SAFETY ISSUES AFFECTING HERBS:
Pyrrolizidine alkaloids (see Figure 1) are complex molecules named for their inclusion of a pyrrolizidine nucleus: a pair of linked pyrrole rings. Each pyrrole can be diagramed as five-sided structure with four carbons and one nitrogen forming the ring. Pyrroles are incorporated into the chlorophyll molecule; the biological role of PAs in plants remains unknown.
Pyrrolizidine alkaloids (PAs) are of special interest currently because several of them have been shown to cause toxic reactions in humans, primarily veno-occlusive liver disease, when ingested with foods or herbal medicines. Comfrey, a well-known medicinal herb characterized by U.S. FDA researchers as having been "one of the most popular herb teas in the world," contains PAs that are capable of causing liver damage (10). Earlier alerts about the potential dangers had reduced demand for comfrey markedly, but herb proponents argued that the laboratory studies showing PA toxicity probably did not apply to human use of the whole herb and that no reports of human toxic reactions to comfrey had appeared (28). Soon after, when clinical reports of such human reactions were published, some herbalists argued that other confounding factors were likely the culprit and that, at any rate, modern drugs were far more likely to cause toxic reactions (29). Comfrey has remained commercially available in the U.S., though in 1993 the American Herb Products Association (AHPA) alerted its members to restrict its use to external applications. On July 6, 2001, the U.S. FDA took official action to remove comfrey from all dietary supplements.
The PAs are primarily found in members of three plant families (7):
A list of plants for which concerns have been raised about their content of PAs is presented in Table 1. Some are foraged by animals, causing toxic reactions if grazed to excess; others are weeds that grow amongst grains harvested for human use where they can contaminate the food supply. Several of the listed herbs have been used as medicinals, a few of them have been extensively relied upon for many centuries. The principal medicinal genera in current use are Senecio, Borago, Lithospermum, Heliotropium, and Eupatorium. Toxic reactions to some of those medicinal herbs have been reported following long-term ingestion, usually after many months. Over 200 PAs have been identified to date, about half of them deemed toxic.
The current leading expert on pyrrolizidine alkaloids is Dr. E. Röder, at the Pharmaceutical Institute of Bonn University. Much of the information available about which species contain pyrrolizidine alkaloids, which alkaloids are present, and in what amounts come from his research and review efforts. He has published extensive literature reports since 1995 on European (7) and Chinese herbs (9) and on the chemical analysis methodology for detecting these compounds (8). Dr. C.C.J. Culvenor, of the Commonwealth Scientific and Industrial Research Organization in Australia, had earlier pioneered work in the areas of PA structures, toxicity, and both animal and human responses to PA ingestion. Included in his efforts were an evaluation of the structure and toxicity of 62 PAs (25) and an analysis of the amount of PAs consumed by persons who had been reported to suffer adverse effects (22). He published articles on PAs from 1968-1992. Dr. R.J. Huxtable at the Department of Pharmacology of the University of Arizona reported frequently on the pharmacological effects of PAs and their toxic metabolites (26, 31) from 1978-1999, apparently inspired by two cases of pyrrolizidine poisoning of infants in 1977 and 1978 in his home state of Arizona (27).
Table 1: Plants that contain pyrrolizidine alkaloids (PAs).
