That foods might provide therapeutic benefits is clearly not a new concept. The

tenet, “Let food be thy medicine and medicine be thy food” was embraced 2500 years

ago by Hippocrates, the father of medicine. However, this “food as medicine”

philosophy fell into relative obscurity in the 19th century with the advent of modern

drug therapy. In the 1900s, the important role of diet in disease prevention and

health promotion came to the forefront once again.
During the first 50 years of the 20th century, scientific focus was on the

identification of essential elements, particularly

vitamins, and

their role in the prevention of various dietary deficiency diseases. This emphasis on

nutrient deficiencies or “undernutrition” shifted dramatically, however, during the

1970s when diseases linked to excess and “overnutrition” became a major public

health concern. Thus began a flurry of public health guidelines, including the Senate

Select (McGovern) Committee's Dietary Goals for the United States (1977), the

Dietary Guidelines for Americans (1980, 1985, 1990, 1996, 2000— a joint publication

of the USDA and the Department of Health and Human Services), the Surgeon

General's Report on Nutrition and Health (1988), the National Research

Council's Diet and Health (1989) and Healthy People 2000 and 2010 from the U.S.

Public Health Service. All of these reports are aimed at public policy and education

emphasizing the importance of consuming a diet that is low in saturated fat, and high

in vegetables, fruits, whole grains and legumes to reduce the risk of chronic

diseases such as heart disease, cancer, osteoporosis, diabetes and stroke.
Scientists also began to identify physiologically active components in foods from

both plants and animals (known as phytochemicals and zoochemicals, respectively) that

potentially could reduce risk for a variety of chronic diseases. These events,

coupled with an aging, health-conscious population, changes in food regulations,

numerous technological advances and a marketplace ripe for the introduction of

health-promoting products, coalesced in the 1990s to create the trend we now know as

“functional foods.” This report includes a discussion of how functional foods are

currently defined, the strength of the evidence both required and thus far provided

for many of these products, safety considerations in using some of these products,

factors driving the functional foods phenomenon, and finally, what the future may

hold for this new food category.
What are functional foods?
All foods are functional to some extent because all foods provide taste, aroma

and nutritive value. However, foods are now being examined intensively for added

physiologic benefits, which may reduce chronic disease risk or otherwise optimize

health. It is these research efforts that have led to the global interest in the

growing food category now recognized as “functional

foods.” Functional foods have no universally accepted definition. The concept

was first developed in Japan in the 1980s when, faced with escalating health care

costs, the Ministry of Health and Welfare initiated a regulatory system to approve

certain foods with documented health benefits in hopes of improving the health of the

nation's aging population (1). These foods, which are eligible to bear a special

seal, are now recognized as Foods for Specified Health Use (FOSHU).3 As of July 2002,

nearly 300 food products had been granted FOSHU status in Japan.
In the United States, functional foods have no such regulatory identity. However,

several organizations have proposed definitions for this new food category. In 1994,

the National Academy of Sciences' Food and Nutrition Board defined functional

foods as “any modified food or food healthcare ingredients that may provide a health benefit beyond

the traditional nutrients it contains” (2). The International Life Sciences

Institute defines them as “foods that, by virtue of the presence of

physiologically-active components, provide a health benefit beyond basic nutrition”

(3). In a 1999 position paper, the American Dietetic Association defined functional

foods as foods that are “whole, fortified, enriched, or enhanced,” but more

importantly, states that such foods must be consumed as “… part of a varied diet on

a regular basis, at effective levels ” for consumers to reap their potential health

benefits (4).
Another term often used interchangeably with functional foods, although it is

less favored by consumers, is “nutraceuticals,” a term coined in 1991 by the

Foundation for Innovation in Medicine to refer to nearly any bioactive component that

delivers a health benefit. In a 1999 policy paper, Zeisel (5) astutely distinguished

whole foods from the isolated components derived from them in his following

definition of nutraceuticals: “those diet supplements that deliver a concentrated

form of a presumed bioactive agent from a food, presented in a nonfood matrix, and

