RADIATION RESEARCH 180, 539–545 (2013)0033-7587/13 $15.00
Ó2013 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR13421.1

Radiation Exposure and the Risk of Mortality from Noncancer Respiratory
Diseases in the Life Span Study, 1950–2005
Truong-Minh Pham,a Ritsu Sakata,a Eric J. Grant,a Yukiko Shimizu,a Kyoji Furukawa,b Ikuno Takahashi,a Hiromi
Sugiyama,a Fumiyoshi Kasagi,c Midori Soda,d Akihiko Suyama,d Roy E. Shoree and Kotaro Ozasaa,1Departments of a Epidemiology and b Statistics, and e Vice Chairman and Chief of Research, Radiation Effects Research Foundation, 5-2 Hijiyama
Park, Minami-ku, Hiroshima, 732-0815, Japan; d Department of Epidemiology, Radiation Effects Research Foundation, 1-8-6 Nakagawa, Nagasaki,
850-0013, Japan; and c Institute of Radiation Epidemiology, Radiation Effects Association, 1-9-16, Kaji-cho, Chiyodaku, Tokyo, 101-0044, JapanINTRODUCTION
Pham, T-M., Sakata, R., Grant, E. J., Shimizu, Y.,
Furukawa, K., Takahashi, I., Sugiyama, H., Kasagi, F., Soda,
M., Suyama, A., Shore, R. E. and Ozasa. K. Radiation
Exposure and the Risk of Mortality from Noncancer
Respiratory Diseases in the Life Span Study, 1950–2005.
180, 539–545 (2013).

The Life Span Study (LSS) cohort of survivors of theatomic bombings in Hiroshima and Nagasaki has provided
comprehensive evaluations of the health risks of exposure toionizing radiation (1). Excess risks of both cancer incidence
and mortality have been documented (2–4). In recent years,
there has been increasing interest in examining possible
associations of radiation exposure and subsequent noncancer diseases (5–7). Recent LSS mortality studies haveshown associations of radiation exposure with several
noncancer diseases, including elevated risks of both strokeand heart disease (8). Further, associations of radiation withother noncancer conditions, such as benign thyroid
neoplasms, chronic liver disease, cataract, uterine myoma
and calculus of the kidney have also been reported (9).
With regard to noncancer respiratory diseases (NCRD),
significant excess relative risks of respiratory deaths havebeen reported in the LSS cohort (3–6), however theseanalyses were based on all subtypes combined and did not
examine the possibility of artifactual associations. Resultsfrom other radiation-exposed cohorts (7, 10–18) have been
inconclusive, as summarized in the Discussion section ofthis article.
The fact that subtypes of noncancer respiratory diseases
differ in their risk factors and in their etiology andpathogenesis suggested the need for an in-depth examination of the risks of radiation exposure by subgroups. Sincesome types of noncancer respiratory diseases (e.g.,pneumonia) are often the end-of-life condition caused byother disease processes (cancer or cardiovascular disease,for instance), we will examine the impact upon theradiation-noncancer respiratory diseases associations ofpotential death certificate misdiagnosis. The potential for
confounding by lifestyle and sociodemographic variations
will also be examined, as will temporal variations in theassociations.
In the current study, we examined the risks of radiation
exposure associated with finer categories of noncancer
respiratory diseases among atomic-bomb survivors in
Hiroshima and Nagasaki, from 1950–2005. We also

An apparent association between radiation exposure andnoncancer respiratory diseases (NCRD) in the Life Span
Study (LSS) of atomic bomb survivors has been reported, but
the biological validity of that observation is uncertain. This
study investigated the possibility of radiation causation of
noncancer respiratory diseases in detail by examining
subtypes of noncancer respiratory diseases, temporal associations, and the potential for misdiagnosis and otherconfounding factors. A total of 5,515 NCRD diagnoses listed
as the underlying cause of death on the death certificate wereobserved among the 86,611 LSS subjects with estimatedweighted absorbed lung doses. Radiation dose-response
analyses were conducted using Cox proportional hazard
regression for pneumonia/influenza, other acute respiratory
infections, chronic obstructive pulmonary disease and asthma. The linear excess relative risks (ERR) per gray (Gy) were0.17 (95% CI 0.08, 0.27) for all NCRD and 0.20 (CI 0.09, 0.34)
for pneumonia/influenza, which accounted for 63% of noncancer respiratory disease deaths. Adjustments for lifestyleand sociodemographic variations had almost no impact on
the risk estimates. However, adjustments for indications ofcancer and/or cardiovascular disease decreased the risk
estimates, with ERR for total noncancer respiratory diseases
declined by 35% from 0.17 to 0.11. Although it was
impossible to fully adjust for the misdiagnosis of otherdiseases as noncancer respiratory diseases deaths in thisstudy because of limitations of available data, nevertheless,the associations were reduced or eliminated by the adjustment that could be made. This helps demonstrates that theassociation between noncancer respiratory diseases andradiation exposure in previous reports could be in part be
attributed to coincident cancer and/or cardiovascular diseases. Ó 2013 by Radiation Research Society

1 Address for correspondence: Department of Epidemiology,
Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima, 732-0815, Japan; e-mail: ozasa@rerf.or.jp.

