Radiation Effects Research Foundation News and Views
Hiroshima and Nagasaki, Japan
Volume 13, Issue 1, Spring 2002

Table of Contents
RERF NewsThe 36th Board of Directors Meeting ........................................................................... 1
The 28th Scientific Council Meeting ............................................................................ 2
New Chairman and Chief of Research ........................................................................ 4
Staff News .......................................................................................................................... 4
Multinational Peer Review of Clinical Studies ......................................................... 5
Current Status of Dosimetry Revision ......................................................................... 7

ArticlesTen Thousand Days Atop Hijiyama, by Akio Awa .................................................. 9
Radiation Risk, Longevity, and the Impact of the Comparison Group ............. 17
on Low-Dose Risk Estimates, by John B. Cologne and Dale L. Preston
Multifactorial Diseases in the Post-Genomic-Sequencing Era and ................... 23
Our Current Position, by Norio Takahashi

Facts and Figures ........................................................................................................ 28
Historical Vignette 1955, by Robert W. Miller ...................................................... 29
In Memoriam, R.M. Heyssel, ABCC Chief of Medicine 1956–58 ...................... 30
Research Protocols and Publications
Research Protocols ........................................................................................................... 31
Recent Publications ......................................................................................................... 32
This newsletter is published by the Radiation Effects Research Foundation (formerly the Atomic
Bomb Casualty Commission), established in April 1975 as a private, nonprofit Japanese foundation.
It is supported equally by the government of Japan through its Ministry of Health, Labour andWelfare and that of the United States through the National Academy of Sciences under contract
with the Department of Energy.
RERF conducts research and studies—for peaceful purposes—on the medical effects of radiation
on humans with a view toward contributing to the maintenance of the health and welfare of atomicbomb survivors and to the enhancement of the health of all mankind.
Editor: Donald Pierce, Department of Statistics
Technical Editor: Yuko Ikawa, Editorial & Publications Section
Editorial Policy
Contributions to Update receive editorial review only and do not receive scientific peer review.
The opinions expressed herein are those of the authors only and do not reflect RERF policies orpositions.
Contact: Mailing address: RERF Editorial & Publications Section, 5-2 Hijiyama Park,
Minami-ku, Hiroshima 732-0815 Japan
Telephone: 81-82-261-3131; Facsimile: 81-82-263-7279
Internet: update@rerf.jp



RERF NewsThe 36th Meeting of the Board of Directors, Hiroshima
The 36th meeting of the Board of Directors washeld on May 26–27, 2001 in the Auditorium of theHiroshima Laboratory. Seventeen people were in attendance, including directors, supervisors, andobservers from the Ministry of Health, Labour andWelfare (Japan), Department of Energy (U.S.), andNational Academy of Sciences (U.S.). The Board
normally meets once per year to consider important
operational issues of RERF.
Following approval of the minutes of the 34th and35th Board meetings, Dr. Shigenobu Nagataki, RERF
Chairman, presented three reports: “Summary of thepast four years,” “Present problems,” and “Future research plans.” With regard to the Health Effects Studyon the Children of A-bomb Survivors, it was reported
that the full-scale mail survey had been initiated basedon the agreement with the All Japan Second Generation A-bomb Victims Liaison Council.
Dr. Nagataki further commented on three additional issues: “Role of the Operating Committee,”“Role of the Chief Scientist,” and “Future plans.” In
terms of the future plans, he emphasized the need topromote collaboration with other research organizations.
Dr. Seymour Abrahamson, Vice Chairman andChief of Research, explained in detail proposals forestablishing liaisons with statistics programs at universities and promoting the recruitment of researchscientists, based on the recommendations of theMultinational Peer Review of the Statistics Program.
That was followed by deliberation on the past year’s
research activities and audit reports, current year’s
working budget, and coming year’s provisional budget plan, all of which were approved.
Finally, the Board elected Dr. Burton G. Bennett(former Secretary of the United Nations ScientificCommittee on the Effects of Atomic Radiation[UNSCEAR]) as Chairman, Senjun Taira (RERF
Permanent Director) as Vice Chairman, and Dr. Eiichi
Tahara (professor emeritus of Hiroshima University
School of Medicine) as Permanent Director. Theirterms of office begin on 1 July 2001 and extend for aperiod of four years.
List of Participants

Senjun Taira, Permanent Director
Visiting Directors:
Patricia A. Buffler, Dean Emeritus and Professor of
Epidemiology, School of Public Health, University of California, Berkeley
Jonathan M. Samet, Professor and Chairman, Department of Epidemiology, The School of Hygieneand Public Health, The Johns Hopkins University
Richard B. Setlow, Senior Biophysicist, Brookhaven
National Laboratory, and Adjunct Professor of
Biochemistry and Cell Biology, State Universityof New York at Stony Brook (submitted a letterof attorney)Kazuaki Arichi, Councilor, The Japan Institute ofInternational Affairs
Toshiyuki Kumatori, Consultant, Radiation Effects
Association (submitted a letter of attorney)
Masumi Ohike, Former Chairman, Board of Directors, Japan Anti-Tuberculosis Association
Supervisors:
David Williams, Senior Financial Advisor, National
Academy of Sciences
Shudo Yamazaki, Former Director-General, National
Institute of Infectious Diseases
Scientific Councilor:
Tomio Hirohata, Professor Emeritus, Kyushu University Faculty of Medicine
Representatives of Allied Agencies:
Kazuhiro Kanayama, Chief, Medical Care Activities
Unit, General Affairs Division, Health Service
Bureau, Ministry of Health, Labour and Welfare
James H. Hall, Minister-Counselor (Science), Embassy of the United States of America
Giulia R. Bisconti, Energy Attaché, Director, U.S.
Department of Energy Asia Office, Embassy of
the United States of America
Evan Douple, Director, Board on Radiation Effects
Research, National Research Council, National
Academy of Sciences
Catherine S. Berkley, Administrative Associate,
Board on Radiation Effects Research, National
Research Council, National Academy of Sciences
Secretariat:
Masaharu Yoshikawa, Chief of Secretariat
Richard D. Sperry, Administrative Advisor, Secretariat

Permanent Directors:
Shigenobu Nagataki, Chairman
Seymour Abrahamson, Vice Chairman and Chief ofResearch
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RERF Update Volume 13, Issue 1, Spring 2002

RERF NewsThe 28th Meeting of RERF Scientific Council
The 28th meeting of the Scientific Council was heldin Hiroshima on April 9–11, 2001. The meeting wasco-chaired by Dr. J. Martin Brown of Stanford University and Dr. Tomio Hirohata of Kyushu University.
After introductory remarks by RERF Chairman, Dr.
Shigenobu Nagataki, and Vice Chairman/Chief of Research, Dr. Seymour Abrahamson, presentations weremade by each of the RERF departments: Clinical Studies, Epidemiology, Statistics, Radiobiology, andGenetics.
In addition to overview presentations, more specific reports of RERF projects were presented asfollows:
Breast cancer molecular analysis (Yuko Hirai, Radiobiology)
Immunological homeostasis (Yoichiro Kusunoki,
Radiobiology)
In utero cytogenetics (Yoshiaki Kodama, Genetics)
Molecular analysis of induced mutations in mice
(Junichi Asakawa, Genetics)
Progress in DNA microarray technology (Norio
Takahashi, Genetics)
Plans for the F1 clinical study (Saeko Fujiwara,
Clinical Studies)
Microbial infection in the Adult Health Study(Masayuki Hakoda, Clinical Studies)F1 mail survey and mortality in the F1 population(Akihiko Suyama, Epidemiology, Nagasaki)
Radiation interactions in lung, breast, and livercancer (Gerald B. Sharp, Epidemiology)
DS86 dosimetry revision (Shoichiro Fujita andHarry M. Cullings, Statistics)
Effect of radiation on menopause (Michiko
Yamada, Clinical Studies)
Natural menopause in Nagasaki women (Shizue
Izumi, Statistics)
Role of body mass index, serum cholesterol, systolic blood pressure, and menopause (Masazumi
Akahoshi, Clinical Studies, Nagasaki)
The Scientific Council affirmed the emphasis
given at RERF to the main core projects on thehealth effects of radiation. In addition to the epidemiology and clinical studies, the Council
recognized that research to elucidate the etiology
of diseases is important to keep RERF in the forefront of scientific research and to attract young
scientists. The primary general recommendations
were as follows, along with brief indication of RERF
follow-up on them:• Reiteration of the previous Scientific Council recommendation that there be small-group “brainReturn to Table of Contents

storming” sessions where scientists discuss researchgoals. [Such sessions have been initiated or resumed
at the department level and are contributing to development of a Long Range Plan for RERF.]• The Scientific Council might henceforth conduct
their formal review only on alternate years, with someless formal interaction in the non-review years. [TheBoard of Directors requested that a decision on thisbe postponed. Discussions are continuing in regard
to a possible restructuring of the review process.]• Careful consideration should be given to the possibility of individual RERF scientists obtaining theirown research grants. [The Ministry of Education,
Culture, Sports, Science and Technology (MEXT) has
recently recognized RERF as eligible for submitting
grant applications, and proposals for Grants-in-Aid
from MEXT have been made for 13 projects. Sevenof these have now been awarded.]• Consideration should be given to longitudinalcontinuation of the new F1 clinical study beyond theinitial investigation, with biennial mail contact andrepeat clinical visits each 10 years. [Very serious consideration is being given to that, including clinicalvisits more frequently than each 10 years.]
Extensive recommendations were then made foreach research department, which are summarized below.
Radiobiology – Appointment of 2–3 new staff at thedoctoral level should be made. The animal facilities
should be upgraded. Additional tumor tissue, especially breast cancer tissue, should be obtained fromthe Adult Health Study (AHS) participants for use instudies utilizing modern genomic techniques such as
profiling of genetic expression in tumors, e.g., in earlyand late onset breast cancers. The department should
continue to develop expertise in this area and institute the necessary collaborations to perform thesestudies.
Genetics – The current direction of the department
to develop expertise in new molecular-based technologies to identify genetic alterations is supported.
The staff should be expanded with young, short-term
investigators. Collaborations should be establishedwith other scientists both within and outside RERF.
Joint departmental retreats organized around a research theme may be helpful for problem solving,
technology sharing, and generation of new researchideas. The department should be involved in the
RERF F1 study during the planning and implementation stages to be sure that appropriate data andspecimen collection plans are included.
RERF Update Volume 13, Issue 1, Spring 2002

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RERF News
Clinical Studies – The F1 study should be made intoa longitudinal study using mail contact with participants every 2 years, and a repeat full clinical study
should be performed every 10 years. Current studies
that are inactive or making poor progress should beclosed and a mechanism should be set up to limit
approval of clinical research proposals to five years
with resubmission with a progress report if it is necessary for the study to continue for a longer period.
A clinical research review committee should be created, made up of clinicians and statisticians to review
clinical research proposals for scientific validity. Itshould include outside experts as well as RERF personnel.
Epidemiology –The continued surveillance of theLife Span Study (LSS) sample, in utero cohort, andF1 cohort is essential for the mission of RERF. Because of improved survival of cancer patients,
analysis based on cancer incidence is becoming more
important than mortality analysis. RERF should continue to be involved in the tumor registries in
Hiroshima and Nagasaki cities in order to maintainthe current high standards of the tumor registries,
which enables RERF to make nearly complete assessment of incidence cancer cases among survivors.
The maintenance of the current system to abstract
cancer records of survivors at hospitals in both
Hiroshima and Nagasaki cities is desirable. The information obtained during the surveillance of many
years of the LSS cohort, such as several mail surveys
should be explored. Cooperation between the Departments of Clinical Studies and Epidemiology isdesirable to conduct “nested” case-control studies
using stored serum. Careful consideration should begiven to develop first-rate scientific hypotheses tobe tested in such studies.
Statistics – The Council endorsed the recommendations of the recently completed peer review of the
Department of Statistics. In response to these, thedepartment will make further efforts to increase its
visibility to the Japanese statistical community andto recruit Japanese as well as foreign statisticians to
RERF. At least one statistician should be added to
the Scientific Council in the future. Efforts to develop
new statistical techniques applicable to RERF data

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will be increased. These will include: improved dose
response models for predicting health effects at low
radiation exposures and continued exploration of
mechanistic models for cancer induction. Analysesof data on the primary RERF cohorts will continue
to be a major focus, and attention will be given to thecommittee’s specific suggestions in this regard. These
include use of adjusted survivor doses taking into
account random errors. More discussion within thedepartment and throughout RERF will be necessary
on confounding, adjustment, and interpretation issues.
Also, further discussion will be needed to consider
whether there should be an oversight group to consider design, analysis, access, and documentation of
databases for current and future studies.
Members of the Scientific Council
Tomio Hirohata, Professor Emeritus, Kyushu University Faculty of Medicine/Professor, Nakamura
Gakuen University
Yusuke Nakamura, Director of Human Genome Center, Laboratory of Molecular Medicine, Instituteof Medical Science, The University of Tokyo (absent)
Masao Sasaki, Professor Emeritus, Kyoto University (absent)
Yasuhito Sasaki, Chairman, Board of Directors, National Institute of Radiological Sciences
Shinichiro Ushigome, Visiting Professor, Jikei University School of Medicine
J. Martin Brown, Professor and Division Chairman,
Division of Radiation Biology, Department ofRadiation Oncology, Stanford University Schoolof Medicine
Joe W. Gray, Professor of Laboratory Medicine, Radiation Oncology, University of California, San
Francisco (absent)
Gloria M. Petersen, Professor of Clinical Epidemiology, Mayo Medical School
Theodore L. Phillips, Professor and Chairman, Radiation Oncology, Cancer Center, School of
Medicine, University of California, San Francisco
Susan Preston-Martin, Professor, Department of Preventive Medicine, Keck School of Medicine,
University of Southern California

