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Dietary Supplements: A Framework for Evaluating Safety Appendix D Chaparral: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS A. Summary Reports of chaparral toxicity are inconsistent. Native populations in the southwest United States appear to have used chaparral tea for decades without reported evidence of toxicity. In addition, a clinical study looking at the use of chaparral tea and nordihydroguaiaretic acid (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 1 This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format 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. The full prototype monograph and its data tables on chaparral may be accessed at http://www.iom.edu/fnb.
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Dietary Supplements: A Framework for Evaluating Safety complete the trial (25 percent of the subjects). This evidence is somewhat inconsistent with other information on chaparral use. 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 exhibited documented recovery after cessation of chaparral use and one 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.” There appeared to be no dose-response relationship, although evidence of toxicity was clearly reflected in abnormal liver function tests. The absence of pharmacokinetic data or even characterization of the formulations ingested made it difficult to determine actual dose in the various case reports. 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. Ideally, if the contents were an extract, then the solvent should have been described as well as the ratio of solvent to plant material. This is all assuming that the plant material was properly identified and that the plant parts used were fine leaves/stems. In addition, no chemical profiles were available for the products, making it difficult to compare the different doses ingested by the subjects. Further, without examination of the quality of the product, contamination or adulteration cannot be ruled out. In only one of the 15 case reports of chaparral-associated hepatotoxicity was it reported that a chaparral tea had been ingested. This is important because the chemical profile of the product will depend upon the preparation used. 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 instead exhibited renal proximal tubular damage and cyst formation. In other stud-
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Dietary Supplements: A Framework for Evaluating Safety ies, 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 imine 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, may 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 the Safety of the Ingredient Based on the Strength of the Scientific Evidence Conclusions (concerns and caveats): The available literature raises concern for hepatic, renal, and reproductive toxicity. The reasons for concern about hepatotoxicity/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. 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 glutamicoxaloacetic 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 number of subjects in the study) 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
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Dietary Supplements: A Framework for Evaluating Safety 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. Hepatotoxicity: The temporal clustering of the majority of the hepatotoxicity cases (1992–1993) provides some suggestion of localized contamination or a variation in constituent concentration, probably 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. It is possible that some of the individuals who experienced the adverse events had pre-existing liver disease, including excessive alcohol use, hepatitis, or chronic acetaminophen use, which predisposed them 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; toxicity over a range of doses was a common finding (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 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 the 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). The in vitro data on chaparral are incomplete and do not provide the necessary details either to generate hypotheses of mechanisms or to determine doses that might cause toxicity in intact animals. In a large number of in vitro studies, NDGA was used at pharmacological doses as a scientific tool to inhibit lipoxygenase in basic research. This lyoxygenase inhibition, at pharmacological doses, while indicating a possible pathway of NDGA action, was not viewed as particularly helpful in assessing the safety of chaparral because the degree to which enzyme inhibition would occur with chaparral consumption was not readily apparent. However, this inhibition
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Dietary Supplements: A Framework for Evaluating Safety of a prostanoid pathway does provide a mechanistic explanation for the reproductive effects observed in animals (see below). Of the 15 reported cases of chaparral-associated hepatotoxicity, only one case 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 it 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 extraction 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. Nephrotoxicity: There are no reports of renal damage following chaparral ingestion in humans or in relevant animal feeding studies. Toxicology studies of NDGA administration in rodents have repeatedly shown nephrotoxicity, including proximal tubular damage and cyst formation. 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 and colleagues (1995). A plausible mechanism of cytotoxicity of NDGA is cytochrome P450-dependent metabolism of NDGA to a toxic quinone with failure to remove this reactive metabolite by conjugation if glutathione is limiting. It is possible that there is a link between the nephrotoxicity of NDGA in animals and hepatotoxicity of chaparral in humans based on the fact that both the renal proximal tubules and the liver are major sites of xenobiotic metabolism. A parallel finding has been demonstrated in rodents; both renal and hepatic toxicity develop in response to the toxic quinone imine from acetaminophen. Reproductive toxicity: Since reproductive effects are less likely to be detected in humans, animal data deserve careful consideration. Reproductive toxicity has been demonstrated by one group studying chaparral administered to female rats and three groups studying NDGA administered to female rats or mice. The chaparral study identified anti-implantation activity while the NDGA studies identified inhibition of ovulation and increased resorption of fetuses. These data are supported by the findings that NDGA inhibits prostaglandin synthesis, cyclooxygenase, and lipoxygenases. Because of the important role of eicosanoids in reproduction and fetal development, inhibitors of prostanoid pathways are contraindicated during the first and third trimesters of pregnancy (Mikuni et al., 1998).
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Dietary Supplements: A Framework for Evaluating Safety Summary of the conclusions: Although substantial limitations exist in the available information, concerns about the safety of chaparral remain based on the weight of the evidence discussed above. The most significant concern is hepatotoxicity, but some concerns also exist for reproductive and renal toxicities. This is especially applicable for certain groups, including those with pre-existing hepatic or renal problems, those taking drugs that affect liver function, those with current or prior alcohol abuse, and women of child-bearing age. 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 Concern for possible adverse effects in American Indian and Hispanic populations that use local botanical remedies prompts the panel to propose research needs that will help in the evaluation of the human clinical data. This concern would be increased if a resurgence in public interest in chaparral occurs. 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 (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 that there are differences in the bioavailability of the components of chaparral that result from differences in the chemical composition of the various 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 quantitative determina-
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Dietary Supplements: A Framework for Evaluating Safety tion 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. REFERENCES Ashby J. 2002. Scientific issues associated with the validation of in vitro and in vivo methods for assessing endocrine disrupting chemicals. Toxicology 181–182:389–397. Gardea-Torresdey JL, Arteaga S, Tiemann KJ, Chianelli R, Pingitore N, Mackay W. 2001. Absorption of copper(II) by creosote bush (Larrea tridentata): Use of atomic and x-ray absorption spectroscopy. Environ Toxicol Chem 20:2572–2579. Goodman T, Grice HC, Becking GC, Salem FA. 1970. A cystic nephropathy induced by nordihydroguaiaretic acid in the rat. Light and electron microscopic investigations. Lab Invest 23:93–107. Kacew S. 2001. Confounding factors in toxicity testing. Toxicology 160:87–96. Mikuni M, Yoshida M, Hellberg P, Peterson CA, Edwin SS, Brännström M, Peterson CM. 1998. The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary. Biol Reprod 58:1211–1216. Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland AE, Page SW. 1995. Chemical studies of phytoestrogens and related compounds in dietary supplements: Flax and chaparral. Proc Soc Exp Biol Med 208:6–12.
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