Prediction of genotoxicity

The inconsistent data reported for the animal models, the human cell assays, and the Ames tests with the various fuel oils preclude the use of the data for the prediction of genotoxic hazards to humans (refer to Tables 2-4 and 2-5 for a further summary of these studies). 

The prediction of genotoxicity based on chemical structure began in earnest after Ashby and Tennant [15,16] established that there are correlations between chemical structure. Salmonella mutagenicity and carcinogenicity - and that genotoxic and... 

Ashby and Tennant (1988) have identified this chemical as showing structural features predictive of genotoxicity. No genotoxic effects were seen in three different assays, but the data-set is inadequate to allow firm conclusions. 

Snyder, R.D. and Smith, M.D. (2005) Computational prediction of genotoxicity room for improvement. Drug Discov. Today, 10 (16), 1119-1124. 

Snyder RD, Smith MD. Computational prediction of genotoxicity Room for improvement. Drug Discov Today 2005 10(16) 1119-24. 

Benigni, R Conti, L Crebelli, R Rodomonte, A. and Vari, M.R. (2005) Simple and a,p-unsaturated aldehydes correct prediction of genotoxic activity through structure-activity relationship models. Envir. Mol. Mutag., 46, 268-280. 

This chapter describes technology platforms in Mettox, a BTG business focused on preclinical assays with the capability to predict phase I metabolism mediated by liver cytochrome P450s and, in the case of GreenScreen GC, where positive results are predictive of genotoxic-ity in mandated regulatory tests. 

Toxicol., 18, 1071-1080 (2005). Prediction of Genotoxicity of Chemical Compounds by Statistical Learning Methods. 

Custer, L. L, Durham, S. K., Pearl, G. M. Probabilistic neural network multiple classifier system for predicting the genotoxicity of quinolone and quinoline derivatives. Chem. Res. Toxicol. 2005, 18, 428-440. 

I. Y. Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ. Mol. Mutagen. 2004,... 

Pyrethrins (I) Pyrethrins induce the formation of liver and thyroid tumors by mechanisms that appear to be similar to those of other non-genotoxic, mitogenic substances, e.g., phenobarbital, which produce tumors in rodents, and these tumors are not predictive of hazard in humans at relevant exposures [99]... 

DEREK Expert system for the prediction of toxicity (genotoxicity, carcinogenicity, skin sensitization, etc.)... 

Zebrafish Brachydanio/Danio rerio) embryos can be produced in large numbers and carry sufficient nutrients within the egg sack to allow development within micro plate volumes [52, 53]. Mutation frequency has been estimated indirectly using transgenic fish [54[ and UDS, comet, MNT and alkaline filter elution methods have been used effectively [55]. At present, there has been insufficient study of the model to understand predictivity of mammalian genotoxicity, and none of the methods has been demonstrated at throughputs sufficient for hit and lead screening. 

We do not address early toxicology profiling in this section, that is, those phenotypic assays for which molecular targets are hardly known and which attempt to be predictive of the standard later stage assays, such as those covering genotoxicity, hepatotoxicity or phototoxicity. These are all covered elsewhere in this book. 

Cash, G.G., Prediction of the genotoxicity of aromatic and heteroaromatic amines using electrotopological state indices, Mutation Res., 491, 31-37, 2001. 

Mattioni, B.E., Kauffman, G.W., and Jurs, P.C., Predicting the genotoxicity of seconddary and aromatic amines using data subsetting to generate a model ensemble, J. Chem. Inf. Comput. Sci., 43, 949-963, 2003. 

Uncertainty about its range of predictiveness for genotoxic carcinogens... 

Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum IY (2004) Assessment of the sensitivity of the computational programs DEREK, TOPKAT and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ Mol Mutagen 43 143-158 Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors. In the series of Methods and Principles in Medicinal Chemistry, Vol. 11. Wiley VCH Weinheim... 

---