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? II. Construction and analysis of a consolidated database☆
Construction of a consolidated database of >700 Ames-positive chemicals.
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Evaluation of patterns of in vitro mammalian cell tests results.
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Ames +ve results categories with different in vivo genotox or carcinogenic concern.
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Two −ve mammalian cell test results are indicative of absence of in vivo activity.
Abstract
A Workshop sponsored by EURL ECVAM was held in Ispra, Italy in 2013 to consider whether the in vitro mammalian cell genotoxicity test results could complement and mitigate the implications of a positive Ames test response for the prediction of in vivo genotoxicity and carcinogenicity, and if patterns of results could be identified. Databases of Ames-positive chemicals that were tested for in vivo genotoxicity and/or carcinogenicity were collected from different sources and analysed individually (Kirkland et al., in this issue). Because there were overlaps and inconsistent test results among chemicals in the different databases, a combined database which eliminated the overlaps and evaluated the inconsistencies was considered preferable for addressing the above question. A database of >700 Ames-positive chemicals also tested in vivo was compiled, and the results in in vitro mammalian cell tests were analysed. Because the database was limited to Ames-positive chemicals, the majority (>85%) of carcinogens (103/119) and in vivo genotoxins (83/88) were positive when tested in both in vitro gene mutation and aneugenicity/clastogenicity tests. However, about half (>45%) of chemicals that were not carcinogenic (19/28) or genotoxic in vivo (33/73) also gave the same patterns of positive mammalian cell results. Although the different frequencies were statistically significant, positive results in 2 in vitro mammalian cell tests did not, per se, add to the predictivity of the positive Ames test. By contrast, negative results for both in vitro mammalian cell endpoints were rare for Ames-positive carcinogens (3/119) and in vivo genotoxins (2/88) but, were significantly more frequent for Ames-positive chemicals that are not carcinogenic (4/28) or genotoxic in vivo (14/73). Thus, in the case of an Ames-positive chemical, negative results in 2 in vitro mammalian cell tests covering both mutation and clastogenicity/aneugenicity endpoints should be considered as indicative of absence of in vivo genotoxic or carcinogenic potential.
Abbreviations
EURL ECVAM
EU Reference Laboratory for Alternatives to Animal Testing
GLP
Good Laboratory Practices
IARC
International Agency for Research on Cancer
MLA/tk
mouse lymphoma Tk+/− gene mutation assay
Hprt
hypoxanthine-guanine phosphoribosyl transferase locus
MNvit
in vitro micronucleus test
CAvit
in vitro chromosomal aberration test
MNviv
in vivo micronucleus test
NTP
National Toxicology Program
CAviv
in vivo chromosomal aberration test
Carc
carcinogenicity
TGR
in vivo transgenic rodent mutation assay
UDSviv
in vivo unscheduled DNA synthesis test
DNAviv
in vivo DNA strand breakage (e.g., comet or alkaline elution) assay
Disclaimer: This document represents the consensus of the authors’ views expressed as individual scientists and does not necessarily represent the policies and procedures of their respective institutions.