Nongenotoxic Carcinogenicity of Chemicals: Mechanisms of Action and Early Recognition through a New Set of Structural Alerts

Mutagenic and carcinogenic structural alerts and their mechanisms of action

“…Benigni and Bossa (24) summarised structural alerts as follows: "The Structural Alerts are molecular substructures or reactive groups that are related to the carcinogenic and mutagenic properties of the chemicals, and represent a sort of 'codification' of a long series of studies aimed at highlighting the mechanisms of action of the mutagenic and carcinogenic chemicals". Structural alerts are very helpful not only in the classification of potential carcinogens, but are also important in understanding the mechanisms of genotoxicity (24)(25)(26)(27)(28). …”

“…Epigenetic factors are common in cells that are constantly under stress. Such chemicals do not form DNA adducts nor do they alter DNA but affect the expression of certain genes (28). All epigenetic factors (physical, chemical, and biological) mainly operate in two ways: either via methylation or via post-translational modifications of histones (acetylation).…”

International regulatory needs for development ofan IATA for non-genotoxic carcinogenic chemical substances

“…(Q)SAR models predict the biological activity of a given chemical using quantitative parameters describing structure but also physico-chemical and/or reactivity are considered more important than structural alerts (Silva Lima and Van der Laan, 2000), but these can be combined. A few models describing a number of structural alerts and/or characteristics of several types of NGTxC, such as PPARα activators and inducers of oxidative stress, have been developed (Woo and Lai, 2003;Benigni et al, 2013).…”

REACH and in silico methods: an attractive opportunity for medicinal chemists

“…Enoch [23] developed tools implemented as a DNA-binding profiler in the OECD QSAR Toolbox (http://www.qsartoolbox.org) based on 26 new SAs to predict covalent and noncovalent binding to DNA. Benigni [25] proposed a new set of nongenotoxic SAs, included in the publicly available ToxAlert platform [26]. Despite the A c c e p t e d M a n u s c r i p t existence of many models mostly based on electrophilicity as the key feature, only a few fine-tuned mutagenicity models are known [27,28] to achieve the same reproducibility level (i.e., 85%) as that of the Ames test.…”