539

540

PHAM ET AL.

TABLE 1
Description of Codes for Noncancer Respiratory Diseases from the ICD-7 to ICD-10 Revisions
Causes of deathICD-7 codes

ICD-8 codes

ICD-9 codes

ICD-10 codes

All noncancer respiratory diseases
Acute respiratory infections
Pneumonia/Influenza
Chronic obstructive pulmonary disease
AsthmaOther respiratory diseases

470–527, 241
470–475, 500
480–483, 490–493
501–502, 526, 527
241
510–525

460–519
460–466
470–474, 480–486
490–492, 518
493
500–517, 519

460–519
460–466
480–487
490–492, 494, 496
493, 495
470–478, 500–519

J00–J99
J00–J06, J20–J22
J10–J18
J40–J44, J47
J45–J46
J30–J39, J60–J99

considered the effects of potential confounding factors aswell as misdiagnoses of coexistent cancer and cardiovascular disease (CVD) on the radiation risks. Cardiovasculardisease was added as a potential misdiagnostic factor
because cardiovascular disease mortality is apparently
associated with radiation exposure in the LSS (8) although
the detailed dose-response or causal nature of therelationship has not been fully elucidated.
MATERIALS AND METHODS
Study Subjects
The study subjects were members of the LSS cohort (1), which was
originally defined on the basis of the 1950 Japanese National Census
and associated surveys between 1950–1953. The present analyses

were based on 86,611 atomic bomb survivors whose estimated lungdoses were available. This study was approved by the Human
Investigation Committee of the Radiation Effects Research Foundation and the collection of vital status and cause of death of the subjects
was approved by the Ministry of Justice and the Ministry of Health,Labour and Welfare of Japan.
Outcome Determination
Mortality follow-up from 1950 until the end of 2005 used theJapanese national family registration system (koseki). Cause of death
was ascertained from the death certificates. Underlying causes of death
were coded using the International Classification of Diseases andInjuries (ICD), 7th Revision (ICD-7) for deaths in 1950–1968, ICD-8
in 1969–1978, ICD-9 in 1979–1997 and ICD-10 in 1998–2005. Table
1 shows the detailed descriptions of noncancer respiratory diseases
according to several ICD Revisions. In the ICD-10 Revision, the codes
for all noncancer respiratory diseases were defined as J00–J99.

TABLE 2
Characteristics of 86,611 Study Subjects and Numbers of Deaths from Noncancer Respiratory Diseases, 1950–2005
Number of deaths (death rate per 10,000 person-years)
Acuterespiratory
infection

Pneumonia/
Influenza

Chronic
obstructive
pulmonarydiseaseAsthmaOther
respiratory
diseases

Number of
subjects

Person-years

All noncancer
respiratory
diseases

Sex
Men
Women

35,68750,924

1,307,515
2,058,466

2547 (19.48)
2968 (14.42)

84 (0.64)
117 (0.57)

1501 (11.48)
1970 (9.57)

377 (2.88)
299 (1.45)

260 (1.99)
215 (1.04)

325 (2.49)
367 (1.78)

City
Hiroshima
Nagasaki

58,495
28,1162,242,073
1,123,908

3770 (16.81)
1745 (15.53)

149 (0.66)
52 (0.46)

2333 (10.41)
1138 (10.13)463 (2.07)
213 (1.90)

336 (1.50)
139 (1.24)

489 (2.18)
203 (1.81)

Age at the timeof bombings
,10
10–
20–
30–
40–
50þ

17,832
17,564
10,891
12,27013,504
14,550942,026
874,356
505,188465,949
365,383
213,079102 (1.08)
372 (4.25)
618 (12.23)
1487 (31.91)
1532 (41.93)1404 (65.89)

4 (0.04)
5 (0.06)
10 (0.20)
30 (0.64)
47 (1.29)
105 (4.93)

50 (0.53)
219 (2.50)
385 (7.62)
978 (20.99)1036 (28.35)
803 (37.69)

5 (0.05)
34 (0.39)
74 (1.46)
173 (3.71)
179 (4.90)
211 (9.90)

14 (0.15)
23 (0.26)
40 (0.79)
76 (1.63)
105 (2.87)
217 (10.18)

29 (0.31)
91 (1.04)
109 (2.16)
230 (4.94)
165 (4.52)
68 (3.19)

