SOURCES AND EFFECTS
OF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
UNSCEAR 2000 Report to the General Assembly,
with Scientific Annexes
VOLUME II: EFFECTS

UNITED NATIONSNew York, 2000

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Fifty-fifth Session, Supplement No. 46 (A/55/46).
The designation employed and the presentation of material in this publication do not
imply the expression of any opinion whatsoever on the part of the Secretariat of the United
Nations concerning the legal status of any country, territory, city or area, or of its authorities,
or concerning the delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those that were in use
at the time the data were collected or the text prepared. In other cases, however, the names
have been updated, where this was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
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ANNEX I
Epidemiological evaluation of radiation-induced cancer

CONTENTSPage

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
I.

FEATURES OF EPIDEMIOLOGICAL STUDIES . . . . . . . . . . . . . . . . . . . . . .
A. BIAS AND CONFOUNDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. STATISTICAL POWER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. ASSESSMENT OF DOSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. MORTALITY AND INCIDENCE DATA . . . . . . . . . . . . . . . . . . . . . . . .
E. FACTORS THAT MODIFY RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

299
300
302
304
306
307

II.

EVALUATION OF CANCER RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. MEASURES OF RADIATION RISK, INCLUDING LIFETIME RISKS .
B. TRANSFER OF RISKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. TYPES OF EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. RELEVANT STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
E. SITE-SPECIFIC RISKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

309
309
309
310
311
311

III. SITE-SPECIFIC CANCERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. OESOPHAGEAL CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. STOMACH CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. COLON CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. LIVER CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
E. LUNG CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
F. MALIGNANT TUMOURS OF THE BONE
AND CONNECTIVE TISSUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
G. SKIN CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
H. FEMALE BREAST CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I.
PROSTATE CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
J.
CANCER OF THE URINARY BLADDER . . . . . . . . . . . . . . . . . . . . . . .
K. BRAIN AND CENTRAL NERVOUS SYSTEM TUMOURS . . . . . . . . . .
L. THYROID CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
M. NON-HODGKIN’S LYMPHOMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
N. HODGKIN’S DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
O. MULTIPLE MYELOMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
P. LEUKAEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

312
312
313
315
316
319
325
328
330
334
335
336
338
343
344
345
346

IV. LIFETIME RISK FOR TOTAL CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
A. EXPRESSIONS OF LIFETIME RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

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Page

B.

C.

METHODS AND ASSUMPTIONS OF CALCULATIONS . . . . . . . . . . .
1. Risk models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Low-dose response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Projection methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Populations and mortality rates . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Transport of risks between populations . . . . . . . . . . . . . . . . . . . . . .
6. Fractionation and dose-rate effects . . . . . . . . . . . . . . . . . . . . . . . . . .
LIFETIME RISK ESTIMATES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

354
355
356
357
357
357
358
358

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

INTRODUCTION
1. Epidemiological studies of the cancer risks associatedwith both external and internal exposure to ionizing radiation
were the subject of an extensive review in the UNSCEAR
1994 Report [U2]. Covered in that review were studies ofcancer mortality and incidence up to 1987 among thesurvivors of the atomic bombings at Hiroshima and Nagasaki,
who received a single dose of radiation; patients exposed toradiation for diagnostic or therapeutic purposes, usually as
multiple doses; and radiation workers and individuals exposed
chronically to environmental radiation. Estimates of risks
observed in the major epidemiological studies of external low
linear energy transfer (low-LET) exposures were presented in
a common format. Data from the Life Span Study of survivorsof the atomic bombings, in particular, were used to estimate
the lifetime risk of total cancer mortality following external
exposure to low-LET radiation [U2]. Lifetime risks for
specific cancer sites were also estimated, based on a Japanese
population.
2.
Information from follow-up through the end of 1990 ofmortality among the survivors of the atomic bombings has
recently been published [P9]. The extended period of followup was not very informative for survivors over 40 years old at
the time of the bombings, since many of these people hadalready died. On the other hand, the data for survivors
exposed at younger ages, particularly in childhood, are highly
valuable, because these people have only recently reached theages at which baseline rates for most solid tumours begin to
increase sharply. Methods used in the UNSCEAR 1994
Report [U2] to project risks beyond the period of follow-up
assume that the relative risks for solid tumours either remain
constant throughout life (following a minimum latencyperiod)or decrease at long times following exposure. It was shownthat lifetime risk estimates based on the latter approach were20%40% lower than estimates based on the former [U2].
This difference was larger for those exposed at young ages.

Further follow-up of this group is needed to reduce theuncertainties in lifetime risk projections.
3.
Although the Life Span Study of survivors of theatomic bombings is the single most informative study on
the effects of low-LET exposure of humans, a considerable
amount of data is available from many other epidemiological studies. For example, studies of people with partialbody exposures, such as those from medical examinations
or treatments, provide valuable information on risks for
specific cancers. Despite the extensive knowledge of radiation risks gained through epidemiological investigations,much still remains to be learned. For example, the effects
of chronic low-level exposures and internal exposures are
not well described. Further data are being obtained throughupdates of individual studies and parallel analyses for sites
such as breast and thyroid. Information is also becoming
available from inter alia further studies of occupational
exposures, including workers at the Mayak nuclear facility
in the Russian Federation and from past radiological eventsin the former Soviet Union, such as at Chernobyl andaround the Techa River.
4.
In addition to individuals exposed to low-LET radiation, various groups with exposure to high-LET radiation
have been studied. Some of these exposures have arisen inoccupational settings (e.g. radon in mines, radium in dial
painting, or plutonium in some nuclear facilities), somefrom medical interventions (e.g. injections with 224Ra or
thorotrast), and some environmentally (e.g. radon inhomes). Combined analyses of existing data, as well as
several studies of residential radon that are in progress,
should provide additional information on the risks of highLET radiation. A review of these data in a format similar
to that for low-LET radiation may be helpful in comparing
risks.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

5. The mortality follow-up of the survivors of the atomic
bombings yields little data on cancers that are usually nonfatal. However, comprehensive cancer incidence data are now
available for the survivors of the atomic bombings in Japan[T1], and comparisons between the two types of endpoint havebeen reported [R1]. Data on cancer incidence from this andother studies will assume greater importance as the treatmentof cancers improves.
6.
While there is a need for estimates of the total risks ofcancer mortality and incidence arising from radiation exposure, there are also situations in which risk estimates for
specific cancer sites are of particular value. These include (a)evaluating the effects of partial-body irradiation arising either
from external exposure or from internal exposure to radionuclides and (b) estimating the probability that a prior radiation exposure led to the development of cancer in an individual, i.e. the probability of causation [I12, N1]. Epidemiological studies carried out in countries with differing baseline
rates for certain cancer sites may also assist in determining
how to transfer radiation-induced risks from one population
to another. This is an important topic in view of thedifferences in baseline rates for cancers such as breast, lung,and stomach between Japan and many other countries.
Depending on the form of the model used to transfer radiation
risks derived from data on the Japanese atomic bomb
survivors to other populations, quite different estimates ofradiation-induced cancer risks can arise for such sites [L12].
It was concluded in the UNSCEAR 1994 Report [U2] that the299

epidemiological data available at that time provided no clear
indication of how to transfer risks. Ongoing and future studies
of genetic (host) susceptibility and interactions with othercarcinogens have the potential toboth increase knowledge andprovide new information on radiation risks.
7.
The UNSCEAR 1994 Report [U2] contained a comparison of risk estimates for specific cancer types derived fromvarious epidemiological studies. The aim of this Annex is toprovide a more detailed comparison of site-specific cancer
risks. It incorporates more recent data, including the updated
mortality follow-up for the survivors of the atomic bombingsand additional analyses of cancer incidence data for thisgroup. The methodology and findings for this and otherstudies are described and compared. The potential for bias orconfounding, the impact of errors in dosimetry, and othersources of uncertainty are discussed. Among the generalconsiderations addressed are the advantages or limitations of
the various types of epidemiological studies, statistical power,
the influence of factors that modify radiation-induced risks,
and the approach to be taken in examining risks. Thisapproach is applied to data for specific cancer sites, namely
oesophagus, stomach, colon, liver, lung, bone and connective
tissue, skin, female breast cancer, prostate, bladder cancer,
brain and central nervous system tumours, thyroid cancer,
non-Hodgkin’s lymphoma, Hodgkin’s disease, multiple
myeloma, and leukaemia. Risk estimates for all cancers
combined are then derived, although it should be recognizedthat cancer is a heterogeneous group of diseases.

I. FEATURES OF EPIDEMIOLOGICAL STUDIES
8. Epidemiology is the study of the distribution anddeterminants of disease in humans [M10]. One of the key
facets of epidemiology is that it is observational rather thanexperimental in nature. In contrast to randomized clinical
trials, there is the possibility that bias or confounding
associated with the design and conduct of an epidemiologicalstudy may give rise to spurious results. Another difficulty,
which may also arise in randomized trials, is the possibility
that low statistical power can hinder the ability to detect, or toquantify with precision, an elevated risk. Bias, confounding,and statistical power are discussed in more detail below. It
should be emphasized that not all epidemiological studies areequally informative or of equal quality. Some have such low
statistical power that they provide very little information onrisks; others are so susceptible to potential or actual biases thatthe findings have little or no validity. It, therefore, is
important to consider such methodological issues wheninterpreting the evidence from different studies.
9.
Epidemiological investigations of radiation effects areusually constructed around either a cohort study or a casecontrol study. In a cohort study, a defined population(preferably with a wide range of exposures) is followed
forward in time to examine the occurrence of effects. Such a

study may be performed either prospectively (i.e. by following
a current cohort into the future) or retrospectively (i.e. byconstructing a cohort of persons alive at some time in the pastand following it forward, possibly to the current time). In acase-control study, people with and without a specified disease(the cases and controls, respectively) are compared to examine
differences in exposures. Some case-control studies are nested
within a cohort study, in that the cases and controls are
selected from the cohort. The nested case-control studydesign
is often used when it is difficult to obtain estimates ofradiation dose or other exposures for all members of a cohort,
but possible to collect them for a smaller number ofindividuals. For example, in an international study of patientstreated for cervical cancer, radiation doses were estimated forpatients with various types of second cancer, as well as formatched control patients [B1]. An alternative approach is tocollect detailed information for cancer cases plus a random
sample of the original cohort. The case-cohort study design[P1], which was utilized in an early analysis of cervical cancer
patients [H1], is useful when studying the occurrence ofseveral different types of cancer.
10. Cohort-based studies, particularly those performed
prospectively, tend to be less susceptible to biases than case-

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control studies, which depend on the retrospective collectionof data [B18]. Case-control studies can be informative aboutrisks, but particular attention needs to be paid to the potential
for biases associated with the fact that the studies are
retrospective. Because randomized controlled trials employan
experimental method, they are less susceptible to bias andhave fewer methodological limitations than either cohort orcase-control studies. However, only a few randomized trials of
the effects of radiotherapy in treating cancer have provided
information on radiation risks (e.g. [F3]). At the otherextreme, results from correlation studies (studies based on data
aggregated over, for example, geographical regions) are often
unreliable. As will be described later, such studies, which aresometimes referred to as “ecological studies”, have highpotential for bias, owing to the lack of data on individual
exposures and confounders. Therefore cohort-based and casecontrol studies that contain data at the individual level form
the main bases for estimating radiation risks in humans.
11. To be able to draw substantive inferences fromepidemiological studies, it is important to ensure that thepotential for bias or confounding is as low as possible and thatthe statistical precision of the results is reasonably high. In
low-dose studies, methodological issues become particularly
important, because even a small degree of bias or confounding
can distort study results substantially. In spite of the
difficulties that can arise in designing and performing
epidemiological studies, epidemiology does have theadvantage over molecular, cellular and laboratory animalstudies of providing direct information on health risks inhuman populations.

A. BIAS AND CONFOUNDING
12. Bias can be defined as any process at any stage ofinference that tends to produce results or conclusions thatdiffer systematically from the truth [S10]. Although it ispossible to address issues such as lack of statistical power or
random errors in dose estimates through statistical
approaches, described later, bias in an epidemiological study
can render its findings meaningless. Bias can arise in a
number of ways. One potential source of bias is the failure toobtain follow-up data for all but a very small proportion of thepeople in a cohort study. Those lost to follow-up are often
more likely to have migrated or died than other members of
the cohort. If they cannot be identified, they will continue tocontribute person-years (PY) to the study beyond the period
during which any cancer that had developed (incident or fatal,
depending on the type of study) would have been recorded.
Thus they will appear, incorrectly, to be immortal. Even if
those lost to follow-up can be identified, specifying the date on
which they should be withdrawn from the study is not always
straightforward. For example, in commenting on a study ofsecond cancers after treatment for Hodgkin’s disease inchildhood [B16], Donaldson and Hancock [D25] pointed outthat in this and other hospital-based studies, patients whodevelop a second cancer would be more likely to return to thehospital or clinic than patients free of the disease. If the endof follow-up is taken as the date last seen at the hospital, thenmany of the disease-free patients may be withdrawn from thestudy at an early time even though, had they later developed
the disease, the follow-up would have been longer. Thus,
hospital-based studies are susceptible to the possibility ofdifferential follow-up, which may lead to an overestimation of
disease rates.
13. It is also important that the completeness of the followup data be uniform and not vary according to the level of
exposure. This is a particular concern for diseases that are notimmediately apparent, such as thyroid tumours without
apparent symptoms. Increased levels of screening in aradiation-exposed population may show a raised disease
incidence relative to an unscreened group. Ideally,
comparisons would be made between groups with a similarlevel of screening, as, for example, in a study of irradiation for
lymphoid hyperplasia [P8] in which both the exposed andcomparison groups were screened. If, however, the level ofscreening was correlated with dose, examination of any doseresponse relationship would be biased.
14. The issue of differential disease ascertainment can also
be important in some occupational studies. If occupationalgroups have better medical care than the general population,
the cause of death for certain diseases (e.g. multiple myeloma
and brain cancer) may be determined with greater accuracy inthese groups. This could lead to spurious findings if
comparison is made with the general population. For example,
an apparent excess of brain tumours among a group of
workers with potential chemical exposure may have been due
to more detailed screening for the disease [G21]. However,this type of problem may be alleviated if disease rates within
occupational groups can be compared. As an example in thecontext of radiation, Ivanov et al. [I13] reported a statisticallysignificant elevated risk of leukaemia incidence among
Chernobyl recovery operation workers when compared withrisks for the general population. However, the workers
received frequent medical examinations, and so the accuracy
and completeness of the leukaemia diagnoses are likely todiffer from those for the general population [B27]. Indications
that differences in the ascertainment of leukaemia may haveaffected these findings came from a case-control study nested
within the cohort of recovery operation workers [I14]. In
contrast to the difference in leukaemia rates between theseworkers and the general population, no correlation between
leukaemia risk and either radiation dose or other aspects of
their work around Chernobyl was found within the cohort. It
is likely that bias arose in the cohort analysis, in part becauseof the over-ascertainment and misdiagnosis of someleukaemias among the recoveryoperation workers and underreporting of leukaemia diagnoses in the general population
used for comparison [B27].
15. The problem of differential disease ascertainment is not
restricted to occupational studies. An example is given in
Section IV.B.2 of how the recording of cancer on deathcertificates for the Japanese atomic bomb survivors may havebeen affected by the knowledge that the person was a survivor[P9]. Even though this type of bias might be small in absoluteterms, it could have a particular impact when the risks of

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cancer mortality at low doses are being estimated [P9]. The
data on cancer incidence for the survivors of the atomic
bombings, by contrast, are less susceptible to this type of bias
because of the more objective means of ascertaining cancer.
16. Another issue of importance when comparing occupational groups with the general population is the healthy
worker effect, whereby individuals selected for employment
tend to have better health than the population as a whole [F4].
The healthy worker effect may be intensified because theworkers who continue to be employed are healthy individuals
and they receive better medical care. As an example of thiseffect, Carpenter et al. [C19] reported that mortality rates for
all cancers combined were significantly lower than national
rates among both radiation workers and non-radiation workers
in three nuclear industry workforces in the United Kingdom.
To overcome the healthy worker problem in studying
occupational radiation cohorts, it is preferable to compareradiation workers receiving different levels of dose or dose
rates rather than to compare radiation workers with thegeneral population.
17. In case-control studies, it is important that the cases andcontrols should be chosen from the same well defined
population and that the ascertainment of both sets should becomplete. In particular, when it is necessary to approach
potential study subjects or their next-of-kin for interviews, therefusal rate should be low for both cases and controls if
selection bias is to be minimized. It should be noted that incohort and case-control studies where exposures, both toradiation and other agents, are ascertained retrospectively, it
is sometimes necessary to rely on the study subjects themselves or surrogates for such information. This might lead tobias, if the ability to assess exposures accurately depends onwhether the disease in question arose or not. For example, ina proportional mortalitystudyof naval shipyard workers in the
United States, an increased risk of cancer and leukaemia
relative to other causes of death was reported among nuclear
workers [N6]. This was based on radiation exposure histories
ascertained by newspaper reporters from the next-of-kin of
deceased workers. However, the findings were not borne out
in a subsequent cohort study in which radiation exposures
were determined using employment records [R12]. The
epidemiological biases associated with the initial study werediscussed in detail byGreenberg et al. [G11]. In particular, therelatives of workers who died from cancer were more likely tohave been located and interviewed than the relatives of otherdeceased workers. This, in combination with the lower allcause mortality among nuclear workers relative to thecomparison group, contributed to the spurious findings. Moregenerally, the use of historical records, where available, is tobe preferred to avoid differential ascertainment of exposures.
18. A particular problem when considering a large numberof hypotheses in a study is that of multiple comparisons. A
statistically significant finding is often referred to as one thatwould arise only once in 20 times by chance alone, i.e. 5% of
the time. Therefore, if 20 non-overlapping cancer categories
are examined in an epidemiological study, one of them would
be expected to show a statistically significant result at the 5%301

level even if the underlying risk was not elevated. This finding
could represent either an excess or a deficit if a two-tailed test
(i.e. a statistical test that looks in both directions) has been
applied. Consequently, it is important to examine the consistency of findings for specific cancer sites across studies, aswell as the consistency with other evidence, e.g. from experimental data. Problems of multiple comparisons can arise instudying not only multiple endpoints but also in testing a large
number of hypotheses. For example, Jablon et al. [J1] studied
cancer around a large number of nuclear facilities throughout
the United States. They found that the facility-specific relative
risks for childhood leukaemia formed a symmetric distribution, with roughly as many values below 1 as above it. Thus,
unless there is prior reason to focus on specific facilities, thoseresults that achieve the nominal levels of statistical significance need to be viewed in the light of the distribution forfacilities overall. An extra problem that requires scrutinyis thepossibility of selective reporting of results, i.e. the greater
tendency for positive findings to be reported than negative
findings. It is possible that some reports of highly specificpositive findings, based on either small studies or sub-analysesof larger studies, reflect such a publication bias. For example,
Carter et al. [C20] published the results of a study that did notshow an association between Down’s syndrome and maternalradiation only after a positive report appeared in the literature.
19. It is also necessary to address the potential for
confounding, which can lead to bias. A confounding factor iscorrelated with both the disease under study and the exposureof primary interest. While many factors other than ionizing
radiation affect cancer rates, in most epidemiological studiesof radiation-exposed groups there is no reason to think suchfactors will be strongly correlated with radiation dose,
although weak associations might arise by chance. For
example, in studies of the survivors of the atomic bombingsand many medically irradiated groups, it is unlikely that there
would be a strong association between, say, levels of smoking
and the dose received. One possible confounder in
occupational studies is time since start of radiation work. This
tends to be correlated with cumulative radiation dose and with
time-related factors associated with the selection ofpeople into
radiation work. However, since the time variation in risks
associated with such selection factors tends to be greatest soonafter starting work [F4], analyses that omit the first few years
of follow-up (when radiation effects would be unlikely to be
manifested in any case) may permit resolution of this point. In
studies of medical exposures, confounding may arise if theclinical indications that lead to the exposures are related to a
subsequent diagnosis of cancer; this is sometimes referred toas “confounding by indication”. For example, in a study ofpatients administered 131I for diagnostic purposes, a slightly
elevated risk of thyroid cancer was found [H4]. However, thisrisk was not related to dose and was concentrated among
patients referred because of a suspected thyroid tumour,indicating that the elevated risk was probably due to theunderlying condition. Similarly, in a another study, an
increased risk of leukaemia and non-Hodgkin's lymphomathat arose shortly after diagnostic x-ray exposures appeared tobe due to pre-symptomatic conditions of the diseases that led
to the exposures [B24].

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20. It is desirable to check for confounding by factors thathave a sizeable influence on cancer rates if the level ofradiation risk is predicted to be low or if the range of doses isnarrow. For example, in case-control studies of indoor radonand lung cancer, it is very important to take account of
individual smoking habits. On the other hand, if the level ofradiation risk is predicted to be high, instances where data are
available on potential confounders may permit not only
adjustment for such factors but also examination of how suchfactors may modify the radiation-induced risk. For example,
data on smoking habits among radon-exposed miners canallow examination of the joint influence of radon and smoking
on lung cancer risks. Risk modification is discussed later inthis Annex and is also covered in Annex H, “Combined
effects of radiation and other agents”.
21. In contrast to cohort, case-cohort, and case-control
studies, which utilize data on specific individuals, correlation studies are based on data averaged over groups. A
particular form of this study is the geographical correlation
study, in which disease rates in geographical areas arecompared with average levels of exposures, e.g. to naturalor environmental radiation. An example of such a study,
which concerns lung cancer and indoor radon in areas of
the United States [C18], is discussed in Section III.E. Since
studies of this type do not involve data on individual
exposures or confounders, they are susceptible to biases
that do not arise in studies for which such data are
available [G2]. These biases can be large, although theirmagnitude is dependent on the particular situation. In
addition, migration can be a large problem in geographicalcorrelation studies, because people exposed in one region
can die or develop the disease of interest in another region.
This suggests that estimates of radiation risks should bebased on cohort, case-control, or case-cohort studies.
However, correlation studies sometimes can be useful for
generating hypotheses or as a means of surveillance forlarge effects, such as in the study of childhood leukaemia
and lymphomas in Europe following the Chernobyl
accident [P12], although the potential biases specific to thisform of investigation should be borne in mind.

B. STATISTICAL POWER
22. A very important facet of any epidemiological study
is its statistical power, i.e. the probability that it will detect
a given level of elevated risk with a specific degree ofconfidence. The power of a cohort study will depend on thesize of the cohort, the length of follow-up, the baseline
rates for the disease under investigation, and the distribution of doses within the cohort, as well as the predictedlevel of elevated risk. Similarly, statistical power in a casecontrol study depends on the number of cases, the numberof controls per case, the frequency and level of exposure,and the predicted exposure effect. Statistical power isgenerallyevaluated before a studyis conducted. Afterwards
it is more correct to refer to statistical precision, which isreflected in the width of the confidence intervals for risk
estimates.

23. The following example illustrates how the above
factors can influence statistical power. Suppose cancer
rates are ascertained in a cohort consisting of two groups,
one of which was unexposed (the control group) and theother of which consists of persons who received a single
common dose, D (the exposed group). The groups are
assumed to have the same distributions for age, gender,
and period of follow-up. (For simplicity, the following
calculations do not take explicit account of these factors.)
Statistical power can be evaluated by simulating thenumber of cancers in the two groups under a model suchthat the ratio of the cancer rate in the exposed group to thatin the control group (i.e. the relative risk) is 1 + aD, wherea is the excess relative risk (ERR) per unit dose. Given the
total number of cancers in the two groups, the statisticalpower depends only on the product of a and D and on theratio of the number of cancers expected in the two groups
if there were no elevated risk. In particular, power iscalculated here by evaluating the proportion of simulations
for which the number of cancers in the exposed group is
greater than the value which, if there were no increased
risk, would be exceeded only 5% of the time. This
represents a one-sided test at the 5% level.
24. An approximate form of the power calculation is asfollows. Let N denote the total number of cancers in the
exposed and unexposed groups, let p denote the proportion of
the total number of cancers expected to arise in the exposedgroup if there were no elevated risk, and let O denote theobserved number of cancers in the exposed group. It can beshown that conditional on the value of N, O has expected value
E = Nq and variance V = Nq(1  q), where q = p(1 + aD)/(1+ paD). Furthermore, provided that Nq and N(1  q) arereasonably large (at least 20 or so), O is approximately
normally distributed. Consequently the statistical power (i.e.
the probability that O will exceed the value that would be
exceeded only 5% of the time if there were no increased risk)
can be approximated using tables for the normal distribution.
In particular, if there were no elevated risk (i.e. a = 0), then q= p, and so O would be approximately distributed normallywith mean E0 = Np and variance V0 = Np(1  p). Therefore a
one-sided test at the 5% level would signal an elevated risk if
T = (O  E0)/V01/2 exceeds 1.645, where the probability that anormally distributed variable with mean zero and variance 1
would exceed 1.645 is 0.05. More generally, let C(x) denotethe probability that a normally distributed variable with mean
zero and variance 1 would exceed x. Then the probability thatT exceeds 1.645 would be C(1.645) = 0.05 if there were no
increased risk. More generally this probability, which equates
to the power, can be calculated as C[(E  E0 + 1.645V01/2)/V1/2].
25. It should be noted that the power is not zero when
there is no increased risk, since there is still a chance thata large number of cases might arise in the exposed group,
which would lead to a statistically significant (butspurious) finding. Under the above test, the probability ofsuch a finding is set to 0.05. Also, since this example
involves an internal comparison group, it does not rely on
the validity of, say, published national or regional baseline
cancer rates.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

POWER (per cent probability)

100

received 1 Sv, then the power to detect an elevated risk is 81%
if the total number of cancers in the two groups is 2,000 but
only 25% if the total number of cancers is 200.

(a)

80

60

40

p

20

0.1
0.1
0.1

ERR
per Sv
2.0
0.2
0.2

Total
cancers
200
200
2000

0
0

POWER (per cent probability)

100

0.5

1.0
DOSE (Sv)

1.5

2.0

(b)

80

60

40

p
0.1
0.1
0.01
0.01

20

ERR
per Sv
0.2
0.2
0.2
0.2

Dose
2 Sv
1 Sv
2 Sv
1 Sv

0
0

303

1000 2000 3000 4000 5000 6000 7000 8000 9000 10000TOTAL NUMBER OF CANCERS

Figure I. Statistical power to detect an increased riskof cancer in an epidemiological study (a) in relation todose with a baseline cancer incidence of 0.1; (b) inrelation to the number of cancers observed with anexcess relative risk (ERR) of 0.2 Sv-1.
p denotes the proportion of total cancers expected in the
exposed group if there were no raised risk.

26. The upper panel of Figure I shows how the power
varies with a and D for various values of the total number ofcases in the situation where, in the absence of an elevated risk,
the expected number of cancers in the exposed group is 10%of that in the total cohort (i.e. p=0.1). Here the power isexpressed as a percentage probability. Usuallyan analysis with
about 80% power would be considered to be quite sensitive in
detecting an underlying effect. The first point that should be
noted from Figure Ia is the effect of the total number ofcancers, N. This number is influenced not only by the size ofthe combined cohort but also by the baseline cancer rates andthe length of follow-up. Thus a study based on a very large
cohort may not be particularly informative if a rare cancer isunder investigation and the follow-up is short. Conversely, a
study based on a fairly small cohort may be quite informative
if a common cancer is being considered and the follow-up islong. For the example illustrated in the upper panel of
Figure I, if the ERR per Sv, a, is 0.2 and the exposed group

27. The second point to note from the upper panel of
Figure I is the effect of the level of elevated risk. If the overall
number of cancers is 200 and the exposed group received adose of 1 Sv, then the probability of detecting an enhanced
risk at the 5% level is 25% if a (the ERR per Sv) is 0.2. In
contrast, if a = 2, the corresponding probability is nearly
100%. The same probabilities would arise if, say, the dose D
is doubled and a is halved. This is because the ERR can be
represented by the product of a and D in this example.
However, the calculation is more complex under alternative
scenarios in which cohort members receive a range ofdifferent doses.
28. The two panels of Figure I are similar, except that in thelower panel the ERR per Sv, a, is fixed at 0.2 and the ratio ofexpected numbers of cancers in the two groups is allowed tovary. It can be seen that for a given total number of cancers
and at a given dose, the power decreases with decreasing
values for the proportion, p, of cancers expected in the
exposed group in the absence of an elevated risk. However, for
given values of a and D, the power tends to be similar if the
proportion p and the total number of cancers vary in such a
way that the expected number of cancers in the exposed groupis roughly constant. For example, based either on p=0.1 anda total of 1,000 cancers or on p=0.01 and a total of 10,000
cancers, the predicted number of cancers in the exposed groupis about 120 at a dose of 1 Sv (an excess of roughly 20). The
lower panel of Figure I shows that the power is similar in thetwo instances (58% and 60%, respectively). An exception tothis arises if p is very high, owing to the difficulty of
establishing baseline cancer rates for a relatively small control
group.
29. The above example is intended to show how certain
factors can influence statistical power. As indicated earlier,the calculations are often more complex, as when the people
in the exposed group receive a range of doses rather than thesame dose. Indeed, errors in the assessment of individual
doses also affect statistical power, as mentioned in thefollowing Section and as Lubin et al. [L10] illustrated forstudies of indoor radon. It should be emphasized thatsummarymeasures of the doses received by a population, suchas collective dose, are not, by themselves, suitable fordetermining statistical power. For example, if the same doseis received by all the members of a cohort, then the usual formof analysis that looks for a trend or difference in risk
according to the level of dose would not be possible. Indeed,
it is essential when calculating statistical power to takeaccount of the distribution of dose within the studypopulation.
30. The above considerations indicate that studies suchas the Life Span Study of survivors of the atomic bombings[P4, P9, S3, T1], which are based on large cohorts withdoses ranging up to several gray and for which the followup has extended over several decades, are particularly
informative about radiation-induced cancer risks. The same

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holds for medically irradiated cohorts that received a wide
range of doses and have a long follow-up, such as instudies of women treated for cervical cancer [B1] or given
multiple chest fluoroscopies [B3, M1]. While studies of
low-dose chronic exposure are of direct relevance to mostoccupational, environmental, and diagnostic medical
exposures, their power is inherently low, owing to the low
predicted level of elevated risk [L3]. In such situations,combining studies with similar designs can be very helpful
in attempting to increase power. However, the possible
influence of residual bias and confounding needs to beborne in mind, since the gain in precision will not lead toa gain in accuracy if bias still exists. Sometimes a metaanalysis is performed based on published findings fromseveral studies. However, as indicated below, it ispreferable, where feasible, to combine the original data andto analyse them using a common format. This approachhas been used, for example, to analyse data for about
95,000 radiation workers from Canada, the United
Kingdom, and the United States [C11, I2]. It has also beenused for studies with greater power and large numbers ofexcess cancers, such as studies of lung cancer in radonexposed miners [L4], thyroid cancer following childhood
exposure [R4], and breast cancer in medically exposedcohorts [L5], to enhance analyses of effect modification as
well as to increase precision.
31. In addition to increasing statistical precision, pooled
or meta-analyses may be able to resolve apparently
conflicting results from different studies [D1]. By aligning
the studies in a parallel fashion and analysing them using
a common approach, it may be possible to explain suchdifferences on the basis of, for example, different
categorizations of the exposure data. One of the maindifficulties that can arise in a meta-analysis is a lack ofcomparability of the studies under consideration, forexample because of differences in the form of the datacollected on exposures and potential confounders.
Summing many studies with potentially biased results may
provide a precise but incorrect estimate of risk;
consequently, meta-analyses can produce results that areseriously misleading [B28, B29]. Parallel analyses which
address the comparability of data and the potential for bias
in the various studies under consideration are therefore
important in determining whether it is sensible to perform
a pooled analysis. Since such an analysis is easier toperform if the individual studies are of a similar design, aprospective approach whereby studies are constructedaround a common protocol is more advantageous than aretrospective pooling exercise. The former approach is
being taken for a very large international collaborative
study of radiation workers that is being coordinated by theInternational Agencyfor Research on Cancer (IARC) [C8].
Another potential problem with retrospective pooling ispublication bias, i.e. selective reporting of results
depending on whether the outcome was judged to bepositive or negative. This bias, however, tends to arise forsmall or ad hoc studies, which would carry less weight ina meta-analysis if a number of large studies with clear, predefined objectives are included.

32. In view of limitations that can arise not only throughconsiderations of statistical power but also through residualbias and confounding, the ability to detect small elevatedrisks using individual or pooled epidemiological studies
can be low. This affects the ability to discern whether or
not there is a dose threshold for radiation carcinogenesis.
Results from epidemiological studies can be used toindicate levels of dose at which elevated risks are apparent,
as well as whether the data are consistent with various
dose-response trends [N3]. The inability to detect increases
at very low radiation doses using epidemiological methods
need not imply that the underlying cancer risks are notelevated; rather, supporting evidence from animal studies
needs to be utilized in addressing risks from low-dose andlow-dose-rate exposures [N3], while recognizing that not
all molecular changes result in tumours. Epidemiologicalstudies of such exposures do, however, enable upperbounds to be placed on radiation-induced risks. Risks at
low doses and low dose rates are discussed in detail in
Annex G, “Biological effects at low radiation doses”.

C. ASSESSMENT OF DOSES
33. A key aspect in estimating cancer risks following
radiation exposure relates to the assessment of radiation
doses. A recent workshop report reviewed sources of
uncertainty in radiation dosimetry and their impact on
dose-response analyses [N15]. Epidemiological studies ofradiation-exposed groups can differ, depending, forexample, on the type of information available on radiation
exposure; the time between a dose having been received
and making the measurement; and the specificity ofassessments of doses to particular organs and particular
individuals. Depending on the method of dose assessment,
doses estimates could be subject to systematic or random
errors or both, which could then affect the dose-response
analyses. These issues are now considered in more detail.
34. The assessment of doses received by individuals in
epidemiological studies may take several forms. In studiesof radiation workers, for example, it is possible to utilize
measurements made using personal dosimeters (e.g. [C11,G4]). For doses received from some types of medical
exposures, it may be possible to reconstruct organ doses
based on patient records, perhaps in combination withcomputer models, as for example, in an international studyof patients treated for cervical cancer [B1]. In otherinstances, information on the past location of individuals
has to be utilized together with measurement data, as for
the Japanese atomic bomb survivors and, for example,
people exposed to radon in dwellings. In the case of theJapanese survivors, there is still uncertainty about neutron
doses at Hiroshima and the associated impact on cancer
risk estimates, particularly at low doses [K20]. Furthermore, as indicated later, studies of indoor radon are
generally hampered by the need to assume that a contemporary measurement of radon concentration can beused to estimate concentrations during the preceding 20 or
30 years.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

35. It was emphasized in the UNSCEAR 1994 Report [U2]that the data available for assessing doses were generally notcollected with epidemiology in mind. For example, radiation
monitoring of workers has often been undertaken to comply
with management policies. Consequently, a detailed examination of dosimetry practices, including sources and magnitudeof errors, is important in considering whether sufficiently
accurate and precise estimates of dose can be obtained for use
in an epidemiological study. A recent example is the examination of dosimetry records and practices in Canada, theUnited Kingdom, and the United States, carried out as part ofa study of workers in these three countries [C15]. Thisaddressed issues such as the practices on who should be monitored (e.g. all personnel at a facility or only those workers who
were likely to receive doses); how missing dosimeter results
should be treated (e.g. by recording zero, the threshold value
for the dosimeter, a percentage of the statutory dose limit, ora best estimate of the likely dose); and the recording of a dosenear or below the dosimeter threshold (e.g. as zero or byentering a “recording threshold”). Also of relevance iswhether data are available on neutron doses and internal
exposures. Gilbert and Fix [G4] urged the use of sensitivity
analyses to examine the effect of potential sources of bias indose estimates in epidemiological studies ofradiation workers.
36. To examine the risks of specific types of cancer in
relation to radiation, it is desirable to use the radiation dose to
the organ under study. In some instances, such as external
whole-body exposures, it may be possible to use a single value
for the dose to an individual and to use this value in analysing
the risk for each organ. This approach is commonly used instudies of radiation workers (e.g. [M46]). However, even in
the case of external whole-body exposures, attenuation of theradiation may lead to some variation in the absorbed doses todifferent organs. For example, the DS86 dosimetry system for
the Japanese atomic bomb survivors incorporated organspecific transmission factors to calculate organ absorbed doses[R24]. These factors reflect the circumstances of individual
exposures, including posture and orientation of the survivors
relative to the explosion hypocentre; average values for theorgan gamma-dose transmission factor range from 0.72 forthe pancreas to 0.85 for the female breast [S51]. Also, as partof an international study of radiation workers [C15],
calculations were made of the ratio of organ to “deep dose”(i.e. dose to 1 cm below the skin [I19]), both for the lung andthe red bone marrow, and for various photon energies androtational exposure geometries. This yielded ratios ofapproximately 1 for the lung and 0.70.8 for the red bonemarrow for photon energies between 100 keV and 1 MeV,
with the consequence that estimates of the leukaemia risk perunit dose were multiplied by 1.2 whereas no adjustment wasmade for other cancer types [C15].
37. In situations where the exposure involves radiation overa limited range of energies, it is possible to convert organ
absorbed doses (in gray) to organ equivalent doses (in sievert)
using the radiation weighting factors cited by ICRP [I1]. For
most low-LET radiations, the absorbed and equivalent doses
would be numerically equal. In contrast, ICRP recommends,
for example, applying a factor 20 to convert organ absorbed

305

doses from high-LET alpha radiation to the correspondingorgan equivalent dose. In these situations, it may be more
direct to relate organ-specific risks to organ absorbed doses
than to include the radiation weighting factor by using
equivalent dose. However, if the exposure is totallyor virtually
all due to low-LET radiation, then the use of absorbed dose orequivalent dose would give the same values for risk per unit
dose. Alternatively, if the exposure arises solely from, say,internal alpha irradiation, then estimates of the risk per unitorgan absorbed dose can be related by a simple factor to therisk per unit organ equivalent dose. However, if the exposure
involves radiations ofwidelydiffering energies, including both
high- and low-LET radiation, such as arose for workers at the
Mayak plant in Russia [K32], then it is desirable to examine
organ-specific risks in relation to absorbed doses split byradiation energy. If this information is not available, analternative may be to use a total equivalent dose, based on
applying weighting factors to the component absorbed doses
and summing these values. However, it should be recognizedthat the choice of weighting factors would influence theanalysis of risk in relation to dose.
38. An additional difficulty that can arise in studies involving internal high-LET exposure concerns the estimation oforgan absorbed (or equivalent) doses. For example, plutonium
uptake among potentially exposed workers can be assessedusing urine measurements of plutonium excretion, together
with information on factors tied to each individual’s occupational history [O1, K32]. These assessments are dependent on
aspects of the monitoring procedures, such as the level ofdetection and the sampling periods. To arrive at organ-specificabsorbed doses, it is then necessary to use a dosimetric modelfor the distribution of activity between organs (e.g. [I4]).
These calculations depend in turn on factors such as thesolubility of plutonium in the workplace at a given time [O1]
as well as on physiological factors. It should therefore berecognized that estimates of individual organ-specific doses
from internal radiation are subject to uncertainty. However,this may be less of a problem if, as was the case in a study ofplutonium workers in the United Kingdom, estimates of organ
doses from internal radiation are generally lower than thosefrom external radiation, even after applying a weighting factor
to the absorbed doses [O1]. It should also be noted that someepidemiological studies of internal exposures present theirresults in terms not of organ doses but of some measure ofintake (e.g. the amount of thorotrast administered to thepatients [V8, V3]) or, say, the plutonium body burden (e.g.
[K32]).
39. The use of recent measurements in estimating doses
received many years ago, as for example in assessments ofindoor radon exposures, carries particular difficulties.
Changes in the intervening period (to, say, the structure of
the dwelling in the case of radon) may well influence
exposure levels. Again, it is important to understand which
factors may have a substantial impact on exposure levels
and the magnitude of these impacts. For example,
investigations have been made of factors affecting temporalconcentrations of indoor radon [B7]. Supplementary
information may sometimes be available through assess-

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ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

ments of contemporary exposures. For example, in the caseof radon, there has been interest in whether CR-39 surface
measurements using a piece of glass possessed by a person
over many years [M7] or in vivo measurements of 210Pb in
the skull [L25] can assist in assessing cumulative radon
exposure. The former approach was used recently in an
epidemiological study of indoor radon, alongside
traditional track-etch measurements [A24], althoughfurther validation of the glass-based approach would bedesirable in view of the effects of factors such as smoking[W19]. Furthermore, in contrast to measurements of radonin dwellings, radon exposures to persons can be influenced
by occupancy patterns, particle size distributions, andbreathing rates, although their effect tends not to be as
great as those of factors affecting radon concentrations inhouses. In general, it is essential to evaluate in detail thefeasibility of estimating exposures accurately enough andprecisely enough for the purposes of epidemiology.
40. In addition to the above methods of dosimetry, otherbiological and physical methods are now being incorporated into epidemiological studies. Such methods include
classical cytogenetics for translocations, used for example
in a study of women with benign and malignant
gynaecological disease [K14]; the glycophorin A mutational assay of red blood cells and the fluorescent in situ
hybridization (FISH) technique for chromosome stabletranslocation analysis, used by Bigbee et al. [B19] andLloyd et al. [L26], respectively, in investigations ofChernobyl recovery operation workers; and electron spinresonance (ESR), also known as electron paramagnetic
resonance (EPR), of tooth enamel, used for example inatomic bomb survivors in Japan [I8] and workers at the
Mayak facility in Russia [R28]. Several factors can affectthe utility of these methods in epidemiology. First, it isgenerally difficult to evaluate individual doses of less than100200 mGy using these methods, although in the caseof FISH, for example, it is possible to assess average doses
to populations at around these levels. For example, in spiteof evaluating more than a quarter of a million metaphases,
Littlefield et al. [L31] were unable to detect any increase inchromosome aberrations in lymphocyte cultures from
Estonian men who took part in the clean-up of theChernobyl nuclear power site, compared with men who did
not participate in this work. Secondly, it can be difficult
and/or expensive to collect, store, and analyse material forthousands or tens of thousand of people. This suggests thatcollection for only a subgroup of a cohort (e.g. for cancer
cases and matched controls) may be a more efficientapproach, although the possible effect of cancer treatment
on such material needs to be considered. Thirdly, somebiological measures can be affected by factors other thanradiation. For example, Moore and Tucker [M49] reported
that adjusting for age and smoking improved estimates ofdoses for Chernobyl recovery operation workers based on
chromosome translocation frequencies. Fourthly, the effectof radiation on some biological measures, such as dicentricaberrations, is relatively short-lived, so the collection ofrelated materials is unlikely to be useful in studying
exposures received many years previously [L26].

41. Provided that assessment of doses is performed“blind” to whether or not the study subjects develop
particular diseases, there will not be bias owing todifferential misclassification of exposures, as, for example,
would arise from selective recall by the subjects of past
exposures. However, non-differential misclassification canstill lead to bias in estimating dose-response relationships.
For example, random errors in individual dose estimates
tend to bias the dose response towards the null [A1].
Statistical methods have been developed to allow for suchrandom errors in analyses, based on estimates of themagnitude of the errors, and have been applied to several
radiation-exposed groups, such as the survivors of theatomic bombings [P2]. However, such errors can have a
profound effect on statistical power, particularly when thepredicted elevated level of risk is low [L1].
42. In some studies it is not possible to estimate doses on
an individual basis, so average doses for a cohort must
suffice. For example, in the study in the United Kingdomof ankylosing spondylitis patients treated with x rays,
average doses were estimated for a number of organs, but
only for the red bone marrow were doses estimated for asample of individuals [L2, W1]. However, such studies canstill provide information on, for example, the temporal
pattern of radiation-induced risks in instances where theserisks are large.

D. MORTALITY AND INCIDENCE DATA
43. It is often easier to obtain data on cancer mortality thanon cancer incidence, since death certification tends to be more
complete than cancer registration. For example, essentiallycomplete follow-up for mortality of the survivors of the atomic
bombings can be attained via the compulsory system of family
registration (koseki) in Japan. Cancer incidence data for thesesurvivors, however, are generally limited to cases arising
within the areas covered by the Hiroshima and Nagasaki
tumour registries [M2]. It was therefore necessary to allow for
migration from these areas when analysing incidence data forthe survivors of the atomic bombings [S4]. Elsewhere,
complete follow-up for cancer incidence is achievable inseveral countries; the Nordic countries in particular have longrunning cancer registries. Some countries, however, either do
not have cancer registries or have strict confidentiality lawsthat prevent the linkage of names to diagnoses; others, e.g. theUnited States, have high-quality cancer registries, but only incertain regions [P5].
44. Although mortality data are often more complete, it iswell known that the cause of death is recorded incorrectly orwith low specificity on a non-trivial proportion of deathcertificates [H5]. As well as on occasion recording the wrong
type of cancer, owing to metastases, there is a generaltendency to under-report cancers. This affects estimates ofboth site-specific and total cancer risks. For example, based on
linkage of death certificates to autopsy data for the Life Span
Study of survivors of the atomic bombings, Ron et al. [R2]found that 24% of cancers diagnosed at autopsy were missed

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

on death certificates. Most of these deaths had been assigned
to non-neoplastic diseases of the same organ system. Taking
account also of non-cancer deaths mistakenly recorded ascancer, Hoel et al. [H5] concluded that total cancer mortality
within the Life Span Study had been consistently underestimated by about 18%. Sposto et al. [S5] showed that
adjustment for errors in death certification would increase
estimates of radiation-induced cancer deaths in the Life Span
Study relative to published values by about 10%. In contrast
to mortality, there tend to be fewer diagnostic errors in theregistration of incident cancers, and histological subtypes ofsome cancers can be studied using incidence data. However,the proportion of histologically verified cancers varies among
registries, and consideration of completeness as well as
accuracy is important in judging the value of incidence data.
45. A particular advantage of incidence data over mortality data is the information they provide for cancers that areoften non-fatal. Of special interest within the field ofradiation carcinogenesis are cancers of the thyroid, skin,and breast. For the first two of these cancers, elevated risks
have been demonstrated only in cancer incidence data forthe survivors of the atomic bombings and not in mortality
data [R1]. While elevated risks of breast cancer mortality
are apparent in this cohort, the larger number of incident
breast cancer cases both in this group and in other cohorts
permits a much more detailed evaluation of risks for thiscancer site, particularly because survival rates may havebeen increasing over time. Another advantage of incidence
data is that latency periods may be determined moreaccurately, given that the time between exposure and death
could be affected by aspects of the cancer treatment.
46. It is clear that high-quality data on cancer incidence
should be utilized when these are available. However, careful
examination of the completeness and accuracy of data on
cancer registrations is important, since mortalitydata are morereliable than incidence data in some countries. Furthermore,data on total mortality are important as an indicator of theoverall health of populations, although incidence data can beof value for site-specific examinations. It is therefore worth
considering mortality data, not only to compare levels of
incidence and mortality but also as an adjunct to incidencedata.

E. FACTORS THAT MODIFY RISK
47. Analyses for several cancer sites have shown that thelevel of the radiation-induced risk is dependent not solely on
the magnitude of the radiation dose but can be modified byfactors such as age at exposure and time since exposure. For
example, data on the survivors of the atomic bombings [P4,P9] and on some other irradiated groups [U2] show that the
ERR per unit dose for leukaemia began to decrease
approximately 1015 years after exposure and that the ERR
is greater for people exposed in childhood than in adulthood.
The Japanese data, in particular, also show that for all solidcancers combined, the ERR decreases with increasing age at
exposure and, among those exposed early in life, tends also to307decrease with increasing time since exposure [P9, T1]. Basedon an earlier version of the mortality data, Kellerer and
Barclay [K21] suggested that these age and time trends could
be described by a model under which the ERR depends simply
on attained age. However, Little et al. [L32] showed that the
Kellerer-Barclay model is not sufficient to explain the age andtime trends in solid cancer risks based on the most recent
Japanese incidence data, in contrast to the earlier mortality
data; in particular, it is necessary to take account of both age
at exposure and time since exposure when modelling the
ERR, rather than just the sum of these quantities.
48. As will be discussed later in this Annex, age andtemporal factors can also have a large impact on risks for
specific types of solid cancer. In the case of radon-exposedminers, Lubin et al. [L4] showed that the ERR of lung cancer
decreases with increasing time since exposure and attained
age and is also influenced by exposure rate. For thyroid
cancer, there is clear difference between the effects ofirradiation in childhood and adulthood [R4]. In someinstances, it may be possible to associate the effect of age witha specific biological factor; for example, there does not appear
to be an elevated risk of breast cancer following postmenopausal irradiation (e.g. [B3, T1]), showing that
hormones can modify the radiation risk. Apart from age,other factors that may affect radiation-induced risks are
gender and baseline cancer rates, which are considered in
more detail later. Indeed, factors that affect cancer rates
generally, such as smoking, diet, and chemicals, may also
modify the carcinogenic effect of radiation and so have to beborne in mind when, for example, evaluating probability of
causation [N1, I12]. Particular examples are smoking in thecase of lung cancer and chemotherapy for patients who arealso treated with radiation. The combined effects of radiationand other agents are considered in more detail in Annex H,“Combined effects of radiation and other agents”.
49. In common with endogenous factors such as gender andage at exposure, the ability to detect a modifying effect ofexogenous factors is commonly related to the strength of theseparate carcinogenic effects of these factors. For example,
studies on smoking among radon-exposed miners [L4] and on
chemotherapy for patients treated with radiation, e.g. forleukaemia [C9], are reasonably informative about possible
interactions, owing to the high risks associated with bothradiation and the other factors on their own. In contrast,
epidemiological investigations of the joint effect of radiation
and another factor are unlikely to be informative when theeffect of either or both is weak, e.g. for a low radiation dose ora weak chemical carcinogen. An exception would be where
one agent is a promoter that has an effect only in the presenceof a carcinogen; however, such situations are rarely identified
in epidemiological studies.
50. In addition to exogenous factors, hereditary factors may
affect both baseline and radiation-induced risks. For example,
retinoblastoma, a rare cancer of the eye, is frequently caused
by inherited mutations of the RB1 tumour-suppressor gene.
Radiation treatment for the disease appears to enhance theinborn susceptibility to development of a second cancer,

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particularly osteosarcoma and soft-tissue sarcoma [E1, W11],
although this effect is seen only at high therapeutic doses(above 510 Gy). The extent to which radiation may modify
cancer risks associated with other genetic disorders such as
ataxia-telangiectasia and Li-Fraumeni syndrome remains to be
determined [L28]. The potential for genetic predispositions to
influence radiation-induced risks is addressed further in
Annex F, “DNA repair and mutagenesis”, as well as in recent
publications by ICRP [I20] and NRPB [N13].
51. Examination of potential modifying factors may behampered by the relatively small numbers of excess cancers
observed for particular sites. First, a lack of statistical power
may prevent some modifying effects from being discerned.
Secondly, if separate analyses are performed for a large
number of cancer sites, some trends with factors such as age
at exposure or time since exposure might appear simply
through chance variations. Toaddress these difficulties, Pierce
and Preston [P6] recommended joint analysis of site-specificcancer risks. In this approach, a general model is fitted
simultaneously to data for each of several cancer sites orgroupings of sites. This can be achieved by incorporating
cancer type as another factor in the usual cross-tabulation ofdata for analysis. Some of the parameters in this model may
be the same for all cancer types; other parameters may be
type-specific. Using this approach, significance tests can be
performed to examine the compatibility of parameters in therisk model across cancer types. Furthermore, Pierce andPreston [P6] suggested that such comprehensive models may
provide a clearer understanding of modifying factors such as
gender, age at exposure, and time since exposure.
52. Pierce and Preston [P6] applied this approach to theatomic bomb survivor mortality data that had previously been
analysed by the BEIR V Committee [C1]. BEIR V divided
solid cancers into four categories (breast cancer, digestivecancers, respiratory cancers, and other cancers) and analysedthem separately. The models derived by BEIR V for thesecategories had different modifying effects of gender, age at
exposure, and time since exposure. For example, the ERR for
respiratory, but not digestive and other cancers, decreased
with increasing time since exposure. Also, the ERR was
higher for females than for males in the case of respiratory
cancers but was the same for both genders for digestive andother cancers. However, re-analysing these data using a joint
analysis approach, Pierce and Preston [P6] showed that thedata were consistent with a common model for the ERR foreach cancer group except breast cancer. In the model of
Preston and Pierce, the difference in relative risk between
genders reflected the corresponding difference in baseline
rates, the ERR decreased with increasing age at exposure at acommon rate for each cancer grouping, and the ERR did notdepend on time since exposure.
53. This joint analysis therefore suggested that some of thedifferences between the risk models developed by BEIR V
might be artefacts arising from overinterpretation of the data
for separate cancer groupings. On the other hand, there areprior reasons for considering certain cancer sites. For
example, leukaemia and other haematopoietic cancers arenormally considered separately from solid cancers (as well asfrom each other) owing to differences in aetiology, in the levelof radiation-induced risk, and in the latency period. Also,
gender-specific cancers such as breast cancer should beconsidered separately from non-gender-specific solid cancers,
owing to the differences in factors affecting baseline rates aswell as (possibly) differences in the radiation-induced risks. It
is therefore intended that any modelling of radiation risks
conducted in this Annex should be based on either specificcancer sites for which a large amount of data is available (e.g.
breast cancer and lung cancer) or groupings such as digestivecancers. However, attention needs to be given to possible
differences among cancer sites within such categories (e.g.
stomach, colon, and oesophagus in the case of digestivecancers), which may preclude the modelling of combined
data. In this regard, reviews of the information available forsome individual sites are important, just as they may be forcertain cancer subtypes. For example, observations fromstudies of cancer incidence among the survivors of the atomic
bombings, namely that radiation-induced skin cancers arelimited primarily to basal-cell carcinomas [R15, T1] and thatchronic lymphatic leukaemia and virus-related adult T-cellleukaemia [P4] do not appear to be radiation-inducible, may
have significant implications for biomedical research as wellas radiological protection. Furthermore, it would still bepossible to derive estimates of measures of risk for anindividual cancer site by applying the risk model derived fora wider grouping of cancers to baseline rates for the cancersite of interest. One measure of risk that may be calculated is
the risk of exposure-induced death (REID), i.e. the probability
that an individual will die from a cancer that arose from an
exposure [U2]. The approach just outlined has been used, forexample, in applying mainly BEIR V-type models to obtainvalues of REID for specific cancer sites in the population of
the United Kingdom [N2].
54. Another point concerns the data available fromvarious studies. Whereas a complete cross-tabulation by
factors such as gender, age at exposure, and time since
exposure is available for specific cancer sites in the case of
the survivors of the atomic bombings, for most studies only
summaryvalues in publications are available. Furthermore,these values are sometimes not given separately for
different levels of factors such as age at exposure or timesince exposure, particularly in small studies. The
comparison of risks across studies can therefore be difficult
if the levels of these factors differ between studies. The
UNSCEAR 1994 Report presented estimates of the ERR
and the excess absolute risk (EAR), i.e. the absolutedifference in cancer rates, derived from various studies ofexternal low-LET exposures, generally without adjustment
for modifying factors (Table 8 of Annex A [U2]). While
such a presentation is useful for comparing the generallevel of risks seen in various studies, it would be helpful,where possible, to consider results specific to particularranges for age at exposure (e.g. childhood and adulthood)or to each gender, if these factors are likely to be importantin modifying risks. Where such factors are important,results that do not allow for them should be interpretedwith caution.

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309

II. EVALUATION OF CANCER RISK
A. MEASURES OF RADIATION RISK,INCLUDING LIFETIME RISKS
55. Analyses of epidemiological data on radiation-exposedgroups often yield estimates of ERR or EAR. These terms
represent the increased cancer rates relative to an unexposedgroup, measured on proportional and absolute scales,
respectively. For example, an ERR of 1 corresponds to adoubling of the cancer rate, while an EAR may be expressed
as, for example, the extra annual number of cancers per
10,000 persons. If these values have been derived from a
linear dose-response analysis, they may additionally be
expressed as amounts per unit dose, e.g. ERR per Sv;
otherwise, they may be quoted for a specific dose, e.g. 1 Sv.
As was pointed out earlier, the level of radiation-induced
cancer risks, either on a relative or an absolute scale, may vary
according to various factors. Therefore, one possibility inpresenting epidemiological results is to give values for ERR
and/or EAR specific to particular values for these factors, forexample, specific to gender and age at exposure or time since
exposure, when sufficient data are available.
56. Alternatively, it has become increasingly popular inrecent years to present models, based on relative or absolute
scales, that describe such modifying effects. Particular
examples are the models developed by BEIR V [C1] and themodels for cancer incidence among the survivors of theatomic bombings [P4, T1]. These models are generally
empirical, in that they attempt mainly to provide a good fit to
the relevant data. To some extent they can be related topossible biological mechanisms, in that a roughly timeconstant relative risk would be predicted if radiation acted at
an early stage in a multi-stage process, whereas the EAR
would more nearly be constant over time if radiation acted at
a late stage [L7]. However, more recent research has focusedon the explicit fitting ofmechanistic models for carcinogenesis
to data on radiation-exposed groups. For example, Little et al.
[L8] analysed data on leukaemia among the survivors of theatomic bombings and cervical cancer patients using theArmitage-Doll multi-stage model [A2] and the MoolgavkarVenzon-Knudson (MVK) two-mutation model [M11, M12].
This analysis suggested that neither model provided anadequate fit to these data, which led to the development of ageneralized MVK model involving more than two mutations[L9]. Another type of mechanistic model has been proposedby Pierce and Mendelsohn [P34], in which it is assumed thatcancer is caused by mutations that accumulate in a stem cellthroughout life and that radiation can cause virtually any ofthese mutations. This model, in which the relative risk
depends mainlyon attained age rather than on age at exposure
or time since exposure, yields age-specific risks similar to
those in the Japanese atomic bomb survivors for all solidcancers combined [P34].
57. As was indicated earlier, the presentation of ERRs or
EARs specific to particular levels of factors such as age at

exposure and time since exposure can facilitate comparison
across studies. A disadvantage of this approach, however, isthat the sampling errors in these values may be high if thedata are split finely. On the other hand, comparing models
fitted to data from different studies may not be straightforward if the investigators concerned have used different
types of models. For example, the respiratory cancer model
derived by the BEIR V Committee [C1] for low-LET
radiation and the lung cancer models developed by BEIR IV[C2] and BEIR VI [C21] for high-LET radon exposure
incorporate different time-since-exposure patterns.
58. If it is desired to make comparisons across studies, one
possibility is to incorporate the estimated ERRs or EARs
(either specific to certain levels of factors or modelled) into alife-table calculation to produce estimates of the REID, theexcess lifetime risk (ELR), or the loss of life expectancy(LLE). These terms, together with a description of theiradvantages and disadvantages, are given in Annex A of the
UNSCEAR 1994 Report [U2]. Some caveats should be
attached to this approach, however. First, for the purpose of
these calculations it may be necessary to extrapolate beyond
the scope of the data, for example, from a limited follow-up
period to the end of life, to form a lifetime risk estimate. It is
important to be aware of the potential impact of such
extrapolations on the comparison of results from different
studies. However, lifetime risk estimates such as REID and
ELR are of interest in their own right, although additional
calculations specific to the types of follow-up periods arisingin the studies in question may be desirable. Secondly, it isimportant to use the same type of life-table calculation foreach study, e.g. the calculations must be based on the samebaseline cancer rates and survival probabilities. If this is notdone, study-to-study differences in values such as REID mightarise artefactually as a result of differences in life-tables
between countries rather than as a result of variation inradiogenic risks. The aim in these calculations would not, inthe first instance, be to derive values of REID etc. that are ofgeneral applicability but to provide a basis for inter-study
comparison. Thirdly, single values of REID etc. may notencapsulate fully the findings of each study. As aconsequence, graphical displays of trends in risk in different
studies could usefully complement summary risk estimates.
59. In addition to making comparisons across studies, itwould be desirable to compare the main risk estimatescalculated in this Annex with those calculated in previous
UNSCEAR Reports. This topic is considered in
Chapter IV.

B. TRANSFER OF RISKS
60. As indicated earlier, an important factor in thequantification of radiation risks is how to transfer sitespecific risks across populations with different baseline
rates; in other words, how to take a risk coefficient

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estimated for one population and apply it to anotherpopulation with different characteristics. To give some ideaof the likely impact of the method of transfer employed, it
is useful to consider variations in baseline rates between
different populations. Table 1 builds on the corresponding
table in Annex A of the UNSCEAR 1994 Report [U2],showing some of the highest and lowest cancer rates invarious populations. Since cancer rates can vary over time,
this table is restricted to information over a particular time
period (late 1980s and early 1990s) [P5]. Although someof the variation is likely to reflect small numbers and low
levels of cancer registration in some areas, broad patterns
are discernible. For example, baseline rates for breast andlung cancer are generally higher in North America andwestern Europe than in Asia, whereas Japan has one of thehighest stomach cancer rates in the world [P5]. Even
within broad regions, baseline rates may differ in specificareas (e.g. [C22]). For breast, lung, and stomach cancer,
Land and Sinclair [L12] showed that, depending onwhether the ERR or the EAR (i.e. the multiplicative andadditive transfer models, respectively) is assumed to beconstant across populations, the values of REID predicted
for the United Kingdom and the United States using dataon the Japanese atomic bomb survivors can differ by afactor of at least 2. In contrast, differences in the total
radiation-induced cancer risk tend to be smaller, reflecting
the fact that there is less variation across populations in thebaseline rates for all cancers combined. ICRP [I1] compared the risks estimated for five different populations
using both of the above approaches in arriving at its mostrecent risk estimates.
61. To some extent it is possible to investigate methods
for transferring risks across populations by studying themodifying effect of factors known to account for at least
some of the differences in baseline rates. Particular
examples are smoking in relation to lung cancer (e.g.
[C21]) and, for persons living near the Techa River in
Russia, the effect of ethnicity on cancer rates [K5].
However, in many instances either little is known about the
specific factors responsible for differences in baseline rates
or there are few data from analytical (i.e. cohort, casecontrol, or case-cohort) epidemiological studies on the joint
effect of radiation and such factors. As a consequence, it isnecessary in most cases to directly compare measures ofradiation risk, such as ERR and EAR, obtained fromstudies conducted in different countries on groups known
to have different baseline rates. In doing so, care must be
taken to ensure that the data being studied are compatible,
so as to avoid confounding due, for example, to temporalchanges in baseline rates. It should also be recognized thatneither the multiplicative nor the additive transfer model
is likely to be “correct”, for individual cancer types or forgroups of cancers, and that the true modifying effect isprobably much more complicated. However, the paucity of
relevant data imply that only a descriptive approachcomparing fairly simple measures of risk is warranted inthis Annex, although the presentation of data in parallel
across studies can provide some idea of the influence ofbaseline rates.

