1 sisi .functional foods the us perspective

8/12/2019 1 SisI .Functional Foods the US Perspective

1/6

ABSTRACT Widespread interest in the possibility that

selected foods might promote health has resulted in the coining

of the term functional food, although agreement about what is

and what is not a functional food is lacking. Public interest in

functional foods is increasing because of higher health care

costs; the passage of federal legislation affecting many food cat-

egories, including the expanded category of dietary supplements;

and recent scientific discoveries linking dietary habits with the

development of many diseases, including coronary heart disease

and some cancers. A variety of foods have been proposed as pro-viding health benefits by altering one or more physiologic

processes. Biomarkers are needed to assess the ability of func-

tional foods or their bioactive components to modify disease and

to evaluate the ability of these foods to promote health, growth,

and well-being. Evidence suggests that several biomarkers may

be useful for distinguishing between diseased and nondiseased

states and even for predicting future susceptibility to disease. A

variety of biomarkers will probably be needed to develop a pro-

file for an individual that reflects the impact of diet on perfor-

mance and health. Another area of interest is the interaction of

nutrients and their association with genetics. These interactions

may account for the inconsistent interrelations observed between

specific dietary constituents and the incidence of disease.

Greater understanding of how diet influences a persons geneticpotential, overall performance, and susceptibility to disease can

have enormous implications for society. As new discoveries are

made in this area, consumers will need access to this information

so that they can make informed decisions. Am J Clin Nutr

2000;71(suppl):1654S9S.

KEY WORDS Functional food, biomarkers

INTRODUCTION

Cultural beliefs in the mystical powers of foods have been

handed down for generations (1). The ability of specific foods to

prevent or reduce the severity of symptoms arising from what are

now frequently recognized as nutritional inadequacies has beenrecorded in a variety of historical documents. Interestingly, as

scientists unravel the mysteries about specific nutritional needs,

it becomes apparent that some dietary components that may not

be required for human existence may indeed markedly influence

quality of life by modifying one or more physiologic processes.

The ability of such foods to influence these processes is likely

dependent on several factors, including interactions with other

constituents in the overall diet and the consumers physiologic

state, behavior pattern, and genetic background. People through-

out the world are becoming increasingly convinced that the

foods they consume can not only modulate performance but also

influence their risk of acquiring a variety of diseases (2). It is

logical to assume that consumer demand for these health-

promoting foods and the physiologically active compounds they

contain will continue to grow in the foreseeable future, as will

the availability of novel foods.

Consumers must be provided with the information necessary

to make informed decisions as to whether they should adjusttheir intake of specific foods and their associated components.

Several fundamental issues that need addressing become imme-

diately apparent, however, when attempting to provide infor-

mation about potential benefits and risks accompanying

increased consumption of any food or component. Unlike the

case with drugs, it is generally assumed that increased con-

sumption of foods and food constituents is safe and that any

response will be associated with a reduction in risk rather than

with a cure or treatment. Even these general beliefs are ques-

tionable, however, because toxicity is a function of the quantity

consumed. Hence, it is inappropriate to consider use of func-

tional foods and their bioactive components as being without

some degree of risk. A more fundamental issue is the relative

benefit or risk that might accrue from the increased ingestion ofsuch foods. To assess the relative merits and concerns about

this issue, some scientific agreement is needed, even though

such agreement is also somewhat relative because some per-

sons may value particular information more than others when

establishing beliefs and opinions.

Experience has taught us that scientific opinion can be in

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

reduces its probability. The alternative of an ill-informed soci-

ety based on minority agreement or, perhaps even worse, agree-

ment based on an inadequate science base, would unquestion-

ably raise the chance for error and probably result in deleterious

effects to society. History has revealed that although knowledge

Am J Clin Nutr2000;71(suppl):1654S9S. Printed in USA. 2000 American Society for Clinical Nutrition

Functional foods: the US perspective13

John A Milner

1654S

1 From the Department of Nutrition, The Pennsylvania State University,

University Park.2 Presented at the 17th Ross Research Conference on Medical Issues, held

in San Diego, February 2224, 1998.3 Address reprint requests to JA Milner, The Pennsylvania State University,

Department of Nutrition, S126 Henderson Building, University Park, PA 16802.

