Radiation Effects Research Foundation News and Views
Hiroshima and Nagasaki, Japan
Volume 12, Issue 1, SpringSummer 2001

Table of Contents
34th Board of Directors Meeting ...................................................................................... 1
27th RERF Scientific Council Meeting ............................................................................ 2
Staff News .............................................................................................................................. 4
New Study of the Children of A-bomb Survivors ........................................................ 5
Current Status of Dosimetry Revision ............................................................................ 5
Multinational Peer Review of Statistics ......................................................................... 6
New Datasets Available on RERF Home Page ............................................................. 7
Analysis of the Longitudinal Hematology Data in the Adult ................................... 8
Health Study, by F.L. Wong
Randomness of Radiation-induced Translocations Depends on ........................... 12
Chromosome Length or Surface Area as Target, by N. Nakamura,
K. Ohtaki, Y. Kodama, M. Nakano, M. Itoh, A.A. Awa, and J.B. Cologne
Cancer Risks at Low Doses among A-bomb Survivors, ............................................ 15
by D.A. Pierce and D.L. Preston
Research Protocols .............................................................................................................. 18
Recent Publications ............................................................................................................ 21

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-in-Chief: Seymour Abrahamson, Vice Chairman and Chief of Research
Managing Editor: Donald Pierce, Department of Statistics
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 34th Board of Directors Meeting Held in Washington, D.C.
The 34th meeting of the Board of Directors washeld at the National Academy of Sciences (NAS) in
Washington, D.C. on the 21 and 22 June 2000. The
meeting was attended by 18 people including directors, supervisors, and observers. An animateddiscussion took place concerning RERF management
and other issues.
Dr. Shigenobu Nagataki, Chairman, presented astatus report on RERF. He also expressed the viewsof the Executive Committee on the five items thatthey had carried over from the previous Board meeting: US-Japan negotiation of funding, the number of
directors, extending the retirement age of researchstaff and research staff increase, the reserve for retirement allowance and measures to cope withfluctuations in currency exchange rates, and the facilities and relocation.
Dr. Paul Seligman, Deputy Assistant Secretary for
Health Studies, US Department of Energy (DOE),
reported on the results of the US-Japan negotiation
held prior to the Board meeting. He said that the US
intends to secure 14 million US dollars for RERF
annually for the next five years, and to observe theagreement made during the 1996 US-Japan negotiations that there would be only one permanent US
director.
At this Board meeting, Dr. Warren R. Muir, Executive Director, Commission on Life Sciences,
National Research Council, brought to light the following proposals from the National Academy of
Sciences. He announced that the Clegg Committee
would be organized to review the long-term institutional arrangements between the Academy, DOE and
RERF. Discussion of the role of the US Permanent
Director was emphasized.
The agenda of reports included the following: thepresent personnel status, the fiscal year 1999 salaryrevision, the Labor Union’s fiscal year 2000 demands
for the improvement of working conditions, international collaboration, and the health effects study forthe children of A-bomb survivors (F1). In the explanation of the Labor Union’s demands, it was notedthat the Union had acted as a mediator between RERF
and F1 groups concerning the F1 health effects study
issues.
It was reported that a full-scale survey would beinitiated for the F1 health effects study after the results of pilot study questionnaires were reviewed.

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On the items for deliberation and action, Dr. Wolff
presented the recommendations of the Multinational
Peer Review of the Department of Genetics. He alsopresented a response to the recommendations of the27th meeting of the Scientific Council. He highlighted
the suggestion that the working scientific staff of
RERF should engage in a process to define their own
future. Dr. Shudo Yamazaki, Supervisor, presented
the audit report of the fiscal year 1999 research activities.
Secretariat Chief Kazumasa Kunitoshi, delivered
an explanation of the fiscal year 1999 settlement ofaccounts report. The working budget for fiscal year
2000 was approved.

List of Participants
Permanent Directors:
Shigenobu Nagataki, Chairman
Sheldon Wolff, Vice Chairman and Chief of Research
Senjun Taira, Permanent Director
Visiting Directors:
Patricia A. Buffler, Dean and Professor of Epidemiology, Division of Public Health Biology andEpidemiology, School of Public Health, University of California, Berkeley
Toshiyuki Kumatori, Consultant, Radiation Effects
Association
Jonathan M. Samet, Professor and Chairman, Department of Epidemiology, Johns Hopkins University
School of Hygiene and Public HealthRichard B. Setlow, Senior Biophysicist, Biology Department, Brookhaven National Laboratory,
Adjunct Professor of Biochemistry and Cell Biology Department, State University of New Yorkat Stony Brook
Kazuaki Arichi, Councilor, Japan Institute of International Affairs (submitted a letter of attorney)
Masumi Oike, Chairman, Japan Anti-Tuberculosis
Association (submitted a letter of attorney)
Supervisors:
Shudo Yamazaki, former Director-General, National
Institute of Infectious Disease
David Williams, Senior Financial Advisor, US National Academy of Sciences
Scientific Councilor:
J. Martin Brown, Professor and Chairman, Divisionof Radiation Biology, Department of Radiation
Oncology, Stanford University School of Medicine

RERF Update Volume 12, Issue 1, Spring–Summer 2001

RERF NewsThe 27th Meeting of RERF Scientific Council
The Scientific Council met at RERF in Hiroshima on April 17–19, 2000. The meeting was cochaired by Drs. J. Martin Brown, Professor, Stanford University, and H. Matsudaira, Chairman,
Radiation Effects Association.
Dr. S. Nagataki, Chairman of RERF, opened the meeting. Dr. S. Wolff, Vice Chairman and Chiefof Research, gave a brief review of RERF activities over the past 12 months and invited the Council’s
advice regarding future research directions.
The remainder of the first day was devoted to recent research and future plans in the Departmentsof Clinical Studies (Drs. G. Suzuki and M. Akahoshi), Radiobiology (Dr. D. MacPhee), Epidemiology (Drs. Y. Shimizu and A. Suyama), and Statistics (Dr. D. Preston). In the afternoon, there was abrief review of the recent US-Japan Joint Dosimetry Workshop (Drs. S. Fujita and H. Cullings) anddiscussion about current problems with the dosimetry system.
The morning of the second day was devoted to a review of database construction (Messrs. E.
Grant and H. Katayama), and to a review of the use of stored serum samples (Drs. S. Fujiwara, M.
Hakoda, G. Sharp, and J. Cologne). In the afternoon, Dr. N. Nakamura led a discussion concerning
the responses to the November 1999 departmental peer review meeting recommendations for the
genetics program.
On the third and final day, the Council co-chairmen, Drs. Brown and Matsudaira, presented asummary of the Council’s report and its recommendations. The final report was presented to the
RERF Board of Directors when they met in Washington, D.C. in June 2000.

The Scientific Council’s recommendations and RERF’s responses [in italics]
by Sheldon Wolff, Vice Chairman
The Scientific Council made two general recommendations and several recommendations pertaining
to specific individual departments.
Like many previous review groups that have indicated they would like to see RERF foster independent
investigator originated research, this Council, too, has
expressed such a desire, but have presented a variation on the theme by suggesting a procedure thatmight help to bring this about. They suggested that
this should involve meetings of the scientific staff ingroups of 5–10 for one or more hours every few
weeks, or at one or more all-day retreats to discuss
the questions “what could we be doing, or what would
we like to be doing, at RERF in 10 years,” and “whatscientific environment would we like at RERF in 10
years?” The Council also presented a possible scheme
for holding such meetings in which the members
would sit in a circle and have flip charts on which towrite their ideas. It was hoped that this somewhat
informal approach would stimulate outspokenness
and interaction between the scientists.
The second general recommendation of the Council was that instead of having a dinner attended onlyby the Council, the senior leadership of RERF, andthe department chiefs, the initial social gathering andperhaps even some of the luncheons, should be an
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RERF wide reception. The purpose of this would be
to increase the opportunity for more general and informal discussions with the working scientists, with
opportunities for general mingling of the staff andcouncilors for one-on-one discussions.
This constitutes a reprise of the way in which earlier
Councils were run and which was very popularamong the staff. RERF agrees wholeheartedly withthis idea and intends to implement it at the next Council meeting.
The Council then moved on to make specific recommendations for each department. It noted that in
the Department of Clinical Studies there are a large
number of active projects, some dating back to 1985.
Some are closely related such as the various studies
related to calcium metabolism and to cardiac disease.
The Council recommended that the Department ofClinical Studies should review, consolidate, and further prioritize its studies to reduce the total number
and to focus on those statistically most promising,where a relationship to radiation exposure can beshown.
RERF believes that this recommendation is mosttimely and could even be implemented in other departments where Research Protocols haveaccumulated and could profit by consolidation.
The long awaited F1 study is about to get underway and the Council recommended that RERF

RERF Update Volume 12, Issue 1, Spring–Summer 2001

!

RERF News
determine whether any increase in malignant tumors
or non-neoplastic conditions occur in this group.
The study as recommended by other advisory groups,
however, is mainly a genetic study designed to determine if multifactorial diseases are increased in
the offspring of the exposed survivors. The recommendation of the Council will be passed on to the
Scientific Committee for the F1 study to see if it fitswith their assessment of what should be done in the
study.
Because RERF’s statisticians might need tutelage
in new techniques that are under development, it wasrecommended that scientists in the department beallowed to take short sabbatical leaves at other institutions where they can learn the new methods.
RERF finds that this recommendation really applies
to our ongoing programs in all departments including statistics, whereby we regularly send our people
abroad to learn new techniques.
RERF was also urged to investigate and solve
some of the ethical issues confronting epidemiological studies and to investigate solutions to these issues
agreed upon in the U.S. (e.g., at the Fred Hutchinson
Research Center in Seattle) and elsewhere to see ifsome of these might be proposed for use here.
RERF points out that individual institutions can nolonger solve these issues independently since eachcountry is promulgating separate national rules in thisarea. Currently Japan has a commission that is proposing a national law for Japan that will define whatmust be done legally in this country. This response
also applies to a recommendation made to the Department of Radiobiology that the ethical issues thatare currently hampering the collection of archival tumor material be resolved as soon as possible.

