Radiat Environ Biophys (2007) 46:299–310
DOI 10.1007/s00411-007-0122-3
REVIEW
Are cancer risks associated with exposures to ionising radiation
from internal emitters greater than those in the Japanese A-bomb
survivors?
Mark P. Little Æ Per Hall Æ Monty W. Charles
Received: 24 February 2007 / Accepted: 23 June 2007 / Published online: 17 July 2007

Springer-Verlag 2007
Abstract After ingestion or inhalation of radionuclides,
internal organs of the human body will be exposed to ion-
ising radiation. Current risk estimates of radiation-associated
cancer from internal emitters are largely based on extrapo-
lation of risk from high-dose externally exposed groups.
Concerns have been expressed that extrapolated risk esti-
mates from internal emitters are greatly underestimated, by
factors of ten or more, thus implying a severe underesti-
mation of the true risks. Therefore, data on cancer mortality
and incidence in a number of groups who received exposure
predominantly from internal emitters are examined and ex-
cess relative risks per Sv are compared with comparable
(age at exposure, time since exposure, gender) matched
subsets of the Japanese atomic bomb survivor cohort. Risks
are examined separately for low LET and high LET internal
emitters. There are eight studies informative for the effects
of internal low LET radiation exposure and 12 studies
informative for the effects of internal high LET radiation.
For 11 of the 20 cancer endpoints (subgroups of particular
study cohorts) examined in the low LET internal emitter
studies, the best estimate of the excess relative risk is greater
M. P. Little (&)
Department of Epidemiology and Public Health,
Imperial College London, Faculty of Medicine,
St Mary’s Campus, Norfolk Place, London W2 1PG, UK
e-mail: mark.little@imperial.ac.uk
P. Hall
Department of Medical Epidemiology and Biostatistics,
Karolinska Institute, P.O. Box 281,
171 77 Stockholm, Sweden
M. W. Charles
School of Physics and Astronomy,
University of Birmingham,
Edgbaston, Birmingham B15 2TT, UK
than the corresponding estimate in the Japanese atomic
bomb survivors and for the other nine it is less. For four of
these 20 studies, the relative risk is significantly (2-sided
P < 0.05) different from that in the Japanese atomic bomb
survivors, in three cases greater than the atomic bomb sur-
vivor relative risk and in one case less. Considering only
those six low LET studies/endpoints with 100 or more
deaths or cases, for four out of six studies/endpoints the
internal emitter risk is greater than that in the Japanese
atomic bomb survivors. For seven of the 24 cancer endpoints
examined in the high LET internal emitter studies the best
estimate of the ERR in the internal emitter study is greater
than the corresponding estimate in the Japanese atomic
bomb survivors and for the other 17 it is less. For six studies,
the relative risk is significantly (2-sided P < 0.05) different
from that in the Japanese atomic bomb survivors, in one case
greater than the atomic bomb survivor relative risk and in
five cases less. Considering only those eight high LET
studies/endpoints with 100 or more deaths or cases, for five
out of eight studies/endpoints the internal emitter risk is
greater than that in the Japanese atomic bomb survivors.
These results suggest that excess relative risks in the internal
emitter studies do not appreciably differ from those in the
Japanese atomic bomb survivors. However, there are sub-
stantial uncertainties in estimates of risks in the internal
emitter studies, particularly in relation to lung cancer asso-
ciated with radon daughter (alpha particle) exposure, so a
measure of caution should be exercised in these conclusions.
Introduction
Cancer risk is the largest component of radiation-induced
detriment for a general population [1]. Most standards-
123
300
setting bodies rely on cancer risks derived from cohorts
exposed at high doses and dose-rates, in particular the
Japanese atomic bomb survivor Life Span Study (LSS)
cohort [1, 2], although risk estimates for certain other sites
(e.g., liver, bone cancer) have also been derived from
studies of medical uses of alpha-emitting radionuclides [1].
Traditionally, assessments of cancer risk associated with
internal emitters require extrapolation of risk from high-
dose groups and use of dosimetric models, because direct
evidence of low-dose and low-dose-rate risk from internal
emitters is scarce, limited to certain medically, occupa-
tionally and environmentally exposed groups [2–4]. Con-
ventionally this has been of most importance for high linear
energy transfer (LET) radiation, such as 239Pu, where
radiation weighting factors of 20 are recommended [1].
There has been considerable recent interest and contro-
versy, associated with estimation of risks from internal
emitters [5, 6], with claims that risks from internal emitters
could be greatly underestimated, by ‘‘well over a factor of
10’’, by current International Commission on Radiological
Protection (ICRP) risk factors and dosimetric models [5];
enhancements of risk from 90Sr by factors of 300 have been
derived [7], although with less justification [5]. In part as a
consequence of this, there have been recent reviews of risks
in groups who received high LET internal emitters, for
example from medical exposures (e.g., patients given the
diagnostic contrast medium Thorotrast or 224Ra to treat
ankylosing spondylitis and other non-malignant conditions)
or from occupational exposure (e.g., radium dial painters,
underground miners) [8–10].
In this article, we systematically review the epidemio-
logical literature on internal emitters. We shall concentrate
on the main groups exposed to internal emitters and com-
pare risks with comparable subsets of the latest Japanese
atomic bomb survivors [11–15]. This survey therefore ex-
tends a similar survey in relation to cancer after medical
treatment for malignant and non-malignant disease [8, 16].
