- Email: [email protected]
Mission and activities of the NIH Office of Dietary Supplements
ARTICLE IN PRESS
JOURNAL OF FOOD COMPOSITION AND ANALYSIS
Journal of Food Composition and Analysis 17 (2004) 493–500 www.elsevier.com/locate/jfca
Report
Mission and activities of the NIH Office of Dietary Supplements Johanna T. Dwyera,b,*, Mary Frances Piccianob, Joseph M. Betzc, Paul M. Coatesb a
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Frances Stern Nutrition Center, Tufts-New England Medical Center, Friedman School of Nutrition Science and Policy, School of Medicine. Boston, MA 02111, USA b Office of Dietary Supplements, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA c Dietary Supplement Methods and Reference Materials Program, Office of Dietary Supplements, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA Received 24 June 2003; received in revised form 5 March 2004; accepted 15 March 2004
Abstract Major initiatives of the US National Institutes of Health Office of Dietary Supplements (ODS) include development of analytical methods and reference materials to make the development of analytically substantiated dietary supplement databases possible in the future. ODS has an active evidence-based review program focused on efficacy and safety of dietary supplements. It also sponsors basic and clinical research, and information and educational resources, including continuing education conferences and training efforts. r 2004 Published by Elsevier Ltd. Keywords: Dietary supplements; Analytical substantiation; Dietary supplement composition; Certified Reference Materials; Standard Reference Materials
1. Introduction This paper describes some of the current work of the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) relating to the composition of dietary supplements and databases for dietary supplements. Dietary supplement databases are needed to provide more accurate
*Corresponding author. Schools of Nutrition and Medicine, Tufts University, 750 Washington St, Boston, MA 02111, USA. Tel.: +1-617-636-5273; fax: +1-617-636-8325. Email-address: [email protected] (J.T. Dwyer). 0889-1575/$ - see front matter r 2004 Published by Elsevier Ltd. doi:10.1016/j.jfca.2004.03.021
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estimates of total intakes of nutrients and other bioactive substances and to relate these to health outcomes. The Dietary Supplement Health and Education Act (DSHEA), became law in the United States (US) in 1994. It defined dietary supplements, assured American consumers access to dietary supplement products, and established a regulatory framework administered by the Food and Drug Administration (FDA). DSHEA treated dietary supplements as foods, not as drugs, and it specified rules for the contents of a dietary supplement label. In addition, DSHEA also established the ODS at NIH in the Office of the Director. The mission of the ODS is to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, stimulating and supporting research, disseminating research results, and educating the public to foster an enhanced quality of life and health for the US population. The components of interest in dietary supplements include botanicals, nutrients, and other constituents, such as contaminants and pesticide residues. Congress has recognized the need for research and related activities on dietary supplements, and it has been generous in its support. In fiscal year 2002, the ODS budget was $17 million, and it supported 59 new and continuing grants in collaboration with other Institutes and Centers (ICs) at NIH.
2. Key questions Several critical questions have been posed concerning dietary supplements (see Fig. 1). Some of the current efforts of the ODS to answer them are summarized below. 2.1. Evaluation of total intakes of nutrients The associations between diet and health outcomes require accurate estimates of total dietary intakes from all sources of nutrients. Appropriate methods for the collection of food and dietary supplement intake, appropriate databases, and appropriate methods for estimating total intakes are all needed (Dwyer et al., 2003a–d). Total dietary intakes can best be evaluated by taking into account all sources of intakes: foods, beverages, fortified products, dietary supplements, and some medications. In the US today, dietary supplements are widely used. Nutrient-containing supplements are used so frequently and by so many individuals that in certain age/sex/ physiological groups, dietary intakes will be underestimated if supplements are not included. •
How can total dietary intakes of nutrients best be evaluated?
•
What is known about the bioavailabiliy of dietary supplements?
•
Do critical questions that need to be answered about dietary supplement use vary by target group, such as age or physiological condition?
•
Is there a need for analytical methods and reference standards for dietary supplements?
•
Are dietary supplement databases valid and current?
•
What is the evidence for efficacy and safety of dietary supplements?
•
What research gaps need to be filled?
Fig. 1. Critical questions involving dietary supplements.
