RADIATION RESEARCH 180, 422–430 (2013)0033-7587/13 $15.00
Ó2013 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RR3273.2

Glaucoma in Atomic Bomb Survivors
Yoshiaki Kiuchi,a Tomoko Yokoyama,a Michiya Takamatsu,a Eiko Tsuiki,b Masafumi Uematsu,b Hirofumi
Kinoshita,b Takeshi Kumagami,b Takashi Kitaoka,b Atsushi Minamoto,c Kazuo Neriishi,d,1 Eiji Nakashima,e Ravindra
Khattree,f Ayumi Hida,g Saeko Fujiwarah and Masazumi AkahoshiiaDepartment of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan;
Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Hiroshima, Japan; c Minamoto
Eye Clinic, Hiroshima, Japan; d Yachiyo Hospital, Department of Medicine, Yachiyo, Akitakata, Japan; e Department of Statistics, Radiation Effects
Research Foundation (RERF), Hiroshima, Japan; f Department of Mathematics and Statistics, Oakland University, Rochester, Michigan;g
Department of Clinical Studies, Radiation Effects Research Foundation (RERF), Nagasaki, Japan; h Health Management & Promotion Center,
Hiroshima Atomic Bomb Casualty Council; i Department of Medicine, Keiju Hospital, Nagasaki, Japanbbomb radiation dose, but uncertainties associated with
nonparticipation (59% participation) suggest caution in theinterpretation of these results until they are confirmed byother studies. Ó 2013 by Radiation Research Society

Kiuchi, Y., Yokoyama, T., Takamatsu, M., Tsuiki, E.,
Uematsu, M., Kinoshita, H., Kumagami, T., Kitaoka, T.,
Minamoto, A., Neriishi, K., Nakashima, E., Khattree R., Hida,
A., Fujiwara, S. and Akahoshi, M. Glaucoma in Atomic Bomb
Survivors. Radiat. Res. 180, 422–430 (2013).

INTRODUCTION

Radiation has been associated with increases in noncancerous diseases. An effect of low-dose radiation on theprevalence of clinically detected glaucoma has not beenpreviously reported. We therefore investigated the prevalenceof glaucoma in A-bomb survivors and its possible association
with radiation dose. A total of 1,589 people who participatedin the clinical examination program for A-bomb survivors at
the Radiation Effects Research Foundation (RERF) between
October 2006 and September 2008 and who had reconstructed radiation doses, were recruited into this cross-sectional
screening study. The prevalence of glaucoma and its doseresponse relationship to A-bomb radiation were measured.
Each subject underwent an initial screening consisting of aninterview and ophthalmological examination. Questionablecases with any indication of ocular disease, including
glaucoma, were referred to local hospitals for more comprehensive evaluation. A diagnosis of glaucoma was made basedon specific optic disc appearance, perimetric results andother ocular findings. Of 1,589 eligible people, we detected
284 (17.9%) cases of glaucoma overall, including 36 (2.3%)
cases of primary open-angle glaucoma with intraocularpressure levels greater than 21 mmHg, 226 (14.2%) cases ofnormal-tension glaucoma and 25 (1.6%) cases of primary
angle-closure glaucoma. Seven glaucoma risk factors were
examined as potential confounders but only two needed to be
included in the final model. Binary regression using ageneralized estimating equation method, with adjustment
for gender, age, city, cataract surgery or diabetes mellitus,
revealed an odds ratio at 1 Gy of 1.31 (95% confidence
interval 1.11–1.53, P ¼ 0.001) in the case of normal-tension
glaucoma, but no association for other types of glaucoma. The
prevalence of normal-tension glaucoma may increase with A-

Glaucoma, a major cause of blindness worldwide, shows
characteristic changes in the optic nerve head and visual
fields (1). Progressive degeneration of retinal ganglion
accompany those changes and leads to blindness. Glaucoma
is associated with many risk factors including: increased
intraocular pressure; family history; aging; vascular factorsthat alter ocular blood flow like arteriosclerosis; elevatedsystemic blood pressure; vasospasms and corneal thickening (2, 3). The Tajimi study, a major population based
epidemiologic study of glaucoma in Japan (11, 12), reported
a prevalence of glaucoma of 5.8% in males and 6.7% infemales at ages 60–69 and 10.6% in males and 10.5% infemales at ages 70–79 (12).
As a complication of high radiotherapy doses to the eye,
neovascular glaucoma has been found in 7–11% of patients(4–7). Doses of radiation more than about 10 Gy obstruct
the microcirculation due to plaque formation that reduces
ocular blood flow in the eye and leads to neovascularizationin the iris or angle that results in high intraocular pressure.
However, relatively low doses of radiation have not shown
excess ocular hypertension in radiation workers in the few
available studies (8, 9). Yamada et al. reported that theincidence of glaucoma significantly decreases with increasing A-bomb radiation doses (10), but the diagnoses in thatstudy were based on medical history alone and not on ocularreexaminations, so that there may have been many false
negatives. For instance, in the Tajimi study, 90% of subjects
diagnosed with glaucoma by systematic screening andevaluation had no prior diagnosis of glaucoma. (11).
To further elucidate the effects of low doses of radiation,
we investigated the prevalence of glaucoma in A-bomb

