Environmental Health Perspectives Volume 107, Number 12, December 1999
The National Toxicology Program (NTP) has announced that it will
design and initiate studies to identify and characterize possible
adverse health effects that may be associated with prolonged use or
higher doses of some of the most popular medicinal herbs, including Ginkgo biloba , Echinacea angustifolia, and Panax quinquefolius (American Ginseng).
The NTP studies a large variety of substances to which the population
may be exposed in the environment, occupationally, in the food supply,
or elsewhere.
Little has been scientifically confirmed regarding either the
adverse or beneficial health effects of most of the 1,500-plus herbal
products stocked in America's drug stores, grocery stores, and numerous
other retail outlets that market these formulations. Many consumers
mistakenly assume that because herbal preparations are natural, they
are safer, gentler, and less "medicinal" than conventional drugs.
Furthermore, they may neither think nor choose to tell their doctors
they are using a particular herb and thus risk potential herb-drug
interactions. The extent of the nation's self-medication is evidenced
by the cornucopia of readily available remedies and the blossoming
herbal product market, expected to reach $5 billion next year.
Under the Dietary Supplement Health and Education Act of 1994,
herbal products are not required to be proven safe before marketing. To
date, there has been no legal requirement for the testing of herbal
products either before or after marketing. Once marketed, the burden of
proof is on the U.S. Food and Drug Administration to prove that a
dietary supplement is unsafe before it can be removed from shelves.
Thus, it falls to the government to test these formulations.
As part of its congressional mandate, the NTP studies biological or
physical agents that might not be tested without federal involvement.
This includes commercial agents first marketed prior to current testing
requirements; orphan drugs, which are used to treat relatively rare
diseases affecting fewer than 200,000 people and which might not be
developed without federal involvement; and mixtures of chemicals for
which evaluations are not required of industry. Medicinal herbs fall
under each of these categories. Studies of medicinal herbs cannot be
required of manufacturers unless they plan to market their products as
drugs (rather than as dietary supplements).
Substances approved for NTP study undergo a series of assays to
determine acute, subchronic, and chronic effects. In each case the
route of exposure is designed to simulate the anticipated route of
human exposure. Initially the substance is administered daily for 14
days to determine palatability (if administered in food) and how well
it is tolerated. The substance may next be administered for 90 days to
simulate extended exposure and any related toxicity. Finally, it may be
administered chronically for up to 2 years to determine its potential
to induce chronic toxicity and/or carcinogenicity. The animal models
usually used are Fischer 344 rats and B6C3F1 mice. Most substances
tested in animals also undergo one or more assays for genetic toxicity,
and additional assays testing for specific health effects such as
reproductive toxicity, neurotoxicity, or immunotoxicity may be designed
and administered if the test substance is suspected of affecting one or
more of those systems. Assays may be terminated at any point if the
results of these or other studies make it apparent that further testing
is not needed.
To date, the NTP has received several nominations for medicinal
plants to be studied. Currently, studies are under way for the herb Hydrastis canadensis (Golden Seal). Studies on Symphytum officinale (Comfrey)
and pulegone, a chemical found in Mentha pulegium pennyroyal), are
being planned, and investigators are currently gathering materials for
studies on ginkgo and echinacea. Other plants and substances approved
for full studies include Aloe Vera, Ginseng, Piper methysticum (kava kava), Silybum marianum (milk thistle),
and thujone, a compound found in several different spices and herbs.
The studies will be conducted by members of the General Toxicology
Group within the Toxicology Operations Branch of the Environmental
Toxicology Program.