Methods
A Medline search was conducted on 15 February 2007
using the terms ‘‘internal’’ + ‘‘emitter’’ + ‘‘radiation’’ (49
references from 1990 onwards), ‘‘internal’’ + ‘‘emitter’’
(72 references from 1990 onwards) and ‘‘inter-
nal’’ + ‘‘radiation’’ + ‘‘epidemiology’’ (579 references
from 1990 onwards). This was supplemented by searches
of appropriate tables in the most recent UNSCEAR report
[2]. Only those studies in which there was reliable ascer-
tainment of cancer incidence or mortality were considered
and in which the majority of organ-specific dose came from
internal emitters. Only peer-reviewed papers in English
were considered; abstracts and conference proceedings
123
Radiat Environ Biophys (2007) 46:299–310
were not included. In general, studies were excluded if
there was no reliable estimation of organ dose. In some
cases (e.g., all malignancies other than stomach in the
study of Holm et al. [17], non-haemopoietic malignancies
in the study of Ron et al. [18] and the studies of Nekolla
et al. [19, 20] and Wick et al. [21]) the only comparison
group available was the appropriate national population
mortality or incidence rates, otherwise, internal comparison
groups were generally available. In the case of haemo-
poietic malignancies in the study of Ron et al. [18] and in
the study of Dickman et al. [22], Poisson linear relative risk
models were refitted to the data given in the published
material. For the Techa River study of Krestinina et al. [3],
only leukaemia was examined, since only for this endpoint
is the dose predominantly (92%) from internal emitters
(mainly 90Sr and 137Cs).
The latest versions of the cancer incidence [11, 12] and
mortality [13–15] datasets for the Japanese atomic bomb
survivors LSS cohort were employed. Follow-up for the
haemopoietic (leukaemia, lymphoma, multiple myeloma)
cancer incidence data [11] was from October 1950 to
December 1987 and follow-up for the solid cancer inci-
dence data [12] was from January 1958 to December 1998.
Mortality follow-up started for all cases in October 1950,
ending in December 1990 for the haemopoietic mortality
dataset of Pierce et al. [13], in December 1997 for the solid
cancer mortality dataset of Preston et al. [14] and in
December 2000 for the solid cancer and leukaemia mor-
tality data of Preston et al. [15]. Most of these data [11, 13,
14] employed the older DS86 dosimetry system [23], the
only exceptions being the most recent solid cancer inci-
dence [12] and mortality [15] datasets, which use the most
current DS02 dosimetry [15, 24]. The basis of comparison
is the value of the excess relative risk (ERR) coefficient
(ERR Sv–1). To make such comparisons, a simple linear
relative risk model was fitted to various subsets of the
Japanese data, in which it was assumed that the expected
number of cases in stratum i and dose group d with average
organ dose D (in Sv) is given by:
PYid ki ½1 þ aD
ð1Þ
where PYid is the number of person-years of follow-up in
stratum i and dose group d.
The dose to the atomic bomb survivors is a mixture of
gamma rays and neutrons, with most dose imparted by
radiation with high energy (>2 MeV) [23, 24]; the Sv organ
dose is derived using the ICRP recommended [1] weighting
factor for high energy neutrons of 10, as employed in other
analyses of these data [11–15]. The background cancer rates
ki for each stratum i as well as the ERR coefficient a were
estimated by Poisson maximum-likelihood [25]. The strat-
ification was defined by city, sex, time since exposure and
Radiat Environ Biophys (2007) 46:299–310
age at exposure in the haemopoietic cancer incidence data
[11] and by city, sex, attained age and age at exposure in the
mortality data [13–15]; this is identical to the stratification
employed in the original analyses of these datasets [11, 13–
15]. In the solid cancer incidence data [12] stratification was
by city, sex, attained age, age at exposure, time since
exposure and distance from hypocentre (<3,000 m,
>3,000 m) for analysis of cancers other than thyroid cancer;
for thyroid cancer, stratification was by city, sex, attained
age, age at exposure, time since exposure and membership
of the Adult Health Study (AHS). Distance from the hyp-
ocentre could not be used as a stratifying variable for thy-
roid cancer because such model fits were subject to
numerical instability. Stratification by AHS membership is
critical for thyroid cancer. AHS membership is propor-
tionally greater in higher dose groups [26]. Diagnosis of
thyroid cancer is highly dependent on the efficiency of the
cancer registration process, which is more thorough in the
AHS, so that it is possible that the ‘‘true’’ magnitude of the
dose-response curve in the Japanese dataset could be dis-
torted by variations in the completeness of ascertainment
between the various dose groups within the cohort. Again,
this stratification is similar to that used by Preston et al. [12]
in their analysis of this dataset. All bomb survivors with
shielded kerma dose >4 Gy were excluded from the anal-
ysis because of possible errors in dose estimates at high
doses. The group not in either city at the time of the
bombings was also excluded, as in the most recent analyses
of this data [11–15]. Because of the well-known modifying
effects of age at exposure, time since exposure and sex as
modifiers of the relative risk of radiation-associated cancer
[2], appropriate subsets of the Japanese data were selected
so that the period of follow-up, the age at exposure and the
sex corresponded as nearly as possible to those of the
respective internal emitter dataset. Consequently, the pos-
sible biasing effects of these variables in the comparisons
will be minimized. Therefore, in Tables 1 and 2 two ERR
estimates are given: the first being that obtained from the
internal emitter study and the second based on an analysis of
a relevant subset from the LSS cohort, both given as ERR
Sv–1. The authors compared ERR estimates for studies of
cancer incidence with those derived from the LSS incidence
datasets [11, 12] and those for cancer mortality with the
ERR estimated from the LSS mortality data [13–15]. We
have divided the internal emitter studies into those associ-
ated with low LET exposure (Table 1) and those associated
with high LET exposure (Table 2). Because one would
expect a dose-rate reduction for the protracted low LET
exposures that characterise all of the studies considered in
Table 1, we multiply the risks in these studies by the central
estimate of the dose and dose-rate effectiveness factor
(DDREF) used by the BEIR VII committee [27], namely
1.5. There is no reduction associated with the protraction of
301
dose associated with high LET radiation, as would be ex-
pected on the basis of radiobiological data [28], so for the
studies given in Table 2 we leave the estimates derived
from each study unchanged.