Weighted
absorbedlung dose,0.0050.005–
0.1–
0.2–
0.5–
1.0–
2.0þ

37,71329,695
6,232
6,418
3,696
2,029
828

1,468,898
1,158,582
242,122
246,070
141,733
77,73230,8442,353 (16.02)
1,917 (16.55)
418 (17.26)
411 (16.70)
215 (15.17)
141 (18.14)
60 (19.45)

82 (0.56)
79 (0.68)
16 (0.66)
12 (0.49)
8 (0.56)
4 (0.51)0 (0.00)

1,478 (10.06)
1,200 (10.36)
262 (10.82)
260 (10.57)
147 (10.37)
88 (11.32)
36 (11.67)

274 (1.87)
261 (2.25)
50 (2.07)
40 (1.63)
24 (1.69)
23 (2.96)
4 (1.30)

209 (1.42)
151 (1.30)
44 (1.82)
38 (1.54)
14 (0.99)
12 (1.54)
7 (2.27)310 (2.11)
226 (1.95)
46 (1.90)
61 (2.48)
22 (1.55)
14 (1.80)
13 (4.21)

Characteristics

541

RADIATION AND NONCANCER RESPIRATORY MORTALITYTABLE 3
Excess Relative Risk (ERRa) Estimates per Gy and 95% Confidence Interval (95% CI) for Noncancer Respiratory Disease Deaths,
1950–2005
For both sexes
Causes of deathAll noncancer respiratory
diseases
Acute respiratory
infections
Pneumonia/Influenza
Chronic obstructive
pulmonary disease
AsthmaOther respiratory

For menFor women

DeathsERR (95% CI)

P

DeathsERR (95% CI)

P

DeathsERR (95% CI)

P

5515

0.17 (0.08; 0.27)

,0.01

2547

0.14 (0.03; 0.27)

0.01

2968

0.22 (0.08; 0.37) ,0.01

201
3471

–0.16 (,0;b 0.40)
0.20 (0.09; 0.34)

0.38
,0.01

84
1501

0.10 (,0;b 1.18).0.50
0.14 (0.01; 0.31)
0.06

117
1970

–0.22 (,0;b 0.35)
0.27
0.30 (0.11; 0.51) ,0.01

676
475
692

0.08 (0.14; 0.37) .0.50
0.16 (0.10; 0.52)
0.27
0.20 (0.01; 0.48)
0.07

377
260
325

0.20 (0.09; 0.60)
0.2
0.22 (0.11; 0.71)
0.23
0.06 (0.18; 0.41) .0.50

299
215
367

–0.12 (,0;b 0.33) .0.50
0.05 (,0;b 0.66) .0.50
0.37 (0.02; 0.85)
0.04a
ERR was estimated using the linear-dose model without effect modifiers, in which the background rates included sex, city, age at exposure,but sex was not included for sex-specific risk estimates.
b
Less than zero (,0) was designated for the lower confidence bounds, when these could not be estimated (see Materials and Methods).

Among these, subtypes included acute upper respiratory infections andacute bronchitis (J00–J06, J20–J22); pneumonia/influenza (J10–J18);
chronic obstructive pulmonary disease (COPD, J40–J44, J47); asthma(J45–J46); and other diseases of the respiratory system (J30–J39; J60–
J99). The risk of noncancer respiratory disease was estimated by thefollow-up period of 1950–1964, 1965–1979 and 1980–2005.
Radiation Exposure and Other Variables
We used weighted absorbed lung dose (gamma dose plus ten times
the neutron dose) in Gy according to DS02 (4). The cohort covered alarge range of doses, however more than 90% of subjects were
exposed to less than 0.5 Gy of absorbed lung dose. To consider
confounding factors, information on sociodemographic and lifestylefactors was collected through four mail surveys carried out between
1965–1991, and through clinical interviews performed in the 1960s
among members of the Adult Health Study (AHS), a clinical study ofa subset of the LSS. About 60% of the study subjects (n ¼ 55,132) had
provided information for assessing potential confounding variables,
which were determined as follows: smoking habits were identified aslast known smoking status with categories of never smoker, pastsmoker and current smoker. Alcohol consumption was documented as
grams of ethanol per week. Body mass index was computed as weightin kilograms divided by the square of height in meters (kg/m2).
Educational level was classified as primary school or less, secondary
school and college/university. Diabetes mellitus was a yes/no variable.
Occupational histories were classified as professional/technical,
clerical/sales, farmer/craftsman, transportation/service and otheroccupation categories. Those variables were included in an analysis
that adjusted for potential confounding factors.
Statistical Analysis
Partial-likelihood survival analyses (19) were conducted using avariant form of the Cox model to estimate the excess relative risk
(ERR) for mortality from noncancer respiratory diseases. Age at risk
(i.e., attained age) was used as the primary time scale in the models(20). We used the PEANUTS program in the Epicure software
package (19) to estimate the ERR per gray of radiation. The model forthe expected hazard took the form:k0 ðc; s; bÞ½1 þ ERRðd; s; eÞ
where k0(.) is the background death rate, depending on city (c), sex (s)and birth year (b). The ERR(.) is described as a function of the form
q(d)x(s,e), in which q(d) is a radiation dose-response function, andx(s,e) is an exponential function of the effect modifier terms for sex(s) and age at exposure (e). Confidence intervals (CIs) for the risk
estimates were based on the maximum likelihood profile. Because therelative risk [1 þ ERR(.)] should not be negative, the dose parametersin this linear model should be larger than 1/maximum dose. Due tothis restriction, negative lower confidence bounds could sometimes
not be estimated, which were then designated as ‘‘,0’’ (see forexample in Table 3). To examine the linearity or curvature of the ERR
function, we used the following models:qðdÞ ¼ bd

