Polyphenols and disease risk in epidemiologic studies1–4
In addition to their antioxidant properties, polyphenols show
Plant polyphenols, a large group of natural antioxidants, are serious
several interesting effects in animal models and in vitro systems;
candidates in explanations of the protective effects of vegetables and
they trap and scavenge free radicals, regulate nitric oxide, de-
fruits against cancer and cardiovascular diseases. Epidemiologic
crease leukocyte immobilization, induce apoptosis, inhibit cell
studies are useful for evaluation of the human health effects of
proliferation and angiogenesis, and exhibit phytoestrogenic ac-
long-term exposure to physiologic concentrations of polyphenols,
tivity (3– 6). These effects may contribute to their potentially
but reliable data on polyphenol contents of foods are still scarce. The
protective role in cancer and CVDs. The question remains of
aim of this review is to summarize available epidemiologic data on
whether these data are relevant for human disease outcomes,
the health effects of polyphenols, focusing on the flavonoid sub-
where exposure to polyphenols is chronic and at relatively low
classes of flavonols, flavones, and catechins and on lignans. Data
concentrations, depending on bioavailability and metabolism.
obtained to date suggest beneficial effects of both flavonoids and
An important phenomenon is that, after absorption, polyphenols
lignans on cardiovascular diseases but not on cancer, with the pos-
are subject to phase II metabolism, yielding methoxylated, glu-
sible exception of lung cancer. There is a need for more research on
curonidated, and sulfated compounds (7). This may greatly in-
stroke and lung diseases such as asthma and chronic obstructive
fluence their bioactivity, but only a few studies have examined
pulmonary disease. Most studies to date have included only fla-
this to date. In addition, bacteria present in the human colon
vonols and flavones. With data becoming available for other poly-
metabolize polyphenols. The major polyphenol metabolites are a
phenols, these compounds should be included in future studies.
variety of phenolic acids such as homovanillic acid (8). As a
Careful design of prospective studies is important to offset some of
consequence, body tissues are exposed to high concentrations of
the major drawbacks of epidemiologic studies, including residual
confounding (by smoking and other dietary factors) and exposure
Although no information on causality can be obtained, epide-
Am J Clin Nutr 2005;81(suppl):317S–25S.
miologic studies are useful for evaluation of the human health
effects of long-term exposure to physiologic concentrations of
polyphenols. Reliable data on polyphenol contents of foods are
vonoids, flavonols, catechins, lignans, antioxidants, phytoestrogens,
needed for studies of the potential role of dietary polyphenols in
cancer and CVD prevention. Comprehensive data are availableonly for the flavonoid subclasses of flavonols, flavones, andcatechins, but data on other polyphenols, such as lignans, are
forthcoming. In this article, we provide an overview of epidemi-
Epidemiologic studies suggest a protective effect of vegeta-
ologic studies on the health effects of flavonols, flavones, cat-
bles and fruits against cancer and cardiovascular diseases
echins, and lignans conducted to date.
(CVDs) (1, 2). Various hypotheses have been suggested to ex-plain these beneficial effects of increased consumption of veg-etables and fruits. An attractive hypothesis is that vegetables and
fruits contain compounds that have protective effects, indepen-
dent of those of known nutrients and micronutrients. Plant poly-phenols, a large group of natural antioxidants ubiquitous in a diet
Of the 6 major classes of flavonoids, comprehensive data on their
high in vegetables and fruits, certainly are serious candidates. All
contents in foods are available only for the flavonols (quercetin,
plant phenols are derived from the common intermediate phe-nylalanine, or its close precursor shikimic acid, through the
1 From RIKILT-Institute of Food Safety, Wageningen University and
shikimic acid pathway in plants. They can be divided into at least
Research Centre, Wageningen, The Netherlands.
10 different classes on the basis of their general chemical struc-
Presented at the 1st International Conference on Polyphenols and Health,
tures, with the common characteristic being at least one aromatic
held in Vichy, France, November 18 –21, 2004.