Scientific Councilors
J. Martin Brown, Professor and Chairman, Divisionof Radiation Biology, Department of Radiation
Oncology, Stanford University School of Medicine (co-chairman)
Hiromichi Matsudaira, Chairman, Radiation Effects
Association (co-chairman)
Maurice S. Fox, Lester Wolfe Professor of Molecular Biology, Massachusetts Institute ofTechnology
Joe W. Gray, Professor of Laboratory Medicine andRadiation Oncology, University of California, San
Francisco (Absent)
Tomio Hirohata, Professor Emeritus, Kyushu University Faculty of Medicine, and Professor,
Nakamura Gakuen University
Yusuke Nakamura, Director, Human Genome Center, Institute of Medical Science, University ofTokyo
Theodore L. Phillips, Wun-Kon Fu Distinguished
Professor and Associate Director, University ofCalifornia San Francisco Cancer Center
Susan Preston-Martin, Professor, Department of Preventive Medicine, University of Southern
California
Masao Sasaki, Professor, Radiation Biology Center,
Kyoto University
Shinichiro Ushigome, Professor, Department of Pathology, Jikei University School of Medicine

ERRATAIn the Autumn 1999 Update, 10(2), on page seven in the article “Radiation and Noncancer Disease Mortality,” the last sentence in the legend of Figure 2 (bottom line) should read: “ERR
estimates and standard errors are given for six dose categories: <0.005, 0.005–, 0.2–, 0.5–, 1.0–,
and ≥2.0 Sv.”
In the Spring 2000 Update, 11(1), the following two errors were made:MOn page one in the article “U.S. Ambassador and Osaka Consul General Visit RERF,” thebottom line in the photo caption should read: “Pictured at left is Ms. Fumiko Gregg, an interpreter for the ambassador.”
MOn page 11 in the article “Hiroshima and Nagasaki Open Houses,” under the upper-leftphoto “Radiobiology and Genetics Above,” the names of the left two persons were reversed.
So, the first man on the left is Yoichiro Kusunoki and the next man is Tomonori Hayashi.

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

"RERF News

Staff NewsRERF Chairman Dr. Shigenobu Nagataki completes his four-year term in June 2001. Replacing him,as the first American Chairman of RERF, will be Dr.
Burton Bennett, who recently completed 12 years
service as UNSCEAR Secretary. The next issue ofUpdate will carry more information about him. Dr.
Senjun Taira, a Permanent (i.e. Resident) Director
for the past four years, will become Vice Chairman.
The first Permanent Director from Hiroshima will
be Dr. Eiichi Tahara, who recently retired from theHiroshima University Department of Pathology. In
the fall, Dr. Charles Waldren of Colorado State University will join RERF as Chief Scientist, the newtitle for what has recently been Associate Chief ofResearch.
After extending his anticipated term for some time,
Dr. Sheldon Wolff retired as Vice Chairman and Chiefof Research in fall 2000, returning to California.
As a temporary measure, at the request of RERF
scientists and Board of Directors, Dr. Seymour
Abrahamson returned to serve RERF in October
2000, for the fifth time, to fill the Vice Chairman andChief of Research positions for a period that willend this June. Readers will appreciate that Dr.
Abrahamson is responsible for the publication of thisissue of Update, even though there is presently no
managing editor.

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Dr. Kei Nakachi has recently taken the post of
Chief of Epidemiology, Hiroshima, coming from the
Saitama Cancer Center. In addition to his other duties as department chief, he will be developing a
program in molecular epidemiology.
Dr. James Cao joined Radiobiology as Research
Scientist this May, having recently worked for Proctor and Gamble in Kobe following postdoctoral
positions at Columbia and Stanford. Dr. Misa
Imaizumi joined Clinical Studies, Nagasaki, as
Research Scientist early this year, coming from Mount
Sinai Medical College in the U.S. Dr. Shizue Izumi
recently completed her Ph.D. in Biostatistics at
Hiroshima University, and has been promoted from
Research Assistant to Research Scientist in Statistics. Dr. Renju Maeda, former Director of Tarami
Hospital, Nagasaki Prefectural Adult Disease Center,has joined RERF in Nagasaki as Senior Consulting
Scientist.
Dr. Sadayuki Ban, Radiobiology, has left RERF
after 21 years to take a position at the National Institute of Radiological Sciences. Dr. Ken Kuramoto,Clinical Studies, Hiroshima, has moved on after one
year at RERF to take a Fellowship position at the
National Heart, Lung, and Blood Institute in the U.S.
National Institutes of Health.

RERF Update Volume 12, Issue 1, Spring–Summer 2001

#RERF NewsNew Study of the Children of A-bomb Survivors
Following a recommendation from the Blue Ribbon Panel and consultations with various advisorycommittees, it was decided about three years ago that
RERF should carry out a clinical study of the F 1cohort. Although no radiation effects were found instudies of this cohort as children, nor in continued
mortality and cancer incidence investigation, it might
be that as these persons reach middle age there would
be clinically ascertainable effects, particularly inadult-onset multi-factorial diseases such as hypertension, diabetes, and cardiovascular diseases.
A large number of survivors’ children were examined shortly after birth, and again at 9 months, forclinical abnormalities. When they were teenagers,cytogenic and molecular protein analyses of blood
samples were carried out for a large number of them.
No radiation effects were seen in these studies, although it is known from experiments using animals
and insects that the mutational effects of high-dose
irradiation of male and female germ cells can be foundin offspring. A cohort of 80,000 is followed up to
study mortality and cancer incidence through Hiroshima and Nagasaki tumor registries. The newclinical study is thus an extension of those activities.
The purpose is to estimate and obtain confidence limits for excess prevalence of diseases, which will be
useful even if no apparent, or statistically significant,risks are seen.

After careful consideration, including consultations with experts on medical ethics and discussions
with survivor groups, a pilot mail survey of about
300 of an identified cohort of 18,000 was done. The
purposes were to determine the level of interest forparticipating in a clinical study, and to validate thequestionnaire which will provide useful information
on lifestyle and other matters, for purposes of themortality and cancer incidence follow-up. About
77% of the 300 were reached and responded, andamong respondents about 65% expressed such willingness to participate. It is estimated that
8,000–11,000 of the cohort will actually participate
in the clinical study, which will be done over a fouryear period. For each year the mail survey will becompleted for one-fourth of the 18,000—the first having been mailed by now—and those willing toparticipate in the clinical study will be contacted. A
pilot clinical study of 500 selected from the first groupwill begin in a few months. As usual at RERF, careful attention is being given to obtaining proper
informed consent of the participants, and privacy of
personal information. The informed consent will pertain distinctly to three different aspects ofinvestigation: (1) the basic clinical study, (2) preservation of sera and plasma for future investigations
not involving DNA, and (3) preservation of blood
samples for genetic studies involving DNA.

Current Status of Dosimetry Revision
Many readers will know that there have beenmajor concerns in recent years regarding the adequacy of the DS86 radiation dose estimates. In
particular, it was suggested—based on thermal
neutron activation measurements in sampled materials—that the Hiroshima neutron estimates could
be too low by factors of 10 at 1,600 m and 30 at
2,000 m. If this were true, correction could havesubstantial effect on both neutron and gamma-ray
cancer risk estimates, partly involving reconsideration of the neutron relative biological effectiveness(RBE) used in cancer analyses if this became morecritical than in the past. However, activation measurements also suggested that the current neutron
estimates near the hypocenter are too high, leading to a dilemma in that re-evaluation of source
term and transport calculations failed to provide
results that would agree with both of these typesof correction. That is, it was considered implausible that neutron doses could decrease as slowly
with distance as suggested by the measurements.

Very good progress has now been made on resolving the uncertainties, through international
activities organized by the Department of Energy andthe Ministry of Health and Welfare, along with efforts of a National Academy of Sciences Dosimetry
Committee. Several binational meeting were held, theuncertainties in activation measurements were evaluated, and further measurements on new samples weremade—including important work done at the University of Munich.

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

It is now expected that the basic elements of a new
dosimetry system will be in place before the end of
2001, and that the implementation might be completeby the middle of 2002. Preliminary indications are thatthe earlier activation measurements at substantial distance may have been misleading, and that changes inthe distal Hiroshima neutron estimates will probably
not exceed about 1/10 of those suggested above. Theremay be distance independent increases in Hiroshima
gamma-ray estimates on the order of 10%.

$RERF News

Multinational Peer Review: Department of Statistics
Activities strongly supported and personnel increase advised
The fourth Multinational Peer Review was held
on 7–9 November 2000 at the Hiroshima laboratory
to evaluate RERF’s statistics program. In accordancewith the recommendations of the Blue Ribbon Panel,
the RERF research departments have undergone
multinational peer review on an annual rotating basis. The first department to undergo Multinational
Peer Review was the Department of Radiobiology,
second was the Department of Epidemiology, andnext the Department of Genetics.

On the final day of the meeting, Dr. David W.
Gaylor, panel chairman, provided general comments
and some panel members spoke on certain aspects ofthe draft recommendations. The Panel strongly supported the activities of the Department of Statistics
and requested an increase in number of statisticians
to enable the department to collaborate fully with,and provide required statistical assistance to, the other
RERF departments. Their final report, received later,
included the recommendations paraphrased here:• Additional statistics staff to ensure adequate support and collaboration with other departments• That there should be a statistician on the Scientific Council• Continuing support for the development of statistical techniques for the dose response analysisof health effects from low-dose radiation• Continued support for description of age patternsof radiation-related cancer and the implications
for mechanistic models of cancer induction• Continued analyses of F1 cancer incidence anduntoward pregnancy outcomes in relation to parental radiation exposure• Further development for case control studies ofweighted sampling designs, generalizing on“matching on dose” and “counter matching”
ideas, and study of their efficiency• Continued work on analysis of the AHS taking
care to distinguish between confounding and intermediate variables for radiation effects• Continue longitudinal analysis of AHS measurements, including assessment of the sensitivity todifferent correlation structures• Adjusted survivor doses allowing for imprecisionin radiation dose estimates should be used in most
RERF analyses, revisiting the methods for dealing with this when a revised dosimetry system
becomes available• RERF should consider the formation of a researchdata management committee to consider the design, access, and documentation of databases; thiscommittee needs a member from the Departmentof Statistics• Preliminary statistical power analyses for detecting familial sensitivity to radiation should be
carried out before continuing a large scale family
pedigree study• Participation in outside professional activities
related to radiation effects on health, and the improved analysis of such data, is encouraged• Continue efforts for recruiting Japanese statisticians, including participation in professional
meetings, links with university statistics programs
including teaching, student internships, and collaborative research• Consider the improved retention and recruitmentof staff by investigating ways to compete for outside funding for projects related to the RERF
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RERF Update Volume 12, Issue 1, Spring–Summer 2001

The gathering opened with greetings from Chairman Dr. Shigenobu Nagataki and an overview of
RERF by Dr. Seymour Abrahamson, Vice Chairman
and Chief of Research. Following an overview of thestatistics program by Dr. Dale L. Preston, Chief ofthe Department of Statistics, the review proceededwith the following presentations and active discussions: Donald A. Pierce, Age-time patterns of cancer
risk to be anticipated in mutagenic exposure data,
and also Joint effects on lung cancer of smoking andradiation; Shizue Izumi, Current analysis of F1 mortality, and also Family pedigree study; John Cologne,
Confounding and effect modification of radiation risk
by other factors, and also Breast cancer molecularstudy design; Fumiyoshi Kasagi, The Adult HealthStudy population, and also Cardiovascular disease
study; Eiji Nakashima, Radiation dose effect onheight of atomic-bomb survivors—a longitudinal
study of stature in adulthood; Lennie Wong, Longitudinal analyses of the Adult Health Study
measurement data; Shoichiro Fujita, Atomic-bomb
dosimetry; Harry M. Cullings, Analysis of physicalmeasurements related to the A-bomb dosimetry; Eric
Grant, RERF’s research database
The Department of Statistics provides statisticalassistance to other departments (Epidemiology, Clinical Studies, Genetics, and Radiobiology) and isclosely related to them scientifically. Thus, an additional session was held to allow the Panel to interact
with chiefs of the other departments and laboratories
in Hiroshima and Nagasaki and to listen to their requests concerning the Department of Statistics.

