Dietary reference intake (DRI) value for dietary polyphenols: are we heading in the right direction?

Dietary reference intake (DRI) value for dietary polyphenols: are we heading

in the right direction?

Gary Williamson

* and Birgit Holst

Chair of Functional Food, Procter Department of Food Science, University of Leeds, Leeds LS2 9JT, UK

Nestle

Waters M T, PTC Water, BP 101, 88804 Vittel CEDEX, France

Dietary Reference Intake (DRI) values exist for vitamins and minerals, and provide a guideline on the optimal dose range to avoid deﬁciency and

prevent toxicity. Polyphenols are widely distributed in plant foods, and have been linked to improved human health through reduced risk of chronic

diseases, especially cardiovascular. Although they do not cause classical deﬁciencies, recently they have been discussed as ‘lifespan essentials

because they are needed to achieve a full lifespan by reducing the risk of a range of chronic diseases. A recent meta analysis shows promising

actions of polyphenols from cocoa, soya and tea on ﬂow mediated dilation, blood pressure and LDL cholesterol. Many epidemiological studies

support the action of polyphenols or polyphenol-rich foods on health, but there are still many gaps in our knowledge. More adequately powered,

randomised, placebo controlled human studies are needed on polyphenols. There is a large number of structurally different polyphenols which are

relevant for health, and obtaining enough information to set a DRI for each of these will not be feasible in the foreseeable future. A new approach

is needed, and a new way of thinking, which would apply not only to polyphenols but also to other phytochemicals. Today, a target intake value of

polyphenols as ‘lifespan essentials’ needs to be based on the amount of polyphenols in ‘5-a-day’. We are heading in the right direction towards a

DRI, but bioavailability and dose-effects, including toxic levels, need to be established before DRIs can be considered.

Polyphenols: Bioavailability: Chronic disease prevention: Lifespan essential: Dietary requirements

This is not intended to be a comprehensive review of the litera-

ture as several in-depth reviews have appeared in the last few

years which summarize the results of human studies in

relation to polyphenols

(1 – 9)

. Furthermore, although isoﬂavones

are polyphenols, we have not made recommendations for this

class.

What are polyphenols?

Signiﬁcant research effort is now focused on minor dietary

constituents, vitamins and trace elements, phytochemicals

(carotenoids, ﬂavonoids, indoles, isothiocyanates, etc.),

zoochemicals (conjugated linoleic and n-3 fatty acids, etc.),

fungochemicals and bacteriochemicals (formed during food

fermentations and by the gut microﬂora).

The best studied polyphenols (also called ﬂavonoids, and

belonging to the bigger class of phytochemicals or phytonutri-

ents) are (epi)catechins (including green tea polyphenols) and

procyanidins (class: ﬂavanols), quercetin (class: ﬂavonols),

and the isoﬂavones (genistein and daidzein, found in soya).

Other, less studied classes, at least for health effects in

humans, are anthocyanins and hydroxycinnamic acids.

Biological activities

All polyphenols share several structural features, particularly

phenolic rings, and are amongst the most powerful of all the

dietary antioxidants in vitro. This property led to extensive

use of the word ‘antioxidant’, and overall polyphenol content

of a food source is commonly evaluated by measuring the

antioxidant activity e.g. by TEAC, ORAC, TRAP, etc

(10)

.In

the past, direct conclusions from in vitro antioxidant activity

of a food were extrapolated to health beneﬁts in vivo

in humans. However, it is now clear that this was far too sim-

plistic. Polyphenol action in vivo is through indirect antioxi-

dant protection by activating endogenous defence systems,

modulating cellular signalling processes involving nuclear

factor-kappa B (NF-kB), activator protein-1(AP-1) DNA bind-

ing, glutathione biosynthesis, phosphoinositide 3 (PI3)-kinase/

protein kinase B (Akt), mitogen-activated protein kinase

(MAPK), translocation into the nucleus of nuclear factor ery-

throid 2 related factor 2 (Nrf2), and inhibition of oxidative or

pro-inﬂammatory enzymes such as cyclo-oxygenase, lipoxy-

genase, NADPH oxidase, and some metalloproteins. For

example, the inhibition of one speciﬁc enzyme, COX-2,

affects inﬂammation, and consequently the development of a

larger number of chronic diseases

(11)