Goldenseal. The root of the goldenseal plant is traditionally
used to treat wounds, ulcers, digestive problems, and eye and ear
infections. Today, the herb is also used as a laxative, tonic, and
diuretic. Goldenseal is used in feminine products such as vaginal
douches and is claimed to help with menstrual disorders such as
irregular cycle and excessive bleeding. Berberine, one of the chief
active components in goldenseal, has antimicrobial and vasodilatory
properties and may also be effective in preventing the growth of cancer
cells. The other major component of goldenseal, hydrastine (which can
be made from berberine), has abortifacient effects and has been shown
to induce labor in pregnant women when taken orally. Large internal
doses of goldenseal may cause convulsions and irritation of the mouth,
throat, and stomach, tingling of the skin, paralysis, respiratory
failure, and possibly death at very high doses. Chronic use may inhibit
vitamin B absorption. Goldenseal was recommended to the NTP for study
of reproductive toxicity, developmental toxicity, chronic toxicity, and
carcinogenicity.
Comfrey. Applied externally, comfrey acts as an
anti-inflammatory to promote healing of bruises, sprains, and open
wounds. The roots and leaves of the plant contain the protein
allantoin, which stimulates cell proliferation. Comfrey is said to help
wounds to heal and broken bones to knit. It is also taken internally as
an herbal tea to treat gastric ulcers, rheumatic pain, arthritis,
bronchitis, and colitis. This is a matter of some concern because
comfrey contains several pyrrolizidine alkaloids, primarily symphytine,
which have been linked to liver and lung cancer in rats.
Because the hepatotoxic effects of pyrrolizidine alkaloids are well
established in both animals and humans, there are no plans to reproduce
earlier carcinogenicity studies on comfrey that linked the herb with
liver cancer in rats. Rather, the study is anticipated to focus on the
reproductive toxicity effects of the herb.
Pulegone. Pulegone is the active ingredient in pennyroyal and
is also found in several other species of mint. Pennyroyal is
traditionally used as a carminative, insect repellent, emmenagogue, and
abortifacient. Prior studies have demonstrated hepatic, renal, and
pulmonary toxicity in humans, as well as central nervous system
toxicity resulting in seizure, coma, and death.
Pulegone was particularly recommended to the NTP for study because
of its toxicity to the developing fetus. In addition to the standard
toxicity assays, the substance will be studied for reproductive
toxicity, chronic toxicity, and carcinogenicity.
Ginkgo. After several thousand years of use in China, ginkgo
has recently enjoyed a swift rise to popularity in the United States.
The extract of the ginkgo leaf contains a balance of flavone glycosides
(including one suspected high-dose carcinogen, quercetin) and terpene
lactones. Ginkgo acts as a blood thinner; it improves circulation and
is therefore used to treat migraine headaches, depression, and a range
of lung and heart problems. In the United States, ginkgo is probably
most popularly known for its purported memory-enhancing effects.
However, although studies such as that published by researchers at
Tarrytown's New York Institute for Medical Research in the 22-29
October 1997 issue of the Journal of the American Medical Association
indicate that ginkgo may help stabilize and perhaps enhance cognitive
function in dementia and Alzheimer disease patients, the herb has not
been shown to improve memory in normal, healthy people.
Ginkgo has been recommended to the NTP for studies of neurotoxicity,
chronic toxicity, and carcinogenicity. At this point, the study is
expected to focus on histopathological changes in the brain effected by
the herb. A possible collaboration with the University of North
Carolina at Chapel Hill is in the works.
Echinacea. This member of the daisy family is one of the top
medicinal herb sellers in the United States. Although once used for
everything from snake bites to typhoid, echinacea is most commonly used
today as an immunostimulant to treat the common cold, sore throat, and
flu. Echinacea is not known to have any serious adverse side effects,
although there have been reports of skin rash and insomnia among users.
The herb is available in many forms--dried root or leaf, liquid
extract, powder, capsules, tablets, creams, gels, and injections
(outside of North America). It has yet to be determined how echinacea
is best administered or exactly how--or if--the plant's complex mixture
of polysaccharides, flavonoids, essential oils, and other compounds
actually produces beneficial effects. Echinacea was recommended to the
NTP for study of immunotoxicity, subchronic toxicity, chronic toxicity,
and carcinogenicity.