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RERF News
Review Panel Members
David W. Gaylor, Principal Scientist, Sciences International Incorporated, Virginia (chairman)
Tomio Hirohata, Professor Emeritus, Kyushu University Faculty of Medicine, and Professor,
Nakamura Gakuen University (RERF ScientificCouncilor)
Susan Preston-Martin, Professor, Department of Preventive Medicine, University of Southern
California (RERF Scientific Councilor)
T. Shun Sato, Professor, Department of Epidemiol-ogy and Biostatistics, Kyoto University Schoolof Public Health
Takao Shohoji, Professor, Section of Information and
Behavioral Sciences, Hiroshima University Faculty of Integrated Arts and Sciences
Daniel O. Stram, Associate Professor, Departmentof Preventive Medicine, Division of Biostatistics,
University of Southern California
Toshiro Tango, Director, Division of Theoretical
Epidemiology, Department of Epidemiology,
National Institute of Public HealthN e w Datasets Av a i l a b l e on RERF Home Page
Two datasets have recently been added to the scientific archives section of the RERF home page(www.rerf.jp/eigo/archives/archvtoc.htm). One is the
LSS Report 12 noncancer mortality data for theperiod from 1950 through 1990.1 Detailed descriptions of the models used in the paper, and examples
illustrating how they were fitted, are included withthe dataset. See www.rerf.jp/eigo/scidata/
R12noncancer.pdf for more information.
The other dataset is a special version of the LSS
Report 11 mortality data with additional informationon the occurrence of acute radiation effects: epilation, flash burn, oropharyngeal lesions, and bleeding.
These data have been used by Stewart and colleagues
in recent efforts to investigate the potential impactof selection effects on LSS risk estimates. 2,3
See www.rerf.jp/eigo/scidata/R11acuteData.pdf
for more information about these data.
Other datasets available from the RERF homepage
include the LSS Report 12 cancer mortality data,detailed LSS solid cancer and leukemia incidencedata, and data on stable chromosome aberrations.

References
1.

Shimizu Y, Pierce DA, Preston DL, and Mabuchi K, Studies of the mortality of atomic bomb survivors. Report
12, part II. Noncancer mortality: 1950-1990. Radiation Research 1999, 152(4):374-89.

2.

Stewart A and Kneale G, A-bomb survivors: factors that may lead to a re-assessment of the radiation hazard.
International Journal of Epidemiology 2000, 29:708-714.

3.

Stewart A, A-bomb data: detection of bias in the Life Span Study cohort. Environmental Health Perspectives
1997, 105 Suppl 6:1519-21.

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

Analysis of the longitudinal hematology data in the AHS&

Analysis of the Longitudinal Hematology Datain the Adult Health Study
F. Lennie Wong
Department of Statistics
Various laboratory measurements have been collected from the Adult Health Study (AHS) subjects
since the program’s inception in 1958. These include
total serum cholesterol levels, blood pressure, hemoglobin and hematocrit, sedimentation rate, red andwhite blood cell counts, and lymphocyte and monocyte counts. Over the years, other laboratory data havebeen added. Anthropometric measurements such asof height, weight, and head circumference (in the inutero subjects) have been collected as well. Since
the subjects are invited to participate in the clinicalexamination on a biennial basis, the AHS has amassed
an inordinately large amount of data on nearly 20,000
individuals of all ages. The AHS is currently in its
twenty-second examination cycle, so for subjects who
have attended every examination since 1958, 22
measurements will be available by mid-2002. The
serial data spanning over a 40-year period provide a
unique opportunity for elucidating the temporal trendsof these physiological determinations. They also enable examination of whether and how exposure toatomic-bomb radiation modified these trends.
Although appropriate statistical methodologies
have been available for the analysis of longitudinal
serial data, it was only within the last decade when,coupled with the ever-increasing computing speed
and data storage space, efficient computer software
became available that have made the analysis of themassive AHS measurement data feasible. Prior tothat, data examination was relegated to cross sectional
methods at each examination cycle, as was done in
the AHS Report 6,1 rather than taking full advantageof the longitudinal nature of the data that allowed
one to examine and tease out birth cohort effects.
The crude method also was not conducive for generalizing secular trends and radiation effects gleaned
at each examination cycle.

els among birth cohorts were evident, which were
attributed to changes in Japanese dietary habits andlifestyle over three decades. Significant radiation effects were also demonstrated for cholesterol, withhigher levels shown for the irradiated subjects, andgreater increase for irradiated women than for irradiated men.7 Atomic-bomb radiation doses were also
shown to significantly affect the long-term trends ofblood pressures, although the direction of the effects
depended on age at the time of bombing or birth cohort status.6 More recently, we performed similar
analysis of the hemoglobin and hematocrit data, forwhich radiation effects had been suggested in crosssectional analyses conducted before 1990.1,8 The
details of our preliminary analysis of hemoglobin data
are described below.
Hemoglobin (Hb) levels of 12,323 subjects obtained from AHS examinations 1–20 (1958–2000)
were used. The study population excluded those who
were Not-In-City at the time of bombing (ATB) andthose for whom Dosimetry System 1986 (DS86)
doses were unavailable. Hb obtained at ages 80 years
or more were excluded because of the low participating rate in the AHS of persons beyond that age,making the data non-representative. Hiroshima female represented the largest group in the data (45%),
followed by Hiroshima male (26%), Nagasaki female(17%), and Nagasaki male (12%). Age ATB ranged
from 0 to 66 years, and Hb data were available forages 13 to 80 years. The median number of Hb determinations available was 10, with a range of 1 to20.

Using the mixed-effects model for the analysis ofserial measurement data,2 which takes into accountthe correlation among measurements within a person, and the appropriate computing software,3,4 longitudinal trends have been estimated for total serum
cholesterol and systolic and diastolic blood pressuresin the AHS.5,6 Notable differences in cholesterol lev-

As an initial step, the mean Hb was plotted against
mean age at each examination cycle by city and sex
according to birth cohort grouped into decades ofage ATB (Figure 1). At first glance, a sizable difference appears to exist among the birth cohorts, withthe levels of Hb being higher for younger than for
older birth cohorts. Further examination reveals thatmean Hb levels at some examination cycles are consistently high or low, and that there is a discernable
pattern of peaks and valleys in mean Hb by examination cycles among the various birth cohorts in eachcity. In fact, a similar plot using examination cycle

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

'Analysis of the longitudinal hematology data in the AHS
as the horizontal axis, instead of age, would reveal
consistent patterns over examination cycles, suggesting that the observed cohort differences may be an
artifact of the systematic variation associated withexamination periods. The sources of systematic variation may include changes in equipment, personnel,
study procedure, laboratory drift, and other unknown
factors, all of which can occur in studies with long
durations, such as the AHS. Thus, examination cycle
variations must be taken into account to elucidate an
accurate picture of the longitudinal trend of Hb.

examination cycle were allowed to interact with one
another and only the statistically significant terms
were retained in the final model estimate. The examination cycle indicators were kept in the model
regardless of statistical significance.
The estimate of the longitudinal model of Hb,adjusted for examination cycle, is shown in Figure 2.
For males in general, Hb levels rise from 18 years ofage to about 30 years, then decline thereafter. For
females, there is an initial tendency for Hb levels todecrease during the reproductive years, followed byan increase associated with menopausal period, andfinally declining again with further aging. Even after
adjusting for examination cycle variation, birth cohort differences appear to persist, with a tendency
for Hb levels of the older cohort, particularly those
who were 21–40 years ATB, to be lower than theyounger, 0–20 years ATB, cohort. Those who wereolder than 40 years ATB appear to have the lowest
Hb levels.

To begin the analysis, we assumed that Hb levelin each person is described by a linear-quadratic-cubic function of age at the time each Hb value wasobtained. This function was allowed to vary by cityand sex, and birth cohort differences were included
through the use of indicator variables of age ATBgrouped into decades (0–10, 11–20, 21–30, 31–40,
41–50, >50 years). Examination cycle variation was
adjusted for by including a set of indicator variables
for the 20 examination cycles for each city. The firstexamination cycle in each city served as the respective baseline. All variables except the indicators of

To determine if DS86 radiation doses significantly modify the longitudinal trend estimated for

Figure 1. Mean Hb level by mean age at AHS examination cycles 1–20, by birth cohort
groups in males and females of Hiroshima and Nagasaki.

16

16

Hiroshima Male

Nagasaki Male
15

14

14

Hb

15

13

12

age ATB (years)
0-10
11-20
21-30
31-40
41-50
> 50

13

12

11

11
20

30

40

50

60

70

80

16

20
16

Hiroshima Female
15

14

14

13

13

12

12

40

50

60

70

80

50

60

70

80

Nagasaki Female

Hb

15

30

11

11
20

30

Hb-DEC (graph 10)
1.09.01

Return to Table of Contents

40

50

Age (years)

60

70

80

20

30

40

Age (years)

RERF Update Volume 12, Issue 1, Spring–Summer 2001

Analysis of the longitudinal hematology data in the AHS
Hb, dose parameters were included in the model asa constant term of dose and as interactions with age,
age,2 and age.3 The parameters in the resultant model
were re-estimated and the significance of the doseterms tested. Dose effects were highly significant(p < 0.1 × 10 –13). The predicted Hb levels of theirradiated AHS subjects were decreased comparedto those of the minimally irradiated subjects (Figure 3). At 1 Gy exposure, the average reduction in
Hb ranged from –0.3% to –1.8%, with the least reduction seen at the youngest age and the most at theoldest age considered. No difference in radiation
effects was detected between Hiroshima and Nagasaki. The question of whether radiation effects
are modified by sex and birth cohort status is currently under examination.

Using the mixed-effects model, we were able toestimate the longitudinal trend of the Hb levels in the
AHS subjects. We also were able to show that Hb levels of the irradiated subjects were lower than those of
the minimally exposed subjects, confirming statistically the impression obtained in earlier analyses basedon cross-sectional methods. Thus it appears that exposure to atomic-bomb radiation is associated withmild anemia. Additional investigation underway includes re-analyses of the data by excluding subjects
diagnosed with diseases that are associated with reduced levels of Hb, including cancer, chronic liverdiseases, renal failure, collagen disease, and ulcer. This
will be useful for determining whether primary anemia, not the secondary form that results as a symptomof these diseases, also occur as a result of exposure toatomic-bomb radiation.

