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Dietary Supplements: A Framework for Evaluating Safety Appendix C Plant Family Information This appendix provides additional information about the genera listed in Table 6-1. Discussions are organized by families rather than genera because characteristics may be common to a particular family, but inclusion of a family in this list does not necessarily indicate toxicity. Instead, whether belonging to a particular family is sufficient to raise concern should be informed by the text describing which families are generally considered unsafe, which may include only a few unsafe members, and which contain both commonly ingested foods and toxic members. GENERAL REFERENCES CONSULTED The information in the following section was generated by committee members knowledgeable in botanicals by consulting the following resources:1 Cheeke PR. 1998. Natural Toxicants in Feeds, Forages, and Poisonous Plants, 2nd ed. Danville, IL: Interstate Publishers, Inc. Colegate SM, Dorling PR, eds. 1994. Plant-Associated Toxins: Agricultural, Phytochemical and Ecological Aspects. Wallingford, UK: CAB International. 1 Kingsbury’s (1964) Poisonous Plants of the United States and Canada is an especially useful resource and, while not consulted for all the families below, Dewick (2002) is also especially helpful.
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Dietary Supplements: A Framework for Evaluating Safety Everist SL. 1981. Poisonous Plants of Australia. London: Angus & Robertson Publishers. Garland T, Barr AC, eds. 1998. Toxic Plants and Other Natural Toxicants. Wallingford, UK: CAB International. James LF, Keeler RF, Cheeke PR, Bailey EM, Hegarty MP, eds. 1992. Poisonous Plants. Ames, IA: Iowa State University Press. Keeler RF, Tu AT, eds. 1983. Handbook of Natural Toxins. Volume 1. Plant and Fungal Toxins. New York: Marcel Dekker. Keeler RF, Tu AT. 1991. Handbook of Natural Toxins. Volume 6. Toxicology of Plant and Fungal Compounds. New York: Marcel Dekker. Keeler RF, Van Kampen KR, James LF, eds. 1978. Effects of Poisonous Plants on Livestock. New York: Academic Press. Kellerman TS, Coetzer JAW, Naudé TW. 1988. Plant Poisonings and Mycotoxicoses of Livestock in Southern Africa. Cape Town, South Africa: Oxford University Press. Kingsbury JM. 1964. Poisonous Plants of the United States and Canada. Englewood Cliffs, NJ: Prentice-Hall. Seawright AE, Hegarty MP, Keeler RF, James LF, eds. 1985. Plant Toxicology. Brisbane, Australia: Queensland Poisonous Plants Committee. INFORMATION ON TOXICITY IN SELECTED PLANT FAMILIES The Agavaceae is of primary concern for the species Agave lecheguilla (lechuguilla), which causes secondary (hepatogenic) photosensitization; sheep and goats are frequently poisoned. The toxin is a saponin that is hepato- and nephrotoxic (Camp et al., 1988). Damage to the liver results in incomplete metabolism of chlorophyll, leading to peripheral circulation of phylloerythrin with excessive absorption of solar radiation (Keeler and Tu, 1983). Also, Nolina texana (sacahuista, bear grass) has been responsible for poisoning in livestock, especially the buds, blooms, and fruits, which are readily consumed (Cheeke, 1998; Keeler and Tu, 1983). In sheep, a toxic dose is 1.1 percent of the animal’s body weight (Kingsbury, 1964). Primary damage is to the liver, with progressive deterioration and death, but the toxin is unknown. The Amaryllidaceae, especially the genera Amaryllis, Crinum, Galanthus, Haemanthus, Narcissus, and Nerine, have caused poisonings in humans and animals when consumed during times of food shortages (Kingsbury, 1964). The bulbs of these species contain galanthamine, a competitive cholinesterase inhibitor, as well as other related alkaloids (Lopez et al., 2002). The Anacardiaceae contains a number of species that produce
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Dietary Supplements: A Framework for Evaluating Safety alkenylcatechol derivatives capable of producing severe allergic dermatitis (Everist, 1981; Keeler and Tu, 1983). Toxicodendron species (poison ivy, poison oak, and poison sumac) contain these alkenylcatechol allergens, the major constituent of which is urushiol, in all parts of the plant (Cheeke, 1998; Keeler and Tu, 1983). Most adverse reactions reported from this plant family are through dermal contact (Cheeke, 1998), but there is reason to be concerned about ingestion of plants containing urushiol and its analogs. Some cases of severe damage to gastric mucosa and death have been reported in humans ingesting these species (Kingsbury, 1964). Presumably, the severe reactions have occurred in response to internal immune/allergic response. Given that individual susceptibility to dermal reactions in humans varies widely, but most animals are not affected (Cheeke, 1998), it would probably not be prudent to regard lack of adverse effects following animal ingestion of dietary supplement ingredients containing these compounds as an indication of safety in humans. The Apiaceae contains plants commonly consumed as vegetables or condiments, such as carrots, parsnips, celery, and dill (Anethum, Apium, Daucus, Pastinaca species). The phytochemicals of concern in this family include piperidine alkaloids, polyacetylenes, and coumarins (Cheeke, 1998; Everist, 1981). Conium (piperidine) alkaloids are of concern because they can cause nervousness, nausea, vomiting, ataxia, coma, and death due to respiratory failure in many different animals, including humans (Cheeke, 1998; Colegate and Dorling, 1994). Alkaloid levels vary considerably with plant growth stage and are particularly high in flowers and seeds. Poisoning in humans has resulted from mistaking Conium maculatum (poison hemlock) for parsley or anise seeds (Kingsbury, 1964). The most toxic alkaloid, γ-coniceine, has an LD50 in a mouse bioassay of 2.5 mg/kg (Burrows and Tyrl, 2001). Some polyacetylenes are acutely toxic, resulting in rapid death due to complete paralysis and respiratory failure. The compounds act on the central nervous system, causing extremely violent convulsions, abdominal pain, and delirium in humans (Cheeke, 1998). Levels of the toxin (cicutoxin) are very high in roots of Cicuta species and a single root is capable of killing a cow (Kingsbury, 1964). There are structurally related compounds in carrot roots, although evidence of toxicity in humans from these compounds is minimal, probably because of extremely low levels (Cheeke, 1998). Simple coumarins can block the vitamin K pathway, thus inhibiting blood coagulation, and also can cause photosensitivity on exposure to sunlight. Photosensitivity, resulting in severe sunburn, has been observed following ingestion of celery soup, and sensitivity also occurs via dermal contact with the vegetable (Boffa et al., 1996; Seligman et al., 1987). Celery oil and celery
