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The Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45252
2To whom correspondence should be addressed. E-mail: cooper.da{at}pg.com.
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ABSTRACT |
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 TOP ABSTRACT CONCLUSIONSLITERATURE CITED |
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KEY WORDS: • carotenoids • dietary recommendations • public health • consumer
In 1981, Peto et al. eloquently summarized the epidemiological and laboratory evidence in support of the hypothesis that dietary ß-carotene plays a role in the prevention of human cancer (1). These authors pointed out that epidemiological studies showed consistent inverse associations between intake of total vitamin A (carotenes and retinol) and risk of certain cancers and lower serum carotenoids and retinol in people with, compared to those without, cancer. Furthermore, laboratory studies had demonstrated that ß-carotene was protective against tumors in animal studies and was antiproliferative in cell culture studies. Other laboratory studies showed that ß-carotene was the most efficient compound known to quench singlet oxygen, raising the possibility that ß-carotene may prevent cancer by means of an antioxidant mechanism. In addition, the authors argued that while ß-carotene and vitamin A both had anticancer effects in animals and cells, ß-carotene was a better candidate for protection in humans. This was because blood and tissue levels of ß-carotene increase in proportion to dietary intake, whereas retinol levels do not increase in relation to intake in well-nourished individuals due to homeostatic regulation of blood concentrations.
This paper by Peto et al. (1) is also important because it laid the groundwork for future research in the carotenoid and cancer field. These authors proposed that prospective epidemiological studies examining the relationship between serum carotenoids and cancer risk be carried out, and that dietary intake questionnaires and food nutrient databases be refined to improve the specificity of diet-based observational epidemiology studies. They also proposed further work to characterize the effects of ß-carotene on animal carcinogenesis, to understand metabolism to retinoids and to determine if ß-carotene prevents oxidative damage in vivo. One of the most notable research recommendations that these authors made was that intervention trials be initiated immediately. The intervention trials they recommended were double-blind placebo-controlled clinical trials of high dose ß-carotene for the prevention of cancer and other chronic diseases. This recommendation was based on the premise that intervention trials, but not epidemiological or biological studies, can prove there is a cause and effect relationship between ß-carotene and lower risk of disease.
Evaluations of the role of carotenoids in chronic disease prevention
Much of the research proposed by Peto et al. has been carried out in the past two decades and used by authoritative scientific panels to reevaluate the evidence for a protective effect of carotenoids against chronic disease. The impetus to conduct such evaluations came from public health officials, consumers and companies eager to understand and take advantage of the potential benefits of dietary antioxidants. The body of research became most complete after the results of the ß-carotene intervention trials were published and were then followed by three very comprehensive and authoritative reports supported by three groups: 1) the American Institute for Cancer Research/World Cancer Research Fund (AICR/WCRF) (2), 2) the International Association for Cancer Research (IARC) (3), and 3) the Food and Nutrition Board of the National Academy of Sciences (4).
These evaluations serve at least three important functions. First, they are the best efforts of scientists to translate a complex body of evidence into dietary recommendations with the potential to impact disease risk and public health policy around the world. Secondly, they affirm or modify prevailing paradigms about the role of carotenoids in disease prevention. Third, they clarify research directions needed to advance the state of knowledge in this field. It is no surprise that James Olson contributed his great intellect to this endeavor.
The objective of the WCRF/AICR evaluation was to create international dietary and lifestyle recommendations to reduce the worldwide incidence of cancer (2). This evaluation was performed by a panel of 16 international scientists. The panel made food-based recommendations based on the evaluation of 92 putative dietary factor/cancer relationships, including an evaluation of the relationship between carotenoid intake and cancer. Regarding the carotenoid relationship, the panel concluded that carotenoid intake probably decreases the risk of lung cancer, possibly decreases cancers of the esophagus, stomach, colon, rectum, breast and cervix, but that there is insufficient evidence for effects on cancers of the larynx, ovary, endometrium and bladder. Lastly, the panel concluded the evidence for a role of vegetables and fruits and most cancer sites was stronger than for carotenoids. This supported their food-based recommendations to increase vegetable and fruit intake and to not take dietary supplements.