Figure 2. Estimate of the longitudinal model of Hb levels.

E(Hb)

16

16

Hiroshima Male

15

15

14

14

13

13

age ATB (years)
0-10
11-20
21-30
31-40
41-50

12

12

11

11
20

E(Hb)

16

Nagasaki Male

30

40

50

60

70

80

20
16

Hiroshima Female

15

15

14

14

13

13

12

12

11

30

40

50

60

70

80

50

60

70

80

Nagasaki Female

11
20

30

40

50

Age (years)

60

70

80

20

30

40

Age (years)

Hb-Dec (GRAPH 11)
1.3.01Return to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

Analysis of the longitudinal hematology data in the AHS
Figure 3. Percent reduction in the expected Hb level of the 1 Gy exposed subjects comparedto 0 Gy exposed subjects.
0.05
95% upper
confidence bound

0.00

E(Hb1 Gy ) - E(Hb0 Gy )

-0.05
-0.10
-0.15

95% lower
confidence bound

-0.20
-0.25
-0.30
-0.35
20

30

40

50

60

70

80

Age (years)

References
1.

Sawada H, Kodama K, Shimizu Y, Kato H. Adult Health Study Report 6. Results of six examination cycles,
1968–80, Hiroshima and Nagasaki. RERF TR 3-86.

2.

Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982; 38: 963–974.

3.

Cook N. A FORTRAN program for random-effects models. Department of Biostatistics, Harvard School of
Public Health, Boston, 1982.

4.

Goldstein H, Rabash J, Plewis I, Draper D, Browne W, Yang M, Woodhouse G, Healy M. A user’s guide to
MlwiN. Multilevel Models Project. Institute of Education, University of London, 1998.

5.

Yamada M, Wong FL, Kodama K, Sasaki H, Shimaoka K, Yamakido M. Longitudinal trends in total serum
cholesterol levels in a Japanese cohort, 1958–1986. Journal of Clinical Epidemiology 1997; 50: 425–434.

6.

Sasaki H, Wong, FL, Yamada M, Kodama K. The effects of aging and radiation exposure on the blood pressurelevels of atomic-bomb survivors. (In review)

7.

Wong FL, Yamada M, Sasaki H, Kodama K, Hosoda Y. Effects of radiation on the longitudinal trends of total
serum cholesterol levels in the atomic bomb survivors. Radiation Research 1999; 151: 736–746.

8.

Finch SC, Finch CA. Summary of the studies at ABCC–RERF concerning the late hematologic effects of atomic
bomb exposure in Hiroshima and Nagasaki. RERF TR23-88.

Return to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

Randomness of radiation-induced translocations

Randomness of Radiation-induced Translocations
Depends on Chromosome Length or
Surface Area as Target
Nori Nakamura, department chief; Kazuo Ohtaki, research scientist; Yoshiaki Kodama, chief,
Cytogenetics Laboratory; Mimako Nakano, assistant senior scientist; Masahiro Itoh, researchscientist; and Akio A. Awa, consultant, Department of Genetics, and John B. Cologne, seniorscientist, Department of Statistics
Summary
G-banded translocation data in blood lymphocytes from A-bomb survivors show an apparent linear relation between the number of translocations and chromosome length or DNA content. However, theobserved-to-expected (O/E) ratio seems to be inversely related to DNA content. Do smaller chromosomes undergo exchanges preferentially? We think this is arguable because the inverse relation disappears when chromosome
surface area rather than DNA content is considered the target for the expected aberration frequency. Under either
hypothesis, our results indicate positive associations between satellite- and/or heterochromatin-bearing chromosomes in interphase nuclei, supporting earlier perceptions of such associations.

Repeatedly, it has been argued whether radiationinduced chromosome aberrations distribute randomly
either within a chromosome or among chromosomes.1,2 In the former case, aberration breakpoints
may have appeared to cluster at certain bands of chromosomes, and in the latter case, aberrations may haveoccurred disproportionately in certain chromosomes
according to DNA content. As ionization itself is arandom physical process, if such a deviation fromrandomness exists, it is most likely biological. Constitutive associations among satellite- or
heterochromatin-bearing chromosomes, which may
undergo exchanges among themselves at higher-thanexpected frequencies because of their spatial
proximity, appear to be one factor influencing randomness.
However, in past cytogenetic studies, because only
limited data were available, possible interchromosomal associations were not taken into account. We
can now address this issue analyzing our latest Gband data, which comprise more than 11,000

radiation-induced reciprocal translocations in blood
lymphocytes from A-bomb survivors among nearly
48,000 cells examined. The survivors were all proximally exposed and the mean kerma dose estimatedby Dose System 1986 (DS86) is about 2 Gy. Identical aberrations from any one individual, i.e., clonalaberrations, and complex exchanges involving threeor more breaks were excluded.
Two alternative models are considered to calculate expected translocation frequency (Figure 1). The
classic chromosome length hypothesis assumes thatradiation can induce chromosome breaks in proportion to DNA content and that all breaks participate
in forming the exchanges with equal probability. The
new surface area model assumes that though radiation can induce chromosome breaks in proportion to
DNA content, only such damage near the surfaces of
the two chromosome masses can interact because
each chromosome occupies a discrete domain in interphase, and the interaction distance between the twolesions to generate dicentrics is suggested to be ex-

Figure 1. Two alternative models to describe radiation-induced interchromosomal exchanges ininterphase nuclei. The figures indicate possible exchanges between one large and two
small chromosomes.
Chromosome length model

Surface area modelReturn to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

!

Randomness of radiation-induced translocations
tremely short (equal to or less than 7 nm).3,4 In thismodel, we assume that each chromosome domain ininterphase nuclei comprises a simple spherical structure whose volume is in proportion to DNA content.
The model’s general impact is that the smaller chromosomes have a larger surface-to-volume ratio thanthe larger chromosomes and thus bear more damage
sites, which leads to the higher exchange rate per unit
content of DNA.

is highly significant (p < 0.0001), while the reanalyzed results following the surface area hypothesis
are no longer (p = 0.15) (Figure 3A and B). Thus, it
is clear that translocation distribution becomes closer
to random according to the surface area model.
In addition to the surface area hypothesis, under
the chromosome length hypothesis, two other explanations, not mutually exclusive, are possible for theapparent preferential occurrence of the aberrations
in smaller chromosomes. Namely, exchanges of small
segments may be detected more effectively by Gbanding if they occur in smaller chromosomes, and/or smaller chromosomes may tend to position more
centrally while larger chromosomes position nearer
the periphery within nuclei.7 The first explanation
seems less likely because FISH data also showed asimilar trend when regressed by chromosome length.2
By contrast, the latter explanation suggests no obvious reason to be rejected and, indeed, seems
reasonable provided that such chromosome-lengthdependent, nonrandom positioning occurs
constitutively. Here, the outermost or larger chromosomes have no interactive counterpart at their further
outer space, which would limit their ability to undergo interchromosomal exchanges. Unfortunately,
current data do not allow us to evaluate relative contributions among these possibilities.

Results using the chromosome length model showthat translocation frequency relates linearly to chromosome length while the O/E ratio of eachchromosome varied from 0.80 to 1.36, mostly within
1 plus minus 0.2 (Figure 2A). Further, the ratio appears to be inversely related to the DNA content of
the chromosomes. This inverse relation between
O/E ratio and chromosomal DNA content is not a
new finding; Cook reported the largest G-band data,comprising nearly 1,500 exchanges,5 and Barquinero
et al.2 and Cigarran et al.6 reported fluorescence insitu hybridization (FISH) results comprising about
3,600 and 1,000 exchanges, respectively.
Following the surface area model, we find thatthe negative trend observed in Figure 2A no longer
holds and O/E ratios are more or less unified (Figure2B). Cigarran et al.6 reached a similar conclusion
based on the same spherical model. Although theoverall trend is now positive and statistically significant (p = 0.0015), the results largely depend on a
few influential points. Exclusion of chromosome 1
and the smallest two chromosomes, Y and 21, forexample, abolishes the significance of the relation (p= 0.15). Thus, the apparent positive relation should
not be concluded generally. In fact, lower O/E ratios
in small chromosomes are observed in neither the Gband 5 nor the FISH studies. 2 The FISH results
reported by Barquinero et al.2 show that, under thechromosome length hypothesis, the overall relation

Irrespective of the DNA content or surface area
hypothesis, four observations stand out when we
dissect the present translocation data into all possiblecombinations of two-chromosome pairs. First,
translocations occur with significantly higher-thanexpected frequencies (O/E ratio = 1.5–1.8) between
chromosomes bearing heterochromatin(chromosomes 1, 9, 15, 16, and Y) and/or satellites(chromosomes 13 to 15) (results for chromosomes
21 and 22 vary according to the model) and between
their homologues, supporting earlier ideas of such

Figure 2. Observed-to-expected ratio of radiation-induced translocations observed in blood lymphocytes from
A-bomb survivors in relation to A) DNA content (Mb) and B) surface area (arbitrary unit). Results forchromosomes X and Y in males are corrected because they are present as single copies whereas
other chromosomes are present as pairs.

A

1.5
1.4

B

1.6
1.4

1.3
1.2

O/E ratio

1.2
1.1

1.0

1.0
0.8
0.9
0.6

0.8
50

100

150

DNA content (Mb)

Return to Table of Contents

200

250

60

80

100

120

140

160

180

200

Surface area (arbitrary unit)

RERF Update Volume 12, Issue 1, Spring–Summer 2001

"Randomness of radiation-induced translocations
associations. Second, there are no clear remoteassociations of one inactive X chromosome from theremaining chromosomes in females. This is in linewith in vitro FISH results in which aberration
frequency of X chromosomes in female cells is similar
to that for autosomes of similar lengths2 and active
and inactive X chromosomes contribute more or lessequally to the pool of translocations induced byradiation exposures.8 Third, no pairs of autosomal
homologues underwent exchanges less frequently
than expected, failing to support Nagele’s suggestionof separate locations of autosomal homologues ininterphase nuclei.9 Finally, because O/E ratio varies
among certain large chromosomes frequently used
for FISH painting, for biodosimetric purposes, one
should be cautious to use the same combination ofchromosomes painted by FISH for both calibrationand sample testing or to select combinations ofchromosomes so that the results may represent a meanfrequency of aberrations in the whole genome.
In conclusion, although the surface area model,
which assumes a simple spherical structure, is far
from the real organization of chromosome domains
in interphase nuclei, the surface area hypothesis is
more attractive than the physical length hypothesis
not only on theoretical grounds, but because the O/E
ratio is closer to unity irrespective of chromosome
size, which is an indication for the randomness. And,in either hypothesis, it seems clear that certain chromosomes undergo positive associations in interphasenuclei, though the contribution of such associations
to the aberrations in the whole genome is rather limited.