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Dietary Supplements: A Framework for Evaluating Safety root are also known causes of acute food-induced anaphylaxis (Pauli et al., 1988). The Apocynaceae contains three genera (Apocynum, Nerium, and Thevetia) that are of concern because some species are acutely toxic to livestock and humans (Cheeke, 1998; Colegate and Dorling, 1994; Kellerman et al., 1988). Accidental poisoning of children has been frequent and it has been estimated that a single leaf of oleander (Nerium oleander) can be fatal (Cheeke, 1998; Everist, 1981; Keeler et al., 1978). The toxins are cardiac glycosides with symptoms similar to digitalis toxicity and may occur at up to 4 percent of the weight of the plant (Kingsbury, 1964). Plant species in the Araceae that are toxic contain crystals of calcium oxalate (Cheeke, 1998; Everist, 1981; Keeler et al., 1978). In humans, this compound produces numbness of the mouth and throat (Cheeke, 1998; Keeler et al., 1978), resulting in the common name, dumbcane, for Dieffenbachia seguine. Death due to nephritis occurs on occasion in humans, but is more common in cats and laboratory animals (Burrows and Tyrl, 2001). Colocasia esculenta (taro, dasheen) leaves are generally recognized as being toxic (Burrows and Tyrl, 2001). The Araliaceae is of concern primarily because of the species Hedera helix (English ivy), ingestion of the berries having been reported to poison children (Kingsbury, 1964). There have been occasional reports of poisoning in cattle when large amounts of the vine have been consumed, and the toxicity has been attributed to the saponin hederagenin (Kingsbury, 1964). In addition, H. helix contains the polyacetylene falcarinol, which also occurs in a number of species in the Apiaceae and is responsible for contact dermatitis in some individuals (Keeler and Tu, 1991). Falcarinol has structural affinities to the extremely toxic cicutoxin of water hemlock (Cicuta virosa). No toxicity appears to have been associated with the many other Hedera species. The only other potentially toxic species in the Araliaceae is the Devil’s walking stick (Aralia spinosa), which has been suspected of poisoning livestock (Kingsbury, 1964). The Arecaceae encompasses a number of palm species growing in Asia and the Indian subcontinent. Betel nuts, the seeds of Areca catechu, are of concern, but the plant family is not considered to be of concern. Betel nuts are chewed when mixed with lime and wrapped in leaves of the betel pepper (Piper betle). This has a stimulant effect and produces slight intoxication. The seed contains approximately 0.45 percent of several tetrahydropyridine alkaloids, the primary active alkaloid being arecoline, an agonist of muscarinic acetylcholine receptors; it is used as an anthelmintic
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Dietary Supplements: A Framework for Evaluating Safety in humans (Hirschhorn, 1983). Betel quid chewing is an etiologic factor for oral cancer, and arecoline is suspected to contribute to the pathogenesis of cancer by producing mucosal inflammation and growth of oral epithelial cells (Keeler and Tu, 1983). The Aristolochiaceae has a number of Aristolochia species that contain the nephrotoxic nitrophenanthrenes aristolochic acids, such as A. serpentina (snakeroot). These plants have been used in traditional medicines, especially in Chinese and Indian herbal remedies, which are consumed only for short periods. In European use, where the plant was consumed over several weeks, there is good evidence based on misidentification that they are responsible for acute kidney failure and possibly urothelial carcinoma (Cosyns et al., 1998; Violon, 1997). The Asclepidaceae is known to contain a considerable number of Asclepias species (milkweeds) that are acutely toxic to livestock and domestic fowl (Cheeke, 1998; James et al., 1992). As little as 0.05 percent of an animal’s weight of green A. labriformis can result in death; most species are toxic at 0.25 to 1 percent (Kingsbury, 1964). Poisoning is characterized by symptoms of weakness, staggering, seizures, and coma, appearing within a few hours, followed by death within 1 or 2 days (Everist, 1981; James et al., 1992). The toxins are usually cardiac glycosides (cardenolides) structurally related to digitoxigenin (Cheeke, 1998). The Asteraceae encompass a significant number of genera that contain hepatotoxic unsaturated pyrrolizidine alkaloids. Among these are Eupatorium species (gravelroot) and Tussilago farfara (coltsfoot) (Keeler and Tu, 1983). Others such as Packera candidissima (hierba de milagro) (Bah et al., 1994) and Senecio longilobus (gordolobo yerba) are also hepatotoxic, with the latter having been documented as causing severe hepatic fibrosis and death in infants and children (Cheeke, 1998; Stillman et al., 1977) Senecio species have a particular propensity to accumulate high levels of the alkaloids (up to 18 percent dry-weight basis in S. riddellii), and are a frequent cause of poisoning in livestock (Kingsbury, 1964; Molyneux and Johnson, 1984). Seeds of Senecio and Heliotropium spp have caused large-scale poisonings of humans in southern Africa, central Asia, and India (Cheeke, 1998; Colegate and Dorling, 1994; Kellerman et al., 1988). The alkaloids can also be sequestered in milk, eggs, and honey (Colegate and Dorling, 1994; Keeler et al., 1978). Pyrrolizidine alkaloid toxicity is characterized primarily by progressive hepatic cirrhosis (veno-occlusive disease) (Everist, 1981; Garland and Barr, 1998). The alkaloids have been demonstrated to be genotoxic and mutagenic, and cause cancer in rats, but evidence is insufficient to establish carcinogenicity in humans (Garland and Barr, 1998;
