The Journal of Nutrition

Proceedings of the Fourth International Scientific Symposium on Tea and Human Health

A Review of the Epidemiological Evidence on
Tea, Flavonoids, and Lung Cancer

1–3

Ilja C. W. Arts*

Department of Epidemiology, Nutrition, and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, 6200 MD,
Maastricht, The Netherlands

Abstract

Tea and its main bioactive ingredients, the flavonoids, have been associated with human cancer for several decades. In

this article, an overview is provided of observational epidemiological studies of lung cancer incidence in relation to intake of

green tea, black tea, flavonols/flavones, and catechins. A PubMed search was conducted in September 2007. Articles

were selected if they provided risk ratios (relative risk or odds ratio) for lung cancer and were of observational design

(cohort, case-control, or case-cohort). Three of 12 studies reported a significantly lower risk of lung cancer with a high

intake of flavonoids, whereas 1 study reported a significantly increased risk. After stratification by type of flavonoid,

catechin intake was no longer associated with lung cancer risk in 3 of 4 studies available. For tea, 4 of 20 studies reported

significantly reduced risks with high intake. Two studies found signficantly increased risk ratios, but both were older

studies. Findings were similar for green and black tea but became more significant when only methodologically sounder

cohort studies were considered. When tea intake and lung cancer were studied among never- or former smokers to

eliminate the confounding effect of smoking, 4 of 7 reported associations were significantly protective. In general, the

studies on tea, flavonoids, and lung cancer risk indicate a small beneficial association, particularly among never-smokers.

More well-designed cohort studies, in particular for catechins, are needed to strengthen the evidence on effects of long-

term exposure to physiological doses of dietary flavonoids.

J. Nutr. 138: 1561S–1566S, 2008.

Introduction

Tea consumption has been associated, both positively and
negatively, with human cancer for several decades. The first
epidemiological report on tea and cancer was published in 1966
(1). Since then, an increasing number of epidemiological studies

on tea intake and cancer have appeared. A PubMed search
conducted in September 2007 with the keywords ‘‘tea and
cancer and epidemiolog*’’ yielded 556 hits. In recent years the
collective evidence available for several types of cancer has been
summarized in systematic reviews and meta-analyses (2–4), but
to date, no such review has been published for lung cancer.

Tea, from a biological standpoint, is not a clearly defined

substance. All tea is produced from the leaves of Camellia
sinensis, but differences in processing result in several types of
tea, of which green and black tea are the most consumed world-
wide. Moreover, tea is a complex mixture of a large number of
bioactive components, including catechins, flavonols, lignans,
and phenolic acids. Theaflavins and thearubigins are present
only in black tea as a result of oxidative processes (5). All types
of tea and the major phenolic compounds present in tea have
been the subject of epidemiological studies. The debate is still
open as to which of these phenolic compounds might be of
primary importance, whether the combination of compounds is
essential, or if perhaps unknown components might be respon-
sible for any health-modulating effects of tea.

An earlier review on flavonoids and chronic diseases (6)

found evidence suggestive of a lower risk of lung cancer with a
higher intake of flavonols/flavones. However, at the time, only 4
cohort studies were available. Data from studies on asthma
incidence (7) and lung function (8) also suggested beneficial
effects from flavonoids. In an animal study, where rats were
given the major flavonol quercetin for 11 wk, the highest tissue

1

Published in a supplement to The Journal of Nutrition. Presented at the

conference ‘‘Fourth International Scientific Symposium on Tea and Human
Health,’’ held in Washington, DC at the U.S. Department of Agriculture on
September 18, 2007. The conference was organized by the Tea Council of the
U.S.A. and was cosponsored by the American Cancer Society, the American
College of Nutrition, the American Medical Women’s Association, the American
Society for Nutrition, and the Linus Pauling Institute. Its contents are solely the
responsibility of the authors and do not necessarily represent the official views of
the Tea Council of the U.S.A. or the cosponsoring organizations. Supplement
coordinators for the supplement publication were Lenore Arab, University of
California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA.
Supplement coordinator disclosure: L. Arab and J. Blumberg received honorar-
ium and travel support from the Tea Council of the U.S.A. for cochairing the
Fourth International Scientific Symposium on Tea and Human Health and for
editorial services provided for this supplement publication; they also serve as
members of the Scientific Advisory Panel of the Tea Council of the U.S.A.