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Some examples of nutrients likely to be underestimated when supplement use is not considered include folic acid intakes of women in the reproductive age group and calcium in middle-aged and older persons. Adequate assessment of total nutrient intake is especially important in the dietary component of population-based surveys such as the National Health and Nutrition Examination Survey (NHANES), because data from them are often considered when setting national nutrition policy. To accurately evaluate total dietary intakes of nutrients in population-based surveys, research is needed on the best methods for assessing dietary supplement use, development of databases for dietary supplements, and methods for estimating total nutrient intakes from all sources. These issues were the subject of a 2002 conference of federal stakeholders sponsored by the USDA’s Agricultural Research Service, ODS, and the National Institute for Child Health and Development in collaboration with other federal agencies. The deliberations recently appeared as a supplement in the Journal of Nutrition (Dwyer et al., 2003a–d). 2.2. Bioavailability of dietary supplements The bioavailability of nutrients and other bioactive constituents both in foods and in dietary supplements is often unknown. Bioavailability varies by source of the constituent in the diet, but there is no hard and fast rule about which source is most highly bioavailable; that depends on several factors. For example, folic acid is more highly bioavailable from dietary supplements than it is from food sources, whereas vitamin E appears to be more highly bioavailable in food sources. Dietary and supplement composition also affect bioavailability, as do physiological state and age, among many other factors that still must be identified. To identify knowledge gaps and develop a research agenda, ODS held a conference on bioavailability of dietary supplements and also addressed these issues in a workshop on dietary supplement use in children, women and the elderly (Picciano and Raiten, 2001; Picciano et al., 2003; Raiten et al., 2002; ODS, 2004b). 2.3. Variation by target group The dietary supplements of health significance, health outcomes of interest, and safety and efficacy vary by target group as delineated by age, sex, and physiological state. A series of conferences over the past 2 years explored these and other issues in relevant target groups (Picciano, 2003; Raiten et al., 2002, 2003). Dietary supplement use and their effects on health outcomes were found to vary strikingly across the lifespan. For example, the prevalence of dietary supplement use was higher among the elderly than among younger adults. 2.4. Analytical standards and reference materials There is a pressing need for better analytical methods and reference materials for dietary supplements. Safety, economic and efficacy issues are just a few of the considerations that point to the need for better analytical methods and reference materials. Both qualitative and quantitative methods are needed. For example, from the qualitative standpoint with respect to safety it is important to identify the plant source of the supplement appropriately; if it is not identified correctly it might contain an allergen or some other substance with adverse health consequences in some people. In addition, if the wrong plant, or an inferior plant, is used, efficacy may be affected
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and label claims may not be met. From the quantitative standpoint, for some constituents like ephedra, contaminants (lead) and pesticide residues (DDT) may render the product unsafe. Similarly, if a ginseng product contains few or no ginsenosides, efficacy would be compromised and claims might be fraudulent. Improving analytical methodology in dietary supplement research is a major ODS goal. A coordinated programmatic effort has now been in place for about 2 years and it is beginning to influence the future direction of dietary supplement research. The goal of the ODS work with analytical approaches to dietary supplement research is to ‘‘quantify quality’’. The initial focus is on the most commonly used products that include essential nutrients (i.e., those in multivitamin– mineral supplements, antacids, and single micronutrient supplements). ODS is working to develop and disseminate validated analytical methods and reference materials with partners in the federal agencies, non-governmental organizations, academic centers, and industry. The ODS program’s ultimate goals are to work toward the development of a compendium of official methods of analysis for dietary supplements, accompanied by a companion compendium of methods validated at the appropriate level for other intended uses such as quality control to ensure the integrity of materials in clinical trials (Saldanha et al., 2004), and provision of certified reference materials. Some examples of the current work in this area follow. 2.4.1. ODS/FDA/AOAC Partnership ODS, the FDA, and the Association of Official Analytical Chemists (AOAC) International are partnering to validate analytical methods for dietary supplements using AOAC’s Official MethodsTM Program. This program is already producing results. One example is methods for analyzing ephedra, using FDA’s liquid chromatography/mass spectrometry/mass spectrometry and high-pressure liquid chromatography-non-mass spectrometry techniques. These methods are being validated on the botanical raw material, a common extract, a finished product, a complex mixture of multiple dietary supplements, a high protein drink, and specimens of human urine and serum. For aristolochic acid, the analytical method is the FDA liquid chromatographic and liquid chromatography/mass spectrometry technique. The methods will be applicable to Aristolochia, Asarum, Akebia, Clematis, and Stephania (spiked) and a botanical tablet. Over the next 5 years in collaboration with AOAC, 20 methods will be validated and training programs on how to develop and validate methods will be offered. In addition, a system for electronic peer review of methods will be developed and implemented, and a NIH-style expert review committee will be used to select technically sound methods. 2.4.2. ODS/NHLBI/ARS Collaboration A second effort is to augment a cooperative agreement already in place between the National Heart, Lung and Blood Institute (NHLBI) and the US Department of Agriculture (USDA) Agricultural Research Service (ARS) to update nutrient values for special USDA nutrient tables and to develop analytical methods for other constituents of interest, such as the isoflavonoids, lutein and zeaxanthine. For example, the flavonoids represent a large number of different phytochemical compounds that are currently of interest in health-related research (Dwyer and Peterson, 2002). ODS is providing supplementary funding to the NHLBI/ARS project for development of analytical methods for the determination of flavonoid glycosides in plants and dietary supplements.