C. TYPES OF EXPOSURE
62. In the UNSCEAR 1994 Report [U2], epidemiologicalstudies of radiation carcinogenesis were considered for thefollowing types of exposure:
(a)
(b)
(c)

external low-LET irradiation, subdivided into highdose-rate and low-dose-rate exposures;internal low-LET irradiation; andinternal high-LET irradiation, subdivided into radonand other exposures.

63. There are several reasons for considering thesestudies separately. First, the experimental studies reviewed
in Annex F of the UNSCEAR 1993 Report [U3] indicatedthat the cancer risk per unit dose for external low-LET
exposures at high dose rates (taken as >0.1 mGy min1)
tends to be higher than that at low dose rates. Secondly, in
addition to being protracted and specific to certain organs,
it is important to note that internal exposures generally
give rise to heterogeneous irradiation within organs, incontrast to most external instantaneous whole-body
exposures. Thirdly, experimental studies as well as someepidemiological results indicate that, relative to low-LET
radiation, the relative biological effectiveness (RBE) of
high-LET radiation is a complex quantity that depends onradiation type and energy, on the dose and dose rate, andon the endpoint under study [N2].
64. The procedure adopted in the UNSCEAR 1994 Report[U2], which considered the above types of studies separately,
will therefore be used in this Annex as well. However, somestudies involve more than one type of exposure, e.g. external
and internal exposures to workers at the Mayak plant and to
the population around the Techa River in the southern Urals;these studies will therefore be considered under the type of
exposure that is of greatest relevance to the cancer in question.
In addition, there is value in comparing some of the resultsfrom studies based on different types of exposure; for example,
in the case of external low-LET radiation, the results of highdose-rate studies to which a dose and dose-rate effectivenessfactor (DDREF) has been applied might be compared with theresults of low-dose-rate studies. However, the distinction
between high-dose-rate and low-dose-rate studies is notalways clear. For example, exposures to diagnostic x rays areoften fractionated but are delivered at a high dose rate. As aconsequence, a comparison of findings from the instantaneous exposure of the Japanese atomic bomb survivors andfindings from the fractionated exposures of tuberculosis
patients who received multiple fluoroscopies [H7, H20, L39]
may be more informative about the effects of fractionation
than of dose rate. The main difficulty with this type ofcomparison, as will be shown, is the relatively low statisticalpower of studies of fractionated or chronic exposures for mostindividual cancer sites. While other types of comparison canbe made concerning, for example, low- and high-LET studies,
the complicating factors described above make this exercise
difficult. In general, studies of specific types of exposure, suchas exposure to radon, are best suited to estimating theassociated risks.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

D. RELEVANT STUDIES
65. In this Annex, information is examined from wellconducted cohort, case-control, and case-cohort studies ofradiation-exposed groups that include some assessment of themagnitude of radiation exposures. In describing and comparing these studies, attention is paid to, inter alia, thefollowing:
(a)
(b)
(c)
(d)
(e)

the potential for bias or for confounding by unmeasured
factors;
statistical power;
the quality of estimates of radiation doses;
the availability and quality of data on potential confounders and modifiers of radiation risk; andthe availability and quality of data on cancer incidence
and on cancer subtypes.

66. Relevant studies of the effects of exposures to lowLET radiation were listed in Table 2 of Annex A of the
UNSCEAR 1994 Report [U2], while the strengths andlimitations of these studies were summarized in Table 3 ofthe same Annex. Tables 2 and 3 of the current Annex
expand on the tables in the earlier report by including more
recent low-LET studies that incorporate estimates of themagnitude of radiation exposure. Chapter III of this Annex
focuses on the more informative of these studies, based on
the criteria cited in the preceding paragraph. Of thesestudies, the extended follow-up of mortality among theJapanese atomic bomb survivors [P9] is particularly
important, since one of the main uncertainties in theassessment of radiation-induced cancer risks relates to thepattern of risk with time since exposure. Compared to thefollow-up to 1985 [S3], this analysis contains 10,500
additional survivors with recently estimated DS86 doses,
plus a further five years of follow-up. About 25% of theexcess deaths from cancers other than leukaemia during
19501990 in this cohort arose in the last five years,
between 1986 and 1990; for those exposed as children, thispercentage rises to about 50%.
67. Tables 2 and 3 also cover studies of patients withtherapeutic or diagnostic exposures, some of which areextensions of studies considered in the UNSCEAR 1994
Report [U2]. These tables are restricted to studies of
postnatal and prenatal exposures. However, pertinent
results from investigations of preconception irradiation are
mentioned in this Annex. It should also be noted thatcombined analyses of some studies covered in Tables 2 and
3 of Annex A of the UNSCEAR 1994 Report [U2] were
published subsequently; these included, in particular,
analyses of nuclear workers [C11, I2] and of the effects ofexternal irradiation of the thyroid [R4]. The results fromthese analyses are described in Chapter III of this Annex.
68. To complement Tables 2 and 3, which are specific to
low-LET radiation, Table 4 lists studies of the effects of
exposure to high-LET radiation that attempted to quantify
levels of exposure, and Table 5 summarizes the strengths

311

and limitations of the studies. Most of these studies wereconsidered in the UNSCEAR 1994 Report [U2], although
not in the same format as for the low-LET studies. It is
important to note that, in some cases (e.g. for some of theearly uranium miners and for exposures to residential
radon many years ago), the exposure assessment was
performed in the absence of measurements at the time of
exposure. However, this caveat also applies to some studiesof low-LET exposures.

E. SITE-SPECIFIC RISKS
69. One objective of this Annex is to derive and compare
site-specific risk estimates from information provided in
the various epidemiological studies. Relative and absoluterisk estimates are presented and discussed in Chapter III.
There are inherent differences in the exposure conditions,the study populations, and the evaluation procedures.
Where the risk estimates available from various studies are
in different formats with respect to the classification by
factors such as age at exposure or where only fitted models
have been presented, some life-table calculations have been
performed to derive summary values that can be comparedacross studies. These calculations have been performed forthree types of cancer, namely stomach, colon, and lungcancer. However, potential difficulties in the interpretationof such values need to be borne in mind. One of theseconcerns the consistency across studies of trends inradiation risks according to dose or modifying factors,
which is examined in the relevant sections of Chapter III.
Also, the comparison of summary values from studies indifferent countries with different baseline rates for certain
cancer sites may be used in attempting to assess theappropriate means for transferring risks from one
population to another.
70. As mentioned earlier, the main aim of these life-tablecalculations is to permit comparison across studies. To
calculate values of measures such as REID that are ofgeneral applicability, it is preferable to use models derived
for cancer sites for which large amounts of data are
available or, possibly, for certain groupings of cancers,
although the validity of this approach requires carefulassessment. Clearly, the data on the survivors of the atomic
bombings, both for mortality and cancer incidence, play apivotal role in such an exercise. This topic is consideredfurther in Chapter IV.
71. In assessing uncertainties, attention will be paid not
only to sampling errors but also to factors such as dose anddose-rate effects, as well as variation with age, gender, andtime. The extent to which such factors can explain differences
between studies will be examined by, for example, presenting
summary risk values based on a lifetime projection and on aperiod covered by the most recent follow-up. While it isunlikely that all of the uncertainties can be quantified, it isintended that the largest sources of uncertaintyfor each cancersite can be identified.

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III. SITE-SPECIFIC CANCERS
72. Site-specific cancer risks following radiation exposure
are examined in this Chapter. The organs, tissues, or types ofcancer considered are those 15 cancer sites for which adequate
epidemiological data are available. Each site is discussed in a
separate Section, and the summary data and inferred risks arepresented in the Tables listed below.
Site of cancer type

ICD number(9th revision)

Table(s)Oesophagus
Stomach
Colon
Liver
Lung
Bone and connective tissue
Skin
Female breast
Prostate
Urinary bladder
Brain and central nervous system
Thyroid
Non-Hodgkin's lymphoma
Hodgkin's disease
Multiple myeloma
Leukaemia

150
151
153
155
162
170171172173174
185
188
191192
193
200, 202201
203
204208

6
7, 22
8, 22
9
10, 2225
11
12, 2613
14
15
16, 2717, 28, 29
18
19
20
21, 3073. A short description is given of the general epidemiological findings for each cancer site considered, including
rates in different countries, trends over time, and factors
other than radiation that are known to influence rates.
Information on risks in relation to both low-LET and highLET exposures is then considered in some detail, andconclusions are drawn.
74. The results included in Tables 621 are grouped
according to the type of exposure (external or internal) andthe radiation quality (low-LET or high-LET). Studies thatprovide very small numbers of cases or that do not quotesufficient detail have not been included in these Tables. Since
the conditions of exposure, the characteristics of the study
populations, and the extent and quality of the dosimetry,follow-up, etc. differ widely, the risk estimates are not strictly
comparable. They do, however, illustrate the range andsignificance of estimates obtained and give some indication of
the influence of the study-specific factors involved. Where
possible, the estimates of the excess relative risk and theexcess absolute risk in Tables 621 have been taken from theoriginal publications. However, for the Life Span Study andfor studies for which estimates were not cited in the associatedpublications, the methods described in Section I.C of Annex Aof the UNSCEAR 1994 Report [U2] have been employed. In
particular, if O denotes the observed number of deaths orcancer cases in the exposed population, E denotes thecorresponding expected number, D the average dose and PY
the number of person-years of follow-up, then the excess
relative risk at 1 Sv is estimated by (O  E)/(E × D), and theexcess absolute risk per unit dose and per unit time at risk isestimated by (O  E)/(PY × D). Instances where thisapproach has been implemented are indicated by a footnote inTables 621. It should be noted that the results based on thismethodologymight differ from those based on a dose-response
analysis, if data subdivided into intervals of dose wereavailable for the exposed population.
75. Lifetime risk estimates for those studies for which
estimates of ERR are available are given in Table 22. The
values in this table, which are restricted to stomach, colon,
and lung cancer, arise from applying the ERR estimates tobaseline mortality rates for Japan, as was done in the
UNSCEAR 1994 Report, and extrapolating over time bothwith the ERR remaining constant and with the ERR
declining to zero at age 90 years, again in line with the
UNSCEAR 1994 Report [U2]. As mentioned earlier, the aimof these calculations is to permit comparison across studies.

A. OESOPHAGEAL CANCER
76. Cancer of the oesophagus is the ninth most common
cancer in the world and is characterized by remarkable variations from country to country and among ethnic groups inindividual countries [M40]. Oesophageal cancer rates are
generally low in many countries. Extremely high rates areobserved in China and among Chinese immigrants and incentral Asia; intermediately high rates are seen in black
populations in Africa and the United States and in some
Caribbean and South American areas [M43]. Oesophageal
cancer is almost always fatal, so mortality verycloselyapproximates incidence. Heavy consumption of alcohol and tobacco
has long been known to increase the risk of oesophageal
cancer, and this contributes to the geographic distribution.
Secular trends of oesophageal cancer vary among different
populations. There has been a marked decrease in China as
the lifestyle changes, a steady increase among blacks in the
United States, a possible decline in central Asia, and a slow
decline in Finland, India, and Latin America [D28].
77. Few epidemiological studies have evaluated the roleof radiation in the aetiology of cancer of the oesophagus.
The limited data for external and internal low-LET
exposures are presented in Table 6.
1. External low-LET exposures
78. Overall, the Life Span Study data do not provide
convincing evidence of a link between oesophageal cancer
and radiation, although a significant excess in oesophageal
cancer mortality occurred in the early years of follow-up,
i.e. from 5 to 12 years after exposure. The Life Span Studymortality data also show a higher, although not significant,
ERR for this cancer in females than males. Higher relative
risks in females have been observed for most other solidcancers [P9]. Cancer incidence data from the Life Span
Study, which began 12 years after exposure, do not show
a significant excess risk of oesophageal cancer [T1].

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

79. The ankylosing spondylitis study is the only one toreport a significant risk ofradiation-associated oesophageal
cancer. In contrast to the atomic bomb data, there was no
significant variation in risk since first treatment [W1].
Data from other medically exposed populations consideredhere show no excess oesophageal cancer risk (Table 6).

313

stomach cancer risks [K12]. Infection with Helicobacter
pylori [S43], which in developing countries can often reoccur
rapidly following antimicrobial therapy [R36] and which canlead to gastritis, has been associated with elevated stomach
cancer risks in descriptive and cohort studies [C14, K12]. In
addition, smoking has been linked to modest excesses ofstomach cancer in some cohort studies [D11, H28].

2. Internal low-LET exposures
80. Very little epidemiological information is available foroesophageal cancer associated with internal low-LET
exposures. The data that are available from patients treatedwith 131I for adult hyperthyroidism [R14] show no increased
risk of this cancer, but the doses received by the oesophagus
were considered to be small.
3. Internal high-LET exposures
81. Data on oesophageal cancer following high-LET
exposures are available from several worker studies, most ofwhich involve small numbers of oesophageal cancers. The
most informative studies are those of nuclear workers in the
United Kingdom. In a study of the three nuclear industry
workforces in the United Kingdom, 23 deaths from oesophageal cancer were observed among plutonium workers
when 21.3 had been expected [C33]. An analysis of workers
who were monitored for exposures to uranium, polonium,
actinium, and other radionuclides (apart from tritium),
showed 9 deaths from oesophageal cancer compared with
16.1 expected [C33]. Doses to the oesophagus were notavailable but are considered to be small.
4. Summary
82. Cancer of the oesophagus has been associated withradiation exposure in some studies. Much of the information
is for external low-LET exposures, with few data available forinternal high-LET exposures. The results from the Life Span
Study of survivors of the atomic bombings indicate an excess
risk only in the early period following exposure. The
ankylosing spondylitis data show a continuing risk, whileother medical studies have not demonstrated excess cases ofoesophageal cancer. Very few epidemiological data are
available on radiation risks for this type of cancer, which isinfrequent in many countries. Since oesophageal cancers are
extremely common in some parts of the world and for someethnic groups (e.g. in China and for Chinese populations),
more studies are needed to understand the magnitude andnature of the risk, especially the temporal pattern.

B. STOMACH CANCER
83. Incidence rates for stomach cancer vary considerably
throughout the world [P5], with particularly high rates inJapan (Table 1). Many countries, including Japan, have seen
decreases in incidence and mortality rates during the past few
decades [C14]. These changes are likely in large part to reflectchanges in diet, in particular, increases in the consumption of
fresh vegetables and fruits and de-creases in salt intake, which
case-control studies have shown to be linked to reduced

84. Several epidemiological studies have shown enhanced
stomach cancer risks following exposure to radiation. Studies
of external low-LET, internal low-LET, and high-LET
radiation are considered separately in this Section.
1. External low-LET exposures
85. Included in Table 7 are the cohort and case-control
studies of low-LET exposure for which radiation doses havebeen assessed. Among these studies, the Life Span Study ofthe survivors of the atomic bombings in Japan [T1, P9] has
the largest number of observed stomach cancers. This is
primarily a reflection of the high baseline rates in Japan, since
it has been estimated that fewer than 10% of the cancers
among exposed survivors are attributable to radiation [T1,
P9]. Indeed, compared with national or regional rates, theestimated excess number of cases in the international cervicalcancer study [B1] is larger than in the Life Span Study [T1],owing mainly to the higher mean dose in the former study.
However, the large numbers of cancers in the Life Span Study
make it possible to examine factors that maymodifyradiationinduced risks. In particular, based on the cancer incidencedata, Thompson et al. [T1] showed that the dose response wasconsistent with linearity and that the ERR per Sv was higher
for females than for males, decreased with increasing age at
exposure, and did not vary significantly with time since
exposure. The mortalityfindings up to 1990 [P9], summarizedin Table 7, accord with the incidence results up to 1987 [T1].
86. Only a few of the other studies listed in Table 7 havesufficient statistical precision to permit meaningfulcomparison with the Life Span Study. The case-control studyof patients treated for cervical cancer [B1] showed a trend instomach cancer risk with dose that was of borderline
significance. It is notable that the ERR per Sv estimated fromthis study appears to be consistent with that for female
survivors of the atomic bombings irradiated in adulthood andthat the estimate from the cervical cancer study of the EAR
per Sv is lower than that from the Life Span Study, although
the confidence intervals are wide. This might suggest that intransferring radiation-induced stomach cancer risks fromJapan (which has high baseline rates) to countries in North
America and Europe (which contributed to the cervical cancer
study and which have lower baseline rates), it would be better
to use a multiplicative than an additive model, that is, totransfer the ERR per Sv rather than the EAR per Sv. This isreinforced by Part A of Table 22, which shows that estimatesof lifetime risk based on applying estimates of the ERR per Sv
to Japanese baseline mortality rates are similar across the Life
Span Study, the cervical cancer study, and other studies.
Caution is called for, in that a range of other transfer methods
would be consistent with these data. However, it is noteworthy

314

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

that the estimates of EAR per Sv from the Life Span Study arehigher than those from several of the other external low-LET
studies in Table 7, whereas the estimates of ERR per Sv areless variable between the studies with the greatest statisticalprecision.
87. Another important study that can be compared with theLife Span Study of survivors of the atomic bombings is that ofpatients in the United Kingdom irradiated for ankylosing
spondylitis [W1]. Overall there was no excess of stomach
cancer in the latter study, although there was some suggestionof an elevated risk 524 years after exposure. While there was
no evidence of an increasing trend in risk with the number oftreatment courses, data on individual stomach doses were notavailable [W1], compli-cating the comparison of risk
estimates. Another study, that of peptic ulcer patients [G6],showed similar values for males and females of the ERR
per Sv, in contrast to the Life Span Study, although thenumber of cancers in the former study was much smaller andthe mean dose (about 15 Sv) was much larger.
88. Studies of occupational exposure to external low-LET
radiation may be of value in examining risks associated withprotracted or low-dose-rate exposure. In a combined analysisof radiation workers in Canada, the United Kingdom, and theUnited States, Cardis et al. [C11] found no statisticallysignificant trend in stomach cancer risk with dose. Although
the number of stomach cancers in this study was quite highrelative to other the studies considered in Table 7, thegenerallylow radiation doses received bythese workers meantthat the study had low statistical precision to estimate risks forthis type of cancer. Similarly, a study of nuclear workers inJapan [E3], where (as just noted) baseline rates of stomach
cancer are higher than in other countries, lacked precisionbecause of the small doses. In contrast, a case-control study ofstomach cancer among workers at the Mayak plant in Russia
included some individuals with doses in excess of 3 Gy [Z1].
Although the number of cases in this dose category wasmodest (see Table 7), doses of this magnitude were associatedwith a statistically significant elevated risk. Comparison ofthese results for protracted exposure with the estimated ERR
per Sv from the studies of acute exposure included in thistable is made difficult by the lack of details on, for example,
the mean doses in the categories considered in the Mayakstudy[Z1]. In addition, there was no significant dose responseover the full range of external doses in this study, whereas
there was weak evidence of an elevated risk associated withthe level of plutonium body burden and with occupational
chemical exposure [Z1]. Stomach cancer risks among theseworkers were also reported to be positively associated withgastritis and smoking, in line with other studies referenced
earlier. In particular, there was some suggestion that external
doses above 3 Gy interacted submultiplicatively with gastritis
and multiplicativelywith smoking in the incidence of stomach
cancer, although as already indicated, the numbers in thisdose category are not large. Additional details of the study
design, for example, the means by which the study subjects
were identified and information on factors such as smoking
was collected, would have to be known to evaluate thesefindings.

89. Low-dose, protracted exposure from backgroundradiation has been studied in the Yangjiang area of China[T25, T26]. While this did not show an association withstomach cancer risk (see Table 7), the precision of thestudy was not great, in common with the low-dose occupational studies mentioned above [C11, E3].
2. Internal low-LET exposures
90. In a study of about 10,000 Swedish patients treatedwith 131I for hyperthyroidism, raised incidence [H23] andmortality [H24] from stomach cancer relative to national
rates were reported (see Table 7). Furthermore, there wereindications of an increasing trend in risk with increasing
administered activity of 131I, although this trend was notstatistically significant. Some caution should be attached tothe interpretation of these findings. The authors examineda range of different cancer sites, so it is quite possible that
one of them would show a positive finding by chance.
However, it is notable that the mean dose to the stomach inthis study, namely 0.25 Gy, was higher than that to otherorgans apart from the thyroid and was similar to the mean
stomach dose among exposed atomic bomb survivors (seeTable 7). Some other studies of hyperthyroid patientstreated with 131I [F8, G10, H25] have not reported raised
rates of stomach cancer, although in some instances theirstatistical precision was low. Statistical precision was also
a problem for studies in Sweden [H26], Italy [D15],
Switzerland [G13], and the United Kingdom [E2] ofthyroid cancer patients treated with 131I, owing to the small
number of subsequent stomach cancers; furthermore, risks
in these studies were not analysed according to the level of
exposure. In contrast, a large study of hyperthyroidism
patients in the United States [R14] has reported rates ofstomach cancer mortality that are generally consistent withnational rates and that do not appear to show a relation
with the level of 131I administered, although there was somesuggestion of an elevated risk associated with anti-thyroid
drugs.
91. The relevant part of Table 7 also shows that theestimate of the ERR at 1 Gy from the Swedish hyperthyroidism study [H23, H24] is consistent with that fromstudies of external low-LET exposure. However, given thelimited number of cases, the study is likely to be consistent
with a range of other values. It is therefore difficult, based on
this study, to reach a conclusion about how stomach cancer
risks from acute, external, low-LET exposure compare withthose from protracted internal low-LET exposure.
3. Internal high-LET exposures
92. The studies of patients with exposures to radium andthorotrast listed in Table 7 do not tend to indicate elevatedrisks of stomach cancer relative to unexposed patients. This
probably reflects both the modest numbers of cases and,more particularly, the likely low doses to the stomach
compared with some other organs. It should also be pointed
out that these studies have not analysed risk in relation toindividual exposures.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

93. Stomach cancer was one of the cancers studied in acollaborative analysis of data from 11 cohorts of underground miners exposed to radon [D8]. Stomach cancer
mortality among this group of over 64,000 men was
significantly higher than national or local rates (relativerisk = 1.33; 95% CI: 1.161.52, based on 217 deaths).
However, there was no trend in stomach cancer mortality
with the cumulative radon exposure received by theseminers [D8]. Furthermore, excesses of stomach cancer
have been reported in some other groups of miners, such asgold miners [K13] and coal miners [S25]. This, together
with the low doses to the stomach from radon exposure,suggests that exposures in mining environments to agentsother than radon or other factors such as smoking habits
are responsible for these excesses. Among female radium
dial workers in the United States, there was a statisticallysignificant increase, relative to regional rates (SMR=3.89),
in mortality from stomach cancer among those who started
work in 1930 or later, although this was based on only
seven deaths [S16]. The absence of an elevated risk among
those who started work before 1930 and whose exposuresfrom radium tended to be higher, suggests that the finding
for the later workers is not due to ingested radium [S16].
4. Summary
94. Much of the information on stomach cancer risks
following radiation exposure comes from the Life Span
Study of survivors of the atomic bombings. This reflects
not only the large cohort, long follow-up, and wide rangeof doses but also the high baseline rates for the disease inJapan. The Life Span Study indicates that the dose
response is consistent with linearity and that the ERR
per Sv decreases with increasing age at exposure, does notappear to vary with time since exposure, and may be higher
for females than for males (although one study of medical
irradiation may not agree with the latter finding). Some,but not all, studies of external low-LET medical irradiation
also show an association between radiation exposure andstomach cancer risk. In particular, the findings from theLife Span Study and the study of cervical cancer patientssuggest that it might be more appropriate to transfer
relative risks, rather than absolute risks, from Japan toother countries. Studies of low-dose, occupational, lowLET exposure lack precision; a study of protracted, highdose, occupational exposure did indicate an elevated risk,
although it is difficult to use it to quantify a dose or doserate-effectiveness factor. Studies of internal low-LET andhigh-LET exposures generallyprovide little information on
stomach cancer risks.

C. COLON CANCER
95. Incidence rates for colon cancer vary considerablyaround the world [P5, P17] (see Table 1). The highest rates
are mainly in North America and western Europe,
although some countries with previously low colon cancer
rates, such as Japan, now have rates just as high [P17].
Descriptive studies indicate that these patterns are largely

315

associated with diet. Cohort and case-control studies tend
to confirm this, with meat consumption being related to anincreased risk and vegetable consumption to a decreased
risk [P17]. Studies of this type have also shown coloncancer risk to be related inversely to the degree of physicalactivity [P17]. In addition to lifestyle factors, several rare,
genetically determined conditions affect risks [U15]. In
particular, familial clustering of colon cancer is thought tobe due to an autosomal recessive gene [M22].
96. Colon cancer risks have been examined in various
epidemiological studies of radiation-exposed groups. The
findings of these studies, classified according to radiation
type, are summarized in Table 8. Although it sometimes canbe difficult to distinguish rectal cancer from colon cancer, therole of ionizing radiation appears to differ substantially in the
aetiology of the two cancers, with cancer of the rectum rarely
showing a link with radiation [T1, P9].
1. External low-LET exposures
97. The Life Span Study shows a clear association between
external dose and colon risk to the survivors, based both onincidence [T1] and mortality [P9] data. Detailed analysis of
the incidence data shows that the dose response is consistent
with linearity [T1]. However, it is noticeable from Table 8 thatstudies with mean colon doses of several Sv or more, namely
those of patients treated for cervical cancer [B1] or peptic
ulcer [G6], show little or no evidence of an elevated risk. Thissuggests a possible cell-killing effect at very high doses.
However, an excess of stomach cancer was seen among the
peptic ulcer patients [G6], whose mean stomach dose
exceeded the dose to the colon, although this might be
explained by differences from organ to organ in the degree ofcell killing. There is no clear pattern in the ERR per Sv bygender or age at exposure among the atomic bomb survivors,
which may reflect statistical imprecision. In contrast, while
the incidence data suggest that the ERR per Sv may bedecreasing with increasing time since exposure [T1], thecorresponding values for mortality in Table 8 would suggest,
if anything, a trend in the opposite direction, although theconfidence intervals are wide. However, it is clear from
Table 8 that the EAR per Sv for mortality is increasing withincreasing time since exposure.
98. The comparison of risk estimates across studies, inconsidering how colon cancer risks should be transferred
across populations, is complicated bythe changing baseline
rates in Japan referred to earlier. Furthermore, theconfidence intervals for values of the ERR and EAR per Sv
estimated from the studies listed in Table 8 are wide andare consistent with various transfer methods. This isconfirmed by Part B of Table 22, which shows lifetime risk
estimates (based on an implicit multiplicative transfer
across populations) that are fairly similar in the Life Span
Study and the study of women in the United States treatedfor benign gynaecological disease [I16] but smaller in otherstudies of populations in North America and western
Europe. It is therefore not possible to come to a firm
conclusion on how to transfer colon cancer risks across316

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

populations. It is also not possible to make a meaningfulcomparison of risks from high- and low-dose-rate
exposures, owing to the large imprecision in estimatesderived from studying nuclear workers [C11, E3].
2. Internal low-LET exposures
99. Few data are available on colon cancer followinginternal exposure to low-LET radiation. Among Swedish
patients treated with 131I for hyperthyroidism, thestandardized incidence ratio for colon and rectal cancer
combined was 1.17 (95% CI: 0.971.39) after 10 or more
years of follow-up [H23]. However, results for colon cancer
alone were not presented or analysed in relation to the levelof iodine administered. It should be noted that the meandose to the colon and rectum from this treatment wasestimated to be 0.05 Gy [H23], suggesting that any analysis
of risk in relation to the level of exposure would have had
low statistical precision. Studies of patients treated with 131I
for hyperthyroidism in the United States [G10, H25, R14]
and for thyroid cancer in Sweden [H26], together with astudy of diagnostic exposures in Sweden [H27], did notreport findings specifically for colon cancer. However, alarge study of hyperthyroidism patients in the United States
provided little indication of an elevated risk of colorectal
cancer mortality [R14].
3. Internal high-LET exposures100. Numbers of colon cancers reported from studies ofthorotrast patients are included in Table 8. Here, as in the
combined analysis of underground miners exposed to radon[D8] and in studies of radium patients [N4] and radium dial
workers [S16], the very low doses to the colon associated withthese exposures preclude meaningful inferences.
4. Summary
101. Data on the Japanese atomic bomb survivors are
consistent with a linear dose response. The effect of gender,
age at exposure, and time since exposure on the ERR per Sv
is not clear, although the EAR per Sv does increase withincreasing time since exposure in the Life Span Study.
Changes over time in baseline rates in Japan make it difficult
to decide how to transfer risks across populations. Also, thelack of precision in low-dose studies of external low-LET
radiation and of internal low-LET and high-LET radiation do
not allow conclusions to be drawn.

D. LIVER CANCER
102. The liver is one of the most frequent sites for metastatic
cancer. Since a large proportion (as high as 40%50%) ofliver cancers reported on death certificates are tumours
originating in other organs, mortality data are usually a poor
measure of the magnitude of primary liver cancer. It istherefore difficult to obtain reliable estimates of the magnitudeof liver cancer in many countries and populations. Cancer
incidence data, which provide more reliable diagnostic

information, are available for various parts of the world, but
their quality also varies. Liver cancer is one of the eight mostcommon cancers in the world, accounting for 5.6% of the newcancers in males and 2.7% in females, but there is a wide
geographic variation [M40]. Liver cancer is a common diseasein many parts of Asia and Africa but is infrequent in the
United States and Europe [P29]. The incidence of liver cancer
has been increasing in Japan and the Nordic countries [S45],
although some of the increasing trends may be explained bychanges in disease classification and coding practices.
103. The great majority of primary liver cancers in adults arehepatocellular carcinomas. It has been estimated that about
80% of hepatocellular carcinomas are aetiologically associated with chronic infection with hepatitis B virus [L43].
Infection with hepatitis C virus also plays an important role insome countries, notably in Japan. Alcohol consumption andliver cirrhosis have been shown to increase the risk of hepatocellular carcinoma, but their precise roles have yet to beclarified. In general, hepatocellular carcinoma occurs much
more frequently in men than in women (male:female ratio of
45:1). Other types of liver cancer include cholangiocarcinoma and angiosarcoma, which are rare in adults. The
male preponderance is less pronounced for cholangiocarcinoma (male:female ratio of 12:1) than for hepatocellular
carcinoma. Liver cancer has been associated with infestations
with liver flukes in certain areas as well as with exposure tothorotrast [P29, T1].
1. External low-LET exposures104. Epidemiological data on liver cancer associated withexternal exposures to low-LET radiation exposure are limited.
Far more information is available on internal high-LET
exposure, especially thorotrast (see below). The available data
are presented in Table 9. None of the medically andoccupationally exposed populations included in this review
suggest an association between radiation exposure and livercancer. Where an increased standardized mortality ratio(SMR) for liver cancer is found, further analyses do notsupport a dose-response relationship. Furthermore, because alarge number of metastatic tumours may be misclassified as
liver cancers on death certificates, some of the observed excess
liver cancer may be attributable to the inclusion of tumours
originating in other organs. The most convincing evidence forexcess liver cancer associated with low-LET exposure comesfrom the Life Span Study. In the latest Life Span Study report[P9], there are 432 deaths from primary liver cancer (939including those specified as primary and those specified as
secondary), the third leading cause following stomach andlung cancers. A significant dose response is found for livercancer, with an ERR per Sv of 0.52 for males and 0.11 forfemales, both exposed at age 30 years.
105. Cancer-incidence-based data obtained from thesystematic collection of information reported by hospitals
to tumour registries have better diagnostic accuracy. The
analysis of the Life Span Study cancer incidence data
showed for the first time a significantly increased risk ofliver cancer associated with radiation exposure from theANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

atomic bombings. A subsequent study involved 518 casesof liver cancer, mostly hepatocellular carcinoma, verified
by a detailed pathology review of each case [C37]. The
dose response was linear and an ERR was estimated to be
0.81 per Sv (liver dose). Males and females had a similar
relative risk so that, given a three-fold higher backgroundincidence for males, the radiation-induced excess incidence
was substantially higher for males. The excess risk peaked
for those exposed in the early 20s with essentially no
excess risk in those exposed before age 10 or after 45 years.
2. Internal low-LET exposures106. Epidemiological data are even more sparse on livercancer and internal low-LET exposures. In the UnitedStates thyrotoxicosis study in which about 21,000 hyperthyroid patients treated with 131I were followed up to 45
years, 39 liver cancer deaths were observed with an SMR
of 0.87 [R14]. The doses received by the liver were notestimated but are presumably very low.
3. Internal high-LET exposures107. Thorium-232 is a primordial, long-lived, alphaemitting radionuclide. Colloidal (232Th) thorium dioxide(thorotrast) was used widely as an intravascular contrast
agent for cerebral and limb angiography in Europe, theUnited States and Japan from 1928 to 1955. Intravascularly
injected thorotrast aggregates tend to be incorporated into
the tissues of the reticuloendotheial system, mainly theliver, bone marrow, and lymph nodes. Deposition results incontinuous alpha-particle irradiation throughout life at low
dose rate. The radiation dosimetry is complex because of
the non-uniform distribution of thorium dioxide in theliver, bone marrow and lymph nodes and the possible
effects of the colloidal material on cancer risk [C2]. It has
been estimated that the typical annual dose from alpharadiation following an injection of 25 ml of thorotrast is
0.25 Gy to the liver [K28, M41], but a re-evaluation ofliver organ mass has indicated that the annual dose is0.40 Gy [K41]. A revised whole-body organ partition of232
Th has shown a small reduction in the relative partition
to the liver, but the estimated liver dose remains essentiallythe same [I25]. Patients who were administered thorotrast
from the late 1920s through to 1955 have been followed inGermany, Portugal, Denmark, Sweden, Japan and theUnited States. The total number of people being followed
is approximately 5,500, and over 90% of them have died.
108. In Germany, about 5,000 patients treated with thorotrast
for cerebral angiography (about 70%) or arteriography of thelimbs (about 30%) between 1937 and 1947 at different
hospitals were identified [V3, V7, V8]. As controls, a similar
number of age- and gender-matched non-thorotrast treatedpatients were identified among patients at the same hospitals.
When the follow-up study was started in 1968, a large numberof the patients had already died. The causes of death among
those patients were identified from hospital examinations ordeath certificates. There were 2,326 thorotrast patients (1,718
males and 608 females) and 1,890 controls (1,407 males and317

483 females) who survived three years or more after treatment, could be traced. The patients (899 thorotrast patientsand 662 controls) who were still alive at that time have since
been followed through clinical examination every two years.
The latest follow-up data show 48 thorotrast patients and 239
controls who are still alive [V8]. In the deceased patients, themost common neoplastic disease is liver cancer (454 thorotrast
patients compared with 3 controls) [V8]. Previous data
showed that cholangiocarcinoma and haemangiocarcinoma,
which are norm-ally rare types of liver tumour, accounted forabout 54% and hepatocellular carcinoma for only 17%;
histological types were unknown for the remaining 29%.
109. In the German study, the cumulative rate of liver cancer
was correlated with the mean dose of administered thorotrast,
although no formal dose-response analyses were performed.
No age-at-exposure effect was observed, as the cumulative rateof liver cancer was similar for the three cohorts having
different ages at injection (114, 1529, 3044, and 4559
years) [V8]. Recent data suggest an increase in liver cancer
among those who received less than one ampoule of thorotrast(less than 6 or 612 ml thorotrast) [V8]. Although there wasno gender difference with regard to age at injection and mean
volume of injected thorotrast and exposure time, thecumulative rate of liver cancer was significantly higher inmales than in females. As a measure of the total risk, thecumulative rate was calculated using the sum limit method,i.e. by taking the cumulative number of liver cancers after
injection (excluding those dying within the first 15 years of
exposure as they are not considered to be due to thorotrast) as
the numerator and the cumulative dose of all patients up to 10
or 15 years (wasted dose or time) before clinical manifestation of liver cancer as the denominator. The cumulative riskof liver cancer was estimated to be 607 104 Gy1 (with 10
years wasted dose) and 774 104 Gy1 (with 15 years wasteddose) [V8].
110. The continuing follow-up of the Danish thorotrast
study, although based on a smaller number of patients thanthe German study, has provided further detailed epidemiological information [A5, A18, A19]. The thorotrast groupconsisted of 999 neurological patients treated withthorotrast for cerebral angiography between 1935 and1947. The group has been followed through linkage to thenational death register and the cancer registry in Denmark.
Previous analyses of cancer incidence data from this cohort
study had been based on SIRs compared to the national
cancer data. To avoid possible confounding due to theneurological conditions for which the patients were treated,a control group (1,480 persons) was identified frompatients who had been examined during 19461963 withcerebral arteriography using contrast agents other thanthorotrast [A5].
111. The latest analyses of the Danish thorotrast study
data are based on 751 deaths in the thorotrast group and
797 deaths in the control group up to January 1992 [A5].
At the end of follow-up, 40 thorotrast patients and 422
controls were still alive. Since the thorotrast and control
groups differed with respect to calendar period and were318

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

not matched for gender, age at arteriography, or neurological condition, multiplicative regression models werefitted, allowing the SMR to vary with gender, age atarteriography, and calendar period. For the thorotrast
patients, the models included the amount of thorotrast
injected (as a measure of dose rate) and the amountinjected multiplied by the time since the injection (as ameasure of the cumulative alpha-radiation dose). Whenevaluated in multiple regression analyses, the effect ofinjected volume was significant for cancer (relative risk per
10 ml = 11.1; 95% CI: 3.534.0) and benign liverconditions (relative risk per 10 ml = 1.2; 95% CI: 1.11.3).
Analyses of specific cancer types were based on cancer
incidence cases (315 cases in the thorotrast group and 201
cases in the control group). Primary liver cancer was themost frequent type of cancer among the thorotrast-exposed
patients. There were 84 cases reported as primary livercancer, 16 reported as liver cancer not specified as
primary. A significant effect of injected volume ofthorotrast was seen for liver cancer (relative risk per 10 ml= 194; 95% CI: 311,220) and as a consequence for all
cancers combined (relative risk per 10 ml = 14.7; 95% CI:
5.241.5). No effect of the surrogate measure of
cumulative dose was seen.
112. The earlier analyses of the Danish thorotrast cancer
incidence data showed a positive trend in SIR for liver
tumours with young age at injection. However, the cumulative frequency of liver cancer relative to the estimatedcumulative radiation dose to the liver showed no significant
difference between those injected at different ages (025,
2645, 4659, and older than 59 years). The female:maleratio for liver cancer was 1.6, but the cumulative frequency ofliver cancer relative to the estimated cumulative radiation doseto the liver did not differ for males and females. This is incontrast to the German study, which suggested a larger
absolute risk for males than females [V8]. In a separate study
in Denmark [A18], cases of primary liver cancer werereclassified by a pathology review. As with the German
thorotrast series, cholangiocarcinoma (34%) and haemangiosarcoma (28%) were relatively common, while hepatocellular
carcinoma accounted for 38% of cases. However, no significant differences were found between three histological types
with respect to such factors as age at injection of thorotrast,
mean amount injected, mean time from injection to diagnosis,
or mean estimated cumulative alpha-radiation dose. The
incidence of all histological subgroups was described most
simply as a function of the estimated cumulative dose up to 15
years previously.
113. In Japan, two cohorts of thorotrast patients have been
followed. An early study initiated in 1963 involves 262 war
veterans who received intravascular injection of thorotrast(with a mean of 17 ml per injection) for diagnosis of
injuries during 19371945 and a control group of 1,630
war-wounded veterans [M42]. As of 1998, 244 (93%)
thorotrast patients had died, of whom 79 died from livercancer [M47]. The second study began in 1979 after anationwide survey of thorotrast patients with diagnostic
x rays, and this cohort includes 150 thorotrast patients[K33]. As of 1998, 132 (82%) patients had died, of whom
64 died from liver cancer. Analyses of combined data fromthese two cohorts show the rate ratio for all causes,
compared to controls, to start to increase after a latency
period of 20 years after the thorotrast injection [M14]. The
rate ratio is highest for liver cancer (35.9) [M14]. Using
previous data, the risk of liver cancer was estimated to be
330 104 Gy1 with a linear dose-response model [U2]. A
study of an autopsied series of 106 thorotrast-related liver
malignancies showed that 44 (42%) were cholangiocarcinoma, 42 (40%) were angiosarcoma, 17 (16%) were
hepatocellular carcinoma, and three were double cancers[K29].
114. The Portuguese thorotrast study was set up in 1961.
It involved about 2,500 patients injected with an average of
26 ml of thorotrast between 1929 and 1955 and 2,000
controls [D27, H46]. They were followed for 30 years. Of
1,244 traced thorotrast patients, 955 had died, 137 of themfrom malignant tumours, including 87 primary liver cancer.
The BEIR IV Committee estimated the risk for liver cancer
to be 275 104 Gy1 [C2]. The follow-up of this cohort wasinterrupted in 1976, but has recently been reactivated. The
results of the follow-up extended through 1996 have been
made available [D31]. A total of 1,931 patients who
received thorotrast systemically and 2,258 unexposed
subjects were initially identified from medical records.
Follow-up was possible for 1,131 (59%) of the thorotrast
patients and 1,032 (46%) of the unexposed patients. By theend of 1996, 92% of the thorotrast patients and 5% of theunexposed patients had died. The relative risk was significantly elevated for liver cancer (70.8) and for leukaemia(15.2), which accounted for most of the excess mortality
from malignancies.
115. Liver cancer mortality has been studied among about
11,000 workers exposed to both internally deposited
plutonium and to external gamma radiation at the Mayaknuclear plant in the Russian Federation [G23]. Within thiscohort, liver cancer risks were elevated among workers withplutonium body burdens estimated to exceed 7.4 kBq,
compared to workers with burdens below 1.48 kBq (relativerisk 17; 95% CI: 8.036), based on 16 deaths in the formergroup. In addition, trend analyses using plutonium bodyburden as a continuous variable indicated an increasing
risk with increasing burden (p<0.001). However, becauseof limitations in the current plutonium dosimetry, it was
not possible to quantify liver cancer risks form plutonium
in terms of organ dose, nor to make a reliable evaluation of
the risk from external radiation in this cohort [G23].
4. Summary
116. While an association of liver cancer with radiation
exposure has not been demonstrated in medical and worker
studies involving external or internal low-LET exposures,the mortality data from the Life Span Study of survivors of
the atomic bombings indicate a significant dose response.
This relationship is strengthened by the analysis ofincidence data based on histologically and clinically

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

verified primary liver cancer cases. Studies of thorotrastexposed patients consistently show increased risks of livercancer from alpha-radiation exposure.
117. While the types of liver cancer associated withthorotrast exposure are typically cholangiocarcinoma,
followed by angiosarcoma and hepatocellular carcinoma,
the excess risk associated with low-LET exposure in theJapanese atomic bomb survivors is primarilyhepatocellular
carcinoma. Liver cancer rates are high in Japan, especiallyin males, and the high rates have been attributed to
infection with hepatitis viral infection, particularly
hepatitis C virus. In transferring liver cancer risks fromone population to another, differences in background livercancer rates, as affected by the prevalence of hepatitis viral
infection, should be considered.

E. LUNG CANCER
118. Although lung cancer was once a rare disease, it is
now one of the leading causes of cancer mortality inindustrialized countries and is rising in incidence in many
developing countries [G1]. Table 1 illustrates the wide
variation in rates between different populations. The
geographical and temporal differences in incidence andmortality largely reflect cigarette smoking, which has beenshown by epidemiological and toxicological evidence to be
the main cause of the disease [U17]. Assessments made in
the early 1980s indicate that occupational exposures toagents such as arsenic, asbestos, chromium, and nickel
may account for 5%15% of lung cancers in the general
population of industrialized countries such as the UnitedStates [D6, S6], while outdoor air pollution arising fromfuel combustion and industrial sources is thought to be
responsible for only a few percent of cases in most areas[D6].
119. In addition to the above factors, ionizing radiation
has been shown in numerous epidemiological studies to bea lung carcinogen [U2]. Increased risks have been shown
not only with respect to exposure to low-LET radiation but
also from exposure to radon and its progeny. Suchincreases have also been reported in animal studies [C4,U16]. Results from epidemiological studies of low-LET
and high-LET exposures are presented in Table 10.
1. External low-LET exposures120. The results from the latest mortality follow-up of theJapanese atomic bomb survivors [P9] bear out many of theresults of the previous mortality and incidence studies. In
particular, the dose response is consistent with linearity,and the ERR per Sv is higher for females than for males.
However, compared with the previous follow-up, there ismore indication now of similarities in the EAR per unit
dose for males and females (see Table 10). Taking into
account the wide confidence intervals, there is little tosuggest that the ERR varies in a consistent fashion witheither age at exposure or attained age, either in the319

incidence [T1] or the mortality data [P9]. In contrast,
Pierce et al. [P9] showed that the EAR per Sv for mortality
increases sharply with increasing attained age, reflecting
the pattern in baseline rates, whereas (after adjusting for
attained age) age at exposure does not appear to influence
the EAR per Sv.
121. It should be noted that these analyses do not takeaccount of smoking habits. As indicated above, much of
the variation in baseline rates between populations reflects
differences in smoking habits, so examination of the joint
effect of radiation and smoking is highly pertinent to theissue of how to transfer risks across populations. The
UNSCEAR 1994 Report [U2] gave some details of a 1986
study of radiation and smoking among a subgroup of theatomic bomb survivors [K8]. The findings from this study
may need to be qualified, since they are based on the use of
the previous dosimetry system for the survivors and on dataon cancer incidence only up to the end of 1980. Furthermore, as in an earlier analysis based on mortality up to1978 [P13], neither an additive nor a multiplicative modelfor the joint effect of smoking and radiation was totallyinconsistent with the data. However, the suggestions fromthis analysis of an additive rather than multiplicative effectof low-LET radiation and smoking on lung cancer risk
might explain the higher ERR per Sv for females than formales. It is possible that smoking could explain some ofthe other findings described earlier, such as the lack oftrend in the ERR with age at exposure.
122. Further information on the joint effect of radiation andsmoking comes from a case-control study of lung cancer
incidence among patients treated for Hodgkin's disease in the
Netherlands [V2]. In contrast to the Life Span Study findings,
there was a statistically significant supramultiplicative effectof radiotherapy dose to the affected lung area and thecumulative amount smoked after diagnosis of Hodgkin's disease. Indeed, a trend in lung cancer risk with radiation dose
was evident only among those who had smoked more than asmall amount in the period following the original diagnosis.
Some caution should be attached to these results. There were
only 30 persons in total with lung cancer, of whom 8 were
either non-smokers or light smokers. Furthermore, othermeasures of smoking, such as the number of years smoked
before diagnosis of Hodgkin's disease or lifetime consumption, did not show the above supramultiplicative effect.
Therefore the possibility of a chance finding cannot be
excluded. An alternative interpretation is that smoking may
have a strong promoting effect on the induction of lung cancer
following an earlier radiation exposure. However, it should berecognized that many of those who smoked after the diagnosis
of Hodgkin's disease had also smoked before that time, whichmakes examination ofthe interactions even more complicated.
A larger, international study of lung cancer incidence
following Hodgkin's disease [K9] also collected information
on smoking, although this was limited to never/ever smokedand may have been reported more fully for cases thancontrols. In contrast to some other studies (e.g. [V2]), thisinternational study showed an elevated risk associated withchemotherapy. Risks by type of therapy were reported to be

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ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

similar for smokers and for all subjects, although a formal
statistical analysis of the joint effect of radiation and smoking
was not undertaken. Although, if anything, there appeared tobe more evidence of a radiation-induced risk among thepatients who did not receive chemotherapy (relative risk =1.6; 95% CI: 0.664.12, for lung doses above 2.5 Gy relative
to less than 1 Gy), neither among those patients nor among
patients who received chemotherapy did the trend withradiation dose approach statistical significance.
123. The only other study in Table 10 that shows an excess
of lung cancer associated with low-LET radiation and that has
sufficient numbers to permit examination ofmodifying factors
is that of patients in the ankylosing spondylitis study in the
United Kingdom [W1]. It should be borne in mind that, incontrast to other studies, in the ankylosing spondylitis study it
was not possible to estimate individual doses to organs otherthan the bone marrow. This makes it difficult to address thetransfer of risks between populations, although it might beworth noting from the above table that the ERR per unit dose
estimated for the ankylosing spondylitis study is lower thanthat from the Life Span Study of the atomic bomb survivors.
Indeed, the indications from Part C of Table 22 of higher
lifetime risk estimates based on ERR values from the Life
Span Study data compared with those from other data sets
may suggest that the variation in radiation risks acrosspopulations is closer to additive than multiplicative. The latest
mortality follow-up of the ankylosing spondylitis study
continues to show, in contrast to the Life Span Study, a strong
decrease in the relative risk more than 25 years following firsttreatment. The interpretation of this result is complicated by
the absence of smoking data for the ankylosing spondylitis
study. However, Weiss et al. [W1] pointed out that relative tonational lung cancer rates, the risk among unirradiatedpatients showed little trend with time since diagnosis ofspondylitis. While this suggests that the temporal trend in risk
among irradiated patients may not be explained solely bychanges over time in smoking habits, the number of lungcancer deaths among unirradiated patients was relatively
small.
124. Of particular interest among the low-LET studies isthe discrepancy between the lung cancer risks observed
among the survivors of the atomic bombings in Japan andthe findings from studies of patients who received multiple
fluoroscopies in the course of treatment for tuberculosis.
Studies of the latter type in both Canada [H7] and theUnited States (Massachusetts) [D4] found no evidence ofa positive association between dose and risk of lung cancer.
The Canadian result is particularly important, since it isbased on a large cohort of exposed persons (25,000 withlung doses in excess of 10 mSv), while the mean age at
exposure, follow-up time, and total number of lung cancer
deaths are similar to the corresponding values for theatomic bomb survivors. Table 23 gives details by dose
range of lung cancer mortality in both the Canadianfluoroscopy study and the latest follow-up of the atomic
bomb survivors. This table clearly shows the lack ofevidence for a dose response for lung cancer in the former
study, which contrasts with the corresponding results forbreast cancer among female members of the cohort [H20](see Section III.H.1). Furthermore, the large number ofdeaths means that the discrepancy with the atomic bomb
survivor results cannot be explained by a lack of statisticalprecision.
125. Howe [H7] addressed a number of possible reasonsfor the difference between the Canadian and Japanese
results. He pointed out that the effect of non-differential
measurement errors on estimates of risk per unit dose in
the Canadian study was likely to be similar in magnitude
to that in the Japanese study for solid tumours, i.e.
4%11% [P2]. Most of the measurement error was
associated with estimating the dose per fluoroscopy, which,since it was not performed individual-by-individual, should
not bias risk estimates [A1]. In contrast to breast doses[H20], lung doses were similar for anterior-posterior andposterior-anterior orientations and, consequently, weresimilar in Nova Scotia (where the former orientation
predominated) and in the rest of Canada (where the latterorientation predominated). It is difficult to evaluate thepotential for systematic errors in dose estimates, but it
seems highly unlikely that such errors could explain thediscrepancy with the atomic bomb survivor findings. Howealso addressed the effect of possible misclassification ofsome lung cancer deaths as deaths from tuberculosis. Had
the lack of an association between lung cancer and dose
been due to differential misclassification concentrated at
higher doses, this would have led to an increasing trendwith dose in deaths classified as tuberculosis. However, nosuch trend was apparent, even among those patients at aminimal or moderate stage of tuberculosis, for whom thepotential to detect any such effect is likely to have been
greatest [H7]. Finally, although individual data on smoking
habits were not available for all members of the Canadiancohort, information for over 13,000 of these patients
indicated that heavy smokers had not tended to havereceived lower doses.
126. Several other possible explanations can be considered
for the difference between the results of the Canadian and
Massachusetts fluoroscopy studies and the Life Span Study.
First, the fluoroscopy studies were performed on groups inNorth America, in contrast to the atomic bomb survivor study
in Japan. In particular, baseline rates for lung cancer in North
America are higher than the corresponding values in Japan[P5]. However, elevated risks of lung cancer in other groups
exposed to low-LET radiation in North America or western
Europe are indicated in Table 10, most notablythe ankylosing
spondylitis study [W1], demonstrating that genetic factors or
differences between countries in smoking habits cannot bythemselves explain the difference in risks. Secondly, Howe
[H7] drew attention to the differences in the fractionation ofdose and in dose rate between the atomic bomb survivors andthe fluoroscopy patients. Whereas people in the former group
received a single dose averaging several hundred mGy in
about one second, the latter group received fractionated doses,with an average dose rate of 0.6 mGy s1 to the lungs. In thisregard, Elkind [E5] has suggested that complete repair may
occur between fractions of sub-effective lung cancer initiation.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

It should be noted that, even if fractionation or low dose rate
does considerably reduce the risk of lung cancer from lowLET radiation, this need not imply that similar effects would
be seen for other cancers or for high-LET exposures, as will
be discussed later. Thirdly, the effect of radiation on inducing
cancer in the lung may differ between patients withtuberculosis and healthy persons. However, the lack of an
association with radiation dose in the Canadian study wasobserved for those with tuberculosis in its early stages as well
as for those with a more advanced stage of the disease [H7].
On the other hand, even within categories of tuberculosis, theseverity of the disease was related to the degree of lungcollapse, and hence to both the number of fluoroscopies andthe degree of surgery [B15]. The latter would have involved
the removal of lung tissue and may have affected the lungcancer risk. Consequently, there remains the possibility thatthe severity of the tuberculosis may have had someconfounding effect.
127. Inferences from the other high-dose-rate, low-LET
studies listed in Table 10 are limited by the smaller numberof lung cancers and the general lack of data on smoking
habits. Furthermore, the comparison of risks at high andlow dose rates, even in large studies of radiation workers[C11, E3], is made difficult both by the low statisticalprecision associated with low doses received and by thelack of data on smoking. However, early workers at the
Mayak plant in Russia tended to receive higher cumulative
doses than many other groups of radiation workers, so dataon them may be more informative. For a group of 1,841
men who started working at the nuclear reactors at Mayakbetween 1948 and 1958 and who had a mean external
whole-body gamma dose of 1.02 Gy (low-LET), there was
no indication of an increasing trend in lung cancer risk
with gamma dose (see Table 10) [K34]. It should be noted
that, in contrast to other groups of Mayak workers,
described in Section III.E.3 below, these reactor workers
did not have potential for plutonium exposure [K34]. A
study of natural radiation in the Yangjiang area of China
did not indicate an elevated risk associated with low-dose,
protracted exposure [T25, T26] (see Table 10). Although
the precision of this study was limited, information on
smoking habits collected in an associated survey [Z2]suggested that smoking was not associated with dose andtherefore might not be a confounder.
2. Internal low-LET exposures128. Several studies of patients given 131I have examined
the risks of lung and other respiratory cancers. Most ofthese studies were reviewed in the UNSCEAR 1994 Report[U2]. Among Swedish patients treated for hyperthyroidism,
Hall et al. [H24] reported increased mortality relative tonational rates more than 10 years after treatment (based on
63 deaths, SMR = 1.80; 95% CI: 1.392.31). However,there appeared to be no clear trend in the risk of respiratory
cancers with the level of 131I administered. It should be
noted that the mean lung dose in this study was only
70 mGy. Studies of hyperthyroid patients in the UnitedStates [G10, H25] and of thyroid cancer patients in Sweden

321[H26] treated with 131I did not show raised rates of
respiratory cancer, although both studies were based on
smaller numbers than the study of Hall et al. [H24]. A
larger study of hyperthyroid patients in the United States[R14] provided slight evidence of a trend in lung cancer
mortality with increasing administered 131I activity, but thiswas weaker after allowing for a 10-year latency. A study ofSwedish patients with diagnostic exposures to 131I [H27]
had more respiratory cancers but lower doses than in the
Swedish hyperthyroidism study [H24]; the former study
again showed no elevated risk. Bearing in mind not only
the low risks predicted in these studies but also the generalabsence of individual lung dose estimates and smoking
histories, it is not possible to compare the risks ofprotracted internal low-LET exposure with the risks ofacute external exposure.
129. Kossenko et al. [K5] drew attention to differences
between the Techa River cohort and the Japanese atomic
bomb survivors with respect to the proportion of cancers of
the lung. In particular, lung cancer accounted for 27% of allcancers among men in the former cohort, compared with 10%
in the latter. Conversely, among women the corresponding
percentages were 4% and 10%, respectively. While differencesin the type of exposure and in ethnic background might beresponsible for some of these variations, smoking habits arelikely to be of importance. However, the available data did notallow investigating this issue.
130. Wing et al. [W14] reanalysed data on cancer incidence
near the Three Mile Island nuclear plant in the United States,
originally analysed by Hatch et al. [H37]. These data involve
scaled estimates of doses associated with the 1979 accident.
Wing et al. [W14] suggested that their results, in contrast to
those of Hatch et al. [H14], indicate an increasing trend inlung cancer with the radiation dose estimates; they speculated
that this may be due to inhaled radionuclides that might becorrelated with external doses. However, Hatch et al. [H38]
pointed out that their original analysis did indicate an
association for lung cancer, and that many of the differences
claimed by Wing et al. [W14] were matters of interpretation
rather than new findings. In view of the very low doses
received (generally less than 1 mSv), the lack of individual
doses, the short follow-up (to the end of 1985), the lack ofindividual smoking data, and the possibility of chancefindings when many different cancer types are studied, thesedata are not informative on radiation and lung cancer.
3. Internal high-LET exposures131. Results from various studies of radon exposures areincluded in Table 10. Particularly informative are thestudies of radon-exposed miners, in view of the large
numbers of excess lung cancers observed. The joint
analysis of 11 miner cohorts by Lubin et al. [L4] permitted
detailed examination of factors that may modify the risk ofradon-induced cancer. This analysis and the component
studies were considered in detail in the UNSCEAR 1994
Report [U2]. In summary, the ERR per working levelmonth (WLM) was found to decrease with attained age,

322

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

time since exposure, and time after cessation of exposure
to radon, but not with age at first exposure. The joint effectof radon and smoking on lung cancer risk was greater thanadditive, although it is difficult to quantify this further; inparticular, only a small proportion of miners neversmoked. Similarly, the modifying effect of exposure toother agents encountered in mines is not clear, although
the ERR per WLM was lower after adjusting for arsenic
exposure [L4].

exposures received 1524 years earlier and those received 25
or more years earlier. Furthermore, these models allow for
effects of either duration of exposure or average radon
concentration, again in contrast to the BEIR IV model.
Separate models were derived [C21]: “exposure-age-duration”
and “exposure-age-concentration”, with no preference being
given by the BEIR VI Committee to either. Under thesemodels, the ERR associated with a given cumulative exposure
increases as the exposure duration increases or the average
concentration decreases.

132. The exposure-response relationship in the various
studies of radon-exposed miners is consistent withlinearity. However, at relativelyhigh cumulative exposures,the slope of the exposure-response relationship is steeper
at lower than at higher exposure rates [L4, L6]. It shouldbe emphasized that this inverse exposure-rate effect does
not imply that low exposures carry a greater risk thanhigher exposures; rather it suggests that for a given total
exposure, the risk is higher if the exposure is received overa longer rather than a shorter period of time. Table 24,
based on the analysis of Lubin et al. [L6], shows that thisinverse exposure-rate effect (as measured by the modification factor γ) is seen, to varying degrees, in all of thestudies except the French cohort; workers in the latterstudy [T8] often worked for many years at low exposure
rates. However, a reanalysis of the Beaverlodge data basedon revised exposure estimates [H18] provided no evidenceof an inverse exposure-rate effect, in contrast to previous
analyses. It should be noted that the highest exposure rates,
which generally gave rise to the highest cumulative exposures, occurred in the earliest years of mining, when the
fewest measurements were made. Furthermore, concentrations of radon rather than radon progeny were measured in
the earliest years in many of the studies, requiring
assumptions to be made in calculating working levels(WL). Errors in estimating WL were therefore likely to begreatest in the early years of mining and would havetended to lessen the observed effects of high exposure rates,
inducing an apparent inverse exposure-rate effect.
However, adjustments by Lubin et al. [L4, L6] by calendar
year of first exposure, calendar year of exposure, attained
age, and years since the last exposure yielded patterns
similar to those in Table 24. It, therefore, seems unlikelythat WL measurement errors can explain the entire inverse
exposure-rate effect. It is also evident from Table 24 that
there is wide variation between studies in the estimate of
ERR per WLM at an exposure rate of 1 WL, i.e. β. Thisvariation reflects uncertainty in extrapolating to low
exposure rates. Another possible explanation for what
appears to be an inverse exposure-rate effect actually may
be the effect of cell killing at high doses.

134. Animal studies using very high exposure rates haveshown that a longer duration of radon exposure at a lower rateinduces more lung cancers than a shorter duration exposure
at a higher rate [C3, C4]. As for possible mechanisms,
Moolgavkar et al. [M5, M6] suggested, based on the two-stage
initiation-progression model for carcinogenesis, that extended
duration allows time for the proliferation of initiated cells andthus for higher disease occurrence rates. Furthermore, byincorporating cell killing into such a model, Luebeck et al.
[L23] hypothesized that the inverse exposure-rate effect may
be reduced in the absence of ore dust, in view of effects on net
cell proliferation. Using a different approach, Brenner [B5]
postulated that the inverse exposure-rate effect comes fromcell cycling, whereby cells in a particular period of their cycle
are more sensitive to radiation than at other times. For thesame total dose, a greater proportion of cells is predicted to be
exposed during the sensitive period if the dose is protracted
rather than acute. Multiple traversals of a cell by alphaparticles are necessaryfor such an inverse exposure-rate effect,
although it should be recognized that not all traversals willlead to transformation. At sufficiently low exposure rates,
there would probably be at most one traversal of any cell.
Consequently the inverse exposure-rate effect would be
predicted to disappear, owing to the absence of multiple
traversals and their associated interaction. Little [L33]
outlined a biological justification for using data fromepidemiological studies ofminers exposed to high radon levels
to estimate risks at low exposure rates. This was based on
research by Hei et al. [H34], which showed that traversal bya single alpha particle has a low probability of being lethal toa cell, and that many cells survive traversal by one to fouralpha particles to express a dose-dependent increase in thefrequency of mutations. In a recent cell transformation study,
Miller et al. [M53] found that the oncogenic potential of asingle alpha particle, with an energy similar to that of radon
decay progeny, was significantly less than that from a Poisson
distributed mean of one alpha particle. This finding suggests
a non-linear response at low doses of high-LET; however,these results need to be replicated by others.

