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Global Health & Medicine Open
Volume 1, Number 2
December, 2021

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Print ISSN: 2436-293X
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GHM Open
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ii

CONTENTS		

Volume 1, Number 2, 2021

Original Article
43-50

Burden of cancer attributable to tobacco smoke in Japan in 2015.
Kota Katanoda, Mayo Hirabayashi, Eiko Saito, Megumi Hori, Sarah Krull Abe, Tomohiro Matsuda,
Manami Inoue; the Cancer PAF Japan Collaborators

51-55

Burden of cancer attributable to consumption of alcohol in Japan in 2015.
Mayo Hirabayashi, Norie Sawada, Sarah Krull Abe, Eiko Saito, Megumi Hori, Kota Katanoda,
Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

56-62

Burden of cancer attributable to excess bodyweight and physical inactivity in Japan in 2015.
Mayo Hirabayashi, Sarah Krull Abe, Norie Sawada, Eiko Saito, Megumi Hori, Kota Katanoda,
Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

63-69

Burden of cancer attributable to infection in Japan in 2015.
Yingsong Lin, Chaochen Wang, Shogo Kikuchi, Tomoyuki Akita, Junko Tanaka, Sarah Krull Abe,
Mayo Hirabayashi, Eiko Saito, Megumi Hori, Kota Katanoda, Tomohiro Matsuda, Manami Inoue;
the Cancer PAF Japan Collaborators

70-75

Burden of cancer attributable to insufficient vegetable, fruit and dietary fiber consumption in
Japan in 2015
Junko Ishihara, Ribeka Takachi, Sarah Krull Abe, Mayo Hirabayashi, Eiko Saito, Megumi Hori,
Kota Katanoda, Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

76-84

Burden of cancer attributable to air pollution in Japan in 2015.
Megumi Hori, Kota Katanoda, Kayo Ueda, Tomoki Nakaya, Eiko Saito, Sarah Krull Abe,
Mayo Hirabayashi, Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

Brief Report85-90

Burden of cancer attributable to consumption of highly salted food in Japan in 2015.
Ribeka Takachi, Junko Ishihara, Sarah Krull Abe, Mayo Hirabayashi, Eiko Saito, Megumi Hori,
Kota Katanoda, Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

91-96

Burden of cancer attributable to excess red and processed meat consumption in Japan in 2015.
Sarah Krull Abe, Ribeka Takachi, Junko Ishihara, Mayo Hirabayashi, Eiko Saito, Megumi Hori,
Kota Katanoda, Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

97-101

Burden of cancer attributable to exogenous hormone use in Japan in 2015.
Mayo Hirabayashi, Chisato Nagata, Sarah Krull Abe, Norie Sawada, Eiko Saito, Megumi Hori,
Kota Katanoda, Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

102-105

Burden of cancer attributable to never breastfeeding in Japan in 2015.
Mayo Hirabayashi, Chisato Nagata, Sarah Krull Abe, Eiko Saito, Megumi Hori, Kota Katanoda,
Tomohiro Matsuda, Manami Inoue; the Cancer PAF Japan Collaborators

iii

iv

Original Article

GHM Open. 2021; 1(2):43-50.
DOI: 10.35772/ghmo.2021.01013

Burden of cancer attributable to tobacco smoke in Japan in 2015
Kota Katanoda1,*, Mayo Hirabayashi2, Eiko Saito1, Megumi Hori1, Sarah Krull Abe2, Tomohiro Matsuda3, Manami Inoue2;
the Cancer PAF Japan Collaborators
1

Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;
Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
3
National Cancer Registry Section, Center for Cancer Registries, Center for Cancer Control and Information Services/Office of International
Affairs, Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Tobacco is the greatest single cause of many non-communicable diseases, including cancer. We calculated
the proportion of cancer incidence and mortality in 2015 attributable to tobacco smoking and exposure to secondhand
smoke (SHS). Data on the prevalence of active smoking were derived from the 2005 Japanese National Health andNutrition Survey by age group and gender. For SHS exposure prevalence, data from a nationwide cross-sectional
survey from 2004-2005 were used. Based on standard formulas, population attributable fractions (PAFs) for eachcancer causally associated with active smoking, namely the oral cavity and pharynx, esophagus, stomach, colon,
rectum, liver, pancreas, nasal, larynx, lung, uterine cervix, kidney, renal pelvis and ureter, bladder, and acute myeloid
leukemia, were calculated for each sex and age group and aggregated to obtain the PAF among total cancer incidence
and mortality. For SHS exposure, PAFs for lung cancer and total cancer were calculated using the same method. For
Japan in 2015, 145,765 new cancer cases and 72,520 cancer deaths, corresponding to a PAF of 15.2% for total cancer
incidence and 19.6% for total cancer mortality, were attributable to active tobacco smoking. For SHS exposure, 0.5%of total cancer incidence and 0.7% of total cancer mortality in 2015 were attributable. Tobacco is still one of the major
causes of cancer in Japan.
Keywords: cancer, tobacco smoke, secondhand smoke, population attributable fraction, Japan

Introduction

consequences attributable to smoking (9). Following
the U.S. Surgeon General's Report (10), this report
made comprehensive and systematic assessments of thecausal relationships between smoking and disease in theJapanese population. This report and studies conducted
before and after it included meta-analyses and pooled
analyses of large-scale cohort studies performed inJapanese populations, which aimed to explore theassociation between active smoking and head andneck cancers (11), bladder cancer (12), hematologic
malignancies (13), cervical cancer (14), and colorectal
cancer (15), and the association between SHS exposureand lung cancer (16). Thanks to these studies, it is now
possible to select smoking-related diseases specificto the Japanese population and to calculate their RRs
using more representative data. Additionally, theprevalence of smoking in Japanese, particularly amongmen, has declined over the past 10 years (4,17), which
is likely a major contributor to changes in the estimatesof smoking-attributable cancer incidence and mortality.
Therefore, this study aimed to estimate the proportionof cancer incidence and mortality in 2015 attributable toactive tobacco smoking and exposure to SHS.

Tobacco smoking is the greatest single preventablecause of cancer (1). Globally, there are estimated to be
1,820,000 cancer deaths every year due to active smoking
and 125,000 cancer deaths due to secondhand smoke(SHS) exposure (2). The incidence of tobacco-caused
diseases is particularly high in East Asia. Japan ranks
sixth in the world for tobacco consumption (3). Smoking
prevalence among men aged 30-49 years is 37% (4). The
latest estimates on the population-attributable fractions(PAFs) of tobacco-related cancers in Japan were released
in 2005 (125,898 cases for active smoking and 4,152
cases for SHS exposure) (5). With regard to active
smoking, other studies have reported similar estimates by
including non-cancer diseases attributable to smoking,using data obtained in 2005 (6), 2007 (7), and 2008 (8).
These estimates are now somewhat out of date, however,and their selection of smoking-related diseases was basedon studies conducted mostly among Westerners.
In 2016, the Committee on Health Effects of
Smoking of the Ministry of Health, Labour and Welfare(MHLW) released a comprehensive report on health(43)

GHM Open. 2021; 1(2):43-50.

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Materials and Methods

former, and never smokers by sex and age group.
Smoking prevalence from year 2000 of the JNHNS (23)was further used for sensitivity analysis. Sex- and agegroup-specific prevalence of tobacco smoking in Japan in2005 is shown in Table 1. For SHS exposure prevalence,
data from a nationwide cross-sectional survey from2004-2005 funded by Grants-in-aid from Ministry of
Health, Labour, and Welfare were used (24). This survey
collected data on the proportion of non-smoking men
and women who were exposed to SHS. The two possible
exposure locations considered were home and work.
The sex- and age-group-specific prevalence (%) of SHS
exposure in Japan in 2005 is shown in Table 2.

Cancers associated with tobacco smoking
The International Agency for Research on Cancer (IARC)
confirmed that tobacco smoking, SHS exposure, andsmokeless tobacco were all reaffirmed as carcinogenic
to humans (Group 1) (18). There are major global
and domestic comprehensive assessments: an IARC
monograph published in 2012 (19), a report of the
US Surgeon General in 2014 (20), and a domestic
assessment by the Research Group for the Development
and Evaluation of Cancer Prevention Strategies inJapan (21). In Japan, these assessments were further
comprehensively evaluated and integrated into the mostrecent report by the Committee on Health Effects of
Smoking in 2016 (9). Therefore, we applied the target
cancers causally associated with tobacco smoking
concluded by this evaluation, namely those that showedsufficient evidence for a positive association withtobacco smoking and for which RR estimates in Japan
were available, including cancer of the oral cavity andpharynx, esophagus, stomach, colon, rectum, liver,pancreas, nasal cavity and paranasal sinuses, larynx,
lung, cervix uterine, kidney, renal pelvis and ureter,urinary bladder and acute myeloid leukemia. For SHS
exposure, the only cancer retained in the analysis waslung cancer among never-smokers.

Cancer incidence and mortality in Japan in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by the
Monitoring of Cancer Incidence in Japan (25). Thisestimate was done using an age and period spline model,
a method which is used for short-term projections forcancer incidence in Japan (26). The sex- and age-specificincidence data for target cancers were coded by theInternational Statistical Classification of Diseases andRelated Health Problems, 10th edition (ICD-10), using
the morphology code of the International Classificationof Disease for Oncology, 3rd edition (ICD-O-3).
The data on cancer mortality statistics from 2015
were obtained from the vital statistics of Japan (27). We
sourced sex- and age-specific mortality data by causeof death from the Health, Labour, and Welfare Statistics
Association (28). Similar to the cancer incidence data,
4-digit ICD-10 codes were used to classify the cause ofdeath.

Prevalence of tobacco smoking
The data on smoking status were derived from theJapanese National Health and Nutrition Survey (JNHNS)
from 2005 (22), which presents the proportion of current,

Table 1. Sex- and age-group-specific prevalence of tobacco smoking in Japan in 2005
2005
Age at exposure

0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Total

2000

Men

Women

Men

Women

Current Former

Ever

Current Former

Ever

Current Former

Ever

Current Former

Ever

0.0
0.0
1.0
7.0
44.4
52.3
54.7
55.3
49.7
44.9
48.1
43.4
37.7
30.1
24.2
18.8
40.8

0.0
0.0
1.0
7.0
47.7
60.6
64.7
69.1
69.9
69.6
72.8
71.1
67.2
60.6
59.3
54.1
64.4

0.0
0.0
0.5
2.5
15.4
20.7
19.6
16.0
14.5
13.9
13.6
10.2
8.7
5.5
4.5
2.5
11.1

0.0
0.0
0.5
2.5
19.0
28.0
29.4
24.0
21.6
19.1
18.3
13.1
12.5
8.3
7.1
5.7
15.9

0.0
0.0
2.5
18.8
52.3
63.9
56.0
59.1
58.0
56.2
55.5
49.0
42.2
34.7
34.2
26.9
47.6

0.0
0.0
2.5
18.8
56.2
69.4
65.6
70.6
74.6
76.0
76.8
73.2
72.3
73.0
76.8
75.0
72.6

0.0
0.0
0.9
5.5
17.6
17.5
16.3
16.8
14.5
12.0
11.0
7.9
7.2
6.8
4.2
3.2
10.6

0.0
0.0
0.9
5.5
20.5
23.6
21.4
21.3
18.8
14.4
13.2
10.6
9.1
8.7
7.4
5.7
13.7

0.0
0.0
0.0
0.0
3.2
8.4
10.0
13.8
20.2
24.7
24.7
27.6
29.5
30.5
35.1
35.3
23.5

0.0
0.0
0.0
0.0
3.5
7.3
9.8
8.0
7.0
5.2
4.7
2.9
3.8
2.9
2.7
3.1
4.9

Data source: The National Health and Nutrition Survey, Japan, 2005.

(44)

0.0
0.0
0.0
0.0
3.9
5.5
9.6
11.5
16.6
19.8
21.3
24.2
30.1
38.2
42.6
48.1
25.0

0.0
0.0
0.0
0.0
2.9
6.1
5.1
4.5
4.3
2.4
2.1
2.8
1.9
1.9
3.2
2.5
3.2

GHM Open. 2021; 1(2):43-50.

www.ghmopen.com

smoking, RRc is the RR for current smokers comparedto never smokers, Pf is the proportion of the populationof former smokers, and RR f is the RR of former
smokers compared to never smokers.
For SHS, PAF was calculated using the method
described by Gan et al. (31). First, the PAF of nonsmokers exposure to SHS (PAFshns) was calculated using
the following formula:

Table 2. Sex- and age-group-specific prevalence (%) of
secondhand smoking in Japan in 2005
Age at exposure
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75

Men

Women

At home At work

At home At work

6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2

0.0
0.0
0.0
0.0
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4
29.4

31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1
31.1

0.0
0.0
0.0
0.0
18.2
18.2
18.2
18.2
18.2
18.2
18.2
18.2
18.2
18.2
18.2
18.2

Where P and RR refer to the proportion of SHS
exposure and RR for non-smokers, respectively,
compared to non-smokers who were not exposed to
SHS. We then calculated the PAF for SHS (PAFshs) forthe entire population by:

Data source: Report of the nationwide survey on adolescent smoking
behavior in Japan, Grants-in-aid for the Comprehensive Health
Sciences from the Ministry of Health, Labour, and Welfare, Japan.
2016 (24).

Where PAF c refers to PAF of current smokers and
Pc refers to the proportion of current smokers in the
population. PAF for SHS was only separated by gender;
age groups were pooled due to the limited sample sizeand prevalence.

Estimation of relative risks
The sources for the site-specific RR of cancer withrelation to active smoking and SHS exposure are shownin Table 3. As a general rule, we prioritized metaanalyses or pooled analyses published for Japanese
populations, followed by Asian populations, then studies
from other nations. Studies that differentiated between
current and past smokers were prioritized over studies
that differentiated between ever- and non-smokers. RRspresented by sex were used. If the studies only presented
RR for ever- or current smokers, these were used byconsidering the RR of former smokers to be 1.
For SHS exposure at home, the summary RR wasderived from a meta-analysis of Japanese studies; for
SHS exposure at work, summary RR was derived froman international meta-analysis since a sufficient numberof studies was not available for Japan.

Results
Table 4 summarized the estimated PAF of cancer
incidence and mortality in 2015 attributed to tobaccosmoke in Japan.
Active smoking was estimated to have caused 23.6%of total cancer incidence among men and 4.0% among
women. For major cancers, smoking caused 61.7% (men)and 20.9% (women) of lung cancer cases, and 57.5%(men) and 20.4% (women) of esophageal cancer cases.
Similarly, the estimated number and PAF of cancer
mortality in 2015 attributed to active smoking were 29.8%
for men and 4.7% for women. For lung cancer deaths,
60.9% (men) and 18.3% (women) of cases may be
attributable to smoking. For men and women combined,
15.2% of cancer incidence and 19.6% of cancer mortality
in 2015 could be attributable to active tobacco smoking.
Based on these results, 145,765 cases of cancer incidence(129,502 in men and 16,263 in women) (Table S1, online
data, https://www.ghmopen.com/site/supplementaldata.
html?ID=32) and 72,520 cancer deaths (65,416 in men
and 7,105 in women) (Table S2, online data, https://www.
ghmopen.com/site/supplementaldata.html?ID=32) were
estimated to be attributable to active smoking.
Likewise, SHS was estimated to have caused 0.2%
of total cancer incidence among men and 0.9% among
women. Lung cancer incidence in 2015 attributable
to SHS exposure at home and work in total was 1.3%(men) and 8.7% (women). The PAFs for mortality were

Estimation of population attributable fractions (PAFs)
For active smoking, PAFs were calculated using themethod of Levin's formula for multiple categories (29),
proposed by Hanley (30). This method distinguishes
between current and former smokers. PAF for active
smoking was calculated for each sex and age groupaccording to the formula:

Where Pc is the proportion of the population currently(45)

GHM Open. 2021; 1(2):43-50.

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Table 3. Relative risk of cancer associated with passive and secondhand smoking compared with never smoking in Japan
Cancer site (ICD-10 code)

Exposure category

RR (95% CI)

Sources

Men

Women

Current
Former2.68 (2.08 - 3.44)
1.49 (1.05 - 2.11)

2.68 (2.08 - 3.44)
1.49 (1.05 - 2.11)

Koyanagi et al. (Japanese meta-analysis) (11)Esophagus (C15)

Current
Former3.73 (2.16 - 6.43)
2.21 (1.60 - 3.06)

3.73 (2.16 - 6.43)
2.21 (1.60 - 3.06)

Oze et al. (Japanese meta-analysis) (43)

Stomach (C16)

Current
Former

1.79 (1.51 - 2.12)-

1.22 (1.07 - 1.38)-

Nishino et al. (Japanese meta-analysis) (44)Colon (C18)

Current
Former

1.18 (1.06 - 1.31)
1.20 (1.09 - 1.32)

1.12 (0.96 - 1.31)
0.98 (0.73 - 1.30)

Akter et al. (Japanese pooled analysis) (15)Rectum (C19-C20)

Current
Former

1.27 (1.12 - 1.44)
1.10 (0.95 - 1.26)

1.05 (0.83 - 1.34)
1.42 (0.99 - 2.04)

Akter et al. (Japanese pooled analysis) (15)Liver (C22)

Current
Former

1.81 (1.49 - 2.20)
1.63 (1.32 - 2.01)

1.73 (1.21 - 2.48)
1.23 (0.63 - 2.39)

Katanoda et al. (Japanese pooled analysis) (6)

Pancreas (C25)Ever

1.57 (1.30 - 1.89)

1.83 (1.35 - 2.48)

Matsuo et al. (Japanese meta-analysis) (45)Nasal cavity (C30)Ever

2.49 (1.86 - 3.34)

3.12 (1.62 - 5.99)

Koyanagi et al. (Japanese meta-analysis) (11)Larynx (C32)

Current
Former

5.47 (1.29 - 23.11) 1.00
3.03 (0.65 - 14.01) 1.00

Katanoda et al. (Japanese pooled analysis) (6)Lung (C33-C34)

Current
Former

4.65 (3.70 - 5.85)
2.38 (1.86 - 3.05)

3.75 (2.89 - 4.86)
2.96 (1.92 - 4.56)

Meta-analysis of Japanese studies (32)

Cervix uteri (C53)Ever

2.03 (1.49 - 2.57)

Sugawara et al. (Japanese meta-analysis) (14)Kidney (C64)

Current
Former

1.57 (0.81 - 3.06)
1.46 (0.71 - 3.00)

0.60 (0.08 - 4.47) Katanoda et al. (Japanese pooled analysis) (6)1.55 (0.21 - 11.52)

Renal pelvis and ureter (C65-C66)

Current
FormerEver

5.35 (2.47 - 11.57)
2.76 (1.21 - 6.31)

Katanoda et al. (Japanese pooled analysis) (6)

Bladder (C67)Ever

2.14 (1.87 - 2.44)

2.14 (1.87 - 2.44)

Masaoka et al. (Japanese meta-analysis) (12)Acute myeloid leukemia (C92.0,
C92.4, C92.5)

Current
Former

1.44 (0.97 - 2.14)
1.42 (0.91 - 2.22)

1.44 (0.97 - 2.14)
1.42 (0.91 - 2.22)

Ugai et al. (Japanese pooled analysis) (46)Home
Workplace

1.28 (1.10 - 1.48)
1.12 (0.86 - 1.50)

1.28 (1.10 - 1.48)
1.22 (1.10 - 1.35)

Hori et al. (Japanese meta-analysis) (16)Surgeon General Report meta-analysis (39)

Active smoking
Oral cavity and pharynx (C00-C14)

Secondhand smoking
Lung (C33-C34)

1.30 (0.59 - 2.88)

Discussion

0.3% for men and 1.3% for women for total cancers,
and 1.4% and 9.1% for lung cancer, respectively.
For men and women combined, 0.5% of total cancer
incidence (3.7% of lung cancer) and 0.7% of totalcancer mortality (3.6% of lung cancer) in 2015 were
attributed to SHS. Based on these results, 4,579
cancer cases (1,095 in men and 3,483 in women; total
number is not equal to the sum of men and women
due to rounding) (Table S3, online data, https://www.
ghmopen.com/site/supplementaldata.html?ID=32) and
2,667 cancer deaths (735 in men and 1,932 in women)(Table S4, online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=32) were estimated to be
attributable to SHS exposure.

In this study, we estimated that in Japan, 145,765 (15.2%)
newly diagnosed cancer cases and 72,520 (19.6%) cancer
deaths in 2015 were attributable to active smoking.
The PAFs were nearly 50% or even larger for lung,
larynx, and esophagus for both cancer incidence andmortality. Men exhibited a much larger PAF of active
smoking than women (23.6% vs. 4.0% for incidence and29.8% vs. 4.7% for mortality of total cancers). For SHS
exposure, we estimated that 4,579 (3.7%) cases of lungcancer incidence and 2,667 (3.6%) lung cancer deaths
were attributable in Japan annually. In contrast to active
smoking, the PAF of SHS exposure was larger in women(46)

GHM Open. 2021; 1(2):43-50.