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2.4.3. ODS/NIST Efforts ODS and the National Institute of Standards and Technology (NIST) are also collaborating to provide Standard Reference Materials (SRMs) for analytical methods performance evaluation. Over five years (2003–2007), it is hoped that the ODS/NIST program will produce a suite of 6–8 standard reference materials. For each, this will involve obtaining authentic biological reference materials and products, developing and validating analytical methods to determine bioactives and/or markers for them, and assigning values. Using NIST’s Office of Analysis certification approach, measurements will be made with two or more methods and/or laboratories. Values will also be assigned for heavy metal and pesticide content. In 2002, NIST provided a SRM for ephedra. In 2003, saw palmetto and St. John’s wort were evaluated. However, there is a dilemma. NIST can only provide 1–2 standard reference materials per year, and yet there are over 3000 plants used in dietary supplements presently on the market. Other interested stakeholders in the private and public sectors must join in this work. 2.5. Adequacy of dietary supplement databases Dietary supplement databases used in NHANES and available from private sources are incomplete in that they are not analytically substantiated, and for many herbs, the active constituents are unknown. Improvements in analytical methods, enhanced development of certified standard reference materials, and more research to identify the bioactive substances of interest are needed . The ultimate goal of the ODS program is to eventually have analytically substantiated databases that can be used in national surveys and for other research purposes. However, this effort will take many years to accomplish. In the meantime, an improved labelbased database is needed for interim use over the short term as analyses proceed. The label-based dietary supplement database is being developed as part of the National Health and Nutrition Examination Survey (NHANES) and a public use version may be ready in 2004. It will be useful to provide information on the prevalence of dietary supplement use. Based on prevalence of use data from that survey, product types and ingredients will be chosen for substantiation. The analytical work on substantiation is being done by the ARS in collaboration with ODS. The labelbased and analytically substantiated databases must be interactive so that they can easily relate to one another. 2.6. Dietary supplement efficacy and safety NIH has a large portfolio of research, but it is primarily targeted at disease prevention and treatment. The role of dietary supplement use in health promotion has just begun to be examined. The latter is more difficult for obvious reasons. ODS has launched an evidence-based review program to assist in the development of an appropriate research agenda and to answer questions about safety and efficacy. Clinical trials take place in phases. Phase I determines safe dosage levels and acceptable modes of administration and documents physiological effects. Phase II determines efficacy, especially whether the supplement is effective for its intended purpose and at what doses. Phase II compares the supplement to standard treatments and/or to a placebo. Each study will involve a systematic, evidence-based review of the literature, with meta-analysis as appropriate, on dietary supplement efficacy and safety.
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ODS has completed systematic reviews for chromium and type 2 diabetes mellitus (Althuis et al., 2002), and for ephedra and weight management and athletic performance enhancement (Shekelle et al., 2003). Reviews now in progress include n-3 fatty acids for a variety of clinical indications, including cardiovascular disease/stroke, cancer, and mental health. More evidencebased reviews are planned for the future. 2.7. Filling research gaps There are many gaps in dietary supplement research (Swanson, 2002). ODS’s efforts to establish botanical research centers, stimulate investigator-initiated research, and provide informational and educational support help to fill them. ODS, working in partnership with the NIH National Center for Complementary and Alternative Medicine (NCCAM), and the National Institute of Environmental Health Sciences (NIEHS) (and with additional financial support from the National Institute of General Medical Sciences (NIGMS) and the Office of Research on Women’s’ Health (ORWH)) has made awards of $1.0–$1.5 million a year each for 5 years to six universities in the US to focus research on dietary supplements with special emphasis on botanicals. The universities include the University of California at Los Angeles, the University of Illinois at Chicago, the University of Arizona, Purdue University/University of Alabama at Birmingham, University of Missouri, and Iowa State University/University of Iowa. These botanical research centers have research programs targeted to identifying and characterizing botanicals, assessing their bioavailability and bioactivity, identifying active constituents, exploring their mechanisms of action, and performing phase I (safety) and phase II (dose ranging) clinical evaluations. There is also an active program of investigator-initiated research. Many of the topics for the projects were recommended to ODS by the other NIH ICs. Some of these projects include: folate receptors and craniofacial malformations, chromium and insulin action, B vitamins and atherosclerosis intervention trial, studies of St. John’s wort and cytochrome P-450-3A (CYP3A) metabolism, investigations of conjugated linoleic acid and adipose tissue metabolism, investigations of S-adenosylmethionine and Parkinson’s disease, analyses of phenolic phytochemicals, and studies of the inhibition of angiogenesis by green tea catechins. ODS also provides information and education resources on dietary supplements, and strives to improve standards for reporting on supplements in scientific communications (Swanson, 2002). These efforts include continuing education conferences and workshops on dietary supplements in the US, and an international component in developing countries, a website and a listserv, as well as fact sheets and databases on scientific articles that deal with dietary supplements. Computer Access to Research on Dietary Supplements (CARDS) is a database of federally funded research projects pertaining to dietary supplements. Currently, CARDS contains projects funded by NIH ICs beginning with fiscal year 1999, the first year that NIH ICs began reporting research related to dietary supplements. Projects funded by other Federal agencies will be added to CARDS as they become available. The International Bibliographic Information on Dietary Supplements (IBIDS) Database provides access to bibliographic citations and abstracts from published, international scientific literature on dietary supplements. The ODS produces this database to help consumers, health care providers, educators and researchers to find credible, scientific information on a variety of dietary supplements including vitamins, minerals, and botanicals. IBIDS was developed
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and is maintained through an interagency partnership between ODS and the Food and Nutrition Information Center, National Agricultural Library, USDA. We encourage other groups to link to IBIDS via this web page (http://www.nal.usda.gov/fnic/foodcomp/index.html—see ‘‘food composition and nutrition resource links’’). Finally, ODS has an active program of training and career development. This includes both intramural and extramural support of pre-doctoral and postdoctoral trainees. Information about ODS is available at: http://ods.od.nih.gov. 2.8. Strategic planning for the future ODS reexamined the original ODS Strategic Plan that guided its work from 1998–2003 (Office of Dietary Supplements, 1998) and formulated a revised plan for 2004–2009 (Office of Dietary Supplements, 2004a). Comments and suggestions on the 2004–2009 Strategic Plan, available at the ODS website, are welcome.
