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ORIGINAL ARTICLE
Dietary acrylamide intake and risk of breast cancer: The
Japan Public Health Center-based Prospective Study
Ayaka Kotemori
1
|
Junko Ishihara
2
|
Ling Zha
3
|
Rong Liu
3
|
Norie Sawada
1
|
Motoki Iwasaki
1
|
Tomotaka Sobue
3
|
Shoichiro Tsugane
1
|
for the JPHC Study Group
†
1
Epidemiology and Prevention Group,
Center for Public Health Sciences, National
Cancer Center, Tokyo, Japan
2
Department of Food and Life Science,
Azabu University, Kanagawa, Japan
3
Department of Environmental Medicine
and Population Sciences, Graduate School
of Medicine, Osaka University, Osaka,
Japan
Correspondence
Junko Ishihara, Department of Food and Life
Science, Azabu University, Kanagawa, Japan.
Email: j-ishihara@azabu-u.ac.jp
Funding information
National Cancer Center (Grant/Award
Number: ‘the National Cancer Center
Research and Development’), the Food
Safety Commission, No. 1503, Cabinet
Office, Government of Japan (Grant/Award
Number: ‘Research Program for Risk
Assessment Study on Food’), the Ministry of
Health, Labour and Welfare of Japan (Grant/
Award Number: ‘a Grant-in-Aid for Cancer
Research’).
Acrylamide forms during cooking and is classified as a probable carcinogen in
humans, mandating the need for epidemiological studies of dietary acrylamide and
cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japa-
nese women has not been assessed. We investigated the association between diet-
ary acrylamide intake and risk of breast cancer in the Japan Public Health Center-
based Prospective Study. The present study included 48 910 women aged 45-
74 years who responded to a 5-year follow-up survey questionnaire. Dietary acry-
lamide intake was assessed using a validated food frequency questionnaire. Cox
proportional hazards regression models were used to estimate hazard ratios and
95% confidence intervals. During an average of 15.4 years of follow up, 792 breast
cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associ-
ated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest
tertile =.95, 95% confidence intervals: 0.79-1.14, P-trend =.58). Further, no signifi-
cant associations were observed when stratified analyses were conducted by smok-
ing status, coffee consumption, alcohol consumption, body mass index, menopausal
status, estrogen receptor status, and progesterone receptor status. In conclusion,
dietary acrylamide intake was not associated with the risk of breast cancer in this
population-based prospective cohort study of Japanese women.
KEYWORDS
acrylamide, Asia, breast cancer, diet, epidemiology
1
|
INTRODUCTION
Acrylamide was classified as a probable human carcinogen (group
2A) by The International Agency for Research on Cancer in
1994.
1
Until 2002, the main sources of acrylamide exposure were
thought to be through specific occupations or smoking.
2
However,
Swedish researchers found that acrylamide occurs in carbohydrate-
rich foods cooked at over 120°C, showing that one of the most
common forms of acrylamide exposure in the population was from
meals.
3
The carcinogenicity of dietary acrylamide is considered to occur
through a genotoxic pathway.
4
Acrylamide is soluble in water,
absorbed from the gastrointestinal tract, and transported to several
organs.
5
Acrylamide is metabolized by 2 pathways,
5
a direct pathway
by glutathione conjugation of acrylamide by GST, and a second by
Abbreviations: BMI, body mass index; CI, confidence interval; DCO, death certificate only;
DR, dietary record; ER, estrogen receptor; FFQ, food frequency questionnaire; HR, hazard
ratio; ICD-O-3, International Classification of Diseases for Oncology, Third Edition; JPHC
Study, the Japan Public Health Center-based Prospective Study; MOE, margin of exposure;
PR, progesterone receptor.
†
Members of the JPHC Study Group are listed at the following site (as of April 2016):
http://epi.ncc.go.jp/en/jphc/781/3838.html
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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
©2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Received: 9 November 2017
|
Revised: 14 December 2017
|
Accepted: 26 December 2017
DOI: 10.1111/cas.13496
Cancer Science. 2018;1–11. wileyonlinelibrary.com/journal/cas
|
1
glycidamide by cytochrome P450 and conjugation by GST. Both
acrylamide and glycidamide can combine with DNA and cause
genotoxicity.
5
From the national dietary survey in Japan in 2012, acrylamide
intake was estimated by Monte Carlo simulation to be 0.166 lg/kg
bodyweight per day.
6
This level is less than half of that reported in
Western populations, namely 0.45 lg/kg bodyweight per day in the
Dutch
7
and 0.41 lg/kg bodyweight per day in Norwegians.
