POPULATION RISK MODEL FOR ALPHA INDUCED BONE NEOPLASMS

暴露于致骨放射性核素（包括钚、镅、镭和其他放射性核素）的后果已得到充分认识，并引起公众相当大的关注。目前的保护模型主要基于统计假设，只有很少的生物学或实验数据。虽然这些模型可能适用于暴露限值的设定，但我们的目标是继续推导基于实验的辐射剂量-组织相互作用的生物动力学剂量学模型，该模型将预测肿瘤的发生、潜伏期、位置和频率。利用现有数据和组织档案，将实现以下目标：1)基于中子诱导放射自显像（NIAR）的图像分析方法将确定比格犬在单体239Pu暴露后的组织区室、细胞分布和辐射剂量随时间的变化。2)形态计量学和形态学方法将定义用于239Pu定位和剂量学评估的同一标本中比格犬骨组织的生物学特性。3)建立锕系元素在骨骼组织中分布、结合和保留的相关生物学决定因素。这些包括骨皮质/骨小梁对Pu的亲和力比；脂肪/红骨髓部位松质骨；成骨细胞活性/静止表面的表面沉积。4)根据Aims 1-3获得的信息，结合以往寿命研究的肿瘤信息，将继续开发比格犬的肿瘤预测模型。一些重点将放在“组织加权因子”的确定（例如，骨骼内膜与肝脏）和评估潜在的逆剂量率效应。5)人体生物学成分将从文献和档案中的一些人体材料中确定。在预测肿瘤模型中可能很重要的组织特征包括红/脂肪骨髓随年龄的分布、骨骼更新和代谢，以及假定靶细胞的密度。6)人体剂量学信息将主要由beagle模型预测，但通过分析人体骨骼中的239Pu来证实。将对暴露的人类骨骼进行近红外光谱分析。人类样本由USTUR提供，一些组织可从俄罗斯重度暴露的人类（Mayak工人）获得。7)根据实验得出的小猎犬模型和为人类开发的数据，将为人类构建一个基于生物学的“肿瘤预测”模型。这些研究将提供有关Pu和其他寻骨者生物学行为的新知识，并提高预测暴露风险的能力。

The consequences of exposures to bone-seeking radionuclides including plutonium, americium, radium and others are well recognized and of considerable public concern. Current protection models are based largely on statistical assumptions with only minimal biological or experimental data. While these models may be suitable for the setting of exposure limits, our goal is to continue to derive an experimentally based biokinetic-dosimetric model of radiation dose-tissue interactions that will be predictive of tumor occurrence, latency periods, location, and frequency. Using existing data and tissue archives, the following aims will be accomplished: l) Neutron Induced Autoradiography (NIAR) based image analysis methods will determine tissue compartments, cellular distributions and radiation doses with time after monomeric 239Pu exposures in beagle dogs. 2) Morphometric, and morphological methods will define the biology of the beagle osseous tissues in the same specimens used for 239Pu localization and dosimetric evaluations. 3) To establish the relative biological determinants of actinide distribution, incorporation and retention in skeletal tissues. These include the affinity ratios for Pu in cortical/trabecular bone; cancellous bone in fatty/red marrow sites; surface deposition on osteoblastic active/resting surfaces. 4) From information obtained from Aims 1-3 and combined with tumor information from previous lifespan studies, a predictive tumor model for the beagle dog will continue to be developed. Some emphasis will be placed on the determination of "tissue weighting factors" (e.g. skeletal endosteum vs. liver) and evaluation of a potential inverse dose rate effect. 5) The human biology component will be determined from the literature and from some human material in archive. The tissue characteristics of that are likely to be important in the predictive tumor model include distribution of red/fatty marrow with age, skeletal turnover and metabolism, and densities of putative target cells. 6) Human dosimetry information will mostly be predicted from the beagle model, but confirmationed by analysis of 239Pu in the human skeleton. NIAR analyses of bones from exposed humans will be done. The human samples are provided by the USTUR and some tissues may be obtained from heavily exposed humans in Russia (Mayak workers). 7) From the experimentally derived model for the beagle and from data developed for the human, a biologically-based "tumor predictive" model will be constructed for the human. These studies will provide new knowledge on the biological behavior of Pu and other bone-seekers and an improved capability to predict the risks of exposure.