3. Conclusions Many critical issues involving dietary supplements remain to be dealt with. We have become acutely aware of how much we have to learn about the composition not only of food but also of dietary supplements. Training is sorely needed, and research must continue.
Acknowledgements We thank Julia Peterson, MS, for suggestions in the preparation of this manuscript. Partial support for the preparation of this manuscript from the Office of Dietary Supplements, National Institutes of Health, and the American Institute of Cancer Research are acknowledged with thanks. This paper was funded with federal funds from the US Department of Agriculture, Agricultural Research Service, under contract #58-1950-9-001. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture.
References Althuis, M.D., Jordan, N.E., Ludington, E.A., Wittes, J.T., 2002. Glucose and insulin responses to dietary chromium supplements: a meta-analysis. American Journal of Clinical Nutrition 76, 148–155. Dwyer, J.T., Peterson, J.J., 2002. Measuring flavonoid intake: need for advanced tools. Public Health Nutrition 5 (6A), 925–930. Dwyer, J.T., Picciano, M.F., Raiten, D.J. ( Eds.), 2003a Future directions for What We Eat in American-NHANES: The Integrated CSFII-NHANES. Journal of Nutrition 133, 575S–635S Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003b. Collection of food and dietary supplement intake data: What We Eat in America-NHANES. Journal of Nutrition 133, 590S–600S. Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003c. Estimation of usual intakes: What We Eat in America-NHANES. Journal of Nutrition 133, 609S–623S. Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003d Food and dietary supplement databases for What We Eat in America-NHANES. Journal of Nutrition 624S–634S.
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Office of Dietary Supplements, Office of the Director, 1998. Merging quality science with supplement research: a strategic plan for the Office of Dietary Supplements Office of the Director. National Institutes of Health, Bethesda, MD. Office of Dietary Supplements, 2004a. Promoting quality science in dietary supplement research, education, and communication: a strategic plan for the Office of Dietary Supplements 2004–2009. Office of the Director, National Institutes of Health, Bethesda, MD. Office of Dietary Supplements, 2004b. Executive summary: Conference on dietary supplement use in the elderly. Nutrition Reviews 62, in press. Picciano, M.F., 2003. Pregnancy and lactation: physiological adjustments, nutritional requirements and the role of dietary supplements. Journal of Nutrition 133 (6), 1997S–2002S. Picciano, M.F., Raiten, D.J., 2001. Bioavailability of nutrients and other bioactive components fom dietary supplements. Journal of Nutrition 131, 1329S–1400S. Picciano, M.F., Raiten, D.J., Coates, P.M., 2003. Dietary supplement use in women: current status and future directions. Journal of Nutrition 133, 1957S–2010S. Raiten, D.J., Picciano, M.F., Coates, P.M,, 2002. Dietary supplement use in children: who, what, why and where do we go from here? Executive summary, Part 1. Nutrition Today 37, 118–129; 167–169. Raiten, D.J., Picciano, M.F., Coates, P.M., 2003. Dietary supplement use in women: current status and future directions: introduction and conference summary. Journal of Nutrition 133, 1957S–1960S. Saldanha, L.G., Betz, J.M., Coates, P.M., 2004. Development of the analytical methods and reference materials program for dietary supplements at the National Institutes of Health. Journal of AOAC International 87, 1–4. Shekelle, P., Morton, S., Maglione, M., Hardy, M., Suttorp, M., Roth, E., Jungrig, C., Mojica, W.A., Gagne, J., 2003. Ephedra and ephedrine for weight loss and athletic performance enhancement: clinical efficacy and side effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California-RAND Evidence-based Practice Center, under Contract No 290-97-001) , ARHQ Publication No. 03-#022. Agency for Healthcare Research and Quality. March 2003, Rockville, MD, Vol. 1, Evidence Report and Evidence Review, Vol. 2, Appendices. Swanson, C.A., 2002. Suggested guidelines for articles about botanical dietary supplements. American Journal of Clinical Nutrition 75, 8–10.