|Species Evaluated||Toxicity and Constituents|
aka Lithospermum tinctorium
|Popularly known as alkannet; the root yields a red to purple dye from the rind. Used in treatment of skin diseases, internally and topically; also for treating diarrhea. Contains triangularine. Alkaloid content is 0.25-0.3%.|
|Amsinckia intermedia||Commonly called fiddleneck; horses graze on the plant and are susceptible to poisoning by it. Alkaloid content range from less than 0.5% to 1.2%.|
|Anchusa officinalis||Known also as alkannet (see above) or as bugloss. Used to treat skin ailments, also used as an expectorant and a diuretic; applied topically for treatment of injuries and ulcers. Total alkaloid content is about 0.12%.|
|Borago officinalis||Borage is a commonly-used Western herb; used as a blood purifier and diuretic, indicated for inflammatory diseases and cough. The German Commission E put this on its "unapproved list" due to presence of PAs and lack of proof of efficacy. Contains intermedine and lycopsamine. Total alkaloid content is very low, less than 0.001%.|
|Cynoglossum officinale||Commonly called "hound's tongue" and also bugloss, it is used to treat diarrhea; used topically for bruises. Used in Africa as medicinal herb; blamed for liver cancer there. Contains heliosupine, echinatine, lasiocarpine, and cynoglossophine. Total alkaloid content is 0.7-1.5%.|
also: H. popovii, H. lasiocarpum; H. eichwaldii, H. bacciferum
|Known as white heliotrope (not to be confused with valerian). Livestock feed on heliotropium species. Used in Africa as medicinal herb; blamed for liver cancer. Contaminated cereal crops leading to human poisoning. Contains heliotrine and indicine. Total alkaloid content is about 0.01%.|
|Lappula intermedia||Commonly called stickseed, the seeds can be eaten; the plant is mainly used topically for sores and swellings.|
|Lithospermum officinale||Commonly called gromwell, it has been used for contraceptive purposes and found to have some effects on hormones. Also used as antipyretic and treatment for gout, kidney stones, and diarrhea. Contains lithosenine. Total alkaloid concentration is 0.003%. The Chinese herb Lithospermum erythrorhizon is used in the treatment of skin diseases.|
|Myosotis scorpioides||Commonly called forget-me-not. Used as a sedative and tonic; externally as an eye wash. Contains myoscorpine, scropioidine, and symphytine. Total alkaloid conent is 0.08%.|
|Pulmonaria officinalis||Called lungwort or cowslip, this herb is traditionally used for treating coughs. P.A. content is questionable.|
also: S. asperum, S. caucasicum, S. tuberosum, and S. peregrinum
|Commonly called comfrey (S. officinale), this herb has been extensively used as an "alterative." It has been blamed for liver damage in humans. Contains intermedine, lycopsamine, symphytine, echimidine, symglandine. Total content of PAs is nearly 0.5% in S. caucasicum, but lower in S. officinale (leaves: 0.02-0.18%; roots: 0.25-0.29%); S. peregrinum was found to contain about 0.2% alkaloids in the tops.|
also: T. incanum
|Contaminated cereal crops; blamed for human poisoning. Not used as medicine.|
|Adenostyles alliariae||Used in the Alps to treat lung disorders. Contains senecionine, seneciphylline, and spartioidine. Total alkaloid content is about 0.02%. Veno-occlusive disease in an infant was blamed on erroneous ingestion of this herb in place of tussilago.|
|Brachyglottis repens||It is a forage crop for livestock, toxic to horses, causing paralysis of the limbs.|
|Emilia sonchifolia||Commonly called red tasselflower or simply emilia herb, it is an antipyretic and remedy for influenza, cough, and bronchitis. Contains senkirkine and doronine; total alkaloid content of 0.2%.|
also, E. perforatum, E. rugosum
|E. perforatum is commonly called boneset, E. purpreum is commonly called Joe Pye Weed, and E. cannabinum is called hemp agrimony; these herbs are used to induce sweating to alleviate fever; also diuretic (modern use: lowering cholesterol). Contains supinine, rinderine, echinatine, and lycopsamine. In China, E. fortunii, is used as an aromatic herb to remove moisture, especially in treatment of summer-heat syndrome.|
also: P. spurius.