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Dietary Supplements: A Framework for Evaluating Safety Keeler and Tu, 1983). The progressive nature of the poisoning is such that symptoms are not readily apparent and are slow to appear, and it has been categorized as an “iceberg disease” (Everist, 1981). Acute toxicity is rarely observed, but trichodesmine, senecionine, and seneciphylline have LD50 values in rats of 25, 50, and 77 mg/kg respectively (Mattocks, 1986). It is important to note that not all pyrrolizidine alkaloids are toxic per se; they become so only after dehydrogenation by P450 enzymes in the liver. In the plant they exist as a mixture of the free base forms and N-oxides. Although the N-oxides cannot be directly transformed into the toxic forms by P450 enzymes, they can be reduced to the free base in the gut and thence metabolized to the dehydro-alkaloids. It has been estimated that 3 percent of flowering plants worldwide contain some level of pyrrolizidine alkaloids (Colegate and Dorling, 1994). Within the Asteraceae family, certain Baccharis species are acutely toxic to cattle, horses, and sheep (Colegate and Dorling, 1994; Garland and Barr, 1998). Poisoning is characterized by tachycardia, restlessness, recumbancy, and death; lesions are found primarily in the digestive tract (Garland and Barr, 1998). Doses as low as 0.25 to 5.0 g/kg of the green plant can be fatal (Garland and Barr, 1998). The toxicity is probably due to macrocyclic trichothecenes of the roridin and verrucarin type (Colegate and Dorling, 1994). The LD50 intravenous administration of verrucarin A in rabbits is 0.54 mg/kg (O’Neil et al., 2001). These sesquiterpenes are known to be produced by fungi and there is evidence that the DNA of the fungus is transferred to the plant. Their occurrence in Baccharis may be due to the presence of a fungal endophyte, possibly Myrothecium verrucaria (Colegate and Dorling, 1994; James et al., 1992). Centaurea solstitialis (yellow star thistle) produces nigropallidal encephalomalacia (“chewing disease”) in horses, resulting in failure in prehension; as a result, animals usually die of starvation or thirst (Colegate and Dorling, 1994). Eupatorium and Haplopappus spp. on occasion have caused epidemic poisoning of humans in certain parts of the United States. The disease, known as “milksickness,” is characterized by weakness, nausea, muscular tremors, prostration, and death, and is caused by consumption of milk from animals that have consumed the plant (Colegate and Dorling, 1994; James et al., 1992). The toxicity is attributed to tremetone, an acetyl dihydrobenzofuran, but concrete evidence for its toxicity is lacking (Cheeke, 1998; Garland and Barr, 1998). Gutierrezia (broomweed) is toxic to cattle and sheep but is of primary concern for its abortifacient activity in cattle (Cheeke, 1998; Colegate and Dorling, 1994). The amount of plant causing this effect is highly variable, but as little as 20 lb of the fresh plant can produce abortion in cattle (Kingsbury, 1964). Signs of poisoning are very similar to those of “pine
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Dietary Supplements: A Framework for Evaluating Safety needle abortion,” caused by Pinus species (vide infra), and broomweed contains diterpene acids structurally similar to isocupressic acid, established as the abortifacient constituent of pine needles (Cheeke, 1998; Colegate and Dorling, 1994). Both Solidago species (goldenrods) and Tanacetum vulgare (tansy) have been used as abortifacients by humans and have been reported to produce abortions in cattle (Kingsbury, 1964). The latter two species have also been associated with death of cattle, sheep, and horses, but the active constituents are unknown (Kingsbury, 1964). Helenium (sneezeweed) and Hymenoxys species (rubberweeds, pingue) have been responsible for serious losses of livestock, especially sheep (Keeler and Tu, 1983). Poisoning is characterized by severe vomiting, depression, emaciation, and death (James et al., 1992; Kingsbury, 1964). Helenium tenuifolium has been implicated in human poisoning (Kingsbury, 1964). The toxins have been shown to be structurally related sesquiterpene lactones, especially helenalin and hymenovin (Keeler and Tu, 1983; Keeler et al., 1978). Psilostrophe species also have been found to poison sheep, producing a similar vomiting syndrome, but the toxin is unknown (Kingsbury, 1964). Rudbeckia species (coneflowers) are toxic to pigs, sheep, and horses, and occasionally cattle (Kingsbury, 1964). Poisoning is characterized by aimless wandering and incoordination. Deaths in laboratory animals are characterized by fatty degeneration of the liver (Kingsbury, 1964). The nature of the toxin is unknown (Kingsbury, 1964). In spite of the coincidence in the common names, these species should not be confused with the purple coneflower (Echinacea purpurea), which is sold as an herbal remedy. Tetradymia species cause secondary photosensitization in sheep, known as “bighead,” and is toxic at 0.5 percent of the animal’s weight (Kingsbury, 1964). Light-skinned animals are the most sensitive and areas of the body not covered by hair, particularly around the muzzle, become severely inflamed and enlarged. The photosensitization is due to circulation of phylloerythrin, produced from chlorophyll due to liver damage (Keeler and Tu, 1983). The toxins are tetradymol (Cheeke, 1998) and related furanoeremophilane terpenes (Keeler and Tu, 1983). Xanthium species (cockleburs) are toxic to a number of livestock, but especially pigs (Cheeke, 1998). The primary effects are acute nephritis and hepatitis (Everist, 1981). The main toxic compound is concentrated particularly in the seeds, as well as in plants at the cotyledonary growth stage, and has been identified as carboxyatractyloside, a kaurene (diterpene) glycoside (James et al., 1992; Keeler and Tu, 1983). In the Berberidaceae family, the mayapple or mandrake (Podophyllum peltatum) has caused occasional poisoning in cattle, sheep, and pigs, al-
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Dietary Supplements: A Framework for Evaluating Safety though animals generally will not eat it (Kingsbury, 1964). The plant, especially the root, has been used by American Indians and early settlers for medicinal purposes. Poisoning in humans has resulted from overuse of such preparations, and occasionally from use as an herb, resulting in gastroenteritis and vomiting (Kingsbury, 1964). Contact with the milled root can cause ulceration of the skin and conjunctivitis (Kingsbury, 1964). The bioactive constituents are lignans (podophyllotoxin, 4'-demethylpodopyllotoxin, and α- and β-peltatins) (Canel et al., 2000). The Boraginaceae family encompasses a number of plant genera that produce hepatotoxic pyrrolizidine alkaloids (Keller and Tu, 1983). The toxic effects are essentially the same as those discussed for the pyrrolizidine alkaloids occurring in genera of the Asteraceae (vide supra). Of particular concern for poisonings in humans are Heliotropium and Symphytum species. The seeds of H. lasiocarpum and H. popovii have caused extremely large-scale poisonings (as many as 7,800 cases of veno-occlusive disease) when they have contaminated wheat and have been consumed as bread (Mattocks, 1986). Similarly, problems have resulted from H. europaeum contaminating feed grains at 0.6 percent by weight (Mattocks, 1986). Symphytum species (comfrey) of the Boraginaceae family have been used for medicinal purposes since antiquity, primarily for external use to promote healing of wounds. Modern usage has involved internal consumption, either as a salad vegetable or as a tea, both of which have resulted in deaths of humans (Stickel and Sietz, 2000). Teas have been prepared not only from the leaves, but also from roots, which contain higher levels of the alkaloids. It has been determined that a single cup of comfrey root tea contains as much as 8.5 mg of total alkaloids (Roitman, 1981). The Brassicaceae contains a number of plant species, especially Brassica, which are used as vegetables or condiments. Other species are used for forage or are weed species to which livestock may be exposed. All of these contain either cyanogenic or goitrogenic substances (Kellerman et al., 1988). Armoracia rusticana (horseradish) contains glucosinolates, especially glucobrassicin, which generate isothiocyanates, the pungent principles of horseradish on hydrolysis by myrosinase (Shapiro et al., 1998). Glucosinolates are also present in most Brassica species, including B. nigra (black mustard), B. napus (rape), B. rapa (turnip), and varieties of B. oleracea (cabbage, broccoli, Brussels sprouts, and kale) (Keeler and Tu, 1991; Stoewsand, 1995). Under certain conditions, hydrolysis of glucosinolates can also generate thiocyanates or nitriles (Kellerman et al., 1988). Other hydrolysis products from glucosinolates, namely oxazolidine2-thiones, are potent inducers of goiter (enlargement of the thyroid gland) (Stoewsand, 1995). This effect cannot be treated by administration of io-
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Dietary Supplements: A Framework for Evaluating Safety dine. The toxicity of isothiocyanates, thiocyanates, and nitriles, as well as the goitrogenic activity of glucosinolates, suggests that excessive consumption of Brassica and related species should be avoided. Poisoning of livestock by many of these plants when used as forage or feedstuff has been reported, especially when the seeds, which contain the highest levels of glucosinolates, are included (Kellerman et al., 1988). In addition, B. napus (rape) causes respiratory, digestive, nervous, and urinary syndromes and hemolytic anemia in livestock, which may be caused by factors other than glucosinolates; some of these syndromes have also been observed with wild radish (Raphanus raphanistrum) (Kingsbury, 1964). Severe haemolytic anaemia in cattle caused by feeding kale has been shown to be due to the hydrolysis product of S-methyl cysteine sulfoxide, a common constituent of Brassica species (Everist, 1981). Buxus sempervirens (common box), a cultivated ornamental shrub in the Buxaceae family, has been associated with mortality in many types of livestock worldwide (Kingsbury, 1964). Poisoning is usually associated with animals being exposed to clippings of the plant, with as little as 1.5 lbs being lethal to a horse (Kingsbury, 1964). Poisoning is characterized by gastroenteritis, convulsions, and respiratory failure. The toxic constituents are steroidal and triterpene alkaloids that occur in all parts of the plant, including the roots (Atta-ur-Rahman et al., 1997). Korean box (B. microphylla) contains analogous alkaloids and is also planted widely in the United States as an ornamental (Kingsbury, 1964). The Campanulaceae is of concern because of Lobelia species, which are wild and cultivated plants that contain piperidine alkaloids, the most common of which is lobeline (Everist, 1981). Lobelia inflata in excessive doses has proved to be toxic (Kingsbury, 1964). Lobeline has a similar activity to nicotine, but is less potent in stimulating nicotinic receptor sites. Indian tobacco is toxic to sheep at 0.5 percent of the animal’s weight, with symptoms of salivation and nasal discharge, ulceration of the mouth, and coma (Kingsbury, 1964). These symptoms are consistent with those produced by the pure alkaloid, lobeline. The elderberries (Sambucus species) are reputed to be poisonous species in the Caprifoliaceae family. The most common in North America are S. canadensis and S. pubesn; the European elderberry is S. nigra. There have been reports of toxicity to cattle and pigs, and children have been poisoned by using the stems as pea shooters (Kingsbury, 1964). The most poisonous parts of the plant appear to be young growth and the roots (Kingsbury, 1964). The berries can be consumed after cooking, but fresh berries cause nausea and vomiting (Kingsbury, 1964). The toxic constituents include a
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Dietary Supplements: A Framework for Evaluating Safety number of cyanogenic glycosides, especially sambunigrin and prunasin (Buhrmester et al., 2000). The content and presence of these glycosides appears to be highly variable from one population to another. The Caryophyllaceae family has many genera that contain triterpenoid saponins, namely Agrostemma githago (corn cockle), Drymaria species (inkweed, alfombrilla), and Saponaria species (soapwort, cow cockle) (Cheeke, 1998; Everist, 1981). The saponins are present in all parts of the plant but are highest in the seeds, comprising 5 to 7 percent of A. githago seeds (Everist, 1981). Less than 0.25 percent of the animal’s weight of ground corn cockle seed was fatal in cattle and hogs, and 0.5 percent of inkweed or alfombrilla green plant was also lethal (Kingsbury, 1964). Symptoms are severe gastroenteritis, vomiting, diarrhea, coma, and death (Kingsbury 1964). A large number of Euonymus species occur in the Celastraceae, some of which have been incriminated as poisonous plants. These plants occur as both wild and ornamental plants in the form of shrubs, vines, and ground covers. The spindle tree (E. europaeus) and burning bush (E. atropurpureus) are reported as toxic to children and livestock, causing violent purgation, vomiting, and unconsciousness (Kingsbury, 1964). Poisoning in humans has most commonly been attributed to consumption of the fruit, but the bark and leaves are also toxic (Kingsbury, 1964). Various Euonymus species have been shown to contain cytotoxic cardioglycosides, as well as sesquiterpene pyridine alkaloids and a phytohemaglutinin (Jinbo et al., 2002; Kuo et al., 2003). Poisoning has also been attributed to another member of the Celastraceae, the viny bittersweet (Celastrus scandens), and other Celastrus species have been shown to contain sesquiterpene pyridine alkaloids and biologically active agarofuran sesquiterpenes (Jin et al., 2002). The Chinese herb Tripterygium wilfordii (lei gong teng), also a member of the Celastraceae, has been shown to be immunosuppressant and to decrease spermatogenesis. It contains triptolide and related highly epoxidized diterpenoids, which are most likely to be the bioactive constituents (Qui and Kao, 2003). The Convolvulaceae encompasses species of the genera Calystegia and Convolvulus (bindweeds) and Ipomoea (sweet potato) that contain polyhydroxy alkaloid glycosidase inhibitors. The most common of these are the calystegines, nortropane alkaloids with varying degrees of hydroxylation, that are potent inhibitors of glycosidases, especially β-glucosidase and β-galactosidase (Cheeke, 1998; Garland and Barr, 1998). Ingestion of these alkaloids results in inhibition of glycoprotein processing with consequent accumulation of oligosaccharides, particularly in cells of the cerebellum,
