Data selection and treatment of chemicals tested for genotoxicity and carcinogenicity

Abstract

A database containing qualitative and quantitative results of experimental studies in the fields of genotoxicity and carcinogenicity has been developed. By analyzing results of the studies performed by the U.S. National Toxicology Program, or by a similar program developed in Japan, or reported in the scientific literature, as well performed by private organizations, information has been collected relating to 3389 chemicals, identified by their CAS number. The studies considered for the database include three genotoxicity/mutagenicity short-term test (STTs), namely, two in vitro (Salmonella, gene mutation assay, and mammalian cells/human lymphocytes chromosome aberration assay) and one in vivo, the rodent bone marrow micronucleus assay. To investigate the possible predictive value of these STT assays for carcinogenicity, the results of animal long-term bioassays have also been collected. We have re-evaluated all the genotoxicity studies and the majority of those cases studied in different laboratories with contrasting results has been resolved; a small proportion of questionable cases is, however, still present in the database. In total, 2898 (85.5%) of the chemicals have been tested in the Salmonella assay; 1399 (41.3%) have been tested in the in vitro chromosome aberration assay; 319 (9.4%) have been tested in the in vivo rodent bone marrow cell micronucleus assay; 716 (21.2%) of the chemicals have been tested in the in vivo animal long-term bioassay. For 1118 chemicals tested in the Salmonella assay, 30,650 quantitative studies have been included in the database, thus allowing a possible classification of mutagenic chemicals according to their mutagenic potency. One thousand nine hundred chemicals (56.1%) have shown positive results in at least one of the four different assays, thus leaving 1,489 chemicals (43.9%) with negative results. By analyzing the correlation between genotoxicity, as shown by the three STTs considered, and carcinogenicity, we have demonstrated that the positive predictivity increases to a value of 95.6% if the three STTs are considered together (two in vitro and one in vivo STT); similarly, the negative predictivity rises to a value of 89.6% with the same three assays. The accuracy, or the concordance, of the STT results and the carcinogenicity results was 92.5% for the three STTs. Although the results collected are of high interest for scientific and practical actions, the aim of the present study is to prepare a genotoxicity/carcinogenicity database for a further quantitative structure-activity relationship (QSAR) study based on a computer chemistry analysis.