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National Toxicology Program

National Toxicology Program

UPDATE NewsletterUPDATE NewsletterJune 2016

Challenges in studying hazards of botanicals explored at NTP workshop

By Paula Whitacre
Reprinted from Environmental Factor

About 300 representatives of federal agencies, industry, and research institutions participated in “Addressing Challenges in the Assessment of Botanical Dietary Supplement Safety,” convened by the National Toxicology Program (NTP). The workshop took place April 26-27 at the National Institutes of Health (NIH) in Bethesda, Maryland, and was also webcast. The webcast is available on the meeting website.

In the past year, nearly one-fifth of Americans used a botanical dietary supplement, such as green tea extract or black cohosh, according to the National Center for Health Statistics.. NTP is working to identify any potential adverse effects in response to public concern about supplement safety.

“Our overarching goal for this meeting was to communicate current knowledge about how to determine the safety of botanicals, obtain feedback, and identify gaps for future research,” said NTP toxicologist Cynthia Rider, Ph.D., who led the workshop.

“NTP is interested in botanicals as part of its mission to apply tools of toxicology and molecular biology to study substances of public health concern,” said Linda Birnbaum, Ph.D., director of NIEHS and NTP. She pointed to an NTP fact sheet that summarizes and provides links to NTP studies on botanicals.

Food, not a drug

Dietary supplements are regulated as foods, not drugs, said Paul Coates, Ph.D., director of the NIH Office of Dietary Supplements. Under the Dietary Supplements Health and Education Act of 1994, known as DSHEA, the Food and Drug Administration (FDA) does not rule on premarket supplement safety, as it does with drugs.

“There has been immense growth in the industry since DSHEA 20 years ago,” said Cara Welch, Ph.D., special advisor to the FDA Office of Dietary Supplement Programs (ODSP). “We needed to respond.” According to ODSP, the industry has grown from $6 billion in 1994 to more than $35 billion today.


“Botanicals add a layer of complexity that is about eight feet deep — there are so many more variables,” said Craig Hopp, Ph.D., program director at the NIH National Center for Complementary and Integrative Health.

Yet Duffy MacKay, N.D., from the Council for Responsible Nutrition, stressed a different paradigm, common in the industry. “Herbalists embrace [the fact] that the influence of nature and weather creates variability,” he said. “We need new methods to bring the two worlds together.”

Such methods, which involve more rigorous and reproducible studies, require high quality test agents. To that end, NTP is examining phytoequivalence among botanicals, which refers to how a well-characterized reference botanical may relate to others in the marketplace. Rider presented case studies on Ginkgo biloba extract (see text box), black cohosh extract, and Echinacea purpurea extract — three popular supplements with very different properties. The case studies are being submitted to peer-reviewed journals.


According to Bill Gurley, Ph.D., from the University of Arkansas, only about 40 percent of patients discuss supplement usage with their health care providers, despite the potential for harmful interactions with drugs or even between supplements. Children, the elderly, and otherwise vulnerable populations may experience effects different from those of the healthy volunteers used in most studies who take no other supplements or medications during a clinical trial.

Throughout the workshop, presenters and participants raised questions and suggested ways to resolve them, such as taking advantage of advances in analytical chemistry, high-throughput cell-based assays, and new computational tools.

(Paula Whitacre is a contract writer working out of the NIEHS Bethesda office.)

Ginkgo biloba extract — a case study

By Natasha Catlin

Rider presented a case study on Ginkgo biloba extract, providing a glimpse of the complexity facing NTP and other researchers who study botanical supplements. This complexity stems from several sources.

  • The large number of constituents in botanical supplements.
  • The possibility of multiple active constituents.
  • The large fraction of constituents that may remain unidentified.
  • Multiple potential interactions that may occur between these constituents.

In addition, across the marketplace, products vary as a result of differences in raw materials, the plant parts used, processing and manufacturing activities, and adulteration or combinations of products.

Considering such variability, it is challenging to select a single test article and relate findings from that test article to all of the other products in the marketplace. The Ginkgo biloba extract case study was designed to answer such questions.

Researchers began by comparing many different test articles using targeted and untargeted chemical analyses. These studies revealed a surprising level of difference among the Ginkgo biloba extract samples.

All of the samples were assessed in high-throughput human primary hepatocyte studies, revealing different patterns of biological responses to the extracts. A subset of samples was also evaluated in short-term rat studies to evaluate gene expression changes.

Statistical methods were used to determine which lots of Ginkgo biloba extract resembled the reference lot and which were different. In addition to informing the NTP botanical testing program, methods developed in this case study will be useful in other NTP projects involving toxicological evaluation of complex mixtures, such as commercial formulations and environmental contaminants.

(Natasha Catlin, Ph.D., is an Intramural Research Training Award fellow in the NTP Toxicology Branch.)

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Director of Office of Policy, Review, and Outreach and Editor-in-Chief: Mary Wolfe | Managing Editor: Anna Lee Mosley