Perspectives on the Use of Proprietary Blends in Dietary Supplements.

This paper discusses the rationale for use of proprietary blends on dietary supplement labels, and their implications for researchers and consumers. The Dietary Supplement Health Education Act of 1994 allows the listing of nonnutrient dietary ingredients as proprietary blends on dietary supplement labels for companies to protect their unique formulas. The weight of the blend and names of the ingredients within the blends must be declared, but not the amounts of the individual ingredients within the proprietary blend. Thus, from label information, the amount of a dietary ingredient in a proprietary blend is not available for calculating exposures in assessments of intakes or for determining doses in clinical trials.

Do Multivitamin/Mineral Dietary Supplements for Young Children Fill Critical Nutrient Gaps?

BACKGROUND: Nearly a third of young US children take multivitamin/mineral (MVM) dietary supplements, yet it is unclear how formulations compare with requirements. OBJECTIVE: Describe the number and amounts of micronutrients contained in MVMs for young children and compare suggested amounts on product labels to micronutrient requirements. DESIGN: Cross-sectional. SETTING: All 288 MVMs on the market in the United States in the National Institutes of Health's Dietary Supplement Label Database in 2018 labeled for children 1 to <4 years old. MAIN OUTCOME MEASURES: Number of MVM products and amounts per day of micronutrients in each product suggested on labels compared with requirements represented by age-appropriate Daily Values (DV). Micronutrients of public health concern identified by the Dietary Guidelines for Americans (DGA) 2015-2020 (DGA 2015) and DGA 2020-2025 (DGA 2020) or those of concern for exceeding the upper tolerable intake levels. STATISTICAL ANALYSES: Number of products and percent DV per day provided by each micronutrient in each product. RESULTS: The 288 MVMs contained a mean of 10.1 ± 2.27 vitamins and 4.59 ± 2.27 minerals. The most common were, in rank order, vitamins C, A, D, E, B6, B12; zinc, biotin, pantothenic acid, iodine, and folic acid. For micronutrients denoted by the DGA 2015 and DGA 2020 of public health concern, 56% of the 281 products containing vitamin D, 4% of the 144 with calcium, and none of the 60 containing potassium provided at least half of the DV. The upper tolerable intake level was exceeded by 49% of 197 products with folic acid, 17% of 283 with vitamin A, and 14% of 264 with zinc. Most MVMs contained many of 16 other vitamins and minerals identified in national surveys as already abundant in children's diets. CONCLUSIONS: A reexamination of the amounts and types of micronutrients in MVMs might consider formulations that better fill critical gaps in intakes and avoid excess.

Modernization of the National Institutes of Health Dietary Supplement Label Database.

Launched in 2008, NIH's DSLD (https://dsld.nlm.nih.gov/dsld/) currently catalogs information printed on over 125,000 (historical and current) labels of dietary supplement products sold in the U.S.. The database is maintained and updated continuously, and new versions deployed regularly. The new home page includes a prominent search bar and counter that displays the number of searchable labels in the database. The redesigned website yields near-instantaneous label retrieval, a more attractive layout of information, tailored search filters and download options, and the ability to view data in pictorial formats resulting in a much-improved user experience. The modernization of the DSLD ensures that this NIH resource has new forms of data delivery to meet the needs of App developers and data scientists, and improved performance for users. The DSLD is updated frequently to reflect the products sold in the rapidly evolving U.S. dietary supplement market.

Perspective: Characterization of Dietary Supplements Containing Calcium and Magnesium and Their Respective Ratio-Is a Rising Ratio a Cause for Concern?