used to enhance health in dosages that exceed those that could be obtained from

normal food.”
Several factors are responsible for the fact that this is one of the most active

areas of research in the nutrition sciences today: 1) an emphasis in nutritional and

medical research on associations between diet and dietary constituents and health

benefits, 2) a favorable regulatory environment, 3) the consumer self-care

phenomenon, and 4) rapid growth in the market for health and wellness products.
Criteria for sound science
According to the Department of Health and Human Services, diet plays a role in 5

of 10 of the leading causes of death, including coronary heart disease (CHD), certain

types of cancer, stroke, diabetes (noninsulin dependent or type 2) and

atherosclerosis. The dietary pattern that has been linked with these major causes of

death in the United States and other developed countries is characterized as

relatively high in total and saturated fat, cholesterol, sodium and refined sugars

and relatively low in unsaturated fat, grains, legumes, fruits and vegetables. An

accumulating body of research now suggests that consumption of certain foods or their

associated physiologically active components may be linked to disease risk reduction

(6). The great majority of these components derive from plants; however, there are

several classes of physiologically active functional food ingredients of animal or

microbial origin.
Claims linking the consumption of functional foods or food



advanced health ingredients with health outcomes require sound scientific

evidence and significant scientific agreement. The Food and Drug Administration (FDA)

outlined the criteria for “significant scientific agreement” in a guidance document

released on December 22, 1999 (7). As summarized in the schematic shown in Figure 1,

there is a clear discrepancy between “emerging evidence” (characterized by in vitro

or animal studies, uncontrolled human studies, and inconsistent epidemiological

evidence) and “significant scientific agreement.” To reach such agreement requires

the support of a body of consistent, relevant evidence from well-designed clinical,

epidemiologic and laboratory studies, and expert opinions from a body of independent

scientists. Claims about the health benefits of functional foods should be based on

sound scientific evidence, but too often only so-called “emerging evidence” is the

basis for marketing some functional foods or their components. Table 1 categorizes a

variety of functional foods according to the type of evidence supporting their

functionality, the strength of that evidence and the recommended intake levels.
Functional foods of animal origin
Probably the most intensively investigated class of physiologically-active

components derived from animal products are the (n-3) fatty acids, predominantly

found in fatty fish such as salmon, tuna, mackerel, sardines and herring (8). The two

primary (n-3) fatty acids are eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic

acid (DHA; 22:6). DHA is an essential component of the phospholipids of cellular

membranes, especially in the brain and retina of the eye, and is necessary for their

proper functioning. DHA is particularly important for the development of these two

organs in infants (9), and just recently, the FDA cleared the use of DHA and

arachidonic acid for use in formula for full-term infants (10). Hundreds of clinical

studies have been conducted investigating the physiologic effects of (n-3) fatty

acids in such chronic conditions as cancer, rheumatoid arthritis, psoriasis,

Crohn's disease, cognitive dysfunction and cardiovascular disease (11), with the

best-documented health benefit being their role in heart health. A recent meta-

analysis of 11 randomized control trials suggests that intake of (n-3) fatty acids

reduces overall mortality, mortality due to myocardial infarction and sudden death in

patients with CHD (12).
The 2000 American Heart Association Dietary Guidelines recommend two servings of

fatty fish per week for a healthy heart (13), and the FDA authorized a qualified

health claim on dietary supplements linking the consumption of EPA and DHA (n-3)

fatty acids to a reduction of coronary heart disease risk (14). The qualified claim

states: “Consumption of omega-3 fatty acids may reduce the risk of coronary heart

disease. FDA evaluated the evidence and determined that, although there is scientific

evidence supporting the claim, the evidence is not conclusive.” A “qualified”

claim was authorized because of certain safety concerns regarding the consumption of

high levels of (n-3) fatty acids, including: 1) increased bleeding times; 2)

increased risk for hemorrhagic stroke; 3) the formation of biologically active

oxidation products from the oxidation of (n-3) fatty acids; 4) increased levels of