E-mail: [email protected].


2/6

is important, wisdom about how and when to use this informa-

tion is critical. Unfortunately, consequences other than those

intended have been documented when intake of foods or their

components is excessive (3, 4).

FUNCTIONAL FOOD

Widespread interest in the possibility that selected foods

might promote health has resulted in the coining of the genericterm functional food. The Food and Nutrition Board (FNB) of

the National Academy of Sciences defines a functional food as

one that encompasses potentially healthful products, including

any modified food or food ingredient that may provide a health

benefit beyond that of the traditional nutrients it contains (5).

Although the term functional foodis increasingly recognized as

a household word, it has not been embraced totally by the health

and scientific communities. Controversies about what is and

what is not a functional food remain at the forefront of discus-

sions (68). Many believe that the promotion of food as good

or bad is inappropriate and scientifically indefensible. Fur-

thermore, many nutritionists are adamant that only diets can be

classified as good or bad, not foods per se (9). It is unlikely that

a nonfunctional food exists. Thus, in the broadest context, allfoods must be considered functional. Nevertheless, some foods

may be particularly beneficial in selectively altering specific

physiologic processes that improve the quality of life or reduce

the risk of acquiring a disease. The wholesomeness of any diet

depends on the supply of individual food components, interac-

tions among components, and meeting needs dictated by an indi-

viduals genetic background and physiologic state.

The suggestion that certain foods or their components might

offer some unique health benefit has blurred the distinction

between foods and drugs. Classically, a drug is any article

intended for use in the diagnosis, cure, mitigation, treatment, or

prevention of disease. Modification of the FNB definition to

reflect functional rather than health might help to resolve

some of these drugs-versus-nutrients concerns. In addition, thepromotion of increased consumption of functional foods and

their associated bioactive components should be viewed as an

approach to optimized nutrition rather than as an endorsement

of enhanced consumption of good foods or as a simple market-

ing strategy. Whether or not functional foods persists as a term,

it is imperative that consumer confidence in the food supply not

be jeopardized. Promotion of good and bad foods must be

avoided.

REASONS FOR PUBLIC INTEREST

Increased interest in functional foods is likely occurring for

3 reasons: increased health care costs, recent legislation, and sci-

entific discoveries. Expenditures associated with health services, asa percentage of national wealth (the gross national product, or

GNP), continue to rise worldwide (10). Health care in the United

States accounts for14% of the GNP. Inappropriate dietary habits

are viewed by many as contributing to poor health and associated

health care costs (11). Dietary factors are seen as contributing to

the leading causes of death of Americans, including coronary heart

disease and certain types of cancers (1113). It would be foolhardy

to believe that foods might be used as magic bullets against dis-

eases, but it would also be unwise to reject evidence that inappro-

priate dietary habits can exacerbate unhealthy conditions. The

belief that foods and their components have unusual health bene-

fits is one possible explanation for the expanding use of supple-

ments among Americans. A large percentage of apparently healthy

people residing in the United States are using supplements (14,

15), with use influenced by several factors, including age, sex, and

previous medical condition.

Coronary heart disease is the most common cause of death

today. It accounts for 44% of the mortality and much of the

morbidity in the United States (13). It accounts for two-thirds ofdeaths from heart disease and accounts for 70% of all deaths

among persons older than 75 y. As the worlds population

increases in age, concerns will certainly intensify about how best

to reduce the risk of death and disability from this disease. A

recent estimate put the economic cost of atherosclerotic cardio-

vascular disease at $259 billion. The role of diet in this disease

has yet to be clarified, but if this estimate of cost is accurate, a

small percentage of responders to dietary change could have a

substantial impact on health cost. Tucker and Miguel (16) esti-

mated that improving the nutritional status of some persons can

be expected to reduce hospital costs. Although the benefits of

reducing hospital costs should not be understated, it is likewise

important to recognize that preventive nutrition strategies will

likely have an even greater impact on health care costs.Correlations have been reported between dietary habits and

60% of cancers in women and >40% of cancers in men (17). It

is likely that several essential and nonessential dietary components

influence the risk of developing cancer. Because 25% of Ameri-

cans will ultimately deal with the complications of cancer, anything

that reduces its risk can substantially reduce health care costs.