Low magnesium intakes coupled with high calcium intakes and high calcium-to-magnesium (Ca:Mg) intake ratios have been associated with increased risk for multiple chronic conditions such as cardiovascular disease and metabolic syndrome, as well as some cancers (colorectal, prostate, esophageal), and total mortality. A high dietary Ca:Mg ratio (>2.60) may affect body magnesium status while, on the other hand, high intakes of magnesium could adversely impact individuals with an exceedingly low dietary Ca:Mg ratio (<1.70). Thus, a Ca:Mg ratio range of 1.70-2.60 (weight to weight) has been proposed as an optimum range. Data from NHANES surveys have shown the mean Ca:Mg intake ratio from foods alone for US adults has been >3.00 since 2000. One-third of Americans consume a magnesium supplement with a mean dose of 146 mg/d, and 35% of Americans consume a calcium supplement with a mean dose of 479 mg/d. Our review of Ca:Mg ratios in dietary supplements sold in the United States and listed in NIH's Dietary Supplement Label Database (DSLD) found a mean ratio of 2.90 across all calcium- and magnesium-containing products, with differences by product form. The ratios ranged from a low of 0.10 in liquid products to a high of 48.5 in powder products. Thirty-one percent of products fell below, 40.5% fell within, and 28.3% fell above the ratio range of 1.70-2.60. Our findings of calculated Ca:Mg ratios from dietary supplements coupled with food-intake data suggest that, in individuals with high calcium intakes from diet and/or supplements, magnesium supplementation may be warranted to establish a more favorable dietary Ca:Mg ratio in their total diet. Additional research may provide greater insight into whether the Ca:Mg ratio is a biomarker of interest for moderating chronic disease and which population groups may derive benefit from moderating that ratio.

Analytical Challenges and Metrological Approaches to Ensuring Dietary Supplement Quality: International Perspectives.

The increased utilization of metrology resources and expanded application of its' approaches in the development of internationally agreed upon measurements can lay the basis for regulatory harmonization, support reproducible research, and advance scientific understanding, especially of dietary supplements and herbal medicines. Yet, metrology is often underappreciated and underutilized in dealing with the many challenges presented by these chemically complex preparations. This article discusses the utility of applying rigorous analytical techniques and adopting metrological principles more widely in studying dietary supplement products and ingredients, particularly medicinal plants and other botanicals. An assessment of current and emerging dietary supplement characterization methods is provided, including targeted and non-targeted techniques, as well as data analysis and evaluation approaches, with a focus on chemometrics, toxicity, dosage form performance, and data management. Quality assessment, statistical methods, and optimized methods for data management are also discussed. Case studies provide examples of applying metrological principles in thorough analytical characterization of supplement composition to clarify their health effects. A new frontier for metrology in dietary supplement science is described, including opportunities to improve methods for analysis and data management, development of relevant standards and good practices, and communication of these developments to researchers and analysts, as well as to regulatory and policy decision makers in the public and private sectors. The promotion of closer interactions between analytical, clinical, and pharmaceutical scientists who are involved in research and product development with metrologists who develop standards and methodological guidelines is critical to advance research on dietary supplement characterization and health effects.

Perspective: Time to Resolve Confusion on Folate Amounts, Units, and Forms in Prenatal Supplements.

Folate-containing prenatal supplements are commonly consumed in the United States, but inconsistencies in units of measure and chemical forms pose challenges for providing authoritative advice on recommended amounts. New regulations require folate to be declared as micrograms of dietary folate equivalents (DFE) on product labels, whereas intake recommendations for reducing the risk of neural tube defects (NTDs) and the Tolerable Upper Intake Level are expressed as micrograms of folic acid. Today, >25% of prenatal supplements contain folate as synthetic salts of L-5-methyltetrahydrofolate (L-5-MTHF), but recommendations do not include this form of the vitamin. Harmonizing units of measure and addressing newer forms of folate salts in intake recommendations and in the prevention of NTDs would resolve the confusion.

Disintegration and Dissolution Testing of Green Tea Dietary Supplements: Application and Evaluation of United States Pharmacopeial Standards.

Approved performance quality tests are lacking in the United States Pharmacopeia (USP) for dietary supplements (DSs) containing green tea extracts. We evaluated the applicability of USP <2040 > general chapter protocols for disintegration and dissolution testing of botanicals to GT DSs. Of 28 single-ingredient GT DSs tested in 2 to 4 lots, 9 (32.1%) always passed the disintegration test, 8 (28.6%) always failed, and 11 (39.3%) showed inconsistent results. Of 34 multi-ingredient DSs tested in 2 lots, 21 (61.8%) passed and 8 (23.5%) failed in both lots, and 5 (14.7%) exhibited inconsistent performance. When stronger destructive forces were applied (disk added), all of the capsules that had failed initially, but not the tablets, passed. In dissolution testing, for the release of epigallocatechin-3-gallate (EGCG), only 6 of 20 single-ingredient DSs passed. Unexpectedly, with the addition of pepsin (prescribed by USP), only one additional DS passed. These results raise concerns that EGCG was not released properly from GT DS dosage forms. However, the general USP protocols may be inadequate for this botanical. More biorelevant destructive forces may be needed to break down capsules and tablets strengthened by the EGCG's interaction with shell material and to overcome the inhibition of digestive enzymes by EGCG.

