Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.

中文翻译：

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电离辐射和乳腺癌的不良结局途径涉及直接和间接的DNA损伤，氧化应激，炎症，基因组不稳定以及与乳腺癌荷尔蒙调节的相互作用。

通过确定关键的机械事件，有关确定的乳腺癌致癌物的知识可以支持改进的现代化毒理学检测方法。电离辐射（IR）会增加患乳腺癌的风险，尤其是对于女性以及更年轻的女性而言，并且证据总体上支持线性的剂量反应关系。我们使用不良结果途径（AOP）框架来概述和评估将电离辐射与乳腺癌的分子引发事件与通过中间关键事件引起的不良后果联系起来的证据，从而形成定性的AOP。我们根据评论文章确定了关键事件，在PubMed上搜索了有关关键事件和IR的最新文献，并使用了参考文献确定了其他论文。我们手动策划出版物并评估数据质量。直接和间接电离辐射会导致DNA损伤，并增加活性氧和氮物质（RONS）的产生。RONS导致DNA损伤和表观遗传变化，导致突变和基因组不稳定性（GI）。增殖会放大DNA损伤和导致乳腺癌AO的突变的作用。另外，RONS和DNA损伤也会加剧炎症。炎症通过对RONS和DNA损伤的积极反馈而导致直接和间接作用（IR无法直接到达细胞的作用），并通过对细胞和组织的致癌作用而分别增加增殖和乳腺癌。例如，基因表达的变化改变了炎症介质，从而导致癌细胞的存活和生长提高，以及更友好的组织环境。所有这些事件都在多个点上重叠，并具有“背景”诱发乳癌发生的特征性事件，包括激素反应性增殖，氧化活性和DNA损伤。这些重叠使乳房特别容易受到电离辐射的影响，并增强了这些生物活性是致癌物的重要特征。增加这些生物学过程的因素应被认为是潜在的乳腺癌致癌物，并且需要预测方法来识别增加这些过程的化学物质。现有技术可以测量RONS，DNA损伤和突变，细胞增殖以及某些炎症蛋白或过程。需要改进的测定方法来测量胃肠道和慢性炎症，以及与激素驱动的发育和增殖的相互作用。有几种方法可测量各种表观遗传学变化，但尚不清楚哪些变化与乳腺癌有关。另外，大多数的毒理学分析不是在乳腺组织中进行的，因此，评估其他组织的结果是否可推广到乳腺或在乳腺组织中进行分析是当务之急。开发和应用这些测定法以识别关注的暴露将有助于降低后续乳腺癌风险的努力。