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Open AccessResearch

A prospective follow-up study of theassociation of radiation exposure withfatal and non-fatal stroke among atomic
bomb survivors in Hiroshima andNagasaki (1980e2003)
Ikuno Takahashi,1,2 Robert D Abbott,3 Tomohiko Ohshita,2,4 Tetsuya Takahashi,2
Kotaro Ozasa,5 Masazumi Akahoshi,6 Saeko Fujiwara,1 Kazunori Kodama,7Masayasu Matsumoto2

To cite: Takahashi I, Abbott
RD, Ohshita T, et al. A
prospective follow-up studyof the association of radiation
exposure with fatal andnon-fatal stroke among
atomic bomb survivors in
Hiroshima and Nagasaki(1980e2003). BMJ Open2012;2:e000654.
doi:10.1136/
bmjopen-2011-000654< Prepublication history forthis paper is available online.
To view these files please
visit the journal online (http://dx.doi.org/10.1136/
bmjopen-2011-000654).
Received 20 November 2011
Accepted 11 January 2012
This final article is available
for use under the terms of
the Creative Commons
Attribution Non-Commercial
2.0 Licence; see
http://bmjopen.bmj.com

For numbered affiliations see
end of article.
Correspondence to
Dr Ikuno Takahashi;
iktakaha@rerf.or.jp

ABSTRACT
Objective: Use of medical radiotherapy has increased
markedly in recent decades. Whether the consequence
includes an increased risk of cardiovascular diseaseremains to be determined. The purpose of this study
was to examine the association between radiation
exposure and the incidence of stroke among Japaneseatomic bomb survivors.
Design: A prospective follow-up study.
Setting and participants: Radiation exposure
from the atomic bombing was assessed in 9515
subjects (34.8% men) with 24-year follow-up from1980. Subjects were free of prevalent stroke when
follow-up began.
Outcome measures: Stroke events and theunderlying cause of death were reviewed to confirm
the first-ever stroke. Subtypes (ischaemic andhaemorrhagic events) were categorised based on
established criteria according to the definitions oftypical/atypical stroke symptoms.
Results: Overall mean radiation dose (6SD) in unitsof gray (Gy) was 0.3860.58 (range: 0e3.5).
During the study period, 235 haemorrhagic and 607
ischaemic events were identified. For men, after
adjusting for age and concomitant risk factors, therisk of haemorrhagic stroke rose consistently from
11.6 to 29.1 per 10 000 person-years as doses
increased from <0.05 to $2 Gy (p¼0.009).
Incidence also rose within the dose range <1 Gy(p¼0.004) with no dose threshold. In women, therisk of haemorrhagic stroke rose with increasingradiation exposure but not until doses reacheda threshold of 1.3 Gy (95% CI 0.5 to 2.3). Among
women, for doses <1.3 Gy, differences in stroke risk
were modest (13.5 per 10 000 person-years), while it
increased to 20.3 per 10 000 person-years for dosesthat ranged from 1.3 to <2.2 Gy and to 48.6 per
10 000 person-years for doses that were higher(p¼0.002). In both sexes, dose was unrelated toischaemic stroke.
Conclusion: While the risk of haemorrhagic strokeincreases with rising radiation exposure for both

ARTICLE SUMMARY
Article focus
Use of medical radiotherapy has increased inrecent decades.
- Whether the consequence includes an increased
risk of cardiovascular disease is unknown.
- Our purpose was to examine the association
between radiation exposure and the incidence ofstroke among atomic bomb survivors in Japan.
-

Key messages
Risk of haemorrhagic stroke increased withrising radiation exposure for both sexes,
although effects in women were less apparent
until doses exceeded a threshold at 1.3 Gy.
- Radiation exposure was unrelated to ischaemic
stroke.
-Strengths and limitations of this study
This report provides information on the incidenceof stroke using data from clinical examinations
and mortality records following a structured
research protocol.
- Measurement of radiation exposure adheres toa precise system of quantification.
- While best attempts were made to properlyclassify strokes outcomes, diagnostic uncertainties
persist.
-sexes, effects in women are less apparent until doses
exceed a threshold at 1.3 Gy.

