Radiation and Smoking Effects on Lung Cancer Incidence among Atomic
Kyoji Furukawa,a,1Dale L. Preston,bStefan Lo ¨nn,cSachiyo Funamoto,aShuji Yonehara,dTakeshi Matsuo,e
Hiromi Egawa,fShoji Tokuoka,aKotaro Ozasa,aFumiyoshi Kasagi,aKazunori Kodamaaand Kiyohiko Mabuchig
aRadiation Effects Research Foundation, Hiroshima and Nagasaki, Japan;bHirosoft International, Eureka, California;cKarolinska Institutet,
Stockholm, Sweden;dWelfare Association Onomichi General Hospital, Japan;eNagasaki Health Promotion Corporation, Nagasaki, Japan;
fHiroshima City Asa Hospital, Hiroshima, Japan; andgDivision of Cancer Epidemiology & Genetics, National Cancer Institute,
Furukawa, K., Preston, D. L., Lo ¨nn, S., Funamoto, S.,
Yonehara, S., Matsuo, T., Egawa, H., Tokuoka, S., Ozasa, K.,
Kasagi, F., Kodama, K. and Mabuchi, K. Radiation and
Smoking Effects on Lung Cancer Incidence among Atomic
Bomb Survivors. Radiat. Res. 174, 72–82 (2010).
While radiation increases the risk of lung cancer among
members of the Life Span Study (LSS) cohort of atomic bomb
survivors, there are still important questions about the nature of
its interaction with smoking, the predominant cause of lung
cancer. Among 105,404 LSS subjects, 1,803 primary lung
cancer incident cases were identified for the period 1958–1999.
Individual smoking history information and the latest radiation
dose estimates were used to investigate the joint effects of
radiation and smoking on lung cancer rates using Poisson
grouped survival regression methods. Relative to never-smokers,
lung cancer risks increased with the amount and duration of
smoking and decreased with time since quitting smoking at any
level of radiation exposure. Models assuming generalized
interactions of smoking and radiation fit markedly better than
simple additive or multiplicative interaction models. The joint
effect appeared to be super-multiplicative for light/moderate
smokers, with a rapid increase in excess risk with smoking
intensity up to about 10 cigarettes per day, but additive or sub-
additive for heavy smokers smoking a pack or more per day,
with little indication of any radiation-associated excess risk. The
gender-averaged excess relative risk per Gy of lung cancer (at
age 70 after radiation exposure at 30) was estimated as 0.59
(95% confidence interval: 0.31–1.00) for nonsmokers with a
female:male ratio of 3.1. About one-third of the lung cancer
cases in this cohort were estimated to be attributable to smoking
while about 7% were associated with radiation. The joint effect
of smoking and radiation on lung cancer in the LSS is dependent
on smoking intensity and is best described by the generalized
interaction model rather than a simple additive or multiplicative
g2010 by Radiation Research Society
Lung cancer is the most common cancer worldwide (1).
While lung cancer rates are largely determined by
smoking patterns, medical, occupational and environ-
mental radiation exposures have also been shown to
increase risks of lung cancer (2). There is considerable
interest from both biological and practical perspectives in
the joint effect of radiation and smoking on lung cancer.
The Life Span Study (LSS) is a long-term continuing
follow-up of a cohort of atomic bomb survivors in
Hiroshima and Nagasaki, Japan, comprising a large
number of men and women exposed at all ages to a range
of radiation doses from 0–4 Gy, mostly c rays, from the
bombs. With detailed information on smoking available
for most cohort members, the LSS offers one of the best
opportunities for investigating the joint effects of
radiation and smoking on lung cancer risks.
Lung cancer is the second most common cancer in the
LSS, with world-population age-standardized rates of
76.8 per 100,000 persons for men and 25.1 for women.
LSS lung cancer rates are also strongly associated with
radiation, with an estimated excess relative risk (ERR)
per Gy of 0.81 and excess absolute risk (EAR) of 7.5 per
10,000 person-year Gy (3). Those estimates do not take
into account a possible modifying effect of smoking on
the radiation risk. While earlier analyses (4, 5) of the
LSS data were unable to describe sufficiently the nature
of the interaction between radiation and smoking for
lung cancer risk, due mostly to limited numbers of cases,
the latest analysis by Pierce et al. (6) suggested that the
interaction was sub-multiplicative and consistent with
The present study was based on lung cancer incidence
data from a special pathology review that provided
diagnostic confirmation on cases diagnosed between
1958 and 1999. A reassessment of smoking history data
assembled from multiple sources provided enough
detailed information to consider models in which the
1Address for correspondence: 5-2 Hijiyama Koen, Minami-ku,
Hiroshima, Japan, 732-0815; e-mail: firstname.lastname@example.org.
RADIATION RESEARCH 174, 72–82 (2010)
g2010 by Radiation Research Society.
All rights of reproduction in any form reserved.
effect of cumulative amount smoked could be modified
by smoking duration and intensity and to consider both
the additive and multiplicative interaction models used in
many analyses of the joint effects of carcinogenic agents
and some useful generalizations of these models. In this
study, wepresent the results from the effort to evaluate all
types of lung cancer as a group. We will report separately
on results regarding different histological types.
MATERIALS AND METHODS
Study Population and Case Ascertainment
The LSS cohort includes 120,321 residents of Hiroshima and
Nagasaki who were born prior to the atomic bombings in August
1945 and were still alive on October 1, 1950. Additional details about
the cohort can be found in ref. (7). For the present analyses, we
excluded cohort members who could not be traced, had died or were
known to have had cancer prior to January 1, 1958 (8,396 subjects) or
those with radiation dose estimates not available (6,521 subjects),
resulting in a total of 105,404 eligible subjects. A special pathology
review provided diagnostic confirmation for lung cancer cases. The
primary sources used to identify potential cases for pathology review
were the Hiroshima and Nagasaki tumor and tissue registries.
