Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise

Figures & data

Figure 1. Twenty-five key questions categorized to guide future areas of AOPs in radiation research and policy work.

Figure 2. Hypothetical example of how radiation exposures conditions (acute or chronic) can lead to a common molecular initiating event of deposition of energy (DOE) to multiple different key events (KEs) depending on the radiation exposure parameters. Not all KEs are sufficient to progress to adverse outcome (AO). Red X represents a no-go to the AO, the blue zig zag represents multiple KEs. For the purposes of this example low dose and low dose-rate refers to <100 mGy/<0.1 mGy/min and high dose and high dose-rate refers to >1Gy/>0.01 Gy/min.

Table 1. Focus areas for future advancements of AOPs.

Focus Area	Description
Data Integration and Standardization	Efforts could be directed toward consolidating diverse data sources, including radiobiological studies and epidemiological/clinical data, to build robust AOPs. Standardizing data formats and terminologies (vocabularies) will facilitate effective integration and comparison.
Data Sharing and Collaboration	Encouraging open data sharing and collaborative efforts will enhance the collective knowledge base and accelerate AOP development. Platforms for sharing AOP-related data, models, and tools can foster a collaborative research and regulatory community guided by the FAIR (Findable, Accessible, Interoperable and Reusable) principle.
Longitudinal Studies and Multigenerational Effects	Long-term studies exploring multigenerational effects of radiation exposure can enrich AOPs, providing insights into transgenerational health risks and their mechanisms of induction.
Non-Adverse Effects	Currently the framework is directed to toxic pathways. However, if the framework could include pathways leading to protective effects induced by exposure to low dose radiation, it may be possible to rename “Adverse Outcome Pathways” to “Outcome Pathways”.
Multi-Omics and Systems Biology	Leveraging advancements in multi-omics and systems biology approaches can provide a more holistic understanding of the molecular mechanisms underpinning radiation-induced adverse outcomes. By integrating multi-omics data can reveal intricate pathways and interactions.
High-Throughput Screening	Utilizing the most current methods such as high-throughput screening techniques, computational modeling and other relevant new approach methodologies (NAMs) can expedite the identification of KEs and relevant MIEs, supporting the construction of AOPs.
Emerging Technologies	Embracing emerging technologies like artificial intelligence and machine learning can facilitate the identification of novel relationships within complex AOP networks and aid in predictive modeling.
Quantitative AOPs	Developing quantitative AOPs is crucial for risk predictions in support of regulatory decision-making. This involves translating biological events into their quantitative relationships, enabling the prediction of adverse outcomes at varying exposure levels.
Translational Research	Bridging the gap between basic research and real-world applications is vital. Collaborations between basic researchers, clinicians, and policy makers can facilitate the translation of AOP findings into actionable strategies for radiation protection and health management.
Regulatory Integration	Working closely with regulatory agencies to integrate AOPs into radiation protection frameworks is essential. Collaborative efforts can result in policies that are informed by new scientific developments.
Education and Communication	Continued efforts to inform the scientific community, regulatory bodies, and the public about the essential role for AOPs is essential. Transparent communication of AOP concepts, methodologies, and their implications will foster broader adoption.