Long-term Effects of Occupational Radiation Exposures

描述（由申请人提供）：对美国核武器工作人员进行的流行病学研究允许对多年或数十年就业积累的低剂量、低剂量率辐射照射的影响进行评估。在这项拟议的研究中，我们将在橡树岭国家实验室（ORNL）检查一组受徽章监控的工人。对这一流行病学重要队列的最后一次死亡率随访是在18年前进行的，并考虑了1943年至1972年期间雇用的工人。对这些数据的分析表明，职业辐射剂量与所有癌症死亡率之间存在显著关联。我们建议将这一队列扩大到包括1943年至1984年雇用的工人，并更新死亡率随访至2007年;根据生命表预测，我们预计死亡人数是ORNL队列最后一次死亡率随访中观察到的死亡人数的2.4倍。延长该队列的随访时间不仅对统计功效很重要，而且因为放射研究中的许多重要问题涉及放射的长期影响，特别是对进展缓慢的恶性疾病，如非霍奇金淋巴瘤和慢性淋巴细胞白血病。拟议的分析将从评价作为辐射效应时间修正因素的自照射以来的时间开始。除了使用暴露滞后和时间窗分析的方法外，我们还将应用创新方法进行分布滞后模型的核估计。先前对ORNL和其他队列的研究表明，暴露年龄是辐射-癌症关联的另一个重要修正因素。延长对这一群体的随访，并扩大名册，以包括更多的新雇员，将使我们能够更好地评估暴露年龄作为辐射影响的时间修正因素。除了暴露年龄效应的经验模型外，我们还将根据这些数据拟合基于生物学的多阶段癌症模型。非放射性物剂也可改变电离辐射的影响。我们提出了两种方法来评估非放射性效应修饰因子：一种是考虑整个队列;另一种是应用巢式病例对照方法来评估辐射剂量-肺癌死亡率关联的修饰因子。在整个队列中，重点关注石棉，苯和铍暴露，我们将制定这些危害的工作暴露矩阵，并根据ORNL现有的石棉和铍工人的历史名单以及NIOSH最近评估ORNL工人中苯的工作。我们将采用创新的方法来研究这些非放射性暴露的时间顺序是否会影响其联合效应。在肺癌死亡率的巢式病例对照研究中，我们将利用病历来评估吸烟的改变或混杂，以及详细的工业卫生方法来评估石棉和铍暴露的可能性。将根据其他DOE机构研究的观察结果对该USDOE队列的研究结果进行评价;并且，将以便于未来汇总分析的方式汇编研究数据。这样，拟议的工作将大大加强关于美国能源部队列中低水平辐射影响的现有流行病学信息。 公共卫生相关性：拟议的研究直接评估了低剂量、低剂量率职业辐射照射的长期影响，这是一个长期辩论的主题，具有明确的政策含义。这项工作是创新的，在其关于没有辐射对淋巴癌的影响的既定范例的质疑。我们提出了新的模型与时间相关的暴露影响，以考虑问题的潜伏期和暴露时的年龄，应用生物为基础的致癌模型，并调查非放射性暴露的工作，这将提高我们的理解暴露于多种化学和物理剂的后果在DOE复杂。

DESCRIPTION (provided by applicant): Epidemiological studies of US nuclear weapons workers allow evaluation of the effects of low dose, low dose rate radiation exposures accrued over years or decades of employment. In the proposed study, we will examine a cohort of badge-monitored workers at the Oak Ridge National Laboratory (ORNL). The last mortality follow-up of this epidemiologically important cohort was conducted 18 years ago and considered workers hired between 1943 and 1972. Analyses of these data revealed a significant association between occupational radiation dose and all cancer mortality. We propose to expand this cohort to include workers hired between 1943 and 1984 and update mortality follow-up through 2007; based on life table projections, we expect 2.4 times the number deaths observed in the last mortality follow-up of the ORNL cohort. Extending follow-up of this cohort is important not just for statistical power, but also because many important questions in radiation research concern the long term effects of irradiation, particularly on slow-progressing malignant diseases, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia. The proposed analyses will commence with evaluation of time-since- exposure as a temporal modifier of radiation effects. In addition to using methods of exposure lagging and time-window analysis, we will apply innovative methods for kernel estimation of distributed lag models. Prior research on ORNL and other cohorts suggests that age-at-exposure is another important modifier of radiation- cancer associations. Extending follow-up of this cohort, and expanding the roster to include more recent hires, will allow us to better assess age-at-exposure as a temporal modifier of radiation effects. In addition to empirical models of age-at-exposure effects we will fit biologically-based multistage cancer models to these data. Non-radiological agents may also modify the effects of ionizing radiation. We propose two approaches to assessing non-radiological effect modifiers: one considering the full cohort; the other applying a nested case- control approach to assess modifiers of radiation dose- lung cancer mortality associations. In the full cohort, focusing on asbestos, benzene, and beryllium exposures, we will develop job-exposure-matrices for these hazards, informed by historical lists of asbestos and beryllium workers available at ORNL and recent work by NIOSH to assess benzene among ORNL workers. We will apply innovative methods to examine whether the temporal ordering of these non-radiological exposures impacts their joint effects. In the nested case-control study of lung cancer mortality, we will utilize medical records to assess modification or confounding by cigarette smoking as well as detailed industrial hygiene methods to assess asbestos and beryllium exposure potential. Study results for this USDOE cohort will be evaluated in relation to observations from studies of other DOE facilities; and, study data will be compiled in a manner that will facilitate future pooled analyses. In this way, the proposed work will substantially strengthen the available epidemiological information about low level radiation effects in USDOE cohorts. Public Health Relevance: The proposed study directly evaluates the long term effects of effects of low dose, low dose rate occupational radiation exposures, the subject of long debate and clear policy implications. This work is innovative in its questioning of an established paradigm regarding the absence of radiation effects on lymphatic cancers. We propose to novel models of time-related exposure effects to consider issues of latency and age at exposure, apply biologically-based carcinogenesis models, and investigate non-radiological exposures in work that will improve our understanding of the consequences of exposure to multiple chemical and physical agents in the DOE complex.