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Table 4. Proportion (%) of cancer in 2015 attributable to tobacco smoke in Japan
Cancer Site (ICD-10)
Active tobacco smoking
Oral cavity and pharynx (C00-C14)
Esophagus (C15)
Stomach (C16)
Colon (C18)
Rectum (C19-C20)
Liver (C22)
Pancreas (C25)
Nasal (C30-C31)
Larynx (C32)
Lung (C33-C34)
Uterine cervix (C53)
Kidney (C64)
Renal pelvis and ureter (C65-C66)
Bladder (C67)
Acute myeloid leukemia (C92.0, C92.4, C92.5)
Total
Secondhand smoking
Lung (C33-C34)
Total

Incidence

Mortality

Men

Women

Both sexes

Men

Women

Both sexes

43.4
57.5
21.5
10.8
11.5
31.9
26.8
48.9
68.5
61.7

34.1
51.7
15.3
6.2
8.2
22.6
17.5
38.8
63.6
48.5
15.6
18.5
43.9
33.5
14.5
15.2

41.8
56.5
19.9
10.6
11.0
31.3
26.7
48.4
66.7
60.9

25.8
66.1
41.6
20.6
23.6

13.3
20.4
1.6
0.9
2.0
5.2
7.7
19.7
0.0
20.9
15.6
2.2
2.8
9.5
5.3
4.0

24.6
64.7
40.7
21.2
29.8

10.0
18.3
1.3
0.7
1.8
3.4
7.2
17.1
0.0
18.3
13.1
1.8
2.4
8.0
4.4
4.7

32.6
50.1
13.6
5.6
7.7
21.8
17.1
36.4
61.7
48.8
13.1
17.0
39.9
30.5
14.8
19.6

1.3
0.2

8.7
0.9

3.7
0.5

1.4
0.3

9.1
1.3

3.6
0.7

than in men (8.7% vs. 1.3% for incidence and 9.1% vs.
1.4% for mortality of lung cancer). We reconfirmedthat tobacco is still one of the major causes of cancer inJapan.
The PAFs estimated in the present study wereslightly smaller than those reported in previously. Inmen, the PAF of cancer incidence attributable to active
smoking was 29.7% in 2005 (5), which decreased to23.6% in the present study (in 2015). A major reason
for this is the decrease in smoking prevalence in Japan.
Male ever smoking prevalence reduced from 72.9% (in1990) (5) to 64.4% (in 2005) in the present study. Our
additional analysis showed that the PAF estimates wereclosely similar when we applied the same value for eversmoking prevalence (data not shown). Another factor
is a change in methodology. First, we assumed a 10year latency period from exposure to outcome versus
a 15-year period in our previous study. In a sensitivity
analysis we used a 15-year latency period instead (i.e.
smoking prevalence in 2000), and found that the PAFs
for all cancers combined were slightly larger, particularly
for men (incidence: 26.3% for men, 4.0% for women,
and 16.8% for men and women combined; mortality:
33.9% for men, 5.0% for women, and 22.1% for men
and women combined). Second, we used age-specificsmoking prevalence in the present study versus agepooled prevalence in the previous one (5). When weused age-pooled prevalence in the present study, thePAFs were slightly larger (e.g. 64.5% vs. 61.7% for malelung cancer incidence), probably due to overestimationof smoking prevalence among the elderly. Thus, thePAFs in men decreased due to both a decline in smoking
prevalence and pooling age. By contrast, in women,

although the PAF of cancer incidence attributable toactive smoking reduced from 5.0% (in 2005) (5) to 4.0%
in the present study (in 2015), ever smoking prevalence
increased from 12.3% (in 1990) (5) to 15.9% (in 2005).
However, when we applied age-pooled prevalence tothe calculation, the PAF became larger (e.g. 28.6% vs.
20.9% for female lung cancer incidence). The effects ofincreased smoking prevalence and age-pooling in women
were therefore balanced out.
The PAFs of lung cancer incidence attributable to
SHS exposure in the present study were slightly smaller
than those in our previous estimates (1.3% vs. 1.6% formen, 8.7% vs. 12.6% for women) (5). The main reason isprobably the decrease in the prevalence of SHS exposure,particularly at the workplace (men: 6.2% vs. 8% at homeand 29.4% vs. 58% at workplace; women: 31.1% vs.
35% at home and 18.2% vs. 32% at workplace). Indeed,
our PAF estimates were comparable to more recently
published values (32,33). In April 2020, the revised
Health Promotion Act came into force in Japan, bywhich indoor smoking at the workplace and in public
places was partially banned. This legislative measure is
expected to accelerate the decrease in SHS exposure, but
the high prevalence of SHS exposure at home remains amajor problem in Japan.
In men, our PAF estimates of active smoking
in Japan were comparable to or larger than those inWestern populations. According to recent publications,the PAF cancer incidence attributable to active smoking
for men was 23.6% in United States (US) in 2014(34), 17.7% in United Kingdom (UK) in 2015 (35),
and 15.8% in Australia in 2010 (36) (corresponding
value was 23.3% in the present study). This reflects the(47)

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higher male smoking prevalence in Japan, because the
RR of lung cancer associated with active smoking was
lower in Japanese than in Western populations (e.g.
current smoking RR: 4.65 for men and 3.75 for womenin Japan versus 8.96 for men and women in the UK
study (35)). By contrast, in women, our PAF estimatesof active smoking were smaller than those in Western
populations (14.5% in US (34), 12.4% in UK (35),
10.1% in Australia (36) (corresponding value was 3.8%
in the present study), reflecting the lower lung cancer
RR and smaller female prevalence as well. The PAFs ofactive smoking reported in the Republic of Korea werecomparable to our estimates (20.8% in men and 1.0% in
women for cancer incidence) (37), probably because ofsimilar values for RR and smoking prevalence.
The strength of this study is the representativenessof the data. The data for smoking prevalence and SHS
exposure were based on national representative surveys.
Most of the RRs used here were derived from the latest
meta-analysis or pooled large-scale cohort studies in
the Japanese populations. The selection of causally
related cancers was also based on an up-to-date andcomprehensive review of the literature of Japanese
population.
This study has some potential limitations. First, someof the RRs we used were based on values that were
not sufficiently adjusted for confounding factors (i.e.
liver, laryngeal and kidney cancers) (6). In particular,
the RRs of liver cancer which were unadjusted forhepatitis B and C virus infection need to be interpretedwith caution. However, the pooled RRs we used wereclose to those reported in a study that adjusted forthese infectious factors (38). The RR we used for SHS
exposure at the workplace was also not derived from adomestic meta-analysis but based on a value reported
in the U.S. Surgeon General Report (39). However,this comprehensive review showed that there were no
substantial geographical variation in the RR of SHS at
the workplace (39).
Second, we only included cancers that were evaluatedas "causally related to tobacco smoke exposure" incomprehensive evaluation reports. There are manyother cancers that may potentially have causal link totobacco. In that sense, the PAFs presented here areconservative estimates, which could be increased by
future accumulation of scientific evidence.
Third, we assumed a 10-year latency period fromexposure to outcome. Although this assumption was
also adopted by many recent studies of PAF estimates(35,36,40), latency from exposure to cancer occurrence
is not well defined and could vary among cancers. We
assumed that a longer lag time (15 years) resulted inlarger PAF estimates for men, as stated above. Peto etal. proposed an alternative method that uses lung-cancer
mortality as an indirect indicator of the accumulated
hazards of smoking (41), which was adopted in the
Global Bureau of Diseases Study (1,42). However, wepreviously confirmed that this difference in methodology
did not lead to any substantial changes in PAF estimates(6-8).
Conclusion
We estimated that in Japan, 145,765 (15.2%) newly
diagnosed cancer cases and 72,520 (19.6%) cancer
deaths in 2015 were attributable to active smoking. For
SHS exposure, 4,579 cancer cases (0.5%) and 2,667
cancer deaths (0.7%) in 2015 were attributed to SHS.
This result reconfirms that tobacco is still a major causeof cancer in Japan.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received June 11, 2021; Revised October 29, 2021; Accepted
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Released online in J-STAGE as advance publication December
11, 2021.
*Address correspondence to:
Kota Katanoda, Division of Cancer Statistics Integration,
Center for Cancer Control and Information Services, National
Cancer Center. 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045,
Japan.
E-mail: kkatanod@ncc.go.jp(50)

Original Article

GHM Open. 2021; 1(2):51-55.
DOI: 10.35772/ghmo.2021.01014

Burden of cancer attributable to consumption of alcohol in Japan in2015
Mayo Hirabayashi1, Norie Sawada2, Sarah Krull Abe1, Eiko Saito3, Megumi Hori3, Kota Katanoda3, Tomohiro Matsuda4,
Manami Inoue1,2,*; the Cancer PAF Japan Collaborators
1

Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
Division of Cohort Research, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
3
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;
4
National Cancer Registry Section, Center for Cancer Registries, Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Alcohol can cause or contribute to the development of many non-communicable diseases, including cancer.
We calculated the proportion of cancer incidence and mortality in 2015 attributable to alcohol consumption in 2005.
Data on alcohol consumption, provided in go, a traditional Japanese alcohol measurement unit, was derived from the2005 Japanese National Health and Nutrition Survey for each sex and age group, then converted into grams of ethanol
per day. The optimal consumption of alcohol for the purpose of this study was determined to be none, based on a
global assessment derived from previous observational studies that have looked at the association between alcohol
consumption and cancer. Using standard formulas, population attributable fractions (PAFs) for all cancers positively
associated with alcohol drinking - oral cavity, pharynx, esophagus, stomach, colorectum, liver, larynx, and female
breast - were calculated for each sex and age group and aggregated to obtain the PAF among total cancer incidence andmortality. For Japan in 2015, 59,838 cases of cancer incidence and 23,929 cancer deaths were attributable to alcohol
consumption. The estimated PAF for cancer incidence and mortality attributable to alcohol consumption was 6.2%
and 6.5%, respectively. For both cancer incidence and mortality, the highest percentage of alcohol-attributable cancer
sites was esophageal (54.0% for incidence, 52.3% for mortality). Avoidance of alcohol consumption would reduce theburden of alcohol on cancer in Japan.
Keywords: cancer, alcohol, population attributable fraction, Japan

Introduction

Materials and Methods

Since 1998, alcohol consumption has been classified
as a human carcinogen by the International Agency for
Research on Cancer (IARC) (1). In the most updated
review in 2010, the IARC concluded that alcohol
consumption is a risk factor for cancers of the oralcavity, pharynx, larynx, esophagus, liver, colorectum,
and breast (women only) (2). In addition to these cancer
sites, the World Cancer Research Fund/American
Institute for Cancer Research (WCRF/AICR) concluded
that alcoholic drinks increase the risk of colorectal andstomach cancer in their latest report (3). The report also
noted that there is no evidence of safe level of alcohol
consumption (3).
Despite these established evidences, drinking
patterns between countries and regions differ due totheir cultural background. In this report, we examined
the fraction of cancers occurring in 2015 attributable toalcohol consumption in Japan.

Cancers associated with alcohol
The IARC reconfirmed the consumption of alcohol
as "group 1", carcinogenic to humans (1,2,4,5). For
this study, we selected cancer sites associated with theconsumption of alcoholic beverages that IARC reports
found sufficient evidence for a positive association,and for which relative risk estimates were available.
The cancer sites included in this study were oral cavity,
pharynx, esophagus, stomach, colorectum, liver, larynx,
and breast (women only).
Prevalence of exposure to alcohol
The latent period between 'exposure' to alcohol andthe appropriate increase in risk of these cancers has
not been well established. We assumed that this would
be 10 years on average, and therefore examined the(51)

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effects of cancer incidence and mortality in 2015 from
non-optional levels of alcohol consumption in the year2005.
We used data from the Japanese National Healthand Nutrition Survey (JNHNS) from 2005 (6). JNHNS
targets household members aged at least one year old
in all households within 300 districts (10 districts perprefecture; 15 districts for Tokyo) selected throughstratified random sampling, which totaled about 5,000
households and 15,000 participants in Novemberof 2005. The survey provides the proportions ofindividuals (by sex and age group) consuming different
quantities of alcohol per day in go. In Japan, one unitof alcohol is measured by a traditional measurement,"go", which assumes 23g of ethanol for 180mL of sake,10g ethanol for 30mL of whiskey or brandy, 6g ethanolfor 60mL of wine, or 23g of ethanol for 633mL of beer,
for ages 20 and over. Table 1 summarizes the sex- andage-group-specific proportion of alcohol drinkers (1-3times/month or more) and average consumption amountof alcohol (g of ethanol/day) in Japanese in 2005.

the Monitoring of Cancer Incidence in Japan (7). Thiswas done using an age and period spline model, atype of model which is used for short-term projectionsof cancer incidence in Japan (8). The sex- and agespecific incidence data for target cancers were codedin accordance with the International Statistical
Classification of Diseases and Related Health Problems,
10th edition (ICD-10), using morphology codes of theInternational Classification of Disease for Oncology, 3rdedition (ICD-O-3).
The data on cancer mortality statistics from 2015
were based on the vital statistics of Japan (9). We
obtained sex- and age-specific mortality data by causeof death from available data sources from the Health,Labour, and Welfare Statistics Association (10), and used
4-digit ICD-10 codes to classify the cause of death.
Estimation of relative risks
Table 2 shows the increase in risk associated with alcohol
consumption. The estimates derived from the studies
listed below have been adjusted for potential major
confounders.
Relative risks (RR) for esophagus, breast, and livercancers were derived from epidemiological studies
included in the WCRF/AICR's report (3). RR for oral,
pharynx, larynx were derived from a published Japanese
population-based cohort study (11). The RR for stomach
cancer were estimated using a pooled analysis ofJapanese studies (12,13). The RR for colorectal cancer
was derived from a pooled analysis of five Japanesecohorts (14).
The risk for oral, pharynx, and larynx cancers wascalculated in comparison to those who never drank.

Theoretical minimum risk exposure level
The optimum level of alcohol consumption wasconsidered to be none, based on previous observational
studies that looked at the association between alcohol
consumption and cancer and found that cancer riskincreases with increased consumption of alcohol.
Cancer incidence and mortality in Japan in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by

Table 1. Sex- and age-group specific proportion of alcohol drinkers and average consumption amount of alcohol (g ofethanol/day) in Japanese in 2005
Age at exposure (2005)

0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Total

Men

Women

Proportion of drinkers*(%)

Average intake (g/day)(Excess from 0 g/day)

Proportion of drinkers*(%)

Average intake (g/day)(Excess from 0 g/day)

0.0
0.0
0.0
0.0
60.3
66.2
68.1
71.9
75.8
78.7
79.8
78.7
75.7
72.3
70.2
57.9
71.7

0.0
0.0
0.0
0.0
15.9
21.1
31.5
30.4
33.7
33.9
34.2
34.2
31.3
28.6
24.0
20.2
29.5

0.0
0.0
0.0
0.0
52.4
49.0
52.1
50.8
49.1
47.5
41.9
36.4
31.6
25.4
19.4
15.0
36.9

0.0
0.0
0.0
0.0
10.1
13.0
14.8
17.3
16.0
14.5
15.1
12.8
12.2
11.0
7.8
7.8
13.4

Data source: The National Health and Nutrition Survey, Japan, 2005 *Drinker: Frequency of drinking 1-3 times/month or more.

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Table 2. Increase in risk associated with alcohol consumption
Studies

RR reference group

RR (95% CI)

Increase in risk pergram alcohol per day

Lu et al. (2018) (11)Ishiguro et al. (2009) (24)*Meta-analysis of six Japanese studies*
Ohishi et al. (2008) (13)*,
Shimazu et al. (2012) (12)Mizoue et al. (2008) (14)*Suzuki et al. (2010) (25)*Never
10g per day
10g per day
10g per day

1.50 (1.02 - 2.22)
1.34 (1.25 - 1.55)
1.03 (1.00 - 1.06)
1.14 (0.90 - 1.44)

N/A
0.02927
0.002960.00677

15g per day
10g per day

1.07 (1.06 - 1.09)b
1.05 (0.98 - 1.14)

0.01310.0131

Cancer type
Oral cavity, pharynx, larynx
Esophagus
StomachLiver
Colorectal
Breasta*

Included in the WCRF/AICR report (3). aCalculated for women only. bAdjusted for 10g per day. Abbreviations: RR = relative risk; CI =confidence interval; WCRF/AICR = World Cancer Research Fund, American Institute for Cancer Research

Table 3. Proportion (%) of cancer in 2015 attributable to alcohol consumption in Japan
Cancer Site (ICD-10)
Oral cavity and pharynx (C00 ─ C14)
Esophagus (C15)
Stomach (C16)
Colorectum (C18-C20)
Liver (C22)
Larynx (C32)
Breast (C50)
Total

Incidence

Mortality

Men

Women

Both sexes

Men

Women

Both sexes

26.8
58.7
5.6
18.1
31.9
27.0

12.9
28.3
2.1
7.2
12.7
13.5
6.4
3.5

22.5
54.0
4.5
13.4
25.2
26.0
6.4
6.2

26.6
57.4
5.4
17.3
30.8
26.1

10.5
26.7
2.0
6.6
11.8
6.5
5.8
3.0

21.9
52.3
4.2
12.4
24.3
25.1
5.8
6.5

8.3

For esophagus, breast, liver, and stomach cancers, risk
was calculated based on that for 10g of ethanol intake
per day. The risk of colorectal cancer was presented for
15g of ethanol intake per day, but was adjusted to thatfor 10g of ethanol intake per day. The increase in risk
for an increase of one gram of ethanol consumption per
day was calculated, based on a log-linear relationshipbetween exposure and risk of cancer onset. The increased
risk for one gram of increased ethanol consumption was
calculated using the following formula:

8.8

following formula (16):Cancer site-specific PAF was multiplied by the numberof incident cases or mortality of the site-specific cancer
to obtain a site-specific number of attributable cancer
incidence and mortality.
By summing these site-specific numbers of attributed
cases of cancer incidence and mortality, we obtained theattributed number of total cancer incidence and mortality.
Total cancer PAF was then obtained by dividing thenumber of attributed total cancer incidence and mortality
by the number of observed total cancer incidence andmortality.

Estimation of population attributable fractions (PAFs)
PAFs were calculated for each gender and age group.
For cancers of the oral cavity, pharynx, and larynx,
which compared the risk of ethanol consumption withnever drinkers, PAFs were calculated according to theformula (15):Results
In Japan in 2005, 72% of male and 37% of female
adults drank alcohol 1 to 3 times per month or more.
The proportion peaked at nearly 80% among men aged
45-59 and around 50% in women aged 20-44. Average
daily ethanol consumption was 29.5g in men and 13.4g
women (Table 1).
Table 3 summarized the estimated PAF ofcancer incidence and mortality in 2015 attributed toconsumption of alcohol in Japan. The estimated cancer
cases attributed to alcohol consumption were 8.3% for
men and 3.5% for women, or 6.2% of cancers overall,where P refers to the proportion of those who were
drinkers in the total population.
For the remaining cancers, for which the risk
was calculated based on the risk for 10g of ethanol
consumption per day, PAFs were calculated using the(53)

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and the estimated cancer deaths were 8.8% for men,
3.0% for women, and 6.5% overall.
Cancers of the liver (25.2%), oral cavity and pharynx,
larynx, and esophagus had the highest proportion of
alcohol-attributed cases (22.5% for cancers of the oralcavity and pharynx, 26.0% of the larynx, and 54.0%
of esophagus). Although fractions for cancers of thestomach (4.5%), colorectum (13.4%), and breast (6.4%)
were much lower, the number of cases of alcoholattributable cancers was high. Detailed results on cancer
incidence for each cancer, sex and age-group are shownin Table S1 (online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=33).
The results of cancer mortality were similar to thatof cancer incidence attributable to alcohol consumption.
Cancers of aero-digestive sites also accounted for highest
percentages of alcohol-attributed mortality (21.9% ofcancers of the oral cavity and pharynx, 25.1% of cancersof larynx, and 52.3% of cancers of the esophagus Similar
to cancer incidence attributable to alcohol consumption,
there were a gender difference in the mortality of
aero-digestive cancers. Deaths attributable to alcohol
consumption for four of the cancers for men were about
twice of those attributable for women (oral cavity andpharynx: 26.6% for men, 10.5% for women; larynx:
26.1% for men, 11.8% for women; esophagus: 57.4%
for men, 26.7% for women; and stomach: 5.4% for men,
2.0% for women). Detail results on cancer mortality
for each cancer, sex and age-group were shown in
Table S2 (online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=33).

to acetaldehyde, a possible carcinogenic metabolite ofalcohol (23). This genetic difference may have resulted
in the stronger association between alcohol consumption
and cancer we found (14).
There are several limitations to the study. The
calculation of PAF depends on the accuracy of selfreported alcohol consumption. Further, the number ofrecently published epidemiological studies on alcohol
consumption and cancer in Japan from which risk
estimates could be obtained is limited. Therefore,
it is possible that our PAF estimate may have been
underestimated.
Conclusion
Alcohol consumption was attributed to 6.2% of cancer
incidence, and 6.5% of cancer mortality, respectively.
The results of this study may provide useful evidence for
reducing the cancer burden in Japan.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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Discussion
In this study, we estimated that 59,838 (6.2%) newly
diagnosed cancer cases and 23,929 (6.5%) cancer deathsin 2015 could be attributed to consumption of alcoholfrom 2005 in Japan. PAFs were highest for the oralcavity and pharynx, larynx, and esophagus, for bothcancer incidence and mortality.
Our results are comparable to those of previous
studies. A previous Japanese estimate for 2005 showedcancer incidence and mortality attributable to alcohol
consumption of 6.3% and 6.2%, respectively (17). A
Canadian study (18) published in 2019 found 5.2%of alcohol-associated cancer cases were attributable
to alcohol consumption. A United Kingdom study(19) published in 2011 showed 4.0% of alcoholassociated cancer cases were attributable to alcohol
consumption. These numbers are lower than those of
our study. The difference in findings between Japan andWestern countries could be explained in part by genetic
differences. Mutation of the aldehyde dehydrogenase 2
gene (ALDH2) is one of the most common hereditarydisorders, affecting over 8% of the world population (20).
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---Received June 11, 2021; Revised October 29, 2021; Accepted
December 4, 2021.
Released online in J-STAGE as advance publication
December 11, 2021.
*Address correspondence to:
Manami Inoue, Division of Prevention, Center for Public
Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuoku, Tokyo 104-0045, Japan.
E-mail: mnminoue@ncc.go.jp(55)Original Article

GHM Open. 2021; 1(2):56-62.
DOI: 10.35772/ghmo.2021.01015

Burden of cancer attributable to excess bodyweight and physicalinactivity in Japan in 2015
Mayo Hirabayashi1, Sarah Krull Abe1, Norie Sawada2, Eiko Saito3, Megumi Hori3, Kota Katanoda3, Tomohiro Matsuda4,
Manami Inoue1,2,*; the Cancer PAF Japan Collaborators
1

Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
Division of Cohort Research, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
3
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;
4
National Cancer Registry Section, Center for Cancer Registries, Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Overweight and obesity are known contributors to many non-communicable diseases, including cancer, andaffect over one-tenth of the global population. One way to maintain a healthy weight and reduce the risk for cancer isthrough increased physical activity. We estimated the fraction of cancer incidence and mortality in 2015 attributable
to excess bodyweight as well as lack of physical activity among the Japanese population. The optimal body-massindex (BMI) for the purposes of this study was determined to be less than 23 kg/m2. Mean BMI for each sex and age
group was calculated using measured weight and height data extracted from the 2005 Japanese National Health andNutrition Survey (JNHNS). For the data on physical activity, we extracted the answers from the same survey froma question regarding whether the respondent did regular exercise. Population attributable fractions (PAFs) for eachcancer positively associated with excess bodyweight - esophageal adenocarcinoma, stomach (cardia), colorectum, liver,gallbladder, pancreas, female breast (pre- and post- menopausal), ovary, endometrium, advanced prostate and kidney- and for those positively associated with physical inactivity - colorectum, female breast and endometrium - were
calculated for each sex and age group and aggregated to obtain the PAF among total cancer incidence and mortality.
Excess bodyweight was attributable to 0.7% of cancer incidence and mortality, while lack of regular exercise wasattributable to 1.3% of cancer incidence and 0.8% of cancer mortality. Around 1% of cancer incidence and mortality inJapan in 2015 are attributable to excess bodyweight and physical inactivity.
Keywords: cancer, excess bodyweight, physical inactivity, population attributable fraction, Japan

Introduction

The fundamental cause of excess bodyweight isan energy imbalance between calories consumed andcalories expended. One of the ways to maintain a healthy
bodyweight is through exercise. Regular physical activity
is essential for optimal health. Exercising regularly has
significant benefits, even at a modest level, including
lower cancer incidence (3). The World Cancer Research
Fund (WCRF) and American Institute for Cancer
Research (AICR) have reported that there is a probableassociation between physical inactivity and risk ofcancers of colon, breast and endometrium (3).
Here, we estimated the fraction of cancer incidence
and mortality in 2015 attributable to excess bodyweightand physical inactivity in the Japanese population.

The World Health Organization (WHO) defines
overweight (body-mass index (BMI) greater than orequal to 25) and obesity (BMI 30 or over) as abnormal
or excessive fat accumulation that may impair health(1). Since 1975, worldwide obesity has nearly tripled.
In 2016, more than 1.9 billion adults aged 18 years orover were overweight- of these, over 650 million (13%of the global population) were obese (1). Overweight
and obesity are known to be major risk factors for noncommunicable diseases (1). In 2016, the International
Agency for Research on Cancer (IARC) reaffirmed that
overweight and obesity increase risk for cancers of thecolon, rectum, gastric cardia, liver, gallbladder, pancreas,kidney, and esophageal adenocarcinoma, with positive
dose-response relationships (2). The same report also
noted positive associations between adult obesity andpostmenopausal breast cancer and endometrial cancer (2).

