Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities

Sutter, Andreas; Amberg, Alexander; Boyer, Scott; Brigo, Alessandro; Contrera, Joseph F.; Custer, Laura; Dobo, Krista L.; Gervais, Véronique; Glowienke, Susanne; Gompel, Jacky Van; Greene, Nigel; Muster, Wolfgang; Nicolette, John; Reddy, M. Vijayaraj; Thybaud, Véronique; Vock, Esther; White, Angela; Müller, Lutz

doi:10.1016/j.yrtph.2013.05.001

Cited by 116 publications

(64 citation statements)

References 37 publications

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“…For evaluation of impurities in drug substances and products, computational toxicology assessment should be performed using (Q)SAR methodologies that predict the outcome of a bacterial mutagenicity assay [67]. Two (Q)SAR prediction methodologies that complement each other should be applied, one methodology should be expert rule-based and the second should be statistical-based.…”

Section: Case Ultra (Commercial Model)mentioning

confidence: 99%

Testing the Mutagenicity Potential of Chemicals

Verheyen¹

2017

J Genet Genome Res

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All information for the proper development, functioning and reproduction of organisms is coded in the sequence of matched base-pairs of DNA. DNA mutations can result in harmful effects and play a role in genetic disorders and cancer. As mutations can arise through exposure to chemical substances, testing needs to be done on substances that humans and animals can be exposed to. This review focuses on the different testing strategies for risk assessment of chemicals for genotoxicity and carcinogenicity. This review is not meant to cover all testing methodologies, but rather to give an overview of the main methodologies that are used in a regulatory context. In silico and in vitro tools are playing an increasingly important role, in order to reduce in vivo animal testing. Especially in silico tools like (Q)SARs are promising as they are non-testing methods and thereby also reduce the costs and time that are needed to perform in vitro assays. (Q)SARs are not sufficiently reliable to be used as stand-alone tools, and should be associated with expert judgment or used in combination with other Weight of Evidence such as in vitro and in vivo data and data derived from other similar molecules (read-across). For some product (sub) categories, testing (in vitro/in vivo) will be unavoidable; however the future may bring reliable approaches for ensuring human safety.

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Section: Case Ultra (Commercial Model)mentioning

confidence: 99%

Testing the Mutagenicity Potential of Chemicals

Verheyen¹

2017

J Genet Genome Res

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“…Olası GS'lerin GS olup olmadığı Ames mutasyon testi veya in vitro kromozomal aberasyon testi ile belirlenir. 21 Ancak bu testlerin sonuçları pozitif/negatif olduğundan, maruziyet limitlerini belirlemek için kullanılamaz. Test sonucuna göre safsızlığın genotoksik olması durumunda alternatif sentez yolları ile bu safsızlık-tan kaçınılmaya çalışılsa da bu ürünlerin kullanıl-ması ve oluşumlarından kaçınılması pek de mümkün değildir.…”

Section: Avrupa İlaç Ajansi Yaklaşimiunclassified

“…5,7,26 Safsızlıkların genotoksisiteleri ve karsinojeniteleri, yapı-aktivite ilişkisi analizi [structure-activity relationship (SAR)] ve nicel yapı-aktivite ilişkisi [quantitative-SAR (QSAR)] modelleri kullanılarak "in silico" denilen yöntemlerden elde edilen yapısal alarmlar ile değerlendirilebilir. 21 …”

Section: Safsizliklarin Genotoksi̇si̇teleri̇ni̇n Beli̇rlenmesi̇nde Kullanilunclassified

“…Bu veri tabanlarında herhangi bir bileşiğin ya da bu bileşiğe yapısal olarak benzeyen bir bileşiğin daha önce belirlenmiş genotoksisite verisi araştırılır. 6,21 Yapısal olarak alarm veren bileşiğin genotoksisitesi bakteriyel mutasyon testleri ve kromozomal hasar için in vitro memeli hücre testleri (metafaz test veya fare lenfoma testi) ile belirlenir. İzole edilen safsızlıklar kullanılarak yapılan çalışmalar bazen yeterli olsa da bu çalışma-ların safsızlık içeren yeni ilaç ham maddesi için de yapılabileceği kılavuzlarda bildirilmiştir.…”

Section: Safsizliklarin Genotoksi̇k Potansi̇yelleri̇ni̇n Değerlendi̇ri̇lmesi̇unclassified

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Genotoxic Impurities in Drugs for Human: Review

Palabıyık¹,

Baydar²,

Şahin³

2016

Turkiye Klinikleri J Pharm Sci

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“…This guideline accepts the analysis of structure-activity relationships (SAR) using in silico methods for mutagenic hazard assessment of actual and potential impurities if data for bacterial mutagenicity are not available. The guideline states that the assessment should be conducted using two different in silico approaches, i.e., an expert rule-based system and a statistics-based system (Sutter et al, 2013), because these approaches complement each other and are suitable to predict the outcome of the Ames test.…”

Section: Introductionmentioning

confidence: 99%

Prediction of genotoxic potential of cosmetic ingredients by an in silico battery system consisting of a combination of an expert rule-based system and a statistics-based system

et al. 2015

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-Genotoxicity is the most commonly used endpoint to predict the carcinogenicity of chemicals. The International Conference on Harmonization (ICH) M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk offers guidance on (quantitative) structure-activity relationship ((Q)SAR) methodologies that predict the outcome of bacterial mutagenicity assay for actual and potential impurities. We examined the effectiveness of the (Q)SAR approach with the combination of DEREK NEXUS as an expert rule-based system and ADMEWorks as a statistics-based system for the prediction of not only mutagenic potential in the Ames test, but also genotoxic potential in mutagenicity and clastogenicity tests, using a data set of 342 chemicals extracted from the literature. The prediction of mutagenic potential or genotoxic potential by DEREK NEXUS or ADMEWorks showed high values of sensitivity and concordance, while prediction by the combination of DEREK NEXUS and ADMEWorks (battery system) showed the highest values of sensitivity and concordance among the three methods, but the lowest value of specificity. The number of false negatives was reduced with the battery system. We also separately predicted the mutagenic potential and genotoxic potential of 41 cosmetic ingredients listed in the International Nomenclature of Cosmetic Ingredients (INCI) among the 342 chemicals. Although specificity was low with the battery system, sensitivity and concordance were high. These results suggest that the battery system consisting of DEREK NEXUS and ADMEWorks is useful for prediction of genotoxic potential of chemicals, including cosmetic ingredients.

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Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities

Cited by 116 publications

References 37 publications

Testing the Mutagenicity Potential of Chemicals

Testing the Mutagenicity Potential of Chemicals

Genotoxic Impurities in Drugs for Human: Review

Prediction of genotoxic potential of cosmetic ingredients by an in silico battery system consisting of a combination of an expert rule-based system and a statistics-based system

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