Roger H Clarke
Chairman
1996
CONTENTS
1. Preamble
2. Overview
3. The Population
4. Review of the Scientific
Programme
5. Future Activities
6. Strategic Planning and
Programme Management
7. National and International
Collaborations
8. Summary of Conclusions
and Recommendations
1. PREAMBLE
1.1 In April 1995 the Science Council of
the Radiation Effects Research Foundation (RERF) issued a statement, considering
it "appropriate and desirable that the scientific activities of RERF be
assessed carefully and in depth by an outside expert group that has not
been previously involved in RERF activities". The Council recommended
that "a high-level international Committee of distinguished scientists
be appointed to carry out an assessment of RERF's current and future scientific
activities". The United States Department of Energy (DOE) and the Ministry
of Health and Welfare of Japan (MHW) agreed to accept the recommendation
to establish an international Blue Ribbon Panel and on 11 October 1995
they jointly appointed Professor Roger H. Clarke, Director of the United
Kingdom National Radiological Protection Board, as its Chairman.
1.2 The Panel was composed of scientists
representing diverse disciplines related to radiation research and public
health. Individuals with experience in medicine, epidemiology, radiation
biology, immunology, health physics, biostatistics, genetics and public
health were nominated.
1.3 The Ministry of Health and Welfare and
the Department of Energy nominated four members each; MHW nominated two
Japanese and two third-country nationals while DOE nominated two US and
two third-country nationals. The final composition of the Panel, shown
at Annex I, was of a Chairman, two Japanese nationals, two US nationals,
and four third-country nationals.
1.4 The Panel was charged with conducting
a thorough review of RERF activities for the purpose of making recommendations
regarding future research. Specifically the Panel was asked to focus on
the following:
In addition, guidance was given to the Panel
that it should:
1.5 The original time schedule set for the
panel by MHW and DOE was that it be appointed in October 1995, and would
meet in March/April 1996 at Hiroshima and Nagasaki. Preliminary results
would be presented to the Board of Directors meeting in May/June 1996
and the final report would be delivered to MHW, DOE and the Board of Directors
by the end of July 1996.
1.6 In the event the Panel held its first
meeting at RERF in Hiroshima from 4-7 February and in Nagasaki 7-8 February
1996. On the first day the Panel heard of the early history of the Atomic
Bomb Casualty Commission (ABCC), the precursor to RERF, and visited the
Hiroshima Peace Museum, after which a commemorative wreath was laid at
the Cenotaph.
1.7 The Panel was welcomed to its formal
session by the Chairman of RERF, Dr. Shigematsu. During the following
days, presentations were made by the six Department Chiefs on their programmes
in: Epidemiology, Statistics, Information Technology, Clinical Studies,
Genetics and Radiobiology. Each presentation was followed by an informal
session during which detailed discussions were held with a wide range
of Departmental staff so that the Panel could probe the depth of scientific
and medical knowledge.
1.8 The Panel also received a presentation
from a representative of the US National Academy of Sciences on the management
of its review and oversight programme at RERF.
1.9 The Panel had the honour to meet Governor
Fujita of Hiroshima Prefecture and heard of his tentative plans for the
establishment of a Cancer Centre in Hiroshima which would have international
links.
1.10 At Nagasaki the presentations and discussions
centred on the two Departments of Epidemiology and Clinical Studies, after
which one of the co-chairmen of the Science Council presented a summary
of the Council's views.
1.11 The Panel held its second meeting at
the Headquarters of the NRPB in the UK from 19-21 May 1996, during which
time the content of the report was agreed upon. The report was finalised
at the beginning of June 1996.
2. OVERVIEW
2.1 The RERF research programme forms the
most comprehensive study of a large, well-defined population that includes
all ages and both sexes subjected to an instantaneous and wide range of
radiation exposures. Several major research foci have evolved over time.
These currently include epidemiological studies of cancer mortality and
incidence and non-cancer mortality among the atomic-bomb survivors; ongoing
clinical follow-up with the collection of biological specimens and longitudinal
clinical measurements and data on morbidity in a fixed subset of the survivor
population; genetic and epidemiological studies of the children of the
survivors; and application of modern molecular, cytological, physiological
and other technologies to the unique biological samples provided by the
survivors in order to identify radiation-induced changes and to investigate
the underlying biological mechanisms of these changes.
2.2 Data on cancer mortality derived from
the atomic-bomb survivors have become the primary source of cancer risk
estimates. Other sources now largely provide substantiation of, rather
than alternatives to, the atomic-bomb survivor-based assumptions. Worldwide,
radiation protection standards for workers and the public are based on
the survivor risk estimates, as promulgated in the 1990 recommendations
of the International Commission on Radiological Protection. Risks associated
with population exposures due to accidental radiation releases and individual
exposures (for example, in probability of causation lawsuits) also are
estimated based on atomic-bomb survivor data. RERF studies have shown
that fetal radiation exposures affect physical and mental development
and, as the in utero cohort ages, the nature of the excess cancer
risks in this group is being clarified. RERF is also the primary source
of information on the occurrence and nature of genetic effects in humans
following radiation exposure.
2.3 Basic biological research at RERF already
has clarified issues previously which cannot be resolved by physical dosimetric
and epidemiological approaches. With recent and continuing worldwide advances
in molecular genetics, RERF should be able to play a unique and central
role in determining radiation's effects at the gene locus level.
2.4 RERF is a unique research enterprise,
studying an unparalleled population unlikely to exist again. At this juncture,
there is an incomplete understanding of the late effects of radiation
exposure during childhood and early adulthood while studies are just reaching
a point at which important insights into the existence and nature of genetic
effects can be gained. The follow-up of the Life Span Study (LSS) cohort
of atomic-bomb survivors is the centre of the RERF epidemiology programme.
The follow-up is based on the family registries which assure virtually
complete ascertainment of death. LSS Report 12 on cancer mortality
among the LSS cohort from 1950 through 1990 emphasises how the excess
cancer risks associated with radiation exposure depend on modifying factors
such as sex, age-at-exposure, and attained age.
2.5 The genetics programme at RERF is the
singular study worldwide on the genetic effects of irradiation in humans.
An important part of the genetic studies is the ongoing epidemiological
follow-up of mortality and cancer incidence on over 80,000 first generation
(F1) offspring, about 43% being born to exposed parents and
the rest to non-exposed parents. The follow-up has been based on both
death certificate-based mortality and tumour registry-based cancer incidence.
Epidemiology as well as studies on congenital defects, stillbirths, sex
chromosome abnormalities and reciprocal translocations have not demonstrated
a significant radiation-related increase in any endpoint.
2.6 The Adult Health Study (AHS) operated
by RERF and its predecessor, the Atomic Bomb Casualty Commission (ABCC),
continues to be one of the largest and longest running clinical cohort
studies in the world. During the 40 years of its existence, the AHS clinical
programme has played a key role in obtaining and sustaining support for
ABCC-RERF from the survivors and the local communities. The biennial AHS
medical examination is the only part of the RERF programme that involves
direct contact with survivors and thus serves as the main direct benefit
that RERF provides to the survivors. It is RERF's primary source of information
for understanding non-cancer effects of radiation, although information
is also available from the mortality follow-up of the LSS. Through the
AHS, biological materials are collected which will become increasingly
useful for molecular and other bio-marker studies of cancer and non-cancer
diseases. Again, it is stressed here that the effects of radiation exposure
on diseases other than cancer remain largely unknown. The RERF clinical
programme is an irreplaceable source of biochemical and physiological
measurements that underpins all of RERF's epidemiological analyses, including
those of non-cancer disease incidence.
3. THE POPULATION
3.1 The health of over 200,000 people from
Hiroshima and Nagasaki, covering both exposed and unexposed persons together
with their offspring, has been under surveillance by RERF since the 1950s.
Table 3.1 summarises the cohorts being followed and gives brief details
about the way in which the subjects are being followed.
3.2 The Life Span Study population followed
at RERF is unique for many reasons. Firstly, it includes large numbers
of subjects with well-documented information about their exposure to ionising
radiation. Secondly, for most subjects there is detailed information of
high quality about personal characteristics (e.g. height and weight),
and about habits (e.g. smoking, alcohol consumption and diet). For about
10% of the total population (i.e. the 22,000 people included in the Adult
Health Study; see Table 3.1), clinical and biological characteristics
are available. Thirdly, follow-up for cancer incidence and death has been
continuing since the 1950s and very few subjects have been lost to follow-up.
Finally, substantial numbers were exposed at young ages and, even though
50 years have elapsed since their exposure to radiation, the majority
of these persons are still alive (see Table 3.2: among the approximately
86,000 persons with doses estimated under the DS86 Dosimetry System, about
31,000 of the 35,000 aged under 20 at the time of bombing were still alive
in 1994).