133. The BEIR VI Committee [C21] reexamined the dataon the radon-exposed miners of Lubin et al. [L4], adding
new data from China, the Czech Republic, France, and theUnited States (Colorado Plateau). Table 25 describes themathematical format of the models derived by thisCommittee. In contrast to the model derived by the BEIR
IV Committee [C2], the BEIR VI models include an extra
time-since-exposure category, so as to distinguish between

135. Epidemiological backing for the absence of an inverse
exposure-rate effect at low exposure rates comes in particularfrom the study of miners in western Bohemia, which showedthat below 10 WL the ERR per WLM did not appear todepend on duration of exposure [T3]. Furthermore, in theirjoint analysis of the miner studies, Lubin et al. [L6] concluded
that the inverse exposure-rate effect diminishes, and possibly
disappears, when the duration of exposure becomes very long.
Animal data have also been used to address this issue. In a

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

136. Results from a meta-analysis of eight case-control
studies of residential radon and lung cancer published up to
the mid-1990s are summarized in Table 10 [L21], together
with the results from some more recent large studies. Lubin etal. [L10] pointed out that the results of these studies appear to
be consistent with a wide range of underlying risks. The
variability in the findings is likely to reflect, at least in part,the impact of errors in assessing radon exposures. In
particular, Lubin et al. [L1, L10] showed that errors due, forexample, to the use of recent measurements to characterize
past levels and gaps in measurements in previous homes cansubstantially reduce the statistical power of such studies. As
was indicated in Section I.C, it is possible to adjust estimatesof the exposure-response relationship to allow for the bias
towards the null that tends to arise from random errors in
exposure assessment. For example, the central estimate of the
ERR per 100 Bq m3 in a study in the United Kingdom
increased from 0.08 (95% CI: 0.030.20) to 0.12 (95% CI:
0.050.33) after adjusting for uncertainties in theassessment of radon exposure, although the width of theassociated confidence interval also increased [D30]. Anotherexample of the possible effect of errors in exposure assessment
occurs in a study in western Germany [W17]. Here theevidence for an association between radon and lung cancer
incidence was stronger in a subanalysis of radon-prone areas
than in the analysis of the entire study region (see Table 10);
the authors suggested that the latter findings may have beenbiased by the inclusion of many dwellings with low, but
imprecisely estimated, radon levels [W17]. In addition, a
recent study in Missouri (United States) showed stronger
evidence of an association between radon and lung cancer
based on CR-39 surface (i.e. glass-based) measurements rather
than on the more traditional track-etch measurements, which
has been suggested to reflect the effect of the more precise
assessments ofcumulative exposure achieved using the surface
technique [A24]. However, as pointed out in Section I.C,
further validation ofglass-based techniques would be desirable[W19]. In addition to the weak indications from some of theserecent studies, a meta-analysis of eight earlier case-control
studies yielded some direct support for an elevated risk fromresidential radon exposure [L21]. Based on over 4,000 lungcancer cases, the trend in risk in the meta-analysis was
significantly greater than zero (p=0.03) and was consistent
with the results from the miner studies, as illustrated in
Figure II. In particular, the relative risk estimated at 150 Bqm3 was 1.14 (95% CI: 1.01.3). It should be noted that a loglinear model was fitted to the case-control and miner data.
Importantly, no single study dominated the overall results,

although there were significant differences in the exposureresponse trends among the studies considered [L21].
5

Indoor studies (case-control)
Miner studies (cohort)
Log-linear fit to indoor studies
95% CI on fit to indoor studies

4
3

RELATIVE RISK

study of about 3,000 rats, Morlier et al. [M3] found that lungcancer incidence among rats that received a total of 25 WLM
appeared to be lower when the exposure was protracted over
18 months rather than 46 months; although thecorresponding number of cases was small, the study excluded
an inverse exposure-rate effect at this level of exposure.
Similar conclusions were drawn from an analysis of anotherdata set, based on more than 4,000 rats with a wide range of
exposures and exposure rates; namely, risk per unit exposure
decreased with increasing duration of exposure for exposure
rates below 10 WL [H41].

323

2

1
0.9
0.8
0.7
0.6
0.5

Relative risk = 1

Estimates from correlation study

0.4
0.3
0

50

100

150

200

250

300

350

400

450

500

CONCENTRATION OF RADON (Bq m -3)

Figure II. Risk estimates of lung cancer from exposure
to radon (based on [L21]).
Shown are the summary relative risks from meta-analysis
of eight indoor radon studies and from the pooled analysis
of underground miner studies, restricted to exposures
under 50 WLM [L22] and the estimated linear relative risk
from the correlation study of Cohen [C18].

137. Several analyses of lung cancer in the United States inrelation to average levels of indoor radon have been publishedby Cohen (e.g. [C5, C6, C18]). These analyses show decreasing trends in area-specific lung cancer rates with increasingarea-averaged radon levels. The findings contrast with thoseof cohort studies of radon-exposed miners and of case-control
studies of indoor radon [L21]. In both the cohort and casecontrol studies, radon exposures have been estimated forindividual study subjects. Furthermore, in the residential
studies and some of the miner studies, individual smoking
data have been collected. In contrast, the data on radon andthe many potential confounders considered in Cohen's correlation studies are averages over geographical areas. Resultsfrom such studies are vulnerable to biases not present inresults based on individual-level data, such as from cohort orcase-control studies. Radon studies are particularly vulnerable
to biases associated with the use ofgeographical area-averaged
radon levels because of extreme variation in radon levels
within areas. Greenland and Robins [G2] pointed out that alack of confounding in grouped data need not imply theabsence of confounding in data for individuals, and viceversa. This is particularly important in the case of indoor
radon, because smoking habits have a much greater impact onlung cancer risk [B35]. Whereas individual smoking habits
form the main potential confounder in an individual-levelstudy, the corresponding potential confounder in a geographical correlation study consists of the distribution of all smoking
histories across all individuals within each area. Consequently,
particularlyif the effects of variables such as smoking are nonlinear or non-additive at the individual level, the corresponding data available at the area level are unlikely to be
sufficiently detailed to adjust for confounding. Furthermore,

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ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

the data available in correlation studies do not take account ofresidential histories. For example, a person who had justmoved into an area from another area with different radonlevels would be categorized solely by the current area ofresidence rather than by a time-weighted average exposure.
Additionally, residential radon levels often vary widely, even
within small geographical areas. On the other hand, Cohen[C7] has drawn attention to the lower statistical uncertainty
associated with his studies, relative to case-control studies.
However, greater statistical precision needs to be weighedagainst the potential for substantial bias.
138. The interpretation of geographical correlation studies ofradon and lung cancer has continued to be the subject of
debate. In examining this issue, it should first be considered
whether it is possible mathematically that spurious results
could arise from a correlation study. This is possible; there
have been numerous mathematical proofs that results fromsuch studies can differ systematically from those based on datafor individuals (e.g. [G2, L35]). Secondly, it should beconsidered whether it is plausible that the results reported by
Cohen could be explained simply by the methodologicalaspects described above. In the absence of data for individuals
throughout the regions studied by Cohen, it is difficult to becertain on this point. Lubin [L35] presented examples
showing that results of the type described by Cohen can ariseeven with weak correlations between radon and smoking, but
Cohen [C25] stated that correlations far beyond the limits ofplausibility cannot explain an appreciable part of the discrepancy with extrapolations from miner data. Smith et al.
[S2] reported that a negative correlation seen in the state of
Iowa, United States, disappeared when mortality data were
replaced by incidence data, although Cohen [C26] wasdubious about the value of these data. It should be emphasizedthat epidemiological studies of all types have their strengths
and weaknesses and that none is perfect. As pointed out
above, individual residential case-control studies often lackstatistical precision, in part because of uncertainties in
exposure assessment. However, greater precision should beobtained from planned combined analyses of these studies,
which in contrast to the Lubin and Boice’s [L21] metaanalysis based on published summary data, will incorporate
subject-specific data. For the time being, considering themethodological aspects of the various studies, the data on
miners appear to provide the soundest basis for estimatingradon-induced risks. Furthermore, it should be noted that risk
models based on the full range of miner exposures yield
results that are similar to those based on miner exposures ofless than 50 WLM [L22].
139. In connection with the development byICRP of a model
for internal doses to the respiratory tract [I4], there has beensome interest in comparing risk estimates for lung cancerfrom studies of low-LET and radon-exposed groups. However, Howe [H7] drew attention to the difficulty of arriving ata single value for the low-LET dose to the lung that could leadto the same lung cancer risk as 1 WLM exposure to radon. In
particular, the comparison of data on the Japanese atomic
bomb survivors and on fluoroscopy patients referred to earlier
suggests a strong fractionation/dose-rate effect for low-LET

radiation, while the data on radon-exposed miners indicate ahigher risk per unit exposure at low than at high exposure
rates. Furthermore, when attention is confined to low-dose
protracted exposures, the derivation of a conversion factor
between low-LET and radon exposures is complicated by thepaucity of data that are directly relevant.
140. Studies of groups with internal exposures fromthorotrast and 224Ra generally provide little evidence ofelevated risks of lung cancer; see Table 10. In the case ofthorotrast, irradiation of the lung arises principally fromexhalation of 220Rn (thoron), one of the daughter nuclidesof 232Th [H21]. However, the distribution of dose within thelung is different from that in underground miners exposed
to radon. The incidence of lung cancer among neurologicalpatients in Denmark given thorotrast was elevated relative
to national rates but not relative to a control group ofpatients not given thorotrast, after adjusting for gender, age
at angiography, and calendar period [A5]. In an analysis of
the combined series of Japanese patients, Mori et al. [M14]
indicated an elevated risk of lung cancer relative to acontrol group, although this was based on only 11 deaths.
Among female radium dial painters in the United States,
there was some suggestion of an increasing trend in lungcancer mortality with increasing intake of 226Ra/228Ra,
although there were only 6 deaths in that analysis [S16]. In
general, the statistical precision of these studies waslimited by the relatively low numbers of lung cancers;
furthermore, information on individual smoking habits was
not always available.
141. Information from studies of workers with high-LET
exposures from plutonium, uranium, and polonium wasreviewed in the UNSCEAR 1994 Report [U2]. Since then,more information has been published for workers at the
Mayak nuclear plant in the Russian Federation, many ofwhom were exposed to both plutonium and external lowLET radiation. Koshurnikova et al. [K10, K11] showedthat relative to a control group of workers, lung cancer
mortality was raised significantly among workers at theradiochemical processing plants and at the plant forplutonium production but not among workers at thenuclear reactors at Mayak, who were exposed predominantly to external gamma radiation (see Table 10). The
elevated risk appeared to be concentrated among workers
with plutonium body burdens. A subsequent, more detailed
analysis of lung cancer deaths among 1,479 men who
started work at Mayak during 19481958 showed a clear
trend in lung cancer risk with estimated alpha dose to thelung, consistent with linearity [K34]. In addition, aseparate analysis of data for Mayak workers is consistent
with a linear dose response from less than 1 Sv to morethan 100 Sv, although it was based on a weighted sum of
high- and low-LET doses to the lung rather than the highLET dose alone [K37]. In contrast to these findings, a casecontrol study of Mayak radiochemical plant workers [T2]appears to indicate a non-linear dose response. The
methodology for this study is summarized in Tables 4 and5. In particular, in addition to individual measurements ofplutonium body burden and gamma dose, information on

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

smoking habits and other potential confounders was
utilized in this analysis [T2]. There was a clear excess oflung cancer among workers with a 239Pu body burden inexcess of 5.6 kBq (see Table 10). This association wasapparent for adenocarcinoma, squamous-cell carcinoma,
and small-cell carcinoma. Further analysis found little
evidence of an elevated risk for plutonium body burdens
below about 3.7 kBq (corresponding to a lung dose of
0.8 Gy), in qualitative agreement with the form of the dose
response reported in animal studies by Sanders et al. [S38].
There was some suggestion of an elevated risk for gamma
doses in excess of 2 Gy (low-LET) relative to lower doses,
although this finding was not statistically significant [T2,
T14]. The wide range of internal doses encountered in the
Mayak studies, from less than 0.5 to over 120 Sv [K34],
together with the individual data on possible confounders
in the case-control study [T2], contribute considerably tothe potential ability of the studies to provide informationon the carcinogenic effects of plutonium in the lung. The
reasons for the differences in the dose-response relationship between the cohort and case-control studies are notclear. One possibility is that the cohort findings have been
confounded by smoking. Another possibility relates to thefact that the average lung doses to female workers in thecase-control study were higher than those to males,
whereas virtually all of the male cases and only one of thefemale cases were smokers [T2]. Based on this, Khokhryakov et al. [K37] have suggested that curvilinearity in thedose response in the case-control study may be an artefact
associated with combining two subgroups with different
characteristics, whereas the cohort findings are based exclusively [K34] or largely [K37] on data for males. Further
investigation may shed more light on the reasons for theapparent differences in the findings.
142. Other studies of plutonium-exposed workers, such asat the Sellafield plant in the United Kingdom [O1] and at
the Los Alamos National Laboratory in the United States[W8], did not show statistically significant elevated risks
of lung cancer relative to other workers at the same plants(see Table 10). The internal exposures in these studies
were generally much lower than those to Mayak workers;
as well as which it was not possible to control for smoking.
4. Summary
143. Results from the Japanese atomic bomb survivors andfrom several groups of patients with acute high-dose
exposures show elevated risks of lung cancer associated withexternal low-LET radiation. The risk for the atomic bomb
survivors is consistent with a linear trend. These data also
show similar values for the ERR per Sv by age at exposureand for the EAR per Sv by gender, although without taking
account of smoking habits. Indeed the large influence ofsmoking on lung cancer risks is likely to be of great
importance in determining how radiation-induced risks differ
from one population to another. There is some suggestion thatthe joint effect of low-LET radiation and smoking is closer toan additive than a multiplicative relationship, although thedata are sparse and not entirely consistent. Studies of325

tuberculosis patients whoreceived multiple chest fluoroscopies
have not demonstrated increased risks of lung cancer, in spiteof the large number of patients with moderate or high lungdoses. The fractionation ofthese exposures, compared with theacute doses received by the atomic bomb survivors, may
explain the difference in findings. However, the severity oftuberculosis may have confounded the results for some of thepatients with this disease.
144. In contrast to internal low-LET irradiation, there is a
substantial amount of information on lung cancer in relation
to internal high-LET exposure. Most of this information
comes from studies of radon-exposed miners. In particular, therisk appears to increase linearly with cumulative radon
exposure, measured in WLM, but the ERR per WLM
decreases with increasing attained age and time since
exposure. Furthermore, at high cumulative exposures, theERR per WLM appears to increase with decreasing exposure
rate, but both epidemiological and experimental evidence
indicate that this phenomenon does not arise at low exposures.
Findings from case-control studies ofdomestic radon exposure
have been variable but are consistent with predictions from theminer studies. Among studies of other types of high-LET
exposure, the most informative are those of workers at the
Mayak plant in the Russian Federation, which show anelevated risk for high lung doses from plutonium; further
investigation of the shape of the dose-response relationshipwould help to understand apparent differences in findings fordifferent groups of workers.

F. MALIGNANT TUMOURS OF THE BONE
AND CONNECTIVE TISSUE
145. Malignant tumours of the bone account for about
0.5% of malignant neoplasms in humans [M39], while
soft-tissue sarcomas, which include connective tissue
malignancies, account for about 1% of all malignancies[Z3]. Among bone sarcomas, dissimilarities in cell type
between oesteosarcoma and Ewing’s sarcoma indicate thatthese tumours have different origins. The role of genetic
susceptibility has been identified through molecular andcytogenetic studies of the gene loci for these types ofsarcomas, as well as by the linkages of osteosarcoma withhereditary retinoblastoma and the Li-Fraumeni syndrome[M39]. Li-Fraumeni syndrome has also been investigated
together with connective tissue malignancies [Z3]. As will
be described below, a variety of studies with external lowLET and internal high-LET studies exposures haveestablished that bone sarcomas can be induced byradiation. Human and animal studies have suggested a
possible association between exposure to chromium and therisk of bone and soft-tissue malignancies [M39].
1. External low-LET exposures
146. The results from studies of bone and connective tissue
malignancies following external low-LET exposures are
given in Table 11. Among the Japanese atomic bomb
survivors overall, the estimated trend in risk per unit dose

326

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

is positive but is not statistically significantly greater thanzero [P9, R1, T1]. However, there is an indication that therisk is higher for exposure in childhood than in adulthood,
although this finding is based on small numbers. Statistically more powerful information comes from studies ofpatients treated for cancer in childhood. Three studies withreasonably large numbers of cases [H44, T17, W11] havereported a statistically significant increasing trend in risk
with dose, based on mean doses between 10 and 30 Gy;
another such study reported similar results, although withfewer details [D33]. While the high doses contributed tothe detection of an elevated risk, these studies are lessinformative about risks at doses of a few gray or less,although no excess is apparent at these levels. Comparedwith some other cancer types, the estimated ERR per Sv ofaround 0.10.2 for bone malignancies and/or soft-tissue
sarcomas is not large. A notable finding from the study ofWong et al. [W11] of retinoblastoma patients was that therisk of bone and soft-tissue sarcomas was concentrated
among those with hereditary retinoblastoma. Tucker et al.
[T17] reported a similar result, and found that therelationship between relative risk and dose was similar for
retinoblastoma and other patients; the retinoblastoma
patients had a higher absolute excess risk by virtue of theirhigher baseline risk. These results suggest that genetic
predisposition may modify the radiation-associated risk athigh doses.
147. Few studies of adult exposure are informative, owing inpart to the rarity of malignant tumours of the bone orconnective tissue. However, the study of cervical cancer
patients involved mean doses comparable to those in theabove childhood cancer studies [B1]; in that instance, nosignificant increasing trend in risk with dose was found.
Among ankylosing spondylitis patients in the United
Kingdom, the total number of deaths was significantly greaterthan expected from national rates, but the data were notanalysed in relation to estimates of dose [W1]. In a group ofover 120,000 women in Sweden treated for breast cancer, theincidence of soft-tissue sarcomas was about double that
expected from national rates [K35]. In a case-control study
based on this Swedish cohort, which analysed information on
the energy imparted from radiotherapy (i.e. the product of themass of the patient and the dose absorbed) because organ dose
estimates were not available, angiosarcoma was not found to
be related radiotherapy energy, whereas the risk of other typesof soft-tissue sarcomas was found to increase with increasingenergy [K35]. A review of medical records at a cancer centre
in the United States indicated that fewer than 3% of cases ofbone and soft-tissue sarcoma had previously received
radiotherapy [B40]. In a study of over 50,000 men in the
United States who had received radiotherapy for prostatecancer, the proportion who subsequently developed sarcomas
was also low, although there was an elevated risk for sarcomas
at sites within the treatment field, in contrast to more distantsites that received lower doses [B42]. An analysis of 53 casesof soft-tissue sarcomas that were identified following
radiotherapyshowed no definite relation with age at exposure,although there was some suggestion of a shorter latency fortherapy involving higher doses [L48].

2. Internal low-LET exposures148. Studies of groups with medical exposures to radioactive
iodine are uninformative about the risks of bone malignancies,
owing to the low doses to bone surfaces from this type of
exposure and to the rarity of the disease. Even in a large studyof patients treated for hyperthyroidism in the United States,
deaths from bone malignancies were not listed separately[R14]. More information may be obtained from studies ofbone-seeking radionuclides. Residents of the area around the
Techa River in the Southern Urals received internal
exposures, mainly from 90Sr, which has been shown to induce
osteosarcomas in rats [N18, S55], as well as external
exposures. In the period 19501989, 12 deaths from bonemalignancies were observed in a cohort of 26,485 residents in
the Techa River region [K5]. This represents about 1% of allcancer deaths in this cohort [K5], compared with acorresponding value of 0.4% in the Life Span Study [P9].
Risk estimation using the Techa River data is made difficult
by the absence of information on vital status for over a thirdof the cohort and by uncertainties in the estimates ofindividual doses. However, a major dose reconstruction projectis in progress that aims to provide more reliable individual
dose estimates for cohort members [D37]. Direct measurements of 90Sr have already been made for about half of the
population exposed in the Techa River region, either using awhole-body counter or by in vivo measurements of teeth.
These measurements have shown a clear correlation with yearof birth [D37]. Total doses to soft tissue, from external andinternal exposures, are likely to be less than 0.1 Sv for most
Techa River residents, although a small proportion isestimated to have received doses in excess of 1 Sv [K5]. Withfurther improvements in the quality of the dosimetry and thefollow-up, this cohort has the potential to provide quantitative
estimates of risks from chronic exposures.
3. Internal high-LET exposures149. Most of the information on bone tumour risks andinternal high-LET irradiation comes from studies ofintakes of radium. Data from medical intakes of 224Ra andoccupational intakes of predominantly 226Ra are consideredin turn.
150. In the early 1950s, Spiess initiated a follow-up studyin Germany of 899 patients with ankylosing spondylitis,
tuberculosis, or a few other diseases who had received
multiple injections of 224Ra [S14]. Up to the end of 1998, a
total of 56 malignant bone tumours had occurred in 55 ofthese patients [N14], whereas less than one tumour would
have been expected. Most of the tumours occurred within
25 years of the first 224Ra injection [N14]. Among thosecases for which histopathology information was available,
about half of the cancers were osteosarcomas. However,there was a relatively high proportion of fibrous-histiocytic
sarcomas, compared with spontaneous bone tumours[G22]. In particular, the ratio of osteosarcomas to fibroushistiocytic sarcomas in this study, 1.8, is similar to that inother groups where radiation-related excesses have been
seen, such as the radium dial painters [G22].

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

151. Bone sarcoma risk among these 224Ra patients wasrecentlyanalysed [N14] taking intoaccount revised dosimetriccalculations [H8]. In particular, these calculations indicate that
doses to the bone surface for those exposed at young ages are
smaller than had previously been estimated. As a consequence, the new risk analysis indicates that absolute risks ofbone tumours decrease with increasing age at exposure [N14].
Nekolla et al. modelled the absolute excess risk in terms ofattained age, age at first injection, duration of treatment, andmean absorbed dose to the bone surface; no effect of gender
was seen [N14]. A linear dose-response model provided agood fit to the data, although models involving a quadraticcomponent in dose could not be excluded. Also, while the risk
for a given cumulative dose was higher if the dose wasprotracted rather than acute, this difference was estimated tobe small for cumulative doses below about 10 Gy. In addition,
the excess absolute risk decreased from about 12 years
following exposure onwards. Based on this model, the lifetime risk of bone sarcoma incidence for an acute exposure up
to several gray (high-LET) of a population aged 075 years
was estimated to be 1.8 (0.62.4) 103 Gy1. This value issimilar to estimates made previously by, for example, theBEIR IV Committee [C2]. However, as indicated earlier, the
new calculations indicate that risks are higher for exposure atyounger ages. In particular, the lifetime risk for the incidenceof bone sarcomas was estimated to be 4 103 Gy1 for an acuteexposure up to several gray (high-LET) at age 15 years,
compared with 0.8 103 Gy1 for an acute exposure at age 45
years [N14]. It should also be noted that, while these absoluterisk coefficients are small, the corresponding estimates of the
ERR per Sv (based on a radiation weighting factor of 20),
between about 0.45 and 0.04, depending on age at exposure,are consistent with those seen for many other solid tumours[N14].
152. Nekolla et al. [N14] drew attention to uncertainties inthe extrapolation of their findings to low doses. In particular,
they compared their findings with those of Wick et al. [W20],
who studied a more recent group of about 1,500 patients inGermany treated for ankylosing spondylitis with lower
activities of 224Ra than patients in the Spiess study. The modelof Nekolla et al. [N14] predicts 7.8 excess bone sarcomas in
the study of Wick et al. up to 1995, whereas only four
malignant tumours of the skeleton, none of them osteosarcomas, have been observed, compared with 1.3 expectedspontaneous cases [W20]. Since the mean dose to the bonemarrow in [W20] is lower by a factor of about five than thatin [N14], the results of this comparison suggest that the linear
extrapolation in [N14] may overestimate risks at low doses.
153. Studies of over 4,000 radium dial painters, radiumchemists, and patients given 226Ra or 228Ra therapeuticallyin the United States were reviewed in the UNSCEAR 1994
Report [U2] and by the BEIR IV Committee [C2]; Fry [F9]recently published a detailed history of the radium dial
painter studies. Some of these individuals had beeninternally contaminated with pure 226Ra, which has a halflife of 1,620 years, whereas others received a mixture of226
Ra and 228Ra, which has a half-life of 5.75 years. The
BEIR IV Committee reported 87 bone sarcomas in 85 of

327

4,775 persons whose vital status had been ascertained on
at least one occasion [C2]. Among those 2,403 individuals
for whom there was an estimate of skeletal dose, 66 sarcomas
in 64 persons were reported, whereas fewer than 2 cases ofsarcomas would have been expected from national rates [C2].
The elevated risk in dial workers was particularly evident
among women who entered the industry before 1930 andwhose exposures were higher than those for later workers;
among those earlyworkers there were 46 bone sarcoma deaths
up to the end of 1990 [C27, R35].
154. Various attempts have been made to model the risks ofbone sarcoma in the United States series. Based on 1,468
female radium dial workers who entered the dial industry
before 1950 and who were followed to the end of 1979,
Rowland et al. modelled the annual rate of bone sarcoma as(α + βA2)exp(γA), where A is the activity of radium thatentered the blood during the exposure period [R33]. In a later
analysis with follow-up to the end of 1990, Rowland suggested
that the exponent of A was nearer to 3 than to 2 [R35].
Marshall et al. developed a two-target model, proposing that
two successive initiating events are required for osteosarcoma
induction and also allowing for the effects of cell killing[M51, M52]. Using information on time to death and averageskeletal dose, Raabe et al. drew attention to the effects of dose
rate in both human and animal data on bone sarcomas
following intakes of 226Ra, in particular to the finding thatrisks may not be elevated at low dose rates [R34]. Morerecently, Carnes et al. analysed data on 820 women who
started radium dial work before 1930 and who were followed
for mortality through to 1990 [C27]. In contrast to some otheranalyses, the models of Carnes et al. took account of time
distributions for both risk and exposure and examined 226Ra
and 228Ra separately [C27]. Their preferred model for theexcess absolute risk of bone sarcoma consisted of the sum of
a quadratic term in the accumulating skeletal dose from 226Ra
and a linear term in the accumulating skeletal dose from
228
Ra. In addition, the excess relative risk was higher for
exposure at ages associated with active bone growth than atolder ages, when the skeleton was fully developed, although
the excess absolute risk did not appear to vary by age at
exposure [C27]. However, all of these analyses should beinterpreted with caution: the intake of radium was estimatedmany years after the event and may be inaccurate; thedistribution of radium in the bone is probably non-uniform
and hot spots capable of extensive cell killing may haveoccurred; the continuous receipt of dose makes it difficult toseparate out the fraction of dose associated with cancer
induction; the contributions from alpha emitters and otherradiations accompanying radium decay cannot be separated;
and the fraction of the total dose to the endosteal cells cannot
be specified precisely [B47].
155. In a group of about 1,200 women in the United
Kingdom who worked with paint containing radium from
1939 to 1961, one fatal bone sarcoma occurred up to theend of 1985, compared with 0.17 expected [B14]. The
difference between these findings and those from theUnited States series can be explained by the much lower
radium exposures received by the United Kingdom

328

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

workers, although it should be noted that both groups
would have also received external exposures from theproximal containers of radioactive paint. The results fromthe United Kingdom study, the models fitted to the UnitedStates data that are at least quadratic in dose at low doses,
and the findings from animal studies have prompted thesuggestion that there is a “practical threshold” of about
10 Gy for the induction of bone sarcomas. However, the
UNSCEAR 1994 Report drew attention to a few cases ofbone sarcomas and head sinus carcinomas that had arisen
at lower doses, down to about 1 Gy, in the United States
series [U2]. Furthermore, the bone sarcoma case observedin the United Kingdom study was in a worker with anestimated skeletal dose of 0.85 Gy. It would appear,
therefore, that any practical threshold, if it exists, isunlikely to be greater than about 1 Gy [U2].
156. Some studies of thorotrast patients, such as the one inPortugal [D31], have indicated elevated risks of bonesarcomas (see Table 11). However, the numbers of cases inthese studies were smaller than among the 224Ra patients andthe United States radium dial workers. Based on thorotrast
studies, the BEIR IV Committee assessed the lifetime risk ofbone cancer to be 1 102 Gy1 (high-LET) [C2]. This value issomewhat higher than that derived by Nekolla et al. from the224
Ra patients [N14]. However, the estimate based on thethorotrast studies is likely to be more uncertain, because thesestudies had fewer cases than the studies of the 224Ra patientsand because dose estimation may have been more difficult inthe thorotrast studies.
157. Studies of workers from the United Kingdom and theUnited States monitored for exposure to plutonium havereported few if any cases of bone malignancies (e.g. [W8,O1]). In contrast, bone tumour deaths were significantly
elevated among plutonium-monitored workers at the Mayakplant in the Russian Federation [K42]. Bone tumour mortality
increased with increasing levels of plutonium body burden(p<0.001); however, additional plutonium dosimetryis needed
before reliable risk estimates can be calculated.

United States. Because of the long half-lives of 226Ra and228
Ra (the source of the high-LET exposures in the UnitedStates study) relative to the half-life of 224Ra (the source of
exposure in the German study), it is easier to model risks
using the latter study. Analysis of the 224Ra data indicatesthat the excess absolute risk decreases with increasing timesince exposure (beyond about 12 years) and age at
exposure, and that the effect on risks of exposure rate issmall at doses below around 10 Gy. The 224Ra data areconsistent with a linear dose response over a range up to
more than 100 Gy, although there is uncertainty inextrapolating the findings down to doses of a few gray. The
United States study on 226Ra and 228Ra offers little evidenceof an elevated risk at these lower doses, although it isdifficult to evaluate the dose associated with any “practicalthreshold” in risk.

G. SKIN CANCER
160. Non-melanoma skin cancers are extremely common inlight-skinned populations but relatively rare in populations
with highly pigmented skin [A9, S26]. Malignant melanoma
incidence is also strongly correlated with skin pigmentation,
but it is about 10 times less common than non-melanoma skincancer. Annual incidence rates for melanoma varyfrom about
0.5 per 100,000 persons in Asia to over 20 per 100,000 in
Australia, whereas rates for non-melanoma skin cancers
range from almost 5 per 100,000 in Africa to about 200 per
100,000 in Australia [P5]. Non-melanoma skin cancer
incidence rises rapidly with age, with such cancers being
common among the elderly. Over the past decades, there has
been a dramatic increase in the incidence of both nonmelanoma and melanoma skin cancer [A10, M24]. Much of
the increase in incidence appears to be due to sun exposure.
Total accumulated exposure appears to be the main risk factor
for non-melanoma skin cancer [S26], but for melanoma thisrelationship is not a simple one and may be related tointermittent sun exposure of untanned skin [N8]. Survival formelanoma depends on stage. Non-melanoma skin cancer is atreatable malignancy with a very high cure rate.

4. Summary
158. Studies of patients treated for childhood cancer
demonstrate an increasing risk of bone sarcomas with dose,over a range of several tens of gray (low-LET). These studies
are not informative about risks at doses below a few gray, but
a study of retinoblastoma patients in particular indicates thatgenetic predisposition may affect risks associated with highdose therapeutic radiation exposure. Other studies of external
low-LET exposure are less informative, although there issome suggestion that the relative risk is lower for exposure inadulthood than in childhood. Studies of the population living
near the Techa River in the Russian Federation may in the
future provide more information on bone cancer risks
following internal low-LET exposures.
159. There is extremely strong evidence that large intakesof radium have induced bone sarcomas in a group ofpatients in Germany and in radium dial workers in the161. From a histological standpoint, the two most common
types of non-melanoma skin cancer are basal-cell andsquamous-cell carcinomas. Theyare substantially different
with respect to demographic patterns, survival rates,
clinical features, and aetiological factors. The incidence ofboth types is higher among males than females [S26].
1. External low-LET exposures162. Since publication of the UNSCEAR 1994 Report[U2], additional information from the Life Span Study ofatomic bomb survivors has become available [R15, Y3].
Data from this and other studies are summarized inTable 12 and Table 26.
163. An association between external ionizing radiationand non-melanoma skin cancer risk has been demonstrated
in the Life Span Study of atomic bomb survivors [L29,ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

R15, T1, Y3], the New York and Israeli tinea capitis
studies [R16, S27], the Rochester thymus study [H31],
patients irradiated for enlarged tonsils [S28], patients
irradiated for various benign head and neck conditions[V4], and the American and British radiologists [M25,
S41]. No such relationship has been observed formelanoma, but the number of cases in each study was
extremely small. Most of the significantly increased risks
observed for non-melanoma skin cancer occurred amongpeople irradiated as children (Table 12).
164. In the latest data from the Life Span Study of atomic
bomb survivors, a strong dose-response relationship wasdemonstrated for basal-cell carcinoma (ERR at 1 Sv = 1.9;
90% CI: 0.833.3) (Table 26), but not for squamous-cellcarcinoma or melanoma [R15]. There was non-linearity inthe basal-cell carcinoma dose response. A dose-response
curve having two slopes (with the change in slopes at 1 Sv)
marginally improved the fit (p=0.09); a linear model witha threshold at 1 Sv did not fit the data. In earlier
evaluations of skin cancer in the Life Span Study, nonlinearity was found for all non-melanoma skin cancers
combined [L29, T1].
165. For basal-cell carcinoma in the Life Span Study, theERR decreased substantially with increasing age at
exposure, but gender, time since exposure, and attained age
had little influence on the risk [R15]. Skin tumour
prevalence was assessed among a subgroup of atomic bomb
survivors who were clinically examined. A dose-response
relationship was found for basal-cell carcinoma andprecancerous lesions [Y3]. Consistent with the results fromthe larger study of all Life Span Study members, age at
exposure was predictive of developing a skin neoplasm but
gender was not.
166. The substantial increase in skin cancer incidence
rates and reporting, as well as the wide variation inincidence depending on region and ethnicity, suggests that
relative risks are more suitable than absolute risks fordescribing radiation-induced skin cancer risks. Analyses ofskin cancer conducted by the National RadiologicalProtection Board in the United Kingdom indicate that ageneralized relative risk model describes the data moreparsimoniously (i.e. with fewer model parameters) than an
absolute risk model [N10]. As seen in Table 12, the ERR
at 1 Sv for persons exposed medically ranges from no risk
for cervical cancer patients [B1] to 1 for infants treated forenlarged thymus gland [H31, S30]. In the two studies ofpatients receiving scalp irradiation for tinea capitis, theERRs were about 0.5 [R16, S27, S30]. For children
between the ages of 1 and 15 years, a significant decreasein the ERR with increasing age at exposure wasdemonstrated in the Israeli tinea capitis study [R16].
167. Several recent studies of medical exposures add towhat is known about ionizing radiation and the risk of skincancers of different histological types. Associations
between basal- and squamous-cell skin carcinoma and ahistory of therapeutic x-irradiation were reported from a329

case-control study of male skin cancer patients conductedin Alberta Province, Canada [G14]. Most of the exposure
was from treatment for benign skin disorders. This is oneof the few studies reporting an excess risk for squamouscell carcinoma. Recall bias or misclassification of the skindisease being treated might account for this finding. The
development of a new basal-cell or squamous-cellcarcinoma subsequent to therapeutic radiation was
evaluated in a study of 1,690 patients diagnosed with anearlier non-melanoma skin cancer in New Hampshire,
United States [K16]. A history of radiotherapy was
associated with basal-cell carcinoma (relative risk = 2.3;
95% CI: 1.73.1) but not squamous-cell carcinoma(relative risk = 1.0; 95% CI: 0.51.9). The risk of a second
non-melanoma skin cancer was higher among persons
exposed early in life.
168. In a follow-up study of bone marrow transplantation
patients, an eightfold risk of melanoma was observed
among patients treated with high-dose, total-body
irradiation [C16]. This finding was based, however, on
only nine melanomas. Among Swedish patients treatedwith ionizing radiation for skin haemangioma, theobserved number of melanomas was close to what had been
expected [L16], but no data on non-melanoma wereavailable since follow-up was based on the Swedish Cancer
Registry, which does not register basal cell carcinomas.
169. Several studies of radiation-exposed medical andnuclear workers have been conducted, but most do not haveindividual doses. These studies mainlyevaluated mortality,
so they are not very informative for assessing skin cancer
effects. A significantly increased risk of skin cancer
mortality was reported for radiologists in the United States[M23] and in the United Kingdom [S41]. The risks werelarger for radiologists practicing in the early years, when
exposure is thought to have been highest, than for thosepracticing later. Among radiological technologists in the
United States, skin cancer mortalitywas significantlylower
than expected compared with national rates (SMR = 0.62;
95% CI: 0.440.84) [D23]. Skin cancer incidence waselevated (SIR = 2.8, p<0.05) among Chinese diagnostic
x-ray workers [W10], particularly those who had been
employed for 15 years or more. Among 4,151 medical
workers in Denmark, whose mean cumulative dose wasvery small (18.4 mSv whole-body dose equivalent), skincancer risk was not significantly elevated [A15]. The
difference in these findings is probably due to the longer
duration of employment among the Chinese workers (69%of the Chinese workers had been employed for five or more
years compared with slightly more than 15% of the Danish
workers) or their exposure to higher doses during the earlyyears. Although the mean radiation dose is not known for
the Chinese workers, it is assumed to be relatively high,since improvements in radiation safety practices wereintroduced only in the mid-to-late 1960s.
170. The results for nuclear workers are similarly
inconsistent. An increased incidence of melanoma wasassociated with working with radiation sources at the330

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

United States Lawrence Livermore National Laboratory insome studies [A14, S40] but not in others [M34], and noassociation was observed at the sister laboratory, Los
Alamos National Laboratory, or at most other nuclear
facilities [W13].

500 MBq for hyperthyroid treatment to 5.5 GBq for thyroid
cancer treatment, the dose to the skin would be relatively
small.

171. Using data from the American Cancer Society database, the frequency of various occupational exposures wasevaluated in 2,780 cases of malignant melanoma andapproximately three times that number of matched controls.
A history of occupational exposure to x rays was significantly
more frequent among the cases than the controls [P26]. This
study did not, however, distinguish between medical andnuclear workers, and it was not possible to control for
confounding due to social class.

174. A large, significantly elevated risk of non-melanoma
skin cancer was observed among uranium miners inCzechoslovakia [S29]. In contrast, neither mortality frommelanoma nor non-melanoma skin cancer was significantly
elevated or related to cumulative exposure in an international
pooled analysis of 11 studies of underground miners [D8].
Although the radon levels in the air were high and the study
population large (64,209 miners), the latter study is hamperedby the fact that mortality does not reflect the true risks of skincancer.

172. In a summary of the literature through the late 1980s,
Shore [S30] suggested that there is an interaction between
ultraviolet and ionizing radiation. One reason for thishypothesis was the fact that black patients treated in New
York City with scalp irradiation for ringworm did not develop
skin cancer on the scalp or face, while white patientsdemonstrated a significantly increased risk for developing
basal-cell carcinoma [S27]. A recent National RadiologicalProtection Board publication reported that radiation-associatednon-melanoma skin cancer generally develops on areas of theskin exposed to ultraviolet radiation [N10]. It was estimatedthat for the population of the United Kingdom, the lifetime
risk for non-melanoma skin cancer is 2.3 102 Sv1. The
report concluded that ultraviolet-shielded and heavily
pigmented skin would have lower risks than ultravioletexposed or lightly pigmented skin. The latest Life Span Study
data for basal-cell carcinoma do not support this hypothesis[R15]. First, the ERR for the atomic bomb survivors, whohave moderately pigmented skin and very low natural rates of
non-melanoma skin cancer, was extremely high; second, theERR was not larger for ultraviolet-exposed parts of the bodythan for parts of the body that are generally ultravioletshielded [R15]. Yamada et al. [Y3] reported a high risk forthe development of skin neoplasia among people withoccupational exposure to ultraviolet rays, but they did notreport which parts of the body had higher risks. In the New
Hampshire study, there did not appear to be a higher risk forultraviolet-exposed parts of the body compared withultraviolet-shielded parts [K16]. Thus, the question of a
possible interaction between ionizing radiation and ultraviolet
radiation remains unresolved. Possibly, ultraviolet radiation
exposure plays a less important role in inducing skin cancer
in individuals whose skin has a relatively high melanincontent, but more data are needed to fully understand thiscomplicated relationship.
2. Internal low-LET exposures173. Studies of patients receiving 131I diagnostic
examinations [H27] or 131I treatment for hyperthyroidism[G18, H23, H25] or thyroid cancer [D15, E2, G13, H26] do
not indicate any significantly increased or decreased risks
of skin cancer associated with this exposure. Although theamount of 131I administered varies from about 2 to

3. Internal high-LET exposures175. The major studies of patients treated with internal
high-LET exposures were summarized at two international
meetings [D31, N4, V1, V8, W20]. These results, as well
as results from the Danish thorotrast study [A5], do notsuggest that skin cancer is related to exposure from 224Ra,
226
Ra, 228Ra, or thorotrast.
4. Summary
176. Ionizing radiation can induce non-melanoma skincancer, but the relationship is almost entirely due to a strong
association with basal-cell carcinoma. To date, there has been
little indication of an association between ionizing radiationand malignant melanoma or squamous-cell carcinoma, but thedata are sparse. When radiation exposure occurs duringchildhood, the ERR for basal-cell carcinoma is considerablylarger than when the exposure occurs during adulthood. A
very strong trend for a decreasing risk of basal-cell carcinoma
with increasing age at exposure was observed in the Life Span
Study. Data on the dose-response relation for basal-cellcarcinoma suggest non-linearity, but more data are needed tobetter characterize the shape of the dose response, to further
evaluate the role of ionizing radiation in the development ofsquamous-cell carcinoma and melanoma, and to clarify therole of ultraviolet radiation in relation to ionizing radiation.

H. FEMALE BREAST CANCER
177. Breast cancer is the most commonly diagnosed
cancer and cause of cancer mortality among women in
many countries in North America and western Europe;
incidence rates are lower by a factor of 5 or more in Asian
countries (see Table 1) [P5]. Breast cancer incidence rates
have increased since 1960 at all ages in many countries
throughout the world [U14]. In some countries thisincrease may be explained in part by changes in screening
practices. However, particularly outside western Europe
and North America, the bulk of the increase is likely to be
due to risk factors for the disease. Known risk factors
include age, family history of breast cancer, early
menarche, late age at first birth, nulliparity, late age atmenopause, height, postmenopausal weight, and a history

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

of benign breast disease [K3]. A recent analysis of morethan 50 studies indicated that there is a small increased
risk of breast cancer while women are taking combinedoral contraceptives, although this does not appear to persist
more than 10 years after stopping use [C12]. The potential
role of other possible risk factors, such as birth weight[M19], which may be a marker of intrauterine factors, andsome components of diet [H19], is still unclear.
178. Ionizing radiation is well documented as a cause ofbreast cancer in women [U2]. Mammary tumours have also
been induced in several studies of mice exposed toradiation (e.g. [S11]). Table 13 presents results fromepidemiological studies that have incorporated someassessment of the level of low-LET or high-LET doses.
1. External low-LET exposures
179. Most of the external low-LET studies listed in Table 13
were reviewed in the UNSCEAR 1994 Report [U2]. New
findings include those from the extended follow-up for
mortality of the Japanese atomic bomb survivors [P9].
However, as a consequence of the high cure rate for this typeof cancer, the results for cancer incidence in this cohort [T1]are probablyof greater importance, despite the slightlyshorter
follow-up period for incidence than for mortality. New results
have also been reported from a number of studies, including
the extended follow-up of Swedish patients irradiated for skinhaemangioma in infancy [L46]; this study also incorporated
individual estimates of organ doses [L14] and patients fromboth Stockholm [L17] and Gothenburg [L15].
180. Much of the information that has accumulated since
the UNSCEAR 1994 Report relates to exposure in childhood. For example, Bhatia et al. [B16] reported a very highstandardized incidence ratio in an international study ofbreast cancer among patients treated for Hodgkin's diseasein childhood, as shown in Table 13. Similar results werereported in studies in the Nordic countries [S23], in France
and the United Kingdom [D33], and in the United States[T9]. Furthermore, Bhatia et al. reported evidence of adose-response trend with relative risks of 5.9 (95% CI:
1.230.3) at 2040 Gy and 23.7 (95% CI: 3.7152) atmore than 40 Gy, relative to those with doses to the mantle
region of radiotherapy of less than 20 Gy [B16]. While thestudy of Hodgkin's disease patients by Hancock et al. [H2]gave a lower ratio of observed to expected breast cancer
cases, fewer than 10% of these patients were less than 15
years old when originally diagnosed, and there was noelevated risk among women treated at ages above 30 years.
However, as mentioned in Section I.A, there is thepossibility in the hospital-based study of Bhatia et al. [B16]that patients with a second cancer were more likely toreturn to hospital than those who were disease-free [D25].
There is some suggestion of an elevated breast cancer risk
following scattered radiation received from radiotherapy
for retinoblastoma during infancy [W11], while in a studyof patients who underwent bone marrow transplantation(primarily given during childhood to treat leukaemia andlymphoma) inferences are hampered by the limited period331

of follow-up (mean of 4.5 years) [C16]. It should be notedthat the number of cases in these studies is fairly small, andthat the possible role of both chemotherapy and genetic
susceptibility in the development of the tumours is unclear.
However, from a clinical viewpoint these findings are
extremely important, because Bhatia et al. estimate thataround 35% (95% CI: 1753) of the female patients intheir study will have developed breast cancer by the age of
40 years [B16]. Although other studies, such as those of thesurvivors of the atomic bombings in Japan [P9, T1] and ofpatients who received thymic irradiation [H10], havereported lower risks than that of Bhatia et al. [B16], boththe former studies and the latter indicate that the relative
risks for females exposed to radiation in childhood are
higher than for those exposed in adulthood. In particular,
studies of women irradiated after age 40 years [B3, B10,
H20, P9, S20, T1] generally show low values for the ERR
per Sv. For exposure within childhood, there has beensome variation in the findings; for example, the estimate
for the ERR per Sv in Swedish skin haemangioma study[L46] is lower than in some other studies (see Table 13),possibly owing to the high proportion of children in the
Swedish study who were irradiated in infancy [L46] or to
the lower dose rate in this study. A recent follow-up ofscoliosis patients in the United States irradiated duringchildhood and adolescence indicated a relativelyhigh value
for the ERR per Sv (see Table 13), although potential
confounding associated with the severity of disease andhence reproductive history may explain part of thisincrease [D34].
181. Several of the studies of medical exposures have alonger follow-up than the Life Span Study. The latest
results from an extended follow-up of the Canadianfluoroscopy study[H20] suggest that, after allowing for age
at exposure, the ERR per Sv may be lower between 40 and
57 years following exposure compared with the earlier
period; however, this difference is not statisticallysignificant. In the Massachusetts fluoroscopy study [B3]
the ERR appears to be constant up to 50 years or more after
exposure, again after adjusting for age at exposure. A
reanalysis of data on women in Sweden irradiated forbenign breast disease found no persistent heterogeneity inthe ERR over the period up to more than 40 years after
exposure [M20]. In contrast to the original analysis [M8],this analysis involved more detailed modelling of internal
baseline rates and of age and calendar period effects[M20]. The study of Swedish skin haemangioma patients[L46] also showed that risks were still elevated more than
60 years after exposure. Thus, these studies indicate that,in common with the Life Span Study [T1], the ERR per
unit dose is approximately constant up to at least 40 years
following exposure, and indeed may be constant at followup times of 5060 years.
182. Howe and McLaughlin [H20] reported results froman extended follow-up of breast cancer mortality among
tuberculosis patients in Canada who received multiple
chest fluoroscopies. In common with other studies (e.g.
[B3, S15, T1]), this study showed a linear dose-response

332

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

relationship, although there was some indication of nonlinearity in an earlier analysis of this cohort [M1]. As
before, the slope of the dose trend was greater for patientsin Nova Scotia than that for patients in other parts ofCanada. The reason for this difference is not clear. One
factor that may be pertinent is the higher doses for the
exposures in Nova Scotia. However, Howe and McLaughlin
noted that on both a relative and an absolute scale, the risk
among Nova Scotia patients appeared to be higher than thatamong the survivors of the atomic bombings in Japan.
Furthermore, the risk per unit dose among the non-Nova
Scotia patients is similar to that among the patients in the
Massachusetts study [B3]. The quality of the dosimetry for thevarious sanatoria may also be relevant, although Howe andMcLaughlin emphasized that identical protocols were used toestimate doses. It should also be noted that the Nova Scotia
findings are driven by data at doses in excess of 10 Gy, so the
non-Nova Scotia findings may be more representative of risks
at lower doses.
183. As indicated earlier, comparison of the risks seen instudies of the Japanese atomic bomb survivors and of
populations elsewhere who received medical exposures
may be of value in deciding how to transfer risks acrosspopulations. One complication, however, is the different
degree of fractionation and radiation quality in the twostudies. A parallel analysis of earlier data on breast cancer
among the atomic bomb survivors and patients in severalof the North American studies indicated that the ERR per
unit dose is higher in the latter group, whereas absoluterisks are more similar [L5]. Similar results were found by
Little and Boice [L39], who analysed more recent
incidence data for the Japanese atomic bomb survivors andthe Massachusetts cohorts. Little and Boice concluded thatthese data provide little evidence for a reduction in breast
cancer risk after fractionated irradiation [L39]. However,Brenner [B33] has interpreted these findings as being
consistent with a lower risk for fractionated compared withacute exposure, based on differences, by a factor of about
2, between the number of in vitro cell transformations
observed for the relatively soft x rays received influoroscopy and other medical exposures and the number
observed for the higher energy gamma rays received by theatomic bomb survivors. On the other hand, there is little
evidence from animal studies to indicate a difference
between x rays and gamma rays in inducing breast cancer[U3]. Also, Elkind [E5] has interpreted the results of Little
and Boice [L39] as indicating that breast cancer target cells
may be deficient in repair, in line with a radiobiologicalmodel that he has proposed [E6]. It should also beemphasized that the comparison of the Japanese and North
American cohorts is also influenced by the method oftransferring risks across populations. Since the disparity inthe ERR per unit dose between the Japanese andMassachusetts cohorts [L39] would be greater rather thansmaller if the possible effects of photon energy suggested
by Brenner [B33] were allowed for, it would appear to be
more appropriate to transfer age-specific absolute (rather
than relative) risk coefficients for breast cancer from Japan
to North American and possibly other populations.

184. It has been claimed by Gofman [G8] that about 75%
of current breast cancer cases in the United States are due
to ionizing radiation exposure, mostly from diagnostic
medical procedures. This claim is based not on new
epidemiological findings but on his estimation of medical
doses and breast cancer risk factors. There are a number offlaws and questionable assumptions in his calculations. For
example, the risk estimates are based on old mortality data
for all cancers among the Japanese atomic bomb survivors,
using the previous T65D dosimetry and follow-up to theend of 1982, rather than on recent incidence or mortality
data for breast cancer specifically, using the DS86 dosimetry system. The extrapolation to low doses was based on
an analysis that failed to take account of competing causesof death in the calculation of cancer rates and that did not
adjust for age and gender [M17]; also, a factor introduced
into the calculations to allow for a multiplicative transfer
of risks from Japan to a United States population was toohigh and, in the light of the above findings, probably notnecessary. Furthermore, while Gofman multiplied the risks
from gamma-ray exposure of the atomic bomb survivors by
two, in order to arrive at a risk estimate for x-ray exposure,it was noted above that relative risks are lower among
women in the United States with x-ray exposures [B3, S15,
L39] than among atomic bomb survivors exposed predominately to gamma rays, whereas absolute risks are
similar. Given all these considerations, it is likely that
Gofman's breast cancer risk estimate is too high by a factor
of between 7 and 60 approximately [M18]. Furthermore,doses from past medical practices in the United States arealso likely to have been overestimated. Calculations madeby Evans et al. [E4] based on scientifically sounderapproaches to the estimation of doses and radiation risk
factors indicate that the proportion of breast cancers in the
United States attributable to diagnostic radiography iscloser to 1% than to the much higher values suggested by
Gofman [G8].
185. Most of the studies of occupational exposure to lowLET radiation have not been informative about the risks offemale breast cancer, owing to the small proportion of
women in these studies. The largest amount of information
concerns radiation workers in the medical field. Based ona survey of about 79,000 female radiological technologists
who had worked in the United States since 1926, Boice etal. [B6] conducted a nested case-control study for 528
women with breast cancer. The study demonstrated associations with known risk factors, such as early age at
menarche and family history of breast cancer but did not
find correlations with number of years worked or with jobs
involving radiotherapy, radioisotopes, or fluoroscopic
equipment. However, dosimetry records were available for
only 35% of the study subjects, mainly those who had
worked in more recent years. Owing to the low level ofdoses received by these workers (generally below 0.1 Gy),
the statistical power to detect an elevated risk was weak.
As mentioned, dose data were lacking for earlier workers,
whose cumulative doses may have been up to about 1 Gy.
A subsequent mortality analysis based on a larger versionof the cohort of radiological technologists showed a relative

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

risk of 1.5 (p<0.05) compared with national rates for
women certified before 1940, whereas no enhanced risk
was evident for more recent workers [D23]. This mightreflect the higher doses received by early workers compared with later workers. However, the early workers werealso more likely to be nulliparous than later workers, which
may indicate a confounding effect. An elevated risk ofbreast cancer has also been reported among radiological
technologists and radiologists in China; the doses are notknown, although measured decreased blood counts suggestthat they were generally high [W10].
2. Internal low-LET exposures186. Several studies of patients given 131I have examinedbreast cancer risks. Most of these studies were reviewed in
the UNSCEAR 1994 Report [U2]. While a study in
Massachusetts in the United States showed a higher risk ofbreast cancer among women treated for hyperthyroidismwith 131I compared with patients treated by other methods,
there was no consistent trend in risk with the amount of 131I
administered [G10]. Similar conclusions were reached ina larger study including this and other hyperthyroid
patients in the United States [R14]. In addition, a study ofpatients treated for hyperthyroidism in Sweden [H23, H24]
did not show an elevated breast cancer risk overall, nor did
it indicate a trend in risk according to the level of activity
administered. It should be noted that the mean dose to thebreast in the Swedish study was estimated to be 0.06 Gy[H23], indicating that such studies are unlikely to havesufficient statistical precision to detect an elevated risk.
This problem also applies to studies of patients given
diagnostic exposures to 131I, where the number of cases waslarger but the doses substantially smaller [H27], and ofpatients treated with 131I for thyroid cancer, where the doses
were higher but the number of breast cancers was lower[H26]. In neither of the last two studies were breast cancer
rates raised significantly relative to national rates.
187. Among people residing on the banks of the Techa
River who received both internal and external low-LET
exposures as a consequence of radionuclide releases from
the Mayak facility in the southern Urals, the proportion of
female cancer deaths from breast cancer (4%) is similar tothat among the Japanese atomic bomb survivors [K5].
However, without information on the breast doses in the
Techa River cohort, it is difficult to make inferences.
3. Internal high-LET exposures
188. Continued follow-up of the early cohort of 224Ra
patients in Germany [N4] has indicated an excess of female
breast cancers compared with the general population, as
shown in Table 13. Calculations [H8] have yielded
estimated breast doses from 224Ra of several milligray toabout 0.45 Gy [N19], with an average of about 0.1 Gy(high-LET). Analyses of these data indicated that the best
fit was with a model in which the relative risk variedlinearly with dose and decreased with increasing age at
exposure [N4]. In particular, the estimate of the ERR

333

per Sv was 2.9 among females treated at ages less than 21
years, compared with an ERR per Sv of 0.9 for the fullcohort, although these estimates are based on small
numbers of cases. To identify potential confounders, acontrol group was constructed based on 182 patients who
had not been treated with 224Ra. In this group, 7 female
breast cancer cases were observed, compared with 3.8
expected. Although the numbers were small, there was asuggestion that some of the cases in the control group may
have been associated with repeated fluoroscopic x-ray
examinations in the course of pneumothorax therapy [N4].
In contrast, the patients in the 224Ra cohort had not ingeneral received pneumothorax therapy, so this may not
explain the excess seen in this group. Another possible
reason for the excess is that patterns of reproductive risk
factors may differ between these patients and the general
population. In view of the results for the control group ofpatients, it seems unlikely that this could explain all of theexcess, although the severity of the original disease may
have affected whether or not radium was used, as well as
the patient's subsequent reproductive history (and hence
the risk of breast cancer). It may be that a combination offactors has led to the observed increase.
189. The study of neurological patients in Denmark [A5]gave some suggestion of an elevated breast cancer risk
among women exposed to thorotrast for cerebral angiography relative to unexposed women, although this increase
was not statistically significant (relative risk = 2.1; 95% CI:
0.85.7). Autopsy findings suggest that the dose to the breast
from thorotrast is likely to be lower than that to many otherorgans [M21]. There is also some indication of an excess ofbreast cancer among female dial painters in the United
Kingdom who had used a paint containing radium [B13,
B14]. While there was no significant excess of breast cancer
relative to local rates among radium dial workers in the
United States, the cohort included not only dial painters but
also women who carried out other tasks in this workplace[S16]. In contrast, a study restricted to the dial painters in the
United States provided some suggestion of a raised breast
cancer rate [R11]. However, as described in the UNSCEAR
1994 Report [U2], any effect of radiation is more likely to be
due to external irradiation of the breast from paint incontainers than to exposures arising from intakes of 226Ra. In
addition, reproductive risk factors may be of relevance to thebreast cancer findings in these studies.
190. In view of the uncertainties in quantifying breast
doses and cancer risks in studies of women exposed tohigh-LET radiation, it is not possible to directly compare
the risks of female breast cancer associated with low-LET
and high-LET radiation.
4. Summary
191. Extensive information from the Japanese atomic bomb
survivors and several medically exposed groups demonstrates
elevated risks of female breast cancer following external lowLET irradiation. The trend in risk with dose is consistent withlinearity, and the ERR per Sv is particularly high for exposure

334

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

at young ages. In contrast, there is little evidence of increased
risks for exposure at ages of more than 40 years. While the
ERR per Sv seems to be fairly constant with time since
exposure, the EAR per Sv appears to be more stable acrosspopulations with differing baseline rates. Examination of data
for the atomic bomb survivors and some of the medical studies
tend to suggest that dose fractionation has little influence on
the risk per unit dose, although different interpretations havebeen placed on these analyses.
192. Data from studies oflow-dose chronic external low-LET
irradiation and of internal low-LET and high-LET exposures
are limited. The interpretation of some reports of increased
risks is complicated by the potential for confounding as aconsequence of reproductive factors or other exposures.

I. PROSTATE CANCER
193. Worldwide, prostate cancer is one of the most common
malignancies in men, but with wide variations in rates
between countries [P5]. Specifically, incidence rates arehighest in North America and some European countries andlowest in China and Japan. However, there is less international variation in prostate cancer mortality than inincidence [R32]. Studies of migrants suggest that the variations between countries cannot be explained solely on thebasis of genetic predisposition [R32]. Both incidence andmortality rates have increased over the past few decades inmany countries, although a substantial proportion of theseincreases may reflect improved detection of the disease [W6].
194. Prostate cancer is rare before 40 years of age, following which incidence rates double for each subsequent yearof life, such that the age-specific curve has a steeper slope
than for any other cancer [R32]. Survival rates are related
strongly to the stage of the disease at diagnosis. The
aetiology of prostate cancer is largely unknown. However,there is some evidence of effects associated with hormonal
factors (e.g. levels of testosterone), family history of thedisease, and dietary factors (e.g. possibly, fat intake [R32]).
1. External low-LET exposures
195. As indicated in Table 14, there is little evidence of an
association between radiation and prostate cancer in theLife Span Study of the Japanese atomic survivors [T1]. In
other studies, the point estimate of the ERR per Sv fromthe study of ankylosing spondylitis patients in the United
Kingdom coincides with that for the atomic bomb
survivors, but with a tighter confidence interval that
excludes values below zero [W1]. However, the latter
finding should be viewed cautiously, in that it is based on
a combination of the number of x-ray treatments and meanorgan dose rather than on individually-based estimates ofdoses, as in the Life Span Study. Among patients in the
United States treated for peptic ulcers, raised mortality
from prostate cancer relative to the general population wasobserved for both those who received radiotherapy andthose who did not; rates in the two groups did not differ

significantly [G6]. An international study of patientstreated for testicular cancer, many of whom received meandoses of several tens of gray, indicated an elevated risk of
prostate cancer (SIR = 1.26, 95% CI: 1.071.46). However, this increase was apparent even in the first few years
after treatment, and, in the absence of individual dose data,
it might be surmised that this result was due to heightened
medical surveillance of genitourinary conditions [T21].
Studies of medical exposures in childhood have thus far
yielded little information on prostate cancer risks, mainly
because a very long follow-up is required to obtain sufficient cases (given that this disease occurs predominantly inolder persons).
196. Large studies of radiation workers generally do notshow elevated risks of prostate cancer in relation toexternal low-LET radiation (e.g. [C11, M46]). Instances ofworker studies in which increases have been reported may
reflect chance variations (e.g. [A15]) or possibly othertypes of exposure (e.g. [B45, F6, R26], described in moredetail below).
2. Internal low-LET exposures
197. In a large study of hyperthyroidism patients in the
United States [R14], mortality from prostate cancer among
patients treated with 131I was significantlylower than would
have been expected from national rates (SMR = 0.68).
Furthermore, there was no indication of a trend in risk
with the level of 131I administered, although it should be
noted that doses to the prostate are likely to have been low.
Studies in Sweden of patients with medical exposures to131
I have tended not to present results for prostate cancer
specifically [H23, H24, H26, H27]. However, the findings
given in these Swedish studies for all male genital cancers
combined, most of which are likely to have been prostatecancers, showed overall incidence and mortality to beconsistent with national rates. Furthermore, among thegroup of Swedish patients treated for hyperthyroidism,
there did not appear to be a clear trend in mortality fromall male genital cancers combined related to the amount of131
I administered [H24]; however, in common with thecorresponding study in the United States [R14], theprostate doses are unlikely to have been high.
198. A cohort study of employees of the United Kingdom
Atomic Energy Authority showed that while prostate
mortality among all radiation workers was consistent withnational rates, mortality was raised among those workers
who had experienced higher external doses and who had
been monitored for internal radiation exposure [B45, F6].
Based on this cohort, a case-control study was conductedthat looked at individual assessments of exposure toradionuclides and other substances in the workplace, as
well as socio-demographic factors, for 136 workers withprostate cancer and 404 matched controls [R26]. Analyses
were conducted for various radionuclides; however, theresults were often correlated, because there was simultaneous exposure to some radionuclides in certain working
environments. Rooney et al. [R26] reported significantly

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

elevated relative risks associated either with documented
exposure to 51Cr, 59Fe, 60Co, 65Zn, or 3H or with working inenvironments potentially contaminated by at least one ofthese radionuclides. The latter finding in particular was
based largely on men who worked on heavy water reactors.
Exposure to other radionuclides or to chemicals was not
associated with an elevated risk. While it was difficult todistinguish the findings for the above five radionuclides,
particular attention was paid to 65Zn, because zinc isconcentrated in the prostate gland and Auger electrons
emitted from 65Zn may give rise to high doses at shortrange. However, studies of biokinetics and dosimetry [A7,B46] indicate that even with pessimistic assumptions about
the uptake of zinc in the prostate and the relative biologicaleffectiveness of Auger electrons, the dose to the prostatefrom occupational exposures is likely to be 0.10.2 Sv at
most and, taking account of the findings from the Japaneseatomic bomb survivors [T1], would not be sufficient to
explain the findings of Rooney et al. [R26].
3. Internal high-LET exposures
199. Few studies have reported results for prostate cancer
in relation to internal high-LET exposures. As shown in
Table 14, there is little indication of elevated risks among
patients with intakes of 224Ra [N4] or thorotrast [V8],although the numbers of cases are not very large. Furthermore, information has rarely been presented about level of
exposure. An exception concerns a study of plutonium
workers in the United Kingdom, in which there was noincrease in risk with the sum of the cumulative organspecific dose from plutonium and the external dose [O1].
However, in common with many other studies of workers
high-LET doses to the prostate are likely to have been low.
4. Summary
200. Data for the Japanese atomic bomb survivors andfrom most other studies provide little evidence of anelevated risk of prostate cancer following radiation
exposure. Elevated risks have occasionally been reported,but it is not clear whether these represent chance findings
or facets of particular types of exposure in the workplace,either from radiation and other factors. It should be notedthat the statistical precision of some of the medical andoccupational studies is limited by small numbers of cases
and/or low doses. Also, because prostate cancer is predominantly a disease of the elderly, follow-up studies of
exposure in childhood have not been informative to date.

