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Institute of Medicine (US) and National Research Council (US) Committee on the Framework for Evaluating the Safety of Dietary Supplements. Dietary Supplements: A Framework for Evaluating Safety. Washington (DC): National Academies Press (US); 2005.

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Dietary Supplements: A Framework for Evaluating Safety.

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Appendix JPrototype Focused Monograph: Review of Liver-Related Risks for Chaparral1

I. DESCRIPTION OF THE INGREDIENT

A. Chaparral as a Dietary Supplement Ingredient

Chaparral is one name for an herbaceous woody shrub that grows in the southwestern region of the United States and the northern region of Mexico. It is also called creosote bush or greasewood. The common Spanish names are hediondilla, which means “little smelly one,” because the bush has a strong odor similar to the smell of creosote (a distillate of coal/ wood tar used as a wood preservative), and gobernadora, which means “governess,” because the bushes can dominate an area by creating an adverse environment for the growth of other plants, resulting in a monoculture in some areas (Schultz and Floyd, 1999). One remarkable feature of the chaparral bush is the complex resinous coating on the leaves that serves as a chemical defense against grazing by herbivores and against attack by insects. The chemicals in the resin find their way into the desert soil surrounding the chaparral plant and discourage growth by other plant species, thus effectively reducing competition for water and nutrients (Mabry et al., 1977).

Chaparral is formally known as Larrea tridentata (Sessé and Moc. ex DC.) Coville (synonymous with Larrea mexicana Moric.) of Zygophyllaceae (McGuffin et al., 1997). Historically, the dry leaves, green stems, and fine twig tips of chaparral were used for various ailments. Since about 1969, these same plant components have been used as dietary supplements. Various forms have been available: dried plant material for making teas (water extracts), aqueous-alcoholic extracts or tinctures, and tablets or capsules containing ground, dried plant material. During the past 10 years, chaparral products have not been as readily available as in the past; however, each of these forms is currently available in the U.S. marketplace in varying degrees.

B. Individual Components

Table A contains a list of the components of primary interest in chaparral (i.e., present in leaves, stems, and twigs). Some components of chaparral are common in other plants and are widespread in the human diet. The major components of the resinous coating of chaparral are lignans (Mabry et al. 1977; Sakakibara et al. 1976) which can comprise up to 80 percent of some extracts of chaparral, such as methanol extracts of green leaves or green stems (Hyder, 2001). Lignans are low-molecular-weight plant products made up of phenylpropanoid dimers or trimers. Mature chaparral leaves contain lower amounts of lignans than new leaves (Gisvold and Thaker, 1974). The major lignan in chaparral is nordihydroguaiaretic acid (NDGA) (Downum et al., 1988), which is a derivative of guaiaretic acid and is a catechol having two hydroxyl groups on each of the two phenol rings. NDGA comprises approximately 10 percent of the dry leaf weight, but may be as much as 15 percent in some instances (Obermeyer et al., 1995). NDGA comprises approximately 50 percent of the phenolic resin extracted from the external surface of the leaves (Botkin and Duisberg, 1949; Mabry et al., 1977; Sakakibara et al., 1976). Chaparral also contains guaiaretic acid and other substituted guaiaretic acid derivatives (Table A). Other lignans in chaparral are classified as furanoid lignans and 1 aryl tetralin lignans. The latter are structurally related to podophyllotoxins.

TABLE A. Chaparral: Individual Components.

TABLE A

Chaparral: Individual Components.

Chaparral contains flavonoids as non-water-soluble aglycones, as water-soluble glycosides, and as sulfated flavonoids (Mabry et al., 1977). Chaparral also contains triterpenes, including sapogenins (Mabry et al., 1977). The aglycone forms of the flavonoids and triterpenes are listed in Table A. Chaparral contains volatile oils, wax esters, sterols, and other hydrocarbons (Mabry et al., 1977; Waller and Gisvold, 1945).

Although a number of the known components of chaparral exhibit cytotoxic activity under various conditions, these effects are judged to be weak and require high concentrations of the substance, and thus would extrapolate to the ingestion of large amounts of chaparral in order to exhibit potential toxic activity in humans. Additionally, many of these components are present in the diet from other sources.

C. Description of Dietary Supplement Preparations and Amounts Ingested in Ordinary Use

Chaparral is sold in several forms, one of which is the dried, broken leaves, green stems, and fine twig tips that can be brewed as a tea (i.e., an aqueous extract). An example of the modern preparation of chaparral tea would be to steep 7 to 8 g of crumbled dried leaves, stems, and twigs in one quart of hot water. In ordinary use as a water extract, chaparral might be consumed in the amount of 1 to 3 cups of chaparral tea per day for a period of 2 to 3 weeks (Micromedex, 2002).

Another form of chaparral is a tincture or aqueous alcohol extract. The ordinary use of such an extract might be 20 to 30 drops per day for a period of 2 to 3 weeks (Micromedex, 2002).

Chaparral is also available as a dried leaf powder (frequently sold in capsule or tablet form). Typical suggested uses of such capsules or tablets would be one to two 500-mg capsules or tablets per day for 2 to 3 weeks.