The Chemical Forms of Iron in Commercial Prenatal Supplements Are Not Always the Same as Those Tested in Clinical Trials.

In the US, 70% of pregnant women use an iron-containing prenatal supplement product; however, only 2.6% of pregnant women have iron-deficiency anemia and 16.3% are iron deficient. Yet, published data on the amounts and chemical forms of iron used in formulating these products are not available, although they are known to affect bioavailability. This information is especially important in comparing commercially available products with those that were tested in clinical trials. Our examination of nonprescription and prescription iron-containing prenatal supplement products in NIH's Dietary Supplement Label Database (DSLD) and DailyMed found the labeled amount of elemental iron ranged between 9 and 60 mg/serving in 148 nonprescription supplements and between 4.5 and 106 mg/serving in 101 prescription supplements. Ferrous fumarate was the preferred chemical form used in these products. In contrast, ferrous sulfate was the preferred chemical form of iron reported in the clinical trials summarized in a 2015 Cochrane Systematic review assessing the effects of daily oral iron supplements for pregnant women. Ferrous sulfate was not found on any prenatal supplement product label in the DSLD or DailyMed. The chemical forms of products on the market and those tested in clinical trials are dissimilar, and we believe this may have clinical implications. The findings raise several questions. Do outcomes in clinical trials correlate with the benefits and risks that might adhere to iron supplements with different iron formulations? Should the differences in chemical forms, their bioavailability, and safety profiles, be considered in greater depth when evaluating the effect of the various formulations on maternal iron nutriture? Should new clinical trials for pregnant and lactating women in the US use a form of iron not found in prenatal supplements sold in the US or should a more common form be used?

Challenges in Developing Analytically Validated Laboratory-Derived Dietary Supplement Databases.

The Dietary Supplement Label Database (DSLD) is sponsored by the Office of Dietary Supplements (ODS) and the National Library of Medicine (NLM). It provides a searchable, free database of the contents of ∼65,000 supplement labels. A companion database of analytically verified product labels [the Dietary Supplement Ingredient Database (DSID)] was created by ODS, NLM, and the USDA. There are considerable challenges to populating both databases, but the DSID faces unique analytic chemistry challenges. This article describes the challenges to creating analytically verified marketplace surveys of dietary supplement (DS) product content claims for inclusion in public databases. Nutritionists and public health scientists require information on actual exposures to DS constituents because labeled content may not match labeled product content. Analytic verification of composition of DSs provides a link to actual exposure. A public database of analytically derived DS content was developed to provide more accurate estimates of dietary intake in population-based epidemiologic studies. The DSID has conducted surveys of several types of vitamin- and mineral-containing DSs. Results showing label content claims as analytically derived values are available in the current DSID. A recent pilot project explored the feasibility of adding botanical DS products to the DSID. Candidates for future botanical DSID studies will be based on sales volume, potential public health impacts, and the availability of validated analytic methods and reference materials. Databases like DSID and the DSLD are essential for researchers and clinicians to evaluate dietary ingredient intakes in population-based epidemiologic studies. Together, these databases provide a picture of the DS marketplace. The DSID provides an analytic survey of marketed DSs. However, selection of future botanical supplements for DSID evaluation involves analytic challenges. Even when appropriate resources are available, method selection and data evaluation are resource- and time-consuming.

Dietary Supplement Ingredient Database (DSID) and the Application of Analytically Based Estimates of Ingredient Amount to Intake Calculations.

