Adverse outcome pathway: a path toward better data consolidation and global co-ordination of radiation research

Chauhan, Vinita; Beaton, Danielle; Hamada, Nobuyuki; Wilkins, Ruth; Burtt, Julie; Leblanc, Julie; Cool, D.A.; Garnier‐Laplace, Jacqueline; Laurier, Dominique; Le, Yevgeniya; Yamada, Yukata; Tollefsen, Knut Erik

doi:10.1080/09553002.2021.2020363

Cited by 20 publications

(14 citation statements)

References 44 publications

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“…Inclusion of complementary data such as that generated by combined RNA sequencing and untargeted metabolomics and the associated biostatistical-bioinformatics workflow represents a set of novel NAMs to support AOP development through identifying PODs that collectively contribute to evaluate WoE, develop new AOPs, provide quantitative data for Integrated Approaches to Testing and Assessment (IATA), and identify thresholds for perturbations along the AOP continuum. Although such efforts have been actively pursued in the chemical research field, similar efforts are in their infancy within the radiation research and regulatory community . A lack of standardized and thoroughly evaluated AOPs for ionizing radiation has so far limited the use of OMICSs based POD in radiobiology, radioecology, and radiation protection.…”

Section: Resultsmentioning

confidence: 99%

“…Although the AOP framework is rapidly developing for chemical safety assessment, its application to nonchemical stressors such as radiation remains to be better developed. Establishment of the Radiation and Chemical (Rad/Chem) AOP joint topical group, a sub group of OECD’s Nuclear Energy Agency (NEA) High Level Group on Low Dose Research (HLG-LDR), is envisioned to help facilitate such AOP development in radiation research and foster broader implementation of AOPs into hazard and risk assessment . A number of ionizing radiation AOPs have subsequently been developed and submitted to the AOP repository AOPWiki ().…”

Section: Introductionmentioning

confidence: 99%

“…Establishment of the Radiation and Chemical (Rad/Chem) AOP joint topical group, a sub group of OECD's Nuclear Energy Agency (NEA) High Level Group on Low Dose Research (HLG-LDR), is envisioned to help facilitate such AOP development in radiation research and foster broader implementation of AOPs into hazard and risk assessment. 4 A number of ionizing radiation AOPs have subsequently been developed and submitted to the AOP repository AOPWiki (https://aopwiki.org/). As a type of NAM, OMICS techniques (e.g., genomics, transcriptomics, proteomics, metabolomics, etc.)…”

Section: ■ Introductionmentioning

confidence: 99%

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Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

Shang

Zheng

Brede

et al. 2023

Environ. Sci. Technol.

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While adverse biological effects of acute high-dose ionizing radiation have been extensively investigated, knowledge on chronic low-dose effects is scarce. The aims of the present study were to identify hazards of low-dose ionizing radiation to Daphnia magna using multiomics dose−response modeling and to demonstrate the use of omics data to support an adverse outcome pathway (AOP) network development for ionizing radiation. Neonatal D. magna were exposed to γ radiation for 8 days. Transcriptomic analysis was performed after 4 and 8 days of exposure, whereas metabolomics and confirmative bioassays to support the omics analyses were conducted after 8 days of exposure. Benchmark doses (BMDs, 10% benchmark response) as points of departure (PODs) were estimated for both dose-responsive genes/ metabolites and the enriched KEGG pathways. Relevant pathways derived using the BMD modeling and additional functional end points measured by the bioassays were overlaid with a previously published AOP network. The results showed that several molecular pathways were highly relevant to the known modes of action of γ radiation, including oxidative stress, DNA damage, mitochondrial dysfunction, protein degradation, and apoptosis. The functional assays showed increased oxidative stress and decreased mitochondrial membrane potential and ATP pool. Ranking of PODs at the pathway and functional levels showed that oxidative damage related functions had relatively low PODs, followed by DNA damage, energy metabolism, and apoptosis. These were supportive of causal events in the proposed AOP network. This approach yielded promising results and can potentially provide additional empirical evidence to support further AOP development for ionizing radiation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

Shang

Zheng

Brede

et al. 2023

Environ. Sci. Technol.