Chaparral is also available as a component of various botanical mixtures sold as tinctures and as loose leaves, stems, and twigs for teas. Chaparral dried leaf capsules are also available in combination with silymarin (a flavanolignan complex from milk thistle), vitamin C, or other antioxidants.

II. INFORMATION RELEVANT TO LIVER CONCERNS

A. Human Use Information and Safety Data

1. Historical use

Chaparral has been used for many centuries for a variety of medicinal purposes (Heron and Yarnell, 2001). Native populations in the southwestern United States have used chaparral tea for decades without published evidence of toxicity. Most processing of chaparral used in American Indian cultures involved aqueous extracts, such as hot water teas (Heron and Yarnell, 2001). A tea has very little NDGA (a constituent of concern, see below) compared with an alcoholic extract or the powdered dry leaf because NDGA is poorly soluble in water (Obermeyer et al., 1995). Pima Indians used the tea orally as a diuretic, emetic, or expectorant, and topically as an antiseptic or poultice (Mabry et al., 1977). In many American Indian cultures, chaparral tea has been used to mitigate colds, bronchitis, and other breathing problems; for menstrual cramps; and for numerous intestinal problems. It has also been applied topically for painful joints, skin infections, snakebites, burns, and allergies (Mabry et al., 1977; Moerman, 1998). The leaves have been used both as a decoction in a bath or as an external poultice for rheumatism and arthritis, as well as for scratches, wounds, and bruises (Moerman, 1998). There are a few reports of the use of chaparral extracts by southwest native healers in the management of type 2 diabetes (Gowri et al., 2000). In the medical literature there is a paucity of reports involving the ingestion of chaparral capsules or tablets, except for those resulting in adverse effects (described below).

2. Adverse effects

The clinical data suggest a pattern of hepatotoxicity. This pattern is discussed in more detail below. One difficulty in evaluating the clinical data on chaparral is that in most of the cases, the chaparral preparation ingested was not described in any detail. Additionally, the product purity and quality were not reported.

Clinical trial data: Table B provides a summary of a small clinical trial that was conducted among 59 terminal cancer patients to examine the effect of NDGA and chaparral tea on tumor growth. Thirty-six patients consumed chaparral tea (16–24 oz/d) while 23 patients consumed NDGA (250–3,000 mg/day). Selected blood tests and urinalysis were repeated at 2 to 4 week intervals. An analysis of the 45 patients who were treated for at least 4 weeks suggested that there were no hematological or chemical abnormalities that could be attributed to the treatment. Patients reported minor adverse effects as described in Table B. Of the 59 treated patients, no pattern of hepatotoxicity was reported following consumption of either chaparral tea or NDGA by the terminally ill cancer patients. The reasons why 14 subjects dropped out were not reported.

TABLE B. Chaparral: Summary of Adverse Effects in a Clinical Trial.

TABLE B

Chaparral: Summary of Adverse Effects in a Clinical Trial.

Clinical case reports: Table C-1 summarizes clinical case reports of patients who took chaparral without the added complication of additional ingredients. Careful inspection of Table C-1 reveals 9 cases of well-diagnosed hepatotoxicity (Cases #1–9) and 6 cases of suspected or probable hepatotoxicity (Cases #10–15). The cases are arranged in order of apparent severity with the most severe case, which required a liver transplant, presented as Case #1. Many of these patients ingested chaparral in capsule or tablet form (Cases #1–3, 5–11). Most of the chaparral products were unidentified as to whether they contained dried plant material or extracts. The listed amount of chaparral ingested ranged from 0.3 to 6 g/day; however, this information was not included in all case reports. The duration of chaparral use (which is not indicated in 2 of the cases) ranged from 20 days to “many years.” It is notable that Case #15 was the only patient known to use chaparral tea: 4 bags daily for 1.5 years. The product used by this patient was examined using microscopic and chromatographic analysis and was correctly identified as Larrea tridentata with no evidence of biochemical or biological contamination (Sheikh et al., 1997). The severity of the liver damage in these case reports does not seem to correlate directly with either the amount of chaparral consumed or the duration of use. There are five cases with documented recovery from liver damage after cessation of chaparral use (Cases #2, 5, 8, 9, 10). There is one case (#8) documenting a return of jaundice following resumption of chaparral ingestion.

Table C-2 summarizes the clinical case reports of patients who took chaparral in combination with other supplements or ingredients, primarily other botanicals. The six cases of hepatotoxicity found in Table C-2 are difficult to evaluate because of the confounding factor of possible adverse effects due to these other substances. These cases include well-documented hepatotoxicity (Cases #17–20) but the cause of the liver damage is difficult to interpret. Two cases returned to normal after cessation of chaparral (Cases #18, 22). There are also reports (Cases #25–29 and Series A) of subjects taking an aqueous alcoholic extract (90 percent ethanol) as 8 to 10 percent of a formula with other herbs, ingesting a total of 30 to 240 mL over a period of 40 days to 5 months, with no indication of liver damage according to liver function tests.

Adverse event reports to Special Nutrition/Adverse Event Monitoring System (SN/AEMS): Table D presents the available information on cases reported in the SN/AEMS. The 18 reports include 12 cases indicating varying degrees of liver damage. (These 12 cases are included among the patients in Table C-1.) It should be noted that in the SN/AEMS reports there is no indication of whether a causal relationship exists between the adverse event and chaparral ingestion.

