Aneuploidy plays a significant role in adverse human health conditions including
birth defects, pregnancy wastage and
cancer. Although there is clear evidence of chemically induced
aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced
aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced
aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced
aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop
aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have
aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected
aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive
aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected
aneugens are negative in the bacterial mutation assay. 3. The majority of definitive
aneugens evaluated induce
polyploidy in vitro. With few exception, they also induced structural
chromosome aberrations in vitro. 4. All of the definitive
aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural
chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell
aneugen, that is a chemical that induces
aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce
polyploidy and not
chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of
polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of
polyploidy induction in vitro no further evaluation of
aneuploidy-inducing potential is needed; if
polyploidy is observed, in vitro follow-up testing to investigate further the
aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of
aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell
aneuploidy activity may then be considered;
aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with
DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.