38WWW.CEN-ONLINE.ORG JULY 19, 2010

MANY PEOPLE try to manage their health by taking plant-derived dietary supple-ments. But despite their ubiquity, these pills and potions are not well understood by the scientific community.

Toxicity is an especially murky area. Manufacturers must be on the watch for potential toxicity from multiple sources. Products can be contaminated with some-thing toxic, such as a heavy metal, pesti-cide, herbicide, or microbe. Or, in a case of mistaken identity, a toxic plant species might be used instead of a nontoxic one. Perhaps worst of all, the plant might be in-herently toxic.

“Everything is poisonous; it’s just a matter of dose,” says Stephen Barnes of the University of Alabama, Birmingham, paraphrasing the Renaissance physician Paracelsus. “That’s so true for dietary sup-plements. The big concern is that because you can get them over the counter, there’s always a possibility that people will take ridiculous amounts.”

In May, a study by the Government Ac-countability Office (GAO), the investigative arm of Congress, raised the specter of trace contamination of botanical dietary supple-ments with heavy metals and pesticides. Released during a hearing on dietary supple-ments held by the Senate Special Com-mittee on Aging, the study of 40 randomly

selected botanicals found trace amounts of metals—including lead, arsenic, cadmium, and mercury—in 37 of the samples and one or more pesticides in 18 of the samples. But none of the samples contained levels high enough to pose a health risk—as long as people take the suggested amount.

“People take heavy metals out of con-text,” says Ikhlas A. Khan, a professor of pharmacognosy at the University of Missis-sippi who studies botanical dietary supple-ments. “The plants are grown outside. They’re going to contain trace amounts of heavy metals.”

Douglas MacKay, vice president for sci-entific and regulatory affairs at the Council for Responsible Nutrition, a trade associa-tion for the dietary supplement industry, points out that metals and pesticides are broad-based agricultural concerns. Indeed, preventing such contamination is impor-tant for all plant processors, whether they manufacture foods or dietary supplements, says Richard B. van Breemen, codirector of the UIC/NIH Center for Botanical Dietary

Supplements Research at the University of Illinois, Chicago.

To strike a balance between safety and consumer access, the Food & Drug Admin-istration regulates dietary supplements as foods rather than as drugs. Although companies must notify FDA about any new dietary ingredients, they do not need ap-proval prior to marketing a supplement, and FDA can react only to adverse events. In 2007, FDA further strengthened over-sight by requiring supplement makers to adhere to Good Manufacturing Practices, including testing the products for contami-nants such as metals, pesticides, and phar-maceutical residues. The requirement was phased in over three years, with the largest companies needing to comply first. Last month, the requirement went into effect for even the smallest firms.

“The results of that GAO investiga-tion showed that the dietary supplement industry is doing what the government expects as far as these contaminants” are concerned, MacKay says.

Researchers who study botanical supple-ments are less concerned about contami-nation than they are about the botanicals themselves and their intrinsic toxicity. Con-tamination, they believe, can be adequately addressed by the Good Manufacturing Practices that all supplement manufactur-ers must now follow. But “right now, we do not even understand the chemical composi-tion” of botanicals, Khan says. “Inherent variability blurs the composition.”

AN IMPORTANT STEP toward under-standing possible toxicity, as well as effi-cacy and mechanism of action, is standard-ization of the contents of supplements. “All botanical dietary supplements should be standardized,” UIC’s van Breemen argues.

At the forefront of botanical supplement research, he adds, is the potentially danger-ous effect that botanical supplements might have on drug metabolism. Taking a botani-cal supplement every day could induce or inhibit the activity of liver enzymes that are involved in the metabolism of certain medi-cations, van Breemen notes. “The half-life of a pharmaceutical might change,” he says.

Another area of research, sometimes

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SCIENCE & TECHNOLOGY

“Right now, we do not even understand the chemical composition” of botanicals.

“Inherent variability blurs the composition.”

SUPPLEMENTING KNOWLEDGE

Researchers seek to understand safety of botanical DIETARY SUPPLEMENTS CELIA HENRY ARNAUD, C&EN WASHINGTON

39WWW.CEN-ONLINE.ORG JULY 19, 2010

BOTANICAL PLACEBO Black cohosh shows no signs of toxicity, but it probably

doesn’t stop hot flashes, either.

carried out in conjunction with studies intended to elucidate the mechanisms of perceived efficacy, examines the inherent toxicity of the botanicals themselves. The National Toxicology Program (NTP)—a

joint effort of the National Institutes of Health’s

National Institute of Environmental

Health Sciences, the Centers for Disease Control &

Prevention’s National Institute for Occupational Safety & Health,

and FDA’s National Center for Toxico-logical Research—has been concerned with this question for more than a decade.

NTP researchers evaluate the effects of chronic exposure to dietary supplements,

studying potential toxicity to the liver, other organs, and blood. “We’re looking at things that are hard to evaluate by normal adverse-event reporting,” says Nigel J. Walker, NTP’s deputy program director for science. “If someone develops a long-term disease as the result of taking something daily for most of their life, it’s very hard to relate that to those exposures through adverse-event reporting.”

In its studies, NTP has found that di-etary supplements have a range of toxicity, Walker notes. For example, botanicals such as the stimulant ginseng and milk thistle extract, which is used to improve liver function, show few signs of toxic-ity in experimental animals, even at high doses. Others, such as the antimicrobial goldenseal, demonstrate clear evidence of causing liver toxicity.

Researchers at the UIC/NIH supplement research center have studied toxicity as part of a larger program to determine the mecha-nism of action of different botanicals. In one assay, they look for metabolites of botani-cals that form conjugates with glutathione, an important antioxidant in the body. Such

conjugates suggest that the botanical could cause liver damage, van Breemen says. In the case of kava, typically used to treat anxi-ety and insomnia, they found that kava lac-tones are metabolized to quinones, which can form conjugates with glutathione.

In another study, the researchers as-sessed the safety and efficacy of black cohosh and red clover used by menopausal women to reduce hot flashes. Some reports have linked black cohosh to isolated cases of liver damage. “We found the two bo-tanicals to be safe,” van Breemen says. “No elevated liver enzymes, no evidence of liver toxicity or any other kind of toxicity when taking the supplements daily for a year.” But the supplements “also didn’t reduce hot flashes,” when compared with placebo and estrogen therapy, he notes.

Much is still unknown about the poten-tially toxic effects of dietary supplements. Scientists also don’t know how—or even whether—these botanicals work. “We’ve only been doing really good research for less than one lifetime,” Barnes says. “So for many of these questions, we don’t know the answers, but we have hints.” ■

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