Materials and Methods
Cancers associated with excess bodyweight and physicalinactivity(56)

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For the purposes of this study, we selected cancer sites
associated with overweight and obesity, and physicalactivity, for which IARC or WCRF/AICR foundsufficient evidence to indicate a positive association,
and with data available on relative risk. The cancer
sites included in this study are the esophagus(adenocarcinoma), stomach (cardia), colorectum, liver,gallbladder, pancreas, breast, endometrium, ovary,
prostate (advanced), and kidney for excess bodyweight;
and colorectum, breast, and endometrium for physicalinactivity.

69 years age group among women.
The duration of the latent period between 'exposure'
to excess bodyweight, physical inactivity and an
appropriate increase in the risk of cancers has not been
well established. We assumed that 10 years would
be sufficient time for latency between exposure andoutcome, and therefore examined the effects of cancers
occurring in 2015 due to sub-optimal bodyweight andphysical activity in the year 2005.

Prevalence of excess bodyweight and physical inactivity
estimates

The optimal BMI in Japan for the purposes of thisstudy was determined to be less than 23 kg/m2. Becausemean BMI across all sex- and age-specific categories
was below 25 kg/m2, the PAF of excess body weight
would be 0 if the definition of excess overweight were
BMI ≥ 25 kg/m2. Moreover, there has been controversy
when applying international criteria for obesity to Asian
populations; in response, the WHO expert consultation
recommended a new overweight category of BMI ≥ 23
kg/m2 and obesity of BMI ≥ 25 kg/m2 (5). Accordingly,
as a practical solution to estimating the PAF of excess
bodyweight in a Japanese population, we defined the
optimal BMI as less than 23 kg/m2. The optimal amountof physical exercise in Japan for the purposes of thisstudy was defined as regular exercise.

Theoretical minimum risk exposure level

Data on the prevalence of excess bodyweight wereobtained from the Japanese National Health and Nutrition
Survey (JNHNS) from 2005 (4). This survey reports
mean BMI by age group and sex. BMI was calculatedusing measured weight and height in kg/m2. Table 1
shows the sex- and age-group-specific prevalence ofexcess bodyweight in Japanese derived from the 2005
JNHNS. In 2005, mean BMI slightly exceeded 23 in men
aged between 30 and 70 and women aged between 55
and 74.
Similarly, we used data from the 2005 JNHNS
to determine physical activity level in the Japanese
population. The survey provides data on the proportionof people (by sex and age group) who answered"yes" to a question regarding whether they do regularexercise. Table 2 shows the sex- and age-group-specificprevalence derived from 2005 JNHNS of those who doregular exercise in Japanese. Among men, the proportion
who answered yes to whether they got regular exercise
was highest in the 70-74 years age group, but in the 65-

Cancer incidence and mortality in Japan in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by the
Monitoring of Cancer Incidence in Japan (6) by an age
and period spline model. This type of model is used forshort-term projections of cancer incidence in Japan (7).

Table 1. Sex- and age-group-specific prevalence of excess bodyweight in Japanese in 2005
Men

Women

Age at exposure(2005)

Average body-massindex (BMI) (kg/m2)

Excess from BMI 23
kg/m2

Age at exposure(2005)

Average body-massindex (BMI) (kg/m2)

Excess from BMI 23
kg/m2

0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75

16.0
16.2
18.6
21.3
22.0
22.9
23.4
23.7
24.0
24.1
23.9
23.6
23.8
23.8
23.5
22.7

0
0
0
0
0
0
1.43
0.73
1.01
1.05
0.90
0.61
0.77
0.83
0.49
0

0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75

15.8
15.9
18.6
20.9
20.4
20.6
21.1
21.5
22.2
22.6
22.9
23.1
23.3
23.6
23.2
22.9

0
0
0
0
0
0
0
0
0
0
0
0.10
0.29
0.57
0.21
0

Data source: The National Health and Nutrition Survey, Japan, 2005.

(57)

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Table 2. Sex- and age-group-specific prevalence of Japanese who do regular exercise, 2005
Men

Women

Age at exposure (2005)

Proportion of those who answered "yes"to regular exercise in the population (%)

0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75

0.0
0.0
0.0
0.0
24.5
19.9
15.4
18.0
19.2
20.7
20.4
24.9
38.8
46.4
46.7
38.0

Age at exposure (2005)
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75

Proportion of those who answered "yes"to regular exercise in the population (%)
0.0
0.0
0.0
0.0
17.6
17.3
14.2
17.3
17.0
25.4
26.9
30.6
37.2
40.2
38.7
28.4

Data source: The National Health and Nutrition Survey, Japan, 2005.

The sex- and age-specific incidence data for the target
cancers were coded in accordance with the International
Statistical Classification of Diseases and Related Health
Problems, 10th edition (ICD-10), using the morphology
codes of the International Classification of Disease forOncology, 3rd edition (ICD-O-3).
The statistical data on cancer mortality from 2015
were based on the vital statistics of Japan (8). We
obtained sex- and age-specific mortality data by causeof death from an available data source provided by the
Health, Labour, and Welfare Statistics Association (9).
Similarly to the cancer incidence data, 4-digit ICD-10
codes were used to classify the cause of death.
Due to a lack of information in these statistics,
we regarded the number of case of esophagus
adenocarcinoma as 5% of total esophageal cancer. For
prostate cancer, 30% of prostate cancer incidence and all
for prostate cancer mortality were regarded as advanced
cancer.

reports (3). For the risk of ovarian cancer, a Japanesestudy (10) published in 2012 was used as a reference.
For endometrial cancer, the summary RR of a Japanesestudy included in the WCRF/AICR (11) and a study
published in 2019 (12) was used. For pancreatic cancer,
the results of a pooled analysis of nine Japanese studies
was used (13).
Increase in risk for a 1-unit increase in BMI was
calculated based on the assumption that the relationshipbetween exposure and risk factor is log-linear.
Accordingly, the following equation was used:

For physical activity, many previous studies thatlooked at the effect of physical activity on cancer riskpresented their results in categories of activity (suchas high/medium/low, or in quantiles). In this study,
consistent with the available data, we categorized the
population into two - those who do regular exercise(three or more days/week for breast cancer; three ormore hours/day for colorectal cancer; and three or moretimes/week for endometrial cancer) and those who donot. The RR for all of cancer sites (post-menopausal
breast cancer, colorectal, and endometrial (14)) were
derived from the WCRF/AICR (3).

Estimation of relative risks
The relative risk (RR) estimates associated with excess
weight (BMI ≥ 23 kg/m 2) and physical activity are
shown in Tables 3 and 4, respectively. We prioritizedmeta-analyses or pooled analyses published forJapanese populations, followed by Asian populations,then studies from other nations. RRs from our own
meta-analyses or a single study were used if there was
not enough evidence or if no preceding meta-analysis
was available. If no Japanese data were available,
WCRF/AICR's summary RR was used.
For BMI, RRs for esophageal, gastric cardia,
kidney, gallbladder, liver, prostate, colorectal, andpost-menopausal breast cancers were derived fromepidemiological studies included in the WCRF/AICR

Estimation of population fractions (PAFs)
For excess bodyweight, PAFs were calculated for eachsex and age group according to the formula (15):(58)

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Table 3. Relative risk associated with overweight and obesity
Study

Cancer type
Esophageal adenocarcinomaa
Cardia gastric cancer**
Kidney cancer
Gallbladder cancer
Liver cancer
Pancreas
Advanced prostate cancerc
Ovarian cancerd
Endometrial cancerd
Post-menopausal breast cancer
Colorectal cancer

Summary RR from WCRF-CUP (3)Kuriyama et al. (2005) (11)*
Summary RR of three Japanese studies* (11,23,24)
Summary RR of three Japanese studies* (11,24,25)
Summary RR of four Japanese studies* (11,24,26,27)
Koyanagi et al. (2018) (13)Summary RR of two Japanese studies* (24,28)
Weiderpass et al. (2012) (10)Summary RR of Kuriyama et al. (2005) (11)* andKawachi et al. (2019) (12)Wada et al. (2014) (29)*
Summary RR of Yamamoto et al. (2010) (30)* andMatsuo et al. (2012) (31)

BMI unit for calculated
risk (kg/m2)

RR (95% CI)

5
5
5
5
5
1
5
1
5

1.48 (1.35 - 1.62)
1.41 (0.85 - 2.34)
1.35 (1.02 - 1.79)
1.30 (0.86 - 1.96)
1.36 (0.95 - 1.93)
1.00 (0.95-1.05)
1.44 (1.07 - 1.92)
1.00 (0.94 - 1.08)
1.39 (1.13 - 1.70)

55

1.28 (1.16 - 1.40)
1.24 (1.20 - 1.29)*

Included in WCRF/AICR. aConsidered as 5% of all esophageal cancer. bCalculated by excluding unknown cases. cCalculated for men only; alldeath cases are considered as advanced. dCalculated for women only. Abbreviations: BMI = body mass index; RR = relative risk; CI = confidence
interval; WCRF/AICR = World Cancer Research Fund, American Institute for Cancer Research.

Table 4. Relative risk associated with physical activity
Cancer type

Study

Reference group

Decrease in risk due to physical activity

BreastColorectal
Men
Women
Endometriala

Suzuki et al. (2011) (32)*
Lee et al. (2007) (33)*≥ 3 days/week

0.83 (0.64 - 1.45)≥ 3 hours/day≥ 3 hours/day≥ 3 times/week

0.82 (0.65 - 1.05)
1.06 (0.78 - 1.45)
0.60 (0.38 - 0.93)

Hirose et al. (1996) (34)**

Included in WCRF/AICR. aCalculated for women only. Abbreviations: RR = relative risk; CI = confidence interval; WCRF/AICR= World Cancer
Research Fund, American Institute for Cancer Research.

For physical inactivity, PAFs were calculated using
the formula (16):adenocarcinoma for both men and women (5.0%
for men, 1.2% for women). In total, overweight was
attributed to 0.7% of all cancer incidence and mortality(1.0% in men and 0.3% in women).
Physical inactivity: Physical inactivity attributed
the most to the cancer incidence of colorectal for men(6.8%) and endometrium for women (14.7%). The
trend remained the same for cancer mortality, although
the PAF was slightly increased for both sexes (7.2% ofcolorectal cancer for men, and 16.9% of endometrium
cancer for women). In total, physical inactivity was
attributed to 1.3% of all cancer incidence (1.0% formen, 1.6% for women) and 0.8% of cancer mortality(0.9% for men, 0.8% for women).
Detailed results for each cancer, sex, and agegroup are shown for excess bodyweight in Tables
S1-S2 (online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=34) and for lack of physicalactivity in Tables S3-S4 (online data, https://www.
ghmopen.com/site/supplementaldata.html?ID=34)

where P refers to the proportion of those who arephysically inactive in the total population.
By summing these site-specific attributed numbersof cancer incidence and mortality, we obtained theattributed number of total cancer incidence and mortality.
Total cancer PAF was then obtained by dividing thenumber of attributed total cancer incidence and mortality
by the number of observed total cancer incidence andmortality.
Results
The estimated PAF of cancer incidence and mortality
in 2015 attributed to excess bodyweight and lack ofphysical activity is summarized in Table 5.
Excess bodyweight: For cancer incidence, thesite with the highest PAF value was esophageal
adenocarcinoma for men (5.5%) and liver for women(1.2%). For cancer mortality, the site with thehighest PAF attributed to overweight was esophageal

Discussion
Several previous estimates of the fraction of cancer inJapan attributable to excess bodyweight and physicalinactivity have been published. In 2005, Kuriyama etal. (11) reported PAFs attributable to overweight and(59)

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Table 5. Proportion (%) of cancer in 2015 attributable to excess bodyweight (Body-mass index (BMI) ≥ 23 kg/m2) andphysical inactivity in Japan
Variables
Excess bodyweight (Body-mass index (BMI) ≥ 23 kg/m2)
Esophagus (C15)
Esophagus adenocarcinoma (C15)
Stomach (C16)
Cardia gastric cancer (C16.0)
Colorectum (C18-C20)
Liver (C22)
Gallbladder (C23)
Pancreas (C25)
Breast (C50)
Endometrium (C54)
Ovary (C56)
Advanced prostate (C61)
Kidney (C64)
Total
Physical inactivity
Colorectum (C18-C20)
Breast (C50)
Endometrium (C54)
Total

Incidence

Mortality

Men

Women

Both sexes

Men

Women

Both sexes

0.4
5.5
0.4
4.6
2.8
4.0
3.1
0.0

0.1
1.2
0.1
1.2
0.7
1.2
0.9
0.0
0.4
0.6
0.0

0.3

0.2
5.0
1.1
3.8
2.5
3.6
2.7
0.0

0.1
1.2
0.2
0.9
0.6
1.1
0.8
0.0
0.6
1.0
0.0

0.2

1.4
3.1
1.0
6.8
1.0

obesity of -0.2% for men and 4.5% for women. In
2012, Inoue et al. (17) attributed overweight (BMI ≥ 25
kg/m2) to 0.8% of cancer incidence and 0.5% of cancer
mortality among men, and 1.6% and 1.1% among
women. The same study found that physical inactivity,
defined as the lack of three metabolic equivalents(METs) per day, attributed 0.6% of cancer incidence
and 0.4% of cancer mortality in men, and 0.4% and0.3% in women. These numbers slightly differ to ourfindings, namely that PAFs were lower in men than
women, due to the different definition of physicalinactivity and data source between these estimates.
In an international setting, a recent report from
Canada (18) calculated that country's current burden ofcancer attributable to excess bodyweight (BMI ≥ 25 kg/m2) to be 3.1%. Brown et al. estimated that overweight
and obesity were attributable to 6.3% of all cancers in
the United Kingdom (UK) (19). The greater number of
attributable cases in Europe and Northern America may
be explained by the larger proportion of overweight
and obesity in these populations. In the UK, 36% and
28% of the population are considered to be overweight
and obese, respectively, in 2019 (20); while in Canada,
over 61% were overweight or obese in 2015 (21).
On the other hand, the prevalence of obesity among
Japanese adults in 2018 is 3.8% (4.1% in men and3.6% in women) (22), suggesting a possible gap in theobesity burden between Japan and Western countries.
According to 2018 National Health and Nutrition Survey(22), the prevalence of overweight and obesity among
the Japanese population has not changed statisticallyin the past decade. As long as Japan can maintain thecurrent trend, the cancer burden attributable to excess

0.3

1.0
0.3

1.9
3.0
1.8
0.0
0.4
0.6
0.0
1.4
2.5
0.7

0.0
5.0
14.7
1.6

3.9
5.0
14.7
1.3

3.0
2.5
1.0
7.2
0.9

0.8

0.9
0.3

1.6
2.8
1.6
0.0
0.6
1.0
0.0
3.0
1.9
0.7

0.0
5.6
16.9
0.8

3.9
5.6
16.9
0.8

bodyweight will continue to be marginal. Althoughphysical inactivity was associated with an increaseof certain types of cancer, the overall contribution
was small, perhaps due to insufficient exposure level.
Furthermore, lifestyle factors such as physical inactivity
are associated with other factors such as poor diet andhigh bodyweight. Given that most cancers are have amultifactorial etiology, a multivariate estimation of the
PAF would provide a better estimation of the burden.
There are several limitations to this study. Our
cut-off for excess bodyweight was defined as a BMI
of 23 and over, due to practicality of estimation forJapanese. This cut-off differs to the WHO overweightstandard (BMI of 25 and over), which is often usedin studies from other nations. The PAF of physicalinactivity was calculated using a binominal category
only, and the definition of regular exercise differed foreach cancer site. This prevented us from being able todirectly compare our results to previous studies. As
evidence was insufficient, some of the RRs used forthis study were not derived from a Japanese population.
Additionally, many RRs used to calculate PAF were
derived from a single cohort study. This may have led
to over- or underestimation of the risk. When more data
is available, it will be necessary to update the evidence
by re-calculating these PAFs using RRs from metaanalyses or pooled analyses.
Despite the limitations listed above, these estimateshave major implications for Japan's national healthpolicy for cancer prevention and control strategies.
Although the current Japanese obesity rate is low,
policymakers and public health agencies must be
prepared to intervene if necessary.

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Conclusion

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Cox A, Deas A, Elliss-Brookes L, Gavin A, Hounsome L,
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S, Tsugane S. Risk factors of biliary tract cancer in a

Our analysis provides evidence for the current burden ofcancer attributable to excess bodyweight and physicalinactivity. Excess bodyweight and physical inactivity
contributed to 0.7% and 1.3% of cancer incidence, and
0.7% and 0.8% of cancer mortality, respectively. The
results of this study may provide useful evidence forappropriately reducing the cancer burden in Japan.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received June 12, 2021; Revised November 11, 2021;
Accepted December 4, 2021.
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*Address correspondence to:
Manami Inoue, Division of Prevention, Center for Public
Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuoku, Tokyo 104-0045, Japan
E-mail: mnminoue@ncc.go.jp(62)Original Article

GHM Open. 2021; 1(2):63-69.
DOI: 10.35772/ghmo.2021.01016

Burden of cancer attributable to infection in Japan in 2015
Yingsong Lin1,*, Chaochen Wang1, Shogo Kikuchi1, Tomoyuki Akita2, Junko Tanaka2, Sarah Krull Abe3, Mayo Hirabayashi3,
Eiko Saito4, Megumi Hori4, Kota Katanoda4, Tomohiro Matsuda5, Manami Inoue3; the Cancer PAF Japan Collaborators
1

Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan;
Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima
University, Hiroshima, Japan;
3
Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
4
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Population attributable fraction (PAF) offers a means to quantify cancer burden that is attributable to a
specific etiological factor. To better characterize the current cancer burden due to infection in the Japanese population,
we estimated the PAF for cancer incidence and mortality in 2015 that could be attributable to infectious agents,
including Helicobacter pylori (H. pylori), Hepatitis B and C (HBV/HCV), Human papillomavirus virus (HPV), EpsteinBarr virus, and human T-lymphotropic virus type 1. We estimated the PAFs for each infectious agent on the basis ofrepresentative data on prevalence and risk-outcome associations assuming a latency period of 10 years. Overall, 16.6%
of cancer cases in 2015 in Japan were attributable to the infectious agents included in this analysis. The estimated
PAF was slightly higher in men (18.1%) than in women (14.7%). The highest proportion of cancer deaths attributable
to infectious agents was observed for H. pylori infection, followed by HBV/HCV, and HPV infection. Our findings
corroborated with previous estimates that H. pylori and HBV/HCV infections were the two most important infectious
agents in the Japanese population. Strategies focusing on eradication of infectious agents among infected individuals or
primary prevention through vaccination could decrease the burden of infection-related cancers.
Keywords: cancer, infection, population attributable fraction, Japan

Introduction

Population attributable fraction (PAF), which is
calculated based on prevalence estimates and relativerisk (RR) for exposure-outcome associations, provides aquantitative appraisal of the impact of etiological factors
on cancer incidence and mortality (3). In the case of
infectious agents, PAF indicates the proportion of cancer
cases or deaths that would not have occurred if noone in the population had been infected. An estimated
13% of global cancer incidence was attributable toinfectious agents in 2018, with PAFs varying according
to geographic region and development status (4). In a2005 PAF estimation in Japan, tobacco smoking had thehighest PAF (30% for incidence and 35% for mortality)
in men, followed by infectious agents (23% forincidence and 23% for mortality) (5), whereas infectious
agents had the highest PAF (18% for incidence and 19%
for mortality) in women.
The validity of PAF estimates depends on prevalence
estimates and relative risk for exposure-outcome
associations, which may change over time. In particular,
the prevalence of H. pylori infection in asymptomatic
individuals in Japan has markedly changed over a short

Cancer became the leading cause of death in Japan
in 1981. The number of total cancer deaths increased
continuously thereafter, in parallel with aging of the
population, to reach 370,346 deaths in 2016. Lung,
colorectal, stomach, pancreas, and liver cancers haveconstituted the five leading causes of cancer death inrecent years (1). This mortality pattern reflects thehigh burden of cancers of the digestive system in theJapanese population.
Infectious agents are known to play a role in cancer
etiology. The International Agency for Research on
Cancer (IARC) has classified at least six viruses as Group1, ie. carcinogenic in humans, namely Epstein-Barr virus(EBV), Kaposi sarcoma-associated herpesvirus/humanherpesvirus 8 (KSHV/HHV8), Human papillomavirus(HPV), Hepatitis B virus (HBV), Hepatitis C virus(HCV), human T-lymphotropic virus type 1 (HTLV-1)
and Helicobacter pylori (H. pylori). Persistent infection
with these pathogens is causally linked to several typesof cancer, including liver, stomach, cervical cancers (2).

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period of time (6). To better characterize the current
cancer burden due to infection, we estimated the PAF
of cancer incidence and mortality in 2015 that was
attributable to selected infectious agents in the Japanese
population.

in Japan (6). Based on these results, we obtained thecorresponding prevalence data by sex and 5-year age
group for the year 2005. To capture representative dataon the prevalence of HBV and HCV in the general
population, we referred to the pooled prevalencesof HBsAg and anti-HCV by sex and birth year thatwere estimated by combining three large cohorts
in Japan: first-time blood donors, participants inscreening programs initiated by local governments, andindividuals who underwent a comprehensive medical
checkup (Ningen dock) (10). Estimated prevalence bybirth year was converted to prevalence of HBV or HCV
by 5-year age group in 2005. Because prevalence data
were not available for individuals born before 1930 orafter 1986, we assumed that these individuals had thesame estimated prevalence as the next or preceding birthcohort (1931-1935 and 1981-1985), respectively. As
with previous studies, the prevalence of HPV infection
was assumed to be 100%, based on the fact that HPV
DNA virus can be detected in all cervical cancer cases(4,11). For EBV and HTLV, we quoted the prevalence
data from previously published literature (4), becausevery few data were available for Japanese subjects.

Material and Methods
Cancers associated with infection
The target cancers and infectious agents were selectedbased on the assessment of the carcinogenicity of
biological agents by the IARC Monograph Working
Group (2). Cancers included in the present study were
gastric, gastric non-Hodgkin lymphoma (NHL), liver,cervix uteri, penis, vulva, anus, oral cavity, oropharynx,
nasopharynx, Birkitt lymphoma, and adult T-cell
lymphoma (ATL). These were selected because they each
had sufficient evidence of a supporting role of infectious
agents in their causation. Parasitic agent (Clonorchis
sinensis, Opisthorchis viverrini, and Schistosoma
haematobium)- and human immunodeficiency (HIV)related cancers were excluded because exposure to thesepathogens in the Japanese population is rare.

