Herb Industry and FDA Issue Chaparral Warning: Experts unable to Explain Possible Links to Five Cases of Hepatitis

Herb Industry and FDA Issue Chaparral Warning: Experts unable to Explain Possible Links to Five Cases of Hepatitis

The American Herbal Products Association and the Food and Drug Administration are warning industry and consumers about the potential health hazards of the herb chaparral. The warning follows a published report of two cases of non-viral hepatitis that health officials believe may be associated with the ingestion of chaparral. Three additional reports from physicians -- one of them involving a serious, life-threatening case -- prompted the herb industry and FDA to take action.

Despite these reports, health officials and herb experts have not been able to explain how chaparral could produce hepatitis, or even if the herb is actually to blame.

Chaparral is a desert plant, Larrea tridentata (Sesse & Moc. ex DC.) Coville of the family Zygophyllaceae which grows in the deserts of the Southwestern United States and northern Mexico. A related species grows in South America. It is a popular herb, especially in Southwestern U.S. where infusions (teas) have been used as a folk medicine for centuries with no reports of adverse effects.

On October 30 the Centers for Disease Control and Prevention (CDC) in Atlanta published a report about the first two cases that occurred in July. The CDC report noted that two patients, a 42-year old man and a 41-year old woman had experienced jaundice, abdominal pain, and other symptoms of hepatitis; they had been taking chaparral capsules and tablets, respectively. The CDC report cited a 1990 case report published in a U.S. medical journal in which a similar incident had occurred in Canada in 1983 (Katz and Saibil, 1990). This report is the only previous case of alleged hepatotoxicity associated with chaparral ingestion reported in all the available medical literature.

Upon reading the CDC report, a family physician reported a third case on November 13 which he believed to be associated with chaparral. His patient had experienced hepatitis symptoms, and upon checking, the physician discovered that the patient had been taking some chaparral capsules (Philen, 1992).

The fourth case reported on Decemher 4 involves a woman who was in "grave condition" after having experienced liver and kidney failure. Her pathologist read the CDC report and, upon consulting with the woman's family, learned that she had been consuming chaparral capsules for about one year (FDA, 1992; Philen, 1992).

In a press release issued on December 10, FDA noted that chaparral ingestion had been associated with cases of acute liver problems which have affected at least four Americans. The FDA warned of potentially serious health consequences for people with chronic underlying liver damage due to acute or chronic disease. The agency noted that it was investigating the matter and would take "appropriate action when more information is available." (FDA, 1992)

On December 12 the American Herbal Products Association (AHPA) issued a letter to its members supporting the FDA warning. The AHPA letter said that AHPA "supports the FDA's concern in regard to the safety of any product and is therefore recommending that AHPA member companies immediately suspend sales of chaparral for internal use until further information is available. We further recommend that affected product be securely stored during this interim period pending further investigation." (AHPA, 1992)

On December 16, the National Nutritional Foods Association (NNFA), an organization of health food retailers, distributors and manufacturers, issued an "Industry Alert" in which NNFA urged all health food stores in the U.S. to remove chaparral-containing products from retail shelves. NNFA said that it believes "that it is the industry's first responsibility to ensure the safety of our products and the consumer. The NNFA is, therefore, recommending that the Industry take a very conservative stance in this situation. The NNFA is asking its member companies to suspend distribution of any product that contains chaparral and to notify their distributors and retailers that the product should be removed from store's shelves until the situation is resolved." (NNFA, 1992)

The AHPA, NNFA and FDA positions were partially motivated by the fact that the four cases cited by FDA represented chaparral products from several different manufacturers, thus creating the suspicion that there might be a problem with the herb per se, and not just a problem of a potential case of contamination or mislabeling by one manufacturer.