RERF Update Volume 13, Issue 1, Spring 2002

"RERF NewsNew Chairman and Chief of Research
At the Board of Directors meeting held in
Hiroshima on 26–28 May 2001, Dr. Burton G. Bennett
was appointed to succeed Dr. Shigenobu Nagataki as
Chairman and Dr. Eiichi Tahara was appointed the new
Chief of Research. The Chief of Research’s position
had been held by Dr. Seymour Abrahamson who also
concurrently held the position of Vice Chairman. Dr.
Senjun Taira was continued as a Director for a second
term and was now appointed Vice Chairman.
This series of appointments was a complete breakwith past practice since the founding of RERF with
Dr. Bennett being the first American Chairman, Dr.
Taira being the first Japanese Vice Chairman, andDr. Tahara becoming the first Japanese Chief of Research. The terms of all the Directors began 1 July
2001 and are for four years.
Dr. Bennett comes to RERF after having been formany years Secretary of the United Nations Scientific Committee on the Effects of Atomic Radiation(UNSCEAR). Since UNSCEAR serves as a primaryorganization utilizing the radiation and health research results from RERF, he is in a good position toprovide leadership in maintaining and improving
RERF contributions to the radiation protection community. Dr. Bennett had his basic education in physics
with a M.S. degree from University of Washington
and later a Ph.D. degree in environmental health sciences from New York University. Dr. & Mrs. Bennett
lived in London for ten years where he worked on
the United Nations Environment Programs and they
later moved to Vienna for twelve years when he became Secretary of UNSCEAR. Most recently he had
returned to the DOE Environmental Measurements
Laboratory in New York City before coming to RERF.
When Dr. & Mrs. Bennett arrived in Hiroshima totake up the position of Chairman they were surprised
as they got off the train to be unexpectedly met by atelevision crew and reporter with questions. This was
his introduction to the interest that has been shown by
the media in the first American Chairman of RERF.
Dr. Tahara comes to RERF following a distinguished career as a pathologist at Hiroshima University,and is the first RERF Director to be appointed fromthe local community. In his work he has advanced thearea of molecular methods in pathology, and is thus
well suited to provide leadership to RERF in the newresearch areas stemming from the revolution in
genomics. Dr. Tahara has most recently been a visiting professor at the University of California, San Diegoafter retiring from Hiroshima University in March
2000. He had a long career at Hiroshima University,
beginning in 1968, with positions including Chief of
the Pathology Department and Director of the Facultyof Medicine. He spent two years in Germany at Bonn
University in the early part of his career. Dr. Tahara
played a central role in establishing the Hiroshima
Cancer Seminar Foundation in 1992.
Dr. Senjun Taira is the veteran of this group, now
starting his second term as an RERF Director after along career in the Ministry of Health, Labour andWelfare. He had assignments in many posts including the Japan International Cooperation Agency(JICA) before coming to RERF in 1997.
It is appropriate to mention here that the Chief Scientist, Dr. Charles Waldren, very ably complements
these three directors in functions of the Executive
Committee and other leadership of RERF research.
Dr. Waldren spent most of his career at the Universityof Colorado Health Sciences Center, working in mutagenesis and DNA repair and their relationship to
genetic disease. Before coming to RERF he was Professor of Radiological Sciences at the Colorado State
University School of Veterinary Medicine.

Staff News
Drs. Hidetaka Eguchi and Kazue Imai joined theDepartment of Epidemiology in July 2001 as Research Scientists. Both came from the Saitama Cancer
Center Research Institute, to join Dr. Nakachi (Chief,
Epidemiology), also from there, in the molecularepidemiology program at RERF. Dr. Eguchi received
a Ph.D. in Life Chemistry at Tokyo Institute of Technology and Dr. Imai received a Ph.D. in Psychology
at Tokyo Metropolitan University.

in December 2001. Dr. Ito graduated from Tokyo
University of Agriculture in 1967, taking a research
fellow position at University of Hokkaido. In the earlydays of the ABCC genetics program, Dr. Ito followed
Dr. Awa from Hokkaido to ABCC in 1971, taking a
position in Nagasaki (see Dr. Awa’s article in thisissue of Update). Dr. Ito played an important rolefor 20 years in Nagasaki, continuing in Hiroshima
when the Nagasaki Radiobiology Department wasmerged with Hiroshima departments.

Dr. Masahiro Ito, Department of Genetics, retired
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RERF Update Volume 13, Issue 1, Spring 2002

#RERF News

Multinational Peer Review: Clinical Studies
Performance highly evaluated, with recommended strengthening of theanalysis of modifying factors related to onset of disease
The fifth Multinational Peer Review of RERF departments was held on November 28–30 at Hiroshima
Laboratory Auditorium. Annual peer reviews havebeen held since 1997 in response to the Blue Ribbon
Panel’s recommendation of this practice. This reviewof Clinical Studies for both Hiroshima and Nagasaki
completes the cycle of all departments, including also:Radiobiology, Epidemiology, Genetics, Statistics.
The meeting opened with an address by Dr. Burton
G. Bennett, Chairman of RERF, and an RERF overview given by Chief of Research Dr. Eiichi Tahara.
Following that, Dr. Gen Suzuki, Hiroshima ClinicalStudies Department Chief reported on the major activities of his department and the Adult Health Study(AHS) program, and Dr. Masazumi Akahoshi,
Nagasaki Clinical Studies Department Chief, summarized the activities of his department. Subsequently,
the following presentations were made and active discussions held: F1 Health Study (Saeko Fujiwara); AHS
longitudinal data analysis methodology (Michiko
Yamada); Thyroid diseases (Misa Imaizumi); Inflammatory response and immune response to microbial
infection (Masayuki Hakoda); Radiation exposure anddiabetes mellitus (Saeko Fujiwara); Radiation exposure and senile cataract (Kazuo Neriishi);
Cardiovascular disease (Masazumi Akahoshi); International Collaboration Studies (Ni-Hon-San
comparative study on cardiovascular diseases, NiHon-Sea comparative study on dementia) (Michiko
Yamada); International and domestic collaboration
study (Ni-Hon comparative study on osteoporosis)(Saeko Fujiwara); Future research plan—Sicca syndrome (Ayumi Hida; read by Masazumi Akahoshi);
Future RERF cohort study (Gen Suzuki).
As the RERF departments having direct contact
with the A-bomb survivors and their children, Clinical Studies in Hiroshima and Nagasaki havecontributed in many ways to the health and welfareof the A-bomb survivors and their children, including through the various research programs mentioned
above. The departments also play a crucial role
through the systematic collection of clinical data andbiological samples that are important to research workof other RERF departments. The departments haveplaced special emphasis on research of the radiation
effects on non-lethal diseases. The results are reported
in twenty to thirty-plus scientific papers publishedeach year in the major scientific journals in English
and in Japanese.
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The departments reported on future plans to conduct, in addition to the ongoing F1 health examinations,research using stored biological samples and to perform analyses of newly found modifying factors andgenetic traits related to the onset of diseases.
On the final day of the meeting, Dr. Theodore L.
Phillips, panel chairman, provided a preliminary overview of the recommendations, and some other panel
members added more specific comments. The detailed recommendations, received later, aresummarized below. The review panel highly evaluated the research achievements of the clinical groupand the papers they have published. It also recommended that the departments further strengthen theanalytical program of modifying factors (confounders) related to the onset of diseases. As a conclusion,
the panel encouraged the staff, saying that RERF willcontinue to be acknowledged as a globally important research institute if its future direction isestablished as utilizing RERF’s long-accumulated
data and samples for the research in elucidating the
etiologies of diseases.
Summary of recommendations received in writing later is as follows:• Initial review of new studies should be expanded
to include outside reviewers when the RERF protocol committee does not have expertise in thearea of study proposed.
• There should be a systematic strategy for prioritizing hypotheses and the use of blood products.
Very strict policies on the use of preserved biologic specimens and international review of any
use of limited specimens should be instituted. Division of specimens into multiple tubes should
only take place after such approval for their use,
not on a routine basis.
• An annual review of open studies should be conducted by an RERF committee, to determine that
progress is adequate to justify the investment of
resources.
• The Departments of Clinical Studies should become more involved in studies of multifactorial
influences on cancer incidence and outcome.
• The F1 study should conduct the initial baseline
examinations and contacts with the cohort asplanned. During the initiation of this process the
expected number of events in common diseases
should be calculated in order to refine and reduce the number of clinical endpoints and allow
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$RERF News

•
•
•

•

•

•

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•

focus on high probability events in future re-examinations. High subject participation rates must
be encouraged. Every effort should be made to
maximize the power of the research to identify
the hypothesized effects.
In the AHS longitudinal study more attention
should be paid to validation of endpoints such as
death certificate data versus case-control studies.
The classification systems for disease should bestandardized.
The thyroid disease study is a very nice piece of
research. Consideration should be given to extending the study to Hiroshima and to initiating
follow-up studies in subclinical hypothyroidism.
The studies of infectious agents have shown that
individual agents are not important but that theinitiation of a chronic inflammatory process may
be very important in cardiovascular disease andaging in general. Future studies should focus onmechanisms that trigger chronic inflammatory
responses.
The diabetes mellitus studies are very interesting
but the discrepancy between results in Hiroshima
and Nagasaki needs to be resolved by means of
HLA typing.
The cataract study may be very important in showing that radiation accelerates aging. It should becompleted and consideration given to adding retinal photographs and fluorescein angiograms to
the studies.
The cardiac disease studies should concentrateon specific biochemical risk factors such as cholesterol levels etc. rather than on surrogate
markers.
The osteoporosis work is outstanding. Futurestudies may want to focus on environmental andReturn to Table of Contents

lifestyle factors influencing osteoporosis and oncomparison of Japanese and Caucasians.
• The international studies are of high quality, benefit RERF, and should be continued and expanded
if opportunities arise.
• Broader interaction of the clinical departmentswith the epidemiology departments is encouraged.
Peer Review Panel Members
Theodore L. Phillips, Professor and Chairman, Radiation Oncology, Cancer Center, School of
Medicine, University of California, San Francisco(Panel Chair and RERF Scientific Councilor)
Yasuhito Sasaki, Chairman, Board of Directors, National Institute of Radiological Sciences (RERF
Scientific Councilor)
John Danesh, Professor, Epidemiolgy and Medicine,
Head of the Department of Public Health andPrimary Care, University of Cambridge, Instituteof Public Health
Donald R. Harkness, Professor Emeritus, Universityof Wisconsin Medical School
Yoshitomo Oka, Professor, Molecular Metabolism
and Diabetes, Internal Medicine, Tohoku University School of Medicine
Hajime Orimo, Director, Metropolitan Geriatric
HospitalKazuo Ueda, Professor, Kyushu University Schoolof Health Sciences
Lon R. White, Principal Investigator, Honolulu-Asia
Aging Study, Senior Neuroepidemiologist, Pacific
Health Research Institute, Professor with joint
appointments in the Schools of Nursing and Medicine, University of Hawaii at Manoa

RERF Update Volume 13, Issue 1, Spring 2002

%RERF News

Current Status of Dosimetry Revision
In the previous issue of RERF Update some information was given about reasons for revision of
the DS86 radiation dose estimates for A-bomb survivors, and the progress at that time. Since then there
has been substantial progress, including a meeting in
Hiroshima in April 2002 of the Joint U.S.-JapaneseWorking Groups on the Reassessment of A-bomb Dosimetry. Below we will provide verbatim the press
release following that meeting.

These improvements now make it possible for scientists to measure and calculate trace amounts ofactivation from the bombs in ways and details notpossible in the 1980’s. Over the past 18 months, allof this new technical capability has been brought tobear in a further re-evaluation of the dosimetry system conducted by the Working Groups on the
Reassessment of A-bomb Dosimetry in the U.S. andJapan.

It is now expected that the fundamentals of a new
dosimetry system may be completed by Fall 2002,
with implementation of that system and preparationof a final report continuing for several months after
that. Although there apparently will be smaller overall changes in dose estimates than anticipated, there
will be some more specific improvements in accuracy. For example, there should be substantially
improved shielding calculations for a large numberof Nagasaki factory workers who received high doses,
and for low-dose survivors in both cities who wereat some distance from the bombs but shielded by terrain. Generally, the process of having very carefully
considered every aspect of revision will lead to more
confidence in the dosimetry system.

The joint Japanese and U.S. Working Groups on
the Reassessment of A-bomb Dosimetry met on April
3rd and 4th at the Radiation Effects Research Foundation in Hiroshima to review their work and discuss
final preparations for a new dosimetry system, DS02,
to replace DS86. The most detailed recalculation todate of the Hiroshima and Nagasaki bombs and an
exhaustive evaluation of the data indicate the neutron discrepancy that gave rise to this reassessment
will be resolved.

The April 4, 2002 press release is as follows:
Since the detonation of the A-bombs, the survivorsof the bombings and the international community responsible for radiation protection standards havedepended on the A-bomb radiation dosimetry systems
for the determination of accurate radiation doses. As
advances in technology for dose calculation from thebombs have been made, and the ability to check those
calculations using activation measurements has improved, changes have been made in the dosimetry from
T57D to T65D to the current DS86 system.
It is widely recognized that the DS86 system accurately calculates gamma rays, which constitute themajority of the radiation exposure to survivors. Since
the implementation of DS86, thermal neutron activation measurements have been made that appear
to differ from those calculated by the dosimetry system. Although neutrons are a small fraction of thetotal dose, it was thought to be important that thisapparent discrepancy be addressed in order to givethe survivors and the radiation risk assessment community confidence that the dosimetry system was
accurate in all significant details.
In the 16 years since DS86 was implemented,
remarkable advances have been made in computational capabilities and measurement technology.
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Changes in the nuclear data and calculation techniques of DS02, and extensive verification using
nuclear test data, have refined the Nagasaki dosimetry. These refinements confirm the DS86 conclusionthat 21 kilotons and height of 503 meters above thecity are the most accurate parameters for the detonation. The degree to which the calculations for the
Nagasaki detonation have been verified against
nuclear tests now makes the Nagasaki calculation abenchmark for dose reconstruction. The refinementsin the DS02 calculation for Nagasaki produce anincrease of less than 10% in the dose from gamma
rays while decreasing the neutron dose by 15 to 45%
at distances of 1,000 to 2,000 meters from the bomb.
Significant refinements in calculation of the shielding for workers in the torpedo factories reduceoverall doses for these workers by 20 to 40%.
Similar refinements in the new DS02 calculationof the Hiroshima bomb produce better agreement
between neutron calculations and measurements.
New measurements of high-energy neutron activation at Hiroshima were particularly important in
confirming the calculations. A measurement
intercomparison is being carried out to confirm thisagreement. The reassessment for DS02 confirms theDS86 conclusion that the bomb produced an explosion that was equivalent to 15 kilotons. A careful
review of the data for the height of the detonation
indicates that best agreement is achieved by increasing the burst height by approximately three percent
to 600 meters. While this change produces better
agreement between the calculation and the measurements, it produces almost no change in survivor
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RERF News&

doses. Gamma-ray doses are unchanged within thefirst 2,000 meters of the bomb. Neutron doses are
essentially unchanged for survivors out to approximately 1,500 meters, beyond which they are slightly
decreased.

the DS02 system will be more accurate than DS86,
it will produce little change in the overall radiation
doses for survivors. However, DS02 should produce
a much more confident basis for the entire radiationdose to the survivors than was previously available.

