ANEUPLOIDY - A REPORT OF AN ECETOC TASK-FORCE

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 sy stems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. Howeve r, since there is no reason to assume that chemically induced aneuploi dy will not occur in human beings, it is prudent to address the aneuge nic potential of chemicals in the safety assessment process. A wide ra nge of methods has been described for the detection of chemically indu ced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mamm alian 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 h ave aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known o r suspected aneugens. The conclusions from the review are listed below . 1. At present there are only nine chemicals that can be classified a s definitive aneugens, as determined by positive results in in vivo ro dent 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 exceptions, they also induced structural chromosome aberrations in vi tro. 4. All of the definitive aneugens that have been sufficiently tes ted induce micronuclei in rodent bone marrow cells in vivo. A number o f these chemicals also induced structural chromosome aberrations in vi vo. 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 cell s. Furthermore, an analysis of several databases indicates the proport ion of chemicals which induce polyploidy and not chromosome aberration s in vitro is low. Based on these conclusions, the following recommend ations 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 per formed; in the absence of polyploidy induction in vitro no further eva luation of aneuploidy-inducing potential is needed; if polyploidy is o bserved, in vitro follow-up testing to investigate further the aneuplo idy-inducing potential should be conducted; such follow-up testing wil l 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, f urther information on mechanisms of micronucleus induction can be obta ined 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 in teraction of a chemical or its metabolite(s) with DNA is expected to h ave a threshold. This must be considered in the risk assessment of suc h chemicals; this is not addressed by current risk assessment guidelin es. (C) 1998 Elsevier Science B.V.