Misrejoining of DNA double-strand breaks (DSBs) was measured in human primary fibroblasts after exposure to X-rays and high LET particles (He, N and Fe) in the dose range 10-80 Gy. To measure joining of wrong DNA ends, the integrity of a 3.2 Mbp restriction fragment was analyzed directly after exposure and after 16 hr of repair incubation. It was found that the misrejoining frequency for X-rays was non-linearly related to dose, with less probability of misrejoining at low doses than at high doses. The dose dependence for the high LET particles, on the other hand, was closer to being linear, with misrejoining frequencies higher than for X-rays particularly at the lower doses. These experimental results were simulated with a Monte-Carlo approach that includes a cell nucleus model with all 46 chromosomes present, combined with realistic track structure simulations to calculate the geometrical positions of all DSBs induced for each dose. The model assumes that the main determinant for misrejoining probability is the distance between two simultaneously present DSBs. With a Gaussian interaction probability function with distance, it was found that both the low and high LET data could be fitted with an interaction distance (sigma of the Gaussian curve) of 0.25 {micro}m. This is half the distance previously found to best fit chromosomal aberration data in human lymphocytes using the same methods (Holley et al. Radiat. Res . 158, 568-580 (2002)). The discrepancy may indicate inadequacies in the chromosome model, for example insufficient chromosomal overlap, but may also partly be due to differences between fibroblasts and lymphocytes. Although the experimental data was obtained at high doses, the Monte Carlo calculations could be extended to lower doses. It was found that a linear component of misrejoining versus dose dominated for doses below 1 Gy for all radiations, including X-rays. The calculated relative biological efficiency (RBE) for misrejoining at this low dose region was 31 for the He-ions, 28 for the N-ions and 19 for Fe-ions.

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Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: Experimental and theoretical study for high and low LET radiation

Ultraviolet B (UVB) radiation is a natural nonchemical stressor posing potential hazards to organisms such as planktonic crustaceans. The present study was conducted to revisit the lethal effects of UVB on crustaceans, generate new experimental evidence to fill in knowledge gaps, and develop novel quantitative adverse outcome pathways (qAOPs) for UVB. A combination of laboratory and computational approaches was deployed to achieve the goals. For targeted laboratory tests, Daphnia magna was used as a prototype and exposed to a gradient of artificial UVB. Targeted bioassays were used to quantify the effects of UVB at multiple levels of biological organization. A toxicity pathway network was assembled based on the new experimental evidence and previously published data extracted using a novel computational tool, the NIVA Risk Assessment Database (NIVA RAdb). A network of AOPs was developed, and weight of evidence was assessed based on a combination of the current and existing data. In addition, quantitative key event relationships in the AOPs were developed by fitting the D. magna data to predefined models. A complete workflow for assembly and evaluation of qAOPs has been presented, which may serve as a good example for future de novo qAOP development for chemical and nonchemical stressors.

De Novo Development of a Quantitative Adverse Outcome Pathway (qAOP) Network for Ultraviolet B (UVB) Radiation Using Targeted Laboratory Tests and Automated Data Mining.

Decades of research to understand the impacts of various types of environmental occupational and medical stressors on human health have produced a vast amount of data across many scientific discipl...

Bringing together scientific disciplines for collaborative undertakings: a vision for advancing the adverse outcome pathway framework

Background The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators. To delineate connectivities of events specifically to cardiovascular disease (CVD) initiation and progression, the adverse outcome pathway (AOP) approach was used with consultation from field experts. AOPs are a means to organize information around a disease of interest to a regulatory question. An AOP begins with a molecular initiating event and ends in an adverse outcome via sequential linkages of key event relationships that are supported by evidence in the form of the modified Bradford-Hill criteria. Detailed guidelines on building AOPs are provided by the Organisation for Economic Cooperation and Development (OECD) AOP program. Here, we report on the questions and discussions needed to develop an AOP for CVD resulting from IR exposure. A recent workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations brought together experts from the OECD to present the AOP approach and tools with examples from the toxicology field. As part of this workshop, four working groups were formed to discuss the identification of adverse outcomes relevant to radiation exposures and development of potential AOPs, one of which was focused on IR-induced cardiovascular effects. Each working group comprised subject matter experts and radiation researchers interested in the specific disease area and included an AOP coach. Conclusion The CVD working group identified the critical questions of interest for AOP development, including the exposure scenario that would inform the evidence, the mechanisms of toxicity, the initiating event, intermediate key events/relationships, and the type of data currently available. This commentary describes the four-day discussion of the CVD working group, its outcomes, and demonstrates how collaboration and expert consultation is vital to informing AOP construction.

Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation.

Increasing grasp of disease processes leading to cancer and concomitantly the establishment of observational data sets for the general population prompted the development of biologically based mode

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Biologically based models of cancer risk in radiation research.

Background: Adverse outcome pathways (AOPs) describe how a measurable sequence of key events, beginning from a molecular initiator, can lead to an adverse outcome of relevance to risk assessment. A...

Samantha Sherman

Papers

A case example of a radiation-relevant adverse outcome pathway to lung cancer.