INTRODUCTION
Worldwide use of radiographic procedures inmedicine has increased markedly in recent
decades.1e3 While health benefits arethought to outweigh the risk of adverse side
effects, increased use of radiotherapy,

Takahashi I, Abbott RD, Ohshita T, et al. BMJ Open 2012;2:e000654. doi:10.1136/bmjopen-2011-000654

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Stroke incidence in atomic bomb survivors
particularly in the age range <65 years,2 raises concerns
over the promotion of a variety of adverse healthoutcomes, most notably cancer. Although equivocal, datafrom patient samples and occupational studies suggestthat a corresponding rise could also occur in the incidence of circulatory disease and asymptomatic atherosclerosis.4e11 Based on mail surveys and vital statistics
records from the Japanese atomic bomb survivors Life
Span Study (LSS), evidence indicates that radiation>0.5 gray (Gy) increases the risk of all-stroke death(1950e2003).12 Associations that include gender effects
and stroke subtypes, however, have not been clearly
identified. Our purpose was to examine the association
between radiation and stroke incidence among atomic
bomb survivors in the Adult Health Study (AHS)
from the Radiation Effects Research Foundation(RERF) over two decades (1980e2003). Stroke
outcomes include morbidity and mortality fromhaemorrhagic and ischaemic events after adjustment forseveral concomitant risk factors.
METHODS
Study population
In 1950, the Atomic Bomb Casualty Commission (nowthe RERF) established the LSS of 120 321 survivors of theatomic bombings of Hiroshima and Nagasaki, Japan.13
Follow-up is limited to periodic mail surveys andmortality outcomes from vital statistics data. In 1958,
a series of comprehensive physical examinations was
performed with the establishment of the AHS cohort
consisting of 19 961 subjects from the LSS subjects. In
the AHS, examinations have been given biennially withinformed consent and approval from the RERF Ethics
Committee. The AHS biennial health examinations
provide clinical information complementary to deathand tumour registries data. The AHS includes individuals exposed to a broad range of doses to enhancedetection of radiation effects on a variety of disease
outcomes. Participation rate has ranged from 70% to
90% throughout the examination cycles. For the current
report, follow-up began at examinations that were given
in 1980. From that time, subjects were followed forincident stroke over a 24-year period (until the end of2003). Of the eligible 11 231 participants, 208 prevalentstroke (35 were haemorrhagic, 117 were ischaemic and
56 were of unknown origin), and 1508 without dose
information were excluded. The final sample includes
9515 AHS participants.
Radiation dosimetry
Estimation of radiation dose exposure for each individual was based on an updated dosimetry system (DS02)
that takes into account biases arising from errors incalculated doses, physical locations and organ shielding
at the time of bombing.14 For all analyses, weighted
colon doses were used in units of gray (Gy), where thedose for an individual corresponds to the total exposurein g rays + 103 the smaller neutron dose.14 Colon dose
was selected a priori because of broad (systemic)
2

cardiovascular processes that are often associated withstroke. This includes the major system-wide precursors
of hypertension, cigarette smoking, total cholesterol,diabetes and body mass. Colon dose was also used in an
earlier study of circulatory disease in the RERF.12
Stroke ascertainment
Possible stroke events and the underlying cause of death
were coded according to International Classification of
Disease (ICD) in the RERF database. The ICD codes ofstroke-related disease are 330e332, 334, 352 and 435(ICD-7); 333, 430e434, 436 and 438 (ICD-8); 430, 431
and 433e438 (ICD-9) and G45, I60, I61, I63e66 and I69(exclude I698) (ICD-10). Virtually all deaths are
assumed accounted for based on access to a comprehensive nationwide registration of deaths in Japan. The
number of missed cases of non-fatal strokes in subjects
who remained alive at the close of follow-up (2003) is
unknown, although with high participation acrossrepeated AHS examinations, it is thought to be small.
There is no indication of bias in the indexing of strokeby radiation exposure. All data (health examinations,death certificates and autopsy reports when available)
were reviewed to confirm the first-ever stroke. Stroke wasdefined as an acute-onset focal neurological deficit ofvascular aetiology, persisting for at least 24 h. Stroke
subtypes (ischaemic and haemorrhagic events) werecategorised based on established criteria that included
clinical features, neuroimaging and non-invasive vascularstudies, and other laboratory criteria according to thedefinitions of typical/atypical stroke symptoms in the
WHO Monitoring of Trends and Determinants in
Cardiovascular Disease Projects.15 Ischaemic stroke wasdiagnosed if there was a focal neurological deficit in theabsence of haemorrhage based on neuroimaging when
the neuroimage showed an ischaemic infarct that
correlated with the clinical deficit or an ischaemic infarct
was documented at autopsy. Not all diagnoses of stroke
were based on neuroimaging studies. Among all strokes,
49.0% were based on death certificates alone (50.2% forhaemorrhagic stroke and 49.3% for ischaemic stroke).
Baseline examination and questionnaires
Baseline concomitant data included the age when followup began, systolic blood pressure (SBP), total cholesterol(T-CHO), body mass index (BMI), diabetes, smoking
and alcohol intake. A priori selection of these risk factors
was based on a perceived need to consider traditional
stroke risk factors, to include adjustments16e18 that weremade in an earlier report from the RERF12 and to
consider possible sources of confounding due to documented relationships between radiation exposure, SBP19
and T-CHO.20 Except for smoking and alcohol intake,the concomitant data were collected at clinical examinations that were given in 1980. In the event that an
examination cycle failed to coincide with 1980, information from the most recent examination was used(with 5 years). Measurement of non-fasting T-CHO is
described elsewhere.20 Sitting SBP was measured in the