Figure 3. Observed-to-expected ratios of radiation-induced interchromosomal exchanges (dicentrics andtranslocations) observed in an in vitro FISH study using blood lymphocytes 2 in relation to A)
chromosomal DNA content (Mb) and B) surface area (arbitrary unit).
1.8

B

1.6

A

1.6

1.4
1.2

1.2
1.0



O/E ratio

1.4

1.0

0.8
0.8
0.6
0.6

0.4

50

100

150

200

DNA content (Mb)

250

60

80

100

120

140

160

180

200

Surface area (arbitrary unit)

References1.

Buckton KE. Identification with G and R banding of the position of breakage points induced in human chromosomes by in vitro X-irradiation. International Journal of Radiation Biology 1976; 29: 475–488.

2.

Barquinero JF, Knehr S, Braselmann H, Figel M, Bauchinger M. DNA-proportional distribution of radiationinduced chromosome aberrations analysed by fluorescence in situ hybridization painting of all chromosomes ofa human female karyotype. International Journal of Radiation Biology 1998; 74: 315–323.

3.

Thacker J, Wilkinson RE, Goodhead DT. The induction of chromosome exchange aberrations by carbon ultrasoft
X-rays in V79 hamster cells. International Journal of Radiation Biology 1986; 49: 645–656.

4.

Goodhead DT, Thacker J, Cox R. Effects of radiations of different qualities on cells: Molecular mechanisms ofdamage and repair. International Journal of Radiation Biology 1993; 63: 543–556.

5.

Cook P, Seabright M, Wheeler M. The differential distribution of X-ray-induced chromosome lesions in trypsinbanded preparations from human subjects. Humangenetik 1975; 28: 221–231.

6.

Cigarran S, Barrios L, Barquinero JF, Caballin MR, Ribas M, Egozcue J. Relationship between the DNA content of human chromosomes and their involvement in radiation-induced structural aberrations analysed by painting.
International Journal of Radiation Biology 1998; 74: 449–455.

7.

Sun HB, Shen J, Yokota H. Size-dependent positioning of human chromosomes in interphase nuclei. Biophysics
Journal 2000; 79: 184–190.

8.

Surralles J, Natarajan AT. Radiosensitivity and repair of the inactive X-chromosome. Insights from FISH and
immunocytogenetics. Mutation Research 1998; 414: 117–124.

9.

Nagele R, Freeman T, McMorrow L, Lee H-Y. Precise spatial positioning of chromosomes during prometaphase:
Evidence for chromosome order. Science 1995; 270: 1831–1835.

Return to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

#Cancer risks at low doses among A-bomb survivors

Cancer Risks at Low Doses among
A-bomb Survivors
Donald A. Pierce and Dale L. Preston
Department of Statistics
The RERF Life Span Study is often referred to asa “high-dose” study, requiring substantial extrapolation to estimate risks of interest for radiation
protection. Further, many people think of the study as
contrasting cancer rates of “A-bomb survivors” tothose in a comparison population that might differ
from the survivors in various respects not related toradiation exposure. Both of these would be serious
limitations, but each characterization is only half true.
Unfortunately most RERF analyses, including ourprevious ones, have done little to dispel such notions—much less to capitalize on the true strengthsof the study in these respects. This article presents
aspects of our recent Radiation Research paper(154:178–86, 2000), which was intended as a start inthis direction. Part of the motivation was the increasing controversy about low-dose radiation risks forcancer, and in particular regarding the suitability of
the “linear, no threshold” (LNT) interpretation.
What do we mean by the two characterizations
being only “half true”? Regarding the first, while itis true that the usual linear risk estimates are largely
determined from effects in the 0.5–2 Sv range, similar estimates result from restricting the dose range tobelow 0.5 Sv or even below 0.2 Sv. About 75% of
the survivors in the significantly-exposed (>0.005 Sv)
part of the population—about 35,000 persons presenting 5,000 cancer cases so far—had doses in therange 0.005–0.02 Sv of primary interest for radiation protection. The real limitation of the study is notlack of information about low doses, but that the exposures were only acute. As for the second
characterization, it is important to realize that resultsfrom conventional analyses are virtually unchanged
if the “comparison group” of those more than 2 or 3
km from the bombs, about half the study cohort, issimply omitted from the analysis. This is because of
the large size of, and the wide variation in doses
within, the proximal component.
Moreover, there is some interplay between the twoissues of directly estimating low-dose cancer risks
and whether this distal comparison group is employed. It appears that the largely rural population
beyond 3 km has had about 5% higher cancer risks
than the part of the urban population with doses ofnearly zero. Such demographic variations in cancer
rates are in general quite common. Such a bias would
have negligible effect on inferences about risks athigh doses; but eliminating it becomes a critical issue when estimating cancer risks at around 0.1 Sv,
where the radiation risk may also be on the order of
5% of normal cancer rates. It greatly strains any epidemiological investigation to estimate risks of thislevel, since within the scope of the study cancer rates
may vary to that extent due to other risk factors correlated with the exposure under investigation. But
the special features of the RERF study, including its
large size, adequate dosimetry, and especially the very
sharp variation of dose with distance (decreasing by
1/3 each 100 m), may make this possible with reasonable confidence. This is extremely rare in any kindof observational study, particularly in epidemiology.
The following table is not intended for analysis,
since adjustment for age and sex is crucial, but rather
is given for perspective on the study.

Table. General summary of the 1958–1994 cancer incidence data
Colon dose, Sv (distance)

Subjects

Solid cancers

Estimated excess>3,000 m

23,4933,230<3,000 m and <0.005 Sv

10,1591,301

10.005–0.1

30,5244,119

69

0.1–0.2

4,775

739

61

0.2–0.5

5,862

982

149

0.5–1

3,048

582

169

1–2

1,570

376

167

>2

470

126

84

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100

RERF Update Volume 12, Issue 1, Spring–Summer 2001

$Cancer risks at low doses among A-bomb survivors
This tabulation shows that there are large numbers of survivors in the study with low doses, andalso that there remains a large comparison group if
those beyond 3 km are omitted. The estimated excess was computed from a linear regression on dose,
but with an additional parameter for the group beyond 3 km.

ing effects suggested by the data. The main point of
the plot is that there is no indication that low-doserisks are overestimated by linear regression on thefull dose range. There is statistically significant riskin the dose range below 0.1 Sv (P = 0.05, one-sidedtest). The upper 95% confidence limit for a threshold, beyond which the risk increases linearly fromzero, is 0.06 Sv. It is visually clear, in view of thealternative baseline shown, that these inferences
would change substantially if the restriction to <3km were not made.

Our primary analytical description is given by thefollowing figure for which the underlying methods are
documented in our paper. The aims of this plot are to“display the data” as clearly as possible, and to provide an unconstrained—or nonparametric—estimateof the dose response function. At the same time, wewish to avoid to the extent possible effects of utilizing
arbitrary dose categories. We achieve that by computing rather imprecise risk estimates for a large numberof categories and then smoothing the results as shown.
The primary focus when looking at such plots shouldbe the smooth curve, and we emphasize that the dashedcurves are ±1 SE limits for the solid smooth curve,
rather than for the plotted points.

In our paper we also investigate whether results
seen in this figure are likely to be markedly changed
by possible revision of DS86 dosimetry system, currently under consideration. For several years there
has been renewed interest and activities pertaining
to discrepancies between physical measurements andDS86 estimates for neutrons in Hiroshima. Althoughother revisions are likely, the neutron issue is the mostinteresting since the suggestion is that required modifications would be distance-dependent, which mightalter the apparent shape of the dose-response curve.
Early suggestions were that to conform to measurements the DS86 Hiroshima neutron estimates would
need to be increased by a factors of 1, 10, and 30 atdistances 800, 1,600, and 2,000 m from the bomb.

We have no idea of the meaning of the “bump” ataround 0.2 Sv, but note that it occurs in both
Hiroshima and Nagasaki.Whether it is statisticallysignificant is questionable, due to difficulties in test-

1.5

2.5

2.0

1.4

Relative Risk

1.5

1.3

1.0
0.0

0.5

1.0

1.5

2.0

1.2

1.1

1.0
0.0

0.1

0.2

0.3

0.4

0.5

Dose with Neutron Weight 10
Figure. Estimated low-dose relative risks. Age-specific cancer rates over the 1958–1994 followup period relative to those for an unexposed person. Averaged over the follow-up andover sex, and for age at exposure 30. The dashed curves represent ±1 standard errors
for the smoothed curve. The straight line is the linear risk estimate computed from therange 0–2 Sv. Because of an apparent distinction between distal and proximal zerodose cancer rates, the unity baseline corresponds to zero-dose survivors within 3 kmof the bombs. The dotted line represents the alternative baseline if the distal survivors
were not omitted. The inset shows the same information on the fuller dose range.

Return to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

Cancer risks at low doses among A-bomb survivors
We indicate in our paper why the physicists involved
in radiation transport calculations find such a distance relationship for neutron doses physically
impossible, bringing into question the interpretationof the measurements. These issues are currently under study by a bi-national group of physicists. In thepaper we investigate consequences of a more modest—but perhaps still too large—modification that
reduces the factors given above to 1, 5, and 15. We
also employ for this a variable neutron relative biological effectiveness (RBE), taking values of about
10 at high survivor doses and about 40 at low survivor doses, since the likelihood of such a variable RBE
is a reason that many expect neutron estimate modifications to be potentially important. Our tentative
conclusion is that such a neutron dose estimate modification would not result in less apparent linearity ofthe dose response than seen in the figure here.

%radiation dose with distance from the bombs meansthat useful comparisons are available between persons within a narrow distance range. Since substantial
heat and blast effects reached further than radiation,
those persons experienced similar effects of thebombings, e.g., severe disruption of their lives, aside
from radiation dose.

So to summarize, our paper clarifies that—contrary
to widespread views—the RERF data provide substantial direct information about low-dose radiation risks
for cancer. Further, the available information is by nomeans restricted to that from comparison of “A-bomb
survivors” to some group not experiencing the disaster. For inference about low-dose risks it is necessary
to take particular care in the choice of comparison
population, which is equally true of any low-dose studyof human radiation risks. The very rapid decrease of

Our results indicate that cancer risks for doses on
the order of 0.05 Sv are not overestimated by theusual regression analysis on much wider dose ranges,
such as 0–2 Sv. In our analysis there is direct statistically significant evidence of risk in the dose range ofapproximately 0–0.1 Sv, but we emphasize that thismode of reasoning, and certainly the precise limitsof such a range, should not dominate interpretationof the data. In view of the highly linear dose response
down to low doses, it is neither sound statistical interpretation nor prudent risk evaluation to take theview that the risk should be considered as zero insome low-dose range due to lack of statistical significance within that range. To do this would be tobase risk protection on the smallest plausible risk at
those low doses, since in statistical reasoning a nonsignificant result means precisely that the lower
confidence limit is zero or less. There is every reason to conclude from the RERF data that the usual
linear cancer risk estimation is appropriate for low
doses.