J. CANCER OF THE URINARY BLADDER
201. Bladder cancer accounts for less than 5% of cancer
incidence and less than 2% of cancer mortality in industrialized countries. There is wide international variation in bladdercancer incidence, with high rates in Europe and North
America and low rates in Latin America and Asia. Incidence
increases steeply with age and is more common among men
than women. In some countries the gender ratio can reach 5:1

335[H47, P5]. The incidence increased from the 1960s to the
1980s, but recently the rates have begun to stabilize. Mortality
has been decreasing in both men and women and at all ages.
The temporal trends are influenced by changes in detection
and improvements in survival.
202. Cigarette smoking is a leading cause of bladder cancer.
In Western countries, approximately 50% of the cancer in
men and 30% in women have been attributed to smoking.
Occupational exposures, particularly to aromatic amines, arealso well known bladder cancer risk factors. Urinary tract
infections are also associated with an increased risk of bladdercancer, especially among women. Use of phenacetincontaining analgesics and cyclophosphamide, as well as
exposure to S. haematobium infection, are also suspected
bladder cancer risk factors [H47, M45, S48].
1. External low-LET exposures203. Estimates of risk for bladder cancer from several
studies are given in Table 15. Statistically significant
excess risks have been derived for incidence [T1] andmortality data [P9, R1] from the Life Span Study, thecervical cancer case-control study [B1], the anklylosing
spondylitis study [W1], the metropathia haemorrhagica
study [D7], and the benign gynaecological disease study[I16]. Although the doses are considerably higher in thelast two studies (~6 Gy), the risk estimates are about thesame as the risk estimate in the ankylosing spondylitis
study [W1]. In the Life Span Study, the effects of age andgender on the risks are unclear. In particular, the incidence
data exhibit a statistically significant gender difference,with the ERR for females exceeding that for males by afactor of about 5 but the average EAR showing no
significant difference [T1]; in the mortality data, the point
estimates of the ERRs and EARs for males are higher thanthose for females, although the differences are notstatisticallysignificant [P9]. Neither the mortalitydata [S3,P9] nor the incidence data [T1] in the Life Span Study
exhibit statistically significant variation with age at
exposure for either the ERR or the EAR. There is,however, a suggestion of some variation with age in thecervical cancer case-control study [B1].
204. Although individual organ doses frequently are notavailable, several, but not all, studies of second cancers
have reported an association between bladder cancer risk
and high therapeutic radiation doses. A non-significant
increased risk of bladder cancer was associated withradiotherapy in a large cohort of non-Hodgkin’s lymphoma
patients [T19] and in a European nested case-control studyof 63 women with bladder cancer who had previously beentreated for ovarian cancer and 188 ovarian cancer patients
who did not develop bladder cancer [K30]. Compared withsurgically treated patients, the relative risks were 1.9 (95%
CI: 0.774.9), 3.2 (95% CI: 0.9710), and 5.2 (95% CI:
1.616) for radiotherapy only, chemotherapy only, andradiotherapyand chemotherapycombined, respectively. Of
32,251 ovarian cancer patients, 20 of the 65 women who
developed bladder cancer were treated solely with

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radiation, resulting in a significantly increased risk (O/E =2.1; 95% CI: 1.62.6) [T20]. The risks increased with timesince exposure, until they were six times greater at 15 ormore years. These results are very consistent with those for
cervical cancer patients who were treated with similarradiation doses [B1]. Risk was not significantly elevatedamong ovarian cancer patients treated with chemotherapy
only [K30].
205. Among men treated for testicular or prostate cancer,
enhanced risks of bladder cancer have been observed.
Among testicular patients with seminoma treated withradiotherapy (mean dose = ~22 Gy), a two- to threefold
greater risk was found five or more years after treatment.
More than 20 years after treatment, the risk rose to 3.2[T21]. Among non-seminoma patients receiving radiotherapy (mean dose = 45 Gy), the risks were elevated but
not statistically significant. Among men treated with highdose radiotherapy for prostate cancer, a statistically significant 40% increased risk was noted five or more years
after therapy [N11]. No excess risk was found among
patients treated surgically. In a reanalysis and update ofthese data, Brenner et al. [B42] reported a 15% (95% CI:
1.021.31) elevated risk of bladder cancer among over
50,000 men treated with high-dose radiotherapy comparedwith over 70,000 patients who underwent surgery. Risks
were much higher, however, for long-term survivors, withradiotherapy patients surviving 10 or more years having arisk of 1.77 (95% CI: 1.142.63).
2. Internal low-LET exposures
206. High doses of 131I are often used to treat thyroid
cancer. The bladder is one of the organs that concentrate
iodine [U2]. The 131I dose to the bladder from treatment forthyroid cancer is about 2 Gy. An excess risk of bladdercancer has been reported in one small study of thyroid
cancer patients [E2] but not in two others [D18, H26].
Patients treated with 131I for hyperthyroidism receive100200 mGy to the bladder. No significantly increased
risks were noted in two studies with a combined study
population of about 30,000 patients [H23, H24, R14]. In a
recent study of hyperthyroid patients treated with 131I in the
United Kingdom, there was a significantly lower risk of
bladder cancer than in the general population, but bladdercancer incidence increased (p=0.005) with increasinglevels of administered activity [F8].

4. Summary
208. Statistically significant excess risks of cancer of theurinary bladder are seen in several populations exposed to
low-LET radiation. The Life Span Study risk estimates are
somewhat greater than those seen for cancer patients;
however, since the cancer patient studies involve extremely
high doses, the differences may reflect cell killing. In
addition, second cancer register-based cohort studies often
obtain information on initial treatment only. Subsequent
treatments can lead to exposure misclassification, which inturn can lead to underestimation of exposure effects.
Potential interactions between smoking and radiation
remain to be studied.

K. BRAIN AND CENTRAL NERVOUS
SYSTEM TUMOURS
209. Depending on tumour location, benign and malignant
tumours of the central nervous system (CNS) can have
similar symptoms and outcomes. As a result, the two typesof tumours are not always easily distinguished, and many
tumour registries routinely include both histological types
in their CNS incidence rates. [I11, P18]. Annual incidence
rates for CNS cancers range from about 1.0 to about 10 per
100,000 persons, but since the quality of medical carevaries from country to country and reporting of benign
tumours is inconsistent among registries, international
comparisons of CNS tumours can be misleading [P5]. The
fact that the lower incidence rates are reported primarily
from cancer registries with uncertain completeness ofascertainment suggests that country-to-country variation isprobablyconsiderablyless than current reporting indicates.
Over the last few decades, brain tumour incidence andmortality have increased, especially among the elderly, butwhether this is a real increase or a result of better diagnosis
and reporting is controversial [I11, P18]. With the exception of meningiomas, CNS tumours occur more frequently
among men than women [P5]. This Section will consider
both benign and malignant CNS tumours occurring within
the cranium (brain, cranial nerves, cranial meninges),
spinal cord, spinal meninges, and peripheral nervous
system because of the potential problem of misclassification by tumour behaviour. In addition, since the comparison rates used in some studies are derived from tumour
registries that combine all CNS tumours in one category,
results are reported for all CNS tumours and not for
malignant tumours only.

3. Internal high-LET exposures
207. The recent follow-up of a cohort of German patientstreated with 224Ra has demonstrated an excess relative riskof bladder cancer compared with the general population(ERR per Sv = 0.4) [N4]. The relative risk was higher forpatients who were older at diagnosis. No excess of bladdercancer has been reported in another cohort of patientstreated with 224Ra [W20] or among patients receiving
thorotrast as a contrast medium for arteriography [A5,
D31, M14, V8].

210. While the aetiology of CNS tumours remains elusive,
therapeutic irradiation of the head and neck duringchildhood is an established risk factor, and social class,trauma, diet, and some chemicals have been identified as
potential risk factors [B43, D35, I11, P18]. Primarymalignancies of the central nervous system are among themost lethal of all cancers. In the United States, five-year
survival for malignant CNS tumours is approximately 30%
and shows little relation with stage at diagnosis [K17].
Survival for benign meningiomas has improved

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

considerably over the last few decades, but depending on
tumour size and location, the quality of life can be severely
impaired [L30].

1. External low-LET exposures211. As summarized in Table 16, the epidemiologicalliterature provides evidence for an association between
ionizing radiation and tumours of the CNS. Since publication of the UNSCEAR 1994 Report [U2], additional information on the incidence and mortality of CNS tumours in
the Life Span Study of atomic bomb survivors has become
available [P9, P19]. As in earlier reports, the most recent
mortality data from the atomic bomb survivors provide noevidence of a radiation effect for brain tumours but doshow a non-significant excess risk for tumours of the CNS
outside the brain [P9]. New incidence data that assess
histologic types separately demonstrate a strong dose
response for neurilemmomas (ERR at 1 Sv = 4.0) and amoderate dose response for meningiomas (Table 27) [P19].
The excess risk for neurilemmomas was observed for
persons of all ages at the time of the bombings. Other
studies of atomic bomb survivors in Hiroshima andNagasaki show an association between meningioma
incidence and radiation exposure [S33, S39, S42].
212. A significant relationship between radiation dose and
CNS tumour risk was demonstrated in the Israeli tinea
capitis study [R17]. An average dose of 1.5 Gy from childhood radiotherapy to the scalp was associated with anincreased incidence of CNS tumours in the head and neck(relative risk = 8.4). The relative risks ranged from 2.6 forgliomas to 9.5 for meningiomas to 33 for neurilemmomas.
Large relative and absolute risks for CNS tumours werealso observed in the New York tinea capitis study [A15,S31]. Similarly, an association between radiotherapy andbenign CNS tumours was reported following childhood
irradiation for inflamed tonsils and other benign head andneck conditions [S28, S46] and irradiation in infancy foran enlarged thymus gland [H31]. Following low doses ofradiation from 226Ra treatment for haemangioma during
infancy in Stockholm, intracranial tumours were notelevated [L16]. In contrast, the incidence of gliomas andmeningiomas was significantly greater in 1,805 infants
treated with similar doses of 226Ra for haemangioma in
Gothenburg, Sweden, but no clear dose response wasobserved [K22, L15]. In a recent pooled analysis of the twostudies, 86 patients with intracranial tumours wereobserved among exposed and unexposed patients comparedwith 61 expected (SIR = 1.42; 95% CI: 1.131.75) [K23].
A linear dose-response relationship fit the data best (ERR
at 1 Gy = 2.7), and within the narrow age-at-exposure
range (081 months) the risk increased with decreasing
age at exposure. In a small cohort of children treated withnasopharyngeal radium implants to prevent deafness, three
adult brain cancers occurred [S32]. Although the incidence
was raised, chance could be one explanation for theincrease [S47]. CNS mortality was not elevated in a larger
study of children treated with smaller doses [V5].

337

213. A higher-than-expected number of second primary
CNS tumours among survivors of childhood cancers has been
noted in several studies. Neglia et al. [N9] demonstrated thatradiotherapy during childhood was a significant factor in theexcess of CNS tumours occurring among acute lymphoblastic leukaemia patients. A cohort of 4,400 childhood
cancer survivors in France and the United Kingdom has
been followed to evaluate the risk of developing second
cancers [D19, L32, L36, L37]. Based on 12 cases withmalignant brain tumours and an equal number of caseswith benign brain tumours, each matched to 15 controls, asignificant dose response was demonstrated for both typesof tumours. The risk was higher for benign tumours (ERR
= 3.15; 95% CI: 0.37n.a.) than for malignant tumours(ERR = 0.12; 95% CI: n.a.0.55), and no modifying effectof age at exposure was found. This pattern of a higher risk
for benign tumours has been seen in other studies [P19,
R17]. Eng et al. [E1] reported that bilateral retinoblastoma
patients treated with radiation had a large excess ofmortality from benign and malignant neoplasms of thebrain and meninges. More recently, an increased risk of
CNS tumour incidence was found among these patients[W11]. In a small study with limited statistical power, no
excess risk was observed among retinoblastoma patients[M26]. Young children who received cranial irradiation as aconditioning regimen before bone marrow transplantation
were found to have a significantly elevated relative risk ofdeveloping brain or other CNS cancers; however, it was likelythat earlier cranial radiotherapy to treat acute lymphocytic
leukaemia prior to bone marrow transplantation (andassociated total-body irradiation) played an important role inthe development of these neural malignancies [C16].
214. Data on adult exposures are considerably more
limited. Following high-dose (~40 Gy) fractionated radiotherapy, an excess risk of CNS tumours was observed
among pituitary adenoma patients [B22, T11]. In several
case-control studies of patients with CNS tumours ofvarious histological types, a history of diagnostic x-ray
examinations [H32] or x-ray treatments to the head wasmore often reported for cases than for controls [B23, P20,
P21]. In contrast, a mean brain dose of about 0.6 Gy was
not associated with an increase in CNS tumour incidenceor mortality in two small cohorts of infertile women
irradiated to the pituitary gland and ovaries [R18, R30],
and ankylosing spondylitics did not have an excess ofmortality from spinal cord tumours after being exposed tohigh radiation doses to their spinal cords [W1].
215. Dental diagnostic x-rayexposures have been assessedin several studies conducted by Preston-Martin et al. in
relation to various types of CNS tumours [P20, P21, P22,
P23, P24]. They found associations between meningiomas
and frequent annual full-mouth x-ray examinations andx-ray examinations performed many years ago, whenradiation doses were relatively high. Risks were higher
when exposure occurred during childhood. In other studies,
however, brain tumour cases did not have a history ofdental x-ray exposure significantly more often thancontrols [K18, M27, R19].

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216. Radiation workers in general receive low, fractionateddoses with relatively little exposure to the brain. To date, mostoccupational studies have been negative with respect to thissite of cancer [C11, M46, W10]. Brain cancer incidence andmortality rates were elevated among airline pilots in a few
studies [B48], but no dose-response relation was observed andconfounding due to non-ionizing radiation and socioeconomic status has been postulated [G15].
217. The issue of whether CNS tumours are related to fetal
exposure to radiation remains controversial. Most recently,
Doll and Wakeford [D17] carefully reviewed the literatureand concluded that in utero exposure to a mean dose of
approximately 10 mGy increases the risk of childhood
cancer. This conclusion was largely based on the Oxford
Survey of Childhood Cancers. In the Oxford Survey,
mortality from childhood CNS tumours was associatedwith fetal irradiation (relative risk = 1.4; 95% CI: 1.21.7)[B2]. Miller and Boice [M31] expressed concern about the
Oxford Survey results, noting that all childhood cancers
were increased about 40%, whereas such commonality is
not seen in either animal or human studies. Among atomic
bomb survivors exposed in utero, an association between
dose and cancer mortality has not been found, but the inutero survivor cohort is small, and the negative result iscompatible with a wide range of risks [D14].
2. Internal low-LET exposures
218. Little is known about brain and CNS tumours followinginternal exposure to low-LET radiation. A small increased
risk of CNS tumours was observed among 35,000 Swedish
patients receiving diagnostic 131I examinations (SIR = 1.19;
95% CI: 1.001.41) [H27]. Since the dose to the brain was<10 mGy, the observed excess is not likely to be due to theradiation exposure. Significant excess risks were notdemonstrated among patients receiving 131I therapy for
hyperthyroidism [H23, H24, R14] or thyroid cancer [D15, E2,
G13, H26]; however, among ten-year survivors, brain tumour
incidence was significantly elevated in the Swedish
hyperthyroid patients [H23].
3. Internal high-LET exposures
219. Danish patients exposed to thorotrast had a significantly elevated incidence of brain tumours, but the fact thatthese tumours developed very soon after the thorotrast
examination suggests that they are related to the underlying disease or better ascertainment rather than to thethorotrast itself [A5]. Thorotrast was given in conjunction
with cerebral angiography because of a suspected brain
disorder. Often this disorder was later found to be a brain
tumour, especially among epileptic patients. Brain malignancies and other CNS tumours have not been linked to
exposure to radium [S34] or to radon among miners [D8].
4. Summary
220. Ionizing radiation can induce tumours of the CNS,
although the relationship is not as strong as for many othertumours, and most of the observed radiation-associatedtumours are benign. Indeed, neurilemmomas, which arehighly curable, are the only tumours that consistently
exhibit high risks. Overall, exposure during childhood
appears to be more effective in tumour induction than adultexposure, but the data on adult exposure are fairly sparse,
and the most recent study of atomic bomb survivors
demonstrated an excess relative risk for neurilemmomas
following exposure at all ages. Little is known about otherfactors that modify risk. The association between benign
tumours, particularly meningiomas and neurilemmomas,
and radiation appears to be substantially stronger than withmalignant tumours. Malignant brain tumours are seen only
after radiotherapy. Additional data are needed to bettercharacterize the dose response for CNS tumours of various
histological types.

L. THYROID CANCER
221. Thyroid cancer is one of the less common forms ofcancer [P5]. Unlike most cancers, its incidence is relatively
high before age 40 years, increases comparatively slowly
with age, and is about three times higher in women thanmen. This female predominance is also observed for benign
thyroid tumours. The degree of malignancy varies widelywith histological type, ranging from the rapidly fatal
anaplastic type to the relatively benign papillary type [F2,
R13]. Data from most countries suggest that mortality is
falling while incidence is increasing [F1]. Ionizing
radiation is a well documented cause of thyroid cancer. The
relative risk of thyroid cancer is also substantially
increased among persons with a history of benign nodules
and goitre. There is some evidence that elevated levels of
thyroid-stimulating hormone, multiparity, miscarriage,
artificial menopause, iodine intake, and diet also may berisk factors for thyroid cancer[F2, R13].
222. Shore [S8] reviewed the epidemiological studies ofradiation and thyroid cancer conducted through the early
1990s. Since then, more information has become available
from continued follow-up of some cohorts and from apooled analysis of seven studies of external radiation [R4].
Additional data on the occurrence of thyroid cancers
among children living in radiation-contaminated areas in
Belarus [D13], the Russian Federation [I23], and Ukraine[T23] as a result of the Chernobyl nuclear power plant
accident have recently been published. New data on
Chernobyl recoveryoperation workers (“liquidators”) havealso been published in the last few years [K15]. These
results are discussed below and in more detail in Annex J,“Exposures and effects of the Chernobyl accident”.
1. External low-LET exposures
223. The results for thyroid cancer incidence that were
presented in Table 8 of Annex A in the UNSCEAR 1994
Report [U2] are updated here in Table 17. This Table
contains findings from a pooled analysis of studies ofexternal irradiation of the thyroid [R4]. This analysis,

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

339

which included seven studies and was based on almost
120,000 people with about 700 thyroid cancers and 3
million person-years of follow-up, allowed a more detailed
evaluation of the dose-response relationship and of
modifying factors than had previously been possible.
Nearly 500 thyroid cancers occurred in the half of the study
population exposed during childhood or adolescence.

increased risk of thyroid cancer was reported among bonemarrow transplantation patients treated with high-dose,
total-body irradiation, especially during childhood (4 cases
observed compared with 0.02 expected); however, radiotherapyreceived before bone marrow transplantation might
have played a role in the development of thesemalignancies [C16].

224. In the analysis of the five cohort studies of persons
irradiated before age 15 years, 436 thyroid cancers werediagnosed among the exposed population. The pooled ERR
per Gy was 7.7 (95% CI: 2.128.7). No single study was
found to have an undue influence on the overall estimatesof risk. The ERR per Gy for females was nearly twice thatfor males, but the results were not consistent [R4]. Since
thyroid cancer naturally occurs two to three times more
frequently among females than males, the absolute
radiation-induced risk was correspondingly higher among
women. Even within the narrow range of ages at exposure,there was strong evidence of a decrease in the ERR withincreasing age at exposure, which suggests that the thyroidis particularly sensitive to tumour induction at the time of
rapid cell proliferation. The ERR per Gy was highest
1529 years following childhood exposure, but it remained
high for more than 40 years after exposure [R4]. While thelatter finding was also reported from an extended follow-up
of the Stockholm skin haemangioma cohort [L13], few
other studies have more than 40 years of follow-up. In
contrast to the well described carcinogenic effects ofchildhood exposure, there is little evidence of an excess of
thyroid cancer associated with external exposure after age
20 years. Among atomic bomb survivors exposed after age
40 years, the ERR was negative [R4, S8, T1].

227. Information on fractionated and low-dose-rate exposures mostly comes from studies of high-backgroundareas, diagnostic radiation procedures, and occupational
exposures. Studies of residents living in areas of highnatural background radiation were conducted in China[T25, T26, W9] and India [P3]. They did not show anassociation between the prevalence of thyroid nodules andlifetime exposure to elevated background radiation. However, since the doses received in childhood generally were
only a few tens of milligray, the statistical power to detecta radiation effect was low. Diagnostic x rays, even thoseresulting in higher thyroid gland doses or those occurring
during childhood, were not linked to thyroid cancer in astudy in Sweden [I9]. This study is unique because theascertainment of diagnostic x-ray procedures was based noton personal recall but on a search of hospital radiation
records.

225. Each of the studies in the pooled analysis wasconsistent with a linear dose-response relationship, although
the range of doses varied considerably among studies [R4]. In
the childhood cancer study [T5], which was the only study
with doses over 6 Gy, there was some indication that theeffects of cell killing flattened the dose response at high doses.
Exposures were received in fractions, from all in one day toseveral years apart in three of the studies included in thepooled analysis. There was very weak evidence that for thesame total dose, exposures received in two or more fractions
were less carcinogenic than acute exposures by an estimatedfactor of 1.5, with wide confidence limits [R4]. Although noformal assessment of risk byhistologytype was conducted, therisk for papillary carcinomas appeared to be higher than forfollicular cancer in the individual studies. To date, no clear
association between ionizing radiation and either medullarycancer or anaplastic carcinoma has been observed, although
there have been reports of anaplastic carcinoma occurring
after medical irradiation.
226. An elevated risk of thyroid cancer was reported forpatients treated with high-dose radiotherapy for Hodgkin’s
disease [D33, D36, H9, T5] and for childhood cancers[H30, T5]. New studies emphasize that Hodgkin’s disease
survivors have a high risk of thyroid cancer if they received
radiotherapy as children [B16, S23]. Recently, a large

228. While early mortality studies of radiation workers
provided no evidence for an elevated risk of thyroid cancer[M23], there have been reports of an increased risk ofthyroid cancer among x-ray technologists. Among 27,000
x-ray workers and a similar number of non-radiation
medical workers in China, 8 thyroid cancers were foundcompared with 4.5 expected [W10]. The relative risk waslarger for personnel working at relatively early ages andduring the period when exposures were greatest. In the
United States, a twofold greater risk of thyroid cancer
incidence was reported in preliminary results from a surveyof over 100,000 predominately female x-ray technologists[B20]. These preliminary results were based on selfreported diagnoses on questionnaires and might haveincluded benign nodules or adenomas. In a recent mortality
study of the x-ray technologists, no excess of thyroid cancer
deaths was noted [D23]. Consistent with the incidence
results are findings from a Swedish record-linkage study inwhich x-ray technicians had double the risk of thyroid
cancer compared with the general population of Sweden[C17] and from a small Italian study in which male hospitalradiation workers had a higher prevalence of thyroid nodules
than comparable non-exposed workers [A8]. Based on only
nine thyroid cancer deaths, a significantly elevated mortality,
but no dose response, was observed in mostly male nuclear
workers in the United Kingdom [L20]; the evidence for an
excess diminished with longer follow-up [M46]. No
association was reported for nuclear workers in the UnitedStates [G12] or in the combined international analysis of
nuclear workers from Canada, the United Kingdom, andthe United States [C11]. Since adult, acute radiation
exposures have not been linked to thyroid cancer, thereports of excesses are surprising. Each of these studies,
however, has methodological weaknesses for studying

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thyroid cancer that might have influenced the findings. For
example, except for the nuclear worker studies, individual
doses were not available; multiple comparisons were tested
in most studies; and the number of cases was generally
small, which produces unstable risk estimates. Furthermore,
the well known association between radiation and thyroid
cancer may have led to more complete case ascertainment forradiation workers.
229. As a consequence of the Chernobyl accident, large
numbers of men from all over the former Soviet Union
were brought in to participate in recovery operations at thereactor and in the surrounding areas. Altogether
approximately 600,000 workers were involved, about
240,000 of them during 1986 and 1987. Most of the
exposure of the workers came from external gamma andbeta irradiation. Internal exposure from radionuclides wasminor after the first few weeks [U4]. Several investigationsof recovery workers from the Baltic countries have been
conducted. In a systematic clinical evaluation, including
palpation and ultrasound, of the nearly 2,000 Chernobyl
recovery operation workers from Estonia, no excess of
thyroid nodularity or cancer was detected [I10]. Doses were
estimated for each worker based on medical records,
responses to a questionnaire, and biodosimetry. Filmbadges suggested that workers had been exposed to a meandose from external sources of approximately 100 mGy, butbiodosimetry indicated that the doses might have been
considerably lower [L31]. Thyroid cancer incidence andmortality were evaluated in a cohort of nearly 5,000
Estonian workers [R20]. No thyroid cancers were observed,
whereas 0.21 would have been expected based on age,gender, and calendar-specific cancer rates in Estonia. In acohort of Lithuanian Chernobyl workers, the threeobserved thyroid cancers did not significantly differ fromthe expected number based on Lithuanian cancer rates[K39]. Given the low dose and late age at exposure, thesenegative findings are consistent with data from the Life
Span Study of atomic bomb survivors [T1].
230. In a much larger study of 168,000 Russian recovery
operation workers, Ivanov et al. [I13, I18] reported anincreased risk of thyroid cancer compared with the
population of Russia. Comparing cancer incidence in theseworkers to that in a general population is questionable,
because the recovery operation workers had a higher levelof medical surveillance, especially of their thyroid glands[B4]. However, Ivanov et al. [I17] noted that they adjusted
for a screening effect. Further data regarding these findings
are needed.
2. Internal low-LET exposures
231. Studies of medical exposures to 131I were reviewed
extensively in the UNSCEAR 1994 Report [U2]. Since
then, further information has become available from threelarge follow-up studies of 131I-exposed patients. In addition
to an extended period of follow-up (as much as 40 years
following exposure), the Swedish study of over 34,000
patients administered 131I for diagnostic purposes now

incorporates individual estimates of thyroid doses [H4].
Dose quantification was based on the amount of 131I
administered and the 24-hour thyroid uptake. Informationon the size of the thyroid gland was available for nearly
half of the patients, and adjustments to dose estimates on
the basis of these data did not affect the results. Basicdetails of the study cohort are given in Table 2, Table 3,
and Table 17, while Table 28 presents thyroid cancer
incidence in relation to dose. Although overall incidence,
after excluding the first five years following exposure, wasgreater than that in the general population, there was no
indication of a dose-response trend. Furthermore, analyses
based on the reason for the initial referral showed thatincidence was higher than expected only among thosereferred for suspicion of a thyroid tumour. Among thosereferred for other reasons, thyroid cancer incidence waslower than expected compared with national rates. Amongthe 34,000 patients evaluated by Hall et al. [H4], 7% were
under 20 years of age at the time of exposure and less than
1% were under 10 years of age. Among the 2,408
adolescents and young adults (average thyroid dose of
1.5 Gy), 3 thyroid malignancies were observed comparedwith 1.8 expected based on national rates (SIR = 1.69; 95%
CI: 0.354.9). These data do not allow inferences aboutchildhood exposures. No excess of thyroid nodules was
detected when 1,005 women who had been examined years
before with 131I (mean thyroid dose of 0.54 Gy) and 248
non-exposed women were screened for thyroid disorders[H36]; however, among the exposed women the prevalenceof thyroid nodules was correlated with dose.
232. Studies of patients treated with 131I for hyperthyroidism
have dealt almost entirely with adults. Although individual
thyroid doses have not been calculated, the intention is todeliver 60100 Gy to the thyroid [B21]. At doses of thismagnitude, the ERR per Gy for children receiving externalradiation begins to level off, probably due to cell killing [R4].
Among 10,000 Swedish patients, 18 thyroid cancers wereobserved, yielding a standardized incidence ratio of 1.29 (95%
CI: 0.762.03) [H23]. Among 23,000 patients evaluated in a
new follow-up of the thyrotoxicosis study in the United States,
an increased risk of thyroid cancer mortality was observed[R14]. The excess risk was primarily due to a large risk
during the first five years following treatment and was higher
among toxic nodular goitre patients than Graves’ disease
patients. Franklyn et al. [F8] reported an elevated incidence of
thyroid cancer and thyroid cancer deaths in a follow-up of
7,417 hyperthyroid patients treated with 131I in England.
Compared with the population of England and Wales, boththe SIR (3.25; 95% CI: 1.76.2) and the SMR (2.78; 95% CI:
1.26.7) were elevated, but no dose response wasdemonstrated. These findings suggest that some of the excess
may be due to the underlying thyroid disease.
233. While the data from the medical radioiodine studies
are informative, the uncertainties associated with estimating thyroid doses from 131I, especially in persons withthyroid abnormalities, reduce the precision of the risk
estimates. The non-uniformity of the dose distribution in
the thyroid gland results in some areas of tissue receiving

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

such high doses that cell killing could occur and otherareas receiving extremely low doses [N7]. Thus, thetumorigenic effects of the exposure might be lower thanwould be expected based on the average dose. Nevertheless,131
I dose estimation in medical studies is far better than forthe studies of environmental 131I exposure.
234. Four years after the 1986 accident at the Chernobyl
nuclear plant, a substantial increase in childhood thyroid
cancer was observed in contaminated regions of the former
Soviet Union [S49]. For a more detailed discussion of
thyroid cancer risk following the Chernobyl accident, see
Annex J, “Exposures and effects of the Chernobyl
accident”. In Belarus, and particularly in the Gomel region
to the north of Chernobyl, the number of childhood thyroid
cancers diagnosed between 1990 and 1992 was muchhigher than in 19861989 [K6]. The diagnoses of most of
the thyroid cancers were confirmed by an international
pathology review [W5]. An unusually high frequency of
thyroid cancer continues to occur in Belarus [B49, D13]and in heavily contaminated areas in Ukraine [L19, T23]
and the Russian Federation [T10, I23, I24] among persons
who were less than 15 years of age at the time of theaccident. Childhood thyroid cancer rates in these areas in19911994 were higher by a factor of almost 10 than in
the preceding five years (Table 29). The number of cases
identified among persons born less than 17 years before theaccident reached about 1,800 in 1998 (Annex J,“Exposures and effects of the Chernobyl accident”). Risk
appears to increase with decreasing age at exposure [A3,
K31, P31, W16]. Recent data from Belarus suggest thatwhile increases in thyroid cancer incidence are still
occurring among individuals who were less than 5 years ofage at the time of the accident, rates for older children
might be stabilizing [K31]. In the Ukraine, rates are stillrising for persons less than 14 years of age, but a similarleveling off of the risk among those 1418 years old at thetime of the accident was observed [T23]. Age-at-exposure
effects warrant further investigation.
235. Following early reports of an increased frequency of
thyroid cancer, questions were raised about the effects ofscreening the exposed population [B8, R3, S22]. While thescreening programmes being conducted in the contaminatedareas are responsible for some increases in thyroid cancer
ascertainment, the majority of tumours reviewed by aninternational panel were not microcarcinomas. In fact, many
showed direct invasion of extrathyroidal tissues and lymph
node spread [W5].
236. A study of 107 thyroid cancer cases and 214 matched
controls was conducted in Belarus [A26]. Taking into accountthe reason for diagnosis, a strong dose response wasdemonstrated. Although the estimated doses in the study haveconsiderable uncertainty, the results indicate that the excess of
thyroid cancers is related to the radiation exposure.
237. A strong correlation between estimated exposure
from 131I and thyroid cancer rates has been reported inseveral studies [J4, J5, L19, L51]. In a well designed

341

correlation study, Jacob et al. [J5] compared average thyroid
doses from 131I exposure in many regions in Belarus and theRussian Federation with 19911995 incidence rates for the19711986 birth cohort. A linear dose-response relationshipwas found (EAR per 104 PY Gy = 2.3; 95% CI: 1.43.8; ERR
per Gy = 23; 95% CI: 8.682). Likhtarev et al. [L51] also
conducted a correlation study using recent data (19901997)
from the Ukraine. They reported an EAR per 104 PY Gy of
1.6 (95% CI: 0.73.4) and an ERR per Gy of 38 (95% CI:
1697) for the 19711986 birth cohorts. While these studies
provide reasonable risk estimates, they are based on
geographical correlations and are subject to the limitations
inherent in such evaluations.
238. No radiation-associated thyroid malignancies havebeen observed less than five years after external exposure[R4]. Despite some early occurrence of childhood thyroid
cancers after the Chernobyl accident, most cases werediagnosed after 1991 (Table 29). A minimal latency period
for radiation-induced thyroid tumours of four years might
have resulted from the ability to detect an effect because of
the millions of children exposed to radiation from the
Chernobyl accident or because of the advancement of time
to diagnosis due to screening.
239. A high frequency of RET/PTC oncogene rearrangements is found in the thyroid cancers occurring in the
Chernobyl area. Some studies have reported specific types of
RET/PTC in Chernobyl cases [B25, K24] compared withtumours associated with external radiation [B26]; however,findings have not been consistent [W4]. Both RET/PTC1 andPTC3 rearrangements have been reported in Chernobylrelated patients, and recent research suggests that age at
exposure, time since exposure, and morphology may be
important in determining the type of PTC rearrangement[P10, S13, T34].
240. Taking all of the data together, screening and otherselection effects may explain some of the increase inthyroid tumours seen among the children living around
Chernobyl, but radiation exposure from the reactor
accident clearly plays a major role. The associatedmechanism is not yet well understood, and the magnitudeof the risk from 131I per se remains uncertain. The
geographical distribution of these tumours coincides moreclosely with the areas of 131I contamination than with theareas of 137Cs contamination, but there is also a correlation
with the distribution of shorter-lived radioisotopes (e.g. 132I,
133
I, and 135I) [A3]. Other factors that might influence
radiation risks have been identified. Many of the regions
around Chernobyl are iodine-deficient [G20, P37], andiodide dietary supplementation had been terminated before
the accident [W5]. Although large amounts of stable iodine
were distributed to the population living near the plant asprophylaxis shortly after the accident, the distribution wasincomplete and is thought not to have been very effective[M32]. Genetic susceptibility to radiation-associated thyroid
cancer also has been suggested as a potential modifier of risk
[C36]. Finally, other potential environmental contaminants
need to be investigated.

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241. The health effects of exposure to 131I fallout fromatmospheric nuclear tests conducted at the Nevada test site in
the 1950s have been studied for the last four decades. In themost recent follow-up, 2,500 children were examined andindividual doses to the thyroid reconstructed. Nineteen
neoplasms, of which eight were malignant, were diagnosed.
The ERR per Gy was about 7 (p=0.02). When the analysis
was restricted to malignancies, the ERR per Gy was 7.9 but
was not statistically significant [K36]. The 131I doses from
weapons testing at the Nevada Test Site were assessed by theUnited States National Cancer Institute [N12]. Iodine-131 is
the radionuclide of main concern because it is the principal
radionuclide in fallout and is ingested by drinking
contaminated milk. Approximately 5.6 EBq of 131I werereleased into the atmosphere, resulting in radioiodine
deposition throughout the United States. Iodine-131 thyroid
doses were estimated for each countyin the continental UnitedStates by age group, gender, and level of milk consumption.
242. The average thyroid dose to the approximately 160
million people living in the United States at the time oftesting was 20 mGy. The estimated dose varied substantially depending on geographic location, age at the time of
exposure, and quantity, source, and type of milk intake.
Doses were highest east of the test site in Nevada and Utah
and in some counties in Idaho, Montana, New Mexico,
Colorado, and Missouri and were lowest on the West
Coast, on the border with Mexico, and in parts of Texas
and Florida. Owing to geographic differences, doses
ranged from 0.01 to 160 mGy. The average dose to young
children was approximately 10 times higher than theestimated adult dose, because the thyroid gland of smallchildren concentrates more iodine and because children
drink much more milk than adults. While the uncertainty
associated with estimating the average thyroid dose to the
population of the United States is about a factor of 2, theuncertainty in dose estimates for individuals is about afactor of 3.
243. Gilbert et al. [G19] related age-, calendar year-,gender-, and county-specific thyroid cancer mortality andincidence rates in the United States to 131I dose estimates,
taking geographic location, age at exposure, and birthcohort into account. Neither cumulative dose nor dose
received between 1 and 15 years of age was associated withthyroid cancer incidence or mortality, but an association
was suggested for dose received before 1 year of age (ERR
at 1 Gy = 10.6; 95% CI: 1.129 and ERR at 1 Gy = 2.4;
95% CI: 0.55.6 for mortality and incidence data,
respectively).
244. From 1949 to 1962, the former Soviet Union conducted 133 atmospheric nuclear tests at the Semipalatinsk
test site in Kazakhstan [B44, R31]. Local fallout wasparticularly high from tests carried out in 1949, 1953, and1962. Approximately 10,000 persons living near the testsite and 40,000 living in the Altai region in the RussianFederation were exposed to over 250 mSv effective dose.
Effects on the health of populations living near Semipalatinsk in Kazakhstan and in the Altai region are currently

being studied. An excess of benign and malignant thyroid
tumours has been reported for the Kazakhstan population[B44, R31]. It is expected that new data from the ongoingstudies in both Kazakhstan and the Russian Federation will
become available soon.
245. Between 1944 and 1957, the Hanford Nuclear Site in
Washington State, United States, released 2025 PBq of131
I into the atmosphere. In January 1999, the results of the
Hanford Thyroid Disease Study were released to the public[D29]. In total, 5,199 people born between 1940 and 1946
in seven counties in eastern Washington State wereidentified for study. Ninety-four percent were located,
4,350 (84%) were alive, and 3,441 (66%) agreed toparticipate in the study. Study participants provided
information on place of residence, consumption of milk
and other relevant foods, occupational history, selected
lifestyle factors, and medical history. Thyroid doses were
estimated for the 3,193 study participants who had lived
near Hanford at the time of atmospheric releases based on
individual characteristics, e.g. level and type of milk
consumption and dosimetry information from the Hanford
Environmental Dose Reconstruction project. The other 248
participants had moved from the Hanford area and wereconsidered to have received no exposure. The mean andmedian doses were 186 mGy and 100 mGy, respectively.
The distribution of dose was skewed (range 0 to
2,840 mGy), with a high percentage of participants having
low doses and only a small percentage having high doses.
Each participant was evaluated clinically by two study
physicians. The examination included ultrasound, thyroid
palpation, and blood tests. Eleven categories of thyroid
disease, ultrasound-detected abnormalities, and hyperparathyroidism were evaluated in terms of estimated 131I
radiation dose to the thyroid.
246. A total of 19 participants were diagnosed withthyroid cancer and 249 with benign thyroid nodules. No
evidence of a dose-response relationship was found for
malignant or benign nodules or any of the other outcomesstudied. The final report is yet to be published, and there
has been criticism of the large degree of uncertainty in thedose estimates. Nevertheless, the results do not provide
evidence that 131I doses on the order of 100 mGy increase
the risk of developing thyroid neoplasia.
247. Although some animal studies have suggested that
I may be less carcinogenic than external radiation [N5],a large study of rats found similar carcinogenic effects for
131
I and external radiation [L11]. The strain of rat used has
a high rate of developing follicular thyroid carcinomas, yetRoyal [R22] noted that the study is particularly relevant,since it was well designed and the rats were the equivalentof young adolescents at the time of exposure and were
exposed to low as well as moderate and high radiation
doses. In summary, the very limited human data onchildhood exposure to 131I and adult exposure to externalradiation are insufficient for concluding that there are
significant differences between these types of radiation
with regard to thyroid cancer induction.
131

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

3. Internal high-LET exposures
248. Radium is primarily a bone seeker, and the development of thyroid cancer has not been associated with
exposure in most studies, but a statistically significant
elevated risk, based on a small number of cases, wasobserved among radium dial painters in the United States
who worked before 1940 [P27] and among patients treatedwith 224Ra in Germany [N4].
249. Neither thyroid cancer mortality nor incidence waselevated among Danish thorotrast patients [A5]. Radon
exposure in mines did not increase the risk of thyroid
cancer mortality in a pooled analysis of 11 studies ofunderground miners [D8].
4. Summary
250. The thyroid gland is highly susceptible to the
carcinogenic effects of external radiation during childhood.
Age at exposure is an important modifier of risk, and avery strong tendency for risk to decrease with increasing
age at exposure is observed in most studies. Although
thyroid cancer occurs naturally more frequently among
women, the ERR does not appear to differ significantly formen and women. Among people exposed duringchildhood, the ERR of thyroid cancer is highest 1529
years after exposure, but elevated risks persist even 40
years after exposure. The carcinogenic effects of 131I areless well understood. Most epidemiological studies haveshown little risk following a wide range of exposure levels,
but almost all of them looked at adult exposures. Recent
results from Chernobyl indicate that radioactive iodine
exposure during childhood is linked to thyroid cancer
development, but the level of risk is not yet well quantified.

M. NON-HODGKIN’S LYMPHOMA
251. Non-Hodgkin’s lymphoma (NHL) is a collection of
distinct disease entities that are malignant expansions oflymphocytes. The lymphomas that make up this grouping
can generally be separated into those with B-cell or T-celllineage. The precise definition of NHL has varied overtime; a recent classification that is widely used is the
Revised European American Lymphomas classification[H42].
252. Rates of NHL have increased in many countries overthe past few decades, particularly at older ages [H39]. In
part this is likely to be due to changes in the definition of
NHL and to improved ascertainment, although thesefactors are unlikely to explain all of the increases [H39].
Epidemiological studies have shown associations withchronic immunosuppression, for example, amongtransplant recipients and other patients who received
immunopressive therapy [H43, K26]. Associations withcertain viruses, such as Epstein-Barr [M37] and HIV[S44], have also been identified. Some studies suggest
elevated risks for those employed in agriculture,343

particularly those working with pesticides (e.g. [C31]),although other studies have not shown such a link (e.g.
[W15]).
1. External low-LET exposures
253. Information on incidence and mortality from NHL
following external exposure to low-LET radiation ispresented in Table 18. As can be seen from this Table, theresults are mixed, with many of the studies listed having
failed to show a statistically significant association withradiation exposure. The Life Span Study of survivors of theatomic bombings falls into this category, although Preston
et al. [P4] reported some evidence of an increasing dose
response for males (p=0.04) but not for females, amongwhom, if anything, the trend is negative. The latter
findings might appear to contradict those for the cervicalcancer patients, where there is borderline evidence of apositive dose response; however, among exposed patients,
there was little indication of an increasing trend withincreasing dose [B1]. Furthermore, studies of women
treated for benign gynaecological disorders [D7, I6] havenot suggested associations with radiation. Comparison of
the Life Span Study findings for males with those findings
for the ankylosing spondylitis patients might be informative,
given that most of these patients were male. Weiss et al. [W1]reported that NHL mortality among spondylitis patients wasraised significantly compared with national rates (relativerisk = 1.73; 95% CI: 1.232.36), and that this elevated risk
appeared to disappear more than 25 years after exposure;
however, no dose-response analysis was performed. In
another study of a mostly male population, Cardis et al.
[C11] did not find an association between NHL andexternal radiation among nuclear industry workers,
although the precision of the study was limited by thegenerally low doses. The same limitation affected a studyof diagnostic x-ray procedures [B39], which also did notshow an association when based on a two-year lag;however, this study used numbers of x-ray procedures
rather than doses.
254. The Life Span Study also provided no evidence thatany elevated risk would be greater for exposure inchildhood than in adult life [P4]. There are few other dataon childhood exposure. The study of Swedish children
treated for benign lesions in the locomotor system [D12]
showed rates of NHL incidence and mortality similar tonational values, although no dose-response analyses werereported.
2. Internal low-LET exposures
255. There are few data that allow examining the risks of
NHL specifically in relation to internal low-LET radiation.
The data that are available are for groups with medical
exposures to 131I (see Table 18). Among over 35,000 patientswith diagnostic exposures, Holm et al. [H27] reported an SIR
of 1.21. This value was not significantly different from 1 (atthe 5% level), although the SIR of 1.24 for all lymphomas was
significantly raised. However, while total cancer risk was

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ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

analysed in relation to level of the activity of iodine
administered, no results were reported for NHL. Furthermore,doses to this cohort were generally very small (mean bonemarrow dose = 0.19 mGy). Doses were higher in a study ofSwedish patients treated for hyperthyroidism [H23]. In thisinstance, the observed number of cases was less than
expected from national rates, significantly so after omitting
the first 10 years of follow-up (SIR = 0.40, although basedon only seven cases). Again, however, NHL incidence was
not analysed in relation to level of exposure. Ron et al.
[R14] studied NHL mortality among hyperthyroidism
patients in relation to estimated bone marrow dose from 131I
therapy; most of the patients were from the United States
but for this analysis some patients from the United
Kingdom were included. There was no evidence of a trend
in risk with dose, although the generally low doses limited
the precision of the analysis [R14].
3. Internal high-LET exposures
256. There is limited information on NHL risks amonggroups exposed internally to high-LET radiation. Relevant
findings are summarized in Table 18. Among German
patients who received thorotrast, van Kaick et al. [V8]reported 15 cases among 2,326 patients, which represented
a relative risk of about 2.5 compared to a group of unexposed patients. However, there was no analysis in relation
to the level of exposure. Among thorotrast patients in
Denmark [A5] and ankylosing spondylitis patients inGermany treated with 224Ra [W3], the numbers of cases
were too small to permit detailed inferences. Larger
numbers arose in the combined analysis of radon-exposedminers [D8]; here the total number of deaths observed was,
if anything, less than that expected from national andregional rates (SMR = 0.80, 95% CI: 0.561.10), but noanalysis was conducted according to the level of exposure.
4. Summary
257. Results from studies of NHL risk among groups
exposed to external low-LET radiation are mixed. The
Japanese atomic bomb survivors as a whole do not show anassociation, although there is some evidence of anincreasing trend in incidence with dose among males (butnot females). Findings from other studies are variable, withno clear consistency. Overall, there is little evidence of an
association between NHL and external low-LET radiation.
258. There is limited information on NHL risk in relation tointernal low- or high-LET radiation. The general absence ofanalyses in relation to level of exposure and the limited
statistical precision of one such analysis that was conducted
hinders interpretation of the data that are available.

N. HODGKIN’S DISEASE
259. Hodgkin’s disease is distinguished from otherlymphomas mainly by the presence of giant Reed-Sternberg cells [B34]. While changes over time in the classi-

fication of Hodgkin’s disease are likely to have had someeffect on analyses of trends in rates, there are indications
from various countries of a slight decrease in incidence
rates [H39]. More pronounced decreases have been seen inmortality rates during recent decades, reflecting improved
treatment [H39]. Internationally, incidence rates tend to bemuch higher in North America and Europe than in Asia
[P5] (see also Table 1). Clustering of cases of Hodgkin’s
disease has been reported in some studies (e.g. [A17]), anda viral origin has been suggested by associations withcertain childhood environments, such as small family size
and uncrowded conditions, that could reduce or delay
infections [G18]; Epstein-Barr virus has been cited as
possibly being relevant [M36].
1. External low-LET exposures260. The studies of external low-LET radiation includedin Table 19 have not always reported estimates of trend
based on dose-response analyses but have, at least in someinstances, indicated whether there were any statisticallysignificant trends with dose. For the Japanese atomic bomb
survivors, Preston et al. [P4] found no evidence of a dose
response, although the confidence intervals were fairly
wide owing to the small number of cases (see Table 19).
Studies of patients treated for benign gynaecologicaldisease [I6] and of nuclear workers [C11] also showed notrend with dose, although based on small numbers ofdeaths in the former instance and low doses in the latter.
For the other studies of external low-LET exposure listed
in Table 19, the observed number was sometimes greaterthan the number expected, although not to a statisticallysignificant extent.
2. Internal low-LET exposures
261. There are few data that allow examining the risks of
Hodgkin’s disease specifically in relation to internal lowLET radiation. The data that are available concern groups
with medical exposures to 131I (see Table 19). Among over
35,000 patients with diagnostic exposures, Holm et al.
[H27] reported an SIR of 1.35. This value was not
significantly different from 1 (at the 5% level), although
the SIR for all lymphomas, 1.24, was significantly raised.
However, while total cancer risk was analysed in relation
to the activity of iodine administered, no results werereported for Hodgkin’s disease. Furthermore, doses to thiscohort were generally very small (mean bone marrow dose
= 0.19 mGy). Doses were higher in a study of Swedish
patients treated for hyperthyroidism [H23]. However, thesmall number of cases observed, while consistent withnational rates, limited inferences. Furthermore, theincidence of Hodgkin’s disease was not analysed in relation
to level of exposure [H23]. Ron et al. [R14] studied
Hodgkin’s disease mortality among hyperthyroidism
patients, mostly from the United States, in relation toestimated bone marrow dose from 131I therapy. There was
no evidence of a trend in risk with dose, although the small
number of deaths and the generally low doses limited theprecision of the analysis [R14].

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

3. Internal high-LET exposures
262. Relevant findings are summarized in Table 19. Studiesof German [V8] and Danish [A5] thorotrast patients, while
not indicating elevated risks, are based on verysmall numbersof cases. A combined analysis of radon-exposed miners [D8]reported an SMR for Hodgkin’s disease of 0.93 (95% CI:
0.541.48), but the 17 deaths were not analysed in relation tolevel of exposure.
4. Summary
263. While dose-response analyses have not always been
performed in the relevant studies and the numbers of cases
have sometimes been fairly small, the available data do notindicate an association between Hodgkin’s disease andradiation, either for external or internal exposures.

O. MULTIPLE MYELOMA
264. This group of conditions consists of plasma cellmalignancies, which include Waldenstrom’s macroglobulinaemia as well as multiple myeloma [H48]. It is
more common among men than women and is rare,
particularly at young ages [C23]. Mortality rates have been
increasing during the past few decades in various
countries, but this increase has largely been confined toolder ages and may be due in large part to earlier
incompleteness in ascertainment [C23]. Some case-control
studies have indicated associations between myeloma andemployment in agriculture or in the food industry [B30,
B31, C24].
1. External low-LET exposures
265. Table 20 contains information on multiple myeloma
following exposure to external low-LET radiation. Of
particular note is the discrepancy between the findings for
mortality and incidence among the Japanese atomic bomb
survivors. The most recent mortality follow-up [P9], in
common with an earlier analysis of mortality in thispopulation [S3], showed a statistically significant association between myeloma risk and dose. However, data on
myeloma incidence yield a much lower estimate for thetrend in risk with dose; furthermore, it is consistent withthere being no effect of dose [P4]. The authors of theincidence report noted that the mortality findings appeared
to be heavily dependent on the inclusion of questionablediagnoses and on both second primaries and cases above
4 Gy that were excluded from the incidence analysis [P4].
In view of the care taken to review the myeloma diagnoses
in the incidence analysis, it seems reasonable to place
greater weight on these findings.
266. Results from the other studies of external low-LET
exposure cited in Table 20 are mixed. Some, e.g. theinternational studyof cervical cancer patients [B1], provide
no evidence of an elevated risk. On the other hand, Darbyet al. [D7] reported a significant elevated risk of myeloma

345

mortality among metropathia patients in the United
Kingdom, although there was less evidence of an associationfrom a similar study in the United States [I6]. The number of
myeloma deaths among ankylosing spondylitis patients in the
United Kingdom was significantly greater than that expectedfrom national rates but was not analysed in relation to dose
[W1]. An international study of cancer mortality among
nuclear workers found a significant association with dose[C11], although this finding was influenced strongly byjust a few cases with doses above 0.4 Sv. In a study ofdiagnostic x rays, Boice et al. [B39] found that the risk of
myeloma incidence was similar among those who had andthose who had not received x rays under two health plans;
however, there was some evidence of an increasing trend
in risk with an increasing number of x-ray procedures,
although actual dose estimates were not available.
267. It is noticeable that of the studies of external lowLET exposures listed above and in Table 20, those thatsuggest an elevated risk of myeloma tend to be studies ofmortality, in contrast to the few studies of incidence.
Indeed, in common with the atomic bomb survivors study,
the Swedish study of treatment for benign lesions of thelocomotor system indicated an elevated risk of mortality
relative to national rates, but not of incidence [D12]. It is
unclear whether these findings might be due to differential
recording of myeloma on death certificates, based on
knowledge of prior radiation exposure. However, in viewof the greater accuracy in diagnoses of incident cases of
myeloma, inferences from incidence data are likely to be
more sound.
2. Internal low-LET exposures
268. There are few data on multiple myeloma risks inrelation to internal low-LET radiation. In studies of Swedish
patients with exposure to 131I for diagnostic purposes [H27]and as treatment for hyperthyroidism [H23], the observed
numbers of incident cases were close to those expected fromnational rates. However, the risk of myeloma was not analysed
in relation to level of exposure. Indeed, the bone marrow doses
were generallylow in the two studies (means of 0.19 mGyand
60 mGy, respectively). Ron et al. [R14] studied myeloma
mortality among hyperthyroidism patients, mostly from theUnited States, in relation to estimated bone marrow dose from131
I therapy. Although the estimated trend was greater thanzero, it was not significantly different from zero (p=0.3); thesmall number of cases and the generally low doses limited theprecision of the analysis [R14].
3. Internal high-LET exposures269. Relevant findings are shown in Table 20. There issome evidence of an excess of myeloma incidence among
Danish thorotrast patients, relative both to national rates
and to an unexposed control group [A5], although based on
only four cases. Among German thorotrast patients, vanKaick et al. [V8] reported ten cases of plasmacytoma
among 2,326 patients, which represented a relative risk ofabout 4.1 compared to a group of unexposed patients.

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ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Among patients in Germany treated with 224Ra, twoplasmacytomas were cited in the Spiess study [S14], andone medullary plasmacytoma was reported in the study ofWick et al. [W20]. In the combined analysis of radonexposed miners [D8], there was an indication of elevatedmortality from myeloma relative to national and regional
rates, although the difference was not significant (SMR =1.30; 95% CI: 0.851.90); however, the risk of myeloma
was not analysed in relation to level of exposure. For a
subgroup of these miners, namely uranium miners inwestern Bohemia, Tomášek et al. [T16] reported a statistically significant positive trend in myeloma risk withincreasing cumulative radon exposure, but based on only
three deaths. Similarly, while there was a statisticallysignificant excess of multiple myeloma deaths among
radium dial workers in the United States (SMR = 2.79;
95% CI: 1.026.08), this was based on only six deaths, andthe risk did not appear to be related to internal radium
body burden [S16].
4. Summary
270. Several mortalitystudies have indicated an increasing
trend in the risk of multiple myeloma with increasing dosefrom external low-LET radiation. However, such
associations are not generally apparent in studies of
myeloma incidence, even for groups (such as the atomic
bomb survivors) where the corresponding mortality data
point towards an elevated risk. This suggests that theclassification of myeloma on death certificates may havebeen conducted differentially, according to whether there
was a past radiation exposure, although it is difficult to becertain. Given the generally better quality of diagnoses
recorded in incidence data, the findings from the atomic
bomb survivors, in particular, would suggest that there islittle evidence of an association with low-LET radiation.
271. There is limited information on internal low- andhigh-LET exposures. Some studies have suggested anelevated risk, but based on small numbers of cases.

P. LEUKAEMIA
272. Although one of the rarer cancers, leukaemia is ofparticular interest because there is substantial information,
both epidemiological and experimental, on the effects ofionizing radiation. In terms of its general epidemiology, it canbe seen from Table 1 that the variation in rates between
different populations is not as great as for most solid tumours.
In considering trends and aetiological factors, it is importantto take account of the various subtypes of leukaemia and theirdifferent age-specific rates. Modern classifications of leukaemia and other lymphatic and haematopoietic malignancies(e.g. [B32]) are based on cytogenetic and molecular principles
that do not always coincide with the International Classification of Diseases. Three main subtypes will be considered
here: acute lymphatic leukaemia (ALL), which is a leukaemia
of precursor cells of either B-cell or T-cell origin; acute
myeloid leukaemia (AML), whose lineage and subtype are

generally defined according to the FAB system [B32]; andchronic myeloid leukaemia (CML), whose predominanthaematological feature is an elevated white cell count in the
peripheral blood and which is characterized cytogeneticallyby
the Philadelphia chromosome [L52]. Reference will also bemade to chronic lymphatic leukaemia (CLL), which has a
B-cell or a T-cell lineage [L52].
273. Most leukaemia cases in childhood are ALL, whereas
CML and CLL make up a high percentage of cases inadulthood. In the case of childhood ALL, the most striking
and consistent trend in different countries since 1950 has been
the decline in mortality [K1], reflecting the introduction ofeffective chemotherapy and cranial radiotherapy. Childhood
ALL incidence, in contrast, has been fairly constant or has
perhaps shown a small increase over the same period [D2].
Apart from ionizing radiation, risk factors for childhood ALL
include alkylating chemotherapeutic agents and geneticfactors
such as Down's syndrome. Greaves [G5] suggested that theincrease in rates during this century would be consistent withmany acute lymphatic leukaemias in children being due todelayed exposure to childhood infections. Kinlen suggested,
however, that a specific infective agent (or agents) underlies
childhood leukaemias, as is true for several animal leukaemias[K1].
274. For adult leukaemia, rates at ages 7584 years haveincreased in several countries since 1950 [K1]. These trends
are consistent with improvements in cancer registration andin the detail of death certification. Ionizing radiation, benzene,
and cytotoxic agents are known causes of leukaemias inadults; there is also some evidence that cigarette smoking is arisk factor, particularly for myeloid leukaemia [K1].
275. Information on the induction of leukaemia by theirradiation of laboratory animals was reviewed in the
UNSCEAR 1977 and 1986 Reports [U5, U7]. A variety oflymphatic and myeloid leukaemias have been induced indifferent animals, although with differing dose-response
relationships. However, studies of myeloid leukaemia in miceare consistent in showing a lower risk for a given total dosewhen exposure to low-LET radiation is protracted rather thanacute [U3].
1. External low-LET exposures
276. Risk estimates for leukaemia are presented in Table 21.
For the Life Span Study of atomic bomb survivors, only theleukaemia incidence results are shown, because larger
numbers are involved relative to the corresponding mortality
data [P9]and because the diagnoses of the incident cases havebeen reviewed [P4]. In the review in the UNSCEAR 1994
Report [U2], it was concluded that the incidence of acuteleukaemias or of chronic myelogenous leukaemia exhibits
strong associations with exposure to external low-LET radiation. In contrast, several large studies of groups with medical
exposures (e.g. [B12, C9, C10, W2]) show no association
between radiation and CLL. Although the Life Span Study ofatomic bomb survivors also fails to show an association with
CLL, the medical studies provide much stronger evidence,ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

owing to the low baseline rates in Japan. Furthermore, forleukaemia other than CLL, the temporal pattern of radiationinduced risks differs between exposures in childhood andadulthood, although in both instances the minimal latency
period is less than for most solid cancers. Further data on themodifying effects of age and time have become available fromthe extended mortalityfollow-up of the atomic bomb survivors[P9]. These data show that, whereas both the ERR and EAR
decrease soon after exposure in childhood, the decline in risk
tends to be less pronounced for exposures in adulthood.
Additional information on temporal trends comes from studiesof medical exposures in adulthood, such as therapy for cervical cancer [B12], cancer of the uterine corpus [C10] (in thiscohort, a considerable number of women were exposed at ages
over 65 years), benign gynaecological disease [I6], and ankylosing spondylitis [W2]. The first and last of these studies
found the ERR to decrease substantially about 10 years after
exposure. However, as in the study of patients with benign
gynaecological disease, most of the evidence for this decrease
related to CML, whereas the ERR for acute leukaemia(principally AML) was more stable with time since exposure.
These results are generally in accord with findings for CML
and AML incidence among the atomic bomb survivors [P4],as confirmed by a parallel analysis [L47] of these data in
combination with data from the cervical cancer [B12] andankylosing spondylitis [W2] studies. The combined analysis
showed some evidence overall of a decrease in the ERR for
AML with increasing time since exposure, but to a lesser
extent than for CML [L47]. In connection with this, it can benoted that acute leukaemias formed the majority of the nonCLL leukaemias in the study of uterine corpus patients, forwhom there was no clear trend in ERR with time since
exposure [C10].
277. Interpretation of the dose-response relationships instudies of groups exposed in adulthood to at least several grayis complicated by the effect of cell killing at high doses. The
degree of partial-body irradiation, fractionation, and dose rate
mayalso be relevant, while there is some suggestion (although5

2.5

Acute myeloid leukaemia

based on small numbers) that, for example, the joint effect onleukaemia risk of total-body irradiation and chemotherapy
may be more than additive [C9]. Table 30 presents resultsfrom modelling of the dose response for leukaemia (other than
CLL) in four large, well conducted studies with individual
dosimetry. These studies are based on patients treated for
cervical cancer, uterine corpus cancer, and ankylosing
spondylitis, plus the Japanese atomic bomb survivors. The
latter study accords with a linear-quadratic dose response over
the range 03 Gy, such that the risk per unit dose at low doses
is lower than at higher doses. Most of the evidence for thisnon-linearity arises for AML [P4]. However, a parallel
analysis of the atomic bomb data and those from the cervicalcancer and ankylosing spondylitis studies [L47] showed thatthe data for CML and ALL were also consistent with acurvilinear dose response over doses less than 1 Gy (seeFigure III). At doses above 34 Gy, the risk per unit dose
subsequently decreases. This effect is seen at lower doses inthe three studies of medical irradiation listed in Table 30.
However, while it appears to be particularly strong among theankylosing spondylitis patients (whose exposures were fromx rays given in fractions) and those uterine cancer patients
who received brachytherapy (radium implants) alone, it was
weaker for the cervical cancer patients, most of whom
received a mixture of brachytherapy and external radiation. In
addition, Table 30 shows that the estimated ERR at 1 Gy is
reasonablysimilar in the studies of the atomic bomb survivors,
the ankylosing spondylitis patients, and the uterine corpus
cancer patients given brachytherapy only, but higher than the
ERR at 1 Gy for the cervical cancer patients or for the uterine
cancer patients treated with external radiation. The risk
estimates included in Table 21 from three other large studiesof medical exposures in adulthood, namely of breast cancer
patients [C9], patients treated for benign lesions in thelocomotor system (e.g. arthrosis and spondylosis) [D12], andpatients treated for benign gynaecological disease [I6], are alsovariable, although they are lower than the risk estimates forthe atomic bomb survivors.

