nakamura N. Single stem cell could give riseto nearly one half of the total blood T lymphocytes? Very high frequencies of clonal chromosome aberrations observed in two A-bomb survivors. Hiroshima Igaku [Journal of the Hiroshima
Medical Association] 2004 (April); 57(4):359-61.
(Proceedings of the 44th Late A-bomb Effects
Research Meeting, 2003) (Japanese)
Kyoizumi S, Kusunoki Y, Hayashi T. Flowcytometric measurement of mutant T cells withaltered expression of TCR: Detecting somatic
mutations in humans and mice. Keohavong P,
Grant SG, eds. Methods in Molecular Biology
Volume 291, Molecular Toxicology Protocols.
Totowa, USA: Human Press Inc.; 2005, pp 197204.
Kyoizumi S, Kusunoki Y, Hayashi T. Lymphocyte
lifespan, immunological memory and homeostasis—With the focus on T cells. Biotherapy 2004
(July); 18(4):267-77. (Japanese)
Kyoizumi S, Kusunoki Y, Hayashi T, Ohara T. Expressions and functions of CD43 in CD4 memory
T cells. Rinsho Meneki [Clinical Immunology]
2004 (April); 41(4):490-5. (Japanese)
Kyoizumi S, Ohara T, Kusunoki Y, Hayashi T,
Koyama K, Tsuyama N. Expression characteristics and stimulatory functions of CD43 in humanCD4+ memory T cells: Analysis using a monoclonal antibody to CD43 that has a novel lineage
specificity. Journal of Immunology 2004 (June 15);172(12):7246-53. (RERF Report 24-03)
Matsuo K, Akahoshi M, Nakashima E, Seto S, Yano
K. Clinical characteristics of subjects with the
Brugada-type electrocardiogram: A case control
study. Journal of Cardiovascular Electrophysiology 2004 (June); 15(6):653-7. (RERF Report 1303)
Minamoto A, Taniguchi H, Yoshitani N, Mukai S,
Yokoyama T, Kumagami T, Tsuda Y, Mishima HK,
RERF Update Volume 16, 2005

Research Protocols and Publications
Amemiya T, Nakashima E, Neriishi K, Hida A,
Fujiwara S, Suzuki G, Akahoshi M. Cataract inatomic bomb survivors. International Journal of
Radiation Biology 2004 (May); 80(5):339-45.
(RERF Report 18-03)
Nagasaka T, Sakamoto H, Notohara K, Cullings HM,
et al. Colorectal cancer with mutation in BRAF,
KRAS, and wild-type with respect to bothoncogenes showing different patterns of DNA
methylation. Journal of Clinical Oncology 2004
(November); 22(22):4584-94.
Nakachi K. Unique cancers in the northern part ofThailand-liver—cancer and lung cancer. Tajima K,
et al., eds. Frontiers of cancer prevention (Vol.2),
Latest study results and preventive strategy. Kyoto:Showado; 2005 (March 30), pp 151-7. (Japanese)
Nakachi K. Individual characteristics and carcinogenesis. Tajima K, et al., eds. Frontiers of cancer
prevention (Vol.2), Latest study results and preventive strategy. Kyoto: Showado; 2005 (March30), pp 17-26. (Japanese)
Nakachi K, Hayashi T, Imai K, Kusunoki Y. Perspectives on cancer immuno-epidemiology. Cancer
Science 2004 (December); 95(12):921-9.
Nakamura N. A hypothesis: Radiation-related leukemia is mainly attributable to the small numberof people who carry pre-existing clonally expanded
preleukemic cells. Radiation Research 2005
(March); 163(3):258-65. (RERF Report 14-04)
Nakamura N, Nakano M, Kodama Y, Ohtaki K, Cologne JB, Awa AA. Mechanisms of clonal chromosome aberrations: Indication of bone marrowstem cell kinetics. Hoshasen Seibutsu Kenkyu[Radiation Biology Research Communications]
2004; 39(2):113-22. (Japanese)
Nakamura N, Ohtaki K, Kodama Y, Nakano M, Itoh
M, Cologne JB, Awa AA. Chromosome damage
inflicted by radiation exposure is not recorded inlymphocytes from A-bomb survivors exposed inutero. Hiroshima Igaku [Journal of the Hiroshima
Medical Association] 2004 (April); 57(4):353-5.
(Proceedings of the 44th Late A-bomb Effects
Research Meeting, 2003) (Japanese)
Nakanishi S, Suzuki G, Kusunoki Y, Yamane K,
Egusa G, Kohno N. Increasing of oxidative stressfrom mitochondria in type 2 diabetic patients. Diabetes/Metabolism Research and Reviews 2004
(September); 20(5):399-404.
Nakanishi S, Yamada M, Hattori N, Suzuki G. RelaReturn to Table of Contents

