ARSENIC BIOMARKER EPIDEMIOLOGY

在有毒物质和疾病登记机构(ATSDR)最新的超级基金地点危险物质优先名单中，砷排名第一。我们建议继续我们的国际砷生物标志物流行病学计划，将新的重点放在摄入饮用水中的无机砷对肺部健康的恶性和非恶性影响上。这种焦点的转移与这样一个事实有关，即基于三个不同国家的研究结果的风险估计，包括我们在阿根廷和智利进行的研究，表明肺癌对因摄入砷而增加的死亡率的贡献，超过了所有其他由砷引起的癌症的总和。因此，改善人群癌症风险评估至关重要地依赖于对砷诱发肺癌的更好理解。除了肺癌，我们在西孟加拉邦和智利的研究证据表明，摄入砷的方式也会导致慢性非恶性肺部疾病，儿童时期接触砷尤其重要。因此，我们提出了几项研究，以调查摄取饮用水中无机砷对肺部的恶性和非恶性影响。阿根廷的一项肺癌病例对照研究将使用个人暴露数据，重点关注剂量反应问题以及砷与吸烟的潜在协同作用。个体易感性将通过尿砷甲基化模式以及口腔细胞DNA中的谷胱甘肽转移酶(GST)和亚甲基四氢叶酸还原酶(MTHFR)基因类型进行评估。这项研究和智利的一项肺癌研究都将评估长肿瘤DNA的基因变化，包括p53突变、DNA甲基化和可通过比较基因组杂交检测到的变化。在智利，我们还将调查与儿童砷暴露有关的由砷引起的年轻人慢性呼吸道疾病死亡率。印度西孟加拉邦的一项研究将对慢性呼吸道疾病、砷引起的皮肤损伤和营养易感性进行调查。砷对儿童的影响将是这项研究的一部分，以及对孟加拉国和智利皮肤损害儿童的研究。综上所述，我们建议调查无机砷摄入对肺部的恶性和非恶性影响，包括儿童时期接触砷对健康的影响。这项研究的总体目标是提供信息，使人们能够更准确地评估饮用水中砷的人口风险。

Arsenic is ranked number one on the most recent priority list of Superfund site hazardous substances by the Agency for Toxic Substances and Disease Registry (ATSDR). We propose to continue our international arsenic biomarker epidemiology program with a new focus on the malignant and non-malignant pulmonary health effects of ingesting inorganic arsenic in drinking water. This shift in focus is related to the fact that risk estimates based on findings from three separate countries including studies performed by us in Argentina and Chile, show that lung cancer contributes more to increased mortality due to arsenic ingestion than all other arsenic-caused cancers combined. Thus, improving population cancer risk estimation is critically dependent on a better understanding of arsenic-induced lung cancer. In addition to lung cancer, evidence from our studies in West Bengal and Chile suggest that ingested arsenic way also cause chronic non-malignant pulmonary disease, which exposures during childhood being particularly important. We therefore propose several studies to investigate the malignant and non-malignant pulmonary effects originating from the ingestion of inorganic arsenic in drinking water. A lung cancer case-control study in Argentina will use individual exposure data to focus on dose-response issues and the potential synergy of arsenic with cigarette smoking. Individual susceptibility will be assessed by urinary arsenic methylation patterns, plus glutathione transferase (GST) and methylenetetrahydrofolate reductase (MTHFR) genotypes in buccal cell DNA. Long tumor DNA from both this study and a lung cancer study in chile will be assessed for genetic alterations including p53 mutations, DNA methylation, and changes detectable by comparative genomic hybridization. In chile, we will also investigate arsenic-induced chronic respiratory disease mortality in young adults in relation to childhood arsenic exposures. Chronic respiratory disease, arsenic-caused skin lesions, and nutritional susceptibility will be investigated in a study in West Bengal, India. Arsenic effects in children will be part of this study, as well as studies of children with skin lesions in Bangladesh and Chile. In summary, we propose to investigate both the malignant and non-malignant pulmonary effects of inorganic arsenic ingestion, including the health effects resulting from childhood exposure. The overall goal of this research is to provide information that will allow the population risks from arsenic in drinking water to be more accurately assessed.