Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity?: I. Reports of individual databases presented at an EURL ECVAM Workshop

Positive results in the Ames test correlate well with carcinogenic potential, at least in rodents. However, the correlation is not perfect because mutagenesis is not carcinogenesis, and mutations are only one of many stages in tumour development. Also, situations can be envisaged where the mutagenic response may be specific to the bacteria or the test protocol, for example bacterial-specific metabolism, exceeding a detoxification threshold or the induction of oxidative damage to which bacteria may be more sensitive than mammalian cells in vitro or tissues in vivo. Since most chemicals are also tested for genotoxicity in mammalian cells, the pattern of mammalian cell results (positive, negative) may help identify whether Ames-positive results predict carcinogenic or in vivo mutagenic activity. A workshop was therefore organised and sponsored by the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) to investigate this further. Participants presented data on results from other genotoxicity tests with Ames-positive compounds. Data came from published, regulatory agency and industry sources. The question was posed whether negative results in mammalian cell tests were often associated with absence of carcinogenic or in vivo genotoxic activity. In the limited time available, the presented data were combined and an initial analysis suggested that the association of negative in vitro mammalian cell test results with lack of in vivo genotoxic or carcinogenic activity could have some significance. Possible reasons why a positive Ames test may not be associated with in vivo activity and what additional investigations/tests might contribute to a more robust evaluation were discussed. Because a considerable overlap was identified among the different databases presented, it was recommended that a consolidated database should be built, with overlapping chemicals removed, so that a more robust analysis of the predictive capacity for potential carcinogenic and in vivo genotoxic activity could be derived from the patterns of mammalian cell test results obtained for Ames-positive compounds.

KIRKLAND David;  ZEIGER Errol;  MADIA Federica;  GOODERHAM Nigel;  KASPER Peter;  LYNCH Anthony;  MORITA Takeshi;  OUEDRAOGO G;  PARRA MORTE Juan Manuel;  PFUHLER Stefan;  ROGIERS Vera;  SCHULZ Markus;  THYBAUD Veronique;  VAN BENTHEM Jan;  VANPARYS Philippe;  WORTH Andrew;  CORVI Raffaella; 

2014-12-01

ELSEVIER SCIENCE BV

JRC91204

1383-5718,   

http://www.sciencedirect.com/science/article/pii/S1383571814002836,    https://publications.jrc.ec.europa.eu/repository/handle/JRC91204,   

10.1016/j.mrgentox.2014.10.005,