In estimating the dose from alpha particles (the only
source of radiation exposure for all studies considered in
Table 2), we use the ICRP [1] recommended weighting
factor of 20. In converting risk estimates per working level
months (WLM) to risk per Sv associated with the BEIR VI
[29] 11-cohort underground miner analysis, we also as-
sumed the mean of the conversion factors (17.2 mSv/
WLM, 22.5 mSv/WLM) derived by Birchall and James
[30]. In converting the risks associated with the exposure
rate (per Bq m–3) used in the domestic radon daughter
exposure studies [31–33], we also assumed the conversion
factor of 0.13 WLM/y/100 Bq m–3 derived by Strom et al.
[34] and assumed a mean occupancy of 30 years (5–
35 years before case diagnosis) in the study of Darby et al.
[32] and a mean occupancy of 25 years (5–30 years before
case diagnosis) in the studies of Wang et al. [31] and
Krewski et al. [33]. For the Thorotrast studies listed in
Table 2 [35–38], a common estimate of 31.2 years expo-
sure of the respective organs was used, a figure derived
from van Kaick et al. [35], combined with appropriate
organ dose per year, which for all except the Japanese
Thorotrast series [36] was also taken from Table 2 in [35].
For the 224Ra study of Nekolla et al. [19], a breast dose of
0.1 Gy = 2 Sv was employed, as indicated by Boice [39].
Also shown are the 95% confidence intervals (CI),
which unless stated otherwise are likelihood-based (see
below). All parameter estimates and CIs for the Japanese
A-bomb survivors are estimated using AMFIT [40].
The last column of Tables 1 and 2 gives the P-values for
the consistency of the Japanese and internal emitter data-
sets, calculated from the square of the normalized differ-
ence in ERR estimates:
v2 ¼ ½ERRj  ERRm
2 =½r2j þ r2m
ð2Þ
where the estimated standard errors, rj, rm, for the
Japanese and internal emitter data are computed from the
95% CI for the ERR of the Japanese data, (CIlj, CIuj) and
from the 95% CI, (CIlm, CIum), for the internal emitter data,
by means of the relation:
(
rj ¼ ½CIuj  ERRj
=1:96
if ERRj \ERRm
rm ¼ ½ERRm  CIlm
=1:96
( ð3Þ
rj ¼ ½ERRj  CIlj
=1:96
if ERRj  ERRm
rm ¼ ½CIum  ERRm
=1:96
The P-values given in Tables 1 and 2 are derived from
Eq. 2, which is assumed to have the distribution of a v2
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123
Table 1 Risk estimates for cancer incidence and mortality from studies of internal low LET radiation exposure, adjusted to high dose rate using a DDREF of 1.5 [27]
Cancer Reference Age at Follow-up Endpoint Observed Observed Mean Person-years Excess relative Excess relative risk
endpoint exposure (years) deaths/cases deaths/cases dose (Sv) risk at 1 Sv at 1 Sv in comparable
(years) in comparable (and 95% CI), A-bomb group
A-bomb group adjusted to (and 95% CI)
high dose rate

All solid [42] 0 to >40 0 to >40 Mortality 889 10,071 0.63 582,750 1.22 (0.69, 2.00)a 0.48 (0.39, 0.58)b##
a
Oesophagus [42] 0 to >40 0 to >40 Mortality 317 288 0.63 582,750 0.27 (–0.14, 0.99) 0.71 (0.20, 1.41)c
Stomach [17] 13 to 74 (mean 57) 1 to 28 (mean 15) Incidence 58d 1,575 0.25 139,018 1.98 (1.14, 2.97) 0.25 (0.05, 0.49)e###
Stomach [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 28 2,852 0.178 738,831 –0.25 (–3.00, 3.39) 0.30 (0.14, 0.48)f
a
Stomach [42] 0 to >40 0 to >40 Mortality 150 2,852 0.63 582,750 1.43 (0.26, 5.24) 0.30 (0.14, 0.48)f
a
Stomach [18, 42] 0 to >60 0 to >40 Mortality 178 2,852 0.45 1,321,581 0.79 (–2.15, 3.73) 0.30 (0.14, 0.48)f
a
Liver [42] 0 to >40 0 to >40 Mortality 60 1,234 0.63 582,750 –0.12 (–0.62, 1.50) 0.51 (0.26, 0.80)g
Lung [42] 0 to >40 0 to >40 Mortality 130 1,260 0.63 582,750 2.64 (0.72, 13.25)a 0.79 (0.51, 1.11)c
a
Female breast [42] 0 to >40 0 to >40 Mortality 61 269 0.63 582,750 1.64 (–0.08, 23.70) 1.42 (0.75, 2.31)h
Bladder [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 14 149 0.128 738,831 –0.35 (–5.50, 7.35) 1.09 (0.19, 2.46)i
d
Kidney [17] 13 to 74 (mean 57) 1 to 28 (mean 15) Incidence 37 41 0.05 139,018 15.3 (1.8, 32.4) –0.06 (<–0.06, 1.91)j#
