通过动物致癌研究和细胞标志物预测宇航员的癌症发病率。

Williams J R, Zhang Y, Zhou H, Osman M, Cha D, Kavet R, Cuccinotta F, Dicello J F, Dillehay L E

Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD, USA.

Mutat Res. 1999 Dec 6;430(2):255-69. doi: 10.1016/s0027-5107(99)00137-2.

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.

辐射空间环境包含质子和多种重离子等粒子，人体对这些辐射的暴露大多发生在极低的平均剂量率下。用于预测此类辐射对人类致癌风险的数据库存在重大局限性，目前无法确定此类预测是否足够精确或准确。在本文中，我们概述了基于对代表性空间辐射诱发癌症及相关细胞终点的剂量反应关系有更深入理解的动物致癌数据的必要性。我们强调需要一个能够将人类和动物致癌数据与细胞机制相互关联的模型。使用一个我们称为“亚α-α-ω（SAO）模型”的广泛剂量反应模式模型，我们在文献中探讨了辐射诱发癌症和辐射诱发细胞事件的例子，以说明需要在特定剂量范围内更精确地定义剂量反应模式的数据，尤其要关注低剂量、低剂量率暴露。我们展示了细胞中多种终点的数据，这些终点的放射敏感性各不相同，也支持了所提出的模型。我们测量了两种空间辐射（铁离子和质子）在多种细胞类型中诱发复杂染色体畸变的情况，并将其与高剂量率或低剂量率的光子进行了比较。我们的数据表明，与光子相比，至少有三个因素调节铁离子的相对效能：（i）受辐照细胞的固有放射敏感性；（ii）剂量率；（iii）另一种可能与DNA损伤修复能力有关的未明确效应。这些因素分别可产生高达至少7倍、6倍和3倍的变异性。这些数据表明需要更好地理解固有放射敏感性和剂量率效应在哺乳动物细胞对电离辐射反应中的作用。这种理解对于在细胞反应、动物致癌和人类致癌之间推断数据库至关重要，我们认为SAO模型是进行此类推断的有用工具。