8
These
levels are lower than in animal studies;
9,10
however, when the
benchmark dose lower confidence limit (BMDL
10
) is 0.31 mg/kg
bodyweight per day for mammary tumors in rats, the MOE is
<10 000.
2
Therefore, the Food Safety Commission of Japan is
vigilant about the possibility of a carcinogenic effect of dietary
acrylamide.
2
Currently, 8 studies have examined the relationship between
dietary acrylamide exposure and breast cancer.
11-18
A recent meta-
analysis of these studies observed that dietary acrylamide intake was
not associated with the risk of breast cancer.
19
However, these stud-
ies were all conducted in Western countries and no study has
assessed the risk of acrylamide intake on breast cancer in Asians.
Moreover, the meta-analysis included 7 studies, and some estimates
were from stratified analyses, such as in premenopausal women
16
or
by hormone receptor status of breast cancer.
17
The results might
therefore not be robust, and further investigation among a variety of
populations with various levels of acrylamide intake may be
necessary.
The aim of the present study was to investigate the association
between dietary acrylamide intake and the risk of breast cancer in
the JPHC Study.
2
|
MATERIALS AND METHODS
2.1
|
Study participants
The JPHC Study is a population-based prospective study which aims
to investigate the associations between lifestyle and lifestyle dis-
eases in 2 cohorts. Cohort I was launched in 1990 in Iwate, Akita,
Nagano, Okinawa-Chubu, and Tokyo, whereas Cohort II was started
in 1993 in Ibaraki, Niigata, Kochi, Nagasaki, Okinawa-Miyako, and
Osaka. The study protocol has been described previously.
20,21
Partic-
ipants were 140 420 inhabitants (68 722 men and 71 698 women)
aged 40-69 years in the jurisdictional area of these 11 public health
centers. Inhabitants in the Tokyo area were not included as partici-
pants in this study because their incidence data were not available.
The study protocol was approved by the institutional review boards
of the National Cancer Center, Tokyo, Japan, Osaka University and
Azabu University. The authors confirm that some access restrictions
apply to the data underlying the findings.
A dietary survey using a self-administered FFQ was conducted at
baseline, and at 5- and 10-year follow up. The FFQ of the 5-year
follow-up survey obtained more detailed dietary information than
the FFQ of the baseline survey because it included more food items
and portion size options than the baseline survey questionnaire. We
therefore used the 5-year follow-up survey as the starting point of
the present study.
After excluding participants who were disqualified (non-Japanese
nationality, incorrect late report of migration occurring before the
starting point, or incorrect birth data) or had died, moved out of a
study area, or were lost to follow up before the starting point,
62 750 women were eligible for participation. Of these, 52 483
women responded to the 5-year follow-up questionnaire (response
rate 83.6%).
Participants with a past history of breast cancer as identified by
the questionnaire (N =478) and those diagnosed with breast cancer
from the baseline survey to the time of the 5-year follow-up survey
were excluded (N =27). Participants with missing or extreme (upper
and lower 2.5 percentiles) energy intake data were also excluded
(N =3068). Finally, 48 910 participants were included in the study
(Figure 1).
FIGURE 1 Flowchart of study participants in the Japan Public
Health Center-based Prospective Study on dietary acrylamide intake
and risk of breast cancer
2
|
KOTEMORI ET AL.
2.2
|
Assessment of energy and acrylamide intake
from FFQ
The FFQ is based around a list of 138 food and beverage
items, each with 9 categories of eating frequency (never, 1-3
times/mo, 1-2 times/wk, 3-4 times/wk, 5-6 times/wk, 1 time/d,
2-3 times/d, 4-6 times/d, or ≥7 times/d). The food items also
have 3 categories of portion size (less than half the standard
portion size, standard portion size, or more than 1.5-fold the
standard portion size). Intake amount of each food and beverage
was estimated by multiplying the eating frequency with the
portion size.
Energy intake was estimated using the Fifth Revised and
Enlarged Edition of the Standard Tables of Food Composition in
Japan.
22
A validation study of the FFQ was previously conducted by
comparing intake from a 28-day DR as reference in a subcohort of
the JPHC study.
23-25
Correlation coefficients of energy intake among
women were 0.41 and 0.24 in Cohort I (n =113) and II (n =176),
respectively.
23
We previously reported the validity of acrylamide
intake measurement from the FFQ using this existing data and our
database of measured values of acrylamide content in common Japa-
nese foods elsewhere.
