A systematic process for identifying key events for advancing the development of nanomaterial relevant adverse outcome pathways

Adverse outcome pathways (AOPs) represent a sequence of key events (KEs) between a molecular initiating event (MIE) and an adverse outcome (AO) and span many levels of biological organization including molecular, cellular, tissue, organ, organism, and population. AOPs link specific biological observations with AOs. AOPs are not specific to individual chemicals; however, they were traditionally developed for chemicals. The objective of the present study is to advance the identification of KEs using existing nanotoxicology literature as part of an Organisation for Economic Cooperation and Development (OECD) Working Party on Manufactured Nanomaterials (WPMN) project aiming to support the future development of AOPs relevant for Manufactured Nanomaterials (MNs). A database of 11,000 nanotoxicology studies published between 2000 and 2013 was assessed for the types of MNs investigated and for the assays, endpoints and toxicity effects presented. Since tissue inflammation is one of the consistently observed and reported effects following MN exposure, the large database was processed to select those studies reporting specifically on inflammation to identify inflammation-associated KEs. This exercise resulted in 191 publications describing ~60 different endpoints for 45 different MNs, which were used in identification of MN-induced KEs and selection of single or multiple KEs that are relevant to AOs of regulatory interest. This report summarises the key findings of the study describing the various KEs identified, and the reported assays and specific measurements used to assess the KEs. The report also describes a single KE ‘Tissue Injury’, selected by the process for further development in a case study as part of the OECD WPMN project to show its relevance to MN-induced AOs, and in turn, to future MN risk assessment. Finally, the challenges and limitations of the existing nanotoxicology literature for the development of MN-relevant AOPs are highlighted.