It has been suggested that common fragile sites (cFSs) are related to cancer development. This appears to be the case for FRA3B and FRA16D, localized in two tumor-suppressor genes (FHIT and WWOX, respectively) that are altered by deletions or loss of heterozygosity (LOH) in many cancers. The features responsible for fragility have not yet been identified. Furthermore, it is still unclear whether instability at these regions causes chance deletions and loss of function of the associated genes, or whether the gene function itself is related to the appearance of fragility. In this study, we analyzed cFS expression in lymphocytes from 20 healthy or thyroid cancer-affected subjects exposed to radiation after the Chernobyl accident. The same cells were examined for apoptosis, a principal function of both the FHIT and WWOX genes. Exceptionally elevated chromosome fragility was observed, particularly in cancer patients, affecting FRA3B, FRA16D, and a cluster of less highly expressed cFSs; levels of chromosome fragility were found to be correlated among these cFSs. Interestingly, most expressed cFSs were sites of LOH reported for thyroid tumors; moreover, cells with the highest fragility also had a reduced ability to undergo apoptosis. These findings reveal previously unknown genetic interactions affecting fragile loci, suggestive of a shared function inside mitotic cells. Attenuation of checkpoint control and apoptosis resistance seem to be the cell phenotypes associated with unusual chromosome fragility. We propose that breakage at specific cFS could derive from early epigenetic events at loci involved in radiation carcinogenesis. This article contains supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

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The identification of the hazard of chemicals to man has relied on the use of several animal models. However, the availability of various cell toxicity models as alternatives to the use of animals has stimulated attempts to evaluate in vitro data for use in the prediction of human toxicity. The cell toxicity models developed previously are capable of indicating a variety of endpoints susceptible to the activity of various chemical substances. The in vitro data derived so far from testing a variety of types of chemicals, have been used to develop toxicology profiles for twenty chemicals, which are presented in this paper. Data have been selected from among those already entered in the Galileo Data Bank, a computerised data system containing all the available existing data derived using in vitro methods.

Toxicity testing of chemicals by means of in vitro alternative methods to the use of animals has been extensively developed, as documented by a variety of studies. The interpretation of results and the comparative evaluation of data derived from various cell toxicity studies require organisation by a computerised data system, capable of handling the large number of variables included in different assays, such as cell lines, methods of treatment with the chemical, methods used to evaluate the biological effect, endpoints considered, etc. The Galileo Data Bank has been developed by the Laboratory of Genetic Toxicology at the University of Pisa, as a scientific instrument to be used in the analysis and organisation of results obtained in the toxicity testing of chemicals by means of in vitro alternative methods.