Parameterisation of hematopoietic acute radiation syndrome mortality based on models of neutrophil kinetics

Planning and preparedness for response to radiological and nuclear incidents and accidents requires accurate predictions of radiation-induced mortality. Present estimates are primarily based on empirical fits to historical data sets which can be idiosyncratic and may be limited in general applicability. To provide an alternative approach based on more fundamental principles, we present a hematopoietic acute radiation syndrome mortality dose response parameterisation based on model calculations relating absolute neutrophil count (ANC) kinetics to overall survival (OS) probability. ANC-to-OS calculations were performed using a kinetic-pharmacodynamic approach for acute whole-body radiation doses from 0 to 15 Gy. Results were approximated with a two-parameter Weibull distribution function. The resulting dose response curve is in agreement with radiation-induced mortality data from historical incidents and accidents, while differing from commonly used dose response curve estimates. When applied to a notional prompt-exposure scenario, the new dose response curve results in a 6×greater requirement (approximately 1500 savable persons) for administration of life-saving medical countermeasures (MCMs) compared to estimates based on the Nuclear Regulatory Series (NUREG) dose-response curve (approximately 260 savable persons). We briefly comment on the prospects for extending the present work to include the impact of MCMs and biological factors, such as illness/injury, age, and possibly sex.