Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish

Adverse outcome pathways (AOPs) organize the knowledge on the progression of toxicity through levels of biological organization. By elucidating the linkages between toxicity events on different levels, the AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. We have previously suggested that development of chronic toxicity AOPs can improve understanding of chronic toxicity and facilitate development of alternative tests. Here, we illustrate this process by focusing on fish growth, which is an apical adverse outcome commonly assessed in chronic toxicity tests, for which the alternatives are actively sought-for. Based on four criteria, namely importance of a particular process for growth-related outcomes, pathway conservation across species, frequency of occurrence of a certain disruption and environmental relevance of chemical-induced effects, we selected to focus on reduction in food intake to initiate middle-out AOP development. To explore the link between reduction in food intake and growth impairment, as well as the mechanisms that cause reduction in food intake, we developed three AOP case studies for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis demonstrated that the reduction in food intake is strongly linked to growth impairment in case of pyrethroids and SSRIs, but not cadmium. For pyrethroids, impairment of locomotion is strongly linked to the effects on food intake and growth, but in case of SSRIs, their direct effects on appetite may play a role more important than their impacts on locomotion. For cadmium, the main cause of growth impairment is reallocation of energy resources due to increased maintenance costs. We further discuss which alternative tests can be developed and used to inform on the key events we identified to be predictive of effects on growth. In conclusion, our work demonstrated how the AOP concept can be used in practice to critically assess the knowledge available for specific chronic toxicity cases in order to identify existing knowledge gaps and potential alternative tests.

JRC.H.1 - Water Resources