Exploring the benefits and challenges of establishing a DRI-like process for bioactives.

Bioactives can be defined as: "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status" (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Reg 69:55821-55822, 2004). Although traditional nutrients, such as vitamins, minerals, protein, essential fatty acids and essential amino acids, have dietary reference intake (DRI) values, there is no such evaluative process for bioactives. For certain classes of bioactives, substantial scientific evidence exists to validate a relationship between their intake and enhanced health conditions or reduced risk of disease. In addition, the study of bioactives and their relationship to disease risk is a growing area of research supported by government, academic institutions, and food and supplement manufacturers. Importantly, consumers are purchasing foods containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects. This conference, Bioactives: Qualitative Nutrient Reference Values for Life-stage Groups?, explored why it is important to have a DRI-like process for bioactives and challenges for establishing such a process.

Nutrient reference values for bioactives: new approaches needed? A conference report.

Nutrients can be classified as either "essential" or "non-essential," the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

A review of calcium supplements and cardiovascular disease risk.

A group of academic and industry experts in the fields of nutrition, cardiology, epidemiology, food science, bone health, and integrative medicine examined the data on the relationship between calcium supplement use and risk of cardiovascular events, with an emphasis on 4 of the Bradford Hill criteria for causal inference: strength, consistency, dose-response, and biological plausibility. Results from 2 epidemiological studies and a meta-analysis of randomized, controlled clinical trials, including a subgroup analysis from the Women's Health Initiative, have prompted concern about a potential association between calcium supplement use and a small increase in the risk of adverse cardiovascular events. However, a number of issues with the studies, such as inadequate compliance with the intervention, use of nontrial calcium supplements, potential bias in event ascertainment, and lack of information on and adjustment for known cardiovascular risk determinants, suggest that bias and confounding cannot be excluded as explanations for the reported associations. Findings from other cohort studies also suggest no detrimental effect of calcium from diet or supplements, with or without vitamin D, on cardiovascular disease risk. In addition, little evidence exists for plausible biological mechanisms to link calcium supplement use with adverse cardiovascular outcomes. The authors do not believe that the evidence presented to date regarding the hypothesized relationship between calcium supplement use and increased cardiovascular disease risk is sufficient to warrant a change in the Institute of Medicine recommendations, which advocate use of supplements to promote optimal bone health in individuals who do not obtain recommended intakes of calcium through dietary sources.

Under the law, FDA must grant different standards for new dietary ingredients and food additives.

The FDA's draft Guidance on notifications for new dietary ingredients attempts to narrow the scope of "old" dietary ingredients that do not require notification to FDA and repeats some mistakes from the past by going beyond what is required or permitted by the Food, Drug & Cosmetic Act, as amended by the Dietary Supplements Health and Education Act of 1994. The draft Guidance attempts to apply the notification requirement to new supplements, not just new ingredients, and it expands the working definition of "chemically altered" to include many changes that were not foreseen in the Congressional Record in 1994. Through these misinterpretations, FDA attempts to impose a food additives-like safety standard, and gain de facto premarket approval against the overt wishes of Congress.

Nutrition issues in Codex: health claims, nutrient reference values and WTO agreements: a conference report.

BACKGROUND: Codex documents may be used as educational and consensus materials for member governments. Also, the WTO SPS Agreement recognizes Codex as the presumptive international authority on food issues. Nutrient bioavailability is a critical factor in determining the ability of nutrients to provide beneficial effects. Bioavailability also influences the quantitative dietary requirements that are the basis of nutrient intake recommendations and NRVs. HEALTH CLAIMS: Codex, EFSA and some national regulatory authorities have established guidelines or regulations that will permit several types of health claims. The scientific basis for claims has been established by the US FDA and EFSA, but not yet by Codex. Evidence-based nutrition differs from evidence-based medicine, but the differences are only recently gaining recognition. Health claims on foods may provide useful information to consumers, but many will interpret the information to mean that they can rely upon the food or nutrient to eliminate a disease risk. NUTRIENT REFERENCE VALUES: NRVs are designed to provide a quantitative basis for comparing the nutritive values of foods, helping to illustrate how specific foods fit into the overall diet. The INL-98 and the mean of adult male and female values provide NRVs that are sufficient when used as targets for individual intakes by most adults. WORLD TRADE ORGANIZATION AGREEMENTS: WTO recognizes Codex as the primary international authority on food issues. Current regulatory schemes based on recommended dietary allowances are trade restrictive. A substantial number of decisions by the EFSA could lead to violation of WTO agreements.