3.3 Although other populations have been
exposed to ionising radiation since the bombing of Hiroshima and Nagasaki,
in no other situation has it been possible to set up detailed studies
of large numbers of subjects of all ages and both sexes, who have substantial
exposures to radiation with such reliable information both on radiation
exposure and on subsequent health. Furthermore, this is one of the very
few populations in which it is possible to study the effects of known
exposures at early ages when more than 50 years have elapsed since the
exposure.
CONCLUSIONS
3.4 The population studies at RERF are
unique not only because of the type of exposure received by such large
numbers of subjects, but also because the quality of the information recorded
about each individual is extremely high. It seems unlikely that a comparable
opportunity to study the effects of ionising radiation on health in such
a detailed way will present itself in the future: and even if it does,
it will take 50 years to accrue as much information as now exists at RERF.
TABLE 3.1 - RERF COHORTS
|
Name of Cohort
|
Number of Subjects
|
| Life span study (LSS) *
|
120,300
22,400
|
| In utero exposure
*
|
3,300
1,100
|
| Offspring of the survivors
( F1 generation) |
88,500
|
| TOTAL |
212,100
|
TABLE 3.2 - NUMBERS RECRUITED INTO THE
LIFE SPAN STUDY IN 1950 AND
NUMBERS STILL ALIVE IN 1994, BY AGE AT THE TIME OF THE BOMBING*
|
Age at the time of bombing
|
Numbers in 1950
|
Approximate number alive in 1994
|
|
0-9
|
17,824
|
16,500 (93%)
|
|
10-19
|
17,557
|
14,700 (84%)
|
|
20-29
|
10,882
|
7,700 (71%)
|
|
30-39
|
12,270
|
5,000 (41%)
|
|
40-40
|
13,489
|
1,000 (8%)
|
|
50 +
|
14,550
|
<100 (<1%)
|
4. REVIEW OF THE SCIENTIFIC
PROGRAMME
General comments
4.1 In reviewing "the content and quality"
of the Radiation Effects Research Foundation's scientific studies, the
importance of this large group of research projects cannot be overestimated.
Its importance lies in the uniqueness of the survivor cohort under study
and in its central role in assessing radiation carcinogenesis and providing
the basis for radiation protection standards throughout the world. It
furnishes an as yet unfinished landmark study of radiation effects in
humans that, it is hoped, will never be feasible again. The very nature
of a large amount of the research done at RERF in epidemiology, in genetics,
and in the Clinical Studies Programme requires that it is necessarily
systematic and unchanging in character.
4.2 The lifetime attributable cancer risk
for radiation exposures in childhood is one of the most important unresolved
problems of radiation protection of the population, and at present it
is based on uncertain assumptions. Future observations at RERF are necessary
to resolve this question. These observations will have to continue for
several decades, when those who were exposed as infants will have reached
the age of highest cancer rates.
4.3 Risk estimates for radiation-induced
cancer have in the past been based predominantly on the cancer mortality
data and their analysis at RERF. The recent extensive work on cancer incidence
has added a second and equally important base for risk modelling and thus
for the derivation of nominal risk factors.
4.4 The scientific programme is reviewed
in six topic areas, Epidemiology, Statistics, Information Technology,
Clinical Studies, Genetics, and Radiobiology, in each of which work is
undertaken at Hiroshima. The programmes at Nagasaki are in Epidemiology
and Clinical Studies and are reviewed together with the work in those
areas at Hiroshima.
(i) EPIDEMIOLOGY
4.5 The main responsibilities of the two
Departments of Epidemiology are:
4.6 Overall the Departments of Epidemiology
are responsible for the follow-up of about 200,000 people. The largest group
being followed are members of the Life-Span Study (LSS). So far about 8,000
cancers have occurred among the members of that population with DS86 doses;
and about 20,000 tissue specimens are held from surgery and autopsies. Lifestyle
information for most of the LSS population has been collected from four
postal surveys carried out at about 10 yearly intervals, in approximately
1960, 1970, 1980 and 1990.
4.7 Staff in the Departments of Epidemiology,
working closely with staff in the Department of Statistics, have contributed
to regular reports on deaths in the LSS population in relation to radiation
exposure. As the mortality data have accumulated, these reports have evolved
from a relatively straightforward presentation of tests for radiation
effects to detailed analyses and characterisation of factors that affect
the risk of death from cancer or other causes. The most recent report
(LSS Report 12) addresses cancer mortality between 1950 and 1990.
The excess relative risk per unit dose has been estimated for 12 solid
cancer sites for which there were at least 100 deaths. For most of these
cancer sites there has been a statistically significant increase in risk
associated with radiation exposure. Furthermore, the data for many of
the solid cancer sites are consistent with a common value for the excess
relative risk.
4.8 The mortality data for all solid cancers
combined show a remarkably linear dose-response over the range 0-3 Sv,
whereas for leukaemia the trend in risk with dose is non-linear with an
upward curvature. While most of the excess leukaemia risk occurred in
the first 15 years following exposure, the absolute excess rate for solid
cancers increased during the follow-up in a manner that is roughly proportional
to the increase in background rates with increasing age. The excess relative
risk tends to be higher for exposure in childhood than in adulthood, and
is higher for females than for males for most non-sex-specific cancer
types. However, the age-specific excess absolute risks generally depend
little on sex or age at exposure.
4.9 The earliest programme for monitoring
cancer incidence in the atomic bomb survivors grew out of efforts initiated
in the late 1940s to register leukaemia and other haematological disorders.
With the cooperation of medical associations in the locality, population-based
tumour registries were established in 1957 in Hiroshima and 1958 in Nagasaki.
These registries have been operated by staff at ABCC-RERF since their
inception and are generally regarded as the best tumour registries in
Japan. Data on cancer incidence in the LSS up to 1987 formed the basis
of comprehensive reports published in 1994. These data represent an important
complement to the cancer mortality data; despite the shorter follow-up
period for solid cancer incidence, the number of cancer cases is greater
than the number of deaths. Furthermore, the incidence data provide risk
estimates for cancers with relatively low fatality, such as those of the
breast, thyroid and skin, and clarify the examination of cancers for which
death certificate information is often incomplete or inaccurate (eg. liver
cancer). Work on cancer incidence in the LSS is continuing with a series
of detailed site-specific studies.
4.10 The previous LSS follow-up indicated
some association between non-cancer mortality and radiation dose. This
topic has been studied as part of the Adult Health Study (see section
4(iv)). In addition, a report based on the extended mortality follow-up
is being prepared. Follow-up of those exposed in utero has indicated
a possible increase related to radiation, although based on a small total
number of cases. In contrast, no statistically significant trends with
dose in mortality or cancer incidence have been observed in the F1
cohort. As well as the continuation of these investigations, studies of
familial aggregation of cancer in members of the LSS cohort are being
planned.
4.11 The cohorts being followed by the Departments
of Epidemiology are among the largest and best documented in the world.
Even if it were not for the unique exposure to ionising radiation of the
population, the value of the information collected about lifestyle and
health over such a long period of time is virtually unrivalled elsewhere.
The epidemiology programme is central to the work of RERF. There is a
great deal of interest in the effects of various aspects of Japanese lifestyle
on health (especially dietary factors) and on the effects of the changes
in lifestyle over the last 50 years. To make full use of the scientific
data already held within RERF, a substantial additional epidemiological
effort would be required. Collaboration with epidemiologists from within
Japan and abroad, especially on exploring some of the aspects of the data
that do not relate directly to radiation exposure, should be of great
benefit to all concerned.
CONCLUSIONS
4.12 The data held by the Departments
of Epidemiology are of enormous importance, not only for assessing the
effects of radiation on health, but also for determining the influence
of various lifestyle factors on health and their interactions with radiation
exposure. There is currently insufficient effort available to analyse
the data and present reports, and much of the potentially valuable information
collected has so far not been fully utilised.
RECOMMENDATION 1.
We recommend that the Departments of Epidemiology
should continue to collect data on mortality and cancer incidence, and
that they be strengthened. The management of RERF should give these studies
the highest priority in view of the size and scope of the data. In addition,
research should be carried out by collaborating with epidemiologists from
other institutions both in Japan and elsewhere, so that the full range
of potentially valuable information already collected can be analysed.
(ii) STATISTICS
4.13 The Departments of Epidemiology and
the Department of Statistics are closely interlinked and jointly form
the central core of RERF. Their tasks are specific and indispensable
to the continuing follow-up of the A-bomb survivors and other aspects
of the research programme.