Aloe. The gel of the succulent aloe plant has been used as a
balm for minor burns since the time of the ancient Egyptians. Aloe is
also taken internally to treat constipation, colitis, peptic ulcers,
and diabetes. Thanks to its highly touted powers as a skin moisturizer,
aloe now appears in an extensive array of cosmetic products such as
soaps, lotions, and skin creams. Several aloe juice health drinks are
being marketed as general tonics. Aloe was recommended to the NTP for
study in the Tg.AC transgenic mouse. No special toxicity studies were
indicated.
Ginseng. Ginseng has long been a popular remedy in Eastern
medicine; its Latin name Panax is derived from the same root as
"panacea," which gives some idea of the esteem in which this herb is
held among its users. Ginseng is used as a mood enhancer, stress
reducer, and aphrodisiac. It is also used to treat upset stomach,
depression, diabetes, and hypertension. Reports of so-called ginseng
abuse syndrome, a condition symptomized by nervousness, hypertension,
insomnia, skin eruptions, diarrhea, and depression that was first
described in the 13 April 1979 issue of the Journal of the American
Medical Association, have been largely debunked. Ginseng was
recommended to the NTP for testing of reproductive toxicity,
neurotoxicity, chronic toxicity, and carcinogenicity.
Kava kava. Among the peoples of Oceania, kava kava has a long
history of recreational, medicinal, and ceremonial use. Today, the herb
is quickly becoming popular in the West as a calmative and
antidepressant. The same psychoactive properties that induce restful
sleep and promote sociability also make kava kava a likely candidate
for abuse; chronic heavy use of the herb has been associated with skin
problems, liver and kidney dysfunction, and possible hypertension. Kava
kava has been recommended to the NTP for genotoxicity, reproductive
toxicity, neurotoxicity, chronic toxicity, and carcinogenic testing.
Milk thistle. Milk thistle is used to treat a number of liver
conditions including cirrhosis and hepatitis, and has been shown to
stimulate protein synthesis within the liver, leading to tissue
regeneration. Milk thistle is noted for its potency as an antidote to
the toxins of the death cap mushroom, which attack the liver and can
cause death if not treated promptly. The herb has also been used
historically to treat depression and to increase breast milk
production; today it is a staple for pregnant and nursing mothers who
embrace the alternative medicine approach. Milk thistle has been
recommended to the NTP for genotoxicity, metabolism, reproductive
toxicity, chronic toxicity, and carcinogenicity testing.
Thujone. Thujone is a monoterpene found in several different herbs, including sage, cedar, tansy, and wormwood.
Thujone is believed to be the culprit behind the hallucinations,
tremors, convulsions, and paralysis that result from drinking the
wormwood-based liqueur absinthe. Although the use of thujone in food is
banned in the United States, the compound appears in over 20 approved
flavorings and food additives. In addition, several readily available
nonfood items (including medicinal products such as Vicks VapoRub,
fragrances, and perfume additives) contain thujone. Thujone has been
recommended to the NTP for genotoxicity, neurotoxicity, reproductive
toxicity, chronic toxicity, and carcinogenicity testing.
The NTP continually solicits and receives new nominations for
substances to be studied from numerous sources including academia,
industry, other government agencies, and the general public. Three
committees are involved in reviewing nominations for NTP studies: the
Interagency Coordinating Committee for Evaluation of Chemicals (ICCEC,
which is made up of scientists representing 11 federal health
agencies), the NTP Board of Scientific Counselors (which reviews each
nominee's background information and the recommendations made by the
ICCEC), and the NTP Executive Committee (which considers the
recommendations of the other two committees and formally accepts or
rejects each nomination). As public exposure to herbal products
continues to grow and usage trends of medicinal plants become more
apparent, the NTP will continue to characterize the acute and chronic
effects of these products along with those of other chemicals and
agents that industry cannot be required to study.
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