Safety and Functional Food Development

Today, when consumers reach for their favorite products, chances are they're getting something extra. For years, food manufacturers have fortified certain foods with vitamins and minerals to ensure their customers' well-being. Now, whether it's added calcium or vitamin B12, or more exotic supplements like ginseng, the days of unmodified foods are long gone. As the link between food and good health becomes cemented, interest in nutrients grows. Manufacturers are responding, making it easier for consumers to ingest those nutrients in food form, rather than swallowing a capsule. But this also means that food manufacturers have a responsibility to protect consumers from adverse reactions, ensure that foods and beverages don't contain toxic amounts of ingredients, and teach the consumer about potential interactions and harmful side effects.

FDA's jurisdiction over the functional-food industry can be confusing. Since the introduction of the Dietary Supplement Health and Education Act (DSHEA) in 1994, many products can escape close scrutiny by claiming they're a supplement rather than a food. Under DSHEA, a supplement - and its ingredients - doesn't have to be proven safe, as opposed to food ingredients, which require GRAS (generally recognized as safe) status or approval as a food additive. In foods, FDA does have the power to deny approval for food use if it believes a compound is unsafe. Once a dietary supplement enters the marketplace, however, officials can only step in after a product has been proven dangerous to the public.

When do functional foods cross the line between supplement and food? Unfortunately, no official definition of "functional foods" exists, which sometimes leads to misinterpretation, or actual abuse. DSHEA does, however, define a supplement as: "a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combination of these ingredients." But for consumers, as well as for some marketers, the line seems to blur when a chocolate-coated soy-protein- and vitamin-enriched meal-replacement bar sits on a grocery shelf next to a chocolate-coated ginseng- and creatine-enriched energy bar. The latter may not be "unsafe;" but, due to its ingredients, it's most definitely not a "food."

However, even conventional foods may pose a problem, depending on what else a person has ingested. Grapefruit juice has been linked to numerous reports of drug interaction, from antifungal to antidepression medicines. Now, the United Kingdom's Committee on Safety of Medicines has warned heart-disease patients medicated with warfarin to avoid cranberry juice, after reports that it increases the drug's potency. The agency reported one death from gastrointestinal hemorrhage due to a drastic change in blood-clotting levels after the patient drank cranberry juice. This was attributed to the fruit's flavonoids, which inhibit the enzymes that break down warfarin.

Among functional ingredients, herbs might pose the biggest problem. "Herbs are a hybrid between food and drugs," says Phil Harvey, Ph.D., chief science officer and director of science and quality assurance for National Nutritional Food Association, Newport Beach, CA.

Because anyone going to the convenience store can pick up herb-containing products, they don't consider that herbs contain active ingredients, capable of significantly influencing hormones and the physiological reactions of their bodies. Problems could arise from excessive and improper use, plus potential herb-drug interactions, toxicities and side effects.

Currently, no regulations require manufacturers to list the amount of herbal ingredients in their products; consequently, it's difficult to determine the amounts by merely reading a label. Plus, the quantity of active ingredient in an herb may vary if the supplier does not have a program in place that ensures a certain level.

However, considering cost and taste issues, "most of the herbs are in such minor quantities, toxicity isn't an issue," explains Mark Blumenthal, founder and executive director of the Austin, TX-based American Botanical Council. Moreover, insurance companies charge higher premiums to the manufacturers of the less-safe or more-notorious herbs, like ephedra and kava kava. This forces manufacturers to remove unsafe or controversial ingredients, not necessarily because of government intervention, but because it becomes too expensive to promote them.

When considering using herbs or other functional ingredients, formulators must ask: Is this product safe for general consumption?

Think about safety, and ephedra may come to mind. Used to promote weight loss, ephedra increases the metabolic rate and speeds the heart rate, posing a problem for those people with pre-existing conditions, like hypertension, and is linked to several deaths in the United States. The herb Ephedra sinica, also known as ma huang, contains ephedra as an active ingredient, and is the most notorious - and perhaps one of the most dangerous - on the market. U.S. public-health officials have issued strong warnings against the use of ephedra-containing products, especially during strenuous exercise and in combination with other stimulants, including caffeine.

Ephedra is the exception to the rule, as most herbs aren't that potent. Many have been used in beverage form, such as teas, decoctions and infusions, for centuries, says Blumenthal. "The safety of these [herbs] is established by the marketplace and by a long history of use," he notes. Particular applications of even seemingly innocent herbs, however, can present risks.