4.14 The most recent studies of cancer amongst
the survivors have provided information that supports modified risk models,
intermediate between the so-called absolute risk models and the relative
risk models. The continuation of this work and the growing need to interlink
analyses from the mortality and the incidence data will - beyond the obvious
extension of the epidemiological efforts - require a broadened and stabilized
team of scientists in the Department of Statistics.
4.15 Through its extensive body of work
on the A-bomb survivors the Statistics Department at RERF has had great
influence on other radiation studies worldwide. Recently the Department
began a very active cooperation with the radioepidemiological investigations
on the highly exposed nuclear workers of Mayak in the Southern Urals and
on the population of the villages on the contaminated Techa river in the
former Soviet Union. These two studies deal with the health effects resulting
from continued exposures and will, thus, be an essential complement
of the studies on the atomic-bomb survivors who were subject to exposure
over a short time. The new studies can largely be patterned on the
work done on the A-bomb survivors, and this will give important feedback
and added importance - but also added responsibilities - to the programme
of RERF.
4.16 The Departmental staff in conjunction
with collaborators have developed the software package EPICURE which is
currently used worldwide for the analysis of epidemiological data. It
is important that the development of this software be continued because
it facilitates comparability between different studies.
4.17 The work on cancer mortality and incidence
has been the subject of extensive publications, and for a number of years
now - in a significant departure from earlier policies - well - documented
basic data sets have been made available for analysis by other groups.
For work on malformations due to prenatal exposure - and specifically
the important observations on mental retardation and the reduction of
IQ - similar progress has not yet been achieved. Important analyses have
been performed, but the statistical treatment has been less systematic,
and publications are less complete. The basic data sets - for example
on the results of intelligence tests and other studies on the prenatally
exposed - have not yet been made available outside RERF.
CONCLUSIONS
4.18 Highly successful work has been performed
in the Department of Statistics, which is a source of great strength for
the entire organisation. Its input has been essential in making the accumulated
data sets the worldwide basis for the estimation of human radiation risks.
RECOMMENDATION 2.
We recommend that the Department of Statistics
should continue to produce analyses of the risks of radiation exposure in
collaboration with the Epidemiology Departments and that the high quality
of the research in the Statistics Department be maintained.
RECOMMENDATION 3.
We recommend that the Department of Statistics
should continue to make available basic data sets on mortality and cancer
incidence for analysis by other groups. This should now be extended to
making available those data sets relating to mental retardation, IQ, and
related outcomes of exposure in utero.
(iii) INFORMATION
TECHNOLOGY
4.19 The Panel received an informative presentation
from the Information Technology Department, in which it learned that for
most of RERF's lifetime, data associated with the separate research programmes
have been maintained on a series of mainframes and often analysed using
specialised software, which has had to be developed within the organisation.
4.20 It was recognised by the late 1980s
that the increasing power and decreasing costs of PCs and RISC based workstations,
together with the availability of much general software for inter-computer
communications, database management, data analysis and graphics pointed
to a move from mainframe computing to a distributed network. A major programme
was therefore begun in 1991 to install an integrated system of networked
IBM-compatible PCs and Unix workstations, and at the end of 1994 the previous
mainframe was removed.
4.21 This change in direction has brought
many advantages to RERF. Internal communications within RERF - including
communications between Nagasaki and Hiroshima - are much improved, access
to Internet and its facilities are available and RERF can now use readily
available commercial software packages for business management. In addition,
the individual PCs can readily manage much of the statistical analysis,
data handling and graphics associated with particular projects on a stand-alone
basis.
4.22 In practice, it has turned out that
the move to a distributed network has led to significant economies and
the present system, which is overall more powerful than its predecessor,
has been less expensive, both to install and to maintain.
4.23 Perhaps the most important innovation
has been the installation of a new relational database in the Unix environment,
and the transfer to it of the major data files such as the Master File,
the tumour registry, tissue registries, the LSS and the DS86 dosimetry.
Apart from eliminating many redundancies, this amalgamation of data from
overlapping research programmes greatly facilitates the capture into working
files of all available information on cohort members for subsequent analysis
and study.
4.24 There is still much to be done to include
further data still held in independent files, so that all relevant data
on individuals can be assembled efficiently, and we understand that further
incorporations are in train. At the same time, the discipline of operating
within a single coherent database system is seen to be helpful in that
it requires close and careful scrutiny of the various data sources in
order that they may be included in a systematic way. At the end of the
day, this coordination of all of RERF's major data holdings within the
one system should lead to a richer and more robust body of data for the
cohort studies in general.
4.25 From the perspective of research outcomes,
the Panel believes that the changes to the computing environment will
enhance the quality of the studies and open up ways in which any new directions
may be followed in an efficient manner.
4.26 The Information Technology Department,
in its presentation to the Panel, acknowledged that there are still many
things to be completed in support of RERF's research and appears to have
a clear sense of direction in its future planning. Its members also pointed
out that the introduction of a new and unfamiliar system has required
them to enhance their user support and to provide training and assistance
when users encounter difficulties.
CONCLUSION
4.27 Efficient data management and computing
are the backbones to the success of research at RERF. The Panel believes
that RERF has taken the right strategic decisions with respect to computing
infrastructure, and the Department has gone about implementing them with
considerable skill and intelligence. Impressive progress has been made
over the last few years in creating a central linked database.
RECOMMENDATION 4.
We recommend that strong support continue
to be given to the Department of Information Technology because it is
essential that the large body of data collected over many decades is properly
stored, documented and accessible to researchers at RERF.
(iv) CLINICAL STUDIES
4.28 The Clinical Studies Research Programme
is based largely on the Adult Health Study (AHS), the cohort of about
20,000 out of the Life Span Study (LSS) of 120,000. Since 1978, about
2400 Life Span Study participants and 1000 in utero exposed persons
have been added to this sample. Every other year, all participants are
examined in detail, including history, physical examinations, ECG, chest
x ray, ultrasonography, blood tests, etc. Other data, such as information
on lifestyle and results of special tests including bone density and gynaecologic
examinations, are also collected.
4.29 The necessarily repetitive nature of
many of the research projects was apparent in the presentations to the
Panel. Many of the current projects are very much like those of yesterday;
some essentially provide further documentation of prior findings. Yet
this kind of organised, iterative, systematic, and meticulous study and
clinical follow up is essential to fulfil the goal of providing a precise
database for determining cancer risk estimates and for exploring non-cancer
diseases associated with radiation exposure. Like the Life Span Study,
the Adult Health Study derives its importance from the unique value of
the survivor cohort.
4.30 An important function of the Clinical
Studies Programme is to bind the exposed populations in Hiroshima and
Nagasaki to the Radiation Effects Research Foundation and its scientific
programme. The AHS is literally the only systematic link of RERF with
survivors; it provides them with a visible service, one which they obviously
value, as indicated by the high level of voluntary participation. The
biennial medical examinations of the AHS cohort also provide elements
of medical social work - support, attention and respect - without which
it seems doubtful that the full cooperation of the surviving populace
of the two cities could be attained. The AHS should be considered as one
of the important measures directly beneficial to the health of the survivors.
4.31 The contributions of the AHS may be
described in three broad categories:
4.32 A major function of the clinical programme
is the early detection of carcinoma in the AHS. Furthermore, a unique contribution
of the AHS lies in its exploration of the possible associations between
radiation exposure and diseases other than cancer. The non-cancer AHS studies
may be grouped into three categories: those in which significant radiation-related
effects have been established; those in which suggestive (but not definitively
established) radiation-related effects have been noted; and those in which
no radiation-related effects have been found.
4.33 Significant radiation-related effects
to those exposed in utero were mainfest in small head size and
mental deficiency. In addition, brain damage has been found in severely
mentally retarded individuals examined later in life and exposed in
utero between the eighth and fifteenth week of gestation. A significant
and dose-related increase in the incidence of uterine myomas has been
found among the survivors, as well as a significant and dose-related increase
in the incidence of parathyroid adenomas. Lenticular opacities, which
are well-known to be radiation-induced, were found in increased incidence
in this population in studies conducted twenty years ago. An update is
planned. It is desirable - and also urgent in the view of the aging of
the survivor cohort - to conduct more sophisticated cataract studies.
4.34 Suggestive radiation-related increases
in cardiovascular disease incidence, specifically the incidence of myocardial
infarcation, cerebral infarction, and the prevalence of aortic arch calcification
and systolic hypertension, require further studies to confirm a real association
between radiation exposure and atherosclerosis. Similarly, suggestive
increases in the incidence of thyroid adenomas and chronic liver disease
in the exposed population have been noted in AHS studies, although the
latter finding may reflect a high level of hepatitis virus infection.