linear modelqðdÞ ¼ bd þ cd 2

linear  quadratic model

To examine the effects of potential misdiagnosis and/or misclassification of other major causes of death (cancer and cardiovasculardisease) with noncancer respiratory diseases, we performed ananalysis that censored persons who had previously been diagnosed
with cancer from tumor registry data as of the date of cancer diagnosis.
Those with diagnoses of cancer and/or cardiovascular disease listed
anywhere on the death certificate also were censored at two years prior
to the date of death.
We used Stata (version 9.2) to estimate the radiation risk when
performing the analysis adjusting for potential confounders among thesubset of 55,132 subjects with information available from mailsurveys or clinical interviews. Adjustments for the potential effect ofcancer and/or cardiovascular disease were also conducted in thissubanalysis. For these analyses, person-years were counted from thetime of a subject’s first mail survey. We identified some proportions of
missing variables among the respondents of surveys/interviews,
ranging from 1.5% for smoking habit to 8.6% for drinking habit. To
account for such missing data in the analyses, we applied a multiple
imputation approach (21) in Stata (ice command for multiple
imputation by chained equations). Then the Cox proportional hazard
regression was used to estimate the hazard ratio (HR) of radiation risk
and mortality of noncancer respiratory diseases, adjusted for the
potential confounding factors.

RESULTSOver the course of more than 50 years of follow-up
among 86,611 subjects, we observed 5,515 people whose
primary cause of death was listed as some form of
noncancer respiratory disease. Table 2 shows the numbersof subjects, persons-years of follow-up, number of deaths

542

PHAM ET AL.

FIG. 1. Dose response of excess relative risk for all noncancer
respiratory diseases by periods based on the changes in disease
structure of noncancer respiratory disease in Japan. The closed circles
and bars represent point estimates of ERR and 95% confidence
intervals for the dose categories without effect modifiers, in which thebackground rates included sex, city and age at exposure. Solid line
shows dose-response curve based on the linear-quadratic model.

and death rates per 10,000 person-years by sex, city, age at
the time of the bombings and weighted absorbed lung dose
categories. The most common subtype was pneumonia/
influenza, accounting for about two thirds of all noncancer
respiratory disease deaths, followed by COPD and asthma.
The category ‘‘other respiratory disease’’ represents a large
variety of diseases, many of which are rare. For example,
diffuse interstitial lung diseases represent many different
entities including interstitial pneumonia (22).
Table 3 shows the ERR/Gy estimates of noncancer
respiratory disease associated with lung dose for the entire
follow-up period. The ERR estimates were 0.17 (95% CI:
0.08; 0.27) for all NCRD and 0.20 (0.09; 0.34) for thepneumonia/influenza subtype. The ERR estimates of total
noncancer respiratory diseases were significant for both
men and women, and those for pneumonia/influenza also
were significant for women but were marginal for men.
Table 4 shows radiation risks by follow-up periods.
Increased ERR estimates were apparent in the late periods(1980–2005), while ERR estimates for the early (1950–1964) and the middle period (1965–1979) were smaller anddid not reach statistical significance. Figure 1 graphically
depicts period-specific dose-responses for all noncancer
respiratory diseases using linear-quadratic models and by
categorical estimates. In the early period, a linear-quadraticmodel fit better than a linear model (P , 0.01), but not forthe middle and late periods. No increased risks among lowdose survivors were observed in the early and middle
periods, but a mostly linear increase in risk appeared in thelate period.
One major question was the degree to which the apparent
association between radiation and noncancer respiratory
disease may be due to cancer or cardiovascular disease being
misdiagnosed as noncancer respiratory disease on the deathcertificate. About 10% of noncancer respiratory disease cases
also had been diagnosed with any cancer and about another
20% with cardiovascular disease. When adjusting for therecords of cancer by censoring those with cancer incidence
and/or cancer comorbidity on the death certificate, theradiation risk estimates were decreased by about 35% for
all noncancer respiratory diseases, by about 15% forpneumonia/influenza and by about 56% for asthma but thestatistical significance did not change (Table 5). However,further adjustment for cardiovascular disease comorbidity did
not substantially change the ERR estimates (Table 5).
Table 6 shows radiation risks adjusted for potential
confounding factors, and additionally adjusted for comorbidity due to cancer and/or cardiovascular disease in thesubset of 55,132 subjects with information on lifestylefactor. Hazard ratio estimates that were adjusted for the six
potential confounding factors related to lifestyle orsociodemographics tended to be slightly lower for most of
the noncancer respiratory disease subtypes compared withestimates that were not adjusted, but the patterns of theassociations remained. For instance, the HR for all
noncancer respiratory diseases decreased slightly from