3 Supported by grant QLK1-CT-1999-00505 from the European Commu-
ring structure with one or more hydroxyl groups. A large variety
nity, Framework V Programme (POLYBIND), by the Dutch Ministry of
of plant (poly)phenols exist, including cinnamic acids, benzoic
Agriculture, Nature Management, and Fisheries, and by the Netherlands
acids, flavonoids including proanthocyanidins, stilbenes, cou-
Organisation for Health Research and Development (grant 014-12-014).
marins, lignans, and lignins. Within each family of plant phenols,
4 Address correspondence to ICW Arts, RIKILT-Institute of Food Safety,
many compounds may be present. For example, 6000 different
Wageningen University and Research Centre, PO Box 230, 6700 AE,
flavonoids occurring in plants have been described.
Wageningen, The Netherlands. E-mail: firstname.lastname@example.org. Am J Clin Nutr 2005;81(suppl):317S–25S. Printed in USA. 2005 American Society for Clinical Nutrition
TABLE 1 Prospective studies of flavonoid intake and risk of CVDs1
MI, myocardial infarction; —, no data provided. 2 Flavonols: quercetin, kaempferol, myricetin; flavones: apigenin, luteolin; flavanones: hesperetin, naringenin, eriodictyol; catechins: (ѿ)-catechin, (ѿ)-gallocatechin,
(Ҁ)-epicatechin, (Ҁ)-epigallocatechin, (Ҁ)-epicatechin gallate, (Ҁ)-epigallocatechin gallate. 3 Mean, median, or category cutoff value. 4 Death, unless indicated otherwise. 5 95% CI in parentheses. 6 Quartiles were constructed for men and women separately, but RR is provided for sexes combined only.
kaempferol, and myricetin), flavones (apigenin and luteolin), and
Finnish Mobile Clinic Health Examination Survey (significant
catechins [(ѿ)-catechin, (ѿ)-gallocatechin, (Ҁ)-epicatechin, (Ҁ)-
among men only) (22), the Iowa Women’s Health Study, a cohort
epigallocatechin, (Ҁ)-epicatechin gallate, and (Ҁ)-epigallocatechin
study of 34 500 women in the United States (20), the Alpha-
gallate]. The flavonoid data used in most epidemiologic studies
Tocopherol, Beta-Carotene Cancer Prevention Study among
were based on analyses conducted in the Netherlands (9 –12) but
25 000 male smokers (19), the Dutch Zutphen Elderly Study for
were supplemented in some studies with data for additional food
catechins (18), and the Rotterdam Study in the Netherlands, a
items. Recently, data became available for flavanones in Finnish
cohort study of 4800 men and women (16). In a large cohort study
foods (hesperetin, naringenin, and eriodictyol) (13). Except for
of 35 000 male US health professionals, a suggestion of a reduc-
one study from the United Kingdom (14), all epidemiologic
tion in coronary mortality rates with high flavonol intake was
studies of flavonoids are from the Netherlands, Finland, or the
found only among men with a previous history of CAD [relative
risk (RR): 0.63; 95% CI: 0.33, 1.20] (23). In contrast, a trend forincreased CAD mortality rates (P for trend ҃ 0.12) was found in
the Caerphilly Study, a cohort study of 1900 Welsh men (14). It
To date, 12 cohort studies on flavonoid intake and the risk of
was suggested that the English habit of adding milk to tea (the
coronary artery disease (CAD) and 5 cohort studies on the risk of
major source of flavonols for this cohort) could inhibit the ab-
stroke have been published (Table 1). Seven of these prospective
sorption of flavonols, thus explaining the lack of protection of tea
studies found protective effects of flavonols and flavones or of
flavonols against CAD. Proteins bind phenols efficiently and
catechins with respect to fatal or nonfatal CAD, and reductions
therefore might inhibit absorption from the gastrointestinal tract
of mortality risk were up to 65%. These studies were as follows:
when consumed together with flavonoids. However, it was
the Zutphen Elderly Study, with a small cohort of 805 men in the
shown that the absorption of flavonols was not impaired with the
Netherlands after 5 and 10 y of follow-up monitoring (21, 24), the
addition of milk (27). Residual confounding by lifestyle factors
might have affected evaluation of the results of this study among
Enterolignans are found in biological fluids of humans and ani-
mals (6, 39). It was shown, that in addition to the well-known
Two of 5 studies of flavonoid intake and stroke risk found an
enterolignan precursors secoisolariciresinol and matairesinol,
inverse association, ie, the Zutphen Elderly Study and the Finn-
several other plant lignans were converted into enterolactone and
ish Mobile Clinic Health Examination Survey (Table 1). In the
enterodiol, although with varying degrees of efficiency (40). The
Zutphen Elderly Study, a protective effect was observed for
health effects of lignans were evaluated in epidemiologic studies
flavonols and flavones (26) but not for catechins (18).
