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

Abstract

Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests.

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

“…This has led to the development of integrated testing strategies which use a combination of computational models (such as structural alerts, read across, QSARs and modelling) along with in vitro testing in order to develop alternative methods. The integration of alternative methods with pathways of toxicity has, in part, also catalysed the formation of the Adverse Outcome Pathway (AOP) framework concept (Ankley et al, 2010;Groh et al, 2015;Vinken, 2013Vinken, , 2015. An AOP describes the causal linkage between a molecular initiating event (MIE) and an adverse outcome at individual or population levels (Patlewicz et al, 2015).…”

Marine microplastics spell big problems for future generations

“…AOPs are extremely useful in deducing the key events linking an apical end point, such as reduced reproductive output, with a perturbation, such as particle ingestion, because they describe generalized motifs of biological response, or key events that are not necessarily specific to any one chemical or substance. For example, applying the AOP concept to growth retardation in fish allowed Groh et al (18) to distinguish the mode of action of cadmium, which reduced growth through increased metabolic demand, from the mode of action of pyrethroid pesticides and selective serotonin reuptake inhibitors, which reduced food intake through changes in behavior and appetite (18). In relation to microplastics, the situation is further complicated by their potential to associate with chemical contaminants and the as-yet-unknown extent to which these absorbed contaminants are transferred from the ingested particle into the organism's tissues.…”

Short-term exposure to municipal wastewater influences energy, growth, and swimming performance in juvenile Empire Gudgeons (Hypseleotris compressa)

“…The overall effects on swimming suggest a possibility for outcomes related to higher-level biological processes (Sárria et al, 2011;Groh et al, 2015), and further research is therefore, warranted to explore and understand the implications of such responses in the context of ecotoxicology (Weis et al, 2001;Melvin and Wilson, 2013). For example, the observed differences in angular velocity may have implications for predator avoidance ability (Benhaïm et al, 2012), and this could be particularly important in juvenile fish.…”

“…This raises concerns about the potential for wastewater discharge and emerging wastewater contaminants to impact aquatic organisms, and highlights the need for research exploring sub-lethal toxicological outcomes in wildlife (Boxall et al, 2012;Rudd et al, 2014). Alterations to an animal's growth, energy reserves, and/or functional performance (e.g., swimming abilities) are all indicative of potential broader ecological concerns that may result from exposures, since these endpoints often correlate well with higherlevel biological processes like survival and reproduction (Sárria et al, 2011;Amiard-Triquet et al, 2012;Groh et al, 2015). Several studies have described increased growth and condition in fish exposed to domestic wastewater (Clark and Fraser 1983;Galloway et al, 2003), and altered energy status and swimming performance have been observed with exposure to various complex effluents (Adams et al, 1989;Smolders et al, 2003;Goertzen et al, 2011).…”