k k k
Thyroid [22] 0 to 74 (mean 43) 2 to 47 (mean 27) Incidence 36 398 0.94 886,618 1.63 (–0.01, 11.16) 1.20 (0.63, 1.99)l
Thyroid [43] 0 to 14 6 to 12 Incidence 276 13 0.37m NA 9.90 (3.00, 16.65)n 8.53 (<0, 49.16)o
p p
NHL [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 74 170 0.042 738,831 0.90 (–44.83, 83.74) 0.05 (<0, 0.70)q
Hodgkin’s disease [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 12 21 0.042p 738,831 –1.50 (–157.0, 49.6)p 0.48 (<0, 3.96)q
Multiple myeloma [17] 13 to 74 (mean 57) 1 to 28 (mean 15) Incidence 10d 22 0.06 139,018 –1.75 (–13.75, 17.75)p 1.23 (<0, 6.01)r
p
Multiple myeloma [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 28 49 0.042 738,831 16.50 (–7.65, 85.73)p 0.60 (<0, 2.55)s
t p p
Leukaemia [44] 0 to 6 0 to 14 Incidence 421 12 0.0063 NA 48.60 (13.17, 126.00) 97.39 (<0, 5989)u
Leukaemiav [45] 1 to 65 0 to >47 Incidence 53 192 0.34, 0.29pw NA 3.75 (–0.45, 27.00)p 5.79 (3.95, 8.35)s
v p p
Leukaemia [3] 0 to >70 0 to >49 Mortality 49 284 0.30 865,812 9.75 (2.70, 36.00) 4.09 (2.90, 5.64)s
v p p
Leukaemia [18] 0 to >60 (mean 46) 1 to 44 (mean 21) Mortality 82 284 0.042 738,831 –1.50 (–5.60, 0.87) 4.09 (2.90, 5.64)s###
v p p
Leukaemia [3, 18] 0 to >70 0 to >49 Mortality 131 284 0.18 1604,643 –1.09 (–5.85, 3.67) 4.09 (2.90, 5.64)s#
Radiat Environ Biophys (2007) 46:299–310
 Table 1 continued

NHL Non-Hodgkin’s lymphoma

a
Based on a dose-response analysis, restricted to the exposed group only
b
Based on colon dose
c
Based on lung dose
d
Restricted to the period 10 or more years after treatment
e
Based on stomach dose, >15 years age at exposure, <30 years since exposure
f
Based on stomach dose
g
Based on liver dose
h
Based on female breast dose
i
Based on urinary tract dose
j
Radiat Environ Biophys (2007) 46:299–310

Based on bladder dose, >15 years age at exposure, <30 years since exposure
k
Among group without previous exposure to external radiation therapy of the neck, referred for a reason other than suspicion of thyroid cancer
l
Based on thyroid dose
m
Median dose to all Belarus subjects
n
Based on linear model fitted to cases and controls with dose < 1 Gy
o
Based on thyroid dose, <15 years age at exposure, <20 years since exposure
p
Bone marrow dose
q
Based on bone marrow dose, fitted to incidence data [11]
r
Based on bone marrow dose, >15 years age at exposure, <30 years since exposure
s
Based on bone marrow dose
t
Acute leukaemia
u
Based on bone marrow dose, acute radiogenic leukaemia (AML + ALL), <10 years age at exposure, <15 years since exposure
v
Leukaemia excluding chronic lymphocytic leukaemia
w
Mean internal emitter bone marrow doses for cases, controls, respectively
#
LSS and radiation therapy ERR statistically inconsistent with P < 0.05
##
LSS and radiation therapy ERR statistically inconsistent with P < 0.01
###
LSS and radiation therapy ERR statistically inconsistent with P < 0.001
303

123
304
random variable with one degree of freedom (df) [25]. If
the errors in the ERR estimates in the LSS and the medical
data are both independently normally distributed, then
Eq. 2 is equivalent to the likelihood-ratio test of the
equality of the ERR. As the size of the samples gets
sufficiently large this is, therefore, guaranteed to have
the asymptotic distribution of a v2 random variable with
1 df [41]. Alternatively, one may derive the distribution
of this test statistic by considering, for simplicity, the
case of normal random variables Xj  Nðlj ; r2j Þ and
Xj  Nðlm ; r2m Þ; Z ¼ Xj  Xm  Nðlj  lm ; r2j þ r2m Þ; so
that under the null hypothesis H0 : lj ¼ lm ; it is seen that
Z 2 ¼ ½Xj  Xm
2 =½r2j þ r2m
has the distribution of a v2
random variable with one df. Although this statistic be-
haves correctly asymptotically, for small samples the CIs
are not approximately normal in the way that correct
interpretation of this statistic requires; for this reason in
those studies with five or fewer cases, we do not estimate
this statistic.