1 Address for correspondence: Radiation Effects Research Foundation, 5-2 Hijiyama park, Minami Ku, Hiroshima, Japan, 732-0815;
e-mail: neriishi@rerf.or.jp.

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GLAUCOMA, ATOMIC BOMB SURVIVORS

2699 Adult Health Study participants in biennial health examination during 2006. 10
2008.9746 (28%) did not agree to undertake screening examination1953 (72%) participated in screening examination
915 (34%) were found to be normal in screening examination
1038 (38%) were referred for detailed examinations
355 (13%) did not agree to undertake detail examinations
378 (14%) were found not to have glaucoma nor ocular hypertension in thedetailed examination
305 (11%) were diagnosed as having glaucoma or ocular hypertension
9 (.3%) were excluded because information on diabetes mellitus was not available.
1589 were included in the analysis (59% of the 2699 AHS participants)
FIG. 1. Number of subjects.

survivors based on comprehensive ophthalmologic examinations and conducted a dose-response analysis. The
examinations were performed during 2006–2008, 51–53
years after the A-bomb radiation exposure.
STUDY SUBJECTS AND METHODSThis study was conducted as part of the Adult HealthStudy (AHS) of A-bomb survivors at the Radiation Effects
Research Foundation (RERF) in Hiroshima and Nagasaki
and was approved by the RERF Human Investigation
Committee (IRB). The AHS, originally consisting of about
17,000 participants matched across the radiation-dose range
on gender and age, has been conducting biennial healthexaminations since 1958 (13). Among 2,699 AHS attendees
between October 2006 and September 2008 with known
radiation doses, 1,953 people (72%) agreed to participate in
the visual examination study (Fig. 1). Among theparticipants, 1,038 people were suspected to have anabnormality and were requested to undergo a detailed
examination at Hiroshima or Nagasaki University hospitals.
However, 355 (34%) did not undergo the detailed
examination and 9 whose information on diabetes mellitus
was not available were excluded. The analysis include
1,589, 59% of the 2,699 AHS participants (Fig. 1).
Information on a number of the potential confounding
factors, such as education, smoking, hypertension andobesity, were obtained from the AHS database.
Screening Examination at RERF

After providing informed consent, participants were asked
to complete questionnaires for their glaucoma-related
medical history. Examiners were not aware of the radiation
doses of study subjects. Refraction and intraocular pressure(IOP) was measured three times with a noncontact

TABLE 1
Medication for Glaucoma and Participation in the Glaucoma Study by Radiation Dose Group[No. Medication Cases/Total No. in Group and (%)]
Dose (mGy)
Study status,5

All potential examinees
Screening nonparticipants
Referral nonparticipants

80/1,168 (6.8)
29/296 (8.9)
25/147 (17.0)

Participantsab

5 – ,200

200 – ,1,000

1,000 – ,2,000. ¼ 2,000

37/385 (9.6)
52/676 (7.7)
14/331 (4.2)
12/139 (8.6)
16/120 (13.3)
17/205 (8.3)
6/87 (6.9)
4/38 (10.5)
15/49 (30.6)
24/99 (24.2)
5/35 (14.3)
7/25 (28.0)
Odds ratio for nonparticipants, 1.00, P ¼ 0.98a
26/725 (3.6)
6/216 (2.8)
11/372 (3.0)
3/209 (1.4)
1/76 (1.3)
aOdds ratio for participants, 0.63, P ¼ 0.09
Comparison of dose response slopes between nonparticipants and participants, P , 0.001

Total
195/2699 (7.2)
72/746 (9.7)
76/355 (21.4)
47/1598b (2.9)

Odds ratio at 1 Gy based on a dose-response analysis.
Among 1,598 participants, 9 people whose information on diabetes was not available were excluded from further analyses.

