CYTOGENETIC MODELS FOR ASSESSING LOW DOSE RADIATION RISK

对稀疏电离辐射造成的环境或职业癌症风险进行的科学评估，估计的剂量与典型的实验剂量相比非常小，甚至与流行病学上可处理的剂量相比也很小。一个优先事项是在流行病学可行的中等剂量范围（高达2戈伊或更高）和最相关的低剂量范围（<0.1戈伊）建立可信的剂量-反应关系。相关的初始损伤，如DNA双链断裂，几乎可以肯定是与剂量呈线性关系，因此主要问题是通过分子修复/错误修复途径对初始损伤进行细胞处理，这可能导致更复杂的终点，如染色体畸变，最终导致癌症。在GOIG 1细胞周期阶段产生并在下一个中期评分的交换型染色体畸变是复杂的终点，是电离辐射损伤的特征，与致癌风险估计高度相关。我们的项目的目标是使用在人体细胞的体外实验和定量，机械建模，以找到现实的剂量-反应关系，从0.08-2戈伊的剂量范围内的这种畸变，作为一个实际的替代研究在体内低剂量致癌作用。生物物理和蒙特卡罗计算机分析，比较目前最好的可用模型的分子畸变形成途径的数据强调作为一个相对便宜的方法。我们已经为这个项目召集了一个由来自加州大学伯克利分校、哥伦比亚和哈佛的建模师和实验放射生物学家组成的团队。在人淋巴细胞的γ-照射后，将使用最先进的荧光原位杂交技术测量交换型染色体畸变。建模将使用复杂的CAS（染色体畸变模拟器）计算机软件的扩展，以前写的，并成功地应用于我们的团队成员。该提案的主要创新之处是：将机械计算机建模与低剂量实验紧密结合;使用重复的低剂量分数来增强背景以上的响应;包括用于风险估计目的的畸变测量中的倒置和复杂畸变;以及明确考虑重组修复畸变形成模型。通过对低剂量和低剂量率相关的分子机制进行定量研究，该项目将有助于加强风险估计并使其更加可信。

Science-based assessments of environmental or occupational cancer risks from sparsely ionizing radiation estimate effects on large populations from doses that are very small compared to typical experimental doses and small compared even to epidemiologically tractable doses. A priority is developing credible dose-response relationships, both in an intermediate-dose range (up to 2 Gy or more) where epidemiology is feasible and in the most relevant, low-dose range (<0.1 Gy). The pertinent initial damage, such as DNA double strand breaks, is almost certainly produced linearly with dose, so the main issue is cellular processing of initial damage, via molecular repair/misrepair pathways, which can result in more complex endpoints such as chromosome aberrations and, ultimately, cancer. Exchange-type chromosome aberrations, produced during the GOIGl cell cycle phase and scored at the next metaphase, are complex endpoints, characteristic of ionizing radiation damage and highly relevant to carcinogenesis risk estimation. The goal of our project is using in vitro experiments on human cells and quantitative, mechanistic modeling to find realistic dose- response relations for such aberrations in a dose range from 0.08-2 Gy, as a practical surrogate for studying carcinogenesis in vivo at low doses. Biophysical and Monte Carlo computer analysis, comparing the best currently available models of molecular aberration formation pathways to data is emphasized as a relatively inexpensive approach. We have assembled a team of modelers and experimental radiobiologists from UC Berkeley, Columbia, and Harvard for the project. Exchange-type chromosome aberrations will be measured with state-of-the-art fluorescent in situ hybridization techniques after y-irradiation of human lymphocytes. Modeling will use extensions of sophisticated CAS (chromosome aberration simulator) computer software previously written and successfully applied by members of our team. The main novelties in the proposal are: close integration of mechanistic computer modeling with low-dose experiments; using repeated low-dose fractions to enhance response above background; including inversions and complex aberrations among the aberrations measured for risk-estimation purposes; and explicit consideration of the recombination-repair aberration formation model. By studying molecular, mechanisms relevant to low doses and low dose-rates quantitatively the project will help firm-up risk estimates and make them more credible.