TABLE D. Chaparral: Summary of Adverse Event Reports from the Special Nutritionals Adverse Event Monitoring System (SN/AEMS).

TABLE D

Chaparral: Summary of Adverse Event Reports from the Special Nutritionals Adverse Event Monitoring System (SN/AEMS).

3. Interactions

There are no known interactions with chaparral.

4. Consequences of unusually large intake or chronic cumulative use

There may be adverse effects associated with consumption of excessively large amounts of chaparral (Heron and Yarnell, 2001). This type of overuse is typically related to encapsulated chaparral products.

B. Animal Studies

Animal studies on chaparral: There were no animal studies identified that showed liver toxicity as the result of chaparral administration. In studies with rats, significant toxic effects were demonstrated following administration of chaparral; however, the nature of the toxicity was not documented (Nakazato et al., 1998; Ulreich et al., 1997). The ethanol:water tincture of chaparral administered to the rats was lethal in the relatively large amounts administered in these studies. In all, there is evidence of considerable toxic effects from four different animal models: using rats (Konno et al., 1987; Nakazato et al., 1998; Ulreich et al., 1997), hamsters (Granados and Cardenas, 1994), chickens (Zamora, 1984), and insects (Mabry et al., 1977) with relatively high exposures to chaparral. In considering all of the animal studies (Table E), the evidence evaluating any aspects of the safety of chaparral in animal studies is minimal.

TABLE E. Nordihydroguaiaretic Acid (NDGA): Summary of Animal Studies.

TABLE E

Nordihydroguaiaretic Acid (NDGA): Summary of Animal Studies.

Acute studies on NDGA in animals: The evidence evaluating the safety of NDGA, a major component of chaparral, is more substantial but is still incomplete (Table E). NDGA administered by gavage to rats and mice was reported to have an LD50 of > 4 g/kg body weight. NDGA was somewhat more toxic in guinea pigs, with an LD50 of 0.8 g/kg body weight. Thus, the LD50 is less than 100× a typical human intake.

Chronic studies on NDGA in animals: Chronic studies on the safety of NDGA are limited to toxicity studies conducted primarily in small rodents (Table E). Rats fed NDGA at 0.5 percent of their diet exhibited massive hemorrhages and multiple renal cysts in experiments reported only in abstract (Cranston et al., 1947) and reviews (Lehman et al., 1951). Strong evidence has been published that NDGA fed to rats at high doses (1 or 2 percent of the diet) clearly leads to various pathological changes. In various rat models, growth inhibition and structural changes in or near the kidney have been shown to develop within 2 to 6 months (Cranston et al., 1947; Gardner et al., 1986, 1987; Lehman et al., 1951). Renal and mesenteric cysts form within 6 to 12 months of NDGA feeding (Goodman et al., 1970; Grice et al., 1968; Lehman et al., 1951). By 18 months of feeding 1 percent NDGA (Grice et al., 1968) or 6 months of feeding 2 percent NDGA (Evan and Gardner, 1979), the development of renal and mesenteric cysts is profound. The renal cysts contained degenerating tubular cells and the renal damage was predominantly in the proximal convoluted tubules. Biochemical analysis showed no free NDGA in the lymph nodes or kidney extracts; only the orthoquinone metabolite of NDGA could be detected (Grice et al., 1968).

In complementary studies, single dose administration of 250 mg of NDGA into the small intestine of rats revealed formation of the orthoquinone metabolite at the region of the ileocecal junction (Grice et al., 1968).

Studies using other species and/or other routes of administration verify the toxicity of NDGA (Giri and Hollinger, 1996; Hsu et al., 2001; Madrigal-Bujaidar et al., 1998; Mikuni et al., 1998; Telford et al., 1962).

Other observations: Pretreatment of rats with NDGA (50 mg/kg body weight, by gavage) significantly aggravated indomethacin-induced gastric ulcers (Cho and Ogle, 1987). Treatment of rats with NDGA (10 μg/kg body weight, by intravenous administration) worsened ischemia-reperfusion injury to liver (Okboy et al., 1992).

C. In Vitro Studies

Investigations on the in vitro effects of chaparral and NDGA on a variety of chemical and biological systems are summarized in Tables F-1 and F-2. While a few studies involved extracts of chaparral, most focused on the effects of NDGA, and a few considered the effects of other lignans with structural similarities to NDGA.

TABLE F-1. Chaparral: Summary of In Vitro Studies.

TABLE F-1

Chaparral: Summary of In Vitro Studies.

TABLE F-2. Nordihydroguaiaretic Acid (NDGA): Summary of In Vitro Studies.

TABLE F-2

Nordihydroguaiaretic Acid (NDGA): Summary of In Vitro Studies.

Some cytochrome P450 oxidations are inhibited by NDGA in vitro (Agarwal et al., 1991; Capdevila et al., 1988).

D. Liver-Related Information About Related Substances

Studies on taxonomically related substances: Five species of Larrea are recognized: the bifolate species, L. tridentata (native to the southwestern United States and northern Mexico), L. divaricata (native to northwestern Argentina and parts of Peru), and L. cuneifolia (native to Argentina), plus two multifolate species that grow at high altitudes, L. nitida (native to certain parts of South America, especially Argentina) and L. ameghinoi (native to a few parts of South America) (Brinker, 1993–1994). No useful safety data were found on L. cuneifolia, L. nitida, or L. ameghinoi. The toxicity of L. divaricata, a South American species that is taxonomically related to L. tridentata, has been studied to a very limited extent. A water extract of the dried leaves was injected into mice intraperitoneally and the LD50 was found to be 10 g/kg body weight for males and 4 g/kg for females (Anesini et al., 1997).

Substances related to the individual components of chaparral: Table G contains a list of substances that were considered as structurally, taxonomically, or functionally related to the components of chaparral (present in leaves, stems, and twigs). Known toxicities of these related substances were considered in evaluating the potential toxicity of chaparral. For comparison, Table A contains a listing of the known components of chaparral with the chemical structures of those that may be relevant to the safety of chaparral. In Table G it should be noted that larreantin is a potential hepatotoxin and is known to be present in the root of L. tridentata (Luo et al., 1988). Several mechanisms were considered whereby it might be possible that chaparral products could contain larreantin. First, chaparral root might be included with the other plant material (leaves, stems, and twigs). Second, under certain environmental conditions, a component of the root of a plant might physiologically be present in the leaves. Third, the presence of trace amounts of larreantin in the leaves, stems, or twigs could have been undetected. Although each of these mechanisms is possible, it seems unlikely that larreantin is present in chaparral preparations in significant amounts.

TABLE G. Chaparral: Related Substances That Might Suggest Risk.

TABLE G

Chaparral: Related Substances That Might Suggest Risk.

Functionally related substances: It was reported that NDGA is metabolized to an orthoquinone derivative (De Smet, 1993; Grice et al., 1968), which could be further metabolized by conjugation to glutathione. Because hepatic levels of glutathione are often limiting, drugs undergoing glutathione conjugation could interact negatively with the quinone derivative of NDGA by both substances drawing on glutathione reserves in the liver, leading to glutathione depletion (Slattery et al., 1987).

Knowledge about chemical structures of chaparral components: As stated above, NDGA is metabolized to an orthoquinone derivative (De Smet, 1993; Grice et al., 1968). Acetaminophen is also a quinone, but one that is understood to be cytotoxic and to cause substantial liver problems. Large doses of acetaminophen cause centrilobular hepatic necrosis (Hojo et al., 2000). The current understanding is that the hepatotoxicity of acetaminophen is due to cytochrome P450-dependent formation of N-acetyl para-(benzo)quinone imine (NAPQI) in the centrilobular region of the liver (Harman et al., 1991; Hojo et al., 2000; Holme et al., 1984).

By extrapolation, the site of chaparral toxicity might be expected to reflect the site of metabolism of NDGA to the quinone. NAPQI causes mitochondrial damage, including inhibition of oxidative phosphorylation (Andersson et al., 1990; Fujimura et al., 1995; Moore et al., 1985). Likewise, NDGA causes inhibition of the mitochondrial electron transport chain. Thus there are some similarities between NAPQI toxicity and NDGA toxicity that can be used to hypothesize a mechanism of hepatotoxicity based on the formation of a NDGA quinone. Acetaminophen-induced toxicity is also seen in the kidney, another site of metabolism of the drug to NAPQI. Therefore, one might hypothesize that chaparral ingestion would lead to toxicity in the kidney also if chaparral toxicity is related to NDGA metabolism to a toxic quinone, which is purely theoretical. Indeed, renal toxicity of NDGA is evident in animal studies (Table E).

III. OTHER RELEVANT INFORMATION

A. Sources

Chaparral grows as a wild desert shrub. It is an evergreen bush that grows in arid regions and can reach a height of 9 feet (Brinker, 1993–1994). The identification of the plant used as L. tridentata is very important to the safety of the chaparral product.

Misnaming and species identification: There may be some instances of substitution of another plant product for L. tridentata. L. divaricata has been commonly confused with L. tridentata. The two species are very similar in appearance (Brinker, 1993-1994), but originate from distinct locations. The major source of confusion is the misnaming of the two species, even in published reports of clinical or experimental data (Gisvold, 1947; Smart et al., 1970).

Contaminants and adulterants: Adulteration has not been reported.

Processing issues: As described in the human use information section, most processing of chaparral used in American Indian cultures involved aqueous extracts, such as hot water teas (Heron and Yarnell, 2001). A tea has very little NDGA compared with an alcoholic extract or the powdered dry leaf because NDGA is poorly soluble in water (Obermeyer et al., 1995).

The extraction liquid generally used to make a tincture of chaparral has a high percent of ethanol (up to 95 percent, v/v) so that the extract will contain phenolic compounds, such as NDGA and flavonoids. The amount of solvent-extractable natural products does not change considerably regardless of whether fresh or dried leaves are used in processing (Mabry et al., 1977). The solvent used does make a considerable difference in the quantity of individual components. Diethyl ether gives a high yield, as compared with 85 percent aqueous methanol, which also extracts considerable chlorophyll (Mabry et al., 1977).

Analytic issues: Analytical methods have been published for the determination of a number of components of chaparral. These methods include gas liquid chromatography, high pressure liquid chromatography, and mass spectrometric analysis of lignans (Gonzalez-Coloma et al., 1988; Obermeyer et al., 1995; Valentine et al., 1984), and the ammonium molybdate spectrophotometric assay for NDGA (Duisberg et al., 1949). Pharmacokinetic analysis of NDGA administered to mice used a method with a limit of detection of 0.5 μg/mL plasma or serum (Lambert et al., 2001).

B. Conditions of Use Suggested or Recommended in Labeling or Other Marketing Material

Common popular uses: Chaparral has had numerous ethnomedicinal, homeopathic, and folk medicine uses. Homeopathic medicine has used chaparral tea in the treatment of colds, cold sores, coughs, bronchitis, viral infections, urinary tract infections, indigestion, heartburn, abdominal cramps, enteritis, dysentery, parasites, dysmenorrhea, menstrual cramps, premenstrual syndrome, neuritis, and sciatica (Heron and Yarnell, 2001; Mabry et al., 1977). Chaparral has been used as an abortifacient and as a means to increase fertility (Heron and Yarnell, 2001). Chaparral products have been described as having a beneficial impact on liver metabolic functions (Heron and Yarnell, 2001).

In folk medicine, chaparral has been used for leukemia and many different types of cancers. It has been suggested that chaparral contains immune-stimulating polysaccharides and that NDGA may have some antitumor properties. From conventional medical sources there is anecdotal and in vitro evidence of cytotoxic activity with varying toxicity depending on the concentration of NDGA.

Currently chaparral is marketed to consumers for arthritis, rheumatism, and bursitis; as an antioxidant; for immune function; for various cancers, such as melanomas, leukemia, breast cancer, ovarian cancer, and Kaposi's sarcoma; as a blood and liver cleanser; as a diuretic; for colds and the flu; for herpes family viruses including herpes simplex, herpes zoster, cytomegalovirus, and Epstein-Barr; and for acne and skin disorders.

C. Liver-Related Cautions Noted

Cautions provided in labeling or other marketing material: A review of chaparral product labels and Internet marketing materials indicates that many (but not all) provide cautions to consumers to seek advice from health care providers before using the product if they have a history of liver or kidney disease or currently have digestive problems and to avoid using if pregnant or nursing. One caution indicated that the chaparral product was not intended for long-term use. Two informational websites that did not sell chaparral products suggested that people consuming chaparral tea should drink 3 cups a day for a maximum of 2 weeks unless under the care of a physician or health practitioner experienced in the use of botanical medicines. At least three informational websites that did not sell products cautioned against the use of chaparral capsules since several adverse event reports were associated with this form.

Cautions issued by manufacturing associations: In 1994 the American Herbal Products Association (AHPA) commissioned a review. Four case studies were examined and it was concluded that:

… since the patients were ingesting chaparral during the time each developed acute hepatitis, most likely of a hepatocellular nature, it is reasonable to conclude a relationship exists between the ingestion and the disease. However, no clinical data were found in the medical records to indicate that chaparral is inherently a hepatic toxin. Moreover, each patient had a medical history not incompatible with prior liver disease. A fair conclusion is [that] the disease in each patient was the result of an individual idiosyncratic reaction to the drug [botanical product], possibly the result of an autoimmunologic reaction, which given the quantity of chaparral ingested in this country, must be exceedingly rare (AHPA, 2002).

Following the Food and Drug Administration (FDA) warning issued in 1992 (see Section IIIE, below), many manufacturers voluntarily removed most products containing this botanical (FDA, 1993). In 1995 AHPA recommended that if member companies chose to sell chaparral, all consumer labeling contain the following informational language:

Seek advice from a health care practitioner before use if you have had, or may have had, liver disease. Discontinue use if nausea, fever, fatigue or jaundice (e.g., dark urine, yellow discoloration of the eyes) should occur (APHA, 2002).

D. Usage Patterns

Prevalence of use in the general population: According to a survey conducted by the Herb Research Foundation from 1973 to 1993, at least 200 tons of chaparral was sold in the U.S. market (Blumenthal, 1993). This would be equivalent to 500 million doses at 500 mg/dose. No current data are available; there has been no recent tracking of sales data.

Knowledge of use by particular groups: There are no published surveys in the literature that provide knowledge about the use of chaparral by specific groups. However, anecdotal reports suggest that indigenous American Indian groups in the southwestern United States and Hispanics may use chaparral, primarily as an aqueous extract (tea).

E. Information on Regulatory Actions

FDA actions: In late August and early September 1992, FDA and the Centers for Disease Control and Prevention (CDC) were informed of two cases in which individuals consuming chaparral over several weeks experienced severe jaundice and abdominal pain. These cases, and the potential link between acute nonviral hepatitis and chaparral, were discussed in an issue of Morbidity and Mortality Weekly Report (CDC, 1992).

In a press release issued in December 1992, the FDA Commissioner conveyed a public advisory against the purchase or consumption of chaparral because it was associated with acute toxic hepatitis (FDA, 1992). FDA advised chaparral users to stop taking chaparral immediately and to consult a physician if a user had a history of liver disease or was not feeling well (FDA, 1992). Subsequent warnings were issued (CFSAN, 1993).

The major lignan in chaparral is NDGA, a potent antioxidant. Beginning in 1943, NDGA (at 0.02 percent, w/w) was used as an antioxidant in many foods (Mabry et al., 1977). In 1968 NDGA lost its status as a generally recognized as safe ingredient. FDA then required removal of NDGA from most foods. The U.S. Department of Agriculture oversees the safety of meats and meat products; at this time, it allows use of NDGA as an antioxidant in lard, animal shortening, and other products that are susceptible to the development of rancidity.

Other relevant regulatory actions: Canadian regulations do not allow chaparral as a nonmedicinal ingredient for oral-use products (McGuffin et al., 1997). The current edition of the German Commission E monographs does not mention chaparral (Blumenthal, 1998).

F. Available Information on Physiological and Biochemical Aspects

Very little is known about the digestion, absorption, distribution, metabolism, and excretion of some chaparral components (triterpenes). Other components have been well characterized (i.e., fatty acids and other hydrocarbons).

There is one pharmacokinetic study on NDGA. In female mice, NDGA was administered i.v. at 50 mg/kg to yield a primary half-life of 30 min and a secondary half-life of 135 minutes, with the peak plasma concentration Cmax being 15 μg/mL (Lambert et al., 2001). It has been reported that a major metabolite of NDGA is the orthoquinone derivative (De Smet, 1993; Grice et al., 1968).

G. Supplementary Information

No information applicable to liver concerns.

IV. TABLES ON CHAPARRAL*

Table AChaparral: Individual Components
Table BChaparral: Summary of Adverse Effects in a Clinical Trial
Table C-1Chaparral: Summary of Clinical Case Reports
Table C-2Summary of Clinical Case Reports and a Case Series Report with Chaparral Used in Combination
Table DChaparral: Summary of Adverse Event Reports
Table ENDGA: Summary of Animal Studies
Table F-1Chaparral: Summary of In Vitro Studies
Table F-2NDGA: Summary of In Vitro Studies
Table GChaparral: Related Substances that Might Suggest Risk

V. SUMMARY AND CONCLUSIONS

A. Summary

Reports of chaparral toxicity are inconsistent. Reportedly native populations in the southwestern United States have used chaparral tea for decades without evidence of toxicity. In addition, a clinical study looking at chaparral tea and NDGA in advanced, incurable cancer patients showed no evidence of hepatotoxicity. Limitations of this study included a lack of detail on those who did not complete the trial (25 percent of the subjects). This evidence is somewhat inconsistent with other information on chaparral use, as follows.

There are nine reported cases of definite hepatotoxicity temporally related to chaparral use as a single known agent; there are an additional six cases of possible hepatotoxicity. Five of the cases exhibited documented recovery after cessation of chaparral use and one case exhibited abnormal liver function upon rechallenge. One patient required an orthotopic liver transplant but had major confounding variables, such as hepatitis C and prior drug and ethanol abuse. In all the other cases, liver function tests became significantly abnormal with clinically evident jaundice that reversed upon discontinuation of chaparral use. In at least three cases of chaparral-associated hepatotoxicity, the patient had prior history of alcohol abuse or underlying liver disease and may represent a vulnerable population.

In determining causation, one looks for a dose-response relationship. The amount of chaparral ingested ranged from 0.3 to 6 g/day over periods ranging from 20 days to “many years.” The absence of pharmacokinetic data or even characterization of the formulations ingested made it difficult to determine actual dose in the various case reports. Thus there was no apparent dose-response relationship, although evidence of toxicity was clearly reflected in abnormal liver function tests.

Another important factor in determining causation is characterization of the product responsible for the adverse effect. In most of the reported cases, the product ingested by the subject was simply described as chaparral capsules or tablets. This description does not reveal whether the contents of the capsule or tablet were dried, ground plant material or dried extract. Further, without examination of the quality of the product, contamination or adulteration cannot be ruled out.

Only in 1 out of the 15 case reports of chaparral-associated hepatotoxicity was it reported that a chaparral tea had been ingested. This is important because chaparral tea contains very little NDGA or other lipophilic compounds as compared with other preparations, such as a dried extract prepared with an organic solvent. If NDGA is the causal agent, the content of NDGA in various preparations becomes an important variable in determining causality.

Animal studies evaluating chaparral did not show hepatotoxicity. Animal studies evaluating NDGA did not exhibit hepatotoxicity, but did exhibit renal proximal tubular damage and cyst formation. In other studies, rodents exhibited both renal and hepatic toxicity in response to the toxic quinone imine from acetaminophen; this involves proximal tubular damage, but not cyst formation. A plausible mechanism in both hepatotoxicity and nephrotoxicity is the cytochrome P450-dependent metabolism of NDGA to a toxic quinone with failure to remove this reactive metabolite by conjugation if glutathione is limiting. The link between the nephrotoxicity of NDGA in animals and the hepatotoxicity of chaparral in humans is not definite, but similar links have been shown with structurally related chemicals, such as the quinone of acetaminophen.

While the human data strongly suggest an association between chaparral consumption and hepatotoxicity, a number of confounding factors also require consideration. The temporal clustering of the majority of the hepatotoxicity cases (1992–1993) provides some suggestion of a localized contamination problem. Inadequate characterization of the preparations used by individual patients does not allow determination of possible product contamination during harvesting/processing or natural alterations in composition of chaparral plants due to environmental factors. If typical chaparral preparations contained hepatotoxic principles, it is possible that many more reports of human hepatotoxicity during the period of significant chaparral use (1970–1992) would have emerged. Pre-existing liver disease, including excessive alcohol use, hepatitis, or chronic acetaminophen use, could possibly have predisposed some of the individuals to hepatotoxicity. Such possibilities are hypothetical, but the quality of the data provided in the case reports is inadequate to rule out such possibilities.

B. Conclusions and Recommendations About Liver Concerns

Conclusions (concerns and caveats): The available literature raises concern for hepatic toxicity. The reasons for concern about hepatotoxicity and possibly related nephrotoxicity can be summarized as case reports showing a pattern of hepatotoxicity, nephrotoxicity in rats given NDGA, and in vitro studies showing that NDGA exhibited cytotoxic activity. The consistency and biological plausibility of these observations is strengthened by knowledge of NDGA structure and knowledge about mechanisms of quinone toxicity.

While the human data strongly suggest an association between chaparral consumption and hepatotoxicity, a number of confounding factors also require consideration. There was a clinical study (published in 1970) in which serum glutamic-oxaloacetic transaminase (SGOT), a marker of liver damage, was evaluated; this was an uncontrolled, poorly designed study, yet no elevation in SGOT was reported. However, the subjects were critically ill cancer patients and 15 of the subjects (25 percent of the total) were removed from the study. At the time of this study, there was no awareness of a possible relationship between chaparral ingestion and hepatotoxicity; these individuals could have been removed from the study because elevations in SGOT were used to indicate a measure of general health and appropriateness, a possible criteria to remain in the study.

The temporal clustering of the majority of the hepatotoxicity cases (1992–1993) provides some suggestion of localized contamination or a variation in constituent concentration, perhaps due to inadequate characterization or lack of standardization. It is unfortunate that animal studies were not conducted at the time this cluster of hepatotoxic events was reported. During a period of 20 years (1973–1993), 200 tons of chaparral was sold on the U.S. market, equivalent to 500 million doses at 500 mg/ dose. If typical chaparral preparations contained hepatotoxic principles, it is possible that many more reports of human hepatotoxicity during the period of significant chaparral use (1970–1992) would have emerged. Traditional uses of chaparral tea by native populations have not revealed reports of hepatotoxicity. Pre-existing liver disease, including excessive alcohol use, hepatitis, or chronic acetaminophen use, may have predisposed some of the individuals to hepatotoxicity. Since the quality of the data provided in the case reports is inadequate to rule them out, such possibilities remain hypothetical.

The evidence for toxicity of chaparral in humans is supported by a similar toxicity observed in animal studies using NDGA. Classic toxicity studies with NDGA were conducted in several species, and toxicity of NDGA was demonstrated over a range of doses; this is a common finding in toxicity studies using different animal species (Ashby, 2002). Of the animal studies reported, only two identified hepatic effects following administration of NDGA to rats or mice; the one mouse study used intraperitoneal administration of NDGA and is confounded by coadministration of endotoxin, a known hepatotoxin. Thus only minimal hepatotoxicity was exhibited in animals treated with NDGA. However, if toxicity of a compound is related to the site of its metabolism, hepatotoxicity would be expected because liver is the major site of xenobiotic metabolism. Instead, nephrotoxicity was the major toxicity found in rats treated with NDGA; this nephrotoxicity is discussed in detail below (Kacew, 2001).

Of the 15 reported cases of chaparral-associated hepatotoxicity, only 1 was associated with ingestion of chaparral tea, whereas 11 cases were associated with ingestion of capsules or tablets containing chaparral. If NDGA contributes to the toxicity, it is important to note that NDGA and other nonpolar compounds, including lignans, appear to be minimal in a water extract/tea in contrast to an alcoholic extract (Obermeyer et al., 1995). This differential extraction of lignans by water versus alcohol extraction (Obermeyer et al., 1995) is explained by the lipophilic character of lignans. Therefore, alcoholic extracts of leaf or other aerial plant parts would contain larger amounts of NDGA and other lipophilic compounds than a water extract/tea.

NDGA can be expected to be a substrate for cytochrome P450-dependent quinone formation based on its chemical structure, as well as on evidence discussed by Obermeyer et al. (1995). A plausible mechanism of cytotoxicity of NDGA is the cytochrome P450-dependent metabolism to a toxic quinone and failure to remove this reactive metabolite by conjugation if glutathione is limiting. The link between the nephrotoxicity of NDGA in animals and hepatotoxicity of chaparral in humans is based on the fact that both the renal proximal tubules and the liver are major sites of xenobiotic metabolism. A parallel finding has also been demonstrated in rodents; both renal and hepatic toxicity develop in response to the toxic quinone imine from acetaminophen.

Summary of the conclusions: Although substantial limitations exist in the available information, concerns about the hepatotoxicity of chaparral remain based on the weight of the evidence discussed above. This is especially applicable for certain groups, including those with pre-existing hepatic conditions, those taking drugs that affect liver function, and those with current or prior alcohol abuse. There is more concern with ingestion of chaparral preparations containing leaves/stems or alcoholic extracts than with the ingestion of aqueous extracts (i.e., teas) because of the higher content of NDGA and other lipophilic compounds in the former preparations.

C. Data Gaps and Future Research Recommended

Detailed toxicity studies in animals are needed to explore the possible dose-response relationship in the development of hepatotoxicity and nephrotoxicity as the result of chaparral ingestion. In animal studies, pair feeding should be included in the experimental protocol due to possible aversion to the chow if NDGA has been added (Goodman et al., 1970). Ideally, studies should compare the different preparations of chaparral (i.e., powdered leaf, alcoholic extract, and water extract).

The differences in the chemical composition of the various preparations of chaparral need to be explored. The literature shows that a preponderance of toxicities were associated with preparations other than tea; hepatotoxicity was not reported in a clinical trial of cancer patients drinking chaparral tea. This suggests there that there are differences in the bioavailability of the various components of chaparral that result from differences in the chemical composition of the preparations. These differences need to be explored in detail.

In all further research, it is important to carry out careful product characterization. A qualified taxonomist should identify the plant material, and a botanical sample should be retained in an herbarium for future reference. It is important to carefully describe the plant part utilized. As an example, newer leaves should be distinguished from older leaves because newer leaves contain a higher proportion of the NDGA-containing resin. Chaparral roots contain a quinone not reported to be present in the aerial parts of the plants and, thus, roots should be carefully excluded. The plant material should be chemically profiled, including a quantitative determination of NDGA and other lignans. As a quality measure, there should be an analysis of metals since chaparral plants concentrate metals from the soil (Gardea-Torresdey et al., 2001). Furthermore, when reporting human experience with ingesting chaparral, the formulation is important to note. The formulation can best be critically evaluated if the manufacturer, date, and lot number are reported.

VI. LITERATURE SEARCH STRATEGY

This prototype focused monograph was prepared by excluding information not possibly related to hepatotoxicity after conducting a literature search for the full prototype monograph. This was probably a more effective approach, although more time consuming, than initially limiting searches to liver information because information not about liver toxicity per se, but possibly related to liver toxicity, could be identified.

To prepare the chaparral monograph, the databases indicated below were searched using the terms [chaparral] OR [Larrea tridentata] (in any field). In the AGRICOLA database, it was necessary to limit the search to exclude other meanings of the word “chaparral.” These searches were conducted in April 2002 and yielded approximately 125 citations (excluding duplicate citations brought up by the various databases). The databases were independently searched for the entire genus Larrea, and articles pertaining to the North American plant were investigated to confirm that all articles that actually reported on L. tridentata were considered. Citations for many references that predate the electronic databases were collected from among the reference sections of the literature reviewed. Because the number of published articles on this topic are limited, an effort was made to collect abstracts representing research in this area. In August 2002, the databases were searched again for more recent articles and a few citations were added. A literature search on NDGA was also conducted in April 2002 and yielded approximately 325 citations (excluding duplicate citations brought up by the various databases). As NDGA is commonly used as a reagent, the search parameters were limited as follows: [nordihydroguaiaretic acid] OR [NDGA] (in title field) for most databases; [nordihydroguaiaretic acid] OR [NDGA] (in any field) for TOXLINE and AGRICOLA.

Electronic searches were conducted using the following databases: PubMed (1966–2002, TOXLINE Core inclusive), TOXLINE (TOXLINE Core and TOXLINE Special), EMBASE (1980–2002), and AGRICOLA (1979–2002). It should be noted that EMBASE contains a considerable amount of foreign literature and AGRICOLA contains a considerable amount of the veterinary literature. WorldCat, EMB/Cochrane Reviews, IBIDS, BEAST, and Dissertation Abstracts were used to a limited extent. NAPRALERT was used for natural products. Patents were accessed using the website of the U.S. Patent and Trademark Office. Information on the SN/AEMS and regulatory actions taken by FDA were obtained from the FDA website. Information on regulatory actions by the Federal Trade Commission (FTC) was obtained from the FTC website. It is highly recommended that Chemical Abstracts also be used, although this database was not used for the prototype monographs due to the limitations of time and resources. In the database search, no restriction was placed on language or type of publication. However, the ability to interpret non-English-language publications was limited. The foreign language literature was included when it was deemed important in order to be complete. The majority of the literature cited is drawn from primary research sources, followed by secondary sources as appropriate.

TABLE C-1 FOLLOWS

TABLE C-1. Chaparral: Summary of Clinical Case Reports.

TABLE C-1

Chaparral: Summary of Clinical Case Reports.

TABLE C-2. Summary of Clinical Case Reports and a Case Series Report with Chaparral Used in Combination.

TABLE C-2

Summary of Clinical Case Reports and a Case Series Report with Chaparral Used in Combination.

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Footnotes

1

This is a focused monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format for focused monographs described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient.

*

Tables appear at the end of this appendix.

Copyright 2005 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK216060

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