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Experimental Colon Carcinogens and Their Mode of Action
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
John H. Weisburger, Emerich S. Fiala
Sequential chemical oxidation of DMH in the laboratory can produce AOM and MAM. Since these chemical reactions are entirely analogous to the transformations occurring in vivo, they are described here in some detail. 1,2-Dimethylhydrazine is readily oxidized either by oxygen in the presence of metal ion catalysts60 or by chemical oxidants such as mercuric oxide,61 to azomethane, a poisonous and explosive gas. Further chemical oxidation converts azomethane to azoxymethane in high yield.61 Interestingly, azoxymethane is also produced during the chemical oxidation of methylam-ine.62 Related model compounds such as phenylethylamine can be converted biochemically to the corresponding azoxy compound.63 Azoxymethane is a more powerful carcinogen than 1,2-dimethylhydrazine, and its organospecificity is essentially identical.1,6,64–66 Bromination of azoxymethane and subsequent reaction with silver acetate produces methylazoxymethyl acetate,61 again a powerful carcinogen with much the same organospecificity as its chemical precursors.8,9 Methylazoxymethyl acetate, a stable liquid, is easily hydrolyzed by various esterases67–69 to the relatively unstable methylazoxymethanol. The latter may also be obtained by hydrolysis of cycasin with β-glucosidase.9
Identification of structural fingerprints for in vivo toxicity by using Monte Carlo based QSTR modeling of nitroaromatics
Published in Toxicology Mechanisms and Methods, 2020
Dipayan Mondal, Kalyan Ghosh, Anurag T. K. Baidya, Anindita Mondal Gantait, Shovanlal Gayen
In the nitroaromatics, oxygen atoms bonded with nitrogen atom are more electronegative than nitrogen. This results in polarization of the oxygen–nitrogen bond and thus, nitro groups possess more electronegative character. As a result, nitro groups are themselves reduced by taking part in oxidation reactions and produce the biologically inert polymeric compounds, e.g. azo, azoxy compounds (Kulkarni and Chaudhari 2007). In our body, the normal functions of some proteins and DNA are blocked by the nitroaromatic compounds as these compounds can combine with the nucleophilic sites (examples –OH, −SH, and NH2 groups) through nucleophilic aromatic substitution (Katritzky et al. 2003). They can also form a complex with electron-donating heterocycles in biomolecules and may alter their normal function. In oxidative phosphorylation, they may also act as an uncoupling agent and may lead to a complex mechanism of toxicity (Donlon et al. 1995).
The safety evaluation of food flavoring substances: the role of genotoxicity studies
Published in Critical Reviews in Toxicology, 2020
Nigel J. Gooderham, Samuel M. Cohen, Gerhard Eisenbrand, Shoji Fukushima, F. Peter Guengerich, Stephen S. Hecht, Ivonne M. C. M. Rietjens, Thomas J. Rosol, Maria Bastaki, Matthew J. Linman, Sean V. Taylor
In a recent publication, describing its updated procedure for the safety evaluation of natural complex mixtures used as flavoring substances, the FEMA Expert Panel incorporated the TTC concept for compounds that are potentially genotoxic (Cohen et al. 2018). Within that publication, the Panel’s approach to the consideration of the genotoxic potential of known and unidentified compounds is described. The updated procedure acknowledges that some constituents of natural complex mixtures, whether identified or unidentified, may possess genotoxic potential and determines whether that potential poses appreciable genotoxicity risk to the consumer, when test data are not available. The TTC for evaluation of genotoxicity risk (TTCgenotox) of 0.15 µg/person/day was proposed by Kroes and colleagues (Kroes et al. 2004) as the dose below which cancer risk does not exceed 1 in 106, specifically for compounds that have structural alerts for genotoxicity other than those of highly potent carcinogens, such as aflatoxin, certain azo- and azoxy-compounds or N-nitroso- compounds, for which no threshold can be determined. The TTCgenotox is 10-fold lower (more stringent) than the threshold of regulation (TOR) for cancer risk previously established for substances with no indication of DNA reactivity [for details, see (Kroes et al. 2004; Boobis et al. 2017; Patlewicz et al. 2018)]. The application of the TTCgenotox is consistent with a risk assessment approach rather than a strict hazard evaluation (EFSA 2016; Nohmi 2018). In the absence of test data, the safety evaluation procedure for flavoring substances proposes that intake below the TTCgenotox presents negligible concern for genotoxicity.