Understanding how mutations occur in chemicals to become carcinogenic or toxic when in contact with human tissue is essential to ensure product safety when developing drugs, foods, cosmetics and agricultural products. Gentotoxicity assays form part of the testing process to identify cancer-causing mutations or determine whether they may result mutations that are passed on to offspring. Testing identifies the mechanisms during the development process, enabling risk and reward assessments of the product. Tests also form part of the requirements to receive relevant product licences.
What are mutagens, and how can point mutations be detected?
Mutagens are chemical, biological or physical agents that can change genetic material permanently. They have the power to alter DNA without killing the cell structurally. Surviving mutations can be perpetuated to all cell descendants. The term genotoxic indicates their ability to mutate and possibly be carcinogenic.. Chemical mutagens react with DNA or the apparatus that maintains the integrity of DNA. Physical mutagens include x-rays, alpha particles and ionizing radiation. Ultraviolet radiation can be as mutagenic also.
To avoid damaging our health, we must identify the mutagenic risk of many elements within our environment, the food we eat and the medicines we use, to avoid damaging our health unnecessarily. Mutagenicity is part of a broader genotoxicity definition, which covers three fundamental types: point mutations, aneugenicity and clastogenicity. A wide range of testing assays must be used to detect all mutagenic capabilities.
Getting help with testing
Companies such as Gentronix can assist with such testing requirements. Leading specialists in predictive toxicology can help provide a range of genetic toxicology tests from early screening to regulatory safety assessments, delivering a range of innovative solutions to advise and assist businesses. There is a strong association between carcinogenicity and point mutations that can be identified early in the process, allowing risk and reward analysis to be carried out. Ames tests are used to identify potential in vivo point mutagens. This is a useful alternative, as in vivo studies require large amounts of purified test items, are time-consuming and expensive, and involve animals. Ames testing and in vitro mammalian gene mutation assays are now seen as the most common lower cost, lower test item requirement and faster timeframe solutions and are usually first to be carried out on new test substances.
What are Clastogens and Aneugens?
We have grouped these to make understanding the testing processes simpler.
Clastogens are mutagenic agents capable of creating breaks, missegregation or disruption within a chromosome, leading to partial deletion, additions or rearrangement of its structure. Aneugens result in complete chromosomal loss or dysfunction or reduced function during cell division, acting primarily on non-DNA targets such as spindle fibres.
Some clastogenic events are part of regular cellular activity. However, reducing exposure to external causes or those attributable to agents or organisms outside normal cell activity is essential to determine the potential genotoxicity of the test substance in human health settings. Both direct and indirect clastogen mechanisms can be detected as well as aneugenic ability. The primary study for investigating these effects is the in vitro micronucleus assay.
Conclusion
Understanding the risks and risk factors of new substances that can impact human health is a must to ensure the safety of new products. Testing through a wide variety of Ames and mammalian genotoxicity assays and follow up mode of action investigations are required for pharmaceutical, cosmetic, industrial chemical and agrochemical industries when developing new compounds. Predictive toxicology processes start with structure-activity (SAR) in silico prediction, and in vitro testing followed by in vivo testing where necessary. Ames tests are off a practical early stage test for mutagenicity as they are well linked to carcinogenicity, and can be conducted in miniaturised forms to reduce the amount of test item required.
In general, an in vitro micronucleus assay will better detect antigenicity and clastogenicity. They are relatively easy to score and amenable to automation, thus identifying the full clastogenic potential of chemicals with expected human exposure.
