METALWORKING FLUIDS AND AERODIGESTIVE CANCER RISK

当这些复杂的化学混合物在金属加工时被喷洒到金属上时，数百万工人经常接触到金属加工液(MWF)。越来越多的证据表明，至少某些类型的MWF具有致癌作用。特别是，迄今对接触工人进行的最大规模的研究(对4.6万名联合汽车工人/通用汽车员工的研究)发现，喉癌和食道癌的风险显著增加。这项拟议工作的目标是通过使用UAW/GM数据集进行一系列统计研究，大幅扩大将MWF与上呼吸道癌症联系起来的流行病学证据。这些分析旨在澄清几个重要的悬而未决的问题，这些问题目前限制了对这些广泛存在的工业化学品的风险的结论。该项目将：1.评估上呼吸道暴露于MWF的癌症风险，而不是通过传统的器官名称(例如喉部和食道)，而是通过与暴露途径和可能的外源性化学物质的目标组织更接近的分组来评估：外咽部和下咽部(吸入和摄取)；内喉部(吸入暴露)；以及不包括食管胃结合部腺癌(主要是摄入)的食道；2.使用间接调整的方法评估该队列中烟草和酒精混合的潜在混杂程度(缺乏关于这些危险因素的个人数据)；3.将Moolgavkar-Knudson两阶段癌症模型应用于MWF的定量暴露数据，提供了一种基于生物学的方法来研究不同类型和成分的MWF对上呼吸道癌症风险的时间(早期和晚期)贡献。除了解决金属加工液与癌症的具体问题外，该项目还将通过展示将更复杂的、基于生物学的建模方法纳入广泛使用的回溯性队列研究的可行性，对环境癌症流行病学做出更广泛的贡献。

Millions of workers are routinely exposed to metal- working fluids (MWF) when these complex chemical mixtures are sprayed on metal as it is machined. Growing evidence suggests that there are carcinogenic effects of at least some types of MWF. In particular, the largest study of exposed workers yet conducted (a study of 46,000 United Automobile Workers/General Motors employees) has found strongly increased risks of laryngeal and esophageal carcinomas. The goal of the proposed work is to substantially expand the epidemiologic evidence linking MWF to cancers of the upper aerodigestive tract by a series of statistical studies using the UAW/GM data set. These analyses are designed to clarify several important outstanding issues which currently limit conclusions on the risk from these widespread industrial chemicals. This project will: 1. Estimate cancer risks from exposure to MWF for the upper aerodigestive tract, not by traditional organ designations (larynx and esophagus, for example), but by groupings which correspond more closely to routes of exposure and likely target tissues for exogenous chemicals: epilarynx and hypopharynx (both inhalation and ingestion); endolarynx (exposure by inhalation); and esophagus excluding adenocarcinoma of the esophagogastric junction (primarily ingestion); 2. Evaluate the magnitude of potential confounding by tobacco and alcohol in this cohort (which lacks individual data on these risk factors) by using the method of indirect adjustment; and 3. Apply the Moolgavkar-Knudson two-stage cancer model to the quantitative MWF exposure data to provide a biologically-based method to investigate the temporal (early versus late stage) contribution of different types and components of MWF to cancer risks in the upper aerodigestive tract. In addition to addressing the specific issue of metalworking fluids and cancer, this project will also contribute more generally to environmental cancer epidemiology by demonstrating the feasibility of incorporating more sophisticated, biologically-based, modeling methods into the widely used retrospective cohort study.