title: Mathematical model of radiation effects on thrombopoiesis in rhesus macaques and humans.
abstract: A mathematical model that describes the effects of acute radiation exposure on thrombopoiesis in primates and humans is presented. Thrombopoiesis is a complex multistage dynamic process with potential differences between species. Due to known differences in cellular radiosensitivities, nadir times, and cytopenia durations, direct extrapolation from rhesus to human platelet dynamics is unrealistic. Developing mathematical models of thrombopoiesis for both humans and primates allows for the comparison of the system's response across species. Thus, data obtained in primate experiments can be extrapolated to predictions in humans. Parameter values for rhesus macaques and humans were obtained either from direct experimental measurements or through optimization procedures using dynamic data on platelet counts following radiation exposure. Model simulations accurately predict trends observed in platelet dynamics: at low radiation doses platelet counts decline after a time lag, and nadir depth is dose dependent. The models were validated using data that was not used during the parameterization process. In particular, additional experimental data was used for rhesus, and accident and platelet donor data was used for humans. The model aims to simulate the average response in rhesus and humans following irradiation. Variation in platelet dynamics due to individual variability can be modeled using Monte Carlo simulations in which parameter values are sampled from distributions. This model provides insight into the time course of the physiological effects of radiation exposure, information which could be valuable for disaster planning and survivability analysis and help in drug development of radiation medical countermeasures.
authors.affiliation: Applied Research Associates, Inc., Arlington, VA, United States. Electronic address: jwentz@ara.com.
authors.forename: J M
authors.initials: JM
authors.lastname: Wentz
authors.affiliation: Neumedicines, Inc., Pasadena, CA, United States.
authors.forename: V
authors.initials: V
authors.lastname: Vainstein
authors.affiliation: Applied Research Associates, Inc., Arlington, VA, United States.
authors.forename: D
authors.initials: D
authors.lastname: Oldson
authors.affiliation: Neumedicines, Inc., Pasadena, CA, United States.
authors.forename: Z
authors.initials: Z
authors.lastname: Gluzman-Poltorak
authors.affiliation: Neumedicines, Inc., Pasadena, CA, United States.
authors.forename: L A
authors.initials: LA
authors.lastname: Basile
authors.affiliation: Applied Research Associates, Inc., Arlington, VA, United States.
authors.forename: D
authors.initials: D
authors.lastname: Stricklin
mesh_terms: D000465:Algorithms; D000818:Animals; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008253:Macaca mulatta; D008954:Models, Biological; D011832:Radiation Injuries / Q000473:pathology / Q000503:physiopathology*; D034061:Thrombopoiesis / Q000528:radiation effects*
keywords: Health effects; Megakaryocyte; Ordinary differential equation model; Platelet