Thus, within the uncertainties of such difficult
measurements and complex calculations, acceptableagreement has been achieved for both the neutronand gamma radiations. As a practical matter, while

Measurement results of exposed samples collectedhave been essential for dose reassessment. We would
like to express our sincere appreciation to the citizens who have helped us collect the samples.

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RERF Update Volume 13, Issue 1, Spring 2002

'

Ten Thousand Days Atop Hijiyama

Ten Thousand Days Atop Hijiyama
Akio Awa
Preamble
As of June 30, 1995, I retired from the Radiation
Effects Research Foundation (RERF). I joined theAtomic Bomb Casualty Commission (ABCC) on
January 16, 1967 and have spent 28 and half years
with this organization. Alternatively put, I have spent
10,393 days at Hijiyama—8 years and 3 months with
the ABCC and the remaining 20 years and 3 months
with the RERF. During this period, I was under theguidance of two ABCC Directors (Drs. George B.
Darling and LeRoy R. Allen) and three RERF Chairmen (Drs. Hisao Yamashita, Masao Tamaki, andItsuzo Shigematsu).
It was my pleasure to participate in research at
the Cytogenetics Laboratory. A number of colleagues have gathered here and departed. At present,
there is virtually no one who is familiar with thehistory of the laboratory. Before everything fades
away and is forgotten, as a former permanent member of the laboratory, I feel obliged to prepare amessage regarding its history. This document is intended to take the form of a personal account of theevents I encountered over the past decades in the
Cytogenetics Laboratory. Fortunately, Dr. Seymour
Abrahamson, former Chief of Research and editorin-chief of RERF Update kindly offered me an
opportunity to publish this here. I am aware that
this article will inevitably contain some errors andam solely responsible for them.
The document will consist of two parts, publishedseparately. This part one details the genesis of Cytogenetics Laboratory, and a series of chromosome
studies based on the Adult Health Study (AHS) population and a summary of this work. Part two will
describe an outline of another important research mission, i.e., cytogenetic study of the children of
atomic-bomb survivors, the so-called F1 study. Included here also are my recollections of many of those
unforgettable people to whom I am indebted in many
ways, and who have—even now—guided me spiritually and scientifically.
Part 1. Cytogenetics Laboratory at ABCC/RERF — Past and Present

1. Prologue
In 1952, I entered the Hokkaido University undergraduate course in science, and completed the
Biology course in the Faculty of Science in 1956. Bycoincidence, the period between 1952 and 1956 wasan epoch-making era in the twentieth century deReturn to Table of Contents

velopment of biology. In April of 1953, Watson andCrick first uncovered a famous double-helix structureof deoxyribose nucleic acid (DNA), and published ashort but path-breaking paper in Nature.1 A few years
later, in early 1956, Tjio and Levan demonstrated
unequivocally that the true number of human chromosomes is 46.2 These important findings had a strong
impact on me throughout my scientific career.
In the postgraduate course at Hokkaido University, my thesis work was to study human andmammalian chromosomes under the guidance of Professor Sajiro Makino (1906–1989). As will be fully
described later, Dr. Makino has been internationallyrecognized as a human and mammalian cytogeneticist. He was also well known as an excellent leader
for the education of his youngster colleagues.
I was a lazy postgraduate student with a short andcapricious temper unsuitable for scientific research.
Surprisingly, I was fond of microscopic work, andwas able to accurately draw and analyze chromosomes directly under the microscope. This may berelated to my hobby since childhood of drawing cartoons. This acquired habit became an indispensable
tool for performing time-consuming work on detection of chromosome aberrations.

2. Human Cytogenetics — çà et là
A. All about Chromosomes in Man*
Chromosomes are present in the cell nucleus. Theirbasic molecular component is DNA. As mentioned
before, the exact number of human chromosomes is
46. They are small and slender, only visible by the useof a microscope; even the longest of the chromosomes
is less than 1/100 mm. Each chromosome carries a
constriction called “centromere,” which is an important landmark to characterize individual chromosomes.
Chromosomes can be observed only when cells
are at a stage of cell division (mitosis) called“metaphase.” The period of metaphase is extremely
short, so that in order to examine chromosomes, it isnecessary to obtain tissue samples whose cells areactively proliferating. Until tissue culture technique
was introduced to biological research, it was difficult to get the required fresh materials from healthypeople. This was the reason why progress in humanchromosome study had been greatly delayed.
In early 1950’s, there occurred a remarkable waveof technical progress in biology. Tissue culture methods, as mentioned above, became in routine use for
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medical and biological research. Particularly noteworthy was a new development of peripheral blood
culture by Moorhead and his colleagues in 1960.3
Fresh human specimens for subsequent culture were
easily obtained aseptically by vein puncture. For chromosome analysis, it requires only a few milliliters ofperipheral blood. Moreover, it takes only two daysof cultivation in vitro to yield sufficient number of
mitotic cells.

fragments, or (2) joined between wrong broken partners, thus newly producing chromosome
aberrations—more precisely, exchange aberrations,or structural rearrangements of chromosomes. The
evidence from experiments to date has shown thatchromosome aberration frequency increases with increasing radiation dose, and that the frequency is
influenced by radiation quality such as neutron, α-,β-, γ-, and X-rays.

Besides tissue culture techniques, other technological improvements have helped expand theknowledge of human chromosomes. These include(1) use of colchicines that arrest the mitotic cells at
metaphase, and (2) an “air-dry” method4 that canspread metaphase chromosomes two-dimensionallyon microscopic slides, and more importantly, overlapping of chromosomes is reduced considerably. Useof enlarged photographic prints of metaphases also
helped facilitate the efficiency of chromosome analysis.

b. Types of chromosome aberrations
As shown in Figure 1, an exchange between two
breaks within a chromosome results in the formationof either a ring chromosome (plus a fragment without centromere, called acentric fragment) or an
inversion of a chromosome. These categories of aberrations are termed “intra-chromosomal exchange.”
Theoretically, both types of aberrations occur withan equal probability. Similarly, exchanges of breaks
between different chromosomes result in a dicentricchromosome plus an acentric fragment, on the one
hand, and on the other hand, two-translocated chromosomes, called “inter-chromosomal exchange.”“Dicentric” means a chromosome having two centromeres. Although there are many other types ofchromosome aberrations, for convenience I will deal
exclusively with the following four main types ofaberrations, i.e., rings, dicentrics, inversions, andtranslocations.

Such technical advances have made detailed chromosome analyses far easier, and have prompted thedevelopment of human clinical genetics. Certain genetic diseases are now known to be associated withchromosome anomalies due either to changes in number (chromosome aneuploidy) or in structure (structural
rearrangement). For instance, the chromosome number of those with Down syndrome is 47, with anaddition of an extra chromosome 21.
The introduction of lymphocyte culture method also
has expanded the research area in radiation cytogenetics. A research group in Edinburgh University
studied lymphocyte chromosomes in patients given Xray treatment for ankylosing spondylitis.5 They
reported that a variety of X-ray-induced chromosome
damage was observed. Furthermore, they later confirmed not only their previous findings but also
demonstrated that cells carrying aberrations could
persist for years in patients’ circulating lymphocytes.6
These findings aroused the interest of scientists in radiation research, and need for investigation of radiation
effects onto atomic-bomb survivors of Hiroshima andNagasaki.
B. All about Radiation-induced Chromosome
Damagea. Formation of chromosome aberrations
Chromosomes are packed in a mass-like structure,
called a nucleus, in the interphase cell—during an interval between two mitoses. When the nucleus is
exposed either to ionizing radiation, or some otheragents such as toxic chemicals and certain kind of viruses, chromosome threads are broken, and the numberof induced breaks is proportional to the amount of dose
administered. With the aid of repair enzyme, broken
ends of affected chromosomes are largely restored toan original state. However, as the radiation dose increases, breaks are (1) left unrestored as chromosome
Return to Table of Contents

Chromosome aberrations are classified in different ways, as seen in Figure 1. One group consists ofrings and dicentrics, while the other with inversions
and translocations. The former is called “asymmetric exchange,” and the latter “symmetric exchange.”
Due to their morphological peculiarity, the former
type of aberration is unequivocally detectable. On
the contrary, symmetric exchange is difficult to identify with certainty, because the changes in shape andlength of aberrant chromosomes often are so subtle
that they are not discriminated as aberrant chromosomes. To score inversions and translocations withfull efficiency requires long experience and expertise.
However, dicentrics and rings are known to cause
mitotic disturbance because of their structural peculiarity. The cells carrying such aberrations are lostin the subsequent cell generations. Thus, their frequency decreases sharply with time, being adrawback in use of dicentrics and rings as a biological marker for those who were irradiated many
years prior to chromosome examination. In contrast,
there is no such disadvantage for translocations andinversions at mitosis, and the level of such frequency
is maintained constantly for decades after exposure
to radiation. For this reason, asymmetric exchanges
are also called unstable aberrations (Cu type), andsymmetric ones as stable aberrations (Cs type). I
shall use this terminology exclusively throughout
this article.
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Figure 1. Diagrammatic representation of four major types of chromosome aberrations following
exposure to ionizing radiation

The types of chromosome aberrations and the way
to detect them have been fully described in the RERF
Home Page (www.rerf.jp/Gene/eng/giemsa.htm).

Adult Health Study (AHS) population. They alsostudied some survivors who experienced prenatal exposure to A-bomb radiation (in utero survivors).

3. Birth of Cytogenetics Laboratory

Their initial AHS study consisted of 174 proximally exposed survivors, whose estimated radiationdose (T65D system) was more than 200 rad,** andthe 181 controls (0 rad group). They reported a significant elevation in the frequency of grosschromosome damage (such as dicentrics, rings, acentric fragments, and abnormal marker chromosomesof exchange type).9,10 In this study, however, they did
not analyze the data for demonstration of a dose-response relationship.

The first ABCC genetics program was the extensive search for untoward pregnancy outcomes(1948–1954) initiated by Dr. James V. Neel and colleagues. In that era chromosome analysis was rather
primitive, e.g. even the number of chromosomes was
not established until the work of Tjio and Levan in
1956.2 It was only in the 1960’s that the ABCC cytogenetic studies began to flourish. See Dr. William
J. Schull’s book7 for further historical perspective.
During the period between 1963 and 1964, bothDrs. Michael A. Bender and Ernest H.Y. Chu, cytogenetic experts in Oak Ridge National Laboratory,came to ABCC for a site visit to seek the possibilityof initiating cytogenetic programs there. Based on
their recommendation, Dr. Richard E. Slavin andcolleagues in ABCC Pathology Department started
the cytogenetic project. One of their results on the
cytogenetic screening of Down syndrome cases in
Hiroshima was published in 1967.8

In the 1960’s Japanese scientists outside ABCC
published reports on chromosome aberrations inatomic-bomb survivors. In 1968 Sasaki and Miyata
examined 52 Hiroshima atomic-bomb survivors
and published an excellent paper in Nature.11 Theyscored mainly dicentrics, rings, and acentric fragments out of an average of more than 1,000

Dr. Arthur D. Bloom began a full study in 1965.
Prior to his assignment with the ABCC, he received
training for human chromosomes under Dr. J.H. Tjio.
The Cytogenetics Laboratory was transferred fromthe Department of Pathology to the Clinical Laboratory headed by Dr. Howard B. Hamilton.
In collaboration with Dr. Nanao Kamada(Hiroshima University, former director of ResearchInstitute of Radiation Biology and Medicine) and Dr.
Tetsuya Iseki (Nagasaki University, current presidentof Nagasaki Prefectural Medical Association), bothDrs. Bloom and Shotaro Neriishi (Nagasaki BranchLaboratory) started the cytogenetic survey on the
Return to Table of Contents

Front row (from left to right): Dr. Shotaro Neriishi, Dr.
Sajiro Makino, and Dr. Howard B. Hamilton. Backrow: Dr. Michihiro C. Yoshida, Dr. Takeo Honda, andDr. Toshio Sofuni [1967]
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Ten Thousand Days Atop Hijiyama
metaphases per person, and made radiation dose
estimations for individual survivors on the basisof their bio-dosimetric formula, called the Q dr
method. Their results showed a close relationshipbetween biological and physical dose estimates,
the latter of which was derived from both the distance from the hypocenter and the types ofshielding materials between A-bomb burst point
and individual survivors.