Return to Table of Contents

RERF Update Volume 12, Issue 1, Spring–Summer 2001

Research Protocols
Research Protocols Approved 1998–2000
RP 1-98 A prospective study of bladder cancer and diet
Nagano J, Kono S, Sharp GB, Fujita S, Moriwaki H,
Mabuchi K
The number of epidemiologic studies that haveinvestigated the role of dietary factors in bladder carcinogenesis is limited. We propose a prospective
study to examine the relation between dietary factors and bladder cancer risk. Specific questions to beaddressed are whether the consumption of green-yellow vegetables or fruits is related to a decreased risk
and whether meat intake is related to an increased
risk. Subjects are approximately 40,000 men andwomen in the Life Span Study (LSS) extended cohort who responded to a mail survey on lifestyleconducted in 1979 and 1980 and whose dose estimates of radiation exposure are available according
to the Dosimetry System 1986 (DS86). Information
on bladder radiation dose will be obtained from Radiation Effects Research Foundation (RERF) files,
and consumption frequency is available for 22 dietary items. Bladder cancer incidence in the period
from 1980 to the latest available year will be used.
Statistical adjustment will be made for tobacco smoking, educational level, and radiation exposure.
Possible interactions between the dietary factors andradiation exposure as well as tobacco smoking will
be examined.
RP 1-99 Primary liver cancer incidence study
among atomic-bomb survivors, 1958–87 (Addendum to RP 5-90)
Sharp GB, Mizuno T, Fujiwara S, Cologne JB,
Mabuchi K, Kodama K
RP 5-90 describes a case-control approach to assessing hepatitis B virus (HBV) infection and testing
the joint effects of radiation and HBV on primaryliver cancer (PLC) in the Life Span Study (LSS).
Originally, HBV was the only hepatitis virus understudy with infections to be measured by staining
methods (orcein and immunohistochemical stain) andby polymerase chain reaction (PCR). The hepatitis
C virus (HCV) was discovered shortly before RP 590 was written and is recognized as a possible PLC
risk factor in the protocol. One specific stated objective of RP 5-90 is “ . . . to lay the groundwork for acontinuing study of the role . . . of hepatitis C virus in
the future incidence of hepatocellular carcinoma in
the LSS sample.” Although there were serum-based
tests for HCV at the time the protocol was written,
there was at that time no method for detecting HCV—an RNA virus—in liver tissue. Subsequent to thewriting of protocol 5-90, it became possible to assess HCV in liver tissue using reverse
transcriptase-polymerase chain reaction (RT-PCR),
and an investigator on this protocol in the DepartReturn to Table of Contents&ment of Radiobiology (T.M.) began testing cases andcontrols for HCV in addition to HBV. To date, 364
cases and 596 matched controls have been tested for
HBV using PCR and for HCV using RT-PCR, although in some instances, lack of tissue or poor tissue
quality resulted in unsuccessful tests. These tissuebased tests are still required on approximately 250
controls.
Although the use of PCR on archival liver tissue
samples is an innovative procedure that has allowed
RP 5-90 to make the most of RERF resources andgreatly increased the value and power of the study,
one problem with this technique is that it has not beenused previously and lacks validation. We, therefore,
propose to utilize serum samples stored in the Adult
Health Study to validate PCR and RT-PCR of livertissue as a means of detecting HBV and HCV. We
also want to compare the pathology staining tests for
HBV against standard serum measures. In total, we
expect to test about 45 serum samples from subjects
for whom both tissue and serum samples are available.

RP 2-99 Thyroid diseases in Hiroshima andNagasaki atomic-bomb survivors
Tominaga T, Akahoshi M, Soda M, Neriishi K,
Fujiwara S, Yamada M, Ezaki H, Kodama K,
Nakashima E, Shibata Y, Okubo M, Ashizawa K, Sera
N, Yokoyama N, Eguchi K
The effect of atomic-bomb radiation on thyroid
diseases will be analyzed in 5,489 Adult Health Study(AHS) participants in Hiroshima and Nagasaki toelucidate thyroid disease incidence. All subjects will
undergo thyroid gland palpation, function testing,autoantibodies testing, and ultrasound examination.
The previous thyroid study conducted in Nagasaki
from 1984 to 1987 demonstrated increased thyroid
tumor prevalence and a radiation-dose-response relationship in autoimmune hypothyroidism among
atomic-bomb survivors. This study will assess whether there is a closer relationship between these diseases
and radiation dose after more than ten years. This is
the first thyroid disease prevalence study of theHiroshima AHS since 1971. Previously detected solitary thyroid nodules will be investigated by precise
ultrasound nodule-volume measurement.
RP 1-00 Molecular mechanisms of radiationinduced hyperparathyroidism
Fujiwara S, Arnold A, Mallya S, Ezaki H
Primary hyperparathyroidism (HPT) is a common
endocrine disorder and most often is due to a solitary adenoma in one of the parathyroid glands.
Irradiation of the head and neck is an established risk
factor for the development of primary HPT.
Dr. Arnold’s laboratory has recently developed atransgenic mouse model to study the pathogenesis ofparathyroid neoplasia in a setting that simulates the
RERF Update Volume 12, Issue 1, Spring–Summer 2001

Research Protocols
human disease. Targeted overexpression of cyclin D1
in the parathyroid glands of these mice (PTH-D1)
causes the animals to develop HPT. To exploit theadvantage offered by this mouse model, we have initiated studies that will ultimately localize and/or
identify genes that contribute to development of radiation-induced murine parathyroid tumors.
This research protocol will apply to future all casesof hyperparathyroidism detected in the Adult HealthStudy (AHS) cohort that require surgical removal of
the parathyroids. The studies proposed here will analyze radiation-induced human parathyroid tumors forchromosomal alterations using molecular genetic andcytogenetic approaches in a way that is intimately
complemented by and intertwined with Dr. Arnold’s
ongoing murine studies. Thus, our studies are designed to localize and/or identify novel tumor
suppressor genes/oncogenes that play a role in radiation-induced human parathyroid neoplasia.

RP 2-00 Studies on microbial infection andcell-mediated immunity in the Adult HealthStudy population
Hakoda M, Kusunoki Y, Yamada M, Kasagi F,
Hayashi T, Shimizu M, Kodama K, Kyoizumi S,
Katayama H, MacPhee DG, Fujiwara S, Suzuki G,
Akahoshi M
Increased mortality from and incidence of atherosclerotic diseases, such as ischemic heart disease andcerebrovascular diseases, with radiation dose havebeen demonstrated among atomic-bomb survivors.
However, biological mechanisms relating radiation
exposure to atherosclerotic diseases among atomicbomb survivors remain unclear. Recently, theinflammatory process has been suggested as playing
important roles in atherosclerosis initiation and progression, with microbial infection regarded as aplausible trigger. A number of reports investigating
the relationship between infection with Chlamydia
pneumoniae, Helicobacter pylori, or cytomegalovirus and atherosclerotic diseases have been published.
Of note, cell-mediated immunity, which is important
for antimicrobial defense, has been reported as impaired in atomic-bomb survivors, and the decreased
cell-mediated immunity is associated with myocardial infarction. Furthermore, laboratory tests haveshown that inflammatory responses in the survivors
increase according to radiation dose, which may suggest the presence of some chronic infection.
Accordingly, it seems important to analyze the interrelationships among radiation dose, microbial
infection, and cell-mediated immunity among thesurvivors to explain the mechanism for atherosclerotic disease development in the survivors. To
evaluate infection with Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus, specificantibodies to these pathogens will be measured in
the sera of Adult Health Study (AHS) participants inReturn to Table of Contents'
this study. Cell-mediated immunity will be evaluated on several subsets of T cells, especially on T-helper
subsets. Among T-helper subsets, the T-helper 1(Th1) subset has been regarded as an important Tcell population for the antimicrobial defense
mechanism. Analysis of study results will clarify
whether atherosclerotic diseases are related to infections among the survivors and if cell-mediatedimmunity impairment is the basis for infections orinfection-related diseases.

RP 3-00 Ophthalmologic study of atomic bomb
survivors
Minamoto A, Taniguchi H, Mishima HK, Amemiya
T, Nakashima E, Neriishi K, Hida A, Fujiwara S,
Suzuki G, Akahoshi M
Almost two decades have passed since the previous ophthalmologic study. Since then, substantial new
information concerning radiation and senile cataracts
has become available, suggesting the need for re-evaluation of cataracts in atomic-bomb survivors. Recent
findings include biological evidence of radiation influence on the lens, new evaluation methods forocular damage, new epidemiological confounders toassess ocular damage, and a better understanding ofrisk factors. Because a simple resection operation has
become available for treatment, this may be a lastopportunity for epidemiological evaluation of cataracts in A-bomb survivors.
Study subjects will be (1) those who participatedin the previous study and (2) those who were age 13
or less at the time of the bombs. In the first group, we
will investigate the natural history of radiation cataracts over a period of several decades. In the second,
we will estimate the risk of radiation on the lens.
Regression analysis will be conducted for possible
late-onset subcapsular axial opacities and polychromal changes and early-onset peripheral opacities
using the Lens Opacity Classification System II for
grading and incorporating a variety of confounding
factors. This study will enable us to make new estimates of the risk of lens changes with enhanced
quantitation and precision and could lead to a moreaccurate description of the shape (threshold) of thedose response for radiation cataracts. Lens photographs will be stored permanently as digital computer
images.
RP 4-00 Pilot mail survey of the children of
atomic bomb survivors
Koyama K, Nagano J, Suyama A, Watanabe T,
Fujiwara S, Takahashi N, Preston DL, Mabuchi K,
Taira SA mail survey is being planned in the RERF F1
cohort to obtain epidemiological information that will
be used for ongoing mortality and cancer incidence
studies and the establishment of a sub-cohort for aclinical health examination program that is being
RERF Update Volume 12, Issue 1, Spring–Summer 2001

Research Protocols
planned. A pilot survey has been designed to test theforms and to identify administrative and other problems that might arise during the full survey. The pilot
survey will be conducted among 300 (200 in Hiroshima and 100 in Nagasaki) F 1 cohort members
randomly selected from the subset of the F1 population that is to be included in the full survey, i.e., thoseF1 subjects who are residing in or around Hiroshima
and Nagasaki and whose parents received doses ofless than 0.005 Gy. A self-administered questionnairethat asks about smoking, alcohol consumption, diet,exercise, occupation, and past and present health status will be sent to the pilot study subjects. In addition,
the subjects will be asked to provide comments on
difficulties they had in answering the questions andon their reaction to some of the questions that areconsidered “sensitive.” Their responses will be evaluated and considered in developing the final study
plan for the full mail survey.