OBJECTIVE: We describe the purpose of the Dietary Supplement Ingredient Database (DSID), the statistical methodology underlying online calculators of analytically verified supplement content estimates, and the application and significance of DSID label adjustments in nutritional epidemiology. BACKGROUND AND HISTORY: During dietary supplement (DS) manufacturing, many ingredients are added at higher than declared label amounts, but overages are not standardized among manufacturers. As a result, researchers may underestimate nutrient intakes from DSs. The DSID provides statistical tools on the basis of the results of chemical analysis to convert label claims into analytically predicted ingredient amounts. These adjustments to labels are linked to DS products reported in NHANES. RATIONALE: Tables summarizing the numbers of NHANES DS products with ingredient overages and below label content show the importance of DSID adjustments to labels for accurate intake calculations. RECENT DEVELOPMENTS: We show the differences between analytically based estimates and labeled content for vitamin D, calcium, iodine, caffeine, and omega-3 (n-3) fatty acids and their potential impact on the accuracy of intake assessments in large surveys. Analytical overages >20% of label levels are predicted for several nutrients in 50-99% of multivitamin-mineral products (MVMs) reported in NHANES: for iodine and selenium in adult MVMs, for iodine and vitamins D and E in children's MVMs, and for iodine, chromium, and potassium in nonprescription prenatal MVMs. Predicted overages of 10-20% for calcium can be applied to most MVMs and overages >10% for folic acid in the vast majority of adult and children's MVMs. FUTURE DIRECTIONS: DSID studies are currently evaluating ingredient levels in prescription prenatal MVMs and levels of constituents in botanical DSs. CONCLUSIONS: We estimate that the majority of MVM products reported in NHANES have significant overages for several ingredients. It is important to account for nonlabeled additional nutrient exposure from DSs to better evaluate nutritional status in the United States.

Characteristics and Challenges of Dietary Supplement Databases Derived from Label Information.

Launched in 2008, the Dietary Supplement Label Database (DSLD) permits the search of any term that appears anywhere on product labels. Since then, the database's search and download features have been periodically improved to enhance use for researchers and consumers. In this review, we describe how to customize searches and identify products and ingredients of interest to users in the DSLD, and provide the limitations of working with information derived from dietary supplement product labels. This article describes how data derived from information printed on product labels are entered and organized in the DSLD. Among the challenges are determining the chemical forms, types of extract, and amounts of dietary ingredients, especially when these are components of proprietary blends. The FDA announced new dietary supplement labeling regulations in May 2016. The 2017 DSLD has been updated to reflect them. These new regulations and examples cited in this article refer to this redesigned version of the DSLD. Search selection characteristics such as for product type and intended user group are as described in FDA guidance and regulations for dietary supplements. For this reason, some age groups (such as teens and seniors) and marketing recommendations for use (e.g., weight loss, performance, and other disease- or condition-specific claims) are not included in the search selections. The DSLD user interface features will be revised periodically to reflect regulatory and technologic developments to enhance user experience. A comprehensive database derived from analytically verified data on composition would be preferable to label data, but is not feasible for technical, logistic, and financial reasons. Therefore, a database derived from information printed on product labels is the only practical option at present for researchers, clinicians, and consumers interested in the composition of these products.

The Dietary Supplement Label Database: Recent Developments and Applications.

Objective: To describe the history, key features, recent enhancements, and common applications of the Dietary Supplement Label Database (DSLD). Background and History: Although many Americans use dietary supplements, databases of dietary supplements sold in the United States have not been widely available. The DSLD, an easily accessible public-use database was created in 2008 to provide information on dietary supplement composition for use by researchers and consumers. Rationale: Accessing current information easily and quickly is crucial for documenting exposures to dietary supplements because they contain nutrients and other bioactive ingredients that may have beneficial or adverse effects on human health. This manuscript details recent developments with the DSLD to achieve this goal and provides examples of how the DSLD has been used. Recent Developments: With periodic updates to track changes in product composition and capture new products entering the market, the DSLD currently contains more than 71,000 dietary supplement labels. Following usability testing with consumer and researcher user groups completed in 2016, improvements to the DSLD interface were made. As of 2017, both a desktop and mobile device version are now available. Since its inception in 2008, the use of the DSLD has included research, exposure monitoring, and other purposes by users in the public and private sectors. Future Directions: Further refinement of the user interface and search features to facilitate ease of use for stakeholders is planned. Conclusions: The DSLD can be used to track changes in product composition and capture new products entering the market. With over 71,000 DS labels it is a unique resource that policymakers, researchers, clinicians, and consumers may find valuable for multiple applications.

