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Dietary Supplements: Making Sure Hype Doesn't Overwhelm Science by Dixie Farley When it comes to dietary supplements, consumers have the right to expect safety and to have information about products they choose so they know what they're getting, according to the Food and Drug Administration. Without the proper safety data, however, says Michael Taylor, FDA deputy commissioner for policy, the agency has no way to ensure that many consumers taking supplements won't be at risk. FDA is responsible under the Federal Food, Drug, and Cosmetic (FD&C) Act for ensuring that manufacturers of foods, including dietary supplements, provide safe ingredients for their products as well as accurate, complete labeling that is truthful and not misleading. Defining a Dietary Supplement The Nutrition Labeling and Education Act of 1990 (NLEA), which amended the FD&C Act, refers to dietary supplements of vitamins, minerals, herbs, or other similar nutritional substances. As commonly consumed, dietary supplements in the marketplace in the form of capsules, tablets, liquids, or powders' include vitamins; essential minerals; protein; amino acids; botanicals such as ginseng and yohimbe; extracts from animal glands; garlic extract; fish oils; fibers such as acacia and guar gum; compounds not generally recognized as foods or nutrients, such as bioflavonoids, enzymes, germanium, nucleic acids, para-aminobenzoic acid, and rutin; and mixtures of these ingredients. The Council for Responsible Nutrition, a trade organization for supplement manufacturers, reports that in 1991 some 40 percent of American adults took vitamin supplements, and retail sales for over-the- counter nutritional products totaled several billion dollars. Most vitamin and mineral supplements usually pose no safety concerns for the general population. Scientists generally know more about these nutrients than about ingredients used in other types of dietary supplements. And, most vitamin and mineral products are accurately labeled for content and are offered at moderate potencies. "Our main concerns," Taylor says, "are with the array of other products that have unsubstantiated safety" such as amino acids and herbs and other botanicals. We know very little about some of these products ingredients. Diet and Disease Recent attention to a possible effect of diet in reducing the risk of certain diseases has raised new safety issues about how FDA should regulate dietary supplements. Growing scientific support for such benefits and increased consumer interest in improving health through diet provided much of the impetus for provisions of the NLEA to allow health claims for foods. (See "Starting This Month: Look for Legit' Health Claims on Foods" in the May 1993 FDA Consumer.) But, because manufacturers believed FDA would limit claims on their supplements under the NLEA, they conducted a rigorous consumer campaign to get Congress to limit FDA's authority. "They wanted us to adopt a more relaxed standard for claims on supplements than Congress had adopted for conventional foods," Taylor says. When the Dietary Supplement Act of 1992 became law on Oct. 29, 1992, a year's moratorium was imposed on implementation of the NLEA with respect to supplements. But it called for FDA to propose NLEA- based labeling rules for supplements by June 15, 1993, which the agency did (see "FDA's Proposals"), and to issue final rules in December. In October, FDA published a proposed rule on allowing a health claim on foods, including supplements that are good sources of folic acid. The claim would discuss the link between folic acid intake by women of childbearing age and a reduced risk of neural tube birth defects in newborns. The agency also proposed amending its food additive rule for folic acid and its standard of identity to require the addition of folic acid to enriched' grain products. FDA is working with manufacturers and scientists on other potential health claims' such as a claim associating antioxidant vitamins like vitamin C with a reduced risk of cancer and other diseases. Potentially Unsafe Supplements While FDA is open to exploring new evidence on the relationships between diet and disease, Taylor says, the agency is concerned that increased attention to these relationships will increase the potential for wider use of possibly unsafe supplements (such as amino acids for bodybuilding) and for development of more untested products. Safety and misleading labeling are prime concerns. FDA is not proposing to regulate dietary supplements as drugs. But if a supplement makes drug claims or contains a substance already regulated as a drug, then consumers deserve to have information about the product's safety and effectiveness, as they do for drugs. "FDA certainly does not regulate personal choice or the practice of medicine," Taylor says. "But we know that many supplements are sold in drug-like formulations and potencies, yet they haven't been subjected to the safety controls of FDA's drug approval process." Lori A. Love, M.D., Ph.D., director of the clinical research and review staff in FDA's Center for Food Safety and Applied Nutrition, cites as an example white willow bark, which contains a substance the body metabolizes into acetylsalicylic acid, aspirin's active ingredient. Firms market this botanical as an ingredient in products for children's use. However, unlike labeling for aspirin, labels for these products do not carry the FDA warning that children and teenagers should not use these products if they have symptoms of chickenpox or influenza, because such use has been associated with Reye syndrome, a rare, but serious illness. In fact, Love says, a number of these products are labeled "aspirin free." Levels of natural constituents in herbs sometimes vary greatly. The concentration of a constituent, for instance, varies with the part of the plant it comes from, growth stage at harvest, and processing and dilution during manufacture. Some ingredients in herbal products naturally contain chemicals that are harmful, such as certain alkaloids. In other words, "natural" doesn't necessarily mean "safe." Substances in supplements that have raised safety issues include: - Chaparral: After learning of five cases of chaparral-related acute toxic hepatitis, FDA warned against consuming this herb, and manufacturers voluntarily removed most products containing chaparral from the market. Promoters claim chaparral slows aging, "cleanses" the blood, and treats skin problems' all unproven claims. - Comfrey: Since 1985, at least seven cases of liver disease, with one death, have been associated with oral use of products made from this leafy plant. Comfrey contains pyrrolizidine alkaloids. People who ingest even small amounts of these alkaloids for a prolonged time may be at risk for developing cirrhosis of the liver. Comfrey is sold as teas, tablets, capsules, tinctures, medicinal poultices, and lotions. - Germanium: Use of this nonessential element for a long time may cause serious, irreversible kidney damage and has resulted in death. Germanium products are promoted as so-called "health promoting" elixirs or as an "electronutrient" for uses such as neutralizing heavy metal toxicity. There is no evidence of effectiveness. - Guar gum: Now banned from use as an active ingredient in drugs, this complex carbohydrate that swells when wet has been used in weight- loss products to produce a feeling of fullness. One brand resulted in hospitalization of at least 10 patients and one death from a blood clot after surgery to remove a throat blockage. Guar gum can cause diarrhea, vomiting, bloating, and intestinal blockages. - Jin Bu Huan: Unapproved labeling claims this Chinese herbal product is useful for relieving pain. After accidentally taking Jin Bu Huan, three preschool children were hospitalized this year in Colorado with life-threatening, very slow heart rates, depressed central nervous systems, and breathing difficulties. After intensive medical care, the children recovered. - Ma huang: Products with Ma huang, derived from an evergreen plant, are under investigation following reports to FDA of serious adverse effects such as high blood pressure, rapid heart rate, nerve damage, muscle injury, psychosis, stroke, and memory loss. Ma huang is sold in products for weight control or boosting energy. These products often contain other stimulants, which, taken together, may increase the potential for adverse effects. - Yohimbe: Yohimbe is a tree bark marketed in products for bodybuilding and "enhanced male performance." Serious adverse effects including kidney failure, seizures, and death have been reported to FDA with products containing yohimbe and are currently under investigation. Nutrients Like other natural substances, even nutrients may be harmful at certain levels. With vitamins and minerals, there may be adverse effects from excessive potency of certain ingredients, or from contaminants or impurities in these products. For example, says John Vanderveen, Ph.D., director of the Office of Plant and Dairy Foods and Beverages in the Center for Food Safety and Applied Nutrition, FDA discovered that some calcium supplements contained lead. "They had to be reformulated," he says. "And some calcium supplements had excessive levels of vitamin D, which would have been toxic if taken continuously at this high intake." Although the margin of safety between the needed level and the toxic level is quite wide for some nutrients, Vanderveen says, it is very narrow for others, such as the mineral selenium. The agency believes that problems with nutrients can be best handled by subjecting them to the same labeling requirements as other foods. Known Risks Some known risks of nutrients consumed at excessive potencies are: - Folic acid: Intakes higher than 1 milligram a day may mask symptoms of vitamin B12 deficiency while pernicious anemia caused by the deficiency progresses undetected. - Iron: As few as six high-potency iron tablets could seriously injure a child weighing 22 pounds or less. Iron is the most common cause of U.S. child poisoning deaths, causing about 2,000 poisonings a year, mainly in young children taking their mothers' prenatal supplements. - Niacin: High intakes can damage the liver and cause severe gastrointestinal problems. - Selenium: High intakes can damage tissue, especially in tissues or organs where selenium concentrates. Toxicity depends on the chemical form and the selenium content of the foods eaten and has occurred with high intakes after a few weeks. - Vitamin A: Continuous high intakes can cause headaches, liver damage (including cirrhosis), bone damage, diarrhea, and, during pregnancy, birth defects. - Vitamin B6: High intakes can cause bone pain, muscle weakness, numbness, or other symptoms of nerve disorder. - Vitamin C: Very high intakes can cause diarrhea and may cause urinary tract problems. - Vitamin D: Continuous high intakes can cause kidney damage and bone deformity. Underreported Reactions Just because there haven't been a lot of reports of adverse effects associated with use of dietary supplements doesn't necessarily mean they're safe. A person taking a supplement may not associate an adverse effect with it, especially if the individual also is taking one or more medications or is chronically ill. For example, muscle weakness or numbness caused by too much vitamin B6 might be ignored as a sign of conditions associated with aging. Or adverse effects may take time to develop, so that it's difficult to link them with a specific supplement. Sometimes, reactions may not be recognized unless large numbers of people are using the supplement. In 1989, for instance, the use of the essential amino acid L-tryptophan was associated with an outbreak of an illness called eosinophilia-myalgia syndrome (EMS), a serious connective tissue disorder. More than 1,500 EMS cases, including 38 deaths, have been associated with L-tryptophan ingestion. All marketed products to which manufacturers had added L- tryptophan were recalled, except for specific medical foods or infant formula products, which require L-tryptophan to provide adequate nutrition. FDA issued an import alert to prevent importation of the raw material, except for those certain permitted uses. Initial studies