In another study, the onset of menopause has been found to occur earlier
among the heavily exposed survivors than among the unexposed; analysis
of serum FSH and oestrogen levels in the remaining premenopausal women
is under way.
4.35 No increases have been found in mortality
or incidence of congenital abnormalities in the F1 progeny,
although no systematic clinical examinations have occurred since the first
year of life in this group. Both dominant disorders and multifactorial
inherited diseases frequently are manifest after the first decade of life
and, in the latter case, usually after adulthood. Further study of this
cohort is essential; while under the Genetics Department, it would require
the direct participation of the Clinical Studies Programme. Studies of
thoracic vertebral fracture have shown no correlation with radiation exposure.
Studies of senile dementia are under way, as is an evaluation of physiological
measurements in more than 8,000 AHS participants as a predictor of mortality
or morbidity associated with aging. Accelerated aging has not been demonstrated.
4.36 The Clinical Studies Programme maintains
a collection of 110,000 frozen serum samples and 11,000 plasma samples
spanning the last thirty years of the programme; in addition, there are
13,000 lymphocyte samples for the Department of Radiobiology, which maintains
its collection in liquid nitrogen. These and other samples will make possible
the retrospective determination of potential confounding factors and contribute
to special studies of the immune system. Further, the Clinical Studies
Programme has been involved in obtaining the cell lines from 800 families
- 1600 parents and 1200 children - for a major project to screen DNA samples
from parent-child trios. This is the largest fixed cohort population in
the world for the detection of radiation effects on human germ line mutations.
Finally, the Clinical Studies Programme is involved in providing the teeth
essential for dosimetry studies based on electron-spin resonance of tooth
enamel.
CONCLUSIONS
4.37 The importance and merit of the research
lies largely in the size and quality of follow-up of the LSS and AHS populations,
the quality of the epidemiology and statistics as they relate to the LSS
and AHS groups, and the continuing assessment of in utero
exposed survivors. The role of the Departments of Clinical Studies is central
to attaining many of the goals of all divisions.
4.38 The content and quality of the research
lies in the collaborative role that the Departments play with all other
Departments:
RECOMMENDATION 5.
We recommend that while many of the Clinical
Studies projects under way should be extended, the programme should be
critically reviewed so that those which are not promising are discontinued.
The continuing surveillance of the cohort who were children in 1945
and are now adults is likely to be revealing, since radiation sensitivity
may be highest in the young.
RECOMMENDATION 6.
We recognise that the AHS is vital to
the well being of the survivors and we recommend that this important service
continue, since we believe it has led to their high level of cooperation
with RERF. As the population ages and health problems become more complex,
consideration needs to be given to ensuring that the voluntary participation
remains high.
(v) GENETICS
4.39 The Genetics Department aims its work
at two major issues. The first and traditional task has been the assessment
of hereditary damage in the offspring of the A-bomb survivors. A second
task is the work in cytogenetics and more recently in other biological
dosimetry, in order to reconstruct doses and/or to assess the validity
of the DS86 dosimetry system.
The offspring of those exposed
4.40 Extensive studies of untoward pregnancy
outcomes, mortality exclusive of cancer, malignant tumours in the first
two decades of life, cytogenetics, and protein biochemical genetics in
the children (F1 generation) of the A-bomb survivors have shown
no evidence of excess. This led to the initial conclusion that human sensitivity
to these effects appears to be substantially less than those derived in
early studies on mice. Recently the mouse data were critically reassessed,
and it is now uncertain whether humans are, in fact, substantially less
sensitive than the mouse to the mutagenic effects of ionising radiations.
4.41 As a consequence of unresolved judgements
on the animal data, it is uncertain whether risk estimates for radiation-induced
hereditary damage can be based on animal studies. For this and other reasons,
full use must be made of the potential insights that can be obtained from
the observations in families of A-bomb survivors. Recent work in the Genetics
Department is focusing on studies in molecular biology that utilize immortalized
B-lymphocyte cell lines, to discover differences in mutation rates between
500 families with exposed parent(s) and an equal number of control families
without exposures. Innovative new techniques (e.g. the examination of
mutations at mini-satellite loci) have been employed on a pilot basis
in these studies but have not, up to now, demonstrated enhanced mutation
rates in the exposed genomes. All of these studies are based on rapidly
evolving techniques of molecular biology and thus must be considered as
initial efforts. Future developments in molecular biology should permit
far more complete analyses. They might ultimately allow the precise assessment
to be made of molecular changes in the genome of family members.
The exposed population
4.42 Cytogenetic studies have long been an
important part of the work of RERF and its predecessor organization. In
earlier times, they were restricted to the determination of unsymmetric
chromosome aberrations - such as dicentrics. As these aberrations are
'unstable', i.e. incompatible with cell proliferation, they have only
limited persistence of, typically, a few years. Although important questions
were still unresolved - especially the apparently different dose dependencies
in Hiroshima and in Nagasaki - it has become, therefore, less attractive
in the recent past to invest work in these studies.
4.43 The advances of molecular biology have
changed the situation and have given new momentum to the work in biological
dosimetry with chromosomes through the technique of FISH (fluorescence
in situ hybridization). This work has made it possible,
by now, to determine symmetric, i.e. stable, chromosome aberrations, without
excessive investment of manpower. This Department has taken effective
leadership in the development and practical use of the FISH technique
which allows retrospective biological dosimetry for exposures that occurred
many years ago.
4.44 The Genetics Department has also taken
the initiative to make the FISH technique available to Russian scientists
working at Mayak and at the Techa river. Together with the involvement
of European groups, this has led to an international network of cooperation
for the intercomparison and improvement of cytogenetic methods. In view
of various aspects of the FISH technique that are still unresolved, it
is essential that the current intercomparisons and the joint application
of the new methods to various exposed populations be continued and even
extended. This relates to the A-bomb survivors, the nuclear workers at
Mayak, the Techa river populations, the populations subjected to fallout
from the Semipalatinsk nuclear tests, and certain groups that have been
exposed after the Chernobyl accident.
4.45 This Department has put into practice
improved techniques of ESR (electron spin resonance)
dosimetry, specifically on teeth. This approach complements the cytogenetics
results and it is, therefore, justified that the ESR dosimetry studies
be given equal priority. While it is essential that the best techniques
be used, there is no requirement for separate methodological work in the
group; it is, therefore, appropriate that the Department has established
external links to share new technical developments, especially the use
of dentin in addition to the tooth enamel.
4.46 Parallel applications of the two techniques,
FISH dosimetry and ESR dosimetry, to A-bomb survivors and other exposed
groups have shown that the chromosome studies will gain greatly from the
intercomparison of the results. The tooth dosimetry studies will be restricted
to fewer cases, but they appear to be applicable to lower doses and are
subject to less variability; they can, therefore, serve as an added 'calibration'
that sharpens the results of the chromosome studies.
CONCLUSIONS
4.47 While molecular biology investigations
will enable the most detailed determinations to be undertaken and will thus
be the focus of future work, there is nevertheless need to continue - and
even to extend - the more conventional studies of the health of the offspring
(F1 generation). They will also have continued importance
because it remains uncertain at what point molecular studies can come sufficiently
close to the resolution of the problem of multifactorial hereditary damage
produced by radiation.
4.48 It does now appear that there can be
a more complete chain linking the evolving physics dosimetry and individual
data on location at the time of the bombing to chromosome data, to tooth
data, and data from solid state dosimetry on other objects, such as building
materials, ceramics, or jewellery. While dosimetry has traditionally not
been the task of RERF, these new interconnections will be very important
for validating the DS86 dosimetry system.
RECOMMENDATION 7.
We recommend that the studies on the health
of the offspring (F1 generation) of the survivors continue,
since they may elucidate data on multifactorial disease while also providing
direct benefit to the survivors and their offspring.
RECOMMENDATION 8.
We recommend the preservation of biological
samples for FISH analysis and for ESR, together with the documentation
that will be needed to compare dose estimates based on biological samples
with those from physics assessments.
RECOMMENDATION 9.
We recommend the continuation of the storage
of biological materials and associated documentation for future molecular
genetic studies.
RECOMMENDATION 10.
We recommend that the most advanced methods
and expertise in cytogenetics continue to be available at RERF.
(vi) RADIOBIOLOGY
4.49 The Department of Radiobiology is a
comparatively recent branch of RERF. It has been established to ensure
that full use is made of the singular biological material available to
RERF, especially the potential for performing molecular biology studies
of familial relations in A-bomb survivors, their children and grandchildren.