In order to maximise statistical power, whenever pos-
sible (when the comparable group being considered in the
Japanese atomic bomb survivors is identical) we derive
joint estimates of internal emitter risks by weighting each
ERR estimate by the inverse of the variance (computed in
most cases by varm ¼ ð½CIum  CIlm
=½2  1:96
Þ2 : This is
the standard best linear unbiased estimator. The variance of
this weighted estimator is easily seen to be given by


P
1= 1=varmi : This is used to derive confidence intervals
i Discussion
for this weighted estimate in the standard way.
Results
Internal low LET radiation exposure
There are eight studies informative for the effects of
internal low LET radiation exposure [3, 17, 18, 22, 42–45].
For 11 of the 20 cancer endpoints (subgroups of particular
study cohorts) represented in Table 1 the best estimate of
the ERR in the internal emitter study is greater than the
corresponding estimate in the Japanese atomic bomb sur-
vivors. For four cancer sites, the risk is significantly (2-
sided P < 0.05) different from that in the Japanese atomic
bomb survivors, in three cases (all solid: [42], stomach,
kidney: [17]) greater than the atomic bomb survivor rela-
tive risk and in one case (leukaemia: [18]) less. Consid-
ering only those six studies/endpoints with 100 or more
deaths or cases, for four out of six studies/endpoints (all
solid, stomach and lung cancer: [42], thyroid cancer: [43])
the internal emitter risk is greater than that in the Japanese
atomic bomb survivors; only for all solid cancer, in Bauer
et al. [42], was this difference statistically significant.
123
Radiat Environ Biophys (2007) 46:299–310
These numbers suggest that the relative risks in the low
LET internal emitter studies do not appreciably differ from
those in the Japanese atomic bomb survivors.
Internal high LET radiation exposure
There are 12 studies informative for the effects of internal
high LET radiation exposure [19–21, 29, 31–33, 35–38,
46]. For 7 of the 24 cancer endpoints (subgroups of par-
ticular study cohorts) represented in Table 2 ,the best
estimate of the ERR in the internal emitter study is greater
than the corresponding estimate in the Japanese atomic
bomb survivors. For six cancer sites the ratio is signifi-
cantly (2-sided P < 0.05) different from that in the Japa-
nese atomic bomb survivors, greater in one case (lung
[31]), and less than the atomic bomb survivor relative risk,
in the other five cases (liver: [36, 37], leukaemia, incidence
and mortality: [38], leukaemia mortality: [35]). Consider-
ing only those eight studies/endpoints with 100 or more
deaths or cases, for five (liver cancer [35, 38], lung cancer
[31–33]) the internal emitter risk is greater than that in the
Japanese atomic bomb survivors; only for lung cancer in
Wang et al. [31] was this difference statistically significant.
These numbers suggest that the relative risks in the high
LET internal emitter studies do not appreciably differ from
those in the Japanese atomic bomb survivors.
The LSS is the principal source of data used to estimate risks
of radiation-related cancer [1, 2, 27, 47]. However, these risk
estimates have also been compared to and generally sup-
ported by data taken from a variety of other sources [2]. In
particular, data from studies of patients exposed to ionising
radiation for the treatment of cancer and non-neoplastic
conditions have been frequently used; previous studies
[8, 16], documented the generally lower relative risks in the
medical series compared with the atomic bomb survivors.
We have analysed data on a variety of malignant endpoints
in various groups predominantly exposed via internal radi-
ation emitters. In general, whether for low LET or high LET
radiation, we find little evidence of systematic departures of
risk estimates in these studies from those in the Japanese
atomic bomb survivors. There is slightly more evidence in
the larger studies (those with 100 or more deaths or cases)
[29, 31–33, 35, 37, 38, 42–44, 46] for there being greater
risks than those in the atomic bomb survivors. However,
there are substantial dosimetric uncertainties in some of
these studies [29, 31–33] and other problems in certain other
studies [42], that we discuss below.
