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Integrated in silico and in vitro genotoxicity assessment of thirteen data-poor substances
- Source :
- Regulatory Toxicology and Pharmacology. 107:104427
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- 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.
- Subjects :
- Quantitative structure–activity relationship
Quantitative Structure-Activity Relationship
010501 environmental sciences
Toxicology
medicine.disease_cause
030226 pharmacology & pharmacy
01 natural sciences
Cell Line
Ames test
03 medical and health sciences
Clastogen
chemistry.chemical_compound
Cricetulus
0302 clinical medicine
medicine
Animals
Humans
Potency
Computer Simulation
Carcinogen
0105 earth and related environmental sciences
Mutagenicity Tests
fungi
General Medicine
Models, Theoretical
Methyl methanesulfonate
Biochemistry
chemistry
Micronucleus test
Genotoxicity
Mutagens
Subjects
Details
- ISSN :
- 02732300
- Volume :
- 107
- Database :
- OpenAIRE
- Journal :
- Regulatory Toxicology and Pharmacology
- Accession number :
- edsair.doi.dedup.....8c81c6f32d7dd7be0733545560daf16e