Work is being performed on molecular oncology, on immunology and on somatic
mutations. The latter is to, some degree, interlinked with the efforts
of the cytogenetics group on biological dosimetry. The studies on molecular
oncology and immunology are closely related, because they are primarily
directed towards the elucidation of the molecular and cellular steps in
the process of carcinogenesis.
Molecular oncology
4.50 One of the most significant developments
in radiobiology and generally in radiation research is the emergence of
what may be called molecular epidemiology. It is still uncertain
whether there are molecular markers, i.e. gene alterations, that are specific
to - or that tend to be correlated with - certain causative factors, such
as ionizing radiation. Molecular biology studies with this aim are now
conducted in many laboratories worldwide. If specific markers can be found,
radiation epidemiology will have an entirely new basis. Obviously this
would be of central importance to the core programme of RERF. The archives
of tumour and normal tissue material from A-bomb survivors are of greatest
importance in view of these developments, and the extension and up-keep
of the repositories is a central task for RERF. It is also essential that
full expertise be available at RERF for adequate planning and for utilization
of any methods that may become practicable. The radiobiology programme
has met this challenge successfully. It is particularly important that
it has been examining the methods to utilize archival material from autopsies
more than 40 years old and that it has, in fact, demonstrated that gene
amplification works as well with this material as with fresh probes. A
variety of known oncogenes and tumour suppressor genes has been examined
in current studies, which attests to the expertise of the research group.
Immunology
4.51 Better insight into the function of
the lymphocyte system will be a precondition for untangling the mechanisms
of carcinogenesis. Important questions are still unsolved and it is therefore
appropriate that RERF utilizes its specific wealth of information to contribute
to the required investigations. The particular strengths of the studies
at RERF are the repeated observations in groups of A-bomb survivors that
extend over sufficiently long periods to demonstrate the effects of aging,
and the combined effect of aging and radiation exposure on the immune
competence of T-cells. Very little is still known about the clonal expansions
that originate from individual normal and stem cells. Recent studies at
RERF on clonal expansion are, therefore, of special interest; these studies
show that one and the same chromosomal aberration can appear in substantial
fractions of T-cells, B-cells, erythroid progenitor cells and myeloid
progenitors. Such studies may become the singular basis of much improved
quantitative knowledge of the kinetics of the haematopoietic system. They
can be the focus of important international cooperation using the observational
material available only at RERF.
Somatic mutations
4.52 Somatic mutations at three different
gene loci, HLA, TCR, and HPRT, are being studied as possible
instruments of an alternative form of biological dosimetry. It appears
that these systems are applicable when exposures are recent, while the
mutations are not sufficiently persistent to provide reliable information
on exposures that occurred a number of years ago or in the more distant
past. There are indications in some of the studies on the A-bomb survivors
that determination of the erythrocyte glycophorin A mutation (GPA)
is more promising as a method to determine past exposures. But, as a whole,
it would appear that FISH in lymphocytes and, in particular, ESR in teeth
are superior approaches for biological dosimetry. The study of somatic
mutations may still be justified in view of possible but still unknown
future advances, but it does not appear to have special priority at this
point.
CONCLUSIONS
4.53 The archives of tumour and normal tissue
material for molecular and biological studies from A-bomb survivors are
of great importance in view of developments in molecular biology, and the
extension and upkeep of the repositories is a central task for RERF.
4.54 The particular strengths of the immunology
studies at RERF are the repeated observations in groups of A-bomb survivors
that extend over sufficiently long periods to demonstrate the effects
of aging, and the combined effect of aging and radiation exposure on the
immune competence of T-cells. Recent studies on clonal expansion are of
special interest.
4.55 Somatic mutation systems are applicable
for biological dosimetry when exposures are recent, but the mutations
are not sufficiently persistent to provide reliable information on exposures
that occurred in the distant past.
4.56 The establishment of causality in epidemiological
studies requires several conditions in addition to a strong association.
Among these conditions the postulation of a "plausible mechanism" is essential.
This postulation, in the form of a mechanistic model, is also the basis
for extrapolations beyond the observations, particularly at very low values
of the cause.
4.57 It is clear, therefore, that RERF radiation
risk studies will always be related, explicitly or implicitly, to mechanisms
and models. The spectacular increase in the understanding of the cancer
process on the basis of molecular genetics indicates that models will
evolve in this direction. While it does not seem appropriate to specifically
include modellers in the staff of RERF, it would be very important that
the implications of data from experimental studies are kept under review
as they may influence the research strategy of the Foundation.
RECOMMENDATION 11.
We recommend that the Department of
Radiobiology should focus on molecular epidemiology and immunology and
that strong links should be forged between RERF and the relevant groups
around the world involved in modelling the carcinogenic process.
5. FUTURE ACTIVITIES
5.1 LSS Report 12 highlights the uncertainties
associated with the current internationally recommended estimates of radiation
induced cancer risk, especially for those exposed as children. The evidence
to date suggests that solid cancer excess risks are likely to persist
and that excess rates will increase throughout life. Excess relative risks
for solid cancers among those exposed as adults have remained fairly constant
throughout their lifetimes. For people exposed in childhood, there is
some evidence that relative risks have declined slightly; however, excess
rates (ie absolute risks) for this group are increasing with age in a
manner consistent with the increases seen for those exposed as adults.
For those exposed as children, the total number of cancer deaths is currently
small; however, this number is doubling every 5 years, and estimates of
the number of excess cases are increasing at about the same rate.
5.2 Although lifetime follow-up is essentially
complete for those exposed when older than age 50, more than half of the
LSS cohort and over 90% of those exposed as children are alive now. Table
5.1 gives both the actual and projected numbers of persons in the cohort.
By the year 2000, the number of cancer deaths among those exposed when
younger than age 20 will be 3 to 4 times that seen up to 1990 and will
continue to increase rapidly throughout the first 10 to 15 years of the
next century. Therefore continued follow-up of those exposed as children
or as young adults is essential to the understanding of radiation-induced
cancer risks in this cohort.
5.3 Continued follow-up together with advances
in analytical methods are making it possible to address more complex issues
than in the past. RERF researchers are developing alternatives to the
time-constant (given sex and age at exposure) relative risk models that
play a central role in current descriptions of radiation effects on solid
cancer risks. These alternative models help to quantify uncertainties
in current risk estimates, especially for those exposed as children, and
may provide useful insights into the nature of radiation carcinogenesis.
5.4 Current data suggest that leukaemia
risks for those exposed as adults have persisted throughout life, whereas
excess risks for those exposed as children have decreased with time. In
view of the complex pattern of excess leukaemia risks following radiation
exposure, continued assessment is necessary for complete understanding.
Additional follow-up is also necessary to clarify the nature of excess
risks for myeloma and lymphoma.
Table 5.1 LSS Cohort* Size, 1950-2020
|
Age at Exposure (y)
|
1950
|
1990
|
1995
|
2000
|
2005
|
2010
|
2015
|
2020
|
|
0-9
|
17,824
|
16,768
|
16,450
|
15,990
|
15,290
|
14,280
|
12,710
|
10,390
|
|
10-19
|
17,557
|
15,163
|
14,500
|
13,540
|
12,040
|
9,800
|
6,780
|
3,620
|
|
>=20
|
51,191
|
16,971
|
12,800
|
8,910
|
5,430
|
2,710
|
970
|
100
|
|
Total
|
86,572
|
48,902
|
43,750
|
38,440
|
32,760
|
26,790
|
20,460
|
14,110
|
|
Average Attained Age (y)
|
33.5
|
61.4
|
64.7
|
67.9
|
71.3
|
74.7
|
78.0
|
81.3
|
|
Average Age ATB (y)
|
28.5
|
16.4
|
14.7
|
12.9
|
11.3
|
9.7
|
8.0
|
6.3
|
5.5 The first comprehensive analysis of
the LSS cancer incidence data was published in 1994. These data represent
an important complement to the cancer mortality data. Despite the shorter
follow-up period for solid cancer incidence (since the tumour registries
did not start operation until 1958), the number of cancer cases is greater
than the number of deaths. The incidence data provide risk estimates for
cancers with lower fatality rates, such as breast, thyroid and skin, than
most other cancers and help to clarify the situation for cancers like
liver cancer for which death certificate information is often incomplete
or inaccurate. A priority is the development of procedures that will allow
the unification of the incidence and mortality data. The tumour registry
incidence data already are being used as the basis for a number of site-specific
incidence studies, and increased use of data on cancer incidence in the
LSS should be used as the basis for case-control studies.
5.6 As evidenced by the attention focused
on the Sellafield (UK) leukaemia cluster, issues related to the heritable
effects of radiation exposure are of great public and scientific concern.