26
Briefly, we developed a database of acry-
lamide-containing foods commonly consumed in Japan using
published reports of measurements and selected the values of the
following foods and beverages: miso, beer, baked fish paste, bread,
rice cake, Japanese-style confectionary, cake, biscuits and cookies,
chocolate, peanuts, fried tofu, green tea, oolong tea, black tea, cof-
fee, and soup.
6,27-35
Further, we considered the amount of acry-
lamide consumed from homemade cooking. Acrylamide intake from
heated starchy vegetables (potato, sweet potato), vegetables (onion,
bean sprouts, sweet pepper, squash, cabbage, snap beans, broccoli),
toast, boiled or stir-fried rice, and fried batter was calculated by mul-
tiplying the amount of raw food, the proportion of heated food cal-
culated from the DR and the concentration of acrylamide in each
heated food.
6
Because Cohort I and Cohort II are independently
conducted studies which collected DR among different populations,
we used the proportion of cooking methods among Cohort I in the
calculation of acrylamide in Cohort II, or vice versa. The de-attenu-
ated correlation coefficients of energy-adjusted acrylamide intake
among women were 0.48 and 0.37 in Cohorts I and II, respec-
tively.
26
2.3
|
Follow up and identification of breast cancer
All participants were followed from the starting point until Decem-
ber 31, 2013 (until December 31, 2012 in the Osaka area only). Res-
idence status was confirmed annually through the residential
registry. During the follow-up period, 6059 (12.4%) participants died,
3330 (6.8%) moved out of the study area, and 33 (0.1%) were lost
to follow up.
Incidence of breast cancer was identified through the following
data sources: active patient notification from major local hospitals in
the study area and data linkage with population-based cancer reg-
istries. Death certificates were used as a supplementary information
source. Cases were coded using the ICD-O-3; breast cancer is
C500-509. The proportion of cases ascertained by DCO was 1.9%.
This percentage was considered satisfactory for the present study.
With a mean follow-up period of 15.4 years, a total of 792 newly
diagnosed breast cancer cases were identified by December 31,
2013.
2.4
|
Statistical analysis
Person-years of follow up were determined from the starting point
until the date of diagnosis of breast cancer, date of death, date of
relocation from the study area, or end of the study period (Decem-
ber 31, 2012 for the Osaka area and December 31, 2013 for other
areas), whichever occurred first. For participants lost to follow up,
data were censored on the last confirmed date of presence in the
study area.
A Cox proportional hazards model was used to estimate HR and
95% CI of breast cancer by tertile of dietary acrylamide intake,
using the lowest (T1) versus the middle (T2) or highest (T3) group.
Trends were assessed by assignment of ordinal values for tertile of
dietary acrylamide intake. For further analysis, 9 quantiles were also
used in the Cox proportional hazards model. Acrylamide intake was
adjusted for energy intake using the residual method. HR were
adjusted for the following potential confounding factors: age, PHC
area, smoking status (current, past, never, or missing), alcohol intake
(<150 g/wk or ≥150 g/wk), BMI (<25, ≥25, or missing), family his-
tory of breast cancer (yes or no), age at menarche (≤13, 14, 15,
≥16, or missing), age at first delivery (<26, ≥26, or missing), number
of deliveries (0, 1-2, 3, ≥4, or missing), menopausal status and age
at menopause (premenopause, postmenopause from age <49, post-
menopause from age 50 to 54, postmenopause from >55, or miss-
ing) and exogenous hormone use (yes, no, or missing). These
variables were obtained from the questionnaire, and are known or
suspected risk factors for breast cancer in the JPHC study. Further,
we also adjusted for physical activity (metabolic equivalents) and
isoflavone intake; as the results did not substantially change, how-
ever, we did not use these variables for adjustment in the final
model. In a sensitivity analysis, we repeated the same analysis after
excluding 120 breast cancer cases diagnosed in the first 3 years of
follow up.
To elucidate the interaction effect, we conducted stratified
analysis by smoking status (current smoker, past smoker, or never
smoker), coffee consumption (<1 cup/wk, 1 cup or more/wk),
alcohol consumption (<150 g/wk or ≥150 g/wk), BMI (<25 or
≥25), and menopausal status at starting point (pre or post-
menopause). A further stratified analysis was conducted for tumor
subtype defined by ER/PR status, namely ER+,ER,PR+,PR,
ER+/PR+, and ER/PR. All P-values were 2-sided and statistical
significance level was set at P<.05 using SAS 9.3 (SAS Institute
Inc., Cary, NC, USA).