that used both the intake of secoisolariciresinol and matairesinoland plasma or urinary concentrations of enterolactone and en-
terodiol as exposure estimates. The calculated intake of secoiso-
Associations between the intake of flavonoids and the inci-
lariciresinol and matairesinol was based on published food com-
dences of a variety of cancers have been studied in 7 prospective
position tables (41– 43), of which that provided by De Kleijn et
cohort studies (Table 2) and 4 case-control studies. Significant
al (41) is the most comprehensive. Of 8 published studies on
associations were observed only for lung cancer and colorectal
enterolignan concentrations and the risk of CVD or cancer, only
cancer. Two Finnish studies with relatively low intakes of fla-
2 measured enterodiol in addition to enterolactone. Enterolac-
vonols and flavones, ie, the Finnish Mobile Clinic Health Exam-
tone is usually measured with a time-resolved fluoroimmunoas-
ination Survey (30) and the Alpha-Tocopherol, Beta-Carotene
say, which is not available for enterodiol (44).
Cancer Prevention Study (32), found inverse associations withlung cancer risk (RR: 0.53; 95% CI: 0.29, 0.97; and RR: 0.56;
95% CI: 0.45, 0.69, respectively). In contrast, a borderline pos-
Two publications (45, 46) from one Finnish cohort study in
itive association was found for colorectal cancer risk in the
which plasma enterolactone concentrations were studied in re-
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
lation to CVD risk reported significant inverse associations (Ta-
(RR: 1.70; 95% CI: 1.00, 2.70; P for trend ҃ 0.10). For catechins,
ble 3). In the Finnish Kuopio Heart Disease Risk Factor Study,
an inverse association was reported for rectal cancer (RR: 0.55;
a 65% lower risk of incident CAD was observed (46). With 2
95% CI: 0.32, 0.95; P for trend ҃ 0.02), but not for colon cancer,
additional years of follow-up monitoring, the risk of CAD death
among postmenopausal women in the United States. No evi-
was of the same order of magnitude (RR: 0.44) and similar,
dence for an effect of flavonoid intake was found for the inci-
although results were only borderline significant for total CVD
dence of any epithelial cancer or cancer of the stomach, urinary
deaths (RR: 0.55) (45). The association between serum en-
tract, prostate, or breast. None of the case-control studies of
terolactone concentrations and plasma F -isoprostane concen-
prostate (34), lung (35), testicular (36), and ovarian (37) cancer
trations (a biomarker of in vivo lipid peroxidation) was studied
cross-sectionally in a subset of 100 male participants in the An-tioxidant Supplementation in Atherosclerosis Prevention Study
Other chronic diseases
(47). With higher enterolactone concentrations, F -isoprostane
Because of their antioxidant and antiinflammatory properties,
concentrations were significantly lower (P ҃ 0.02).