. Epicatechin, a polyphe-

nol found in cocoa, green tea and many fruits, affects nitric

oxide formation via NADPH oxidase

(12,13)

, hence modifying

vascular biomarkers such as ﬂow mediated dilation, an import-

ant diagnostic marker of cardiovascular risk

(14)

Based on the current state of the art, and especially on

published clinical studies, ﬂavanols ((epi)catechins in fruits,

procyanidins in fruit and cocoa, galloylated catechins in

tea), and the ﬂavonols (mainly quercetin, in vegetables, tea

and some fruits) are believed to be the most important

* Corresponding author: G. Williamson, fax þ 44 113 343 2982, email [email protected]k

British Journal of Nutrition (2008), 99, Suppl. 3, S55–S58 doi:10.1017/S0007114508006867

q The Authors 2008

British Journal of Nutrition

https://doi.org/10.1017/S0007114508006867 Published online by Cambridge University Press

polyphenols for human health; actions of the other classes

(ﬂavanones, hydroxycinnamates and anthocyanins) are less

studied in human intervention trials. However, acceptance of

health effects by the nutrition community is mixed, since the

effects are subtle and these types of dietary compounds do

not meet the classical criteria of being essential nutrients for

growth and development.

Most polyphenols are absorbed but the extent of absorption

and metabolism depends on the class of polyphenol. Ileos-

tomy, human in situ perfusion and intervention studies on

healthy subjects show high absorption of some classes.

Human studies show a poor absorption of intact anthocyanins

and procyanidins

(5)

. However, for the latter, it remains to be

seen if the microbial metabolites play an important role in bio-

logical functions. Bioavailability from different matrixes

needs to be established, since the route and extent of absorp-

tion are as important as the extent and pathway of metabolism,

which may lead to an inactivation and fast excretion of some

polyphenols. For others, metabolites (small intestinal, liver or

gut microbial), may have an equal or even higher biological

activity. The best studied example is equol

(15)

Generally polyphenols offer beneﬁts under conditions of

stress, which includes oxidative stress and exposure to

toxins e.g. due to smoking, detrimental microorganisms,

chronic or low-grade inﬂammation, UV exposure. These

lead to, mostly age related, changes of tissue structure and

function and to chronic diseases, including cardiovascular dis-

ease, diabetes, cancer and Alzheimer’s disease. Clinical

studies support reduction of risk of cardiovascular disease,

by effects mediated through LDL, nitric oxide and endothelial

function. Many, but not all, epidemiological studies support

these observations

(9)

. There are very few long-term interven-

tion studies of more than 3 months with polyphenols, and

there are very limited data on the effects of polyphenols in

children. A recent meta-analysis of human intervention studies

has shown effects of polyphenol rich foods on ﬂow mediated

dilation, blood pressure and LDL cholesterol

(2)

Furthermore, genetic predisposition and environmental

factors may affect the biological outcome and lead to further

complications for establishing dose-effect relationships. For

these reasons, large clinical trials linking validated biomarkers

of exposure to biomarkers of health beneﬁts with consider-

ation of inter-individual variability are scarce for most

polyphenols, but are required. Polyphenols may affect ‘sub-

optimal’ biomarkers indicative of a disease risk and thus

disease prevention, and so the need for a long term exposure

at dietary levels is obvious.

