The ‘BlueScreen HC’ assay as a decision making test in the genotoxicity assessment of flavour and fragrance materials

• Published in: Toxicology in vitro 2015-10, Vol.29 (7), p.1425-1435
• Main Authors: Etter, Sylvain, Birrell, Louise, Cahill, Paul, Scott, Heather, Billinton, Nick, Walmsley, Richard M., Smith, Benjamin
• Format: Article
• Language: English
• Subjects: Biological Assay; BlueScreen HC; Cell Cycle Proteins - genetics; Cell Line; Decision Making; Flavoring Agents - toxicity; Flavours; Fragrances; GADD45a; Genes, Reporter; Genotoxicity; Humans; Luciferases - genetics; Mutagenicity Tests; Nuclear Proteins - genetics; Perfume - toxicity; Screening; Sensitivity and Specificity
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2015.05.005

•The genotoxicity of 70 flavour and fragrance substances was assessed using BlueScreen HC.•Positive results are highly predictive of positive regulator-required in vitro assays.•Negative results were highly predictive of negative in vivo results.•A top 1mM or 0.5mg/ml dose maintains sensitivity and increases specificity.•The assay can fill data gaps for materials with no/limited regulatory test data. The genotoxicity of a library of 70 flavour and fragrance substances having a high proportion of in vivo and/or carcinogenicity test data has been assessed using the GADD45a-GLuc ‘BlueScreen HC’ genotoxicity assay, with and without exogenous metabolic activation. There are only limited genotoxicity and carcinogenicity study data for compounds in this applicability domain, but this study allowed the following conclusions: (i) The BlueScreen HC results are highly predictive of positive results from regulator-required in vitro genotoxicity assays for the test set of materials; the moderate negative predictivity of BlueScreen HC from the in vitro test set of material is mainly due to the high rate of false positive in regulatory in vitro mammalian tests. (ii) BlueScreen HC negative results are predictive of negative in vivo results and provide a specific prediction of in vivo genotoxicity assay results. (iii) In this applicability domain, which comprises a large proportion of relatively low molecular weight molecules, a 1mM testing limit maintains the sensitivity of the assay, and increases specificity. (iv) The predictive capacity and specificity to in vivo genotoxins and carcinogens, coupled to a microplate format with low compound requirement supports further investigation of the BlueScreen HC assay as a useful tool in prioritizing the assessment of new F&F materials and in filling data gaps on materials with no or limited regulatory test data for genotoxicity.