Initially, when the first two cases were reported, FDA officials thought that there might be a case of misbranding, adulteration, or possibly contamination. However, according to Dr. Joseph Betz and Dr. William Obermeyer of FDA's Division of Natural Products of the Center for Food Safety and Applied Nutrition, their analysis of the two products revealed that they were indeed chaparral and that they were not adulterated nor contaminated as far as they could tell. They did not run any tests specifically for chemical contamination (e.g. pesticides, etc.). The chromatographic screening procedures used would have detected most pesticides, chemical contaminants, and alkaloids (including pyrrolizidine alkaloids, which are known to cause liver disorders.) Betz and Obermeyer just wanted to verify the authenticity of chaparral and that the samples would correspond with reported values of NDGA, one of the known primary active compounds in the plant. (Obermeyer, 1992).

Meeting in Washington

On December 17, a week after the FDA had issued its initial warning, members of the FDA's Center for Food Safety and Applied Nutrition (CFSAN) met in Washington with representatives of the herb and health food industries and related scientific groups. The meeting was initiated by Dr. Douglas Archer, Deputy Director of Programs, of CFSAN who invited the herb industry to work with FDA on the problem. Archer contacted AHPA President Peggy Brevoort who, in turn, invited others. Included at the meeting were William R. Pendergast, attorney representing AHPA, Stephen R. McNamara, a Washington, D.C. lawyer, Rob McCaleb, President of Herb Research Foundation, and Mark Blumenthal, Executive Director of American Botanical Council (representing herbal research and education organizations), Dr. Burton Kallman, Director of Science and Technology for NNFA, Robert Ullman, attorney for NNFA, and Dr. Alvin Segelman, Vice-President of Research and Quality Assurance at Nature's Sunshine Products, a large manufacturer of herbal products. (Dr. Segelman was formerly a Professor of Pharmacognosy at Rutgers University before leaving academia and moving to the herb industry.) Also present as an observer was Annette Dickinson of the Council for Responsible Nutrition, an industry group of nutritional supplement manufacturers.

FDA representatives included Dr. Archer; Dr. Samuel Page, Director of the Division of Natural Products; Janice Oliver, Acting Director of Field Programs; Dr. Elizabeth Yetley, Acting Director of the Office of Special Nutritionals; and Dr. Lori Love, Acting Director of Clinical Research and Review, Office of Special Nutritionals. Additional FDA officials were also present from areas of epidemiology and enforcement.

This meeting marks the first time that the FDA has invited the industry to Washington for a meeting to discuss a common problem, to share scientific and market information, to ask for industry input and advice, and to pursue possible solutions.

At the meeting, AHPA and NNFA announced that both organizations had issued calls for the temporary suspension of sales of all chaparral products until more information about the potential hepatotoxicity became known. Also, FDA offered to share its data, including patient information (however, patients' confidentiality would be maintained) with industry and organization representatives to assist all parties in helping to resolve the alleged difficulties surrounding chaparral.

One of the points discussed was whether the FDA at this time was only investigating chaparral tablets and capsules, as they are the only products that have been implicated in the hepatitis cases. Although FDA was not looking at teas and combination products, AHPA and NNFA reported that both organizations were recommending that manufacturers, distributors, and retailers suspend sales of all chaparral-containing products for the present time, until more information is known.

No one at the meeting was able to offer a cogent, scientific basis for the alleged hepatotoxicity of chaparral. Dr. Archer said that the FDA believes that there may be a causal relationship between the hepatotoxicity and chaparral but he acknowledged that FDA scientists could not attribute the alleged toxicity to any chemical compounds in chaparral leaves or explain the mode of toxicity.

Dr. Page reported that his group had conducted chemical tests on voucher specimens supplied by Dr. Segelman. He acknowledged that he and others in his department had not found any basis for the toxicity.

Dr. Segelman reported on the clinical study in Utah in the late 1960s in which chaparral tea (two or three 8-oz. glasses per day) was consumed by 59 cancer patients with advanced incurable malignancies. Twenty-three of these patients were also treated with oral doses of NDGA ranging from 250 mg to 3,000 mg daily. All patients' blood parameters were monitored -- among other biomedical parameters -- and no indication of liver toxicity was apparent. (Smart, et al. 1970; Gyllenhaal, 1989) Segelman also indicated that the first two case reports involved consumption of relatively minor doses of the herb, as low as 1500 mg. per day.