Estimation of relative risk

Cancer incidence and mortality in Japan in 2015

The majority of previous PAF studies used an RR of
5.9 for the association between H. pylori and noncardia gastric cancer, as determined by a previous
meta-analysis involving 12 case-control studies on this
topic (12). However, this risk estimate might be anunderestimation given that several studies using moresensitive measurement methods, such as western blot,
demonstrated much stronger associations, with odds
ratios (ORs) ranging from 10.6 to 21.4 (13). Furthermore,in a 2015 meta-analysis of the H. pylori-stomach cancer
association in Japanese subjects, the RR for individuals
who had both H. pylori infection and gastric atrophy was
15-fold greater than that of those with neither H. pylori
infection nor gastric atrophy (14). Therefore, we used
an RR of 15 for the calculation of PAF for both men andwomen. For gastric cardia cancer, we adopted an RR of
2.0, obtained from a meta-analysis of studies conductedin Asian countries, including Japan (15).
Concerning the RR of liver cancer associated with
HBV or HCV infection, no data from meta-analyses ofstudies involving Japanese are yet available. We therefore
adopted results from the Japan Public Health Centerbased Prospective Study, a nationally representative
cohort study. RR was 35.8 (95% CI: 20.4-62.7) for HCVinfected subjects and 16.1 (95% CI: 7.6-33.9) for HBVinfected subjects. These estimates were comparable tothose reported in a 2015 meta-analysis which showed an
OR of 45.3 (95% CI: 25.4-80.6) for HCV infection and38.9 (95% CI: 19.8-38.4) for HBV infection (16).
With respect to RR estimates for EBV and HTLV1, we adopted the corresponding data from a synthesis

Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by
the Monitoring of Cancer Incidence in Japan (MCIJ)(7), as determined by an age and period spline model.
These models are used for short-term projection ofcancer incidence in Japan (8). The sex- and agespecific incidence data for target cancers were codedin accordance with the International Statistical
Classification of Diseases and Related Health Problems,
10th edition (ICD-10), using the morphology code of theInternational Classification of Disease for Oncology, 3rdedition (ICD-O-3).
The data on cancer mortality from 2015 were basedon the vital statistics of Japan (1). We obtained sex- andage-specific mortality data by cause of death from anavailable data source provided by the Health, Labour,and Welfare Statistics Association (9). As with thecancer incidence data, 4-digit ICD-10 codes were used
to classify cause of death.
Prevalence of exposures
Assuming a latency period of 10 years between
infection and cancer occurrence, we extracted the bestavailable data on the prevalence of infectious agentsin the Japanese population in 2005. Because of a clear
cohort effect observed for the prevalence of H. pylori
infection, we previously estimated prevalence bybirth year from 1908 to 2003 in a systematic review
and meta-regression analysis of studies conducted(64)

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analysis of the global burden of cancer attributable toinfections in 2012 (4).

for cervical cancer and 88% for anal cancer), followedby H. pylori (90% for stomach non-cardia cancer) andEBV (80% for nasopharynx cancer) (Table 2) (Table
S1 and S3, online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=35). Similar PAF estimates
were obtained for cancer mortality (Tables 2), (TableS2 and S4, online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=35).
For site-specific cancers, the number of cancer
incidence attributable to infection was highest for
stomach cancer, followed by liver cancer. Among
infectious agents, H. pylori contributed the largest
proportion of attributable cancer incidence, accounting
for approximately 12.0% (14.3% in men and 8.9%
in women) of all incident cases in Japan in 2015
(Table S1, online data, https://www.ghmopen.com/
site/supplementaldata.html?ID=35). HBV and HCV
contributed 2.8% (3.1% in men and 2.4% in women)of attributable cancer incident cases (Table S3, online
data, https://www.ghmopen.com/site/supplementaldata.
html?ID=35). HPV contributed 1.5% of cancer cases in

Estimation of PAF
For H. pylori, HBV, and HCV, PAF was calculatedusing Levin's formula (4):where RR is relative risk and P indicates the prevalenceof infectious agents in the general population.
Regarding the contribution of HTLV-1 to adult
T-cell lymphoma and the contribution of HPV tocervical cancer, infection is thought to be necessary
for carcinogenesis, and thus the PAF was assumed
to be 100%; all of these cancers could be attributed
to persistent infections among exposed subjects (4).
For other HPV-related cancer sites and EBV-related
cancers, PAF was calculated using the prevalence ofeach infectious agent in cases only and RRs associatedwith the infection (4):Table 1. Estimated prevalence for major infectious agentsby sex and 5-year age group in the Japanese population in2005
Age at exposure (2005)
Men
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Women
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75

where Pc is prevalence among cases.
The number of cancer incidence or mortality in2015 attributable to a single infectious agent wascalculated by multiplying total cancer incidence ormortality in that year by PAF.
Results
Table 1 lists the prevalence of H. pylori and HBV/HCV
infections by sex and 5-year age group in the general
population in 2005. Notably, prevalence increased withage for both infections.
Table 2 shows the PAFs of cancer incidence andmortality attributable to infectious agents. HIV was
not included in the present study because of a lackof relevant data. Overall, we estimated that 16.6% ofcancer incidence and 17.7% of cancer mortality in2015 in Japan were attributable to infectious agents.
The PAF estimates were slightly higher in men than inwomen for both cancer incidence (18.1% vs. 14.7%)
and mortality (18.5% vs. 16.5%). Among infectioninduced cancers, the PAF estimates for cancer incidence
ranged from 4.3-100% in men, with the highest PAF
noted for HTLV-1 (100% for ATL), followed by H.
pylori (89% for stomach non-cardia cancer), HPV(88% for anal cancer), and EBV (80% for nasopharynx
cancer). In women, the PAF estimates ranged from 4.3100%, with the highest PAFs observed for HPV (100%H. pylori

HBV

HCV

5.7
8.0
13.0
17.4
22.0
26.4
31.4
37.6
44.7
51.7
56.6
59.9
62.5
65.0
66.8
67.5

0.3
0.3
0.3
0.3
0.3
0.5
0.7
0.9
1.1
1.3
1.4
1.5
1.5
1.2
1.0
1.0

0.1
0.1
0.1
0.1
0.1
0.2
0.3
0.5
1.0
1.2
1.2
1.5
1.9
2.7
4.9
4.9

5.7
8.0
13.0
17.4
22.0
26.4
31.4
37.6
44.7
51.7
56.6
59.9
62.5
65.0
66.8
67.5

0.2
0.2
0.2
0.2
0.2
0.4
0.6
0.6
0.7
0.9
1.1
1.3
1.3
1.1
1.2
1.2

0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.5
0.8
1.0
1.2
1.5
2.0
2.9
4.5
4.5

Abbreviations: H. pylori = helicobacter pylori; HBV = hepatitis B
virus; HCV = hepatitis C virus.

(65)

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Table 2. PAF of cancer incidence and mortality attributable to infectious agents in Japan in 2015
Agent
Men
H. pylori
HBV/HCVHPV

EBVHTLV-1
Total% of cancers
Women
H. pylori
HBV/HCVHPV

EBVHTLV-1
Total% of all cancers
Both sexes
Total% of all cancers

Cancer site

ICD-10Prevalence in cases
(PAF)

Obs.
cases

Attrib.
cases

Obs.
deathsAttrib.
deaths

Stomach cancer
Gastric NHL
Liver cancer
Penis
Anus
Oral cavity
Oropharynx
Nasopharynx
Birkitt Lymphoma
Hodgkin Lymphoma
ATL

C16
5% of C82-C85, C96
C22
C60
C21
C02-C06
C01, C09-C10
C11
C837
C81
C915

74
51
88
4.3
46
80
30
56
100

91,883760
28,222
412
521
6,409
2,688
581
170
805
912
549,241

78,078561
16,823
210
458
276
1,236
465
51
444
879
99,48118.1

30,809328
19,008
141
209
1,844
824
224
36
102
446
219,508

27,009243
11,922
72
183
79
379
179
11
57
446
40,58018.5

Stomach cancer
Gastric NHL
Liver cancer
Cervix uteri
Vulva
VaginaAnus
Oral cavity
Oropharynx
Nasopharynx
Birkitt Lymphoma
Hodgkin Lymphoma
ATL

C16
5% of C82-C85, C96
C22
C53
C51
C52
C21
C02-C06
C01, C09-C10
C11
C837
C81
C915

74
100
48
78
88
4.3
46
80
30
56
100

42,203629
15,087
11,253
867
363
472
4,544
514
277
138
446
663
408,572

35,822
464
9,663
11,253
416
279
415
195
236
222
41
249
638
59,893
14.7

15,870
257
9,881
2813
262
151
202
1,467
169
75
19
58
506
150,838

14,050
190
6,714
2,813
126
118
178
63
78
60
6
32
506
24,93516.5

957,813

159,37416.6

370,346

65,515
17.7

women, while other infectious agents, such as EBV andHTLV, contributed less than 1% of attributable cancer
incident cases.

studies targeting Japanese populations (6,10). Another
difference is that the RR used to calculate PAF was
higher in the present study than in our previous study(15.0 vs. 5.9). Methodological differences aside, ourslightly lower PAF estimates suggest a relatively
decrease in the contribution of infectious agents tocancer, albeit that confirmation of this finding awaits
further study.
We estimated that approximately 90% of non-cardia
gastric cancers were attributed to H. pylori infectionin the Japanese population. This result is similar to
the updated IARC PAF estimate. Recognizing thepossible underestimation of PAF in their previous
study, in which prevalence data were obtained fromserologic antibody tests, the IARC group presented an
updated PAF of 89.0% for gastric cancer associatedwith H. pylori infection based on prevalence datafrom immunoblot (western blot) assay, which provides
greater sensitivity in detecting anti-H. pylori antibodies
than ELISA (13). Collectively, these findings reinforce
the dominant role of H. pylori in the etiology of noncardia gastric cancer. Less consistent, however, isthe role of H. pylori in proximal and gastrointestinal
junction gastric adenocarcinomas, which share acommon pathogenesis with distal cancers but are distinct

Discussion
Based on the best available data, we estimated that
16.6% of cancer incident cases were attributable tosix infectious agents in Japan in 2015. Unlike otherdeveloped countries, in which infection contributes toonly a small proportion of cancer etiology (3,4,17),
infectious agents, particularly H. pylori and HBV/HCV,
are still responsible for a high proportion of cancer
burden among some Eastern Asian countries, including
Japan (18).
The overall PAF estimate in the present study
was slightly lower than that reported for 2005 in an
earlier study (5). One possible reason is the differencein prevalence data used to estimate PAF. The earlier
study used the prevalence of H. pylori and HBV/HCV infections in cases. However, given the dynamicchanges in H. pylori and HBV/HCV infections acrossvarious age groups, we used prevalence data by 5-year
age group in the general population extracted from ourprevious systematic review and meta-regression of(66)

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from them (19). While H. pylori has been shown to bepositively associated with both distal gastric cancer andproximal and gastroesophageal junction cancers in East
Asian countries, including China and Japan (20,21),
no significant associations have been observed inWestern populations (22). Here, to our knowledge forthe first time, we estimated that 38% of gastric cardia
cancers were attributable to H. pylori infection in theJapanese population. However, cautious interpretation
is warranted because of the inconsistent definitionof gastric cardia cancer across studies, and quality of
population-based cancer registry data.
Chronic infection with HBV or HCV is a major risk
factor for liver cancer worldwide. Overall, our study
showed that 59.6% of incident cases and 62.7% ofdeaths were attributed to either HBV or HCV infection
in 2015. This estimate is comparable to the worldwide
estimate of 60%, but is much higher than that in otherdeveloped countries (23). Interestingly, the prevalenceof HBV and HCV infections and their contributions toliver cancer etiology exhibit remarkable geographicalvariation (23). HBV infection is the dominant causeof liver cancer in the majority of Asian countries,
including China and Korea (22), whereas only 16%
of liver cancer cases and deaths were attributable to
HBV infection in Japan, as shown in our study. On theother hand, our data showed that HCV is a predominantcause of liver cancer in Japan, with approximately
46% of cases attributable to it. One striking feature isthat the prevalence of anti-HCV peaked in individuals
born between 1931 and 1935, who also showed highmortality rates of live cancer (10). Unsafe healthcarerelated injections and blood transfusion were thought
to have contributed to the wide transmission of HCVin this birth cohort (10). With the improvement inmedical care since the 1950s, the prevalence of HCV
has continuously decreased in successive younger
generations, and was estimated to be 0.13% in the
1981-1985 birth cohort (10).
HPV is one of the most important infectious agentsfor a wide range of cancers, accounting for 4.6% of
new cancer cases in 2012 (4). According to National
Cancer Registry data, 11,283 women were newly
diagnosed with cervical cancer in 2016. HPV infection
would have contributed to all these incident cases if
we assume a PAF of 100%. Notably, cervical cancer isthe second leading cause of cancer-related deaths for
women between the ages of 20 and 39 (24), suggestingthat early detection is important in reducing the burden
for this age group. In addition to cervical cancer, highrisk HPV also contributes to a varying fraction of headand neck, anal, penile, vulvar and vaginal cancers in
men and women, with the PAF estimates ranging from
4.3% to 100%.
One strength of our study is that we used the best
available, nationwide representative data to estimate
PAFs due to infectious agents for Japanese subjects.

In particular, by using population data by sex and5-year age group, we were able to capture the dynamicchanges occurring in the prevalence of H. pylori andhepatitis infection, two key etiologic factors responsible
for a high proportion of cancer incidence and mortality
in the Japanese population. We also highlight several
methodological weaknesses that should be addressed toallow better interpretation and application of our PAF
estimates. First, uncertainties remain concerning PAF
estimates for EBV and HPV, because prevalence or risk
factor data mostly came from studies involving Western
populations. Second, given the varied latent periods
between exposure and outcome used to estimate PAFs
in the previous studies, we assumed it to be 10 years
in the present study. In the case of H. pylori-induced
gastric cancer, a cascade of carcinogenic processes
for intestinal-type gastric cancer has been established;
the process - starting from H. pylori-induced gastritis,
then moving to gastric atrophy, intestinal metaplasia,
dysplasia, and finally to malignant tumor - may takemore than 10 years (25). Although the latency of 10
years adopted in our study may be too short, analysis
using a latency of 15 years yielded similar results (datanot shown). Third, assuming independent causes ofmortality, we did not take possible interactions between
infectious agents into account. However, the proportionof co-infections with HBV and HCV was 0.1% in aprevious population-based cohort study (16), and the
PAF estimate was 1.8% for co-infections with HBV and
HCV in our earlier study (5). These findings suggestthat the exclusion of coinfection with HBV and HCVin the present study might not have introduced serious
bias.
From a practical point of view, PAF estimates aremost useful in informing public health interventions
when the exposure-disease association is recognized as
causal and the exposure can be avoided through primaryprevention. This notion fits well with pathogen-related
cancers. Elimination of pathogens or vaccination could
theoretically result in a marked decrease in disease
outcomes. For example, the HBV vaccination program
introduced in 1986 contributed to a decrease in ageadjusted mortality rates of liver cancer in childhoodin Japan (26). For H. pylori infection, a populationwide "test-and-treat" strategy may be cost-effective
and worthy of implementation in a country like Japan,
which has both a high incidence of gastric cancer andhigh prevalence of H. pylori (27). The success of this
implementation might also expedite a reduction in
gastric cancer incidence/mortality, eventually making
it a rare cancer. Despite the demonstrated safety andeffectiveness of HPV vaccine, vaccination uptake
plummeted in Japan shortly after it was introduced
in 2013 due to anecdotal reports of adverse effects,
such as complex regional pain and postural orthostatic
tachycardia syndrome (POTS), in a small proportionof girls who had been vaccinated (28). Concerns have(67)

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been raised about a possible increase in the incidenceof HPV-related diseases, including cervical cancer,
if the current suspension of the vaccination program
continues.

7.

8.

Conclusion
An estimated 16.6% of cancer incidence and 17.7%
of cancer mortality were attributable to infection in
Japan in 2015. Our findings corroborate the previous
estimate that H. pylori and HBV/HCV still remain thetwo most important infectious agents in the Japanese
population. Strategies focusing on the eradicationof infectious agents among infected individuals or
primary prevention through vaccination could decrease
the burden of infection-related cancers. As dynamicchanges in exposure prevalence occur over time,
continued efforts to estimate the PAF due to infection isimportant for public health regulation.

9.

10.

11.

Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.

12.

Conflict of Interest: The authors have no conflicts ofinterest to disclose.

13.

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---Received June 12, 2021; Revised November 9, 2021; Accepted
December 4, 2021.
Released online in J-STAGE as advance publication December
11, 2021..
*Address correspondence to:Yingsong Lin, Department of Public Health, Aichi Medical
University School of Medicine, 1-1 Yazakokarimata, Nagakute,
Aichi 480-1195, Japan.
E-mail: linys@aichi-med-u.ac.jp(69)Original Article

GHM Open. 2021; 1(2):70-75.
DOI: 10.35772/ghmo.2021.01018

Burden of cancer attributable to insufficient vegetable, fruit anddietary fiber consumption in Japan in 2015
Junko Ishihara1,*, Ribeka Takachi2, Sarah Krull Abe3, Mayo Hirabayashi3, Eiko Saito4, Megumi Hori4, Kota Katanoda4,
Tomohiro Matsuda5, Manami Inoue3; the Cancer PAF Japan Collaborators
1

School of Life and Environmental Science, Department of Food and Life Science, Azabu University, Kanagawa, Japan;
Department of Food Science and Nutrition, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan;
3
Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
4
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Consumption of vegetables, fruit and dietary fiber is closely associated with cancer incidence and mortality
in the population, especially under conditions of insufficient consumption. We estimated the fraction of cancer
incidence and mortality in 2015 attributable to insufficient consumption of vegetables, fruit and dietary fiber in theJapanese population. Consumption of vegetables, fruit and dietary fiber in grams per day, by sex and age group, isavailable for 2005 from the Japanese National Health and Nutrition Survey. Optimal consumption of vegetables andfruits for this study was assumed to be over 350g and 100g/day, respectively. Optimal consumption of dietary fiber was
defined by age group according to the Dietary Reference consumption for Japanese. Population attributable fractions(PAFs) were estimated for each sex and age group according to a standard formula, and aggregated to obtain the PAF
among total cancer incidence and mortality. Insufficient consumption of vegetables, fruit, and dietary fiber contributed
0.2%, 0.1% and 1.0% of all cancer incidence, and 0.2%, 0.1% and 0.9% of cancer mortality, respectively. The resultsof this study may provide useful evidence in reducing the cancer burden attributable to insufficient consumption ofvegetables, fruit and dietary fiber in Japan.
Keywords: cancer, vegetable and fruit, dietary fiber, population attributable fraction, Japan

Introduction

cause cancer associated with insufficient vegetable andfruit consumption has previously been estimated forseveral countries, including Australia (2), Brazil (3),Germany (4), and the United Kingdom (5). The results
indicated that while the risk attributed to insufficientconsumption varied among countries, it was not low inany. Additionally, PAF for all cancer associated withinadequate dietary fiber consumption was estimatedfor Australia (2) and Germany (4). Because dietaryconsumption is a modifiable factor, identifying the
proportion of cancers attributed to this factor could
have important implications for cancer prevention
strategies.
We previously reported that the fractions of cancer
attributable to insufficient consumption of vegetables
and fruit in 2005 in Japan were 0.4% and 0.8%,
respectively (6). PAFs were the same for incidence
and mortality. In the present report, we updated this tothe fraction of cancer incidence and mortality in Japanfor 2015, and also estimated the fraction attributed todietary fiber consumption.

In 2018, the World Cancer Research Fund andAmerican Institute for Cancer Research confirmedthat consumption of non-starchy vegetables and fruit
together was a probable protective factor for colorectal
cancer (1). Individually, consumption of non-starchy
vegetables was classified as a "limited-suggestive"
protective factor for cancer of the oral cavity, pharynx,
larynx, nasopharynx, esophagus, lung, and breast.
Consumption of fruits was classified as a limitedsuggestive protective factor for cancer of the esophagus
and lung. Consumption of citrus fruits was classified
as a limited-suggestive protective factor for cancer ofthe stomach (1). Foods containing dietary fiber wereclassified as a convincing protective factor of colorectal
cancer. Consumption of these plant-source foods
together might substantially influence cancer incidence
and mortality in the population; specifically, when
consumption level is insufficient.
The population attributable fraction (PAF) for all-(70)

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Materials and Methods

Japanese population in 2005, as derived from theJNHNS, are shown in Table 1. The optimal consumption
levels and the deficit from each for the estimation of PAF
are given by sex and 5-year age group.

Cancers associated with insufficient vegetables, fruit anddietary fiber
The WCRF/AICR classified consumption of non-starchy
vegetables and fruits together as a probable protective
factor for colorectal cancer (1). Individually, consumptionof non-starchy vegetables was classified as a limitedsuggestive protective factor for cancer of the oral cavity,
pharynx, larynx, nasopharynx, esophagus, lung, andbreast. Consumption of fruits was classified as a limitedsuggestive protective factor for cancer of esophagus
and lung. Consumption of citrus fruits was classified asa limited-suggestive protective factor for cancer of thestomach. In addition, non-starchy vegetables and fruitin the aggregate were classified as a probable protective
factor for aerodigestive cancer and some other cancers.
Foods containing dietary fiber were classified asprobable protective factors of colorectal cancer (1).
Therefore, we applied the target cancers associatedwith vegetables, fruit and dietary fiber identified bythis evaluation, namely those which showed sufficientevidence for a positive association with vegetables, fruitand dietary fiber, and for which relative risk estimatesin Japan were available, namely stomach, lung andcolorectal cancer.