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Dietary Supplements: A Framework for Evaluating Safety classified as a lysosomal storage disease (Elbein and Molyneux, 1998). Consumption of Ipomoea species by sheep in Australia and goats in Mozambique has resulted in a neurological syndrome characterized by muscle-twitching, trembling, staggering, and incoordination (de Balogh et al., 1999). In addition to the calystegines, these Ipomoea species also contain the polyhydroxy indolizidine alkaloid swainsonine, the causative agent of locoweed poisoning produced by certain Astragalus, Oxytropis, and Swainsona species of the Fabaceae (vide infra) (Colegate and Dorling, 1994; Garland and Barr, 1998). The polyhydroxy alkaloids have also been shown to occur in the edible tubers of sweet potato (I. batatas), but no episodes of poisoning in humans from this source appear to have been recorded (Asano et al., 1997). The seeds of some species of Ipomoea and Rivea contain D-lysergic acid diethylamide-related alkaloids (Everist, 1981). The alkaloid levels in all of the genera of concern in the Convolvulaceae are very low, but the extraordinary potency of their glycosidase inhibitory properties and cumulative effects results in chronic toxicity. It is reasonable to assume that glycosidase inhibition could also interfere with digestive processes, leading to malabsorption and emaciation. Although the calystegines are structurally related to tropane alkaloids (e.g., scopolamine), they do not have any similarity in their mode of action to the latter class. The Coriariaceae is a very small plant family consisting of the single genus Coriaria. Accidental poisoning by the Mediterranean shrub C. myrtifolia has been reported following ingestion of the fruits, which may be mistaken for blackberries. Toxicity is characterized by vomiting and abdominal pain, convulsions, and respiratory disorders; death has resulted on occasion (Skalli et al., 2002). The picrotoxin-like sesquiterpene lactones coriamyrtin and corianin, together with structurally related compounds, have been identified in a number of Coriaria species (Aguirree-Galviz and Templeton, 1990; Kariyone and Okuda, 1955; Reyes et al., 1980; Wei et al., 1998). The Cupressaceae encompasses cypress and juniper trees. The Monterey cypress (Cupressus macrocarpa) is a native of North America that has been introduced into New Zealand, where it has caused third-trimester abortion and other pregnancy disorders in sheep and cattle that consumed small amounts of the leaves (Everist, 1981). The toxin has been shown to be the labdane diterpene isocupressic acid, identical to that in Pinus species (Pinaceae) that produce the same syndrome (Cheeke, 1998). Relatively high levels of isocupressic acid have also been measured in common juniper (Juniperus communis) and Rocky Mountain juniper (J. scopulorum), which have also been incriminated in abortions (Gardner et al., 1998).
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Dietary Supplements: A Framework for Evaluating Safety At levels of 0.34 percent cyanide potential, 0.5 lb of forage could prove fatal in grazing animals (Kingsbury, 1964). Additional concerns arise with certain species in the Poaceae due to the ability of endophytic fungi to produce toxic compounds. Cynodon dactylon (Bermuda grass) and related species produce high levels of cyanogenic glycosides, but the syndrome known as “Bermuda grass tremors” is caused by the presence of the parasitic fungus Balansia epichloe (Bacon, 1995). The fungus produces nonpeptide ergot alkaloids such as agroclavine, which produce symptoms in livestock (especially horses) ranging from muscle twitching to paralysis of the hind limbs (Bacon, 1995). Peptide-derived ergot alkaloids, based on (+)-lysergic acid, are produced by the fungus Claviceps purpurea growing on rye (Secale cereale) (Dewick, 2002). Claviceps species infect many other cereals and grasses and the risk of ergotism is therefore always present. Ergot alkaloids of the ergopeptine class, produced by infection of Festuca species by the endophyte Acremonium coenophialum, are responsible for “fescue foot,” a lameness and gangrene in the hind feet of cattle (Kellerman et al., 1988). A disease known as “perennial ryegrass staggers” in livestock is produced by infection of Lolium perenne by Claviceps paspali (Cheeke, 1995) and Acremonium lolii (Cheeke, 1998; Garland and Barr, 1998). The toxins are complex tremorgenic mycotoxins (penitrems and lolitrems) (Cheeke, 1998) that are potent inhibitors of calcium-activated potassium channels (Cavanagh et al., 1998). The disease is characterized by tremors, severe incoordination, and collapse. The estrogenic macrolide zearalenone is produced by the fungus Gibberella zeae (Fusarium graminearum) growing on corn (Zea mays) and has produced vulvovaginitis, especially in pigs (Cheeke, 1998). The Polygonaceae includes the genera Fagopyrum, Rheum, Rumex, Halogeton, and Sarcobatus. Most of these contain high levels of soluble oxalates, which have caused death in livestock and humans, and also significant amounts of nitrate (Kingsbury, 1964). Fagopyrum sagittatum (buckwheat) is cultivated as a minor grain crop, generally for milling into flour or as a forage for animals. It has produced photosensitization in humans and animals known as fagopyrism, which appears to be of the primary type rather than secondary since there is no evidence of liver damage (Kellerman et al., 1988). The photoactive pigment is probably fagopyrine, a naphthodianthrone structurally related to hypericin in St. John’s wort (Hypericum perforatum) (Kellerman et al., 1988). Many cases of buckwheat poisoning in humans are the result of an allergic reaction to the plant, and ingestion or inhalation can induce an allergenic reaction (Kingsbury, 1964).
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Dietary Supplements: A Framework for Evaluating Safety The Polypodiaceae includes the bracken fern Pteridium aquilinum, which is worldwide in distribution and is established as acutely and chronically toxic to livestock and laboratory animals. The plant contains the enzyme thiaminase, which results in anorexia and ataxia in horses, bright blindness in sheep due to retinal neuroepithelium degeneration, and depression of bone marrow in cattle (Cheeke, 1998). The plant also produces carcinoma of the upper alimentary tract and urinary bladder, caused by ptaquiloside (Cheek, 1998). A number of other structurally related illudanetype sesquiterpene glucosides have been isolated and identified (Nagao et al., 1989). There is evidence that carcinoma can result in calves from ingestion of the toxin through the milk of cows grazing bracken fern (Smith and Seawright, 1995). Epidemiological studies in Japan and Brazil have suggested a close association between bracken frond (fiddleheads) consumption and cancers of the upper alimentary tract (Alonso-Amelot and Avendano, 2001; Brown et al., 1999), but there is evidence that fiddleheads processed by salting can be eaten safely; other routes of exposure may therefore be a factor (Hirono et al., 1972). The Ranunculaceae includes Aconitum (aconite, wolfsbane, monkshood) and Delphinium (larkspur) species that are acutely toxic to livestock (Kingsbury, 1964). Dried roots of aconite were historically used as an external application for treatment of pain, such as from rheumatism. The plant has been used to poison baits for pest animals, for execution of criminals, and for homicidal purposes. Accidental deaths have been caused by mistaking the root for that of horseradish (Kingsbury, 1964). The dried root can contain up to 1.5 percent by weight of alkaloids with the primary toxic constituent being the diester diterpenoid alkaloid aconitine, comprising approximately 30 percent of the total (Dewick, 2002). Aconitine is acutely toxic, with an oral LD50 in mice of 1 mg/kg, and has been used to produce heart arrhythmia in experimental animals (O’Neil et al., 2001). The root of A. ferox (Indian aconite) is extremely toxic and very small quantities can produce fatal cardiac depression (Klasek et al., 1972). The major alkaloid constituent is pseudoaconitine (Klasek et al., 1972). The extreme toxicity of Aconitum species indicates that use of any parts of the plant or preparations thereof should be a matter of extreme concern. Delphinium (larkspur) species also contain norditerpene alkaloids and have produced large-scale losses of cattle, especially when grazed in the early growth and flower/seed stage (Cheeke, 1998). Death is often rapid, preceded by staggering gait, recumbancy, muscle twitching, and rapid and irregular pulse (Cheeke, 1998). Delphinium species contain over 40 different diterpenoid alkaloids with highly variable compositions and concentrations (Cheeke, 1998). A major constituent is deltaline, generally in excess of 50 percent of the total alkaloid content, with an intravenous LD50
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Dietary Supplements: A Framework for Evaluating Safety in mice of about 200 mg/kg (Garland and Barr, 1998). The most toxic alkaloids are those possessing an N-(methylsuccinyl)-anthranoyl ester substituent on the basic norditerpenoid skeleton, of which methyllycaconitine is the most common, comprising 0.2 percent of the dry weight of D. barbeyi (Manners et al., 1995). These alkaloids reversibly bind and block nicotinic acetylcholine receptors (Garland and Barr, 1998). Whereas methyllycaconitine has a binding constant (KI50) of 1.7 nM, that of its parent, lycoctonine, is only 2,800 nM. Their LD50 values, when administered intravenously to mice, are 4.0 and 444 mg/kg, respectively (Manners et al., 1993). The range in toxicities of these various alkaloids and their tendency to change rapidly from one plant species to another, and within a species in response to growth stage and environmental conditions, makes an assessment of risk problematic. Anemone and Ranunculus species are known to be irritant to livestock and toxic on occasion (Kingsbury, 1964). The plants contain ranunculin, the glucoside of 5-methylene-2(5H)-furanone or protoanemonin (Kingsbury, 1964). Enzymatic hydrolysis of ranunculin releases protoanemonin as a volatile, irritant oil that is unstable and rapidly polymerizes to give a resin of which the dimer, anemonin, is a major constituent (Cheeke, 1998). Anemonin is relatively nontoxic with an LD50 value when administered intraperitoneally to mice of 150 mg/kg (O’Neil et al., 2001). Protoanemonin can be transferred into the milk of lactating animals, on which it confers a bitter taste (Burrows and Tyrl, 2001). The coyotillo or tullidora, Karwinskia humboldtiana, a member of the Rhamnaceae growing in the border areas of the United States and Mexico, has been established as toxic to children and livestock for two centuries (Garland and Barr, 1998). Over 50 confirmed cases of poisoning in humans were reported in Mexico in a 3-year period from 1991 to 1993 (Garland and Barr, 1998). The toxicity is characterized by progressive and symmetrical noninflammatory paralytic neuronopathy, initially in the lower limbs and progressing to respiratory and bulbar paralysis (Burrows and Tyrl, 2001). The fruits contain a series of cytotoxic hydroxyanthracenones known as peroxisomicines and karwinols (Galindo and Waksman, 2001). Administration of a mixture of karwinols to a laboratory animal caused quadriplegia (Garland and Barr, 1998). The Rosaceae contains a number of Prunus species (bitter almond, cherries, peaches, plums), the kernels of which contain cyanogenic glycosides, the most representative being amygdalin, a diglucoside (Kingsbury, 1964). Crushing of the tissue releases glucosidases that hydrolyse amygdalin to the monoglucoside prunasin and subsequently to mandelonitrile, which undergoes aqueous hydrolysis to benzaldehyde and hydrogen cya-