JOURNAL OF FOOD COMPOSITION AND ANALYSIS
Journal of Food Composition and Analysis 17 (2004) 493–500 www.elsevier.com/locate/jfca
Report
Mission and activities of the NIH Office of Dietary Supplements Johanna T. Dwyera,b,*, Mary Frances Piccianob, Joseph M. Betzc, Paul M. Coatesb a
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Frances Stern Nutrition Center, Tufts-New England Medical Center, Friedman School of Nutrition Science and Policy, School of Medicine. Boston, MA 02111, USA b Office of Dietary Supplements, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA c Dietary Supplement Methods and Reference Materials Program, Office of Dietary Supplements, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA Received 24 June 2003; received in revised form 5 March 2004; accepted 15 March 2004
Abstract Major initiatives of the US National Institutes of Health Office of Dietary Supplements (ODS) include development of analytical methods and reference materials to make the development of analytically substantiated dietary supplement databases possible in the future. ODS has an active evidence-based review program focused on efficacy and safety of dietary supplements. It also sponsors basic and clinical research, and information and educational resources, including continuing education conferences and training efforts. r 2004 Published by Elsevier Ltd. Keywords: Dietary supplements; Analytical substantiation; Dietary supplement composition; Certified Reference Materials; Standard Reference Materials
1. Introduction This paper describes some of the current work of the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) relating to the composition of dietary supplements and databases for dietary supplements. Dietary supplement databases are needed to provide more accurate
*Corresponding author. Schools of Nutrition and Medicine, Tufts University, 750 Washington St, Boston, MA 02111, USA. Tel.: +1-617-636-5273; fax: +1-617-636-8325. Email-address: [email protected] (J.T. Dwyer). 0889-1575/$ - see front matter r 2004 Published by Elsevier Ltd. doi:10.1016/j.jfca.2004.03.021
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estimates of total intakes of nutrients and other bioactive substances and to relate these to health outcomes. The Dietary Supplement Health and Education Act (DSHEA), became law in the United States (US) in 1994. It defined dietary supplements, assured American consumers access to dietary supplement products, and established a regulatory framework administered by the Food and Drug Administration (FDA). DSHEA treated dietary supplements as foods, not as drugs, and it specified rules for the contents of a dietary supplement label. In addition, DSHEA also established the ODS at NIH in the Office of the Director. The mission of the ODS is to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, stimulating and supporting research, disseminating research results, and educating the public to foster an enhanced quality of life and health for the US population. The components of interest in dietary supplements include botanicals, nutrients, and other constituents, such as contaminants and pesticide residues. Congress has recognized the need for research and related activities on dietary supplements, and it has been generous in its support. In fiscal year 2002, the ODS budget was $17 million, and it supported 59 new and continuing grants in collaboration with other Institutes and Centers (ICs) at NIH.
2. Key questions Several critical questions have been posed concerning dietary supplements (see Fig. 1). Some of the current efforts of the ODS to answer them are summarized below. 2.1. Evaluation of total intakes of nutrients The associations between diet and health outcomes require accurate estimates of total dietary intakes from all sources of nutrients. Appropriate methods for the collection of food and dietary supplement intake, appropriate databases, and appropriate methods for estimating total intakes are all needed (Dwyer et al., 2003a–d). Total dietary intakes can best be evaluated by taking into account all sources of intakes: foods, beverages, fortified products, dietary supplements, and some medications. In the US today, dietary supplements are widely used. Nutrient-containing supplements are used so frequently and by so many individuals that in certain age/sex/ physiological groups, dietary intakes will be underestimated if supplements are not included. •
How can total dietary intakes of nutrients best be evaluated?
•
What is known about the bioavailabiliy of dietary supplements?
•
Do critical questions that need to be answered about dietary supplement use vary by target group, such as age or physiological condition?
•
Is there a need for analytical methods and reference standards for dietary supplements?
•
Are dietary supplement databases valid and current?
•
What is the evidence for efficacy and safety of dietary supplements?
•
What research gaps need to be filled?
Fig. 1. Critical questions involving dietary supplements.