5

Acute lymphocytic leukaemia

2

1

RELATIVE RISK

3

1.5

1.0

0.5
Observed (95% CI)
Modelled
0
0

0.2
0.4
0.6
0.8
BONE MARROW DOSE (Sv)

1.0

3

2

1

Observed (95% CI)
Modelled

0

Chronic myeloid leukaemia

4

2.0
RELATIVE RISKRELATIVE RISK

4

347

0

0.2
0.4
0.6
0.8
BONE MARROW DOSE (Sv)

1.0

Observed (95% CI)
Modelled

0
0

0.2
0.4
0.6
0.8
BONE MARROW DOSE (Sv)

1.0

Figure III. Observed and modelled relative risk of acute myeloid, acute lymphocytic and chronic myeloid leukaemia
in a combined analysis of data for the Japanese atomic bomb survivors, women treated for cervical cancer, andpatients treated for ankylosing spondylitis [L47].
The values are specific to an attained age of 50 years, after exposure at 25 years,
and depict the dose-response at doses less than 1 Sv.

348

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

278. Reconciling these results is not straightforward. The
differing results on the effect of external irradiation and lowerdose-rate brachytherapy make it difficult to explain thefindings solely on the basis of dose rate. The possible effect oferrors in assessing bone marrow doses should also be borne inmind. However, one potential explanation relates to the degreeof partial-body irradiation. Most of the marrow doses for thecervical cancer and uterine corpus cancer patients were to thepelvis, sacrum, and lower lumbar vertebra only. However, asubgroup of the externally irradiated women in the uterine
corpus study who received substantial doses to the bonemarrow in both the central trunk of the body and the pelvic
marrow (as did the ankylosing spondylitis patients) had agreater risk (relative risk = 5.5; 95% CI: 2.015.1) than
women with more non-uniform exposures (relative risk =1.90; 95% CI: 1.13.2) (p-value for difference = 0.04) [C10].
Furthermore, the estimated ERR per Gy from the study ofSwedish patients treated for benign lesions in the locomotor
system [D12], in which exposures of the bone marrow werehighly non-uniform, appears from Table 21 to be lower thanthat from the studies of more uniform exposure, although no
confidence interval for the former estimate was given.
Another important factor concerns differences between
leukaemia subtypes. In a parallel analysis of the atomic bomb
survivor, cervical cancer, and ankylosing spondylitis studies,
Little et al. [L47] showed that there were statisticallysignificant study-to-study differences in the model fitted todata for all leukaemia other than CLL, but that the models
fitted to AML, ALL, and CML separately were consistentacross the studies. Therefore differences between studies inrange of ages at exposure and length of follow-up mayexplain
at least some of the variation in the observed risks.
279. Occupational studies have the potential to provide
information on how dose rate influences the risk ofleukaemia. In spite of leukaemia being one of the lesscommon cancers, the high ERR per unit dose and the often
shorter induction time relative to many other cancers
means that the comparison of leukaemia risks amongradiation-exposed workers with the risks in groups such as
the atomic bomb survivors may well be informative. The
UNSCEAR 1994 Report [U2] drew attention to the reportsof an association between leukaemia and radiation
exposure among workers at the Mayak facility in the
Russian Federation, some of whom received substantial
bone marrow doses from external gamma irradiation
several decades ago [K7]. It can be seen from Table 21 thatmost of the evidence for an elevated leukaemia risk relates
to workers at the radiochemical plant [K10]. Koshurnikova
et al. [K11] quoted a preliminary lifetime radiation risk
coefficient for men who started work at this plant before
1954 that was similar to that given by ICRP [I1] forworkers, although no confidence interval was given for theformer value. In interpreting these findings, it should beborne in mind that 10% of the cohort had been lost tofollow-up as of the end of 1994, although the cause ofdeath is known for 97% of deaths [K32]. Also, bonemarrow doses from plutonium have yet to be calculated forthese workers, although they are likely to be lower thanthose from external gamma radiation [K32].

280. In contrast to the radiation doses received by early
Mayak workers, occupational exposures received in various
countries in recent years have tended to be low. As aconsequence, studies of small groups of such workers havetended to produce varying results, reflecting their low
statistical power to detect small increases in risk. To obtaingreater statistical precision, it is therefore necessary toassemble as large a cohort with as long a follow-up as
possible. In Japan a cohort of nearly 115,000 nuclear
industry workers was identified [E3], but it could be
followed-up for at most five years, limiting the inferencesthat could be drawn about leukaemia risks. More powerful
information was derived from an international combined
study of nuclear industry workers in Canada, the United
Kingdom, and the United States [I2, C11]. This study was
based on a cohort of over 95,000 workers with individual
dosimetry for external radiation and over 2 million personyears of follow-up. As indicated in Table 21, the total
number of leukaemias is larger than in many of the otherstudies listed but the mean dose is lower. Analysis ofmortality from leukaemia (other than CLL) showed astatistically significant increasing trend in risk with dose.
The central estimate of risk per unit dose corresponded to
0.59 times the value estimated from the atomic bomb
survivors based on a linear dose-response model and 1.59
times the value based on a linear-quadratic model fitted tothe bomb survivor data; the corresponding 90% confidence
interval ranged from about zero up to four times the value
from the linear-quadratic bomb survivor model. The
evidence for a trend with dose was particularly strong for
CML, as has also been reported in a large study of workers
in the United Kingdom [M46, L20], some of whom were
included in the international study.
281. Several points should be noted when interpreting theresults of the international worker study [C11, I2]. First,
the statistical significance of the trend in the worker data
is based largely on a few cases with cumulative doses above
400 mSv [S24]. Dose-response analyses restricted to lower
doses do not show a significant trend, although theestimated trend from these analyses is compatible with thatfrom the full analysis [C11, C13]. However, the small total
number, nine, of estimated excess leukaemias should be
noted. Secondly, much of the evidence for a trend is basedon workers at a reprocessing plant at which there could
have been internal exposures not only to radionuclides but
also to chemicals. However, excluding workers judged tohave potentially received more than 10% of their dose fromexposure to neutrons or from intakes of radionuclides did
not affect the trend with dose. Indeed, while inspection of
the point estimates of the ERR per Sv from the various
facilities included in the study might suggest variability[S24], the findings are statistically consistent [C13]. Thisagain reflects the limited statistical precision of theindividual studies. Thirdly, dosimetry is an importantconsideration in a study that draws on data from different
countries and in which dosimetry practices have varied
over time. A dosimetry committee assembled for the
purposes of this study judged that the dose estimates weregenerally compatible, although bone marrow doses may

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

have been overestimated by about 20%, implying a slightunderestimation of the risk per unit dose [C11]. In
addition, as pointed out previously, random errors inascertaining doses are more likely to bias risk estimates
towards the null than away from it. To conclude, thisinternational study of radiation workers is valuable inaddressing the risks associated with low-dose and lowdose-rate exposures, and additional investigations of thistype should help to reduce uncertainties further.
282. Workers who took part in the recovery operations
following the Chernobyl accident often received doses of
0.10.2 Gy, i.e. greater than those currently being received
by many nuclear industry workers but lower than those of
the early Mayak workers. The study of recovery operation
workers from Estonia lacked statistical precision, owing to
the small cohort and limited follow-up; indeed no
leukaemia cases were identified, although one had been
expected from population rates [R20]. Further information
has been reported from studies of much larger numbers ofworkers from the Russian Federation. As previously notedin Section I.A, the interpretation of these findings depends
on the type of comparison. Ivanov et al. [I13] cited an
excess of leukaemia among these workers relative to rates
for the general Russian population; however, in a casecontrol analysis based on comparisons among recovery
operation workers, no significant correlations with dose orother aspects of their work were found [I14] (see Table 21).
This difference is likely to be due to differences inmethodology; in particular, to a probable bias in the cohort
study [B27].
283. The study of natural background radiation in the
Yangjiang area of China did not show a statistically significant association with leukaemia over all ages [T25, T26]
(see Table 21). A subgroup analysis based on an earlier
follow-up suggested an excess of leukaemias in the firstyear of life, but based on very small numbers (threeobserved compared with 0.4 expected from population
rates) and on mortality rather than incidence data [A11].
A small study in Italy found no positive association
between adult myeloid leukaemia and levels of backgroundgamma radiation measured in homes, in contrast to earlier
suggestions of such an association based on geologicalinferences of the natural radiation dose levels [F7].
284. Information on the incidence of leukaemia amongpeople living near the Techa River was considered in the
UNSCEAR 1994 Report [U2]. Both external and internal
exposures were received by these individuals. As indicatedpreviously, these investigations are potentially importantsources of risk estimates, particularly for leukaemia.
Emigration from this area, the possiblyconfounding effects
of toxic chemicals around the Techa River, and thereconstruction of individual doses are issues pertinent torealizing this potential. Kossenko et al. [K5] noted that thefraction of the total number of deaths due to leukaemia in
the Techa River cohort is slightly higher than thecorresponding fraction in the Life Span Study. While thisresult may reflect differences between the cohorts in the349

level and type of exposure, the inclusion in the former cohortof leukaemias identified from a wide range of sources may
also have influenced the finding [K5]. Studies relating tocontamination as a result of the Chernobyl accident are
addressed in the Section on internal exposures, althoughagain, both internal and external exposures were received. In
contrast, doses to persons exposed to nuclear weapons test
fallout in southwestern Utah in the United States were mainly
from external radiation. The study of this group, which was
discussed in the UNSCEAR 1994 Report [U2], found an
association between bone marrow doses from fallout andleukaemia mortality [S17]. This association was restrictedprimarily to acute leukaemia before the age of 20 years
following the period of highest exposure, although theindication of a similar level of risk for CLL in adults may
suggest caution in interpreting these findings.
285. Findings from another study at low doses were reported
by Boice et al. [B39], who undertook a case-control study ofdiagnostic x-ray procedures. Relative to persons for whom nosuch procedures were recorded within two health plans, therelative risk of leukaemia (other than CLL) associated withdiagnostic x rays was 1.42 (95% CI: 0.92.2), based on a twoyear lag. There was no significant trend in risk with thenumber of procedures, although individual estimates of organ
doses were not available [B39].
286. Information on the risks of leukaemia and other cancers
from irradiation in utero was summarized in the UNSCEAR
1994 Report [U2]. The topic is considered in more detail in
Annex G, “Biological effects at low radiation doses”. Briefly,
various case-control studies of childhood cancer, including
leukaemia, have shown elevated relative risks associated withobstetric x-ray examinations of pregnant women of the orderof 1.41.5 [D17]. Although the relative risk from the Oxford
Survey of Childhood Cancers in the United Kingdom, inparticular, has high statistical precision, concerns have beenraised, most recently by Boice and Miller [B41], about thepossibilityofbias and confounding. Several of these points, forexample, the apparent disparity between the findings of casecontrol and cohort studies and the similarity of the relative
risks for leukaemia and other cancers, have been consideredby Doll and Wakeford [D17]. With respect to these specificpoints, Doll and Wakeford cited problems with some of thecohort obstetric x-ray studies, and noted that the cells that giverise to most childhood cancers other than leukaemia persist
and are capable of dividing for only a short time, if at all, after
birth [D17]. The doses received in the studies of obstetric
x rays are somewhat uncertain, but the mean values are likely
to have been 1020 mGy. It is notable that studies ofchildhood leukaemia following another type of obstetricexamination, namely ultrasound, have not shown elevatedrisks; for example, a recent national case-control study in
Sweden using prospectively assembled data on prenatal
exposure to ultrasound reported relative risks close to 1 [N16].
The other main source of information on leukaemia following
in utero irradiation comes from atomic bomb survivors
exposed in utero. Delongchamp et al. [D14] have reported
some evidence of elevated leukaemia mortality in this grouprelative to controls in the period from October 1950 to May

350

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

1992, although based on only two deaths. No additional
leukaemia cases were reported in an earlier analysis of cancer
incidence [Y1]. In contrast to survivors exposed in childhood,there was no increasing trend in leukaemia risk with doseamong the in utero-exposed survivors, owing to the absenceof deaths at high doses [D14]. Indeed there were no leukaemia
deaths at ages less than 15 years among those exposed inutero. However, the low statistical precision associated withthe small numbers in this group should be noted. Overall, theavailable evidence points to an elevated leukaemia risk fromin utero irradiation, although there is uncertainty over its
magnitude.
287. Some studies of childhood leukaemia in relation topaternal preconception irradiation were also mentioned in the
UNSCEAR 1994 Report [U2]. Although a case-control study
in West Cumbria in the United Kingdom [G7] suggested an
association between paternal preconception irradiation andleukaemia in the offspring of workers at the Sellafield plant,
this finding was specific to workers in the village of Seascalenear Sellafield and was not seen among the offspring of other
Sellafield workers with similar preconception doses [H6].
Furthermore, the paternal preconception irradiation result was
not replicated in subsequent studies of the children ofradiation workers in Scotland [K2] or Canada [M16], and noleukaemia excess has been observed among offspring of theatomic bomb survivors [Y2]. A large study found an elevatedrisk of leukaemia in the children of nearly 120,000 maleradiation workers in the United Kingdom compared withother children (relative risk = 1.83; 95% CI: 1.113.04);
however, no association was found between leukaemia risk
and levels of paternal preconception irradiation [D24]. In a
study based on a cohort of nearly 40,000 children of malenuclear industry employees in the United Kingdom, which
included workers in the just-mentioned study [D24], theincidence of cancer was found to be similar to national rates[R29]. In this instance, the only suggestion of an elevated risk
was based on three cases with total preconception doses of atleast 100 mSv [R29], two of which had already been reported
in the study in West Cumbria [G7]. In reviews of this topic,
Little et al. [L18] and Doll et al. [D10] concluded that theinconsistencynot onlywith the other epidemiological data but
also with experimental data makes it highly unlikely that theassociation observed at Seascale represents a causal relationship.
2. Internal low-LET exposures
288. A study of leukaemia incidence among nearly 47,000
patients in Sweden given 131I for thyroid cancer,
hyperthyroidism, or diagnostic purposes [H12], mostly inadulthood, was considered in detail in the UNSCEAR 1994
Report [U2] (see Table 21). Although there was no evidenceof an association between bone marrow dose and leukaemia
in this study, this may reflect a lack of statistical power
associated with the generally low doses (mean 14 mGy). Ronet al. [R14] studied leukaemia mortality among
hyperthyroidism patients, mostly from the United States, in
relation to estimated bone marrow dose from 131I therapy.
There was no evidence of a trend in risk with dose, either forleukaemia excluding CLL (see Table 21) or CLL alone,although the generally low doses (mean of 42 mGy) limited
the precision of this analysis [R14]. Statistical precision waseven more of a concern in a study of thyroid cancer patientsin France [D18], for which, even though the mean bonemarrow dose was similar in magnitude (34 mGy), the cohortof 1,771 patients was much smaller than in the
aforementioned studies. Although no leukaemias wereobserved in the French study, the number expected fromnational rates was only 1.28 [D18].
289. The European Childhood Leukaemia-Lymphoma
Incidence Study (ECLIS), set up to monitor trends in rates
following the Chernobyl accident, has examined data up to
the end of 1991 from 36 cancer registries in 23 countries,
including Belarus and parts of the Russian Federation [P12].
This is a geographical correlation study, in which doses andrisks have been assessed for geographical areas rather than on
an individual basis. As pointed out earlier, this approach may
give rise to methodological problems and is not suitable forderiving risk estimates, although it does permit a generaldescription of disease rates. The latest report from ECLIS
found an overall increase in age-standardized rates ofchildhood leukaemias during 19801986, which continued atabout the same rate during 19871991 [P12]. No correlation
was found with the geographical distribution of effective dose
due to fallout from the accident, based on values published in
the UNSCEAR 1988 Report [U4]. In view of the very low
bone marrow doses received in most of the areas studied(generally less than 1 mSv), this finding is not surprising.
Indeed, to have any hope of detecting very small elevatedrisks, large studies such as this are required. In contrast,
smaller studies often give variable results. For example,
Petridou et al. [P15] reported an elevated risk of infantleukaemia in Greece among those in utero at the time of orsoon after the Chernobyl accident. However, not only was thisfinding based on a subgroup analysis involving only 12 cases
diagnosed in the first year of life, but it is inconsistent with theresults of obstetric x-ray studies [U2]. Other small studies,such as those in Finland [A6], Sweden [H22], and Romania[D26], have not shown an association between childhood
leukaemia and Chernobyl fallout. In Germany, Michaelis etal. [M30] reported an increased risk of infant leukaemia
among those in utero at or soon after the time of the accident
relative to those born at other times. However, this increase
was, if anything, highest in those regions with the lowest
levels of contamination, and the authors concluded that inutero exposure was not a cause of the elevated risk [M30,
S53]. A study in Belarus [I22] has shown that the relative risk
for infant leukaemia, while it is greater than 1, is not elevatedto a statistically significant extent and is lower than thecorresponding values from the studies in Germany [M30] andGreece [P15]. The issue of infant leukaemia following theChernobyl accident is being examined further using the muchlarger ECLIS database [P25].
290. While much of the dose to those in western Europe
from the Chernobyl accident arose from external exposures,internal exposures may have been more important closer to
Chernobyl. Ivanov et al. [I5] reported similar rates of acuteANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

leukaemia among children in areas of Belarus with varying
levels of radionuclide contamination. Furthermore, in ananalysis of aggregated data from contaminated areas ofBelarus, the Russian Federation, and Ukraine, Prisyazhniuk
et al. [P16] showed that while age-adjusted leukaemia rates
rose from 1980 to 1994, this trend appeared to be similar forthe periods before and after the Chernobyl accident; also, rates
were similar in areas with different levels of contamination.
291. There has been interest in recent years in reports ofcancer clusters in the vicinityof nuclear installations. Many ofthese reports were considered in the UNSCEAR 1994 report[U2] (see also [M34]). In the United Kingdom, excesses ofchildhood leukaemia have been reported around some nuclear
sites, in particular, the Sellafield [C28] and Dounreay [C29]reprocessing plants. However, environmental assessmentssuggest that these findings are unlikely to be attributable toradioactive release from the sites. Indeed, while exposuresassociated with these sites often comprise a mixture ofexternal and internal low-LET and internal high-LET
exposures, they have been assessed to be generally less in total
than exposures from natural radiation [C28, C29]. Elsewhere,studies in, for example, the United States [J1], Canada [M35],
France [H40], western Germany [K25], and Japan [I15], havetended not to show excesses of cancer around nuclear
installations, specifically of childhood cancer and/or
leukaemia in some instances. Some exceptions have beenreported; for example, Wing et al [W14] cited an excess ofleukaemia around the Three Mile Island nuclear power plantin the United States. However, as indicated earlier in relation
to lung cancer, Hatch et al. [H37, H38] interpreted their
original analysis of these data as not providing convincing
evidence of an association with the very low doses resulting
from radiation emissions from the plant.
292. It should be borne in mind that inferences from studies
around nuclear installations are limited by their geographicalnature, the very small doses involved, and, as around some of
the United Kingdom sites, for example, the relatively small
numbers of cases. There are also difficulties in interpretation
with the differing analyses performed; for example, withrespect to age (04, 014, or 024 years), diagnostic category(leukaemia, leukaemia and NHL, all cancers), time period,and proximity to the installation. When many different
analyses are performed, it would not be surprising to obtain astatistically significant finding, i.e. one that would arise 1 in
20 times by chance alone. The unavailability of data can alsopresent a problem; for example, the ascertainment ofchildhood leukaemias may be incomplete owing to a lack ofnational incidence data [H40], or small-area data may not be
available, e.g. as in parts of the United States studied by
Jablon et al. [J1]. Some of these problems can be addressed
through case-control or cohort studies, which collect data at
the individual level. As mentioned earlier, the case-control
approach has been valuable in addressing the issue of paternal
preconception irradiation [D24]. However, difficulties can stillarise in this type of study. For example, Pobel and Viel [P7]suggested an association between childhood leukaemia andthe use of beaches around the La Hague reprocessing plant inFrance. However, this result was dependent on a small

351

number of cases, relied on the recall of habits stretching backseveral decades, and involved multiple comparisons [C30,
L38]. Furthermore, no such association was found around the
Sellafield plant in the United Kingdom [G7].
3. Internal high-LET exposures
293. It has been suggested that uptake of radon by fat cells
in the bone marrow might lead to irradiation of thehaematopoietic stem cells [R10], and there have been someindications from geographical correlation studies, based onlarge-area data, of an association between radon exposurein dwellings and leukaemia [H14]. However, this suggestion has not been replicated in geographical studies
using small-area data and more refined analyses [M13,
R6]. More weight might be given to a large case-control
study in the United States by Lubin et al. [L34] thatcollected data on an individual rather than a geographicalbasis (see Table 4 for details). No evidence was found of an
association between acute lymphoblastic leukaemia inchildhood and individual assessments of indoor radon
exposure. In particular, for time-weighted average radon
concentrations in excess of 148 Bq m 3, the relative risk
compared with concentrations of less than 37 Bq m3 was
1.02 (95% CI: 0.52.0) based on matched case-control
pairs [L34]. A study of childhood acute myeloid leukaemia
in the United States [S52] and smaller studies of childhood
cancers in Germany [K38] and of acute myeloid leukaemia
in Italy [F7], all of which involved measurements of radonin homes, also did not show associations with leukaemia
risks overall.
294. To test for any association between radon and the riskof cancers other than lung cancer in a study with individual
dosimetry, Darby et al. [D8] performed a collaborative
analysis of data from 11 cohorts of underground miners.
Further details of the component cohorts are given in
Table 4, and Table 21 contains some results for leukaemia.
The combined cohort was very large (over 64,000 men)with over 1 million person-years of follow-up. There wasan excess in mortality from leukaemia of all types relative
to national or regional rates within 10 years of first
employment (SMR = 1.93; 95% CI: 1.192.95, based on
21 deaths). However, restricting the analysis to the period
when the 8th and 9th revisions of the International
Classifications of Diseases were in operation, so thatleukaemia subtypes could be distinguished, there was noevidence of an elevated level of leukaemia other than CLL(SMR = 1.28; 95% CI: 0.512.64, based on seven deaths).
The leukaemia subtype with the highest SMR was acute
myeloid leukaemia (SMR = 2.42; 95% CI: 0.512.64),
although based on only three deaths. Perhaps of greaterinterest than SMRs were analyses in relation to cumulative
radon exposure which, although based on small numbers,
showed no trend in the risk of all leukaemia, leukaemia
excluding CLL, or AML. More than 10 years after first
employment, there was no indication of an elevated SMR,
either for all leukaemias or specific subtypes. The possibly
elevated SMR in the earlier period may well be due tochance, since agents encountered in mines, such as diesel

352

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

fumes and arsenic, are thought not to be leukaemogens,and the levels of gamma radiation in mines, although notalways known, are likely to be too low to explain this result[D8]. The study therefore provides evidence that highconcentrations of radon in air do not cause a material riskof leukaemia mortality.
295. An elevated level of leukaemia, in particular, myeloid
leukaemia, was reported in studies of thorotrast patients inGermany [V8], Denmark [A4, A5], Portugal [D31], andJapan [M14]. Results from these studies are summarized inTable 21. Andersson et al. [A4] showed that the risk of
AML and myelodysplastic syndrome increased in relation
to cumulative dose, having taken account not only of theamount injected but also the time since injection. There
was also a suggestion of a cell-killing effect at high doses,
although this was not statistically significant. Based on amean bone marrow dose of 1.3 Gy (high-LET), Andersson
et al. derived a risk estimate for these diseases of 1.7
102 Gy1. While this suggests that the RBE of alpharadiation relative to low-LET radiation may be lower thanthe value of 20 recommended by ICRP [I1], it should be
noted that the latter value was chosen to apply at low
doses, rather than that at the high doses in this study.
Furthermore, there are uncertainties in the risk estimate
derived by Andersson et al. [A4] owing to the relatively
small number of cases and imprecision in the estimation ofindividual doses. Hunacek and Kathren [H33] comparedpublished risk coefficients with values determined fromdose rates based on post-mortem radiochemical analysis oftissues from a thorotrast patient. Using results fromthorotrast studies in Germany, Japan, and Portugal (but not
Denmark), theyobtained a leukaemia risk coefficient of 3.2
102 Gy1 [H33], which is somewhat higher than that
calculated by Andersson et al. [A4]. However, the former
value is likely to be incorrect, owing to an error in
calculating bone marrow dose rates based on data for the
total skeleton. Furthermore, new dose calculations indicatethat the bone marrow dose had been previously
underestimated and that the risk per unit dose had been
overestimated [I25].
296. There is some evidence for an excess of leukaemia
among patients injected with 224Ra [N4, W20], with one ofthese studies [W20] indicating an excess more than 30 years
after the first injection of 224Ra. However, inferences are
restricted by the generally small number of cases and theabsence of dose-response analyses. Among radium dial
workers in the United States, the number of leukaemias
observed was close to that expected in the general population[S7]. Although it has been suggested that the cases among
pre-1930 dial painters arose early [S54], the small numbers inboth this analysis and an analysis by bone marrow dose [S7]limit the interpretability of these data.
297. No leukaemias have been observed in the offspring ofDanish thorotrast patients [A13]. Although this study was

based on a small cohort, its statistical power was enhancedby the high doses to the testes from alpha radiation (meandose = 0.94 Sv).
4. Summary
298. There is a substantial amount of information on therisks of leukaemia from radiation exposure. This reflects
the high relative increase in risk compared with othercancer types and the temporal pattern in risk, with many ofthe excess leukaemias occurring within about the first two
decades following exposure, particularly among those
irradiated at young ages. There are some differences
between the Life Span Study of atomic bomb survivors andsome large studies of medically exposed groups inestimates of both the magnitude of the radiation risk andthe shape of the dose response for external low-LET
exposure. These findings may reflect differences between
studies in the uniformity of exposure to the bone marrowand in the degree of fractionation and protraction of
exposure, as well as differences in the pattern of risk
between leukaemia subtypes. There is clear evidence of
non-linearity in the dose response for leukaemia, which hasa slope that decreases at lower doses.
299. A large international study of radiation workers
suggested an elevated leukaemia risk, although the results
were compatible with a range of values. Case-control
studies of prenatal x rays indicate an increased risk ofleukaemia in childhood due to in utero irradiation,although the absence of a dose-related increase in thesparse corresponding data for atomic bomb survivors adds
uncertainty to the magnitude of the risk. Epidemiologicalevidence does not suggest that irradiation prior toconception gives rise to a material risk of childhood
leukaemia.
300. The data available on internal exposures to low-LET
radiation do not indicate elevated risks of leukaemia; thismay well reflect the low statistical precision associatedwith generally small doses. There is no convincing
evidence of an increased risk of leukaemia due toenvironmental exposures associated with the Chernobyl
accident, although investigations are continuing. Excessesof childhood leukaemia have been reported around somenuclear installations in the United Kingdom, but generally
not in other countries; these excesses are based on small
numbers of cases and have not been explained on the basisof radioactive releases from the installations. Dose-related
increases in leukaemia risk have been seen among patientswith large exposures to high-LET radiation arising frominjections of thorotrast, a diagnostic x-ray contrast
medium. There is less evidence for elevated risks among
patients injected with 224Ra and little or no evidence forincreased risks among radium dial workers or from studies
with individual assessments of radon exposure, either inmines or in homes.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

353

IV. LIFETIME RISK FOR TOTAL CANCER

303. As an example of an analysis based on a collection ofcancer types, Figure IV shows estimates of the ERR per Sv for
various types of solid cancer in survivors of the atomic
bombings based on the most recent mortality data [P9]. These
values have been adjusted for age at exposure and gender.
Pierce et al. [P9] noted that the variation in the ERR per Sv
between cancer sites is not statistically significant. However,they cautioned that this should not be taken as substantial
evidence that the ERR per Sv is the same for all sites, given
the differences in aetiology for different cancer types.
Furthermore, the ERR is only one scale of representation, andthe EAR per Sv should also be considered. However, because
the baseline rates vary for different types of solid cancer, theEAR per Sv is likely to vary much more widely between
cancer types than the ERR per Sv.
304. The increased statistical precision associated with ananalysis of all solid cancers assists in the development of risk
models. In particular, it may be possible to detect variations inrisk with factors such as age, time, and gender that are notapparent in data for specific cancer sites. For example,
Figure V summarizes models fitted to data on mortality fromall solid cancers for the Japanese atomic bomb survivors [P9].
This indicates variations in the ERR per Sv and EAR per Sv
with gender, age at exposure, and attained age that may not be
evident in analyses for specific cancers. However, it should berecognized that such models might be affected by differences
between cancer types in the pattern of risk. On the other hand,as previously mentioned in Section I.E, analyses conducted
separately for various cancer sites may yield differences intrends in risk with, for example, age and/or time, simply as aconsequence of chance variations. One possibility, suggested
by Pierce and Preston [P6], is to analyse data for various
cancer sites, or groupings thereof, in parallel. This may allow
the development of models for which the level of the relativerisk, for example, differs between cancer types but underwhich the variation with factors such as age and time is thesame across cancer types.

2.5
2.0
1.5
1.0
All solid cancers
0.5

OTHER SOLID

BLADDEROVARYUTERUS

BREASTLUNG

PANCREASGALLBLADDERLIVERRECTUM

COLON

STOMACH0

OESOPHAGUS

302. The estimation of total cancer risks is in some ways
easier than the estimation of risks for specific cancer sites.
The most notable difference is the larger number of cancers
available from epidemiological studies of all cancers. Thismeans that the statistical precision of estimates based onsuch data should be greater than the precision for specificcancers. On the other hand, heterogeneity in risks between
cancer types may counterbalance this. Indeed, “cancer” isa multitude of different diseases with different aetiologies.

3.0

EXCESS RELATIVE RISK AT 1 Sv

301. In Chapter III the focus was on risks for specific cancer
sites. The aim in this Chapter is to develop risk estimates for
total cancer, in line with previous assessments of theCommittee, most recently in the UNSCEAR 1994 Report[U2]. Many of the issues associated with producing such
estimates were discussed in Chapters I and II. However, someof them are summarized here, together with points that are
germane to total cancer risks.

Figure IV. Excess relative risk (and 90% CI) for
mortality from specific solid cancers and all solidcancers together (horizontal line) in survivors of theatomic bombings, standardized for females exposed atage 30 years [P9].

305. Related to the above considerations is the issue of
whether one or more data sets should be used to estimate
total cancer risks. Artefactual differences might arise ifdifferent data sets are used for different cancer types.
However, this should be balanced against the quantity ofdata for a particular cancer type that is available from agiven study. Indeed, some studies, such as case-control
studies, have focused on only one or a few cancer sites andtherefore cannot be used by themselves to estimate totalcancer risks.

A. EXPRESSIONS OF LIFETIME RISK
306. There is some confusion in discussions andpresentations of lifetime risks associated with radiation
exposure. To simplify matters, the following discussion isrestricted to mortality, and it is assumed that there are twocauses of death: “cancer” and “non-cancer”. However, thediscussion can be generalized to deal with incident cases
and multiple causes, any number of which may be affectedby exposure.
307. The obvious definition of a lifetime risk is simply thedifference between the proportion of people dying of cancer
in an exposed population and the corresponding proportion
in a similar population with no radiation exposure. Thisdifference is called the excess lifetime risk (ELR). Formal
mathematical expressions for the ELR and related
quantities are given by Thomas et al. [T18].

354

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

308. While the ELR is of some value, it provides anincomplete summary of the effect of exposure on a
population. This can be seen most clearly by considering
death from any cause as the outcome of interest. In thiscase the ELR must be zero, since all people will eventually
die of something, even if radiation changes the risk ofdeath. However, the ELR is also misleading for causespecific mortality. If exposure has the same relative impact
on death rates for all causes, then cause-specific ELR
estimates will be zero. In contrast, suppose that radiation
increases the risk of death for cancer by some fraction but
also increases the risk of death from non-cancer causes bya smaller amount. In this instance, the ELR for cancer
deaths will be positive, while that for non-cancer deaths
will be negative, even though radiation exposure increased
non-cancer death rates.
309. One way to address problems with the ELR is toconsider how exposed and unexposed populations differ
with respect to the expected age at death for all causes
or for specific causes of death. However, average life
expectancies (or more comprehensive summaries of the
distribution of ages at death) are difficult to interpret
without a clear understanding of the general pattern ofdeath rates in a population. In particular, what might beconsidered fairly large increases in death rates areassociated with rather small changes in life expectancy.
For example, based on death rates in the United Statesfor 1985, a 50% increase in all-cause mortality for 20years old would reduce their life expectancies by about
three years. As another illustration of the problem withchanges in life expectancy, consider a situation in which
an exposure reduces life expectancy from 75 to 25 years
for 1% of the population, for example, as a consequenceof leukaemia following an exposure of 1 Gy. In thisinstance, the average life expectancy for the population
would be reduced by 6 months. In general, changes inlife expectancy are not a particularly useful summary of
the exposure effects. To be useful, loss of life expectancy(LLE) should be related to some measure of the numberof people whose life expectancy was affected by the
exposure.
310. A useful alternative to the ELR can be developed byconsidering the (cause-specific) death rate defined by thedifference in death rates for exposed and unexposed
populations as an additional cause of death that has been
introduced into a population. Technically this difference is
not a rate function, since it would assume a negative value
if exposure had a protective effect. However, by treating thedifference as a rate, one can compute the fraction of deaths
attributable to this “new” cause of death or the probability
that an individual will die from a cancer associated withthe exposure. This quantity has been described in [U2,
T18] as the risk of exposure-induced death (REID). In
contrast to the ELR, the REID is positive if exposure
increases death rates and negative if exposure decreases
death rates. Furthermore, cause-specific values of the REID
are zero for any cause for which the rates are not affectedby exposure.

311. The values called excess deaths in recent analyses of
the atomic bomb survivor data (e.g. [P9]) are closely
related to the REID. In particular, the Life Span Study
excess deaths are the sum of REID estimates over thefollow-up period, having allowed for gender, age at
exposure, and dose, with population background rates
determined by the experience of the cohort. The REID
estimates presented later in this Chapter are computed
using background rates from populations other than theLife Span Study, and they estimate the number of excess
deaths for lifetime follow-up after exposure.
312. As in the UNSCEAR 1994 Report [U2] and recent Life
Span Study reports, the quantity LLE divided by the REID,
which can be thought of as the change in life expectancy per
attributable case, provides a helpful summary of the impact of
exposure on life expectancy. In the example given earlier, inwhich 1% of the population is affected, the change in life
expectancy per attributable case is 50 years (i.e. 0.5 years/0.01), which is in line with expectations.
313. Mortality computations are, in principle, relatively
straightforward; further details were given in the UNSCEAR
1994 Report [U2]. Gender-specific, age-dependent baseline
total- and cause-specific death rates for the populations ofinterest are used to define the baseline survival probability
function. For a given age at exposure, gender-specific excess
rates for causes affected by radiation are added to theappropriate cause-specific baseline rates to give the causespecific and total rates for the (hypothetical) exposed
population. Conditional on age at exposure, these adjusted
total rates define the age-specific survival probability in the
exposed population. The risk measures of interest, namely, theELR, REID and LLE, can be computed from these conditional
survival probabilities and cause-specific disease rates.
314. For lifetime incidence computations, the gender- andage-specific survival probabilities for the unexposed
populations are replaced by cancer-free survival probabilities.
These functions are computed from gender- and age-specificrate functions defined as the sum of the total non-cancer death
rate and the total cancer incidence rate. The total non-cancer
death rate is defined as the difference between the total death
rate and the total cancer death rate.

B. METHODS AND ASSUMPTIONSOF CALCULATIONS
315. The results presented here are derived from causespecific attributable risks and the loss of life expectancy per
attributable case in five populations: China, Japan, Puerto
Rico, the United States, and the United Kingdom. Lifetime
mortality risks are computed for the following cancers:
oesophagus, stomach, colon, lung, liver, female breast,
bladder, other solid cancers, and leukaemia, as well as allother (non-cancer) causes. For incidence, radiation effects on
the risk of thyroid cancer are also considered. In thecomputations presented here, it is assumed that all organs
receive the same dose. If exposure is limited to a single organ,355

risks for that organ would be only slightly larger than theorgan-specific risks discussed below. Even in a whole-body
exposure it will be the case that different organs receive
different doses; however, the differences in dose-specific risks
between those from the joint computa-tion and those from acomputation based on the actual doses to each organ will not
be large. For example, in a situation in which the breast
receives a dose of 1 Gy and the stomach a dose of 0.8 Gy,
estimates of the breast cancer risk following a whole-body
1 Gy exposure and of the stomach cancer risk following a
0.8 Gy whole-body exposure will be good approximations to
the actual organ-specific risks.

a+l) to the length of the interval (l), given that one is aliveat a. The hazard function in the absence of radiation exposure
will be called the baseline hazard. It is reasonable to allow thebaseline hazard, denoted as h0(a,s,p), to depend on gender (s)and calendar time period (p) in addition to age. One way todescribe the effect of a radiation exposure is to consider thedifference between the hazard function in the exposed
population and the baseline hazard for this population. Thisdifference is the excess absolute risk (EAR). The ratio of theEAR to the baseline hazard is the excess relative risk (ERR).

316. Risk estimates for mortality are also given for Chineseand Puerto Rican populations. These estimates make use oflife-table and death-rate information given by Land andSinclair [L12]. In these instances, the computations werecarried out in terms of three “causes”: non-cancer deaths, nonleukaemia cancer deaths, and leukaemia deaths.

EXCESS RELATIVE RISK AT 1 Sv

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

(a)

(b)
(c)

(d)

(e)
(f)

the exposed population for which risk estimates aredeveloped, and the models used to describe the excess
risks in this population;
the models used to describe risks at low doses;
the method used to extend the excess risk models
beyond the period of observation for the populationfrom which these models were developed;
the cause-specific mortality (or incidence) rates andthe age structure of the populations to which the rates
are applied;
the methods used to transport excess risks based onmodels for one population to another population; andthe method used to allow for fractionation or doserate effects.

Excess relative risk

Age at exposure: 10, 30, 50 years
Males
Females

1.5
10
1.0

30

0.5

50

0
30

40

50

60

70

80

90

AGE (years)
50
EXCESS CASES PER 10,000 PY AT 1 Sv

317. Primary results are given for uniform whole-body
exposures of 0.1 and 1 Gy for men and women exposed at 10,30, or 50 years of age. These results depend on the following
factors, each of which are discussed briefly below:

2.0

Excess absolute risk

40

30
30

50

20

10

10

Age at exposure: 10, 30, 50 years
Males
Females

1. Risk models
0318. As in the UNSCEAR 1994 Report [U2], the risk
estimates derived in this Section are based on recent data on
the experience of the atomic bomb survivors. The data from
Life Span Study Report 12 [P9], which covers the period from1950 through 1990, were used for the estimation of causespecific mortality risks for solid cancers. Solid cancer
incidence risk estimates are based on linking the Life Span
Study survivor cohort and the Hiroshima and Nagasaki
tumour registry data [M2] for 1958 through 1987 [T1]. The
cause-specific solid cancer mortality and incidence rate
models used here were developed specifically for thesecomputations. The method used to estimate risks at low doses
is discussed in detail below.
319. Radiation effects are often described by models forcause-specific death rates or hazard functions. The hazard
at age a is defined formally in terms of the ratio of theprobability of dying from the cause in a short interval (a,

30

40

50

60

70

80

90

AGE (years)

Figure V. ERR and EAR for solid cancer mortality
among survivors of the atomic bombings in Japan[P9]. The lines show the patterns of risk in the data.

320. The leukaemia EAR model developed by Preston etal. [P4] was used to describe the effect of radiation onleukaemia risks in both the mortality and incidence
computations. To allow for excess leukaemia risks during
the first few years after exposure (about which the Life
Span Study data provide no direct evidence), it is assumed
that excess rates for the first five years are half of thoseseen five years after exposure.
321. Two types of ERR models were developed for solidcancers. These models are similar to those considered by
Pierce et al. [P9] (see Figure V). In the first model, the356

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCERERR depends on gender and age at exposure. For this ageat-exposure model, the cause-specific hazard rate has the
form
LSS

hd

(a,s,e,()  h0

LSS(() [1  β θs d exp (γ e)]322. In the model presented here, the baseline hazard, i.e.
the hazard in the absence of radiation exposure, denoted
here by h 0(a,s,p), depends on age (a), gender (s), andcalendar period (p). The dose-response slope is allowed todepend on gender and, for non-gender-specific cancers, isdescribed in terms of the product of the slope for males(βM) times a gender ratio parameter (θF:M). Unless there wasevidence of a significant lack of fit, the gender ratio andage-at-exposure (e) effects were assumed to be equal tothose for all solid cancers as a whole. Lack of fit was
defined as a deviance change [M38] of more than 4 for asingle parameter or more than 6 for both parameters.
323. Under the second solid cancer risk model, the ERR
depends on gender and attained age (i.e. age at death orcancer incidence, denoted by a) but not on age at exposure.
For this attained-age model, the cause-specific hazard rate
has the form
LSS

hd(a,s,e,()  h0

LSS(()[1  β θs da k]

in which the temporal variation in the ERR is modelled asa power function of attained age. As with the age-atexposure model, the gender ratio and attained-age effects
were taken to be equal to those for all solid cancers as agroup unless there was evidence of a significant lack of fit.
324. The site-specific solid cancer ERR parameters for the
mortality and incidence models are summarized in Table 31.
For each site of interest and each model, the Table presents
the gender-specific ERR per Gy estimates, together with thegender ratio (female:male) and the age-at-exposure andattained-age effects. The age-at-exposure effect is given as thepercentage change in risk associated with a 10-year increasein age at exposure. The attained-age effect is the power of age.
For the age-at-exposure model, the gender-specific estimatesof ERR per Gy are for a person exposed at age 30 years. For
the attained-age model, they are the ERR per Gy estimates fora person at attained age 50 years.
2. Low-dose response
325. The issue of cancer risks at low doses is discussed indetail in Annex G, “Biological effects at low radiation
doses”. Among the points covered there are the minimum
doses at which statistically significant elevated risks havebeen detected in epidemiological studies. As mentioned
earlier in this Annex, the minimum doses for detectableeffects depend on the statistical precision of the relevant
study and can also be influenced by any potential bias in
the study. While statistically powerful studies can allow
effects to be detected at lower doses than small studies,

there will be some small doses at which it will not be
possible to detect an elevated risk. It is difficult to specify
values at which no study will be able to identify an effect,
given that, for example, further follow-up of groups suchas the Japanese atomic bomb survivors will continue toincrease in statistical power and so aid the future
investigation of low-dose risks. However, the results citedin Annex G, “Biological effects at low radiation doses”,
give some idea about minimum doses at which elevatedrisks can be seen at present.
326. Pierce et al. [P9] reported a statistically significant
increasing trend in mortality risks in the 050 mSv range forall solid cancers combined among the Japanese atomic bomb
survivors, based on follow-up to 1990. However, they also
noted that the interpretation of this finding is notstraightforward, since it reflects an increasing risk per unit
dose in the low dose range not seen for cancer incidence inthe survivors [T1]. Observed cancer death rates are increased
by about 5% for survivors with doses in the 2050 mSv range,
which is larger than the roughly 2% increase predicted atthese doses by linear models fitted to the full dose range.
Pierce et al. [P9] suggested that this difference might be due
to differential misclassification of cause of death, i.e. a slightbias towards recording cancer rather than other causes on thedeath certificate for atomic bomb survivors who are known tohave been relatively close to the hypocentre. This illustrates
how potential biases, while small in absolute terms, can affectthe interpretation of low-dose risks. Dose-response relationships for the atomic bomb survivors are discussed further
below.
327. Several authors [C35, L40] have raised questions on
the statistical support for the low-dose findings in [P9].
However, as indicated by Pierce et al. [P28, P36], thestatistical result at low doses is quite robust, although as
noted earlier, the relatively small effects in this dose range
mean that small biases could distort the inferences about
the low-dose response function.
328. Annex G, “Biological effects at low radiation doses”,
refers to some other studies that provide information onminimum doses for detectable effects. It should be noted thatit may be easier to detect elevated risks for particular types ofcancer or in specific age-at-exposure groups for which, owing
to low background rates, small absolute increases in rates maylead to large relative risks. For example, in a combined
analysis of data from seven studies of thyroid cancer after
external radiation exposure, Ron et al. [R4] found that a linear
dose response provided a good fit to the data on childhood
exposure, not only at high doses but also down to 0.1 Gy (lowLET). Annex J, “Exposures and effects of the Chernobyl
accident”, also reviews studies of childhood cancer following
irradiation in utero (see also Sections III.K and III.P of thisAnnex). The Oxford Study of Childhood Cancers shows
elevated risks of childhood cancer following prenatal x-ray
exposures with a mean dose of 1020 mGy [D17]; however,concerns have been raised [M31] about the interpretation ofthis result and the consistency with the findings for the inutero-exposed atomic bomb survivors [D14].

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

329. Analyses of data across a range of doses usually provide
a statistically more powerful approach to considering risks at
low doses than focussing on results for specific dose
categories. Indeed, the latter approach may yield chancefindings owing to multiple significance testing. The mortality
risks for all solid cancers combined and for leukaemia among
the Japanese atomic bomb survivors, over a wide range ofdoses, were illustrated in Figure XVIII of Annex G, “Biological effects at low radiation doses”. Dose-response analyses ofdata on cancer incidence [P4, T1] and mortality [P9] for theatomic bomb survivors have recently been conducted by Little
and Muirhead [L41, L42] and by Hoel and Li [H45] (see also
Annex G). It should be noted that in contrast to Hoel and Li[H45], Little and Muirhead [L41, L42] took account ofrandom errors in dose estimates. These analyses showed thatfor solid cancers, either individually or combined, the atomic
bomb survivor data are consistent with a linear dose response
and that incorporating a threshold into the dose-responsemodel does not significantly improve the fit [L41, L42]. The
only exception may be non-melanoma skin cancer incidence,
for which there is some evidence of a threshold at about 1 Sv
[L41]. A further analysis of the atomic bomb data by Little
and Muirhead [L50] also took account of possible systematic
errors in neutron dose estimates for survivors in Hiroshima.
This analysis showed little evidence of upward curvature in
the dose response for the incidence of all solid tumours
combined over the range 04 Gy (low-LET); there was moresuggestion of upward curvature over the range 02 Gy (lowLET), although this was not significant at the 5% level [L50].
For leukaemia, as has been noted previously [P4, P9], a linearquadratic dose-response model (such that the risk per unit
dose is smaller at low than at high doses) provides asignificantly better fit than a linear model. However, there issome evidence from the leukaemia incidence data thatincorporating a threshold (estimated to be 0.12 Sv; 95% CI:
0.010.28) provides a better fit than the linear-quadraticmodel alone (two-sided p=0.04) [L41]. On the other hand,
there is less evidence for such a threshold based on thecorresponding mortality data (two-sided p=0.16) [L42]. Since
the estimates of relative risk at low dose are similar for theleukaemia incidence and mortality data, Little and Muirhead[L42] suggested that the difference in findings may be due tothe finer division of dose groups in the publicly available
mortality data than in the corresponding incidence data.
330. In view of the above, the calculations given below are
based on linear dose-response models for solid cancers andon a linear-quadratic model for leukaemia. The form of therisk models was described in the preceding Section.
3. Projection methods
331. Generally speaking, the age-at-exposure and attainedage models describe the Life Span Study data equally well.
However, as will be seen below, these models lead to different
projections of risk beyond the current follow-up period forsurvivors exposed as children. For people exposed to theatomic bombings after age 50, little projection is needed since
their follow-up is close to complete. In Figure V, it can beseen that for this group the ERR basically is constant over357

time. For most sites, the age-at-exposure model assumes that
ERRs for those exposed as children will remain at theircurrent relatively high values throughout life; in contrast, theattained-age model assumes that ERRs will decline as thesurvivors get older. Thus, the two models correspond todifferent methods for projecting risks beyond the current
follow-up.
332. In the UNSCEAR 1994 Report [U2], only age-atexposure models were used, and various ad hoc (i.e. nonmodel-based) projection methods were used. One of thosemethods (constant ERR) is equivalent to the use of the ageat-exposure model, while the second method (constant
ERR over the current follow-up, with risks declining in the
future) is similar to the use of the attained-age model.
4. Populations and mortality rates
333. In Table 32, mortality and incidence estimates are
given for five populations: China, Puerto Rico, Japan, theUnited Kingdom, and the United States. Cause-specificmortality rates for Japan, the United States, and the United
Kingdom are based on 1985 national statistics in the three
countries. Mortality rates for China and Puerto Rico aretaken from Land and Sinclair [L12]. Data on cancer
incidence rates were obtained from the current (7th)edition of Cancer Incidence in Five Continents [P5]. For
the United States, data for the combined SEER registries
were used. Japanese rates were computed as theunweighted average of rates for the Hiroshima, Nagasaki,
and Osaka tumour registries. Rates from the Shanghai
Cancer Registry were used for China.
334. Population age distributions were used to compute thepopulation risks shown in Tables 3337. The 1985 age
distributions were used for Japan, the United States, andthe United Kingdom. Estimates for China and Puerto Ricowere based on the summary life-tables given by Land andSinclair [L12].
5. Transport of risks between populations
335. For each risk model, two methods were used totransport site-specific solid cancer risks estimated for a
Japanese population to populations of China, Puerto Rico,the United States or the United Kingdom. These methods
will be called relative risk transport and absolute risk
transport.
336. For the relative risk transport, the cause-specifichazard rate in the target population, T, was computed as
the product of the baseline hazard in the target populationand the (age-at-exposure or attained-age) ERR for theJapanese population, J:
hdi (a,s,e)  h0i (a,s) [1  ERR J (d,s,a,e)]T

T

337. For the absolute risk transport, the cause-specifichazard rate in the target population was computed as the358

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

sum of the target-population baseline hazard and the EAR
for the Japanese population:
hdi (a,s,e)  h0i (a,s)  EAR J (d,s,a,e)
T

T

Here the EAR function for the Japanese population wascomputed as the product of the appropriate ERR function
for the model of interest (age-at-exposure or attained-age)
and the corresponding Japanese baseline rate, namely

340. For leukaemia, the linear-quadratic dose-responsemodel implies a reduction factor of 2 when extrapolating fromacute high doses to low doses or low dose rates. It would,
therefore, not be necessary to apply another reduction factor
to the leukaemia results given for a dose of 0.1 Sv if the
exposure was fractionated or protracted rather than acute.
However, the results at 1 Sv for solid cancers could,
tentatively, be reduced by a factor of 2 for fractionated or
protracted exposures.

EAR J (d,s,a,e)  h0i (a,s) ERR J (d,s,a,e)J

C. LIFETIME RISK ESTIMATES
For leukaemia, EARs were estimated directly in thesurvivors, and all transport was done using absolute rates.
6. Fractionation and dose-rate effects
338. Experimental and epidemiological information on
cancer risks from fractionated or low-dose-rate exposure,
relative to acute or high-dose-rate exposure, was reviewed
in the UNSCEAR 1993 Report [U3] and is also consideredin Annex G, “Biological effects at low radiation doses”.
The UNSCEAR 1993 Report indicated that risks associatedwith low-dose or low-dose-rate exposures may be less thanthose from acute high doses by a factor of as much as 3.
The Committee has not examined all new studies since
1993 to assess potential changes in the range of values.
However, some recent information on this topic is provided
in this Annex, for example, from the comparison of resultsfrom the acutely exposed Japanese atomic bomb survivors
and from tuberculosis patients with fractionated x-ray
exposures from fluoroscopies. For lung cancer, there is no
indication of an elevated risk in the Canadian [H7] andUnited States (Massachusetts) [D4] fluoroscopy studies,
unlike in the atomic bomb survivors [P9, T1]. However, theseverity of tuberculosis may have affected the findings forlung cancer in these patients. For breast cancer, it has beensuggested, based on comparison of the fluoroscopy andatomic bomb survivor findings, that fractionation may notaffect risks [L39], although a different interpretation has
been put on this finding [B33].
339. Further information on low-dose-rate occupational andenvironmental exposures has also become available in recent
years and is summarized both in this Annex and in Annex G,“Biological effects at low radiation doses”. While it has beenpossible in some instances to find some evidence of anelevated risk (e.g. for leukaemia among nuclear industry
workers [C11]), such studies do not currently have sufficient
statistical power to allow those risks to be estimated with great
precision. Furthermore, risk estimation based, for example, ongroups in the former Soviet Union is sometimes complicatedby exposures to both low- and high-LET radiation. Further
investigation, including longer follow-up and more detailed
analyses, may improve the estimation of risks fromfractionated and low-dose-rate exposure. For the time being,
however, the values for a reduction factor of less than 3 thatwere suggested in the UNSCEAR 1993 Report seem to bereasonable, notwithstanding the possibility of differences
between some cancer types.

341. The principal results of the calculation of lifetime
risks are given in Table 33 for an acute whole-body dose of
1 Sv or 0.1 Sv. This Table presents solid cancer results forthe two projection models (age-at-exposure and attainedage dependence of the ERR) and two risk transport models(ERR and EAR transport) for the five populations. As
noted above, leukaemia risks always were based on an
EAR model. The transport method makes little difference
because non-CLL leukaemia rates are similar in the
different populations; consequently, results are presented
only for the EAR transport model.
342. For comparison, the estimates at 1 Sv for a Japanese
population that were derived in the UNSCEAR 1994 Report[U2] are included in Table 33. The UNSCEAR 1994
estimates for the REID (10.9% averaged over gender) werebased on an age-at-exposure model applied to Japanese rates
and are generally comparable to the current estimates for solidcancers (11.2% averaged over gender). The 1994 leukaemia
estimate of 1.1% averaged over gender is slightly higher thanthe current estimate of 0.9%. This difference arises because ofslight differences in the leukaemia risk model and because, forthe current computations, leukaemia was included as another“site” in a joint analysis of the impact of a whole-body
exposure, while in 1994 leukaemia was considered separatelyfrom other causes (i.e. as if only the bone marrow had been
exposed). The difference reflects the impact of increased
hazards for the competing risks of radiation-associated solidcancers.
343. Although the solid cancer REID estimates are based ona linear dose-response model, the REID estimate for a dose of
0.1 Sv is slightly more than 10% of the estimate for a dose of
1 Sv. For example, considering solid cancer mortality in
United States males using an attained age model and relativerisk transport, the REID estimates for 1 and 0.1 Sv are 6.2%
and 0.7%, respectively. This non-linearity reflects the effect ofcompeting risks at lower doses vs. at higher doses. However,for these models, the REID estimates for solid cancers at
lower doses are approximately linear in dose.
344. The use of the attained-age model leads to smaller
lifetime risks for solid cancers than the corresponding ageat-exposure model. The reason for this can be seen in
Table 34, which is based on a Japanese population. The
persistence of high relative risks under the age-at-exposure
model leads to large lifetime risks for those exposed as

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

children. For solid cancer mortality following exposure atage 10 years, the values of REID are 14% for men and
20% for women, while the corresponding gender-specificincidence risks are 31% and 37%, respectively. The
attained-age model, which describes the current Life Span
Study data as well as the age-at-exposure model, allows therelative risks for those exposed as children to decrease as
they reach the ages of high cancer mortality or incidence.
As a result, the estimated gender-specific solid cancer
mortality and incidence risks following exposure at age 10
years are about half the values predicted by the age-atexposure model. The population average lifetime risk
estimates for the attained-age model are about 70% of
those for the age-at-exposure model.
345. Some other measures of radiation detriment, based on
mortality in a male Japanese population, are given in
Table 35. As expected, the excess lifetime risk ELR is similar
to the REID (i.e. the percentage ofradiation-associated deaths)
for leukaemia, but the former is less than the latter for all solidcancers. Furthermore, the excess lifetime risk is negative fornon-cancer causes, since the sum of this measure over allcauses must equal zero. The loss of life expectancy per
attributable solid cancer death is similar under the attainedage and age-at-exposure projection models.
346. As indicated in Table 33, values of REID for solidcancer mortality in men are generally comparable for theJapanese, United Kingdom, and United States populations:about 9% with the age-at-exposure model and 6% with theattained-age model following a dose of 1 Sv. However,
lifetime attributable risks for men in the Chinese andPuerto Rican populations are about 30% lower than thosein Japan, the United Kingdom, and the United States.
There is greater variability in female rates, but the samegeneral pattern is seen in the magnitude of the risk
estimates, with values of REID for Japan, the United
Kingdom, and the United States being considerably greaterthan those for China and Puerto Rico. These differencesreflect almost entirelydifferences in the lifetime probabilityof cancer mortality in these populations, as presented inTable 32, which in turn reflect the population-topopulation variability in baseline rates.
347. Estimates of REID for women are consistently greaterthan those for men, largely reflecting gender differences inlife expectancy and the contribution of breast cancer. REID
estimates for cancer mortality in women exhibit greater
sensitivity to both the risk projection model and the transport
method than do those for men. This difference is primarily
due to variations in breast cancer mortality between these
populations.
348. Estimates of REID for cancer incidence are slightly
lower for Japanese men (19% using the age-at-exposure
model and 13% for the attained-age model) than for UnitedStates men (15% and 11% for the age-at-exposure andattained-age models, respectively), while estimates for men
in the United Kingdom are somewhat higher (26% and22%, respectively). These differences generally reflect359

differences in the baseline rates. Since lifetime baseline
cancer incidence risks for China and Puerto Rico are moresimilar to those in Japan, the United Kingdom and theUnited States than are the corresponding mortality risks,
the differences in incidence estimates of REID between
these two countries and Japan, the United Kingdom, andthe United States are not as marked as they are formortality. REID estimates associated with relative risk
transport tend to be larger for Western women than forJapanese women. This difference is due almost entirely tothe higher breast cancer incidence and mortality in the
United States and United Kingdom populations than in theJapanese population.
349. Tables 36 and 37 give detailed breakdowns by cancer
type of estimates of REID risks for mortality and incidence,
respectively, based on one of the above models, namely theattained-age projection model. When relative risk andabsolute risk transport are compared for the populations of theUnited States and the United Kingdom, the main effect ofusing the latter rather than the former transport method is to
reduce the REID estimates for women. This is due principally
to reductions in the excess associated with breast and lungcancer, whose background rates are lower for Japanese womenthan for Western women. With this reduction, the differencesin REID for the populations considered are less marked thanunder the relative risk transport.
350. Since the UNSCEAR 1994 Report [U2], further work
has been undertaken to assess uncertainties in cancer risk
estimates. In particular, NCRP report 126 [N17] assessed
the uncertainty in the total fatal cancer risk for the UnitedStates population from external low-LET irradiation at low
doses and low dose rates; it took account of the following
factors:
(a)
(b)
(c)
(d)
(e)

(f)
(g)

statistical uncertainties in the estimation of a risk factor,
based on data for the Japanese atomic bomb survivors;
possible bias due to over- or under-reporting of cancer
deaths in the atomic bomb survivors;
the effect of both random and systematic errors in dose
estimates for the atomic bomb survivors;
uncertainty in the method of transferring risks fromJapan to the United States;
uncertainty associated with the projection of risks overtime, from the period of follow-up to a complete lifetime;
uncertainty in the DDREF; anda subjective assessment of any remaining unspecified
uncertainties.

351. Uncertainties associated with each of these factors
were propagated using a Monte Carlo approach [N17]. Fora United States populations of all ages and both genders,the mean value for the total cancer risk at low doses andlow dose rates was estimated as 4.0 102 per Sv, with a
90% confidence interval of 1.28.8 102 per Sv. The shapeof the total uncertainty distribution was skewed towards
higher values, as a consequence of which the median value(3.4 102 per Sv) was smaller than the mean. A sensitivity

360

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

analysis demonstrated that the main contributors to thetotal uncertainty were the DDREF (about 38% of the total),
unspecified uncertainties (about 29%), and the transfer tothe United States population (about 19%).
352. In a separate exercise supported by the United States
Nuclear Regulatory Commission and the European
Commission, uncertainties in cancer risk estimates wereelicited from a series of experts [L27]. Using a formal
analysis, the uncertainties provided by these experts werecombined to obtain an overall distribution of uncertainty thattook account of differences between the various subjective
assessments. Table 38 shows the estimates of REID elicited

for an acute dose of 1 Gy (low-LET) to a hypothetical
European Union/United States population of all ages and bothgenders, together with the associated 90% confidence interval.
For all cancers combined, the limits of the confidence interval
range about a factor of three higher and lower around the
median of 10.2%. This represents a slightly wider interval
than that arising from the NCRP analysis [N17]. For specificcancer types, the uncertainty intervals in the European
Union/United States analysis are wider, in relative terms, than
the interval for all cancers combined, sometimes ranging fromseveral order of magnitudes lower than the median value up
to about an order of magnitude higher [L27]. However, theseranges encompassed previous estimates of risk.

CONCLUSIONS
353. Since the Committee’s assessment of the risks ofradiation-induced cancer in the UNSCEAR 1994 Report[U2], more information has become available fromepidemiological studies of radiation-exposed groups. Someof this information relates to populations exposed to acutedoses of external low-LET radiation. For example,
mortality data have been updated to the end of 1990 for
86,572 survivors of the atomic bombings at Hiroshima andNagasaki. As of December 1990, 56% of the survivors
were still alive, and it was estimated that 421 excess
cancers deaths had occurred; 334 from solid cancer and 87
from leukaemia. Both this study and further follow-up ofpatients who received medical radiation exposure haveprovided additional data on cancer risks at long times
following irradiation, particularly for those exposed atyoung ages. However, there are still uncertainties in the
projection of risks from the current follow-up periods until
the end of life, given that most of the people who were
irradiated at young ages are still alive.
354. The increased statistical precision associated with thelonger follow-up and the resulting larger number ofcancers in the above studies has also assisted in theexamination of dose-response relationships, particularly at
lower doses. For example, the most recent data for theJapanese atomic bomb survivors are largelyconsistent withlinear or linear-quadratic dose trends over a wide range ofdoses. However, analyses restricted solely to low doses arecomplicated by the limitations of statistical precision, thepotential for misleading findings owing to any small,undetected biases, and the effects of performing multiple
tests of statistical significance when attempting to establish
a minimum dose at which elevated risks can be detected.
Longer follow-up of large groups such as the atomic bomb
survivors will provide more information at low doses.
However, epidemiology alone will not be able to resolve theissue of whether there are dose thresholds in risk. In
particular, the inability to detect increases at verylow doses
using epidemiological methods does not mean that theunderlying cancer risks are not elevated.