LDL cholesterol; and 5) reduced glycemic control among people with diabetes. The FDA

concluded that use of (n-3) fatty acid supplements is safe, provided daily intakes of

EPA and DHA from supplements do not exceed 2 g/d (14).
Another class of biologically active animal-derived components that has received

increasing attention in recent years is probiotics. Defined as “viable

microorganisms that are beneficial to human health” (15), the health benefits of

probiotics have been considered since the turn of the century when the Nobel prize-

winning microbiologist Metchnikoff first postulated that lactic acid bacteria

contributed to the longevity of Bulgarian peasants (16). It is thought that a wide

variety of live microorganisms can contribute to human health, although the evidence

is mainly from animal studies. In addition to numerous strains of Lactobacillus

acidophilus, other strains of lactobacillus are being incorporated into functional

food products, as food additives

, now on the market including L. johnsonii La1, L. reuteri, L. GG, and L. casei

Shirota. A recent Scientific Status Summary on probiotics from the Institute of Food

Technologists summarized the scientific support for the therapeutic and/or preventive

use of these functional ingredients for various health concerns including cancer,

intestinal tract function, immune function, allergy, stomach health, urogenital

health, cholesterol lowering and hypertension (17). The review emphasizes that the

future success of probiotics will require strong support from medical and nutrition

scientists and that studies documenting these effects in humans are limited.
More recently, research efforts have focused on prebiotics, i.e., nondigestible

food ingredients that beneficially affect the host by selectively stimulating the

growth and/or activity of one or a limited number of beneficial bacteria in the

colon, thus improving host health (18). Prebiotics include short-chain carbohydrates

such as fructooligosaccharides and inulin, which enter the colon and serve as

substrates for the endogenous colonic bacteria. Newer still is the concept of

“synbiotics,” which are mixtures of probiotics and prebiotics that beneficially

affect the host by improving the survival and implantation of live microbial dietary

supplements in the gastrointestinal tract, by selectively stimulating the growth

and/or by activating the metabolism of one or a limited number of health-promoting

bacteria, and thus improving host welfare (18).
Another nonplant ingredient that has been the focus of increased research efforts

in recent years is conjugated linoleic acid (CLA). This component, which was first

identified as a potent antimutagenic agent in fried ground beef by Pariza and co-

workers (19), is a mixture of structurally similar forms of linoleic acid (cis-9,

trans-11 octadecadienoic acid). CLA is present in almost all foods, but occurs in

particularly large quantities in dairy products and foods derived from ruminant

animals (20). For example, uncooked beef contains 2.9–4.3 mg CLA/g fat, whereas

lamb, chicken, pork and salmon contain 5.6, 0.9, 0.6, and 0.3 mg CLA/g fat,

respectively, and dairy products contain 3.1–6.1 mg CLA/g fat (21). The inhibition

of mammary carcinogenesis in animals is the most extensively documented physiologic

effect of CLA (22), and there is also emerging evidence that CLA may decrease body

fat and increase muscle mass both in rodent models (23) and in humans (24), although

not all human studies have been positive in this regard. There is also preliminary

evidence that CLA may increase bone density in animal models (25).
Functional foods of plant origin (Natural Plant Extract)
Numerous plant foods or physiologically active ingredients, such as

pharmaceuticals, derived from

plants have been investigated for their role in disease prevention and health.

However, only a small number of these have had substantive clinical documentation of

their health benefits. An even smaller number have surpassed the rigorous standard of

“significant scientific agreement” required by the FDA for authorization of a

health claim, which will be discussed in further detail below. Those plant foods

currently eligible to bear an FDA-approved health claim include oat soluble (β-

glucan) fiber (26), soluble fiber from psyllium seed husk (27), soy protein (28) and

sterol- and stanol-ester–fortified margarine (29).
Some plant-based foods or food constituents currently do not have approved health

claims, but have growing clinical research supporting their potential health

benefits, and thus would be described as having moderately strong evidence. These

include cranberries, garlic, nuts, grapes and chocolate and are discussed briefly

below.
Cranberries have been recognized since the 1920s for their efficacy in treating

urinary tract infections. A landmark clinical trial (30) confirmed this therapeutic

effect in a well-controlled study involving 153 elderly women. More recent research

has confirmed that condensed tannins (proanthocyanidins) in cranberry are the

biologically active component and prevent E. coli from adhering to the epithelial

cells lining the urinary tract (31). New preliminary research suggests that the

antiadhesion properties of the cranberry may also provide other health benefits,

including in the oral cavity (32).
Garlic (Allium sativum) has been used for thousands of years for a wide variety

of medicinal purposes; its effects are likely attributable to the presence of

numerous physiologically active organosulfur components (e.g., allicin, allylic

sulfides) (33). Garlic has been shown to have a modest blood pressure–lowering

effect in clinical studies (34), while a growing body of epidemiologic data suggests

an inverse relationship between garlic consumption and certain types of cancer (35),

particularly of the stomach (36). The latter may be due in part to garlic's

ability to inhibit the activity of Helicobacter pylori (the bacterium that causes

ulcers). The best-documented clinical effect of garlic, however, concerns its ability

to reduce blood cholesterol. A meta-analysis of 13 placebo-controlled double blind

trials (37) indicated that garlic component(s) (10 mg steam distilled oil or 600–900

mg standardized garlic powder) significantly reduced total cholesterol compared with

placebo by 4–6%. However, the Agency for Healthcare Research & Quality (38), which

examined randomized, controlled trials at least 1 mo in duration, concluded that,

although clinical trials show several promising, modest, short-term effects of garlic

supplementation on lipid and antithrombotic factors, “effects on clinical outcomes

are not established …” This is likely due to lack of consistency among studies in

type of preparation used and overall study design.
Although foods high in fat have traditionally not been regarded as “heart-

healthy” (except for fatty fish), evidence is accumulating on the cardiovascular

benefits of a variety of nuts, when they are part of a diet that is low in saturated

fat and cholesterol (39). Clinical trials, which have specifically examined the

effect of almonds on blood lipids, have found that these tree nuts significantly

reduced total cholesterol by 4–12% and LDL cholesterol by 6–15% (40,41). More

recently, a Life Sciences Research Office review of six clinical intervention trials

with walnuts consistently demonstrated decreases in total and LDL cholesterol that

should lower the risk of CHD (42).
In the late 1970s researchers noted that residents in certain areas of France,

who were avid drinkers of red wine, had less heart disease than other Western

populations even though they consumed more fat in their diet. This observation

triggered numerous investigations into this so-called “French Paradox” (43) and

subsequent research confirmed the presence of high concentrations of antioxidant

polyphenolics in red grape skins. It must be noted however, that moderate consumption

of any alcoholic beverage, e.g., beer, wine or distilled spirits, has been shown in a

number of studies to reduce the risk of heart disease in selected populations (44).
For those wishing to abstain from alcohol, recent clinical trials demonstrate

that grape juice may also exert beneficial effects similar to those of red wine

because both are rich in phenolic antioxidant compounds. Consumption of grape juice

has been shown to reduce platelet aggregation (45).
Another food that is a source of polyphenolics and is just beginning to be

investigated for its potential benefits to heart health (46) is chocolate. Chocolate

contains flavonoids (procyanidins), which may reduce oxidative stress on LDL

cholesterol. In a recent clinical trial involving 23 subjects consuming a diet

supplemented with chocolate and cocoa powder providing 466 mg procyanidins/d, time to

oxidation of LDL cholesterol was increased by 8% compared with subjects consuming a

normal American diet (47).
Epidemiologic data are accumulating on the health benefits of several additional

functional foods or food components of plant origin, including tea (catechins),

lycopene from tomatoes, particularly cooked and/or processed tomato products, and the

carotenoids lutein and zeaxanthin from green leafy vegetables.
The effect of green or black tea consumption on cancer risk (48) has been the

focus of numerous studies. Studies in animals consistently show that consumption of

green tea reduces the risk of various types of cancers. Only a few studies have thus

far assessed the effects of black tea. Green tea is particularly abundant in specific

polyphenolic components known as catechins (49). The major catechins in green tea are