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Some examples of nutrients likely to be underestimated when supplement use is not considered include folic acid intakes of women in the reproductive age group and calcium in middle-aged and older persons. Adequate assessment of total nutrient intake is especially important in the dietary component of population-based surveys such as the National Health and Nutrition Examination Survey (NHANES), because data from them are often considered when setting national nutrition policy. To accurately evaluate total dietary intakes of nutrients in population-based surveys, research is needed on the best methods for assessing dietary supplement use, development of databases for dietary supplements, and methods for estimating total nutrient intakes from all sources. These issues were the subject of a 2002 conference of federal stakeholders sponsored by the USDA’s Agricultural Research Service, ODS, and the National Institute for Child Health and Development in collaboration with other federal agencies. The deliberations recently appeared as a supplement in the Journal of Nutrition (Dwyer et al., 2003a–d). 2.2. Bioavailability of dietary supplements The bioavailability of nutrients and other bioactive constituents both in foods and in dietary supplements is often unknown. Bioavailability varies by source of the constituent in the diet, but there is no hard and fast rule about which source is most highly bioavailable; that depends on several factors. For example, folic acid is more highly bioavailable from dietary supplements than it is from food sources, whereas vitamin E appears to be more highly bioavailable in food sources. Dietary and supplement composition also affect bioavailability, as do physiological state and age, among many other factors that still must be identified. To identify knowledge gaps and develop a research agenda, ODS held a conference on bioavailability of dietary supplements and also addressed these issues in a workshop on dietary supplement use in children, women and the elderly (Picciano and Raiten, 2001; Picciano et al., 2003; Raiten et al., 2002; ODS, 2004b). 2.3. Variation by target group The dietary supplements of health significance, health outcomes of interest, and safety and efficacy vary by target group as delineated by age, sex, and physiological state. A series of conferences over the past 2 years explored these and other issues in relevant target groups (Picciano, 2003; Raiten et al., 2002, 2003). Dietary supplement use and their effects on health outcomes were found to vary strikingly across the lifespan. For example, the prevalence of dietary supplement use was higher among the elderly than among younger adults. 2.4. Analytical standards and reference materials There is a pressing need for better analytical methods and reference materials for dietary supplements. Safety, economic and efficacy issues are just a few of the considerations that point to the need for better analytical methods and reference materials. Both qualitative and quantitative methods are needed. For example, from the qualitative standpoint with respect to safety it is important to identify the plant source of the supplement appropriately; if it is not identified correctly it might contain an allergen or some other substance with adverse health consequences in some people. In addition, if the wrong plant, or an inferior plant, is used, efficacy may be affected
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and label claims may not be met. From the quantitative standpoint, for some constituents like ephedra, contaminants (lead) and pesticide residues (DDT) may render the product unsafe. Similarly, if a ginseng product contains few or no ginsenosides, efficacy would be compromised and claims might be fraudulent. Improving analytical methodology in dietary supplement research is a major ODS goal. A coordinated programmatic effort has now been in place for about 2 years and it is beginning to influence the future direction of dietary supplement research. The goal of the ODS work with analytical approaches to dietary supplement research is to ‘‘quantify quality’’. The initial focus is on the most commonly used products that include essential nutrients (i.e., those in multivitamin– mineral supplements, antacids, and single micronutrient supplements). ODS is working to develop and disseminate validated analytical methods and reference materials with partners in the federal agencies, non-governmental organizations, academic centers, and industry. The ODS program’s ultimate goals are to work toward the development of a compendium of official methods of analysis for dietary supplements, accompanied by a companion compendium of methods validated at the appropriate level for other intended uses such as quality control to ensure the integrity of materials in clinical trials (Saldanha et al., 2004), and provision of certified reference materials. Some examples of the current work in this area follow. 2.4.1. ODS/FDA/AOAC Partnership ODS, the FDA, and the Association of Official Analytical Chemists (AOAC) International are partnering to validate analytical methods for dietary supplements using AOAC’s Official MethodsTM Program. This program is already producing results. One example is methods for analyzing ephedra, using FDA’s liquid chromatography/mass spectrometry/mass spectrometry and high-pressure liquid chromatography-non-mass spectrometry techniques. These methods are being validated on the botanical raw material, a common extract, a finished product, a complex mixture of multiple dietary supplements, a high protein drink, and specimens of human urine and serum. For aristolochic acid, the analytical method is the FDA liquid chromatographic and liquid chromatography/mass spectrometry technique. The methods will be applicable to Aristolochia, Asarum, Akebia, Clematis, and Stephania (spiked) and a botanical tablet. Over the next 5 years in collaboration with AOAC, 20 methods will be validated and training programs on how to develop and validate methods will be offered. In addition, a system for electronic peer review of methods will be developed and implemented, and a NIH-style expert review committee will be used to select technically sound methods. 2.4.2. ODS/NHLBI/ARS Collaboration A second effort is to augment a cooperative agreement already in place between the National Heart, Lung and Blood Institute (NHLBI) and the US Department of Agriculture (USDA) Agricultural Research Service (ARS) to update nutrient values for special USDA nutrient tables and to develop analytical methods for other constituents of interest, such as the isoflavonoids, lutein and zeaxanthine. For example, the flavonoids represent a large number of different phytochemical compounds that are currently of interest in health-related research (Dwyer and Peterson, 2002). ODS is providing supplementary funding to the NHLBI/ARS project for development of analytical methods for the determination of flavonoid glycosides in plants and dietary supplements.
