Causal, Predictive Or Observational? Different Understandings Of Key Event Relationships For Adverse Outcome Pathways

Abstract

The Adverse Outcome Pathways (AOPs) framework is pivotal in toxicology, but the terminology describing Key Event Relationships (KERs) varies within AOP guidelines. This study examined the usage of causal, observational and predictive terms in AOP documentation and their adaptation in AOP development. A text analysis of key AOP guidance documents revealed nuanced usage of these terms, with KERs often described as both causal and predictive. The adaptation of terminology varies across AOP development stages, with observational and predictive approaches dominating putative and quantitative stages, respectively. Our findings highlight a potential mismatch between terminology in guidelines and methodologies in practice, particularly in inferring causality from predictive models. We argue for careful consideration of terms like causal and essential in AOP guidance to facilitate interdisciplinary communication. Furthermore, integrating known causality into quantitative AOP models remains a challenge. This analysis contributes to ongoing discussions on AOP development and application, emphasizing the need for clarity in terminology and methodology to enhance the robustness and utility of AOPs in regulatory toxicology and risk assessment.