The conclusions that carotenoid intake probably protects against lung cancer and possibly other cancers were based primarily on data from observational epidemiology studies. These epidemiology studies were used to judge causality of carotenoid and cancer relationships based on the classic rules for causality of an epidemiological association defined by Bradford Hill in his classic work (5). He proposed that epidemiological associations be judged to be causal when exposures precede outcomes, and when associations are consistent, unbiased, strong, graded, coherent, repeated, predictive and plausible. For the relationship between ß-carotene and lung cancer, the committee concluded the variety of observational epidemiology studies of this relationship are consistent and that the relative risk values for low versus high ß-carotene exposure levels were generally >1.5. The committee did not review potential biological mechanisms of anti-cancer action by carotenoids, but stated that a plausible mechanism exists among those proposed in the literature such as antioxidant activity, gap junction intercellular communication, inhibition of cell proliferation and enhancement of immunity. The committee’s conclusions did not take into account intervention trial data or animal data, because they were deemed to be not relevant to diet-based recommendations. This reliance on epidemiological evidence to the exclusion of other types of data is a criticism of this report (6,7).
Integrating and weighing various types of data on carotenoids and disease is a difficult task that James Olson worked to simplify. He proposed that the many properties of carotenoids in various systems be classified as functions, actions and associations (8,9). Functions, as he defined them, are essential roles, at least under specified conditions, that support optimal physiological capacity, such as the role of certain carotenoids in serving as a source of vitamin A. Actions are physiological or pharmacological responses to administration of carotenoids that are not essential for physiological well-being. Actions are often demonstrated in clinical or animal studies with high dose carotenoid administration; notable examples are reduced skin reactions in photosensitivity diseases and reduced oral leukoplakia. Associations are correlations between carotenoids and some physiological or medical end point, such as lung cancer, that may or may not be based on a causal relationship. The purpose of making these distinctions is to understand the strengths and weaknesses of each type of data when evaluating them to set public health policy. Ideally, the data from functions, actions and associations should be consistent with each other to ensure the greatest confidence in such decisions.
The judicious examination of the broad range of carotenoid functions, actions and associations was evident in the evaluation performed by the IARC committee on carotenoids, of which James Olson was a member (3). This committee cited as important the activities of ß-carotene against cancer in animal models of cancer of the skin and buccal pouch and in cells in vitro in the inhibition of induction or expression of cancer-related events. However, they pointed out it is unclear how the results relate to human cancer given the lack of understanding of the dose relationships, the carcinogen action and relevance of animal cancers to human conditions. The committee also pointed out that observational epidemiology consistently shows inverse associations between the intake of dietary carotenoids and lung and other cancers. However, it is unknown whether ß-carotene, or some other nutrient or healthful lifestyle that correlates with ß-carotene intake, is the causal factor in this relationship. Lastly, the committee pointed out that ß-carotene alone was not protective against cancer in the three largest intervention trials available at that point. Thus, they concluded that there was inadequate evidence that dietary ß-carotene, or other dietary carotenoids, prevent cancer. Furthermore, they concluded that there was a lack of evidence for cancer prevention by supplemental ß-carotene.
The third major carotenoid-disease evaluation was carried out by the National Research Council’s Dietary Reference Intake Panel on Antioxidants. This panel was charged with the evaluation of the role of dietary carotenoids in health and the establishment of Dietary Reference Intakes for these compounds (4). The panel evaluated not only the putative relationship between ß-carotene intake and lung cancer, but also the relationships between other carotenoids and diseases such as lutein intake and age-related macular degeneration and lycopene intake and prostate cancer. To do this, the panel identified and evaluated indicators of adequacy of carotenoid intake. These indicators were essentially quantifiable biological markers that could be used to determine carotenoid intake levels that potentially provide protection from disease. The markers evaluated included those indicative of antioxidant activity, gap junction communication, immune function and risk of chronic disease in relation to dietary intakes or plasma and tissue concentrations of carotenoids. Data were evaluated from animal models, human feeding studies, observation epidemiological studies and randomized clinical trials.
