Rethinking chemical hazard: an AOP-guided approach to non-conventional endpoints in the environmental assessment of neurotoxic, immunotoxic and metabolic toxic compounds

Chemical pollution is identified as a significant driver of biodiversity loss, raising concerns about the effectiveness of current environmental risk assessment (ERA) practices. Conventional ERA approaches primarily rely on the endpoints of mortality, growth, and reproduction, often failing to capture the full scope of potential effects that chemicals can have on organisms. This is potentially problematic in cases of chemicals causing neurotoxicity, immunotoxicity, and metabolic toxicity, which have recently been introduced to the discussion under REACH by the new report of the European Chemical Agency (ECHA) on Key Areas of Regulatory Challenge . For these modes of action (MoAs), which have to date been discussed primarily in the context of human toxicity, there is currently no established approach for addressing them in ERA. This is despite the fact that these chemicals often have sublethal effects on traits linked to potential effects on population-relevant endpoints (e.g., foraging behaviour). In this study, we evaluated the importance of non-conventional sublethal endpoints for hazard and risk practices. We categorised endpoints into conventional (CE; i.e., defined by standardised guidelines), semi-conventional (semi-CEs; i.e., defined by standardised guidelines but only for a limited number of species), and non-conventional endpoints (NCE; i.e., ecotoxicological measurements not defined by standardised guidelines and so going beyond conventional measurements). In this conceptual review, we selected case studies that evaluated both conventional and non-conventional endpoints to evaluate the importance of NCEs for the assessment of the emerging hazards in comparison to CEs, focusing on (1) sensitivity (effect levels), (2) mechanistic understanding, and (3) population-level effects. Our assessment shows that using NCEs can improve mechanistic understanding of chemical hazards and provide important information about the chemicals’ MoA. Comparisons between NCEs and CEs at the individual and population levels revealed that in 13% of cases, NCEs showed effects when CEs were unaffected. NCEs were generally more sensitive, being on average 56 times more sensitive than mortality, 8 times than reproduction, and 2 times than growth—in 9 cases, the NCEs were more than 1000 times more sensitive than the CE. NCEs showed unconventional links to the population level that would have gone undetected in the current ERA system (e.g., changes in boldness behaviour affecting reproduction in fish). We propose a first approach to address environmental hazard identification and risk prediction for neurotoxic, immunotoxic, and metabolic toxic compounds by organising relevant NCEs according to an Adverse-Outcome-Pathway (AOP) structure, and a MoA-based AOP framework.