Is Nutrient Content and Other Label Information for Prescription Prenatal Supplements Different from Nonprescription Products?

BACKGROUND: Prenatal supplements are often recommended to pregnant women to help meet their nutrient needs. Many products are available, making it difficult to choose a suitable supplement because little is known about their labeling and contents to evaluate their appropriateness. OBJECTIVE: To determine differences between prescription and nonprescription prenatal supplements available in the United States regarding declared nutrient and nonnutrient ingredients and the presence of dosing and safety-related information. DESIGN: Using two publicly available databases with information about prenatal supplement products, information from prescription and nonprescription product labels were extracted and evaluated. For the 82 prescription and 132 nonprescription products, declared label amounts of seven vitamins and minerals, docosahexaenoic acid (DHA), the presence of other nonnutrient components, and the presence of key safety and informational elements as identified in two Department of Health and Human Services Office of Inspector General (OIG)'s 2003 reports were compiled and compared. RESULTS: Compared with nonprescription products, prescription products contained significantly fewer vitamins (9±0.2 vs 11±0.3; P≤0.05) and minerals (4±0.1 vs 8±0.3; P≤0.05). Declared amounts of folic acid were higher in prescription products, whereas vitamin A, vitamin D, iodine, and calcium were higher in the nonprescription products. Amounts of iron, zinc, and DHA were similar. Virtually all products contained levels of one or more nutrients that exceeded the Recommended Dietary Allowances for pregnant and/or lactating women. Product type also influenced ingredients added. Fewer prescription products contained botanical ingredients (6% prescription vs 33% nonprescription) and probiotics (2% prescription vs 8% nonprescription). Only prescription products contained the stool softener docusate sodium. CONCLUSIONS: Our analysis of prenatal supplements indicates that prescription and nonprescription supplements differ in terms of declared composition and nutrient strength, but have labels that are similarly sparse regarding aspects of use such as dosing information.

Analytical ingredient content and variability of adult multivitamin/mineral products: national estimates for the Dietary Supplement Ingredient Database.

BACKGROUND: Multivitamin/mineral products (MVMs) are the dietary supplements most commonly used by US adults. During manufacturing, some ingredients are added in amounts exceeding the label claims to compensate for expected losses during the shelf life. Establishing the health benefits and harms of MVMs requires accurate estimates of nutrient intake from MVMs based on measures of actual rather than labeled ingredient amounts. OBJECTIVES: Our goals were to determine relations between analytically measured and labeled ingredient content and to compare adult MVM composition with Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels. DESIGN: Adult MVMs were purchased while following a national sampling plan and chemically analyzed for vitamin and mineral content with certified reference materials in qualified laboratories. For each ingredient, predicted mean percentage differences between analytically obtained and labeled amounts were calculated with the use of regression equations. RESULTS: For 12 of 18 nutrients, most products had labeled amounts at or above RDAs. The mean measured content of all ingredients (except thiamin) exceeded labeled amounts (overages). Predicted mean percentage differences exceeded labeled amounts by 1.5-13% for copper, manganese, magnesium, niacin, phosphorus, potassium, folic acid, riboflavin, and vitamins B-12, C, and E, and by ∼25% for selenium and iodine, regardless of labeled amount. In contrast, thiamin, vitamin B-6, calcium, iron, and zinc had linear or quadratic relations between the labeled and percentage differences, with ranges from -6.5% to 8.6%, -3.5% to 21%, 7.1% to 29.3%, -0.5% to 16.4%, and -1.9% to 8.1%, respectively. Analytically adjusted ingredient amounts are linked to adult MVMs reported in the NHANES 2003-2008 via the Dietary Supplement Ingredient Database (http://dsid.usda.nih.gov) to facilitate more accurate intake quantification. CONCLUSIONS: Vitamin and mineral overages were measured in adult MVMs, most of which already meet RDAs. Therefore, nutrient overexposures from supplements combined with typical food intake may have unintended health consequences, although this would require further examination.

