Radiation and Chemical Adverse Outcome Pathway Joint Topical Group (Rad/Chem AOP JTG)

Ongoing

A group of researchers and experts operating under the aegis of the High-Level Group of Low Dose Research, a working party of the Committee on Radiological Protection and Public Health (NEA CRPPH)

AOPs

Source: Health Canada

AOPs in radiological protection

In recent decades, a wealth of biological information has emerged, delving into how radiation impacts both humans and non-human organisms. This data serves as a valuable addition to the insights gained from epidemiological studies, providing a more robust basis for decisions regarding radiological protection (RP) regulation. Yet, presently, there is a notable absence of unified incorporation of these varied datasets into a comprehensive framework guided by mechanistic knowledge. This integration is pivotal to fully leverage pertinent data and scientific understanding, aiding in radiation hazard and risk assessments while reducing existing uncertainties.

The Adverse Outcome Pathway (AOP) framework established by the Organisation for Economic Co-operation and Development (OECD) is designed to advance hazard and risk assessments with a foundation rooted in evidence and mechanistic understanding. AOPs represent a theoretical construct which defines the progression of a stressor's impact on a biological system across multiple levels of biological organisation originating with its initial interaction known as the molecular initiating event (MIE). This progression unfolds through a sequence of intermediary critical events (KEs) that are causally connected via key event relationships (KERs), culminating in the adverse outcome (AO).

Building AOPs in the area of radiological research serves several purposes, including the ability to:

Enhance the synthesis of scientific findings to those most relevant for hazard assessment and support development of risk assessment strategies;
Link mechanistic knowledge to physiological changes leading to pathological disorders with relevance to human and wildlife health;
Address uncertainties associated with current radiation risk estimates at low doses and dose-rates;
Prioritise research endeavours that are of particular significance in the context of radiation protection initiatives;
Facilitate co-ordination and co-operation in research undertakings;
Identify new and sensitive biomarkers and test assays to efficiently characterise effects along relevant toxicity pathways;
Identify commonalities and differences between how fundamentally different stressors affect organisms to inform multiple stressor assessments.

RAD/CHEM AOP Joint Topical Group

radchemaop Source: Health Canada

In June 2021, the NEA Committee on Radiological Protection and Public Health (CRPPH) established the High-Level Group on Low Dose Research (HLG-LDR) Rad/Chem AOP Joint Topical Group (JTG) to investigate that adaptation of AOPs into radiation research, reducing uncertainties in low dose health risks. The JTG aims to champion the use of AOPs in radiation hazard and risk assessment, promoting adoption in research and regulations.

The Rad/Chem AOP collaborative group is striving to produce significant outcomes in three main areas: 1) advocating for AOPs; 2) engaging radiation societies and journals; and 3) undertaking AOP development projects. This involves:

Enhancing comprehension of adverse effects and health outcomes in both human and non-human species;
Demonstrating the benefits of collaborative, comprehensive studies derived from constructing AOPs;
Contributing to and advancing the objectives of the OECD AOP Development Programme in relation to non-chemical stressors.

Work plan 2021-2025

Task	Description
Horizon style exercise	Development of a survey that can be distributed to the radiation community to help identify the priority areas that will guide AOP development, identify the Subject Matter Experts, resources, areas for collaborative AOP development.
Strategy for AOP workshops	Development of a strategy and organisation of meetings and workshops to support addressing specific AOP challenges.
Communication and engagement strategy	Development of an actionable work plan for engaging journals and societies in promoting and reviewing AOPs. Creating a web presence, infographics and podcasts.
Building case examples of radiation relevant AOPs	Case examples of AOP development that cover regulatory questions of interest, how to best capture the data using systematic review and data aggregation tools and other specific considerations relevant to radiation AOP development.
Case examples of radiation OMICS-informed AOPs	Development of a strategy to apply omics data to an AOP relevant to the field of ionising radiation. What tools and methods are needed; consideration and drawbacks.
Review of AOPs applied to radioecological challenges	Providing a review of current knowledge of ionising radiation effects, availability of AOPs and challenges associated with application to radioecology.