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Dietary Supplements: A Framework for Evaluating Safety nide (Kingsbury, 1964). Consumption of the foliage of wild cherries and other Prunus species is a frequent cause of poisoning in livestock (Kingsbury, 1964). Symptoms are typical of hydrogen cyanide poisoning, with heart and respiratory failure, as previously discussed. It has been reported that 7 to 10 bitter almond kernels were fatal to a 3-year-old child and 40 to 60 kernels were fatal for a man (Burrows and Tyrl, 2001). The dried leaflets, known as pilocarpus or jaborandi, of various Pilocarpus species belonging to the Rutaceae family, contain up to 1 percent of imidazole alkaloids, the chief of which is pilocarpine (Dewick, 2002). The salts of this alkaloid are useful in ophthalmic practice for the treatment of glaucoma. Pilocarpine has a structural analogy to muscarine and acetylcholine. Toxicity due to ingestion of the plant can occur due to its activity as a cholinergic agent and as a muscarinic agonist (Dewick, 2002). The main source of pilocarpus is P. microphyllus. The Sapindaceae includes the species Blighia sapida (akee), the fruit and oil of which are edible if properly prepared by parboiling and frying. However, it has been the cause of a disease in undernourished humans, especially children, known as “vomiting sickness” (Cheeke, 1998). The causative agent is hypoglycin-A, a cyclopropane amino acid that causes severe hypoglycemia (Cheeke, 1998). Toxicity is characterized by violent vomiting, convulsions, coma, and death in most cases (Cheeke, 1998). In rats, hypoglycin-A has been shown to be teratogenic (Persaud, 1968). These effects may be due to a reduction in the rate of fatty acid oxidation due to inhibition of a flavin-dependent acyl dehydrogenase (Tanaka et al., 1971). The severe toxicity suggests a high concern for use of this plant itself or its aqueous and alcoholic extracts. The family Scrophulariaceae contains Castilleja (paintbrush) and Pedicularis (lousewort) species that have been found to contain relatively low levels of pyrrolizidine alkaloids. The hepatotoxicity of these alkaloids has been discussed in detail under the Asteraceae. There is evidence that these alkaloids are not biosynthesized de novo within the plants, but acquired from other plant species by root parasitism (James et al., 1992). Alkaloid levels are therefore likely to be low, but the unpredictable nature of such parasitism and the cumulative nature of pyrrolizidine alkaloid toxicity raises the level of concern regarding use of these plants. Digitalis purpurea (foxglove) has a long history as a medicinal plant for treatment of heart disease, especially to increase the force of contraction and prolong the duration of diastole (Cheeke, 1998). The plant contains over a dozen cardenolide-type cardiac glycosides, the most important of which are digitoxin and digoxin, yielding digitoxigenin and digoxigenin,
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Dietary Supplements: A Framework for Evaluating Safety respectively, on hydrolysis (Kingsbury, 1964). Although the active compounds are the glycosides, the sugar residues serve an important function in conferring sufficient solubility for oral administration (Kingsbury, 1964). Toxicity is characterized by nausea, vomiting, drowsiness, delirium, hallucinations, and death (Kingsbury, 1964). In humans, poisoning occurs from overdose or too frequent use of the drug, which accumulates in tissues (Kingsbury, 1964). The Solanaceae includes some of the most valuable food plants used by humans, while at the same time encompassing a large number of toxic plant species. The edible plants are confined to the genera Solanum and Lycopersicon and include potato (S. tuberosum), eggplant (S. melongena), tomato (L. esculentum), and other minor vegetables. Even among these foods, certain plant parts are poisonous and should not be consumed. In particular, green sprouting potatoes are known to be toxic and have on occasion caused fairly large-scale poisoning in humans (Burrows and Tyrl, 2001; Cheeke, 1998). The toxicity has been attributed to steroidal glycoalkaloids, typified by solasonine, solanine, and tomatine, which give rise to the aglycones solasodine, solanidine, and tomatidine, respectively, on hydrolysis (Cheeke, 1998; Keeler and Tu, 1991). Glycoalkaloid contents above 140 ppm confer a bitter taste on potatoes and a burning sensation in the throat (Burrows and Tyrl, 2001). The solanine content in fresh potato sprouts is approximately 0.04 percent (400 ppm); potatoes are considered to be toxic to humans at glycoalkaloid levels above 200 ppm, producing vomiting, abdominal pain, diarrhea, and sometimes death (Burrows and Tyrl, 2001). The alkaloids cause membrane disruption in the digestive system and have anticholinesterase activity on the central nervous system; they have also been shown to be potentially teratogenic (Cheeke, 1998). However, recent studies have shown that many food plants in the Solanaceae also contain significant levels of calystegines, which are polyhydroxytropane alkaloids that are potent inhibitors of glucosidases (Asano et al., 1997). These alkaloids may therefore also be involved in digestive disturbances through inhibition of gut enzymes. Atropa, Brugmansia, Datura, Duboisia, and Hyoscyamus are all genera that have been recorded as poisoning livestock. Humans appear to be particularly susceptible to poisoning by these plants as well. All species contain tropane alkaloids, mainly scopolamine and hyoscamine (Cheeke, 1998; Kingsbury, 1964; Seawright et al., 1985). Typical content of total alkaloids ranges from 1 to 3.5 percent in the leaves (Dewick, 2002). The tropane alkaloids act as anticholinergics, binding to the muscarinic site of the parasympathetic nervous system and thus competing with acetylcholine (Dewick, 2002). As a consequence, they have a depressant effect on the central nervous system, they suppress salivary secretions, they have an
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Dietary Supplements: A Framework for Evaluating Safety antispasmodic effect on the gastrointestinal tract, and they dilate the pupil of the eye. Poisoning from ingestion of plant parts or preparations thereof is relatively common and small quantities of the plant will produce observable adverse effects and even death (Cheeke, 1998). It has been calculated that 4 to 5 grams of leaf or seed of Datura is equivalent to a fatal dose for a child (Burrows and Tyrl, 2001). Most of these species have recently been shown to contain glycosidase inhibitory calystegines, as in the Solanum species. The Taxaceae includes a number of Taxus species, all parts of which are acutely toxic to humans and livestock (Garland and Barr, 1998). The most extensive studies on toxicity have been conducted with the English yew T. baccata, native to Europe although it is widely grown as an ornamental plant in North America. Discarded clippings from a garden plant were recently reported to have resulted in the death of 43 cattle in a single night (Panter et al., 1993). Immediate fatalities are due to heart and circulatory failure, although less severely poisoned animals may show trembling, dyspnea, and collapse prior to succumbing (Garland and Barr, 1998; Kingsbury, 1964). The discovery of the Pacific yew T. brevifolia as a source of the anticancer drug, taxol, has stimulated extensive phytochemical examination of various Taxus species and over 100 diterpenoid taxanes have been characterized (Kingston et al., 2002). Daphne species, members of the Thymelaeaceae, have been long recognized as poisonous plants. The most commonly seen is D. mezereum, cultivated as an ornamental, but also naturalized in some areas of the United States. The plants have attractive berries that have poisoned children, and it has been reported that only three berries each resulted in the death of six piglets (Kingsbury, 1964). Chewing on the bark has also caused fatalities in humans, and livestock have been killed by prunings from ornamental plantings (Burrows and Tyrl, 2001; Kingsbury, 1964). The toxic principles are daphnetoxins and mezerein, diterpenes of the phorbol ester type, which may also be cocarcinogenic and allergenic (Burrows and Tyrl, 2001). The Verbenaceae contains Lantana species, which are toxic to sheep and cattle in Australia, South Africa, and the United States (Kellerman et al., 1988). Children are suspected of having been poisoned by consumption of the berries (Kingsbury, 1964). Principle among the poisonous species are L. camara and L. montevidensis (Burrows and Tyrl, 2001; Garland and Barr, 1998). Toxicity is highly variable, and in Australia there have been attempts made to classify the hazard on the basis of their flower color. Primary signs of acute poisoning in livestock is gastroenteritis, but in chronic poisoning secondary photosensitization due to liver damage may be appar-
