National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative

By Harry B. Rice, PhD

Vice-president of Regulatory and Scientific Affairs

United Natural Products Alliance

Editor's note: This article was revised after its original publication and re-uploaded at 12:45pm CST on May 5, 2011.

The National Toxicology Program (NTP) is a US government interagency program with a mission to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology. According to the NTP website, “the program maintains an objective, science-based approach in dealing with critical issues in toxicology and is committed to using the best science available to prioritize, design, conduct, and interpret its studies. To that end, the NTP is continually evolving to remain at the cutting edge of scientific research and to develop and apply new technologies.”¹

Public interest in alternatives to conventional medicine and the increased use of medicinal herbs led the NTP to convene a 2-day workshop in September of 1998, titled, “International Workshop on Evaluating Research Needs on the Use and Safety of Medicinal Herbs.” Recommendations from the workshop included a call for (1) more research on herbals, (2) the identification and standardization of product ingredients by industry, and (3) increased consumer education through package inserts.²

Dietary supplements containing biologically active constituents found in some herbs and herbal extracts have been and continue to be nominated and selected for study by the NTP. The following is a list of some of these constituents (including some non-plant dietary ingredients that the NTP is evaluating or has evaluated):

·      Aloe vera gel (Aloe vera, A. spp.)

·      Bitter Orange (Citrus aurantium)

·      Black cohosh (Actaea racemosa, syn. Cimicifuga racemosa)

·      Chondroitin Sulfate

·      Chromium Picolinate

·      Dong quai (Angelica sinensis) root and extract

·      Evening Primrose (Oenothera biennis) Oil

·      Folic acid

·      Genistein (from soybean, Glycine max)

·      Ginkgo biloba extract

·      Ginseng (Panax spp.)

·      Glucosamine

·      Goldenseal root (Hydrastis canadensis)

·      Green tea (Camellia sinensis) extract

·      Gum guggul extract (Commiphora mukul)

·      Indole-3-carbinol (from broccoli, Brassica oleracea)

·      Kava kava (Piper methysticum) extract

·      Garcinia (Garcinia cambogia)

·      Milk thistle (Silybum marianum) extract

·      Pulegone (from pennyroyal, Mentha pulegium)

·      Resveratrol (from grape [Vitis vinifera] or Japanese knotweed [Polygonum cuspidatum])

·      Senna (Senna alexandrina, Senna spp.)

·      Thujone (found in absinthe [Artemisia absinthium] and other plants)

·      Usnea (Usnea barbata) lichen

·      Valerian root (Valeriana officinalis)

Nominations to the Testing Program

In follow up to the 1998 workshop, the NTP staff began working with the Office of Dietary Supplements at the National Institutes of Health, the Food and Drug Administration, the academic community, and consumer and trade associations to conduct research that would address deficiencies in the present knowledge of herbal dietary ingredients and their potential toxicities. The mandate for NTP was to actively seek herbs and active or toxic constituents for which sufficient information is not available to adequately evaluate potential human health hazards. The NTP accomplishes this goal through a formal open nomination and selection process. Substances considered appropriate for study generally fall into 2 broad yet overlapping categories:³

1. Substances judged to have high concern as a possible public health hazard based on the extent of human exposure and/or suspicion of toxicity.
2. Substances for which toxicological data gaps exist and additional studies would aid in assessing potential human health risks, e.g. by facilitating cross-species extrapolation or evaluating dose-response relationships.”
   
   
   

Types of Studies

“NTP-designed studies focus on the characterization of potential adverse health effects, including general toxicity associated with short-term high-dose exposure and/or long-term exposure to lower doses, as well as system specific toxicities including reproductive toxicity, neurotoxicity, cardiovascular toxicity and immunotoxicity.”⁴

I. Long-Term Studies

“Chemicals [and other agents] selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of human exposure, level of production, and chemical structure. The interpretive conclusions presented in the Technical Reports are based only on the results of these NTP studies. Extrapolation of these results to other species and quantitative risk analyses for humans requires wider analyses beyond the purview of these studies.” Selection of a chemical or agent per se is not an indicator of a chemical's carcinogenic potential.⁵

A complete listing of long-term study reports and abstracts is available at here.

          II. Short-Term Studies           

“The National Toxicology Program (NTP) designs and conducts studies to characterize and evaluate the toxicologic potential of selected chemicals in laboratory animals (usually 2 species, rats and mice). Chemicals selected for NTP toxicology studies are chosen primarily on the bases of human exposure, level of production, and chemical structure.”⁶

A complete listing of short-term toxicity reports and abstracts is available here.

           III. Genetically Modified Model Systems

“An ongoing goal of the NTP is to seek other model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agent's mode of action. The use of genetically modified [animal] models holds promise for improving both the accuracy and efficacy of experimental assessment of the carcinogenic potential of chemicals. Genetically altered or "transgenic" mouse models carry activated oncogenes or inactivated tumor suppressor genes known to be involved in neoplastic processes both in humans and rodents. This trait may allow them to respond to carcinogens more quickly than conventional rodent strains. In addition, the neoplastic effects of agents can be observed in transgenic models within a time frame in which few, if any, spontaneous tumors would arise. The high incidences of spontaneous or background tumors, which occur most often late in the two-year rodent cancer studies, are among the most confounding factors for interpreting the findings of chemical carcinogenesis and their implications for human health.”⁷

A complete listing of studies in genetically modified models is available here.

