Adverse Outcome Pathways Applied to Space Radiation Research
Abstract
IntroductionThe Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) framework is used to organize scientific knowledge in toxicology into linear sequences of causally related events that lead to adverse toxicological endpoints (Ankley et al., 2010; OECD, 2018). AOPs describe the critical interactions of a chemical or non-chemical stressor within a biological system. AOPs begins with a molecular initiating event (MIE) that leads to intermediate key events (KEs) and culminate in an adverse outcome (AO). KEs are connected by key event relationships (KERs) for which causality is evaluated using the modified Bradford-Hill criteria (Becker et al., 2015). These criteria include biological plausibility, evidence for the essentiality of KEs, and empirical evidence in the form of dose-, temporal- and incidence-concordance. The strength of these directional and causal relationships is evaluated through a weight of evidence analysis for each KER (Villeneuve et al., 2014). AOPs are purposefully simplified, describing KEs that can be routinely measured and are essential to pathway progression, to facilitate regulatory utility and test strategy development (Ankley et al., 2010). AOPs are developed in a linear manner; however, shared KEs lead to networks of AOPs. Through these networks, multiple MIEs can converge to lead to the same AOs. In addition, multiple different types of stressors may interact with the same MIE to progress AOPs. Thus, although…
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