Highest Observed Intake: definition, regulatory uses and provisional values.

For nutrients and related substances, the Tolerable Upper Intake Level (UL) has become the internationally accepted risk assessment method. The major limitation of the UL method as applied by authoritative groups thus far is that no UL has been set for nutrients without established adverse effects. In contrast to the limitations inherent in the UL method, an alternative approach is available; it identifies a risk assessment value termed the Highest Observed Intake (HOI). In the absence of a UL, the HOI is the highest intake with adequate data to show, with acceptable confidence, the absence of adverse effects up to that intake. With this concept defined and accepted in a report by the authoritative international organizations FAO and WHO, a complete risk assessment for the nutrients and related substances would have to identify UL values for those with known adverse effects and HOI values for those without known adverse effects. The need for the HOI concept and value is illustrated by the unjustified policy and regulatory actions taken in relation to vitamin B12. Regulatory utility is explained and tentative HOI values are identified for several vitamins and non-essential nutrients. Endorsement of the concept and development of HOI values by authoritative bodies is likely to be required for broad acceptance and use.

Expanded approach to tolerable upper intake guidelines for nutrients and bioactive substances.

The original tolerable upper intake level (UL) method greatly improved the application of risk assessment to the evaluation of nutrient safety for humans, but a UL is only set where the data establish a hazard resulting from high intakes. Absence of a UL for those nutrients with no established hazard has been misinterpreted by regulators and resulted in overly restrictive policies. To prevent such misinterpretation, the observed safe level (OSL) was developed and defined as "the highest intake with convincing evidence of safety, even if there are no established adverse effects at any level." More recently, a FAO/WHO report gave a similar definition for the highest observed intake (HOI). Another disadvantage of the UL method is the application of arbitrary uncertainty factors (UF). An alternative to the traditional adjustment for uncertainty involves arranging the data in decreasing order of daily intake, followed by evaluation of each trial for quantity and quality of data. Studies are selected downward until no adverse effects are observed in a trial of sufficient quality to justify no further correction for uncertainty (i.e. selection of data that qualify for UF = 1). Thus, the no observed adverse effect level or OSL selected requires no further adjustment for uncertainty. For supplemental intakes of some vitamins, many bioactive substances, and most amino acids, no adverse effects that are clearly related to high intakes have been established, but where the dataset is sufficiently robust, application of the OSL-HOI technique can provide risk assessment values.

Are low tolerable upper intake levels for vitamin A undermining effective food fortification efforts?

Vitamin A deficiency (VAD) is a major health problem, particularly in low-resource countries, putting an estimated 125-130 million preschool-aged children at increased risk of morbidity and mortality from infectious diseases. Vitamin A supplementation reduces VAD and increases child survival; it is complemented by fortifying foods with vitamin A. Concern over increased risk of bone fracture associated with vitamin A intakes below the tolerable upper intake level (UL) among populations in affluent countries conflicts with the need to increase intakes in less developed countries, where populations are at greater risk of VAD and intakes are unlikely to reach the UL as diets include fewer foods containing retinol while vitamin A from carotenoids poses no risk of overdose. With the implementation of recently developed risk management tools, vitamin A can be used safely in food fortification, including point-of-use fortification in the context of supplementation among specific target groups in low-resource countries.

Risk assessment for the amino acids taurine, L-glutamine and L-arginine.

Taurine, glutamine and arginine are examples of amino acids which have become increasingly popular as ingredients in dietary supplements and functional foods and beverages. Animal and human clinical research suggests that oral supplementation of these amino acids provides additional health and/or performance benefits beyond those observed from normal intake of dietary protein. The increased consumer awareness and use of these amino acids as ingredients in dietary supplements and functional foods warrant a comprehensive review of their safety through quantitative risk assessment, and identification of a potential safe upper level of intake. The absence of a systematic pattern of adverse effects in humans in response to orally administered taurine (Tau), l-glutamine (Gln) and l-arginine (Arg) precluded the selection of a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL). Therefore, by definition, the usual approach to risk assessment for identification of a tolerable upper level of intake (UL) could not be used. Instead, the newer method described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) was utilized. The OSL risk assessments indicate that based on the available published human clinical trial data, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to 14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Although much higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selected as the OSLs.

Risk assessment for vitamin D.

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 microg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.

Risk assessment for glucosamine and chondroitin sulfate.