Cancer incidence and mortality in Japan in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by the
Monitoring of Cancer Incidence in Japan (10). We usedan age and period spline model. This type of model isused for short-term projections of cancer incidence inJapan (11). The sex- and age-specific incidence data
for target cancers were coded in accordance with theInternational Statistical Classification of Diseases andRelated Health Problems, 10th edition (ICD-10), using
the morphology code of the International Classificationof Disease for Oncology, 3rd edition (ICD-O-3).
The data on cancer mortality statistics from 2015
were based on the vital statistics of Japan (12). We
obtained sex- and age-specific mortality data by causeof death from available data sources from the Health,Labour, and Welfare Statistics Association (13), and used
4-digit ICD-10 codes to classify the cause of death.
Estimation of relative risks
Risk estimates for the association between site-specificcancer and consumption of vegetable, fruit and dietaryfiber are summarized in Table 2. We used relative riskof the highest consumption (quartile or quintile) forthe point estimate of risk, with the lowest respective
category (first quartile or quintile) as reference. Relativerisk for the association between stomach cancer andvegetable consumption was sourced from a pooled
analysis of four Japanese cohorts (14). Because adecrease in risk with higher consumption of vegetables
was observed only for the distal subsite of stomach
cancer, we limited this research to distal stomach
cancer only, which nevertheless accounted for 95%
of total stomach cancer cases. Relative risk for the
association between fruit consumption and lung cancer
was sourced from a pooled analysis of four Japanesecohorts (15). Relative risk for the association between
highest consumption of dietary fiber and colon cancer
was sourced from a published analysis by Wakai et al.
(16) using the method by Levin et al. (17). The risk fora deficit of one gram in decreased consumption was
calculated using the following formula:

Theoretical minimum risk exposure level
The optimal consumption of vegetables and fruits inJapan for this purpose was defined as over 350 and 100
g/day, respectively. These values were based on goals
established for the National Health Promotion Movementin the 21st Century (7). The optimal consumption of
dietary fiber was defined by age group according to theDietary Reference Consumption for Japanese (8).
Prevalence of vegetables, fruit and dietary fiber
consumption
The latent period - the interval between "exposure" toinsufficient consumption and the increase in risk ofcancer - is unknown. For the purpose of this study, thelatent period between being "exposed" to insufficientconsumption and the consequent increase in cancer was
assumed to be 10 years. The 2015 fraction of avoidable
cancers calculated for this study is therefore based on an
estimate of insufficient consumption in 2005.
The data on vegetable, fruit and dietary fiber
consumption by sex and age group were derived from theJapanese National Health and Nutrition Survey (JNHNS)
from 2005 (9), taking the 3-year mean of individual year
data for 2004-2006 obtained from the Ministry of Health,Labour, and Welfare, Japan with permission.
Sex and age group-specific consumption ofvegetables, fruit and dietary fiber in g/day by thewhere gram of deficit is 3-year mean of individual databy age group derived from the JNHNS.
Estimation of population attributable fractions (PAFs)(71)

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Table 1. Sex and age group-specific consumption of vegetables, fruit and dietary fiber in g/day in Japan in 2005
Vegetables

Fruit

Dietary fiber

Mean
Age at exposure
Optimal Deficit from
Mean
Mean
Optimal Deficit from
Optimal Deficit fromconsumption consumption optimal(2005)
consumption consumption optimal
consumption consumption optimal(g/day)(g/day)consumption(g/day)(g/day)(g/day)consumption(g/day)consumption(g/day)(g/day)(g/day)Men
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Women
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75

137
196
258
253
240
268
276
255
260
284
296
316
337
336
329
307

350
350
350
350
350
350
350
350
350
350
350
350
350
350
350
350

213
154
92
97
110
82
74
95
90
66
54
34
13
14
21
43

109
108
108
110
72
68
53
52
67
79
80
117
144
156
163
150

100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100

0
0
0
0
28
32
47
48
33
21
20
0
0
0
0
0

8.4
11.9
14.9
14.0
12.5
13.5
13.6
13.1
13.5
14.4
14.8
16.4
17.6
17.7
17.6
16.3

11.5
15.0
19.5
20.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
20.0
19.0
19.0

0.0
0.0
0.1
5.5
7.5
6.5
6.4
6.9
6.5
5.6
5.2
3.6
2.4
2.3
1.4
2.7

137
195
261
245
231
243
237
240
240
274
292
312
317
322
313
285

350
350
350
350
350
350
350
350
350
350
350
350
350
350
350
350

213
155
89
105
119
107
113
110
110
76
58
38
33
28
37
65

114
111
115
109
82
79
79
73
86
110
137
162
172
181
167
153

100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100

0
0
0
0
18
21
21
27
14
0
0
0
0
0
0
0

8.2
11.5
14.3
12.9
12.3
12.7
12.6
12.7
13.0
14.7
15.6
16.7
17.3
17.5
16.6
15.2

11.0
14.5
17.5
18.0
18.0
18.0
18.0
18.0
18.0
18.0
18.0
18.0
18.0
19.0
19.0

0.0
0.0
0.2
4.6
5.7
5.3
5.4
5.3
5.0
3.3
2.4
1.3
0.7
0.5
2.4
3.8

Table 2. Summary of risk estimates for the association between consumption of vegetables, fruit, and dietary fiber andsite-specific cancer
Exposure

Cancer site

Studies

Vegetable

Stomach
Men
Women
Lung
Men
Women
Colon
Men
Women

Shimazu et al. (2014) (14)Fruit
Dietary fiber

Wakai et al. (2015) (15)
Wakai et al. (2007) (16)Reference group

Estimated risk for the highest (quartile of quintile) consumption

First quintile
First quintile

0.78 (0.63 - 0.97)
0.89 (0.62 - 1.29)

First quintile
First quintile

0.88 (0.66 - 1.16)

First quartile
First quartile

0.52 (0.28 - 0.96)
0.64 (0.36 - 1.13)

PAFs were calculated for each sex and age groupaccording to the formula:across all sex and age categories to show a percentageof the total number of all incident cases and deaths ofcancer in Japan in 2015.
Results

The number of attributable cancers was then totaled

Sex and age group-specific consumption of vegetables,(72)

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fruit and dietary fiber among Japanese people in2005 is shown in Table 1. The deficit from optimal
consumption to mean vegetable intake was high inyounger generations (up to 40-44 years-old) anddecreased for both sexes thereafter. A similar tendency
was seen for fruit, but the decrease was observedslightly later for men (55-59 years-old). The deficit
from optimal consumption to mean dietary fiber intake
was highest among 20-24-year-olds.
Risk estimates for the association between
consumption of vegetables, fruit, and dietary fiber andsite-specific cancer in Japan are summarized in Table
2. For vegetables, the estimated risk of stomach cancer
was 0.78 for men and 0.89 for women. We used thesevalues to calculate PAF. For fruit, the estimated risk oflung cancer was 0.88 for men and women; while for
dietary fiber, the estimated risk of colon cancer was 0.52
for men and 0.64 for women.
The estimated PAF of cancer incidence and mortality
in 2015 attributed to insufficient vegetable, fruit anddietary fiber consumption in Japan is summarized inTable 3. Insufficient consumption of vegetables was
attributed to 1.7% (1.8% in men and 1.3% in women) of
gastric cancer incidence, and to 0.2% (0.3% in men and
0.1% in women) of total cancer incidence. Insufficientconsumption of fruits was attributed to 0.5% (0.7% in
men and 0.2% in women) of lung cancer incidence,and to 0.1% (0.1% in men and 0.02% in women) of
total cancer incidence. Insufficient consumption ofvegetables was attributed to 1.3% (1.3% in men and1.2% in women) of mortality from gastric cancer, andto 0.2% (0.2% in men and 0.1% in women) of totalcancer mortality. Insufficient consumption of fruits was
attributed to 0.4% (0.5% in men and 0.1% in women) of
mortality from lung cancer, and to 0.1% (0.1% in men
and 0.01% in women) of total cancer mortality.
Insufficient consumption of dietary fiber was
attributed to 10.5% (13.6% in men and 7.1% in women)of colon cancer incidence, and to 1.0% (1.2% in men
and 0.8% in women) of total cancer incidence. It was

attributed to 10.2% (12.4% in men and 7.9% in women)of mortality from colon cancer, and to 0.9% (1.0% in
men and 0.9% in women) of total cancer mortality.
Detailed results for each cancer, sex, and agegroup are shown for insufficient vegetable and fruit
consumption in Tables S1-S2 (online data, https://www.
ghmopen.com/site/supplementaldata.html?ID=36)
and for insufficient fiber consumption in Tables S3S4 (online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=36).
Discussion
In this report, we estimated the proportion and absolute
number of cancer incidence and mortality in Japan in2015 that was attributable to insufficient vegetable,
fruit and dietary fiber consumption. According to theresults from a large prospective cohort study or pooled/meta-analysis of cohort studies in Japan, insufficientconsumption of vegetables, fruit and dietary fiber
was attributed to stomach cancer, lung cancer, andcolon cancer, respectively. The results indicate that
insufficient consumption of vegetables and fruit
contributed 0.1-0.2% of both total cancer incidence
and mortality. In addition, insufficient dietary fiber
consumption contributed approximately 1% of totalcancer incidence and mortality.
In a previous study which estimated the effects of
16 risk factors on cause-specific mortality (18), thenumber of cancer deaths attributable to low fruit andvegetable consumption was 3.8 in thousands, similar
to that of our study. In that study, the risk of low
consumption of vegetables and fruit was relatively
minor, at only one-third that of high dietary sodium
consumption, the highest dietary risk factor for cancer
in Japan. Further, low dietary fiber consumption was
not included.
In contrast, several previous estimates of the fractionof cancer attributable to insufficient consumption ofvegetables, fruits and dietary fiber have been published

Table 3. Proportion (%) of cancer in 2015 attributable to insufficient consumption of vegetable, fruit, and dietary fiber in
Japan
Items
Insufficient vegetable consumption
Stomach (C16)
Total cancer (C00 - C96)
Insufficient fruit consumption
Lung (C33 - C34)
Total cancer (C00 - C96)
Insufficient vegetable and fruit consumption
Total cancer (C00 - C96)
Insufficient dietary fiber consumption
Colon (C18)
Total cancer (C00 - C96)

Incidence

Mortality

Men

Women

Both sexes

Men

Women

Both sexes

1.8
0.3

1.3
0.1

1.7
0.2

1.3
0.2

1.2
0.1

1.3
0.2

0.7
0.1

0.2
0.0

0.5
0.1

0.5
0.1

0.1
0.0

0.4
0.1

0.4

0.2

0.3

0.3

0.1

0.2

13.6
1.2

7.1
0.8

10.5
1.0

12.4
1.0

7.9
0.9

10.2
0.9

(73)

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from Western countries. PAFs of all cancer attributed
to vegetables and fruits combined for all cancer cases
were 4.7% in the UK in 2010 (5) and 2.1% in Germany
in 2018 (4). In Australia in 2010, PAFs of all cancer
attributed to insufficient fruits and vegetables were
1.4% and 0.3%, respectively (2). In France, PAFs of
all cancer in 2015 attributed to insufficient fruits andvegetables were 1.4% and 0.5%, respectively (19).
Compared to these percentages, the PAF of all cancer inJapan in the present study is rather low.
According to the National Health and Nutrition
Survey, average consumption of vegetables byJapanese increased until the mid-1990s, and hassince then maintained a steady level between 260300g/day for about two decades (20). On the other
hand, stomach cancer decreased rapidly during thisperiod, both in incidence and mortality. If thesetrends continue, the burden of all cancer attributed toinsufficient consumption of vegetables in the future
will be even lower than now. In contrast, average
consumption of fruit in Japan decreased drasticallyup to the 2000s, to around 120g/day, and has sincecontinued to decrease slowly (20). Considering theincreasing trend of lung cancer in Japanese women,
all cancers attributed to the low consumption offruit might increase in the future. Consumption of
dietary fiber, on the other hand, has remained at
approximately 15g/day for the past two decades(20). Foods which make the greatest contribution
to the total consumption of dietary fiber include not
only fruits and vegetables, but also grains. Since theincidence of colon cancer is increasing in Japanesewomen, all cancers attributable to insufficient dietaryfiber consumption might increase in the future.
There are a few limitations to this study. First, themethodology used to estimate dietary consumption
differed. We adopted the mean consumption levels
from the results of 1-day dietary records collectedin the National Nutrition Survey to take advantageof representative data. Among the various methods
available, dietary records also have the advantage ofaccurately estimating the quantity of consumption.
On the other hand, relative risks were estimated using
FFQs, which are designed for ranking by consumption
level. Moreover, levels of consumption in categories
such as quintiles may vary in the meta- and pooled
analyses. Our present analysis was based on the
hypothesis of a dose-response association between
exposure and outcome; however, the differences in cutoff point caused by the different methods might haveresulted in error if this hypothesis was not applicable todietary consumption. Secondly, the RR used to calculate
the PAF for insufficient dietary fiber consumption wasderived from a single study. This may have led to theover- or underestimation of risk. When additional data
are available, re-calculation of the PAF using RR froma meta-analysis or pooled analysis will be essential for

updating the evidence.
Despite the limitations, these estimates have major
implications for Japan's national health policy forcancer prevention and control strategies.
Conclusion
Our analysis provides evidence for the current burdenof cancer attributable to insufficient consumptionof vegetables, fruit and dietary fiber. Insufficientconsumption of vegetables, fruit, and dietary fiber
contributed 0.2%, 0.1% and 1.0% of all cancer
incidence, and 0.2%, 0.1% and 0.9% of cancer mortality,
respectively. These results may provide useful evidencein efforts to reduce the cancer burden in Japan.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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*Address correspondence to:Junko Ishihara, School of Life and Environmental Science,
Department of Food and Life Science, Azabu University,
1-17-71 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa
252-5201, Japan.
E-mail: j-ishihara@azabu-u.ac.jp(75)Original Article

GHM Open. 2021; 1(2):76-84.
DOI: 10.35772/ghmo.2021.01022

Burden of cancer attributable to air pollution in Japan in 2015
Megumi Hori1,*, Kota Katanoda1, Kayo Ueda2, Tomoki Nakaya3, Eiko Saito1, Sarah Krull Abe4, Mayo Hirabayashi4,
Tomohiro Matsuda5, Manami Inoue4; the Cancer PAF Japan Collaborators
1

Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;
Environmental Health Sciences, Graduate School of Global Environmental Studies, Kyoto University, Kyoto, Japan;
3
Department of Frontier Science for Advanced Environment, Graduate School of Environmental Studies, Tohoku University, Sendai, Japan;
4
Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo; Japan.
2

Abstract: PM2.5 is a major environmental health problem and a risk factor for lung cancer. Exposure to PM2.5 has
attracted growing public concern nationwide. Here, we aimed to estimate the cancer in 2015 attributable to PM2.5
in Japan. Ambient air pollution level due to excess concentration of PM2.5 was estimated using geophysically based
satellite-derived PM2.5 concentrations in 2005, with a spatial resolution of 0.5° × 0.5° longitude-latitude, and population
data presented in a 1 km by 1 km grid. We used the WHO guideline value for PM2.5 exposure (≤ 10 μg/m3) as the
optimal level of PM2.5 exposure. By using relative risk from a large-scale cohort study in Japan, we estimated the
population attributable fraction (PAF) for lung cancer, which is positively associated with PM2.5, and aggregated theresults to obtain the PAF among total cancer incidence and mortality. Population-weighted mean PM2.5 level in 2005
was 14.9 μg/m3. Approximately 95.7% of the population was exposed to levels above the WHO guideline value. Lungcancer attributable to PM2.5 exposure corresponded to 11,922 cases and 7,264 deaths, which accounted for 9.7% and 9.8%of total lung cancer incidence and mortality, respectively, and 1.2% and 2.0% of total cancer incidence and mortality,
respectively. Substantial geographic variation in PM2.5-attributable incidence and mortality fractions was found, withcities in western Japan and metropolitan areas having a higher PAF than other municipalities. This study provides
useful information to aid policy-makers and public health agencies in the efficient establishment of environmental
cancer prevention policies.
Keywords: cancer, air pollution, population attributable fraction, Japan

Introduction

for lung cancer were estimated to range from 4.7%
to 17.4% in different counties (6). An earlier reportfrom the US also revealed starkly localized geographic
variation in this mortality burden (7). In addition toevaluation of the impact of PM2.5 at the national level,a better understanding of geographic patterns in PAF at
the subnational level will help policy-makers and publichealth agencies to improve the quality of public healthpractice. Nevertheless, few studies have focused on
the PAF of cancer due to PM2.5 at either the national or
subnational level in Japan.
Here, we aimed to estimate cancer incidence andmortality attributable to ambient air pollution, with a
special focus on PM2.5 concentration, at the national andsub-national level (city level) in Japan.

Outdoor air pollution, often referred as ambient air
pollution, is a major environmental health problem which
affects people across all socioeconomic strata in low, middle, and high-income countries. Types of ambient
air pollution include gases (e.g., carbon monoxide, sulfur
dioxide, nitrogen oxides, ozone) and fine particulatematter (PM), notably PM 2.5 - particles less than 2.5
micrometers in diameter - and PM 10. In 2013, theInternational Agency for Research on Cancer (IARC)
confirmed that outdoor air pollution, including PM2.5,
is carcinogenetic to humans (1), and the recent Global
Burden of Disease (GBD) study (GBD 2017) foundthat PM2.5 accounted for 5.3% of lung cancer mortality
worldwide, and 5.5% in Japan (2).
Several countries and regions have reported mortality
burdens attributable to PM2.5 at a subnational level (35). In Taiwan, population attributable fractions (PAFs)

Materials and Methods
Cancers associated with air pollution(76)

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GHM Open. 2021; 1(2):76-84.
IARC has classified particulate matter, a major
component of outdoor air pollution, as carcinogenic tohumans (Group 1), finding a consistent association of
outdoor air pollution with lung cancer (1). Accordingly,
we included lung cancer as the target cancer in thepresent estimate.

position (latitude and longitude). The gridded data
covered an area between 122°-154° east longitude and20°- 46° north latitude.
To assign exposure to PM 2.5 , we used surface
PM 2.5 concentrations estimated by the AtmosphericComposition Analysis Group (12). The provided data
were estimates of annual mean exposure to PM 2.5 in2005 and 2000, with a spatial resolution of 0.01° ×
0.01° longitude-latitude. The group estimated PM2.5
concentrations using information from satellite-,
simulation- and monitor-based sources (13). A
geographically weighted regression (GWR) model wasused to correct discrepancies between the satellite-based
estimated PM2.5 and monitor-based PM2.5 levels.
The PM2.5 data used in this study covered an area
between 122°-154° east longitude and 20°- 46° northlatitude. As with the population data, the PM2.5 data in2005 were used for the main analysis and the PM2.5 data
in 2000 were used for sensitivity analysis.
To estimate annual average PM 2.5 concentrations
at the national and city levels, we added the longitudelatitude coordinate code computed from the grid-ID to
the population data, then linked the population and PM2.5
concentration data using the longitude-latitude coordinate
code as the matching key with the nearest neighbormatching method.
Next, city codes were assigned to each grid using theintersect tool (ArcToolbox/Analysis tools/Overlay) of the
ArcGIS (ArcGIS Pro, version 2.5.2; ESRI Inc, Redlands,
CA, USA) geographic information system. This tool
can create geometric intersections of any number offeature layers. In this study, we created an intersection
between the city layer and gridded data layer; where agrid intersected two or more cities, the grid contained
the codes of all intersected cities. Finally, we calculated
population-weighted PM2.5 concentrations at the citylevel using following formula (14):Theoretical minimum risk exposure level
For this study, we used the WHO guideline value forPM2.5 exposure (10 μg/m3) as reference (8). The latent
period - the interval period between "exposure" toPM2.5 above the reference and the increase in risk ofcancer of the lung - is unknown. Based on previous
epidemiological studies of exposure, we assumed alatent period of 10 years, and accordingly calculated thenumber of avoidable cancers in 2015 using the estimatedPM2.5 exposure in 2005.
Distribution of PM2.5 exposure and population-weighted
PM2.5 exposure estimates
Because nationwide observation data of PM2.5 were
not available before 2009, when environmental quality
standards for PM 2.5 were established in Japan, thedistribution of PM2.5 exposure and population-weighted
PM2.5 exposure was estimated using population and PM2.5
concentrations data.
We obtained the population data from Japanese
Census data in 2005 and 2000 (9,10). We used the
population data in 2005 for the main analysis and thatin 2000 for sensitivity analysis. The spatial distributionof population in 2005 is illustrated in Figure 1. The
population data are presented in grids of 45 seconds
longitude by 30 seconds latitude, which is also known
as the Basic Grid Square (11). Each grid-square wasgiven a unique ID computed on the basis of geographicalFigure 1. The spatial distribution of
population in Japan in 2005, with aspatial resolution of 1km × 1km grid.

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the RR per 10-unit increase in the average concentrationof PM2.5, and RRx-x0 is the RR at exposure x comparedto that with the reference exposure x0. In our study,
RRs of PM2.5 on lung cancer incidence and mortality
were assumed to be equal. Consequently, RR10unit (95%
confidence interval) of lung cancer, 1.26 (1.14-1.36)
for men and 1.17 (0.98-1.39) for women, was used for
estimation of PAF of cancer due to air pollution.

where WPM k is the population-weighted PM 2.5
concentration estimate in city k, Nk is the number ofgrid in city k, PMik is the PM2.5 concentration in grid i incity k, Popk is the population in city k, and Popik is the
population in grid i in city k.

Estimation of population attributable fractions (PAFs)
For lung cancer, PAF at the national level was calculated
by sex as:

Cancer incidence and mortality in Japan in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by
the Monitoring of Cancer Incidence in Japan project(15). We used an age and period spline model. This
type of model is often used for short-term projectionof cancer incidence in Japan (16). The sex- and agespecific incidence data for target cancers were codedin accordance with the International Statistical
Classification of Diseases and Related Health Problems,
10th edition (ICD-10), using the morphology code of theInternational Classification of Disease for Oncology, 3rdedition (ICD-O-3).
The data on cancer mortality statistics from 2015
were based on the vital statistics of Japan. We obtained
sex- and age-specific mortality data at both the national(17) and city level (18) by cause of death from available
data sources from the Health, Labour, and Welfare
Statistics Association, with cause of death classified
using 4-digit ICD-10 codes.

where px is the proportion of the population and ERRx isthe excess relative risk at PM2.5 exposure level x.
The excess relative risk for each x level of PM2.5
exposure was calculated using the following formula:

We used the WHO guideline value for PM2.5 exposure(10 μg/m3) as reference (8).
The number of lung cancer cases/deaths attributable
to PM2.5 was calculated by sex as:

where ELC is excess incidence/mortality of lung cancer
and LC is lung cancer incidence/mortality.
The number of attributable cancers was then totaled
across all sex and age categories to show the percentageof the total number of all incidence and mortality ofcancer in Japan in 2015.
In addition, the PAF of mortality of lung cancer was
estimated at the city level, using population-weighted
PM2.5 concentration by city. As we assumed that PM2.5
levels were uniform within each city, that is WPM, PAF
at city k, which is PAF at the city level, was calculated by
sex as:Estimation of relative risk
The relative risk (RR) of air pollution exposure on lungcancer was taken from a prospective population-based
observational study (19), the Three-Prefecture Cohort
study, which was conducted from 1983 to 2000 in threeprefectures (Miyagi, Aichi, and Osaka) (20). The ThreePrefecture Cohort study had a long follow-up period
and covered both high and low PM2.5 concentration
areas. Because RR in the study was reported in 10-unit
increases in the average concentration of air pollutants(µg/m3), we assumed a log-linear association to convert
the RR per 10-unit increase using the following formula:Sensitivity analysis
In addition to the main analysis, the impact of PM2.5
on cancer incidence and mortality was assessed using
three alternative reference levels, namely the national

where β is the parameter estimate for the association
between lung cancer and the exposure of PM2.5, RR10unit is(78)

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ambient air quality standards in Japan (15.0 μg/m3) (21)and the USA (12.0 μg/m3) (22), and a value which may
be close to the background PM2.5 concentration in Japan(4.0 μg/m3), based on a previous estimated backgroundconcentration of about 4.4 μg/m 3 in Taiwan andsurrounding oceanic regions (23). We also investigated
the influence of time lag between PM 2.5 exposureand lung cancer incidence and mortality by using the
population and PM2.5 concentration data in 2000, which
is 15-year time lag analysis.

95th percentiles of population-weighted PM2.5 levelsin that year were 10.2, 15.1, 20.5 μg/m3, respectively,
and the population-weighted annual average exposure
was 14.9 μg/m 3. Approximately 95.7% of the study
population was exposed above the yearly average WHO
guideline value of 10 μg/m3, while 56.6% was above
the Japan standard value of 15.0 μg/m3.
The spatial distribution of population-weighted
PM 2.5 concentrations at the city level in 2005 in
Japan is shown in Figure 3. The Kanto region,
including Tokyo and Kanagawa prefectures, and theKansai region, including Osaka prefecture, had highPM 2.5 concentrations. Western Japan, including the
Kyushu and Chugoku regions, also had higher PM 2.5
concentrations than other areas. In contrast, PM 2.5
concentrations were lower in northern Japan, such as
the Hokkaido and Tohoku regions.

Results
Fine particular matter exposure
The distribution of the population-weighted exposure toPM2.5 in 2005 is shown in Figure 2. The 5th, 50th andFigure 2. Distribution of exposures to PM2.5 in Japan in 2005. Background: Expected value of background PM2.5 concentrationin Japan; WHO: WHO Air quality guideline values for annual average PM2.5 concentrations; US: National Ambient Air Quality
Standards for annual average PM2.5 concentrations in the US; Japan: Environmental Quality Standards for annual average PM2.5
concentrations in Japan.

Figure 3. Annual average of population-weighted PM2.5 concentrations at the city level in 2005 in Japan.

