|
|
Report of the Blue Ribbon Panel on the Review of the
Radiation Effects Research Foundation, 1996 |
Report of the Blue Ribbon Panel on the Review
of the Radiation Effects Research Foundation, 1996
Roger H Clarke, Tadao Shimao, H Jack Geiger, Wataru Mori, Herbert
L Abrams, Dan Beninson, Valerie Beral, Keith H Lokan, Albrecht M
Kellerer, Colin R Muirhead |
Commentary and Review Series 3-96 |
|
|
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)
*
 |
Adult Health Study subset + |
|
|
In utero exposure *
|
Adult Health Study subset + |
|
|
| In utero exposure * Adult
Health Study subset + |
|
| TOTAL |
|
|
* All subjects are followed routinely for death and, within
Hiroshima and Nagasaki Prefectures, for cancer incidence.
In addition, information on lifestyle factors such as smoking,
alcohol consumption, diet and reproductive factors has been
collected on the LSS cohort in four postal surveys conducted
in, or around, 1960, 1970, 1980 and 1990.
+ Subjects in the Adult Health Study subset are
routinely examined every two years and a vast amount of
clinical data and biological specimens has been collected
from these subjects. |
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%) |
40-49 |
13,489 |
1,000 (8%) |
50 + |
14,550 |
<100 (<1%) |
|
| * Restricted to persons with estimated DS86 dose. |
|
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:
(1) the follow-up of the Life-Span Study (LSS), persons exposed
in utero and F1 (i.e. children of exposed subjects)
cohorts for deaths and cancer registrations ;
(2) the maintenance of tumour and tissue registries in Hiroshima
and Nagasaki;
(3) in-depth studies of the relation between radiation exposure
and other lifestyle factors in the aetiology of disease.
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:
- (1) studies that augment, enrich or supplement the findings
of the Life Span Study by supplying additional clinical and
laboratory data on cancer and on potential contributing factors
and/or confounders in the aetiology of disease;
(2) studies that focus on issues other than the central focus
of the Life Span Study: in particular, the detection and analysis
of the effects of radiation that cannot be studied through mortality
or cancer incidence data; and
(3) the provision of biological materials essential to other
investigations at RERF.
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 |
|
合計 |
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 |
* Restricted to persons with known
DS86 dose
Note: ATB = at the time of the bombing |
|
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 ofin 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:
a) by providing clinical data on fatal and non-fatal carcinomas
and on non-cancer effects of radiation exposure;
b) by enabling in-depth investigations of associations to be observed
in the LSS;
c) by furnishing a unique pool of serum, plasma and lymphocyte samples;
and
d) by providing an essential "bridge" function to the survivors.
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
CHAIRMAN OF THE PANEL
PROFESSOR ROGER H. CLARKE
Director
National Radiological Protection Board
Chilton, OXON OX11 0RQ, UK |
|
Dr. TADAO SHIMAO
President
Japan Anti-Tuberculosis Association
1-2-12 Misako-cho
Chiyoda-ku, Tokyo
Japan
|
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 |
Dr. WATARU MORI
President
Japanese Association of Medical Sciences
The Council for Science and Technology
2-2-1 Kasumingaseki
Chiyoda-ku, Tokyo
Japan
|
Dr. HERBERT L. ABRAMS
Professor of Radiology
Stanford University School of Medicine
Room S-056
300 Pasteur Drive
Stanford, CA 94305, USA |
Dr. DAN BENINSON
President of the Board of Directors
National Board of Nuclear Regulation
Avendia del Libertador 8250
1429 Buenos Aires
Argentina
|
Dr. VALERIE BERAL
Director
Imperial Cancer Research Fund
Cancer Epidemiology Unit
Gibson Building
Radcliffe Infirmary
Oxford OX2 6HE, UK |
Dr. KEITH H. LOKAN
Director
Australian Radiation Laboratory
Commonwealth Department of Health
Family Services
Lower Plenty Road
Yallambie, Victoria 3085
Australia
|
Prof. Dr. ALBRECHT M KELLERER
Direktor des Strahlenbiologisches Institut
Schiller-strasse 42
D-80336 Munchen
Germany |
|
| |
TECHNICAL ASSISTANT TO THE PANEL
DR. COLIN R.MUIRHEAD
National Radiological Protection Board
Chilton, Didcot, OXON OX11 0RQ, UK |
|
|
| ANNEX II |
ORGANISATIONAL STRUCTURE OF RERF
|
|
Scientific Council (Japan 5)
(US 5) |
|
Board of Directors (Japan 5)
(US 5) |
|
Supervisors (Japan 1)( US 1) |
|
|
|
|
|
|
|
|
|
|
|
|
Local Liaison Council Hiroshima |
|
|
Executive Committee |
|
|
Operating Committee |
|
|
|
|
|
|
|
|
|
|
|
Local Liaison Council Nagasaki |
|
|
(Chairman, Japan) (Vice Chairman,
US) Permanent Directors) (Japan
2, US 2) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Laboratory (Chief of Research) |
|
|
|
Secretariat (Chief of Secretariat) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hiroshima |
|
Nagasaki |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| Clinical Studies |
|
|
Epidemiology |
|
Clinical Studies |
|
|
Epidemi-ology |
|
|
Hiroshima |
|
|
Nagasaki |
|
|
|
|
|
|
|
|
|
|
|
|
|
Genetics |
|
|
Statistics |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Radiobiology |
|
|
Information Technology |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Publication & Documentation Center |
|
|
|
|
|
|
|
|
|
|
|