Evaluation of metals inin vitroassays, interpretation of data and possible mechanisms of action†

Metal compounds have been investigated in a wide range of in vitro assays for their potential genotoxicity. While inter‐laboratory variability could be responsible for some lack of agreement between different laboratories using the same test methods, there appears to be consistency of results where compounds have been examined with a number of different assay methods, particularly those employing eukaryotic cells. A major barrier for proper evaluation of metals in vitro has been the lack of agreement between eukaryotic and prokaryotic assays. Compounds of nickel, cadmium and beryllium have failed repeatedly to be detected in the widely used Salmonella assay, and yet are active in diverse mammalian cell assay systems. From previous studies with organic chemical mutagens, these major differences in sensitivity of test systems are entirely unexpected, and may be due to a combination of factors: different sensitivity of the various genetic end‐points; variations in physiological state of target cells; variations in test compound cytotoxicity, in relation to genetic toxicity; different test methodologies. DNA damage has been shown to result from nickel, cadmium and chromium exposure of eukaryotic cells, probably accounting for much of the genetic toxicity of compounds of these metals. However, metals affect a variety of other genomic functions including DNA repair synthesis, DNA replication, histone phosphorylation etc., and thus may induce alterations in gene transcription products by means other than direct DNA damage. In vitro assays of the major carcinogenic metals are helping determine which mechanism of action is likely to be the more important in vivo.