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Stroke incidence in atomic bomb survivors
left arm. BMI was defined as weight (kg) divided byheight squared (m). A diagnosis of diabetes was basedon a physician diagnosis or the use of medications fordiabetes.
Data on smoking and alcohol intake were collectedfrom mail surveys that were administered from 1978 to
1980. In the absence of such data, information was takenfrom direct interviews in 1965. Smoking status was
defined as never-, past and current smoker. Alcohol
intake was defined according to typical Japanese
consumption strata in units of ethanol as non-drinker,
light drinker (<34 g/day) and heavy drinker ($34 g/day).21 For the sample with interview data from 1965 andthe mail survey in 1978e1980, smoking status was
unchanged in >87% of the study participants. In
contrast, patterns of alcohol intake are more variable.
The correlation between the repeated alcohol measures
is 0.24, although it is highly significant (p<0.001).
Statistical methods
Crude and age-adjusted incidence of haemorrhagic andischaemic stroke in person-years of follow-up were estimated across common ranges of radiation dose based onstandard analysis of covariance methods.22 Further
description of the procedure used in the calculation of
person-years is given elsewhere, along with its close
relationship with a Cox proportional hazards regression
model.23 Similar methods are also useful for providing
age-adjusted percents and average levels of theconfounding risk factors across the radiation strata.19
The primary method for testing for an independent
effect of radiation on the risk of each stroke subtype isbased on Cox proportional hazards regression models
where radiation dose is modelled as a continuous
predictor variable. Although the number of strokes isoften small (particularly haemorrhagic events), we foundno evidence for a significant departure from theassumption of proportionality. This assumption isfurther relaxed by adjusting for age based on the use of
attained age as the time scale in the non-parametric partof the hazard model, while radiation dose and theconcomitant risk factors were modelled as covariates in
the parametric part.24 Concomitant risk factors included
SBP and the other risk factors. Non-linear relationships
between radiation dose and the stroke risk were also
considered, including a threshold analysis. For the latter,dose was modelled as (Dd) 3 Id(D), where D is a radiation dose, d is a threshold and Id(D) ¼ 1 when D$d and0 otherwise. The dose that minimises 2 3 the log
likelihood provides a point estimate for d. A 95% CI
for d consists of upper and lower threshold values forwhich 2 3 the log likelihood differs from theminimum value by 3.84 (the 95th percentile from a c2
distribution with 1 degree of freedom). If the lower
threshold value is >0 Gy, then a dose threshold isassumed to exist with 95% confidence. Although
primary tests of significance were based on radiationdose being modelled as a continuous risk factor, patternsof association are also described through the use of

