Interpretation of the biological relevance of genotoxicity test results: the importance of thresholds

Despite recent improvements in genotoxicity protocols, we have observed an increase in the occurrence of positive results, particularly in chromosomal aberration tests in vitro, yet very few of these are accompanied by positi ve responses in vivo. Thus, the positive results may not be biologically re levant either for rodents or humans in vivo, but how should we determine "b iological relevance"? Chemicals that produce thresholded dose-responses may well not pose a genotoxic risk at low (relevant to human) exposures, but t hresholds should not just be "seen"; there must be an explanation and under standing of the underlying mechanism. In addition to extremes of pH, ionic strength and osmolality, as have been identified previously, such mechanism s include indirect genotoxicity resulting from interaction with non-DNA tar gets, chemicals/metabolites which are inherently genotoxic but which, at lo w concentrations, are effectively conjugated and unable to form adducts, an d production of specific metabolites under in vitro conditions that are not formed in rodents or humans in vivo. If such thresholded mechanisms can be identified at exposures which are well in excess of expected human exposur e, then there may be a strong argument that the positive results are not bi ologically relevant. (C) 2000 Elsevier Science B.V. All rights reserved.