Dataset Information

Mutagenicity evaluation to UV filters of benzophenone-6, benzophenone-8, and 4-methylbenzylidene camphor by Ames test.

ABSTRACT: Benzophenone (BPs) and 4-Methylbenzylidene Camphor are used as ultraviolet (UV) filters to protect the skin and hair in personal care products. The discharging of the three chemicals may endanger the receiving water ecosystem. In the present study, the mutagenicity of BP-6, BP-8, and 4-Methylbenzylidene Camphor was tested using the Salmonella typhimurium reverse mutation test (Ames test) in the system with and without rat liver microsomal preparations (S9). Four S.typhimurium strains, TA97, TA98, TA100, and TA102 were employed in the Ames tests. The mutagenicity was detected from all three chemicals. The addition of S9 increased the mutation ratios of three chemicals to four strains, except BP-6 to TA100 strain and 4-MBC to TA97 and TA98 strain. In the mixed experiment, all positive effects were detected in the absence of S9. However, the results all became negative in the presence of S9. For the mixture of BP-6 and 4-MBC, positive results were detected on four tester strains except for the TA100 strain. For the mixture of BP-6, BP-8, and 4-MBC, positive results were detected on four strains. The mixture test results showed antagonism in mutagenicity for the mixture of BP-6 and 4-MBC to TA98 and TA100 strains and the mixture of BP-6, BP-8, and 4-MBC to TA100 and TA102 strains.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8412341 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Mutagenicity evaluation to UV filters of benzophenone-6, benzophenone-8, and 4-methylbenzylidene camphor by Ames test.

Zhang Jing J Pei Zhou-Tao ZT Zhao Ya-Ni YN Zhang Meng M Zhang Li-Ling LL Wang Wen-Qiang WQ Wu Jing-Ya JY Yu Ran R Sun Li-Wei LW

PloS one 20210902 9

Benzophenone (BPs) and 4-Methylbenzylidene Camphor are used as ultraviolet (UV) filters to protect the skin and hair in personal care products. The discharging of the three chemicals may endanger the receiving water ecosystem. In the present study, the mutagenicity of BP-6, BP-8, and 4-Methylbenzylidene Camphor was tested using the Salmonella typhimurium reverse mutation test (Ames test) in the system with and without rat liver microsomal preparations (S9). Four S.typhimurium strains, TA97, TA98 ...[more]

PMID: 34473729

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Project description:The robust control of genotoxic N-nitrosamine (NA) impurities is an important safety consideration for the pharmaceutical industry, especially considering recent drug product withdrawals. NAs belong to the 'cohort of concern' list of genotoxic impurities (ICH M7) because of the mutagenic and carcinogenic potency of this chemical class. In addition, regulatory concerns exist regarding the capacity of the Ames test to predict the carcinogenic potential of NAs because of historically discordant results. The reasons postulated to explain these discordant data generally point to aspects of Ames test study design. These include vehicle solvent choice, liver S9 species, bacterial strain, compound concentration, and use of pre-incubation versus plate incorporation methods. Many of these concerns have their roots in historical data generated prior to the harmonization of Ames test guidelines. Therefore, we investigated various Ames test assay parameters and used qualitative analysis and quantitative benchmark dose modelling to identify which combinations provided the most sensitive conditions in terms of mutagenic potency. Two alkyl-nitrosamines, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were studied. NDMA and NDEA mutagenicity was readily detected in the Ames test and key assay parameters were identified that contributed to assay sensitivity rankings. The pre-incubation method (30-min incubation), appropriate vehicle (water or methanol), and hamster-induced liver S9, alongside Salmonella typhimurium strains TA100 and TA1535 and Escherichia coli strain WP2uvrA(pKM101) provide the most sensitive combination of assay parameters in terms of NDMA and NDEA mutagenic potency in the Ames test. Using these parameters and further quantitative benchmark dose modelling, we show that N-nitrosomethylethylamine (NMEA) is positive in Ames test and therefore should no longer be considered a historically discordant NA. The results presented herein define a sensitive Ames test design that can be deployed for the assessment of NAs to support robust impurity qualifications.

Project description:The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.

Project description:BackgroundIn drug discovery, a positive Ames test for bacterial mutation presents a significant hurdle to advancing a drug to clinical trials. In a previous paper, we discussed success in predicting the genotoxicity of reagent-sized aryl-amines (ArNH2), a structure frequently found in marketed drugs and in drug discovery, using quantum mechanics calculations of the energy required to generate the DNA-reactive nitrenium intermediate (ArNH:+). In this paper we approach the question of what molecular descriptors could improve these predictions and whether external data sets are appropriate for further training.ResultsIn trying to extend and improve this model beyond this quantum mechanical reaction energy, we faced considerable difficulty, which was surprising considering the long history and success of QSAR model development for this test. Other quantum mechanics descriptors were compared to this reaction energy including AM1 semi-empirical orbital energies, nitrenium formation with alternative leaving groups, nitrenium charge, and aryl-amine anion formation energy. Nitrenium formation energy, regardless of the starting species, was found to be the most useful single descriptor. External sets used in other QSAR investigations did not present the same difficulty using the same methods and descriptors. When considering all substructures rather than just aryl-amines, we also noted a significantly lower performance for the Novartis set. The performance gap between Novartis and external sets persists across different descriptors and learning methods. The profiles of the Novartis and external data are significantly different both in aryl-amines and considering all substructures. The Novartis and external data sets are easily separated in an unsupervised clustering using chemical fingerprints. The chemical differences are discussed and visualized using Kohonen Self-Organizing Maps trained on chemical fingerprints, mutagenic substructure prevalence, and molecular weight.ConclusionsDespite extensive work in the area of predicting this particular toxicity, work in designing and publishing more relevant test sets for compounds relevant to drug discovery is still necessary. This work also shows that great care must be taken in using QSAR models to replace experimental evidence. When considering all substructures, a random forest model, which can inherently cover distinct neighborhoods, built on Novartis data and previously reported external data provided a suitable model.

Dataset Information

Mutagenicity evaluation to UV filters of benzophenone-6, benzophenone-8, and 4-methylbenzylidene camphor by Ames test.

Publications

Mutagenicity evaluation to UV filters of benzophenone-6, benzophenone-8, and 4-methylbenzylidene camphor by Ames test.

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