Culinary Spice Plants in Dietary Supplement Products and Tested in Clinical Trials.

Dried plant parts used as culinary spices (CSs) in food are permitted as dietary ingredients in dietary supplements (DSs) within certain constraints in the United States. We reviewed the amounts, forms, and nutritional support (structure/function) claims of DSs that contain CS plants listed in the Dietary Supplement Label Database (DSLD) and compared this label information with trial doses and health endpoints for CS plants that were the subject of clinical trials listed in clinicaltrials.gov. According to the DSLD, the CS plants occurring most frequently in DSs were cayenne, cinnamon, garlic, ginger, pepper, rosemary, and turmeric. Identifying the botanical species, categorizing the forms used, and determining the amounts from the information provided on DS labels was challenging. CS plants were typically added as a component of a blend, as the powered biomass, dried extracts, and isolated phytochemicals. The amounts added were declared on about 55% of the labels, rendering it difficult to determine the amount of the CS plant used in many DSs. Clinicaltrials.gov provided little information about the composition of test articles in the intervention studies. When plant names were listed on DS labels and in clinical trials, generally the common name and not the Latin binomial name was given. In order to arrive at exposure estimates and enable researchers to reproduce clinical trials, the Latin binomial name, form, and amount of the CS plant used in DSs and tested in clinical trials must be specified.

Estimating caffeine intake from energy drinks and dietary supplements in the United States.

No consistent definition exists for energy products in the United States. These products have been marketed and sold as beverages (conventional foods), energy shots (dietary supplements), and in pill or tablet form. Recently, the number of available products has surged, and formulations have changed to include caffeine. To help characterize the use of caffeine-containing energy products in the United States, three sources of data were analyzed: sales data, data from federal sources, and reports from the Drug Abuse Warning Network. These data indicate that sales of caffeine-containing energy products and emergency room visits involving their consumption appear to be increasing over time. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 indicate that 2.7% [standard error (SE) 0.2%] of the US population ≥1 year of age used a caffeine-containing energy product, providing approximately 150-200 mg/day of caffeine per day in addition to caffeine from traditional sources like coffee, tea, and colas. The highest usage of these products was among males between the ages of 19 and 30 years (7.6%, SE 1.0). Although the prevalence of caffeine-containing energy product use remains low overall in the US population, certain subgroups appear to be using these products in larger amounts. Several challenges remain in determining the level of caffeine exposure from and accurate usage patterns of caffeine-containing energy products.

A structured vocabulary for indexing dietary supplements in databases in the United States.

Food composition databases are critical to assess and plan dietary intakes. Dietary supplement databases are also needed because dietary supplements make significant contributions to total nutrient intakes. However, no uniform system exists for classifying dietary supplement products and indexing their ingredients in such databases. Differing approaches to classifying these products make it difficult to retrieve or link information effectively. A consistent approach to classifying information within food composition databases led to the development of LanguaL™, a structured vocabulary. LanguaL™ is being adapted as an interface tool for classifying and retrieving product information in dietary supplement databases. This paper outlines proposed changes to the LanguaL™ thesaurus for indexing dietary supplement products and ingredients in databases. The choice of 12 of the original 14 LanguaL™ facets pertinent to dietary supplements, modifications to their scopes, and applications are described. The 12 chosen facets are: Product Type; Source; Part of Source; Physical State, Shape or Form; Ingredients; Preservation Method, Packing Medium, Container or Wrapping; Contact Surface; Consumer Group/Dietary Use/Label Claim; Geographic Places and Regions; and Adjunct Characteristics of food.

Workshop on DHA as a required nutrient: overview.

Early recognition of the importance of docosahexaenoic acid (DHA) in brain, neural, and visual development, prompted professional bodies to establish dietary recommendations for pregnant women and term and preterm infants. More recent studies show that supplemental DHA can play an important role in reducing the risk for certain age-related diseases. Data from nationwide surveys suggest that the average intake of DHA by US adults is considerably lower than levels suggested by researchers to sustain baseline nutritional status and to achieve the beneficial and protective effects of DHA. The Workshop on DHA as a Required Nutrient provided a forum for scientists to present and debate the research in support of more universal dietary recommendations for DHA as an essential nutrient throughout life.