Rob McCaleb of the HRF also reported on a comprehensive review of chaparral compiled by researchers at the University of Illinois at Chicago in 1989 for the National Cancer Institute that had not come up with any scientific findings to suggest hepatotoxicity of chaparral. (Gyllenhaal, 1989).

Mark Blumenthal noted that Professor Norman R. Farnsworth and a team of researchers at the University of Illinois at Chicago had conducted extensive chemical and pharmacological studies on chaparral leaf in the late 1970s and early 1980s as a possible antifertility agent because of its estrogenic activity. The studies were sponsored by the World Health Organization (WHO) as part of a larger review of potential anti-fertility products. These tests for WHO did not suggest any basis for chaparral's alleged hepatotoxicity. (Gyllenhaal, 1989)

Blumenthal also reported that ABC had recently sent to both FDA and CDC several chapters on the chemistry of chaparral from a book on the subject. The book does not mention any chemical or pharmacological basis for human toxicity. (Mabry et al., 1979)

Chaparral Leaf -- A Common Southwestern Herb

Infusions of chaparral leaves have been used by Southwestern Indians, Mexicans and Mexican-Americans as a traditional remedy for a variety of conditions including cancer, arthritis, bruises, dandruff, diarrhea, eczema, venereal diseases, and wounds (Duke 1985). Chaparral has been used as an antiseptic, diuretic, emetic and a "blood purifier." Other common names for the plant include creosote bush and gobernadora. It has also been used for colds and bronchitis (Der Marderosian and Liberti, 1988).

According to herbalist and author Michael Moore, chaparral is a bush that grows up to twelve feet tall, but is usually chest- or head-high. It has many branches and small, curled, yellowish-green leaves that are covered with the aromatic resin. The plant produces small yellow flowers. Moore indicates that it dominates deserts below 3,000 feet elevation, can easily grow up to 4,000 feet elevation, and can sometimes be found growing as high as 5,500 feet. The Spanish name Gobernadora (Governess) describes its ability to develop a virtual monoculture; chaparral usually keeps other plants from growing near it. (Moore, 1989)

An aromatic, sticky resin coats the leaves of chaparral (hence the name creosote bush) which contain a number of chemicals, including nordihidroguaiaretic acid (NDGA), a strong antioxidant. The resin also includes related lignans nor-isoguaiasin, dihidroguairaretic acid and other similar compounds. The total phenolics and the small level of lipids in chaparral range from 16 percent in older plants to 21 percent in younger plants (Der Marderosian and Liberti, 1988; Mabry et al., 1979).

Due to its high antioxidant activity NDGA has been used as a preservative in vegetable offs and fats. Long-term studies of NDGA on rats induced lesions on lymph nodes and kidneys, thus prompting FDA to remove it from the list of GRAS (Generally Recognized As Safe) substances. However, the USDA still permits the use of NDGA in animal shortenings and lard (Tyler, 1987).

Although infusions of chaparral have been used as a folk medicine for centuries, its recent popularity began in the late 1960s and early 1970s after reports that, after refusing surgery, an 85-year old Utah man had cured his own cancer of the neck by drinking a tea from chaparral leaves. Because of this and other reports and increasing interest among the general population, the National Cancer Institute tested chaparral and some of its chemicals. Most studies centered on NDGA, not the whole herb or tea. Due to conflicting results, NCI did not pursue further study of NDGA. The 1989 review of chaparral for NCI noted that "Acute toxicity of NDGA is not great." (Gyllenhaal, 1989)

Studies in the late 1960s on NDGA on rats indicated that the compound can cause kidney problems. However, the LD50 (oral dose that killed 50 percent of a rat population) was relatively high, ranging from 550 mg/kg interperitoneally in mice, to 3,500 mg/kg (Gyllenhaal, 1989). This indicates the relative safety of NDGA. Pharmacological tests were not carried out on chaparral leaf tea or its extracts -- just the concentrated, purified compound NDGA from the plant (Segelman, 1992).

