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Pyrrolizidine alkaloids (PAs) can be found in 6,000 different plant species representing more than 3% of all flower plants throughout the world (EFSA, 2009). In Europe, PAs are particularly found in Cynoglossum spp., Echium spp., Heliotropium spp., and Senecio spp. (EFSA, 2009). Although these plants are generally not consumed by cows, horses and other livestock resulting from the lack of palatability from these plants, intoxications of livestock have been reported (EFSA 2009; Fletcher, 2009; Gardner, 2006; Creeper, 1999). Consequently, humans might inadvertently be exposed to PAs by consumption of animal products like milk (Reviewed in Panter, 1990) and eggs (Edgar et al., 2000). Exposure to these compounds can also occur following the use of honey collected by bees visiting PA-containing plants (Edgar et al., 2002; Deinzer et al., 1977; Culvenor et al., 1981; VWA, â€¦.). Moreover, consumption of grain or grain products contaminated with seeds of PA-contaminated plants may results in human poisonings or even death as occurred in several countries including Afghanistan, South Africa and India among others (WHO-IPCS, 1988; zie Casarett's and Doull; reviewed in Coulombe, 2003). In addition to these unintentional forms of exposure, humans can be intentionally exposed to PAs through the use of herbal teas or traditional herbal medicines that can be prepared from a variety of PA-containing botanicals (WHO-IPCS, 1988). An example of a PA-containing herbal medicine is Comfrey (Symphytum officinale). Comfrey was widely used for over 200 years as a treatment for gastrointestinal illness such as Crohn's disease (Weston, 1987). However, comfrey is reported to induce liver toxicity / veno-occlusive disease in human (Ridker, 1985; Weston et al, 1987; Bach et al, 1989). In response to these adverse effects, the FDA raised serious concerns for human health, and 'the agency strongly recommends that firms marketing a product containing comfrey or another source of pyrrolizidine alkaloids remove the product from the market and alert its customers to immediately stop using the product' (FDA, 2001). Within the same line of reasoning, Health Canada advised Canadian consumers not to use any comfrey containing products (Health Canada, 2003). South Africa, Australia and New Zealand have also restricted the use of comfrey and products derived from this botanical (Department of Health, South Africa, 2002; Food standards Australia New Zealand). Moreover, Australia and New Zealand have prohibited the use of several other PA-containing plants in the food such as Senecio spp. (ragwort), Heliotropium spp. (heliotrope), and Crotalaria spp. (crotalaria) (Food standards Australia New Zealand). In addition, limitations have been adopted in The Netherlands with regard to the exposure to PAs resulting from the use of herbal supplements. Following the Dutch 'Warenwetbesluit Kruidenpreparaten' as adopted in January 2001, the total content of pyrrolizidine alkaloids present in botanical supplements may not exceed 1 Âµg/kg (Warenwetsbesluit Kruidenpreparaten). Aside from the possible liver damage occurring after exposure to PAs, these restrictions were applied based on the suspected carcinogenicity of these compounds (Warenwetsbesluit Kruidenpreparaten).
In general, the liver is considered as the target organ, with hepatic veno-occlusive disease (VOD) being frequently observed, after long-term PAs intoxication in humans (EFSA, 2009). In the previous century, VOD was even an apparent endemic in certain areas of South America. Nevertheless, there is no epidemiological evidence for the occurrence of PA-related increased incidences of (malignant) neoplasms in humans (EFSA, 2009). However, several rodent carcinogenicity bioassays indicated the carcinogenic potentials of PAs including riddelliine, lasiocarpine and monocrotaline, raising the concerns for human exposure to PAs. Moreover, in vitro and in vivo studies indicated a genotoxic mode of action for these substances making the carcinogenic potentials relevant for the human situation (EFSA, 2009).
Aside from ingesting the plants directly, PAs can 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 [26-29]. Zie Rietjens et al., 2005
have largely been limited to third world countries. Generally, these have
been outbreaks where hundreds, and sometimes thousands, have been poisoned from eating staple foods made from cereal crops contaminated with seeds from pyrrolizidine alkaloid-containing weeds. More recently, however, along with an increasing reliance on unconventional medicine and the use of herbal supplements and traditional medicines, there has been a sharp rise in the number of poisonings in industrialized countries. A survey of some of the plants reported to be responsible for incidences of human poisonings, whether from foods or medicines, is presented in Table II. Coulombe, 2003
The agency strongly recommends that firms marketing a product containing comfrey or another source of pyrrolizidine alkaloids remove the product from the market and alert its customers to immediately stop using the product. FDA!!