There are various other studies where there may be
appreciable internal emitter exposure which could not be
 Table 2 Risk estimates for cancer incidence and mortality from studies of internal high LET radiation exposure
Cancer Reference Age at exposure Follow-up Endpoint Observed Observed Mean Person- Excess relative Excess relative
endpoint (years) (years) deaths/ deaths/cases dose (Sv) years risk at 1 Sv risk at 1 Sv in
cases in comparable (and 95% CI) comparable A-bomb
A-bomb group group (and 95% CI)

Liver [38] <20 to 79 2 to >50 Incidence 136 1,142 249.6a 54,734 +¥ (0.17, + ¥) 0.59 (0.30, 0.94)b
a
Liver [35] NA 0 to >50 (mean 31.2) Mortality 454 1,234 249.6 NA 0.61 (0.19, 1.18) 0.51 (0.26, 0.80)b
a
Liver [36] <11 to >60 0 to 54 Mortality 79 1,234 137.3 9,356 0.13 (0.08, 0.19) 0.51 (0.26, 0.80)b##
Liver [37] <20 to >60 5 to >40 Mortality 106 1,234 249.6a 44,648 0.04 (0.02, 0.08) 0.51 (0.26, 0.80)b###
Radiat Environ Biophys (2007) 46:299–310

Liver [38] <20 to 79 2 to >50 Mortality 22 1,234 249.6a 13,691 0.09 (0.00, 1.86) 0.51 (0.26, 0.80)b
Liver [35–38] <11 to 79 0 to >50 Mortality 661 1,234 234.1 67,695 0.06 (0.03, 0.08) 0.51 (0.26, 0.80)b###
c
Lung [32] NA 5 to 35 Incidence 7,148 619 NA NA 2.07 (0.65, 4.00) 0.69 (0.13, 1.16)d
e
Lung [33] NA 5 to 30 Incidence 3,662 440 NA NA 1.71 (0.00, 4.34) 0.89 (0.42, 1.51)f
g
Lung [31] NA 5 to 30 Incidence 768 440 NA NA 4.96 (1.24, 21.24) 0.89 (0.42, 1.51)f#
g
Lung [31, 33] NA 5 to 30 Incidence 4,430 440 NA NA 1.85 (–0.27, 3.97) 0.89 (0.42, 1.51)f
h i
Lung [46] 15 to 60 0 to 55 Mortality: male 167 622 5.00 52,546 0.24 (0.17, 0.34) 0.40 (0.03, 0.86)j
Lung [46] 15 to 60 0 to 55 Mortality: female 25 508 8.42h 17,476 0.95 (0.48, 1.95)i 1.40 (0.76, 2.2)j
k l
Lung [29] 15 to >60 0 to >35 Mortality 2,674 620 3.26 888,906 0.30 (0.17, 0.51) 0.37 (0.07, 0.74)m
k n
Lung [29] 15 to >60 0 to >35 Mortality 2,674 620 3.26 888,906 0.38 (0.11, 1.29) 0.37 (0.07, 0.74)m
o p
Bone [21] NA 0 to >36 Incidence 4 18 100 32,800 0.02 (0.00, 0.07) 1.32 (<0, 6.37)q
r p
Bone [20] 0 to >70 0 to 56 (mean 25.2) Incidence 56 18 612 25,500 0.30 (0.23, 0.39) 1.32 (<0, 6.37)q
Bone [20, 21] 0 to >70 0 to 56 Incidence 60 18 323.9 58,300 0.06 (0.03, 0.10)p 1.32 (<0, 6.37)q
s
Bone [35] NA 0 to >50 (mean 31.2) Mortality 4 27 99.8 NA 0.02 (–0.01, 0.37) 1.29 (<0, 5.16)q
Bone [37] <20 to >60 5 to >40 Mortality 5 27 99.8s 44,648 0.07 (0.00, 3.59) 1.29 (<0, 5.16)q
Bone [35, 37] <20 to >60 0 to >50 Mortality 9 27 99.8s 44,648 0.02 (–0.16, 0.21) 1.29 (<0, 5.16)q
s
Bone [38] <20 to 79 2 to >50 Mortality 2 27 99.8 13,691 +¥ (–0.01, + ¥) 1.29 (<0, 5.16)q
Female breast [19] 0 to >70 0 to 56 (mean 25.2) Incidence 28 834 2t NA 1.25 (0.66, 2.03)p 1.62 (1.16, 2.18)u
v w
NHL [35] NA 0 to >50 (mean 31.2) Mortality 15 170 62.4 NA 0.02 (0.00, 0.05) 0.05 (<0, 0.70)x
v w
Hodgkin’s disease [35] NA 0 to >50 (mean 31.2) Mortality 2 21 62.4 NA 0.00 (–0.01, 0.08) 0.48 (<0, 3.96)x
v v w
Leukaemia [38] <20 to 79 2 to >50 Incidence 28 192 62.4 54,734 0.23 (0.05, 2.38) 5.79 (3.95, 8.35)y###
vz v w
Leukaemia [35] NA 0 to >50 (mean 31.2) Mortality 42 160 62.4 NA 0.06 (0.02, 0.09) 5.25 (3.41, 7.86)xz###
x v w
Leukaemia [37] <20 to >60 5 to >40 Mortality 6 284 62.4 44,648 0.15 (0.00, 7.53) 4.09 (2.90, 5.64)y
Leukaemiax [38] <20 to 79 2 to >50 Mortality 8 284 62.4v 13,691 0.25 (–0.01, 3.38)w 4.09 (2.90, 5.64)y#
x v
Leukaemia [37, 38] <20 to 79 2 to >50 Mortality 14 284 62.4 58,339 0.24 (–1.31, 1.78)w 4.09 (2.90, 5.64)y###
305

123
 Table 2 continued
306

NHL Non-Hodgkin’s lymphoma

a
Based on a liver dose estimate of 0.40 Gy per year (0.22 Gy per year for the Japanese series [36]), assumed given over 31.2 years [35], and using ICRP [1] weighting factor of 20

123
b
Based on liver dose
c
Computed from estimate adjusted for dosimetric error in [32], assuming conversion factor of 0.13 WLM/y/100 Bq m3 [34] and assuming 30 year (5–35 years before exposure) mean
occupancy of houses, and using mean of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
d
Based on lung dose, <35 years since exposure
e
Computed from estimate in [33], assuming conversion factor of 0.13 WLM/y/100 Bq m3 [34] and assuming 25 year (5–30 years before exposure) mean occupancy of houses, and using mean
of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
f
Based on lung dose, <30 years since exposure
g
Computed from estimate adjusted for dosimetric error (1.5 error GSD) in [31], assuming conversion factor of 0.13 WLM/year 100 Bq m3 [34] and assuming 25 year (5–30 years before
exposure) mean occupancy of houses, and using mean of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
h
Mean monitored dose among workers monitored at radiochemical and plutonium plants, obtained by multiplying dose in Table 1 of [46] by the recommended ICRP [1] weighting factor of 20
and adding to this the mean external dose to all workers
i
ERR per Gy at age 60, obtained by dividing the ERR/Gy in Table 3 of [46] by the recommended ICRP [1] weighting factor of 20
j
ERR per Gy at age 60, for LSS cohort [14], aged between 15–60, taken from Table 7 of [46]
k
Computed from mean cumulative WLM in Appendix D of BEIR VI [29], using mean of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
l
Computed from random effects estimate in Appendix A of BEIR VI [29], using mean of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
m
Based on lung dose, males, 15–60 years age at exposure
n
Computed from two-stage estimate in Appendix A of BEIR VI [29], using mean of correction factors (17.2 mSv/WLM, 22.5 mSv/WLM) calculated by Birchall and James [30]
o
Computed from estimate of bone surface dose of 5 Gy, and using ICRP [1] weighting factor of 20
p