(?)-epicatechin, (?)-epicatechin-3-gallate, (?)-epigallocatechin and (?)-

epigallocatechin-3-gallate (EGCG) (50). One cup (240 mL) of brewed green tea contains

up to 200 mg EGCG, the major polyphenolic constituent of green tea.
Although 100 epidemiological studies have examined the effect of tea consumption

on cancer risk, the data are conflicting (51). A recent study (52) involving 26,311

residents from three municipalities in northern Japan found no association of green

tea consumption with the risk of gastric cancer. Phase I clinical trials are

currently ongoing at the MD Anderson Cancer Center (Houston, TX) in collaboration

with the Memorial Sloan-Kettering Cancer Center in New York on the safety and

efficacy of consuming the equivalent of >10 cups of green tea by 30 cancer patients

with advanced solid tumors.
Tomatoes and tomato products are also being investigated for their role in cancer

chemoprevention and are unique because they are the most significant dietary source

of lycopene, a non-provitamin A carotenoid that is also a potent antioxidant (53). A

comprehensive review of 72 epidemiologic studies (54) found an inverse association

between tomato intake or plasma lycopene concentration and the risk of cancer at a

defined anatomical site in 57 of the 72 studies reviewed (79%); in 35 of these

studies, the inverse associations were statistically significant. No study indicated

higher risk with increasing tomato consumption or lycopene blood levels. Further, the

risk reduction for about half of all studies reviewed was 40% (i.e., a relative risk

estimate of 0.6). Cancers of the prostate, lung and stomach showed the strongest

inverse associations, whereas data were suggestive for cancers of the pancreas, colon

and rectum, esophagus, oral cavity, breast and cervix.
Most ongoing clinical trials involving lycopene and cancer prevention are focused

on prostate cancer, in large part because a 1995 study (55) involving > 47,000

participants from the Health Professionals Follow-Up Study (HPFS) followed from 1986

to 1992 found that >10 servings/wk of tomato sauce, tomatoes, tomato juice or pizza

could reduce risk of prostate cancer by 35%; advanced prostate cancer (i.e., more

aggressive tumors) was reduced by 53%. More importantly, of the 46 fruits and

vegetables evaluated, tomato products were the only foods that were associated with

reduced risk of prostate cancer. Additional follow-up data from the HPFS through 1998

further supported the earlier observation that lycopene reduces prostate cancer risk

and, more specifically, found that that intake of tomato sauce (2+ servings/wk) was

associated with a 23% reduction in prostate cancer risk (56). The protective effect

of tomato products may result from lycopene's ability to selectively accumulate

in the prostate gland, perhaps serving an antioxidant function in that organ (57).

This hypothesis was strengthened by a recent study that found that men with localized

prostate adenocarcinoma had significantly reduced prostate DNA oxidative damage after

consumption of tomato-sauce based meals containing 30 mg lycopene for 3 wk (58).
Another carotenoid that has received recent attention for its role in disease

risk reduction is lutein, the main pigment in the macula of the eye (an area of the

retina responsible for the sharpest vision). More specifically, research is focusing

on the role of lutein in eye health due to its ability to neutralize free radicals

that can damage the eye and by preventing photooxidation. Thus, individuals who have

a diet high in lutein may be less likely to develop age-related macular degeneration

(AMD) (59,60) or cataracts (61,62), the two most common causes of vision loss in

adults. Because of the increasing evidence for lutein's role in eye health,

supplements that contain this carotenoid are now appearing on the market. There is

some concern, however, that lutein in supplement form may not provide the same

benefit as the lutein found naturally in foods (63). In March 2000, the National Eye