           IV. Developmental Studies

“The goal of this testing is to identify chemicals that may pose a risk to unborn children if pregnant women are exposed. Because it is often difficult to ascertain the association between chemical exposure in pregnant women and adverse health effects on their children, the results of well-controlled animal studies are used by regulatory agencies to help set human exposure guidelines.”⁸

A complete listing of teratology abstracts is available here. 

How are the NTP Results Interpreted?  

The interpretive conclusions presented in a study report are based only on the results of the NTP study or studies that are detailed in a particular report. Extrapolation of the results to other species and quantitative risk analyses for humans requires a much wider analyses beyond the range of the NTP studies alone.

While the answer to the aforementioned question is outside the scope of this article, for those wondering if the conclusion(s) from a particular report may apply to a specific substance, particularly an herbal ingredient studied by NTP, the first question pertains to the degree of similarity of the substance being used in the marketplace compared to the NTP-tested substance.

For example, consider the recent NTP report on aloe (TR577, A Toxicology and Carcinogenesis Studies of a Nondecolorized Whole Leaf Extract of Aloe barbadensis Miller [Aloe Vera] in F344/N Rats and B6C3F₁ Mice [Drinking Water Study]), which was recently discussed on April 5, 2011, during an NTP Technical Reports Peer Review Panel. The Panel accepted unanimously the conclusions as written in the draft report, clear evidence of carcinogenic activity of a non-decolorized whole leaf extract of Aloe vera in male and female F344/N rats and no evidence of carcinogenic activity in male or female B6C3F mice.⁹

While this report has raised an issue about the safety of aloe in general, it should be noted that not all Aloe vera ingredients in the US market are the same. The subject of this report is, specifically, “Nondecolorized Whole Leaf Extract of Aloe barbadensis Miller (Aloe Vera).” This ingredient is an unpurified Aloe vera juice containing a high concentration of the anthroquinone aloin A (average 6,3000 ppm). According to a recently published NTP information sheet on Aloe vera:

The difference between decolorized and non-decolorized whole leaf extracts is mostly in how the leaf is processed or filtered. In many cases, manufacturers of oral products containing Aloe vera use a charcoal filtration process to decolorize and remove some of the components from the leaf, including anthraquinones. Anthraquinones act like laxatives. Some anthraquinones have previously been shown to be carcinogenic.⁹

With respect to what may have caused the tumors in the rats, NTP speculates that it may have been the anthraquinone, aloin. If true, products processed with activated charcoal or by “filleting” the latex (i.e., decolorized) to remove the high aloin content, presumably would not be implicated as being potentially carcinogenic because of the results presented in the NTP report. Those products at risk for further scrutiny are aloe products that are not decolorized. However, it is still possible that some aloe ingredients in the marketplace—even after decolorizing or filleting—may still have from time to time levels of anthraquinones above the International Aloe Science Council’s certification limit of 10 ppm which could be perceived by the NTP or the Office of Environmental Health Hazard assessment (OEHHA) or other government agencies as having an issue.

It is not clear at this time what the full implications of the NTP report will be for the aloe and dietary supplement industries or how the test data will be viewed or used by other government bodies, such as FDA or OEHHA.

References

1. About the NTP. National Toxicology Program website. Available at: http://ntp.niehs.nih.gov/?objectid=7201637B-BDB7-CEBA-F57E39896A08F1BB. Accessed April 28, 2011.

2. Dietary Supplements and Herbal Medicines Initiative. October 2009. National Toxicology Program. Available at: http://ntp.niehs.nih.gov/NTP/About_NTP/BSC/2009/December/Dietary.pdf.  Accessed April 28, 2011.

3. Nominations to the testing program. National Toxicology Program website. Available at: http://ntp.niehs.nih.gov/?objectid=25BC6AF8-BDB7-CEBA-F18554656CC4FCD9. Accessed April 28, 2011.

4. Herbal medicines. National Toxicology Program website. Available at: http://ntp.niehs.nih.gov/?objectid=7E796614-BDB5-82F8-F5FBA6DDAA9FF7E4. Accessed April 28, 2011.

5. Long-term study reports & abstracts. National Toxicology Program website. Available at:  http://ntp.niehs.nih.gov/index.cfm?objectid=084801F0-F43F-7B74-0BE549908B5E5C1C. Accessed April 28, 2011.

6. Short-term study abstracts. National Toxicology Program website. Available at:   http://ntp.niehs.nih.gov/index.cfm?objectid=0847F4F0-E88B-51DA-B71C0FE0476B8AB2. Accessed April 28, 2011.

7. Genetically modified models. National Toxicology Program website. Available at:    http://ntp.niehs.nih.gov/?objectid=72015FF1-BDB7-CEBA-FD7115836443FFA1. Accessed April 28, 2011.

8. Developmental. National Toxicology Program website. Available at:   http://ntp.niehs.nih.gov/index.cfm?objectid=070C9F1C-A6F9-B112-990A9F55BAC7C407. Accessed May 2, 2011.

9. Aloe Vera fact sheet. National Toxicology Program. Available at: http://www.niehs.nih.gov/about/materials/ntp-aloe-fact-sheet.pdf. Accessed April 28, 2011.