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KIUCHI ET AL.

TABLE 2
Numbers (%) of Glaucoma Cases at Examination by Age and Gender
Age
Diagnosis

–69

70–79

80–

Total

Males (average age ¼ 73.4)
Primary open-angle glaucoma
IOP . 21 mmHg
IOP  21 mmHg
(normal-tension glaucoma)
Primary angle-closure glaucoma
Secondary glaucoma
Other glaucoma
All cases of glaucomaa
Ocular hypertension

Primary open-angle glaucoma
IOP . 21 mmHg
IOP  21 mmHg
(normal-tension glaucoma)
Primary angle-closure glaucoma
Secondary glaucoma
Other glaucoma
All cases of glaucomaa
Ocular hypertension

Primary open-angle glaucoma
IOP . 21 mmHg
IOP  21 mmHg
(normal-tension glaucoma)
Primary angle-closure glaucoma
Secondary glaucoma
Other glaucoma
All cases of glaucomaa
Ocular hypertensiona(N ¼ 199)
32 (16.1)
5 (2.5)27 (13.6)(N ¼ 309)
60 (19.4)
11 (3.6)
49 (15.9)(N ¼ 81)20 (24.7)
2 (2.5)18 (22.2)(N ¼ 589)
112 (19.0)
18 (3.1)
94 (16.0)

2 (1.0)2 (1.0)1 (0.5)34 (17.0)
3 (1.5)3 (1.0)1 (1.2)1 (0.3)
1 (1.2)0 (0)0 (0)60 (19.4)
21 (25.9)
6 (1.9)2 (2.5)
Females (average age ¼ 74.9)(N ¼ 466)(N ¼ 251)
71 (15.2)
54 (21.5)
10 (2.1)
7 (2.8)61 (13.1)
47 (18.7)

6 (1.0)4 (0.7)1 (0.2)115 (19.5)
11 (0.9)(N ¼ 283)
25 (8.8)
1 (0.4)24 (8.5)
2 (0.7)0 (0)0 (0)27 (9.5)
0 (0)(N ¼ 1000)
150 (15.0)
18 (1.8)
132 (13.2)(N ¼ 482)
57 (13.9)
6 (1.2)51 (10.6)

9 (1.9)8 (3.2)4 (0.9)2 (0.8)0 (0)0 (0)80 (17.2)
62 (24.7)
6 (1.3)4 (1.6)
Total (average age ¼ 74.3)(N ¼ 775)(N ¼ 332)
131 (16.9)
74 (22.3)
21 (2.7)
9 (2.7)110 (14.2)
65 (19.6)(N ¼ 1589)
262 (16.5)
36 (2.3)
226 (14.2)

4 (0.8)2 (0.4)1 (0.2)61 (12.3)
3 (0.5)12 (1.5)5 (0.6)0 (0)140 (18.1)
12 (1.5)

25 (1.6)
10 (0.6)
1 (0.1)284 (17.9)
21 (1.3)

9 (2.7)3 (0.9)0 (0)83 (25.0)
6 (1.8)19 (1.9)
6 (0.6)0 (0)169 (16.9)
10 (1.0)

All glaucoma counts individuals only once, even if they had glaucoma in both eyes.

tonometer (Topcon CT-90A) and the mean value was used.
Digital color photographs of the fundus were obtained withthe pupil undilated using a Topcon digital fundus camera(Topcon NW6S) with angles of 30 and 45 degrees. The
visual field was screened using a frequency doubling
technology (FDT) C-20-1 screener (Humphrey Instruments). A definitive glaucoma examination was recommended when the subject was suspected to have any oculardisease. The screening criteria for referral for a definitive
examination and the criteria for glaucoma diagnosis weresimilar to those of the Tajimi study (11). The criteria to referthem for definitive examination were intraocular pressure.18 mmHg and at least one of the following: vertical cupto-disc ratio of optic nerve head .0.6; difference between
the two eyes in vertical cup-to-disc ratio of .0.2; nerve
fiber layer defect or splinter hemorrhage; at least 1 abnormal
test point in the FDT visual field test; or any abnormal
findings in the fundus photograph.