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and 2.0% of cancer mortality (2.6% in men, 1.0% in
women) in 2015 were due to excessive PM2.5 exposure.
Figure 4 shows the geographic variation in PAF oflung cancer mortality associated with PM2.5 exposure at
the city level across Japan. Cities in western Japan had ahigher PAF than other cities, with Kumamoto City in the
Kyushu region having the highest PAF (26% for males,
19% for females). Estimated PAFs were also higher
in cities in Tokyo, Kanagawa, and Osaka prefecturescompared to other cities. On the other hand, PAF was
lower in northern Japan, such as in the Hokkaido andTohoku regions.
Figure 5 shows the number of lung cancer deaths
attributable to PM2.5 exposure at the city level acrossCancer attributable to PM2.5
Table 1 summarized the estimated PAF of cancer
incidence and mortality in Japan in 2015 attributed toambient air pollution (PM2.5). Detailed results by sex andage group are shown in Tables S1 (incidence) and S2(mortality) (online data, https://www.ghmopen.com/site/
supplementaldata.html?ID=40). The estimated PAF was
9.7% (10.7% for men, 7.5% for women) of lung cancer
incidence, corresponding to 11,922 cases (8,907 in men,
3,014 in women), and 9.8% (10.7% for men, 7.5% forwomen) of lung cancer mortality, corresponding to 7,264
deaths (5,682 in men, 1,582 in women). Accordingly,
1.2% of cancer incidence (1.6% in men, 0.7% in women)

Table 1. Proportion (%) of cancer in 2015 attributable to ambient air pollution (PM2.5) in Japan
Factors
Lung (C33-34)
Exceed 10 µg/cm3 (WHOa)
Exceed 12 µg/cm3 (USb)
Exceed 15 µg/cm3 (Japanc)Exceed 4 µg/cm3 (backgroundd)
Total cancer (C00-C96)
Exceed 10 µg/cm3 (WHOa)

Cancer Incidence

Cancer Mortality

Men

Women

Both sexes

Men

Women

Both sexes

10.7
6.9
2.0
22.0

7.5
4.8
1.4
15.8

9.7
6.2
1.8
20.0

10.7
6.8
2.0
22.0

7.5
4.8
1.4
15.7

9.8
6.2
1.8
20.2

1.6

0.7

1.2

2.6

1.0

2.0

a

WHO Air quality guideline values for annual average PM2.5 concentrations; bNational Ambient Air Quality Standards for annual average PM2.5
concentrations in the US; cEnvironmental Quality Standards for annual average PM2.5 concentrations in Japan; dExpected value of backgroundPM2.5 concentration in Japan.

Figure 4. Spatial variations in the PAF (%) of lung cancer
due to PM2.5 at the city level by sex in Japan in 2015.

Figure 5. Spatial variations of the number of lung cancer
deaths due to PM2.5 at the city level by sex in Japan in 2015.

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Japan. Cities in metropolitan areas, such as Tokyo andOsaka prefectures, tended to have a large number ofdeaths associated with PM2.5. In the northern part of the
Kyushu region and southern part of the Chugoku regionalso, many cities had a large number of deaths due toPM2.5 exposure.

words, we assumed a 10-year time lag between PM2.5
exposure and lung cancer mortality. In fact, several
studies have reported that lung cancer has a longlatency period (26-28). To our knowledge, however,uncertainties are still present in the time lag between
PM2.5 and lung cancer mortality. We therefore assumed
that a time lag of 10 years accounted for longer-term
exposure, as has also been done in previous studies(29). In Japan, average PM2.5 concentrations in rural
areas have leveled off, whereas those measured at theroadside have greatly decreased since 2000 (30). The
GBD approach might therefore have provided lower
attributable deaths due to PM 2.5. Another difference
between the GBD and our present study is the choiceof PM2.5 reference level, which has a major impact on
PAF estimation. The GBD study applied a uniform
distribution between 2.4 μg/m3 and 5.9 μg/m3 as thereference level of PM2.5 (25), whereas our main analysis
was set to 10.0 μg/m3. The reference level of 4.0 μg/
m3 in our sensitivity analysis is similar to the reference
level applied in the GBD. Under this setting, our PAFs
were much larger than those of the GBD study. The
large differences in PAF were considered due to thedifferences in PM2.5 exposure data.
Unlike the differences in PM 2.5 exposure data
between the GBD and our present study, the differences
between PM2.5 concentrations in 2000 and 2005 in ourstudy were small. Accordingly, replacement of thePM2.5 concentration in 2005 with that in 2000 resulted
in almost no change in PAF at the national level.
Our estimates revealed the geographic variation in
the PAF of lung cancer due to PM2.5 exposure in Japan.
We found a high PAF in major metropolitan areas suchas Tokyo, Kanagawa and Osaka. In our method, PAFs
are thoroughly dependent on the population-weighted
concentration of PM2.5. Tokyo, Kanagawa and Osaka
are among the most densely populated areas in Japan.
These areas had higher PM2.5 concentrations, mainly
as a result of local industrial and traffic pollution (31).
Accordingly, the PAFs were also relatively high inthe major metropolitan areas. Moreover, Japan's 2005
census showed that 30% of the overall population wasconcentrated in the metropolitan areas (32). Therefore,
trends in PM2.5 in the area would have a substantial
impact on the national estimates of PAF.
Higher concentrations of PM 2.5 and bigger PAF
were also found in many parts of rural areas in westernJapan. The main reason is PM2.5 arising from foreign
anthropogenic sources, especially from the Chinese
mainland (31,33-35). In Japan, the main contributor to
PM2.5 differ according to region. Contributions fromforeign anthropogenic sources were greater than thosefrom domestic pollution in the Kyushu region (33,35).
China has a very large PAF compared to Japan,
although variations in PAF have been assigned
according to the setting of reference levels of PM2.5
and the time lag between PM 2.5 exposure and lungSensitivity analysis
When the PM2.5 reference level was replaced by thenational ambient air quality standards in the US (12.0 μg/m3) and in Japan (15.0 μg/m3), the PAF for both sexes
combined decreased to 6.2% and 1.8% for incidence
and mortality, respectively. When the reference level for
PM2.5 was changed to 4.0 μg/m3, which is regarded asconsistent with the background concentration in Japan,
PAF was 20% for both incidence and mortality. Resultswith the 15-year time lag analysis were similar to thosewith a 10-year time lag analysis.
Discussion
We estimated the cancer incidence and mortality
attributed to ambient air pollution (PM2.5) exposure in
Japan in 2015 by applying GIS spatial analysis data.
This is the first nationwide report of the PAF of cancer
attributable to ambient air pollution in Japan and PAF
of lung cancer mortality due to PM2.5 at a sub-national
level. We identified a large geographic variation in
PAF, namely a higher ratio in the western part in Japan.
Further, the large metropolitan areas around Tokyo andOsaka had a large number of excess attributable cases
due to PM2.5 exposure.
Cigarette smoking is the single biggest risk factor
for lung cancer. In Japan, the PAF of lung cancer
mortality caused by cigarette smoking in 2015 wasabout 60.9% for men and 18.3% for women (24).
Although the PAF of lung cancer due to PM2.5 wassmall compared to that due to cigarette smoking inmen, it was about half as large as that due to cigarettesmoking for women. Moreover, the PAF due to PM2.5
was comparable to that due to secondhand smoking(SHS) for women (8.7%) and larger than that due to
SHS for the total population (3.7%). In addition to
the inclusion of tobacco control in indoor air policies,
environmental approaches to air quality management
are also important for cancer prevention, includinglung.
The GBD 2015 study reported that lung cancer
mortality attributable to PM2.5 was about 6,800 deaths(males 4,700, females 2,000), or 8.7% of total lungcancer mortality in Japan (25). Our national-level
estimates of PAF were higher than the GBD 2015
estimates. One reason is the year of PM2.5 exposure
data: the GBD study used PM2.5 exposure and mortality
data from the same year (2015), whereas we used PM2.5
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cancer mortality/incidence (36-40). One of the Chinesestudies estimated that the PAF in China in 2015 was
23.9% overall (38). However, the study applied a highreference level of PM2.5 (40 μg/m3). If we use the samereference level as the Chinese study, the number oflung cancer deaths attributed to PM2.5 would be zeroin Japan because there were no areas which had aPM2.5 concentration over 30 μg/m3. A previous study
in the Republic of Korea estimated that the PAF was
26.9% (95% CI: 15.5%-37.0%) by applying a uniform
distribution between 2.4 μg/m3 and 5.9 μg/m3 as thereference level of PM2.5 (41). The reference level of
4.0 μg/m3 in our sensitivity analysis is similar to thislevel in the Korean study. Under this setting, the PAFs
were slightly larger in the Korea than Japan. The larger
PAFs in China and Korea were caused by exposure tohigher PM2.5 concentrations. Average concentrations in
China, Republic of Korea and Japan were 66.2 μg/m3,
30.4 μg/m3 , and 14.3 μg/m3 in 2005, respectively (42).
The south and south-east Asia region had much higher
concentrations of PM2.5 than other Asian countries (43).
Japan was considered to have smaller PAFs of PM2.5
among Asian countries.
On the other hand, a recent study in Canada, where
air pollution levels are much lower than in Japan,
estimated that 2-6% of incident lung cancer cases in2012 might have been attributable to PM2.5 exposure by
applying different reference levels of PM2.5 (7.5 μg/m3
and 3.18 μg/m3, respectively) (44). In the GBD study, thefraction of lung cancer mortalities attributable to PM2.5
was estimated to be 8.6% in Western Europe and 4.6%
in the US (25). The health impact of PM2.5 exposure in
Japan is large compared to these European and North
American countries.
One strength of the present study was that we usedthe estimated annual average of PM2.5 concentrationbased satellite-, simulation- and monitor-based
concentrations. Agreement with the estimated data
we used and ground-observed PM 2.5 concentrations
were improved by applying the GWR model. Sinceestablishment of the national ambient air quality
standards in 2009 (21), the number of PM2.5 monitoring
stations in Japan has been increasing year by year (45).
Nevertheless, there are still insufficient monitoring
stations to monitor spatial distribution at the city levelwith ground-based monitoring alone (46). By using
satellite-, simulation- and monitor-based concentration
data, not only monitoring data alone, our analysis
provided subnational information.
Another strength of the present study was that weused small grid-square level mortality data instead ofcity-level mortality data. Our analysis therefore provided
national and subnational information that was moreaccurate than the previous estimate.
The RR used for the present study was based ona large-scale prospective cohort study from threeprefectures in Japan. An advantage of this RR is thatthe large number of confounders (age, smoking status,
pack-years, smoking status of family members, indoor
charcoal or briquette braziers used for heating, andoccupation) were directly adjusted using individual data.
On the other hand, the RR used for present study
involves several uncertainties regarding the estimation of
PM2.5 concentration and time lag between PM2.5 exposureand lung cancer outcome. However, the RR values fromthe analysis were generally comparable to those reported
in previous studies conducted in the US and European
countries (28,47-49).
This study has several limitations. First, our analysis
did not account for cumulative PM2.5 exposure. Adverse
health effects are dependent not only on concentration but
also on the length of PM2.5 exposure. In Japan, more than
two million people move across prefectural boundaries
every year (50). Rates of inter-prefectural migration vary
among prefectures. Migration has an effect on both thelength of PM2.5 exposure and cumulative PM2.5 exposure.
Adjustment for migration may improve the estimation of
PAF and its distribution in Japan.
Second, we could not obtain individual measurementsof exposure to ambient PM2.5 in this analysis. Individuals
also constantly move in time and space. To support
health impact assessment, it is essential to develop abetter understanding of individual exposure pathways
in people's everyday lives by taking account of allenvironments in which people spend time.
Finally, smoking prevalence varies across prefecturesin Japan, ranging in 2019 from 26.5% in Ehime to35.8% in Saga (Japan total: 28.8%) (51). A previous
meta-analysis reported the presence of smoking-related
confounding bias in the RR of PM2.5 on lung cancer,
and suggested that never- and former smokers may havean elevated risk of lung cancer associated with PM2.5
compared to current smokers (52,53). However, because
we had no information on smoking prevalence among
cities, we used the overall RRs adjusted for multiple
covariates, including smoking status, instead of RRs by
smoking status.
Conclusion
Our findings indicate that nearly 10% of lung cancer and
1-2% of total cancer were attributable to excess PM2.5
exposure in Japan, with regional differences. This study
provides useful information for policy-makers and publichealth agencies to aid the efficient development of theirenvironmental cancer prevention policies.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244 and the National Cancer
Center Research and Development Fund Number 30-A19.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.

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---Received June 12, 2021; Revised November 23, 2021;
Accepted December 10, 2021.
Released online in J-STAGE as advance publication December
13, 2021.
*Address correspondence to:
Megumi Hori, Division of Cancer Statistics Integration, Centerfor Cancer Control and Information Services, National Cancer
Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
E-mail: mhori@ncc.go.jp(84)

Brief Report

GHM Open. 2021; 1(2):85-90.
DOI: 10.35772/ghmo.2021.01017

Burden of cancer attributable to consumption of highly salted food inJapan in 2015
Ribeka Takachi1,*, Junko Ishihara2, Sarah Krull Abe3, Mayo Hirabayashi3, Eiko Saito4, Megumi Hori4, Kota Katanoda4,
Tomohiro Matsuda5, Manami Inoue3; the Cancer PAF Japan Collaborators
1

Department of Food Science and Nutrition, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan;
School of Life and Environmental Science, Department of Food and Life Science, Azabu University, Kanagawa, Japan;
3
Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
4
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: Salt consumption is high in most parts of the world, particularly among populations in Asia-Pacific region,
including Japan. The recent portion of global deaths attributable to excess salt was largest among dietary exposures.
We estimated the cancer in 2015 attributable to highly salted food in the Japanese population. Consumption of highly
salted food in grams per day was available by sex and age group for 2005 from the Japanese National Health andNutrition Survey. The optimal consumption of highly salted food for this study was assumed to be 0 g/day. Population
attributable fractions (PAFs) for stomach cancer, which is positively associated with highly salted food intake in Japan,
were estimated for respective sex and age groups according to a standard formula, and aggregated to obtain the PAF
among total cancer incidence and mortality. In both sexes, 2.4% of cancer incidence and 2.2% of cancer mortality in2015 were due to intake of highly salted food. Annually at least 22,000 total cancer cases in Japan could have been
prevented by avoiding highly salted food.
Keywords: cancer, highly salted food, population attributable fraction, Japan

Introduction(IARC) describes stomach cancer as the fifth-mostcommon cancer worldwide, with around 1,033,701
new cases globally in 2018 (5). Salt consumption in
the Japanese population decreased by 1g at most in the
10 years between 2005 and 2015 (6). Despite global
and domestic efforts, 2015 intake levels were still
far from the WHO recommendation. At least 50% of
salt in the diet appears to come from commerciallyprocessed foods with salt (e.g. salted-preserved fish or
salted pickled vegetables). This remains the case evenafter salty seasonings such as soy sauce and miso major sources of personal preference-based discretional
sodium among Japanese - are excluded (7).
The fundamental etiology of stomach cancer byhighly salted food intake is suggested to be as follows(2): high salt levels alter the viscosity of the mucous
protecting the stomach, and intake of highly salted food
may stimulate the colonization of H. pylori, the greatest
known risk factor for stomach cancer. Highly salted foodis not essential for optimal health in stomach cancer.
Here, we estimated the fraction of cancer incidence
and mortality in 2015 attributable to highly salted foodin the Japanese population.

Cancer and cardiovascular disease are the leading
causes of death in many parts of the world. Highsodium consumption and salt-preserved foods are
considered major dietary risk factors of cardiovasculardiseases caused by high blood pressure (1) and somecancers (2). The World Health Organization (WHO)recommends keeping salt intake to less than 5 g/day
to prevent these non-communicable diseases (NCDs)(3). The East Sub-Saharan African region is reported
to have the lowest intake, with an average of 5 gramsof salt per day (4). Most people in the world consume
too much salt. Intake is highest in high income AsiaPacific countries, including Japan, at an average ofapproximately 12 g/day as measured by 24-hoururinary excretion, and in Central Asia, at 13 grams ofsalt per day, in 2010 (4). The World Cancer Research
Fund (WCRF)/American Institute for Cancer Research(AICR) reaffirmed in 2018 that salt-preserved foods
increase risk for cancers of the stomach with a positive
dose-response relationship (2). The latest estimate
by the International Agency for Research on Cancer(85)

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Materials and Methods

and age group for the Japanese population in 2005.

Cancers associated with highly salted foodCancer incidence and mortality in Japan in 2015

The WCRF/AICR reaffirmed that salt-preserved foodincreases risk for cancers of the stomach with a positive
dose-response relationship (2). We therefore included
these target cancers in the present evaluation; specifically,
those with sufficient evidence for a positive association
with highly salted food, and with available relative risk
estimates in Japan, including stomach cancer.

Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by
the Monitoring of Cancer Incidence in Japan project(9). We used an age and period spline model. This
type of model is used for short-term projection ofcancer incidence in Japan (10). The sex- and agespecific incidence data for target cancers were codedin accordance with the International Statistical
Classification of Diseases and Related Health Problems,
10th edition (ICD-10), using the morphology code of theInternational Classification of Disease for Oncology, 3rdedition (ICD-O-3).
The data on cancer mortality statistics from 2015
were based on the vital statistics of Japan (11). We
obtained sex- and age-specific mortality data by causeof death from available data sources from the Health,Labour, and Welfare Statistics Association (12), using
4-digit ICD-10 codes to classify the cause of death.

Theoretical minimum risk exposure level
For this study, the optimal consumption of highly salted
food in Japan was set at 0 g/day. The latent period the interval period between "exposure" to highly salted
food and the increase in risk of cancers of the stomach- is unknown. Based on previous epidemiologicalstudies of exposure, we assumed a latent period of 10
years, and accordingly calculated the 2015 fraction of
avoidable cancers using an estimate of highly salted
food intake in 2005.

Estimation of relative risk

Prevalence of highly salted food consumption

The relative risk (RR) of stomach cancer in relation
to highly salted food consumption was obtained froma meta-analysis of eight cohort studies (91% weightof combined results was sourced from four studies inJapan) conducted by the WCRF (13). This 2018 metaanalysis reported an RR of 1.09 (95% confidence
interval: 1.05-1.13) per 20 g/day. We derived theincrease in risk of stomach cancer for 1 g/day of highly
salted food and average RR for the whole population
based on the average highly salted food consumption,with an assumed log-linear relationship between highly
salted food consumption and stomach cancer risk of:

The data on highly salted food consumption were
derived from the Japanese National Health and Nutrition
Survey (JNHNS) from 2005 (8). For this purpose, weused the 3-year mean of individual data for the years
2004-2006 provided by the Ministry of Health, Labour,and Welfare, Japan, with permission. Highly salted
foods include pickled salty vegetables and salt-preserved
fish. The survey presents mean consumption and its
standard deviation by sex and age group. Table 1 shows
the consumption of highly salted food per day by sex
Table 1. Sex- and age-group-specific average consumptionof highly salted food in Japan in 2005
Age at exposure(2005)
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75
Total

Highly salted food consumption (g/day)
Men

Women

7.2
10.0
13.5
20.3
21.8
25.5
26.7
27.2
30.9
36.9
38.9
43.6
49.0
49.1
50.7
46.8
33.5

7.8
10.5
16.1
20.4
20.4
19.6
20.4
20.5
23.5
29.6
32.4
37.8
39.8
44.8
43.3
41.6
29.6

Estimation of population attributable fractions (PAFs)
For stomach cancer, PAF was calculated for each sex
and age group according to the standard formula (14):The number of attributable cancers was then totaled
across all sex and age categories in order to show thepercentage of the total number of all incidence andmortality of cancer in Japan in 2015.
Results and Discussion
The consumption of highly salted food among Japanese(86)

GHM Open. 2021; 1(2):85-90.

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people in 2005 is shown in Table 1. On average, across
age categories, consumption was 33.5 g/day and 29.6
g/day for men and women, respectively. Consumption
increased by age category up to 65-74 years for men(approximately 50 g/day) and women (approximately
45 g/day).
Tables 2 and 3 show the estimated number ofincidence and mortality of stomach cancer in 2015
attributed to excessive consumption of highly salted
food in 2005. Consumption of highly salted food was
attributed to 17.7% of stomach cancer incidence formen and 15.4% for women. A similar trend was seenfor stomach cancer mortality (18.1% for men, 15.8%
for women). Likewise, consumption of highly salted

food was attributed to 3.0% of total cancer incidence formen and 1.6% for women, and to 2.5% of total cancer
mortality for men and 1.7% for women. Accordingly,
in both sexes, 2.4% of cancer incidence and 2.2% ofcancer mortality in 2015 were due to excessive intake ofhighly salted food. These results were not changed when
the latent period was assumed to be 15 years (exposuremean calculated based on the 2000 National survey).
Our study suggests that 2.4% (22 thousand) of
total cancer incidence and 2.2% (8 thousand) of cancer
mortality in 2015 could have been prevented by
avoiding highly salted food. Three PAFs of cancer werereported, based on inadequate salt intake, a reasonableoptimal intake of ≤ 6 g/day (15,16), and a strict optimal

Table 2. Numbers and proportion of cancer cases in 2015 attributable to highly salted food consumption (> 0 g intake ofhighly salted food consumption)
Age at exposure(2005)
Men
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75
Total% of incident cases
Women
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75
Total% of incident cases
Both sexes% of incident cases

Age at outcome(2015)

Stomach cancer

Total cancers

PAF

Obs. cases

Attrib. cases

Obs. cases

Attrib. cases

10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
≥ 85

0.03
0.04
0.06
0.08
0.09
0.10
0.11
0.11
0.12
0.15
0.15
0.17
0.19
0.19
0.20
0.18
0.18

1
3
13
36
88
231
682
1,476
2,867
4,937
9,056
15,59916,74316,081
13,054
11,01591,883

0
0
1
3
8
24
74
163
357
726
1,398
2,672
3,189
3,065
2,560
2,010
16,249
17.7

410
519
682
974
1,595
2,962
6,281
10,557
17,82729,272
53,23891,09596,96293,37577,03465,753549,241

0
0
1
3
8
24
74
163
357
726
1,398
2,672
3,189
3,065
2,560
2,010
16,2493.0

10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
≥ 85

0.03
0.04
0.07
0.08
0.08
0.08
0.08
0.08
0.10
0.12
0.13
0.15
0.16
0.18
0.17
0.16
0.15

1
6
18
48
120
277
605
912
1,300
1,853
3,104
5,182
5,834
6,358
6,704
9,881
42,203

0
0
1
4
10
22
51
77
125
222
404
778
920
1,117
1,142
1,623
6,497
15.4

351
531
914
1,791
3,780
7,759
14,97019,39722,922
26,46736,091
50,521
49,841
49,96750,482
72,222
408,572

0
0
1
4
10
22
51
77
125
222
404
778
920
1,117
1,142
1,623
6,497
1.6

134,087

22,74617.0

957,81322,7462.4

Abbreviations: Attrib. = Attributable; Obs. = observed; PAF = population attributable fraction.