4. Expanded Cytogenetic Study: 1967–1975
In early December of 1966, Professor Makino in
Hokkaido University was invited to ABCC to explore
collaboration between Hokkaido University and
ABCC. I accompanied Dr. Makino to ABCC, andnegotiated with the representatives of ABCC, i.e.,
Drs. Hamilton, Bloom, and Hiroshi Maki (ABCC Associate Director). Dr. Darling, ABCC Director, did
not attend this meeting since he was out town. Aftera lengthy discussion, we reached to the agreementthat Hokkaido University would support ABCC cytogenetic projects by participation of Dr. Makino’s
research staff.
Only a month later, in January of 1967, Dr. Takeo
Honda and I were assigned to ABCC as permanent
research associates. In the same year, two more members also came to ABCC, Dr. Michihiro Yoshida(1967–1969) to Nagasaki and Dr. Toshio Sofuni(1967–1979) to Hiroshima. In the subsequent years,
others from Hokkaido joined the ABCC: Messrs.
Hachiro Shimba and Kazuo Ohtaki in Hiroshima, andMr. Masahiro Itoh in Nagasaki.
The addition of research staff continued. Dr.
Mimako Nakano from Hiroshima University joined
us in 1977. Mr. Yoshiaki Kodama came to RERF in
1980 as a replacement for Dr. Sofuni, who was assigned to National Institute of Hygienic Science inTokyo. Finally in 1994, Dr. Nori Nakamura, currently
Chief of Genetics Department, was transferred fromthe Radiobiology Department. Dr. Sadayuki Ban was
also part of the Cytogenetics Laboratory from 1985
to 1994.
Dr. Bloom returned to the United States after three

Dr. Howard B. Hamilton[1981]
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Dr. Arthur D. Bloom[1983]


years with the ABCC and joined to Dr. Neel’s groupat University of Michigan Medical School in Ann
Arbor. Indeed, he did a good job and his name should
long be remembered as a founder of ABCC Cytogenetics Laboratory. Mr. Shozo Iida, then chief
technician of the laboratory, also left for the U.S. tohelp Dr. Bloom set up a new cytogenetic laboratory
in Michigan.
After Dr. Bloom’s departure to the U.S., I was
asked to take over the management of the laboratory.
I carefully looked at the ABCC organization chartand tried to remember the names of key staff members in other departments. I also went around in
ABCC to confirm what I had remembered. All of
this helped me a great deal when we had to establish
in inter-departmental management system for Dr.
Neel’s new project on biochemical screening of theF1 children of survivors.
Prior to the onset of laboratory management, I
faced with two urgent issues. Firstly, we all felt the
study should be oriented to the determination of thedose-response relationship in A-bomb survivors. To
do this, however, we needed to expand the sample
size to cover survivors in all dose ranges. Sample
selection from among the AHS participants was madein collaboration with a statistician in charge of cytogenetic project, Mr. Takashi Matsui, now professor
in Statistics at Dokkyo University. Indeed, he wasour best partner. In those days, only statisticians could
deal with radiation dose data (T65D). Any membersother than statisticians were not allowed to obtain
individual dose of survivors, to avoid any observers’
bias prior to or in the course of survey.
Secondly, the level of techniques both for lymphocyte culture and preparation of microscopic slides
was rather poor in our laboratory. At that time, it wasdifficult for us to routinely observe more than 100
cells per person. In addition, it was already more than
20 years since A-bomb explosions in 1945. We hadthus anticipated that most of the cells carrying unstable aberrations might be eliminated fromcirculating blood of survivors. Consequently, evenfor heavily exposed survivors, we might fail to detect any unstable aberrations within the ranges of 100
analyzable metaphases per person. We empiricallyknew that we could find on an average about 5% of
cells bearing stable aberrations at 100 rad.
We thus decided as a routine procedure to score
all types of stable and unstable aberrations per 100
metaphases per survivors. Our decision was quite
contrary to the general strategy of scoring exclusively
unstable aberrations, an easy and well established biodosimetry employed in most of cytogenetic
laboratories in the world. We knew that those researchers who analyze stable aberrations were in theminority group. We were convinced that stable aberration scoring could equally be efficient for the
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Ten Thousand Days Atop Hijiyama
analysis of dose-response relationship, provided thatthe pooled data were analyzed by breakdown of survivors into 100 rad-interval dose groups.
In the course of the routine microscopic work,
what worried us was finding too many metaphaseswith false negative aberrations, i.e., metaphases
judged as normal even when true aberrations were
present. Our data would have lost credibility if aberrations were overlooked by misjudgment of theobservers, though it is impossible to eliminate all
mistakes. In order to minimize the number of false
negative aberrations, all of the cells in which definite and suspected structural aberrations weredetected by direct microscopy were then photographed and subjected to karyotype analysis. Where
possible, we vigorously pursued the origin of chromosomes involved in the exchanges of aberrations
by karyotyping. Our obligatory scoring procedurewas (1) to record on the laboratory score sheets suchitems as case ID number, slide number, cell number,and the X-Y axis location of the cell on the microscopic stage, and (2) to take photographs for all
metaphases suspected by examiners of having any
abnormality. Considering the cost of a frame of 35
mm negative films, this procedure seemed to be themost reliable and the cheapest. By this system, ability of observers to detect aberrations became verymuch improved and consistent. It is worth noting thatnearly 400,000 frames of metaphase pictures in 35
mm negative films have been kept to date in the large
film cabinets of the laboratory.
The results of expanded AHS surveys have beenintermittently reported elsewhere.12,13,14 Major findings of the study are as follows: (1) The frequency ofaberrant cells increased with increasing radiationdose, and was generally higher in Hiroshima than in
Nagasaki. (2) The mode of dose-response relationship was linear in Hiroshima, while it was
dose-squared fashion in Nagasaki. The observed difference might reflect the difference in a mixed ratioof neutron and gamma rays between the two cities.
This view, however, was re-evaluated upon adopting
a new dosimetry system of DS86, in which neutron
dose was drastically reduced from Hiroshima radiation spectrum. The observed inter-city difference inthe neutron-gamma rays thus dimished. Even now,
however, inter-city difference in the frequency ofchromosome aberrations still exists, though lesser
in degree, when data are reanalyzed using DS86
system. (3) Frequency of stable aberrations (translocations and inversions) is predominantly higher
than that of unstable aberrations (dicentrics and rings).
The former type of aberration is the major contributor for the dose-response relationship. The
dose-response for unstable aberrations was also demonstrated. (4) There was evidence of in vivo clones
of cells with cytogenetically identical aberrations inhigh dose survivors. (5) There was a small fractionof survivors either with high dose and low aberraReturn to Table of Contentstion frequency or with low dose and high aberration
frequency. These survivors were regarded as overdispersion cases outlying the normal range of the dose
response relationship. We termed them “cytogenetic
outliers.” Our interpretation was that the outlying
values stemmed from errors in dose estimate rather
than due to biological individual difference. Obviously, we needed further validation of cytogenetically
outlying cases.
In February 1975, before the re-organization of
ABCC to RERF, a special scientific committee meeting was held at ABCC, chaired by Dr. James F. Crow
(professor in Genetics, University of Wisconsin),called the “Crow Committee.” The charge to the committee was to carefully review each item of the ABCC
scientific programs as to which of the items should
be taken over by the new foundation. When the recommendation of the committee15 was reported, we
cytogenetic members were very happy to know thatthe report included the issue of “cytogenetic outliers,” and recommended pursuing this even morevigorously. Part of the Crow Committee recommendation is directly cited as follows.
“It would be especially valuable to study persons
whose cytogenetic findings are grossly discrepantwith regard to estimated dose. On the one hand, sucha study may lead to improved dosimetry; on the other,it might reveal possible human phenotypes with extreme radiation resistance or susceptibility. Much
concern has been expressed for persons who may beespecially susceptible to chemicals; this might well
be a concern also with radiation.”
After the re-organization of ABCC to RERF, except for the F1 cytogenetic work our AHS study wasconcentrated to conduct repeat examinations of survivors who were cytogenetically categorized indifferent groups. In one of the categories, we randomly chose an appropriate number of survivors, forwhom cytogenetic survey had already conducted, inall dose ranges, to see if aberration frequency noted
previously would be consistently maintained. Alternatively put, had our ability to detect aberration been
maintained constantly over time? Important inclusions of survivors into repeat examination were theDr. James F. Crow (left) and the author [1997]
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Ten Thousand Days Atop Hijiyama
outliers, both high-dose with low aberration frequency and low-dose with high aberration. Also
included were survivors carrying a clone of cells withcytogenetically identical aberration.
The results of repeated examinations reconfirmed
our previous findings. Aberration frequency for eachof survivors had been maintained consistently for long
period of time. The same held true for both outliersand clone-carriers. As for controversial cases of outliers, it was proved that the discrepancy of aberration
frequency with regard to the dose was found to stemfrom errors in dosimetry rather than from difference
in radiosensitivity or radioresistance of survivors.
Interestingly, clones of aberrant cells with a constantfrequency still continued to persist for many years inthe body of clone carriers.
In 1982, the T65D A-bomb radiation dose estimate system was criticized as having many problems.
Thus a team of scientists from the U.S. and Japanwas formed, and started a re-evaluation work thattook them several years to complete. In 1986, a new
system “Dosimetry System 1986,” called DS86, wasfinally established. One of the major changes fromthe previous system was a substantial reduction ofneutron dose and increase in gamma dose in
Hiroshima. Thus the ratio of neutron to gamma estimates differed less between Hiroshima and Nagasaki
than before.
When a new system was available, our cytogenetic data were reanalyzed using DS86 values. The
results indicated that the inter-city difference in aberration frequency per unit dose became smaller thanthat of the previous result. The degree of differencein the shape of dose-response curves also became
smaller, but there still existed some inter-city difference; Hiroshima frequency is still higher than in
Nagasaki.16
We had a difficult time between 1982 and 1986
when dosimetric work was still underway. All of ourstudies were directly related to A-bomb radiation
dose. Doing studies without dose was actually impossible. Thus we spent most of the time carryingout a detailed analysis of the types and frequenciesof stable aberrations, data being derived from bothG-band and conventional staining analyses. The data
revealed that translocations were found to be about
two-thirds of the total stable aberrations, and they
were a primary contributor to the dose-response relationship.17 It was also demonstrated that, provided
that G-band method can detect all types of aberrations with a full efficiency, conventional analysis
could detect aberrations of about 70% of the G-band
efficiency.
The year 1988 was a dawn of a new molecularstudy at the Cytogenetics Laboratory. In close collaboration with Lawrence Livermore National
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Microscopy Room in Cytogenetics Laboratory(Hiroshima) [1988]

Laboratory (LLNL) in California, a new techniquecalled a chromosome painting method, or more precisely the FISH technique, an abbreviated form offluorescence in situ hybridization, was introduced to
our laboratory. By this technique translocations canbe detected easily, rapidly, and accurately, so that thetechnique seemed to be promising for identificationof stable aberrations in A-bomb survivors, and it
would be eventually employed as our routine cytogenetic procedure. Since the procedure of technique
is too complicated and highly technical, I do not describe it here in detail. In principle, composite probes
from chromosomes 1, 2, and 4 are hybridized to thesame chromosomes in the microscopic slide. Thus
the chromosome of interest is selectively painted,
while the rest of non-target chromosomes are left
unstained (or stained with other dye). Any translocations involving chromosomes 1, 2, and 4 arevisualized as a bicolor chromosome(s) so that, evenfor lay people, they are easily distinguishable fromother elements in the metaphase. In 1989, a new joint
research program between LLNL and RERF wasapproved.18 This research protocol was to examine the feasibility of the FISH technique as aroutine screening procedure for A-bomb survivors(www.rerf.jp/Gene/eng/fish.htm).
When I visited LLNL in the fall of 1988, I wasstrongly convinced that the technique seemed highly
feasible, as far as I could see from observing all procedures with my own eyes. With a classicalmorphological analysis, I used to engage in analyzing stable aberrations in A-bomb survivors in atime-consuming process, but now it was possible todetect translocations more objectively and accurately
than with the classic conventional technique I had
employed. When those irradiated people who were
exposed to ionizing radiation decades before examination are studied, it is my belief that stable
aberrations are the most reliable cytogenetic marker.
I thought that the dreams could come true, and we
may be able to get rid of the minority.
A preliminary FISH study was conducted in combination with G-band analysis on 22 cases of
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Ten Thousand Days Atop Hijiyama
Hiroshima A-bomb survivors. The results satisfactorily showed that, as had been anticipated, there wasgood agreement of the data between FISH and Gband measurements. The FISH method was thus
validated, and further indicated the utility of translocation frequency analysis for assessment of the levelof acute exposure to radiation.19 Based on the resultof the preliminary FISH study, a new screening
project was proposed to examine AHS participants
to further analyze the relationship between genomictranslocation frequency and DS86 radiation dose for
Hiroshima and Nagasaki survivors.20
Now this document regarding the AHS cytogenetic study is close to the end. Before closing thischapter, I have some questions addressed to myself.
Where do we stand now with a large body of cytogenetic data? How have the results of our data been
evaluated now by others? Finally, have we done thingsin the right direction? It is still premature and thus
difficult to evaluate our work by ourselves. Part of
the answers may be in the evidence described below.
Our data suggests that a better-fitted dose-response
relationship can be obtained when restricting to thosesurvivors who were in individual (Japanese-style)houses at the time of explosion. It is these survivors
whose estimated doses seem to be the most reliable.
Furthermore, the difference in the shape of dose-response curves between Hiroshima and Nagasaki isthereby reduced to a certain extent.
Recently, Nakamura et al collected teeth obtained
from Hiroshima survivors for whom cytogenetic
analysis had already been completed, and estimatedgamma-ray doses received by 69 Hiroshima survivors using electron spin resonance (ESR) of tooth
enamel. The resulting measurement was comparedwith the corresponding stable aberration data. For
40 donors examined by both methods, there was thesame pattern of the dose-response between ESR-estimated gamma dose and aberration data.21

Evidence accumulated to date has shown a possible future study for survivors who were in thefactories at the time of bombing in Nagasaki. They
were relatively proximally exposed, but owing tocomplex shielding situations their physically estimated dose is either unavailable or inaccurate even
if an estimate was attempted. Since they were exposed to appreciable radiation, and cancer risk
estimation is limited by the numbers exposed at suchlevels, further study of the Nagasaki factory workers
is urgently needed.
At present, no one knows the role and function of
cytogenetically abnormal lymphocytes in the humanbody. It seems to me that the presence of lymphocytes with chromosome aberrations may have no
direct bearing on the health of survivors. One of thepotential future objectives would be to elucidate theclonal development of impaired lymphocytes at thesite of the lymphoid stem cells, and determine their
genetic and immunological implications.
– End of Part One –Notes to the readers:* The following is the definition of the terms thatare used frequently in this article. The terms“chromosome study” and “cytogenetic study”
have been used synonymously and indiscriminately among the cytogeneticists. The study on
the structure, function, and role of the chromosomes is called “cytogenetics.” The term
“karyotype” is applied to “a systematized arrayof the chromosomes of a single cell prepared either by drawing or by photography, with extension
in meaning that the chromosomes of a single cell
can typify the chromosomes of an individual oreven a species.”22** The term “rad” is an old radiation unit. A newunit is “gray (Gy)” (1 Gy = 100 rad).