Definitive Examination and Diagnosis

Glaucoma specialists from Hiroshima and Nagasaki
University Hospitals reviewed the examination records
and referred perticipants to those hospitals for a definitive
examination when the subject was suspected to have any
ocular disease. At the time of referral, informed consent was
obtained concerning use of the University Hospital findings
by RERF.
In the definitive examination, a slit-lamp biomicroscopic
examination, applanation tonometry, a visual field test using
a Humphrey Field Analyzer 30-2 SITA standard programand gonioscopy with stereoscopic disc photographs (Topcon TR 80) were performed. If a glaucomatous disc changeor nerve fiber defect was found and if the hemifield-based
visual field abnormality was compatible with optic discappearance or nerve fiber defect, the eye was diagnosed ashaving glaucoma. When the visual field test result was
unreliable or unavailable, diagnosis was made using disc

425

GLAUCOMA, ATOMIC BOMB SURVIVORSTABLE 3
Numbers of Glaucoma Cases by Radiation Dose Intervals
Radiation dose (Gy)
(Mean eye dose)Type of glaucoma
Primary open-angle glaucoma
IOP . 21 mmHg
IOP  21 mmHg
(normal-tension glaucoma)
Primary angle-closure glaucoma
Secondary glaucoma
Other glaucoma
All cases of glaucoma
Ocular hypertensiona0 – ,0.005(0.001)(N ¼ 721)

0.005 – ,0.2
(0.097)(N ¼ 214)

0.2 – ,1(0.561)(N ¼ 369)

1 – ,2(1.375)(N ¼ 209)2–(3.006)(N ¼ 76)

Total(0.468 Gy)(N ¼ 1,589)

17 (2.4)a92 (12.8)

6 (2.8)24 (11.2)

4 (1.1)57 (15.4)

9 (4.3)38 (18.2)

0 (0.0)15 (19.7)

36 (2.3)
226 (14.2)

12 (1.7)
5 (0.7)1 (0.1)122 (16.9)
8 (1.1)5 (2.3)1 (0.5)0 (0.0)32 (15.0)
4 (1.9)6 (1.6)3 (0.8)0 (0.0)68 (18.4)
8 (2.2)2 (1.0)0 (0.0)0 (0.0)47 (22.5)
1 (0.5)0 (0.0)1 (1.3)0 (0.0)15 (19.7)
0 (0.0)25 (1.6)
10 (0.6)
1 (0.1)284 (17.9)
21 (1.3)

Percentage in the dose categories.

change only. When the cup-to-disc ratio of the optic nerve
head was 0.9 or more, the rim width at the superior portion(11–1 o’clock position) or the inferior portion (5–7 o’clock
position) was 0.05 or less of the disc diameter or thedifference of the vertical cup-to-disc ratio was 0.3 or more
between the two eyes, the eye was diagnosed as having
glaucoma. In cases where the optic disc showed glaucomalike changes but the eye did not satisfy the above criteria
and we could not obtain a reliable or compatible hemifieldbased defect in the visual field test, the eye was diagnosed
as having suspect glaucoma.
All six ophthalmologists from Hiroshima and Nagasaki
Universities met periodically to decide the diagnosis ofsuspected cases. Consensus was reached through discussion, referring to all available data. Only definite diagnoses
were included in the analyses.
We categorized the subjects into nonglaucoma, primary
open-angle glaucoma (POAG, IOP . 21 mmHg), normaltension glaucoma (POAG with IOP 21 mmHg or less),primary angle-closure glaucoma (PACG), ocular hypertension (OH) and secondary glaucoma depending on the slit
lamp and gonioscopic findings. Eyes in which we could not
determine the type of glaucoma were classified as ‘‘others’’.
Statistical Analysis

Radiation dose-response analyses were based on the
Dosimetry System 2002 (DS02) (14) eye radiation dose ingray (Gy), using the same methods as in previous studies:
weights of 1 for gamma and 10 for neutron doses, truncationof shielded kerma doses at 4 Gy, and doses adjusted for
35% dosimetry-estimation error (15).
Statistical analyses using generalized estimating equations(GEE) (16) were conducted to find the association between
glaucoma prevalence in both eyes and explanatory variables. We denoted the prevalence of a specific type ofglaucoma as p1 for the right eye and p2 for the left eye andassumed logistic models for these eye-specific prevalences,
for j ¼ 1, 2,

pj¼ a0 þ a1 C þ a2 G þ a3 E þ bD þ a4 ðj  1Þln
1  pjþ a5 DM þ a6 Cataj ;(Model 1)
where C and G are city (Nagasaki vs. Hiroshima) andgender (female vs. male) indicators, E ¼ (age at examination– 75)/10, D is radiation dose to the eye treated as acontinuous variable, DM is an indicator of diabetes mellitus,
Cataj is an indicator of cataract surgery for the jth eye, andthe a’s and b are regression parameters. The common eyespecific odds ratio for a radiation exposure of 1 Gy is^ where b^ is the estimate of dose-response parameterexp(b),
b. The above model was denoted as Model 1.
Model 2 included the variables in Model 1, plus
additional potential confounding variables as shown in
Table 4, including risk factors such as education, smoking,diabetes, hypertension and obesity. Since some variables inModel 2 had missing values, the numbers differ between
models (1,589 for Model 1 and 1,483 for Model 2). The
STATA statistical package was used for analyses. Twosided P values and 95% confidence intervals were based on
the Wald statistic.
RESULTS