Glucosamine and chondroitin sulfate are two popular dietary ingredients present in dietary supplements intended to support joint health. A large body of human and animal research suggests that oral intakes of these ingredients, either alone or in combination, reduces joint pain and improves mobility in persons with osteoarthritis. The increased awareness and use of these ingredients in dietary supplements warrant a comprehensive review of their safety. Systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level (OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence strongly supports safety at intakes up to 2000 mg/d for glucosamine, and 1200 mg/d for chondroitin sulfate, and these levels are identified as the respective OSL. These values represent the highest levels tested in human clinical trials. The complete absence of adverse effects at these levels supports a confident conclusion of their long-term safety.

Risk assessment for carnitine.

Carnitine is a conditionally essential amino acid-like compound involved in the transport of long-chain fatty acids into the mitochondria during the beta-oxidation process. Carnitine has become an increasingly popular ingredient in dietary supplements, especially weight loss and some sports nutrition products. A number of clinical trials have been conducted examining the effect of carnitine supplementation on weight loss and energy balance. Regarding safety, systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level (OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 2000mg/day l-carnitine equivalents for chronic supplementation, and this level is identified as the OSL. Although much higher levels have been tested without adverse effects and may be safe, the data for intakes above 2000mg/day are not sufficient for a confident conclusion of long-term safety.

Risk assessment for creatine monohydrate.

Creatine monohydrate (creatine) has become an increasingly popular ingredient in dietary supplements, especially sports nutrition products. A large body of human and animal research suggests that creatine does have a consistent ergogenic effect, particularly with exercises or activities requiring high intensity short bursts of energy. Human data are primarily derived from three types of studies: acute studies, involving high doses (20 g/d) with short duration (< or = 1 week), chronic studies involving lower doses (3-5 g/d) and longer duration (1 year), or a combination of both. Systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe Upper Level of Intake (UL) derived from it unless the newer methods described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 5 g/d for chronic supplementation, and this level is identified as the OSL. Although much higher levels have been tested under acute conditions without adverse effects and may be safe, the data for intakes above 5 g/d are not sufficient for a confident conclusion of long-term safety.

Risk assessment for coenzyme Q10 (Ubiquinone).

Coenzyme Q10 (CoQ10) widely occurs in organisms and tissues, and is produced and used as both a drug and dietary supplement. Increasing evidence of health benefits of orally administered CoQ10 are leading to daily consumption in larger amounts, and this increase justifies research and risk assessment to evaluate the safety. A large number of clinical trials have been conducted using a range of CoQ10 doses. Reports of nausea and other adverse gastrointestinal effects of CoQ10 cannot be causally related to the active ingredient because there is no dose-response relationship: the adverse effects are no more common at daily intakes of 1200 mg than at a 60 mg. Systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level (OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 1200 mg/day, and this level is identified as the OSL. Much higher levels have been tested without adverse effects and may be safe, but the data for intakes above 1200 mg/day are not sufficient for a confident conclusion of safety.

Risk assessment for the carotenoids lutein and lycopene.

Lutein and lycopene, two prevalent carotenoids in the human diet have become increasingly popular ingredients in dietary supplements. A large body of human and animal research suggests that oral forms of these carotenoids may provide benefits in the areas of eye, prostate, skin and cardiovascular health. The increased awareness and use of these ingredients in dietary supplements warrants a comprehensive review of their safety. Systematic evaluation of the research designs and data provide a basis for risk assessment and the usual tolerable Upper Level of Intake (UL) derived from it if the newer methods described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 20mg/d for lutein, and 75 mg/d for lycopene, and these levels are identified as the respective OSL. Although much higher levels have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety.

Vitamins E and C are safe across a broad range of intakes.

A robust database shows that dietary supplements of vitamins E and C are safe for the general population. Because these nutrients supply antioxidant and other functions for homeostasis and protection against free radical damage, supplementation has been intensively studied. Because of perceived benefits, many persons consume quantities of vitamins E and C well above the recommended dietary allowances. As safety guidance, tolerable upper intake levels have been established by the Food and Nutrition Board, Institute of Medicine, at 1000 mg for vitamin E and 2000 mg for vitamin C in adults. Many clinical trials with these vitamins have involved subjects with various diseases, and no consistent pattern of adverse effects has occurred at any intake. Numerous studies of vitamin C supplementation have provided no pattern of evidence to support concerns about safety other than occasional gastrointestinal upset or mild diarrhea resulting from the osmotic effects of unabsorbed quantities of vitamin C. Evidence of bleeding effects and other potential adverse effects of high vitamin E intakes in humans is not convincing. Evidence of adverse effects of vitamin C that result from its effects on iron absorption and metabolism has not been confirmed in clinical trials. Thus, we conclude from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts