GLYCOPHORIN A BIODOSIMETRY IN I-131 TREATED PATIENTS

基于血型糖蛋白A（GPA）的人体内体细胞突变测定， 由于其对过去遗传毒性的长期生物记忆， 曝光加上其相对较低的成本和较高的样品吞吐量， 在目前可获得的用于实际应用的人类生物标志物测定中是独特的 作为一种回顾性生物剂量计， 人类种群。 在这里，我们建议进一步验证响应的 作为辐射暴露的生物剂量计， 接受131 I治疗的甲状腺疾病患者。 这些患者将 接受临床上充分表征的剂量范围为2至200 cGy的 全身骨髓暴露于电离辐射， 放射性衰变的管理131 I。 外周血标本 将在术前、术中和术后抽取约100名患者 治疗遵循的诱导，积累，和持久性 辐射诱发的骨髓干细胞GPA位点体细胞突变 细胞 有核骨髓祖细胞的这些突变引起 外周循环中表达GPA等位基因缺失的红细胞 变异表型 这些变体在测定中直接计数 使用GPA等位基因特异性单克隆抗体进行免疫标记， 流式细胞仪 基于高辐射剂量下获得的GPA测定结果 这项研究旨在调查辐射剂量， 在外推的剂量范围内的测定响应 试验背景响应的两倍剂量约为30 cGy。 本研究采用纵向设计， 相对较低剂量的131 I，将允许测试实际的极限 通过比较接种后的GPA变异细胞频率， 治疗样品与个体内治疗前样品中观察到的那些 患者 该设计可应用重复测量分析 个人的反应，避免了固有的局限性，研究使用 暴露与匹配的对照人群，其中个体间 响应和背景频率的可变性限制了 检测由以下因素诱导的变异细胞频率的微小增加的测定 低剂量暴露。 这些数据将为评估 试验证明或估计上限的把握度 职业受照者人口调查中的辐射照射情况 工人 此外，由于一些患者接受非常相似的 131I剂量将入组研究，设计还将允许 研究试验中个体响应的范围， 暴露。 这些数据也将大大有助于人口 风险评估模型，试图包括这种异质性，以及 因为缩小了围绕个人估计的不确定性范围， 从测定中的个体响应推断的接收辐射剂量。

The glycophorin A (GPA)-based human in vivo somatic cell mutation assay, because of its demonstrated long-term biological memory of past genotoxic exposures together with its relatively low cost and high sample thruput, is unique among presently available human biomarker assays for practical use as a retrospective biodosimeter in epidemiological investigations of large human populations. Here we propose to further validate the response of the assay as a biodosimeter of radiation exposure in a longitudinal study of patients receiving 131I therapy for thyroid disease. These patients will receive clinically well-characterized doses ranging from 2 to 200 cGy of whole body bone marrow exposure to ionizing radiation resulting from the radioactive decay of administered 131I. Peripheral blood samples from approximately 100 patients will be drawn prior to, during, and following therapy to follow the induction, accumulation, and persistence of radiation-induced somatic mutation at the GPA locus in bone marrow stem cells. These mutations in nucleated bone marrow progenitor cells give rise to erythrocytes in the peripheral circulation expressing a GPA allele-loss variant phenotype. These variants are directly enumerated in the assay using immunolabeling with GPA allele-specific monoclonal antibodies and flow cytometry. Based on GPA assay results obtained in high radiation dose populations, this study is designed to investigate the radiation-dose- response of the assay over a range of doses that surround the extrapolated doubling dose over background response of the assay of approximately 30 cGy. The longitudinal design of the study, applied to patients receiving relatively low doses of 131I, will permit a test of the practical ultimate sensitivity of the assay by comparing GPA variant cell frequencies in post- therapy samples to those observed in pre-therapy samples within individual patients. This design, where a repeated measures analysis can be applied to individual responses, avoids the limitations inherent in studies using exposed versus matched control populations where inter-individual variability in response and in background frequencies limit the power of the assay to detect small increases in variant cell frequencies induced by low-dose exposures. These data will provide critical information to assess the power of the assay to demonstrate, or to estimate the upper limits of radiation exposures in population surveys of occupationally-exposed workers. In addition, since a number of patients receiving very similar 131I doses will enrolled in the study, the design will also permit an investigation of the range of individual responses in the assay to similar exposures. These data will also contribute significantly to population risk assessment models that attempt to include this heterogeneity as well as narrowing the range of uncertainty surrounding individual estimates of received radiation dose inferred from individual responses in the assay.