Because of the relatively high rates of nonparticipation in
the screening (28%) and referral (34%) examinations,extensive analyses were conducted for possible selection
biases. This was done using a history of glaucoma
medication as a health endpoint; information which wasusually available in the routine AHS clinical records.
Analyses were then conducted with respect to both glaucoma
risk factors and glaucoma medication history to determine if
glaucoma-study participants differed from nonparticipants onthese factors, or if their radiation dose-response relationships
differed for these factors. The main findings from the bias
analyses, partly shown in Table 1, were that: (1) city
(Hiroshima or Nagasaki), gender and history of diabetes

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KIUCHI ET AL.

TABLE 4
Association of A-Bomb Radiation with Questionnaire Items Related to Reported Glaucoma (Odds Ratio at 1 Gy)
Items
Ophthalmologic diseases under treatmenta
Cataract (n ¼ 1,762)
Congenital cataract (n ¼ 13)
Glaucoma, types unspecified (n ¼ 112)Retinal bleeding (n ¼ 91)
Retinal detachment (n ¼ 36)
Trauma (n ¼ 43)
Uveitis (n ¼ 9)
Toxic cataract (toxic drug induced cataract, n ¼ 7)
After cataractf (n ¼ 36)
Instillation (use of eye drops, n ¼ 1,510)
Surgical historya for
Cataract (n ¼ 547)
Glaucoma (n ¼ 28)
Retinal bleeding (n ¼ 54)
Detachment (n ¼ 20)
Trauma (n ¼ 9)
Systemic diseases and treatmentsb
Diabetes mellitus (n ¼ 280)
Hypertension (n ¼ 854)
Steroid therapy (n ¼ 70)
Radiotherapy of head and neck (n ¼ 12)
Chemotherapy (n ¼ 67)
Junior high (n ¼ 489) vs. University educationc
High school (n ¼ 857) vs. University educationd
Smoking [smoker (n ¼ 158)]
Underweight [underweight (n ¼ 103)]e
Obese [obese (n ¼ 559)]e
Glaucoma historyb in
Father (n ¼ 9)
Mother (n ¼ 27)
Both parents (n ¼ 34)
Uncle or aunt (n ¼ 14)Brother or sister (n ¼ 38)
Son or daughter (n ¼ 6)

Odds ratio

95% Confidence interval

1.18
0.75
0.70
1.31
1.25
1.14
1.46
–
1.50
1.01

1.03, 1.36
0.33, 1.72
0.49, 0.98
1.04, 1.66
0.96, 1.62
0.82, 1.59
0.84, 2.55–
1.04, 2.14
0.89, 1.15

1.28
0.33
1.33
1.12
–

1.09, 1.50
0.10, 1.14
1.00, 1.77
0.79, 1.58
–

1.20
0.97
0.87
1.19
1.14
0.94
1.07
0.96
1.31
0.84

1.03, 1.40
0.85, 1.11
0.61, 1.23
0.65, 2.17
0.85, 1.51
0.81, 1.09
0.94, 1.22
0.78, 1.19
1.06, 1.63
0.73, 0.97

0.30
0.90
0.72
1.04
0.86
1.80

0.05, 1.78
0.53, 1.53
0.40, 1.28
0.54, 2.01
0.52, 1.43
0.98, 3.33

aNumber of eyes with GEE method.
Number of cases with diseases with logistic method.
cReferent category.
dReferent category.
e
Obesity categories: underweight; BMI ,18, normal; BMI ¼18 – ,24, obese; BMI . ¼24, normal was the referent category.
f
Post-surgical regrowth of epithelial cells in the lens capsule that impair vision.
b