355. New findings have also been published from analysesof fractionated or chronic low-dose exposure to low-LET
radiation, although the statistical precision of these studies
is low in comparison with high-dose-rate results from theatomic bomb survivors. Analyses of data for nuclear
workers indicate that the risk of leukaemia increases withincreasing dose, whereas no dose response has been
established for solid cancers. A comparison of the atomic
bomb survivors with patients who received fractionatedx-ray exposures in the course of treatment for tuberculosis
suggests that dose fractionation may not reduce the risk ofbreast cancer, although this interpretation has beenquestioned in view of the potential effects of radiation
quality. It is difficult to arrive at a definitive conclusion on
the effects of dose rate on cancer risks, since the relevant
epidemiological data are sparse and the effects may differ
among cancer types. For example, no elevated risk of lungcancer was observed in tuberculosis patients who received
fractionated exposures, whereas a statistically significant
elevated risk was found in the atomic bomb survivors;
however, the severity of tuberculosis may have affected theresults for these patients.
356. Information on the effects of internal exposure, fromboth low- and high-LET radiation, has increased since thetime of the UNSCEAR 1994 Report [U2]. In particular, theearly reports of an elevation in thyroid cancer incidence inparts of the former Soviet Union contaminated as a resultof the Chernobyl accident have been confirmed and suggest
a link with radioactive iodine exposure during childhood.
Nevertheless, risk estimation associated with these findings
is still complicated by difficulties in dose estimation and inquantifying the effect of screening for the disease. This
topic is considered in further detail in Annex J,“Exposures and effects of the Chernobyl accident”. Other
studies in the former Soviet Union have provided further
information relevant to internal exposures; for example, onlung, bone and liver cancers among workers at the Mayakplant and, to a lesser extent, on cancers among the
population living near the Techa River, in both instances

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

in the southern Urals. However, the different sources ofradiation exposure (both external and internal) and, in thecase of the Techa River studies, the potential effects of
migration, affect the quantification of risks. Results fromseveral case-control studies of lung cancer and indoor radon
have been published in recent years that, in combination, areconsistent with extrapolations from data on radon-exposedminers, although the statistical uncertainties in the findings
from the indoor studies are still too large to determine a
reliable risk estimate.
357. Particular attention has been paid in this Annex torisks for specific cancer sites. Again, the information thathas become available in recent years has helped in theexamination of risks. However, there are still problems incharacterizing risks for some cancer sites, owing to the low
statistical precision associated with relatively small
numbers of estimated excess cases. This can limit, forexample, the ability to estimate trends in risk in relation tofactors such as age at exposure, time since exposure, andgender. Furthermore, data are sometimes lacking or havenot been published in a format that is detailed enough toallow an assessment of how risks vary among populations.
An exception is breast cancer, where a comparison of dataon the Japanese atomic bomb survivors and women withmedical exposures in North America points to an absolutetransfer of risks between populations. For some other sites,such as the stomach, there are indications that a
multiplicative transfer between populations would beappropriate, although the evidence is generally not strong.
There are some cancer sites for which there is little
evidence for an association with radiation (e.g. nonHodgkin’s lymphoma, Hodgkin’s disease, and multiple
myeloma). While the risk evaluations for lymphomas areaffected by the small numbers of cases in several studies,
these results should be contrasted with the clear relation
found in many populations between radiation and the riskof leukaemia (excluding CLL), which is also a rare disease.
358. The results presented in Tables 3337 illustrate thesensitivity of lifetime risk estimates to variations inbackground rates. These findings suggest that thisvariability can lead to differences that are comparable tothe variations associated with the transport method or
method of risk projection. Issues of uncertainty in lifetime
risk estimates are discussed in more detail in NCRP report
126 [N17]. The variability in these projections highlights
the difficulty of choosing a single value to represent the
lifetime risk of radiation-induced cancer. Furthermore,
uncertainties in estimates of risk for specific types ofcancer are generally greater than for all cancers combined.

361

359. Despite these difficulties, risk estimates are of
considerable value for use in characterizing the impact of aradiation exposure on a population. Using the same approachtaken in the UNSCEAR 1994 Report [U2], namely an age-atexposure model applied to a Japanese population of all ages,
the lifetime risk of exposure-induced death from all solidcancers combined following an acute dose of 1 Sv is estimatedto be about 9% for men, 13% for women and 11% averaged
over genders. The calculations in this Annex show that thesevalues can vary among different populations and withdifferent risk models. Overall, however, the risk estimates are
consistent with the value of 10.9% for an acute dose of 1 Sv
cited in the UNSCEAR1994 Report [U2]. The uncertainties
in the above estimates may be of the order of a factor of 2,
higher or lower. The estimates could be reduced by 50% forchronic exposures, again with an uncertainty factor of 2,
higher or lower. Using the attained-age model, the estimatedlifetime risks of exposure-induced death are about 70% of
those based on the age-at-exposure model. Total solid cancer
incidence risks can be taken as being roughly twice those formortality. Lifetime solid cancer risk estimates for those
exposed as children might be twice the estimates for a
population exposed at all ages. However, continued follow-up
of existing irradiated cohorts will be important in determining
lifetime risks. The experience of the Japanese atomic bomb
survivors is consistent with a linear dose-response for the riskof all solid cancers combined; therefore, as a first
approximation, linear extrapolation of the estimates at 1 Sv
acute dose can be used for estimating solid cancer risks atlower doses. For specific types of solid cancer, the risks
estimated in this Annex are broadly similar to those presented
in the UNSCEAR 1994 Report [U2].
360. The computations in this Annex suggest that lifetime
risks for leukaemia are relatively invariant to the
population used, both because an absolute risk transportmodel was used and because baseline rates of leukaemia,
other than CLL, are less variable among populations thanare baseline rates of solid cancers. For either gender, thelifetime risk of exposure-induced leukaemia mortality canbe taken as 1% following an acute dose of 1 Sv. This issimilar to the value of 1.1% at 1 Sv cited in the UNSCEAR
1994 Report [U2]. Based on a linear-quadratic doseresponse model, decreasing the dose tenfold, from 1 Sv to
0.1 Sv, would be expected to reduce the lifetime risk
estimate by a fraction of 20. Thus, the lifetime risk of
exposure-induced death for leukaemia can be estimated as
0.05%, for either gender, following an acute dose of 0.1 Sv.
No further reduction for chronic exposures is necessary.
The uncertainty in the leukaemia risk estimate may be on
the order of a factor of 2, higher or lower.

362

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 1
Examples of high and low cancer rates in various populations a b[P5]High cancer incidence
Site of cancer

Population
Nasopharynx

Low cancer incidence

Sex
Males

Hong Kong
Singapore (Chinese)
United States, San Francisco (Chinese)

Rate
24.3
18.5
11.6

Population

Rate

Canada, Nova Scotia
United States, New Mexico(Non-Hispanic white)
Ireland, Southern

0.1
0.2
0.2

FemalesHong Kong
Singapore (Chinese)
Canada, Northwest Territories

9.5
7.3
5.1

United Kingdom, south-western
Finland
Norway

0.1
0.1
0.1

Males

United States, Connecticut (black)Hong Kong
France, Haut Rhin

20.1
14.2
14.2

Israel (non-Jews)
Italy, Sicily (Ragusa Province)
Thailand, Chiang Mai

0.5
1.0
2.3

Females

India, Bombay
China, Tianjin
United Kingdom, Scotland, West

8.3
6.2
5.2

United States, New Mexico(American Indian)
Spain, Tarragona
Israel (non-Jews)

0.2

Males

Japan, Yamagata
China, Shanghai
Italy, Romagna

95.5
46.5
39.3

United States, Atlanta (white)
Israel (non-Jews)
Thailand, Chiang Mai

5.2
6.8
7.5

Females

Japan, Yamagata
Italy, Romagna
China, Shanghai

40.1
22.8
21.0

United States, Iowa
Israel (non-Jews)
Canada, Saskatchewan

2.2
3.2
3.7

Males

United States, Detroit (black)
United States, Hawaii (Japanese)
Japan, Hiroshima

35.0
34.4
31.6

India, Madras
Thailand, Chiang Mai
Peru, Trujillo

1.8
4.2
4.4

Females

New Zealand (non-Maori)
Canada, Newfoundland
United States, Detroit (black)

29.6
28.1
27.9

India, Madras
Thailand, Chiang Mai
Singapore (Indian)

1.3
3.7
4.7

Males

Japan, Osaka
China, Shanghai
United States, Los Angeles (Korean)

46.7
28.2
23.9

Canada, Prince Edward Island
Netherlands, Eindhoven
United Kingdom, south-western

0.7
1.3
1.6

Females

Japan, Osaka
China, Shanghai
Thailand, Chiang Mai

11.5
9.8
9.7

Australia, Tasmania
Canada, Prince Edward Island
India, Madras

0.3
0.3
0.5

Males

United States, New Orleans (black)
New Zealand (Maori)
Canada, Northwest Territories

110.8
99.7
90.3

United States, New Mexico(American Indian)Peru, Trujillo
India, Madras

10.3

Females

New Zealand (Maori)
Canada, Northwest Territories
United States, San Francisco (black)

72.9
65.6
44.3

India, Madras
Spain, Zaragoza
Malta

2.4
2.7
3.4

Males

Australia, New South Wales
New Zealand (non-Maori)
United States, Hawaii (white)

33.1
25.0
19.5

Japan, Osaka
China, Shanghai
India, Bombay

0.2
0.3
0.4

Females

New Zealand (non-Maori)
Australia, New South Wales
Austria, Tyrol

29.8
25.7
15.6

Japan, Osaka
China, Shanghai
India, Bombay

0.2
0.3
0.3

BreastFemales

United States, Los Angeles (Non-Hisp white)
United States, Hawaii (white)
Israel (Jews born in Israel)

103.7
96.5
90.5

Thailand, Chiang Mai
Israel (non-Jews)
United States, Los Angeles (Korean)

14.6
21.3
21.4

CervixFemales

Peru, Trujillo
India, Madras
Colombia, Cali

53.5
38.9
34.4

Israel (non-Jews)
China, Shanghai
Finland

3.0
3.3
3.6

Oesophagus

Stomach

Colon

Liver

Lung and bronchus

Melanoma of skin

0.2
0.2

11.9
12.6

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

363

Table 1 (continued)
High cancer incidence
Site of cancer

Population

Rate

Population

Rate

Prostate

Males

United States, Atlanta (black)
United States, Hawaii (white)
Canada, British Columbia

142.3
108.2
84.9

China, Tianjin
India, Madras
Thailand, Chiang Mai

1.9
3.6
4.1

Bladder

Males

Italy, Trieste
Spain, Mallorca
Switzerland, Geneva

38.7
36.4
32.5

United States, New Mexico(American Indian)
United States, Hawaii (Hawaiian)
Canada, British Columbia

2.6

Italy, Trieste
Denmark
United Kingdom, Scotland, West

9.4
7.7
7.5

United States, New Mexico(American Indian)France, Isere
United States, Hawaii (Filipino)

0.6

Males

Italy, Trieste
IcelandUnited States, Hawaii (white)

9.5
9.4
8.7

Singapore (Malay)
Japan, Yamagata
Thailand, Chiang Mai

1.6
1.8
2.0

Females

Italy, Trieste
Poland, Warsaw city
United States, Atlanta (white)

8.7
5.9
5.8

United States, Los Angeles (Chinese)
India, Madras
Japan, Yamagata

1.1
1.1
1.7

Males

IcelandUnited States, Hawaii (Filipino)
United States, Los Angeles (Filipino)

6.1
5.1
4.0

United Kingdom, Wessex
Estonia
Denmark

0.7
0.7
0.8

Females

United States, Hawaii (Filipino)
United States, Los Angeles (Filipino)
Italy, Ferrara

25.5
11.2
11.1

India, Madras
United Kingdom, Yorkshire
Netherlands, Eindhoven

1.6
1.7
1.9

Males

United States, San Francisco (non-Hisp white)
Italy, Romagna
United States, Hawaii (white)

25.0
15.5
15.1

India, Madras
Thailand, Chiang Mai
Singapore (Indian)

3.7
3.8
3.9

Females

Italy, Ferrara
Israel (Jews born in Israel)
United States, San Francisco (Hispanic white)

11.5
11.1
11.0

India, Madras
China, Shanghai
Estonia

2.0
2.5
2.5

Males

United States, San Francisco (non-Hisp white)
Italy, Veneto
Israel (Jews born in Israel)

4.3
4.0
3.2

China, Tianjin
Japan, Miyagi
Singapore (Chinese)

0.3
0.4
0.5

Females

United States, Connecticut (white)
Italy, Veneto
Israel (Jews born in America or Europe)

3.6
3.5
3.1

Japan, Osaka
China, Shanghai
Hong Kong

0.2
0.3
0.3

Males

United States, Los Angeles (black)
New Zealand (Maori)
Australian Capital Territory

9.5
5.7
5.4

Thailand, Chiang Mai
China, Tianjin
United States, Los Angeles (Japanese)

0.4
0.4
0.5

Females

United States, Detroit (black)
New Zealand (Maori)
United States, Hawaii (Hawaiian)

6.4
5.8
4.2

Thailand, Chiang Mai
China, Tianjin
India, Madras

0.3
0.3
0.4

Males

Italy, Trieste
Australia, South Australia
United States, Detroit (white)

15.0
13.3
12.7

India, Madras
Singapore (Indian)Japan, Yamagata

3.0
3.0
4.4

Females

Italy, Trieste
Australia, South Australia
United States, San Francisco (Filipino)

9.0
8.9
8.4

United States, Central Louisiana(black)India, Madras
Japan, Miyagi

1.6

FemalesBrain, central
nervous system

Thyroid

Non-Hodgkin’s
lymphoma

Hodgkin’s disease

Multiple myeloma

Leukaemiaab

Low cancer incidence

Sex

3.9
11.3

2.6
2.7

2.0
3.3

Numbers given are age-standardized (world) annual incidence per 100,000 population.
Registries for which IARC [P5] indicated problems in ascertainment have not been included in this Table. However, some of the differences in rates
may be due in part to variations in the level of ascertainment and to random variation.

Incidence

Mortality/
Incidence

IncidenceCase-control
61 cases
120 controls
from a cohort of
27 106 womenLife Span Study[P4, T1]

Survivors of
atomic bombings(in utero)[D14, Y1]

Cervical cancer
cohort[B11]Lung cancer
following breast
cancer[I7]

50 113 exposed persons c
36 459 unexposed persons
55.5% females
Age: 0 >90 (28.4) d

37 270 exposed persons e
42 702 unexposed persons
55.5% females
Age: 0 >90 (26.8)

Japan

Canada,Denmark,
Finland,
Norway,Slovenia,
Sweden,United Kingdom,
United States
United States

82 616 exposed women
99 424 unexposed
women
Age: <30 >70 (26.8)

38 exposed women
143 unexposed women
Age: 35 72 (50)

Japan

Japan

Followup(years)Total
personyears aType of exposuren.a. i(24.4)

1 950 567 g

2 812 863
(32.5)

Maternal exposure
to gamma andneutron radiation athigh dose rate

Gamma and neutronradiation from
nuclear explosions

Gamma and neutronradiation from
nuclear explosions

10 46(18 years
per case)

1 >30

n.a.

1 278 950
(7.0)

Radiotherapy

Radiotherapy,
including externalbeam and intracavity applicationand experimental
reconstruction

Treatment of malignant disease

5 47

13 42 f

5 45

Exposure to atomic bombings

EXTERNAL HIGH-DOSE-RATE EXPOSURES

National origin

1 078 exposed persons h
2 211 unexposed persons
50.7% females
Exposure: in uteroMortalityLife Span Study[P9]

Characteristics

Population studied







Type of study







Study

Table 2
Cohort and case-control epidemiological studies of the effects of exposures to low-LET radiation

Individual doses fromtherapy records andexperimental
measurements

Data on typical range of
estimates for specificorgans and phantom
measurements

Mother’s estimateduterus dose

Individual estimatesderived from detailed
shielding histories

Individual estimatesderived from detailed
shielding histories

Type of dosimetry

Lung cancer

Oral cavity, salivary gland, oesophagus*,stomach, small intestine*, colon,
rectum*, liver, gallbladder, pancreas*,lung*, breast, uterus, other genital*,kidney, bladder, melanoma, other skin,brain, thyroid, bone, connective tissue,
leukaemia (non-CLL)*, myeloma,
lymphoma

Leukaemia, all solid cancers

Leukaemia*, non-Hodgkin’s
lymphoma*, myeloma, oral cavity,
salivary gland*, oesophagus, stomach*,colon*, rectum, liver*, gallbladder,pancreas, lung*, female breast*, nonmelanoma skin*, uterus, ovary*,
prostate, bladder*, central nervous
system, thyroid*

Leukaemia*, tongue, pharynx,
oesophagus*, stomach*, colon*, rectum,
liver*, gallbladder, pancreas, nose,
larynx, lung*, bone, skin, female breast*,
cervix uteri and uterus, ovary*, prostate,
bladder, kidney, brain, other central
nervous system, lymphoma, myeloma*

Cancers studied b

364
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

United States

449 exposed women
1 395 unexposed women
Age: <45 >60 (51)157 exposed women
901 unexposed women
Age: <45 >60 (51)310 exposed women
86 unexposed women
32 women with unknown
exposure status
Age: 29 86 (59)110 exposed women
244 unexposed women
Age: <50 >70 (61)612 exposed women
351 unexposed women
30 women with unknown
exposure status
Age: <55 >75 (62)303 exposed persons
54 unexposed persons
15% female

Case-control
655 cases
1 189 controls
from a cohort of
41 109 womenCase-control
529 cases
529 controls
from a cohort of
56 540 womenCase-control
107 cases
321controls froma cohort of 122
991 women

Case-control
90 cases
264 controls
from a cohort of
82 700 womenCase-control
218 cases
775 controls
from a cohort of
110 000 womenCase-control
98 cases259 controls

Contralateralbreast cancer,
United States[B10]

Contralateralbreast cancer,
Denmark[S20]

Soft tissue
sarcomafollowingbreast cancer[K35]

Leukaemia
following breast
cancer[C9]

Leukaemia
following cancerof the uterine
corpus[C10]Lung cancer
following
Hodgkin's disease(international)[K9]

Canada,Denmark,
Finland, France,
Norway,Slovenia,
United Kingdom

Canada,Denmark,
Finland,
Norway,United States

United States

SwedenDenmark

Austria, Canada,
Czech Republic,
Denmark,
Finland, France,
Germany,
Iceland, Italy,
Norway,Slovenia,
Sweden,United Kingdom,
United States

10 286 exposed women
782 unexposed women
Age: <30 >70 (26.8)

National origin

Case-control
4 188 cases
6 880 controls

Characteristics

Population studied

Cervical cancer
case-control[B1, B12,B50]Type of study

1 >10

1 50

<12
(~5 years
per case)

1 35(10 years
per case)

12 47
(~16
years per
case)

n.a.

n.a.

n.a.

n.a.

Radiotherapy

Radiotherapy

Adjuvant
radiotherapy

Radiotherapy

Radiotherapy

Radiotherapy

n.a.

7 55
(~13
years per
case)
n.a.

Radiotherapy,
including externalbeam and intracavity applicationand experimental
reconstruction

n.a.

0 >30
(7.0 years
per case)

Type of exposure

Total
personyears aFollowup(years)

















Study









Table 2 (continued)

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Total absorbed energy
from radiotherapy, andlocation of sarcoma in
relation to the treatment
regionIndividual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records

Type of dosimetry

Lung cancer

Leukaemia*

Acute non-lymphocytic leukaemia andmyelodysplastic syndrome*, chronic
myelogenous leukaemia, acutelymphocytic leukaemia

Soft tissue sarcoma

Contralateral breast

Contralateral breast among women lessthan 45 years old at exposure*,contralateral breast in older women

Stomach*, pancreas, small intestine,colon, rectum*, breast, uterine corpus*,
vagina*, ovary, vulva, bladder*, bone,connective tissue, leukaemia (nonCLL)*, myeloma, lymphoma, thyroid

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
365

Case-control
30 cases
82 controls
from a cohort of
1 939 patients

Incidence/
Mortality

Case-control
163 cases
455 controls
from a cohort of
29 552 patients

Case-control
35 cases
140 controls
from a cohort of
11 386 women

IncidenceCase-control
23 thyroid
cancers /89 controls
25 leukaemia /90 controls
64 bone cancers/
209 controls
from a cohort of
9 170 members

Breast cancer
following
Hodgkin’s disease[H2]

Leukaemia
following
Hodgkin's
disease(international)[K40]

Leukaemia
following nonHodgkin's
lymphoma(international)[T6]

Leukaemia
following nonHodgkin's
lymphoma(United States)[T15]

Childhoodcancers(international)[T5, T7, T17]

0 29

Canada,France,Netherlands,
Italy,
United Kingdom,
United States
5 48

50 609
(5.5)

590
(9.7)

2 22

United States

61 exposed persons
50% females
Age: 18 70 (49.5)

n.a.

2 25
(7.6 years
per case)

Canada,Netherlands,
Sweden,United States

123 exposed persons
52 unexposed persons
Age: <50 70

n.a.

Canada,Denmark,
Finland, France,
Germany, Italy,
Netherlands,
Norway,Slovenia,
United Kingdom

112 exposed persons
388 unexposed persons
45% females
Age: 0 18 (7)

n.a.

1 23

8 832
(10)

Total
personyears aFollowup(years)

1 >10

United States

Netherlands

36% exposed
35% females
Age: (40)855 exposed women
30 unexposed women
Age: 4 81 (28)101 exposed persons
11 unexposed persons
4% female
Age: <45 >55 (49.4)







Lung cancer
following
Hodgkin's disease(Netherlands)[V2]

National origin

Population studied

Characteristics

Type of study









Study







Table 2 (continued)

Adjuvant
radiotherapy

Total body
irradiation

Radiotherapy

Radiotherapy

Radiotherapy

Radiotherapy

Type of exposure

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records

Individual doses fromtherapy records andexperimental
measurements

Type of dosimetry

Thyroid*, leukaemia, bone sarcoma*

Acute non-lymphocytic leukaemia*,
all solid cancers

Leukaemia

Leukaemia (non-CLL)

Breast cancer*

Lung cancer*

Cancers studied b

366
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

IncidenceCase-control,
59 cases
220 controls,largely within a
13 175-member
cohortCase-control
26 cases
96 controls

Incidence

Incidence

Incidence

Incidence/
Mortality

Incidence

Bone cancer afterchildhood cancer(United Kingdom)[H44]

Leukaemia afterchildhood cancer(UK) [H11]

Retinoblastoma[W11]

Thyroid cancer
following
childhood cancer[D20]Childhood
Hodgkin's disease[B16]

Childhood skinhaemangioma:
Stockholm[K23, L13, L16,
L17, L24, L46]

Childhood skinhaemangioma:
Gothenburg[K22, K23,
L15, L46]

15 660(11.3)

0 37(median
11.4)

Canada,France,Italy,
United Kingdom,
United States

Sweden

1 380 persons
8% unexposed
35% female
Age: 1 16 (median 11)

14 351 exposed persons j
67% females
Age: 0 1.5 (0.5)

11 914 exposed persons
88% aged <1 year

Swedenn.a.

n.a.
(Median
20)

n.a.

3 29

1 >60

1 43

3 >20

France,United Kingdom

United States

United Kingdom

66 000
(15)

3 48

n.a.

Total
personyears aFollowup(years)2 827 exposed persons

962 exposed persons
642 unexposed persons
47% females
Age: 0 17

88 exposed persons
34 unexposed persons
Age: 0 14

208 exposed persons
71 unexposed persons
Age: 0 14

United Kingdom

France,United Kingdom

3 109 exposed persons
1 291 unexposed persons
45% females
Age: 0 16 (7)Childhoodcancers(France/U.K.)[D19, D33]

National origin

Characteristics

Population studiedRadiotherapy

External
radiotherapy

External
radiotherapy

External
radiotherapy

External
radiotherapy

External
radiotherapy

Type of exposure

0-69

1 67

370 517(31.1)

406 355(39)

Radiotherapy

Radiotherapy

Treatment of benign diseaseType of study



Study


















Table 2 (continued)

Individual organ doses
from therapy records andphantom measurements

Individual organ doses
from therapy records andphantom measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records and experimental measurements

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andexperimental
measurements

Type of dosimetry

Thyroid*, other endocrine glands*,
central nervous system*, all other sites

Thyroid*, breast*, leukaemia, all othersites

Leukaemia*, non-Hodgkin's
lymphoma*, breast*, thyroid*, othersolid cancers*

Thyroid cancer*

Soft tissue sarcoma*, bone and soft
tissue sarcoma*, all other cancers

Leukaemia

Bone cancer

All solid cancers combined*, breast*,
bone*, soft tissue sarcoma*, thyroid*,
brain*

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
367

20 024 exposed persons
49% females
Age: <20 >70 (53)

13 914 exposed persons
16.5% females
Age: <20 >60

Incidence/
Mortality

Mortality

Incidence/
Mortality

Incidence

Incidence

Incidence

Incidence

Incidence

Incidence

Ankylosing
spondylitis[W1, W2] k

Israel tinea capitis[R5, R9,
R16, R17]

New York tinea
capitis[S27, S30]

New York acutepost-partum
mastitis[S15, S30]

Rochester thymic
irradiation[H10, H31, S30]

Tonsil irradiation[S21, S28, S30]

Tonsil, thymus oracne irradiation[D5]

Swedish benign
breast disease[M8, M20, M28]

56 900(18)

5 60

Sweden1 216 exposed women
1 874 unexposed women
Age: 10 >85

88 101(33)

220 777(29.5)

38 784(25.1)

98 881(25.4)

11 000(26.4)

0 50

23 >50

20 35

20 39

26 38
686 210(25.3)

245 413(17.6)

1 57

n.a.

United States

United States

United States

United States

IsraelIncidence:
493 400(24.6)
Mortality:
392 900(19.6)

Total
personyears aUp to 38

Followup(years)United States416 exposed persons
Age:(7.1)



2 634 exposed persons l
40.7% females
Age: 0 15 (4.3)

2 652 exposed persons
4 823 unexposed persons
42% females
Age: 0 1571 exposed women
993 unexposed women
Age: 14 >40 (27.8)

2 226 exposed persons
1 387 unexposed persons
16.1% females
Age: <1 19 (7.7)

10 834 exposed persons
16 226 unexposed persons
50% females
Age: <1 15 (7.1)

United Kingdom

SwedenNational origin

Population studied

Characteristics











Benign lesions inlocomotor system[D12, J2]

Type of study



Study















Table 2 (continued)

X-ray therapy

Radiotherapy

X-ray therapy

X-ray therapy

X-ray therapy

X-ray induced
epilation

X-ray induced
epilation

X-ray therapy

X-ray therapy

Type of exposure

Individual doses fromtherapy records andphantom measurements

Individual doses fromtherapy records

Individual doses fromtherapy records andphantom measurements

Individual doses fromtherapy records

Individual doses fromtherapy records

Representative doses
based on standard
treatment

Individual doses fromphantom measurements
based on institution andage

Individual doses forleukaemia cases and a
1 in 15 sample of the
population

Individual red bonemarrow doses fromtherapy records andphantoms

Type of dosimetry

Breast*, all other sites

Thyroid*

Skin*, thyroid*, benign parathyroid*,
salivary gland*, neural tumours*

Thyroid*, breast*, skin

Breast*Thyroid*, skin*, brain, leukaemia,
salivary gland

Incidence: thyroid*, skin*, brain*,salivary gland*, breast
Mortality: head and neck*, leukaemia*

Leukaemia*, other neoplasms* (except
colon)

Leukaemia*, non-Hodgkin's lymphoma,
Hodgkin's disease, multiple myeloma

Cancers studied b

368
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

4 153 exposed women
Age: 13 88(46.6)

1 195 exposed persons
1 063 unexposed persons
40% females
Age: 0 17 (6.9)

Mortality

Incidence/Prevalence

Mortality

Incidence

Mortality

Mortality

Case-control
565 leukaemia
318 NHL
208 multiple
myeloma
1 390 controls

Benigngynaecologicaldisease[I6, I16]

Lymphoid
hyperplasia
screening[P8]

Peptic ulcer[G6]

Massachusetts TB
fluoroscopy[B3, S30]

Massachusetts TB
fluoroscopy[D4]

Canadian TB
fluoroscopy[H7, H20]

Diagnostic x rays
(US health plans)
[B39]



2 203 exposed persons
278 unexposed persons
39% females
Age: 15 >50

25 007 exposed persons
39 165 unexposed persons
50% females
Age: <20 >35 (28)6 285 exposed persons
7 100 unexposed persons
49% females
Age: 12 50 (26)2 367 exposed women
2 427 unexposed women
Age: 12 50 (26)











1 831 exposed persons
1 778 unexposed persons
21.2% females
Age: <35 >55(49)

United States

CanadaUnited States

United States

United States

United States

United States

United Kingdom

2 067 exposed women
Age: 35 60

Mortality

Metropathia
haemorrhagica[D7]

National origin

Characteristics

Population studied

Total
personyears a53 144

Followup(years)
5 >30

66 000
(29)

12 44

n.a.

0 57

0 >50

0 >50

n.a.

1 608 491
(25.1)

331 206(24.7)

54 609(11.4)

Diagnostic examinations

20 51
77 757(21.5)

109 910(26.5)

0 60







Type of study









Study





Table 2 (continued)

Diagnostic x raysMultiple x-ray chest
fluoroscopies

Multiple x-ray chest
fluoroscopies

Multiple x-ray chest
fluoroscopies

X-ray therapy

Average dose based on
number and type ofprocedures and estimateddoses from publishedliterature

Individual exposuresfrom medical records
and doses from phantom
measurements

Individual exposuresfrom medical records
and doses from phantom
measurements andcomputer simulations

Individual exposuresfrom medical records
and doses from phantom
measurements andcomputer simulations

Individual doses fromtherapy records andexperimental
measurements

Individual doses fromtherapy records andphantom measurements

Individual doses fromtherapy records andphantom measurements

Intrauterine 226Ra

X-ray therapy

Individual doses fromtherapy records andphantom measurements

Type of dosimetry

X-ray therapy

Type of exposure

Leukaemia, non-Hodgkin’s lymphoma,
multiple myeloma

Lung, breast*

Breast*, oesophagus*, lung, leukaemia

Breast*, skin

Stomach*, colon, pancreas*, lung*,
leukaemia*,female breast, oesophagus,
rectum, liver, larynx, bone andconnective tissue, bladder, prostate,kidney, brain, thyroid, non-Hodgkin’s
lymphoma, Hodgkin’s disease, myeloma

Thyroid nodular disease*

Leukaemia*, other haematolymphopoietic
cancers, uterus*, bladder*, rectum*, othergenital*, colon, bone (in pelvis), liver andgallbladder, stomach, kidney, pancreas*

Pelvic sites*, leukaemia* multiple
myeloma*, lymphoma, all other sites m

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER369

3 797 exposed persons
25 185 unexposed persons
56 % females
Exposure: in utero

1 506 exposed persons
14 130 unexposed persons
49.2 % females
Exposure: in utero

Mortality

Case-control
14 491 cases
14 491 controls

Case-control
1 342 cases
14 292 controls

Mortality

Scoliosis[D34]

Oxford Survey ofChildhood
Cancers[S1, B2, M29]

NE USA
childhood cancers[M9]

Nuclear workers
in Japan[E3]

114 900 men

4 822 exposed women
644 unexposed women
Age: <3 10 (10.6)

3->60

218 976(40.1)

Diagnostic x-rays

Diagnostic x rays

Diagnostic x rays

Medical and dental
diagnostic x rays

Type of exposure

Japan

United States

United Kingdom

n.a.

n.a.

Up to 5533 168(4.6)

Occupational exposure

20(max.)

16(max.)

Prenatal exposure

Exposures innuclear power
plants, fuelprocessing, andresearch facilities

Maternal x rays
during pregnancy

Maternal x rays
during pregnancy

EXTERNAL LOW-DOSE OR LOW-DOSE-RATE EXPOSURES

United States

n.a.

5 >50

Sweden736 exposed persons
232 unexposed persons
77% females
Age: <20 >60

Case-control
484 cases
484 controls

Diagnostic x rays
(Sweden)
[I9]

n.a.

3 20

United States

39% females

Case-control
130 cases
130 controls

Diagnostic x rays
(Los Angeles)
[P10]

n.a.

2 64

United States

National origin

Total
personyears aFollowup(years)62% females

Characteristics

Population studied

Case-control
408 cases
408 controls

Type of studyMedical anddental x rays
(Los Angeles)
[P35]

Study







Table 2 (continued)

Recorded exposures toexternal radiation

Number of exposures

Number of exposureswith a model for dose
per exposure

Average dose based on
number of treatments
and estimated doses frompublished literature

Average dose based on
number and type ofprocedures and estimateddoses from publishedliterature

Average dose based on
number and type ofprocedures and estimateddoses from publishedliterature

Average dose based on
number and type ofprocedures and estimateddoses from publishedliterature

Type of dosimetry

Leukaemia, all other cancers

Leukaemia*, solid tumours

Leukaemia*, all solid tumours*

Breast*Thyroid

Chronic myeloid leukaemia*

Parotid gland*

Cancers studied b

370
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

124 743 monitored workers
9% females

10 028 monitored workers
3 711 other workers
19% females

21 344 monitored workers
18 071other workers
8% females

9 389 monitored workers
12 463 other workers
9% females

2 209 monitored workers
419 other workers
14% females

206 620 monitored workers
49% females

11 355 monitored workers
24% females

32 643 monitored workers
24% females

Mortality

Mortality /Incidence

Mortality /Incidence

Mortality

Mortality/
Incidence

Mortality

Mortality

Mortality

Mortality

National Registryfor Radiation
Workers, U.K.
[M46] oSellafield[C19, D21] p

UK Atomic
Energy Authority[C19, F6] p

UK Atomic
Weapons
Establishment[C19, B24] p

Chapelcross[B38, M50]

National Dose
Registry ofCanada [A21] r

Atomic Energy ofCanada Ltd.
[C11, G16] s

Hanford[G12, G17] t

Oak Ridge:
X-10 and Y-12
plants [F5]28 347 men

95 673 workers
15% females

Characteristics

United States(white)United States

CanadaCanadaUnited Kingdom

United Kingdom

United Kingdom

United Kingdom

United Kingdom

CanadaUnited Kingdom
United States

National origin

Population studied

Mortality

Type of study

Nuclear workers
in Canada, United
Kingdom andUnited States[C11] nStudy

Table 2 (continued)

Up to 40

Up to 43

Up to 30

Up to 47

Up to 41

Up to 37

Up to 42

Up to 40

Up to 47

Up to 43

Followup(years)Nuclear and reactor
research and fuelprocessing
Weapons research

534 000 q(25)
216 000 q
(23)

n.a.

633 511(19.4)

198 210(17.5)

2 861 093
(13.8)

Exposures innuclear fuel cycle
and research

Exposures innuclear fuel cycle
and research

Nuclear and reactor
research and related
technologies

Dental, medical,
industrial andnuclear power

Reactor operation

Fuel processing andreactor operation

260 000 q(26)

63 967(24.3)

Exposures innuclear power
plants, fuel cycle,
defence, andweapons production

Exposures innuclear power
plants, fuelprocessing, andresearch facilities

Type of exposure

2 063 300
(16.5)

2 124 526
(22.2)

Total
personyears aRecorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Type of dosimetry

Leukaemia, all other cancers

Leukaemia, all other cancers

Leukaemia, all other cancers

Leukaemia, all other cancers

Buccal cavity and pharynx, prostate,
all cancers combined

Leukaemia, all other cancers

Leukaemia, all other cancers

Leukaemia, all other cancers

Leukaemia, all other cancers

Leukaemia, all other cancers

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
371

78 600(18.8)

797 781
(7.0)

n.a.

Up to 33

0 9

2 7

United States(white)RussianFederation

RussianFederationMales
3 229 monitored workers
953 other workers

114 504 male workers
Age: <2- 61

Males
87.3% with doses
above 0.05 Sv
Age: <20 >55

4 742 men
Age: <30 >60

Mortality

IncidenceCase-control
34 cases
136 controls
from a cohort of155 680 men

Mortality
Incidence

Mortality

Case-control
157 cases
346 controls

Mound facility[W21]

Chernobyl
clean-up workers:
Russian Fed.
(cohort)[I13, I21] uChernobyl
clean-up workers:
Russian Fed.
(Leukaemia
case-control)[I14]

Chernobyl
clean-up workers:
Estonia[I10, R20, T13]

Mayak workers[K10, K11,
K32, K34]

Mayak workers:
stomach cancer
study
[Z1]

40 persons with external
doses above 3 Gy
463 with lower doses
10% females

15 601 persons monitored
for external radiation
3 229 other workers
25% females v
RussianFederation

RussianFederation

Estonia

118 749(26)

Up to 45

United States

4 563 monitored workers
6% females

Mortality

Rocketdyne /Atomics
International
[R27]

n.a.

Up to 26

United States(white)Males
8 960 monitored workers
15 585 other workers

Mortality

Portsmouth Naval
Shipyard[R12]

81 237(13.6)Up to 32

United States(white)National origin

Total
personyears aFollowup(years)5 952 men

Characteristics

Population studied

211 427(31.8) w

0 46

Up to 37n.a.

30 643
(6.5)

0 7









Mortality

Type of study







Rocky Flats[G12, W12]

Study

Table 2 (continued)

Exposures innuclear fuel cycle
and research

Exposures innuclear fuel cycle
and research

Emergency andrecovery work in
the vicinity ofChernobyl

Emergency andrecovery work in
the vicinity ofChernobyl

Emergency andrecovery work in
the vicinity ofChernobyl

Exposures at anuclear researchand production
facility

Exposures at anuclear researchand production
facilityWork onoverhauling andbuilding nuclear
submarines

Exposures innuclear fuel cycle
and research

Type of exposure

Leukaemia, all other cancers

Leukaemia, all other cancers

Digestive*, respiratory, thyroid, all solid
tumours combined, leukaemia*

Leukaemia

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Assessed externalradiation dose

Assessed externalradiation dose

Recorded exposures toexternal radiation andmeasurements ofplutonium

Recorded exposures toexternal radiation

Stomach*Lung, leukaemia*

Thyroid, all other sites

Leukaemia, all lymphatic and haematopoietic neoplasms, all cancers combined

Recorded exposures toexternal radiation

Recorded radiation doses

Leukaemia, all other cancers

Cancers studied b

Recorded exposures toexternal radiation

Type of dosimetry

372
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

10

Italy

Males
Age at diagnosis:
35 80 (68)
76% with gamma dose
rate above 300 nGy h 1

Case-control
44 cases
211 controls

Incidence

Incidence/
Mortality

Incidence/
Mortality

Central Italy[F7]

Diagnostic 131I
[H4, H12,
H27] ySwedish 131I
hyperthyroidism[H23, H24] z

United States
thyrotoxicosis
patients[D22, R14,
S36] bb

23 020 exposed persons
12 573 unexposed persons
79% females
Age: <10 80

10 522 exposed persons
82% females
Age: 13 70

34 104 exposed persons
80% females
Age: 1 75 (43)n.a.

1 698 350
(13.6)

Gamma radiation
Radon

Continuous
backgroundradiationWork in radiotherapy departments

Radiology

Type of exposure

0 45

1 26

5 39

738 831(20.8)

139 018(13.6)

653 093(19.1)

Medical exposures

Treatment ofhyperthyroidism

Treatment ofhyperthyroidism

Diagnostic 131I

INTERNAL LOW-DOSE-RATE EXPOSURES

United States

SwedenSwedenUp to 17China

89 694 persons in highbackground area
35 385 persons
in control area
50% females
All ages

Mortality

Yangjiang[A11, S35,
T12, T25,
T26, Z2 x]

49 553(11.9)

n.a.

Total
personyears aNatural radiation

Up to 32

Denmark

4 151 persons
Age: <20 50

Incidence

Danish radiotherapy staff[A15]

Up to 28

Japan

Followup(years)9 179 radiological
technologists(2 300 with recorded
doses)

National origin

Population studied

Characteristics









Mortality

Type of study











Japaneseradiological
technologists
[A25]

Study

Table 2 (continued)

Individual values ofactivity administered;organ-dose estimates

Average administeredactivity (multiple
treatments)

Individual values ofactivity administered;organ dose estimates forthyroid

Measurements in lastdwelling occupied andcharacteristics ofdwellings

Individual estimates,
both direct (TLD
measurements) andindirect (environmental
measurements andoccupancy patterns)

Recorded exposures toexternal radiation

Recorded exposures toexternal radiation

Type of dosimetry

Buccal cavity, oesophagus, stomach,colorectal, liver, pancreas, larynx, lung*,
breast*, uterus, ovary, prostate, bladder,kidney*, brain and other central nervous
system tumours, thyroid*, lymphoma,
myeloma, leukaemia

Stomach*, kidney*, brain*, all othersites aa

Thyroid, leukaemia, all other sites

Acute myeloid leukaemia

Leukaemia, all other sites

Leukaemia, prostate*, all other cancers

All cancers combined*, oesophagus,
stomach, colorectal, lungCancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
373

834 exposed persons
1 121 unexposed persons
75% females
Age: 5 75 (48)846 persons withtherapeutic exposures
501 persons withdiagnostic exposures
274 unexposed persons
79 % females
Age: 5 89 (40)

Incidence

Incidence

Mortality

Case-control
107 cases
214 controls

PrevalencePrevalence

Swedish 131I
thyroid cancer[H26]

Frenchtherapeutic 131I
[D18]

Techa River
population[K5, K27]

Chernobyl-related
exposure in
Belarus[A26]

Marshall Islands
fallout[H35, R21]

Utah 131I fallout:
thyroid disease[K36]

Belarus52% females
Age: 0 16

2 473 persons

2 273 exposed persons
55% females
Age: 5 >60
United States

Marshall Islands

RussianFederation (ethnic
Russians andTartars/ Bashkirs)







26 485 exposed persons
58% females
Age: 0 96 (29)FranceSwedenUnited Kingdom

7 417 exposed persons
83% females
Age: 49 70 (57)

Incidence/
Mortality

National origin

Characteristics

Population studied

Iodine-131
hyperthyroidism,
United Kingdom[F8]Type of study

14 615
(10)

12 17
and
32 33 cc

29 31

Up to 6Up to 39

n.a.

n.a.

n.a.

n.a.

Type of exposure

Diagnostic andtherapeutic 131I
exposures forthyroid cancer
patients

Treatment of
thyroid cancer

Treatment of hyperthyroidism

Fallout from nuclear
weapons tests

Short-lived
radionuclides from
nuclear explosion

Internal exposure toradioactive iodine inareas contaminatedby the Chernobyl
accident

Internal andexternal exposuresto radioactive waste
discharged by
nuclear weapons
production plant

Environmental exposures

2 37

2 34
25 830(13.2)

72 073
(9.7)

20

1

Total
personyears aFollowup(years)











 

Study







Table 2 (continued)

Based on residence
histories and fallout
deposition records

Estimated average dose;
distance was also used asa surrogate

I dose estimated fromground deposition of137
Cs and 131I,
contemporary thyroid
radiation measurements,and from questionnaires
and interviews

131

Dose reconstruction
based on environmental
measurements of gamma
dose rate and wholebody counting

Individual values ofactivity administeredand organ dose estimates

Individual values ofactivity administered

Individual values ofactivity administered

Type of dosimetry

ThyroidThyroidThyroid*

Leukaemia*, lymphoma, stomach, liver,lung, breast, bone, all other sites

Colon, leukaemia, all other sites

Leukaemia, salivary glands*, kidney*,
all other sites

Thyroid*, bladder, uterine, small bowel*,all other sites

Cancers studied b

374
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
aa
bb
cc

United States

United Kingdom

Males
Age at diagnosis:<65 >75
14% of subjects with
documented internal
exposure

National origin

92 persons with bonemarrow doses of
6 mGy or more
6 415 persons withlower doses

Characteristics

Population studied

n.a.

Total
personyears a

n.a.

n.a.

Occupational exposures

Up to 30

Followup(years)Exposures innuclear fuel cycle
and research

Fallout from nuclear
weapons tests

Type of exposure

Urine measurements andwhole-body monitoring

Based on residence
histories and fallout
deposition records

Type of dosimetry

Prostate*

Leukaemia

Cancers studied b

Mean per person in parentheses.
An asterisk denotes sites for which statistically significant excesses are reported in the exposed group (cohort studies) or for which a higher proportion of the cases were exposed to radiation (case-control studies).
Exposed to more than 0.005 Sv weighted colon dose.
Age at exposure, mean in parentheses.
Exposed to more than 0.01 Sv weighted colon dose.
5 42 years for leukaemia and lymphomas [P4].
Based on the follow-up for solid cancer [T1].
Figures quoted are for the mortality study [D14]. Exposure denotes doses above 0.01 Sv.
Not available.
Figures quoted in [L16].
Figures quoted are for the leukaemia study [W2].
Figures quoted in [S21].
Significance tests based on 5-year survivors (2 years for leukaemia).
Includes workers in studies [B24, C19, D21, F6, G12, G16, G17, W12, W23].
Includes workers in studies [B24, B38, C19, D21, F6].
Figures quoted are from [C19].
Values for monitored workers only.
Includes workers in study [G16].
Figures quoted are from [C11].
Figures quoted are from [G12].
Figures quoted are from [I21].
Figures quoted are from [K32].
Figures are for males employed before 1959 [K34].
Figures quoted are from [T25, T26].
Figures quoted are for the thyroid cancer study [H4].
Figures quoted are for the incidence study [H23].
Significance tests based on 10-year survivors.
Figures quoted are from [R14].
Periods of thyroid examinations, relative to the peak fallout in 1953 [K36].

Case-control
136 cases
404 controls

UK Atomic
Energy Authority:
prostate cancer
study
[R26]

Type of study

Case-control

Utah 131I fallout
[S37]

Study



Table 2 (continued)

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
375

376

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 3
Strengths and limitations of major cohort and case-control epidemiological studies of carcinogenic effects
of exposures to low-LET radiation

Study

Strengths

Limitations

EXTERNAL HIGH-DOSE-RATE EXPOSURES
Exposures to atomic bombings
Life Span Study[P4, P9, T1]

Large population of all ages and both sexes notselected because of disease or occupation
Wide range of doses
Comprehensive individual dosimetry
Survivors followed prospectively for up to 45 years
Complete mortality ascertainment
Cancer incidence ascertainment

Acute, high-dose-rate exposure that provides
no direct information on effects of gradual
low-dose-rate exposures
Restriction to 5-year survivors for mortality(13 years for incidence)
Possible contribution of neutrons somewhat
uncertain
Possible effects of thermal or mechanical injury andconditions following the bombings uncertain

Survivors of atomic
bombings (in utero)[D14, Y1]

Not selected for exposure
Reasonably accurate estimate of dose
Mortality follow-up relatively complete
Follow-up into adulthood

Small numbers of exposed individuals and cases
Incidence determination may not be complete
Mechanical and thermal effects may have influenced
results

Treatment of malignant disease
Cervical cancer cohort[B11, B12, B50]

Large-scale incidence study based on tumour registry
records
Long-term follow-up
Relatively complete ascertainment of cancers
Non-exposed comparison patients

Very large doses to some organs result in cell killing
and tissue damage
Potential misclassification of metastatic disease forsome organs
Potential misclassification of exposure
No individual dosimetry
Characteristics of patients with cervical cancer differ
from general population

Cervical cancer casecontrol[B1]

Comprehensive individual dosimetry for many organs
Dose-response analyses
Other strengths as above [B11]

As above [B11], except problems with individual
dosimetry and comparison with general population
now removed
Small number of non-exposed cases
Partial-body and partial-organ dosimetry complex

Lung cancer following
breast cancer[I7]

Individual estimates of radiation dose to different
segments of the lungs
Large number of non-irradiated patients
Most patients did not receive chemotherapy
Substantial proportion of patients withover 20 years of follow-up

Small number of lung cancers
Lack of data on individual smoking habits
Potential inaccuracies in partial-body dosimetry

Contralateral breast cancer[B10, S20]

Large numbers of incident cases within populationbased tumour registries
Individual radiation dosimetry
Wide range of doses

Limited number of young womenPossibility of over matching, resulting in someconcordance of exposure between cases and controls
Possible misclassification of metastases or recurrence

Soft-tissue sarcoma
following breast cancer[K35]

Incident cases identified from a population-based
tumour registry

Analyses based on estimates of energy imparted fromradiotherapy (i.e. product of the mass of the patient
and the absorbed dose), rather than organ dose

Leukaemia following
breast cancer[C9]Comprehensive individual dosimetry for bonemarrow compartments
Comprehensive ascertainment of treatment
information to separate chemotherapy risk
Dose-response analyses

Very large high-dose partial-body exposure to chest
wall, probably resulting in cell-killing

Leukaemia following
cancer or the uterine corpus[C10]

Large number of incident cases with populationbased cancer registries
Comprehensive individual dosimetry for bonemarrow compartments
Attempt to adjust for chemotherapy
Large non-irradiated comparison group
Dose-response analyses covering doses below
1.5 Gy as well as above 10 Gy

Effects of cell-killing at high doses
Potential inaccuracies in partial-body dosimetry

Lung cancer following
Hodgkin's disease(international)[K9]

Individual estimates of radiation dose to the affectedlungSome data on individual smoking habits
Detailed information on chemotherapy
Relatively large number of cases

Smoking data limited, and reported more fully forcases than for controls
Follow-up period generally less than 10 years

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

377

Table 3 (continued)
Study

Strengths

Limitations

Lung cancer following
Hodgkin's disease(Netherlands)[V2]

Individual estimates of radiation dose to the area ofthe lung where the tumour developed
Individual data on smoking habits
Extensive data on doses from chemotherapy

Small number of cases
Limited follow-up (median 10 years)
Few females

Breast cancer following
Hodgkin's disease[H2]

Individual assessment of doses
Analysis by age at exposure

Small number of cases
Limited follow-up
Mostly very high doses (>40 Gy)

Leukaemia following
Hodgkin's disease(international)[K40]

Individual radiation dosimetry
Detailed information on chemotherapy

Follow-up period generally less than 10 years

Leukaemia following nonHodgkin's lymphoma(international)[T6]

Comprehensive individual dosimetry forbone marrow compartments
Detailed information on chemotherapy

Small number of cases
No dose-response analysis, other than separation
into two groups

Leukaemia following nonHodgkin's lymphoma(United States)[T15]

Individual dosimetry for bone marrow
Detailed information on chemotherapy

Very small cohort; few cases
No comparison group of unexposed patientsChildhood cancers(international)[T5, T7, T17]

Comprehensive individual dosimetry to estimate
organ doses
Attempt to adjust for drug exposure
Dose-response analyses

Only high-dose exposures
Potential for some overmatching since hospital-based
Complete dosimetry not always available

Childhood cancers(France/United Kingdom)[D19, D33]

Incidence follow-up
Doses from radiotherapy and chemotherapy estimatedIndividual dose estimates generally not used in analyses
Lack of external comparison group
Small numbers for specific types of cancers

Bone cancer and leukaemia
after childhood cancer(United Kingdom)[H44, H11]

Incidence follow-up
Individual dosimetry
Information available on chemotherapy

Retinoblastoma[W11]Long-term incidence follow-up
Individual dose estimates for bone and soft sarcoma
sites
Wide range of doses

Little information on chemotherapy
Most of the findings concern doses of 5 Gy or more

Thyroid cancer following
childhood cancers[D20]

Incidence follow-up
Individual organ dose estimates
Wide range of thyroid doses

Lack of external comparison groupChildhood Hodgkin's
disease[B16]

Cohort of persons exposed at young ages to highradiation doses
Individual dosimetry
Information available on chemotherapy doses

Small numbers of cases
No formal modelling of dose-response or ofchemotherapy effects

Most of the findings concern doses of 5!10 Gy or more

Treatment of benign disease
Childhood skinhaemangioma[K23, L13, L15, L16,
L17, L24, L46]

Long-term and complete follow-up
Comprehensive individual dosimetry for many organs
Incidence ascertained
Protracted exposure to radium plaques

Relatively small numbers of specific cancers

Benign lesions inlocomotor system[D12, J2]

Long-term and complete follow-up
Individual dose estimates
Incidence and mortality ascertained

Uncertainties in computing individual doses to sites, based
upon a sample of records

Ankylosing spondylitis[W1, W2]

Large number of exposed patients
Long-term and complete mortality follow-up
Detailed dosimetry for leukaemia cases andsample of cohort
Small non-exposed group evaluated for generalreassurance that leukaemia risk was unrelated
to underlying disease

Comparisons with general population
Underlying disease related to colon cancer andpossibly other conditions
Individual dose estimates available only forleukaemia cases and a 1 in 15 sampleof the population

Israel tinea capitis[R5, R9, R16, R17]

Large number of exposed patients
Two control groups
Ascertainment of cancer from hospital records andtumour registry
Individual dosimetry for many organs

Dosimetry for some sites (e.g. thyroid) uncertain, owing
to possible patient movement or uncertainty intumour location
Limited dose range

378

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 3 (continued)
Study

Strengths

Limitations

New York tinea capitis[S27, S30]

Relatively good dose ascertainment for skin and othercancers

Small number of cancers
No recent follow-up information
Few females

New York post-partum
mastitis[S15, S30]

Individual estimates of breast dose from medical
records
Breast cancer incidence ascertained
Dose-response analyses

All exposed women were parous, but comparison
women were not (380 non-exposed and sisters ofboth exposed and non-exposed)
Inflamed and lactating breast might modify
radiation effectRochester thymic
irradiation[H10]

Individual dosimetry for thyroid and some other sites
Sibling control groupLong follow-up
Fractionation effects could be evaluatedDose-response analyses

Radiation treatment fields for newborns varied, anddosimetry uncertain for some sites
Adjustment in analysis for sibship size uncertain
Questionnaire follow-up may have resulted inunder-ascertainment of cases

Tonsil irradiation[S21, S28, S30]

Individual dosimetry for thyroid and some other sites
Long follow-up
Large numbers of cases for certain sites
Dose-responses analyses

Effect of screening on ascertainment of thyroid cancer
and nodules
No unexposed control group

Tonsil, thymus or acne
irradiation[D5]

Long period between exposure and examination
Prospective as well as retrospective follow-up

Possible screening effect
Small cohort
No unexposed control group

Swedish benign breastdisease[M8, M20, M28]

Incidence study with long-term follow-up
Individual dosimetry for many organs
Fractionated exposure
Unexposed control group

Lack of data on potential confounders
Small numbers for most cancer types, other than breast

Benign gynaecologicaldisease[D7, I6, I16]

Large number of exposed women
Non-exposed women with benign gynaecologicaldiseaseVery long mortality follow-up
Individual dosimetryProtracted exposures to radium implants (10-24 hours)
Dose-response analyses

Uncertainty in proportion of active bone-marrow
exposedSmall numbers of specific types of cancer
Misclassification on certain cancers on deathcertificates (e.g. pancreas)

Lymphoid hyperplasia
screening[P8]

Individual dosimetry
Comparison of questionnaire and clinicalexamination results
Comparison group treated by surgery for the same
condition

Apparent bias in questionnaire data, owing to
self-selection of subjects
Clinical examinations provide data on prevalence
rather than incidence
Study of thyroid nodules; cancer cases not confirmed

Peptic ulcer[G6]

Individual dosimetryNon-exposed patients with peptic ulcer
Exceptionally long follow-up (50 years)
Some risk factor information available in records

Standardized radiotherapy precluded dose-response
analysesNon-homogeneous dose distribution within organs,such that simple averaging may be misleading
Metastatic spread on stomach cancer probably
misclassified as liver and pancreatic cancer on deathcertificates
Possible selection of somewhat unfit patients forradiotherapy rather than surgery

Diagnostic examinations
Massachusetts TB
fluoroscopy[B3, D4, S30]

Incidence study with long-term follow-up (50 years)
Individual dosimetry based on patient records andmeasurements
Non-exposed TB patients
Fractionated exposures occurred over many years
Dose-response analyses

Uncertainty in dose estimates related to fluoroscopic
exposure time and patient orientation
Questionnaire response probably under-ascertainedcancers
Debilitating effect of TB may have modified radiation
effect for some sites, e.g. lungDiagnostic x rays
(US health plans)[B39]

Information on diagnostic x rays abstracted frommedical records
Surveillance bias unlikely, since cases and controls
were at equal risk for having x-ray procedures
recorded and malignancy diagnosed

Potential for ascertainment bias, e.g. through early
diagnosis of a malignancy
Analyses based on number of x-ray procedures rather
than actual doses

Canadian TB fluoroscopy[H7, H20]

Large number of patientsNon-exposed TB comparison group
Individual dosimetry for lung and female breast
Fractionated exposures occurred over many years
Dose-response analyses

Mortality limits comparisons with breast cancer
incidence series, e.g. time response
Uncertainties in dosimetry limit precise
quantification of risk
Different dose responses for female breast cancer
between one sanatorium and the rest of Canada
may indicate errors in dosimetry, differential
ascertainment, or differences in biological responseANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 3 (continued)
Study

Strengths

Limitations

Diagnostic medical anddental x rays
(Los Angeles) [P10, P35]

Dosimetry attempted based on number and typeof examinations

No available records of x rays
Potential for recall bias in dose assessment
Doses likely to have been underestimatedDiagnostic x rays
(Sweden)[I9]

Information on diagnostic x rays over many years
abstracted from medical records

Analyses based on number and type of x-ray procedures
rather than actual doses

Scoliosis[D34]

Adolescence possibly a vulnerable age for exposure
Dosimetry undertaken based on number of films andbreast exposure
Dose-response analysis

Comparison with general population potentiallymisleading, since scoliosis associated with several
breast cancer risk factors (e.g. nulliparity)
Dose estimates may be subject to bias as well as random
error

EXTERNAL LOW-DOSE OR LOW-DOSE-RATE EXPOSURES

Prenatal exposures
Oxford Survey ofChildhood Cancers[S1, B2, M29]

Very large numbers
Comprehensive evaluation of potential confounding
Early concerns over response bias and selection bias
resolved

Uncertainty in fetal dose from obstetric x-ray
examinations
Similar relative risks for leukaemia and other cancers
may point to possible residual confounding

North-eastern United Stateschildhood cancers[M9]Large numbers
Reliance on obstetric records

Uncertainty in fetal dose

Occupational exposures
Nuclear workers

Often large numbers
Personal dosimetry
Low-dose fractionated exposures
Could provide useful information in future

Low doses make clear demonstration of radiation effectdifficult
Possibly confounding influence of chemical and othertoxic exposures in workplace
Healthy worker effectMortality follow-up
Lifestyle factors (e.g. smoking histories) generally notavailable

Chernobyl clean-up
workers

Often large numbers
Low-dose fractionated exposures
Could provide useful information in future

Difficulties in assessing individual exposures
Possible differences in cancer ascertainment relative tothe general population
Short period of follow-up so far

Mayak workers[K10, K11, K32,
K34, Z1]

Wide range of exposures
Individual measurements of external gamma dose andplutonium body burden
Individual information on potential confounders instomach cancer study

Possible uncertainties in assessment of exposures
Further details of ascertainment of stomach cancer casesand controls desirable

Medical workers

Often large numbers
Low-dose fractionated exposures over long periods

General lack of information on individual doses
precludes usefulness to date

Natural radiation
Yangjiang[T12, A11, Z2, S35,
T25, T26]

Large cohorts in high background and control areas
Stable population
Extensive dosimetry for region
Assessment of potential confounders

Mortality follow-up
Small numbers for some cancer types
Low doses

Central Italy[F7]

Individual measurements of domestic gamma
radiation and radon

Small number of cases
Mortality data only
Measurements only in last home
Low doses

INTERNAL LOW-DOSE-RATE EXPOSURES

Medical exposures
131

Swedish I thyroid cancer[H23, H24]

Large numbers
Nearly complete incidence ascertainment
Administered activities of 131I known

Comparison with general population
Dose-response not based on organ doses
High-dose cell-killing probably reduced possible thyroid
effectPatients selected for treatment

379

380

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 3 (continued)
Study

Strengths

Limitations

Diagnostic 131I
[H4, H12, H27]

Large numbers
Unbiased and nearly complete ascertainment ofcancers through linkage with cancer registry
Administered activities of 131I known for each patient
Organ doses to the thyroid computed with some
precision
Dose-response analyses for thyroid cancer andleukaemia, based on wide range of doses
Low-dose-rate exposure

Comparison with general population only, except forthyroid cancer and leukaemia
Reason for some examinations related to high detectionof thyroid cancers, i.e. suspicion of thyroid tumour
was often correct
Doses to organs other than thyroid very low
Population under surveillance

United States
thyrotoxicosis
patients[D22, R14, S36]

Large numbers of patients treated with 131I
Large non-exposed comparison groups
Comprehensive follow-up effort
Administered activities of 131I known

Individual doses computed only for certain organs
Mortality follow-up
Few patients irradiated at young ages
Possibility of selection bias by treatment

Swedish 131I thyroid cancer[H26]

Incidence follow-up
Administered activities of 131I known
Unexposed group

Individual doses not computed
Small numbers for specific cancer types
Few patients irradiated at young ages
Possibility of selection bias by treatment

French therapeutic 131I
[D18]

Incidence follow-up
Administered activities of 131I known
Exclusion of patients who received external
radiotherapy
Unexposed group

Individual doses not computed
Small numbers for specific cancer types
Few patients irradiated at young ages
Possibility of selection bias by treatment

Environmental exposures
Techa River population[K5, K27]

Large numbers with relatively long follow-up
Wide range of estimated doses
Unselected population; attempted use of local
population rates for comparison
Possible to examine ethnic differences in cancer risk
Potential for future

Dosimetry difficult and not individual
Mixture of internal and external exposures complicatesdosimetry
Follow-up and cancer ascertainment uncertain
Contribution of chemical exposures not evaluatedChernobyl-related
exposure[A26]

Large numbers exposed
Wide range of thyroid doses within the states of theformer Soviet Union

Mixture of radioiodines and availability of data
make dose estimation difficult, particularly for
individuals
Possible differences in cancer ascertainment relative
to the general population
Fairly short period of follow-up so far

Marshall Islands fallout[H35, R21]

Population unselected for exposure
Comprehensive long-term medical follow-up
Individual dosimetry attempted

Mixture of radioiodines and gamma radiation preclude
accurate dose estimation
Surgery and hormonal therapy probably influenced
subsequent occurrence of thyroid neoplasms
Small numbers

Utah 131I fallout:
thyroid disease[K36]

Comprehensive dosimetry attemptedProtracted exposures at low rate

Possible recall bias in consumption data used for risk
estimation
Possible under-ascertainment of disease in low-dose
subjects
Small number of thyroid cancers

Utah 131I fallout[S37]

Comprehensive dosimetry attempted
Large number of leukaemia deaths
Protracted exposures at low rate

Uncertainty in estimating bone marrow doses
Estimated cumulative doses lower than from natural
background radiation

UK Atomic Energy
Authority:
Prostate cancer study[R26]

Information abstracted for study subjects on sociodemographic factors, exposures to radionuclides,
external doses and other substances in theworkplaceCases and controls selected from an existing cohort

Occupational exposures
Exposure to some radionuclides tended to be
simultaneous, making it difficult to study them
individually1 131 exposed persons
1 032 unexposed persons
39% females
Age: 5 >65(34 for exposed,
40 for unexposed)

Mortality

Portuguese
thorotrast patients[D3, D31] g
Portugal

0 68

36 321(16.8)

10 077(14.5)

6 60

Sweden693 exposed persons
43% females
Ages: 2 66 (35)Mortality

Swedish thorotrast
patients[M48]

49 883(24.5)

1 >50

Denmark

800 exposed persons
1 236 unexposed persons
49% females
17% aged <20

Incidence/
Mortality

63 500(20.8)

23 400(28.8) d

Diagnostic examinations

0 51

0 54

n.a. eDanish thorotrast
patients[A4, A5] f

Total
personyears a
Type of exposure

Injection withthorotrast

Injection withthorotrast

Injection withthorotrast

Injection withthorotrast

Injection withRa

224

Injection with224
Ra

Treatment of benign disease

Follow-up(years)

3 >50

Germany

2 326 exposed persons
1 890 unexposed persons
26% females

German thorotrast
patients[V1, V8]

Mortality

Ra ankylosing
spondylitis patients[W3, W20]

Germany

National origin

Germany

Incidence

224

899 exposed persons
31% females
24% aged c 20 years

1 577 exposed persons
1 462 unexposed persons

Incidence

Ra TB andankylosing
spondylitis patients[H8, N4, N14,
S14]

224

Characteristics

Population studied











Type of study





Study

Table 4
Cohort and case-control epidemiological studies of the effects of exposures to high-LET radiation

Hospital records of amountinjected; dosimetric factors foralpha dose to liver

Records of amount injected

Records of amount injected;
dosimetric factors for dose toliver and bone marrow

Liver*, gallbladder, lung, bone*,nervous system, leukaemia(excluding chronic lymphatic)*,
unspecific sites, all neoplasms*

All malignant neoplasms*,
all benign neoplasms*

Liver*, leukaemia*, brain andnervous system*, lung, breast,
ovary, all other sites

Liver*, extrahepatic bile ducts*,
gallbladder, myeloid leukaemia*,pancreas*, myelodysplastic
syndrome*, non-Hodgkin's
lymphoma*, plasmacytoma,
larynx, bone sarcoma, lung,mesothelioma*, Hodgkin's
disease, lymphatic leukaemia,
kidney, bladder, prostate, adrenal,
brain, GI tract

Bone and connective tissue,
leukaemia*, non-Hodgkin's
lymphoma, Hodgkin's disease,stomach, liver, lung, urinary
system, female breast

Information on amount injected

Hospital records of amounts
injected; CT measurements ofsome patients; x-ray films

Bone*, breast*, connective
tissue*, liver*, kidney*, thyroid*,
ovary, leukaemia, pancreas,
uterus, prostate, bladder*,stomach, colon, lungCancers studied bInternal dosimetric calculations
based on amount injected

Type of dosimetry

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
381

150 exposed persons
Age: 15 39

2 543 females

4 186 persons withmeasured plutonium bodyburdens(1 479 males employed
before 1959)
14 644 other workers(5 174 males employed
before 1959)
25% females j

283 persons with Pu bodyburden > 0.75 kBq;
217 persons with lower
body burdens
11% females

Mortality

Incidence/
Mortality

Mortality

Mortality

Case-control
162 cases
338 controls

Incidence/
Mortality

Later Japanesethorotrast patients[K33, M14]

United Statesradium luminizers[C27, S12, S16,
S54] hUnited Kingdom
radium luminizers[B13, B14]

Mayak plutonium
workers[G23, K10,
K11, K32
K34, K42] iMayakradiochemical plant
workers:lung cancer study[T2]

Sellafield
plutonium workers[O1]

262 exposed persons
1 630 unexposed persons
Age: 20 39

Mortality

Characteristics

5 203 plutonium workers
4 609 of whom had
plutonium dose assessed
5 179 other radiation workers
4 003 non-radiation workers
19% females

1 203 females

n.a.