Publications

Vinita C. et al. (2022), "Introduction to the special issue on adverse outcome pathways in radiation protection", International Journal of Radiation Biology (Volume 98, Issue 12), DOI: 10.1080/09553002.2022.2123183. This special issue entitled AOPs in Radiation Protection is driven by the increasing global interest in integrating information from radiation biology and epidemiology to enhance the understanding of low-dose radiation health risk assessment. It provides a comprehensive overview of Adverse Outcome Pathways (AOPs), including their origin, the goals of a newly formed topical group, current case examples, and how the radiation field can utilise AOPs to organise knowledge on the biological effects of radiation exposure.

Robert S. et al. (2021), "Challenges in the quantification approach to a radiation relevant adverse outcome pathway for lung cancer", International Journal of Radiation Biology, 97:1, 85-101, DOI: 10.1080/09553002.2020.1820096

Yang C. et al. (2023), "Comparison of a piecewise structural equation modeling and Bayesian network for de novo construction of a quantitative adverse outcome pathway network", ALTEX - Alternatives to animal experimentation, 40(2), pp. 287–298. DOI: 10.14573/altex.2207113 .This research explores quantifying data within AOPs, it evaluates the benefits and obstacles of quantification, gathering evidence from diverse studies to measure key event links.

Vinita C. et al. (2021), "Expert consultation is vital for adverse outcome pathway development", International Journal of Radiation Biology (Volume 97, Issue 11), DOI: 10.1080/09553002.2021.1969466. Experts employ the adverse outcome pathway (AOP) approach to understand how radiation exposure relates to cardiovascular diseases, organising information from molecular changes to adverse outcomes through scientific criteria. The paper stresses the significance of collective expertise in shaping these pathways.

NEA endorsed AOPs

Sherman, S. et al. (2023), "Adverse Outcome Pathway on deposition of energy leading to lung cancer", OECD Series on Adverse Outcome Pathways, No. 32, OECD Publishing, Paris, https://doi.org/10.1787/a8f262c2-en.

The Adverse Outcome Pathway for lung cancer describes how the Deposition of Energy (DoE), induced by stressors like radon gas, initiates a chain of events leading to DNA double strand breaks. These breaks, when inaccurately repaired, can cause mutations in crucial genes and chromosomal abnormalities. This disruption can promote unregulated cell proliferation, resulting in hyperplasia in lung epithelial cells and eventually leading to lung cancer. While there is strong evidence supporting this AOP, uncertainties remain, especially concerning the dose-effect relationships of low doses and dose-rates of DoE exposure.

Carrothers, E. et al. (2025), “Adverse Outcome Pathway on Deposition of Energy Leading to Cataracts”, OECD Series on Adverse Outcome Pathways, No. 40, OECD Publishing, Paris, https://doi.org/10.1787/5ad6b263-en.

This AOP describes the development of cataracts following ionizing radiation exposure, beginning with the deposition of energy into cells of the eye. This event generates an excess of reactive oxygen species, leading to oxidative stress when the balance between oxidants and antioxidants is disrupted. Oxidative stress can damage critical macromolecules, particularly proteins such as crystallins in the lens, which may become structurally altered and aggregate. If these damaged proteins are not removed, they accumulate and cause lens opacity. Simultaneously, radiation-induced oxidative stress can damage DNA, leading to strand breaks and, if not adequately repaired, an increase in mutations and chromosomal abnormalities. When such genetic damage affects genes controlling cell proliferation, it can promote uncontrolled division of lens epithelial cells, further contributing to cataract formation. This AOP is supported by high biological plausibility and moderate evidence for the essentiality of key events. However, there is limited quantitative understanding of dose-response relationships. Despite these limitations, this AOP provides valuable insight for evaluating ocular risks of radiation exposure and guiding radiological protection efforts.

Kozbenko, T. et al. (2025), “Adverse Outcome Pathway on Deposition of Energy Leading to Abnormal Vascular Remodeling”, OECD Series on Adverse Outcome Pathways, No. 39, OECD Publishing, Paris, https://doi.org/10.1787/279aa3af-en.