References
1. Watson JD, Crick FHC: Molecular structure of deoxypentose nucleic acids. Nature 171:738–9, 1953
2. Tjio JH, Levan A: The chromosome number in man. Hereditas 42:1–6, 1956
3. Moorhead PS, et al.: Chromosome preparations of leukocytes cultured from human peripheral blood. Exp CellRes 20:613–6, 1960
4. Rothfels KH, Siminovitch L: An air-drying technique for flattening chromosomes in mammalian cells grown invitro. Stain Technol 33:73–7, 1962
5. Tough IM, et al.: X-ray-induced chromosome damage in man. Lancet ii:849–51, 1960
6. Buckton KE, et al.: A study of the chromosome damage persisting after X-ray therapy for ankylosing spondylitis.
Lancet ii:676–82, 1962
7. Schull WJ: Effects of Atomic Radiation. John Wiley & Sons, Inc., New York, 1995
8. Slavin RE, et al.: A cytogenetic study of Down’s syndrome in Hiroshima and Nagasaki. Jpn J Hum Genet 12:17–
28, 1967
9. Bloom AD, et al.: Cytogenetic investigation of survivors of the atomic bombings of Hiroshima and Nagasaki.
Lancet ii:672–4, 1966
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Ten Thousand Days Atop Hijiyama

10. Bloom AD, et al.: Chromosome aberrations in leucocytes of older survivors of the atomic bombings of Hiroshima
and Nagasaki. Lancet ii:802–5, 1967
11. Sasaki MS, Miyata H: Biological dosimetry in atomic bomb survivors. Nature 220:1189–92, 1968
12. Awa AA, et al.: Chromosome-aberration frequency in cultured blood-cells in relation to radiation dose of Abomb survivors. Lancet ii:903–5, 1971
13. Awa AA: Cytogenetic and oncogenic effects of the ionizing radiations of the atomic bombs. In: German JL (ed).
Chromosomes and Cancer. John Wiley & Sons, Inc., New York, 1974, pp. 637–74
14. Awa AA, et al.: Relationship between the radiation dose and chromosome aberrations in atomic bomb survivorsof Hiroshima and Nagasaki. J Radiat Res (Tokyo) 19:126–40, 1978
15. Crow JF, et al.: Report of the committee for scientific review of ABCC, February 1975. ABCC Technical Report
21-75, 1975
16. Preston DL, et al.: Comparison of the dose-response relationships for chromosome aberration frequencies between
the T65D and DS86 dosimetries. RERF Technical Report 7-88, 1988
17. Ohtaki K: G-banding analysis of radiation-induced chromosome damage in lymphocytes of Hiroshima A-bomb
survivors. Jpn J Hum Genet 37:245–62, 1992
18. Awa AA, et al.: Pilot study to examine a new fluorescence in situ hybridization-based method for chromosome
aberration frequency analysis and a new method for glycophorin A variant erythrocyte frequency analysis todetermine the utilities of these methods in assessing genetic damage in A-bomb survivors. RERF ResearchProtocol 10-89, 1989 [Editor’s note: Superseded by Research Protocol 8-93.]
19. Lucas JN, et al.: Rapid translocation frequency analysis in humans decades after exposure to ionizing radiation.
Int J Radiat Biol 62:53–63, 1992
20. Kodama Y, et al.: Cytogenetic study in the Adult Health Study population by fluorescence in situ hybridization(FISH). RERF Research Protocol 8-93, 1993 [Editor’s note: Supersedes Research Protocol 10-89.]
21. Nakamura N, et al.: A close correlation between electron spin resonance (ESR) dosimetry from tooth enamel andcytogenetic dosimetry from lymphocytes of Hiroshima atomic-bomb survivors. Int J Radiat Biol 73:619–27,
1998
22. International System for Human Cytogenetic Nomenclature (ISCN): Report of the Standing Committee on Human
Cytogenetic Nomenclature. Cytogenet Cell Genet 21:309–404, 1978

Return to Table of Contents

RERF Update Volume 13, Issue 1, Spring 2002%Longevity of A-bomb Survivors

Radiation Risk, Longevity, and the Impact of theComparison Group on Low-Dose Risk Estimates
John B. Cologne and Dale L. Preston
Department of Statistics
Note: This article is based on several recent RERF publications, including: “Longevity of atomicbomb survivors” (Cologne and Preston [2000]1), a modified version of this paper published in Japanese(Cologne et al [2001]2), and “Impact of comparison group on cohort dose response regression: An example using risk estimation in atomic-bomb survivors” (Cologne and Preston [2001]3).
In recent years articles appearing in the popular newspapers and magazines, such as The Washington Post,
The New York Times, and Time magazine, have contained claims that atomic-bomb survivors are outliving theirunexposed peers. The statements in these articles were based on some reports such as those of Mine et al (1990)4
that report increased life expectancy for male survivors in Nagasaki who received doses between 0.5 and 1.5 Gy,
and Hayakawa et al (1989)5 who report that all-cause death mortality rates for survivors who were more than 1
km from the hypocenter were lower for than those for non-exposed residents of Hiroshima Prefecture. Kondo(1993)6 presents a summary of these and other findings (including data from RERF reports) to support hisargument for reduced mortality (increased life expectancy) at low doses. On the other hand, RERF’s analyses ofmortality in the Life Span Study provide clear evidence for dose-related increases in mortality rates from bothcancer, Pierce et al (1996),7 and non-cancer diseases, Shimizu et al (1999).8 In view of these contrasting results—apparent radiation-associated increases in both cancer and non-cancer mortality and reports of greater
longevity in some dose groups—we undertook to analyze recent Life Span Study mortality data (follow-up
through 1994) in order to estimate longevity and to investigate the impact of the choice of a zero-dose comparison group on estimates of risk and longevity.

Increased mortality and life shortening caused byradiation
Table 1 presents our estimates of the risk for total
mortality and longevity for the Life Span Study (LSS)
cohort members in various dose groups. Risks for
total mortality are measured relative to that for cohort members with a total shielded kerma estimateof 0 Gy. Longevity, or median life expectancy, is deTable 1. Life expectancy by radiation dose
Dose range(Gy)

Mean dose(Gy)fined as the age at which half of the population has
died. The life-expectancy estimates are conditionalon being alive at the start of follow-up. Since the estimates depend on city, gender, and age at the start offollow-up, the values in this table are standardized
to represent averages over sex and city and for a person who was 34 years of age at the start of follow-up(the average for the LSS cohort). Median age at deathaNo. ofpeopleNo. ofdeathsRelative
risk

Median age
at death

0 (<0.005)b

0.0

34,064

16,7751.000

81.0820.005−

0.06

40,403

19,641

1.002

81.0250.250−

0.36

4,899

2,548

1.031

80.4350.500−

0.61

2,427

1,296

1.085

80.0680.750−

0.86

1,360

693

1.120

80.3121.000−

1.22

1,527

802

1.138

79.7691.500−

1.90

1,160

619

1.259

77.9942.500+

3.04

732

411

1.580

75.860Unknown

—

7,097

3,151

1.031

80.945a

See also Figure 2.

b

The dosimetry system assigns a dose estimate of zero to all persons whose calculated dose estimate would beless than 0.005 Gy free-in-air kerma.

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RERF Update Volume 13, Issue 1, Spring 2002&Longevity of A-bomb Survivors
for the LSS zero dose group was virtually identicalin the two cities (81 years, 56 days in Hiroshima, 81
years, 15 days in Nagasaki). Females lived an average 7 years, 141 days longer than males. Figure 1
presents the estimated standardized survival curves
for selected dose groups.

least 0.005 Gy (mean dose 0.27 Gy) was a little morethan four months less than that for cohort membersin the zero dose group. Because the LSS cohort wasconstructed to over-represent survivors who were
within 2.5 km of the hypocenters, the average loss oflife among the larger population of all atomic-bombradiation-exposed individuals who survived acutecauses of death would be less than four months. The
results suggest that life shortening in acutely exposed
humans is about 1–2% per Gy. As illustrated in
Figure 2, life expectancy exhibits a nearly linear dependence on dose over the 0 to 1 Gy range withmedian loss-of-life estimates of about 0.12 years at
0.1 Gy and 1.3 years at 1 Gy. At 1 Gy about 60% of
the total life lost can be attributed to solid cancer,
30% to non-cancer, and 10% to leukemia. Becauseof non-linearity in the leukemia mortality dose response and possible non-linearity in the non-cancer

The death rates are increased and lifespan decreased in each non-zero dose group considered here.
For survivors with dose estimates between 0.005 and0.25 Gy (mean 0.055 Gy), the estimated decrease inlife expectancy was three weeks, while that for survivors with dose estimates greater than 1 Gy (meandose 2.25 Gy) was 2.6 years. There is no evidence ofsignificant heterogeneity in the radiation-associatedrisks or longevity changes within the lowest non-zerodose category (P > 0.5). The estimated life expectancy for LSS survivors with estimated doses of at

Figure1. Survival curves for selected dose groups. Survival was estimated with adjustment for
city, gender, and year of birth—all centered at their mean values—using Cox regression.

Proportion surviving

1.0

0.8

0.6
0 Gy (<2.8 km)<0.25 Gy
0.75 – 1 Gy
1.5 – 2 Gy
≥ 2.5 Gy

0.4

0.2

0.0
40

60

80

100

Age (years)

Figure2. Longevity as a function of radiation dose. The curve was estimated using a weighted leastsquares regression fit to the estimated median life expectancies of Table 1, using withinstratum mean doses as the independent variable and numbers of persons as the weights.
The line represents the equation: median age at death = 81 − 1.2 × dose − 0.2 × dose2

Median age at death

90
85
80
75
70
65
0

1

2

3

Dose (Gy)
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RERF Update Volume 13, Issue 1, Spring 2002'Longevity of A-bomb Survivors
mortality dose response, solid cancers are likely tocontribute a greater proportion of the total life lost at
lower doses. Thus, cancer is the major cause, but not
the sole cause, of radiation related life shortening in
the LSS. While the LSS results in Table 1 clearly
indicate radiation-associated increases in risk (anddecreases in lifespan) at doses in excess of 0.25 Gy
they also indicate that mortality risk and longevity
changes associated with lower doses are small. These
results do not support claims that radiation-exposed
atomic-bomb survivors are living longer than theirpeers.
Risk estimates and the choice of comparison group
Because the changes in risk associated with lowdose exposures are small and estimation of themrequires the use of a comparison group, it is difficult
to develop accurate estimates of these risks. The ideal
comparison group should be comparable to the exposed cohort in every way except for the radiation
exposure. However, detection of small changes inrisks is complicated by the fact that, for reasons otherthan the radiation exposure, rates in seemingly similar populations can easily differ by as much or morethan the likely low-dose radiation effects. It may bepossible to measure and make statistical adjustments
for some of the factors that cause these differences,
but even when some such adjustments are feasible(as is the case, for example, with age and sex) theycannot completely eliminate differences between the
exposed and unexposed populations. If the unexposedgroup is not comparable to the exposed group, risk
estimates, particularly those at low doses, will be distorted (biased).
The LSS includes almost 94,000 survivors who
were within 10 km of the hypocenter at the time of
the bomb and a group of a little more than 26,000
people who were temporarily away from the cities at
the time of the bombs. This latter group is referred toas the not-in-city (NIC) group. In order to reduce thelikelihood of bias, the cohort was constructed to insure that the age and sex distribution of distal
survivors and the NIC group is similar to that forsurvivors in the cohort who received significant radiation exposures (i.e., more than 5 mGy). As has
been noted in many RERF reports, despite this matching, cancer and non-cancer death rates for the NIC
portion of the cohort are lower than those for survivors whose estimated dose is less than 5 mGy.
Because of this little-understood difference in rates,
the NIC group has not been used in most recent analyses of LSS mortality and cancer incidence. It is also
useful to consider the degree of variability in death
rates seen for survivors in the LSS cohort who received little or no radiation exposure from the bomb.
This “zero” dose group includes the 25,532 LSS cohort members who were between 3 and 10 km fromthe hypocenter at the time of the bombs and 8,532 of
the 68,137 cohort members who were within 3 km of
the hypocenters.
In order to investigate the degree of heterogeneity in the risks for the zero dose group we divided
this group into four parts based on distance from the
hypocenter and estimated the standardized mortality
ratios (SMR) for these subgroups relative to mortality rates of for all zero-dose in-city survivors withadjustment for city, gender, age, and birth cohort. The
results are shown in Table 2; an SMR of 1 meansthat the rates do not differ from the average rate forall zero-dose cohort members who were within 10
km of the hypocenter at the time of the bombs.
These estimates suggest that background death
rates vary by about 10% within the zero-dose survivor group used for most RERF analyses. They alsosuggest that the SMR tends to increase with distancefrom the hypocenter. (A test for this trend indicatesthat it is statistically significant with P < 0.001.) Variation in mortality rates with distance in the zero-dose
survivor group could be due to geographic differences in lifestyle, socioeconomic status, regional
differences in health care, and/or occupation. In 1945,
areas that were more than 3 km from the hypocenter
were more rural than the urban central city areas onwhich the bombs were dropped and residents of thoseareas were generally poorer than city residents. The

Table 2. Standardized mortality ratio (SMR) for geographicallydistinct zero-dose groups in the Life Span StudyGroup