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2.4.3. ODS/NIST Efforts ODS and the National Institute of Standards and Technology (NIST) are also collaborating to provide Standard Reference Materials (SRMs) for analytical methods performance evaluation. Over five years (2003–2007), it is hoped that the ODS/NIST program will produce a suite of 6–8 standard reference materials. For each, this will involve obtaining authentic biological reference materials and products, developing and validating analytical methods to determine bioactives and/or markers for them, and assigning values. Using NIST’s Office of Analysis certification approach, measurements will be made with two or more methods and/or laboratories. Values will also be assigned for heavy metal and pesticide content. In 2002, NIST provided a SRM for ephedra. In 2003, saw palmetto and St. John’s wort were evaluated. However, there is a dilemma. NIST can only provide 1–2 standard reference materials per year, and yet there are over 3000 plants used in dietary supplements presently on the market. Other interested stakeholders in the private and public sectors must join in this work. 2.5. Adequacy of dietary supplement databases Dietary supplement databases used in NHANES and available from private sources are incomplete in that they are not analytically substantiated, and for many herbs, the active constituents are unknown. Improvements in analytical methods, enhanced development of certified standard reference materials, and more research to identify the bioactive substances of interest are needed . The ultimate goal of the ODS program is to eventually have analytically substantiated databases that can be used in national surveys and for other research purposes. However, this effort will take many years to accomplish. In the meantime, an improved labelbased database is needed for interim use over the short term as analyses proceed. The label-based dietary supplement database is being developed as part of the National Health and Nutrition Examination Survey (NHANES) and a public use version may be ready in 2004. It will be useful to provide information on the prevalence of dietary supplement use. Based on prevalence of use data from that survey, product types and ingredients will be chosen for substantiation. The analytical work on substantiation is being done by the ARS in collaboration with ODS. The labelbased and analytically substantiated databases must be interactive so that they can easily relate to one another. 2.6. Dietary supplement efficacy and safety NIH has a large portfolio of research, but it is primarily targeted at disease prevention and treatment. The role of dietary supplement use in health promotion has just begun to be examined. The latter is more difficult for obvious reasons. ODS has launched an evidence-based review program to assist in the development of an appropriate research agenda and to answer questions about safety and efficacy. Clinical trials take place in phases. Phase I determines safe dosage levels and acceptable modes of administration and documents physiological effects. Phase II determines efficacy, especially whether the supplement is effective for its intended purpose and at what doses. Phase II compares the supplement to standard treatments and/or to a placebo. Each study will involve a systematic, evidence-based review of the literature, with meta-analysis as appropriate, on dietary supplement efficacy and safety.
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ODS has completed systematic reviews for chromium and type 2 diabetes mellitus (Althuis et al., 2002), and for ephedra and weight management and athletic performance enhancement (Shekelle et al., 2003). Reviews now in progress include n-3 fatty acids for a variety of clinical indications, including cardiovascular disease/stroke, cancer, and mental health. More evidencebased reviews are planned for the future. 2.7. Filling research gaps There are many gaps in dietary supplement research (Swanson, 2002). ODS’s efforts to establish botanical research centers, stimulate investigator-initiated research, and provide informational and educational support help to fill them. ODS, working in partnership with the NIH National Center for Complementary and Alternative Medicine (NCCAM), and the National Institute of Environmental Health Sciences (NIEHS) (and with additional financial support from the National Institute of General Medical Sciences (NIGMS) and the Office of Research on Women’s’ Health (ORWH)) has made awards of $1.0–$1.5 million a year each for 5 years to six universities in the US to focus research on dietary supplements with special emphasis on botanicals. The universities include the University of California at Los Angeles, the University of Illinois at Chicago, the University of Arizona, Purdue University/University of Alabama at Birmingham, University of Missouri, and Iowa State University/University of Iowa. These botanical research centers have research programs targeted to identifying and characterizing botanicals, assessing their bioavailability and bioactivity, identifying active constituents, exploring their mechanisms of action, and performing phase I (safety) and phase II (dose ranging) clinical evaluations. There is also an active program of investigator-initiated research. Many of the topics for the projects were recommended to ODS by the other NIH ICs. Some of these projects include: folate receptors and craniofacial malformations, chromium and insulin action, B vitamins and atherosclerosis intervention trial, studies of St. John’s wort and cytochrome P-450-3A (CYP3A) metabolism, investigations of conjugated linoleic acid and adipose tissue metabolism, investigations of S-adenosylmethionine and Parkinson’s disease, analyses of phenolic phytochemicals, and studies of the inhibition of angiogenesis by green tea catechins. ODS also provides information and education resources on dietary supplements, and strives to improve standards for reporting on supplements in scientific communications (Swanson, 2002). These efforts include continuing education conferences and workshops on dietary supplements in the US, and an international component in developing countries, a website and a listserv, as well as fact sheets and databases on scientific articles that deal with dietary supplements. Computer Access to Research on Dietary Supplements (CARDS) is a database of federally funded research projects pertaining to dietary supplements. Currently, CARDS contains projects funded by NIH ICs beginning with fiscal year 1999, the first year that NIH ICs began reporting research related to dietary supplements. Projects funded by other Federal agencies will be added to CARDS as they become available. The International Bibliographic Information on Dietary Supplements (IBIDS) Database provides access to bibliographic citations and abstracts from published, international scientific literature on dietary supplements. The ODS produces this database to help consumers, health care providers, educators and researchers to find credible, scientific information on a variety of dietary supplements including vitamins, minerals, and botanicals. IBIDS was developed
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and is maintained through an interagency partnership between ODS and the Food and Nutrition Information Center, National Agricultural Library, USDA. We encourage other groups to link to IBIDS via this web page (http://www.nal.usda.gov/fnic/foodcomp/index.html—see ‘‘food composition and nutrition resource links’’). Finally, ODS has an active program of training and career development. This includes both intramural and extramural support of pre-doctoral and postdoctoral trainees. Information about ODS is available at: http://ods.od.nih.gov. 2.8. Strategic planning for the future ODS reexamined the original ODS Strategic Plan that guided its work from 1998–2003 (Office of Dietary Supplements, 1998) and formulated a revised plan for 2004–2009 (Office of Dietary Supplements, 2004a). Comments and suggestions on the 2004–2009 Strategic Plan, available at the ODS website, are welcome.