This AOP outlines the progression from deposition of energy by radiation exposure to abnormal vascular remodeling, a precursor to cardiovascular disease. The initiating event is the deposition of energy in vascular tissues during ionizing radiation exposure, leading to the radiolysis of water and an overproduction of reactive oxygen species. These reactive molecules overwhelm antioxidant defenses, resulting in oxidative stress and damage to DNA and other cellular components. This cellular stress activates a cascade of altered signaling pathways, including increased production of pro-inflammatory mediators. In the vascular endothelium, these disruptions can impair the regulation of nitric oxide, a key molecule for maintaining vascular tone and integrity. Altered nitric oxide levels contribute to endothelial dysfunction, compromising the ability of blood vessels to respond to physiological stimuli. Persistent dysfunction leads to abnormal vascular remodeling characterized by structural changes such as vessel wall thickening, increased stiffness, and reduced capillary density. This AOP has strong biological plausibility, supported by evidence from animal studies, clinical radiotherapy data, and epidemiological cohorts. However, knowledge gaps remain regarding effects at low doses, chronic exposures, and sex-specific responses. This framework is essential for developing radiation protection strategies, especially in medical and spaceflight contexts.

Sandhu, S. et al. (2025), “Adverse Outcome Pathway on Deposition of Energy Leading to Occurrence of Bone Loss”, OECD Series on Adverse Outcome Pathways, No. 41, OECD Publishing, Paris, https://doi.org/10.1787/4f3e617e-en.

The above AOP describes the linkage between bone loss and the deposition of energy by radiation, a prototypic stressor relevant to spaceflight and radiotherapy. The initial ionization events cause oxidative stress, defined as an imbalance between oxidants and antioxidants, leading to oxidation of signaling proteins involved in bone-regulating pathways such as Wnt/β-catenin and RANK-L. Oxidative damage also induces cell death, including apoptosis and autophagy in osteocytes and osteoblasts, reducing bone-forming capacity. Additionally, this cell death triggers the release of signals that promote osteoclast activation, disrupting bone cell homeostasis. The result is a shift in bone remodeling dynamics, where bone resorption exceeds formation. These changes lead to decreased bone density and quality, culminating in bone loss. Although the biological plausibility of this AOP is well supported and essentiality of most key events is high to moderate, the overall weight of evidence is considered moderate. Quantitative understanding of dose-response relationships remains limited. Modulating factors such as age and genetic background add further complexity. This AOP provides a valuable framework for assessing skeletal risks associated with radiation exposure and informing protective strategies in clinical and spaceflight settings.

Sleiman, A. et al. (2025), “Adverse Outcome Pathway on Deposition of Energy Leading to Learning and Memory Impairment”, OECD Series on Adverse Outcome Pathways, No. 42, OECD Publishing, Paris, https://doi.org/10.1787/16c49ced-en.

This AOP describes the linkage between cognitive decline, including learning and memory impairment, initiated by the Deposition of Energy (DoE) from ionizing radiation in the central nervous system. Ionizing radiation causes an excess of reactive oxygen species (ROS), leading to oxidative stress and increased DNA strand breaks. This damage activates tissue-resident microglia and astrocytes, which release proinflammatory mediators and alter stress response signaling. Chronic neuroinflammation impairs normal synaptic function and leads to abnormal neural remodeling. These events disrupt communication between neurons, ultimately resulting in measurable deficits in cognitive function. While the biological plausibility of this AOP is strong, particularly due to its relevance to space travel and radiotherapy, the overall weight of evidence remains moderate. Quantitative understanding of dose-response relationships between key events is limited, especially in low-dose exposure scenarios, introducing uncertainty in predictions. Nevertheless, this AOP is broadly applicable to both environmental and clinical radiation exposures.

Educational videos

OECD AOP training videos

AFSA Collaboration training resources

The online learning series discusses development of the AOP framework, the utilisation of AOP Knowledge Base tools and the AOP Wiki, as well as the process of reviewing and evaluating AOPs. The e-course comprises two modules: the first module covers the overall history of AOPs with an introduction to associated tools, while the second module delves into the detailed exploration of the AOP Knowledge Base and AOP Wiki.