HerbalEGram: Volume 8, Number 5, May 2011
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
- Substances judged to
have high concern as a possible public health hazard based on the extent
of human exposure and/or suspicion of toxicity.
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.
Report Number
|
Report Title
|
Report Status / Date
|
TR539
|
Multigenerational Reproductive Toxicology Study of
Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (feed study)
|
Final / March 2008
|
TR545
|
Toxicology and Carcinogenesis Study of Genistein (CAS No.
446-72-0) in Sprague-Dawley Rats (feed study)
|
Final / December 2007
|
TR553
|
Photococarcinogenesis Study of Aloe Vera [CAS
No. 481-72-1 (Aloe-emodin)] in SKH-1 Mice (Simulated Solar Light
and Topical Application Study)
|
Final / September 2010
|
TR556
|
Toxicology and Carcinogenesis Studies of Chromium
Picolinate Monohydrate (CAS No. 27882-76-4) in F344/N Rats and B6C3F1 Mice
(Feed Studies)
|
Final / June 2010
|
TR562
|
Toxicology and Carcinogenesis Studies of Goldenseal Root
Powder (GOLDENSEAL RT) in F344/N Rats and B6C3F1 Mice (Feed studies)
|
Final / August 2010
|
TR563
|
Toxicology and Carcinogenesis Studies of Pulegone (CAS No.
89-82-7) in F344/N Rats and B6C3F1 Mice (Gavage studies)
|
Draft / Peer Reviewed November
19, 2009 with conclusions from draft report approved pending 2 proposed
changes
|
TR565
|
Toxicology and Carcinogenesis Studies of Milk Thistle
Extract (CAS No. 84604-20-6) in F344/N Rats and B6C3F1 Mice (Feed studies)
|
Draft / Peer Reviewed November
19, 2009 with conclusions from draft report approved
|
TR567
|
Toxicology and Carcinogenesis Studies of Ginseng (CAS No.
50647-08-0) in F344/N Rats and B6C3F1 Mice (Gavage studies)
|
Draft / Peer Reviewed November
19, 2009 with conclusions from draft report approved
|
TR571
|
Toxicology and Carcinogenesis Studies of Kava Kava Extract
(CAS No. 9000-38-8) in F344/N Rats and B6C3F1 Mice (Gavage studies)
|
Draft / Peer Reviewed January 26,
2011 with conclusions from draft report approved
|
TR577
|
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)
|
Draft / Peer Reviewed April 5,
2011 with conclusions from draft report approved
|
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.
Report Number
|
Report Title
|
Report Date
|
TOX79
|
Dose Range-Finding Study of
Genistein (CAS No. 446-72-0) Administered in Feed to Sprague-Dawley Rats
|
November 2007
|
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.
Report Number
|
Report Title
|
Report Status / Date
|
GMM15
|
Toxicology Study of Senna (CAS No. 8013-11-4) in IN
C57BL/6NTAC MICE and Toxicology and Carcinogenesis of Senna
Genetically Modified C3B6.129F1-Trp53tm1Brd N12
Haploinsufficient Mice (Feed Studies)
|
Draft / Peer Reviewed April 5,
2011 with conclusions from draft report approved
|
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.
Report Number
|
Report Title
|
Report Date
|
TER99004
|
Developmental Toxicity Evaluation for Goldenseal (Hydrastis canadensis) Root Powder
Administered in the Feed to Swiss (CD-1®) Mice on Gestational Days 6-17
|
July 30, 2002
|
TER98007
|
Developmental Toxicity Evaluation for Goldenseal Root
Powder (Hydrastis canadensis)
Administered in the Feed to Sprague-Dawley (CD®) Rats on Gestational Days 6
to 20
|
April 3, 2003
|
TER96003
|
Developmental Toxicity Evaluation of Melatonin (CAS NO.
73-31-4) administered by gavage to Sprague-Dawley (CD®) Rats on Gestational
Days 6 through 19
|
March 26, 1998
|
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.
|