Bridging the gap: Innovative human-based in vitro approaches for nanomaterials hazard assessment and their role in safe and sustainable by design, risk assessment, and life cycle assessment

The application of nanomaterials in industry and consumer products is growing exponentially, which has pressed the development and use of predictive human in vitro models in pre-clinical analysis to closely extrapolate potential toxic effects in vivo. The conventional cytotoxicity investigation of nanomaterials using cell lines from cancer origin and culturing them two-dimensionally in a monolayer without mimicking the proper pathophysiological microenvironment may affect a precise prediction of in vitro effects at in vivo level. In recent years, complex in vitro models (also belonging to the new approach methodologies, NAMs) have been established in unicellular to multicellular cultures either by using cell lines, primary cells or induced pluripotent stem cells (iPSCs), and reconstituted into relevant biological dimensions mimicking in vivo conditions. These advanced in vitro models retain physiologically reliant exposure scenarios particularly appropriate for oral, dermal, respiratory, and intravenous administration of nanomaterials, which have the potential to improve the in vivo predictability and lead to reliable outcomes. In this perspective, we discuss recent developments and breakthroughs in using advanced human in vitro models for hazard assessment of nanomaterials. We identified fit-for-purpose requirements and remaining challenges for the successful implementation of in vitro data into nanomaterials Safe and Sustainable by Design (SSbD), Risk Assessment (RA), and Life Cycle Assessment (LCA). By addressing the gap between in vitro data generation and the utility of in vitro data for nanomaterial safety assessments, a prerequisite for SSbD approaches, we outlined potential key areas for future development.