Comfrey (Symphytum officinale) is a tall perennial plant with large hairy leaves and small purple flowers (Winship, 1991; Betz et al, 1994). Comfrey is consumed by humans as a vegetable and a tea. It has been used as an herbal medicine for more than 2000 years to treat broken bones, tendon damage, ulcerations in the gastrointestinal tract, lung congestion, and joint inflammation, and to promote wound healing (Rode, 2002). Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. It induced hepatic veno-occlusive disease in humans (Ridker et al, 1985; Weston et al, 1987; Bach et al, 1989; Ridker and McDermott, 1989; Yeong et al, 1990) and hepatocellular adenomas and haemangioendothelial sarcomas in rat liver (Hirono et al, 1978). Although there are no epidemiological data regarding the carcinogenicity of comfrey, these adverse effects have raised questions of its potential carcinogenicity in humans. This concern led the US Food and Drug Administration to request voluntary removal of products containing comfrey from the market in 2001 (FDA, 2001). There are presently, however, no restrictions on the use of comfrey in many parts of the world. Mei, 2005
It induced hepatic veno-occlusive disease in humans (Ridker et al, 1985; Weston et al, 1987; Bach et al, 1989;
Ridker and McDermott, 1989; Yeong et al, 1990) and hepatocellular adenomas and haemangioendothelial sarcomas in rat liver (Hirono et al, 1978). Mei et al., 2005
Despite the relatively low concentration of PAs, comfrey preparations have consistently been documented as being responsible for classic veno occlusive disease (Ridker et al. 1985, Weston et al. 1987, Bach et al. 1989, McDermott and Ridker 1990), and comfrey even was found to have killed a young man who had consumed the leaves as a vegetable (Yeong et al. 1990). NTP background document.
Nederland: De hoeveelheid toxische pyrrolizidine-alkaloÃ¯den van kruidenpreparaten die bestaan uit materiaal dat geheel of ten dele afkomstig is van planten, bedoeld in onderdeel I van de bijlage, of van andere planten waarvan wordt aangenomen dat ze toxische pyrrolizidine-alkaloÃ¯den bevatten, bedraagt niet meer dan 1 Âµg per kg, onderscheidenlijk per liter. http://www.rivendell.eu/library/documents/wetten%20kruiden/WW%20Besl%20Kruidenpreparaten.pdf Besluit van 19 januari 2001, houdende vaststelling van het Warenwetbesluit Kruidenpreparaten. Staatsblad van het Koninkrijk der Nederlanden 2001, 56, 1-12
Health Canada advises consumers not to use or ingest the herb comfrey or health products that contain comfrey
OTTAWA - Health Canada is advising Canadian consumers not to use or to ingest the herb comfrey or any health products that contain comfrey because they might contain a compound called echimidine, which may cause liver damage. As a precaution, consumers are advised not to topically apply comfrey-containing products to broken skin. This advisory applies to both approved and unapproved products.
The comfrey herb is found in herbal and homeopathic preparations, and is marketed to treat digestive problems, lung problems, arthritis, ulcers, bruises, wounds, and sprains/fractures. Comfrey is also found in lip balms, burn salves, diaper rash ointments and other therapeutic skin care products.
There are several different species of comfrey, two of which are already prohibited from being used in therapeutic products in Canada because they contain echimidine. These species are prickly comfrey (Symphytum asperum) and Russian comfrey (Symphytum x uplandicum). While not all comfrey products contain echimidine, some comfrey products do not always identify the species of comfrey in the product. Therefore, consumers are advised to avoid all products containing comfrey.
Consumers are advised to check the labels of their herbal and therapeutic skin care products for the presence of comfrey or echimidine, and not to use any product whose labels list these ingredients. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2003/2003_101-eng.php
Government Gazette Vol. 450, No. 24154,Â 13 December 2002 Regulation Gazette, No.7539 No. R.1541 DEPARTMENT OF HEALTH FOODSTUFFS, COSMETICS AND DISINFECTANTS ACT, 1972 (ACT 54 OF 1972) REGULATIONS RELATING TO THE PROHIBITION OF COMFREY AND COMFREY CONTAINING FOODSTUFFS AND JELLY CONFECTIONERY CONTAINING KONJAC IN FOODSTUFFS http://www.doh.gov.za/docs/regulations/2002/reg1541.html
EGGS: Edgar, J. A., and Smith, L. W. 2000. Transfer of pyrrolizidine alkaloids into eggs: food safety implications. In "Natural and Selected Synthetic Toxins Biological Implications", (A. Tu, and W. Gaffield, eds), pp. 118-128. American Chemical Society, Washington, DC.
Honey: Deinzer, M. L., Thomson, P. H., Burgett, D. M., Isaacson, D. L., Pyrrolizidine alkaloids: their occurrence in honey from tansy ragwort (Senecio jacobaea L). Science 1977, 195, 497-499.
Culvenor, C. C., Edgar, J. A., John, A., Smith, L. W., Pyrrolizidine alkaloids in honey from Echium plantagineum L.
J. Agric. Food Chem. 1981, 29, 958-960
Edgar, J. A., Roeder, E., Molyneux, R. J., Honey from plants containing pyrrolizidine alkaloids: a potential threat to
health. J. Agric. Food Chem. 2002, 50, 2719-2730.
Weston CF, Cooper BT, Davies JD, Levine DF (1987) Veno-occlusive disease of the liver secondary to ingestion of comfrey. BMJ (Clin Res Ed) 295: 183.
McDermott WV, Ridker PM. 1990. The Budd-Chiari syndrome and hepatic
veno-occlusive disease. Recognition and treatment. Arch Surg 125(4): 525-7.
Ridker PM, Ohkuma S, McDermott WV, Trey C, Huxtable RJ. 1985. Hepatic venocclusive disease associated with the consumption of pyrrolizidinecontaining
dietary supplements. Gastroenterology 88(4): 1050-4.
Yeong ML, Swinburn B, Kennedy M, Nicholson G. 1990. Hepatic venoocclusive
disease associated with comfrey ingestion. J Gastroenterol Hepatol
Roitman JN. 1981. Comfrey and liver damage. Lancet 1(8226): 944.