Functional Foods: The US Perspective: John A Milner

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Functional foods: the US perspective1–3

John A Milner

ABSTRACT Widespread interest in the possibility that state, behavior pattern, and genetic background. People through-

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selected foods might promote health has resulted in the coining out the world are becoming increasingly convinced that the
of the term functional food, although agreement about what is foods they consume can not only modulate performance but also
and what is not a functional food is lacking. Public interest in influence their risk of acquiring a variety of diseases (2). It is
functional foods is increasing because of higher health care logical to assume that consumer demand for these health-
costs; the passage of federal legislation affecting many food cat- promoting foods and the physiologically active compounds they
egories, including the expanded category of dietary supplements; contain will continue to grow in the foreseeable future, as will
and recent scientific discoveries linking dietary habits with the the availability of novel foods.
development of many diseases, including coronary heart disease Consumers must be provided with the information necessary
and some cancers. A variety of foods have been proposed as pro- to make informed decisions as to whether they should adjust
viding health benefits by altering one or more physiologic their intake of specific foods and their associated components.
processes. Biomarkers are needed to assess the ability of func- Several fundamental issues that need addressing become imme-
tional foods or their bioactive components to modify disease and diately apparent, however, when attempting to provide infor-
to evaluate the ability of these foods to promote health, growth, mation about potential benefits and risks accompanying
and well-being. Evidence suggests that several biomarkers may increased consumption of any food or component. Unlike the
be useful for distinguishing between diseased and nondiseased case with drugs, it is generally assumed that increased con-
states and even for predicting future susceptibility to disease. A sumption of foods and food constituents is safe and that any
variety of biomarkers will probably be needed to develop a pro- response will be associated with a reduction in risk rather than
file for an individual that reflects the impact of diet on perfor- with a cure or treatment. Even these general beliefs are ques-
mance and health. Another area of interest is the interaction of tionable, however, because toxicity is a function of the quantity
nutrients and their association with genetics. These interactions consumed. Hence, it is inappropriate to consider use of func-
may account for the inconsistent interrelations observed between tional foods and their bioactive components as being without
specific dietary constituents and the incidence of disease. some degree of risk. A more fundamental issue is the relative
Greater understanding of how diet influences a person’s genetic benefit or risk that might accrue from the increased ingestion of
potential, overall performance, and susceptibility to disease can such foods. To assess the relative merits and concerns about
have enormous implications for society. As new discoveries are this issue, some scientific agreement is needed, even though
made in this area, consumers will need access to this information such agreement is also somewhat relative because some per-
so that they can make informed decisions. Am J Clin Nutr sons may value particular information more than others when
2000;71(suppl):1654S–9S. establishing beliefs and opinions.
Experience has taught us that scientific opinion can be in
KEY WORDS Functional food, biomarkers error, such as when disagreements surfaced about the cause of
gastric ulcers. Nevertheless, even though scientific agreement
may not totally eliminate the possibility of error, it certainly
INTRODUCTION reduces its probability. The alternative of an ill-informed soci-
Cultural beliefs in the mystical powers of foods have been ety based on minority agreement or, perhaps even worse, agree-
handed down for generations (1). The ability of specific foods to ment based on an inadequate science base, would unquestion-
prevent or reduce the severity of symptoms arising from what are ably raise the chance for error and probably result in deleterious
now frequently recognized as nutritional inadequacies has been effects to society. History has revealed that although knowledge
recorded in a variety of historical documents. Interestingly, as
scientists unravel the mysteries about specific nutritional needs, 1
From the Department of Nutrition, The Pennsylvania State University,
it becomes apparent that some dietary components that may not
University Park.
be required for human existence may indeed markedly influence 2
Presented at the 17th Ross Research Conference on Medical Issues, held
quality of life by modifying one or more physiologic processes. in San Diego, February 22–24, 1998.
The ability of such foods to influence these processes is likely 3
Address reprint requests to JA Milner, The Pennsylvania State University,
dependent on several factors, including interactions with other Department of Nutrition, S126 Henderson Building, University Park, PA 16802.
constituents in the overall diet and the consumer’s physiologic E-mail: jam14@psu.edu.