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Dietary Supplements: A Framework for Evaluating Safety ent (Cheeke, 1998; Seawright et al., 1985). The toxic principles are lantadenes and hepatoxic triterpene acids (Cheeke, 1998). The Zamiaceae is closely related to the Cycadaceae and consumption of the leaves or seeds produces similar neurological defects in man and animals. Macrozamia (burrawang, Zamia palm, or wild pineapple) are the most common species in this family and contain azoglycosides, especially macrozamin, consisting of the aglycone methylazoxymethanol, glycosylated with various sugars (Everist, 1981). Zamia integrifolia (Florida arrowroot) is a woody, fern-like plant common in peninsular Florida and has been reported to poison cattle in South America; the seeds are suspected of being poisonous to humans (Kingsbury, 1964). Larrea tridentata, a member of the Zygophyllaceae found in the American Southwest and northern Mexico and known as creosote bush or tarbush, has an ethnobotanic reputation as a beneficial plant. A number of reports have shown that products containing L. tridentata induce hepatotoxicity and nephrotoxicity in humans (Garland and Barr, 1998; Lambert et al., 2002). Nordihydroguaiaretic acid, a lignan occurring at up to 10 percent dry weight in the leaves and twigs of the plant, has been demonstrated to be the toxic constituent (Burrows and Tyrl, 2001). Other species of the Zygophyllaceae known to be toxic to livestock are Peganum harmala (African rue), a plant introduced into the United States from deserts of Africa, and Tribulus terrestris (puncture vine or caltrop). P. harmala, although generally unpalatable, causes death in cattle and the ground seed was lethal to guinea pigs at 0.15 percent of the animals’ weight (Kingsbury, 1964); the plant contains β-carboline alkaloids, which are responsible for its toxicity (Burrows and Tyrl, 2001). T. terrestris causes hepatogenic photosensitization in livestock and is a major cause of this disease in sheep, known as bighead or geeldikkop, in Australia and South Africa, respectively (Cheeke, 1998; Kellerman et al., 1988). The plant contains steroidal saponins which have been postulated as the hepatotoxins responsible (Cheeke, 1998). REFERENCES Aguirre-Galviz LE, Templeton W. 1990. Toxic sesquiterpenoid lactones from the leaves of Coriaria microphylla. Planta Med 56:244. Allen CL, Loudon J, Mascarenhas AK. 2001. Sanguinaria-related leukoplakia: Epidemiologic and clinicopathologic features of a recently described entity. Gen Dent 49:608–614. Alonso-Amelot, ME, Avendano M. 2001. Carcinogenic activity of Pteridium aquilinum var latiusculum in humans. Possible association between gastric cancer and bracken fern in Venezuela: An epidemiological study. Int J Cancer 91:252–259.
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Dietary Supplements: A Framework for Evaluating Safety Asano N, Kato A, Matsui K, Watson AA, Nash RJ, Molyneux RJ, Hackett L, Topping J, Winchester B. 1997. The effects of calystegines isolated from edible fruits and vegetables on mammalian liver glycosidases. Glycobiology 7:1085–1088. Atta-ur-Rahman, Noor-e-ain F, Choudhary MI, Parveen Z. 1997. New steroidal alkaloids from Buxus longifolia. J Nat Prod 60:976–981. Bacon CW. 1995. Toxic endophyte-infected tall fescue and range grasses: Historic perspectives. J Anim Sci 73:861–870. Bah M, Bye R, Pereda-Miranda R. 1994. Hepatotoxic pyrrolizidine alkaloids in the Mexican medicinal plant Packera candidissima (Asteraceae: Senecioneae). J Ethnopharmacol 43:19–30. Bedir E, Manyam R, Khan IA. 2003. Neo-clerodane diterpenoids and phenylethanoid glycosides from Teucrium chamaedrys L. Phytochemistry 63:977–983. Boffa MJ, Gilmour E, Ead RD. 1996. Celery soup causing severe phototoxicity during PUVA therapy. Br J Dermatol 135:334. Bradberry SM, Dickers KJ, Rice P, Griffiths GD, Vale JA. 2003. Ricin poisoning. Toxicol Rev 22:65–70. Brown L, Zahm SH, Hoover RN, Fraumeni J. 1999. Bracken fern consumption and human bladder cancer. J Epidemiol Comm Health 53:653. Buhrmester RA, Ebinger JE, Seigler DS. 2000. Sambunigrin and cyanogenic variability in populations of Sambucus cyanogenic variability in populations of Sambucus canadensis L. (Caprifoliaceae). Biochem Syst Ecol 28:689–695. Burrows GE, Tyrl RJ. 2001. Toxic Plants of North America. Ames, IA: Iowa State University Press. California Academy of Sciences. 2003. California Wildflowers: Death Camas. Online. Available at http://www.calacademy.org/research/botany/wildflow/comfrm.htm. Accessed December 11, 2003. Camp BJ, Bridges CH, Hill DW, Patamalai B, Wilson S. 1988. Isolation of a steroidal sapogenin from the bile of a sheep fed Agave lecheguilla. Vet Hum Toxicol 30:533–535. Canel C, Moraes RM, Dayan FE, Ferreira D. 2000. Podophyllotoxin. Phytochemistry 54:115–120. Cavanagh JB, Holton JL, Nolan CC, Ray DE, Naik JT, Mantle PG. 1998. The effects of the tremorgenic mycotoxin peniterem A on the rat cerebellum. Vet Pathol 35:53–63. Cheeke PR. 1995. Endogenous toxins and mycotoxins in forage grasses and their effects on livestock. J Anim Sci 73:909–918. Cheeke PR. 1998. Natural Toxicants in Feeds, Forages, and Poisonous Plants. 2nd ed. Danville, IL: Interstate Publishers. Colegate SM, Dorling PR, eds. 1994. Plant-Associated Toxins: Agricultural, Phytochemical and Ecological Aspects. Wallingford, UK: CAB International. Cosyns JP, Goebbels RM, Liberton V, Schmeiser HH, Bieler CA, Bernard AM. 1998. Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats. Arch Toxicol 72:738–743. de Balogh KKIM, Dimande AP, van der Lugt JJ, Molyneux RJ, Naude TW, Welmans WG. 1999. A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique. J Vet Diagn Invest 11:266–273. Dewick PM. 2002. Medicinal Natural Products. A Biosynthetic Approach, 2nd ed. New York: John Wiley and Sons. Elbein AD, Molyneux RJ. 1998. Inhibitors of glycoprotein processing. In: Stutz AE, ed. Iminosugars as Glycosidase Inhibitors-Nojirimycin and Beyond. New York: Wiley-VCH. Everist SL. 1981. Poisonous Plants of Australia. London: Angus & Robertson Publishers. Galindo VR, Waksman N. 2001. Cytotoxic hydroxyanthracenones from fruits of Karwinskia parvifolia. Nat Prod Lett 15:243–251.
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