27
tion between QT duration and mortality in an elderly Japanese population. American Journal of
Cardiology 2004 (May); 93(9):1182-5. (RERF
Report 16-03)
Nakanishi S, Yamada M, Hattori N, Suzuki G. Relationship between HbA1c and mortality in a Japanese population. Diabetologia 2005 (February);
48(2):230-4. (RERF Report 4-04)
Nakashima E, Neriishi K, Minamoto A, Funamoto
S. Statistical analyses of cataract prevalence inatomic-bomb survivors, 2000-2002. Nagasaki
Igakkai Zasshi [Nagasaki Medical Journal] 2004
(September); 79(Special Issue):234-6. (Proceedings of the 45th Late A-bomb Effects Research
Meeting, 2004) (Japanese)
Nishi N. Site-specific cancers. VII. Tumors of brain
and central nervous system. Hoshasen Kagaku[Radiological Sciences] 2005 (March); 48(3):908. (Japanese)
Nishi N, Kodama K. Epidemiological study on tertiary prevention of cancers of the long-term follow-up population. MHLW Grants: FY-2004 Report of Third Term Comprehensive Control Research for Cancer. 2005 (March), pp 21-5. (Japanese)
Nishi N, Kurosawa M, Nohara M, Oguri S, Chida F,
Otsuka K, Sakai A, Okayama A. Knowledge ofand attitudes toward suicide and depression among
Japanese in municipalities with high suicide rates.
Journal of Epidemiology 2005 (March); 15(2):4855.
Nishi N, Onoda T, Okayama A. Requirement for
operating agreements in epidemiological studies.
Iwate Koshu Eiseigakkaishi [Iwate Journal of Public Health] 2004 (December); 16(2):21-6. (Japanese)
Nishi N, Sugiyama H, Kodama K. Cancer registry
and its challenge for the future. Nihon Ishikai
Zasshi [Journal of Japan Medical Association]2005 (February); 133(3):382-3. (Japanese)
Ogawa T, Hayashi T, Kyoizumi S, Kusunoki Y,
Nakachi K, MacPhee DG, Trosko JE, Kataoka K,
Yorioka N. Anisomycin downregulates gap-junctional intercellular communication via the p38
MAP-kinase pathway. Journal of Cell Science
2004 (April 15); 117:2087-96.
Ohishi W, Chayama K. Lamivudine therapy forchronic hepatitis B. Saishin Igaku [Modern Medicine] 2004 (September); 59(9):1919-23. (Japanese)
RERF Update Volume 16, 2005

Research Protocols and Publications
Ohishi W, Chayama K. The adaptation and problemof lamivudine therapy for hepatitis B. Kan Tan Sui[Liver, Gallbladder and Pancreas] 2004 (October);49(4):479-87. (Japanese)
Ohishi W, Mori N, Tsuge M, Takaki S, Tei S, Hiraga
N, Kodama H, Hiramatsu A, Waki K, Shirakawa
H, Aikata H, Imamura M, Takaishi H, Takahashi
S, Kamiyasu M, Chayama K. Examination about
the clinical usefulness of HBcAb measurement by
Architect. Kanzo [Acta Hepatologica Japonica]
2004 (October); 45(10):555-6. (Japanese)
Ohtaki K, Kodama Y, Nakano M, Itoh M, Awa AA,
Cologne JB, Nakamura N. Human fetuses do notregister chromosome damage inflicted by radiation exposure in lymphoid precursor cells except
for a small but significant effect at low doses. Radiation Research 2004 (April); 161(4):373-9.
(RERF Report 9-03)
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. Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2004
(April); 57(4):356-8. (Proceedings of the 44th Late
A-bomb Effects Research Meeting, 2003) (Japanese)
Pierce DA, Kellerer AM. Adjusting for covariate
errors with nonparametric assessment of the truecovariate distribution. Biometrika 2004 (December); 91(4):863-76. (RERF Report 3-03)
Preston DL, Pierce DA, Shimizu Y, Cullings HM,
Fujita S, Funamoto S, Kodama K. Effect of recentchanges in atomic bomb survivor dosimetry on
cancer mortality risk estimates. Radiation Research
2004 (October); 162(4):377-89. (RERF Report 304)
Sauvaget C, Kasagi F, Waldren CA. Dietary factors
and cancer mortality among atomic-bomb survivors. Mutation Research 2004 (July 13); 551(12):145-52. (RERF Report 23-03)
Sauvaget C, Kasagi F, Waldren CA. Joint effect ofradiation and diet on cancer risk. Journal of Epidemiology and Community Health 2004 (August);
58 (Supplement 1):A116. (Abstract) (Proceedingsof European Congress of Epidemiology, Porto,
Portugal, 8-11 September 2004)
Sauvaget C, Nagano J, Allen NE. Dietary factors andrisk of stroke mortality. Journal of Nutrition,
Health & Aging 2004; 8(6):441. (Abstract) (Proceedings of the 4th European Congress on NutriReturn to Table of Contents