indicator variables that allow for the estimation of therelative hazard of stroke (and 95% CIs) between radiation dose strata $0.05 Gy versus doses considered to besmall (<0.05 Gy). All reported p values were based on
two-sided tests of significance. Statistical modelling andtesting were based on the use of SAS software (V.9.2; SAS
Institute Inc.).
RESULTS
Radiation exposure and study characteristics
Table 1 provides the distribution of radiation exposures,
average baseline ages and age-adjusted means and percent characteristics for the sample of men and women
who were available for follow-up. The average radiationdose (6SD) for men is 0.4160.62 and for women
0.3660.55 (p<0.001). For men, 15.3% were exposed toradiation doses $1 Gy, while 46.5% were exposed todoses <0.05 Gy. For women, corresponding percentswere 11.6% and 44.6%.
After adjusting for differences in baseline age acrossthe ranges of radiation exposure, BMI declined(although modestly) with increased radiation exposure
in men (p¼0.016) but not in women. For women, higher
radiation doses were more likely associated with elevated
SBP (p¼0.013). A similar pattern was absent in men.
While not significant, T-CHO levels were highest in
women who had the greatest dose exposures. For theremaining data, associations with radiation were absent.
Age-adjusted incidence of stroke by radiation exposure
During the course of follow-up, there were 235
haemorrhagic and 607 ischaemic strokes (14.0 and 36.1
per 10 000 person-years, respectively). The average age at
the time of a stroke was 73.2 years (range: 43e98 years)
for those who were haemorrhagic and 77.0 years (range:
48e100 years) for those who were ischaemic. The
average follow-up time before stroke occurrence was
11.1 years (range: 3 monthse23 years) for haemorrhagic
events and 11.5 years (range: 4 dayse23 years) for
ischaemic events. There were an additional 84 strokes
that were of unknown subtype.
Table 2 provides further details on stroke incidence
that was identified according to radiation exposure at
the time of bombing. For men, after adjusting for age,the incidence of haemorrhagic stroke rose consistently
from 12.2 to 25.2 per 10 000 person-years as radiation
exposure increased from <0.05 to $2 Gy (p¼0.006).
Risk of haemorrhagic stroke continued to rise withincreasing doses <1 Gy (p¼0.006). For women, differences in the risk of haemorrhagic events were modest for
doses <2 Gy but more than tripled when doses went
higher (p¼0.002). There were no significant relationships between radiation and the risk of ischaemic eventsfor either sex (table 2). Relationships to total stroke werelargely determined through associations with haemorrhagic events. There were no relationships between
radiation and the incidence of strokes that were of
unknown origin.

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Stroke incidence in atomic bomb survivors
Table 1 Distribution of radiation exposures, average baseline age and age-adjusted means and per cent characteristics forthe sample of men and women available for stroke follow-up
Radiation exposure (Gy)
Characteristic
Men
Sample size
Per cent of sample
Baseline age* (years)
SBP (mm Hg)
T-CHO (mmol/l)
BMIy (kg/m2)
Diabetes (%)
In Nagasaki at exposure
Smoking status (%)
Past
Current
Alcohol intake (%)
Light (<34 g/day)
Heavy ($34 g/day)
Women
Sample size
Per cent of sample
Baseline age* (years)
SBPz (mm Hg)
T-CHOx (mmol/l)
BMI (kg/m2)
Diabetes (%)
In Nagasaki at exposure{
Smoking status (%)
Past
Current
Alcohol intake (%)
Light (<34 g/day)
Heavy ($34 g/day)<0.05

0.05 to <1

1 to <2

‡2

1539
46.5
57613
1356244.5360.88
21.963.0
12.6
40.8

1266
38.2
57613
1356234.6060.85
21.863.0
14.6
31.1

376
11.4
54613
1336204.6560.96
21.762.9
12.5
41.2

130
3.9
51611
1366194.5560.96
21.563.0
15.5
30.2

21.6
66.6

21.0
65.6

22.7
64.2

16.8
68.5

44.3
38.3

42.0
38.3

42.9
41.2

44.1
38.4

2765
44.6
59613
134626
4.9460.91
22.863.6
6.7
31.0

2720
43.8
60613
1356265.0260.96
22.963.5
8.4
26.5

531
8.6
58612
1366255.0961.01
23.063.5
8.0
35.7

188
3.0
56612
137626
5.1560.93
22.363.2
7.2
25.8

5.1
10.6

4.3
14.7

5.3
13.8

7.2
13.1

20.7
0.8

21.3
1.9

21.3
1.3

16.2
0.0

Continuous variables are reported as means 6 SDs. The remaining variables are reported as per cents.
*Significant decline with radiation exposure (p<0.001).
ySignificant decline with radiation exposure (p¼0.016).
zSignificant increase with radiation exposure (p¼0.013).
xSignificant increase with radiation exposure (p<0.001).
{Significant increase with radiation exposure (p¼0.002).
BMI, body mass index; SBP, systolic blood pressure; T-CHO, total cholesterol.