The RERF first-generation (F1) cohort of children of the atomic-bomb
survivors is the most powerful epidemiological study able to address whether
excess cancer or non-cancer risks result from parental exposures. To date,
no evidence of excess risks exists. However, cohort members are relatively
young (with an average age of 39 in 1995), so several more decades of
follow-up will be necessary to obtain a reasonable assessment of cancer
risks (or the lack thereof) in this population. There is increased attention
being devoted to this issue by international radiation protection programmes,
and the RERF prospective study will provide hard data independent of theoretical
considerations.
5.7 The value of AHS is in studying the
modifying effects of other factors, as well as looking at non-radiation
effects generally. The most important epidemiological role of the AHS
programme is monitoring of non-cancer diseases that will subsequently
result in mortality, such as atherosclerotic diseases and chronic liver
diseases, the incidence of which seems to be increased by radiation exposure.
New approaches to study these diseases are being introduced.
5.8 With a collection of 110,000 frozen
samples of serum, it is possible to go back in time to determine if specific
confounders, such as homocysteine levels (recently implicated in coronary
disease), hepatitis C or other infections may have influenced the course
of the above mentioned diseases. The clinical programme also serves as
the source of cell collection for the genetics, cytogenetics, and radiobiology
studies and more recently for the collection of teeth for the ESR dosimetry
analysis.
5.9 While results to date show that the
human genome is not unusually sensitive to irradiation and indeed may
be less sensitive than that of the laboratory mouse, further studies are
needed to resolve the issue. No systematic clinical examinations of the
offspring (F1) have occurred since their first year of life.
The majority of both dominant disorders and multifactorial inherited diseases
are manifest after the first decade of life and, in the latter case, usually
after adulthood. A feasibility study in this area would be of considerable
benefit. Based on the very high participation rate, 75-80%, of the children
of the survivors during the period 1976-84, when the cytogenetics and
protein studies were undertaken, an enthusiastic response from them may
be expected. There is an indication that the offspring are anxious about
possible health effects since media reports on other radiation-related
studies arouse concerns.
5.10 A well-designed clinical study of the
offspring (F1) cohort using currently available screening methods
to identify better defined sentinel phenotypes could provide useful information
about genetically based detriment to health and there should be consideration
of the feasibility of such a study. This may best be done by convening
a workshop on the topic. We believe that during the next two decades,
it will become clear whether subsequent generations (F2) need
to be studied, so that at present we do not recommend their study.
5.11 Molecular studies in genetics should
determine whether mutations were transmitted to the progeny at a variety
of genetic sites and what the molecular changes are. The cytogenetic study
of parent lymphocytes is recommended to substantiate the theoretical DS86
doses.
5.12 The work on radiobiology should concentrate
on the analytical studies of the changes at the molecular level involved
in tumour development. There is rapid advancement around the world in
molecular biology and these developments should be used to focus on the
mechanisms of radiation-induced oncogenesis so as to better quantify the
risks of low doses of radiation.
RECOMMENDATION 12.
We recommend that the LSS research programme
should continue until the survivor cohort has died, so as to provide an
authentic and complete assessment of the neoplastic and non-neoplastic effects
of radiation. We also recognise that there are both medical and social aspects
of the AHS that are of direct benefit to the promotion of the health of
the A-bomb survivors and their offspring.
RECOMMENDATION 13.
We recommend consideration be given to further
investigation into the health of the offspring (F1 cohort)
since it may well yield valuable information on genetic effects, especially
when conducted together with research using the new molecular genetics
techniques.
RECOMMENDATION 14.
We recommend that the recently initiated
work on the molecular mechanisms of carcinogenesis should be focussed
to elicit the shape of the dose-response curve at low doses of radiation.
RECOMMENDATION 15.
RERF has a valuable source of surgical and
autopsy specimens and, serum, plasma and lymphocyte samples and we recommend
that an explicit policy be developed over the management and ethics of
the provision of biological samples for use in research, especially outside
RERF.
6. STRATEGIC PLANNING
AND PROGRAMME MANAGEMENT
6.1 While the work of the various scientific
departments within RERF has generally been effective and in some areas
particularly impressive, there are signs that progress has recently been
hampered by severe pressure on professional resources, a situation which
we understand is likely to prevail to some extent in future. It is very
important therefore that attention is given by the RERF management to
the development of long term forward planning processes to achieve the
best outcomes within the available budget.
6.2 The overall goals and objectives presented
to the Panel and the research strategies adopted to reach these goals
correctly reflect well RERF's charter. They have evolved over time, drawing
on the recommendations of successive reviews and on the outcomes of a
series of ad hoc workshops in particular fields. The Board of Directors
is to be commended for the initiatives it has taken in the past to ensure
that the organisation's research strategies are kept up to date with advances
in the relevant sciences. In the present times, however, it is normal
to take forward planning much further and for management to identify more
clearly their programmes, the sub-programmes and projects which fit within
them, their relative priorities and the resource obligations which go
with them.
6.3 Planning can take many forms, but its
essential ingredient is to provide a stable framework over (say) a five
year time span, against which corporate decisions regarding priorities
and resource allocations can be made, which best reflect RERF's goals.
A strategic plan should be forward looking and flexible enough to take
into account changes as projects within each Department develop and reach
defined milestones or point towards sensible changes in direction. One
of its important functions should be to establish for each of the Departments
a stable level of core funding, so that programme managers can confidently
plan over a five year horizon. We would expect that each passing year
would see the updating of a five year "rolling" strategic plan, which
accommodates to progress over time, and introduces new aspects as they
become relevant.
6.4 Perhaps a good illustrative example
of the need for global setting of priorities is the assessment of the
role and the provision of adequate resources for the Department of Statistics.
The Panel was advised that this Department provides expert guidance throughout
the organisation, especially to the Departments of Epidemiology and the
Department of Information Technology, and in addition has the further
responsibility for the understanding and interpretation of the DS86 dosimetry.
During the recent period of financial stringency, this Department has
endured at least the same degree of attrition and financial constraint
as the other Departments, yet deficiencies in this area may have a disproportionate
impact on the productivity of the entire organisation. RERF will need
to examine its role carefully, since issues such as this can only be addressed
by the senior management.
6.5 Programme management requires a certain
amount of formality to ensure the regular tracking of projects against
planning targets and agreed milestones as well as the airing of proposals
for new or modified projects. An integral part of this is the periodic
external assessment of all sub-programmes and projects. The Panel was
advised that the present processes for external scrutiny, carried out
by the RERF Science Council, are limited and insufficient for detailed
assessment and guidance.
6.6 At the Departmental level, there would
be a need to review annually with the Chief of Research the progress of
individual projects against agreed milestones, to make adjustments where
necessary, to set further milestones where appropriate and to foreshadow
new directions which projects and the programme may follow.
6.7 An additional mechanism, which has been
found to work well, is the formation of an internal review panel, involving
senior staff from all of the Departments (including Department chiefs)
who, over time, review projects in each Department against agreed milestones
and report their assessments to the Chief of Research. Such a process
is helpful also in maintaining an informed understanding amongst the staff
of the work of their colleagues in other Departments and a better appreciation
of the way in which their own work fits within the broader goals of RERF.
CONCLUSIONS
6.8 Programme management in a research environment
such as RERF requires a deftness of touch to ensure that the processes are
not so formalised and heavy handed that they obstruct the development of
new ideas. Nevertheless, it has been the experience in other establishments
that overall strategic planning and a firm commitment to fairly detailed
programme management is needed to secure the best outcomes in the present
(worldwide) climate of constrained resources. In practical terms, the plan
will reach down to the individual Departments, which will need to articulate
their own priorities and plans to manage their own programmes, in accordance
with the general strategic goals. The process is an interactive one, with
the experience and thinking of the Departments contributing to and sharing
ownership of the overall strategic plan.
6.9 It is important for the continued productivity
and success of the RERF programme that external peer review on an intensive
basis be established, with a committee of experts chosen from each discipline
to review each of the programmes once every five years. The external review
committee should have time to assess individual protocols, to review them
in concert with the investigators, and then to make recommendations about
the future direction of the programme. This mechanism would not only stimulate
investigators to improve their projects by exposing them to concentrated
critique and discussion with outstanding experts in the field, but would
also encourage them to discontinue projects that seemed non-productive.
RECOMMENDATION 16.
In the context of the current organisational
structure, we recommend that successive five-year Strategic Plans, with
annual updates, be developed and offered through the Executive Committee
for approval by the Board of Directors.
RECOMMENDATION 17.
We also recommend a new peer review process
be established with multinational teams reviewing each Department every
five years, each team being chaired, for example, by a different member
of the Science Council.
RECOMMENDATION 18.