RP 5-00 The prevalence, incidence, and prognosis of the Brugada type electrocardiogram:
A population-based study of four decades
Matsuo K, Akahoshi M, Nakashima E, Suyama A,
Seto S, Hayano M, Yano K
Brugada syndrome, a new clinical entity causingsudden death due to ventricular fibrillation, was established in 1992. This syndrome has no structuralabnormality in the heart but has characteristic electrocardiogram (ECG) manifestation; right bundle
branch block and ST-segment elevation in leads V1
to V2/V3. Because of a new clinical entity, the prevalence and incidence of such ECG manifestation, i.e.,the Brugada-type ECG, and rate of sudden deathamong those who have the Brugada-type ECG havenot been determined in general population. Using thedata of Adult Health Study cohort, we would like toexamine the prevalence, incidence, and prognosis of
the Brugada-type ECG. Because cardiac sodium
channel gene (autosomal dominant inheritance) is
involved in development of the Brugada syndrome,
we also examine the relationship between the
Brugada-type ECG and radiation dose.


years of age at diagnosis). This study is proposed totest the hypothesis that the high incidence of earlyonset breast cancers in the A-bomb survivor
population may be due to the damaging effect of Abomb radiation on the normal allele of a breast cancer
susceptibility gene in women who are heterozygous
carriers of germline mutations of the gene. The firststep in initiating these investigations will be to collect 700 samples of breast cancer tissue fromsurvivors and suitable unexposed women with breast
cancer for comparison. The second step will be tosearch for damage to, or deletion of, the normal allele of the breast cancer susceptibility genes (BRCA1and BRCA2) using available methods for detectionof alterations in gene expression and protein localization. When abnormalities are detected in ascreening of all cases, DNA will be sequenced tocharacterize the aberrations. With regard to the
Ataxia-telangiectasia mutated (ATM) gene, an immunohistochemical staining technique will be used toscreen for abnormalities and the relationship between
early-onset breast cancer and mutations in the ATM
gene will be investigated. Each specimen will be coded and hence rendered anonymous before being
subjected to molecular analysis. Information linking
individual identification to biological samples will
be maintained by the data linkage coordinator.

RP 6-00 Molecular alterations in early-onset
breast and ovarian cancers among atomic
bomb survivors
Hirai Y, Ban S, MacPhee DG, Mabuchi K, Tokuoka
S, Koyama K, Suyama A, Soda M, Tokunaga M,
Cologne JB, Nakamura N, Katayama H, Dohi K,
Fukuhara T, Matsuura H, Hayashi Y, Fujihara M,
Takahashi R, Yoshikawa K, Land CE, Tucker MA,
Buetow KH, Iwamoto KS
Breast cancer is one of the most obviously radiogenic tumors so far identified among the atomic bomb
(A-bomb) survivor population. Excess relative risk
(ERR) per sievert is especially high for early-onset
cases (i.e., cases where the patient is less than 35
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RERF Update Volume 12, Issue 1, Spring–Summer 2001

Recent Publications
Recent Publications(Japanese): the original article is in Japanese;(JTr): a Japanese translation is available.
Asai T, Inaba S, Ohto H, Osada K, Suzuki G,
Takahashi K, Tadokoro K, Minami M. Guidelines for irradiation of blood and blood components to prevent post-transfusion graft-vs.-hostdisease in Japan. Transfusion Medicine 2000;
10:315–20.
Asakawa J. RLGS method. Rinsho Kensa [Journalof Medical Technology] 2000; 44:653–9. (Japanese)
Asakawa J, Kodaira M, Ishikawa N, Ito K, Ito K,
Nagataki S. Analysis of gene expression in thyroid cancer by using a novel two-dimensional
display method of cDNA. Seibutsu Butsuri
Kagaku [Japanese Journal of Electrophoresis]
2000; 44:177–80. (Japanese)
Ban S. Mitochondrial DNA-defective cells for thecellular life-science study. Igaku no Ayumi [Journal of Clinical and Experimental Medicine]
2000; 193:254–255. (Japanese)
Ban S, Shinohara T, Hirai Y, Moritaku Y, Cologne
JB, MacPhee DG. Chromosomal instability in
BRCA1- or BRCA2-defective human cancer cells
detected by spontaneous micronucleus assay. Mutation Research 2001; 474:15–23. (RERF Report
11-00)
Bonassi S, Fenech M, Lando C, Lin Y, Ceppi M,
Chang WP, Holland N, Kirsch-Volders M, Zeiger
E, Ban S, et al. Human micronucleus project:International database comparison for results withthe cytokinesis-block micronucleus assay inhuman lymphocytes: I. Effect of laboratory
protocol, scoring criteria, and host factors on thefrequency of micronuclei. Environmental andMolecular Mutagenesis 2001; 37:31–45.


Fujiwara S. Osteoporosis-related vertebral fracture
and its prevalence. Morii H, ed. Osteoporosis
Q&A. Tokyo: Iyaku Journal Sha [Medical Journal Co.]; 2000, pp 51–3. (Japanese)
Fujiwara S. Epidemiology of osteoporosis. Kotsu
Kansetsu Jintai [Journal of Musculoskeletal System] 2000; 13:323–7. (Japanese)
Fujiwara S. Environmental factors of osteoporosis:
Lifestyle and osteoporosis. Clinical Calcium
2000; 10:1563–8. (Japanese)
Fujiwara S. The ways of medical treatments for asymptomatic osteoporosis. Medical Practice
2000; 17:411–4. (Japanese)
Fujiwara S. An evaluation of the factors which influence osteoporosis. Life style. Horumon to
Rinsho [Clinical Endocrinology] 2000; 48 (Special issue):98–102. (Japanese)
Fujiwara S. Epidemiology of osteoporotic spine fracture—Prevalence and incidence. Clinical Calcium 2000; 10:760–6. (Japanese)
Fujiwara S, Hosoda Y. Two major radiation eventsin the 20th century—Hiroshima and Nagasaki,
and Chernobyl. Current Topics in Radiology
2000; 2:13–21.
Fujiwara S, Kusumi S, Cologne JB, Akahoshi M,
Kodama K, Yoshizawa H. Prevalence of antihepatitis C virus antibody and chronic liver disease among atomic bomb survivors. Radiation
Research 2000; 154:12–9. (RERF Report 7-99)(JTr)
Fujiwara S, Yamada M, Kodama K. Radiation effects on children. Shonika [Pediatrics of Japan]
2000; 41:2033–9. (Japanese)
Gilbert ES, Koshurnikova NA, Sokolnikov M,
Khokhryakov VF, Miller S, Preston DL,
Romanov SA, Shilnikova NS, Suslova KG,
Vostrotin VV. Liver cancers in Mayak workers.
Radiation Research 2000; 154:246–52.

Cologne JB, Preston DL. Impact of comparisongroup on cohort dose response regression: An example using risk estimation in atomic-bomb survivors. Health Physics 2001 (May); 80(5):491–
6. (RERF Report 3-00)

Hakoda M. Treatment of rheumatoid arthritis withmonoclonal antibodies. III. Ensho to Meneki [Inflammation and Immunology] 2000; 8:84–90.
(Japanese)

Cologne JB, Preston DL. Longevity of atomic-bomb
survivors. Lancet 2000; 356:303–7. (RERF Report 8-99) (JTr)

Hayashi T, Trosko JE, Hamada K. Inhibition of gap
junctional intercellular communication in rat liver
epithelial cells with transforming RNA. FEBS
Letters 2001; 491:200–6.

Fujisawa H, Izumi S. Inference about misclassification probabilities from repeated binary
responses. Biometrics 2000; 56:706–11.
Fujiwara S. Guideline for therapy of osteoporosis.
Nippon Iji Shinpo [Japanese Medical Journal]
2000; No. 3964:26–32. (Japanese)
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Imamura N, Kusunoki Y. Immune functions ofatomic-bomb survivors, especially concerning
their relationships to diseases that are frequently
observed in survivors. Rinsho Kensa [Journal of
Medical Technology] 2001 (June); 45(6):651–9.
(Japanese)
RERF Update Volume 12, Issue 1, Spring–Summer 2001

Recent Publications
Izumi S, Ohtaki M. Estimating cancer risk of atomicbomb survivors considering individual risk variation due to unobserved covariate effects. Journalof Radiation Research 2000; 41:477.
Kabuto M, Akiba S, Stevens RG, Neriishi K, Land
CE. A prospective study of estradiol and breast
cancer in Japanese women. Cancer Epidemiology,
Biomarkers and Prevention 2000; 9:575–9.
(RERF Report 3-99) (JTr)
Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons
A, Crean J, Ishida N, Nakagawa M, Takechi M,
Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue
S, Horiki K, Shiraki M, Ouchi Y, Orimo H. Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: Possible implications for hip-fracture risk. Nutrition 2001 (April);17(4):315–21.
Kato K, Antoku S, Kodama K, Kawamura S, Fujita
Y, Komatsu K, Awa AA. Organ doses from radiation therapy in atomic bomb survivors. Radiation
Research 2001 (June); 155(6):785–95. (RERF
Report 1-00)
Koshurnikova NA, Gilbert ES, Sokolnikov M,
Khokhryakov VF, Miller S, Preston DL, Romanov
SA, Shilnikova NS, Suslova KG, Vostrotin VV.
Bone cancers in Mayak workers. Radiation Research 2000; 154:237–45.
Kusunoki Y, Hayashi T, Kyoizumi S. Long-term immunological defects and their effects on the healthof atomic bomb survivors. Hoshasen Seibutsu
Kenkyu [Radiation Biology Research Communications] 2000; 35:315–32. (Japanese)
Kusunoki Y, Hayashi T, Morishita Y, Yamaoka M,
Maki M, Hakoda M, Kodama K, Bean MA,
Kyoizumi S. T-cell responses to mitogens inatomic bomb survivors: A decreased capacity to
produce interleukin 2 characterizes the T cells ofheavily irradiated individuals. Radiation Research
2001; 155:81–8. (RERF Report 18-99)
Kusunoki Y, Kyoizumi S, Honma M, Kubo Y, Onishi
H, Hayashi T, Seyama T. NK-mediated elimination of mutant lymphocytes that have lost expression of MHC class I molecules. Journal of Immunology 2000; 165:3555–63. (RERF Report 1099)
Kusunoki Y, Kyoizumi S, Kubo Y, Hayashi T,
MacPhee DG. Possible role of natural killer cells
in negative selection of mutant lymphocytes thatfail to express the human leukocyte antigen-A2
allele. Mutation Research 2001 (May 9); 476(12):123–32. (RERF Report 14-00)

vivors. Byori to Rinsyo [Pathology and Clinical
Medicine] 2001; 19:173–6. (Japanese)
Miyai K, Murata Y, Inoue Y, Yokozawa T, Kuma K,
Noguchi S, Yamashita S, Obara T, Takano T,
Amino N, Nagayama Y, Kasagi K, Nagataki S(Editor). Uniqueness of thyroid and its pathological change. Igaku no Ayumi [Journal of Clinicaland Experimental Medicine] 2001; 197:199–238.
(Japanese)
Nagataki S. On this side of the river. Nippon Iji Shinpo[Japanese Medical Journal] 2001; No. 4003:109.
(Japanese)
Nagataki S. The 12th International Thyroid Congress.
The search for thyroid disease countermeasures
for the 21st century. Journal of the American
Medical Association (Japanese Edition) 2000;
21:13–4. (Japanese)
Nagataki S, Neriishi K. Issues involved in long-term
follow-up of people after radiation exposure.
Gusev IA, Guskova AK, Mettler FA, eds. Medical Management of Radiation Accidents. Second
Edition. Washington, D.C., USA: CRC Press LLC;
2001, pp 461–9.
Nakagawa K, Kozuka T, Akahane M, Suzuki G,
Akashi M, Hosoi Y, Aoki Y, Ohtomo K. Radiological findings of accidental radiation injury of
the fingers: A case report. Health Physics 2001;
80:67–70.
Nakajima H, Harigai M, Hara M, Hakoda M, Tokuda
H, Sakai F, Kamatani N, Kashiwazaki S. KL-6 asa novel serum marker for interstitial pneumonia
associated with collagen diseases. Journal of
Rheumatology 2000; 27:1164–70.
Nakamura N. Genetic effects of radiation. Laboratory Animal Technology and Science 2001; 13:9–
14. (Japanese)
Nakamura N. Genetic effects of radiation. Iden [Heredity] 2000; 54:58–63. (Japanese)
Nakamura N. Radiation effects on human health.
Hoken Butsuri [Journal of Health Physics] 2000;
35:283–6. (Proceedings of the 10th International
Congress of International Radiation Protection Association, Hiroshima, Japan, 14–19 May 2000).
(Japanese)
Nakamura N. Introduction of Low Dose Radiation
Research Program at US Department of Energy.
Hoshasen Seibutsu Kenkyu [Radiation Biology
Research Communications] 2000; 35:412–5.
(Japanese)

Mabuchi K. Cancer incidence in atomic-bomb sur-Nakamura N. Health effects of atomic-bomb radiation. Hoken Butsuri [Journal of Health Physics]
2000 ; 35:217–23. (Japanese)

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

Recent Publications
Nakamura N, Asakawa J, Takahashi N, Kodama Y.
Genetic effects of atomic-bomb radiation: Future
prospects for DNA and cytogenetic studies.
Hoshasen Seibutsu Kenkyu [Radiation Biology
Research Communications] 2001; 36:1–11. (Japanese)
Nakano M, Ohtaki K, Kodama Y, Itoh M, Cologne
JB, Awa AA, Nakamura N. Are homologous chromosomes locate randomly in human interphase nuclei?—Deduction from radiation-induced translocation data. Hoshasen Seibutsu Kenkyu [Radiation Biology Research Communications] 2000;
35:401–4. (Japanese)
Nakashima E. Analysis of longitudinal ordered
polytomous data using generalized estimating
equations. Journal of the Japan Statistical Society 2000; 30:1–15. (RERF Report 11-96)
Nakata Y, Uzawa A, Suzuki G. Control of CD4 T
cell fate by antigen re-stimulation with or without
CTLA-4 engagement 24 h after priming. International Immunology 2000; 12:459–66.
Neriishi K. An activity of medical team of the Ministry of Health and Welfare in Tokaimura criticality accident. Innervision 2000; 15:16–7. (Japanese)
Neriishi K, Nakashima E, Delongchamp RR. Persistent subclinical inflammation among A-bomb survivors. International Journal of Radiation Biology 2001; 77:475–82. (RERF Report 9-99)
Nobuyoshi M, Kusunoki Y, Seyama T, Kodama K,
Kimura A, Kyoizumi S. Arrest of human dendritic
cells at the CD34–/CD4+/HLA-DR+ stage in thebone marrow of NOD/SCID-human chimericmice. Blood 2001 (June 1); 97(11):3655–7.
(RERF Report 4-00)
Ohta H, Ezawa I, Hosoi T, Fujiwara S. Round-tablediscussion: Bone and nutrition—from the elementary to clinical point of view. The Bone 2000;
14:473–86. (Japanese)
Ohtaki M, Izumi S, Otani K, Fujita M. Application
development for survival time data analysis considering individual frailty in treatment effects. Advances in Cancer Treatment, Volume 19. Tokyo:
Japanese Foundation for Multidisciplinary Treatment of Cancer; 2000, pp 17–24. (Japanese)
Pierce DA, Preston DL. Radiation-related cancer
risks at low doses among atomic bomb survivors.
Radiation Research 2000; 154:178–86. (RERF
Report 21-99)
Shigematsu I. The 2000 Sievert Lecture—Lessons
from atomic bomb survivors in Hiroshima and Nagasaki. Health Physics 2000; 79:234–41.

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Shimada Y, Nishimura M, Kakinuma S, Takeuchi T,
Ogiu T, Suzuki G, Nakata Y, Sasanuma S, Mita
K, Sado T. Characteristic association between Kras gene mutation with loss of heterozygosity in
X-ray-induced thymic lymphomas of the B6C3F1mouse. International Journal of Radiation Biology 2001; 77:465–73.
Soda H, Oka M, Soda M, Nakatomi K, Kawabata S,
Suenaga M, Kasai T, Yamada Y, Kamihira S,
Kohno S. Birth cohort effects on incidence of lungcancers: A population-based study in Nagasaki,
Japan. Japanese Journal of Cancer Research
2000; 91:960–5.
Suzuki G. Actual state and state-of-art of emergency
medical care for radiation exposure. Shin Iryo
[New Medicine] 2000; 301:75–9. (Japanese)
Suzuki G. Radioactive emergency troubles by theexternal radiation exposure and its therapies. Genankyo Dayori [Tidings of Nuclear Safety Research
Association] 2000; No. 173:4–10. (Japanese)
Suzuki G. The role and activities of NIRS, the thirdlayer institution for the radiation emergency medical plan. Innervision 2000; 15:18–20. (Japanese)
Suzuki G. Early clinical consequences of victims in
JCO criticality accident in Tokaimura. Hoken
Butsuri [Journal of Health Physics] 2000; 35:4–
11. (Japanese)
Suzuki G. The treatment of high dose exposed victims and its problems. Idenshi Igaku [Gene andMedicine] 2000; 4:636–40. (Japanese)
Suzuki G. Radioactive contamination and damages
to the human body. Nihon Rinsho Hifuka Igakkai
Zasshi [Journal of Japanese Organization ofClinical Dermatology] 2000; No. 66:343–7.
(Japanese)
Suzuki G. Treatment of cases caused by radiation
exposure accidents. Byori to Rinsho [Pathology
and Clinical Medicine] 2001; 19:133–8. (Japanese)
Suzuki G, Ohtani M, Yamashita S, Tanaka H, Neriishi
K, Yamada M. Nagataki S (supervisor), Maekawa
K (supervisor), Suzuki G, eds. Fundamentals in
the Medical Management of Irradiated Victims.
2000, 44 p. (Japanese)
Takahashi N, Murakami H, Kodama K, Kasagi F,
Yamada M, Nishishita T, Inagami T. Associationof a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension. Annals of Human Genetics 2000; 64:197–205.
(RERF Report 1-99) (JTr)
Tsuchihashi M, Tsutsui H, Kodama K, Kasagi F,
Takeshita A. Clinical characteristics and progno-

RERF Update Volume 12, Issue 1, Spring–Summer 2001

"

Recent Publications
sis of hospitalized patients with congestive heart
failure-A study in Fukuoka, Japan. Japanese Circulation Journal 2000; 64:953–9.
Tsuyama N, Ide T, Noda A, Iwamoto KS, Mizuno T,
Kyoizumi S, Seyama T. X-rays induce dose-dependent and cell cycle-independent accumulationof p21sdi1/WAF1. Hiroshima Journal of Medical Sciences 2001; 50:1–7. (RERF Report 5-97)
Vickers M, Brown GC, Cologne JB, Kyoizumi S.
Modelling haemopoietic stem cell division by
analysis of mutant red cells. British Journal of
Haematology 2000; 110:54–62. (RERF Report 599)
Yamada M, Mimori Y, Sasaki H, Ikeda J, Nakamura
S, Kodama K. Cognitive dysfunction among theelderly evaluated by the cognitive abilities screening instrument (CASI). Nippon Ronen Igakkai
Zasshi [Japanese Journal of Geriatrics] 2000;
37:56–62. (Japanese)
Yamamoto Y, Ohama K, Fujiwara S, Sawamura A,
Koyama K, Yoshida T, Kawamura T, Sato H, Ishii
Y, Honda N, Watanabe T, Yamanaka I,
Hatakeyama K, Ishihara S, Kawano M, Horie Y,
Sanada K. Report on the results of the twelfth
medical examination of atomic bomb survivors
resident in North America. Hiroshima Igaku[Journal of the Hiroshima Medical Association]
2000; 53:479–503. (Bilingual)

Publications Using RERF Data
The following publications represent research done
by non-RERF scientists based on the data publicly
available from RERF.
Little MP, Muirhead CR. Derivation of low-dose
extrapolation factors from analysis of curvaturein the cancer incidence dose response in Japaneseatomic bomb survivors. International Journal of
Radiation Biology 2000; 76:939–53.
Little MP. A comparison of the degree of curvaturein the cancer incidence dose-response in Japaneseatomic bomb survivors with that in chromosome
aberrations measured in vitro. International Journal of Radiation Biology 2000; 76:1365–75.
Little MP, Deltour I, Richardson S. Projection ofcancer risks from the Japanese atomic bomb survivors to the England and Wales population taking into account uncertainty in risk parameters.
Radiation and Environmental Biophysics 2000;
39:241–52.
McGeoghegan D, Binks K. The mortality and cancer morbidity experience of workers at the
Capenhurst uranium enrichment facility 1946–95.
Journal of Radiological Protection 2000; 20:381–
401.

Yokoyama N, Nagataki S. Thyroid stimulating hormone receptor disease. Ohno Y, Tanaka H,
Nakatani H, Kurokawa K, Saito E, eds. The Newest Information of the Intractable Diseases—From
the Epidemiological Approach to the ClinicalCare. Tokyo: Nanzando; 2000, p 115. (Japanese)

McGeoghegan D, Binks K. The mortality and cancer morbidity experience of workers at the
Springfields uranium production facility, 1946–
95. Journal of Radiological Protection 2000;
20:111–37.

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RERF Update Volume 12, Issue 1, Spring–Summer 2001

Stewart A, Kneale G. A-bomb survivors: Factors that
may lead to a re-assessment of the radiation hazard. International Journal of Epidemiology 2000,
29:708–714.