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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