ARSENIC BIOMARKER EPIDEMIOLOGY

砷在美国有毒物质和疾病登记处（ATSDR）最新发布的超级基金有害物质优先清单中排名第一。我们建议继续我们的国际砷生物标志物流行病学项目，并将新的重点放在饮用水中摄入无机砷的恶性和非恶性肺部健康影响上。这一重点的转变与以下事实有关：基于三个不同国家的调查结果（包括我们在阿根廷和智利进行的研究）的风险估计表明，肺癌对砷摄入导致的死亡率增加的贡献大于所有其他砷引起的癌症的总和。因此，提高人群癌症风险评估严重依赖于更好地了解砷诱导的肺癌。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，儿童时期的接触尤其重要。因此，我们建议进行几项研究，以调查饮用水中无机砷摄入引起的恶性和非恶性肺效应。阿根廷的一项肺癌病例对照研究将利用个人接触数据，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）基因型来评估。来自本研究和智利肺癌研究的长肿瘤DNA将被评估遗传改变，包括p53突变、DNA甲基化和通过比较基因组杂交检测到的变化。在智利，我们还将调查砷引起的青年慢性呼吸道疾病死亡率与儿童砷暴露的关系。印度西孟加拉邦的一项研究将调查慢性呼吸道疾病、砷引起的皮肤病变和营养易感性。砷对儿童的影响将是这项研究的一部分，对孟加拉国和智利皮肤受损儿童的研究也是如此。总之，我们建议调查无机砷摄入对肺部的恶性和非恶性影响，包括儿童期接触对健康的影响。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对人口的风险。

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.