Schöllnberger H, Stewart R D, Mitchel R E J, Hofmann W
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Nonlinearity Biol Toxicol Med. 2004 Oct;2(4):317-52. doi: 10.1080/15401420490900263.
A multistage cancer model that describes the putative rate-limiting steps in carcinogenesis is developed and used to investigate the potential impact on cumulative lung cancer incidence of the hormesis mechanisms suggested by Feinendegen and Pollycove. In the model, radiation and endogenous processes damage the DNA of target cells in the lung. Some fraction of the misrepaired or unrepaired DNA damage induces genomic instability and, ultimately, leads to the accumulation of malignant cells. The model explicitly accounts for cell birth and death processes, the clonal expansion of initiated cells, malignant conversion, and a lag period for tumor formation. Radioprotective mechanisms are incorporated into the model by postulating dose and dose-rate-dependent radical scavenging. The accuracy of DNA damage repair also depends on dose and dose rate. As currently formulated, the model is most applicable to low-linear-energy-transfer (LET) radiation delivered at low dose rates. Sensitivity studies are conducted to identify critical model inputs and to help define the shapes of the cumulative lung cancer incidence curves that may arise when dose and dose-rate-dependent cellular defense mechanisms are incorporated into a multistage cancer model. For lung cancer, both linear no-threshold (LNT-), and non-LNT-shaped responses can be obtained. If experiments demonstrate that the effects of DNA damage repair and radical scavenging are enhanced at least three-fold under low-dose conditions, our studies would support the existence of U-shaped responses. The overall fidelity of the DNA damage repair process may have a large impact on the cumulative incidence of lung cancer. The reported studies also highlight the need to know whether or not (or to what extent) multiply damaged DNA sites are formed by endogenous processes. Model inputs that give rise to U-shaped responses are consistent with an effective cumulative lung cancer incidence threshold that may be as high as 300 mGy (4 mGy per year for 75 years) for low-LET radiation.
开发了一种多阶段癌症模型，该模型描述了致癌过程中假定的限速步骤，并用于研究Feinendegen和Pollycove提出的兴奋效应机制对累积肺癌发病率的潜在影响。在该模型中，辐射和内源性过程会损伤肺部靶细胞的DNA。部分错配修复或未修复的DNA损伤会导致基因组不稳定，并最终导致恶性细胞的积累。该模型明确考虑了细胞的生死过程、起始细胞的克隆扩增、恶性转化以及肿瘤形成的延迟期。通过假定剂量和剂量率依赖性自由基清除，将辐射防护机制纳入模型。DNA损伤修复的准确性也取决于剂量和剂量率。按照目前的形式，该模型最适用于低剂量率下传递的低线性能量传递（LET）辐射。进行敏感性研究以确定关键的模型输入，并帮助定义当剂量和剂量率依赖性细胞防御机制纳入多阶段癌症模型时可能出现的累积肺癌发病率曲线的形状。对于肺癌，可以获得线性无阈（LNT）和非LNT形状的反应。如果实验表明在低剂量条件下DNA损伤修复和自由基清除的效果至少增强了三倍，我们的研究将支持U形反应的存在。DNA损伤修复过程的整体保真度可能对肺癌的累积发病率有很大影响。所报道的研究还强调需要了解内源性过程是否（或在何种程度上）形成多重受损的DNA位点。产生U形反应的模型输入与低LET辐射的有效累积肺癌发病率阈值一致，该阈值可能高达300 mGy（75年中每年4 mGy）。