PeopleSMR
Estimate

95% confidence interval

Survivors (within 10 km of the hypocenter ATBa )within 3 km

8,532

0.95

0.92, 0.98

3−5 km

18,3521.01

0.99, 1.03

5−7 km

5,188

1.03

0.995, 1.07

7−10 km

1,992

1.07

1.00, 1.13

Local residents absent from city ATB
Not in citya

26,531

0.95

0.93, 0.97

At the time of the bombs

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RERF Update Volume 13, Issue 1, Spring 2002Longevity of A-bomb Survivors
low rates for proximal zero-dose survivors (which
we will take as survivors who were within 3 km of
the hypocenter at the time of the bombs) may also
partially reflect a healthy-survivor selection effect.
Although more work on selection is necessary, results from analyses of LSS non-cancer mortality by
Shimizu et al (1999),8 suggest that there is evidence
for such selection for noncancer deaths, but that impact of this selection had largely disappeared by thelate 1960’s.
It is also noteworthy that the SMR for the NIC
group (for whom no selection effects would be expected) is significantly less than 1 and quite similar
to that seen for the proximal zero-dose survivors. The
reasons for this are unclear. However, it is useful toconsider how the NIC group was selected. The primary selection was based on data obtained during
special daytime censuses of people in Hiroshima or
Nagasaki cities on October 1, 1950 and, for
Hiroshima, supplementary censuses carried out on
October 1 of 1951 and 1952. The unexposed group
was defined to include people identified in these surveys whose family registry (honseki) was inHiroshima or Nagasaki but who were not in or near
the cities at the time of the bombs. These surveys
were more likely to identify people who lived in or
fairly near the city centers than people who lived in
the more rural outlying areas. Thus, one might expect members of the NIC group to be more like theproximal-exposed survivors than some of the distallyexposed survivors. The LSS mail survey data provide some evidence to support such a view.
It is of interest to consider the impact of variability
in the death rates among the zero-dose survivors onradiation risk estimates obtained from the LSS. To dothis we examined how the choice of the zero-dosecomparison group affects both the linear dose-response
slope estimate and the evidence for dose-response nonlinearity. Table 3 summarizes our findings (presented
in more detail in Cologne and Preston [2001]3). For
the analyses summarized in the first row of this table,
all information about baseline risks is derived fromsurvivors with non-zero (positive) dose estimates, using a dose-response model in which the baseline risk
is estimated by the model parameters with dose equal

to zero. In the other analyses the 0–3 km zero-dosegroup, the 3–10 km zero-dose group, or all zero-dose
survivors were used to determine the level of thebaseline risks.
These results indicate that the choice of the comparison group has a relatively small effect on theestimate of, or inference about, the slope in a linear
dose response model. Neither did we find that the
choice of comparison group affected inferences ongender effects or age-time patterns in the excess risks.
However, the choice of the comparison group has amarked impact on inference about the shape of thedose response and, hence, low-dose risk estimates
for total mortality. The results presented in Pierce
and Preston (2000)9 also suggest that choice of thecomparison group has some impact on inference
about low dose risks and the shape of the dose response. Analyses based solely on proximal survivors(positive dose only or all proximal survivors) provide no suggestion of significant non-linearity in thedose response, while in analyses in which the moredistal survivors were allowed to contribute to the determination of the baseline rate level, there wereindications of a lack of linearity, specifically significant upward curvature in the dose response as can beseen in Figure 3.
The present work reveals that small biases in therisk estimate can result from the choice of zero-dosecomparison groups in analyzing atomic-bomb survivor data, but demonstrates that primary results fromthe LSS do not depend to a large extent on the traditional comparison group. However, because of thevariability in death rates seen for various groups ofzero-dose survivors in the LSS, it is questionable
whether it is appropriate to include persons beyond
3 km in the analyses, when one is concerned with thenature of the dose response relationship over the lowdose range (e.g., 5 to 200 mGy). Because of the large
number of cohort members with very low doses (e.g.,
5 to 10 mGy), background mortality rates can be precisely estimated from the data for proximal survivors
or even from survivors with positive dose estimates.
Our results suggest that detailed analyses of low-dose
effects should focus on the proximally-exposed(within 3 km) individuals only.

Table 3. Effect of comparison group on estimated excess relative risk
(ERR) of mortality
Comparison group

ERR perGy

Deviation frompositive-dose-only
ERR (%)

P-value fornon-linearity

Positive dose only a

0.212

—

0.11

0−3 km

0.224

5.7

0.22

3−10 km

0.196

−7.5

0.025

0−10 km

0.206

−2.8

0.059

a

The intercept was estimated by the dose-response regression fit to thenon-zero-dose persons; the zero-dose groups were fit by separate parameters.

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RERF Update Volume 13, Issue 1, Spring 2002Longevity of A-bomb Survivors
Figure 3. Relative risk of death by radiation dose using internal standardization. The positivedose points and regression line are from the internally standardized analysis of
only those with significant radiation doses (5 mGy or more). Relative to theestimated background rate from that analysis, the SMR’s for zero-dose proximaland distal survivors are shown separately (triangles), and as a single zero-dosegroup (diamond). The dashed curve is the linear-quadratic dose response when
the distal, but not proximal, zero-dose persons are included in the analysis as issometimes done by others. This is probably misleading because the nonlinearityof that curve is primarily due to the nature of the dose response at zero and very
low doses, reflecting difficulties with the choice of comparison group.

Relative risk

1.6

1.4

1.2
Proximal zero-dose group
Distal zero-dose group
Combined zero-dose groups

1.0
0

1

2

3

4

Dose (Gy)Conclusions
The LSS cohort is well-suited for addressing issuesof relative risk, loss of life, and low-dose radiation
effects for several reasons. It is a well-defined cohort
with virtually complete follow-up, doses are wellcharacterized, and there are substantial numbers ofpeople exposed to low doses. Because of thesefeatures, internal standardization of the risk regression
estimates is possible, so that an external estimate of
background rates is not required. Furthermore,
follow-up began five years after exposure, which
would eliminate mortality due to acute radiation
effects and other bomb-related trauma but not mostdelayed radiation effects on mortality (except for asmall number of early leukemia deaths).
Variation with dose in the relative risk of deathfrom all causes and changes in lifespan are two waysof describing and quantifying the same phenomenon—the effect of exposure on the population
age-specific rate of death. An increase in one measure implies a decrease in the other; when the relativerisk increases, the age-specific mortality rate becomes
higher than the background rate, and so some people
will die at a younger age as a result of their exposure.
Reasons for favoring the use of relative risks or excess rates to summarize radiation risk include theirdirect relationship to impact of radiation exposureon health and the relative ease with which they canbe computed and adjusted for confounding or modifying factors. However, relative risks and excess rates
cannot really be understood without rather extensive
knowledge and understanding of background morReturn to Table of Contents

tality rates. Loss-of-life is a seemingly simple, relatively intuitive, general summary that has somemeaning to people outside of the fields of statistics
and epidemiology. Despite its intuitive appeal, lossof life is not an adequate summary of radiation effects in a population since, among other things, itdoes not provide any information on the proportionof the population that are actually affected by a given
exposure, it fails to indicate when these exposureassociated cases might be expected to occur, and it is
not very useful when one needs to focus on the impact of an exposure on specific outcomes (e.g., solidcancer).
Using total mortality and avoiding the use of any
particular dose-response model by using dose groups,
we found compelling evidence that radiation exposure has increased total mortality rates (and hence
shortened lives) for atomic-bomb survivors withdoses in excess of 0.25 Gy and some indications, albeit not statistically significant, that there is slight
life shortening at lower doses. There is no evidence
of increased longevity in any dose range in the LSS.
We suspect that others’ claims of greater longevity
in certain dose groups may partly reflect biases resulting from the choice of comparison group. At least
for total mortality in the LSS, the zero-dose group is
not necessary for inference about either radiation risk
or effect modification by sex and age at exposure.
We do not recommend the use of total mortality
or dose groups for describing radiation risks. Thisapproach was taken because of our interest in comRERF Update Volume 13, Issue 1, Spring 2002

Longevity of A-bomb Survivors
paring the LSS cohort to other studies. However, themessage seems clear. Studies that compare radiationexposed survivors of the bombings to the distal(zero-dose) survivors or to the general population can
produce biased results, with the bias especially pronounced at low doses. Furthermore our results suggestthat the Life Span Study of atomic-bomb survivors
contains enough proximal, low-dose survivors to support useful inferences about radiation risks,particularly low-dose risks based only on survivors
who were within 3 km of the hypocenters.

References
1.

Cologne JB, Preston DL: Longevity of atomic-bomb survivors. Lancet 356(9226):303–7, 2000

2.

Cologne JB, Preston DL, Izumi S, Nakamura N: Life-shortening in atomic bomb survivors. Hiroshima Igaku [JHiroshima Med Assoc] 54(6):529–34, 2001 (Japanese)3.

Cologne JB, Preston DL: Impact of comparison group on cohort dose response regression: An example using
risk estimation in atomic-bomb survivors. Health Phys 80(5):491–6, 2001

4.

Mine M, Okumura Y, Ichimaru M, Nakamura T, Kondo S: Apparently beneficial effect of low to intermediate
doses of A-bomb radiation on human lifespan. Int J Radiat Biol 58(6):1035–43, 1990

5.

Hayakawa N, Ohtaki M, Ueoka H, Matsuura M, Munaka M, Kurihara M: Mortality statistics of major causes ofdeath among atomic bomb survivors in Hiroshima Prefecture from 1968 to 1982. Hiroshima J Med Sci 38(2):53–
67, 1989

6.

Kondo S: Health Effects of Low Dose Radiation. Medical Physics Press, Madison, WI, USA, 1993

7.

Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K: Studies of the mortality of atomic bomb survivors.
Report 12, Part I. Cancer: 1950–1990. Radiat Res 146(1):1–27, 1996

8.

Shimizu Y, Pierce DA, Preston DL, Mabuchi K: Studies of the mortality of atomic bomb survivors. Report 12,
Part II. Noncancer mortality: 1950–1990. Radiat Res 152(4):374–89, 1999

9.

Pierce DA, Preston DL: Radiation-related cancer risks at low doses among atomic bomb survivors. Radiat Res
154:178–86, 2000

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RERF Update Volume 13, Issue 1, Spring 2002

!

Multifactorial Diseases in the Genomic Era

Multifactorial Diseases in the Post-GenomicSequencing Era and Our Current Position
Norio Takahashi
Department of Genetics
In the field of human genome research, nearlycomplete human chromosome sequences of number
22 and number 21 were published in December 1999
and May 2000, respectively. Subsequently, two different groups have independently published draft
sequences of the entire human genome in the March
2001 issues of Nature and Science, respectively.
Nearly complete information on the base sequencesof chromosome 20 was reported in December 2001.
The International Consortium announced that nearlycomplete sequences of the entire human genome
would be produced by 2003. Now we are entering
the so-called “post-sequence” era, in which the sequence information enables us to analyze functionsof all possible gene products or proteins.
One of the most important aims in studying human genome/genes functions is to identify etiology
of diseases. Post-sequence research that would bedirectly associated with genome information includes
systematic and genome-wide gene expression analyses by utilizing DNA chips and microarrays, as well
as approaches involving genetic epidemiology withthe use of genetic polymorphisms as markers (terms
in bold face are clarified in a Glossary at the end).
Throughout the world, owing to such developments,
it will become a trend to identify disease etiologies
and apply individual information for medical treat-

ment. In the year 2000, the Japanese Government(led by the late Prime Minister Keizo Obuchi) initiated the “Millennium Project”; where one of the goals
is a so-called “conquest of multifactorial diseases(lifestyle diseases).” RERF is on the verge of initiating a clinical health study for children of A-bomb
survivors, primarily focusing on multifactorial diseases. It seems therefore timely to explain multifactorial diseases and strategies to be used in our future
study. It would be my pleasure if this report can help
you in understanding current research directions ofmultifactorial diseases as a whole.
Multifactorial diseases develop as a result ofcomplicated interactions between environmental andgenetic factors. In contrast to single-gene disorders(Mendelian diseases), occurrence of multifactorialdiseases does not generally follow Mendelian patterns of inheritance. This is because many, diverse
genes, such as A to H shown in Figure 1, are involved,
and each gene has only a minute effect. These genes
seem to be talking to each other through a complicated network in which the interaction of gene products varies among individuals both quantitatively andqualitatively. Moreover, expression profiles of genes(i.e., spectrum of genes regarding the amount of proteins produced from each gene) are affected by not
only genetic but also non-genetic factors such as

Figure 1.

Genetic Factors

Environmental Factors
ExerciseB
A

Nutrition

D
C

E

Inflammation

G
F
H

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Aging
StressRERF Update Volume 13, Issue 1, Spring 2002

"Multifactorial Diseases in the Genomic Era
physical exercise, nutrition, inflammation, aging, andstress. These latter factors may further interact witheach other. It is therefore obvious that identifying
genes implicated in human multifactorial diseases isdifficult.

tion/treatment of the diseases, and (4) individual drug
responses including side-effects provided that further relevant individual markers continue to be recognized.
Figure 3 shows the strategy for identifying genes
related to disease etiologies. Shown on the left is theknowledge-based method (also called functional
cloning). This is a classical method to determine candidate genes through etiological, biochemical, or
pathological knowledge. Many genes responsible forcongenital metabolic disorders were identified by thismethod, while only proteins whose functions are wellcharacterized can be used. Human Proteome Project(HUPO), which has been launched by a group of toplevel proteomics researchers, aims at understanding
interactions of all relevant proteins for normal functions of tissues. Theoretically, this approach will enable us to dissect any diseases at the molecular level.

Despite such difficulties, it is socially important
to identify responsible genes because the prevalenceof multifactorial diseases is so high in developed
countries. As shown in Figure 2, if the mechanism
for the development of multifactorial diseases could
be elucidated, (1) new therapies and diagnostic methods and (2) individualized treatment would become
possible. This is because even among patients showing similar symptoms or diagnoses, the etiologies may
be different due to different genetic background or
mechanisms involved. Further, if polymorphic
markers associated with susceptibility in developing the multifactorial disease could be found, it would
become possible to predict (3) individual susceptibility that will facilitate prevention and early detec-

However, it will certainly take many years to fully

Figure 2.

Why etiologies of multifactorial diseases
should be elucidated so rapidly
Prevalence of such diseases is about 70% in general population

Mechanism of development ofdiseases
Genetic markers related todiseases⇒

Personalized
medicine
Prevention

Figure 3.