Risk factor-adjusted associations between haemorrhagic
stroke and radiation exposure
The association between radiation and haemorrhagic
events was further examined after adjustment for age,
SBP, BMI, diabetes, T-CHO, cigarette smoking, alcohol
drinking and city (table 3). For men, the association wasdiminished but remained significant (p¼0.009). For
those exposed to the highest amounts of radiation($2 Gy), there was a 2.5-fold excess risk of stroke ascompared to doses that were <0.05 Gy (29.1 vs 11.6 per
10 000 person-years). Risk of haemorrhagic stroke alsorose with increasing doses <1 Gy (p¼0.004), suggestingthat the doseeresponse relationship in men is notentirely attributed to the excess of haemorrhagic events
that were observed in the highest ranges of radiation.
For women, while a doseeresponse relationship acrossthe entire range of radiation and the risk of haemorrhagic events was absent, evidence in table 2 suggeststhat there may exist a threshold effect. Further analyses
4

identified a significant dose threshold at 1.3 Gy (95% CI
0.5 to 2.3 Gy) where a change occurs in the association
between radiation and the risk of haemorrhagic stroke.
Below the threshold, risk was unrelated to radiation,
while above the threshold, it increased with rising dose.
This can better be seen in table 3 for dose strata <0.05,
0.05 to <1.3, 1.3 to <2.2 and $2.2 Gy. For doses <1.3 Gy,
differences in haemorrhagic risk were modest (14.2 and13.0 per 10 000 person-years), while it increased to 20.3
per 10 000 person-years for doses that ranged from 1.3 to<2.2 Gy and to 48.6 per 10 000 person-years for dosesthat were higher. For men, a dose threshold was absent.
In both sexes, findings do not appear to be influenced
by events that occur at an early age (<55 years).
DISCUSSION
Findings suggest that exposure to increasing radiation
doses among atomic bomb survivors beyond a thresholdof 1.3 Gy is associated with an increase in the future risk

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Stroke incidence in atomic bomb survivors
Table 2 Age-adjusted stroke incidence by radiation exposure
Radiation
exposure (Gy)
Men
<0.05
0.05 to <1
1 to <2$2
p Valuey
Overall
Women<0.05
0.05 to <1
1 to <2$2
p Value
Overall

Haemorrhagic

Ischaemic

Sample size

EventsIncidence*

EventsIncidence*

EventsIncidence*

1539
1266
376
130

33
37
13
5

112
81
20
8

88

40.5
38.5
34.9
46.3
0.788
39.4

154
132
36
13

3311

12.2
17.6
21.4
25.2
0.006z
15.7

56.1
62.7
61.9
72.4
0.202
59.7

2765
2720
531
188

66
63
8
10

173
174
33
6

147

34.4
33.9
39.8
27.9
0.930
34.4

262
264
46
19

6204

13.1
12.4
9.3
41.9x
0.098
13.1

221

386

Total stroke

335

591

52.0
51.6
54.9
85.7{
0.155
52.7

*Incidence rate per 10 000 person-years.
yThe p value is a test for trend with dose modelled as a continuous variable.
zFor men, risk of haemorrhagic stroke continued to rise with increasing doses <1 Gy (p¼0.006).
xRisk of haemorrhagic stroke in women is higher for doses $2 Gy versus lower doses (p¼0.002).
{Risk of total stroke in women is higher for doses $2 Gy versus lower doses (p¼0.027).

of haemorrhagic stroke in women. While 1.3 Gy is only
a point estimate, the lower 95% confidence limit (0.5 to
2.3 Gy) further suggests that there is more than 95%
confidence that the true threshold is 0.5 Gy or higher.
For men, the incidence of haemorrhagic stroke rose
consistently with increasing exposure levels without
evidence for a threshold. Even within the dose range<1 Gy, the doseeresponse observed in men persisted.
The 35-year period from the time of the atomic bombing
in Hiroshima and Nagasaki to the beginning of stroke