18 68

44 883119 020(46.8)

Work with radium

Ingestion of 226Ra
and 228Ra

Up to 46formortality;
up to 40for incidence

42(max.)

RussianFederation

415 432(29)

n.a.

211 427(31.8) k

Exposures toplutonium innuclear fuel cycle
and research

Exposures toplutonium innuclear fuel cycle
and research

Exposures toplutonium innuclear fuel cycle
and research

Occupational exposure: plutonium

47(max.)

0 71.5Up to 47

UnitedKingdom

Injection withthorotrast

Injection withthorotrast

Type of exposure

Occupational exposure: radium

34 65
n.a.

Total
personyears a

Follow-up(years)RussianFederation

UnitedKingdom

United States

Japan

Japan

National origin

Population studied

Early Japanesethorotrast patients[M14, M47]

Type of study







Study





Table 4 (continued)

Stomach, colon, pancreas, lung,
pleura, breast, prostate, bladder,brain and other central nervous
system tumours, ill-defined andsecondary, non-Hodgkin’s
lymphoma, leukaemia

Lung cancer*
Measurement of plutonium
in urine
Recorded exposures toexternal radiation
Measurement of plutonium
in urine
Recorded exposures toexternal radiation

Lung*, liver*, bone*

Breast, leukaemia, osteosarcoma,
all cancers combined

Bone sarcoma*, paranasal sinuses
and mastoid air cells*, stomach,colon, rectum, liver, lung, breast*,
pancreas, brain and other central
nervous system tumours,
leukaemia, multiple myeloma

Liver*, lung, leukaemia*

Liver*, lung, bone sarcoma,
leukaemia*

Cancers studied b

Measurement of plutonium
in urine
Recorded exposures toexternal radiation

Some measurements of bodyburdens
Assessments of external doses

Body burdens of about 1 500
women assessed bymeasurement of gamma rays
and /or exhaled radon; used for
calculation of systemic intake
and skeletal doseAmount injected

Amount injected

Type of dosimetry

382
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCERUp to 47

United States

UnitedKingdom

United States(white)3 775 males with Pu bodyburden of 74 Bq or more
11 952 males with lower
body burdens

17 605 workers monitored
for radionuclide exposure
23 156 other radiation
workers
8% femalesMales
3 490 workers with internal
exposure monitoring data
3 291 other workers
Age at entry: 16 64

4 402 males

23 012 males
Age at entry: (median 25)

Mortality

Mortality

Mortality

Mortality

Mortality

Los Alamos
workers[W8]

Three United
Kingdom industry
workforces[C33]

Oak Ridge,
Y-12 workers[C32]

Mound workers[W22]

Florida phosphateworkers[C34]

456 637(29)

52 772(9.7)

Total
personyears a

Exposures toplutonium innuclear fuel cycle
and research

Exposures toplutonium innuclear fuel cycle
and research

Type of exposure

United States

United States(white)Up to 44

Up to 40

Up to 33

Up to 43545 867(23.7)

104 326(23.7)

133 535(19.7)

1 020 000(25)

Exposures inmining andchemicalprocessing ofphosphate ores

Exposures innuclear fuel cycle
and research

Exposures innuclear fuel cycle
and research

Exposures innuclear fuel cycle
and research

Occupational exposure: others (excluding radon in mines)

Up to 28

United States

National origin

Follow-up(years)

5 413 males with external
and/or plutonium
exposures

Characteristics

Population studied

Mortality

Type of study

Rocky Flats
workers
[W12]

Study

Table 4 (continued)

Oral, oesophagus, stomach, colon,
rectum, liver, pancreas, lung,bone, skin, prostate, bladder,kidney, brain and other central
nervous system tumours, thyroid,
non-Hodgkin’s lymphoma,
Hodgkin’s disease, leukaemia
Lung
Assessments of cumulative
exposures to alpha andgamma radiation, based on
job histories

Lung, brain and other central
nervous system

Measurement of polonium in
urine

Urine measurements and wholebody monitoring of internallydeposited uranium

Lung, pleura, skin, uterus,
prostate, multiple myeloma,
leukaemia, other cancers

Oral, stomach, colon, rectum,
pancreas, lung, bone, prostate,
bladder, kidney, brain and othercentral nervous system tumours, alllymphatic/haematopoietic cancers

Measurement of plutonium
in urine
Recorded exposures toexternal radiation

Data on monitoring forplutonium, tritium, and otherradionuclides

Oesophagus, stomach, colon,
rectum, liver, pancreas, larynx, lung,skin, prostate, bladder, kidney, brain
and other central nervous system
tumours, non-Hodgkin’s lymphoma,
multiple myeloma, myeloid
leukaemia

Cancers studied b

Measurement of plutonium
in urine
Recorded exposures toexternal radiation

Type of dosimetry

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
383

111 286(12.6)Up to 17

China

China

Males
5 985 exposed
2 849 unexposed

13 649 exposed males
3 494 unexposed males
Age: <10 >30

Mortality

Mortality

Mortality

Mortality

Mortality

Mortality

Chinese iron andsteel workers[L49]

Chinese tin miners[D8, L4, X1] lWest Bohemia
uranium miners[D8, L4, T3,
T22] lColorado Plateau
uranium miners[D8, L4, H17] l

Ontario uranium
miners[D8, L4, K4] l

Newfoundland
fluorspar miners[D8, L4, M15] l

1 751 exposed males
337 unexposed males
Age: <20 >30

United States

3 347 exposed males
Age: <25 >45

CanadaCanadaCzech
Republic

4 284 exposed males
Age: <25 >45

0 >25

107 868(25.2)

82 435(24.6)

380 718(17.8)

48 742(23.3)

0 >25

0 >15

0 >15

175 342(10.2)

0 >25









21 346 exposed males
Age: <25 >45

Exposure tothoriumcontaining dust in
an iron and steel
company

Exposures innuclear fuel cycle
and research

Type of exposure

Radon in fluorspar
mines

Radon in uranium
and gold mines

Radon in uranium
mines

Radon in uranium
mines

Radon in tin mines

Occupational exposure: radon in mines

124 177(30.9)Up to 49

United States(white)National origin

Total
personyears a

Follow-up(years)

4 014 males
Age at entry: (30.4)

Characteristics

Population studied

Mortality

Type of study







Fernald workers[D32, R25]

Study

WL estimated from work
environment, architecture andventilation before 1960.
Systematic measurement
programme stated in 1968

Measurements of WL inuranium mines from 1957; nomeasurements in gold mines
before 1961, a few during the
1960s and 1970s and extensive
measurements thereafter

Measurements of radon
progeny during 1951 1968;
few measurements earlier

Measurements of radon
progeny after 1967; radonmeasured since 1949, withequilibrium values based onventilation

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung, leukaemia*

Assessment of lung doses frominhalation

Measurements of WL from
1972; reconstruction of earlier
valuesLung, respiratory tract, uppergastrointestinal tract, lower
gastrointestinal tract, bladder andkidney, haematopoietic andlymphopoietic neoplasms

Cancers studied b

Measurement of uranium,
thorium and radium compounds
in urine, plus environmental
area sampling
Recorded exposures to externalradiation

Type of dosimetry



Table 4 (continued)

384
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

1 294 exposed males
Age: <25 >30

3 457 exposed males
12 unexposed males
Age: <30 >40

6 895 exposed males
1 591 unexposed males
Age: <30 >45

1 420 exposed males
683 unexposed males
Age: <30 >45

1 457 exposed males
1 059 unexposed males
Age: <35 >40

1 769 exposed males
16 unexposed males
Age: <30 >40

Mortality

Mortality

Mortality

Mortality

Mortality

Mortality

Mortality

Case-control
505 cases
443 controls

Case-control
173 cases
254 controls

New Mexico
uranium miners[D8, L4, S19] l

Beaverlodge
uranium miners[D8, L4, H15,
H18] lPort Radium
uranium miners[D8, L4, H16] l

Radium Hilluranium miners[L4, W7] l

French uranium
miners[D8, L4, T8] lCornish tin miners[D8, H13]

United States acutelymphoblastic
leukaemia study[L34]

United States acute
myeloid leukaemia
study
[S52]

51% females
Age at diagnosis: 0 17
Mean time-weighted
average radon
concentration 53 Bq m 3(14% above 100 Bq m 3)

United States

United States

FranceAustralia

CanadaCanadaUnited States

SwedenNational origin

48% females
Age at diagnosis: 0 14
10% with time-weighted
average radon concentrations above 148 Bq m 3UnitedKingdom

2 535 males

Swedish ironminers[D8, L4, R8] lCharacteristics
33 293(25.7)

58 949(17.0)

0 >25

0 >15

66 900(26.4)

44 043(24.7)

51 850(21.9)

52 676(25.2)

n.a.

n.a.

n.a.

n.a.

Residential radon studies

0 >25

0 >25

0 >25

0 >25

0 >20
118 385(14.0)

Total
personyears a

Follow-up(years)Population studied

Radon in homes

Radon in homes

Radon in tin mines

Radon in uranium
mines

Radon in uranium
mine

Radon in uranium
mine

Radon in uranium
mine

Radon in uranium
mines

Radon in iron
mineType of exposure

Measurements of radon during
1954 1961, but not earlier

Measurements for 1945 1958;
no exposures estimated before
1940

Measurements of radon
progeny after 1967; radonmeasurements earlier, mainly
for control purposes

Extensive measurements; forindividual miners since 1969

Radon measurements madeduring 1968 1975, withestimation of WL using
characteristics of natural andmechanical ventilation

Type of dosimetry

Track-etch detector
measurements in homes
occupied by subject at time ofdiagnosis

Track-etch detector
measurements in homes
occupied by subjects

Monitoring of radon
concentrations since 1967; nomeasurements in previous
decades

Systematic monitoring after
1957; only a few measurements
during 1947 1955













Type of study









Study



Table 4 (continued)

Acute myeloid leukaemia

Acute lymphoblastic leukaemia

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Lung cancer*, all other cancers

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
385

Case control
82 leukaemia
cases
82 solid
tumour cases
209 controls

Case-control
44 cases
211 controls

Case-control
433 cases
422 controls

Case-control
308 cases
362 controls

Case-control
210 cases
400 controls

Case-control
1 281 cases
2 576 controls

Case-control
738 cases
738 controls

Central Italy [F7]

New Jersey [S50]

Shenyang[B37]

Stockholm[P32]

Swedishnationwide[P33]

Winnipeg
[L44]

China

Females
Age at diagnosis: 30 69
Mean time-weightedaverage radon
concentration 118 Bq m 3

34% females
Age at diagnosis: 35 80
Mean time-weightedaverage radon
concentration 107 Bq m 3

47% females
Age at diagnosis: 35 74
Mean time-weightedaverage radon
concentration 107 Bq m 3

Females
Age at diagnosis: all
Mean time-weightedaverage radon
concentration 128 Bq m 3

CanadaSwedenSwedenUnited States

Italy

Germany

National origin

Females
Age at diagnosis: all(65% aged 58 or more)
Mean time-weightedaverage radon
concentration 26 Bq m-3(20% above 37 Bq m-3)

Males
Age at diagnosis:
35 80 (68)75% with radon
concentration above
100 Bq m 3

Age at diagnosis: 0 14
Mean time-weighted
average radon
concentration 27 Bq m 3West German
childhood cancer[K38]

Characteristics

Population studied











Type of study





Study





Table 4 (continued)

n.a.

n.a.

n.a.

n.a.

n.a.

10

n.a.

Follow-up(years)

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Total
personyears a

Radon in homes

Radon in homes

Radon in homes

Radon in homes

Radon in homes

Radon and gamma
radiation in homes

Radon in homes

Type of exposure

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Measurements in last dwelling
occupied and characteristics ofdwellings

Track-etch detector
measurements in homes
occupied by subjects for at least
one yearType of dosimetry

Lung cancer

Lung cancer

Lung cancer

Lung cancer

Lung cancer

Acute myeloid leukaemia

Leukaemia, solid tumours

Cancers studied b

386
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Case-control
538 cases
1 183 controls

Case-control
238 cases
434 controls

Case-control
1 055 cases
1 544 controls(517 matchedpairs)

Case-control
1 449 cases
2 297 controls

Case-control
1 053 cases
1 667 controls

Case-control
982 cases
3 185 controls

Finland-I[R23]

Finland-II[A23]

West Germany[W17]

East Germany[W18]

Southwest England[D30]

18% females
Age at diagnosis: <75
Mean radon concentration
49 Bq m 3 (cases)
50 Bq m 3 (controls);
corresponding values of
67 Bq m 3 (cases)
60 Bq m 3 (controls)in radon-prone areas

97% males
Age at diagnosis: all
Mean time-weightedaverage radon
concentration 96 Bq m 3

Males
Age at diagnosis: all
Mean time-weightedaverage radon
concentration 220 Bq m 3

Females
Age at diagnosis: 30 84
Mean time-weightedaverage radon
concentration 67 Bq m 3

12% females
Age at diagnosis: <75
Mean radon concentration
87 Bq m 3 (cases)
90 Bq m 3 (controls)in living room;
corresponding values of
66 Bq m 3 (cases)
63 Bq m 3 (controls)in bedrooms
in radon-prone areas

33% females
Age at diagnosis: <75
Mean time-weightedaverage radon
concentration
58 Bq m 3 (cases)
56 Bq m 3 (controls)
















Missouri-I[A22]

Characteristics

UnitedKingdom

Germany

Germany

FinlandFinlandUnited States

National origin

Population studiedType of study



Study





Table 4 (continued)

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Follow-up(years)

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Total
personyears a

Radon in homes

Radon in homes

Radon in homes

Radon in homes

Radon in homes

Radon in homes

Type of exposure

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Track-etch detector
measurements in homes
occupied by subjects

Type of dosimetry

Lung cancer

Lung cancer

Lung cancer

Lung cancer

Lung cancer

Lung cancer

Cancers studied b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
387

a
b
c
d
e
f
g
h
i
j
k
l

Case-control
512 cases
553 controls

National origin
United States

Characteristics

Females
Age at diagnosis: <75
Mean time-weighted
average radon
concentration 64.6 Bq m 3
based on CR-39 surface
measurements(58.5 Bq m 3 based on
track-etch measurements)

Population studiedn.a.

Follow-up(years)n.a.

Total
personyears a
Radon in homes

Type of exposure

Track-etch and CR-39 detector
measurements in homes
occupied by subjects

Type of dosimetry

Lung cancer

Cancers studied b

Mean per person in parentheses.
An asterisk denotes sites for which statistically significant excesses are reported in the exposed group (cohort studies) or for which a higher proportion of the cases were exposed to radiation (case-control studies).
Age at first exposure, mean in parentheses.
Figures quoted are for 812 persons with complete information [N14].
Not available.
Figures quoted are from [A5], for persons eligible for the cancer incidence analysis.
Figures quoted are for persons followed up to the end of 1996 [D31].
Figures quoted are from [S12].
Figures quoted are from [K10]. Preliminary results from a follow-up to the end of 1993 are given in [K11], but not to the same detail.
Figures based on [K32, K34].
Figures for males employed before 1959 [K34].
Figures are from [L45].

Missouri-II[A24]

Type of study



Study



Table 4 (continued)

388
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCERANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

389

Table 5Strengths and limitations of major cohort and case-control epidemiological studies of carcinogenic effects
of exposures to high-LET radiation
Study

Strengths

Limitations

Treatment for benign disease224

Ra patients

Large number of excess bone cancers
Long-term follow-up
Substantial proportion of patients treated in childhood oradolescence

Uncertainties in organ doses for individual patients
Other aspects of treatment may be relevant (e.g. x rays)
Comparison group constructed only recently
for the Spiess study [S14]Diagnostic examinations
Thorotrast patients

Large number of excess cancers
Long-term follow-up

Uncertainties in organ doses for individual patients
Chemical attributes of thorotrast might influence risks
Occupational exposures

226

Radium luminizers

Protracted exposures from Ra
Large numbers of excess cancers in United States study

Potential inaccuracies in estimating radium intakes
Distribution of radium in bone may be non-uniform
External irradiation may be relevant for breast cancers

Mayak workers

Wide range of exposures
Individual measurements of plutonium body burden
and external gamma dose
Information on smoking and other potential
confounders in the lung cancer case-control study

Possible uncertainties in assessment of exposures
Further details of the ascertainment of subjects in the lungcancer case-control study [T2] would be desirable

United Kingdom andUnited States
nuclear workers

Individual measurements of plutonium body burden
or other internally deposited radionuclides, andexternal gamma dose

General lack of information on smoking and otherpotential non-radiation confounders
Possible uncertainties in assessment of internal exposures

Florida phosphateworkers[C34]

Relatively large number of person-years
Assessment of exposures to other agents(e.g. silica and acid mists)

Not possible to obtain direct quantitative estimatesof exposure levels
Absence of data on smoking habits for lung cancer
analysis

Chinese iron and steel
workers[L49]

Assessments made of lung doses from inhalation ofthorium
Information available on smoking habits

Lung doses generally low
Small number of deaths for specific cancer types

Radon-exposed
underground miners

Large numbers
Protracted exposures over several years
Wide range of cumulative exposures
Exposure-response analyses

Uncertainties in assessment of early exposures
Possible modifying effect of other types of exposure(e.g. arsenic)
Smoking histories limited or not available

Environmental exposures
Residential radon

Large numbers in most studies
Protracted exposures over many years
Individual data on radon and smoking

Uncertainties in assessing exposures (measurement
error, mobility between dwellings, structural changes
to dwellings)
Radon concentrations low for many subjects

390

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 6
Risk estimates for cancer incidence and mortality from studies of radiation exposure: oesophageal cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]Sex
Age at exposure

Male
Female<20 years>20 years

All

Cervical cancer cohort [B11] c

68
16
8
76

66.2
11.2
8.2
69.2

0.23
0.22
0.23
0.22

297 452491 130
297 452491 130

0.12
1.95
!0.11
0.45

0.26
0.44
!0.03
0.63

84

77.4

0.23

788 582

0.37(!0.45!1.31) b

0.36(!0.44!1.28) b

12

11.0

0.35

178 243

0.26 (95% CI:!1.1!1.3) b

0.16 (95% CI:!0.6!1.3) b

Mortality
Life Span Study [P9]Age at exposure
Males<20 years
20-39 years>40 years<20 years
20-39 years>40 years

13
30
61
0
14
19

15.9
31.2
55.0
0.0
10.2
12.9

0.21
0.25
0.23
0.20
0.19
0.17

376 371
117 959
132 009416 447358 988
201 931- 0.87 (-2.44 -1.40)- 0.15 (-1.22 -1.20)
0.48 (-0.50 -1.64)- 0.37 (-1.04 -0.59)- 0.40 (-3.22 -3.18)
1.99 (-2.10 -6.82)

1.94 (-0.88 -5.96)
2.78 (-0.20 -6.81)

0.55 (-0.25 -1.69)
1.77 (-0.13 -4.34)

5-10 years
11-25 years
26-40 years
41-45 years

13
52
51
21

12.9
40.6
49.2
16.2

0.22
0.20
0.20
0.19

261 996658 705
533 369
144 9400.05 (-1.87 -2.81)
1.41 (0.02 -3.08)
0.18 (-0.97 -1.57)
1.55 (-0.67 -4.52)

0.02 (-0.92 -1.38)
0.87 (0.01 -1.90)
0.17 (-0.89 -1.45)
1.73 (-0.75 -5.04)

137

125.2

0.21

1 603 705

0.76 (0.02 -1.59) b

0.56 (0.02 -1.16) b

Ankylosing spondylitis [W1] d

74

38

5.55

287 095

0.17 (95% CI:
0.09!0.25) e

0.23 (95% CI:
0.1!0.3) b

Metropathia haemorrhagica [D7]

9

9.27

0.05

47 144!0.58(<!0.2!13.9) b!0.94(!7.0 !22.5) b

Massachusetts TB fluoroscopy [D4]

14

6.7

0.80

169 425

n.a. fn.a.

Nuclear workers in Canada,
United Kingdom, United States [C11]

104

n.a.

0.04

2 124 526

>0 g

n.a.

Nuclear workers in Japan [E3]

25

37.1

0.014

533 168

>0 g

n.a.

n.a. hn.a.

FemalesTime since exposure
Both sexes

All

!



INTERNAL LOW-LET EXPOSURES
Mortality
United States thyrotoxicosis [R14]
a
b
c
d
e
f
g
h

25

25

n.a.

385 468

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
The values given are for 10-year survivors.
The values given exclude the period within five years of first treatment.
Dose-response analysis based on the number of treatment courses given.
Not available.
Based on a 10-year lag. Trend not statistically significant..
No apparent trend with administered level of 131I, although a significance test was not performed.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

391

Table 7
Risk estimates for cancer incidence and mortality from studies of radiation exposure: stomach cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

679
628
167
1 140

660.4
561.3
142.0
1 079.7

0.24
0.23
0.24
0.23

298 700
493 900
365 200
427 300

0.12
0.52
0.74
0.24

2.61
5.86
2.87
6.15

1 307

1 221.7

0.23

792 500

0.30 (0.2!0.5) b

4.68 (2.5!7.4) b

348

167.3

2

n.a.

0.54 (0.05!1.5)

1.23

Mayak workers [Z1]

20

d

n.a.

>3

n.a.

1.1 (95% CI:
0.01!3.4) en.a.

Swedish benign breast disease [M28]

14

15.6

0.66

26 493

1.3 (95% CI:
0!4.4)

n.a.

Stockholm skin haemangioma [L16]

5

-6

0.09

406 565<0<0

Age at exposure

Male
Female<20 years>20 years

All
Cervical cancer case-control [B1] cMortality
Life Span Study [P9]Age at exposure
Males<20 years
20-39 years>40 years<20 years
20-39 years>40 years

78
193
536
63
257
390

75.2
188.2
527.0
51.6
233.6
369.0

0.21
0.21
0.21
0.21
0.21
0.21

369 372
116 442129 183
414 045357 293
201 0310.18 (!0.7!1.2)
0.12 (!0.4!0.7)
0.08 (!0.3!0.4)
1.05 (!0.1!2.4)
0.48 (!0.0!1.0)
0.27 (!0.1!0.7)

0.37 (!1.4!2.5)
1.96 (!7.1!12.0)
3.30 (!10.2!17.8)
1.31 (!0.1!3.0)
3.12 (!0.3!6.8)
4.97 (!2.6!13.0)

5-10 years
11-25 years
26-40 years
41-45 years

153
610
606
148

151.6
581.0
573.8
137.7

0.21
0.21
0.21
0.21

186 468725 251
530 897
144 7400.04 (!0.6!0.7)
0.24 (!0.1! f)
0.27 (!0.1!0.6)
0.36 (!0.3!1.1)

0.35 (!4.7!6.0)
1.90 (!0.7! e)
2.89 (!0.6!6.6)
3.38 (!3.0!10.5)

1 517

1 444.1

0.21

1 587 355

0.24 (0.03!0.5) b

2.19 (0.30!4.1) b

Ankylosing spondylitis [W1] g

127

128

3.21

287 095!0.004 (95% CI:!0.05-0.05) h!0.02 (95% CI:!0.2-0.2)

Yangjiang background radiation[T25, T26]

70

77.8

n.a. i

1 246 340

!0.27(95% CI:!1.37-2.69) j

n.a.

Peptic ulcer [G6]40

14.4 k

14.8

35 8150.15

FemalesTime since exposure
Both sexes

All

0.25

33

26.8

0.23

47 1441.01 (<!0.2!2.8)

Benign gynaecological disease [I16] m

23

21.8

0.2

71 9580.27(!4.25!4.80) n

0.83 (<0!72.7) b

Nuclear workers in Canada,
United Kingdom, United States [C11]

275

n.a.

0.04

2 124 526

<0 o

n.a.

533 168on.a.

Metropathia haemorrhagica [D7]

Nuclear workers in Japan [E3]

l

149

177.2

0.014

<0

b

5.72 (<!2.4!16) b

392

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 7 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk p

INTERNAL LOW-LET EXPOSURES
Incidence
Swedish hyperthyroid patients [H23]

58

q

43.6

n.a.

2.32 r385 468>0 s

0.25 Gy
Mortality

United States thyrotoxicosis patients
[R14]

82

78.0

0.178

INTERNAL HIGH-LET EXPOSURES
Incidence
224

18

12.2

n.a.

32 8001.56 t, u

224

13

~11

n.a.

25 000~1.2

Danish thorotrast patients [A5]

7

6.9

n.a.

19 3651.82 (0.61!5.66) t

20.6 ml w

n.a.

0.6 t

Ra ankylosing spondylitis patients[W20]
Ra ankylosing spondylitis patients[N4]

Mortality
German thorotrast patients [V3, V8]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w

30 v

n.a.

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on 5-year survivors. The observed and expected numbers are for both exposed and unexposed persons. The excess absolute risk estimate wascomputed using background incidence rates estimated using the cervical cancer cohort study [B11].
Workers with external gamma dose in excess of 3 Gy.
ERR among those with external gamma doses in excess of 3 Gy relative to those with lower doses.
Calculation of upper confidence limit did not converge.
The values given exclude the period within five years of first treatment.
Dose-response analysis based on the number of treatment courses given.
Mean annual effective dose = 6.4 mSv.
Based on a 10-year latent period.
Based on unirradiated patients.
The values given exclude the period within five years of irradiation.
The observed and expected number of cases are for 10-year survivors. The estimated number of expected cases incorporated an adjustment
based on the Poisson regression model given in [I16].
Wald-type CI.
Based on a 10-year lag. Trend not statistically significant.
95% CI in parentheses.
Restricted to the period 10 or more years after treatment.
Relative risk at 1 Gy.
No apparent trend with administered activity of 131I , although a significance test was not performed.
Relative to unexposed controls.
In the control group, 16 stomach cancers were diagnosed, compared with 16.9 expected.
Number quoted in an earlier follow-up [V3].
Amount of thorotrast administered.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

393

Table 8Risk estimates for cancer incidence and mortality from studies of radiation exposure: colon cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

109
114
32
191

90.7
103.0
28.0
165.7

0.23
0.22
0.23
0.22

297 500
491 100
363 300
425 300

0.87
0.48
0.62
0.70

2.66
1.01
0.48
2.71

223

193.7

0.23

788 600

0.67 (0.1!1.3) b

1.65 (0.7!3.0) b

Cervical cancer case-control [B1] c

409

409

24

n.a.

0.00
(!0.01!0.02)

0.01(!0.09!0.18)

Stockholm skin haemangioma [L16]

12

-11

0.07

406 565

0.37 d0.11

Age at exposure

Male
Female<20 years>20 years

AllMortality
Life Span Study [P9]Age at exposure
Males<20 years
20-39 years>40 years<20 years
20-39 years>40 years

18
25
45
9
49
52

13.8
22.7
42.7
5.6
40.4
48.0

0.20
0.20
0.20
0.20
0.20
0.20

369 372
116 442129 183
414 045357 283
201 031

1.52 (!0.8!4.7)
0.51 (!1.2!2.7)
0.27 (!1.0!1.8)
2.96 (!0.8!8.9)
1.06 (!0.3!2.7)
0.42 (!0.8!1.8)

0.57 (!0.3!1.7)
0.99 (!2.3!5.2)
0.88 (!3.2!5.8)
0.40 (!0.1!1.2)
1.20 (!0.3!3.0)
1.00 (!1.8!4.4)

5-10 years
11-25 years
26-40 years
41-45 years

9
41
97
51

9.4
37.7
85.3
41.9

0.20
0.20
0.20
0.20

186 468725 251
530 897
144 740

198

173.2

0.20

1 587 355

!0.22 (!2.5!3.3)
0.44 (!0.9!2.1)
0.69 (!0.2!1.7)
1.08 (!0.2!2.7)
0.71 (0.06!1.4) b!0.11 (!1.3!1.7)
0.23 (!0.5!1.1)
1.10 (!0.4!2.8)
3.14 (!0.7!7.8)
0.78 (0.07!1.6) b

Benign gynaecological disease [I16] e

75

46.6

1.3

71 9580.51 (!0.8!5.61)

3.2 (!0.9!7.1) b

Metropathia haemorrhagica [D7] f

47

33

3.2

47 1440.13 (95% CI:
0.01!0.26)

0.92 (95% CI:
0.1!1.8) b

Peptic ulcer [G6]3124.0 g

6

35 8150.05 (95% CI:!0.05!0.22) b

0.33 b

Nuclear workers in Canada,
United Kingdom, United States [C11]

343

n.a.

0.04

2 124 526

<0 d, h

n.a.

d, h

n.a.

FemalesTime since exposure
Both sexes

All

Nuclear workers in Japan [E3]

Study

51

42.6

0.014

533 168<0

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk i

INTERNAL LOW-LET EXPOSURES
Mortality
United States thyrotoxicosis patients[R14] j282

255

0.108 k385 468

n.a. l

394

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 8 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk i

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish thorotrast patients [A5]

9

n.a.

19 3651.28 (0.54!2.84) m

20.6 ml on.a.

-0.5 m7.1
Mortality

German thorotrast patients [V3, V8]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o

10 n

n.a.

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on 10-year survivors. The observed and expected numbers cover both exposed and unexposed persons. The excess absolute risk estimate wascomputed using background incidence rates, estimated using the cervical cancer cohort study [B11].
Not statistically significantly different from zero.
The observed and expected number of cases are for 10-year survivors. The estimated number of expected cases incorporated an adjustment based on
the Poisson regression model given in [I16].
The values given exclude the period within five years of irradiation.
Based on unirradiated patients.
Based on a 10-year lag.
95% CI in parentheses.
Data for colorectal cancer [R14].
Value for small intestine [R14].
No apparent trend with administered activity of 131I, although a significance test was not performed.
Relative to unexposed controls.
Number quoted in earlier follow-up [V3].
Amount of thorotrast administered.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

395

Table 9Risk estimates for cancer incidence and mortality from studies of radiation exposure: liver cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(106 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1] b
Sex

174
110
63
221

150.1
104.4
48.3
206.2

0.24
0.23
0.24
0.23

299 646496 606
367 003429 249

0.66
0.23
1.27
0.31

3.32
0.49
1.67
1.50

284

254.5

0.24

796 252

0.48 (0.04!0.96) c

1.55 (0.13!3.08) c

Cervical cancer cohort [B11] d

8

8.8

1.50

178 243!0.06(!0.37!0.4) c!0.03(!0.16!0.2) c

Swedish benign breast disease [M28]

12

11.3

0.66

26 4930.09 (95% CI:<0!1.4)n.a.

Age at exposure

Male
Female<20 years>20 years

AllMortality
Life Span Study [P9] e
Age at exposure
Males<20 years
20-39 years>40 years<20 years
20-39 years>40 years

67
73
108
17
65
102

60.2
66.5
99.5
16.2
58.1
97.0

0.20
0.24
0.21
0.20
0.20
0.17

371 456
116 815
129 974416 768359 129
202 0130.57 (!0.50!1.82)
0.41 (!0.44!1.41)
0.40 (!0.38!1.28)
0.23 (!1.62!2.78)
0.60 (!0.50!1.89)
0.29 (!0.65!1.37)

0.92 (!0.81!2.95)
2.34 (!2.52!8.01)
3.06 (!2.90!9.82)
0.09 (!0.63!1.08)
0.96 (!0.81!3.05)
1.40 (!3.13!6.56)

5-10 years
11-25 years
26-40 years
41-45 years

42
112
178
100

38.9
104.1
162.8
90.5

0.22
0.22
0.22
0.22

186 468725 251
530 897
144 740

0.36 (!0.82!1.80)
0.34 (!0.39!1.18)
0.42 (!0.17!1.08)
0.48 (!0.32!1.38)

0.75 (!1.71!3.75)
0.49 (!0.56!1.69)
1.30 (!0.53!3.32)
2.97 (!2.01!8.65)

432

397.6

0.22

1 596 155

0.42 (0.04!0.83) c

1.08 (0.10!2.15) c

Ankylosing spondylitis [W1] f

11

13.6

2.13

287 095!0.09(!0.24!0.2) c!0.04(!0.11!0.1) c

Peptic ulcer [G6]911.4 g4.61

35 815!0.05 (95% CI:!0.15!0.24) c!0.15 cBenign gynaecological disease [I16] h

9i

16.6

0.21

71 958!2.18(!3.26-!0.3) c!5.03(!7.52-!0.7) c

Yangjiang background radiation[T25, T26]

171

213.8

n.a. j

1 246 340

!0.99 (95% CI:!1.60!0.10) kn.a.

Nuclear workers in Canada
United Kingdom, United States [C11]

33

n.a.

0.04

2 124 526

~0

n.a.

Nuclear workers in Japan [E3]

111

128.9

0.014

533 168

>0 l

n.a.

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk m

FemalesTime since exposure
Both sexes

All

Study

INTERNAL LOW-LET EXPOSURES
Mortality
United States thyrotoxicosis patients
[R14]

39

44.8

n.a.

385 468

n.a.

396

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 9 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk m

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish thorotrast patients [A5]

84

0.7

3.9!6.1 Gyn.a.

194.2 n(31.0!1 216)

Mortality

a
b
c
d
e
f
g
h
i
j
k
l
m
n

German thorotrast patients [V1, V8]

454

3.6

4.9 Gyn.a.

25 Gy-1

Portuguese thorotrast patients [D3]

104

6.6

26 ml
thorotrast

16 963

5.7 n

Combined Japanese thorotrast patients
[M14]

143

4

n.a.

10 685n.a.

90% in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Based on histologically verified cases.
Estimates based on method described in the introduction to Chapter III.
Based on 10-year survivors.
Includes deaths coded as primary liver cancer and liver cancer not specified as secondary.
The values given exclude the period within five years of first treatment.
Based on unirradiated patients.
The estimated number of expected cases incorporated an adjustment based on the Poisson regression model given in [I16].
Including gallbladder.
Mean annual effective dose = 6.4 mSv.
Based on a 10-year latent period.
Based on a 10-year lag. Trend not statistically significant.
95% CI in parentheses.
Per 10 ml injected dose.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

397

Table 10
Risk estimates for cancer incidence and mortality from studies of radiation exposure: lung cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

245
211
30
426
85
146
225

224.7
140.1
26.2
338.5
67.8
116.3
186.4

0.25
0.24
0.25
0.24
0.24
0.24
0.24

302 000
500 700
370 000
432 700
288 566
317 535
314 545

0.36
2.08
0.57
1.06
1.04
1.05
0.85

2.67
5.81
0.41
8.27
2.45
3.85
5.05

456

364.7

0.25

802 700

1.00 (0.6!1.4) b

4.55 (2.4!6.0) b

Hodgkin's disease (international) [K9]

79

n.a.

2.2

n.a.

n.a. cn.a.

Hodgkin's disease (Netherlands) [V2]

29

n.a.

7

n.a.

~1 (95% CI:<0! ~10)n.a.

Breast cancer [I7]

17

n.a.

9.8 d

n.a.

0.08 (95% CI:!0.77!0.22) e

0.9

Swedish benign breast disease [M28]

10

11.2

0.75

26 4930.38 (95% CI:<0!0.6)n.a.

Stockholm skin haemangioma [L16]

11

-9

0.12

406 565

1.4

0.33

Age at exposure
Time since exposure

Male
Female<20 years>20 years
5-19 years
20-29 years
30-42 years

All

Mortality
Life Span Study [P9]Age at exposure
Males<20 years
20-39 years>40 years<20 years
20-39 years>40 years

30
97
182
18
125
132

28.4
90.8
164.8
16.6
115.3
115.4

0.23
0.23
0.23
0.23
0.23
0.23

369 372
116 442129 183
414 045357 283
201 0310.24 (!1.0!1.9)
0.30 (!0.5!1.2)
0.45 (!0.1!1.1)
0.37 (!1.3!2.6)
0.37 (!0.3!1.1)
0.63 (!0.1!1.4)

0.18 (!0.8!1.4)
2.32 (!3.5!9.0)
5.80 (!1.5!1.1)
0.15 (!0.5!1.1)
1.18 (!1.0!3.6)
3.60 (!0.4!8.0)

5-10 years
11-25 years
26-40 years
41-45 years

10
158
297
119

8.3
143.7
268.4
107.4

0.23
0.23
0.23
0.23

186 468725 251
530 897
144 7400.87 (!1.5!4.5)
0.43 (!0.2!1.1)
0.46 (0.01!0.9)
0.47 (!0.2!1.3)

0.39 (!0.7!2.0)
0.86 (!0.3!2.2)
2.34 (0.07!4.8)
3.50 (!1.7!9.4)

584

526.1

0.23

1 587 355

0.48 (0.16!0.8) b

1.59 (0.532.7) b

Ankylosing spondylitis [W1] f

563

469

2.54

287 095

0.05 (95% CI:(0.002!0.09) g

0.9 (95% CI:
0.0!1.4) b

Canadian TB fluoroscopy [H7] h

455

473.7

1.02

672 0710.00 (95% CI:!0.06!0.07)

0.0 (95% CI:!0.4!0.4)

Peptic ulcer [G6]9958.2 i

1.79

35 8150.39 (95% CI:
0.11!0.78) b

6.36 bMassachusetts TB fluoroscopy [D4]

69

81.8

0.84

169 425!0.19(<!0.2!0.04) b!0.90(<!1.8!0.2) b

Yangjiang background radiation[T25, T26]

62

76.5

n.a. j

1 246 340

!0.68 (95% CI:!1.58!1.67) kn.a.

Nuclear workers in Canada, United
Kingdom, United States [C11]

1 238

n.a.

0.04

2 124 526

<0 l

n.a.

FemalesTime since exposure
Both sexes

All

398

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 10 (continued)

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk m
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

Nuclear workers in Japan [E3]

117

124.9

0.014

533 168

<0 l

n.a.

Mayak reactor workers (cohort study) n
[K34]

47

56.23

1.02

67 097!0.161 l!11.7 lObserved
cases

Expected
cases

Mean
WLM

Personyears

Average ERR o
at 100 WLM

Study

Study

INTERNAL HIGH-LET EXPOSURES (Occupational radon)
Mortality
Chinese tin miners [L4, X1] p

936

649

277.4

135 357

0.16 (0.1!0.2)

West Bohemia uranium miners [L4, T22] q

702

137.7

219

106 983

0.64 (0.4!1.1)

Colorado Plateau uranium miners[H17, L4] o

327

74

807.2

75 0320.42 (0.3!0.7)

Ontario uranium miners [K4, L4] o

282

221

30.8

319 701

0.89 (0.5!1.5)

Newfoundland fluorspar miners [L4, M15] r

138

32.1

382.8

48 1890.70 (0.44!1.14)

Swedish iron miners [L4, R8] o

79

44.7

80.6

32 4520.95 (0.1!4.1)

New Mexico uranium miners [L4, S19] o

68

23.5

110.3

46 7971.72 (0.6!6.7)

Beaverlodge uranium miners[H15, H18, L4] o

56

15.4

81.3 s68 0403.25 (1.0!9.6) t

Port Radium uranium miners [H16, L4] o

39

26.7

242.8

31 4540.19 (0.1!0.6)

o

32

23.1

7.6

25 5495.06 (1.0!12.2)

French uranium miners [L4, T8] o

45

36.1

68.7

39 4870.36 (0.0!1.3)

Cornish tin miners [D8, H13]

82

n.a.

65

66 9000.045 uObserved
cases

Expected
cases

Mean
concentration(Bq m3)

Personyears

Average ERR k
at 100 Bq m3

Radium Hill uranium miners [L4, W7]

Study

INTERNAL HIGH-LET EXPOSURES (Residental radon)
Incidence
4 263

n.a.

n.a.

n.a.

0.09 (0.0!0.2)

West Germany [W17]
Entire study region
Radon-prone areas

1 449
365

n.a.
n.a.

49 v
67 o

n.a.
n.a.

!0.02 (!0.18-0.17)
0.13 (!0.12-0.46)

East Germany [W18]

1 053

n.a.

87 w

n.a.

0.04 (!0.04-0.12)

o

n.a.

0.08 (!0.03-0.20)

n.a.
n.a.

0.06 (!0.1-0.6)
0.65 (0.1-2.0)

Meta-analysis of eight case-control studies[L21]

Southwest England [D30]

982

n.a.

58

Missouri-II [A24]
Based on track-etch measurements
Based on CR-39 surface measurements

247
372

n.a.
n.a.

58.5
64.6

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

399

Table 10 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Average relativerisk nINTERNAL HIGH-LET EXPOSURES (other than radon)
Incidence
Mayak radiochemical plant workers(case-control study) [T2]

60 x

n.a.

n.a.

n.a.

3.1 (1.8!5.1) y

224

25

35.7

n.a.

32 8001.20 z

224

20

30

n.a.

25 5000.67

Danish thorotrast patients [A5]21

10.9 aa

0.18 Gy ab

19 3650.7 (0.3!1.7) ac

Ra ankylosing spondylitis patients [W20]
Ra ankylosing spondylitis patients [N4]Mortality
Mayak workers (cohort study) j

105

42.18

6.56 Sv ad

31 6930.321 Sv1
(0.20!0.47)

Sellafield plutonium workers [O1]

133

145.8

0.19 Sv

415 432

1.12 aeJapanese thorotrast patients, combined data
[M14]

11

n.a.

17 ml af

10 6852.0 (1.0!3.9)

German thorotrast patients [V1]

53

n.a.

20.6 ml ag

n.a.

0.75 ahPortuguese thorotrast patients [D31]

10

n.a.

26.3 ml af

16 9634.68(0.24!92.1) ai

Los Alamos workers aj [W8]

8

n.a.

n.a.

n.a.

1.78 (0.79!3.99) ak

a 90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
b Estimates based on method described in the introduction to Chapter III.
c Relative risks quoted in Section III.E.
d Average dose to both lungs for irradiated controls.
e Wald-type CI; likelihood-based lower confidence bound could not be identified.
f
The values given exclude the period within five years of first treatment.
g Dose-response analysis based on the number of treatment courses given.
h The values given exclude the period within ten years of exposure and ages at risk less than 20 years.
iBased on unirradiated patients.
jMean annual effective dose = 6.4 mSv.
k Based on a 10-year latent period.
lTrend not statistically significant.
m 90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
n Results presented here for males only.
o 95% CI in parentheses.
p The values cited are from [L4], unless indicated otherwise, and except for the expected number of cases which has been calculated as O/(1+100 αD),
where O is the observed cases, α is the ERR at 100 WLM and D is the mean WLM.
q Values cited are based on data from [T22].
r Values cited are from [M15], and include non-exposed miners.
s Revised value for persons in nested case!control study [H18].
t
Values based on case-control analysis with revised exposure estimates [H18].
u Coefficient based on time-weighted cumulative exposure.
v Value for cases.
w Value for cases, based on measurements in living room [W18].
x Workers with plutonium body burden above 5.55 kBq.
y Comparison group consists of workers with plutonium body burden below 5.55 kBq.
z Relative to unexposed controls, among whom 29 cases were observed, compared with 49.6 expected [W20].
aa Based on national rates [A5].
ab As given in [A12].
ac Relative to unexposed controls, with adjustment for sex, age at angiography, and calendar period.
ad Alpha dose to lung, based on a radiation weighting factor of 20 [K34].
ae Relative to other radiation workers at Sellafield; difference is not statistically significant [O1].
af Mean amount of thorotrast administered in the first series of Japanese patients [M47].
ag Amount of thorotrast administered.
ah Relative to unexposed controls.
ai Based on three deaths in the control group, and excluding the first five years after administration of thorotrast [D31].
aj Workers with plutonium body burden of 74 Bq or more.
ak Comparison group consists of workers with plutonium body burden below 74 Bq.

400

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 11
Risk estimates for cancer incidence and mortality from studies of radiation exposure: malignancies of thebone and connective tissue
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

9
7
4
12

6.4
5.7
1.1
11.0

0.23
0.22
0.23
0.22

297 500
491 100
363 300
425 300

1.78
0.99
11.0
0.42

0.38
0.12
0.34
0.11

16

12.1

0.23

788 600

1.42 (<!0.2!4.5) b

0.22 (<!0.1!0.7) b

Retinoblastoma patients [W11](bone and soft tissue sarcoma) c

81

16.9

0.0 d

n.a.

0.19 (95% CI:
0.14!0.32)

n.a.

Childhood radiotherapy, international
[T17]

54

20.0

27.0

n.a.

0.06 (0.01!0.2) bn.a.

Childhood cancer, United Kingdom(bone) e [H44]

49

18.8

10d

n.a.

0.16 (95% CI:
0.07!0.37)

n.a.

Cervical cancer case-control [B1](connective tissue) f

46

70.8

7.0

n.a.

!0.05
(!0.11!0.13)!0.01(!0.03!0.03)

Cervical cancer case-control [B1](bone) f

15

10.4

22

n.a.

0.02
(!0.03!0.21) bn.a.

Age at exposure

Male
Female<20 years>20 years

AllMortality
Life Span Study [R1]
Sex

14
10
3
21

10.8
8.5
1.9
17.4

0.23
0.23
0.23
0.22

471 800
731 300
574 500
628 600

1.26
0.81
2.58
0.92

0.29
0.09
0.08
0.26

24

19.3

0.23

1 203 100

1.07 (<!0.2!3.3) b

0.17 (<!0.1!0.5) b

Ankylosing spondylitis [W1] g(bone and connective and soft tissue)

19

6.3

4.54

287 095

0.44 b

0.097 b

Nuclear workers in Canada, United
Kingdom, United States [C11](bone)

11

n.a.

0.04

2 124 526

<0 h

n.a.

Nuclear workers in Canada, United
Kingdom, United States [C11](connective tissue)

19

n.a.

0.04

2 124 526

>0 h

n.a.

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk i

Average excess
absolute risk
(104 PYSv)-1

Age at exposure

Male
Female<20 years>20 years

All

Study

INTERNAL HIGH-LET EXPOSURES
Incidence
224

Ra TB and ankylosing spondylitis
patients (bone) [N14]

55

0.2

30.6 Gy

25 500

n.a.

n.a.

224

4

1.3

~6 Gy

32 800

4.3 j

n.a.

Ra ankylosing spondylitis patients(bone and connective tissue) [W20]ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

401

Table 11 (continued)

Study

German thorotrast patients (bonesarcoma [V8]Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk i

Average excess
absolute risk
(104 PYSv)-1

4

n.a.

20.6 ml kn.a.

~3.3 ln.a.

Mortality

a
b
c
d
e
f
g
h
i
j
k
l
m
n

United States radium luminizers m(bone) [C27, R35, S12, S16, S54, S56]

46

<1

8.6 Gy35 819n.a.

~13Portuguese thorotrast patients (bone)
[D31]

16

n.a.

26.3 ml k

16 9637.08(1.65!30.3) nn.a.

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Results are for patients with bone or soft tissue sarcoma for whom dosimetry information was available.
Mean dose for controls of bone cancer cases.
Results are based on a case-control analysis of bone cancer.
Based on one-year survivors. The observed and expected numbers cover both exposed and unexposed persons. The excess absolute risk for connective
tissue was computed using baseline incidence data derived from the cohort study [B11].
The values given exclude the period within five years of first treatment.
Based on a 10-year lag. Trend not statistically significantly different from zero.
95% CI in parentheses.
Relative to unexposed controls, among whom one case was observed compared with 1.4 expected [W20].
Amount of thorotrast administered.
Crude relative risk, based on one case in the control group. This relative risk is not significantly different from 1 (p>0.05) [V8].
Based on pre-1930 workers with an average skeletal dose greater than zero [C27].
Based on five deaths in the control group, and excluding the first five years after administration of thorotrast [D31].

402

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 12
Risk estimates for cancer incidence and mortality from studies of radiation exposure: skin cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]Sex
Age at exposure

Male
Female<20 years>20 years

All

41
57
21
77

31.4
44.4
7.7
68.2

0.33
0.32
0.32
0.33

324 100
538 900
399 300
463 700

0.92
0.88
5.37
0.39

0.89
0.72
1.04
0.58

98

75.9

0.33

863 000

0.88 (0.4!1.9) b

0.78 (0.4!1.4) bChildhood exposure
Israel tinea capitis [R16]

42

10.0

6.8

265 070

0.47 (0.3!0.7) b

0.18 (0.1!0.25) b

New York tinea capitis (whites) c[S27, S30]

83

24.0

5.0

52 000 d

0.49 (0.37!0.63) b

2.5 (1.9!3.2) b

Rochester thymic irradiation c[H31, S30]

14

4.2

2.3

87 000 d

1.05 (0.50!1.9) b

0.50 (0.3!0.9) b

Tonsil irradiation c [S28, S30]

63

45.0

3.8

96 000 d

0.11 (0.03!0.19) b

0.50 (0.2!1.0) b

Adult exposure

a
b
c
d

Cervical cancer cohort [B1]

88

100

10

342 786!0.01(!0.02!0.01) b!0.02(!0.06!0.03) b

Massachusetts TB fluoroscopy c[D16, S30]

80

75.3

9.6

122 000 d

0.01 (0!0.03) b

0.04 (0!0.2) b

New York mastitis c [S30]

14

10.7

2.6

14 000 d

0.12 (0!0.8) b

0.90 (0!2.8) b

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
From data presented by Shore [S30].
Person-years estimated from data presented by Shore [S30].

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

403

Table 13
Risk estimates for cancer incidence and mortality from studies of radiation exposure: female breast cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality. For case-control studies, the observed number of cases covers both exposed and unexposed persons.

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Age at exposure

122
173
49
87
159

62.8
137.1
36.9
63.5
99.5

0.28
0.27
0.28
0.27
0.27

202 600
308 000
161 400
175 800
173 400

3.32 (2.3!4.4)
0.98 (0.4!1.6)
1.19
1.34
2.21

10.3 (7.2!14)
4.36 (1.8!7.2)
2.72
4.86
12.68

295

199.9

0.27

510 600

1.74 (1.1!2.2) b

6.80 (4.9!8.7) b

Massachusetts TB fluoroscopy [B3]

142

107.6

0.79

54 6000.40 (0.2!0.7) b

7.98 (3.6!13) b

New York acute post-partum mastitis
[S15]

54

20.8

3.7

9 800

0.43 (0.3!0.6) b

9.14 (6.0!13) b

Swedish benign breast disease[M8, M20]

115

28.8

8.46

37 4000.35 (0.3!0.4) b

2.72 (2.2!3.3) b

Cervical cancer case control c [B50]
Without ovaries

953 d
91 e

1083.0
82.6

0.31
0.31

n.a.
n.a.

!0.2 (<!0.2!0.3)
0.33 (<!0.2!5.8)<0.3 (<0.30.2)

Contralateral breast
Denmark [S20]
United States [B10]

529
655

508.7
550.4

2.51
2.82

n.a.
n.a.

0.02 (<!0.1!0.2) b
0.07 (<!0.1!0.2) b

n.a.
n.a.

Rochester thymic irradiation f [H10]

22

7.8

0.76

38 2002.39 (1.2!4.0) b

4.89 (2.4!8.1) b

Childhood skin haemangioma f [L46]

245

204

0.33

600 000

0.35 (95% CI:
0.18!0.59)

1.44 (95% CI:
0.78!2.28)

Hodgkin's disease (Stanford) [H2]

25

6.1

-44.0

100 057

0.07 (0.04!0.11) b

0.04 (0.03!0.07) b

Childhood Hodgkin's disease f [B16]

17

0.2

20

n.a.

n.a. gn.a.

Time since exposure<20 years>20 years
5!19 years
20!29 years
30!42 years

All

n.a.

Mortality
Life Span Study [P9]Age at exposure

52
57
33
16
47
54
25

29.1
50.0
30.2
22.3
40.9
36.5
13.5

0.25
0.25
0.25
0.25
0.25
0.25
0.25

414 045357 283
201 031
108 719442 174
330 501
90 964

3.16 (1.61!5.0)
0.56 (!0.4!1.7)
0.37 (!0.8!1.8)!1.12 (!2.2!0.4)
0.60 (!0.4!1.19)
1.19 (0.66!3.4)
3.43 (1.16!6.4)

2.22 (1.13!3.5)
0.78 (!0.5!2.4)
0.55 (!1.2!2.8)!2.30 (!4.5!0.8)
0.55 (!0.4!1.7)
2.11 (0.72!3.8)
5.07 (1.72!9.4)

142

107.6

0.25

972 358

1.28 (0.57!2.1) b

1.42 (0.63!2.3) b

Scoliosis patients f [D34]

70

35.7

0.11

184 508

5.4 (95% CI:
1.2!14.1)

12.9 (95% CI:
4.0!21.0)

Ankylosing spondylitis [W1] h

42

39.3

0.59

n.a.

0.08 (95% CI:!0.30!0.65) in.a.

Canadian TB fluoroscopy [H20]

349

237

0.89

411 706

0.90 (95% CI:
0.55!1.39) j

3.16 (95% CI:
1.97!4.78) k

Nuclear workers in Canada,
United Kingdom, United States [C11]

84

n.a.

0.04

n.a.

>0 l

n.a.

Time since exposure<20 years
20!39 years>40 years
5!10 years
11!25 years
26!40 years
41!45 years

All

404

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 13 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Average ERR at
1 Sv

INTERNAL HIGH-LET EXPOSURES
Incidence
224

Ra TB and ankylosing spondylitis
patients [N4]

a
b
c
d
e
f
g
h
i
j
k
l
m

28

8

-0.1 Gy m

n.a.

0.9

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Excess absolute risk among cervical cancer patients is computed using baseline incidence data derived from the cohort study [B11].
Based on 5-year survivors.
Based on 10-year survivors.
Population exposed as children.
Relative risks by dose group quoted in Section III.H.1.
The values given exclude the period within five years of first treatment.
Dose-response analysis based on the number of treatment courses given.
Including a factor to allow for differences between Nova Scotia and other Canadian provinces. Values apply to exposure at age 15 years.
Including a factor to allow for differences between Nova Scotia and other Canadian provinces. Values apply 20 years following exposure at age 15
years.
Based on a 10-year lag. Trend not statistically significant.
High-LET breast dose from radium-224.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

405

Table 14
Risk estimates for cancer incidence and mortality from studies of radiation exposure: prostate cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Study

Observed
cases

Expected
cases

Mean
dose
(Sv)

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)1

297 500

0.14 (!0.6!1.0) b

0.44 (!1.8!3.0) b

Personyears

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]

95

92.01

0.21
Mortality

Ankylosing spondylitis [W1] c

88

64.7

2.18

n.a.

0.14 (95% CI:
0.02!0.28) dn.a.

Peptic ulcer [G6]2618.7 e0.08

n.a.

4.9 (95% CI:!2.5!15.0) b

n.a.

Nuclear workers in Canada,
United Kingdom, United States [C11]

256

n.a.

0.04

n.a.

<0 f

n.a.

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk g

Study

INTERNAL LOW-LET EXPOSURES
Incidence
UK Atomic Energy Authority workers:
case-control study [R26]

28 h

n.a.

n.a.

2.36 (1.26 !4.43)

<0.1

n.a.

n.a. i

n.a.

n.a.

~1.3

20.6 ml jn.a.

~0.9 kn.a.

Mortality
United States thyrotoxicosis patients
[R14]

36

52.7

INTERNAL HIGH-LET EXPOSURES
Incidence
224

Ra TB and ankylosing spondylitis
patients [N4]

16

~12

Mortality
German thorotrast patients [V8]

a
b
c
d
e
f
g
h
i
j
k

21

n.a.

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
The values given exclude the period within five years of first treatment.
Dose-response analysis based on the number of treatment courses given.
Based on unirradiated patients.
Based on a 10-year lag. One-sided p-value for increasing trend equals 0.953, based on a normal approximation.
95% CI in parentheses.
Men who worked in environments potentially contaminated with 51Cr, 59Fe, 60Co, 65Zn or 3H.
No apparent trend with administered activity of 131I, although a significance test was not performed.
Amount of thorotrast administered.
Relative to unexposed controls.

406

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 15
Risk estimates for cancer incidence and mortality from studies of radiation exposure: cancer of the urinary
bladder
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included survivors
with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

Male
Female<20 years>20 years

76
39
12
103
115

70.3
27.9
10.3
87.8
98.1

0.23
0.22
0.23
0.22
0.23

297 500
491 200
363 300
425 300
788 600

0.35
1.80
0.71
0.79
0.76 (0.3!2.1) b

0.84
1.02
0.20
1.62
0.95 (0.3!2.1) b

Cervical cancer case-control [B1] c

273

65.8

45

n.a

0.07 (0.02!0.17)

0.12 (0.04!0.3)

Age at exposure
All

Mortality
Life Span Study [P9]Age at exposure
Males<20 years
20!39 years>40 years<20 years
20!39 years>40 years

6
5
39
2
7
23

3.4
4.1
35.4
1.7
8.1
19.5

0.20
0.23
0.21
0.20
0.19
0.17

371 260
116 726
129 809416 447358 988
201 931

3.83 (!1.19!12.50)
0.90 (!2.26!6.63)
0.48 (!0.83!2.11)
1.05 (!3.90!13.98)!0.69 (!3.07!3.27)
1.04 (!1.14!3.91)

0.35 (!0.11!1.15)
0.32 (!0.80!2.35)
1.32 (!2.27!5.75)
0.04 (!0.15!0.55)!0.15 (!0.69!0.73)
1.00 (!1.10!3.78)

5!10 years
11!25 years
26!40 years
41!45 years

4
29
35
14

5.0
28.3
26.1
16.6

0.20
0.20
0.20
0.19

258 146658 705
533 369
144 940!1.02 (!3.67!4.14)
0.12 (!1.34!2.00)
1.75 (!0.04!3.98)!0.82 (!2.55!1.65)!0.20 (!0.71!0.81)
0.05 (!0.58!0.86)
0.85 (!0.02!1.94)!0.94 (!2.92!1.89)

82

72.2

0.20

1 595 161

0.58 (!0.40!1.72) b

0.27 (!0.19!0.79) b

Benign gynaecological disease [I16] d

19

9.0

6.00

71 9580.20 (0.08!0.35)

0.24 (0.1!0.4) b

Metropathia haemorrhagica [D7] e

20

6.7

5.20

47 1440.40 (95% CI:
0.15!0.66)

0.55 (95% CI:
0.2!0.9) b

Ankylosing spondylitis [W1] f

71

46.1

2.18

287 095

0.24 (95% CI:
0.09!0.41) g

0.39 (95% CI:
0.19!0.54) b

Nuclear workers in Canada,
United Kingdom, United States [C11]

104

n.a.