543

RADIATION AND NONCANCER RESPIRATORY MORTALITYTABLE 4
Excess Relative Risk (ERRa) Estimates per Gy and 95% Confidence Interval (95% CI) for Noncancer Respiratory Disease Deaths
by Calendar Year Periods
Calendar years 1950–1964
Cause of deathAll noncancer respiratory
diseaseAcute respiratory
infections
Pneumonia/Influenza
Chronic obstructive
pulmonary disease
AsthmaOther respiratory disease

Calendar years 1965–1979

Calendar years 1980–2005

DeathsERR (95% CI)

P

DeathsERR (95% CI)

P

DeathsERR (95% CI)P

849

0.11 (0.08; 0.36)

0.30

1149

0.08 (0.09; 0.29)

0.39

3517

0.21 (0.10; 0.34)

,0.01

59
407

.0.50
–0.24 (,0;b 1.28)
0.20 (0.09; 0.61)
0.20

70
697

0.26 (,0;b 1.59).0.50
0.09 (0.12; 0.37)
0.42

72
2367

–0.22 (,0;b 0.36)
0.23 (0.08; 0.40)

0.25
,0.01

116
211
56

0.29 (0.22; 1.24)
0.36–0.01 (,0;b 0.44).0.50–0.18 (,0;b 0.96)
.0.50

183
124
75

–0.15 (,0;b 0.44)
0.13 (,0;b 0.91)
0.14 (,0;b 1.14)

377
140
561

0.09 (0.17; 0.47) .0.50
0.76 (0.04; 1.90)
0.04
0.23 (0.01; 0.55)
0.07

.0.50
.0.50
.0.50

a
ERR was estimated using the linear-dose model without effect modifiers, in which sex, city, age at exposure were included in the backgroundrates.
bLess than zero (,0) was designated for the lower confidence bounds, when these could not be estimated (see Materials and Methods).

finer disease subtypes as well as by gender and follow-up
periods.
The patterns of associations of ionizing radiation with
noncancer respiratory disease mortality were different by
calendar periods (see Table 4 and Fig. 1). Noncancer
respiratory disease as a whole and most subtypes showedstronger unadjusted associations in the late period, during
which both pneumonia/influenza and asthma appeared to be
associated with significant risks, although those associations
were greatly attenuated or eliminated when adjustments forcancer and cardiovascular disease were made. The lesser
associations in the earlier time period might reflect a healthy
survivor effect, which others have indicated may have been
more operative in the early years after the bombings (23).
Over the long follow-up period, the background disease
structure of respiratory diseases has changed due to factors
such as aging, hygiene, socioeconomic status and medicalcare availability. The national trend of mortality rates from
noncancer respiratory diseases based on the vital statistics
for all of Japan (24) between 1950–2005 suggested two
distinct causal pathways, especially for pneumonia/influenza. The high rates in the early decades are probably
associated predominantly with influenza epidemics and withother respiratory infections that could not be adequately
treated in that era and no association with radiation would

1.22 (95% CI: 1.13; 1.33) to 1.19 (1.09; 1.29) after
adjustment for confounding factors. Similarly, the HR
estimates for subtypes such as pneumonia/influenza, asthma
and other respiratory disease groups were reduced after
adjustment but remained significant.
However, the radiation risks were remarkably reduced
when additionally adjusted for the records of cancer andcardiovascular disease using the same method as in shown
Table 5. Consequently, the HR for all NCRD fell to 1.12
(1.00; 1.25) after performing those adjustments (Table 6).
The risk for only pneumonia/influenza remained significant
with a HR estimate of 1.18 (1.04; 1.35), while the risks forthe remaining subtypes lost their significance.
DISCUSSION

In the current study we examined the association between
radiation and the mortality risks from noncancer respiratory
diseases among the LSS survivors up to 60 years after thedetonation of the atomic bombs. For the whole period, theresults showed a significant dose-response association for
total noncancer respiratory diseases when there was no
adjustment for cancer or cardiovascular disease comorbidity. However, the radiation association appeared to vary by