|Known as pestilence-wort or butterbur, used in Europe for numerous diseases, especially when complicated by abdominal pain. Contains senecionine, integerrimine, retrosine, seneciphylline, jacobine, senkirkine, and others. Total alkaloid content varies markedly: in roots it is less than 0.01% and in the leaf it is negligible. P. spurius contains senkirkine at a concentration of 0.007%.|
also: S. bicolor, S. doronicum, S. jacobaea, S. nemorensis, S. vulgaris, S. Illiciformis, S. longilobus, S. douglasii
|Commonly called golden ragwort; used as a treatment for injuries; also a diaphoretic and diuretic; high doses may induce abortion. S. bicolor has been used in eye drops to treat cataracts and conjunctivitis. Livestock often feed on tansy ragwort (S. jacobea), used medicinally as an antispasmodic. S. longilobus was mistakenly used as an herb remedy and caused liver failure. One or more species of Senecio is used in African herbal medicine and is blamed for high incidence of liver cancer. Contaminated cereal crops blamed for human poisoning. Contains senecionine, riddelline, retrorsine, floridanine, monocrotaline, and otosenine. Total concentration of alkaloids in S. aureus is about 0.02%; in S. bicolor about 0.9%; in S. jacobaea about 0.2-0.3%; in S. vulgaris about 0.16%. S. longilobus ingestion (threadleaf groundsel, substituted for an intended herb, gordolobo) was blamed for death of infants in the U.S. Several species of Senecio are used in Chinese medicine to treat febrile diseases, dysuria, inflammation, diarrhea, and, cataracts.|
|Tussilago farfara||Commonly called coltsfoot; widely used in Europe to treat lung disorders and gastro-intestinal orders (e.g., diarrhea); also used in Chinese herbal medicine for the same purposes. Contains senkirkine in amounts ranging from negligible to 0.015%. Also contains senecionine.|
also: C. juncea, C. nana, C. retusa, C. fulva
|Commonly called rattlebox. Contaminated cereal crops blamed for human poisoning. Contains crotananine, monocrotaline, and cronaburmine. C. sessiliflora is used in Chinese medicine to dispel heat and promote urination.|
Aside from ingesting the plants directly, PAs may be consumed by eating honey collected by bees that visit PA-containing plants (mainly species of Senecio) and by drinking milk or eating eggs produced by animals that have consumed PA-containing plants. In honey originating from species of Senecio, the total concentration of PAs was 0.3-3.2 micrograms per kilogram. PAs could be detected in the concentration range of 30-70 micrograms per kilogram in honey from the Alpine foothills of Switzerland. No cases of PA poisoning have been attributed to ingestion of tainted honey or milk (7). Eggs have been implicated as a source of PA toxicity in a case involving use of unregulated grain feed containing some Heliotropium (32).
The toxic PAs may cause the following liver reactions when ingested in doses of 10-20 mg: enlargement of liver cells and their nuclei, disturbances of liver cell metabolism resulting in functional losses, areas of cell destruction, and fatty degeneration. Long-term administration of smaller doses, 10 micrograms or less per day, may cause liver cirrhosis with exposure to the most toxic of the PAs. In both acute and long-term responses, veno-occlusive liver disease may occur. Although the main site of toxic reaction to the PAs is the liver, a few PAs act on other organ systems or the nervous system; this may be the result of their long half-life, allowing them to migrate to the other parts of the body prior to further metabolism.
The PAs, which have minimal toxicity in their original form, are metabolized in the liver and can become toxic metabolites, depending on the PA and on the particular condition of the liver enzymes (31). The toxic metabolites, highly reactive smaller pyrroles (the dehydro- form of the alkaloids) resulting from action of microsomal enzymes in the liver, can act locally within the liver cells to cause damage at the chromosome level. If the liver becomes damaged, the pyrrolizidine metabolites can overflow and infiltrate the lung fluids and cause damage there. Pulmonary edema and pleural effusions have been observed, sometimes resulting in fatalities with very high levels of PA contamination of food.
The diagnosis that most often is observed when there has been excessive or prolonged exposure to PAs is veno-occulusive liver disease, involving obstruction of the small veins bringing blood from the liver back to the heart. Early clinical signs of veno-occlusive liver disease include nausea and acute upper-gastric pain, acute abdominal distension with prominent dilated veins on the abdominal wall, fever, and elevated liver enzymes. Jaundice may be present and the gallbladder may be distended and full. Chronic illness from ingestion of small amounts of the alkaloids over a long period proceeds through fibrosis of the liver to cirrhosis, which is indistinguishable from cirrhosis of other causes. Removal of PA exposure will usually alleviate the disorder, but liver cirrhosis is only marginally reversible. Young children are most susceptible to the effects of the PAs, yet are more likely than adults to completely recover.