flavonoids may also beneficially influence other chronic dis-
No studies on lignan intake and CVD risk have been published
eases involving oxidative stress or inflammation, such as rheu-
to date, but 2 cross-sectional studies related lignan intake to CVD
matoid arthritis and chronic obstructive pulmonary disease
risk factors. Of several risk factors studied among postmeno-
(COPD). Knekt et al (13) studied the associations between the
pausal US women, only the waist-hip ratio (difference between
intake of flavonols, flavones, and flavanones and the incidences
extreme quartiles: Ҁ0.017; 95% CI: Ҁ0.030, Ҁ0.002; P for trend
of rheumatoid arthritis, type 2 diabetes mellitus, cataracts, and
҃ 0.03) and the metabolic syndrome score, a summary score of
asthma among a cohort of ȁ10 000 male and female participants
several risk factors (difference between extreme quartiles:
in the Finnish Mobile Clinic Health Examination Survey (Table
Ҁ0.55; 95% CI: Ҁ0.82, Ҁ0.28; P for trend ҃ 0.0001), were
2). A significant inverse association was observed only for
associated with intake of secoisolariciresinol and matairesinol
asthma (RR: 0.65; 95% CI: 0.47, 0.90; P for trend ҃ 0.04). This
(48). Aortic stiffness, assessed with pulse-wave velocity mea-
finding supported an earlier cross-sectional study, in which in-
surements of the aorta, was borderline significantly inversely
take of flavonoids was beneficially associated with pulmonary
associated with lignan intake among postmenopausal Dutch
function and symptoms of COPD. Pulmonary function (mea-
women (49). The regression coefficient for those with a high
sured as forced expiratory volume in 1 s) was better among
intake of lignans was Ҁ0.41 (95% CI: Ҁ0.93, 0.11; P for trend ҃
subjects in the highest quintile, compared with the lowest quin-
0.06), compared with those with a low intake. The protective
tile, of intake of flavonols, flavones, and catechins (44 mL; 95%
effect was most pronounced and significant among women with
CI: 18, 69 mL). Catechin intake alone was most strongly asso-
ciated with the forced expiratory volume in 1 s (130 mL; 95% CI:101, 159 mL) and with all 3 symptoms of COPD [cough odds
ratio (OR): 0.72; 95% CI: 0.58, 0.90; phlegm OR: 0.60; 95% CI:0.47, 0.75; breathlessness OR: 0.69; 95% CI: 0.52, 0.90] (38).
To date, 3 prospective, nested, case-control studies and 3 case-
control studies have studied plasma or urinary lignan concentra- tions and cancer risk (Table 4); all except one investigated breast
cancer incidence. The 2 prospective, nested, case-control studieson breast cancer risk, among Dutch postmenopausal women (54)
and among female participants in 3 cohorts in northern Sweden
Plant lignans can be converted by human intestinal bacteria
(53), found no relationship with plasma or urinary enterolactone
into the so-called enterolignans, ie, enterolactone and enterodiol.
concentrations. In contrast, all 3 case-control studies found an
TABLE 2 Prospective studies of flavonoid intake and risk of incident cancer and other chronic diseases1
Flavonols, flavones, M 26.9 vs 4.3,6
Goldbohm et al, 1998 (33) Netherlands 3799 MF
Flavonols, flavones, M 26.9 vs 4.3,6
Goldbohm et al, 1998 (33) Netherlands 3306 MF
Flavonols, flavones, M 26.9 vs 4.3,6
Goldbohm et al, 1998 (33) Netherlands 3726 MF
Flavonols, flavones, M 26.9 vs 4.3,6
Goldbohm et al, 1998 (33) Netherlands 2203 F
TABLE 2 Continued 1 —, no data provided. 2 Flavonols: quercetin, kaempferol, myricetin; flavones: apigenin, luteolin; flavanones: hesperetin, naringenin, eriodictyol; catechins: (ѿ)-catechin, (ѿ)-gallocatechin,
(Ҁ)-epicatechin, (Ҁ)-epigallocatechin, (Ҁ)-epicatechin gallate, (Ҁ)-epigallocatechin gallate. 3 Mean, median, or category cutoff value. 4 Design in parentheses if other than prospective cohort. 5 95% CI in parentheses. 6 Quartiles were constructed for men and women separately, but RR is provided for sexes combined only.