TABLE 5
Excess Relative Risk (ERRa) Estimates per Gy Adjusted for the Records of Cancer and Cardiovascular Disease (CVD)
Adjusted for cancerb

Not adjusted for cancer or CVD
3,365,981 person-years
Cause of death

DeathsAll noncancer respiratory
diseasesPneumonia/Influenza
Asthma

5515
3471
475

a

ERR (95% CI)

Adjusted for cancer and/or CVDc

3,273,363 person-years
P

0.17 (0.08; 0.27),0.01
0.20 (0.09; 0.34),0.01
0.16 (0.10; 0.52)
0.27

Deaths
4935
3115
455

ERR (95% CI)

3,260,476 person-years
P

0.11 (0.02; 0.21)
0.01
0.17 (0.04; 0.30),0.01
0.07 (0.17; 0.42) .0.50

DeathsERR (95% CI)

P

3978
2439
411

0.11 (0.01; 0.22)
0.17 (0.04; 0.33)
0.05 (0.19; 0.40)

0.04
0.01
.0.50

ERR was estimated using the linear-dose model without effect modifiers, in which the background rates included sex, city and age at exposure.
Subjects with the records of incidence/comorbidity of cancer were censored (see Materials and Methods).
cSubjects with the records of incidence/comorbidity of cancer and/or comorbidity of CVD were censored (see Materials and Methods).
b

544

PHAM ET AL.

TABLE 6
Hazard Ratios (HR) at 1 Gy and 95% Confidence Intervals (95% CI) for Noncancer Respiratory Disease Deaths Adjusted for
Both Potential Confounding Factors and The Records of Cancer and Cardiovascular Disease (CVD)

Cause of deathAll noncancer
respiratory
diseases
Acute respiratory
infections
Pneumonia/
Influenza
Chronic
obstructive
pulmonarydiseaseAsthmaOther respiratory
diseaseNot adjusted for cancer or CVDa

Adjusted for cancera,bAdjusted for cancer and/or CVDa,c1,252,159 person-years

1,182,124 person-years

1,172,628 person-years

P

DeathsHR2 (95% CI)

P

DeathsHR2 (95% CI)

P

2850

1.12 (1.02; 1.24) 0.02

2216

1.12 (1.00; 1.25)

0.05

0.34

68

0.53 (0.18; 1.56) 0.25

41

0.93 (0.35; 2.42)

0.88

2157

1.23 (1.11; 1.37) ,0.01 1.19 (1.07; 1.33) ,0.01

1882

1.17 (1.04; 1.31) 0.01

1445

1.18 (1.01; 1.35)

0.01

379
161

1.06 (0.81; 1.39)
1.47 (1.08; 2.00)

0.67 1.00 (0.76; 1.31)
0.01 1.43 (1.04; 1.96)

0.98
0.03

322
147

0.92 (0.66; 1.28) 0.62
1.30 (0.90; 1.87) 0.16

266
120

0.93 (0.64; 1.33)
1.28 (0.86; 1.88)

0.68
0.23

517

1.31 (1.07; 1.60) ,0.01 1.28 (1.04; 1.57)

0.02

431

1.08 (0.83; 1.40) 0.56344

0.92 (0.66; 1.28)

0.61

HR1 (95% CI)

3292

1.22 (1.13; 1.33) ,0.01 1.19 (1.09; 1.29) ,0.01

78

0.65 (0.27; 1.56)

HR2 (95% CI)

P

Deaths0.34 0.64 (0.27; 1.57)

Notes. HR1 was adjusted for sex, city and birth year. HR2 was adjusted for the variables for HR1 plus 6 potential confounding factors(smoking, alcohol consumption, body mass index, education, diabetes and occupation).
aAnalyses were conducted among a subset of 55,132 subjects with the information of lifestyle factor.
bSubjects with the records of incidence/comorbidity of cancer were censored (see Table 5).
cSubjects with the records of incidence/comorbidity of cancer and/or comorbidity of CVD were censored (see Table 5).

be evident. In more recent decades, as acute respiratory
infections became more treatable and deaths from pneumonia among the elderly increased, deaths designated as
noncancer respiratory disease often represent the terminal
stage of other lethal conditions such as cancer andcardiovascular disease. As such, the association of radiation
with death-certificate diagnoses of noncancer respiratory
disease may be attributed to death certificate misdiagnosis.
Coexistent cancer or cardiovascular disease that was
misclassified or misdiagnosed as noncancer respiratory
disease apparently increased the nominal noncancer respiratory disease radiation risk estimates. A previous comparison of death certificates and autopsy reports among LSS
subjects showed a large amount of diagnostic misclassification, such that only 28% of death certificates with
noncancer respiratory disease listed as the underlying cause
were attributed to noncancer respiratory disease at autopsy(25). These figures, based on deaths primarily before themid-1970s, indicate that death certificate attribution of
noncancer respiratory disease was both erroneous andincomplete; however, death certificates may be moreaccurate in recent decades. In this study, the association
with radiation decreased appreciably by adjusting forindications of concomitant cancer and/or cardiovasculardisease on the death certificate or for a prior incident cancer
recorded in the tumor registry. The censoring that might
have eliminated the radiation effect on cancer/cardiovascular disease cases, might subsequently lower the power ofdetecting radiation effects for noncancer respiratory disease.
The risk of pneumonia/influenza was also reduced, although
it was the sole subtype whose risk remained significant after
such adjustment (see Tables 5 and 6).