1654S Am J Clin Nutr 2000;71(suppl):1654S–9S. Printed in USA. © 2000 American Society for Clinical Nutrition
FUNCTIONAL FOODS: THE US PERSPECTIVE 1655S

is important, wisdom about how and when to use this informa- belief that foods and their components have unusual health bene-
tion is critical. Unfortunately, consequences other than those fits is one possible explanation for the expanding use of supple-
intended have been documented when intake of foods or their ments among Americans. A large percentage of apparently healthy
components is excessive (3, 4). people residing in the United States are using supplements (14,
15), with use influenced by several factors, including age, sex, and
previous medical condition.
FUNCTIONAL FOOD Coronary heart disease is the most common cause of death
Widespread interest in the possibility that selected foods today. It accounts for <44% of the mortality and much of the
might promote health has resulted in the coining of the generic morbidity in the United States (13). It accounts for two-thirds of
term functional food. The Food and Nutrition Board (FNB) of deaths from heart disease and accounts for <70% of all deaths
the National Academy of Sciences defines a functional food as among persons older than 75 y. As the world’s population
one that encompasses potentially healthful products, including increases in age, concerns will certainly intensify about how best
“any modified food or food ingredient that may provide a health to reduce the risk of death and disability from this disease. A
benefit beyond that of the traditional nutrients it contains” (5). recent estimate put the economic cost of atherosclerotic cardio-

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Although the term functional food is increasingly recognized as vascular disease at $259 billion. The role of diet in this disease
a household word, it has not been embraced totally by the health has yet to be clarified, but if this estimate of cost is accurate, a
and scientific communities. Controversies about what is and small percentage of responders to dietary change could have a
what is not a functional food remain at the forefront of discus- substantial impact on health cost. Tucker and Miguel (16) esti-
sions (6–8). Many believe that the promotion of food as “good” mated that improving the nutritional status of some persons can
or “bad” is inappropriate and scientifically indefensible. Fur- be expected to reduce hospital costs. Although the benefits of
thermore, many nutritionists are adamant that only diets can be reducing hospital costs should not be understated, it is likewise
classified as good or bad, not foods per se (9). It is unlikely that important to recognize that preventive nutrition strategies will
a nonfunctional food exists. Thus, in the broadest context, all likely have an even greater impact on health care costs.
foods must be considered “functional.” Nevertheless, some foods Correlations have been reported between dietary habits and
may be particularly beneficial in selectively altering specific <60% of cancers in women and > 40% of cancers in men (17). It
physiologic processes that improve the quality of life or reduce is likely that several essential and nonessential dietary components
the risk of acquiring a disease. The wholesomeness of any diet influence the risk of developing cancer. Because <25% of Ameri-
depends on the supply of individual food components, interac- cans will ultimately deal with the complications of cancer, anything
tions among components, and meeting needs dictated by an indi- that reduces its risk can substantially reduce health care costs.
vidual’s genetic background and physiologic state. However, increased supplement usage among cancer patients raises
The suggestion that certain foods or their components might questions not only about effective dosages of dietary constituents
offer some unique health benefit has blurred the distinction and their cost but also about their safety (14, 15).
between foods and drugs. Classically, a drug is any article An estimated 6% of the national health expenditure is associ-
intended for use in the diagnosis, cure, mitigation, treatment, or ated with treatment of obesity (18). Several dietary components
prevention of disease. Modification of the FNB definition to may influence energy intake and metabolism (19, 20). Recent
reflect “functional” rather than “health” might help to resolve evidence that conjugated linoleic acid, a functional food compo-
some of these drugs-versus-nutrients concerns. In addition, the nent found primarily in animal tissues and fluids, can alter lipid
promotion of increased consumption of functional foods and homeostasis provides evidence that the potential health benefits
their associated bioactive components should be viewed as an of foods are not limited solely to plant sources (21).
approach to optimized nutrition rather than as an endorsement Three US legislative acts of the 1990s have likely had a signi-
of enhanced consumption of good foods or as a simple market- ficant effect on the promotion of the concept of functional foods.
ing strategy. Whether or not functional foods persists as a term, The first, the Nutrition Labeling and Education Act, passed in
it is imperative that consumer confidence in the food supply not 1990 (22), mandated that the Food and Drug Administration
be jeopardized. Promotion of good and bad foods must be (FDA) establish regulations requiring most foods to have a uni-
avoided. form nutrition label and also established circumstances under
which claims about content and disease prevention could be
made about nutrients in foods. The second piece of legislation,
REASONS FOR PUBLIC INTEREST the Dietary Supplement Health and Education Act of 1994 (23),
Increased interest in functional foods is likely occurring for defined dietary supplements as any product that contains one or
3 reasons: increased health care costs, recent legislation, and sci- more dietary ingredients, such as vitamins, minerals, herbs or
entific discoveries. Expenditures associated with health services, as other botanicals, amino acids, or other ingredients used to sup-
a percentage of national wealth (the gross national product, or plement the diet. Additionally, it created a mechanism for deal-
GNP), continue to rise worldwide (10). Health care in the United ing with safety issues, regulation of health claims, and labeling
States accounts for <14% of the GNP. Inappropriate dietary habits of dietary supplements; provided for good manufacturing prac-
are viewed by many as contributing to poor health and associated tices; established new government entities to review regulations;
health care costs (11). Dietary factors are seen as contributing to and encouraged research on dietary supplements. Finally, the
the leading causes of death of Americans, including coronary heart FDA Modernization Act of 1997 (24) amended the Federal Food,
disease and certain types of cancers (11–13). It would be foolhardy Drug, and Cosmetic Act by allowing health claims that are not
to believe that foods might be used as “magic bullets” against dis- preauthorized by FDA if the claims are based on “authoritative
eases, but it would also be unwise to reject evidence that inappro- statements” of government agencies such as the National Acad-
priate dietary habits can exacerbate unhealthy conditions. The emy of Sciences or the National Institutes of Health.
1656S MILNER