However, increased supplement usage among cancer patients raises

questions not only about effective dosages of dietary constituents

and their cost but also about their safety (14, 15).

An estimated 6% of the national health expenditure is associ-

ated with treatment of obesity (18). Several dietary components

may influence energy intake and metabolism (19, 20). Recent

evidence that conjugated linoleic acid, a functional food compo-

nent found primarily in animal tissues and fluids, can alter lipidhomeostasis provides evidence that the potential health benefits

of foods are not limited solely to plant sources (21).

Three US legislative acts of the 1990s have likely had a signi-

ficant effect on the promotion of the concept of functional foods.

The first, the Nutrition Labeling and Education Act, passed in

1990 (22), mandated that the Food and Drug Administration

(FDA) establish regulations requiring most foods to have a uni-

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,

the Dietary Supplement Health and Education Act of 1994 (23),

defined dietary supplements as any product that contains one or

more dietary ingredients, such as vitamins, minerals, herbs or

other botanicals, amino acids, or other ingredients used to sup-plement the diet. Additionally, it created a mechanism for deal-

ing with safety issues, regulation of health claims, and labeling

of dietary supplements; provided for good manufacturing prac-

tices; established new government entities to review regulations;

and encouraged research on dietary supplements. Finally, the

FDA Modernization Act of 1997 (24) amended the Federal Food,

Drug, and Cosmetic Act by allowing health claims that are not

preauthorized by FDA if the claims are based on authoritative

statements of government agencies such as the National Acad-

emy of Sciences or the National Institutes of Health.

FUNCTIONAL FOODS: THE US PERSPECTIVE 1655S


3/6

Epidemiologic and laboratory findings are continuing to pro-

vide convincing evidence that increased consumption of fruit

and vegetables can significantly modify disease risk. Interest-

ingly, a rather large number of chemical compounds found in

fruit and vegetables appear to offer protection (25, 26). Evidence

exists that these essential and nonessential nutrients modify sev-

eral cellular processes. Unquestionably, dietary habits are not the

sole determinant of disease states, but adjusting the diet likelyrepresents a significant way of reducing risk.

CHARACTERIZATION OF FOODS

A partial list of foods that have been proposed to provide ben-

efits by altering one or more physiologic processes is presented

in Table 1. Nuts, whole grains, fruit, and vegetables contain a

variety of compounds associated with reduced risk of heart dis-

ease, cancer, diabetes, hypertension, and a variety of other med-

ical conditions. Although substantial evidence exists that foods

such as grains, garlic, and soybeans can decrease the risk of both

heart disease and cancer, evidence for other foods is equivocal

(2527). Widely diverse components in whole grains that may

provide protection by influencing the environment of the gas-trointestinal tract include dietary fiber and other indigestible

components; several types of antioxidants, such as trace miner-

als and phenolic compounds; and several phytoestrogens that

may alter hormonal homeostasis (28, 29).

Cabbage, onions, garlic, celery, cucumber, endive, parsley,

radish, and legumes are among the nongrains that have been

reported to have some health benefits (25, 29). The benefits of

functional foods are not limited to natural foods, however,

because they can result from the generation of novel foods as

well. For example, low-fat foods may provide some benefits in

reducing the risk of heart disease. Gould (30) suggested that vig-

orous lowering of cholesterol by using low-fat foods and lipid-

active drugs, controlling hypertension, and abstaining from

smoking stabilizes plaque and markedly reduces coronary eventsand angina pectoris, with greater improvement in survival than

reported for elective, invasive revascularization procedures.

Many types of compounds found in foods may be responsible

for the health benefits attributed to functional foods. Allyl com-

pounds, such as those found in garlic and related foods, have

been used in various parts of the world not only for aroma and

flavor but also as antimicrobials, insect repellants, and modifiers

of the risks of cancer and heart disease (27). Other compounds

that may contribute to observed protection include carotenoids,

which are found in vegetables and fruit; flavonoids, found in

fruit, vegetables, nuts, and grains; and indoles and isothio-

cyanates, both found in cruciferous vegetables.

