S10-01 From AOPs to IOPs: Bridging Human and Environmental Impact Assessment in Safe and Sustainable by Design Through Mechanistic Integration

Abstract

Safe and Sustainable by Design (SSbD) is a framework that aims to ensure the safety and sustainability of chemicals and materials across their life cycle. However, current SSbD approaches evaluate human health and environmental impacts separately, limiting their ability to capture cross-domain interactions and cumulative risks. Additionally, SSbD as defined by the Joint Research Centre (JRC) still relies on traditional hazard classifications, which hampers the direct use of non-animal methods (NAMs) in regulatory and industrial decision-making.

To address these limitations, we reviewed Next Generation Risk Assessment (NGRA) concepts and their potential to better integrate risk assessment and life cycle assessment (LCA) within SSbD. We found NAMs to be particularly key for SSbD, as their mechanistic insights foster the integration of human health and environmental assessments, addressing one of the most important limitations of current SSbD frameworks. Additionally, NAMs enable rapid, early-stage, predictive assessments of safety and sustainability, supporting proactive design choices and reducing the need for costly redesigns.

A key tool for integrating NAMs within NGRA is the Adverse Outcome Pathway (AOP) framework. Because many toxicity mechanisms are evolutionarily conserved, AOPs enable cross-species and ecosystem-wide assessments, providing a mechanistic understanding of chemical hazards in environmental health and improving predictions. Building upon the mechanistic and multi-scale characteristics of AOPs, we introduce Impact Outcome Pathways (IOPs) as an extended framework that integrates human and environmental health assessments with LCA in SSbD. IOPs describe sector-specific causeeffect chains that link chemical impacts to outcomes across environmental, health, social, and economic domains. Interconnected Key Event Relationships (KERs) bridge these domains, ensuring that mechanistic insights are transferred between different dimensions, while Modulating Factors (MFs) capture context-dependent variables reflecting indirect effects across biological, ecological, and socio-economic scales. Using case studies on per- and polyfluoroalkyl substances (PFAS) and graphene-based advanced materials, we exemplify how the IOP framework may achieve a more holistic and mechanistic assessment of the chemical or material and improve decision-making in SSbD.

By integrating (eco)toxicological pathways with broader sustainability mechanisms, IOPs enable a unified, cross-domain assessment of chemical risks. Their multiscale nature allows incorporation of diverse NAM-based mechanistic data and computational models, making IOPs a flexible and evolving tool for implementing a One Health approach within SSbD.

This research has been funded by the European Union Project INSIGHT (Integrated Models for the Development and Assessment of High Impact Chemicals and Materials) SSbD (GA101137742). Views andopinions expressed are however those of the author(s) only and do notnecessarily reflect those of the European Union. Neither the EuropeanUnion nor the granting authority can be held responsible for them.