A methodology for developing key events to advance nanomaterial-relevant adverse outcome pathways to inform risk assessment

Abstract

Significant advances have been made in the development of Adverse Outcome Pathways (AOPs) over the last decade, mainly focused on the toxicity mechanisms of chemicals. These AOPs, although relevant to manufactured nanomaterials (MNs), do not currently capture the reported roles of size-associated properties of MNs on toxicity. Moreover, some AOs of relevance to airborne exposures to MNs such as lung inflammation and fibrosis shown in animal studies may not be targeted in routine regulatory decision making. The primary objective of the present study was to establish an approach to advance the development of AOPs of relevance to MNs using existing, publicly available, nanotoxicology literature. A systematic methodology was created for curating, organizing and applying the available literature for identifying key events (KEs). Using a case study approach, the study applied the available literature to build the biological plausibility for ‘tissue injury’, a KE of regulatory relevance to MNs. The results of the analysis reveal the various endpoints, assays and specific biological markers used for assessing and reporting tissue injury. The study elaborates on the limitations and opportunities of the current nanotoxicology literature and provides recommendations for the future reporting of nanotoxicology results that will expedite not only the development of AOPs for MNs but also aid in application of existing data for decision making.

Keywords:

• Adverse outcome pathway
• key event
• nanomaterial
• risk assessment

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health (NIOSH).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

J.A.S. acknowledges the support of this work by Health Canada and Environment and Climate Change Canada. E.D.K. would like to thank Theresa E. Boots, M.S., NIOSH (formerly an Oak Ridge Associated Universities, ORAU, fellow); and Alyssa Kogel, M.S., formerly an ORAU fellow at NIOSH, for their assistance in extracting and verifying information in the database and running benchmark dose-response models of selected data. I.M. and I.L. acknowledge funding from the EU H2020 research infrastructure for nanosafety, NanoCommons [Grant Agreement No. 731032] which supported the population of the Nano-AOP database. R.J.V. acknowledges funding from the Dutch Interdepartmental Working Group on Risks of Nanotechnology (IWR). S.H. acknowledges funding from Health Canada’s Genomics Research and Development Initiative.