An enormous number of carotenoids are found throughout the

plant kingdom. These compounds, many of which do not possess

vitamin A activity, can influence numerous biological functions

by serving as antioxidants, modulators of cell growth regulation,

regulators of gene expression, and immunoregulators (31, 32).

Indole-3-carbinol is one of several carotenoids found in cabbage,

broccoli, Brussels sprouts, and other Brassica vegetables reportedto exhibit anticarcinogenic properties in experimental animals. In

addition, recent studies suggest indole-3-carbinol may be a safe,

well-tolerated, and efficacious treatment for recurrent respiratory

papillomatosis (33).

More than 100 sulfur-containing glycosides known collec-

tively as glucosinolates occur naturally in cruciferous vegeta-

bles. On hydrolysis, they yield thiocyanate, nitrite, and isothio-

cyanates. Isothiocyanates influence a variety of biological

reactions (17, 25, 29).

More than 4000 flavonoids, which are polyphenolic com-

pounds found ubiquitously in foods of plant origin, have been

described and categorized into flavonols, flavones, catechins,

flavanones, anthocyanidins, and isoflavonoids. Flavonoids poten-

tially have a variety of biological effects, including serving asantioxidants, influencing drug detoxification mechanisms, and

altering cell proliferation (34).

BIOMARKERS

Almost any measurement that reflects a change in a bio-

chemical process, structure, or function that results from an

interaction between a biological system and an environmental

agent, including a dietary component, can serve as a biomarker.

Biomarkers are needed not only to assess the value of func-

tional foods and their biological components as modifiers of

disease, but also to evaluate their ability to promote health,

growth, and well-being. Evidence is emerging that several bio-

markers may be used successfully to distinguish between dis-ease and nondisease states and, in some instances, to predict

future susceptibility to disease (35). Use of such biomarkers as

indicators of biological responses to selected foods and food

components is critical because long-term dietary interventions

are virtually impossible to conduct for numerous reasons,

including cost.

Several sensitive, reliable biomarkers are likely needed to ade-

quately assess the benefits and risks associated with increased

consumption of specific foods and their bioactive components,

but without question these biomarkers must not be extremely

expensive. Intake, biological effect, and susceptibility biomark-

ers will probably be needed to evaluate adequately the effective-

ness of functional foods and their bioactive components (Figure 1).

Intake biomarkers are useful for reflecting the amount of foodor metabolite present in cells, tissues, or body fluids. With these

biomarkers, differences between absorption and accumulation

must be considered. Assessment of intake indicators is relatively

straightforward analytically, but their use is complicated by the

need to know the best time for their measurement after con-

sumption and by variability in rates of metabolism and accumu-

lation across tissues and biological fluids (36).

The usefulness of biological effect biomarkers can also be

influenced by several methodologic issues. Among the most

germane of these issues are the association of these biomark-

1656S MILNER

TABLE 1

Partial list of functional foods and their physiologic effects

Food Physiologic effect

Apple, barley, blackberry, blueberry, carrot, Lipid lowering

eggplant, oats, garlic, ginger, ginseng, mushroom,

onion, soybean, tea

Lemon, apple, cranberry, garlic, beet, cucumber, Enhanced drug

squash, soybean, cabbage, Brussels sprouts, detoxification

cauliflower, kale, broccoli, spinachGinseng, licorice, oats, parsley Antiinflammatory

Cranberry, garlic, onion, green tea Antimicrobial

Anise, fennel, soybean, cabbage Antiestrogenic

Orange, green tea, garlic Antiproliferative


4/6

ers with causal pathways and their probability of detecting

effects coinciding with either the maintenance of health or

progression to a disease state. Effect biomarkers are particu-

larly useful if they can predict a potentially detrimental

response long before it occurs. Unfortunately, at present, few

biomarkers are universally accepted as being this reliable. The

range of effect biomarkers required is immense because they

are needed to detect a variety of metabolic events that alter

cognitive and physical performance or change the risk of dis-ease. Associating genetic polymorphisms with carcinogen-

DNA adduct measurements to assess cancer risk is beginning

to show promise (37). Other creative approaches will likely be

needed to develop a battery of biomarkers that can be used to

evaluate the effectiveness of the food supply in influencing the

overall quality of life.

