With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable ways of testing NM safety-preferably using in vitro approaches, to avoid the ethical dilemmas associated with animal research. Data are needed for developing intelligent testing strategies for risk assessment of NMs, based on grouping and read-across approaches. The adoption of high throughput screening (HTS) and high content analysis (HCA) for NM toxicity testing allows the testing of numerous materials at different concentrations and on different types of cells, reduces the effect of inter-experimental variation, and makes substantial savings in time and cost. HTS/HCA approaches facilitate the classification of key biological indicators of NM-cell interactions. Validation of in vitro HTS tests is required, taking account of relevance to in vivo results. HTS/HCA approaches are needed to assess dose- and time-dependent toxicity, allowing prediction of in vivo adverse effects. Several HTS/HCA methods are being validated and applied for NM testing in the FP7 project NANoREG, including Label-free cellular screening of NM uptake, HCA, High throughput flow cytometry, Impedance-based monitoring, Multiplex analysis of secreted products, and genotoxicity methods-namely High throughput comet assay, High throughput in vitro micronucleus assay, and γH2AX assay. There are several technical challenges with HTS/HCA for NM testing, as toxicity screening needs to be coupled with characterization of NMs in exposure medium prior to the test; possible interference of NMs with HTS/HCA techniques is another concern. Advantages and challenges of HTS/HCA approaches in NM safety are discussed. WIREs Nanomed Nanobiotechnol 2017, 9:e1413. doi: 10.1002/wnan.1413 For further resources related to this article, please visit the WIREs website.

ANSES Fougères Laboratory Contaminant Toxicology Unit France

CIBER Epidemiología y Salud Pública ISCIII Spain

Comet Biotech AS and Department of Nutrition University of Oslo Norway

Commissariat à l'Energie Atomique et aux Energies Alternatives Direction des Sciences du Vivant Institut de Radiobiologie Cellulaire et Moléculaire Service de Radiobiologie Expérimentale et d'Innovation Technologique Laboratoire de Cancérologie Expérimentale Fontenay aux Roses cedex France

Department of Clinical Dentistry Faculty of Medicine and Dentistry University of Bergen Norway

Department of Electrical Engineering Faculty of Engineering Bergen University College Norway

Directory of Life Sciences Applied Metrology National Institute of Metrology Quality and Technology Rio de Janeiro Brazil

GAIKER Technology Centre Bizkaia Science and Technology Park Zamudio Spain

Grup de Mutagènesi Departament de Genètica i de Microbiologia Facultat de Biociències Universitat Autònoma de Barcelona Bellaterra Spain

Health Effects Group Department of Environmental Chemistry NILU Norwegian Institute for Air Research Kjeller Norway

Human Genetics Department National Institute of Health Doutor Ricardo Jorge and Centre for Toxicogenomics and Human Health NMS FCM UNL Lisbon Portugal

Institute of Biophysics and Medical Physics University of Leipzig Leipzig Germany

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Experimental Medicine AS CR Prague Czech Republic

Nanomedicine Group Trinity Centre for Health Sciences Trinity College Dublin Dublin Ireland

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