The Antioxidant Panel determined there was inadequate evidence for a role of carotenoids in disease and therefore, did not establish dietary reference intakes for ß-carotene or other carotenoids. The panel found that pro-vitamin A carotenoids serve a function as a source of vitamin A, but that no other specific nutrient functions could be assigned to carotenoids. For instance, although higher blood concentrations of carotenoids are consistently associated with lower risk of certain chronic diseases, this risk could not be used to establish intake requirements because the associations may be due to other nutrients or behavioral correlates of carotenoid intake. Also, carotenoids can be shown to possess antioxidant activity in vitro, but a potential antioxidant role in humans in vivo is still controversial.
These three evaluations, and others not mentioned here, are consistent in finding that there is no definitive evidence to assign a role for carotenoids in disease prevention or to establish required intake levels. This is based on the large body of research that stemmed from the recommendations by Peto et al. (1), including intervention trial results that were thought by many to be able to provide the definitive evidence needed to draw conclusions regarding carotenoids and disease. Thus, the current evaluations indicate the relationship of carotenoids to disease is more complex than initially thought, leaving a measure of uncertainty for public health officials, consumers and companies.
Recommended future research directions
Authoritative scientific groups such as those described above as well as other leading thinkers in the field of diet and health have published recommendations for research that they believe should be carried out subsequent to the ß-carotene intervention trials (10–13). A major question is whether to continue to do the same kinds of research Peto et al. recommended twenty years ago, or whether new approaches are needed to generate breakthroughs.
A common theme of these recommendations is the need for a new approach characterized by integration of a variety of scientific disciplines and consideration of the interrelation of many factors involved in the disease process (10,11). This contrasts with the current reductionist approach exemplified by the testing of a single carotenoid in intervention trials. The recommendations maintain that the putative role of carotenoids and other dietary factors in reduction of disease risk should be evaluated with an appreciation for the complexities of other diet, gene and environmental factors. These complexities can be made easier to deal with by use of new technologies such as those developed to identify genes and gene polymorphisms in the field of genomics.
A key building block in this process is the identification of newer and better biomarkers of carotenoid effects in disease processes. Biomarkers are clinical, cellular or molecular measurements indicative of a certain stage of disease. Improved markers are needed with more specificity, more clearly defined relation to disease and responsiveness to carotenoid intake. To identify potential biomarkers, intervention trial information and samples could be used to relate disease outcome with biomarkers at baseline. Promising biomarkers could then be validated in further observational trials. The dose responsiveness of validated markers should be tested over a broad range of intakes of carotenoids and their metabolites, isomers and analogues.
Additional proposals for future research include characterization of interactions between key dietary factors. For instance, certain carotenoids have been shown to increase gap junction communication between cells in vitro. However, since other phytochemicals and nutrients such as retinoids, green tea extracts, flavones, cholesterol and vitamin D also increase gap junction communication, it is necessary to understand the relative contribution of this effect by carotenoids and how various factors interact (14). There is also a need to understand better carotenoid absorption, in vivo kinetics and metabolism. The enzymes involved in carotene cleavage have recently been cloned and there is a search for cell membrane transporters and carrier proteins for carotenes (15). It may be possible in the future to manipulate carotenoid metabolism genes by means of transgenic or knockout technologies to create animal models that absorb and metabolize carotenoids more similarly to humans. Finally, it is hoped that eventually adequate evidence will exist to support conducting intervention trials to test the effects of promising carotenoids on validated biomarkers at appropriate doses in responsive individuals. This could lead to a more conclusive understanding of the role of carotenoids in health.
Carotenoid related diet recommendations and the consumer
The result of recent carotenoid evaluations has been the inability to recommend to consumers, public health officials and industry that individuals will decrease the risk of disease as a result of consumption of a specific amount of carotenoids. In spite of the absence of clear evidence for a role in prevention of chronic disease, carotenoids continue to play a role in the diet of consumers and continue to be debated in light of recent dietary trends. This demonstrates the continuing need for further research on carotenoids.