Reports of human toxic reactions to PAs are mostly limited to cases where grain has been contaminated by seeds of PA-containing plants, causing acute reactions in a substantial number of people. This has occurred, for example, in Uzbekistan and Afghanistan in 1948 and again in 1976, in Jamaica in 1954, and in India in 1975 (drought conditions during those years encouraged growth of the weeds, mainly Senecio, Crotalaria, and Heliotropium, and led to high PA content of flour). Agricultural controls have prevented further occurrences, except in times of disruption by wars: there was a small outbreak of liver disease, with 2 deaths, in northern Iraq in 1994. During the past century, thousands were poisoned central Asia, and other cases have been reported around the world in countries with poorly developed agricultural systems. It has been suggested that the Kwashiorkhor disease, frequently observed with children in Central Africa, is also related to a damage of liver cells by PAs taken in with foods, characterized by the liver losing its ability to synthesize essential proteins.
An extensive review of the medical literature conducted for the current article reveals that there have been only about a dozen formal reports (a few of them then repeated in different journals or with differing details) involving about 20 people with PA-related toxic reactions from taking excessive doses of herbs or taking incorrect herbs. Each of these reports are mentioned here. Some researchers have suggested that the problem is more widespread in certain areas of the world, such as Africa and South America, and simply not reported.
Pyrrolizidine alkaloids became an issue of safety concern in relation to herbal medicine about 20 years ago, when an herb enthusiast consumed comfrey (Symphytum officinale) on a daily basis and suffered liver damage (2). Three additional cases of human toxic response to comfrey were eventually reported (a possible fifth one has been mentioned, see reference 31), including one death attributed to the effects of the herb. The four widely-reported cases, all occurring in the 1980s, were outlined in a presentation by the National Institute of Medical Herbalists (London), to the Department of Health in January 1993 (29):
Though not of special notice at the time, because the herbs were not so widely used, cases of veno-occlusive disease associated with medicinal herbs had been reported just a few years earlier. In the U.S., a two-month-old infant in Arizona experienced veno-occlusive liver disease after being treated with gordolobo yerba, one of the most popular of Mexican herbs, usually obtained from Gnaphalium, but sometimes substituted by the similarly appearing Senecio longilobus. The case, involving portal hypertension and extensive hepatic fibrosis, was first reported in 1977 (19); the child died of the disease. An additional case of an infant administered Senecio longilobus as gordolobo yerba, used to make herbal cough medicine, involved a 6-month-old female. She had acute hepatocellular disease, ascites, portal hypertension, and a right pleural effusion in 1978. She improved with treatment. However, after 6 months, a liver biopsy revealed extensive hepatic fibrosis, progressing to cirrhosis over 6 months (27). It was found that one supply house in Arizona routinely stocked Senecio as the source of gordolobo. The U.S. FDA provided the following additional report from the same time period without references to documentation: an American woman who had used a medicinal tea for 6 months while visiting Ecuador developed typical hepatic veno-occlusive disease, with voluminous ascites, centrilobular congestion of the liver, and increased portal vein pressure. The patient completely recovered within one year after ceasing to consume the tea.
In England, veno-occlusive disease was blamed on long-term consumption of large amounts of Paraguay tea (yerba mate, Ilex paraguensis), from which small amounts of pyrrolizidine alkaloids were reportedly isolated (18). However, later studies did not find these alkaloids in Ilex; the patient may have had a contaminated source. Veno-occlusive disease was said to be caused by medicinal herb use in India in a report published in 1978 (16). Three patients with the disease had taken Heliotropium eichwaldii. The authors of the medical report suggested that: "The medicinal use of the herb may possibly be responsible for a significant proportion of acute and chronic liver disease in India." However, such a conclusion seems unjustified; in India, Heliotropium species are mainly used in external therapies, and only rarely being taken in teas or other internal forms. In 1985, there appeared a report linking ingestion of an unidentified herb from India, used as a treatment for psoriasis, to three cases of liver damage, with one death. Pyrrolizidine alkaloids were identified, with mean dose estimated at 30 mg/day. The herb may have been a species of Heliotropium, as these species are used as remedies for various skin diseases. A case of Heliotropium induced veno-occlusive disease was reported in England in 1986 (17); the species ingested was H. lasiocarpum.
