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 simple in concept, the AOP network is the fundamental unit of application for risk assessment and can broadly reflect complex, multi-stressor interactions and outcomes. AOPs have primarily been used to describe the impacts of chemicals on human and ecological outcomes. However, there is growing interest in applying AOPs in the radiation field (NCRP 2020, Chauhan et al., 2019; Chauhan et al., 2024). A case example AOP to lung cancer that is relevant to stressors such as radon inhalation has been endorsed by the Nuclear Energy Agency (NEA) and the Working Group of the National Coordinators of the Test Guidelines Programme (WNT) and Working Party on Hazard Assessment (WPHA) of the OECD (https://aopwiki.org/aops/272). Furthermore, since June 2021, a Radiation/Chemical AOP Joint Topical Group under the auspices of the NEA High Level Group on Low Dose Research has been working to promote and integrate AOPs into radiation research and risk assessments (Chauhan, Beaton et al., 2022a; Chauhan, Hamada et al., 2022b; Chauhan, Beaton et al., 2024). As part of these efforts, AOPs are being developed to multiple AOs including those relevant to space exploration (Kozbenko et al., 2024; Carrothers et al., 2024; Sleiman et al., 2024; Sandhu et al., 2024). Herein we describe four AOPs (AOP#478; AOP#483; AOP#470; AOP#482) that form a network leading to non-cancer AOs of relevance to space travel.

Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. It has been shown that fractionated radiation exposure at high doses (3-17 Gy) to the heart increases the incidence of CVD, as evident from radiotherapy studies. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted which informed final key event (KE) selection and facilitated evaluation Bradford Hill criteria of the key event relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which concurrently causes the release of pro-inflammatory mediators and alters signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction and subsequent vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.