mellitus or of cataract surgery showed no associations ofconsequence with study participation, although a larger
percentage of nonparticipants, irrespective of radiation dose,
had a prior history of glaucoma medication; (2) age had astrong effect on study participation, with more nonparticipation at older ages, so age clearly needed to be adjusted for in
the analyses; and (3) there was no clear association between
radiation dose and prevalence of glaucoma medication
history in nonparticipants (odds ratio at 1 Gy of 1.00, P ¼
0.98) and participants (odds ratio 0.63, P ¼ 0.09). The slopesof the two linear dose-response functions did differ (P ,0.001) for glaucoma medication, but the direction of thedifference would not suggest that participants were biased
toward glaucoma in an upward direction.
The ophthalmologic examination identified 284 people(17.9%) as having glaucoma. Table 2 shows a further

breakdown of glaucoma subtypes by age and gender in thecurrent study. Glaucoma was slightly more prevalent among
males and it increased with age for both genders. Table 3
indicates the breakdown by glaucoma subtype and radiation
dose. The percentages indicate an increased prevalence withdose for normal-tension glaucoma.
Table 4 examines the association of various individualglaucoma risk factors with radiation exposure. Significant
associations with radiation were observed for history ofcataract, glaucoma, retinal bleeding, aftercataract, cataract
surgery and diabetes mellitus. It should be noted that theassociation of radiation with reported glaucoma was in thenegative direction. Radiation did not show any association
with a familial history of glaucoma.
Based on the factors in Table 4 that were statisticallysignificant, GEE logistic regression analysis was conducted

GLAUCOMA, ATOMIC BOMB SURVIVORS427

TABLE 5Results of Binary Regression Analysis of Glaucoma
Prevalence: Odds Ratios for Radiation at 1 Gy with
Adjustment for Gender, Age, City, Cataract Surgery
and Diabetes Mellitus
Diagnosis

Primary open-angle
glaucoma
IOP . 21 mmHg
36 (58)a
IOP  21 mmHg
226 (417)(normal-tension glaucoma)
Primary angle-closure
25 (47)glaucoma
Secondary glaucoma
10 (13)
Other glaucoma
1 (1)All cases of glaucoma
284 (535)
Ocular hypertension
21 (32)a

Odds ratio(95%CI)P

0.79 (0.52, 1.21)
1.31 (1.11, 1.54)

0.28
0.001

0.54 (0.29, 1.02)

0.06

–
–
–
0.57 (0.30, 1.10)

–
–
–
0.10

N

Number of eyes are in parentheses.

with adjustment for gender, age, city and history of cataract
surgery and diabetes mellitus. The analyses revealed
significant increases in normal-tension glaucoma; the odds
ratios at 1 Gy (OR1Gy) were 1.31 (95% CI: 1.11, 1.53, P ¼
0.001) (Table 5 and Fig. 2). Primary angle closure glaucoma
showed a suggestive decrease with dose (OR1Gy ¼ 0.54, 95%
CI: 0.29, 1.02, P ¼ 0.06).
Table 6 (Models 1 and 2) indicates regression analyses ofrisk factors for normal-tension glaucoma. Among thefactors, such as city (Nagasaki vs. Hiroshima), gender(female vs. male), age at examination, radiation dose (at 1Gy), diabetes mellitus, cataract operation in the past and left
vs. right eye, statistical significance was observed only forage at examination and radiation. The interaction between
age at examination and radiation dose was not significant
for normal-tension glaucoma as shown in Model 1 in Table
6. The variables for education, smoking, hypertension andobesity index were added, with results shown as Model 2 inTable 6. The effects of hypertension and the obesity index
were significant for normal-tension glaucoma, but after
adjustment for all the factors, radiation dose was still
statistically significant for normal-tension glaucoma.
DISCUSSION

The prevalence of normal-tension glaucoma significantly
increased with increasing A-bomb radiation dose (P ¼
0.001), which appears to be inconsistent with a previous Abomb survivor study (8) and the findings from reported
glaucoma treatment in the current study (Table 4). One
important difference between the current and previous
studies on A-bomb survivors is the diagnostic procedure;
diagnoses in the previous study were based on medical
history, whereas in the current study they were based on
ophthalmologic examination. Elderly survivors may notnotice visual disturbances until the symptoms become
severe, which could result in false negatives using medical

FIG. 2. Relationship between odds ratio of normal-tension
glaucoma and radiation dose, OR 1.31 (CI: 1.11, 1.53). Results are
based on binary regression analysis using the GEE method withadjustment for gender, age, city, cataract surgery, and diabetes
mellitus.