A new concern arose with use of another popular herb: coltsfoot (Tussilago farfara). Coltsfoot was widely used for coughs in Europe and America, and has also been used by the Chinese for the same purpose. There was a report from Switzerland in 1988 of liver damage leading to death of a newborn due to consumption of coltsfoot tea by the mother during pregnancy (20). The adverse reaction was attributed to the herb's pyrrolizidine alkaloids, and that herb was then withdrawn from the market in Europe in 1992. However, later investigation indicated that the coltsfoot was probably not a contributor to the infant's death (23). Still, other PAs may have been responsible in this case: the tea mixture included Petasites (pestilence wort), a source of toxic PAs.
In 1995, three more reports appeared in the medical literature indicating liver damage from ingestion of PA-containing herbs. An infant in Austria who was given a tea that was understood to contain peppermint and coltsfoot (not a commercial product) developed veno-occlusive disease that was, fortunately, reversible (5). An analysis showed that the coltsfoot was again a substitute, this time from Adenostyles xalliariae (common name alpendost). It was estimated that the child consumed at least 60 micrograms PAs per kilogram of body weight each day over a 15 month period. It was noted that an elderly patient taking a tea of Senecio vulgaris for two years continuously suffered from veno-occlusive liver disease (3) and that a younger woman taking Senecio tephrosioides as a cough remedy on an occasional basis but for many years also suffered from this liver disease (4).
To sum up the cases reported thus far: there are four (possibly five) incidents related to comfrey ingestion in adults, two incidents of Senecio ingestion in infants and two incidents of Senecio ingestion in adults; four cases of Heliotropium ingestion in adults, two cases involving coltsfoot substitution by other PA-containing herbs in infants, and five other cases involving adults with unknown PA-containing herbs (three in China, one during a visit to Ecuador, and one using a tea product from South America). Although some cases of liver damage may have been due to something other than the herbs, in most instances, other sources of the disorder were not evident or were deemed improbable.
The dose and duration of exposure to the toxic PAs that have been associated with liver damage in humans was estimated by Culvenor (22). For heliotrine, an intake of 4-10 mg/kg per day for 3-7 weeks led to liver necrosis and veno-occlusion; the combination of crotanine and cronaburnime at a dose of less than 1 mg/kg per day for several months led to the same disorders. Retrorsine and riddelline, among the most toxic of the PAs caused liver necrosis, liver fibrosis, and cirrhosis within 2 weeks of intake from 0.7-1.5 mg/kg per day. In one of the reports of an unidentified herb from India, the PA ingestion rate was 30 mg/day, and in one of the infants, the reported PA intake was 0.06 mg/kg per day. Thus, the range of toxic doses in humans appears to be in the range of about 0.1-10 mg/kg per day. In most instances of PA liver toxicity in adults, the daily intake was several milligrams or hundreds of milligrams per day. However, it has been suggested by the World Health Organization in 1989 that the lowest intake rate of PAs that reportedly caused veno-occlusive disease in a human was just 0.015 mg/kg of body weight per day, based on use of comfrey. For a 70 kg adult, that would correspond to 1 mg total per day.
Exposure to PAs can vary markedly when using any given herb. Determination was made of PA content of comfrey roots and leaves by Couet and his colleagues (21); the roots had a range of 1400-8300 ppm, while the leaves had from 15-55 ppm. In an evaluation of 300 comfrey root samples in Germany, the PA range was found to be 450-5990 ppm (30). An evaluation of commercial comfrey products (10), showed that the PA content varied markedly: none detected in 2 products, to a range 0.2-220 ppm among 8 other products tested with detectable levels, and one with 1520 ppm (a comfrey root product). To reach a 1 mg per day dose, just 0.7 grams of herb at 1,520 ppm would be needed, about the amount that would be found in 3 of the 250 mg capsules, indicating that this product would be too toxic to consume on a regular basis. On the other hand, products with no detectable PAs and those with less than 1 ppm might be entirely safe. Further, method of preparation is also important. A decoction of root and leaf samples of comfrey lowered the available PAs by 75-95%. Different species of comfrey contain different types and amounts of toxic PAs.
