Radiation Protection Bureau, Health Canada, Ottawa, Canada.
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
Int J Radiat Biol. 2021;97(1):85-101. doi: 10.1080/09553002.2020.1820096. Epub 2020 Sep 30.
Adverse outcome pathways (AOPs) provide a modular framework for describing sequences of biological key events (KEs) and key event relationships (KERs) across levels of biological organization. Empirical evidence across KERs can support construction of quantified AOPs (qAOPs). Using an example AOP of energy deposition from ionizing radiation onto DNA leading to lung cancer incidence, we investigate the feasibility of quantifying data from KERs supported by all types of stressors. The merits and challenges of this process in the context of AOP construction are discussed.
Empirical evidence across studies of dose-response from four KERs of the AOP were compiled independently for quantification. Three upstream KERs comprised of evidence from various radiation types in line with AOP guidelines. For these three KERs, a focused analysis of data from alpha-particle studies was undertaken to better characterize the process to the adverse outcome (AO) for a radon gas stressor. Numerical information was extracted from tables and graphs to plot and tabulate the response of KEs. To complement areas of the AOP quantification process, Monte Carlo (MC) simulations in TOPAS-nBio were performed to model exposure conditions relevant to the AO for an example bronchial compartment of the lung with secretory cell nuclei targets.
Quantification of AOP KERs highlighted the relevance of radiation types under the stressor-agnostic intent of AOP design, motivating a focus on specific types. For a given type, significant differences of KE response indicate meaningful data to derive linkages from the MIE to the AO is lacking and that better response-response focused studies are required. The MC study estimates the linear energy transfer (LET) of alpha-particles emitted by radon-222 and its progeny in the secretory cell nuclei of the example lung compartment to range from to keV/µm.
Quantifying AOP components provides a means to assemble empirical evidence across different studies. This highlights challenges in the context of studies examining similar endpoints using different radiation types. Data linking KERs to a MIE of 'deposition of energy' is shown to be non-compatible with the stressor-agnostic principles of AOP design. Limiting data to that describing response-response relationships between adjacent KERs may better delineate studies relevant to the damage that drives a pathway to the next KE and still support an 'all hazards' approach. Such data remains limited and future investigations in the radiation field may consider this approach when designing experiments and reporting their results and outcomes.
有害效应途径（AOP）为描述跨生物组织层次的生物关键事件（KE）和关键事件关系（KER）序列提供了一个模块化框架。KER 中的经验证据可以支持定量 AOP（qAOP）的构建。本文以电离辐射在 DNA 上沉积导致肺癌发生的 AOP 为例，研究了定量描述各种应激源支持的 KER 数据的可行性。讨论了在 AOP 构建背景下该过程的优点和挑战。
为了进行定量，独立地对 AOP 的四个 KER 中来自各种研究的剂量-反应的经验证据进行了汇编。三个上游 KER 由与 AOP 指南一致的各种辐射类型的证据组成。对于这三个 KER，对来自α粒子研究的数据进行了重点分析，以便更好地描述对氡气应激源的不良结局（AO）的过程。从表格和图表中提取数值信息，以绘制和列出 KE 的反应。为了补充 AOP 量化过程的各个方面，在 TOPAS-nBio 中进行了蒙特卡罗（MC）模拟，以模拟与肺部支气管腔室分泌细胞核靶标相关的 AO 的暴露条件。
KER 的 AOP 量化突出了在 AOP 设计的无应激源意图下辐射类型的相关性，这促使我们关注特定类型。对于给定类型，KE 反应的显著差异表明，缺乏从 MIE 到 AO 的链接所需的有意义数据，需要进行更好的基于反应的研究。MC 研究估计了氡-222 及其子体在肺部支气管腔室分泌细胞核中发射的α粒子的线性能量转移（LET）范围为 至 keV/µm。
对 AOP 成分进行量化为跨不同研究整合经验证据提供了一种手段。这突出了使用不同辐射类型研究类似终点时面临的挑战。将 KER 与“能量沉积”的 MIE 相关联的数据与 AOP 设计的无应激源原则不兼容。将数据限制在描述相邻 KER 之间的反应-反应关系上，可以更好地划定与驱动途径进入下一个 KE 的损伤相关的研究范围，同时仍然支持“全危害”方法。这种数据仍然有限，辐射领域的未来研究在设计实验和报告结果和结果时可能会考虑这种方法。