28
tion and Health in the Elderly, Toulouse, France,
4-5 November 2004)
Sauvaget C, Nagano J, Hayashi M, Yamada M. Animal protein, animal fat, and cholesterol intakes andrisk of cerebral infarction mortality in the Adult
Health Study. Stroke 2004 (July); 35(7):1531-7.
(RERF Report 19-03)
Shigematsu I. Medical activities at the time of theChernobyl accident. Radiation Emergency Medicine News 2004 (September); No. 11:1-4. (Japanese)
Shimada H, Shimizu K, Mimaki S, Sakiyama T, Mori
T, Shimasaki N, Yokota J, Ohta T, Nakachi K, Ohki
M. First case of aplastic anemia in a Japanese childwith a homozygous missense mutation in the NBS1
gene (I171V) associated with genomic instability.
Human Genetics 2004 (August); 115:372-6.
Suyama A. Radiation-induced carcinogenesis onesophagus, stomach, colon and liver. Hoshasen
Kagaku [Radiological Sciences] 2004 (September); 47(9):286-90. (Japanese)
Suzuki G. Development of examination for stomach cancer using serum samples. MHLW Grants:
FY-2004 Report of Third Term Comprehensive
Control Research for Cancer. 2005 (March), pp
26-9. (Japanese)
Suzuki G. Acute medicine for acutely exposed subjects. Hiroshima Igaku [Journal of the Hiroshima
Medical Association] 2004 (April); 57(4):307-10.
(Proceedings of the 44th Late A-bomb Effects
Research Meeting, 2003) (Japanese)
Suzuki G, Izumi S, Hakoda M, Takahashi N. LTA
252G allele containing haplotype block is associated with high serum C-reactive protein levels.
Atherosclerosis 2004 (September); 176(1):91-4.
(RERF Report 12-03)
Suzuki G, Shimada Y, Hayashi T, Akashi M, Hirama
T, Kusunoki Y. An association between oxidative
stress and radiation-induced lymphomagenesis.
Radiation Research 2004 (June); 161(6):642-7.
(RERF Report 28-03)
Taguchi A, Fujiwara S, Masunari N, Suzuki G. Selfreported number of remaining teeth is associatedwith bone mineral density of the femoral neck, but
not of the spine, in Japanese men and women. Osteoporosis International 2004 (October);15(10):842-6. (RERF Report 21-03)
Tahara E. Genetic pathways of two types of gastric
RERF Update Volume 16, 2005