However, the misdiagnosis adjustment that was possible
to perform may have been an under-adjustment for several
reasons: (1) the recording of contributing causes of death on
death certificates by physicians is irregular and incomplete:some death certificates list no contributing causes whileothers list several; (2) there may be other conditions besides
cancer and cardiovascular disease which are misdiagnosed
as noncancer respiratory disease on the death certificate andwhich were not investigated; (3) the cancer incidence data
are incomplete because such data did not begin until 1958,
whereas mortality data began in 1950, and the incidence
data do not cover cancer diagnoses occurring outside ofHiroshima or Nagasaki prefectures. If those missed due tothe intrinsic methodological limitations could be ascertained, they might further reduce the noncancer respiratory
disease radiation risk estimates. Hence, it is unclear whether
there would still be an association of radiation withpneumonia/influenza if ascertainment of other potential
underlying causes of death were complete, so the results ofthe present study require some caution in interpretation. In
contrast, other lifestyle risk factors for noncancer respiratory
disease had little impact as confounders of the radiation
risks (see Table 6).
Subtypes of noncancer respiratory diseases have different
physiological and pathological features. Our results indicatethat noncancer respiratory diseases subtypes do not share thesame degree of association with radiation. Once adjustment
was made for cancer misdiagnosis, the categories acuterespiratory infections, chronic obstructive pulmonary disease,asthma, and other respiratory disease were not associated withradiation (see Table 6). However, the most common subtype,pneumonia/influenza, was still statistically significant. The

RADIATION AND NONCANCER RESPIRATORY MORTALITY

nature of diseases in this category was thought to change fromacute infectious diseases in the earlier years to mostly theterminal conditions in the elderly in recent decades, whichmight imply a different potential for association with radiation
over time. Given the limitations of the comorbidity data(above) this association may not be genuine. But, if it is, it
may reflect infections associated with diminished immune
competence as a function of radiation dose (26, 27).
With regard to studies among other radiation-exposedcohorts that examined noncancer radiation risks, study
subjects were mostly workers at nuclear facilities (7, 10–18)
who were typically exposed at chronic low-dose levels.
Most studies have shown no association of noncancer
respiratory disease with radiation (7, 10, 12–18), although astudy of UK radiation workers reported an elevated ERR of
0.8 (90% CI: 0.04; 1.8) with respiratory diseases not related
to smoking (11).
ACKNOWLEDGMENTS
We would like to thank the Hiroshima and Nagasaki cancer registries
for use of the cancer incidence data. We are also grateful to the
Department of Clinical Studies for offering the information of lifestyle in
the Adult Health Study, the staff of the Master File Section for theirdiligent efforts to provide accurate data on mortality in the Life Span
Study and Ms. Mikiko Hayashi for the dataset preparation. The Radiation
Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a
public interest foundation funded by the Japanese Ministry of Health,Labour and Welfare (MHLW) and the U.S. Department of Energy (DOE).
The research was also funded in part through DOE award DE-HS0000031
to the National Academy of Sciences. This publication was supported by
RERF Research Protocols 1–75 and A-1-11. The views of the authors do
not necessarily reflect those of the two governments.
Received: June 4, 2013; accepted: August 5, 2013; published online:
October 23, 2013

REFERENCES
1. Kodama K, Mabuchi K, Shigematsu I. A long-term cohort study of
the atomic-bomb survivors. J Epidemiol 1996; 6:S95–105.
2. Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, etal. Solid cancer incidence in atomic bomb survivors: 1958–1998.
Radiat Res 2007; 168:1–64.
3. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K.
Studies of mortality of atomic bomb survivors. Report 13: Solidcancer and noncancer disease mortality: 1950–1997. Radiat Res
2003; 160:381–407.
4. Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, etal. Studies of the mortality of atomic bomb survivors, Report 14,
1950–2003: an overview of cancer and noncancer diseases. Radiat
Res 2012; 177:229–43.
5. Shimizu Y, Kato H, Schull WJ, Hoel DG. Studies of the mortalityof A-bomb survivors. 9. Mortality, 1950–1985: Part 3. Noncancer
mortality based on the revised doses (DS86). Radiat Res 1992;
130:249–66.
6. Shimizu Y, Pierce DA, Preston DL, Mabuchi K. Studies of themortality of atomic bomb survivors. Report 12, part II. Noncancer
mortality: 1950–1990. Radiat Res 1999; 152:374–89.
7. McGeoghegan D, Binks K, Gillies M, Jones S, Whaley S. The
non-cancer mortality experience of male workers at British
Nuclear Fuels plc, 1946–2005. Int J Epidemiol 2008; 37:506–18.
8. Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, et545