Case Reports

One of the cases first reported by CDC was a 42-year-old man who had taken only three 500 mg. capsules of chaparral per day for the previous six weeks. He visited his family physician who noted symptoms of scleral icterus (yellowing of the whites of the eyes) and diffuse jaundice. He had stopped using the chaparral, according to the CDC report "because he had considered it the cause of his illness. He reported no other unusual dietary practices, had not consumed alcohol during the previous 3 years, and had no other known exposure to hepatotoxins" (CDC, 1992).

The second case involved a 41-year-old woman who visited her family doctor due to abdominal pain in the right upper quadrant and jaundice of 4 week's duration. She reportedly had consumed 150 chaparral tablets for a skin condition over an 11-week period but had stopped taking them at the onset of symptoms. (CDC, 1992)

There is only one other published reference to any report of human hepatotoxicity associated with chaparral. In this case a 33-year old woman was self-medicating with up to 15 chaparral tablets per day. She exhibited symptoms of dark urine, anorexia, nausea, and burning chest pains about three months after she began using the herb. She reduced the tablets to one per day, experienced an abatement of symptoms, which returned when she increased dosage up to seven tablets per day. She was hospitalized and symptoms once again abated upon discontinuation of chaparral (Katz and Saibil, 1990). A fifth case involving a female was reported after both the CDC article and the FDA warning were published. At presstime, HerbalGram had not yet received specific information on these cases.

All other reports regarding potential toxicity associated with chaparral indicate potential kidney problems associated with rat tests on purified, concentrated doses of NDGA, the primary known active ingredient in chaparral leaf resin.

Experts "Baffled"

HerbalGram interviewed a variety of experts and checked a number of authoritative references to help shed light on this puzzle.

Regarding the toxicity of chaparral, Dr. Ara Der Marderosian, Professor of Pharmacognosy and Medicinal Chemistry at the Philadelphia College of Pharmacy and Science wrote, "No cases of toxicity have been reported with the use of chaparral tea." (Der Marderosian and Liberti, 1988).

Varro E. Tyler is the Lilly Distinguished Professor of Pharmacognosy at Purdue University and author of the textbook Pharmacognosy. In his updated version of The Honest Herbal (3d edition, in press) he includes the 1990 reference to liver toxicity (Katz and Saibil, 1990). Previous versions of the book only mentioned potential kidney problems associated with tests of NDGA on rats. (Tyler, 1993).

Tyler is still concerned about the safety of chaparral. "I have never really recommended chaparral. Since it possesses no scientifically confirmed therapeutic utility, and since FDA has removed the primary ingredient NDGA from the GRAS list, I do not recommend its use. I honestly don't know why it is appearing to be hepatotoxic. Perhaps, as others have suggested, it is idiosyncratic." (Tyler, 1992).

Professor Norman R. Farnsworth is the Research Professor of Pharmacognosy and Senior University Scholar at the University of Illinois at Chicago and universally acknowledged as one of the leading medicinal plant experts in the world. As already briefly noted, during the late 1970s and early 1980s he headed a collaborative research team for the World Health Organization to look for natural plant-derived anti-fertility compounds. Because of the folk medicinal use of chaparral for various female conditions, the herb was tested for estrogenic activity and safety. "We've ripped this plant apart as part of the WHO program and we have not found any hepatotoxic properties. We only found estrogenic activity," he said. (Farnsworth, 1992)

HerbalGram contacted Dr. Tom Mabry, Professor of Botany at the University of Texas at Austin and author of a book on chaparral and its chemistry. (Mabry et al. 1979) Mabry, who is an expert on plant chemistry, thinks that there is simply too little evidence to support the indictment of chaparral as the primary cause of the reported cases of hepatitis. "I think the reports are overexaggerated compared with the long history of use of chaparral. It should not be taken off the market, in my opinion." (Mabry, 1993)

According to Rob McCaleb of the Herb Research Foundation, "Neither we nor the FDA have found sound scientific information in the literature to denote hepatotoxic properties of chaparral." The HRF has conducted a survey of four leading herbal companies and has calculated that the amount of chaparral sold in U.S. is at least 200 tons over the last 20 years. This figure translates into 500 million individual dosages or capsules (estimated at 500 mg. each). According to McCaleb, "This constitutes significant use as a dietary supplement." (McCaleb, 1992)