KOTEMORI ET AL.
|
3
3
|
RESULTS
3.1
|
Characteristics of participants
Table 1 shows participant characteristics according to acrylamide
intake. Mean (SD) dietary acrylamide intake overall was 7.0 (3.7) lg/
d, corresponding to 0.14 (0.13) lg/kg bodyweight/day. There were
significant differences in the following characteristics between ter-
tiles. The highest acrylamide intake group tended to be younger and
have a lower BMI; have a higher proportion of current smoking,
younger menarche, premenopausal status, and exogenous female
hormone non-use; have a lower proportion of older first delivery,
and non- or few deliveries; and to consume less alcohol, and more
coffee, green tea, biscuits and cookies, potatoes, and vegetables.
There was no significant difference between tertiles in the propor-
tion of a family history of breast cancer.
Figure 2 shows the contribution of acrylamide-containing foods
among the total study population. The food group with the greatest
contribution was beverages (total 49%; 24% for coffee, 23% for
green tea, and 2% for others), followed by confectioneries (total
19%; 13% for biscuits and cookies, 3% for chocolate, and 3% for
others), potatoes and starches (total 13%; 12% for potatoes and 1%
for others), vegetables (total 11%; 4% for sweet pepper, 3% for
onion, 3% for bean sprouts, and 1% for others), and cereals (total
6%; 3% for rice and 3% for others). The main contributing foods
were common in each acrylamide intake group, but the trend slightly
differed (Figure 3). As acrylamide intake increased, the contribution
from coffee, green tea, and biscuits and cookies increased, whereas
that from potatoes, vegetables and rice decreased.
3.2
|
Association between dietary acrylamide intake
and breast cancer
Table 2 shows the results of dietary acrylamide intake and risk of
breast cancer. There was no association between dietary acrylamide
intake and breast cancer. Compared to the lowest group, HR (95%
CI) was 1.00 (0.84-1.18) in the middle group and 0.95 (0.79-1.14) in
the highest (Pfor trend =.58). This result was consistent with the
results obtained when cases occurring within 3 years after the start
of follow up were excluded.
To clarify the risk in extremely high dietary acrylamide con-
sumers among these study participants, we conducted a further anal-
ysis between 9 quantiles of acrylamide intake (Figure 4). Mean (SD)
dietary acrylamide intake was 2.5 (0.7) lg/d among the lowest 9
quantile consumers and 14.6 (3.6) among the highest 9 quantile con-
sumers. No significant association was observed. Compared to the
lowest quantile, HR (95% CI) of the highest quantile was 0.91 (0.66-
1.25) and Pfor trend was .81.
Although we also conducted stratified analyses by major con-
founding factors, significance associations were not observed among
current or past smokers (Pfor trend =.64), never smokers (Pfor
trend =.43), lower coffee consumers (Pfor trend =.58), coffee con-
sumers (Pfor trend =.71), lower alcohol consumers (Pfor
trend =.52), higher alcohol consumers (Pfor trend =.60), women
with a normal BMI (Pfor trend =.62), obese women (Pfor
trend =.74), premenopausal women (Pfor trend =.37), or post-
menopausal women (Pfor trend =.97). Further, when stratified by
estrogen receptor and progesterone receptor status, there were no
significant associations among ER+(Pfor trend =.99), ER(Pfor
trend =.48), PR+(Pfor trend =.91), PR(Pfor trend =.33), ER+/
TABLE 1 Characteristics of the study participants
Tertile of acrylamide intake
P-
value
a
Lowest Middle Highest
(T1) (T2) (T3)
Number of
participants
16 303 16 304 16 303
Acrylamide intake
Range, lg/d
b
0.0-5.1 5.1-7.8 7.8-63.0
Mean and SD,
lg/d
b
3.6 1.0 6.3 0.8 11.1 3.3
Mean and SD,
lg/kg
bodyweight
per day
b
0.07 0.06 0.12 0.11 0.22 0.16
Age at 5-y
follow-up
survey, year
58 8578558<.001
Body mass
index, kg/m
2
24 3233233<.001
Smoking status, % <.001
Current 4.0 4.4 7.0
Past 0.8 1.0 1.2
Never 88.1 88.3 85.6
Missing 7.0 6.4 6.1
Family history of breast cancer, % .482
Yes 0.9 1.1 1.0
No 99.1 99.0 99.0
Age at menarche, years <.001
≤13 18.5 23.7 27.2
14 18.8 21.4 22.0
15 19.1 18.8 17.2
≥16 28.6 24.0 20.2
Missing 15.0 12.1 13.4
Age at first delivery, % <.001
<26 y 50.6 51.1 48.9
≥26 y 25.8 28.5 29.7
Missing 23.6 20.4 21.4
Number of deliveries, % <.001
None 4.9 5.5 5.6
1-2 32.9 36.1 36.4
3 times 23.6 24.6 23.8
≥4 times 19.7 18.5 18.0
Missing 19.0 15.4 16.2
(Continues)
4
|
KOTEMORI ET AL.
