Genotoxicity and computational methods.

What is genotoxicity?

Genotoxicity, or genetic toxicity, refers to the induction of permanent changes in the amount or structure of the genetic material of cells or organisms. These changes may involve a single gene or gene segment, a block of genes or chromosomes. Inside the genotoxicity flag lies mutagenicity, carcinogenicity, developmental toxicity, etc.

Several methods can be used to measure the genetic toxicity of compounds, such as comet assay, micronucleus assay (MN), chromosomal aberration assay, bacterial reverse mutation test, and sister chromatid exchange assay.

Due to their irreversible adverse consequences on human health, identifying and eliminating these kinds of compounds has particular relevance. Such is the importance that the European Chemicals Agency (ECHA) has implemented the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) legislation, which requires the industry to evaluate the toxicity of chemical substances that are in use but have never been subjected to regulatory testing.

QSAR models for genotoxicity

The Salmonella typhimurium assay (Ames test) is a validated in vitro test for genotoxicity evaluation, and another alternative is the COMET assay, based on the evaluation of the break of the DNA pairs. So, if we have already some reliable models, why do we need robust QSAR models to predict these toxicological properties?

Although its importance, REACH regulation has also provoked strong criticism and concern from society and the industrial sector because of ethical and economic reasons. The toxicity evaluation of chemicals requires costly, time-consuming, and ethically questionable animal experiments. As consequence, the use of alternative methods is clearly stimulated by the European Chemicals Agency (ECHA) [1], which stipulates that :

“every effort must be made so that testing of chemicals on animals is a last resort – when there is no other scientifically reliable way of showing the impact on humans or the environment”.

Computational (in silico) tools are non-testing methods, and among them, “Quantitative Structure-Activity Relationships” (QSAR) modeling is one of the most established in drug design, toxicology, industrial and environmental chemistry [2]. Besides, they are recognized from a regulatory point of view and can be included in integrated testing strategies (ITS) for hazard and risk assessment, classification, and labeling.

Therefore, nowadays the generation of robust and reliable QSAR models takes huge relevance within the scientific and industrial community, becoming a field of increasing importance. And for this reason, from ProtoQSAR, we are putting our best efforts into developing new and more accurate QSAR models for different genotoxic endpoints.

Figure 1: Published papers by year with the keywords "genotoxicity" and "QSAR". Source: Pubmed

1.????Regulation (EC) No. 1907/2006 of the European Parliament and the Council, of December 18, 2006, concerning REACH, establishing the ECHA.

2.????Casano et al. Journal of Environmental Science and Health, Part C, 32:273–298, 2014