Environmental Health Science Research Bureau, Health Canada, Ottawa, ON, Canada.
Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Center for Computational Toxicology and Exposure, Duluth, MN, USA.
Int J Radiat Biol. 2021;97(6):815-823. doi: 10.1080/09553002.2020.1857456. Epub 2021 Jan 20.
Disease prevention and prediction have led to the generation of phenotypically based methods for deriving the limits of safety across toxicological disciplines. In the ionizing radiation field, human data has formed the basis of the linear-no-threshold (LNT) model for risk estimates. However, uncertainties around its accuracy at low doses and low dose-rates have led to passionate debates on its effectiveness to derive radiation risk estimates under these conditions. Concerns arise from the linear extrapolation of data from high doses to low doses, below 0.1 Gy where there is considerable variability in the scientific literature. Efforts to address these controversies have led to a mountain of mechanistic data to improve the understanding of molecular and cellular effects related to phenotypic changes. These data provide fragments of information that have yet to be combined and used effectively to improve modeling, reduce uncertainties, and update radiation protection approaches. This paper suggests a better consolidation of mechanistic research may serve to guide priority research and facilitate translation to risk assessment. An effective approach that may be implemented is the organization of data using the adverse outcome pathway (AOP) framework, a programme that has been launched by the Organization for Economic Cooperation and Development in the chemical toxicology field. The AOP concept has proved beneficial to human health and ecological toxicological fields, demonstrating possibilities for better linkages of mechanistic data to phenotypic effects. A similar approach may be beneficial to the field of radiation research. However, for this to work effectively, collaborative efforts are needed among the scientific communities in the area of AOP development and documentation. Studies will need to be evaluated, re-organized and integrated into AOPs. Here, details of the AOP approach and areas it could support in the radiation field are discussed. In addition, challenges are highlighted and steps to integration are outlined. Organizing studies in this manner will facilitate a better understanding of our current knowledge in the radiation field and help identify areas where more focused work can be undertaken. This will, in turn, allow for improved linkage of mechanistic data to human relevance and better support radiation risk assessments.
疾病预防和预测导致了基于表型的方法的产生,这些方法旨在确定毒理学各学科的安全界限。在电离辐射领域,人类数据为风险估计的线性无阈(LNT)模型提供了基础。然而,由于其在低剂量和低剂量率下的准确性存在不确定性,因此围绕其在这些条件下得出辐射风险估计的有效性展开了激烈的争论。人们对从高剂量到低剂量(0.1Gy 以下)的线性外推数据的准确性表示担忧,因为在科学文献中存在相当大的变异性。为了解决这些争议,人们做出了大量的机制研究努力,以提高对与表型变化相关的分子和细胞效应的理解。这些数据提供了一些信息片段,但尚未得到有效组合和利用,以改进建模、降低不确定性和更新辐射防护方法。本文提出,更好地整合机制研究可能有助于指导优先研究并促进向风险评估的转化。一种可行的方法是使用不良结局途径(AOP)框架组织数据,该框架是经济合作与发展组织在化学毒理学领域发起的一个项目。AOP 概念已被证明对人类健康和生态毒理学领域有益,表明将机制数据与表型效应更好地联系起来具有可能性。类似的方法可能对辐射研究领域有益。然而,要使这种方法有效,需要在 AOP 开发和文件记录领域的科学界之间开展合作。需要对研究进行评估、重新组织并整合到 AOP 中。在此,讨论了 AOP 方法的细节及其在辐射领域可能提供支持的领域。此外,还强调了挑战并概述了整合步骤。以这种方式组织研究将有助于更好地了解我们在辐射领域的现有知识,并有助于确定可以更集中开展工作的领域。这反过来又将允许更好地将机制数据与人类相关性联系起来,并更好地支持辐射风险评估。