PR+(Pfor trend =.92), or ER/PR(Pfor trend =.35) (Table 2).
Additionally, there were no significant associations when stratified
by green tea intake (data not shown).
4
|
DISCUSSION
We found that dietary acrylamide intake was not associated with
breast cancer risk in a large prospective cohort study among
Japanese women. In addition, we also found no associations when
stratified analyses were conducted by smoking status, coffee con-
sumption, alcohol consumption, BMI, menopausal status, or the hor-
mone receptor status of breast cancer tumors.
These results showing no association between dietary acrylamide
intake and breast cancer are consistent with the results of a meta-ana-
lysis by Pelucchi et al of 5 prospective cohort studies, one case-
TABLE 1 (Continued)
Tertile of acrylamide intake
P-
value
a
Lowest Middle Highest
(T1) (T2) (T3)
Menopausal status, % <.001
Pre-
menopause
15.3 21.0 28.3
Post-
menopause
from
unknown age
2.0 1.6 1.5
Post-
menopause
from age
<49 y
37.1 34.9 33.1
Post-
menopause
from age 50-
54 y
35.9 36.0 31.7
Post-
menopause
from age
>55 y
4.7 3.8 3.3
Missing 5.0 2.7 2.1
Exogenous hormone use, % <.001
Yes 2.6 2.5 2.7
No 89.4 92.7 93.1
Missing 8.1 4.9 4.2
Dietary intake
Energy, kcal/d 1838 576 1866 555 1848 562 <.001
Alcohol intake,
g/wk
16 80 13 58 14 55 <.001
Coffee, g/d
b
36 50 91 90 230 240 <.001
Green tea, g/
d
b
342 352 543 430 798 705 <.001
Biscuits and
cookies, g/d
b
112368<.001
Potatoes,
g/d
b
12 10 19 15 23 24 <.001
Vegetables, g/
d
b
202 122 230 124 234 136 <.001
Data represent mean (standard deviation) or percentages.
a
Kruskal-Wallis test for continuous variables and chi-squared test for cat-
egorical variables.
b
Energy adjusted intake by residual method.
FIGURE 2 Contribution of acrylamide-containing foods among all
participants
FIGURE 3 Comparison of the contribution of acrylamide-
containing foods between tertiles of acrylamide intake
KOTEMORI ET AL.
|
5
TABLE 2 Acrylamide intake and risk of breast cancer
Total
Tertile of acrylamide intake
Pfor trend
Lowest (T1) Middle (T2) Highest (T3)
HR (95% CI) HR (95% CI) HR (95% CI)
All women
No. participants 48 910 16 303 16 304 16 303
No. cases 792 266 268 258
Person-years 754 623 253 736 251 712 249 176
Age- and area-adjusted 1.00 (Reference) 1.00 (0.84-1.19) 0.95 (0.79-1.13) .55
Multivariate-adjusted
a
1.00 (Reference) 1.00 (0.84-1.18) 0.95 (0.79-1.14) .58
Multivariate-adjusted (excluding cases <3y)
a
1.00 (Reference) 1.05 (0.87-1.26) 0.96 (0.79-1.17) .70
By smoking status
Current or past smoker
No. participants 3014 796 871 1347
No. cases 46 15 12 19
Person-years 43 381 11 598 12 452 19 332
Multivariate-adjusted
a
1.00 (Reference) 0.77 (0.35-1.66) 0.83 (0.41-1.70) .64
Never smoker
Number of participants 42 708 14 359 14 388 13 961
Number of cases 701 239 238 224
Person-years 666 754 226 260 224 636 215 859
Multivariate-adjusted
a
1.00 (Reference) 0.97 (0.81-1.17) 0.93 (0.77-1.12) .43
By coffee consumption
<1 cup/wk
No. participants 13 967 8003 3731 2233
No. cases 206 121 62 23
Person-years 213 780 123 302 56 865 33 613
Multivariate-adjusted
a
1.00 (Reference) 1.19 (0.87-1.62) 0.77 (0.49-1.20) .58
1 cup or more/wk
No. participants 34 943 8300 12 573 14 070
No. cases 586 145 206 235
Person-years 540 843 130 434 194 847 215 563
Multivariate-adjusted
a
1.00 (Reference) 0.93 (0.75-1.16) 0.95 (0.77-1.18) .71
By alcohol consumption
<150 g/wk
No. participants 47 536 15 800 15 887 15 849
No. cases 757 254 258 245
Person-years 734 543 246 259 245 643 242 641
Multivariate-adjusted
a
1.00 (Reference) 1.00 (0.84-1.19) 0.94 (0.78-1.13) .52
≥150 g/wk
No. participants 1374 503 417 454
No. cases 35 12 10 13
Person-years 20 081 7477 6068 6535
Multivariate-adjusted
a
1.00 (Reference) 0.94 (0.38-2.30) 1.26 (0.53-3.01) .60
By BMI
<25 kg/m
2
No. participants 34 090 11 012 11 344 11 734
No. cases 506 163 173 170
(Continues)
6
|
KOTEMORI ET AL.
