Innovations to Inform Occupational Disease Etiology Using Biomonitoring Methods

描述(申请人提供)：由于在工作场所环境中接触有害化学物质和疾病的临床表现之间可能有很长的潜伏期，职业病病因学一直难以定义。虽然我们通常监测工作场所空气中是否存在危险化学品，但我们通常一次只监测其中一种化学品，而没有评估化学混合物的协同效应。我们使用生物监测技术测量体内化学污染物存在的能力继续快速发展，往往是在我们清楚地理解结果的意义之前。我们的研究小组已经确定了一组40多种被归类为已知或疑似动物神经致癌物质的化学物质。通过将我们的清单与国家职业安全与健康研究所(NIOSH)完成的全国职业暴露调查(NOES)进行比较，我们检查了我们清单中在工作场所发现的24种化学物质的暴露情况。我们假设，通过使用自我报告的工作历史，可以创建一个算法来量化已知或可疑的动物神经致癌物质的累积职业暴露。我们进一步假设，当病例和对照进行比较时，两组的累积暴露分数之间可能存在统计学上的显着差异。此外，我们假设1，3-丁二烯和丙烯酰胺的血红蛋白加合物是暴露的有效生物标志物，可用于验证暴露评分方法。最后，我们假设，通过使用诱变剂敏感性试验，一种评估DNA损伤和修复能力的通用方法；我们将能够识别环境暴露之间的相互作用，通过相对暴露分数来衡量，以及对某些化学物质造成的损害的遗传易感性。根据这一建议的结果，可能会产生额外的假设来研究特定的行业和职业。这项研究提案将检查已经参与脑癌病例对照研究的研究参与者的工作历史。参与者在参加最初的研究时完成了一份广泛的问卷和工作经历。根据工作历史，将生成一个相对累积暴露分数，该分数将评估上述24种化学品的暴露历史。在考虑到各种效果修饰物的情况下，将比较病例和对照之间的相对暴露分数。使用这些相对得分，研究控制人群中的一个子集将被确定，以比较他们当前职业中潜在的工作场所暴露与两种常见化学物质--丙烯酰胺和1，3-丁二烯--的血红蛋白加合物，这两种化学物质作为暴露的生物标志物。实验室分析结果将与相对分数相关联，作为验证评分方法的手段。最后，将使用这些化合物的诱变剂敏感性试验来分析敏感性的生物标记物，并将结果与相对累积暴露分数相关联。

DESCRIPTION (provided by applicant): Occupational disease etiology has been difficult to define due to the potentially long latency period between exposure to the harmful chemicals in workplace environment and the clinical manifestation of disease. While we typically monitor the air in the workplace for the presence of hazardous chemicals, we usually monitor for only one of these chemicals at a time and fail to evaluate the synergistic effects of chemical mixtures. Our ability to measure the presence of chemical contaminants in the body using biomonitoring technology continues to progress at a rapid pace, often before we clearly understand the meaning of the results. Our research group has identified a group of over 40 chemicals classified as known or suspected animal neurocarcinogens. By comparing our list to the National Occupational Exposure Survey (NOES) completed by the National Institute for Occupational Safety and Health (NIOSH) we have examined exposure to 24 chemicals from our list that are found in the workplace. We hypothesize that through the use of self-reported work histories an algorithm can be created to quantify cumulative occupational exposures to known or suspected animal neurocarcinogens. We further hypothesize that when cases and controls are compared there may be a statistically significant difference between the cumulative exposure scores of the two groups. Additionally, we hypothesize that hemoglobin adducts of 1, 3-butadiene and acrylamide are valid biomarkers of exposure and can be used to validate the exposure scoring method. Finally, we hypothesize that, by employing a mutagen sensitivity assay, a versatile method for evaluating DNA damage and repair capacity; we will be able to identify an interaction between environmental exposures, as measured by the relative exposure scores, and a genetic susceptibility to the damage caused by certain chemicals. From the results of this proposal, additional hypotheses may be generated to study specific industries and occupations. This research proposal will examine the work histories of study participants who have already participated in a brain cancer case-control study. Participants completed an extensive questionnaire and work history at the time of enrollment in the original study. From the work histories, a relative cumulative exposure score will be generated which evaluates exposure history to the 24 chemicals referenced above. The relative exposure scores will be compared between cases and controls with consideration made for various effect modifiers. Using these relative scores, a sub-set of the study control population will be identified to compare potential workplace exposures in their current occupation with hemoglobin adducts to two common chemicals, acrylamide and 1, 3-butadiene, which act as biomarkers of exposure. Laboratory analysis results will be correlated with the relative scores as a means of validating the scoring method. Finally, a biomarker of susceptibility will be analyzed using a mutagen sensitivity assay for these compounds, and results will be correlated with the relative cumulative exposure scores.