Non-Animal Strategies for Toxicity Assessment of Nanoscale Materials: Role of Adverse Outcome Pathways in the Selection of Endpoints

Sabina Halappanavar*, Penny Nymark, Harald F. Krug, Martin J.D. Clift, Barbara Rothen-Rutishauser, Ulla Vogel

*Corresponding author for this work

Research output: Contribution to journalReviewResearchpeer-review

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Faster, cheaper, sensitive, and mechanisms-based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM-induced lung fibrosis, are proposed.

Original languageEnglish
Article number2007628
Issue number15
Number of pages20
Publication statusPublished - 2021

Bibliographical note

Funding Information:
S.H. acknowledges Saba Berhane, Jiao Jianli, Luna Rahman, and Silvia Solorio-Rodriguez for serving as Health Canada's internal reviewers. S.H. acknowledges help of Silvia Solorio-Rodriguez in formatting the manuscript according to journal's standards.S.H. acknowledges the funding from Health Canada's Genomics Research and Development Initiative. S.H., P.N., M.J.D.C., B.R.R., and U.V. acknowledge the support by the PATROLS project, the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No 760813, and S.H. and U.V. acknowledge SmartNanoTox, grant agreement No 686098. B.R.R. acknowledges the support by the Adolphe Merkle Foundation. U.V. acknowledges "FFIKA, Focused Research Effort on Chemicals in the Working Environment" from the Danish Government. H.F.K. acknowledges the support of the Swiss Federal Office of Public Health (FOPH) and the German Chemicals Industry Association (VCI, Verband der Chemischen Industrie e.V.).


  • In vitro toxicity
  • Lung fibrosis
  • Nanoparticles
  • Nanotoxicity
  • Risk assessment


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