TABLE 2 (Continued)
Total
Tertile of acrylamide intake
Pfor trend
Lowest (T1) Middle (T2) Highest (T3)
HR (95% CI) HR (95% CI) HR (95% CI)
Person-years 524 930 171 394 174 710 178 825
Multivariate-adjusted
a
1.00 (Reference) 1.01 (0.82-1.26) 0.95 (0.76-1.18) .62
≥25 kg/m
2
No. participants 13 495 4754 4551 4190
No. cases 266 97 85 84
Person-years 211 475 75 034 71 292 65 149
Multivariate-adjusted
a
1.00 (Reference) 0.89 (0.66-1.20) 0.95 (0.70-1.29) .74
By menopausal status
Premenopause
No. participants 10 523 2493 3422 4608
No. cases 201 52 72 77
Person-years 166 575 39 997 54 362 72 216
Multivariate-adjusted
a
1.00 (Reference) 1.04 (0.73-1.49) 0.86 (0.60-1.24) .37
Postmenopause
No. participants 36 803 13 000 12 450 11 353
No. cases 572 203 193 176
Person-years 564 230 201 595 190 725 171 910
Multivariate-adjusted
a
1.00 (Reference) 1.00 (0.82-1.22) 1.00 (0.81-1.23) .97
By hormone receptor status
ER+
No. subjects 48 344 16 113 16 117 16 114
No. cases 226 76 81 69
Person-years 749 403 252 011 249 953 247 439
Multivariate-adjusted
a
1.00 (Reference) 1.11 (0.81-1.52) 1.00 (0.71-1.40) .99
ER
No. subjects 48 218 16 074 16 069 16 075
No. cases 100 37 33 30
Person-years 748 275 251 669 249 587 247 020
Multivariate-adjusted
a
1.00 (Reference) 0.92 (0.57-1.49) 0.83 (0.51-1.38) .48
PR+
No. subjects 48 287 16 093 16 096 16 098
No. cases 169 56 60 53
Person-years 748 965 251 875 249 815 247 275
Multivariate-adjusted
a
1.00 (Reference) 1.10 (0.76-1.59) 1.02 (0.69-1.50) .91
PR
No. subjects 48 268 16 094 16 086 16 088
No. cases 150 57 50 43
Person-years 748 702 251 820 249 715 247 167
Multivariate-adjusted
a
1.00 (Reference) 0.93 (0.63-1.37) 0.82 (0.54-1.23) .33
ER+/PR+
No. subjects 48 277 16 089 16 095 16 093
No. cases 159 52 59 48
Person-years 748 933 251 862 249 808 247 262
Multivariate-adjusted
a
1.00 (Reference) 1.18 (0.81-1.72) 1.02 (0.68-1.52) .92
(Continues)
KOTEMORI ET AL.
|
7
control study and 2 case-cohort studies of the risk of dietary acry-
lamide intake for breast cancer in Western countries, which reported
that there was no association between dietary acrylamide intake and
breast cancer.
19
The 5 prospective cohort studies and 2 case-cohort studies were
conducted in Sweden, the Netherlands, the USA and the UK.
11,13-18
Although all studies showed no association between dietary
acrylamide intake and breast cancer risk in all women, a positive
association was observed in premenopausal women in the UK. The
authors suggested that this positive association appears to represent
a proxy for an unhealthier diet, because mean dietary acrylamide
intake was less than in other countries and the main sources of diet-
ary acrylamide intake were chips and crisps.
16
In the present study, daily mean (SD) dietary acrylamide intake
was 7.0 (3.7) lg in Japanese women. Western women consume 2-3
times more acrylamide than Japanese women, and mean levels of
intake among Japanese women correspond to the lowest or second
lowest quintile in Western women.