2

I. C. W. Arts is supported by a VENI Innovational Research Grant from the

Netherlands Organisation for Scientific Research—Earth and Life Sciences
(NWO-ALW).

3

Author disclosure: I. C. W. Arts received compensation from the supplement

sponsor for speaking at the Fourth International Scientific Symposium on Tea
and Human Health.
* To whom correspondence should be addressed. E-mail: ilja.arts@epid.
unimaas.nl.

0022-3166/08 $8.00

ª 2008 American Society for Nutrition.

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concentrations were found in the lung (9). Taken together, these
data suggested a beneficial effect of tea and/or flavonoids on lung
health. This article provides an overview of observational ep-
idemiological studies considering lung cancer incidence or
mortality in relation to intake of green tea, black tea, flavonols/
flavones, and catechins.

Methods

A search in the PubMed database was conducted in September 2007
using the keywords tea, flavon*, flavan*, catechin, polyphenol, cancer,
tumor, cohort, case-control, case-cohort, intervention, meta-analysis,
and epidemiolog*. Reference lists of original articles on tea or flavonoids
and lung cancer and reviews on tea or flavonoids and cancer were
checked for relevant studies. Articles were selected for this review if they
provided risk ratios [relative risk or odds ratio (OR)] for lung cancer and
were of observational design (cohort, case-control, or case-cohort). Two
studies were excluded because no risk ratios were presented (10,11).
Studies on both incidence and mortality were included, but only 2
articles used lung cancer mortality data (12,13). From the articles, we
retrieved the number and gender of the participants, years of follow-up
(cohort and case-cohort studies only), and type of tea and/or flavonoids
studied. The most adjusted risk estimates, comparing the highest versus
the lowest intake category, corresponding 95% confidence intervals (CI),
and P-values for dose-response trend tests were extracted for this review.
If the original article did not present aggregated risk estimates, data for
subgroups (e.g., male/female, smokers/nonsmokers) were taken instead.
The 3 studies that did not specify the type of tea were from the United
States, Canada, and Sweden and were assumed to pertain to black tea.
Flavonols and flavones were grouped together because the intake of
flavones is minor compared with the intake of flavonols.

Case-control studies are vulnerable to recall bias, a phenomenon that

leads to attenuation of associations and that occurs because diseased
subjects may remember their diet differently from control subjects.
Therefore, results from cohort studies and case-control studies were also
discussed separately. A second major methodological issue in the analysis
of observational studies is confounding. Confounding is particularly
important when weak associations are studied in the presence of strong
confounders. In the case of the tea/flavonoid-lung cancer association,
smoking is one such strong confounder. Even after meticulous adjust-
ment for smoking behavior, residual confounding may exist. To reduce
the residual confounding presented by the strong smoking confounder,
we also summarized studies that only considered never- or former
smokers who had quit .20 y ago.

Results

Twelve studies, including 8 cohort studies, reported on the
association between intake of flavonoids and lung cancer
incidence (Table 1). None of the flavonoid studies considered
lung cancer mortality. All studies, except those by Arts et al.
(18,19) reported risk estimates for flavonols/flavones. More
recent studies have started to include catechins as well. Three
articles reported a significantly lower risk of lung cancer with a
high intake of flavonoids (15,17,20), whereas 1 article (24)
reported a significantly increased risk. The association between
flavonol/flavone intake and lung cancer incidence was similar to
that for flavonoids as a whole, but leaving out the methodolog-
ically less strong case-control studies allowed a stronger sug-
gestion of a protective association to emerge. Of the 6 cohort
studies, 3 showed a significant inverse association, and 3 showed
no effect. Only 1 of 4 studies on catechins and lung cancer found
a significant effect, with a risk ratio of 0.94 and a 95% CI of
0.91–0.98 (20). Leaving out the case-control study by Lagiou
et al. (24) did not change the findings for catechins.