Research Protocols and Publications
cancer. Buffler P, Rice J, Bean R, Bird M, Boffetta
P, eds. Mechanisms of Carcinogenesis: Contributions of Molecular Epidemiology (IARC Scientific Publications No. 157). Lyon, France: International Agency for Research on Cancer; 2004,
pp 327-49.
Tahara E. Development study on comprehensive
cancer prevention by a new cancer prevention/
early cancer detection system. MHLW Grants: FY2004 Report of Third Term Comprehensive Control Research for Cancer. 2005 (March), pp 2-11.
(Japanese)
Tahara E. Molecular aspects of invasion and metastasis of gastric cancer. Proceedings of the 3rd International Conference on Tumor Microenvironment:
Progression, Therapy and Prevention, Prague,
Czech Republic, October 12-16, 2004. Bologna,
Italy: MEDIMOND S.r.l.; 2004, pp 11-6.
Tahara E. Study on atomic bomb diseases. Comprehensive report. FY-2004 Report of Atomic Bomb
Disease Research Project Entrusted by MHLW.
Tokyo: Japan Public Health Association; 2005
(March), pp 3-15. (Japanese)
Tahara E (Editor). MHLW Grants: FY-2004 Reportof Third Term Comprehensive Control Research
for Cancer. Development Study on Comprehensive Cancer Prevention Publications and Reprints
of Research Results; 2005 (March), 257 p. (Japanese)
Taira S. The late effects research study on atomic
bomb survivors in RERF. Nagasaki Igakkai Zasshi[Nagasaki Medical Journal] 2004 (September);79(Special Issue):115-23. (Proceedings of the 45th
Late A-bomb Effects Research Meeting, 2004)(Japanese)
Takahashi N. Comprehensive manual for biochemical and immunological aspects of clinical pathology. VII. Phosphoglucomutase (PGM). Nippon
Rinsho [Japanese Journal of Clinical Medicine]2004 (December); 62(Suppl 12):804-8. (Japanese)
Tsuda Y, Kumagami T, Minamoto A, Taniguchi H,
Yokoyama T, Yoshitani N, Mukai S, Mishima HK,
Amemiya T, Neriishi K, Nakashima E, Hida A,
Fujiwara S, Suzuki G, Akahoshi M. Ophthalmologic study in A-bomb survivors. Hiroshima Igaku[Journal of the Hiroshima Medical Association]
2004 (April); 57(4):336-8. (Proceedings of the44th Late A-bomb Effects Research Meeting,2003) (Japanese)29
lived radicals (LLR) in radiation-induced mutation and persistent chromosomal instability: counteraction by ascorbate and RibCys but not DMSO.
Mutation Research 2004 (July); 551(1-2):255-65.
Yamada M, Wong FL, Fujiwara S, Akahoshi M,
Suzuki G. Noncancer disease incidence in atomic
bomb survivors, 1958-1998. Radiation Research
2004 (June); 161(6):622-32. (RERF Report 17-03)
Yamaoka M, Kusunoki Y, Kasagi F, Hayashi T,
Nakachi K, Kyoizumi S. Effects of atomic-bombradiation on human immune responses. Report 21:
Long-term effects of radiation exposure on naiveand memory CD8 T-cell subsets. Nagasaki Igakkai
Zasshi [Nagasaki Medical Journal] 2004 (September); 79(Special Issue):192-9. (Proceedings of the
45th Late A-bomb Effects Research Meeting,2004) (Japanese)
Yasui W, Arihiro K, Daimaru Y, Takeshima Y,
Taniyama K, Hayashi Y, Fukuhara T, Fujihara M,
Matsuura H, Katayama H, Kodama K, Takahashi
N, Nakachi K. Genetic abnormality relating to theoccurrence of solid cancers among A-bomb survivors and its molecular epidemiological study—
Comprehensive report of Hiroshima group. FY2004 Report of Atomic Bomb Disease Research
Project Entrusted by MHLW. Tokyo: Japan Public Health Association; 2005 (March), pp 17-30.
(Japanese)
Yokoyama T, Minamoto A, Yoshitani N, Mukai S,
Mishima HK, Taniguchi H, Kumagami T, Tsuda
Y, Kitaoka T, Neriishi K, Nakashima E, Hida A,
Imaizumi M, Fujiwara S, Suzuki G, Akahoshi M.
Risk factors of cataract in atomic bomb survivors.
Nagasaki Igakkai Zasshi [Nagasaki Medical Journal] 2004 (September); 79(Special Issue):237-41.
(Proceedings of the 45th Late A-bomb Effects Research Meeting, 2004) (Japanese)
Yonehara S, Brenner AV, Kishikawa M, Inskip PD,
Preston DL, Ron E, Mabuchi K, Tokuoka S. Clinical and epidemiologic characteristics of first primary tumors of the central nervous system andrelated organs among atomic bomb survivors in
Hiroshima and Nagasaki, 1958-1995. Cancer 2004
(October 1); 101(7):1644-54. (RERF Report 9-04)
Yoshida N, Omoto Y, Inoue A, Eguchi H, Kobayashi
Y, Kurosumi M, Saji S, Suemasu K, Okazaki T,
Nakachi K, Fujita T, Hayashi SI. Prediction of
prognosis of estrogen receptor-positive breast cancer with combination of selected estrogen-regulated genes. Cancer Science 2004 (June);
95(6):496-502.

Waldren CA, Vannais DB, Ueno AM. A role for longReturn to Table of Contents

RERF Update Volume 16, 2005

Research Protocols and Publications

30

Publications Using RERF Data
The following publications represent research done
by non-RERF scientists based on the data publicly
available from RERF.
Little MP. Threshold and other departures from linear-quadratic curvature in the non-cancer mortality dose-response curve in the Japanese atomic
bomb survivors. Radiation and Environmental
Biophysics 2004; 43:67-75.
Little MP, Muirhead CR. Derivation of low-dose
extrapolation factors from analysis of curvaturein the cancer incidence dose response in JapaneseA-bomb survivors. International Journal of Low
Radiation 2004; 1(3):285-99.

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RERF Update Volume 16, 2005