Knowledge-based method

Statistics-based method

Function of proteins(Functional proteins, receptors)

Surrogate markers(Microsatellite & SNPs)

Affected sib-pair
Association (case-control study)
TDT (transmission disequilibrium tests)

Identification of candidate genes
Transgenic model
In vitro experiments
Identification of polymorphisms
related diseases

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RERF Update Volume 13, Issue 1, Spring 2002

#Multifactorial Diseases in the Genomic Era
understand the molecular mechanisms of every disease as the proteomics study has just begun. Therefore, a temporal and alternative option is to find candidate genes from patients’ polymorphism information characteristic to the disease (right panel of Figure 3). Namely, this is to trace regions in the humangenome that are highly associated with the phenotypes of concern. This method is commonly used inongoing studies (including the Millennium Project),
although there are some differences among methods
in the details of applications (i.e., pedigree analysis,
affected sib-pair analysis, association study, transmission disequilibrium tests, etc.).
In either approach, the candidate genes need tobe confirmed by creating transgenic or knock-out
models in animals or cells. Thereafter, typical polymorphisms affecting enzyme activities or enzyme
stabilities, for example, will be used for clinical applications (Figure 2).
Figure 4 shows a typical strategy to identify candidate genes. This method has been widely adopted
by researchers involved in the Japanese Millennium
Project because it is believed to be the most effective and efficient method. The strategy uses a combination of microsatellites and SNPs (single nucleotide polymorphisms) as markers. Microsatellites
represent base sequences comprising tandem repeatsof short core sequences (2 to 9 bases) and the number of repeat units (n) varies among individuals (i.e.,large number of alleles are present; n = 1, 2, 3, 4,…etc). Selected sites with heterozygosity indicesof usually ≥0.7 are to be used. However, microsatellites are not suitable for fine mapping of candidate genes because polymorphisms exist on the average in every 11 K base pairs (bp). This points to

the role of SNP because they are more abundant andhence more effective in fine mapping; existing inevery 300–1000 bp. However, it is necessary to examine many markers because the heterozygosity index of a SNP is only about 0.3 because of its biallelic nature (i.e., there are only two alternative states
at one site, either 0 or 1). Depending on the locationof either microsatellite or SNPs in the genome, they
are classified into several groups; c (exists on mature mRNA or its copy, cDNA), i (on intron), r (onregulatory sequence which controls RNA productionof the gene), and g (on genome). In Japan, the predominant view is that we should focus on c, i, and r
but not g, as the latter is considered to have little
relevance to protein structure or its expression. In
contrast, in the U.S., it is believed that all the markers should be probed exhaustively, because no one
knows yet if g is really irrelevant or not.
The basic plan in the Millenium Project is to use
30,000 microsatellites uniformly distributed throughout the genome, i.e., one in every 100 Kb, for brief
mapping of relevant genes. A statistical approach will
clarify significant association of these markers withvarious phenotypes; presence or absence of a symptom, physiological measurement values such as bloodpressure, thickness of a blood vessel wall, blood glucose level, blood concentration of stimulatory substances involved in physiological responses, etc. This
first screening will use a relatively small number ofsubjects (100–200 people) because it aims at detecting the best candidate regions in the genome. Subsequently, a large number of subjects will be tested tonarrow down the regions using SNP information andto confirm that the genes are indeed relevant to thedisease.

Figure 4.

Strategy for genome-wide mapping of
disease related genes
g-microsatellite

iSNP

rSNP

cSNP

c-microsatellite

gSNP

Courtesy of Professor Tetsuro Miki, Ehime University, School of Medicine
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RERF Update Volume 13, Issue 1, Spring 2002

$Multifactorial Diseases in the Genomic Era
On the other hand, some critics argue that the
microsatellite markers will not work well for mapping the disease-related genes, since these markers are not always associated with the genes. Thus,
they assert that SNPs should be used from the beginning, even though SNPs typing is still very laborious.
In FY2000, five Japanese Ministries establishedthe Millenium Project consisting of 11 major
projects among which is included the “Genome
Project.” Figure 5 shows an outline of the “Genome
Project” which can be divided into four large fields.
One of the key study projects, named “Diseaserelated Gene,” is expected, within FY2000 to 2005,
to identify the relevant genes to common diseases(such as dementia, cancer, diabetes, hypertension,
asthma) and drug response following treatment ofpatients suffering from these five diseases. For the“Millenium Genome Project,” tens of billions of yen
a year is being invested in finding polymorphic
markers, developing detection methods of SNPs (including a cohort study), and developing statisticalmethods to handle the data to be obtained. The
project of the “Disease-related Gene” is intent oncollecting samples from patients of five target diseases and appropriate control subjects. This groupclosely collaborates with the “Human Genome Typing Center” to which the members send specimens(DNA in many cases). The Center will undergo themost extensive typing systematically apart fromsmall-scale typing effort in individual laboratories.
Currently, the Center is making headway, having
obtained over 20,000 SNPs, a number that will certainly continue to increase. The “Microsatellites
Typing Center,” under the direction of Professor

Inoko at Tokai University, has obtained 30,000 informative markers. The results from these centers will
be analyzed statistically in collaboration with the“Bio-Informatics” group.
After completion of the Project, it is expectedthat many SNPs associated with the five main multifactorial diseases mentioned earlier, and that the
drug responses will be found. Turning our eyes tothe world, TSC (the SNP Consortium consisting often pharmaceutical companies and five academicorganizations in USA and Europe) has alreadymapped more than 300,000 SNPs. Celera Genomics
announced that they could provide more than 3.5
million SNP data identified by themselves, in addition to public data bases such as the Human Gene
Mutation Database and the data base of SNPs
(dbSNP) of National Center for Biological Information (NCBI).
Lastly, I would like to express my personal view
how to use the massive data sets to be produced for
RERF studies. If individual susceptibility could become predictable for development of multifactorialdiseases, then, there will be little doubt that prevention of development of their diseases by introduction of appropriate change of their life style andearly detection/treatment of their diseases would become possible to the participants of the on-going F1
clinical study. The huge amount of polymorphism
data (SNPs and microsatellites) would provide us
good hint for understanding why incidence of some“non-cancer” diseases are higher in high dose survivors than non-exposed individuals. We should
keep further discussions on the possible applicationsof the technique.

Figure 5.

Bio-Informatics

Rice Genome

Millennium Genome Project
Development • Differentiation •Regeneration

Human Genome Typing Center

Disease-related Gene Project

Dementia

CancerDiabetes

Hypertension

AsthmaDrug Responsibility
From the Homepage of Ministry of Education, Culture, Sports, Science and Technology
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RERF Update Volume 13, Issue 1, Spring 2002

%Multifactorial Diseases in the Genomic Era
Glossary
Allele; A gene that differs from the wild-type gene is
generally called a mutant gene. Usually, the mutant
gene has its function altered. However, if the difference is subtle and the mutant gene exists frequently
in a population, it is difficult to describe which form
is normal or mutant. Under such circumstances, different forms of genes are called alleles. In theory,
any gene may have a number of alleles including functionally normal and abnormal ones.
DNA chip or microarray; Slide glasses containing
multiple spots of DNA at a high density are generally termed DNA chips or microarrays. Each spot
consists of multiple copies of a cloned DNA fragment so that a test DNA sample or a cDNA sample(artificial copy of mRNA) may hybridize quantitatively on the spot of homologous base sequences. The
test DNA is tagged with fluorescent dye(s) before
hybridization so that scanning of the slide with a narrow laser beam and measuring the emitted fluorescent light intensity will tell us the spots that showed
scarce to intensive hybridization of the test DNA.
Heterozygosity index; This generally indicates thefrequency of individuals bearing two different alleles in a population examined.
Mendelian inheritance or Mendelian diseases;
Most of the human hereditary diseases that are notseriously affected by acquired conditions follow either dominant or recessive forms of inheritance that

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were originally discovered by Mendel. Hemophilia
is the well-known autosomal recessive disease among
European Royal families. If the mutation happened
in a gene located on the X chromosome, the affectedindividuals are mostly and characteristically males
as females have two X chromosomes while males
have only one. Color blindness is one of the wellknown examples of X-chromosomal mutation.
Multifactorial diseases; In contrast to Mendeliandiseases, multifactorial diseases are unique in thatno single dominant mutation usually affects the disease onset but multiple genes provide the diseasesusceptibility. Because contribution of each gene israther small, improved life style may affect the onsetof the diseases. Diabetes mellitus and high-bloodpressure are the examples.
Polymophism; The traits that differ among apparently normal individuals are called polymorphism,
such as ABO blood type. In the case of DNA polymorphism, base sequences differ among individuals
whereas most of them have no effect on the phenotype.
SNP (pronounced as [snip]); Abbreviation of Single
Nucleotide Polymorphism, which exists frequently
in our genome. In most of the cases, a single base,say Guanine, is altered as another base, say Cytosine,
in a fraction of population.

RERF Update Volume 13, Issue 1, Spring 2002

28

Facts and Figures

Facts and Figures
Department of Statistics

Effect of AHS Participation on Cancer Survival
We recently addressed the question of whether inthe Life Span Study (LSS) there are differences insurvival times between radiation-related and spontaneous cancers. Dr. Nori Nakamura of the Departmentof Genetics, in particular, raised the issue. Although
our investigation, which will be reported elsewhere,
found no evidence of association between survival
time and atomic bomb radiation dose, it is noteworthy that we did find it necessary to adjust forparticipation in the RERF Adult Health Study (AHS).
As we indicate and discuss here, participants in the
AHS have tended to have longer survival times than
non-participants, particularly during the program’s
earlier years. Because a larger proportion of highdose than low-dose LSS cohort members were invited
to participate in the AHS, it is essential that analysesof survival after cancer diagnosis be adjusted for AHS
participation. Without this adjustment, there is a spurious indication that survival times are longer for
those at higher radiation doses.
The figures here compare AHS participants (forat least one cycle) and other LSS members, showing
the proportions who had not died of the originallydiagnosed cancer as a function of time sincediagnosis. Survival times depend on age at diagnosis

Particularly during the earlier part of the AHS
program, participants had both longer survival times
and higher cure rates than non-participants. This isprobably because participation leads to referrals
based on suspicious clinical findings, which in turnleads to earlier diagnosis of cancer. It is for stomach
cancer and female genital cancers that the distinction is greatest. Since earlier detection would in itself
lead rather unremarkably to longer times between
diagnosis and death, the difference in cure rates withparticipation is the more important aspect of the results seen. The smaller distinction seen during thelatter part of the AHS program is probably due tointroduction of alternative screening programs in thecommunity and generally improved health care. Notethat the cure rate for both groups in the latter period
is somewhat higher than even that for AHS participants in the earlier period, probably reflecting agenerally improved effectiveness of cancer therapy.

Survival of Cancers Diagnosed 1958 –1975

100%

Survival of Cancers Diagnosed 1976 –1995

100%

80%

Chance of Survival

Chance of survival

and are here standardized to age 70. The curves tend
to level off after about 10 years, at levels that can beconsidered as cure rates. Survival times, cure rates,
and the contrast between AHS participants and others, all differ between the earlier and later parts of
the AHS program.

60%

AHS participants
40%

80%

60%

AHS participants
Non-participants

40%

Non-participants
20%

20%

0%

0%
0

5

Survival time (years)

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10

0

5

10

Survival time (years)

RERF Update Volume 13, Issue 1, Spring 2002

29

Historical Vignette 1955

Historical Vignette 1955:
Hiroshima Diary and The Hiroshima Maidens
Robert W. Miller
Clinical Genetics Branch, National Cancer Institute, U.S.A
Reproduced with permission from Radiation Research 155, 378 (2001)
In July 2000, the Mayor of Hiroshima asked several alumni of the Atomic Bomb Casualty
Commission (ABCC) to send him Peace Messages
for the 55th anniversary of the explosion on August
6. To my knowledge, these have not been published.
My message was a historical vignette concerning twomonumental ventures that gained international attention in 1955. They concerned collaborations between
the U.S. physicians and Japanese with regard to theeffects of the bomb. I witnessed the unfolding of these
events when I was Chief of Pediatrics at theHiroshima ABCC. In one, an American surgeon was
key to the literary success of a Japanese physician.
In the other, a daring venture sponsored by an American medical group owed its success largely to a
Japanese-American woman who had returned to Japan to marry before the war.
In 1951, Dr. Warner Wells, a surgeon from the
University of North Carolina, was at the ABCC (namechanged in 1975 to the Radiation Effects Research
Foundation), where survivors of the bomb are examined by the Japanese and American staff for late effectsof radiation exposure. There was little need for a surgeon there, so he visited medical clinics in Hiroshima,
where he lectured on surgical diseases and pursued
his interest in overgrown scar tissue (keloids). He
learned that Dr. Michihiko Hachiya, Director of theCommunications Hospital, had written a diary during
his 56-day hospitalization for wounds from the bomb.
Dr. Wells sought him out and received permission tohave the diary translated for publication in English. It
had been published serially in the Journal of the Communications Bureau, where it circulated only among
the medical staffs who provided care nationally for
postal, telephone, and telegraph workers. Dr. Wells
brought the publication to ABCC, where it was translated into imperfect English with an attractive Japanese“accent.” It was inevitable that this feature would be
lost in editing, carefully done by Dr. Wells.

It was very exciting to read the book reviews ofHiroshima Diary (1) in 1955. They were prominently
featured by The New York Times, Saturday Review,
Newsweek, and Atlantic Monthly, among others, andtranslated into 14 languages. The royalties, whichmust have been substantial, were declined for personal use by Dr. Hachiya and Dr. Wells. Dr. Hachiya
requested $10,000 for a fund to pay for the education of children who were made orphans by the bomb.
When they repaid the loans, the funds were recycled.
Also in 1955, Norman Cousins, editor of the Saturday Review, arranged for 25 young Hiroshima
women with severe scar contractures to be treated at
Mt. Sinai Hospital in New York. At the last minute,while at ABCC, the New York group realized theyneeded as a chaperone a mature friend, guide andinterpreter who knew both cultures. The visitors discussed the problem as they stood beside the desk of
Helen Yokoyama, a Nisei interpreter who had majored in psychology at UCLA. Her travel documents
were in order, and she was immediately available.
She left with the maidens and was with them as they
adjusted to the homes of Quaker families, where they
stayed. She was with them at the hospital when they
underwent surgery. Without her, the 18-month mission during which 138 operations were performed,
would have had a rough course and may well havecollapsed. The story is told in books by Rodney
Barker [The Hiroshima Maidens (2)] and Anne
Chisholm [Faces of Hiroshima (3)], which unfortunately are out of print. Helen Yokoyama repeatedly
turned aside appeals to record the history of her experience.
Thus did working together in medicine help to heal
the animosity from a war that had ended 10 years
earlier.