(87)

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Table 3. Numbers and proportion of cancer mortality in 2015 attributable to highly salted food consumption (> 0 g intake ofhighly salted food consumption)
Age at exposure(2005)
Men
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75
Total% of cancer deaths
Women
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75
Total% of cancer deaths

Age at outcome(2015)

Stomach cancer

Total cancers

PAF

Obs. deaths

Attrib. deaths

Obs. deaths

Attrib. deaths

10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
≥ 85

0.03
0.04
0.06
0.08
0.09
0.10
0.11
0.11
0.12
0.15
0.15
0.17
0.19
0.19
0.20
0.18
0.18

0
0
8
19
30
66
141
256
524
992
2,199
4,108
4,939
5,504
5,710
6,312
30,809

0
0
0
2
3
7
15
28
65
146
339
704
941
1,049
1,120
1,152
5,571
18.1

52
86
112
153
260
521
1,225
2,035
3,923
7,622
16,17929,36734,86037,82040,65044,515219,508

0
0
0
2
3
7
15
28
65
146
339
704
941
1,049
1,120
1,152
5,571
2.5

10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
≥ 85

0.03
0.04
0.07
0.08
0.08
0.08
0.08
0.08
0.10
0.12
0.13
0.15
0.16
0.18
0.17
0.16
0.16

0
3
5
13
52
75
141
211
279
436
803
1,352
1,617
1,991
2,739
6,153
15,870

0
0
0
1
4
6
12
18
27
52
105
203
255
350
467
1,011
2,510
15.8

55
61
64
170
394
763
1,623
2,484
3,841
5,501
9,146
14,322
16,783
20,32925,87649,345150,838

0
0
0
1
4
6
12
18
27
52
105
203
255
350
467
1,011
2,510
1.7

46,6798,081
17.3

370,346

8,081
2.2

Both sexes% of cancer deaths

Abbreviations: Attrib. = Attributable; Obs. = observed; PAF = population attributable fraction.

intake of ≤ 0.5 g/day (17). These were a PAF of 1.6%of cancer incidence in 2005 for Japanese (15), 0.5% ofcancer incidence in 2010 for the UK (16), and 14,000
cancers cases (4%) among 335,000 deaths of totalcancer in 2007 for Japanese (17). The difference in
consumption of highly salted foods, such as pickled
vegetables, and stomach cancer incidence between
Japanese or Asian countries and Western countries
suggests the presence of a burden gap between Japanand Western countries (7,18). Exposure prevalence inthe present study was estimated based on the intake
of highly salted food rather than of salt, from thesuggestion that the intake of highly salt-concentrated
preserved foods confers a greater risk of stomach cancer

than that of whole salt (19). Similarly, the 2018 WCRF
report summary for stomach cancer was updated todescribe exposure to highly salted food, from salt intake
in the preceding 2007 report (13). A further strength of
our present study is that exposures (mean intake) were
calculated for individual survey-derived age classes,
compared to a representative mean for all ages basedon household surveys in the previous 1990 estimation.
This improvement was permitted by a change in datacollection methods in the 1995 JNHNS, and revealed
higher mean intake for older age classes, with higher
stomach cancer incidence and mortality (8).
This study has some potential limitations. In a metaanalysis of salt-preserved foods and digestive cancers,(88)

GHM Open. 2021; 1(2):85-90.

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only a single large study from Japan showed positive
associations between intake of salt-preserved fish or
salt-preserved fish roe and risk of colorectal cancer(19). Therefore, the PAF of highly salted food was
calculated for stomach cancer only, which may have
led to an underestimation of risk. Also, we used an RR
of 1.09 per 20 g increment in this estimation based on ameta-analysis for salted vegetables in the WCRF 2018
report (2), because this meta-analysis included nearly
all the published Japanese studies and clearly defined
the exposure. A meta-analysis by Kim et al. of pickled
vegetables and stomach cancer in Japanese and Korean
populations reported an RR of 1.28. That study included
observational case-control and cohort studies for highest
vs. lowest intake in quantitative amounts or combined
frequency (20). The WCRF 2018 report included anothermeta-analysis of stomach cancer estimates, with an RR
of 1.70 for unspecified highly salted food, including
salty confectionary and foods deep boiled in soy sauce(tsukudani) (2). PAFs of highly salted food for cancers
may be slightly larger than the present results if otherdetailed food items were used for mean exposure
calculation. Carcinogenesis by highly salted food intake
may be confounded by other factors, such as H. pylori
infection. Given that stomach cancer has a multifactorial
etiology, a multivariate estimation of PAF would provide
a better estimation of the burden.
Allowing for these limitations, these estimates have
major implications for Japan's national health policy forcancer prevention and control strategies. In a previous
study of the burden of non-communicable disease
death, including death due to cardiovascular disease andcancers, assessed for dietary factors in Japan, the burden
for cardiovascular disease attributable to salt intake waslarger than that for cancer, with corresponding numbersof 19,000 and 14,500, respectively (17). In the global
burden of death attributable to behavioral, environmental,
occupational, and metabolic risk factors, the major
portion for diet risks, and the portion due to excess salt
was largest among dietary exposures such as fruit orvegetables (21). The current Japanese salt intake levelis highest in the world. Policymakers and public healthagencies must invest in and implement interventions
to reduce salt intake and diets with highly salted foods
to control the burden of non-communicable diseases inJapan, including cancers.

Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.

2.

3.
4.

5.
6.

7.

8.

9.

10.

Conclusion
11.

Our analysis provides evidence for the current burdenof cancer attributable to intake of highly salted foods.
In 2015, at least 22,000 cancer cases in Japan could
have been prevented by avoiding highly salted foods.
The results of this study may provide useful evidence toreduce the cancer burden in Japan.

12.

Funding: This study was supported by JSPS KAKENHI

13.

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---Received June 12, 2021; Revised November 12, 2021;
Accepted December 8, 2021.
Released online in J-STAGE as advance publication December
13, 2021.
*Address correspondence to:
Ribeka Takachi, Department of Food Science and Nutrition,
Graduate School of Humanities and Sciences, Nara Women's
University, Kitauoya Nishimachi, Nara 630-8506, Japan.
E-mail: rtakachi@cc.nara-wu.ac.jp(90)Brief Report

GHM Open. 2021; 1(2):91-96.
DOI: 10.35772/ghmo.2021.01019

Burden of cancer attributable to excess red and processed meat
consumption in Japan in 2015
Sarah Krull Abe1, Ribeka Takachi2,*, Junko Ishihara3, Mayo Hirabayashi1, Eiko Saito4, Megumi Hori3, Kota Katanoda4,
Tomohiro Matsuda5, Manami Inoue1; the Cancer PAF Japan Collaborators
1

Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
Department of Food Science and Nutrition, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan;
3
School of Life and Environmental Science, Department of Food and Life Science, Azabu University, Kanagawa, Japan;
4
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, National Cancer Center, Tokyo, Japan.
2

Abstract: The International Agency for Research on Cancer has evaluated red meat as probably carcinogenic andprocessed meat as carcinogenic to humans. The World Cancer Research Fund and American Institute for Cancer
Research concluded there is convincing evidence that consumption of processed meat increases the risk of colorectal
cancer. We estimated the number and fraction of cancer incidence and mortality in 2015 that could be attributed toexcess red and processed meat consumption in 2005 among the Japanese population. Data on the consumption of
red and ptocessed meat, in g/day, by sex and age group, is available for 2005 from the Japanese National Health andNutrition Survey. For the present study, the optimal consumption of red meat in Japan was considered as less than
500 g/week, or 71.4 g/day, and 0 g/day for processed meat. Population attributable fractions (PAFs) were calculated
for each sex and age group according to a standard formula, and aggregated to obtain the PAF among total cancer
incidence and mortality. We found that 0.01% and 0.4% of cancer incidence was attributable to red and processedmeat consumption, respectively, while 0.0002% and 0.3% of cancer mortality was attributable to red meat and toprocessed meat consumption. Based on the current evidence, monitoring red and processed meat consumption may
not contribute to reducing cancer incidence and mortality in Japan.
Keywords: cancer, red meat, processed meat, population attributable fraction, Japan

Introduction

Potential mechanisms by which red and processedmeat may effect cancer risk derive from high cooking
temperatures: heme iron may catalyze lipid peroxidation,
leading to tissue damage (4,5) and the formation ofcarcinogenic N-nitroso compounds (6-8). Cooking
meat at high temperatures also induces the formationof heterocyclic aromatic amines and polycyclicaromatic hydrocarbons, which might also contribute tocarcinogenesis of various sites (9-12).
Globally, red and processed meat have been linked
to an increased risk of colorectal cancer incidence(3,13). National-level estimates of the burden for all
cancers due to red and processed meat were 2.3% inAustralia (14), 2.4% in Germany (15), and 2.7% in
the UK (16). In the Japanese setting, red meat was notincluded in former studies of PAF for cancer (17) or
non-communicable diseases (18) due to relatively low
consumption compared to Europe and the US. The
2013 Japanese National Health and Nutrition Survey(JNHNS) (19) reported that an individual's averageLifestyle factors, including diet, are key determinantsof cancer risk (1). The International Agency for
Research on Cancer (IARC) has rated red meat asprobably carcinogenic (Group 2a) and processed meatas carcinogenic to humans (Group 1) (2). An expert
report by the World Cancer Research Fund (WCRF)
and American Institute for Cancer Research (AICR)
titled Food, Nutrition, Physical Activity and Preventionof Cancer concluded there was strong evidence thatthe consumption of processed meat - defined as meat
preserved by smoking, curing, salting, or the additionof chemical preservatives - and of red meat increase therisk of colorectal cancer (3). The report recommended
limiting weekly consumption to no more than about
three portions (350-500 g/week). It also reported that
consumption of processed meat was associated witha limited-suggestive increase in risk for nasopharynx,
esophagus, lung, stomach, and pancreatic cancer (3).

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daily red and processed meat consumption was 63 g and
13 g, respectively - among the lowest in the world (1921). The Japan Public Health Center-based Prospective
Study (JPHC Study) (13) found no significant
association between processed meat consumption andrisk of colorectal cancer for Japanese men and women,
but did find a significantly increased risk for red meatin the highest level consumption group, suggesting
the possibility of a risk difference between Japan andEurope or North America. A Japanese meta-analysis
reported a significant risk of colorectal cancer (22) with
red meat and a non-significant risk with processed meat,
providing the rationale for the present study.
In this report, we estimated the number and fractionof cancer incidence and mortality in 2015 that could be
attributed to excess red and processed meat consumption
in 2005 among the Japanese population.

The data on red and processed meat consumption by
sex and age group were derived from the JNHNS from2005 (24). For this purpose, we used the 3-year meanof individual datas for 2004-2006, obtained from the
Ministry of Health, Labour, and Welfare, Japan, withpermission.
Cancer incidence and mortality in Japan in 2015
We estimated cancer incidence data in 2015 using theannual estimate of cancer incidence in 2013 by the
Monitoring of Cancer Incidence project in Japan (25).
We used an age and period spline model, a type used forshort-term projection of cancer incidence (26). The sexand age-specific incidence data for target cancers werecoded using the International Statistical Classificationof Diseases and Related Health Problems, 10th edition(ICD-10), with the morphology code of the International
Classification of Disease for Oncology, 3 rd edition(ICD-O-3).
The data on total and colon cancer mortality statistics
from 2015 were obtained from Japan's vital statistics(27). We obtained sex- and age-specific mortality databy cause of death from available data sources from the
Health, Labour, and Welfare Statistics Association (28).
Similar to the cancer incidence data, we used the 4-digit
ICD-10 codes to classify the cause of death.

Materials and Methods
Cancers associated with red and processed meat
IARC rated red meat as probably carcinogenic (Group2a) and processed meat as carcinogenic to humans (Group1) (2). Additionally, the WCRF and AICR concluded
there was strong evidence that the consumption ofprocessed meat, as well as red meat, increases the risk ofcolorectal cancer (3). In the present study, therefore, we
evaluated target cancers identified by this evaluation to
be associated with red and processed meat. We included
colorectal cancer, which showed sufficient evidence for apositive association with red and processed meat and forwhich relative risk estimates were available in Japan.

Estimation of relative risk
The relative risk (RR) for colorectal cancer associatedwith consumption of red and processed meat was
sourced from a meta-analysis of Japanese cohort andcase-control studies (Table 1) (22). First, colon andrectal cancers were considered separately. However,rectum was excluded as the RR was lower than 1.00.
Consequently, we estimated PAF for only colon cancer
applying the meta-analysis RR value of cohort studies.
We used estimated risk (95% confidence interval) of
colon cancer for the highest quintile of consumption by
1.20 (1.00-1.44) and 1.18 (0.92-1.53) for red meat andprocessed meat, respectively (22). Increase in the riskby an increment of 1 g/day of red and processed meat
consumption, respectively, was calculated, based on anassumption that the relationship between exposure andcolon cancer risk is log-linear. The following equation
was used for red and processed meat consumption,
respectively, and the risk of colon cancer:

Theoretical minimum risk exposure level
For the purpose of this study, we considered the optimal
consumption of red meat in Japan - defined as beef, pork,
ham, sausage, other animal meat such as mutton, andorgan meat such as tripe - was less than 500 g/week. In
the present study, 1/7 of 500 g/week, or 71.4 g/day, wasadopted as a theoretical minimum risk exposure level.
In addition, we considered the optimal consumption ofprocessed meat, defined as ham and sausage, as 0 g/day(23).
Prevalence of excess red and processed meat estimates
The latent period, as in the interval between "exposure"to
red and processed meat and the increase in the risk ofcancer of the colon is unknown. The average followup period of the six cohorts included in the systematic
review by Pham et al. (22) was 13 years. For the present
study, we assumed that a mean latency of 10 years would
be sufficient, and therefore calculated the 2015 fractionof avoidable cancers due to red and processed meat
consumption in 2005.

Estimation of population attributable fractions (PAFs)
PAF was calculated for each sex and age group according
to the formula:(92)

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Table 1. Summary of risk estimates for the association between red and processed meat consumption and site-specific cancer
Exposure
Red meat
Processed meat

Theoretical minimum risk exposure level

Cancer type

Estimated risk for the highest
quintile of consumption

Ref.

< 500 g/week or < 71.4 g/day
0 g/day

Colon
Colon

1.20 (1.00 - 1.44)
1.18 (0.92 - 1.53)

Pham et al. (22)Pham et al. (22)

Table 2. Sex- and age-group-specific consumption of red and processed meat, in g/day in Japan in 2005
Age at exposure(2005)Red meat

Processed meat

Mean consumption (g/day)

Excess from 71.4 g/day

Mean consumption (g/day)

Excess from 0 g/day

Men
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Total

34.93
54.66
79.99
106.92
88.76
90.13
88.87
81.45
80.58
76.47
69.84
67.06
59.93
48.35
43.69
34.42
67.54

0.00
0.00
8.56
35.49
17.33
18.70
17.44
10.03
9.15
5.04
0.00
0.00
0.00
0.00
0.00
0.00
0.00

10.3
13.0
15.8
22.5
16.9
18.1
17.9
14.9
17.0
15.0
12.3
12.5
11.0
8.7
7.8
7.0
13.3

10.3
13.0
15.8
22.5
16.9
18.1
17.9
14.9
17.0
15.0
12.3
12.5
11.0
8.7
7.8
7.0
13.3

Women
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
≥ 75
Total

33.44
50.61
65.68
78.25
61.06
60.79
58.12
58.51
60.00
56.96
49.84
49.81
41.82
37.98
36.43
27.93
49.53

0.00
0.00
0.00
6.82
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00

9.7
11.8
14.3
18.4
13.3
12.9
13.5
12.4
13.3
11.5
10.1
10.3
7.6
7.5
7.5
5.3
10.5

9.7
11.8
14.3
18.4
13.3
12.9
13.5
12.4
13.3
11.5
10.1
10.3
7.6
7.5
7.5
5.3
10.5

Red meat: beef, pork, ham, sausage, other meat such as mutton, and organ meat; processed meat: ham and sausage consumption; and excess,reported as mean g/day.

Results and Discussion
Table 2 shows the age- and sex-stratified red andprocessed meat mean consumption, in g/day, and theexcess over 71.4 g/day for red meat and over 0 g/
day for processed meat for the Japanese population,
derived from the JNHNS in 2005. Red and processedmeat consumption in all categories peaked in the

The number of attributable cancers was then totalled
across all sex and age categories, in order to show thepercentage of the total number of all cancer incidence
and mortality recorded in Japan in 2015.

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Table 3. Proportion (%) of cancer in 2015 attributable to excess red and processed meat consumption in Japan
Factors
Red meatColon (C18)
Total cancer (C00-C96)
Processed meat
Colon (C18)
Total cancer (C00-C96)

Incidence

Mortality

Men

Women

Both sexes

Men

Women

Both sexes

0.1
0.0

0.0
0.0

0.1
0.0

0.1
0.0

0.0
0.0

0.0
0.0

4.3
0.4

3.3
0.4

3.8
0.4

4.0
0.3

3.0
0.3

3.0
0.3

15-19-year age group. In men, the trend of excess
consumption continued until age 49 for red meat andcontinued until the oldest age group for processed meat.
Japanese women overall consumed less red meat thanmen. While only 15-19-year-old women consumed redmeat in excess, women of all age categories consumed
processed meat in excess.
The estimated PAF of cancer incidence andmortality in 2015 attributed to red and processed meat
consumption in Japan is summarized in Table 3.
Table S1 (online data, https://www.ghmopen.com/
site/supplementaldata.html?ID=39) shows the PAF
of cancer incidence in Japan in 2015 due to red andprocessed meat consumption in 2005. Excess red meat
consumption was attributable to 0.01% of total cancer
incidence in Japan (0.01% in men and 0.0001% in
women). Excess processed meat consumption attributed
to 0.4% of total cancer incidence in Japan (0.4% forboth men and women). Table S2 (online data, https://www.ghmopen.com/site/supplementaldata.html?ID=39)
shows the PAF of cancer mortality in 2015 attributed
to red and processed meat consumption in Japan in
2005, where excess red meat consumption attributed to
0.0002% of total cancer mortality (0.01% in men and
0.0002% in women) and the excess processed meat
consumption attributed to 0.3% of total cancer mortality(0.3% for both men and women).
Additionally, using a similar approach as anAustralian study (14), we performed a sensitivity
analysis by changing the cut-off to 0 g/day insteadof 71.4 g/day for red meat consumption. The PAFs
were 0.6% (0.6% for both men and women) for cancer
incidence and 0.5% (0.5% in men and 0.6% women)
for cancer mortality.
In summary, our study suggests that 0.01% and0.4% of cancer incidence may be attributable to
red and processed meat consumption, respectively,
while 0.0002% and 0.3% of cancer mortality may
be attributable to red meat and to processed meat
consumption, respectively. The results do not greatly
differ from the theoretical minimum risk exposure levelof zero. Regarding RR, an IARC monograph reported
17% increased risk for every 100 g/portion of red meat
eaten daily (2). This is not substantially different fromthe RR used in this study (13% and 14% for every
100 g of meat consumption among men and women,
respectively), based on a meta-analysis of Japanesestudies (22).
Colorectal cancer incidence and mortality trends inJapan follow a different pattern compared to Europe
and the United States (27). This difference may be
due higher consumption of fish and less meat among
Japanesean (21).
A recent 2016 review of cancer attributable tomodifiable factors by Whiteman et al. (29) provides aninsufficient overview of the global situation for red andprocessed meat, and includes only two reports, from
Australia (14) and the UK (16). In the UK study, thetheoretical minimum risk exposure level for red meat
was nil (16), and thus was stricter than our study cut
off. The study reported that 2.7% of all cancers were
attributable to red and processed meat. The Australianstudy found men aged 19 years and older that consumed
121 g/day of red meat and 64 g/day of processed meataccounted for 2.3% of all cancers (14), with a theoreticalminimum risk exposure level of zero. In addition to thesestudies, a 2018 German study reported that 2.4% of allcancers were attributable to red meat, with a theoreticalminimum risk exposure level of 500 g red meat/week
and 0 g processed meat/week (15). Red and processedmeat is not as popular or heavily consumed in Japan asin Western countries, resulting in the low attributed PAF
in Japan. Therefore, policies to control red and processedmeat consumption will likely not be effective to reducecancer incidents and mortality in Japan.
Conclusion
Our analysis provides evidence for the relatively smallburden of cancer attributable to red and processed meat
consumption in Japan. From the results, 0.01% and 0.4%
of cancer incidence, and 0.0002% and 0.3% of cancer
mortality is attributable to red and processed meat
consumption, respectively. These findings may provide
critical evidence for the priority ranking of programs
aimed to reduce the cancer burden in Japan.
Funding: This study was supported by JSPS KAKENHI(94)

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Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.

15.

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bunya/kenkou/eiyou07/01.html (accessed October 20,2021). (in Japanese)
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A, Matsuda A, Nishino Y, Hattori M, Soda M, Ioka A,
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stat/statistics/data/dl/en.html (accessed November 8,2021).
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Received June 12, 2021; Revised November 17, 2021;
Accepted December 8, 2021.
Released online in J-STAGE as advance publication December
13, 2021.
*Address correspondence to:
Ribeka Takachi, Department of Food Science and Nutrition,
Graduate School of Humanities and Sciences, Nara Women's
University, Kitauoya Nishimachi, Nara 630-8506, Japan.
E-mail: rtakachi@cc.nara-wu.ac.jp(96)Brief Report

GHM Open. 2021; 1(2):97-101.
DOI: 10.35772/ghmo.2021.01020

Burden of cancer attributable to exogenous hormone use in Japan in2015
Mayo Hirabayashi1, Chisato Nagata2, Sarah Krull Abe1, Norie Sawada3, Eiko Saito4, Megumi Hori4, Kota Katanoda4,
Tomohiro Matsuda5, Manami Inoue1,3,*; the Cancer PAF Japan Collaborators
1

Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan;
3
Division of Cohort Research, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
4
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;5
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International Affairs,
Strategic Planning Bureau National Cancer Center, Japan, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
2

Abstract: Exogenous female hormone use has not been as popular in Japan as in western populations. Here, weestimated the population-attributable fraction (PAF) of cancers in Japan in 2015 attributed to exogenous female
hormone use. We used the most recent prevalence data for oral contraceptives (OC) and hormone replacement therapy(HRT), available from a large-scale population-based cohort study started in 2011-2016. For the purpose of this study,
optimal usage of exogenous hormones was considered to be none. PAF was calculated for each age group using astandard formula. Overall, a negligible fraction, 0.4% of cancer incidence and 0.2% of cancer mortality in Japanesewomen was attributable to exogenous hormone use (OC use and HRT), and 0.2% of cancer incidence and 0.1% ofcancer mortality overall when both sexes combined. The relatively low prevalence of exogenous hormone use in Japan
compared to Western countries may explain the low fraction of cancer attributable to exogenous hormones among
Japanese women.
Keywords: cancer, exogenous hormone use, oral contraceptives, hormone replacement therapy, population attributablefraction, Japan

Introduction

to the regimens.
The usage of hormonal preparations in Japan has
always been low. Despite the popularity of using HRT
in the US and European nations, in 2011-2016, only
2.4% and 4.8% of women aged 40-74 had reported everuse of any type of OC and HRT, respectively, based onrecent cohort study data in Japan (2).
In this report, we explore the population-attributablefractions (PAF) of cancers in Japan in 2015 attributed toexogenous female hormone use.