On the association of tea and lung cancer, 20 studies were

published, including 6 cohort studies (Table 2). Two of the
cohort studies used data for cancer mortality instead of in-
cidence (12,13). Two studies were excluded from this overview
because they did not report a risk ratio estimate: Heilbrun et al.
(10), who were the first to report on tea and lung cancer in 1986,
found no significantly different age-adjusted lung cancer pro-
portion for frequent consumers of black tea. Huang et al. (11)
only mentioned that the association between green tea and
jasmine tea and lung cancer in their small case-control study was
not significant. The overview of all studies on tea and lung
cancer is fairly symmetrical, although it appears slightly skewed
toward a protective association of tea intake (Fig. 1). Four risk
ratios reported were significantly below 1 (27,34–36). Two
studies reported risk ratios that were significantly higher than
1 (12,31). Both were older studies, and Kinlen et al. (12) did not
report a CI. Stratifying by type of tea consumed did not
substantially change the distribution of risk estimates (data
not shown). When the case-control studies were omitted from
consideration, few studies remained. Of the 3 cohort studies on
black tea, only the study by Kinlen et al. (12) showed a
significantly increased risk for lung cancer. For green tea, the

TABLE 1

Risk estimates from observational epidemiological studies on intake of flavonoids and risk of lung cancer

First author (ref)

Country

Year

Participants, n

Sex

Follow-up time, y

Type of flavonoids

RR

(95% CI)

1

P-trend

Prospective cohort studies

Hertog (14)

2

Netherlands

1994

740

M

5

Flavonols

1.02

(0.51 22.04)

0.96

Knekt (15)

Finland

1997

9,959

MF

24

Flavonols

0.53

(0.29 20.97)

—

Goldbohm (16)

Netherlands

1998

120,852

MF

4

Flavonols

0.99

(0.69 21.42)

0.68

Hirvonen (17)

Finland

2001

27,110

M

6

Flavonols

0.56

(0.45 20.69)

0.0001

Arts (18)

Netherlands

2001

728

M

10

Catechins

0.92

(0.41 22.07)

0.8

Knekt (7)

Finland

2002

5,218

M

30

Flavonols

0.64

(0.39 21.04)

0.02

Arts (19)

U.S.A.

2002

34,651

F

13

Catechins

0.94

(0.72 21.23)

0.94

Wright (20)

Finland

2004

27,111

M

11

Catechins 1 flavonols

0.94

(0.91 20.98)

0.005

Case-control studies

Garcia-Closas (21)

Spain

1998

103/206

3

F

Flavonols

0.98

(0.44 22.19)

0.98

De Stefani (22)

Uruguay

1999

541/540

M

Flavonols

0.80

(0.50 21.20)

—

Le Marchand (23)

U.S.A.

2000

582/582

MF

Flavonols

0.80

(0.50 21.40)

0.89

Lagiou (24)

Greece

2004

154/145

F

Catechins

1.02

(0.70 21.49)

0.91

Flavonols

1.83

(1.22 22.72)

0.003

1

RR: relative risk for prospective cohort studies; OR for case-control studies; 95% CI in parentheses.

2

Lung cancer and gastrointestinal tract cancer combined.

3

Number of cases/controls.

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study by Nakachi et al. (27) was the only 1 of 3 cohort studies
that found a significantly decreased risk for lung cancer.

To study the association between tea intake and lung cancer

incidence without the confounding effect of smoking, studies
reporting risk estimates for never- or former smokers are summa-

rized in Figure 2. Four of seven studies that reported associations
among nonsmokers showed a significant protective association
for a high intake of tea. The other 3 associations were not
significantly different from 1. All studies were among women,
presumably because in most countries there are too few never-
smoking men to conduct meaningful analyses. In the studies by
Kubik et al. (37,40), nonsmokers were defined as women who
had never smoked and women who had quit .20 y ago. The
other 3 studies included never-smokers only. Only 2 studies on
flavonoid intake and lung cancer incidence presented risk
estimates for never-smokers. Garcia-Closas et al. (21) reported
that findings were similar to those for the whole sample (i.e., a
nonsignificant risk ratio of 0.98). Lagiou et al. (24) likewise
found no significant interaction between smoking status and
flavonoid intake, with risk estimates that were comparable to
those for the whole group.

Discussion

The collective evidence available so far from observational
epidemiological studies on tea, flavonoids, and lung cancer risk
tends toward a small beneficial association for green and black
tea, particularly among never-smokers, and for flavonols/
flavones but not for catechins. Studies that report increased
risks with a high intake of tea are mostly older studies that were
published at a time when tea was considered a possible car-

TABLE 2

Risk estimates from observational epidemiological studies on intake of tea and risk of lung cancer

First author (ref)

Country

Year

Participants, n

Sex

Follow-up time, y

Type of tea

RR

(95% CI)

1

P-trend

Prospective cohort studies

Kinlen (12)

2

UK

1988

14,085

M

17

Black

1.66

—

,0.05

Goldbohm (25)

Netherlands

1996

120,852

MF

4

Black

1.07

(0.73 21.57)

