CYTOGENETIC MODELS FOR ASSESSING LOW DOSE RADIATION RISK

稀疏电离辐射对环境或职业癌症风险的科学评估估计，与典型的实验剂量相比非常小的剂量，甚至与流行病学上可处理的剂量相比，都很小的剂量对大量人口的影响。当务之急是发展可信的剂量-反应关系，既在流行病学可行的中剂量范围(最高2Gy值或更高)，也在最相关的低剂量范围(0.1Gy值)。相关的初始损伤，如DNA双链断裂，几乎肯定是随着剂量的增加而线性产生的，所以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，如染色体异常，并最终导致癌症。交换型染色体异常发生在GOIG1细胞周期阶段，并在下一个中期记分，是复杂的终点，具有电离辐射损伤的特征，与致癌风险评估高度相关。我们项目的目标是利用人体细胞的体外实验和定量的机制建模，在0.08-2GY的剂量范围内为这种畸变找到现实的剂量-反应关系，作为研究低剂量在体内致癌的实用替代品。生物物理学和蒙特卡罗计算机分析，将目前可用的最好的分子像差形成路径模型与数据进行比较，强调这是一种相对便宜的方法。我们为这个项目组建了一个由加州大学伯克利分校、哥伦比亚大学和哈佛大学的模型师和实验放射生物学家组成的团队。用最先进的荧光原位杂交技术测量人淋巴细胞辐射后的交换型染色体畸变率。建模将使用我们团队成员先前编写并成功应用的复杂CAS(染色体畸变模拟器)计算机软件的扩展。该提案的主要创新之处在于：机械计算机模拟与低剂量实验的紧密结合；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测量的像差中的反转和复杂像差；以及明确考虑重组-修复像差形成模型。通过定量研究与低剂量和低剂量率相关的分子机制，该项目将有助于巩固风险估计并使其更可信。

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.