Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

Abstract

Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test

Prediction of Chronic Inflammation for Inhaled Particles: the Impact of Material Cycling and Quarantining in the Lung Epithelium

“…have highlighted the need to explain the molecular mechanisms involved and to define the key events in toxicity pathways governed by a chain of the material‐specific bio–nano interactions. Only then do these adverse outcome pathways [ 27–29 ] gain their power in mechanism‐based prediction of the apical endpoints using solely in vitro systems.…”

Particle characterization and toxicity in C57BL/6 mice following instillation of five different diesel exhaust particles designed to differ in physicochemical properties

“…This could suggest that other particle components affecting the nanostructure in relation to the organic carbon content, in addition to SSA, are important contributors to the acute phase response of diesel exhaust particles. The acute phase response is an important cardiovascular disease risk factor [47], and inflammation may be linked to other pathologies including fibrosis [68] and secondary genotoxicity [69,70].…”

Translating Scientific Advances in the AOP Framework to Decision Making for Nanomaterials

“…In addition to these efforts, various stakeholders have supported projects aimed at evaluating and promoting the development of AOPs for MNs. The EU, through its H2020 initiative, has supported several projects focused on the development and application of AOPs for MNs; these include SmartNanoTox (Smart Tools for Gauging Nano Hazards) and PATROLS (Physiologically Anchored Tools for Realistic nanOmateriaL hazard aSsessment) [ 9 , 14 ]. Since 2016, the OECD Working Party on Manufactured Nanomaterials (WPMN) has included in its program the project Advancing Adverse Outcome Pathway (AOP) Development for Nanomaterial Risk Assessment and Categorisation [NanoAOP Project; ENV/CHEM/NANO(2017)5].…”

“…Doing so will require a coordinated response that adopts science into decision making processes and bridges current knowledge gaps. The AOP framework is an evidence-based approach that is expected to aid in the resolution of several twenty-first century challenges regarding chemical and nano-specific safety assessments [ 7 , 8 , 9 ]. Significant progress has been made in AOP development, application and use over the last decade, including methods, resources and tools to adopt AOPs as part of an integrated approach to testing and assessment (IATA) that utilizes alternative testing data for decision making.…”