history. Similar to our study, in the Tajimi study only 6.7%
of POAG, including normal-tension glaucoma patients, hadbeen previously diagnosed with glaucoma. Glaucoma is adisease in which patients may readily and unknowingly
become adapted to progressive visual limitations during thelengthy course of the disease. However, detecting thepresence of glaucomatous change is very important even in
the early subclinical stage of the disease to effectively treat
the disease.
A total of 284 cases were diagnosed as having glaucoma
based on ophthalmologic examinations in the current study(n ¼ 1,589). Only 14% of those had already been diagnosed
as part of routine medical or ophthalmological care. Nearly
all the newly diagnosed cases were normal-tension
glaucoma. This suggests that there is gross underdiagnosis
of normal-tension glaucoma in routine medical caresettings, and/or that the present study diagnosed numerous
cases that are considered subclinical in nature in thosesettings.
The prevalence of primary open-angle glaucoma (POAG)
among A-bomb survivors is higher than that in the Tajimi
study (11, 12) in all age groups, while those of primary
angle-closure glaucoma and of secondary glaucoma aresimilar to the prevalence in the Tajimi study. In two types ofPOAG, IOP . 21 mmHg and IOP  21 mmHg (normaltension glaucoma), normal-tension glaucoma constitutes
86% of POAG and contributes to the dose-related increase
in POAG prevalence in A-bomb survivors. The highprevalence of normal-tension glaucoma, as high as 12.8%
in the 0 Gy group (Table 2), indicates that there was a highbackground prevalence without A-bomb radiation. Possible
reasons why we observed a high prevalence of normal-

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TABLE 6
Odds Ratio of Various Risk Factors for Normal-Tension Glaucoma
Model 1a (N ¼ 1,589)
Dose at 1 Gy
City (Nagasaki vs. Hiroshima)
Gender (female vs. male)Age at examination (given per 10 years at reference age 75)
Diabetes mellitus
Cataract operation
Eye side (left vs. right)
Model 2 (N ¼ 1,483)
Dose at 1 Gy
City (Nagasaki vs. Hiroshima)
Gender (female vs. male)Age at examination (given per 10 years at reference age 75)
Junior high vs. University educationb
High school vs. University educationc
Smoking (smoker vs. nonsmoker)
Hypertension (yes vs. no)
Underweight (underweight vs. normal)dObese (obese vs normal)dDiabetes mellitus (yes vs. no)Cataract operation (yes vs. no)Eye side (left vs. right)

Odds ratio (95% CI)

P1.31 (1.11 1.53)
0.78 (0.58 1.04)
0.77 (0.57 1.04)
1.60 (1.29 2.00)
0.73 (0.48 1.09)
1.07 (0.80 1.42)
1.05 (0.99 1.12)

0.001
0.09
0.09
,0.001
0.12
0.65
0.14

1.33 (1.13 1.57)
0.79 (0.58 1.07)
0.72 (0.53 0.99)
1.41 (1.12 1.77)
0.89 (0.50 1.57)
1.13 (0.66 1.92)
0.70 (0.40 1.26)
1.54 (1.11 2.12)
1.85 (1.13 3.01)
1.04 (0.75 1.44)
0.74 (0.49 1.14)
1.00 (0.75 1.33)
1.04 (0.98 1.11)

0.001
0.12
0.04
0.001
0.69
0.66
0.24
0.01
0.01
0.83
0.17
0.98
0.21

Notes. Model 1 used generalized estimating equations (GEE) (16) to find the association between glaucoma
prevalence in both eyes and explanatory variables, such as city (Nagasaki vs. Hiroshima), gender (female vs.
male), age at examination, radiation dose to the eye, diabetes mellitus, cataract surgery and the constantdifference of prevalence between eyes (left vs. right). Model 2 included the variables in Model 1, plus additional
potential confounding variables, such as education, smoking, hypertension and obesity. Since some variables
had missing values, the numbers differ between models (1,589 for Model 1 and 1,483 for Model 2). The STATA
statistical package was used for analyses. Two-sided P values and 95% confidence intervals were based on theWald statistic.
a
Dose by age at examination interaction was not significant (P ¼ 0.342).
b
Referent category.
cReferent category.
d
Obesity categories: underweight; BMI ,18, normal; BMI ¼ 18 – ,24, obese; BMI . ¼24, normal was thereferent category.