In 2007, the International Agency for Research on Cancer(IARC) published a monograph on carcinogenic risk tohumans that concluded that combined oral-progestogencontraceptives (OC) are carcinogenic to humans (1),particularly for cancers of the breast, cervix, and liver.
On the contrary, however, there is also convincing
evidence that these agents may act as protective factors
for cancer of the endometrium and ovary.
The same review by IARC also concluded that,with regard to hormone replacement therapy (HRT),
there is sufficient evidence in the association between
combined estrogen-progestogen menopausal therapies
and cancer of the breast (1). The finding of increased
breast cancer risk associated with HRT has mainly
been found among current users. Combined estrogenprogestogen menopausal therapy was considered tobe carcinogenic to humans if progestogens are taken
for less than 10 days per month; however, the risk forendometrial cancer was inversely associated with thenumber of days per month that progestogens are added

Materials and Methods
Cancers associated with exogenous hormone use
IARC has confirmed the usage of both OC (combined
estrogen-progestogen) and HRT (combined estrogenprogestogen menopausal therapy) as Group 1,
carcinogenic to humans (3). For the purpose of thisstudy, we chose sites associated with OC and HRT
for which IARC has found sufficient evidence forpositive associations using available data on relative(97)

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risk. The cancer sites included in this report are breast,
endometrium, and ovary.

Cancer incidence and mortality in 2015
Cancer incidence data in 2015 were estimated using
the annual estimate of cancer incidence in 2013 by
the Monitoring of Cancer Incidence in Japan (5) using
an age and period spline model, which are used as ashort-term projection method for cancer incidence inJapan (6). The sex- and age-specific incidence data fortarget cancers were coded based on the International
Statistical Classification of Diseases and Related Health
Problems, 10th edition (ICD-10), using the morphology
code of the International Classification of Disease forOncology, 3rd edition (ICD-O-3).
The data on cancer mortality statistics from 2015
were based on the vital statistics of Japan (7). We
obtained sex- and age-specific mortality data by causeof death from an available data source from the Health,Labour, and Welfare Statistics Association (8). Similarly
to the cancer incidence data, 4-digit ICD-10 codes wereused to classify the cause of death.

Theoretical minimum risk exposure level
PAF of cancers associated with exogenous hormone
use is the proportion of cancers diagnosed in acertain period in a population that could possibly
have been prevented if no one in the population used
OC or HRT. Accordingly, the optimal exposure toexogenous hormone use in this study was defined as
no use. Analyses were conducted based on the type of
exogenous hormone used (OC use or HRT).
Prevalence of exposure to hormonal use
No latent period was assumed in relation to female
hormonal use, as current and recent users of female
hormones are thought to be at the highest risk. To obtain
Japanese data from a study or survey as close to 2015as possible, we used data from the Japan Public HealthCenter-based Prospective Study for the Next Generation(JPHC-NEXT) (4) for both OC and HRT use. These
data were based on a self-administered questionnaire
given at baseline, which included exogenous hormone
use. The generally healthy women (n ≈ 60,000) wereasked if they had ever used OC and HRT. The baseline
summary for OC and HRT use was reported (2). We
further obtained age group-specific data from theresearch group for the purpose of this study. Since theJPHC-NEXT study includes participants aged 40-74,
we assumed that the prevalence of OC use by those
aged under 40 years was equal to that of those aged 4044, and that the prevalence of HRT use by those aged
over 75 was equal to that those aged 70-74.
Table 1 shows the proportion of the Japanesewomen with recent OC use and HRT by age group.

Estimates of relative risk of exposure to exogenous
hormonal use
Given that previous studies on exogenous hormone use
and cancer risk conducted in Japanese women werelimited, we used results from global meta-analyses as
described below.
OC useBreast cancer: In 1996, the Collaborative Groupon Hormonal Factors in Breast Cancer (9) conducted
an analysis of global epidemiological evidence on theassociation between use of OC and breast cancer risk.
The relative risks associated with current and former
use of OC (estrogen and progesterone) showed that OC
use lead to a slight increase in risk.

Table 1. Proportion of exogenous hormone use with oral contraceptives (OC) and hormone replacement therapy (HRT) inJapan
Age at exposure and outcome(2015)
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84≥ 85

Proportion of oral contraceptive(OC) usage in the population (%)

Proportion of hormone replacement therapy (HRT)
usage in the population (%)

0.0
0.0
3.5
3.5
3.5
3.5
3.5
2.8
2.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0

0.0
0.0
0.0
0.0
0.0
0.0
1.3
3.4
6.3
6.5
5.9
5.9
4.8
4.8
4.8
4.8

Data source: Reference (2,4)(98)

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Table 2. Summary of risk estimates of site-specific cancers associated with exogenous hormone use for the present analysis
Factors

Cancer type

Oral contraceptiveuseBreast

HRT use

Ovary

Endometrium

BreastOvary*

Studies

Reference group

Increase in risk

Collaborative Group on Hormonal Factors in Breast Cancer(1996) (9)Collaborative Group on Epidemiological Studies on
Endometrial Cancer (2015) (10)Collaborative Group on Epidemiological Studies of Ovarian
Cancer (2008) (11)Kim et al. (2018) (18)Meta-analysis of the result of prospective studies fromCollaborative Group on Epidemiological Studies on ovarian
Cancer (2015) (19)Never

1.07 ± 0.02*

Never

0.69 (0.66 - 0.73)

Never

0.73 ± 0.02**

Never
Never

1.33 (1.24 - 1.44)
1.22 (1.06 - 1.38)

Standard deviation. **Standard error.

Endometrial cancer: In 2007, IARC concluded
that there is strong evidence that the use of estrogenprogestogen OC has a protective effect against
carcinogenicity in the endometrium (1). Based on theirreview of four cohorts and 21 case-controls, risk forendometrial cancer among women who had taken these
medications, and the reported risk reduction generally
correlated with the duration of use and persisted forat least 15 years after cessation of use. A more recent
meta-analysis published in 2015 (10) echoed theseprevious findings, although the risk reduction was
marginally smaller.
Ovarian cancer: A 2007 review by IARC concluded
that OC use had a protective effect against ovariancancer among women (1). Not only was risk reduction
associated with the duration of OC use, its protective
effect persisted over two decades. An analysis conductedby the Collaborative Group on Epidemiological Studies
of Ovarian Cancer in 2008 (11) showed that ever usersof OC had 27% risk reduction compared to never users.

Estimation of population attributable fractions (PAFs)
PAF was calculated using the standard formula (20):Where P refers to the prevalence of hormonal usage
by age. For the PAF estimation, we included age 2054 for OC use and age 40 and over for HRT use. The
numbers of attributable cancers were then totalled
across age categories to show a percentage of the total
number of all incidence and mortality of cancer inJapan in 2015.
Results and Discussion
Table 1 shows the proportion of exogenous hormone
use among Japanese women around 2015 by age group.
Around 3% in the age 20-54 group was using OC andaround 5% of the population aged 40 and over wasusing HRT.
Table 2 shows a summary of risk estimates for eachof the cancer sites associated with exogeneous hormone
use. For the present study, we included breast cancer for
OC use and breast and ovarian cancer for HRT use.
The estimated PAF of cancer incidence and mortality
in 2015 attributed to exogenous hormone use (OC use
and HRT), individually and aggregated in Japan issummarized in Table 3. In the Japanese setting, only
breast cancer incidence and mortality were attributable
to OC use, with 62 incident cases and 5 deaths.
Accordingly, the overall PAF for OC use was 0.02%
for cancer incidence and 0.003% for cancer mortality
in Japanese women. Likewise, breast and ovariancancer were attributed to recent HRT, accounting for
1,391 cases and 274 deaths. Overall PAF for the HRT
was 0.3% for cancer incidence and 0.2% for cancer
mortality. In total, 0.4% of all cancer incidence and0.2% of all cancer mortality in Japanese women in2015 were attributable to exogenous hormone use, and
0.2% of total cancer incidence and 0.1% of total cancer

HRT
Breast cancer: The magnitude of the risk of HRT
for risk of breast cancer has now been well established,mainly through studies conducted in the United States,
Europe, and the UK (12-16). In the Million Women
Study (17), compared to never users, the RR of current
HRT users was 1.66 (95% Confidence Interval (CI):1.58-1.75), while among past HRT users the risk did
not differ from never users. For the present study, wederived HR for breast cancer from a meta-analysis
conducted by Kim et al. (18) conducted in 2018, which
reported the pooled HR of 23 prospective cohort studies
and two randomized controlled trials to be 1.33 (95%
CI: 1.24-1.44).
Ovarian cancer: The RRs of ovarian cancer by
duration of HRT use in current and past users was
obtained from a meta-analysis of individual participant
dataset (19). We further conducted a meta-analysisof these RRs to obtain a summary RR of HRT use in
ovarian cancer.
Table 2 shows a summary of the studies used in thisestimate to derive RRs.

(99)

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Table 3. Proportion (%) of cancer in 2015 attributable to exogenous hormone use in Japan
Factors
Oral contraceptive use (OC)Breast (C50)
Endometrium (C54)
Ovary (C56)
Total cancer (C00-C96)
Hormone replacement therapy (HRT)
Breast (C50)
Ovary (C56)
Total cancer (C00-C96)
Exogenous hormone use (OC and HRT)
Breast (C50)
Endometrium (C54)
Ovary (C56)
Total cancer (C00-C96)

Incidence
Women

Mortality

Both sexes

Women

0.1
0.0
0.0
0.02

0.04
0.0
0.0
0.003

1.5
1.0
0.3

1.6
1.1
0.2

1.6
0.0
1.0
0.4

1.2
0.0
1.0
0.2

mortality when both sexes were combined. Detailed
results for each cancer, sex, and age group are shownfor in Tables S1-S2 (online data, https://www.ghmopen.
com/site/supplementaldata.html?ID=37).
In this study, we estimated the impact of exogenous
hormone use on cancer incidence and mortality among
Japanese women in 2015. We found that 0.4% of allcancer incidence and 0.2% of all cancer mortality were
attributable to exogenous hormone use by Japanesewomen. Our findings (0.02% for OC, 0.3% for HRT
among Japanese women) are lower than those fromrecent studies in Australia for 2010 (21-23) and in the
UK for 2015 (24), where PAFs among overall cancers inwomen in Australia were 0.3% for OC use and 1.1% for
HRT use, and 0.5% and 0.8% in the UK, respectively.
The low prevalence data for OC and HRT use in Japanapplied in this study may explain the low PAF of cancer
attributable to exogenous hormones. Published data on
the prevalence of exogenous hormone use in Japaneseare limited. In the present study we used the most recent
prevalence data for OC and HRT usage from the baseline
data of a large-scale cohort study obtained in 20112016, which reflect recent exposure level to exogenous
hormone use in the general Japanese population.
The Japan Nurses' Health Study (JNHS) reported theprevalence of OC and HRT use among female nurses
by cross-sectional survey between 2001-2007 (25), in
which the lifetime prevalence of exogenous hormone use
was 6.0% for OCs and 13.8% for HRT, albeit that these
are relatively high compared with other studies focusing
on general Japanese populations (2,26). According
to the recent estimates from the United Nations thatshowed the estimated prevalence of contraceptive use
among women of reproductive age (15-49) in 2019,
the estimated prevalence of use of the pill was 2.9% inJapan (27), which accorded with our referenced data. We
applied the prevalence data closest to the year 2015, andin the general population. More accurate estimates forrisk would allow a better understanding of the impact of

1.6
0.0
1.1
0.2

Both sexes

1.6
0.0
1.1
0.1

usage of exogenous hormones on cancer burden among
Japanese women.
Conclusion
Our estimate found an overall negligible fraction, 0.4%
of cancer incidence and 0.2% for cancer mortality
in Japanese women, was due to exogenous hormone
use (OC use and HRT). The low fraction of cancer
attributable to exogenous hormones among Japanesewomen may be explained by the relatively low
prevalence of exogenous hormone use in Japan comparedwith Western countries.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received June 12, 2021; Revised November 23, 2021;
Accepted December 8, 2021.
Released online in J-STAGE as advance publication December
13, 2021.
*Address correspondence to:
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Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuoku, Tokyo 104-0045, Japan.
E-mail: mnminoue@ncc.go.jp(101)

Brief Report

GHM Open. 2021; 1(2):102-105.
DOI: 10.35772/ghmo.2021.01021

Burden of cancer attributable to never breastfeeding in Japan in 2015
Mayo Hirabayashi1, Chisato Nagata2, Sarah Krull Abe1, Eiko Saito3, Megumi Hori3, Kota Katanoda3,
Tomohiro Matsuda4, Manami Inoue1,*; the Cancer PAF Japan Collaborators
1

Division of Prevention, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan;
Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan;
3
Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan;
4
National Cancer Registry Section Center for Cancer Registries Center for Cancer Control and Information Services/Office of International
Affairs, Strategic Planning Bureau National Cancer Center, Japan, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
2

Abstract: We estimated the population attributable fraction (PAF) of cancers in Japan attributed to neverbreastfeeding in 2015. The data on breastfeeding in Japan were derived from two sources. Data on women aged
younger than 40 were obtained from the Longitudinal Survey of Babies in the 21st Century (LSB21); those forwomen aged 40 to 69 was derived from the Japan Public Health Center-based Prospective Study for the Next
Generation (JPHC-NEXT). For the present study, the optimal frequency of breastfeeding was a history of everbreastfeeding. The PAF was calculated for each age group using a standard formula. Overall, 0.3% of total cancer
incidence and 0.1% of total cancer mortality in Japanese women were attributable to never breastfeeding. The highprevalence of women who breastfed children may explain the lower fraction of cancer attributable among Japanesewomen compared to studies from other parts of the world.
Keywords: cancer, breastfeeding, population attributable fraction, Japan

Introduction
The Continuous Update Report (CUP) on Food,
Nutrition, Physical Activity and Prevention of Cancer by
the World Cancer Research Fund (WCRF) and American
Institute for Cancer Research (AICR) concluded that
there is probable evidence for an association between
breastfeeding and decreased risk of breast cancer(1). In 2002, the Collaborative Group on Hormonal
Factors in Breast Cancer showed that for every yearof breastfeeding, the risk of breast cancer decreases by
4.3% (2). On the other hand, the association between
breastfeeding and cancer risk of female reproductive
organs is unknown. There is a limited or suggestive
evidence for an association between breastfeeding
and increased risk for ovarian cancer (1). While thatreport also discussed evidence for endometrial cancer,
it was considered too limited to allow the drawing of aconclusion (1).
Here, we estimated the population-attributablefractions (PAF) of cancer incidence and mortality inJapan in 2015 attributed to never breastfeeding.
Materials and Methods
Cancers associated with breastfeeding

We defined the PAF of cancers associated withbreastfeeding as the proportion of cancers diagnosed
in a certain period in a population that could possibly
have been prevented if everyone in the population everbreastfed children. In this study, we included cancers
that were discussed in the WCRF/AICR CUP project (1).
The cancer sites included in this estimate were breast,
endometrium, and ovary.
Theoretical minimum risk exposure level
The optimum level of breastfeeding was considered asa history of ever breastfeeding.
Prevalence of breastfeeding
The latent period between cancer onset and breastfeeding
is unknown. Therefore, for this study, we decided
the optimal exposure to breastfeeding is a history ofever breastfeeding. Since 2001, the Japanese Ministryof Health, Labour and Welfare (MHLW) has been
implementing a survey, called the Longitudinal Surveyof Babies in the 21st Century (LSB21), with the aim ofdeveloping strategies to combat the declining fertility
rate in Japan (3). The LSB21 surveyed families fromall over Japan with newborns delivered between the(102)

GHM Open. 2021; 1(2):102-105.

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10th and 17th of January or July of 2001. The baseline
questionnaire was sent to all of the families six orseven months after the baby was born. Followup questionnaires were then sent annually. Eachparticipating child's birth records were linked with theJapanese vital statistics, which includes informationsuch as birth length and weight, gestational age, sex andparental age.
For the history of breastfeeding, LSB21 obtained
this information from the baseline questionnaire. The
question asked whether the mother breast fed, formulafed, or both, in addition to the duration (ranging fromzero to seven months). For people aged 40 and over,
we used data from the Japan Public Health Centerbased Prospective Study for the Next Generation(JPHC-NEXT), launched in 2011 (4). JPHC-NEXTis population-based cohort study being conducted inseven prefectural areas all over Japan. Self-administeredquestionnaires about lifestyle were provided to all
residents aged 40 to 74 at the time of the baseline survey.
The questionnaire asked female participants if they had
ever breastfed their child, and if they answered yes, theduration. Table 1 shows the proportion of women who
were breastfeeding in 2005.
Cancer incidence and mortality in 2015
Cancer incidence in 2015 was estimated using theannual estimate of cancer incidence in 2013 by
the Monitoring of Cancer Incidence in Japan (5).
Estimation was done using an age and period spline
model, a type of analysis which is used for short-term
projection of cancer incidence in Japan (6). The sexand age-specific incidence data for target cancers werecoded in accordance with the International Statistical
Classification of Diseases and Related Health Problems,
10th edition (ICD-10), using the morphology code of theInternational Classification of Disease for Oncology, 3rd
Table 1. Staining Intensity of ALM and SSM lesions
Age at exposure (2005)
0-4
5-9
10 - 1415 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 4445 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74≥ 75

Proportion of ever breastfeeding (%)
Ever (%)

Never (%)

0
0
0
0
94
94
94
94
94.4
93.5
91.2
90.4
90.6
92.1
92.1
92.1

100
100
100
100
6
6
6
6
5.6
6.5
8.8
9.6
9.4
7.9
7.9
7.9

edition (ICD-O-3).
The data on cancer mortality from 2015 were basedon the vital statistics of Japan (7). We obtained sexand age-specific mortality data by cause of death froman available data source from the Health, Labour, andWelfare Statistics Association (8). Similar to the cancer
incidence data, 4-digit ICD-10 codes we used to classify
the cause of death.
Estimates of relative risk of history of breastfeeding
Table 2 shows a summary of relative risk estimates usedin the present estimate, in which relative risk (RR) was
measured compared to women who had no history ofbreastfeeding. The estimates, derived from the studies
listed, were adjusted for potential major confounders.
For breast (9) and ovarian cancer (10), the RRs were
derived from a Japanese-based cohort study among
women who were parous. For the risk of endometrial
cancer, the RR was derived from a meta-analysis
consisting of 15 studies, including three Japanesestudies (11).
Since RRs for ever breastfeeding comparedwith never were estimated for the target cancers, we
calculated the reciprocal of each RR to obtain the RR
for never breastfeeding versus ever.
Estimation of population attributable fractions (PAFs)
PAF was calculated using the standard formula (12):Where P refers to the prevalence of neverbreastfeeding by age. The numbers of attributable
cancers were then totalled across age categories, in orderto show a percentage of the total number of all cancer
incidence and mortality in Japan in 2015.
Results and Discussion
Table 1 shows the proportion of Japanese women withever and never experience of breastfeeding in 2005 byage group. Among women aged 20 and over, over 90%
have breastfed at least once. In comparison to women
who had no history of breastfeeding women who
breastfed had the following RR: breast 0.86 (0.65-1.15)(9), ovarian 1.00 (0.5-1.90) (10), and 0.88 (0.72-1.06) (11)(Table 2).
The estimated PAF of cancer incidence and mortality
in 2015 attributed to never breastfeeding in Japan issummarized in Table 3. Detailed results for each cancer,
sex, and age-group are shown for in Tables S1-S2 (online
data, https://www.ghmopen.com/site/supplementaldata.
html?ID=38). In the Japanese setting, the only breast(103)

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Table 2. Summary of risk estimate of site-specific cancers associated with breastfeeding for the present analysis
Factors

Cancer typeStudies

Reference group

Decrease in risk

Breastfeeding

BreastOvarianEndometrium

Iwasaki et al. (2007) (9)Weiderpass et al. (2012) (10)Zhan et al. (2015) (11)

Never
Never
Never

0.86 (0.65 - 1.15)
1.00 (0.5 - 1.90)
0.88 (0.72 - 1.06)

Table 3. Proportion (%) of cancer in 2015 attributable to never breastfeeding in Japan
Factors
Breast (C50)
Endometrium (C54)
Ovary (C56)
Total cancer (C00-C96)

Incidence
Women

Mortality

Both sexes

Women

Both sexes

0.1

1.3
1.1
0.0
0.1

0.1

1.3
1.1
0.0
0.3

cancer incidence and mortalities attributable to neverbreastfeeding were of breast and endometrium, with
about 1% of incidence and mortality for each (breast:
1,066 attributable cases, 176 attributable deaths;
endometrium: 165 attributable cases, 22 attributable
deaths). Overall, in 2015, there were 1,231 cases and 202
deaths attributable to a history of never breastfeedingin 2005. Accordingly, the overall PAF for neverbreastfeeding was 0.3% for cancer incidence and 0.1%
for cancer mortality in Japanese women.
In this report, we used RRs calculated for cancers in
relation to never breastfeeding on the number of cancer
incidence and mortality among Japanese women in 2015.
We estimated that 1,231 cancer incident cases (0.30%
of total cancer incidence) and 202 cancer deaths (0.13%
of total cancer mortality) in 2015 could be attributed tonever breastfeeding. These estimates are relatively low
compared to results from the United Kingdom (UK)(1.5%) (13) but similar to the results from Australia(0.5%) (14).
With regard to breast cancer risk, these UK andAustralian studies (13,14) found that 4.7% and 1.7% ofcases were attributable to breastfeeding, respectively.
These numbers are higher than our present finding(1.3%). This could be attributable to the difference inthe proportion of women who have breastfed, as wellas in the duration of breastfeeding used for calculation.
In the UK (13) and Australia (14), 52-66% and 83% of
women had initiated breastfeeding upon the birth of achild in 2000 and 2001, respectively. Compared to these
two Western studies, over 90% of all Japanese women
included in the study had breastfed. Further, the definition
used as a history of breastfeeding differed - while the UK
and Australia studies had clear definitions of what wasconsidered breastfeeding, our study defined a historyof breastfeeding as a history of ever breastfeeding. The
result from Australian study suggested that breastfeeding
for less than 12 months is associated with an increased
risk of cancer. Given these methodological differences,

it is difficult to make direct comparisons between theseprevious and our present studies.
The protective effect of breastfeeding on breast
cancer is not direct, but likely an indirect cause, suchas due to lactation. According to the CUP project, thereduction in breast cancer may result from the hormonal
influence of the associated period of amenorrhea andinfertility (1). A longer lactation period leads to a reduced
number of menstrual cycles throughout life, altering
the cumulative exposure to sex hormones, which are
known risk factor for post-menopausal breast cancer.
The exfoliation of breast tissues during lactation, as wellas the apoptosis of epithelial cells after the breastfeeding
period is over, might eliminate cells with DNA damage
and mutations, leading to lower breast cancer risk (1).
A more accurate history of lactation history estimatesfor risk would allow a better understanding of the impact
of possible protective factors of breastfeeding on cancer
burden among Japanese women.
Conclusion
Our estimate found an overall 0.3% of total cancer
incidence and 0.1% of total cancer mortality in Japanesewomen was attributable to never breastfeeding. The highprevalence of women who breastfed may explain thelower fraction of cancer attributable among Japanesewomen compared to studies from other parts of theworld.
Funding: This study was supported by JSPS KAKENHI
Grant Number 16H05244.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received June 12, 2021; Revised November 17, 2021;
Accepted December 8, 2021.
Released online in J-STAGE as advance publication December
13, 2021.
*Address correspondence to:
Manami Inoue, Division of Prevention, Center for Public
Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuoku, Tokyo 104-0045, Japan.
E-mail: mnminoue@ncc.go.jp(105)

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Suggested Reviewers: A list of up to 3 reviewers whoare qualified to assess the scientific merit of the study iswelcomed. Reviewer information including names, affiliations,addresses, and e-mail addresses should be provided at thesame time the manuscript is submitted online. Please do notsuggest reviewers with known conflicts of interest, including
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