Serum Organochlorine Levels and Primary Liver Cancer: A Nested Case-Control Study

描述(申请人提供)：尽管多氯联苯(PCbs)和某些有机氯农药会诱发动物肝脏肿瘤，但由于方法学上的挑战，支持流行病学数据有限。对于接触低水平黄曲霉毒素的风险，流行病学研究也很少。黄曲霉毒素是一种已知的致癌物质，通常在发达国家发现。我们建议使用已经收集的血清和来自两个大型、基于人群的预期队列(总受试者=451,000人)的数据来调查这些关系，他们在20世纪60年代中期至70年代中期提供了血液样本和风险因素信息。在这些队列中，一个在挪威，一个在加利福尼亚州北部，后续行动和病例确认率非常高，并且可以获得关于潜在混杂因素的数据。这项研究的目的是确定较高的血清有机氯浓度是否与肝癌风险增加有关；血清黄曲霉毒素生物标志物是否与这种风险相关；以及这些因素之间是否存在相互或与乙肝病毒或丙型肝炎病毒感染的协同作用。我们将纳入所有在抽血后一年或一年以上诊断为原发性肝癌的病例(n=278)，并按队列、抽血年龄、抽血日期、性别、种族和居住地(n=1112)随机抽取3：1与病例匹配的对照样本。我们将测量39种多氯联苯同系物、11种有机氯农药和黄曲霉毒素-白蛋白加合物的血清浓度，并使用储存的血清评估乙肝和丙型肝炎病毒的感染状况。我们还将检查第二份血清样本，从一组受试者中收集，平均在第一次样本后8年。我们将通过与以前收集的健康检查数据(在抽血时收集)以及每个队列的临床、人口普查和出生登记数据的联系来获得关于潜在混杂因素的信息。据我们所知，这项研究将是第一次检查与体内多氯联苯负担有关的肝癌风险。为了有效，这项研究需要前瞻性地收集生物标本，因为肝病可能会影响有机氯的新陈代谢和随后的消除。这项研究中的血清样本是在这些有机氯化合物在美国和挪威被禁止的时候收集的，因此，应该反映这些国家普通人口中这些化学物质的峰值或接近峰值水平。尽管许多国家禁止生产和使用这些化学品，但由于食物链中的生物积累、欠发达国家持续使用有机氯农药、设备和垃圾填埋场的泄漏以及环境的持久性和再分配，人类继续接触这些化学品。这项研究不仅为研究有机氯和低水平黄曲霉毒素暴露与肝癌风险的关系提供了一个有效的机会，而且也是以严格的方法研究它的为数不多的机会之一。

DESCRIPTION (provided by applicant): Although polychlorinated biphenyls (PCBs) and certain organochlorine pesticides induce liver tumors in animals, there is limited supporting epidemiologic data because of methodological challenges. There has also been little epidemiologic research into the risk associated with exposure to the low levels of aflatoxin, a known liver carcinogen, typically found in developed countries. We propose to investigate these relationships using already-collected serum and data from two large, population-based, prospective cohorts of men and women (total subjects =451,000) who provided blood samples and risk factor information between the mid- 1960s and mid-1970s. Follow-up and case ascertainment in these cohorts, one in Norway and one in Northern California, is very high and data on potential confounders are available. The aims of this study are to determine whether higher serum concentrations of organochlorines are related to increased risk of liver cancer; whether serum aflatoxin biomarkers are related to this risk; and if a synergy exists for these factors with each other or with HBV or HCV infection. We will include all cases of primary liver cancer diagnosed one or more years after blood draw (n=278) and a random sample of controls matched 3:1 to cases by cohort, age at blood draw, date of blood draw, sex, race, and county of residence (n =1,112 subjects total). We will measure serum concentrations of 39 PCB congeners, 11 organochlorine pesticides, and aflatoxin- albumin adducts, and assess HBV and HCV infection status using banked serum. We will also examine a second serum sample collected from a subset of subjects an average of 8 years after the primary sample. We will obtain information on potential confounders via linkage with previously collected health examination data (collected at blood draw), as well as clinical, census, and birth registry data available for each cohort. To our knowledge, this study would be the first to examine liver cancer risk in relation to body burden of PCBs. To be valid, such a study requires prospectively collected biospecimens because liver disease may affect the metabolism and subsequent elimination of organochlorines. The serum samples in this study were collected around the time that these organochlorines were banned in the U.S. and Norway and, thus, should reflect peak or near-peak levels of these chemicals in the general population of these countries. Although the production and use of these chemicals are banned in many countries, human exposure continues because of bioaccumulation in the food chain, ongoing use of organochlorine pesticides in less developed countries, leakage from equipment and landfills, and environmental persistence and redistribution. This study offers not only an efficient opportunity to examine the association of organochlorines and low-level aflatoxin exposure with risk of liver cancer, but also one of the few opportunities to study it in a methodologically rigorous way.