Integrated in silico and in vitro genotoxicity assessment of thirteen data-poor substances
- DOI
- Language of the publication
- English
- Date
- 2019-07-20
- Type
- Article
- Author(s)
- Yen K. Tran, Yen K. Tran
- Julie K. Buick, Julie K. Buick
- Jennifer L.A. Keir, Jennifer L.A. Keir
- Andrew Williams, Andrew Williams
- Carol D. Swartz, Carol D. Swartz
- Leslie Recio, Leslie Recio
- Paul A. White, Paul A. White
- Iain B. Lambert, Iain B. Lambert
- Carole L. Yauk, Carole L. Yauk
- Publisher
- Elsevier
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.
Plain language summary
"Health Canada is responsible for the assessment and management of health risks posed by chemicals in their environment to Canadians. Genotoxicity (i.e., ability of a chemical to damage DNA) can lead to adverse health effects like heritable genetic diseases and cancer. Genotoxicity testing is therefore a critical component of human health risk assessment. New chemicals must be assessed for genotoxicity prior to commercial use. However, the Canadian Domestic Substances List (DSL) contains chemicals that have not been tested for genotoxicity as their use pre-dates this requirement; these chemicals are thus referred to as ‘data-poor’. In the present study, 13 of these data-poor chemicals from the DSL were assessed for genotoxicity. First, chemicals were screened using computer modeling of their structures. Subsequently, tests on cells in culture were conducted to confirm genotoxic hazards. Mutagenicity (i.e., the ability to cause mutation) was measured in Salmonella bacteria; damage to mammalian chromosomes was measured in human cells in culture using a method called the micronucleus test. Six of the chemicals were flagged as mutagenic based on chemical structure, and these were all confirmed by the bacterial test. Of nine chemicals with (Q)SAR flags for damage to mammalian chromosomes, eight were also positive in the micronucleus test indicating potential for chromosome damage. Analysis of the dose at which these effects occurred revealed that several of the chemicals were as potent as well some known environmental mutagens. Overall, the work suggests that 11 of the 13 chemicals may be genotoxic, and potency assessment identified four chemicals as priority for further investigation. The data on these chemicals were shared with evaluators in the Existing Substance Risk Assessment Bureau to support their chemical evaluations."
Subject
- Health,
- Health and safety