Biomarkers of Formaldehyde Exposure and Toxicity

描述（由申请人提供）：甲醛是一种重要的工业化学品，全世界有数百万工人接触到甲醛。由于新的移动房屋中的废气和燃烧，环境暴露也可能是重要的。国际癌症研究机构（IARC）最近将甲醛列为一种导致鼻咽癌的人类致癌物，并得出结论，“有强有力但不充分的证据表明白血病与职业接触甲醛之间存在因果关系”。虽然一些流行病学研究和我们的新荟萃分析支持甲醛与白血病的关联，但一些研究人员认为，吸入甲醛不能到达骨髓，对造血系统无毒，因此不会导致白血病。为了提高我们对甲醛诱导白血病发生的生物学合理性的理解，我们提出了一些工作假设，我们将在中国甲醛暴露工人的两项生物标志物群体研究（甲醛生物标志物1和2:FAB1和FAB2）中提出的五个具体目标中进行测试。我们计划开发甲醛暴露和FAB1早期生物学效应的有效生物标志物；确定甲醛毒性能否在体外重现；并在1000名工人的大型生物标志物研究中确认其血液毒性和遗传毒性，并检查剂量-反应关系（FAB2）。为了实现这些目标，我们将首先采用在著名的白血病原苯的研究中开发和验证的OctoChrome FISH技术，首次确定人类甲醛暴露与外周血淋巴细胞（Aim 1）和循环髓祖细胞（Aim 2）中白血病特异性染色体畸变之间是否存在直接联系。然后，我们将测量dna -蛋白质交联作为甲醛暴露个体内剂量和基因毒性损伤的生物标志物，并将这些发现与染色体改变联系起来（目的3）。将进行体外人类细胞培养研究，试图验证我们在人群研究中的发现，以确定在暴露工人中观察到的染色体变化和DNA损伤是否可归因于甲醛（目标4）。我们将与美国NCI、中国GDPCC和乌得勒支大学的研究人员合作，开展一项更大规模的生物标志物群体研究（FAB2），研究范围广泛，以确认甲醛的血液毒性和遗传毒性，并检查剂量-反应关系（目标5）。具体而言，在FAB2研究中，我们将确定中国500名暴露于甲醛的工人和500名未暴露于甲醛的频率匹配对照者的全血细胞计数；同时，我们将培养100名高度暴露者和100名对照者的祖细胞，这样就可以测量集落形成和白血病特异性染色体改变。这些发现预计将为甲醛诱发白血病的潜在机制提供重要信息，这将有助于甲醛的公共卫生风险评估和监管。公共卫生相关性：甲醛是一种可能导致白血病的重要工业化学品，但缺乏合理的机制使这一话题备受争议。我们计划对接触甲醛的工人进行两项研究，其中我们将检查与白血病相关的DNA损伤和染色体变化。这些研究产生的数据将有助于公共卫生机构评估甲醛引起的白血病风险。

DESCRIPTION (provided by applicant): Formaldehyde is an important industrial chemical to which millions of workers are exposed worldwide. Environmental exposures can also be significant as a result of off-gassing in new mobile homes and from combustion. The International Agency of Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is "strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde". Although several epidemiological studies and our new meta-analysis support an association with leukemia, some investigators have argued that inhaled formaldehyde cannot reach the bone marrow, is not toxic to the hematopoietic system, and thus cannot cause leukemia. In order to improve our understanding of the biological plausibility of formaldehyde-induced leukemogenesis, we have developed a number of working hypotheses that we will test in five Specific Aims proposed as part of two biomarker population studies of formaldehyde- exposed workers in China (Formaldehyde Biomarker 1 and 2: FAB1 & FAB2). We plan to develop valid biomarkers of formaldehyde exposure and early biological effect in FAB1; to determine if formaldehyde toxicity can be reproduced in vitro; and, to confirm its hematotoxicity and genotoxicity, and examine dose-response relationships in a larger biomarker study of 1,000 workers (FAB2). To achieve these goals, we will first employ the OctoChrome FISH technique, developed and validated in studies of the well-known leukemogen, benzene, to determine for the first time if a direct link exists between human formaldehyde exposure and leukemia- specific chromosomal aberrations in peripheral blood lymphocytes (Aim 1) and circulating myeloid progenitor cells (Aim 2). We will then measure DNA-protein crosslinks as a biomarker of internal dose and genotoxic damage from formaldehyde in the exposed individuals and correlate the findings with chromosome alterations (Aim 3). Human cell culture studies in vitro will be performed in an attempt to validate our findings from the population studies, to determine if the chromosome changes and DNA damage observed in exposed workers can be attributed to formaldehyde (Aim 4). In collaboration with investigators at U.S. NCI, China GDPCC and Utrecht University, we will conduct a larger biomarker population study (FAB2) with a wide range of exposure to confirm the hematotoxicity and genotoxicity of formaldehyde and to examine dose-response relationships (Aim 5). Specifically, in the FAB2 study, we will determine complete blood cell counts in a population of 500 exposed workers and 500 unexposed frequency-matched controls in China with well-characterized exposures to formaldehyde; and, we will culture progenitor cells from 100 highly exposed and 100 control subjects, so that colony formation and leukemia-specific chromosome alterations can be measured. These findings are anticipated to provide important information on the potential mechanisms of formaldehyde-induced leukemia that will assist in the public health risk assessment and regulation of formaldehyde. PUBLIC HEALTH RELEVANCE: Formaldehyde is an important industrial chemical that may cause leukemia, but the absence of a plausible mechanism makes this topic highly controversial. We plan to perform two studies of formaldehyde-exposed workers in which we will examine DNA damage and chromosome changes associated with leukemia. The data produced from these studies will be useful to public health agencies in their evaluation of the leukemia risk presented by formaldehyde.