Modeling deterministic effects in hematopoietic system caused by chronic exposure to ionizing radiation in large human cohorts

Abstract

A new model of the hematopoietic system for humans chronically exposed to ionizing radiation allows for quantitative description of the initial hematopoiesis inhibition and subsequent increase in the risks of late stochastic effects such as leukemia. This model describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the three blood cell types (leukocytes, erythrocytes, and platelets). The model parameters are estimated from the results of other experiments. They include the steady-state numbers of hematopoietic stem cells and peripheral blood cell lines for an unexposed organism, amplification parameters for each blood cell line, parameters describing the proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity in respect to cell death and non-lethal cell damages. The dynamic model of hematopoiesis is applied to the data on a subcohort of the Techa River residents with hematological measurements (e.g., blood counts) performed in 1950-1956 (which totals to about 3,500 exposed individuals). Among well-described effects observed in these data are the slope values of the dose-effect curves describing the hematopoietic inhibition and the dose rate patterns of the fractions of cytopenic states (e.g., leukopenia, thrombocytopenia). The model has been further generalized by inclusion of the component describing the risk of late stochastic effects. The risks of the development of late effects (such as leukemia) in population groups with specific patterns of early reactions in hematopoiesis (such as leukopenia induced by ionizing radiation) are investigated using simulation studies and compared to data.

Fig. 1

The model of hematopoiesis under chronic exposure to IR. The circles describe four model compartments corresponding to HSC (S) and mature leukocytes (N), erythrocytes (R), and platelets (P). The pentagons denote compartments for amplification and maturation of blood cells. The square shows the compartment of HSC proliferation. Solid lines show the cell transitions between compartments, and dash-dotted lines show feedback loops regulating the blood counts.

Fig. 2

Model prediction and blood counts measured in 1956 for two groups of dose pattern histories. The lower lines and dots correspond to the group with higher exposure histories. See the text for further details on the design of the simulation study.

Fig. 3

Data on leukopenia frequency (dots) and model prediction (line).

Fig. 4

The scheme of a compartmental model implementing the sequence of barrier breaking when a cell undergoes changes from a normal (ABC) to a malignant (M) state. Transitions correspond to the failure of a specific barrier, e.g., apoptosis (A), repair (B), antioxidant defense (C). Letters on the blocks denote which barriers are effective in a certain state.