Introduction to the special issue on adverse outcome pathways in radiation protection

This special issue of the International Journal of Radiation Biology entitled ‘Adverse Outcome Pathways in Radiation Protection’ is inspired by growing global interest in approaches for integrating information from radiation biology and epidemiology to improve scientific understanding of low dose radiation health risk assessment. The adverse outcome pathway (AOP) represents a conceptual framework characterizing a stressor associated with a sequential set of causally linked key events at different levels of biological organization, beginning with a molecular initiating event and culminating in an adverse health outcome. The special issue provides a comprehensive overview of AOPs, a summary of origin, the goals of a newly formed topical group, current case examples of AOPs and how the radiation field can harness AOPs to structure the available knowledge on the biological effects of radiation exposure. The special issue consists of a commentary (Chauhan, Beaton, et al. 2022), four reviews (Azimzadeh et al. 2022; Chauhan, Hamada, Wilkins, et al. 2022; Chauhan, Hamada, Garnier-Laplace, et al. 2022; Jaylet et al. 2022) and seven research articles (Adam et al. 2022; Burtt et al. 2022; Klokov et al. 2022; Kozbenko et al. 2022; Stainforth et al. 2022; Tollefsen et al. 2022; Yu et al. 2022).

It is envisioned that AOPs could contribute toward better delineating and defining early mechanistic changes and a sequence of events from radiation exposures that are causally linked to health outcomes relevant to public and ecosystem protection. The data informing AOPs could then be used for designing robust bioassays and risk model strategies relevant to regulatory decision-making. However, before this goal is reached, some important questions need to be addressed as to how different types, doses and dose rates of radiation exposure can accurately inform AOP development and how AOPs can reflect the latency of adverse health outcomes in a simplified form. These and other questions posed by the radiation community can only be addressed through practical AOP construction, and through shared experiences from the AOP experts in the chemical toxicology field.

To facilitate this, the Organisation for Economic Co-operation and Development (OECD) Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) and the OECD AOP Development Programme have been working to identify opportunities for cooperation and collaboration. Toward this aim, a newly formed Radiation/Chemical (Rad/Chem) AOP joint topical group (JTG) is geared to promote the use of the AOP framework in areas of radiation research and regulation. The end goal is to make AOPs appealing to international and national radiation protection agencies, and the community of regulators, policy-makers and researchers (Chauhan, Beaton, et al. 2022).

The JTG will work alongside the OECD AOP Development Programme to help advance areas of common interest by offering recommendations for harmonization of the AOP framework to accommodate non-chemical stressors. The special issue provides the AOP enthusiast with a high-level overview of the OECD AOP Development Programme, and its work toward regulatory implementation including aspects that could drive interest for use in the radiation field (Chauhan, Hamada, Wilkins, et al. 2022). Additionally presented is a communication and engagement strategy to relay the important messages and attract the appropriate audience to facilitate acceptance of AOP use in radiation research and regulation (Chauhan, Hamada, Garnier-Laplace, et al. 2022). A key aspect to this is to address some of the ongoing challenges that have been raised by the radiation community on AOPs. For this purpose, an international horizon-style exercise was considered an important step to understand where the clear hesitations on the use of AOPs arise and some misperceptions on their scope (Burtt et al. 2022).

In addition, the readership is presented with the key elements needed to construct transparent and well-synthesized AOPs using systematic review tools (Kozbenko et al. 2022). These methods are being recognized as a means to improve the literature gathering process for AOP development, thereby providing confidence for use in regulatory decision-making. Notably, many AOP case examples are presented to radiation relevant-adverse outcomes, these AOPs were intiated through a recent workshop held in April 2020, organized by the Multidisciplinary European Low Dose Initiative (MELODI) and the European Radioecology Alliance (ALLIANCE) associations. As part of the workshop, four working groups were formed to develop AOPs for adverse health outcomes of importance in the radiation field: vascular disease (Chauhan et al. 2021; Azimzadeh et al. 2022), reproductive effects (Tollefsen et al. 2022), microcephaly (Jaylet et al. 2022) and leukemia (Klokov et al. 2022). Jaylet et al. (2022) have also proposed the use of a machine-learning approach to assist in the screening of the available literature to develop AOPs. These case studies are working to organize scientific knowledge using decades of mechanistic and epidemiology studies, informing on the state of science and guiding future research in the areas with knowledge gaps.

Lastly, presented is a vision for integrating ‘omics’ data into AOPs. These efforts seek to understand how new high throughput technologies that assess macromolecular events in cells can be correlative in response to conventional assesssements of latent phenotypic changes within organs and tissues following radiation exposure. Two case examples of cardiovascular disease (CVD) and lung cancer were presented (Azimzadeh et al. 2022; Yu et al. 2022). The CVD example (Azimzadeh et al. 2022) provides a narrative review on the benefits and challenges of using omics data to inform a CVD AOP proposed by Chauhan et al. (2021). The review also stresses the knowledge gap in scientific and analytical areas of radiation research where sufficient omics data are not yet generated and interpreted. The lung cancer example (Yu et al. 2022) describes the steps needed for the interpretation of underlying transcriptomic effects to key events in an AOP for lung cancer (AOP 272: https://www.aopwiki.org/aops/272). Also explored is benchmark dose modeling as a means to identify a point of departure (POD) for adverse phenotypic effects using transcriptional dose-response data (Chauhan et al. 2016). For this approach to provide meaningful outputs, it is important to understand the impact of dose selection and spacing on the PODs (Stainforth et al. 2022) and whether or not these PODs change with confounding factors of sex and smoking (Adam et al. 2022).

It is our hope that this special issue will spur interest among radiation professionals, and possibly sustain a community of practice. The long-term vision is to have AOPs integrated for use in identifying knowledge gaps, prioritizing research and designing informative biological experiments that can effectively help advance radiation protection. Lastly, we would greatly appreciate the authors of this special issue for their important contributions, and are likewise most grateful to the multiple reviewers for their worthy and timely feedback. We would also like to acknowledge the International Journal of Radiation Biology for an opportunity to guest edit this special issue, and for the ongoing support of Dr. Gayle E. Woloschak (the Editor-in-Chief of the journal) and Ms. Dianne Dixon (the Managing Editor of the journal).

Disclosure statement

No potential conflict of interest was reported by the author(s). The authors alone are responsible for the content and writing of the editorial. The views expressed in this editorial represent the collective opinions of the authors, and are not necessarily those of their professional affiliations.