The current limitations of in vitro genotoxicity testing and their relevance to the in vivo situation

- Various origins of misleading predictive results with in vitro genotoxicity tests (metabolic activation system, cell type …).
- Knowledge of actual limitations of in vitro genotoxicity test systems to avoid or reduce misleading interpretations.
- Knowledge of the underlying mechanism(s) of genotoxicity action to assess the level of relevance for the in vivo situation.

The standard regulatory core battery of genotoxicity tests generally includes 2 or 3 validated tests with at least one in vitro test in bacteria and one in vitro test on cell cultures. However, limitations in in vitro genotoxicity testing may exist at many levels. The knowledge of the underlying mechanisms of genotoxicity is particularly useful to assess the level of relevance for the in vivo situation. In order to avoid wrong conclusions regarding the actual genotoxicity status of any test substance, it appears very important to be aware of the various origins of related bias leading to 'false positives and negatives' by using in vitro methods. Among these, mention may be made on the metabolic activation system, experimental (extreme) conditions, specificities of the test systems implemented, cell type used etc. The knowledge of the actual 'limits' of the in vitro test systems used is clearly an advantage and may contribute to avoid some pitfalls in order to better assess the level of relevance for the in vivo situation.