Many biomarkers are beginning to emerge that might be

used effectively to monitor the impact of dietary habits on

growth and development, including platelet-derived growth

factor, transforming growth factor, basic fibroblast growth fac-

tor, epidermal growth factor, insulin-like growth factor, and

hepatocyte growth factor (38). New approaches will be

required to unravel the effects of dietary habits on these and

other effect biomarkers.Susceptibility biomarkers are also critical for evaluating the

merits of changing ones dietary habits. These biomarkers allow the

measurement of individual differences associated with genetic

background, or variation associated with many environmental fac-

tors (35, 39). The ability of genetic differences to activate or detox-

ify genotoxic agents is becoming increasingly recognized as an

appropriate susceptibility biomarker. Many genes, associated prod-

ucts, or receptors are now under investigation as markers of sus-

ceptibility, including those associated with OB, UCP, erbB-2, ras,

myc, p53,BCL-2, Ki-67, and HNF-1- (3941). Although several

single-gene mutations have been shown to cause problems in

experimental animal models, such as those that occur in some

causes of obesity, the situation in humans is likely to be consider-

ably more complex. Interactions among several genes, environ-

mental factors, and behavior make the search for appropriate gene

markers especially challenging. Nevertheless, new markers are

being developed that should offer exciting opportunities for clari-

fication of the effect of genes and the environment.

Overall, a variety of biomarkers will probably be needed todevelop a profile for an individual that reflects the effect of diet

on performance and health. To assess the benefits of foods or

their components, additional attention must be paid to examining

the variability in response among populations and individuals,

the strengths of any association or correlation, the specificity of

the relation, the reversibility of the response, and the biological

basis for any proposed benefits.

The development and application of biomarkers have enor-

mous importance not only in improving health but also in demon-

strating the importance of dietary habits. Without question, any

information related to a biomarker must be consistent with scien-

tific standards for statistical significance. Before a claim is made

about the benefits of a particular functional food or bioactive

component, the following types of information must be evaluated:epidemiologic evidence (25%), intervention studies (35%), ani-

mal models (25%), and mechanism of action (15%). These esti-

mates (percentages in parentheses) of the weighting that might

appropriately be given to each type of evidence in evaluating the

totality of information are presented to initiate debate rather than

to establish a meaningful basis for evaluation. This is in no way a

novel approach; it was used in preparing 6 consensus statements

about chronic disease (42). The opinion reflected here repre-

sents the thoughts of one individual (with no statistical freedom)

and, therefore, is not an expression of an official position. The


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 theuptake, 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.


5/6

following questions must be asked: What is the minimal accept-

able score for a claim? Would this minimum value differ if a func-

tional or a health claim was being proposed?

INTERACTIONS AMONG NUTRIENTS

Elucidation of the specific roles and interactions of nutrients

and their associations with genetics will assist in the identifica-

tion of critical times for intervention and lead to sound and accu-rate dietary guidance that can be tailored to reduce disease risk

of individuals. Interactions among dietary constituents may con-

tribute to the inconsistent relations observed between specific

dietary constituents and the incidence of disease.

Although interactions among nutrients have been inade-

quately examined, a few examples of negative and positive inter-

actions exist. Vitamin C has been reported to reduce seleniums

effectiveness against chemically induced colon cancer (43). The

significance of such interactions may be even more pronounced

because selenium has been shown to enhance the ability of gar-

lic to inhibit chemically induced mammary cancer in experimen-

tal animals (44). Nonessential and essential nutrients cannot be

considered to operate in isolation; rather, they work in a dynamic,

constantly changing milieu. Greater attention to all componentsof the diet and elaboration of their interactions should make pos-

sible specific and appropriate recommendations for the general

population and allow for recommendations tailored to specific

subgroups or individuals.

