The assessment of genotoxicity represents a key component of the safety assessment of any substance. Various in vitro tests are available at different stages of development and acceptance, but are not currently considered sufficient to replace animal tests necessary to assess the safety of substances. For a general development of the traditional genotoxicity testing paradigm, some new activities have been performed. These include improving existing tests, developing new tests, and establishing and investigating approaches to optimize in vitro test accuracy. In addition, useful tools such as databases or reference chemical lists have been developed to support progress in this area.

Genotoxicity assessment is a key component of the safety assessment of medicines, industrial chemicals, pesticides, biocides, food additives, cosmetic additives, veterinary medicines, all substances in the context of international legislation on human protection.

 Various well-structured in vitro assays are available and have been used successfully to predict genotoxicity. However, they are not considered to completely replace the currently used animal tests to evaluate the safety of the substances. Over the last decade, significant activities have been carried out worldwide to optimize strategies for genotoxicity tests, both for the basic in vitro test battery and the in vivo follow-up tests. This reflects the fact that science is progressing considerably and significant experience has been gained in the 40 annual regulatory toxicology test in this field. Furthermore, the need to ensure in vitro assays does not produce a high number of false positive results, triggering unnecessary in vivo studies, hence producing undesirable effects for animal welfare.

Genotoxicity Test

The genotoxicity test includes measuring DNA primary damage that can be repaired and thus reversible, as well as detecting fixed and irreversible damage (ie gene mutations and chromosomal aberrations) that can be transmitted to the next generation when they occur in germ cells. and perturbation in the mechanisms involved in maintaining the integrity of the genome. For an adequate assessment of genotoxicity, the three main endpoints (gene mutation, structural chromosome aberrations and numerical chromosome aberrations) should be evaluated, as each of these events plays a role in carcinogenesis and hereditary diseases.

 The standard in vitro test battery includes bacterial reverse mutation analysis (OECD TG 471) in vitro, chromosomal aberration test (OECD TG 473), in vitro mammalian cell gene mutation test (OECD TG 476 [Hprt] and TG 490 [MLA / tk]) and in vitro mammalian cell micronucleus test (OECD TG 487) Any confirmatory in vivo follow-up test should cover the same endpoint as in vitro positive results. The most widely used in vivo tests today include mammalian erythrocyte micronucleus test (OECD TG 474), mammalian bone marrow chromosomal aberration test (OECD TG 475), transgenic rodent somatic and germ cell gene mutation analysis (OECD TG 488) and in vivo alkali-tailed test (OECD TG 489).

Can the performance of the genotoxicity test be improved?

Several options are being sought to improve the overall assessment of genotoxicity. A strategic plan to prevent and reduce animal use in genotoxicity testing, previously different EU legislation, the state of science and EURL ECVAM (based on regulatory needs between the latest and ongoing efforts undertaken by various organizations, including ECVAM)

There are three recommended tests in different regulatory sectors that have three recommendations for in vitro bacterial gene mutation, a test for induction of gene mutation in mammalian cells, a test for an induction test battery, an in vitro chromosomal abnormality and a micronucleus test.