0.04

2 142 526

>0 h

n.a.

FemalesTime since exposure
Both sexes

All

a
b
c
d
e
f
g
h

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on 10-year survivors. The observed and expected numbers cover both exposed and unexposed persons. The excess absolute risk estimate wascomputed using background incidence rates estimated using the cervical cancer cohort study [B11].
The observed and expected number of cases are for 10-year survivors. The estimated number of expected cases incorporated an adjustment
based upon the Poisson regression model given in [I16].
The values given exclude the period within five years of irradiation.
The values given exclude the period within five years of first treatment.
Dose-response analysis based on the number of treatment courses given.
Based on a 10-year lag. Trend not statistically significant.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

407

Table 16
Risk estimates for cancer incidence and mortality from studies of radiation exposure: brain and central
nervous system tumours
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence.
Study

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]
Sex

Male
Female<20 years>20 years

20
51
20
51

21.7
45.3
15.7
51.4

0.27
0.26
0.26
0.26

307 100509 300
376 100
440 200

!0.30

!0.21

0.48
1.05
!0.03

0.43
0.44
!0.03

All

71

67.1

0.26

816 300

0.22 (<0 !1.3) b

0.18 (<0 !0.8) b

Israel tinea capitis [R17]

60

8.4

1.5

283 930

4.08 (3.1 !5.2) b

1.2 (0.9 !1.5) b

New York tinea capitis [A16]

8

1.4

1.4

48 1153.4 (1.3 !6.7) b

0.98 (0.4 !1.9) b

Swedish pooled skin haemangioma
[K23]

83

58.0

0.07

913 402

2.7 (95% CI:
1.0!5.6)

2.1 (95% CI:
0.3!4.4)

Age at exposure

Mortalityabc

Pituitary adenoma (UK) [B22]

5

0.5

45

3 760

0.20 (0.07!0.45) b

0.27 (0.09!0.59) b

Nuclear workers in Canada,
United Kingdom, United States[C11]

122

n.a.

0.04

2 142 526

<0 c

n.a.

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on a 10-year lag. Trend not statistically significant.

408

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 17
Risk estimates for cancer incidence and mortality from studies of radiation exposure: thyroid cancer
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [T1]Sex
Age at exposure

Male
Female0!9 years
10!19 years
20!29 years>30 years

All
Tuberculosis, adenitis screening[H3, S8]
Age at exposure<20 years>20 years

22
110
24
35
18
55

14.9
79.4
7.6
14.6
17.5
54.5

0.27
0.26
0.21
0.31
0.28
0.25

307 167
510 388
185 507190 087
132 738
309 224

1.80
1.49
10.25
4.50
0.10
0.04

0.87
2.32
4.21
3.46
0.13
0.06

132

94.3

0.26

817 600

1.5 (0.5!2.1) b

1.8 (0.8!2.5) b

6
2

0.0
0.2

8.20
8.20

950
3 100

36.5 (16!72) b
1.2 (0.1!3.7) b

7.7 (3.3!15) b
0.7 (0.1!2.4) b

Cohort studies of childrenLife Span Study [T1]
Age at exposure

0!19 years

59

22.2

0.26

375 600

6.3 (5.1!10.1) b

3.8 (2.7!5.4) b

Israeli tinea capitis [R9] c

43

10.7

0.1

274 180

34 (23!47) b

13 (9.0!18) b

New York tinea capitis [S8]

2

1.4 d

0.1

79 5007.7(<0!60) b

1.3 (<0!10.3) b

Rochester thymic irradiation e [S18]

37

2.7

1.4

82 2049.5 (6.9!12.7) b

3.0 (2.2!4.0) b

Childhood cancer f [T5]

23

0.4

12.5

50 6094.5 (3.1!6.4) b

0.4 (0.2!0.5) b

Stockholm skin haemangioma [L13]

17

7.5

0.26

406 355

4.9 (95% CI:
1.3!10.2)

0.9 ((95% CI:
0.2!1.9)

Gothenburg skin haemangioma [L15]

15

8

0.12

370 5177.5 (95% CI:
0.4!18.1)

1.6 (95% CI:
0.09!3.9)

Screening studies of children
Lymphoid hyperplasia screening e, g
[P8, S8]

13

5.4 b

0.24

34 7005.9 (1.8!11.8) b

9.1 (2.7!18.3) b

Thymus adenitis screening [M4, S8]

16

1.1 b

2.9

44 3104.5 (2.7!7.0) b

1.2 (0.7!1.8) b

Michael Reese, tonsils h [S21]

309

110.4

0.6

88 1013.0 (2.6!3.5) b

37.6 (32!43) b

Tonsils/thymus/acne screening[D5, S8]

11

0.2 b

4.5

6 800

12.0 (6.6!20) b

3.5 (2.0!5.9) bn.a.

7.7 (95% CI:
2.1!28.7)

4.4 (95% CI:
1.9!10.1)

Pooled analysis of five studies of childrenLife Span Study
Israeli tinea capitis
Rochester thymic irradiation
Lymphoid hyperplasia screening
Michael Reese tonsil [R4]

436

n.a.

n.a.

Studies of adults
Cervical cancer case-control d [B1]

43

18.8

0.11

n.a.

12.3 (<0!76) b

6.9 (<0!39.2) b

Cervical cancer cohort d, i [B11]

16

12.5

0.11

342 786

2.5 (<0!6.8) b

0.9 (<0!2.5) b

Stanford thyroid [H9]

6

0.4

45

17 7000.3 (0.1!0.7) b

0.07 (0.03!0.1) b

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

409

Table 17 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk

INTERNAL LOW-LET EXPOSURES
Incidence
Diagnostic 131I [H4]
a
b
c
d
e
f
g
h

i
j

67

49.7

1.1

653 093n.a. j90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Doses to the thyroid in this study may be much more uncertain than doses to organs directly in the x-ray beam.
Expected number of cases computed using excess relative risk estimates given in [S8].
Known dose. PY and expected number of cases estimated from data given in [S8].
Based on cohort members with 15 or more years of follow-up and population-expected rates.
This was a study of nodular disease, and cancer cases were not confirmed.
Study includes no unexposed controls; estimates of the number of expected cases were computed using the fitted excess relative risk reported in[S21]. Results are based on the new dosimetry described in [S21]. The large excess absolute risk in this study illustrates the impact of screening
on thyroid cancer risk estimates. As described in [S21], a special thyroid screening programme in this cohort was initiated in 1974. This
screening led to a large increase in the number of incident cases detected among both cases and controls. The paper describes an analysis inwhich allowance was made for the effect of screening. The screening-adjusted excess absolute risk was estimated as 1.7 (10 4 PYGy)1.
Excludes cases diagnosed during first 10 years of follow-up.
Trend not statistically significant (see Table 28).

410

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 18
Risk estimates for cancer incidence and mortality from studies of radiation exposure: non-Hodgkin’s lymphoma
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence.

Observed
cases

Study

Expected
cases

Mean
dose
(Sv) aPersonyears

Average excess
relative risk b
at 1 Sv

Average excess
absolute risk b(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [P4]
Sex

Male
Female<20 years>20 years

41
35
17
59

33.2
38.3
15.8
55.7

0.26
0.25
0.26
0.25

412 400
664 500
478 100
598 800

76

71.5

0.25

Cervical cancer case-control d [B1]

94

37.5

Benign lesions in the locomotor system [D12]

81

80.3

Age at exposure
All

0.91

0.73

!0.34

!0.20

0.30
0.24

0.10
0.22

1 076 900

0.25 (<0.2!1.1) c

0.17(<0.30.8) c

7.10

n.a.

0.21
(!0.03!0.93) c

n.a.

0.39

392 900

0.02 c0.05 cMortality
Benign lesions in the locomotor system [D12]

50

56.9

0.39

439 400!0.31 c!0.40 cAnkylosing spondylitis [W1] e

37

21.3

4.38

287 095

0.17 c0.77 cBenign gynaecological disease [I6]

40

42.5

1.19

246 821

0.05 (<-0.20.2) c

0.08 (<-0.30.3) c

Massachusetts TB fluoroscopy [D4]

13 f

13.1

0.09

157 578!0.05(<!0.2!6.5) c

0.04 (<-0.25.4) c

Peptic ulcer [G6]

12

6.4 g

1.55

35 8150.57 (95% CI:!0.19!2.6) c

1.01 cNuclear workers in Canada, United Kingdom
and United States [C11]

135

n.a.

0.04

2 142 526

<0 h

n.a.

Study

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk
at 1 Sv

INTERNAL LOW-LET EXPOSURES
Incidence
Diagnostic 131I [H27]

95

78.5

0.00019 i

527 056

n.a.

Swedish 131I hyperthyroid [H23]

22

32.4

0.06

139 018n.a.

Mortality
United States thyrotoxicosis j [R14]

Study

74

n.a.

0.042

735 255

0.6 h

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk k

19 3651.47 (0.19-8.87) l

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish Thorotrast patients [A5]

2

1.6

n.a.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 18 (continued)

224

Study

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk
at 1 Sv

Ra ankylosing spondylitis patients [W3]2

0.9!1.8

n.a.

n.a.

-2 m

20.6 ml nn.a.

-2.5 oMortality
German Thorotrast patients [V8]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o

15

n.a.

Mean dose to red bone marrow.
90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on 5-year survivors. The observed and expected numbers cover both exposed and unexposed persons.
The values given exclude the period within five years of first treatment. Mean dose to bone marrow taken from [W2].
Includes deaths from multiple myeloma.
Based on unirradiated patients.
Not statistically significantly different from zero.
Mean dose to bone marrow given in [H12].
Some patients from the United Kingdom were included in this analysis [R14].
95% CI in parentheses.
Risk relative to an unexposed control group, in which three cases were observed compared with 3.5 expected.
Risk relative to an unexposed control group, in which one case was observed compared with 1.0!2.3 expected.
Amount of thorotrast administered.
Crude relative risk, based on five cases in an unexposed control group.

411

412

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 19
Risk estimates for cancer incidence and mortality from studies of radiation exposure: Hodgkin’s disease
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence.

Observed
cases

Study

Expected
cases

Mean
dose
(Sv) aPersonyears

Average excess
relative risk b
at 1 Sv

Averageexcessabsolute risk b(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [P4]

10

9.02

0.23

1 076 500

0.43 ( !1.6!3.5) c

0.04 (0.1-0.3) c

Cervical cancer case-control [B1] d

14

n.a.

7.10

n.a.

n.a. en.a.

0.39

392 900!0.61

Benign lesions in the locomotor system [D12]

17

22.3

c

!0.35 cMortality
Benign lesions in the locomotor system [D12]

21

15.4

0.39

439 400

0.93 c0.33 cAnkylosing spondylitis [W1] f

13

7.9

4.38

287 095

0.15 c0.04 cBenign gyenaecological disease [I6]

10

6.6

1.19

246 8210.43 c0.12 cNuclear workers in Canada, United Kingdom,and United States [C11]

43

n.a.

0.04

2 142 526

>0 g

n.a.

Study

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk
at 1 Sv

INTERNAL LOW-LET EXPOSURES
Incidence
I [H27]27

20.0

0.00019 h

527 056

n.a.

Swedish 131I hyperthyroid [H23]

6

7.2

0.06

139 018n.a.

Diagnostic

131

Mortalityi

United States thyrotoxicosis [R14]

Study

12

n.a.

0.042

735 255!1 g

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk j

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish thorotrast patients [A5]

1

0.65

n.a.

19 365

1.6 (0.06 !40.4) k224

1

0.8!1.1

n.a.

n.a.

n.a. l20.6 ml mn.a.

-0.8 nRa ankylosing spondylitis patients [W3]Mortality
German thorotrast patients [V8]

a
b
c
d
e
f
g
h
i
j
k
l
m
n

2

n.a.

Mean dose to red bone marrow.
90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on one-year survivors. The observed number of cases covers both exposed and unexposed persons.
Unmatched relative risk of 0.63 (90% CI: 0.2-2.6), compared to those with <2 Sv.
The values given exclude the period within five years of first treatment. Mean dose to bone marrow taken from [W2].
Trend not statistically significant.
Mean dose to bone marrow given in [H12].
Some patients from the United Kingdom were included in this analysis [R14].
95% CI in parentheses.
Risk relative to an unexposed control group, in which one case was observed compared with 1.04 expected.
In an unexposed control group, no cases were observed compared with 0.8!1.1 expected.
Amount of thorotrast administered.
Crude relative risk, based on two cases in an unexposed control group.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

413

Table 20
Risk estimates for cancer incidence and mortality from studies of radiation exposure: multiple myeloma
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence and 0.005 Sv or more (weighted colon dose) for
mortality

Observed
cases

Study

Expected
cases

Mean
dose
(Sv) aPersonyears

Average excess
relative risk b
at 1 Sv

Average excess
absolute risk b(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [P4]
Sex

Male
Female<20 years>20 years

12
18
4
26

9.2
19.3
3.1
25.4

0.26
0.25
0.26
0.25

412 400
664 500
478 100
598 800

30

28.6

0.25

Cervical cancer case-control d [B1]

56

n.a.

Benign lesions in the locomotor system
[D12]

65

67.5

Age at exposure
All

0.17

0.26

!0.28

!0.08

1.07
0.09

0.07
0.04

1 076 900

0.20 (<!0.2!1.7) c

0.05 (<!0.05!0.4) c

7.10

n.a.

!0.10 (<0!0.23) c

n.a.

0.39

392 900!0.09 c!0.16 cMortality
Life Span Study [P9]
Sex

16
35

14
31

0.23
0.23

614 997
972 359

1.13 (<0!6.41)
1.16 (0.01!3.9)

0.15 (<0!0.51)
0.19 (0.001!0.5)

51

45

0.23

1 587 355

1.15 (0.12!3.27) c

0.17 (0.02!0.4) c

Benign lesions in the locomotor system
[D12]

80

63.8

0.39

439 400

0.65 c0.95 cAnkylosing spondylitis [W1] e

22

13.6

4.38

287 095

n.a.

n.a.

Benign gynaecological disease [I6]

14

12.4

1.19

246 8210.11 (<!0.2!0.6) c

0.05 (<!0.1!0.3) c

Peptic ulcer [G6]

3

2.2 f

1.55

35 8150.23 (95% CI:!0.6!10)0.13

Metropathia haemorrhagica [D7] g

9

3.5

1.30

47 144

1.23 (0.3!2.7) c

0.90 (0.2!2.0) c

Nuclear workers in Canada, United
Kingdom, and United States [C11]

44

n.a.

0.04

2 142 526

4.2 (0.3!14.4)

n.a.

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk
at 1 Sv

Male
FemaleAll

Study

INTERNAL LOW-LET EXPOSURES
Incidence
Diagnostic 131I [H27]

50

45.9

0.00019 h

527 056

n.a.

Swedish 131I Hyperthyroid [H23]

21

20.0

0.06

139 018n.a.

735 255

11 j

Mortalityi

United States thyrotoxicosis [R14]

28

n.a.

0.042

414

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 20 (continued)

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk k

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish thorotrast patients [A5]

4

0.95

n.a.

19 3654.34 (0.85!31.3) ln.a.

-4.1 oMortality
German thorotrast patients [V8]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o

10 m

n.a.

20.6 ml n

Mean dose to red bone marrow.
90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
Based on one-year survivors. The observed number of cases covers both exposed and unexposed persons.
The values given exclude the period within five years of first treatment. Mean dose to bone marrow taken from [W2].
Based on unirradiated patients.
The values given exclude the period within five years of irradiation.
Mean dose to bone marrow given in [H12].
Some patients from the United Kingdom were included in this analysis [R14].
Not statistically significantly different from zero (p=0.3).
95% CI in parentheses.
Risk relative to an unexposed control group, in which two cases were observed compared with 2.1 expected.
Diagnosis of plasmacytoma.
Mean amount of thorotrast administered, based on hospital records.
Crude relative risk, based on two cases in an unexposed control group (p>0.05).

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

415

Table 21
Risk estimates for cancer incidence and mortality from studies of radiation exposure: leukaemia
The number of observed and expected cases as well as the mean dose and person-years for cohort studies arecomputed throughout this Table for exposed persons only. In the Life Span Study the exposed group included
survivors with organ doses of 0.01 Sv or more for incidence.

Observed
cases

Study

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
Life Span Study [P4]
Sex

Male
Female<20 years>20 years
5-10 years
11-20 years
21-30 years
31-42 years

71
70
46
95
29
45
34
33

35.3
32.1
17.9
49.5
5.1
40.3
18.5
28.1

0.26
0.25
0.26
0.25
0.25
0.25
0.25
0.25

412 300
664 500
478 100
598 700
160 900
367 200
277 900
270 800

3.91
4.75
6.11
3.70
18.69
0.46
3.32
0.70

3.35
2.29
2.28
3.06
5.87
0.50
2.21
0.72

141

67.4

0.25

1 076 800

4.37 (3.2!5.6) b

2.73 (2.0!3.5) b

Cervical cancer case-control c e[B12]

141

n.a.

7.2

n.a.

0.74 (0.1!3.8)

0.50 (0.1!2.6)

Cancer of the uterine corpus d, e [C10]

118

n.a.

5.4

n.a.

0.10 (95% CI:<0.0!0.23)

n.a.

Benign lesions in the locomotor system
[D12]

116

98.5

0.39

392 900

0.46 b

1.14 b

Hodgkin’s disease e, f [K40]

60

n.a.

n.a.

n.a.

0.24 (95% CI:
0.04!0.43)

n.a.

Breast cancer therapy g [C9]

38

n.a.

7.5

n.a.

0.19 (0.00!0.6)

0.89 (0.00!3.0)
0.91 (0.4!15) b

Age at exposure
Time since exposure

All

Techa River population [K27]

37

19.3

0.5

388 880

1.84 (0.9!3.1)

UK childhood cancers f, h [H11]

21

n.a.

n.a.

n.a.

0.241 (95% CI:
0.01!1.28)

n.a.

International childhood cancer h, i [T7]

25

n.a.

10

n.a.

0.0 (0.0!0.004)

n.a.

Chernobyl recovery operation workers
in Russian Federation j [I14]

24

n.a.

0.115

n.a.

1.67 (!5.90!9.23)

n.a.

b

Mortality
Benign lesions in the locomotor system
[D12]

115

95.5

0.39

439 400

0.52 b

1.14 bAnkylosing spondylitis e, k [W2]

53

17.0

4.38

245 4136.00 ln.a.

e

Benign gynaecological disease [I6]

47

27.6

1.19

246 8212.97 (2.2!4.0)

1.25 (0.9!1.7)

Massachusetts TB fluoroscopy e [D4]

17

18

0.09

157 578<!0.2(<!0.2!4.5) b<!0.2(<!0.2!5.1) b

Israeli tinea capitis h, m [R5]

14

6

0.3

279 901

4.44 (1.7!8.7) b

0.95 (0.4!1.9) b

Stockholm skin haemangioma h [L24]

14

~11

0.2

373 5421.6 (95% CI:(!0.6!5.5) nn.a.

Metropathia haemorrhagica o [D7]

12

5.6

1.3

53 1440.74 (95% CI:!0.11!1.59)

0.85 b

Peptic ulcer e [G6]

8

2.9 p

1.55

35 815

1.13 (95% CI:!0.2!6.5)

0.92 b

Nuclear workers e in Canada,
United Kingdom, United States [C11]

119

n.a.

0.04

2 142 526

2.18 (0.13!5.7) q

n.a.

416

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 21 (continued)

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk a
at 1 Sv

Average excess
absolute risk a(104 PYSv)-1

Nuclear workers in Japan r [E3]

23

25.5

0.014

533 168

>0 s

n.a.

Yangjiang background radiation[T25, T26]

33

29.7

n.a. t1 246 340

1.61 (95% CI:<0!28.4) u

n.a.

27
11
6

10.8
5.19
6.74

1.71
0.72
0.87

162 556
67 08687 3071.65 vn.a.
n.a.

0.89 rn.a.
n.a.

Observed
cases

Expected
cases

Mean
dose
(Sv)

Personyears

Average excess
relative risk
at 1 Sv

Study

Mayak workers (cohort study) [K10]Radiochemical plant
Plutonium production
Reactors

Study

INTERNAL LOW-LET EXPOSURES
Incidence
Diagnostic and therapeutic 131I [H12]

130

119

0.014

943 944

n.a. sMortality
United States thyrotoxicosis e w [R14]

82

n.a.

0.042

735 255

~1 s

Study

Observed
cases

Expected
cases

Mean
dose

Personyears

Averagerelative risk x

INTERNAL HIGH-LET EXPOSURES
Incidence
Danish thorotrast patients [A5]224

Ra ankylosing spondylitis
patients [W20]

20 ab

1.3

n.a.

19 365

12.7(2.4!138.4) y

13

4.2

n.a.

32 8002.4 zMortality

a
b
c

d
e
f
g
h
i
j
k
l
m
n
o

Radon-exposed miners[D8]

69

59.5

155 WLM aa

1 085 000

n.a. sGerman thorotrast patients [V8]

42 ab

n.a.

20.6 ml ac

n.a.

-4.9 adPortuguese thorotrast patients [D31]

11 ab

n.a.

26.3 ml ac

16 96315.2 (1.28181.7) ae

Japanese thorotrast patients (combineddata) [M14]

10

n.a.

17 ml af

10 685

12.5 (4.5!34.7)

90% CI in parentheses derived from published data for Life Span Study and using exact Poisson methods for the other studies.
Estimates based on method described in the introduction to Chapter III.
The observed number of cases covers both exposed and unexposed persons. The excess relative risk was estimated using a linear-exponential doseresponse model, and the associated CI was estimated from the confidence region curves in [B9]; the excess absolute risk estimate uses incidence
estimates from the cohort study [B11].
Risk estimate based on a linear dose-response model fitted to data for all radiation types [C10].
Excludes cases of chronic lymphatic leukaemia.
Risk estimate based on analysis in [L52].
The excess absolute risk for this study is computed based on annual incidence estimates and average follow-up times reported in [C9].
Population exposed as children.
The observed number of cases covers both exposed and unexposed persons. Risk estimates based on an unmatched analysis of data given in [T5].
Excludes cases of chronic lymphatic leukaemia. Results are not restricted according to the date of starting work.
The values given exclude the one-year period following the treatment.
Risk estimate based on a linear exponential dose-response model averaged over the period 1!25 years after exposure [W2].
A re-estimate of the dose to bone marrow in this study indicates a mean dose of 0.60 rather than 0.30 Sv. Consequently the excess relative risk
becomes 2.22 Sv-1 [R7].
Based on those with doses above 0.1 Sv.
The values given exclude the period within two years of irradiation.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 21 (continued)
p
q
r
s
t
u
v
w
x
y
z
aa
ab
ac
ad
ae
af

Based on unirradiated patients.
Doses lagged by two years.
No cases of chronic lymphatic leukaemia (CLL) in cohort. Expected number based on rates for leukaemia excluding CLL.
Trend not statistically significant.
Mean annual effective dose = 6.4 mSv.
Based on a two-year latent period.
Based on male workers followed to the end of 1993, as given in [K11].
Some patients from the United Kingdom were included in this analysis [R14].
95% CI in parentheses.
Relative to unexposed controls, adjusted for gender, age at administration and calendar period [A5].
In the control group, seven leukaemias were observed, compared with 5.4 expected [W20].
Mean cumulative radon exposure.
Excludes cases of chronic lymphatic leukaemia.
Mean amount of thorotrast administered, based on hospital records.
Crude relative risk, based on seven cases in the control group.
Based on two deaths in the control group, and excluding the first five years after administration of thorotrast [D31].
Mean amount of thorotrast administered in the first series of Japanese patients [M47].

417

418

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 22
Estimates of the projected lifetime risk of cancer mortality following an organ dose of 1 Sv, based onstudies of radiation exposure

PART A: STOMACH
Risk of exposure-induced death (REID) (%) a for a projection method witha 10year latent period and a relative risk for exposure at ages
Study

20 years<20 years

GenderAssumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

Assumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

EXTERNAL LOW-LET EXPOSURES
Values based on incidence studies
Life Span Study [T1]

Both

0.38

0.17

0.10

0.08

Cervical cancer case-control [B1]

Females!

!

0.18 (0.03!0.49)

0.14 (0.03!0.39)

Mayak workers [Z1]

Males

!

!

0.15 (95% CI:
0!0.5) c

0.12 (95% CI:
0!0.4) c

Swedish benign breast disease [M28]

Females!

!

0.43 (0!1.4)

0.34 (0!1.1)

Values based on mortality studiesabcLife Span Study [P9]Males
FemalesBoth0.11 (<0!0.76)
0.40 (<0!0.93)
0.26

0.05 (<0!0.37)
0.17 (<0!0.40)
0.11

0.06
0.13
0.09

0.05
0.09
0.07

Ankylosing spondylitis [W1]

Males

!

!

<0 (95% CI:<0!0.03)<0 (<0!0.02)

Peptic ulcer [G6]

Both

!

!

0.07

0.05

Metropathia haemorrhagica [D7]Females!

!

0.33 (<0!0.92)

0.26 (<0!0.73)

Benign gynaecological disease [I16]

Females!

!

0.09 (<0!1.57)

0.07 (<0!1.2)

Estimated percentage of population that would die of radiation-induced cancer. Computed using relative risks estimated from the relevant studies (split
by gender and age at exposure where possible), and applied to Japanese death rates for 1985 [J3]. The calculations have been performed for the genderand age-specific groupings that predominate in the relevant study. 90% CI in parentheses unless otherwise stated.
Constant relative risk for first 45 years after exposure. Relative risk then decreases linearly with increasing attained age to zero at age 90 years.
Based on the excess relative risk among those with external gamma doses in excess of 3 Gy relative to those with lower doses, divided by an(arbitrary) value of 4 in order to estimate risks at 1 Gy.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

419

Table 22 (continued)
PART B: COLON
Risk of exposure-induced death (REID) (%) a for a projection method witha 10year latent period and a relative risk for exposure at ages
Study

20 years<20 years

GenderAssumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

Assumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

EXTERNAL LOW-LET EXPOSURES
Values based on incidence studies
Life Span Study [T1]

Both

0.55

0.25

0.51

0.42

Cervical cancer case-control [B1]

Females!

!

0.00(!0.01!0.02)

0.00(!0.01!0.02)

Stockholm skin haemangioma [L16]Both0.33 c0.15!

!

Values based on mortality studiesabcLife Span Study [P9]Males
FemalesBoth

1.5 (<0!4.6)
2.2 (<0!6.7)
1.8

0.73 (<0!2.3)
0.95 (<0!2.9)
0.84

0.35
0.48
0.42

0.28
0.34
0.31

Benign gynaecological disease [I16]

Females!

!

0.31 (<0!3.5)

0.25 (<0!2.7)

Metropathia haemorrhagica [D7]Females!

!

0.08 (95% CI:
0.01!0.21)

0.06 (95% CI:
0.00!0.17)

Peptic ulcer [G6]

Both

!

!

0.04 (95% CI:!0.04!0.18)

0.03 (95% CI:!0.03!0.13)

Estimated percentage of population that would die of radiation-induced cancer. Computed using relative risks estimated from the relevant studies (split
by gender and age at exposure where possible) and applied to Japanese death rates for 1985 [J3]. The calculations have been performed for the genderand age-specific groupings that predominate in the relevant study. 90% CI in parentheses unless otherwise stated.
Constant relative risk for first 45 years after exposure. Relative risk then decreases linearly with increasing attained age to zero at age 90 years.
Not statistically significant.

420

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 22 (continued)
PART C: LUNG
Risk of exposure-induced death (REID) (%) a for a projection method with a10year latent period and a relative risk for exposure at ages
Study

20 years<20 years

GenderAssumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

Assumed constantfrom 10 years
after exposure

Decliningto zero risk
at age 90 years b

EXTERNAL LOW-LET EXPOSURES
Values based on incidence studies
Life Span Study [T1]

Both

2.1

1.0

3.3

2.9

Hodgkin’s disease (Netherlands) [V2]

Both

!

!

~3 (<0 ! ~30)

~3 (<0 ! ~30)

Breast cancer [I7]

Females!

!

0.19 (95% CI:<0!0.52)

0.16 (95% CI:<0!0.45)

Swedish benign breast disease [M28]

Females!

!

0.43 (95% CI:
0!1.4)

0.34 (95% CI:
0!1.1)

Stockholm skin haemangioma [L16]

Both

5.2

2.5

!

!

Values based on mortality studiesabLife Span Study [P9]Males
FemalesBoth

1.1 (<0!8.7)
1.1 (<0!7.5)
1.1

0.52 (<0!4.1)
0.48 (<0!3.4)
0.50

1.5
1.2
1.3

1.3
1.0
1.2

Ankylosing spondylitis [W1]

Males

!

!

0.20 (95% CI:
0.01!0.36)

0.18 (95% CI:
0.01!0.32)

Canadian TB fluoroscopy [H7]Both0.00 (95% CI:<0!0.26)

0.00 (95% CI:<0!0.12)0.00 (95% CI:<0!0.22)0.00 (95% CI:<0!0.19)

Peptic ulcer [G6]

Both

!

!

1.2 (95% CI:
0.34!2.4)

1.1 (95% CI:
0.31!2.2)

Massachusetts TB fluoroscopy [D4]Both

<0 (<0!0.15)<0 (<0!0.07)<0 (<0!0.13)<0 (<0!0.11)

Estimated percentage of population that would die of radiation-induced cancer. Computed using relative risks estimated from the relevant studies (split
by gender and age at exposure where possible), and applied to Japanese death rates for 1985 [J3]. The calculations have been performed for the genderand age-specific groupings that predominate in the relevant study. 90% CI in parentheses unless otherwise stated.
Constant relative risk for first 45 years after exposure. Relative risk then decreases linearly with increasing attained age to zero at age 90 years.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

421

Table 23
Lung cancer mortality in the Canadian fluoroscopy study and in the study of survivors of the atomic
bombings

Lung dose(Sv)
Observed
deathsRelativerisk a b

95% CI

Observed
deathsRelativerisk a b

95% CI

723
180
92
114
41
28

1.00
0.87
0.82
0.94
1.09
1.04

0.74!1.03
0.66!1.02
0.77!1.15
0.80!1.50
0.72!1.53

349
477
43
39
11
5

1.00
1.16
1.35
2.05
2.80
1.65

1.02!1.34
0.97!1.83
1.40!2.96
1.41!5.06
0.61!3.70

0c>0!0.49
0.50!0.99
1.00!1.99
2.00!2.99
$3.00
a
b
c

Study of survivors of atomic bombings(19501990)[P9, P11]

Canadian fluoroscopy study(19501987)[H7]

Adjusted for age at risk, calendar year at risk and sex.
Excludes person-years for age at risk <20 years and deaths and person-years at risk within 10 years of exposure.
Defined as less than 0.01 Sv for the fluoroscopy study and less than 0.005 Sv for the study on survivors of atomic bombings.

Table 24
Lung cancer cases and parameters for risk estimates in studies of radon-exposed underground miners a[L6, L45]

Study cohort

China tin miners
Western Bohemia uranium miners
Colorado Plateau uranium miners
Ontario uranium miners
Newfoundland fluorspar
Sweden iron miners
New Mexico uranium miners
Beaverlodge uranium miners
Port Radium uranium miners
Radium Hill uranium miners
France uranium miners
a

b
c
d

Cases

980
661
294
291
118
79
69
65
57
54
45

b

Averagecumulative
exposure(WLM)

Excess relativerisk
per 100 WLM(β × 100)

277.4
198.7
595.7
30.8
367.3
80.6
110.3
17.2 d
242.8
7.6
68.7

0.59
5.84
14.5
2.40
5.14
1.55
6.56
7.42
1.15
5.68
1.92

Modification
factor(γ)

Test ofsignificance
(p) c

!0.79
!0.78
!0.79
!0.55
!0.53
!1.02
!0.30
!0.67
!0.42
!0.63

<0.001<0.001<0.001
0.002<0.001
0.03
0.17
0.001
0.24
0.30
0.57

0.57

Background lung cancer rates are adjusted for attained age (all studies), other mine exposures [China, France, Ontario, United States (Colorado, New
Mexico)], and indicator of radon progeny exposure (Beaverlodge) and ethnicity (New Mexico). United States (Colorado) data are restricted to
exposures under 3,200 WLM. The relative risk is modelled by the form RR = 1 + β × WLM × (WL)γ.
Total number of cases is 2,701 and omits 12 cases that were included in both United States studies (New Mexico and Colorado).
P-value for test of significance of continuous variation of ERR/WLM by WL.
Howe and Stager [H18] quote a revised mean of 81.3 WLM for exposed miners, compared with an earlier mean of 50.6 WLM for miners with nonzero exposure.

422

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 25
Parameter values used by BEIR Committees in risk models for lung cancer following radon exposure[C2, C21]
Parameter value
BEIR VI preferred models a

Parameter

BEIR IV model
Exposure-age-duration

Exposure-age-concentration

Time since exposure, θ (years)
5!14
15!24
$25

1
0.72
0.44

1
0.78
0.51

1
0.5
0.5

Attained age, φage (years)
<55
55!64
65!74
$75

1
0.52
0.28
0.13

1
0.57
0.29
0.09

1
0.83
0.33
0.33

Duration of exposure, γz (years)
<5
5!14
15!24
25!34
$35

1
2.78
4.42
6.62
10.20

1
1
1
1
1

1
1
1
1
1

1
1
1
1
1
1

1
0.49
0.37
0.32
0.17
0.11

1
1
1
1
1
1

Exposure rate (WL)
<0.5
0.5!1.0
1.0!2.99
3.0!4.99
5.0!14.99$15.0a

ERR = β (w514 + θ1524 w1524 + θ25+w25+)φage γz, i.e. a product of terms representing: (a) exposure in three time periods, i.e. 5-14, 15!24 and 25+ years
previously (Note: BEIR IV used 514 and 15+); (b) attained age (φage); (c) duration of exposure or average concentration (γz) (Note: not included in
BEIR IV model).

Table 26
Basal-cell skin cancer incidence in the Life Span Study[R15]

Variable
All b
GenderMale
FemaleAge at exposure<10 years
10!19 years
20!30 years>40 yearsabc

Observed cases a

Average excess relative risk
at 1 Sv

90% CI80

1.9

0.83!3.3

32
48(Heterogeneity c p > 0.5)

2.7
1.6

0.5!9.1
0.5!4.1

3
8
28
41(Heterogeneity c p = 0.03)

21
6.7
1.7
0.7

4.1!73
2.1!17
0.5!3.8!0.05!2.2

Includes exposed and non-exposed cases.
Estimates are for a person exposed to the atomic bombings at age 30 years. The estimates depend on age at exposure with larger risks for those
exposed earlier and smaller risks for thoses exposed later in life. The risks change by about 11% for a one-year change in age at exposure.
Test of the hypotheses that effects differ across categories.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

423

Table 27
Numbers and rates of tumours of the brain and central nervous system in the Life Span Study of atomic
bomb survivors (19581994)[P19]
Brain dose a(Gy)

Number of cases

Incidence rate
per 10,000 person years

Glioma, astrocytoma<0.0005
0.0005!0.099
0.1!0.99
>1

19
12
7
3

0.24
0.16
0.20
0.46

Meningioma<0.0005
0.0005!0.099
0.1!0.99
>1

33
28
19
5

0.42
0.38
0.53
0.76

Neurilemmoma<0.0005
0.0005!0.099
0.1!0.99
>1

18
11
17
9

0.23
0.15
0.48
1.37

Not specified and other<0.0005
0.0005!0.099
0.1!0.99
>1

15
18
9
3

0.19
0.24
0.25
0.46

HistologyaTotal person years at <0.0005 Sv: 791,456; at 0.0005!0.099 Sv:7425,831; at 0.1!0.99 Sv: 355,877; and at >1 Sv: 65,844.

Table 28
Thyroid cancer risk in patients receiving diagnostic administration of 131I a[H4]Dose b(Gy)

Observednumber of cases

Standardized incidence ratio(SIR)

95% CI

Referred for suspicion of a thyroid tumour#0.25
0.26!0.50
0.51!1.00
>1.00

6
12
4
20

3.57
4.30
1.39
2.72

1.31!7.77
2.22!7.51
0.38!3.56
1.66!4.20

All

42

2.86

2.06!3.86

Referred for other reasons#0.25
0.26!0.50
0.51!1.00
>1.00

5
4
5
11

0.55
0.68
0.47
1.04

0.18!1.29
0.18!1.73
0.20!1.46
0.52!1.86

All

25

0.75

0.48!1.10

All patients

a
b

#0.25
0.26!0.50
0.51!1.00
>1.00

11
16
9
31

1.03
1.84
0.46
1.60

0.51!1.83
1.05!2.98
0.38!1.57
1.09!2.27

All

67

1.35

1.05!1.71

The first five years after exposure were excluded.
Estimated without considering thyroid weight.

0.5
0.1

149
97

60
21

n.a.
10.0
3.4
11.5

n.a.
1.2
1.1
2.0

2
n.a.

n.a.
0

7
5

n.a.
n.a.
n.a.
n.a.

n.a.
n.a.
95
n.a.

n.a.
0.06 1.8
n.a.
0.05 2.0

n.a.
n.a.
n.a.
40

-

8%
(1 14%)
4%( 40 23%)0.05

59%(30 75%)
1.91

47%(17 79%)47%(17 79%)6.00 f

1.88f

0.74

5.13

-

0.88
( 0.50 2.23)

0.05(<0 0.55)

4.69(1.10 13.4)

5.18(0.81 23.63)

12.37(2.25 52.07) e

1.56

-

-

Time since exposure>25 years

Estimates derived from the compartmental linear-exponential model allowing for the effect of time since first treatment, assuming that each bone marrow compartment received the same dose and using national rates
as baseline risk [W2].
Estimates derived from the linear-exponential model [C10].
Estimates based on case-control analysis [B12].
Estimates for survivors of the atomic bombings in Japan aged over 20 years at exposure [P11].
95% CI.
Predicted relative risks in the two periods are the average relative risks at 1 25 years and 25 40 years after first treatment, respectively.

Predicted excess relative risk
at a uniform dose of 1 Gy

Reduction in excess relative risk
at 1 Gy due to cell sterilization

Linear component of excess
relative risk Gy-1

Time since exposure= 1 25 years

Any external
irradiation

Cervical cancer study cBrachytherapy
irradiation

Uterine corpus cancer study b

Life Span Study d

91
n.a.

96
n.a.

n.a.
0.15 5.7

62
n.a.

Cases
confirmedbyinternational
review(%)

Cases ofpapillarycancer(Gy)

Range ofestimatedthyroid doses

Cases found byannual medical
examination
since 1986(%) b

Time since exposure= 25 years







Time since exposure= 10 years



Risk parameter

Ankylosing spondylitis study aTable 30
Fitted risks of leukaemia (other than chronic lymphatic leukaemia) in four studies of low-LET irradiation of adults





b
c
d
e
f

n.a.
0

n.a.
20

n.a.
3

30.6
96.4

4.0
10.5

 




a

25
1

UkraineFive most northerly regions d

0.3
0.5

286
143

47
21

1991 1994

1986 1990

Aged under 15 years at diagnosis; rates are expressed as annual averages per million children under 15 in the regions and periods specified.
Annual medical examination includes palpation and ultrasound scanning of neck and, in some cases, thyroid hormone tests.
Data made available by Drs. Demidchik, Astakhova, Okeanov, and Kenigsberg.
Kiev, Chernikov, Cherkassy, Rovno, and Zhitomir.

n.a.
0

Russian Federation
Bryansk and Kaluga regions

1981 1985

1991 1994

1986 1990

Number ofchildren withthyroidcancer born
since 1986





a
b
c
d

3
1

Belarus c
Gomel

1981 1985

Country / region

Incidence rate (10-6)







Number of cases















Table 29
Childhood thyroid cancer in Belarus, Russian Federation and Ukraine before and after the Chernobyl accident a [S9]424
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCERANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

425

Table 31
Models for risks of solid cancer mortality and incidence used in the lifetime risk computations
based on the Life Span Study
Age-at-exposure model
Cancer type

Excess relative risk per Sv a
Male

FemaleSex
ratio(female/male)

Attained-age model
Change in risk
per 10-yearincrease in age
at exposure (%)

Excess relative risk per Sv b

Sex
ratio
(female/
male)

Power
of ageMale

Female

0.38
1.04
0.27
0.68
0.29
0.68
0.00
0.97
0.32

0.88
2.37
0.63
1.56
0.29
1.55
2.35
2.21
0.74

2.3
2.3
2.3
2.3
1.0
2.3
2.3
2.3

!1.5
!1.5
!1.5
!1.5

0.58
0.78
0.39
0.83
0.66
0.51
0.00
1.53
1.14
0.65

1.10
1.48
0.73
1.56
0.66
2.19
2.22
2.90
2.15
0.38

1.9
1.9
1.9
1.9
1.0
4.3
1.9
1.9
0.6

!2.1
!2.1
!2.1
!2.1
!0.6

Cancer mortality risks
All solid cancer
Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Other cancer

0.38
0.91
0.26
0.46
0.61
0.30
0.00
0.46
0.38

0.77
1.88
0.54
0.95
1.66
0.99
1.34
0.94
0.77

!32
!32
!32
!32
!13

2.1
2.1
2.1
2.1
1.0
3.3
2.1
2.1

26
!32
33
!32

1.4

!1.5
!1.5
!1.5
!1.5

Cancer incidence risks
All solid cancer
Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Thyroid
Other cancer
a
b

0.38
0.41
0.29
0.46
0.58
0.50
0.00
1.18
0.89
0.47

0.79
0.84
0.60
0.95
0.58
2.18
1.55
0.98
1.84
0.28

!33

2.1
2.1
2.1
2.1
1.0
4.3
0.8
2.1
0.6

0
0
0
!7
7
0
!61
0
!50

0.2

!2.1
!2.1
!2.1
!3.2

For age at exposure 30 years.
For attained age 50 years (ages at exposure <40 years).

Table 32
Estimated lifetime probabilities of solid cancer and leukaemia in unexposed populations
Lifetime probability (%)
Cancer
type

China
Male

Japan

FemaleMale

Puerto Rico

FemaleMale

United Kingdom

United States

FemaleMale

FemaleMale

Female

19.9
0.5

39.6
0.7

33.6
0.5

33.9
0.6

30.4
0.5

11.1
0.1

24.0
0.6

20.1
0.5

21.6
0.6

17.9
0.5

Incidence
Solid cancer
Leukaemia

24.3
0.3

16.2
0.3

37.2
0.4

15.3
0.3

26.2
0.6
Mortality

Solid cancer
Leukaemia

12.8
0.1

9.5
0.1

23.3
0.4

25.2
0.3

13.9
0.1

RR

AR

UNSCEAR 1994
[U2]

Age- and timevarying
UNSCEAR 1994
[U2]

AR

RR
AR
RR
AR

Age- and timevarying

Age-at-exposure

Attained-age

Attained-age

RR
AR
RR
AR

Age-at-exposure

AR

RR b
AR c
RR
AR

Age-at-exposure

Attained-age

Risktransport
model

Projection
model a

0.9
0.9
0.5
0.6

1.27

14.8
18.7
10.2
13.0

0.94

8.2
8.6
4.9
5.3

Male

1.3
1.2
0.7
0.7

0.84

17.6
19.7
13.8
14.7

0.56

11.7
10.5
7.1
6.8

Female

China

1.1
1.1
0.6
0.6

1.06

16.2
19.2
12.0
13.8

0.75

9.9
9.5
6.0
6.0

Both

1.0
1.0
0.7
0.7

1.00

18.6
18.6
13.3
13.3

1.04

10.4

9.5
9.5
6.2
6.2

Male

1.4
1.4
0.9
0.9

0.73

21.0
21.0
16.2
16.2

0.79

11.4

12.9
12.9
8.5
8.5

Female

Japan
Male

7.3
9.9
4.4
6.1

0.91

17.5
20.4
8.6
14.0

1.29

1.2
1.2
0.8
0.8

0.8
1.1
0.5
0.6

Solid cancer mortality

Dose of 0.1 Sv d

0.87

Leukaemia incidence

19.8
19.8
14.7
14.7

Solid cancer incidence

1.1

0.92

Leukaemia mortality

10.9

11.2
11.2
7.4
7.4

Solid cancer mortality

Dose of 1 Sv

Both

1.3
1.4
0.8
0.9

1.12

19.8
21.7
13.8
16.2

0.52

11.9
12.8
7.9
8.2

FemalePuerto Rico

REID (%)

1.1
1.3
0.6
0.8

1.21

18.6
21.1
11.2
15.1

0.72

9.6
11.3
6.1
7.2

Both

1.1
1.2
0.7
0.7

1.19

22.1
22.1
12.9
14.6

1.02

9.5
10.8
6.6
6.7

Male

2.3
1.6
1.5
1.0

0.96

29.9
23.2
22.6
17.0

0.87

19.3
14.4
13.5
9.1

FemaleUnited Kingdom

1.7
1.4
1.1
0.8

1.08

26.0
22.7
17.8
15.8

0.95

14.4
12.6
10.1
7.9

Both

0.9
0.9
0.7
0.6

1.24

18.7
14.1
12.3
10.7

1.13

8.5
8.2
6.2
5.4

Male

1.9
1.3
1.4
0.8

0.94

27.4
17.0
23.1
13.5

1.25

16.4
11.5
12.4
7.6

FemaleUnited States

1.4
1.1
1.0
0.7

1.09

23.0
15.5
17.7
12.1

1.19

12.5
9.9
9.3
6.5

Both

Table 33
Estimates of lifetime risk of exposure-induced death (REID) or exposure-induced cancer incidence following an acute whole-body exposure to a population of all ages

426
ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

a
b
c
d

RR
AR
RR
AR

AR

Age-at-exposure

Age- and timevarying

0.05

1.8
2.4
1.1
1.4

0.04

Male

0.03

2.1
2.4
1.5
1.6

0.02

Female

China

0.04

1.9
2.4
1.3
1.5

0.03

Both

0.04

2.4
2.4
1.5
1.5

0.05

Male

0.03

2.6
2.6
1.8
1.8

0.03

Female

Japan
Male

0.04

2.3
2.7
0.9
1.6

0.04

0.06

Leukaemia incidence

2.5
2.5
1.6
1.6

Solid cancer incidence

0.04

Leukaemia mortality

Both

0.05

2.5
2.7
1.5
1.8

0.02

FemalePuerto Rico

REID (%)

0.06

2.4
2.7
1.2
1.7

0.03

Both

0.05

3.0
2.9
1.4
1.6

0.04

Male

0.04

4.1
2.9
2.6
1.9

0.04

FemaleUnited Kingdom

0.05

3.5
2.9
2.0
1.8

0.04

Both

0.06

2.6
1.7
1.4
1.2

0.06

Male

0.04

3.8
2.1
2.8
1.5

0.06

FemaleUnited States

The projection models are described in Section IV.B.1 of this Annex, with the exception of those cited from the UNSCEAR 1994 Report [U2].
Relative risk transportation.
Absolute risk transportation.
The estimates presented for solid cancers at 0.1 Sv do not involve a reduction factor for low doses or low dose rates. In contrast, the leukaemia estimates at 0.1 Sv are based on a linear-quadratic dose response.

Attained-age

AR

Risk
transport
model

Age- and timevarying

Projection
model aTable 33 (continued)

0.05

3.2
1.9
2.1
1.3

0.06

Both

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER
427

428

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 34
Estimates of REID for an acute whole-body dose of 1 Sv to a Japanese population
REID (%)
Projection modelAge
at exposure(years)Solid cancer mortality

Solid cancer incidence

Leukaemia incidence

Male

FemaleMale

FemaleMale

FemaleAge-at-exposure model

10
30
50
All

13.9
8.6
6.2
9.5

19.6
11.9
8.8
12.9

31.0
15.4
9.1
18.6

36.5
18.8
10.7
21.0

1.9
0.8
0.6
1.0

1.0
0.9
0.6
0.7

Attained-age model

10
30
50
All

6.7
6.7
6.3
6.2

9.7
9.5
8.2
8.5

14.9
13.3
11.4
13.3

20.1
18.1
13.0
16.2

1.9
0.8
0.6
1.0

1.0
0.9
0.6
0.7

Table 35
Estimates of measures of radiation detriment associated with an acute whole-body dose of 1 Sv to a male
Japanese population
Unexposed
Age atexposure(years)Exposed

Cause
of
death

Age-at-exposure model
Lifetimerisk

Lifetime
risk

Attained-age model

Radiationassociateddeaths,REID(%)

Excesslifetime
risk,
ELR
(%)

Loss oflife
expectancy,

Lifetimerisk

LLE(years)Radiationassociateddeaths,REID(%)

Excesslifetime
risk,
ELR
(%)

Loss oflife
expectancy,

LLE(years)10

Solid cancer
Leukaemia
Other causes

23.6
0.5
75.9

34.6
2.4
63.0

13.9
2.0
0.0

11.0
1.9
!12.9

12.7
53.1
0.0

28.6
2.4
69.0

6.7
2.0
0.0

5.0
1.9
!6.9

15.0
53.0
0.0

30

Solid cancer
Leukaemia
Other causes

23.8
0.5
75.7

30.7
1.3
68.0

8.6
0.9
0.0

6.9
0.9
!7.7

12.0
29.0
0.0

29.1
1.3
69.6

6.7
0.9
0.0

5.3
0.9
!6.1

13.9
28.9
0.0

50

Solid cancer
Leukaemia
Other causes

23.9
0.4
75.7

28.9
1.0
70.1

6.2
0.6
0.0

5.0
0.6
!5.6

10.3
13.9
0.0

28.9
1.0
70.1

6.3
0.6
0.0

5.0
0.6
!5.7

11.4
14.0
0.0

All ages

Solid cancer
Leukaemia
Other causes

23.3
0.4
76.3

30.9
1.4
67.7

9.5
1.0
0.0

7.6
1.0
!8.6

11.1
30.6
0.0

28.2
1.5
70.4

6.2
1.0
0.0

4.9
1.0
!5.9

12.8
30.6
0.0

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

429

Table 36
Estimates of REID for cancer mortality under the attained-age model, based on acute whole-body exposure
at age 30 years a
REID (%)
Cancertype

China

Puerto Rico

United Kingdom

United States

Japan
RR b

AR c

RR

AR

RR

AR

RR

AR

Dose of 1 Sv (males)
Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Other solid cancer
All solid cancers
Leukaemia

2.6
0.7
0.2
0.6
0.5
0.0
0.1
0.7
5.3
0.5

0.6
0.9
0.3
1.5
1.0
0.0
0.2
1.1
5.6
0.5

0.7
1.0
0.4
1.2
1.8
0.0
0.2
1.3
6.7
0.9

1.2
0.5
0.3
0.9
0.2
0.0
0.2
1.4
4.8
0.5

0.7
1.0
0.4
1.7
1.1
0.0
0.2
1.2
6.4
0.5

0.5
0.3
0.6
0.1
3.6
0.0
0.5
1.4
7.1
0.7

0.8
1.1
0.4
1.3
2.0
0.0
0.3
1.4
7.3
0.7

0.3
0.1
0.9
0.2
3.1
0.0
0.4
1.8
6.8
1.0

0.7
0.9
0.4
1.0
1.6
0.0
0.2
1.1
5.9
1.0

Total

5.9

6.1

7.6

5.3

6.9

7.8

8.0

7.8

6.9

Dose of 0.1 Sv (males) d
Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Other solid cancer
All solid cancers
Leukaemia

0.27
0.07
0.02
0.06
0.05
0.00
0.01
0.07
0.55
0.02

0.07
0.09
0.04
0.16
0.10
0.00
0.02
0.11
0.59
0.02

0.08
0.11
0.04
0.12
0.19
0.00
0.02
0.14
0.70
0.04

0.13
0.05
0.03
0.09
0.02
0.00
0.03
0.15
0.50
0.02

0.07
0.10
0.04
0.18
0.12
0.00
0.02
0.13
0.66
0.02

0.06
0.03
0.06
0.01
0.38
0.00
0.06
0.15
0.75
0.03

0.08
0.12
0.05
0.14
0.21
0.00
0.03
0.15
0.77
0.03

0.03
0.01
0.10
0.02
0.33
0.00
0.04
0.19
0.71
0.05

0.07
0.10
0.04
0.11
0.17
0.00
0.02
0.12
0.62
0.05

Total

0.57

0.61

0.74

0.5

0.7

0.78

0.80

0.76

0.67

Dose of 1 Sv (females)
Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Other solid cancer
All solid cancers
Leukaemia

3.2
0.9
0.3
0.6
0.3
0.6
0.1
1.8
7.7
0.5

0.4
1.0
0.5
1.8
0.4
1.2
0.2
1.8
7.2
0.5

0.6
1.4
0.7
0.6
2.5
1.3
0.2
2.3
9.5
1.0

1.3
0.6
0.8
1.0
0.1
2.2
0.3
2.8
9.0
0.5

0.5
1.3
0.6
2.4
0.5
1.3
0.2
2.3
9.1
0.5

0.7
0.4
1.5
0.1
3.5
5.8
0.5
2.8
15.2
1.0

0.6
1.5
0.7
0.6
2.6
1.4
0.3
2.5
10.1
1.1

0.2
0.2
1.9
0.2
3.2
5.2
0.3
3.2
14.4
1.5

0.5
1.2
0.6
0.5
2.3
1.3
0.2
2.2
8.8
1.6

Total

8.1

7.6

10.4

9.6

9.7

16.2

11.2

15.9

10.3

Dose of 0.1 Sv (females) d

a

b
c
d

Oesophagus
Stomach
Colon
Liver
Lung
BreastBladder
Other solid cancer
All solid cancers
Leukaemia

0.34
0.09
0.03
0.06
0.03
0.06
0.01
0.19
0.81
0.02

0.04
0.11
0.05
0.19
0.04
0.12
0.02
0.19
0.76
0.02

0.06
0.14
0.07
0.06
0.26
0.14
0.02
0.25
1.00
0.04

0.14
0.07
0.09
0.10
0.01
0.23
0.03
0.29
0.96
0.02

0.06
0.14
0.07
0.25
0.06
0.14
0.02
0.24
0.98
0.02

0.08
0.04
0.17
0.01
0.38
0.63
0.05
0.32
1.68
0.04

0.06
0.16
0.08
0.06
0.28
0.14
0.03
0.27
1.08
0.04

0.03
0.02
0.22
0.02
0.34
0.56
0.04
0.36
1.58
0.06

0.05
0.13
0.06
0.06
0.24
0.13
0.02
0.23
0.93
0.06

Total

0.83

0.78

1.04

1.0

1.0

1.72

1.12

1.64

0.99

Owing to rounding errors, the sum of the individual values in each column sometimes differs from the total, which has been calculated to greater
accuracy. Also, in a few instances, the mortality estimates in this Table are greater than the corresponding incidence values in Table 37 owing to theuse of baseline rates that differ by the region studied within a country or that differ by time period (see Section IV.B.4).
Relative risk transportation.
Absolute risk transportation.
The estimates presented for solid cancers at 0.1 Sv do not involve a reduction factor for low doses or low dose rates. In contrast, the leukaemia
estimates at 0.1 Sv are based on a linear-quadratic dose response.

430

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

Table 37
Estimates of REID for cancer incidence under the attained-age model, based on acute whole-body exposure
at age 30 years a
REID (%)
Cancertype

China

Puerto Rico

United Kingdom

United States

Japan
RR b

AR c

RR

AR

RR

AR

RR

AR

Dose of 1 Sv (males)
Oesophagus
Stomach
Colon
Liver
Lung
BreastThyroid
Bladder
Other solid cancer
All solid cancers
Leukaemia

0.6
1.1
0.6
0.7
3.2
0.0
0.2
0.5
2.6
9.4
0.8

0.5
1.7
1.3
2.4
2.4
0.0
0.3
0.7
2.7
12.0
0.8

0.5
1.9
1.4
2.6
2.8
0.0
0.3
0.8
2.9
13.3
0.8

0.5
0.4
0.8
0.3
1.3
0.0
0.1
0.7
4.0
8.0
0.9

0.5
1.9
1.4
2.5
2.9
0.0
0.3
0.8
2.9
13.1
0.9

0.5
0.5
1.2
0.2
5.0
0.0
0.4
0.1
5.1
12.9
0.9

0.6
2.1
1.6
2.8
3.4
0.0
0.9
0.3
3.2
14.9
0.9

0.2
0.2
1.1
0.1
2.9
0.0
0.4
0.4
6.8
12.1
0.7

0.4
1.5
1.2
2.1
2.0
0.0
0.6
0.3
2.5
10.6
0.7

Total

10.2

12.8

14.1

8.9

14.0

13.8

15.8

19.7

13.8

Dose of 0.1 Sv (males) d
Oesophagus
Stomach
Colon
Liver
Lung
BreastThyroid
Bladder
Other solid cancer
All solid cancers
Leukaemia

0.06
0.12
0.07
0.08
0.35
0.00
0.02
0.05
0.27
1.01
0.04

0.05
0.19
0.14
0.26
0.27
0.00
0.03
0.08
0.29
1.30
0.04

0.05
0.21
0.16
0.28
0.32
0.00
0.04
0.09
0.32
1.46
0.04

0.05
0.04
0.09
0.03
0.14
0.00
0.02
0.07
0.43
0.85
0.04

0.05
0.20
0.15
0.27
0.33
0.00
0.03
0.09
0.31
1.44
0.04

0.05
0.05
0.13
0.02
0.55
0.00
0.04
0.01
0.55
1.40
0.02

0.06
0.23
0.17
0.31
0.39
0.00
0.10
0.04
0.35
1.65
0.02

0.02
0.02
0.13
0.02
0.32
0.00
0.04
0.04
0.74
1.33
0.05

0.04
0.17
0.13
0.23
0.23
0.00
0.07
0.03
0.26
1.16
0.05

Total

1.05

1.34

1.50

0.89

1.48

1.42

1.67

1.38

1.21

Dose of 1 Sv (females)
Oesophagus
Stomach
Colon
Liver
Lung
BreastThyroid
Bladder
Other solid cancer
All solid cancers
Leukaemia

0.4
1.0
1.1
0.6
4.7
4.6
0.6
0.2
1.1
14.4
0.8

0.1
1.6
1.6
0.6
3.4
4.9
1.2
0.3
1.4
15.1
0.8

0.2
1.9
2.0
0.8
4.6
5.3
1.3
0.4
1.6
18.1
0.9

0.3
0.4
1.5
0.1
2.4
8.4
0.5
0.5
1.4
15.5
1.2

0.2
1.9
2.0
0.8
4.5
5.3
1.3
0.4
1.6
17.9
1.2

0.4
0.4
2.0
0.1
7.4
12.3
0.5
0.3
2.4
25.7
1.1

0.2
2.0
2.1
0.9
5.1
5.4
0.4
1.3
1.6
19.0
1.2

0.1
0.1
1.9
0.1
7.5
13.6
0.5
1.0
2.2
27.0
1.0

0.1
1.6
1.7
0.7
3.5
4.9
0.3
1.2
1.4
15.4
1.1

Total

15.2

15.9

19.0

16.7

19.0

26.8

20.1

30.2

17.9

Dose of 0.1 Sv (females) d

a
b
c
d

Oesophagus
Stomach
Colon
Liver
Lung
BreastThyroid
Bladder
Other solid cancer
All solid cancers
Leukaemia

0.05
0.11
0.12
0.07
0.54
0.49
0.06
0.03
0.12
1.58
0.03

0.02
0.17
0.18
0.07
0.39
0.52
0.12
0.04
0.15
1.67
0.03

0.02
0.21
0.22
0.10
0.54
0.56
0.14
0.05
0.17
2.02
0.04

0.03
0.04
0.17
0.02
0.28
0.90
0.06
0.05
0.15
1.70
0.05

0.02
0.21
0.22
0.09
0.53
0.56
0.14
0.05
0.17
1.99
0.05

0.05
0.05
0.24
0.01
0.91
1.39
0.06
0.03
0.27
3.01
0.02

0.02
0.22
0.24
0.10
0.61
0.57
0.05
0.14
0.18
2.13
0.02

0.01
0.02
0.24
0.01
0.95
1.57
0.06
0.11
0.26
3.23
0.05

0.02
0.17
0.19
0.41
0.07
0.52
0.04
0.13
0.15
1.70
0.05

Total

1.61

1.70

2.06

1.75

2.04

3.03

2.15

3.28

1.75

Owing to rounding errors, the sum of the individual values in each column sometimes differs from the total, which has been calculated to greater accuracy.
Relative risk transportation.
Absolute risk transportation.
The estimates presented for solid cancers at 0.1 Sv do not involve a reduction factor for low doses or low dose rates. In contrast, the leukaemia
estimates at 0.1 Sv are based on a linear-quadratic dose response.

ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

431

Table 38
Comparison of elicited high dose and high-dose-rate lifetime low-LET fatal cancer risks for a general
population (European Union / United States) with those derived from other sources(Risks expressed per 100 at 1 Sv)(Based on [L27])

a
b
c
d
e
f
g

Cancer typeElicited risk a

Bone
Colon
Breast g
Leukaemia
Liver
Lung
Pancreas
Skin
StomachThyroid
All other cancers

0.035 (<103! 0.88)
0.98 ( 0.011!3.35)
0.78 ( 0.11!3.78)
0.91 ( 0.026!2.33)
0.86 (<103!2.02)
2.76 ( 0.59!8.77)
0.17 (<103!1.26)
0.039 (<103!0.37)
0.30 (<103!4.01)
0.059 (<103!0.71)
2.60 (<103!10.8)

All cancers

10.2 (3.47!28.5)

BEIR V b

ICRP 60 c

UNSCEAR 1994 d

0.35
0.95

3.24
0.97
0.95

1.7

2.92

0.6
1.0
1.1
1.2
2.5

0.6
0.6
1.0
0.9
2.1

0.03
0.51

1.4

1.2

12.05

12

7.9

UNSCEAR 2000
(Age-at-exposure) e

UNSCEAR 2000
(Attained age) f

12

REID for a joint European Union / United States population (90% CI in parentheses). Elicitation of risks involved questioning a range of experts.
ELR for a United States population [C1].
REID averaged over United Kingdom and United States populations, using a relative risk projection model (data extracted from [I1]).
REID for a Japanese population, using an age-at-exposure model [U2].
REID for a Japanese population of both genders and all ages, using an age-at-exposure model (derived from Table 34 of this Annex).
REID for a Japanese population of both genders and all ages, using an attained-age model (derived from Table 36 of this Annex).
Averaged over genders.

9ANNEX I: EPIDEMIOLOGICAL EVALUATION OF RADIATION-INDUCED CANCER

433

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