Table 3 Risk factor-adjusted incidence and relative
hazards of haemorrhagic stroke by radiation exposure
Radiation
exposure (Gy)
Men
<0.05
0.05 to <1
1 to <2$2
p Value*
Women
<0.05
0.05 to <1.3
1.3 to <2.2
$2.2
p Value

Incidence

Relative hazard(95% CI)

11.6
17.7
20.2
29.1
0.009yReference
1.5 (0.8 to 2.7)
1.7 (0.7 to 4.1)
2.5 (0.8 to 7.3)

14.2
13.0
20.3
48.6
0.002

Reference
0.9 (0.6 to 1.4)
1.4 (0.6 to 3.7)
3.5 (1.4 to 9.0)

Incidence rate per 10 000 person-years and relative hazards areadjusted for age, systolic blood pressure, body mass index,
diabetes, total cholesterol, cigarette smoking, alcohol drinking
and city.
*The p value is a test for trend with dose modelled as a continuous
variable. For women, a dose threshold model is used with a dosethreshold at 1.3 Gy (95% CI 0.5 to 2.3 Gy).
yFor men, risk of haemorrhagic stroke continued to rise withincreasing doses <1 Gy (p¼0.004).

follow-up in 1980 may be especially meaningful withregard to the increased use of radiotherapy at younger
ages and the increased opportunity for a stroke todevelop in later life.2
Patterns of association persisted for the period that
predated the 1980 baseline, during a time when enrolment in the AHS continued to be ongoing. For the 1980
baseline used in the current report, >97% of the AHS
participants had been enrolled. The 1980 baseline also
provides a uniform beginning with a fixed lag timesince the bombing of Hiroshima and Nagasaki. Morecomplete data from clinical examinations and a recently
conducted mail survey were also available. Althoughmany stroke diagnoses were based on death certificatesalone (about 50%), confounding due to changes in the
diagnosis of stroke through the advent of neuroimaging
in the late 1970s was also thought to be minimised. With
regard to the diagnostic uncertainty that is common in
any large-scale study, best attempts were made for theproper classification of fatal and non-fatal strokes withthe opportunity for adjudication among the study
investigators. In the absence of neuroimaging, however,diagnostic limitations are difficult to avoid. In spite ofevidence from Japanese samples that suggest thaterrors in stroke classification could be small,25 26 subtle
distinctions between primary intracerebral haemorrhage
and ischaemic events can still exist when neuroimaging
is available.
There is also evidence of an excess risk of circulatory
disease at low and moderate doses (<5 Gy) in Japaneseatomic bomb survivors in the LSS cohort12 where followup began in 1950. Although there were no clinicalexaminations in the LSS, there was a 9% excess risk ofdeath due to all strokes combined per unit Gy (p¼0.02).
The 5% excess RR (95%CI 6 to 17) that was observed