EFFECT OF PROCESSING

The processing of foods can influence the availability of nutri-

ents either positively or negatively. Stahl and Sies (45) found that

lycopene bioavailability was improved by heating tomato prepa-

rations in the presence of oil. On the other hand, Ali (46) found

that boiling garlic for 15 min markedly reduced its ability to

inhibit thromboxane B2 synthesis in rabbit lung. Similarly, recent

studies from our laboratory (47) showed that heating of garlic ina microwave or conventional oven before peeling can dramati-

cally reduce its ability to alter the bioactivation of a known

experimental mammary carcinogen. The effect of different pro-

cessing methods on the biological availability and effectiveness

of physiologically active components in various functional foods

remains to be determined.

CONCLUSION

Development of the scientific underpinning of functional foods

and their bioactive components as health promoters is emerging as

a new frontier for nutritionists and other health professionals.

Greater understanding of how diet influences an individuals

genetic potential, overall performance, and susceptibility to dis-ease can have enormous implications for society. As new discov-

eries are made in this area, the new information will be needed by

consumers so that they can make informed decisions.

REFERENCES

1. Leach HM. Popular diets and anthropological myths. N Z Med J

1989;102:4747.

2. Wrick KL. Consumer issues and expectations for functional foods.

Crit Rev Food Sci Nutr 1995;35:16773.

3. Macdonald K, Holti G, Marks J. Is there a place for beta-

carotene/canthaxanthin in photochemotherapy for psoriasis? Der-

matologica 1984;169:416.

4. Ernst E. Harmless herbs? A review of the recent literature. Am J

Med 1988;104:1708.

5. Thomas PR, Earl R, eds. Committee on Opportunities in the Nutri-

tion and Food Sciences, Institute of Medicine. Opportunities in the

nutrition and food sciences: research challenges and the next gener-

ation of investigators. Washington, DC: National Academy Press,

1994:109.6. Hasler CM. Functional foods: the western perspective. Nutr Rev

1996;54(suppl):6S10S.

7. Glinsmann WH. Functional foods in North America. Nutr Rev

1996;54(suppl):33S7S.

8. Clydesdale FM. A proposal for the establishment of scientific crite-

ria for health claims for functional foods. Nutr Rev 1997;55:

41322.

9. Herron DG. Strategies for promoting a healthy dietary intake. Nurs

Clin North Am 1991;26:87584.

10. Braden BR, Cowan CA, Lazenby HC, et al. National health expen-

ditures, 1997. Health Care Finance Rev 1998;20:83126.

11. US Department of Health and Human Services, Public Health Ser-

vice. The Surgeon Generals report on nutrition and health. Wash-

ington, DC: US Government Printing Office, 1988 (DHHS publica-

tion PHS 88 50210).

12. Bidlack WR. Interrelationships of food, nutrition, diet and health:

the National Association of State Universities and Land Grant Col-

leges White Paper. J Am Coll Nutr 1996;15:42233.

13. Kannel WB. Overview of atherosclerosis. Clin Ther 1998;20:2B17B.

14. Newman V, Rock CL, Faerber S, et al. Dietary supplement use by

women at risk for breast cancer recurrence. The Womens Healthy

Eating and Living Study Group. J Am Diet Assoc 1998;98:28592.

15. Eliason BC, Kruger J, Mark D, Masmann DN. Dietary supplement

users: demographics, product use, and medical system interaction.

J Am Board Fam Pract 1997;10:26571.

16. Tucker HN, Miguel SG. Cost containment through nutrition inter-

vention. Nutr Rev 1996;54:11121.

17. Wynder EL, Gori GB. Contributions of the environment to cancer inci-

dence: an epidemiologic exercise. J Natl Cancer Inst 1977;58:82532.

18. Milner JA. Nonnutritive components in foods as modifiers of the

cancer process. In: Bendich A, Deckelbaum RJ, eds. Preventivenutrition. Totowa, NJ: Humana Press, Inc, 1996:13552.

19. Wolf AM. What is the economic case for treating obesity? Obes Res

1998;1(suppl):2S7S.

20. Saltzman E, Roberts SB. Soluble fiber and energy regulation: current

knowledge and future directions. Adv Exp Med Biol 1997;427:8997.

21. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid

on body composition in mice. Lipids 1997;32:8538.

22. Nutrition Labeling and Education Act. Code of Federal Regulations

101:14(a)(1). 1990.

