Mycotoxins can cause toxicity when ingested by humans and animals. Although the rumen is supposed to be a barrier against mycotoxins, some studies demonstrate that carry-over of mycotoxins to milk is possible. Different studies have found mycotoxin levels in animal milk, mainly related to contaminated feed for ruminants. Aflatoxin M1 is the most studied mycotoxin in milk and levels exceeding the EU maximum level for this mycotoxin in this matrix (0.050 μg/kg) have been found. Maximum levels in milk for other mycotoxins have not been established; however ochratoxin A, aflatoxins G1, G2, B1, B2 and M2, fumonisin B1, cyclopiazonic acid, zearalenone and its metabolites and deepoxydeoxynivalenol have also been found in milk samples. Taking into account that multi-exposure to mycotoxins is the most likely scenario and co-occurrence of mycotoxins could affect their toxicological effects in humans and animals, there is a need to determine the co-occurrence of mycotoxins in milk.

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Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substitutents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V). The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 63, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.

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