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Stroke incidence in atomic bomb survivors
for cerebral haemorrhage was indistinguishable from
a 4% excess RR (10 to 20) for cerebral infarction.12
Corroborating evidence also appears elsewhere,5 10 while
reports of uncertainty in the association between radiation and stroke are common,11 27 most likely due to theextreme difficulties in quantifying radiation exposure instudies that often rely on limited record keeping andhistorical recall.
Given that the association between radiation and therisk of stroke is plausible, an explanation for the association is far from clear. At high doses (>10 Gy), there iswell-established evidence from radiotherapy patients ofdirect damage in circulatory systems, predominantly theconsequence of excessive cell killing and the associatedresponse to cell damage. In contrast, epidemiologicalstudies suggest that the mechanisms associated with lowand moderate-dose ionising radiation (<5 Gy) are
different.16e18 More direct mechanistic derangementsthat might explain an association with haemorrhagic
stroke include fibrinoid necrosis of the small arteries
and arteriole, a common underlying cause for intracerebral haemorrhage due to hypertension in murine
brain28 or arteriovenous malformations in humans.29
Fibrinoid necrosis in vessels is also preceded by proinflammatory cytokines and observed in late cerebral
radionecrosis at radiotherapy doses <0.05 Gy.30 Elevatedblood pressure,19 hypertension31 and inflammation (Creactive protein and interleukin-6) among the atomic
bomb survivors32 33 might further promote a fibrinoid
necrosis link with haemorrhagic stroke. Hypertension
has a greater impact on haemorrhagic stroke incidence
than cerebral infarction.34 In the absence of a clear
explanation for the reported findings, further study ofsubclinical arteriosclerosis or biological evidencesamong the AHS may provide additional insight into therole that radiation has on promoting stroke and its
subtypes.
In the current report, several notable limitations need
to be addressed. Whether findings apply to otherethnicities is unknown. Genetic susceptibilities may bedifferent. The number of haemorrhagic events is also
limited and too insufficient to allow for a carefulassessment of the effect of radiation on the risk of stroke
between risk factor strata. In spite of the limitations,findings from the AHS warrant consideration andfurther study. Attractive features include the high rate ofparticipation between examination cycles and free accessto standardised medical care and evaluation. Measurement of radiation exposure also adheres to a rigorous
system of quantification.14 Among large cohort studies,
the dosimetry in the AHS is unusually precise. In
conclusion, the risk of haemorrhagic stroke increases
with rising radiation exposure for both sexes. In men, it
seems to occur across the full range of radiation exposures, while in women, the risk becomes apparent whendoses exceed a threshold at about 1.3 Gy. Given theobserved latency between radiation exposure andhaemorrhagic stroke in the current study, a consequence
6of the expanded use of radiotherapy in younger individuals2 could be an increased opportunity for thedevelopment of adverse outcomes in later life.
Author affiliations
1
Department of Clinical Studies, Radiation Effects Research Foundation(RERF), Hiroshima, Japan2
Department of Clinical Neuroscience and Therapeutics, Hiroshima University,
Hiroshima, Japan3
Department of Statistics, Radiation Effects Research Foundation (RERF),
Hiroshima, Japan
4
Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima, Japan
5
Department of Epidemiology, Radiation Effects Research Foundation (RERF),
Hiroshima, Japan
6
Department of Clinical Studies, Radiation Effects Research Foundation(RERF), Nagasaki, Japan
7
Chief Scientist, Radiation Effects Research Foundation (RERF), Hiroshima,Japan

Contributors IT contributed to the study design, interpreted the data and took
the lead in writing the paper. RDA conducted the statistical analyses,interpreted the data and made substantial contributions to drafting themethods and results sections of the paper. TO and TT played a lead role in dataacquisition. They also contributed to the study design and in writing the paper.
KO, MA and SF had important roles in data interpretation, in writing andreviewing the paper and provided essential oversight and supervision of thestudy design. KK and MM assisted in writing and supervision of the final draftof the paper. Their oversight of the final product for verification of the study
findings was essential. Credit for all authors is based on (1) substantial
contributions to conception and design (IT, RDA, TO, TT, KO, MA, SF),
acquisition of data (TO, TT) or analysis and interpretation of data (IT, RDA, TO,
TT, KO, MA, SF, KK, MM); (2) drafting the article or revising it critically forimportant intellectual content (all authors) and (3) final approval of the version
to be published (all authors). Each author participated sufficiently in the workand accepts public responsibility for appropriate portions of the content inwhich they have an expertise. All authors critically revised the manuscript forimportant intellectual content.
Funding The Radiation Effects Research Foundation (RERF), Hiroshima andNagasaki, Japan, is a private non-profit foundation funded by the Japanese
Ministry of Health, Labour and Welfare and the US Department of Energy(DOE), the latter in part through DOE Award DE-HS0000031 to the National
Academy of Sciences. This publication was supported by RERF ResearchProtocol(s) RP # 2-75. The views of the authors do not necessarily reflect
those of the two governments.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There is no additional data available.

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7

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A prospective follow-up study of theassociation of radiation exposure with fatal
and non-fatal stroke among atomic bomb
survivors in Hiroshima and Nagasaki (1980 −2003)
Ikuno Takahashi, Robert D Abbott, Tomohiko Ohshita, et al.
BMJ Open 2012 2:

doi: 10.1136/bmjopen-2011-000654

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Data Supplement"Supplementary Data"
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References

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