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

Laurent Gaté,Sarah Søs Poulsen,Jorid Birkelund Sørli,Sybille van den Brule,Tobias Stöger,Penny Nymark,Ulla Vogel,Henrik Wolff,Andrea De Vizcaya,Andrey Boyadziev,Pernille Høgh Danielsen,Vadim Zhernovkov,Carole Seidel,Sarah Valentino,Sabina Halappanavar

doi:10.1186/s12989-020-00344-4

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 methods for hazard and risk assessment of nanomaterials.

Highlights

Introduction to putativeAdverse Outcome Pathway (AOP) that are currently explored for potential applications in nanotoxicologyadverse outcome pathways (AOPs) 173: substance interaction with lung resident cell membrane components leading to fibrosis Lung fibrosis is an AO of the dysregulated tissue repair process
The Organisation for Economic Co-operation and Development (OECD) Working Party for Manufactured Nanomaterials (WPMN) AOP project reviewed a database of 191 individual studies selected from a larger collection of 11,000 studies published between 2000 and 2013, which included in vivo and in vitro reports on ~ 60 endpoints associated with inflammation for 45 different nanomaterials [40]. These individual studies were reviewed to identify Key event (KE) and the results showed that inflammation, oxidative stress and cytotoxicity events are overrepresented in the nanotoxicology literature, which are frequently identified KEs in many of the AOPs for chemicals documented on AOPwiki
When the stressor interacts with the alveolar cell membrane (MIE), the resulting cell injury leads to the release of damage associated molecular patterns (DAMPs), which in turn, initiate the pro-inflammatory cascade, during which multiple pro-inflammatory mediators and proteinases are secreted (KE1) [71] that signal the recruitment of pro-inflammatory cells into the lungs (KE2)

Summary

Introduction

Introduction to putativeAOPs that are currently explored for potential applications in nanotoxicologyAOP 173: substance interaction with lung resident cell membrane components leading to fibrosis Lung fibrosis is an AO of the dysregulated tissue repair process. The AOP 173 (Fig. 1) describes the qualitative linkages between interactions of substances (e.g. physical, chemical or receptor-mediated) with membrane components (e.g. receptors, lipids) of lung cells leading to fibrosis (https:// aopwiki.org/aops/173).

Results

Conclusion