inverse association between lignan concentrations and breast
breast cancer among premenopausal women (RR: 0.49) but not
cancer risk (52, 55, 56). When a subset of postmenopausal
postmenopausal women (RR: 0.72) in western New York State
women only was included in the analysis of the Shanghai Breast
(58). In contrast, breast cancer risk was borderline significantly
Cancer Study, the inverse association was no longer significant
elevated with a high intake of secoisolariciresinol and mataires-
and the RR increased from 0.40 (95% CI: 0.24, 0.64) to 0.50
inol among a large group of women participating in the multi-
(95% CI: 0.23, 1.10) (51). In all of these case-control studies,
ethnic Bay Area Breast Cancer Study (RR: 1.3) (59) and of
plasma or urine was collected after diagnosis and sometimes
secoisolariciresinol only in the prospective California Teachers
even after initiation of treatment of the disease, which might have
Study (RR: 1.4) (57). In the latter study, the association was
influenced lignan concentrations through changes in the diet as a
substantially attenuated to a RR of 1.2 (95% CI: 0.9, 1.6) after
result of disease or through other mechanisms. The only study on
adjustment for wine consumption. This led the authors to con-
prostate cancer risk conducted to date found no association with
clude that the increased risk with secoisolariciresinol was attrib-
plasma enterolactone concentrations among a large cohort of
utable to confounding by alcohol consumption.
male residents of Finland, Norway, and Sweden (50).
Significant or borderline significant protective associations
Intake of the lignans secoisolariciresinol and matairesinol was
were also reported for endometrial cancer (60), ovarian cancer
studied in relation to the risk of several cancers in 1 prospective
(37), and thyroid cancer (61) among female participants. No
cohort and 3 case-control studies, all from the United Stated
associations between lignan intake and incident prostate (34) or
(Table 4). A significant inverse association was observed for
TABLE 3 Prospective studies of serum lignans and risk of CVDs1 1 ENL, enterolactone. 2 Design in parentheses if other than prospective cohort. 3 Death, unless indicated otherwise. 4 95% CI interval in parentheses. TABLE 4 Prospective and case-control studies on plasma or urinary lignan concentrations or dietary lignan intake and incident cancer1 1 ENL, enterolactone; END, enterodiol; SECO, secoisolariciresinol; MAT, matairesinol; —, no data provided. 2 Mean, median, or category cutoff value; plasma values in nmol/L, urine values as indicated, intake levels in mg/d. 3 Follow-up time in parentheses. 4 95% CI in parentheses. 5 ENL and END production from foods determined by in vitro fermentation with human fecal microflora. DISCUSSION
0.44) for 3 studies from continental Europe, and 0.95 (95% CI:
In the past decade, several well-designed, prospective, cohort
0.84, 1.08) for 8 studies from the United States. Explanations for
studies in which the health effects of flavonoids were studied
this phenomenon, which also seems to occur for flavonoids,
have been published. The data regarding CVD suggest protective
include differing associations with a healthy lifestyle and publi-
effects of high intakes of flavonols and flavones and possibly of
cation bias. However, no satisfactory explanation has been pro-
catechins. However, only a few studies are available for cat-
vided, and research into these differences seems worthwhile.
echins and for stroke; given the results obtained to date, these
Attempts to distinguish the effects of flavonols and flavones
deserve more study. A meta-analysis of tea consumption in re-
from those of catechins were undertaken with data from the
lation to CAD and stroke, including all studies published up to
Zutphen Elderly Study (18, 29) and demonstrate one of the major
October 2000, was conducted by Peters et al (62). Most studies
limitations of component-based epidemiologic studies. Each
included in the current review were also included in that meta-
food contains a large number of different compounds, some
analysis, because they provided data not only for tea, which is a
known and quantified, some less well characterized, and some
major flavonoid source, but also for flavonoids. Peters et al (62)
unknown or unmeasurable. Many compounds tend to be present
found evidence for publication bias, particularly with respect to
in the same foods or families of foods. The intake of catechins, for
stroke, and therefore urged caution in interpreting the results for
example, was positively correlated with the intake of fruits and
this endpoint. Publication bias might have occurred for flavonoid
vegetables and their constituents, eg, vitamin C, vitamin E, caro-
epidemiologic studies as well. Another striking finding is that
tenoids, folate, and fiber. For the intake of vitamin C, ␤-carotene,
studies of CAD or myocardial infarction conducted in continen-
and fiber, correlations in several European populations on the
tal Europe reported strong inverse associations, whereas studies