A concern that has arisen during the past two decades is that persons who take an herbal preparation regularly for many months or years might experience a cumulative effect from the PAs. Although these ingredients do not accumulate in the liver or elsewhere in the body, the prolonged use of amounts that cause no acute reactions may increase the chances for developing liver disease, including liver cancer. Laboratory studies indicate that some of the PAs have a high mutagenic capacity. This determination is made through tests in bacteria or fruit flies, but the results may imply a carcinogenic potential for humans. According to one study using fruit flies, the mutagenic potential of 16 PAs can be rated as follows (7):
senkirkine > monocrotaline > seneciphylline > senecionine > 7-acetyl intermedine >
heliotrine > retrorsine > 7-acetyllycopsamine > symphytine > jacoline > symlandine >
intermedine > indicine > lycopsamine > indicine N-oxide > supinine
That is, senkirkine has the highest mutagenic potential in the test system, while supinine had no detectable mutagenic activity. Indicine N-oxide (from heliotrope) is an antitumor agent currently investigated for treatment of brain tumors; formerly it was found useful in treating leukemia in infants, except that it produced liver damage as a side effect in some cases (thus, it was withdrawn from further consideration). Senkirkine is found in coltsfoot, petasites, and other herbs that were routinely recommended in Switzerland and Germany as remedies suited for long-term administration.
Despite the findings in laboratory studies, including mutagenic activity, adducts of pyrrolizidine alkaloids and their metabolites in tissue of test animals, and induction of cancer in animals (some PAs cause hemangioendothelial sarcomas in rats), the potential carcinogenic effects on humans have been questioned. On the one hand, the frequent occurrence of primary liver tumors in the natives of Central Africa and South Africa has been ascribed to the consumption of traditional medicinal plants of the genera Crotalaria, Cynoglossum, Heliotropium and Senecio. On the other hand, in a recent review of PAs in the human diet (2), the authors concluded that "while humans face the risk of veno-occlusive diseases and childhood cirrhosis, PAs are not carcinogenic to humans."
As recent studies revealed the presence of pyrrolizidine alkaloids in several plants used in herbal medicines, concern has arisen about exposure to these compounds and how to limit that exposure. Bulletins have been issued by the U.S. Food and Drug Administration (FDA) and Centers for Disease Control (CDC) on this subject. In Belgium it is proposed that the limit for pyrrolizidine alkaloids in herbs be set at 1 ppm, a very small amount (1 microgram per gram of herb). The German Health Administration has set a standard for use of the herb Petasites such that the daily dose should not contain more than 1 microgram of PAs, with limited duration of administration of six weeks total per year; for tea mixtures including PAs, a total limit of 10 micrograms per day is permitted for up to six weeks. The American Herb Products Association (AHPA) has issued the following recommendation (adopted July 1996): "AHPA recommends that all products with botanical ingredients which contain toxic pyrrolizidine alkaloids bear the following cautionary statement on the label: For external use only. Do not apply to broken or abraded skin. Do not use when nursing." The Consumer Healthcare Products Association established a voluntary program for manufacturers with the same recommendation (adopted March 2001).
Based on the Belgium recommended limit for PAs in herbs at 1 ppm, it would require ingestion of 1 kilogram (2.2 pounds) of an allowed herb to yield 1 mg (the smallest amount cited as toxic for comfrey ingestion), so the limit set would appear to be quite safe, in terms of any potential for acute reactions. Normal daily intake of herbs is usually only a few grams, so there is a large margin of safety; a 10 gram dose would yield a maximum of 10 micrograms of PAs from an allowed herb. The German recommended limit, just 1 to 10 micrograms per day, is consistent with the Belgium proposal based on PA content. In Europe, efforts are underway to develop coltsfoot and other desirable medicinal plants that are naturally low in PAs and will then meet the standards that have been set. In addition, extract manufacturers have sought methods of removing the PAs from their finished products.