3. Conclusions Many critical issues involving dietary supplements remain to be dealt with. We have become acutely aware of how much we have to learn about the composition not only of food but also of dietary supplements. Training is sorely needed, and research must continue.
Acknowledgements We thank Julia Peterson, MS, for suggestions in the preparation of this manuscript. Partial support for the preparation of this manuscript from the Office of Dietary Supplements, National Institutes of Health, and the American Institute of Cancer Research are acknowledged with thanks. This paper was funded with federal funds from the US Department of Agriculture, Agricultural Research Service, under contract #58-1950-9-001. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture.
References Althuis, M.D., Jordan, N.E., Ludington, E.A., Wittes, J.T., 2002. Glucose and insulin responses to dietary chromium supplements: a meta-analysis. American Journal of Clinical Nutrition 76, 148–155. Dwyer, J.T., Peterson, J.J., 2002. Measuring flavonoid intake: need for advanced tools. Public Health Nutrition 5 (6A), 925–930. Dwyer, J.T., Picciano, M.F., Raiten, D.J. ( Eds.), 2003a Future directions for What We Eat in American-NHANES: The Integrated CSFII-NHANES. Journal of Nutrition 133, 575S–635S Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003b. Collection of food and dietary supplement intake data: What We Eat in America-NHANES. Journal of Nutrition 133, 590S–600S. Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003c. Estimation of usual intakes: What We Eat in America-NHANES. Journal of Nutrition 133, 609S–623S. Dwyer, J.T., Picciano, M.F., Raiten, D.J., 2003d Food and dietary supplement databases for What We Eat in America-NHANES. Journal of Nutrition 624S–634S.
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Office of Dietary Supplements, Office of the Director, 1998. Merging quality science with supplement research: a strategic plan for the Office of Dietary Supplements Office of the Director. National Institutes of Health, Bethesda, MD. Office of Dietary Supplements, 2004a. Promoting quality science in dietary supplement research, education, and communication: a strategic plan for the Office of Dietary Supplements 2004–2009. Office of the Director, National Institutes of Health, Bethesda, MD. Office of Dietary Supplements, 2004b. Executive summary: Conference on dietary supplement use in the elderly. Nutrition Reviews 62, in press. Picciano, M.F., 2003. Pregnancy and lactation: physiological adjustments, nutritional requirements and the role of dietary supplements. Journal of Nutrition 133 (6), 1997S–2002S. Picciano, M.F., Raiten, D.J., 2001. Bioavailability of nutrients and other bioactive components fom dietary supplements. Journal of Nutrition 131, 1329S–1400S. Picciano, M.F., Raiten, D.J., Coates, P.M., 2003. Dietary supplement use in women: current status and future directions. Journal of Nutrition 133, 1957S–2010S. Raiten, D.J., Picciano, M.F., Coates, P.M,, 2002. Dietary supplement use in children: who, what, why and where do we go from here? Executive summary, Part 1. Nutrition Today 37, 118–129; 167–169. Raiten, D.J., Picciano, M.F., Coates, P.M., 2003. Dietary supplement use in women: current status and future directions: introduction and conference summary. Journal of Nutrition 133, 1957S–1960S. Saldanha, L.G., Betz, J.M., Coates, P.M., 2004. Development of the analytical methods and reference materials program for dietary supplements at the National Institutes of Health. Journal of AOAC International 87, 1–4. Shekelle, P., Morton, S., Maglione, M., Hardy, M., Suttorp, M., Roth, E., Jungrig, C., Mojica, W.A., Gagne, J., 2003. Ephedra and ephedrine for weight loss and athletic performance enhancement: clinical efficacy and side effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California-RAND Evidence-based Practice Center, under Contract No 290-97-001) , ARHQ Publication No. 03-#022. Agency for Healthcare Research and Quality. March 2003, Rockville, MD, Vol. 1, Evidence Report and Evidence Review, Vol. 2, Appendices. Swanson, C.A., 2002. Suggested guidelines for articles about botanical dietary supplements. American Journal of Clinical Nutrition 75, 8–10.