23. Dietary Supplement Health and Education Act of 1994. Public Law

103-417, section 13[a]. 1994.

24. Federal Drug Administration Modernization Act. Public law 105-

115. 1997.

25. Milner JA. Reducing the risk of cancer. In: Goldberg I, ed. Functional

foods. New York: Van Nostrand Reinhold Publishing Co, 1994:3970.26. Craig WJ. Phytochemicals: guardians of our health. J Am Diet

Assoc 1997;97(suppl):199S204S.

27. Milner JA. Garlic: Its anticarcinogenic and antitumorigenic proper-

ties. Nutr Rev 1996;54(suppl):82S6S.

28. Slavin J, Jacobs D, Marquart L. Whole-grain consumption and

chronic disease: protective mechanisms. Nutr Cancer 1997;27:1421.

29. Potter JD, Steinmetz K. Vegetables, fruit and phytoestrogens as pre-

ventive agents. IARC Sci Publ 1996;139:6190.

30. Gould KL. New concepts and paradigms in cardiovascular medi-

cine: the noninvasive management of coronary artery disease. Am J

Med 1998;22(suppl ):2S17S.

1658S MILNER


6/6

31. Clinton SK. Lycopene: chemistry, biology, and implications for

human health and disease. Nutr Rev 1998;56:3551.

32. Rock CL. Carotenoids: biology and treatment. Pharmacol Ther 1997;

75:18597.

33. Rosen CA, Woodson GE, Thompson JW, et al. Preliminary results

of the use of indole-3-carbinol for recurrent respiratory papillo-

matosis. Otolaryngol Head Neck Surg 1998;118:8105.

34. Hollman PC, Katan MB. Bioavailability and health effects of

dietary flavonols in man. Arch Toxicol 1998;20:23748.

35. Perera FP, Whyatt RM. Biomarkers and molecular epidemiology inmutation/cancer research. Mutat Res 1994;313:11729.

36. Kohlmeier L. Biomarkers of fatty acid exposure and breast cancer

risk. Am J Clin Nutr 1997;66(suppl):1548S56S.

37. Warren AJ, Shields PG. Molecular epidemiology: carcinogen-DNA

adducts and genetic susceptibility. Proc Soc Exp Biol Med 1997;

216:17280.

38. Brody AR, Liu JY, Brass D, Corti M. Analyzing the genes and peptide

growth factors expressed in lung cells in vivo consequent to asbestos

exposure and in vitro. Environ Health Perspect 1997;105 (suppl):16571.

39. Caporaso N, Goldstein A. Issues involving biomarkers in the

study of the genetics of human cancer. IARC Sci Publ 1997;142:

23750.

40. Lee E, Park I, Lee C. Prognostic markers of intravesical bacillus

Calmette-Guerin therapy for multiple, high-grade, stage T1 bladder

cancers. Int J Urol 1997;4:5526.

41. Brandt-Rauf PW. Biomarkers of gene expression: growth factors

and oncoproteins. Environ Health Perspect 1997;4:80716.

42. Ahrens EH Jr. The evidence relating six dietary factors to the nations

health. Introduction. Am J Clin Nutr 1979;32(suppl):262731.

43. Ip C. Interaction of vitamin C and selenium supplementation in the

modification of mammary carcinogenesis in rats. J Natl Cancer Inst

1986;77:299303.44. Amagase H, Schaffer EM, Milner JA. Dietary components modify

the ability of garlic to suppress 7,12-dimethylbenz(a)anthracene-

induced mammary DNA adducts. J Nutr 1996;126:81724.

45. Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is

greater from heat-processed than from unprocessed tomato juice in

humans. J Nutr 1992;122:21616.

46. Ali M. Mechanism by which garlic inhibits cyclooxygenase activity.

Effect of raw versus boiled garlic extract on the synthesis of

prostanoids. Prostaglandins Leukot Essent Fatty Acids 1995;53:

397400.

47. Kun S, Milner JA. Heating blocks garlics ability to suppress 7,12-

dimethylbenz(a)anthracene bioactivation. J Nutr 1999;129:65761.


1 sisi .functional foods the us perspective

Documents