Many use kava kava, Piper methysticum, to promote relaxation and reduce anxiety because it contains a mixture of components called kava pyrones (kavalactones). However, it suppresses the nervous system, which may result in excessive sleepiness, and is potentially linked to very rare instances of liver damage. On March 25, 2002, in response to five case reports (four in Europe and one in the United States), FDA issued a consumer advisory that kava-kava products may be associated with severe liver injury. Germany, Switzerland, Canada, Australia and France have restricted the sale of products containing kava kava.

Ginkgo biloba, used to improve mental function, has also been linked to potential drug interaction. Because it can act as a blood thinner, when paired with anticoagulants, like warfarin and even aspirin, ginkgo may lead to hemorrhaging or excessive bleeding. Medicinal doses of garlic, ginger and many other nutraceuticals may also promote this reaction.

Echinacea angustifolia is a popular herb that promises to enhance immune function and prevent colds. But recent studies conducted in Australia and published in Annals of Allergy, Asthma, & Immunology (2002, Vol. 88: 7-9, 42-51) have linked it to allergic reactions, especially for people already allergic to substances like grass pollen, ragweed and mold. It may also increase the incidences of asthma attacks in those already suffering from this condition. Because it stimulates the immune system, it may interact with drugs taken for this purpose.

St. John's wort, Hypericum perforatum, promises to be an alternative to conventional medicines for treating minor bouts of depression due to its hypericin content. However, this herb can potentially interact with more-conventional, prescriptive antidepressants or certain heart medications.

Those with depressive disorders, as well as those with hypertension, should also avoid excessive amounts of ginseng, commonly used to stave off fatigue. When combined with other stimulants, the root can take place in drug interactions.

Other herbs that experts consider risky include chaparral, comfrey, senna (Cassia angustifolia), pennyroyal and sassafras. Even licorice, used as a natural heartburn remedy, can raise blood pressure when consumed in large quantities, due to its glycyrrhetinic-acid content.

Mineral malefactorsAlthough they have been used for a long time for the fortification of foods and it's not very likely, vitamins and minerals aren't exempt from potential trouble. "The vitamins and minerals have been in the marketplaces for years and years. There are recommended daily allowances, so you know what your dosages should be," says Phil Katz, president of Shuster Laboratories, an STR Company Inc., Canton, MA.

The problem stems from potential toxicities when consumers go overboard - for instance, eating large quantities of fortified cereals and drinks, and then taking multivitamins and high-potency supplements. This makes it easier than ever for consumers to reach the upper limits of the recommended intake of nutrients. Some of the potential toxicities include:

Calcium. Although essential for bone health and suggested as a possible tool in colon-cancer prevention, the National Academy of Science, Washington, D.C., has set the upper limit at the amount of 2,500 mg per day to prevent calcium toxicity. Although this toxicity is rare, when consumed long-term at amounts greater than 3,000 mg per day, calcium can cause kidney damage, increase the risk of kidney stones, reduce the absorption of iron, as well as interfere with certain antibiotic regimens. Yet, it's one of the most common functional ingredients. This increasess the chance of side effects when combining different calcium sources, such as fortified orange juice, dairy products, sports bars, and a multivitamin.

Iron. This also can be dangerous at high amounts. The upper limit for iron is set at 45 mg per day; at higher doses, gastrointestinal upsets may occur. FDA warns that accidental overdose of iron-containing supplements is a leading cause of fatal poisoning in children under age 6. A fatal dose for children is typically more than 250 mg/kg, although doses as low as 60 mg/kg have caused death, according to the Centers for Disease Control and Prevention, Atlanta. Studies show that men and women with high levels of iron have an increased risk of developing heart disease.

Vitamin A. Also called retinol, excess levels of this vitamin can be toxic and are linked to the increased risk of fractures. A 2003 study ("Serum Retinol Levels and the Risk of Fracture," New England Journal of Medicine, 2003, Vol. 348 (4): 287-294) found that the risk of bone fractures was highest among men with the highest levels of serum retinol. Another study published in 2002 ("Vitamin A Intake and Hip Fractures among Postmenopausal Women," The Journal of the American Medical Association (JAMA), Vol. 287 (1): 47-54), found that postmenopausal women who didn't undergo hormone-replacement therapy, and who consumed retinol at levels above 3,000 mg per day, were 48% more likely to suffer from bone fractures than those who ingested less than 1,250 mg per day.

Vitamin D. This also can pose a risk at high amounts. The upper limit of vitamin D intake is set at 50 mcg per day, although a person would have to consume amounts exceeding this for several months to exhibit toxic effects. Some overdose symptoms include anorexia, nausea and muscle weakness. Because it influences the absorption of calcium, too much vitamin D may also result in hypercalcemia, which exhibits the same symptoms as calcium toxicity. Vitamin D overdoses rarely occur from consuming food alone, but rather through the use of supplements like cod-liver oil.