In spite of the absence of definitive recommendations regarding carotenoids, the recommendation to consume more fruits and vegetables to lower the risk of chronic disease has been a key component of dietary guidelines since the publication of Peto et al. (1), and it seems to be having a positive impact on fruit and vegetable consumption in the U.S. A recent effort among key scientific organizations involved in the study and prevention of chronic disease, such as the American Cancer Society, American Heart Association and others, concluded that consumption of fruits and vegetables is one of several recommendations in common among all seven organizations (16). The sustained efforts to promote fruit and vegetable intake may have contributed to a trend of increasing consumption of fruits and vegetables since the 1970s (17). According to recent results from the Continuing Survey of Food Intake of Individuals (CSFII 1994–1996), adults are consuming a mean of 5.2 ± 3.2 servings per day of fruits and vegetables (17). This is in the recommended range of 5–9 servings per day and greater than past intakes of 2–3 servings per day.
Unfortunately, many of the vegetables consumed to meet these goals are not those that are most consistently associated with reduced disease risk and efforts to provide the benefits of fruits and vegetables in the diet can be controversial (17). For instance, even though vegetable intake is 3.6 ± 2.3, only 25% of vegetables consumed are classified as being rich in putative protective phytochemicals and associated with reduced risk of disease: dark green and deep yellow vegetables and tomato products. In addition, fruits that are most closely associated with reduced disease risk (citrus, melons and berries) make up 48% of fruit servings. Technologies to overcome the barriers to increased fruit and vegetable consumption have been developed recently. These technologies overcome barriers such as convenience (precut, prepackaged) and taste (addition to other foods and juice mixtures). Newer technologies include enrichment of vegetables with carotenoids via biotechnology or traditional plant breeding, dehydrated vegetables, fortification of foods or use in supplements of antioxidant mixtures or individual carotenoids. These latter alternatives tend to be more controversial because of recent studies showing lack of benefit from isolated phytochemicals.
A second dietary trend with relevance to carotenoids is the current rapid growth and epidemic proportions of overweight and obesity in the US. This trend has the potential to impact carotenoid nutriture through efforts to meet dietary guidelines to reduce fat intake and treatment guidelines for obesity related diseases such as diabetes and heart disease (16,18). Currently, over 26% of US adults are obese and an additional 35% are overweight (19). In the decade from 1985 to 1995, diabetes, a disease associated with high body mass index, increased by about one-third (20). In order to meet dietary guidelines to reduce fat and maintain a healthy body weight, consumers are increasingly using reduced-fat and fat-free foods modified with various fat replacement technologies (21). Many of these foods can impact carotenoid absorption because the intestinal absorption of carotenoids is exquisitely sensitive to factors that affect the amount or process of absorption of dietary fat (22–24). In addition, prescription medications for weight loss and functional foods for blood lipid abnormalities associated with overweight and obesity similarly impact carotenoid absorption (25–27). Thus, there is a dilemma between meeting key dietary and disease treatment recommendations and the potential that carotenoid absorption efficiency may be decreased. This dilemma can only be resolved through further research.
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CONCLUSIONS |
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TOPABSTRACTCONCLUSIONSLITERATURE CITED |
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTCONCLUSIONSLITERATURE CITED |
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1. Peto, R., Doll, R., Buckley, J. D. & Sporn, M. B. (1981) Can dietary beta-carotene materially reduce human cancer rates?. Nature 290:201-208.[Medline]
2. WCRF/AICR (1997) Food, nutrition and the prevention of cancer: a global perspective 1997 World Cancer Research Fund/American Institute of Cancer Research Long, UK/Washington, D.C.
3. World Health Organization International Agency for Research on Cancer (1998) IARC Handbooks of Cancer Prevention. Carotenoids 2 IARC Lyon, France.
4. National Research Council Food and Nutrition Board (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids 2000 National Academy Press Washington, D.C.
5. Hill, A. B. (1965) The environment and disease: association or causation?. Proc. R. Soc. Med. 58:295-300.[Medline]
6. Campbell, T. C. (2001) Critique of report on "Food, Nutrition and the Prevention of Cancer: A Global Perspective.". Nutr. Today 36:80-87.
7. Cohen, L. A. (2001) Nutrition and cancer prevention: differing perspectives on the best research to achieve it. Nutr. Today 36:78-79.