Dr. Samuel Page of FDA indicates that the agency and CDC feel that there is a strong correlation between these hepatitis cases and chaparral. His research indicates that the first two products have differing levels of NDGA and thus there appear to be two distinct types of chaparral on market. They have different chemical component profiles. He and his staff are looking for compounds that are structurally similar to NDGA which may or may not be NDGA metabolites. In response to a statement that other experts appear to be baffled, Dr. Page admitted, "We are baffled, too. The situation is probably idiosyncratic [a problem of individual sensitivity] but perhaps no one recognized it before. Physicians may have been unaware of the patients' taking chaparral and thus did not relate this to liver problems."

In attempting to explain the possible mechanism of toxicity, Dr. Lori Love, M.D, Ph.D., Acting Director of Clinical Research and Review at the Office of Special Nutritionals at FDA, explained that the etiology and pathogenesis (the origin of disease) are unknown but may be multifactoral and include such factors as immunogenetics and individual susceptibility. The known estrogenic activity of chaparral may also be involved with the reported liver problems, since it is known that women on birth control pills can have liver problems. (Love, 1992).

Dr. Andrew Weil is a physician with an undergraduate degree in botany from Harvard, where he also graduated from medical school. He relies heavily on botanical medicines in his Tucson, Arizona medical practice and recommends them in his lectures as an adjunct professor of medicine at the University of Arizona School of Medicine. In his most recent book, Natural Health, Natural Medicine Dr. Weil recommends chaparral in tincture or tea form for cervical dysplasia (p.270), the tea used topically for eczema (p.283), and chaparral capsules combined with the Chinese herb dong quai (Angelica sinensis), and damiana leaf (Turnera diffusa) for hot flashes associated with menopause (p.309) (Weil, 1990).

In his clinical experience of using this herb for almost 20 years, Dr. Weil has found it to be both safe and effective. Regarding the recently suggestions of hepatotoxicity of chaparral, Dr. Weil says, "We need a lot more information. It seems unlikely that chaparral is hepatotoxic. If these cases are correlated with chaparral ingestion, they are probably idiopathic sensitivity and the incidence of them out of the total number of people taking chaparral must be very very small." (Weil, 1992).

Carlos Hernandez is a Hispanic herbalist and massage therapist with over 20 years experience in the use of herbs. He has completed three years of pharmacy school and began his herbal studies with his grandfather who was a pharmacist in the Rio Grande Valley of South Texas. Hernandez says he has used chaparral successful to help cure a case of food poisoning. He says curanderos (folk healers) in Mexico use it for sluggish digestion, among other things, and that it is one of the most widely used herbs in Mexican herbalism, being found in every herb market in Mexico. He does not use it long-term but suggests it for short-term conditions such as bronchial mucous, in which chaparral will he used in tincture of tea form. He also uses it topically for infections in ointment form; he claims it is one of the best salves to increase granulation of open wounds. (Hernandez, 1993)

Hernandez's wife Kathy claims that chaparral cured her of chronic stomach difficulties she had experienced for many years. After using chaparral regularly, she says that, for the last five to six years, she no longer has had the problem. (Hernandez, 1993)

New Mexico herbalist and author Michael Moore normally recommends moderate doses. He says that chaparral itself is not normally toxic. (Moore, 1992)

Unanswered Questions

As HerbalGram goes to press, the matter of the alleged hepatotoxicity of chaparral has not yet been resolved. No etiologic agent has been identified in the present cases of hepatotoxicity nor has one been reported yet for chaparral in the scientific literature. The FDA, CDC, AHPA, HRF and ABC are cooperating in developing a scientific assessment of all of the available information. Until some type of resolution is reached, it is not clear whether there are reasonable grounds for concern over the use of this traditional herb, given its relatively wide and long history of use, or whether the cases reported are merely examples of idiosyncratic reactions. Additionally, there are questions being raised in the marketplace where virtually all products containing chaparral are being voluntarily suspended from sale by the industry. This includes, for the time being, products containing relatively small quantifies of chaparral in combination with other ingredients, despite the fact that most experts consider them to be safe.

