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Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.

ABSTRACT: Interest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g., the European Union's Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the project presented in this publication was to develop substance categories for a read-across with complex endpoints of toxicity based on existing databases. The basic conceptual approach was to combine structural similarity with shared mechanisms of action. Substances with similar chemical structure and toxicological profile form candidate categories suitable for read-across. We combined two databases on repeated dose toxicity, RepDose database, and ELINCS database to form a common database for the identification of categories. The resulting database contained physicochemical, structural, and toxicological data, which were refined and curated for cluster analyses. We applied the Predictive Clustering Tree (PCT) approach for clustering chemicals based on structural and on toxicological information to detect groups of chemicals with similar toxic profiles and pathways/mechanisms of toxicity. As many of the experimental toxicity values were not available, this data was imputed by predicting them with a multi-label classification method, prior to clustering. The clustering results were evaluated by assessing chemical and toxicological similarities with the aim of identifying clusters with a concordance between structural information and toxicity profiles/mechanisms. From these chosen clusters, seven were selected for a quantitative read-across, based on a small ratio of NOAEL of the members with the highest and the lowest NOAEL in the cluster (< 5). We discuss the limitations of the approach. Based on this analysis we propose improvements for a follow-up approach, such as incorporation of metabolic information and more detailed mechanistic information. The software enables the user to allocate a substance in a cluster and to use this information for a possible read- across. The clustering tool is provided as a free web service, accessible at http://mlc-reach.informatik.uni-mainz.de.

SUBMITTER: Batke M

PROVIDER: S-EPMC5030828 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.

Batke Monika M Gütlein Martin M Partosch Falko F Gundert-Remy Ursula U Helma Christoph C Kramer Stefan S Maunz Andreas A Seeland Madeleine M Bitsch Annette A

Frontiers in pharmacology 20160921

Interest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g., the European Union's Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the proje ...[more]

PMID: 27708580

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Project description:Boron nitride (BN) nanomaterials have been increasingly explored for potential applications in chemistry and biology fields (e.g., biomedical, pharmaceutical, and energy industries) due to their unique physico-chemical properties. However, their safe utilization requires a profound knowledge on their potential toxicological and environmental impact. To date, BN nanoparticles have been considered to have a high biocompatibility degree, but in some cases, contradictory results on their potential toxicity have been reported. Therefore, in the present study, we assessed two commercial 2D BN samples, namely BN-nanopowder (BN-PW) and BN-nanoplatelet (BN-PL), with the objective to identify whether distinct physico-chemical features may have an influence on the biological responses of exposed cellular models. Morphological, structural, and composition analyses showed that the most remarkable difference between both commercial samples was the diameter of their disk-like shape, which was of 200-300 nm for BN-PL and 100-150 nm for BN-PW. Their potential toxicity was investigated using adenocarcinomic human alveolar basal epithelial cells (A549 cells) and the unicellular fungus Saccharomycescerevisiae, as human and environmental eukaryotic models respectively, employing in vitro assays. In both cases, cellular viability assays and reactive oxygen species (ROS) determinations where performed. The impact of the selected nanomaterials in the viability of both unicellular models was very low, with only a slight reduction of S. cerevisiae colony forming units being observed after a long exposure period (24 h) to high concentrations (800 mg/L) of both nanomaterials. Similarly, BN-PW and BN-PL showed a low capacity to induce the formation of reactive oxygen species in the studied conditions. Even at the highest concentration and exposure times, no major cytotoxicity indicators were observed in human cells and yeast. The results obtained in the present study provide novel insights into the safety of 2D BN nanomaterials, indicating no significant differences in the toxicological potential of similar commercial products with a distinct lateral size, which showed to be safe products in the concentrations and exposure conditions tested.

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Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.

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Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.

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