Drastic restriction of PAs, such as avoidance of any amount in an herb intended for internal use as suggested by AHPA, may not be justified. There is a great diversity of alkaloid structures among the pyrrolizidine group. Some of the pyrrolizidine alkaloids, such as farfugine and tussilagine, are considered non-toxic. Although the AHPA recommendation specifically mentions "toxic PAs," the burden of proof as to whether the PAs are to be considered toxic would fall on the seller of the herb material, a burden unlikely to be undertaken. The range of amounts of PAs in plants (and different parts of the same plant) is also quite large: from less than 0.001% to 0.1.2%, more than a 1,000-fold range among samples with reported levels. This variability in amounts and toxicity makes it difficult to rationally suggest that no pyrrolizidines, including the toxic ones, are acceptable in herbs used medicinally as internal remedies. As test methods improve, tiny amounts of these compounds may be found in very popular herbs. Thus, for example, echinacea (in the Asteracea family), one of the most commonly used herbs in America and Europe, has been shown to contain small amounts of PAs. These are thought to be non-toxic (based on the chemical structure), but they remain suspects in potential liver toxicity from long-term use (over 8 weeks) of the herb (33).
It is potentially problematic to deem any amount of any such alkaloid a contraindication for using the herb at all, especially as test methods improve and miniscule amounts of a wider range of PAs are revealed. PAs have been detected in plant families other than the three mentioned above, including the Apocynaceae, Celastraceae, Euphorbiaceae, Orchidaceae, Poaceae, Ranunculaceae, Rhiophoraceae, Santalaceae, Sapotaceae, and Scrophulariaceae, and have been suggested to be present in up to 3% of the species of flowering plants (24). Therefore, numerous medicinal herbs may fall under restriction from oral consumption if there is zero tolerance for presence of PAs. Further, the implications of such a restrictive policy for the future are that any time a natural compound is found to have some level of toxicity, all medicinal herbs containing that compound could be eliminated from use, greatly limiting the ability to rely on a natural health care approach.
The commonly used Chinese herbs that are currently known to contain pyrrolizidine alkaloids are these (24):
In an evaluation of 20 herbs of the Asteracea, only species of Eupatoreum were found to contain pyrrolizidine alkaloids (1), with content ranging from less than 5 ppm for E. chinensis, to 65-95 ppm for E. fortunei, and 172-422 ppm for E. japonicum. The PA-free herbs (less than 1 ppm) included species of Arctium, Artemisia, Aster, Atractylodes, Carthamus, Centipeda, Chrysanthemum, Circium, Eclipta, Inula, Saussurea, Taraxacum, Tussilago, and Xanthium. The reported absence of PAs in Chinese samples of Tussilago is consistent with findings of negligible amounts in some European samples. In a study of three Chinese herbs, two species of Eupatoreum (E. japonicum and E. cannabinum) were shown to contain PAs and a species of Crotalaria (C. assamica) was found to contain one PA, monocrotaline (6). Other Chinese herbs with PAs include various species of Senecio used in folk medicine (e.g., S. argunensis and S. integrifolius), Emilia sonchifolia (Asteraceae), and Crotalaria sessiliflora. Heliotropium indicum (Boraginaceae) is a folk remedy in Taiwan, used for treatment of lung diseases and sore throat.
In order to meet the Belgium standard for PAs, the alkaloid content of an herb would have to be no more than 0.0001%, which is lower by far than that for Arnebia euchroma a Chinese herb with very low levels of PAs. To meet the German standard of a maximum daily dose of 10 mg of PAs, an herb containing 0.02% of these compounds (as reported for Lithospermum erythrothrizone) would be limited to just 50 mg per day, an amount far less than is likely to be used in Chinese herbal formulas. Therefore, elimination of the herbs with established PA content from Chinese herb prescribing would be necessary to meet Western standards.
Figure 1: Chemical structures of various PAs.