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.