11,16-18
This low and narrow
intake pattern in Japanese women may affect the association toward
null. Therefore, dietary acrylamide intake does not seem to increase
the risk of breast cancer in Japanese women. However, 1 reason
that most studies showed no association between dietary acrylamide
intake and breast cancer is that country-specific analyses failed to
ensure a wide distribution of intake such that the influence of diet-
ary acrylamide could be detected.
The main sources in our Japanese population were coffee and
green tea. Although green tea is specific for Japanese participants,
coffee is also a common contributing food for acrylamide intake in
Western countries.
11,14,18
In a meta-analysis, coffee had a weakly
preventive effect on breast cancer.
36
However, no preventive or
causative effect was observed for our cohort between coffee or
green tea intake and breast cancer risk.
37
Further, stratified analysis
by coffee or green tea consumption indicated there was no interac-
tion effect in our study. Although coffee/green tea is the major
source of acrylamide intake in Japan, the intake of coffee/green tea
did not have a causative effect on breast cancer in this study.
We also found no associations when our study participants were
stratified by alcohol consumption and BMI level. When acrylamide
was consumed, it is partly metabolized by CYP2E1 to glycidamide,
which is a more reactive compound than acrylamide.
5
In a cross-sec-
tional study, the ratio of hemoglobin adduct concentrations of acry-
lamide to glycidamide differed according to alcohol drinking habit and
BMI level, because the activity of CYP2E1 is affected by alcohol
TABLE 2 (Continued)
Total
Tertile of acrylamide intake
Pfor trend
Lowest (T1) Middle (T2) Highest (T3)
HR (95% CI) HR (95% CI) HR (95% CI)
ER/PR
No. subjects 48 205 16 070 16 067 16 068
No. cases 87 33 31 23
Person-years 748 237 251 657 249 575 247 005
Multivariate-adjusted
a
1.00 (Reference) 1.01 (0.61-1.66) 0.76 (0.44-1.32) .35
CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor.
a
Multivariable Cox proportional hazard models were adjusted for age (year), area (10 public health center areas), body mass index (BMI) (<25, ≥25, or
missing), family history of breast cancer (yes or no), age at menarche (≤13, 14, 15, ≥16, or missing), age at first delivery (<26, ≥26, or missing), number
of deliveries (0, 1-2, 3, ≥4, or missing), menopausal status and age at menopause (premenopause, postmenopause from age <49, postmenopause from
age 50 to 54, postmenopause from >55, or missing), use of exogenous female hormones (yes, no, or missing), smoking status (current or past, never, or
missing), and alcohol intake (<150 g/wk or ≥150 g/wk).
FIGURE 4 Hazard ratios (HR) of breast cancer within 9 quantiles
of energy-adjusted dietary acrylamide intake. The reference group
was the lowest of 9 quantiles. HR and 95% confidence intervals
were adjusted for age (years), area (10 public health center areas),
body mass index (<25, ≥25, or missing), family history of breast
cancer (yes or no), age at menarche (≤13, 14, 15, ≥16, or missing),
age at first delivery (<26, ≥26, or missing), number of deliveries (0,
1-2, 3, ≥4, or missing), menopausal status and age at menopause
(premenopause, postmenopause from age <49, postmenopause from
age 50 to 54, postmenopause from >55, or missing), use of
exogenous female hormones (yes, no, or missing), smoking status
(current or past, never, or missing), and alcohol intake (<150 g/wk or
≥150 g/wk). Numbers of cases from the lowest to the highest of 9
quantiles were 86, 83, 97, 80, 93, 95, 80, 102, and 76, respectively
8
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KOTEMORI ET AL.
consumption and BMI level.
38,39
However, we could not detect any
associations in a stratified analysis. As acrylamide metabolism is also
affected by polymorphisms in CYP2E1, differences in the distribution
of these single-nucleotide polymorphisms (SNP) may also have
affected the results.
40,41
We also conducted stratified analysis by menopausal status and
the hormone receptor status of tumors, but observed no associations
between dietary acrylamide intake and breast cancer. This result is
consistent with previous studies.
14,15,17,18
However, the effect of
trace acrylamide intake on hormone concentration in humans is cur-
rently under investigation and the results to date are not consistent.
Hogervorst et al
42
reported that the hemoglobin adduct concentration
of acrylamide was positively associated with estrogen concentration in
premenopausal American women whose BMI was <25. In contrast,
Nagata et al
43
showed that dietary acrylamide intake assessed by FFQ
was negatively related to estrogen concentration among pre-
menopausal Japanese women. In a nested case-control study by Ole-
sen et al,
44
the hemoglobin adduct concentration of acrylamide was
positively associated with the risk of ER+breast cancer in smokers.
Therefore, further studies are needed before the effect of acrylamide
intake on the hormone-related pathway can be conclusively deter-
mined.
The major strength of the present study was its prospective
cohort study design. Recall bias of exposure and confounding factors
was avoided because data collection was conducted before breast
cancer was diagnosed. Participants were selected from the general
population, the sample size was large, the response rate to the ques-
tionnaire was acceptable (83.6%) for study settings such as this, and
the loss to follow up (0.1%) was negligible. The proportion of cases
ascertained by DCO was 1.9%. Furthermore, the cancer registry in
the study population was of sufficient quality to reduce the possibil-
ity of misclassification of outcome.
This study has several limitations. First, there is a possibility of
misclassification of acrylamide intake groups. The correlation coeffi-
cients among dietary acrylamide intake from the DR and FFQ were
low to moderate and kappa coefficients in quintiles were over 0.8.
High kappa coefficients showed categorical agreement, but the pos-
sibility of the attenuation of relative risk by misclassification of expo-
sure assessment still remains. Moreover, the JPHC study and the
validation study for the FFQ were conducted in the 1990s, but we
calculated acrylamide intake using the measured values of acrylamide
in foods in the 2000s because measured values were not available in
the 1990s. This time lag may have lead to underestimation and mis-
classification because of the efforts of food companies in reducing
acrylamide content in foods. However, the concentrations of acry-
lamide in coffee, which was the most important food in total acry-
lamide intake, did not dramatically differ between the recent
decades,
6
and the effect is therefore considered to be relatively
small. Second, assessment of dietary acrylamide intake by FFQ may
not reflect the true acrylamide and glycidamide exposure because
acrylamide metabolism may be affected by individual enzyme activ-
ity
40
and lifestyle.
38
Further epidemiological study using biomarkers
is needed to clarify acrylamide and glycidamide exposure in terms of
internal dose. Third, the occurrence of breast cancer in Japan is less
than in Western countries. Despite a reasonably large cohort popula-
tion (48 910 women) and long follow-up period (average 15 years),
the number of cases of breast cancer in this cohort was relatively
small (n =792), reflecting the low incidence rate in Japan (age-stan-
dardized rate per 100 000 world population in 2012, 51.5 in Japan
and 92.9 in the USA for comparison).
45
The lack of subjects and
cases may have rendered some null associations in the stratified
analyses less robust, and interpretation may therefore need caution.
Fourth, other confounding factors might have affected the results.
Although we adjusted for several confounding factors in the statisti-
cal model to the maximum degree possible, the effects of unmea-
sured confounders cannot be totally discarded.
In conclusion, we found that there was no association between
dietary acrylamide intake and breast cancer risk regardless of smok-
ing status, coffee consumption, alcohol consumption, BMI, menopau-
sal status, or hormone receptor status of breast cancer tumors in a
large prospective cohort study among Japanese women. Our findings
suggest that dietary acrylamide intake is unlikely to increase the risk
of breast cancer in Japanese women.
ACKNOWLEDGMENTS
This study was supported by a grant from the Food Safety Commis-
sion, Cabinet Office, Government of Japan (Research Program for Risk
Assessment Study on Food Safety, No. 1503; principal investigator is
TS), the National Cancer Center Research and Development Fund
(since 2011, principal investigator is ST), and a Grant-in-Aid for Cancer
Research from the Ministry of Health, Labour and Welfare of Japan
(from 1989 to 2010, principal investigator from 1997 to 2010 is ST).
CONFLICTS OF INTEREST
Authors declare no conflicts of interest for this article.
AUTHORS’CONTRIBUTION
JI and TS designed the research; ST, TS, JI, NS, and MI conducted
research; AK contributed to the calculation of dietary acrylamide
intake; AK, LZ, and RL carried out statistical analysis; AK interpreted
the results and wrote the paper; and JI had primary responsibility for
final content. All authors reviewed the manuscript and contributed
to the discussion.
ORCID
Ayaka Kotemori http://orcid.org/0000-0003-3954-8615
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How to cite this article: Kotemori A, Ishihara J, Zha L, et al.
Dietary acrylamide intake and risk of breast cancer: The
Japan Public Health Center-based Prospective Study. Cancer
Sci. 2018;00:1–11. https://doi.org/10.1111/cas.13496
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