Computed from given observed and expected number of cases, using exact 95% Poisson CI [56]
q
Based on skeletal dose
r
Computed using ICRP [1] weighting factor of 20
s
Based on a bone dose estimate of 0.16 Gy per year, assumed given over 31.2 years [35], and using ICRP [1] weighting factor of 20
t
Based on a breast dose estimate of 0.1 Gy (39), and using ICRP [1] weighting factor of 20
u
Based on breast dose
v
Based on a bone marrow dose estimate of 0.1 Gy per year, assumed given over 31.2 years [35], and using ICRP [1] weighting factor of 20
w
Bone marrow dose
x
Based on bone marrow dose, fitted to incidence data [11]
y
Based on bone marrow dose
z
Myeloid leukaemia
#
LSS and radiation therapy ERR statistically inconsistent with P < 0.05
##
LSS and radiation therapy ERR statistically inconsistent with P < 0.01
###
LSS and radiation therapy ERR statistically inconsistent with P < 0.001
Radiat Environ Biophys (2007) 46:299–310
Radiat Environ Biophys (2007) 46:299–310
used in this paper. In particular, the study of Sellafield
plutonium workers [4] presumably contains some infor-
mation on this route of exposure, although only 355 person
Sv of the dose is due to internally deposited plutonium,
compared with 959 person Sv of external dose. No separate
information is provided on risk associated with internal
emitter dose (results are only presented for internal emitter
and external dose combined) so that this study cannot yet
be used to estimate risks from internal emitters. A study of
thyroid cancer risk in relation to 131I exposure from the
Hanford plant also could not be employed, because of
insufficient information in the published paper to facilitate
calculation of relative risk [48]. There are many funda-
mentally ecological studies in relation to various groups
exposed as a result of the Chernobyl accident, which we
have not considered here. The possibilities for bias in
ecological studies are well known [49].
The method used to compare risks between the inter-
nally exposed and the Japanese atomic bomb survivors is
to assess the ERR coefficients. The underlying assumption
is that the ERR per unit dose should be invariant between
these studies. This may well not be correct. A number of
different ways can be used to transport cancer risk be-
tween two populations with different underlying suscep-
tibilities to cancer. As well as the multiplicative transfer
of risks, assumed here, one could also assume an additive
transfer of excess absolute risks (EAR), in which the
radiation-induced excess cancer rates in the two popula-
tions are assumed to be identical. The data that are
available suggest that there is no simple solution to the
problem [50]. For example, there are weak indications
that the ERRs of stomach cancer following radiation
exposure may be more comparable than the EARs in
populations with different background stomach cancer
rates [50]. A comparison of breast cancer risks observed
in the Japanese atomic bomb survivor incidence data with
those in various medically exposed populations, many
from North America and Europe, where underlying breast
cancer rates are higher than in Japan, suggests that ERRs
are rather higher in the LSS than those in the medically
irradiated groups, but (time- and age-adjusted) EARs are
more similar [51, 52]. The observation that gender dif-
ferences in solid tumour ERR are generally offset by
differences in gender-specific background cancer rates
[50] might suggest that EARs are more alike than ERRs.
In summary, these considerations suggest that in various
circumstances relative or absolute transfers of risk be-
tween populations may be advocated or, indeed, the use of
a hybrid approach such as that employed by Muirhead and
Darby [53] and Little et al. [54]. The information given in
many of the papers considered does not permit calculation
of an EAR and for this reason we concentrated on com-
parison of ERRs.
307
The most serious shortcomings of the present study are
in relation to the estimates of risks from internal high LET
exposure. In particular and as noted in the Methods section,
in considering all the studies relating to radon daughter
exposure and lung cancer [29, 31–33] a number of dosi-
metric and other factors had to be assumed. For example, to
convert from risk estimates per WLM in the miner studies
[29] to risk per Sv we assumed a mean dosimetric con-
version factor derived by Birchall and James [30]. In
converting the risks associated with the exposure rate (per
Bq m–3) used in the domestic radon daughter exposure
studies [31–33], we also had to assume an additional
conversion factor (to derive WLM/year from exposure rate
in Bq m–3) as given by Strom et al. [34] and make addi-
tional assumptions on mean period of occupancy in these
studies. These factors could well be incorrect, although
most of these, in particular the dosimetric conversion fac-
tors [30], are unlikely to be substantially biased [9]. For the
Thorotrast studies listed in Table 2 [35–38] a common
estimate of 31.2 years exposure of the respective organs
was used, a figure derived from [35], combined with the
appropriate organ dose per year, which for all except the
Japanese series [36] was also taken from Table 2 in van
Kaick et al. [35]. This reflects lack of information in all the
studies apart from van Kaick et al. [35], but again, the
estimates are unlikely to be much out, as many of the
Thorotrast cohorts were exposed and assembled for follow-
up at similar times. The risks in all these studies of internal
high LET radiation exposure may change when more
information, for example from microdosimetric re-evalua-
tions, becomes available.