8. Olson, J. A. (1989) Biological actions of carotenoids. J. Nutr. 119:94-95.
9. Olson, J. A. (1993) Molecular actions of carotenoids. Ann. N.Y. Acad. Sci. 691:156-166.[Abstract]
10. Zeisel, S. H., Allen, L. H., Coburn, S. P., Erdman, J. W., Failla, M. L., Freake, H. L., King, J. C. & Storch, J. (2001) Nutrition: A reservoir for integrative science. J. Nutr. 131:1319-1321.
11. Greenwald, P., Milner, J. A. & Clifford, C. K. (2000) Creating a new paradigm in nutrition research within the National Cancer Institute. J. Nutr. 130:3103-3105.
12. Halliwell, B. (1999) Establishing the significance and optimal intake of dietary antioxidants: the biomarker concept. Nutr. Rev. 57:104-113.[Medline]
13. Peto, J. (2001) Cancer epidemiology in the last century and the next decade. Nature 411:390-395.[Medline]
14. Yamasaki, H. (1997) Cellular and molecular methods to study the role of gap junctional intercellular communication in toxicology. Tox. In Vitro 11:535-542.
15. Redmond, T. M., Gentleman, S., Duncan, T., Yu, S., Wiggert, B., Gantt, E. & Cunningham, F. X. (2001) Identification, expression, and substrate specificity of a mammalian beta-carotene 15,15'-dioxygenase. J. Biol. Chem. 276:6560-6565.
16. Deckelbaum, R. J., Fisher, E. A., Winston, M., Kumanyika, S., Lauer, R. M., Pi-Sunyer, F. X., St. Jeor, S., Schaefer, E. J. & Weinstein, I. B. (1999) Summary of a scientific conference on preventive nutrition: pediatrics to geriatrics. Circulation 100:450-456.
17. Johnston, C. S., Taylor, C. A. & Hampl, J. S. (2000) More Americans are eating "5 a day" but intakes of dark green and cruciferous vegetables remain low. J. Nutr. 130:3063-3067.
18. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Circulation 285:2486-2497.
19. Hill, J. O., Goldberg, J. P., Pate, R. R. & Peters, J. C. (2001) Introduction to the summit on promoting healthy eating and active living: developing a framework for progress. Nutr. Rev. 59(II):S4-S6.
20. National Center for Health Statistics (1998) Health, United States, 1998 1998 Government Printing Ofice Washington, D.C.
21. Schwenk, N. E. & Guthrie, J. F. (1997) Trends in marketing and usage of fat-modified foods: implications for dietary status and nutrition promotion. Fam. Econ. Nutr. Rev. 10:16-31.
22. Riedl, J., Linseisen, J., Hoffman, J. & Wolfram, G. (1999) Some dietary fibers reduce the absorption of carotenoids in women. J. Nutr. 129:2170-2176.
23. Cooper, D. A., Webb, D. R. & Peters, J. C. (1997) Evaluation of the potential for olestra to affect the availability of dietary phytochemicals. J. Nutr. 127:1699S-1709S.
24. White, W. S., Brown, M. B., Ferruzzi, M. G., Nguyen, M. L., Cooper, D. A., Eldridge, A. L. & Schwartz, S. J. (2001) Use of electrochemical detection to quantify the effect of added fat on intestinal carotenoid absorption from fresh vegetables in humans. Presented at the Keystone Symposium: Manipulating Plant Metabolism to Enhance Nutritional Quality, April 6–11 2001 Breckenridge, CO.
25. Gylling, H. & Miettinen, T. A. (1999) Cholesterol reductions by different plant stanol mixtures and with variable fat intakes. Metabolism 48:575-580.[Medline]
26. James, W.P.T., Avenell, A., Broom, J. & Whitehead, J. (1997) A one-year trial to assess the value of orlistat in the management of obesity. Int. J. Obesity 21(Suppl. 3):S24-S30.
27. Elinder, L. S., Hadell, K., Johansson, J., Molgaard, J., Holme, I, Olsson, A. G. & Walldins, G. (1995) Probucol treatment decreases serum concentrations of diet-derived antioxidants. 15:1057-1063.
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