Aßenmacher Matthias, Kaiser Jan Christian, Zaballa Ignacio, Gasparrini Antonio, Küchenhoff Helmut
Department of Statistics, Ludwig-Maximilians-Universität, 80539, Munich, Germany.
Institute of Radiation Medicine, Helmholtz Zentrum München, 85764, Oberschleißheim, Germany.
Radiat Environ Biophys. 2019 Aug;58(3):321-336. doi: 10.1007/s00411-019-00800-6. Epub 2019 Jun 19.
Exposure-lag-response associations shed light on the duration of pathogenesis for radiation-induced diseases. To investigate such relations for lung cancer mortality in the German uranium miners of the Wismut company, we apply distributed lag non-linear models (DLNMs) which offer a flexible description of the lagged risk response to protracted radon exposure. Exposure-lag functions are implemented with B-Splines in Cox models of proportional hazards. The DLNM approach yielded good agreement of exposure-lag-response surfaces for the German cohort and for the previously studied cohort of American Colorado miners. For both cohorts, a minimum lag of about 2 year for the onset of risk after first exposure explained the data well, but possibly with large uncertainty. Risk estimates from DLNMs were directly compared with estimates from both standard radio-epidemiological models and biologically based mechanistic models. For age > 45 year, all models predict decreasing estimates of the Excess Relative Risk (ERR). However, at younger age, marked differences appear as DLNMs exhibit ERR peaks, which are not detected by the other models. After comparing exposure-responses for biological processes in mechanistic risk models with exposure-responses for hazard ratios in DLNMs, we propose a typical period of 15 year for radon-related lung carcinogenesis. The period covers the onset of radiation-induced inflammation of lung tissue until cancer death. The DLNM framework provides a view on age-risk patterns supplemental to the standard radio-epidemiological approach and to biologically based modeling.
暴露-滞后-反应关联揭示了辐射诱发疾病发病机制的持续时间。为了研究德国维斯穆特公司铀矿矿工肺癌死亡率的此类关系，我们应用了分布滞后非线性模型（DLNMs），该模型能灵活描述对长期氡暴露的滞后风险反应。暴露-滞后函数通过比例风险的Cox模型中的B样条实现。DLNM方法在德国队列和先前研究的美国科罗拉多矿工队列的暴露-滞后-反应面上取得了良好的一致性。对于这两个队列，首次暴露后约2年的风险起始最小滞后能很好地解释数据，但可能存在较大不确定性。DLNMs的风险估计值与标准放射流行病学模型和基于生物学的机制模型的估计值直接进行了比较。对于年龄大于45岁的人群，所有模型都预测超额相对风险（ERR）估计值会下降。然而，在较年轻的年龄组，DLNMs出现ERR峰值，而其他模型未检测到，从而出现明显差异。在将机制风险模型中生物过程的暴露-反应与DLNMs中风险比的暴露-反应进行比较后，我们提出氡相关肺癌发生的典型周期为15年。该周期涵盖了肺组织辐射诱发炎症的起始直至癌症死亡。DLNM框架提供了一种补充标准放射流行病学方法和基于生物学建模的年龄-风险模式观点。
