ARSENIC BIOMARKER EPIDEMIOLOGY

砷被毒物和疾病登记署（ATSDR）列为超级基金网站危险物质最新优先名单的第一位。我们建议继续开展国际砷生物标志物流行病学项目，新的重点是饮用水中无机砷对肺部健康的恶性和非恶性影响。这一重点的转变与以下事实有关：基于三个不同国家的研究结果（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，改善人群癌症风险评估关键取决于更好地了解砷诱导的肺癌。除了肺癌，我们在西孟加拉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，其中儿童时期的暴露尤为重要。因此，我们提出了几项研究，调查恶性和非恶性肺的影响，从饮用水中的无机砷的摄入。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和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中谷胱甘肽转移酶（GST）和亚甲基四氢叶酸还原酶（MTHFR）基因型进行评估。将评估来自本研究和智利肺癌研究的长肿瘤DNA的遗传改变，包括p53突变、DNA甲基化和通过比较基因组杂交可检测到的变化。在智利，我们也将调查砷引起的慢性呼吸道疾病死亡率与儿童期砷暴露的关系。印度西孟加拉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敏感性。砷对儿童的影响将是这项研究的一部分，对孟加拉国和智利儿童皮肤病变的研究也将是这项研究的一部分。总之，我们建议调查无机砷摄入的恶性和非恶性肺效应，包括儿童期暴露造成的健康影响。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.