0.91

Zheng (26)

USA

1996

35,369

F

8

Nonherbal

1.05

(0.71 21.55)

0.54

Nakachi (27)

Japan

2000

8,552

MF

11

Green

0.33

(0.11 20.94)

—

Nagano (28)

Japan

2001

38,540

MF

13

Green

0.79

(0.59 21.10)

0.21

Kuriyama (13)

2

Japan

2006

40,530

MF

7

Green

1.18

(0.81 21.72)

0.36

Case-control studies

Koo (29)

China

1988

88/137

3

F

Any type

1.59

—

0.15

Mettlin (30)

USA

1989

569/569

MF

—

1.09

(0.62 21.93)

—

Tewes (31)

China

1990

200/200

F

Black

1.43

(0.88 22.33)

—

Green

2.74

(1.10 26.80)

—

Ohno (32)

Japan

1995

333/666

F

Green

0.38

(0.12 21.18)

0.03

M

0.57

(0.31 21.06)

0.05

Axelsson (33)

Sweden

1996

308/504

M

—

0.74

(0.33 21.64)

—

Mendilaharsu (34)

Uruguay

1998

427/428

M

Black

0.34

(0.01 20.84)

—

Le Marchand (23)

USA

2000

582/582

MF

Black

1.10

(0.70 21.80)

0.83

Green

0.90

(0.50 21.60)

0.62

Zhong (35)

China

2001

649/675

F

Green

0.65

(0.45 20.93)

4

—

0.94

(0.40 22.22)

5

—

Hu (36)

Canada

2002

161/483

F

—

0.40

(0.20 20.70)

0.001

Kubik (37)

Czech Republic

2004

451/1,710

F

Black

1.04

(0.80 21.34)

0.75

Green

1.02

(0.74 21.40)

0.94

Bonner (38)

China

2005

122/121

MF

Green

0.59

(0.26 21.37)

0.20

Baker (39)

USA

2005

993/986

MF

Black

0.90

(0.66 21.24)

0.93

Kubik (40)

Czech Republic

2007

569/2,120

F

Black

0.99

(0.80 21.23)

—

Green

0.92

(0.73 21.15)

—

1

Risk estimate for the highest versus the lowest category of intake: RR for prospective cohort studies; OR for case-control studies; 95% CI in parentheses.

2

Mortality.

3

Number of cases/controls.

4

Nonsmokers.

5

Smokers.

FIGURE 1

Risk estimates from observational epidemiological case-

control and cohort studies on intake of tea and risk of lung cancer.
Plotted are the most adjusted RR with 95% CI (if reported) for the
highest versus the lowest category of intake, sorted by increasing risk
ratio. F, females; M, males; NS, nonsmokers; G, green tea; S,
smokers; B, black tea.

Tea, flavonoids, and lung cancer

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cinogenic and mutagenic (10,31). Several authors found that in
the Ames test, 1 cup of black or green tea was more mutagenic
than the smoke condensate of 1 cigarette (31,41). Epidemiolog-
ical data published later have not confirmed these concerns.
Peters et al. (42) found evidence for publication bias in a meta-
analysis on tea consumption and risk of stroke. We have not
examined publication bias. However, it seems unlikely that
studies finding increased lung cancer risks with increased tea or
flavonoid consumption would remain unpublished, given the
increased risk ratios reported in early studies and also in the light
of more recent reports regarding the increased mortality risks
that seem to be associated with taking antioxidant supplements,
particularly among smokers (43,44). Studies that found in-
creased risks with higher tea or flavonoid intake were mostly of
the case-control design. Only 1 cohort study found a risk
estimate that was significantly above 1: the 1988 study by Kinlen
et al. (12). In this study, tea intake was adjusted for smoking only
but not for other risk factors.

Accurate assessment of exposure to tea and/or flavonoids is

not easy. In general, food frequency questionnaires were not
designed to assess tea or flavonoid intake. In recent years,
assessment of tea consumption has received more attention (45),
but certainly baseline measurements of the older epidemiolog-
ical studies have yielded imprecise exposure estimates. Even if
the level of tea consumption is assessed accurately, differences in
cultivars and production methods and in brewing methods at
home also significantly influence the tea composition (46) and,
consequently, the internal exposure to bioactive ingredients.
Several databases have been used to estimate flavonoid intake
from dietary data. The Dutch values (46–49) that were most
frequently used in epidemiological studies are now part of the
comprehensive USDA flavonoid database (50), which has
rigorous quality control. It is my hope that more studies will
use this database in the near future. Inaccurate assessment of
exposure to tea/flavonoids has probably led to nondifferential
misclassification and an underestimation of the true associations
in the epidemiological studies presented here.