order of 0.40-0.70 were reported (63). When the correlation is too
conducted elsewhere did not. Summarized RRs for drinking 3
high, it is impossible to ascertain independent effects of dietary
cups per day compared with no tea were 1.62 (95% CI: 1.15,
components, because of multicollinearity. This was the case for
2.30) for 2 studies from the United Kingdom, 0.27 (95% CI: 0.16,
flavonols and catechins in the Zutphen Elderly Study. Tea
supplied 87% of this population’s intake of catechins and 61% of
should be conducted on the lignan-cancer association before any
the intake of flavonols and flavones (24). To circumvent multi-
collinearity problems but still distinguish the effects of catechins
The quality of dietary intake assessment and of food compo-
from those of flavonols, subgroups were defined, ie, tea, cat-
sition tables is crucial in the component-based epidemiologic
echins from sources other than tea, and flavonols from sources
approach. Imprecision of exposure measurement is an important
other than tea. Independent effects on CAD mortality rates were
limitation of these studies. If valid biomarkers are available, then
borderline significant for tea (P ҃ 0.06) and catechins from other
these may replace questionnaire-based assessment of exposure;
sources than tea (P ҃ 0.11). For correct interpretation of results
for most compounds, however, no biomarkers that reflect long-
of dietary component-based epidemiologic studies, adjustment
term exposure are available. No studies using biomarkers of
for other dietary factors (both nutrient and nonnutrient) is of
flavonoid intake have been conducted to date. In contrast, several
studies have used plasma or urinary enterolactone concentrations
Data are less convincing for cancer. Of several cancers stud-
as biomarkers of lignan exposure. A major drawback of most of
ied, protective effects have been reported only for lung cancer in
those studies was that enterodiol, the other enterolignan pro-
relation to flavonol and flavone intake. Together with data from
duced by the colonic microflora, was not measured. It was re-
one cohort study and one cross-sectional study suggesting ben-
cently shown that not only secoisolariciresinol and matairesinol
eficial effects on asthma and lung function, these data suggest a
but also several other plant lignans, including pinoresinol and
role for flavonoids in lung health that merits additional investi-
lariciresinol, are converted into enterolignans (71). We deter-
gation. For colorectal cancer, data are inconsistent, with 1 posi-
mined the concentrations of these 2 additional lignans in plant
tive, 1 inverse, and 4 null associations. Residual confounding by
foods and found that their intake is severalfold higher than that of
smoking is the most serious drawback of the flavonoid studies
secoisolariciresinol and matairesinol (IEJ Milder, ICW Arts, and
published to date. Unhealthy (or healthy) behaviors tend to clus-
PCH Hollman, unpublished results, 2004). These compounds
ter. Smoking, which is the single most important risk factor for
should be included in future evaluations of the health effects ofdietary lignans.
many cancers and an important determinant of CVDs, is associ-
Epidemiologic studies can be useful tools to study the health
ated with higher intakes of energy, alcohol, and fat, lower intakes
effects of polyphenols. Data obtained to date suggest of a bene-
of fruits and vegetables, lower socioeconomic status, and phys-
ficial effect on CVD but not on cancer, with the possible excep-
ical inactivity (64 – 66). Previous studies showed that consump-
tion of lung cancer. There is a need for more research on stroke
tion of important sources of flavonoids, such as tea in the Neth-
and lung diseases such as asthma and COPD. Most studies have
erlands (67) and in Japan (68) and wine in Denmark (69), is
included flavonols and flavones only. With data becoming avail-
associated with healthy dietary patterns. Residual confounding
able for other polyphenols, these should be included in future
occurs if confounders such as smoking are insufficiently ac-
studies. Careful design of prospective studies is important to
counted for in statistical analyses. Insufficient control for con-
offset some of the major drawbacks of epidemiologic studies,
founders can occur as a result of misclassification of the con-
including residual confounding (by smoking and other dietary
founding factors, and control thus depends on the quality and
amount of detail with which the confounders are measured. Inparticular, if the confounding is strong, as is usually the case forsmoking, then misclassification of the confounder can yield spu-
rious associations (70). Studying associations among lifelong
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Massachusetts Department of Public Health Emergency Preparedness Bureau May 6, 2009 Situation Report: Massachusetts Swine Flu Response Situation Report: Massachusetts Swine Flu Response Massachusetts : 45 confirmed cases as of May 6, 2009 at 1100 hrs **Please see the end of this report for a detailed listing of confirmed cases New England : 54 confirmed case