We recommend that the Science Council takes
a more active role with a closer involvement in the assessment and guidance
of RERF. Its membership should reflect all of the major disciplines involved
in the work of RERF. We further recommend that appointment to the Council
be for 5 year terms, with no more than a single reappointment, and that
two members retire each year.
7. NATIONAL AND INTERNATIONAL
COLLABORATIONS
7.1 Currently, there is a group of strong
and effective leaders and well trained support staff at RERF. A stable
cadre of personnel, with the flexibility and capacity to replace those
lost by attrition (especially in Statistics and Epidemiology), is essential.
One of the problems of RERF inheres in the culture of Japanese institutions,
whereby a relatively fixed cohort of workers is predictable because of
lifetime guarantees of jobs. This obviously has its strengths, but it
also has its limitations, both in preventing RERF from responding quickly,
and in limiting personnel openings to new developments in basic science
that may have an impact on the RERF programmes. It would be advantageous
for RERF if a process could be established for short-term appointments
from within Japan, possibly through collaboration with the universities.
7.2 In particular, stronger links with universities
or other research institutions, especially the universities at Hiroshima
and Nagasaki, may be appropriate. These would provide the possibility
of PhD students becoming involved in RERF research activities since there
are sufficient data for a number of original research studies. Links could
be foreseen with mathematical, physical, biological, epidemiological and
medical sciences on both radiation and non-radiation related research.
In comparison to Hiroshima, some links already exist between RERF Nagasaki
and Nagasaki University, with papers being co-authored by staff from both
organisations.
7.3 The Governor of Hiroshima Prefecture
is considering the construction of a cancer centre in Hiroshima city.
Were this to proceed, participation in the planning by RERF would be profitable
for the conduct of future work in epidemiology and clinical studies.
7.4 Work on particular projects may be funded
from research fellowships in Japan or, for example, from the Research
Directorate of the European Commission (EC). The EC has a research programme
into the health effects of ionising radiations which already involves
support for projects in the former Soviet Union. Coordination with the
work at RERF would seem logical to share scarce expertise from RERF and
to try to elicit confirmatory data from other potential databases of occupationally
or publicly exposed groups at Chelyabinsk and Mayak. By so doing, the
Panel believes, RERF would become internationalised with support from
Japan, Europe and the US. A particular problem that was described to the
Panel and that particularly affects US cooperation, is the lack of career
prospects in the US for those who return from a period at RERF. The Panel
believes that this contrasts with the situation in the European Union
where such practices are common.
7.5 The Panel considers that it is not profitable
and indeed positively inefficient for the practice to continue whereby
within a single year somewhat in excess of 100 scientists can be imposed
upon RERF for 2 or 3 days each. They learn an insufficient amount and
distract the staff from their research programmes. A more structured exchange
of fewer staff for longer periods would be an improvement, but careful
selection of apt fellows is vital.
CONCLUSIONS
7.6. While RERF is internationally known
as a centre for radiation research, the results of its diverse programmes
need to be more widely disseminated both in Japan and in the global scientific
community. In order to continue the core research programmes of RERF,
as well as the collaborative studies, recruiting and maintaining a strong
and motivated scientific staff is a vital objective. It would be advantageous
to seek short term appointments from other institutions in Japan, as well
as to strengthen interactions with universities, especially those in the
locality, and to enter into some additional formal overseas arrangements.
RECOMMENDATION 19.
We recommend that consideration be given
to formal links being established, or strengthened, to universities or other
research institutions in Japan and especially to the universities in Hiroshima
and Nagasaki, with RERF Department Chiefs having visiting or part-time Professorships
and undertaking teaching commitments together with PhD students being involved
on projects at RERF.
RECOMMENDATION 20.
In addition to the bilateral arrangements
between Japan and the US, we recommend that consideration be given to
RERF entering into formal programmes of exchange of research fellows with
other countries, and with regional or international bodies.
RECOMMENDATION 21.
We recommend that, in view of the accumulated
knowledge at RERF, it be developed as an Information Centre to promote
informed public understanding of the risks of radiation.
8. SUMMARY OF CONCLUSIONS
AND RECOMMENDATIONS
CHAPTER 3. THE POPULATION (Para 3.4).
The population studies at RERF are unique
not only because of the type of exposure received by such large numbers
of subjects, but also because the quality of the information recorded
about each individual is extremely high. It seems unlikely that a comparable
opportunity to study the effects of ionising radiation on health in such
a detailed way will present itself in the future: and even if it does,
it will take 50 years to accrue as much information as now exists at RERF.
CHAPTER 4. REVIEW OF THE SCIENTIFIC PROGRAMME
EPIDEMIOLOGY (Para 4.12)
The data held by the Departments of Epidemiology
are of enormous importance, not only for assessing the effects of radiation
on health, but also for determining the influence of various lifestyle
factors on health and their interactions with radiation exposure. There
is currently insufficient effort available to analyse the data and present
reports, and much of the potentially valuable information collected has
so far not been fully utilised.
RECOMMENDATION 1.
We recommend that the Departments of Epidemiology
should continue to collect data on mortality and cancer incidence and
that they be strengthened. The management of RERF should give these studies
the highest priority in view of the size and scope of the data. In addition,
research should be carried out by collaborating with epidemiologists from
other institutions both in Japan and elsewhere, so that the full range
of potentially valuable information already collected can be analysed.
STATISTICS (Para. 4.18)
Highly successful work has been performed
in the Department of Statistics, which is a source of great strength for
the entire organisation. Its input has been essential in making the accumulated
data sets the worldwide basis for the estimation of human radiation risks.
RECOMMENDATION 2.
We recommend that the Department of Statistics
should continue to produce analyses of the risks of radiation exposure in
collaboration with the Epidemiology Departments and that the high quality
of the research in the Statistics Department be maintained.
RECOMMENDATION 3.
We recommend that the Department of Statistics
should continue to make available basic data sets on mortality and cancer
incidence for analysis by other groups. This should now be extended to
making available those data sets relating to mental retardation, IQ, and
related outcomes of exposure in utero.
INFORMATION TECHNOLOGY (Para. 4.27)
Efficient data management and computing are
the backbones to the success of research at RERF. The Panel believes that
RERF has taken the right strategic decisions with respect to computing
infrastructure, and the Department has gone about implementing them with
considerable skill and intelligence. Impressive progress has been made
over the last few years in creating a central linked database.
RECOMMENDATION 4.
We recommend that strong support continue
to be given to the Department of Information Technology because it is
essential that the large body of data collected over many decades is properly
stored, documented and accessible to researchers at RERF.
CLINICAL STUDIES (Paras. 4.37 - 4.38)
The importance and merit of the research
lies largely in the size and quality of follow-up of the LSS and AHS populations,
the quality of the epidemiology and statistics as they relate to the LSS
and AHS groups, and the continuing assessment of in utero
exposed survivors. The role of the Departments of Clinical Studies is central
to attaining many of the goals of all divisions.
The content and quality of the research
lies in the collaborative role that the Departments play with all other
Departments:
RECOMMENDATION 5.
We recommend that while many of the Clinical
Studies projects under way should be extended, the programme should be
critically reviewed so that those which are not promising are discontinued.
The continuing surveillance of the cohort who were children in 1945
and are now adults is likely to be revealing, since radiation sensitivity
may be highest in the young.
RECOMMENDATION 6.
We recognise that the AHS is vital to
the wellbeing of the survivors and we recommend that this important service
continue, since we believe it has led to their high level of cooperation
with RERF. As the population ages, and health problems become more complex,
consideration needs to be given to ensuring that the voluntary participation
remains high.
GENETICS (Paras. 4.47 and 4.48)
While molecular biology investigations will
enable the most detailed determinations to be undertaken, and will thus
be the focus of future work, there is nevertheless need to continue - and
even to extend - the more conventional studies of the health of the offspring
(F1 generation). They will also have continued importance
because it remains uncertain at what point molecular studies can come sufficiently
close to the resolution of the problem of multifactorial hereditary damage
produced by radiation.
It does now appear that there can be a more
complete chain linking the evolving physics dosimetry and individual data
on location at the time of the bombing to chromosome data, to tooth data,
and data from solid state dosimetry on other objects, such as building
materials, ceramics, or jewellery. While dosimetry has traditionally not
been the task of RERF, these new interconnections will be very important
for validating the DS86 dosimetry system.
RECOMMENDATION 7.
We recommend that the studies on the health
of the offspring (F1 generation) of the survivors continue,
since they may elucidate data on multifactorial disease while also providing
direct benefit to the survivors and their offspring.
RECOMMENDATION 8.