tension glaucoma in our study include: (1) since all A-bomb
survivors are taxied to RERF for the examination,
physically poorer individuals, including those with visual
disturbances, could be included in our study, whereas in theTajimi study such support was not available; (2) since thenumber of participants over age 70 (1,017) in our study isgreater than that in the Tajimi study (595), our study could
better represent the prevalence in that age category than theTajimi study; (3) since malnutrition-induced glaucomatouschanges have been reported in animals (17, 18) and humans(19), the same thing could have occurred in A-bomb
survivors, many of whom had restricted nutrition during andafter the war; and (4) there were several technicaldifferences between the two studies in screening anddiagnostic criteria for normal-tension glaucoma.
Only a substantial imbalance in participation related toboth radiation exposure and glaucoma status would
completely explain the observed odds ratio of 1.31 fornormal-tension glaucoma if in fact there were no radiation
effect. The evidence of differential participation jointly byradiation dose and glaucoma status is weak at best, so bias

in the estimated odds ratio due to nonparticipation isprobably small but the uncertainty still mandates somecaution in the interpretation. Even though the radiation
dose-response slopes for prior glaucoma medication were
not statistically significant for either participants or
nonparticipants (Table 1), they were not completely parallel:
there was a more negative dose-response slope inparticipants than in nonparticipants (P , 0.001). If one
were to assume that the more negative dose vs. glaucoma
slope for participants compared with nonparticipants was
accurate, this would imply there was a negative bias so thatthe expected association for participants and nonparticipants
combined should be even larger than the positive doseresponse slope that was found.
A number of other glaucoma risk factors besides radiation
were examined as possible confounding factors, including
gender, age, city, cataract surgery, diabetes mellitus,
education, smoking, hypertension and obesity, but astatistically significant radiation dose-response effect remained for normal-tension glaucoma after adjusting forthese factors (Table 6).

429

GLAUCOMA, ATOMIC BOMB SURVIVORSThe tendency for the prevalence of primary angleclosure glaucoma (PACG) and ocular hypertension to
decrease with radiation dose appears consistent withresults in animals. The glaucoma-prone DBA/2J mouseis a well-established model of pigmentary glaucoma withhigher IOP than normal, and Anderson et al. reported thathigh-radiation doses followed by bone marrow transplantprevented neurodegeneration in DBA/2J mice with
inherited glaucoma (20).They proposed several possible
mechanisms for consideration in regards to radiation
protection, including immune alterations and release oftrophic factors (20). However, a murine pigmentary
dispersion model of glaucoma may not be directly relevant
to human disease.
The biological mechanism by which ionizing radiation
exposure may increase the dose-dependent prevalence of
normal-tension glaucoma among A-bomb survivors is notknown with certainty. Some possible risk factors to consider
may be neuronal excitotoxicity (21), inflammation (22),genetic predisposition (23–26), autoimmunity (27) andretinal circulation disturbance (28, 29). Among them, we
believe that retinal circulation disturbance may be the most
likely candidate because there is evidence that radiationinduces poor choroidal circulation 30 or 45 years after
exposure (30), and that retinal arteriolosclerosis in A-bomb
survivors is significantly associated with A-bomb radiation
55 years after exposure (31). It is possible that radiation
eventually causes normal-tension glaucoma through retinal
arteriolosclerosis. Studies are under way to confirm this.
In conclusion, our results suggest that the prevalence of
normal-tension glaucoma significantly increases with increasing A-bomb radiation dose. However, the large
number of study nonparticipants, especially among thosewith prior glaucoma medication, contributes substantial
uncertainty so that caution is required in interpreting theresults. Because the present findings are relevant for theradiation safety community, it is important that the issue be
examined in other irradiated populations.
ACKNOWLEDGMENTS
We thank Dr. John Cologne, Department of Statistics, Radiation Effects
Research Foundation for his analysis and discussion of bias analyses andDr. Masahide Yanagi, Department of Ophthalmology and Visual Sciences,
Graduate School of Biomedical Sciences, Hiroshima University and Dr.
Ryo Kawasaki, Retinal Vascular Imaging Centre, Centre for Eye Research
Australia for their suggestions and comments. The Radiation Effects
Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private,nonprofit foundation funded by the Japanese Ministry of Health, Labourand Welfare (MHLW) and the U.S. Department of Energy (DOE), thelatter in part through DOE Award DE-HS0000031 to the National
Academy of Sciences. This publication was supported by RERF ResearchProtocol 1–05. The views of the authors do not necessarily reflect those of
the two governments. We declare no conflicts of interest including
relevant financial interests, activities, relationships, nor affiliations.
Received: December 5, 2012; accepted: July 8, 2013; published online:
September 23, 2013

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