Adverse outcome pathways: hype or hope?

Abstract

reproductive toxicity, voltage-gated sodium channel-mediated neural toxicity, hemolytic anemia induced by anilines, nephrotoxicity induced by 4-aminophenols (OECD 2011), skin sensitization (OECD 2012b), phototoxicity, aryl hydrocarbon receptor-mediated toxicity (Ankley et al. 2010), drug-induced liver fibrosis, and steatosis (Landesmann et al. 2012) as well as drug-induced cholestasis (Vinken et al. 2013). The advent of AOPs in toxicology has been acknowledged and is being brought forward by the OECD, which issued a guidance document and reporting template for the development of newly postulated AOPs and the assessment of its completeness (OECD 2012a). According to these OECD guidelines, AOPs rely on 2 anchors, namely the molecular initiating event and the adverse outcome, that are interconnected by a series of causally linked intermediate steps, of which some are to be considered as key events. Being designed to shed light onto the mechanisms that underlie pertinent toxicological effects, AOPs are typically represented as stand-alone processes that consist of a set of consecutive events (OECD 2012a). This portrayal of the toxicity landscape is not without criticism because of its inherent simplicity and reductionism. Indeed, toxicological processes in real life encompass entangled networks of serial, parallel, and intersecting pathways that are often difficult to decouple. The identification of the different building blocks of AOPs is mainly based upon a survey of the scientific literature to mine out relevant data, such as in chemico, in vitro, in vivo, and chemical structure information on reference chemicals associated with particular AOPs. Importantly, AOPs must be considered as open and flexible structures that should be continuously updated by feeding in established and newly generated data. Such iterative refinement exercises should ideally include the elaboration and quantification of the toxicodynamic relationships between neighboring events Toxicity testing typically focuses on generating data concerning the adverse effects of chemical substances on human health or the environment. However, there is an increasing desire to go beyond observation and prioritize the elucidation of the molecular machinery that drives the manifestation of toxicological apical end points (Andersen et al. 2012). This view was clearly embodied with the introduction of so-called toxicity pathways, which denote cellular response cascades that, when sufficiently perturbed, are expected to result in an adverse health outcome (NRC 2007; OECD 2012a). This designation has been criticized, as by definition it excludes true stress response pathways that only become activated by perturbation (Jennings 2013). A more comprehensive conceptual framework is based upon the adverse outcome pathway (AOP) approach. Having emerged initially in the field of ecotoxicology, an AOP refers to an analytical construct that portrays existing knowledge concerning the causal linkage between a direct molecular initiating event, i.e., the interaction of a chemical with a biological system, and an adverse outcome at a biological level of organization relevant to risk assessment (OECD 2012a). Over the last few years, the AOP tool has been proven equally applicable to describing toxicological processes underpinning human-relevant adverse effects, with examples including estrogen receptor-mediated