We recommend the preservation of biological
samples for FISH analysis and for ESR, together with the documentation
that will be needed to compare dose estimates based on biological samples
with those from physics assessments.
RECOMMENDATION 9.
We recommend the continuation of the storage
of biological materials and associated documentation for future molecular
genetic studies.
RECOMMENDATION 10.
We recommend that the most advanced methods
and expertise in cytogenetics continue to be available at RERF.
RADIOBIOLOGY (Paras. 4.53 - 4.57)
The archives of tumour and normal tissue
material for molecular and biological studies from A-bomb survivors are
of great importance in view of developments in molecular biology, and the
extension and upkeep of the repositories is a central task for RERF.
The particular strengths of the immunology studies at RERF are the repeated
observations in groups of A-bomb survivors that extend over sufficiently
long periods to demonstrate the effects of aging, and the combined effect
of aging and radiation exposure on the immune competence of T-cells. Recent
studies on clonal expansion are of special interest.
Somatic mutation systems are applicable
for biological dosimetry when exposures are recent, but the mutations
are not sufficiently persistent to provide reliable information on exposures
that occurred in the distant past.
The establishment of causality in epidemiological
studies requires several conditions in addition to a strong association.
Among these conditions the postulation of a "plausible mechanism" is essential.
This postulation, in the form of a mechanistic model, is also the basis
for extrapolations beyond the observations, particularly at very low values
of the cause.
It is clear, therefore, that RERF radiation
risk studies will always be related, explicitly or implicitly, to mechanisms
and models. The spectacular increase in the understanding of the cancer
process on the basis of molecular genetics indicates that models will
evolve in this direction. While it does not seem appropriate to specifically
include modellers in the staff of RERF, it would be very important that
the implications of data from experimental studies are kept under review
as they may influence the research strategy of the Foundation.
RECOMMENDATION 11.
We recommend that the Radiobiology Department
should focus on molecular epidemiology and immunology and that strong
links should be forged between RERF and the relevant groups around the
world involved in modelling the carcinogenic process.
CHAPTER
5. FUTURE ACTIVITIES
RECOMMENDATION 12.
We recommend that the LSS research programme
should continue until the survivor cohort has died, so as to provide an
authentic and complete assessment of the neoplastic and non-neoplastic effects
of radiation. We also recognise that there are both medical and social aspects
of the AHS that are of direct benefit to the promotion of the health of
the A-bomb survivors and their offspring.
RECOMMENDATION 13.
We recommend consideration be given to further
investigation into the health of the offspring (F1 cohort)
since it may well yield valuable information on genetic effects, especially
when conducted together with research using the new molecular genetics
techniques.
RECOMMENDATION 14.
We recommend that the recently initiated
work on the molecular mechanisms of carcinogenesis should be focussed
to elicit the shape of the dose-response curve at low doses of radiation.
RECOMMENDATION 15.
RERF has a valuable source of surgical and
autopsy specimens and, serum, plasma and lymphocyte samples and we recommend
that an explicit policy be developed over the management and ethics of
the provision of biological samples for use in research, especially outside
RERF.
CHAPTER 6. STRATEGIC PLANNING AND PROGRAMME
MANAGEMENT (Para. 6.8 and 6.9)
Programme management in a research environment
such as RERF requires a deftness of touch to ensure that the processes are
not so formalised and heavy handed that they obstruct the development of
new ideas. Nevertheless, it has been the experience in other establishments
that overall strategic planning and a firm commitment to fairly detailed
programme management is needed to secure the best outcomes in the present
(worldwide) climate of constrained resources. In practical terms, the plan
will reach down to the individual Departments, which will need to articulate
their own priorities and plans to manage their own programmes, in accordance
with the general strategic goals. The process is an interactive one, with
the experience and thinking of the Departments contributing to and sharing
ownership of the overall strategic plan.
It is important for the continued productivity
and success of the RERF programme that external peer review on an intensive
basis be established, with a committee of experts chosen from each discipline
to review each of the programmes once every five years. The external review
committee should have time to assess individual protocols, to review them
in concert with the investigators, and then to make recommendations about
the future direction of the programme. This mechanism would not only stimulate
investigators to improve their projects by exposing them to concentrated
critique and discussion with outstanding experts in the field, but would
also encourage them to discontinue projects that seemed non-productive.
RECOMMENDATION 16.
In the context of the current organisational
structure, we recommend that successive five-year Strategic Plans, with
annual updates, be developed and offered through the Executive Committee
for approval by the Board of Directors.
RECOMMENDATION 17.
We also recommend a new peer review process
be established with multinational teams reviewing each Department every
five years, each team being chaired, for example, by a different member
of the Science Council.
RECOMMENDATION 18.
We recommend that the Science Council takes
a more active role with a closer involvement in the assessment and guidance
of RERF. Its membership should reflect all of the major disciplines involved
in the work of RERF. We further recommend that appointment to the Council
be for 5 year terms, with no more than a single reappointment, and that
two members retire each year.
CHAPTER 7. NATIONAL AND INTERNATIONAL
COLLABORATIONS (Para. 7.6)
While RERF is internationally known as
a centre for radiation research, the results of its diverse programmes
need to be more widely disseminated both in Japan and in the global scientific
community. In order to continue the core research programmes of RERF,
as well as the collaborative studies, recruiting and maintaining a strong
and motivated scientific staff is a vital objective. It would be advantageous
to seek short term appointments from other institutions in Japan, as well
as to strengthen interactions with universities, especially those in the
locality, and to enter into some additional formal overseas arrangements.
RECOMMENDATION 19.
We recommend that consideration be given
to formal links being established, or strengthened, to universities or other
research institutions in Japan and especially to the universities in Hiroshima
and Nagasaki, with RERF Department Chiefs having visiting or part-time Professorships
and undertaking teaching commitments together with PhD students being involved
on projects at RERF.
RECOMMENDATION 20.
In addition to the bilateral arrangements
between Japan and the US, we recommend that consideration be given to
RERF entering into formal programmes of exchange of research fellows with
other countries, and with regional or international bodies.
RECOMMENDATION 21.
We recommend that, in view of the accumulated
knowledge at RERF, it be developed as an Information Centre to promote
informed public understanding of the risks of radiation.
ANNEX 1
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CHAIRMAN OF THE PANEL
PROFESSOR ROGER H. CLARKE
Director
National Radiological Protection Board
Chilton, OXON OX11 0RQ, UK
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Dr. TADAO SHIMAO
President
Japan Anti-Tuberculosis Association
1-2-12 Misako-cho
Chiyoda-ku, Tokyo
Japan
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Dr. H. JACK GEIGER
Chairman
Department of Community Health & Social Medicine
City University of New York Medical School
138th St & Convent Avenue
New York, NY 10031, USA
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Dr. WATARU MORI
President
Japanese Association of Medical Sciences
The Council for Science and Technology
2-2-1 Kasumingaseki
Chiyoda-ku, Tokyo
Japan
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Dr. HERBERT L. ABRAMS
Professor of Radiology
Stanford University School of Medicine
Room S-056
300 Pasteur Drive
Stanford, CA 94305, USA
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Dr. DAN BENINSON
President of the Board of Directors
National Board of Nuclear Regulation
Avendia del Libertador 8250
1429 Buenos Aires
Argentina
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Dr. VALERIE BERAL
Director
Imperial Cancer Research Fund
Cancer Epidemiology Unit
Gibson Building
Radcliffe Infirmary
Oxford OX2 6HE, UK
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Dr. KEITH H. LOKAN
Director
Australian Radiation Laboratory
Commonwealth Department of Health
Family Services
Lower Plenty Road
Yallambie, Victoria 3085
Australia
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Prof. Dr. ALBRECHT M KELLERER
Direktor des Strahlenbiologisches Institut
Schiller-strasse 42
D-80336 Munchen
Germany
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TECHNICAL ASSISTANT TO THE PANEL
DR. COLIN R.MUIRHEAD
National Radiological Protection Board
Chilton, Didcot, OXON OX11 0RQ, UK
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ANNEX II
ORGANISATIONAL STRUCTURE OF RERF
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Scientific Council (Japan 5) (US 5)
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Board of Directors (Japan 5) (US 5)
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Supervisors (Japan 1)( US 1)
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Local Liaison Council Hiroshima
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Executive Committee
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Operating Committee
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Local Liaison Council Nagasaki
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(Chairman, Japan) (Vice Chairman, US)
Permanent Directors) (Japan 2, US 2)
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Hiroshima
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Nagasaki
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Epidemiology
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Clinical Studies
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Epidemi-ology
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Nagasaki
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Genetics
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Radiobiology
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Information Technology
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Publication & Documentation Center
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