Bridging the gaps in nanosafety for animal-free prediction of adverse outcomes

Bridging the gaps in nanosafety for animal-free prediction of adverse outcomes

The current animal-based testing of materials’ short- and long-term health effects is slow, expensive, and has limited capacity, which stifles the development of new (nano)materials and hinders efficient regulation of the market. To enable cost-efficient high-throughput screening required for industry and regulation, we here propose to shift the focus of nanosafety testing from late endpoints to early key events (KEs) leading to adverse outcomes (AOs). As such tests can only be based on mechanistic understanding, we need to close the knowledge gaps and match KEs in vitro and in vivo, which the nanoPASS consortium is in a unique position to provide. Our key bridging methods are intravital in vivo microscopy, quantitative time-lapse in vitro microscopies, and automated identification of the modes of action (i.e. KE relationships) with proprietary in silico algorithms, supported by datamining of the worlds’ largest in vivo database and single-cell omics data, and computational modelling of structure-function relationships. With this toolset, we aim to 1) develop new in vitro systems that can replicate early KEs leading to AOs related to inhalation of NMs, 2) identify methods to track the dynamics of these KEs, 3) develop quantitative in silico models to predict AOs, and 4) calibrate the in vitro/in silico AO predictions against in vivo data for 40+ well-characterised benchmark materials. Finally, we will 5) validate the AO predictions on several families of industrial materials, sampled from different stages of their life cycle, and then propose reliable testing protocols and guidelines to OECD and ECVAM. With the consortium of 6 complementary research laboratories, SME as technology developer and provider, material producing company as potential end-user, and an industrial association to facilitate dissemination, nanoPASS covers the whole value chain of the new animal-free safety testing technology, and thus paves the way towards safe adoption of new nanotechnologies.