Although lung cancer is treated here as a single disease,

etiologically and histologically clearly distinct types of lung
cancer can be distinguished. Yet few authors of articles on this
subject have stratified their data by type of lung cancer. Le
Marchand et al. (23) found a stronger inverse trend with quer-
cetin intake among cases with squamous cell carcinoma (OR in
the highest quartile ¼ 0.5; 95% CI ¼ 0.2–1.9) compared with

cases with adenocarcinoma (OR ¼ 0.9; 95% CI ¼ 0.4–2.0).
Similarly, Zhong et al. (35) also reported a lower OR for
nonsmoking women with nonadenocarcinomas compared with
adenocarcinomas, but the numbers of cases were small, and
trends were not significant. Baker et al. (39), on the other hand,
found similar associations for black tea intake with different
subtypes (adeno-, squamous cell, small cell, and large cell
carcinoma) of lung cancer. More research is needed to determine
whether lung cancer type is of importance.

Residual confounding occurs if confounders, extraneous

factors that are associated with both the outcome and the
exposure under study, are not or insufficiently accounted for in
the statistical analysis. Studying associations in never-smokers is
an effective way of ruling out residual confounding by smoking.
Zhong et al. (35) have elegantly shown that the manner in which
models are adjusted for confounding by smoking can greatly
influence the results. The OR between green tea drinking and
lung cancer among women was 1.69 (95% CI ¼ 0.78–3.62)
without adjustment for smoking. When 4 categories of pack-
years were added to the model, the OR changed to 1.09, whereas
adding the number of cigarettes per day (as 3 categories) instead
gave an OR of 1.23. A smoothing technique, which allows more
precise adjustment for confounding, changed the estimated OR
to 1.23 and 0.94 for pack-years and number of cigarettes per
day, respectively. So, with use of different techniques to adjust
for smoking, the effect estimate changed significantly from 1.69
to 0.94, although none of the estimates was significant. In the
same article, Zhong and co-workers (35) also reported the OR
for never-smokers, which was 0.65 (95% CI ¼ 0.45–0.93) and
significant. Thus, residual confounding for strong confounders
such as smoking can lead to higher risk estimates in populations
where smoking is associated with tea drinking. Our overview of
studies among nonsmokers suggests that, indeed, protective
associations become more distinct in this group. On the other
hand, when tea drinking is associated with a healthy lifestyle,
associations may become more beneficial as a result of residual
confounding. More research among never-smokers is needed to
resolve this issue, taking into account exposure to environmental
smoke and other determinants of lung cancer among never
smokers.

In tea-drinking populations, the correlation between tea

intake and flavonoid intake is high. For example, in the Zutphen
Elderly Study in The Netherlands, the correlation between
catechins and tea was 0.98, making the 2 variables essentially
interchangeable (18). Which approach is preferred then, the
food-based one or the component-based approach? Of course
that depends on the hypothesized mechanism: if flavonoids are
considered to be the active compounds in tea, then it makes
more sense to look at flavonoids directly. In countries where tea
intake is low, such as many Mediterranean countries, other
sources of flavonoids will become important. However, if other
compounds in tea, or combinations of compounds, are believed
to be important, then tea would be the preferred exposure. In
that case, calculating flavonoid intake will merely introduce
additional error. The results presented in this overview show that
a similar picture emerges, whether tea or flavonoids are used as
exposure estimates. For catechins, too few studies have been
published to draw any conclusions. Despite its drawbacks,
observational epidemiology is the only type of research that is
able to assess the effects of long-term exposure to physiological
doses of bioactive compounds on real disease endpoints. It
therefore has great value in the study of the association between
intake of tea and flavonoids and lung cancer risk. Accumulating
more data from well-designed studies, together with more

FIGURE 2

Risk estimates from observational epidemiological case-

control studies on intake of tea and risk of lung cancer among never-
or former ($20 y ago) smokers. Plotted are the most adjusted RR with
95% CI (if reported) for the highest versus the lowest category of
intake, sorted by increasing RR. G, green tea; B, black tea.

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mechanistic intervention studies, will bring us closer to firm
conclusions about the health effects of tea and its bioactive
ingredients.

Other articles in this supplement include references (51–60).

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