Multi-Scale Evaluation and Mitigation of Toxicities Following Internal Radionuclide Contamination

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OVERALL: ABSTRACT History has taught us that exposures to radionuclides can happen any day almost anywhere in the US and elsewhere and we have done little to prepare ourselves. Our ability to perform dosimetry modeling for such scenarios and efforts into biomarker and mitigation discovery are archaic and our tendency to rely on external beam radiation to model these is utterly misplaced. We should and we can do much better. This program centers on the hypothesis that radiation from internal emitters is very unevenly distributed within a body, amongst organs, and even within organs, tissues and cells. The half-life and decay schema of the radionuclide, its activity and concentration, particle size and morphology, and its chemical form and solubility are all critical, as are the route of uptake, tissue structure, genetic makeup, physiology, danger signaling and the crosstalk with the immune system. Conceptually this suggests that the analysis of radionuclide distribution requires measurements at the MESO, MICRO and NANO level for accurate dosimetry modeling and biokinetics analyses, that will much better align with biological endpoints, and therefore with meaningful countermeasure development. In many ways our program integrates the three main pillars of radiation science, namely radiation physics, radiation chemistry and radiation biology, taking into account pharmacokinetics and pharmacodynamics aspects of particle distribution at subcellular, cellular, and tissue levels. In other words, to understand the biological effects of internal emitters and find the best possible mitigation strategies a systematic study is called for, one that includes but is not limited to: a) radionuclide physical and chemical form and intravital migration, b) protracted exposure times, c) radiation quality parameters, d) novel virtual phantom modeling beyond few MACRO reference models ; e) novel biokinetics with sex- and age- specificity; f) MESO, MICRO and NANO scale histology and immunohistochemistry with integrated radionuclide distribution information; g) exploration of molecular biomarkers of radionuclide intake and contamination and h) countermeasures that modulate radionuclide distribution and possibly also improve DNA, cell and tissue repair. We have assembled a team with diverse scientific expertise that can tackle these challenges within an integrated program. There is an incredibly impressive technological toolbox at our disposal and our goal is to generate a meaningful blueprint for understanding and predicting biological consequences of exposure to radionuclides. The possible benefits of this program to the radiation research community and the general population are immense.