TABLE 1 fruit, vegetables, nuts, and grains; and indoles and isothio-
Partial list of functional foods and their physiologic effects cyanates, both found in cruciferous vegetables.
Food Physiologic effect An enormous number of carotenoids are found throughout the
plant kingdom. These compounds, many of which do not possess
Apple, barley, blackberry, blueberry, carrot, Lipid lowering
vitamin A activity, can influence numerous biological functions
eggplant, oats, garlic, ginger, ginseng, mushroom,
onion, soybean, tea
by serving as antioxidants, modulators of cell growth regulation,
Lemon, apple, cranberry, garlic, beet, cucumber, Enhanced drug regulators of gene expression, and immunoregulators (31, 32).
squash, soybean, cabbage, Brussels sprouts, detoxification Indole-3-carbinol is one of several carotenoids found in cabbage,
cauliflower, kale, broccoli, spinach broccoli, Brussels sprouts, and other Brassica vegetables reported
Ginseng, licorice, oats, parsley Antiinflammatory to exhibit anticarcinogenic properties in experimental animals. In
Cranberry, garlic, onion, green tea Antimicrobial addition, recent studies suggest indole-3-carbinol may be a safe,
Anise, fennel, soybean, cabbage Antiestrogenic well-tolerated, and efficacious treatment for recurrent respiratory
Orange, green tea, garlic Antiproliferative papillomatosis (33).
More than 100 sulfur-containing glycosides known collec-

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tively as glucosinolates occur naturally in cruciferous vegeta-
Epidemiologic and laboratory findings are continuing to pro- bles. On hydrolysis, they yield thiocyanate, nitrite, and isothio-
vide convincing evidence that increased consumption of fruit cyanates. Isothiocyanates influence a variety of biological
and vegetables can significantly modify disease risk. Interest- reactions (17, 25, 29).
ingly, a rather large number of chemical compounds found in More than 4000 flavonoids, which are polyphenolic com-
fruit and vegetables appear to offer protection (25, 26). Evidence pounds found ubiquitously in foods of plant origin, have been
exists that these essential and nonessential nutrients modify sev- described and categorized into flavonols, flavones, catechins,
eral cellular processes. Unquestionably, dietary habits are not the flavanones, anthocyanidins, and isoflavonoids. Flavonoids poten-
sole determinant of disease states, but adjusting the diet likely tially have a variety of biological effects, including serving as
represents a significant way of reducing risk. antioxidants, influencing drug detoxification mechanisms, and
altering cell proliferation (34).

CHARACTERIZATION OF FOODS
A partial list of foods that have been proposed to provide ben- BIOMARKERS
efits by altering one or more physiologic processes is presented Almost any measurement that reflects a change in a bio-
in Table 1. Nuts, whole grains, fruit, and vegetables contain a chemical process, structure, or function that results from an
variety of compounds associated with reduced risk of heart dis- interaction between a biological system and an environmental
ease, cancer, diabetes, hypertension, and a variety of other med- agent, including a dietary component, can serve as a biomarker.
ical conditions. Although substantial evidence exists that foods Biomarkers are needed not only to assess the value of func-
such as grains, garlic, and soybeans can decrease the risk of both tional foods and their biological components as modifiers of
heart disease and cancer, evidence for other foods is equivocal disease, but also to evaluate their ability to promote health,
(25–27). Widely diverse components in whole grains that may growth, and well-being. Evidence is emerging that several bio-
provide protection by influencing the environment of the gas- markers may be used successfully to distinguish between dis-
trointestinal tract include dietary fiber and other indigestible ease and nondisease states and, in some instances, to predict
components; several types of antioxidants, such as trace miner- future susceptibility to disease (35). Use of such biomarkers as
als and phenolic compounds; and several phytoestrogens that indicators of biological responses to selected foods and food
may alter hormonal homeostasis (28, 29). components is critical because long-term dietary interventions
Cabbage, onions, garlic, celery, cucumber, endive, parsley, are virtually impossible to conduct for numerous reasons,
radish, and legumes are among the nongrains that have been including cost.
reported to have some health benefits (25, 29). The benefits of Several sensitive, reliable biomarkers are likely needed to ade-
functional foods are not limited to natural foods, however, quately assess the benefits and risks associated with increased
because they can result from the generation of novel foods as consumption of specific foods and their bioactive components,
well. For example, low-fat foods may provide some benefits in but without question these biomarkers must not be extremely
reducing the risk of heart disease. Gould (30) suggested that vig- expensive. Intake, biological effect, and susceptibility biomark-
orous lowering of cholesterol by using low-fat foods and lipid- ers will probably be needed to evaluate adequately the effective-
active drugs, controlling hypertension, and abstaining from ness of functional foods and their bioactive components (Figure 1).
smoking stabilizes plaque and markedly reduces coronary events Intake biomarkers are useful for reflecting the amount of food
and angina pectoris, with greater improvement in survival than or metabolite present in cells, tissues, or body fluids. With these
reported for elective, invasive revascularization procedures. biomarkers, differences between absorption and accumulation
Many types of compounds found in foods may be responsible must be considered. Assessment of intake indicators is relatively
for the health benefits attributed to functional foods. Allyl com- straightforward analytically, but their use is complicated by the
pounds, such as those found in garlic and related foods, have need to know the best time for their measurement after con-
been used in various parts of the world not only for aroma and sumption and by variability in rates of metabolism and accumu-
flavor but also as antimicrobials, insect repellants, and modifiers lation across tissues and biological fluids (36).
of the risks of cancer and heart disease (27). Other compounds The usefulness of biological effect biomarkers can also be
that may contribute to observed protection include carotenoids, influenced by several methodologic issues. Among the most
which are found in vegetables and fruit; flavonoids, found in germane of these issues are the association of these biomark-
FUNCTIONAL FOODS: THE US PERSPECTIVE 1657S

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FIGURE 1. Biomarkers needed to assess the response to functional foods and their bioactive components. Biomarkers evaluating intakes, biologi-
cal effects, and susceptibility are interconnected throughout the process. Broken lines are used to reflect the influence that susceptibility has on the
uptake, metabolism, and biological response to functional foods. Genetics, physiologic state, and the environment may markedly influence suscepti-
bility and, therefore, any step within the process.

ers with causal pathways and their probability of detecting single-gene mutations have been shown to cause problems in
effects coinciding with either the maintenance of health or experimental animal models, such as those that occur in some
progression to a disease state. Effect biomarkers are particu- causes of obesity, the situation in humans is likely to be consider-
larly useful if they can predict a potentially detrimental ably more complex. Interactions among several genes, environ-
response long before it occurs. Unfortunately, at present, few mental factors, and behavior make the search for appropriate gene
biomarkers are universally accepted as being this reliable. The markers especially challenging. Nevertheless, new markers are
range of effect biomarkers required is immense because they being developed that should offer exciting opportunities for clari-
are needed to detect a variety of metabolic events that alter fication of the effect of genes and the environment.
cognitive and physical performance or change the risk of dis- Overall, a variety of biomarkers will probably be needed to
ease. Associating genetic polymorphisms with carcinogen- develop a profile for an individual that reflects the effect of diet
DNA adduct measurements to assess cancer risk is beginning on performance and health. To assess the benefits of foods or
to show promise (37). Other creative approaches will likely be their components, additional attention must be paid to examining
needed to develop a battery of biomarkers that can be used to the variability in response among populations and individuals,
evaluate the effectiveness of the food supply in influencing the the strengths of any association or correlation, the specificity of
overall quality of life. the relation, the reversibility of the response, and the biological
Many biomarkers are beginning to emerge that might be basis for any proposed benefits.
used effectively to monitor the impact of dietary habits on The development and application of biomarkers have enor-
growth and development, including platelet-derived growth mous importance not only in improving health but also in demon-
factor, transforming growth factor, basic fibroblast growth fac- strating the importance of dietary habits. Without question, any
tor, epidermal growth factor, insulin-like growth factor, and information related to a biomarker must be consistent with scien-
hepatocyte growth factor (38). New approaches will be tific standards for statistical significance. Before a claim is made
required to unravel the effects of dietary habits on these and about the benefits of a particular functional food or bioactive
other effect biomarkers. component, the following types of information must be evaluated:
Susceptibility biomarkers are also critical for evaluating the epidemiologic evidence (25%), intervention studies (35%), ani-
merits of changing one’s dietary habits. These biomarkers allow the mal models (25%), and mechanism of action (15%). These esti-
measurement of individual differences associated with genetic mates (percentages in parentheses) of the weighting that might
background, or variation associated with many environmental fac- appropriately be given to each type of evidence in evaluating the
tors (35, 39). The ability of genetic differences to activate or detox- totality of information are presented to initiate debate rather than
ify genotoxic agents is becoming increasingly recognized as an to establish a meaningful basis for evaluation. This is in no way a
appropriate susceptibility biomarker. Many genes, associated prod- novel approach; it was used in preparing 6 consensus statements
ucts, or receptors are now under investigation as markers of sus- about chronic disease (42). The opinion reflected here repre-
ceptibility, including those associated with OB, UCP, erbB-2, ras, sents the thoughts of one individual (with no statistical freedom)
myc, p53, BCL-2, Ki-67, and HNF-1-a (39–41). Although several and, therefore, is not an expression of an official position. The
1658S MILNER

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