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“…Mechanisms behind these phenomena (e.g., cumulativeness, additivity, and synergism of damage, accelerated cellular senescence, and role of adaptive response [ 5 ]) remain unclear at this stage. Identification of such mechanistic underpinnings necessitates more investigations, which will be indispensable for considering implications for radiation oncology, radiology, and radiation protection, and for developing adverse outcome pathways and biology-based dose-response models for DCS [ 26 , 27 , 28 , 29 , 30 , 31 ]. With the endpoints determined in our studies to evaluate prelesional aortic changes, further studies are ongoing to examine dose protraction effects in the carotid artery as the other large artery implicated in DCS pathogenesis following radiation exposure [ 1 , 2 , 3 ].…”

Section: Discussionmentioning

confidence: 99%

Temporal Changes in Sparing and Enhancing Dose Protraction Effects of Ionizing Irradiation for Aortic Damage in Wild-Type Mice

Hamada

Kawano

Nomura

et al. 2022

Cancers

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In medical and occupational settings, ionizing irradiation of the circulatory system occurs at various dose rates. We previously found sparing and enhancing dose protraction effects for aortic changes in wild-type mice at 6 months after starting irradiation with 5 Gy of photons. Here, we further analyzed changes at 12 months after stating irradiation. Irrespective of irradiation regimens, irradiation little affected left ventricular function, heart weight, and kidney weight. Irradiation caused structural disorganizations and intima-media thickening in the aorta, along with concurrent elevations of markers for proinflammation, macrophage, profibrosis, and fibrosis, and reductions in markers for vascular functionality and cell adhesion in the aortic endothelium. These changes were qualitatively similar but quantitatively less at 12 months than at 6 months. The magnitude of such changes at 12 months was not smaller in 25 fractions (Frs) but was smaller in 100 Frs and chronic exposure than acute exposure. The magnitude at 6 and 12 months was greater in 25 Frs, smaller in 100 Frs, and much smaller in chronic exposure than acute exposure. These findings suggest that dose protraction changes aortic damage, in a fashion that depends on post-irradiation time and is not a simple function of dose rate.

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“…The debate should not really be centered on whether low doses of radiation are good or bad but should be concerned with how systems deal with low doses of stressors and whether improved modelling or approaches such as adverse outcome pathway (AOP) analysis can improve our ability to understand and thus predict individual responses. Moves to do this are happening now [ 33 , 34 , 35 ]. It is also worth noting here that in environmental radiation protection where survival of the individual (or prevention of every single cancer) is not the protection goal, threshold models are widely used.…”

Section: Introduction To Low Dose and Non-targeted Radiobiologymentioning

confidence: 99%

Low Dose and Non-Targeted Radiation Effects in Environmental Protection and Medicine—A New Model Focusing on Electromagnetic Signaling

Mothersill

Cocchetto

Seymour

2022

IJMS

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The role of signalling in initiating and perpetuating effects triggered by deposition of ionising radiation energy in parts of a system is very clear. Less clear are the very early steps involved in converting energy to chemical and biological effects in non-targeted parts of the system. The paper aims to present a new model, which could aid our understanding of the role of low dose effects in determining ultimate disease outcomes. We propose a key role for electromagnetic signals resulting from physico-chemical processes such as excitation decay, and acoustic waves. These lead to the initiation of damage response pathways such as elevation of reactive oxygen species and membrane associated changes in key ion channels. Critically, these signalling pathways allow coordination of responses across system levels. For example, depending on how these perturbations are transduced, adverse or beneficial outcomes may predominate. We suggest that by appreciating the importance of signalling and communication between multiple levels of organisation, a unified theory could emerge. This would allow the development of models incorporating time, space and system level to position data in appropriate areas of a multidimensional domain. We propose the use of the term “infosome” to capture the nature of radiation-induced communication systems which include physical as well as chemical signals. We have named our model “the variable response model” or “VRM” which allows for multiple outcomes following exposure to low doses or to signals from low dose irradiated cells, tissues or organisms. We suggest that the use of both dose and infosome in radiation protection might open up new conceptual avenues that could allow intrinsic uncertainty to be embraced within a holistic protection framework.

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Adverse outcome pathway: a path toward better data consolidation and global co-ordination of radiation research

Cited by 20 publications

References 44 publications

Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

Temporal Changes in Sparing and Enhancing Dose Protraction Effects of Ionizing Irradiation for Aortic Damage in Wild-Type Mice

Low Dose and Non-Targeted Radiation Effects in Environmental Protection and Medicine—A New Model Focusing on Electromagnetic Signaling

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