Integrated in silico and in vitro genotoxicity assessment of thirteen data-poor substances
The Canadian Domestic Substances List (DSL) contains chemicals that have not been tested for genotoxicity as their use pre-dates regulatory requirements. In the present study, (quantitative) structure-activity relationships ((Q)SAR) model predictions and in vitro tests were conducted for genotoxicity assessment of 13 data-poor chemicals from the DSL (i.e. CAS numbers 19286-75-0, 13676-91-0, 2478-20-8, 6408-20-8, 74499-36-8, 26694-69-9, 29036-02-0, 120-24-1, 84696-48-9, 4051-63-2, 5718-26-3, 632-51-9, and 600-14-6). First, chemicals were screened by (Q)SAR models in Leadscope® and OASIS TIMES; two chemicals were excluded from (Q)SAR as they are complex mixtures. Six were flagged by (Q)SAR as potentially mutagenic and were subsequently confirmed as mutagens using the Ames assay. Of nine chemicals with clastogenic (Q)SAR flags, eight induced micronuclei in TK6 cells. Benchmark dose analysis was used to evaluate the potency of the chemicals. Four chemicals were bacterial mutagens with similar potencies. Three chemicals were more potent in micronuclei induction than the prototype alkylating agent methyl methanesulfonate and three were equipotent to the mutagenic carcinogen benzo[a]pyrene in the presence of rat liver S9. Overall, 11 of the 13 DSL chemicals demonstrated at least one type of genotoxicity in vitro. This study demonstrates the application of genotoxic potency analysis for prioritizing further investigations.
|Keywords||Ames assay, Anthraquinones, Benchmark dose, Genetic toxicology, Micronucleus assay, QSAR|
|Journal||Regulatory Toxicology and Pharmacology|
Tran, Y.K. (Y. K.), Buick, J.K. (Julie K.), Keir, J.L.A. (Jennifer L.A.), Williams, A. (Andrew), Swartz, C.D. (Carol D.), Recio, L. (Leslie), … Yauk, C.L. (2019). Integrated in silico and in vitro genotoxicity assessment of thirteen data-poor substances. Regulatory Toxicology and Pharmacology, 107. doi:10.1016/j.yrtph.2019.104427