Institute of the NIH released a statement on lutein and its role in eye disease

prevention (64): “Claims made about an association between lutein and eye health

should be approached with caution. The possible benefits of lutein on the eye remain

uncertain.” The statement indicates that there is little direct scientific evidence

at this time to support a claim that taking supplements containing lutein can

decrease the risk of developing AMD or cataract. Nevertheless, the possibility that

lutein may reduce the risk of oxidant-related diseases of the eye clearly warrants

further research. Good sources of lutein include green leafy vegetables such as

spinach (7.4 mg/100 g) and cooked cabbage (14.4 mg/100 g).
Although not yet supported by clinical or epidemiologic data, evidence from in

vitro and in vivo (animal) studies supports the cancer-preventive benefits of

flaxseed lignans (65), citrus fruit limonoids (66) and various cruciferous vegetable

phytochemicals, including isothiocyanates and indoles (67). With respect to the

latter, broccoli sprouts are currently being marketed both as a dietary supplement,

highlighting the potential cancer-preventive action of one purported physiologically

active component, sulforaphane, and as a food containing high levels of sulforaphane.

In vitro and in vivo, this component has been shown to be a potent inducer of Phase

II detoxifying enzymes in the liver. Such enzymes speed the inactivation of toxic

substances and thus accelerate their elimination from the body (68). The marketing of

conventional foods as dietary supplements has engendered controversy, however, as

will be discussed below.
Safety considerations
Although there is evidence that certain functional foods or

food ingredients can play a role in disease

prevention and health promotion, safety considerations should be paramount. Safety

concerns have recently been raised, particularly with regard to the seemingly

indiscriminate addition of botanicals to foods. A plethora of “functional” bars,

beverages, cereals and soups are being enhanced with botanicals, some of which may

pose a risk to certain consumers. The safety issues related to herbs are complex and

the issue of herb-drug interaction has received increasing attention. One example is

St John's wort, a popular herb utilized for treating mild depression. Hypericum

extract from St. John's wort significantly increases the metabolic activity of

liver cytochrome P450. This enzyme inactivates several drugs, and thus would be

expected to decrease their levels and activities in the body. Consuming St.

John's wort has been shown to cause concomitant decreases in plasma

concentrations of theophylline, cyclosporine, warfarin and

ethinylestradiol/desogestrel (oral contraceptives) (69). Such data prompted the FDA

to issue a Public Health Advisory about St. John's wort in February of 2000, as

have Canadian authorities. In the United States, some consumer groups have lobbied

the FDA to halt the sale of 75 functional foods enhanced with St. John's wort as

well as the following additional herbs: guarana, gotu kola, ginseng, ginkgo biloba,

echinacea, kava kava and spirulina. Also in 2000, the General Accounting Office (GAO)

released a report that raised concerns about the safety of certain functional foods

(70). The GAO report stated that the FDA “has not developed regulations or provided

guidance to companies on the type of safety-related information that should be

included on their labels for functional foods and dietary supplements. The absence of

such safety information poses a significant safety risk to some consumers.” In June

of 2001, the FDA issued warning letters to the food industry concerning the use of “

novel ingredients” such as St. John's wort in conventional food (71). The GAO

has made the following recommendations regarding the safety of functional foods:
Develop and promulgate regulations or other guidance for industry on the evidence

needed to document the safety of new dietary ingredients in dietary supplements
Develop and promulgate regulations or other guidance for industry on the safety-

related information required on labels for dietary supplements and functional foods
Develop an enhanced system to record and analyze reports of health problems

associated with functional foods and dietary supplements
A favorable regulatory environment
Three important changes that affected the dissemination of information to

consumers about the relationship between diet and health in food regulations occurred

in 1990, 1994 and 1997. The first of these is the Nutrition Labeling and Education

Act of 1990 (NLEA). The NLEA allows statements on food labels that characterize the

relationship of any food or food component to a disease or health-related condition.

Such “health claims” must be preapproved by the FDA before their use. Under the

NLEA, the FDA was mandated by Congress to review 10 diet-disease relationships, eight

of which were eventually approved as health claims.