The safety of other ingredients at high levels, like isoflavones and fiber, has been called into question.

Isoflavones. A large amount of research suggests that soy may lower the risk of prostate, colon, endometrial and breast cancers, help prevent osteoporosis, and reduce high blood pressure. However, some researchers believe that the same isoflavones (particularly genistein) that could exert a positive effect on cancer risk, might also promote growth of existing breast tumors - both effects due to the isoflavones' role as a weak (plant-based) estrogen.

A 2002 study on mice ("The Phytoestrogen Genistein Induces Thymic and Immune Changes: A Human Health Concern?" Proceedings of the National Academy of Sciences, 2002, Vol. 99 (11): 7,616-7,621) raised the possibility that genistein may be capable of producing thymic and immune abnormalities in soy-fed infants, although the authors stated that more studies were needed before a conclusion could be made. However, in another study ("Exposure to Soy-based Formula in Infancy and Endocrinological and Reproductive Outcomes in Young Adulthood," JAMA, 2001, Vol. 286 (7): 807-814), researchers did not find any major differences in general health or reproductive outcomes between those fed soy formulas and those fed dairy formulas as infants.      

Fiber. The majority of Americans don't consume even the recommended 20 to 35 grams of fiber per day. However, when fortifying foods with fiber, it's easier to reach and exceed the daily recommended amount. In excess, fiber may cause flatulence and inhibit the absorption of key nutrients like iron and calcium.

Some consumers may have a false sense of security, especially with botanical ingredients, believing that most, if not all, functional ingredients are safe at any level. What steps can food scientists take to protect consumers from potential interactions and toxic effects?

Ensure a product is safe, says Katz, by making safety part of the marketing plan. Manufacturers can ensure product safety before products enter the market - during formulation, processing and once products enter the store - by setting up a tracking system to identify potential problems before they become widespread.

Companies should also conduct studies on both humans and animals. Manufacturers should develop processes that make certain that finished products contain quality ingredients, in consistent amounts. In addition, implement a process to eliminate potential toxic ingredients from the final product. "You have to develop your own methodology and validate in the delivery system that you have," explains Katz.

Another way manufacturers can protect consumers is to use Good Manufacturing Practices (GMP) to make certain that functional foods are safe, reliable and free of contamination, and contain the appropriate amount of active components. To achieve GMP status, companies must undergo third-party inspections that track development of manufacturing, processing, packaging and transportation.

Currently, no universal guidelines exist, making it mostly the manufacturer's responsibility to ensure product safety and reliability. Organizations like the National Nutritional Foods Association, Newport Beach, CA, do offer third-party certification. In addition, FDA is currently developing cGMPs for the manufacturers of dietary supplements and dietary-supplement ingredients, which promise to incorporate universal guidelines to ensure product quality and safety, while eliminating inaccurate labeling and claims.

The industry needs a reliable and accurate adverse-event tracking system. Some current systems commonly in place have pitfalls, such as inaccurate and inconsistent reporting, making it difficult to obtain meaningful data. And, depending on who recorded it, it could be worthless, notes Harvey. Adverse reactions also tend to be underreported. This could be corrected by training health-care personnel to provide detailed, consistent reporting. The American Botanical Council is developing a system to track ill effects of herbal products, as well as other functional ingredients. Currently, the FDA's Center for Food Safety & Applied Nutrition posts warnings and safety information regarding dietary supplements at http://www.cfsan.fda.gov/~dms/ds-warn.html.

Perhaps the most effective system is education, with the best information sources potentially being manufacturers' Websites and consumer hotlines. Manufacturers could encourage consumers to seek the advice of health professionals before taking a food for therapeutic effects. In addition, they should be vigilant in avoiding misleading health claims and inaccurate clinical trials.

Labeling offers another potential educational tool. For instance, the American Botanical Society has teamed up with Pharmavite Corp., Mission Hills, CA, maker of Nature's Resource(r) herbs, to include voluntary labels on the company's supplements. These mini-brochures detail scientific data about recommended use and potential drug interactions, while providing safety precautions. Blumenthal says this could be the future of herbal labeling on food and drink products.

No one food can be safe for everyone. While consumers should take some responsibility by educating themselves, food manufacturers are ultimately responsible for the health of their customers, and subsequently, a healthy bottom line.

Vanessa Selene Williams is a food and nutrition writer based in Cataula, GA. She holds a bachelor's degree in nutrition and food science from Auburn University in Auburn, AL.

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