References
1.

Hachiya M: Hiroshima Diary. The Journal of a Japanese Physician, August 6–September 30, 1945. Universityof North Carolina Press, Chapel Hill, 1955 and 1995

2.

Barker R: The Hiroshima Maidens. A Story of Courage, Compassion and Survival.Viking Penguin, New York,
1985

3.

Chisholm A: Faces of Hiroshima. A Report. Jonathan Cape, London, 1985

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RERF Update Volume 13, Issue 1, Spring 2002

30

In Memoriam

In Memoriam: Robert M. Heyssel
Dr. Heyssel served as Chief of the ABCC Department of Medicine during 1956–1958. Later, during a
distinguished career at Johns Hopkins University, hebecame a member of the National Academy of Sciences Institute of Medicine. He received his B.S. in1951 from the University of Missouri and his M.D. in
1953 from St. Louis University. In 1956, he joined the
U.S. Public Health Service as a Senior Assistant Surgeon and was stationed at the ABCC in Hiroshima
and Nagasaki for two years. After returning to the U.S.,
he did a fellowship in hematology at Washington University in St. Louis, then spent 10 years at the
Vanderbilt University School of Medicine. Heyssel began his tenure at Johns Hopkins in 1968 as an Associate
Dean of the School of Medicine and as an Administrator of the Johns Hopkins Hospital. He retired as
President of the Johns Hopkins Health Care System
in 1992, widely recognized as the chief architect of
the Institution’s highly regarded model of diversified
modern health care delivery enterprise. He continued

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to serve in many capacities until his death at age 72 on
June 13, 2001 in Seaford, Delaware. His wife Maria,
who kindly provided his picture for Update, survives
him.

RERF Update Volume 13, Issue 1, Spring 2002

Research Protocols
Research Protocols Approved 2001
RP 1-01 Culture of Permanent Lymphocyte
Cell Lines as Sources of Biological Samples for
Investigation of Genetic Effects of Radiation
on Children of Atomic Bomb Survivors
The Acquisition of Signed Informed Consent
Forms from the Donors (or Their Proxies) for
Whom Permanent Cell Lines Have Been Established (Addendum to RP 5-85)
Takahashi N, Murakami H, Fujiwara S, Akahoshi M,
Nakamura N
Based on RP 5-85, since 1985, blood samples havebeen collected from about 1,000 families consistingof both parents (at least one of whom is a survivor)
and their children, and their permanent lymphocyte
cell lines have been established. At that time the explanation for this project was carried out by the letter
which was initially sent, and orally later when thesubjects visited RERF for blood donation. However,this procedure for getting an informed consent does
not necessarily seem to be suited to current conditions. Therefore, in this addendum we propose that a
written informed consent be obtained from those whohave previously donated blood, and their agreement
be confirmed again.

31
diseases (hypertension, atherosclerosis, diabetes,
asthma, osteoporosis, rheumatoid arthritis, etc.) in
Japan. Informed consent is also requested of the donors if they so desire for use in these other studies.
All of these studies will follow the requirements ofthe ethical guidelines developed by the Ministry of
Health and Welfare.

RP 2-01 Pilot Study of Genetic Background of
AHS Population: Identification of Markers in
Potential Candidate Genes Associated with Hypertension
The Acquisition of Signed Informed Consent
Forms from the Donors (or Their Proxies) for
Genomic Studies Conducted either at RERF
or at Other Research Institutes as Collaborative Study Using Previously Collected Blood
Samples (Addendum to RP 1-97)
Takahashi N, Murakami H, Yamada M, Kasagi F,
Suzuki G
Based on RP 1-97, we examined the association
between hypertension and polymorphic markers ofhypertension-related candidate genes in the reninangiotensin system among approximately 300 Adult
Health Study (AHS) participants. However, only oral
consent was obtained from the participants. We now
wish to obtain signed consent forms, necessary forcontinued work on hypertension at RERF, from the
AHS participants who donated their blood for DNA
analysis. In addition, we propose to conduct a collaborative study with outside research organizations,by collaborating in the study “Elucidation of Hypertension-related Gene Groups,” if informed consent
for this study is independently obtained. This study
is being conducted by Professor Akira Hata of the
Department of Public Health, Asahikawa Medical
College, as part of a nationwide study known as theMillennium Project, seeking to identify the candidate genes associated with a number of leading
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RRERF Update Volume 13, Issue 1, Spring 2002

Recent Publications
Recent Publications(Japanese): the original article is in Japanese;(JTr): a Japanese translation is available.
Akahoshi M, Amasaki Y, Soda M, Tominaga T,
Ichimaru S, Nakashima E, Seto S, Yano K. Correlation between fatty liver and coronary risk factors: A population study of elderly men andwomen in Nagasaki, Japan. Hypertension Research 2001 (July); 24(4):337–43. (RERF Report
9-98)
Akahoshi M, Soda M, Nakashima E, Tsuruta M,
Ichimaru S, Seto S, Yano K. Effects of age atmenopause on serum cholesterol, body mass index, and blood pressure. Atherosclerosis 2001
(May); 156(1):157–63. (RERF Report 14-99)
Arisawa K, Nakano A, Saito H, Liu XJ, Yokoo M,
Soda M, Koba T, Takahashi T, Kinoshita K.
Mortality and cancer incidence among a population previously exposed to environmental cadmium. International Archives of Occupational
and Environmental Health 2001 (May);
74(4):255–62.
Burak LE, Kodama Y, Nakano M, Ohtaki K, Itoh
M, Okladnikova ND, Vasilenko EK, Cologne JB,
Nakamura N. FISH examination of lymphocytes
from Mayak workers for assessment of translocation induction rate under chronic radiation exposures. International Journal of Radiation Biology 2001 (August); 77(8):901–8. (RERF Report
3-01)
Fleischer RL, Fujita S, Hoshi M. Hiroshima neutron fluence on a glass button from near groundzero. Health Physics 2001 (December);81(6):720–3.
Fujiwara S, Masunari N, Suzuki G, Ross PD. Performance of osteoporosis risk indices in a Japanese population. Current Therapeutic Research
Clinical and Experimental 2001 (August);
62(8):586–94. (RERF Report 9-01)
Fukuhara T, Sharp GB, Mizuno T, Itakura H,
Yamamoto M, Tokunaga M, Tokuoka S, Cologne
JB, Fujita Y, Soda M, Mabuchi K. Liver cancer
in atomic-bomb survivors: Histological characteristics and relationships to radiation and hepatitis B and C viruses. Journal of Radiation Research 2001; 42:117–30. (RERF Report 2-00)
Hirai Y, Hayashi T, Kubo Y, Hoki Y, Arita I, Tatsumi
K, Seyama T. X-irradiation induces up-regulation of ATM gene expression in wild-type
lymphoblastoid cell lines, but not in their heterozygous or homozygous ataxia-telangiectasia
counterparts. Japanese Journal of Cancer ReReturn to Table of Contents

32
search 2001 (June); 92(6):710–7. (RERF Report22-99)
Imai K, Nakachi K. Personality types, lifestyle, andsensitivity to mental stress in association with NK
activity. International Journal of Hygiene andEnvironmental Health 2001 (October);
204(1):67–73.
Kambara T, Matsubara N, Nakagawa H, Notohara
K, Nagasaka T, Yoshino T, Isozaki H, Sharp GB,
Shimizu K, Jass J, Tanaka N. High frequency of
low-level microsatellite instability in earlycolorectal cancer. Cancer Research 2001 (November); 61(21):7743–6.
Kodama Y, Pawel DJ, Nakamura N, Preston DL,
Honda T, Itoh M, Nakano M, Ohtaki K, Funamoto
S, Awa AA. Stable chromosome aberrations inatomic bomb survivors: Results from 25 years ofinvestigation. Radiation Research 2001 (October); 156(4):337–46. (RERF Report 17-00)
Koh LKH, Sedrine WB, Torralba TP, Kung A,
Fujiwara S, Chan SP, Huang QR, Rajatanavin R,
Tsai KS, Park HM, Reginster JY. A simple tool
to identify Asian women at increased risk of osteoporosis. Osteoporosis International 2001;
12(8):699–705.
Kusunoki Y, Hayashi T, Kyoizumi S. T-cell responses to mitogens in atomic bomb survivors:
Radiation effects on mitogen responsiveness areapparent in survivors who had not been diagnosed
with cancer prior to testing (Letter to the editor).
Radiation Research 2001 (November);
156(5):564–5. (RERF Report 8-01)
Kusunoki Y, Kyoizumi S, Umeki S, Hirai Y,
MacPhee DG. Characterization of mutant clones
lacking T-cell receptor alleles in a cell line froman adult T-cell leukaemia patient. British Journal of Haematology 2001 (August); 114(2):485–
7. (RERF Report 4-01)
Kyoizumi S, Koyama K. Human radiation biology
using SCID-hu mice. Laboratory Animal Technology and Science 2001 (July); 13(4):197–201.
(Japanese)
Matsuo K, Akahoshi M, Nakashima E, Suyama A,
Seto S, Hayano M, Yano K. The prevalence, incidence and prognostic value of the Brugada-type
electrocardiogram. A population-based study offour decades. Journal of the American College
of Cardiology 2001 (September); 38(3):765–70.
(RERF Report 8-00)
Nagano J, Kono S, Preston DL, Mabuchi K. A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki (Japan).
Cancer Causes and Control 2001 (August);
12(6):501–8. (RERF Report 10-00)
RRERF Update Volume 13, Issue 1, Spring 2002

Recent Publications

33

Nakachi K, Imai K, Eguchi H, Higashi Y. Green tea
prevents recurrence of breast cancer. BIO Clinica
2001; 16(12):1091–5.(Japanese)

ety for Social Medicine and the International Epidemiological Association European Group, Oxford, 12–15 September 2001).

Nakano M, Kodama Y, Ohtaki K, Itoh M,
Delongchamp RR, Awa AA, Nakamura N. Detection of stable chromosome aberrations by FISH
in A-bomb survivors: Comparison with previous
solid Giemsa staining data on the same 230 individuals. International Journal of Radiation Biology 2001 (September); 77(9):971–7. (RERF Report 18-00)

Sharp GB, Cologne JB, Fukuhara T, Itakura H,
Yamamoto M, Tokuoka S. Temporal changes inliver cancer incidence rates in Japan: Accounting
for death certificate inaccuracies and improving
diagnostic techniques. International Journal ofCancer 2001 (September); 93(5):751–8. (RERF
Report 16-00)

Nose M, Uzawa A, Ogyu T, Suzuki G. OK-432 reduces mortality and bacterial translocation in irradiated and granulocyte-colony stimulating factor (G-CSF)-treated mice. Journal of Radiation
Research 2001 (June); 42(2):191–200.
Ogawa T, Hayashi T, Yorioka N, Kyoizumi S, Trosko
JE. Hexamethylene bisacetamide protects peritoneal mesothelial cells from glucose. Kidney International 2001 (September); 60(3):996–1008.
Ohkubo T, Hozawa A, Nagatomi R, Fujita K,
Sauvaget C, Watanabe Y, Anzai Y, Tamagawa A,
Tsuji I, Imai Y, Ohmori H, Hisamichi S. Effects
of exercise training on home blood pressure values in older adults: A randomized controlled trial.
Journal of Hypertension 2001 (June); 19(6):1045–
52.
Ojima M, Ishii K, Hayashi T, Ito A. Induction of radio-adaptive response in colony formation by low
dose X-ray irradiation. Physiological Chemistry
and Physics and Medical NMR 2001; 33:41–8.

Shibata Y, Yamashita S, Masyakin VB, Panasyuk GD,
Nagataki S. 15 years after Chernobyl: New evidence of thyroid cancer. Lancet 2001 (December8); 358(9297):1965–6
Shimizu Y. Epidemiological study of radiation effect. Koshu Eisei [Public Health] 2001 (June);
65(6):429–33. (Japanese)
Suzuki T, Kusunoki Y, Tsuyama N, Ohnishi H,
Seyama T, Kyoizumi S. Elevated in vivo frequencies of mutant T cells with altered functional expression of the T-cell receptor or hypoxanthine
phosphoribosyltransferase genes in p53-deficientmice. Mutation Research 2001 (November);
483(1-2):13–7. (RERF Report 16-99)
Thomas GA, Williams ED, Becker DV, Bogdanova
TI, Demidchik EP, Lushnikov E, Nagataki S,
Ostapenko V, Pinchera A, Souchkevitch G, Tronko
MD, Tsyb AF, Tuttle M, Yamashita S. Creationof a tumour bank for post Chernobyl thyroid cancer (Letter to the editors). Clinical Endocrinology 2001 (September); 55(3):423.

Park SC, Lim IK, Paik N-S, Yamamoto T, Yuasa Y,
Nakachi K, Fujiki H. Japan-Korea cancer research
symposium: Investigation on the balanced cooperation of cancer cells with the human body. Journal of Cancer Research and Clinical Oncology
2001 (November); 127(11):692–5.
Rouillard JM, Erson AE, Kuick R, Asakawa J,
Wimmer K, Muleris M, Petty EM, Hanash SM.
Virtual genome scan: A tool for restriction landmark-based scanning of the human genome. Genome Research 2001 (August); 11(8):1453–9.
Sasaki MS, Hayata I, Kamada N, Kodama Y, Kodama
S. Chromosome aberration analysis in persons
exposed to low-level radiation from the JCO criticality accident in Tokai-mura. Journal of Radiation Research 2001 (September); 42(Supplement):S107–16.
Sauvaget C, Nagano J. Vegetables and fruit consumption and risk of mortality from cancer, coronary
heart disease, and cerebrovascular disease. Journal of Epidemiology and Community Health 2001
(September); 55 (Supplement 1):A33. (Abstract)(Proceedings of the joint conference of the SociReturn to Table of Contents

RRERF Update Volume 13, Issue 1, Spring 2002