Additional sources included the RERF autopsy program and death
certificate data routinely obtained for LSS follow-up. The review
considered cases diagnosed through the end of 1999, resulting in
followed-up ages ranging from about 12 to more than 100 and ages at
diagnosis from 27 to 104.
An initial screening identified 5,711 LSS cohort members who were
coded as having tumors of the lung or related regions. Three study
pathologists independently reviewed those cases and developed a
consensus diagnosis for each potential case. The reviews were based
on all available information, including tumor tissue slides, pathology
and clinical records, and death certificates. Lung tumors were
diagnosed using the latest WHO diagnostic criteria (8). The review
identified 2,446 lung tumors, including 2,368 cancers.
Cases were ineligible for the analyses if they were not the first
primary tumors (242 cases) or were not classified as malignant tumors
(52 cases). Cases were excluded if the individual was not resident in
Hiroshima or Nagasaki prefecture at the time of diagnosis (171 cases
diagnosed primarily from death certificate information), was diag-
nosed or lost to follow-up prior to 1958 (47 cases), or did not have a
radiation dose estimate computed (131 cases). The primary analyses
described herein considered 1,803 primary lung cancer cases
diagnosed among 105,404 cohort members, including 40,980 subjects
(677 cases) with no information on smoking status prior to the
Radiation Dose and Smoking Information
Weighted DS02 (9) lung dose estimates computed as sum of the c-
ray dose and 10 times the neutron dose were used for these analyses.
As in ref. (3), cohort members who were not in either Hiroshima or
Nagasaki at the times of the bombings were included in the analysis to
improve the characterization of the variation in the baseline (zero
dose) lung cancer rates by age, gender and birth cohort. However,
radiation effects were quantified in relation to rates for survivors who
were in the cities at the time of the bombings but received negligible
radiation from the bombs, due to their large distances from the
Most of the data on smoking habits of LSS cohort members
comes from a series of mail surveys conducted between 1965 and
1991. The 1965 survey was limited to men who were between ages
40 and 69, and the 1969 survey included only females. The 1978
and 1991 surveys included all surviving cohort members who were
in the cities at the time of the bombings. Information on smoking
habits included amount smoked, duration of smoking, and, for
past-smokers, when he/she stopped. Additional information on
smoking was available from a series of questionnaires administered
to members of a fixed subset of the full LSS cohort known as the
Adult Health Study (AHS), who participated in biennial clinical
examinations (10). We used summary information on smoking
history that made use of the AHS data for the previous analyses by
Pierce et al. (6).
Smoking history was summarized by an indicator of smoking status
(never-smoker, past-smoker or current-smoker) at the time of the
latest information, age started smoking, age stopped smoking, the
average number of cigarettes smoked per day, and the year in which
data on smoking were first obtained. Age started smoking was
defined as the minimum starting age reported from all surveys to
which a person responded; a person was taken to be a past-smoker
only if they indicated that they had quit smoking at the time of their
most recent survey response, and the number of cigarettes per day was
defined as the average of the numbers of cigarettes per day over all
surveys in which a person reported having smoked. In some cases,
smokers did not answer questions about the amount smoked or age at
start of smoking. Values were imputed for those subjects as the
gender- and birth cohort-specific mean values among smokers with
Smoking information was available for 62% of the eligible cohort
members. The smoking summary data were based on one or more of
the four mail surveys for 92% of the subjects with smoking data. The
amount smoked was imputed for 4% of those who indicated that they
had ever smoked while the age at the start of smoking was imputed
for 9.5% of this group. Additional information on smoking status in
the cohort is given in the Results section with further details
concerning the creation of the smoking summary variables in the
Data Organization for Analyses
The risk analyses were based on incidence rates computed from a
table of person-years and lung cancer cases stratified by general
factors, radiation exposure-related factors, and smoking-related
factors. The general stratification factors included city (Hiroshima
and Nagasaki), gender, attained age (5-year categories from age 15 to
85 with categories for subjects less than 15 or 85 or more), and period
(nine 5-year categories from 1961 through 1999 plus a category for
1958–1960). The radiation exposure-related stratification factors were
age at exposure (14 5-year categories to age 70 and a category for
subjects aged 70 or more), exposure status (within 3 km of the
hypocenter, 3–10 km from the hypocenter, or not in city), and
radiation dose (14 categories with cutpoints at 0.005, 0.05, 0.1, 0.15,
0.2, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5 and 3 Gy).
The time-dependent smoking-related stratification factors used in
analyses were smoking status (unknown, never-, current- and past-
smoker), average number of cigarettes per day (seven categories with
cutpoints at 0, 7.5, 12.5, 17.5, 22.5 and 27.5 and a category for
unknown smoking status), years smoked (six categories with
cutpoints at 0, 5, 10, 20 and 30 for ever-smokers and categories for
never-smokers and unknown smoking status), and years since
quitting smoking (four categories with cutpoints at 5, 10 and 15 for
past-smokers and categories for unknown smoking status and
current-/never-smokers). Note that a smoker was considered as a
current-smoker from the date at which he/she first provided
information on smoking habits to either the date of the end of
follow-up or the date of reported cessation of smoking, whichever
came first. All cohort members were classified as unknown smoking
status prior to the date at which they first provided information on
smoking habits to avoid biasing risk estimates by overcounting
person years in known smoking-status categories.
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