In any event the current situation raises more questions than answers and casts a cloud over an herb that has a history of relatively safe use. On the brighter side, the chaparral issue might mark a new era of cooperation and mutual respect among FDA, the herb industry, and medicinal plant experts.

References:

American Herbal Products Association. 1992. Alert to Membership. December 11, 1992.

Brinker, Francis. 1991. Chaparral. in Native Healing Gifts: Rediscovering Indigenous Plant Medicines of the Greater Southwest. Tucson, AZ (unpublished).

Brinker, Francis. 1989. Larrea tridentata (Creosote Bush) Leaves and Twigs. Eclectic Dispensatory of Botanical Therapeutics. Portland, OR: Eclectic Medical Publications.

Centers for Disease Control and Prevention. 1992. Epidemiologic Notes and Reports. Chaparral-Induced Toxic Hepatitis -- California and Texas, 1992. Morbidity and Mortality Weekly Report. Vol. 41, No. 43, 812-814.

Der Marderosian, Ara and Liberti, Larry. 1988. Natural Products Medicine. Philadelphia: Geo. F. Stickley Co.

Duke, James A. 1985. CRC Handbook of Medicinal Herbs. Boca Raton, FL: CRC Press.

Farnsworth, Norman R. Personal communication, December 14, 1992.

Food and Drug Administration. 1992. HHS News: press release on chaparral consumption. December 10, 1992.

Gyllenhaal, Charlotte. 1989. Chaparral Tea, a Report Prepared for Emprise, Inc. Contract for National Cancer Institute Study of Unconventional Cancer Treatments. Washington, DC: Emprise, Inc. (unpublished)

Hernandez, Carlos and Kathy, personal communication, January 10, 1993.

Katz, Miriam and Saibil, Fred. 1990. Herbal Hepatitis: Subacute Hepatic Necrosis Secondary to Chaparral Leaf. Journal of Clinical Gastroenterology 12(2):203-206.

Love, Lori. Personal communication, December 14, 1992.

Mabry, T.J. personal communication, January 19, 1993.

Mabry, T.J., Hunziker, J.H., DiFeo, D.R. 1979. Creosote Bush: Biology and Chemistry of Larrea in New World Deserts. Stroudsburg, PA: Dowden, Hutchinsen, & Ross.

McCaleb, Robert M. Personal communication, December 14, 1992.

Moore, Michael. personal communication, December 27, 1992.

Moore, Michael. 1989. Medicinal Plants of the Desert and Canyon West. Santa Fe: Museum of New Mexico Press.

National Nutritional Foods Association. 1992. Industry Alert: FDA Issues Warning Against Consumption of Chaparral: NNFA Recommends Removal of the Herb. NNFA Update. Costa Mesa, CA. Dec. 16, 1992.

Obermeyer, William. Personal communication, December 15, 1992.

Page, Samuel. Personal communication, December 14, 1992.

Philen, Rossanne. Personal communication, December 14, 1992.

Philen, Rossanne. Personal communication, January 8, 1993(a). Philen, Rossanne, Personal communication, January 19, 1993(b).

Segelman, Alvin. 1992. Chaparral. 6th International Conference on Folklore and Folk Medicine. Kingsville, TX. December, 1992.

Smart, C.R., C.R. Hogle, H. Vogel, A.D. Broom and D. Bartholemew. 1970. Clinical experience with nordihydroguaiaretic acid. Rocky Mr. Med. Journal. 1970: 39-43.

Tyler, Varro E. 1993. The Honest Herbal. Binghampton, NY: Haworth Press. (in press)

Tyler, Varro E. personal communication, December 15, 1992.

Tyler, Varro E. 1987. The New Honest Herbal. Philadelphia: Geo. F. Stickley Co.

Weil, Andrew T. Personal communication, December 14, 1992.

Weil, Andrew T. 1990. Natural Health, Natural Healing. Boston: Houghton Mifflin.

American Botanical Council.

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By Mark Blumenthal

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