In addition to the above issues, all plant foods contain a

large range of bioactive molecules, which may act synergis-

tically or antagonistically. At what point should the whole

food rather than individual compounds be studied? On the

basis of epidemiological and/or in vivo evidence, in vitro

assays (cell culture, reporter assays, etc.) using extracts pur-

iﬁed individual compounds, AND their potential metabolites

could give a ﬁrst insight into bioactive compounds of a

certain food and help to establish and/or select appropriate

biomarkers. Once established, there is no substitute for

long term human intervention studies consistently applying

these biomarkers. In the future, intervention studies could

be supplemented by applying genomics, proteomics and

metabolomics techniques whenever possible. This requires

interdisciplinary, often multicentre approaches, a common

registration of clinical trials, such as on clinicaltrials.gov,

and the design of future trials to comply with todays well

established criteria, including randomization, placebo control,

and cross-over. Studies should be designed as far as possible

to have potential for inclusion in meta-analyses. Because of

the large number of polyphenols, there is a need to focus

on and examine the most promising actions of a few selected

compounds and end-points. Consideration of realistic effects

needs to take into account the dose, since some effects are

only seen at ‘mega-doses’ in vitro. It is essential to focus

on certain disease endpoints such as cardiovascular disease

via effects on endothelial function, sugar and lipid metab-

olism, LDL oxidation and anti-inﬂammatory effects.

Lifespan essential concept

Unlike vitamins, polyphenols are not required for growth and

development and for maintaining vital body functions

throughout life. Nevertheless, for selected polyphenols and

polyphenol plant sources, there is clinical and epidemiological

evidence showing reduction in the risk of chronic diseases.

This means that they are, like some other nutrients, essential

for reaching the full (genetically-determined) lifespan; we

have termed this ‘lifespan essential’

(1)

Concept of a dietary reference intake

The Food and Nutrition Board (FNB) of the IOM/NAS is cur-

rently expanding the list of nutritional substances that are

included in the Dietary Reference Intakes (DRIs) and recog-

nizes that there may be dietary substances other than the

classic nutrients for which recommendations should be

given. The DRI committee emphasizes that (i) functional end-

points, other than a clinical manifested deﬁciency, might be

important in establishing dietary recommendations and that

(ii) biologically active dietary substances, including nutrients,

might have substantially different functional outcomes at

different intake levels. These functional outcomes could

include toxic or other adverse responses, even for nutrients.

This takes into account the U shaped response curve and is

based almost entirely on human studies. In fact, for some clas-

sical nutrients, the recommended daily allowance (RDA) is

close to the upper (recommended) limit (UL) (Fig. 1). The

low toxicity of polyphenols would be expected to give rise

to a ratio close to that of vitamin C, although data remain to

be properly established and correlated. In addition, the exact

values will be different for each class of polyphenols and

even individual compounds.

The US Department of Agriculture (USDA) and the Depart-

ment of Health and Human Services are currently updating the

government dietary guidelines for 2010 in line with scientiﬁc

and medical advances. Dietary guidelines have existed since

1980, revisions are made every ﬁve years, and they aim to

advise the public on how to follow a healthy, balanced diet

and indicate to manufacturers the areas of development to

boost the healthy proﬁle of their products in line with govern-

ment guidelines followed by consumer awareness and

selection.

G. Williamson and B. HolstS56

British Journal of Nutrition

https://doi.org/10.1017/S0007114508006867 Published online by Cambridge University Press

Dietary reference intake for polyphenols?

The expected intakes of polyphenols from 5-a-day are shown

in Table 1, using data derived from the USDA database

(http://www.nal.usda.gov/fnic/foodcomp/Data/). Table 1 does

not include hydroxycinnamic acids, beverages such as tea

or coffee, or cocoa. However, like all nutrients, there is vari-

ation with cultivar, year, growing conditions, etc. It can be

seen that an individual who consumes 5-a-day could take

in . 500 mg of polyphenols daily. Consumption of cocoa,

tea or coffee, and consideration of the related hydroxycin-

namic acids, could easily increase this by 500– 1000 mg.

However, processed food may contain different amounts. It

should not be assumed that a food containing e.g. 2 apples

will contain the same amount of polyphenols as 2 apples

eaten raw. This is a challenge for the food industry, and a

target intake value would help in this respect as the

amount of polyphenols could be indicated on the label as a

percentage of that actually present in the original food. How-

ever, an assessment of dietary intakes in a deﬁned population

is difﬁcult to determine due to the lack of comprehensive

food composition data of processed foods. For a single poly-

phenol in food, content estimation is no more difﬁcult than

analytical issues for other nutrients, but there are very few

approved and certiﬁed methods for determining polyphenols

in food, unlike for vitamins and minerals.