Another weakness of the present study is that for certain
studies, in particular stomach cancer in [17], and various
non-haemopoietic malignancies in [18–21], the only com-
parison group available was the appropriate national pop-
ulation mortality or incidence rates. It is not clear to what
extent national rates are representative of the expected
cancer incidence or mortality in these populations.
Internal dose for the Techa River [3] and Semipalatinsk
[42] cohorts was based on age-dependent group-level
(village) internal dose estimates, so that these studies are,
as presently constituted, fundamentally ecological ones in
relation to their dosimetry. The possibilities for bias in
ecological studies are well known [49]. Reinforcing this,
the patterns of variation of risk for solid cancer in the
Techa River cohort are unusual, with indications that ERR
increases both with age at first exposure (2-sided P = 0.08)
and with attained age (2-sided P = 0.03) [3]; these patterns
are not observed for leukaemia, although there is a sug-
gestion of an increase in ERR with increasing age at first
exposure (2-sided P = 0.10). Likewise, the ERR was sta-
tistically significantly increased with increasing age at
exposure (P < 0.0001) in the Semipalatinsk cohort [42].
123
308
Such patterns are the reverse of what is observed in the
Japanese atomic bomb survivor cancer mortality data [13–
15] and in many other radiation-exposed groups [2].
However, the magnitude of such bias is likely to be lower
for leukaemia in the Techa River cohort [3] than for solid
cancers in this group and in the Semipalatinsk cohort [42],
where environmental carcinogens (e.g., tobacco use) and
occupational exposure other than ionising radiation are
more likely to severely influence the risk.
Fundamental to our adjustment of risk from low LET
radiation to estimate the effective high dose rate risk, is the
value of DDREF used to adjust the risk estimates upwards,
or downwards if the risk is negative. The value of DDREF
that we use, 1.5, is the central estimate recommended by
the BEIR VII committee [27]. BEIR VII estimated the 95%
uncertainty range in this parameter to be 1.1–2.3 [27].
Clearly use of the larger value of DDREF of 2 recom-
mended by ICRP [1] would elevate the effective high dose
rate risks that we estimate further and equally, use of a
value of 1 or even less, as implied by others [7], would
reduce these risks. Generally, use of DDREF in the range
1.1–2.3 [27] would scarcely affect the conclusions of this
paper. Even when using the upper extreme value of 2.3,
only for one further endpoint (lung cancer in the Semi-
palatinsk study [42]) does the discrepancy in risk from that
in the atomic bomb survivors become significant.
Arguably there is more that could be done to obtain
pooled estimates of risk for certain endpoints, for example
stomach, liver, lung, bone and leukaemia where there are
multiple studies reporting risks (Tables 1, 2). We have
conducted simple meta-analyses combining those studies
that we judge similar enough with respect to years of fol-
low-up and range of ages at exposure (Tables 1, 2). A more
thorough analysis would require fitting models to the var-
ious datasets, ideally based on access to individual data and
this is beyond the scope of the present paper.
As noted in the Introduction, there have been other
reviews [8, 10] comparing the risks of internal emitters in
medically exposed cohorts with those seen in the atomic
bomb survivors. In general there is little evidence of
discrepancy in risks between these groups [8, 10]. There
have also been comparisons of risks associated with ra-
don-daughter exposure in miners and among residentially
exposed groups with those in the A-bomb data by various
researchers [9, 10, 30] and more general comparisons of
risks from alpha-particle emitters in occupationally-ex-
posed groups [55]. Again, there is little evidence of dis-
crepancy between the risks in these groups [9, 10, 30, 55].
Therefore, consideration of the totality of epidemiological
evidence provides little evidence that cancer risks from
internal emitters have been substantially underestimated,
for example by the factors of 300 or more claimed by
some groups [7], although until the dosimetric uncer-
123
Radiat Environ Biophys (2007) 46:299–310
tainties in the alpha-particle-exposed cohorts considered
here are resolved, there remain uncertainties in these risk
estimates.
Acknowledgments The authors are grateful for the detailed and
helpful comments of the two referees. This report makes use of data
obtained from the Radiation Effects Research Foundation (RERF) in
Hiroshima and Nagasaki, Japan. RERF is a private, non-profit foun-
dation funded by the Japanese Ministry of Health, Labour and Wel-
fare (MHLW) and the U.S. Department of Energy (DOE), the latter
through the National Academy of Sciences. The data include infor-
mation obtained from the Hiroshima City, Hiroshima Prefecture,
Nagasaki City and Nagasaki Prefecture Tumour Registries and the
Hiroshima and Nagasaki Tissue Registries. The conclusions in this
report are those of the authors and do not necessarily reflect the
scientific judgment of RERF or its funding agencies. The work was
funded in part by the UK Department of Health and by the European
Commission under contract FI6R-CT-2003-508842 (RISC-RAD).
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