The science of genetic toxicology
Genetic toxicology is the study of genetic damage that results in alterations to heritable information. Included in this broad definition are the agents that cause genotoxicity, the mechanisms by which damage occurs and the cellular response(s) to that damage. It is a complex science because there are a number of different types of genome damage, which arise through a diversity of mechanisms:
- Chromosomes might be broken (clastogenesis)
- The information within a DNA sequence might become altered or re-arranged (mutagenesis)
- Whole chromosomes might be mis-segregated (aneugenesis)
- There can be interchange of sections of chromosomes which can alter gene regulation (recombination)
These diverse outcomes are the consequence of different mechanistic interactions between the different classes of genotoxin and the exposed cell/organism. These vary from direct DNA interaction (e.g. alkylation), through the generation of reactive intermediates by cellular metabolism of a parent chemical, to interference with the processes of DNA replication and repair.
Genotoxicity is not an uncommon chemical property or environmental hazard, and in crude terms as with other toxicities, ‘the dose makes the poison’. Thus whilst we are exposed to ionizing radiation, UV light, and many other environmental genotoxins, evolution has provided us with effective cellular defences against genome damage which mitigate the harmful effects. These processes ensure efficient repair, or the elimination of damaged cells.
However, we live in a world where we are constantly exposing ourselves to new man-made or man-formulated chemicals in the form of pharmaceuticals, cosmetics, pesticides, flavours, fragrances etc. Since cancers can arise as a consequence of exposure to genotoxins all new chemicals such as pharmaceuticals, agrochemicals and consumer products that come into contact with humans have to be tested for genotoxicity. Regulatory bodies have produced guidance covering the assessment of genetic toxicity, the types of assay that are expected or required to be performed, and even how the assays might be carried out. At the core of each sector-specific guidance is a consensus approach to genotoxicity testing for regulatory safety assessment: firstly, investigate the ability of a chemical to cause mutation and/or chromosome damage in vitro; secondly, is any in vitro activity reproduced in an in vivo setting or simulated setting.
Given the critical nature of genetic toxicity evaluation in the assessment of chemical safety, consideration of the accuracy of genotoxicity tests is extremely important. For safety assessment, tests need a high degree of sensitivity, providing confidence that genotoxins (hence, potential carcinogens) will be detected, and that exposure to them can be limited. For hazard assessment, tests need a high degree of specificity, providing confidence that non-genotoxins are not misclassified as genotoxins, and hence aiding chemical profiling and supporting candidate chemical selection for development.