pathways emerge from this cytotoxic intermediate, both of which produce similar tumorigenic DNA adducts. Neither pathway has been proven to be the more predominate mechanism. The first mechanism involves a movement of electrons intramolecularly to break the ester bond. This creates a carbocation that can bind to a DNA base covalently. By hydrolyzing the rest of the riddelliic acid from the original molecule, the resulting dehydropyrrolizine (DHP) can bind to another DNA base, which introduces a covalent cross-linking. The second mechanism involves hydrolyzing the riddelliic acid to produce dehydropyrrolizine (DHP). By hydrolyzing both hydroxyl groups attached at carbons 3 and 8 of DHP, the resulting carbocation can bind to two DNA bases, producing another cross-linked DNA adduct. In both cases, the covalently bonded DHP molecule can be further modified to induce stronger covalent bonding. To date, 8 DHP-derived DNA adducts have been observed, all of which contribute to the tumorigenicity of riddelliine. Toxicity Riddelliine is isolated from plants grown in the western United States and is a prototype of genotoxic pyrrolizidine alkaloids (PAs). Human exposure to PAs occurs through consumption of herbal dietary supplements, including comfrey, and through contaminated livestock products (e.g., milk). PAs are probably the most common plant constituents that poison livestock, wildlife, and humans worldwide. Riddelliine has been shown to have clear evidence of carcinogenic activity in male and female rats but there are no human studies done on the effects of riddelliine on humans. There have been cases of human poisoning due to PA intake. These cases consists of the following incidents: Heliotrope poisoning is endemic in central Asia, where seeds of Heliotropium species enter the wheat crop. The typical clinical picture is that of ascites, hepatosplenomegaly, veno-occlusive disease of the liver, and abnormal liver function. In South Africa, a disease known as "bread poisoning," found among poor Europeans, was traced to the inclusion of Senecio and Crotalaria seeds and flowers in whole grain processed for bread flour. A veno-occlusive disease outbreak in Jamaica was traced to the widespread use of "bush tea," an herbal medicine used to treat children for colds. In the Southwest of the United States, the popular herbal tea, gordolobo yerba, is a potential hazard for exposure to toxic PAs. Indications In rats gavaged with riddelliine, a set of DNA adducts of dehydroretronecine (DHS) in liver DNA can serve as biomarkers for the tumorigenicity induced by riddelliine and related pyrrolizidine alkaloids. Adverse