suggested that the cause of the outbreak was an impurity or other component in the product from a particular Japanese manufacturer. Today, however, the exact cause of EMS remains uncertain, despite intense research in this area. "Cases of EMS, as well as a related illness, eosinophilic fasciitis, were associated with the use of L-tryptophan even before the 1989 EMS epidemic," Love says. "And cases of EMS and related illnesses have occurred with the use of a compound [L-5-hydroxytryptophan] that's similar to L-tryptophan, but not manufactured with the same fermentation process and, therefore, not associated with the same impurities." Thus, Love says, FDA believes the overall findings point to multiple factors, including L-tryptophan itself, as playing a role in the cause of EMS. Approaches to Safety FDA last June published a notice (along with the NLEA-based proposals) to solicit public comment and scientific data on the best approaches to ensuring the safety of dietary supplements, particularly amino acids and botanical products. The notice summarized the report of FDA's Dietary Supplements Task Force on alternatives for regulating supplement products. The task force made 20 recommendations, including stricter amino acid regulation, required good manufacturing practices for supplements, and stronger adverse reaction reporting requirements for supplements. However, FDA Deputy Associate Commissioner for Regulatory Affairs Gary Dykstra, who headed the task force, points out, "Contrary to claims by FDA critics, we have no plans to close health food stores, and we aren't going to take safe, properly labeled supplements off the market or make all supplements available only by prescription. The agency favors personal choice as much as possible within the constraints of the FD&C Act." Also included in the notice were findings by the Federation of American Societies for Experimental Biology, with which FDA had contracted to provide information on whether the use of amino acids in dietary supplements presents any particular safety concerns. The group found data to be inadequate to determine safe upper levels of use and advised that consumers not take amino acids except under responsible medical supervision. FDA is evaluating these reports and other submitted data. Precautions For consumers who choose to take dietary supplements, FDA's Love suggests these precautions: - Be wary of unfounded medical claims for dietary supplements, and be sure to tell health-care providers about all supplements you take, including concentrations and amounts. - Children, adolescents, older or chronically ill people, and women who are pregnant or are breast-feeding should not use high-potency supplements or those used for medicinal purposes unless they have responsible medical supervision. - Keep supplements out of the reach of children. n Dixie Farley is a staff writer for FDA Consumer. FDA's Proposals As required by the Dietary Supplement Act of 1992, FDA last June proposed dietary supplement labeling rules based on the Nutrition Labeling and Education Act of 1990. In announcing the proposals, FDA Commissioner David A. Kessler, M.D., said, "FDA's goal is simple: We want people to have access to products that are safe, and we want to assure consumers that claims made about the health and nutritional benefits are truthful." Among these proposals are the following: - Special rules for nutrition labeling would apply to dietary supplements of vitamins or minerals. (Nutrition labeling for products consisting of herbs or other nutritional substances would be like that for conventional foods.) - Vitamin and mineral nutrition labeling would be in a "Nutrition Facts" panel (see p. xx) that is as similar as possible to the conventional foods panel. (See "Nutrition Facts" to Help Consumers Eat Smart" in the May 1993 FDA Consumer.) - If a supplement bears a nutrient content claim, an adjacent referral statement would direct consumers to the nutrition panel. - If a claim uses either the term "free" or "low," the wording would have to make it clear the claim is true for all products of that type for example, instead of brand X, a fat-free vitamin C supplement, the claim would read brand X vitamin C, a fat-free supplement. - Supplements, including those for infants and children under 2, could be labeled with the term "sugar free" and its synonyms, such as "sugarless," "no sugar," and "trivial source of sugar." - The term "more" could be used in a claim if a product has 10 percent more of the Daily Value of a nutrient than the food to which it's being compared. - For health claims, supplements would be subject to the same scientific standard and procedures that are required for conventional foods. (See "Starting This Month: Look for Legit' Health Claims on Foods," in the May 1993 FDA Consumer.) - Supplements would be exempt from the conventional foods requirement that, to bear health claims, products must contain 10 percent or more of the Daily Value of the nutrients vitamin A, vitamin C, iron, calcium, protein, or fiber. n -D.F. How Supplements Are Regulated Under the Federal Food, Drug, and Cosmetic (FD&C) Act, FDA regulates dietary supplements as foods, as long as no drug claims are made for them. The FD&C Act includes provisions to ensure that foods are safe and their labels are truthful and not misleading. The Proxmire Amendment of 1976, introduced by then Sen. William Proxmire, D-Wis., restricts FDA's authority to limit supplement potency and the composition of most multi-nutrient products, except for safety reasons. It prohibits the agency from deeming a vitamin or mineral a drug solely because of potency. When products are marketed for therapeutic use, FDA regulates them through its Center for Drug Evaluation and Research. The FD&C Act defines "drugs" as products intended to diagnose, cure, mitigate, treat, or prevent disease, or non-food products intended to affect the structure or a function of the body. Between November 1990 and June 1993, FDA took actions against 188 products perceived as dietary supplements on grounds that they made unsubstantiated claims about serious medical conditions. -D.F.