al. Radiation exposure and circulatory disease risk: Hiroshima andNagasaki atomic bomb survivor data, 1950–2003. BMJ 2010;
340:b5349.
9. Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G.
Noncancer disease incidence in atomic bomb survivors, 1958–
1998. Radiat Res 2004; 161:622–32.
10. Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H,
et al. Mortality from diseases other than cancer following low
doses of ionizing radiation: results from the 15-Country Study of
nuclear industry workers. Int J Epidemiol 2007; 36:1126–35.
11. Muirhead CR, O’Hagan JA, Haylock RG, Phillipson MA,
Willcock T, Berridge GL, et al. Mortality and cancer incidence
following occupational radiation exposure: third analysis of the
National Registry for Radiation Workers. Br J Cancer 2009;
100:206–12.
12. Boice JD, Jr., Cohen SS, Mumma MT, Chadda B, Blot WJ. A
cohort study of uranium millers and miners of Grants, New
Mexico, 1979–2005. J Radiol Prot 2008; 28:303–25.
13. Berrington A, Darby SC, Weiss HA, Doll R. 100 years ofobservation on British radiologists: mortality from cancer andother causes 1897–1997. Br J Radiol 2001; 74:507–19.
14. Silver SR, Daniels RD, Taulbee TD, Zaebst DD, Kinnes GM,
Couch JR, et al. Differences in mortality by radiation monitoring
status in an expanded cohort of Portsmouth Naval Shipyard
workers. J Occup Environ Med 2004; 46:677–90.
15. Wiggs LD, Cox-DeVore CA, Wilkinson GS, Reyes M. Mortality
among workers exposed to external ionizing radiation at a nuclear
facility in Ohio. J Occup Med 1991; 33:632–7.
16. Wiggs LD, Johnson ER, Cox-DeVore CA, Voelz GL. Mortality
through 1990 among white male workers at the Los Alamos
National Laboratory: considering exposures to plutonium andexternal ionizing radiation. Health Phys 1994; 67:577–88.
17. Loomis DP, Wolf SH. Mortality of workers at a nuclear materials
production plant at Oak Ridge, Tennessee, 1947–1990. Am J Ind
Med 1996; 29:131–41.
18. Matanoski GM. Health Effects of Low-Level Radiation in
Shipyard Workers, Final Report, DOE Contract: DE-AC0279EV10095. Baltimore, MD: Johns Hopkins University; 1991.
19. Preston DL, Lubin J, Pierce DA. Epicure: Risk regression and data
analysis software. Seatle: Hirosoft International Corporation; 1991.
20. Korn EL, Graubard BI, Midthune D. Time-to-event analysis of
longitudinal follow-up of a survey: choice of the time-scale. Am J
Epidemiol 1997; 145:72–80.
21. van der Heijden GJ, Donders AR, Stijnen T, Moons KG.
Imputation of missing values is superior to complete case analysis
and the missing-indicator method in multivariable diagnostic
research: a clinical example. J Clin Epidemiol 2006; 59:1102–9.
22. Demedts M, Wells AU, Anto JM, Costabel U, Hubbard R,
Cullinan P, et al. Interstitial lung diseases: an epidemiologicaloverview. Eur Respir J Suppl 2001; 32:2s–16s.
23. Pierce DA, Vaeth M, Shimizu Y. Selection bias in cancer risk
estimation from A-bomb survivors. Radiat Res 2007; 167:735–41.
24. Ministry of Health Labour and Welfare, Vital Statistics of Japan,
1950–2005. Tokyo: Health, Labor, and Welfare Statistics
Association; 1953–2007.
25. Ron E, Carter R, Jablon S, Mabuchi K. Agreement between deathcertificate and autopsy diagnoses among atomic bomb survivors.
Epidemiology 1994; 5:48–56.
26. Kusunoki Y, Hayashi T. Long-lasting alterations of the immune
system by ionizing radiation exposure: implications for diseasedevelopment among atomic bomb survivors. Int J Radiat Biol
2008; 84:1–14.
27. Kusunoki Y, Yamaoka M, Kubo Y, Hayashi T, Kasagi F, Douple
EB, et al. T-cell immunosenescence and inflammatory response inatomic bomb survivors. Radiat Res 2010; 174:870–6.