Could we use currently available data to arrive at a Target

Intake value, based on the estimates represented in Table 1?

Potential toxicity could arise from intakes of mega-doses of

polyphenols via supplements or too highly fortiﬁed foods.

This has not been observed in human intervention studies,

but some issues have arises for antioxidant vitamins e.g. the

meta-analysis of intake of vitamin E, C and selenium

(16,17)

Dealing with the multiple types of polyphenols needs to be

discussed and considered.

Although we and many others propose that polyphenols are

important dietary constituents, insufﬁcient data are currently

available to establish DRIs. To obtain the required data is an

enormous undertaking, requiring public-governmental fund-

ing. We highly encourage coordinated research by funding

agencies in the area of polyphenols to address the questions

above. It should be emphasized that intervention studies

which examine a polyphenol dose-response are quite rare

and very deﬁnitely required.

Dietary recommendations and regulation for any (functional)

food enriched in polyphenols, polyphenol-rich extracts and

polyphenol based dietary supplements should limit their con-

sumption to dietary reference levels and avoid mega-doses.

DRIs should be partly based on epidemiological data concerning

the consumption of major food sources in a representative group

of the population. However limiting this approach might appear

for industry and functional foods, it still opens a wide area of

development opportunities: many bioactive polyphenols occur

in food sources that are not palatable for all groups of consumers

(e.g. the isoﬂavones in soy products or the green tea catechins),

are unstable during processing and storage, or are lost as by-pro-

ducts e.g. during juicing.

The initiatives by the EU (EURECCA) and the USA (ILSI)

In June 2005, the Food and Drug Administration (FDA), USA

rejected a claim on green tea and (mainly breast and prostate)

cancer because of the absence of credible evidence (there are

many animal and mechanistic studies, but very little human

data), and in May 2006 also rejected a claim on green tea

and cardiovascular diseases (evidence was supportive, but

not conclusive). There is a need for well-conducted clinical

studies in this area before further petitions are made. FDA

allowed a claim in 1999 on soya (which contains isoﬂavones,

although not speciﬁcally stated as such) on lowering levels of

total cholesterol and low-density lipoprotein, but this was

based on 27 human studies and clearly illustrates that there are

not yet enough studies on polyphenols to get a claim approved.

The European Union-funded project, EURECCA, is

attempting to harmonise recommended intake values across

Europe, since they all draw upon the same publicly available

published data. Consideration is being given to polyphenols

and other phytonutrients. This review was requested as a

result of this project.

Table 1. Intake of polyphenols (mg) from 100 g of selected foods according to the USDA database

Flavanones Flavonols Flavanols Procyanidins Anthocyanins Total

Orange 44 0 0 0 0 44

Red onion 0 39 0 0 13 52

Blueberries 0 4 3 325 113 445

Strawberry 0 2 4 140 ? 146

Apple 0 4 9 128 ? 141

Total 44 49 16 593 126 828

Fig. 1. Ratio between Recommended Daily allowance (RDA) and Upper

Limit (UL) values for selected vitamins.

Daily recommended intakes of phytochemicals S57

British Journal of Nutrition

https://doi.org/10.1017/S0007114508006867 Published online by Cambridge University Press

ILSI USA has already published a review on the state of

the art in preparation for considering DRI values. The con-

clusions

(9)

and the main recommendations are to develop

reference standards and reference libraries for commonly

consumed ﬂavonoids, develop sufﬁcient data to set a DRI

or to allow for public health recommendations for one or

more of the subgroups of ﬂavonoids, and to determine

whether a nutrient model, such as the DRI, is appropriate

for bioactive components such as ﬂavonoids. This includes,

but is not limited to, determining the risk of deﬁciency

and/or excess in certain instances (e.g. speciﬁc tissues or

special populations).

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