Perfluoroalkyl Substances (PFASs) and Liver Cancer Risk in the United States

项目摘要/摘要 在过去的几十年里，肝癌是美国增长最快的癌症之一。这个 这种长期增加的原因尚不清楚，但可能源于接触可能致癌的物质。 环境污染物。一个可能的来源是全氟和多氟烷基物质(PFAS)，一组 具有高度持久性并在人体肝组织中积累的合成化学物质。新兴、融合 来自实验室动物和职业死亡率研究的证据有力地支持了全氟辛烷磺酸在肝脏中的作用。 致癌。然而，这些研究受到样本量小、职业限制等因素的限制 暴露，并研究单一类型的全氟辛烷磺酸。因此，我们提出了第一个综合前瞻集合 非职业环境中的队列研究，以检查现实世界中人类暴露于(多种类型的)全氟辛烷磺酸 和混合物)与肝癌发病率的关系。我们的长期目标是确定新的肝脏风险因素。 癌症减轻肝癌负担。此外，非裔美国人的肝癌发病率更高， 西班牙裔与白人相比，但造成这些差异的原因尚不清楚。此外，更多的肝脏 美国的癌症病例不是由慢性乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙肝)引起的 感染，但非病毒性肝癌的危险因素仍然知之甚少。这项提议的目标是 为了全面评估接触全氟辛烷磺酸混合物与整体肝癌风险的关系， 按种族/民族和乙肝病毒/丙型肝炎病毒状况分列。为此，我们建议进行第一项全面研究，以 通过一个利用广泛资源的集合项目暴露于全氟辛烷磺酸和肝癌风险的日期 来自六个特征良好的队列研究。这一汇集项目包括种族/民族多元化的人口 长达32年的跟踪调查，以及诊断前的血浆样本和经验证的协变量数据。我们的 具体目的是确定血浆中全氟辛烷磺酸水平与肝脏发育风险之间的关系。 用测量的乙肝病毒/丙型肝炎病毒状态数据进行的这项合并嵌套病例对照研究中的癌症(目标1)； 某些全氟辛烷磺酸混合物模式协同作用增加肝癌风险的程度(目标2)。在……里面 为了探索性的目的，我们将根据主要的肝癌亚型来量化上述相关性，并进一步 评估血浆PFAS水平与肝癌患者生存期之间的关系。这 该提案在解决PFAS和肝癌这一重要但尚未得到充分研究的研究领域方面具有创新性 通过将PFAS分析的尖端技术和先进的混合物分析方法整合到 纵向队列研究。这一贡献意义重大，因为这项研究将产生对 肝癌的病因学，使设计新的预防/干预策略和行动能够减少 肝癌发病率和死亡率及相关差异。这些发现还将提供有关 全氟辛烷磺酸对从业者和监管机构的健康影响，以做出可靠的决策、法规和 改善公共卫生的行动计划。

Project Summary/Abstract Liver cancer is one of the most rapidly increasing cancers over the past decades in the United States. The causes for this long-term increase are unclear, but could stem from exposures to possibly carcinogenic environmental contaminants. One likely source is per- and polyfluoroalkyl substances (PFAS), a group of synthetic chemicals that are highly persistent and accumulate in human liver tissue. Emerging, converging evidence from laboratory animals and occupational mortality studies strongly support the role of PFAS in liver carcinogenesis. However, these studies are limited by small sample sizes, restriction to occupational exposure, and studying single types of PFAS. Hence, we propose the first comprehensive prospective pooled cohort study in non-occupational settings to examine real-world human exposure to PFAS (of multiple types and mixtures) in relation to liver cancer incidence. Our long-term goal is to identify novel risk factors for liver cancer to reduce liver cancer burden. Moreover, liver cancer incidence is higher in African Americans and Hispanics compared with whites, but the causes of these disparities remain unclear. Furthermore, more liver cancer cases in the United States are not caused by chronic hepatitis B virus (HBV) and C virus (HCV) infections, but risk factors for non-viral liver cancer remain poorly understood. The objective of this proposal is to comprehensively assess the relationship between mixture exposure to PFAS and liver cancer risk overall, by racial/ethnic groups, and by HBV/HCV status. To do so, we propose this first comprehensive study to date of exposures to PFAS and liver cancer risk through a pooling project that leverages extensive resources from six well-characterized cohort studies. This pooling project includes a racially/ethnically diverse population followed for up to 32 years, along with pre-diagnosis plasma samples and validated covariate data. Our specific aims are to characterize the associations between plasma levels of PFAS and risk of developing liver cancer in this pooled nested case-control study with measured HBV/HCV status data (Aim 1); and assess the extent to which certain PFAS mixture patterns act synergistically to increase liver cancer risk (Aim 2). In exploratory aims, we will quantify the aforementioned associations by major liver cancer subtypes, and further estimate the associations between plasma PFAS levels and survival among patients with liver cancer. This proposal is innovative in addressing an important, yet understudied research area of PFAS and liver cancer through integrating cutting-edge technologies of PFAS assays and advanced methods of mixture analyses into longitudinal cohort studies. The contribution is significant because this research will generate new insights into the etiology of liver cancer, enable design of new prevention/intervention strategies and actions that reduce liver cancer morbidity and mortality and related disparities. These findings will also provide new information on health effects of PFAS for practitioners and regulatory agencies to make solid decisions, regulations, and action plans to improve public health.