Gentronix develops technology for the accurate identification of genotoxic compounds. These are compounds which in various different ways damage the information stored in chromosomes. Since cancers can arise as a consequence of exposure to genotoxins all new chemicals such as pharmaceuticals and consumer products that come into contact with humans have to be tested for genotoxicity.
The challenge for genetic toxicologists is to provide tests that are accurate. For safety assessment, tests need a high degree of sensitivity, providing confidence that 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-carcinogens are not misclassified as carcinogens, as this can lead to ‘scare stories’ in the media, needless concern about chemicals that are safe, and rejection of potentially valuable pharmaceuticals and other products.
Genetic Toxicology
Genetic toxicology is a complex science because there are many different types of genome damage, which arise through a diversity of mechanisms. Chromosomes might be broken (clastogenesis) or the information within the DNA sequence might become altered or re-arranged (mutagenesis). Whole chromosomes might be mis-segregated (aneugenesis), and there can be interchange of sections of chromosomes which can alter gene regulation. 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 oxidative DNA damage to interference with the processes of DNA replication and repair. Genotoxicity is not an uncommon chemical property, and as with other toxicities, ‘the dose makes the poison’. Thus whilst we are exposed to ionizing radiation, UV light, and the many genotoxins in food, evolution has provided us with effective cellular defenses against genome damage which mitigate the harmful effects. These processes ensure efficient repair, or the elimination of damaged cells. It is the activity of these defense systems that Gentronix exploits to detect cellular exposure to genotoxins.
It is important to recognize that genotoxic chemicals are not the only chemical carcinogens. There are also many different types of cancers where genotoxin induced genome damage is probably not the initiating event. For these, the cause might abnormal hormonal events, mitogenic events or epigenetic changes. It is not always simple to determine mechanisms of chemical carcinogenicity, not least because of poor specificity in some of the in vitro mammalian genotoxicity tests, which as a consequence, frequently wrongly suggest a genotoxic mechanism.
The Regulatory Battery of Gentoxicity Tests
The Ames Salmonella mutation test was the first genotoxicity test. It produces positive results for about 60% of genotoxic carcinogens (sensitivity ~ 60%). The 40% of genotoxins that are not detected by the Ames test are largely those with targets found only in eukaryotic or animal cells. The in vitro mammalian tests, such as the micronucleus test (MNT), and the mouse lymphoma assay (MLA) are effective in detecting these missed genotoxic carcinogens, as well as many of the compounds identified by Ames (sensitivity ~80%). Hence to ensure that the whole diversity of genetic damage is detected, current regulatory guidelines require a battery of genotoxicity tests including both Ames and in vitro mammalian assays, followed by in vivo testing. This regulatory battery is effective in producing positive results for carcinogens.
BUT! recent re-evaluation of a great deal of in vitro regulatory data has shown the battery to be rather less effective in producing negative results for non-carcinogens - well over half of which produce a positive result in one or other of the in vitro regulatory tests. In particular the regulatory in vitro mammalian assays have poor specificity – less than 50% of non-carcinogens give expected negative results. The obvious need for more accurate tests has been recognized by the pharmaceutical industry and by the various regulatory authorities. The result of this poor accuracy is that a positive in vitro result is often not seen as serious, and animal testing is used to distinguish the real genotoxins from the mistakes. Hence, more animals are used, at great cost, to identify the compounds that were of genuine risk to humans.
The Advantage of Using Gentronix Technology
The Gentronix in vitro mammalian cell assays have a very much higher specificity than the current regulatory MNT and MLA. 95% of non-carcinogens produce negative results, and this is not at the cost of sensitivity, over 80% of genotoxic carcinogens produce positive results in the assay. Together these properties mean that compounds producing positive results present a serious hazard. If there is chance or intention that humans will be exposed to such chemicals, a full risk assessment should be undertaken.