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 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 value 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.

New stochastic carcinogenesis model with covariates: An approach involving intracellular barrier mechanisms

“…The concept of barrier mechanisms could potentially serve as a bridge between epidemiologic and mechanistic description of carcinogenesis through inclusion of molecular biology findings [52,53]. The approach based on this concept could allow for inclusion into the model not only of a single gene alteration (which reflects only a small component of each tumor's mutational composition), but also of combined contributions of multiple genes to carcinogenesis (which could represent the same barrier and/or be functionally equivalent - i.e., affecting net cell growth through the same molecular pathway) [54].…”

Modeling hematopoietic system response caused by chronic exposure to ionizing radiation

“…An approach allowing for a description of the relationship between deterministic reactions of hematopoiesis and late stochastic effects will define the future direction of model development (outlined in Akushevich et al, 2010). This is discussed below in a separate subsection.…”

“…Both types of effects are related, and this relationship has to be reflected in the developed models. In a recent report (Akushevich et al, 2010) it was demonstrated how the model of deterministic effects can be joined to a model of late stochastic health effects. The main stochastic effect of chronic exposure to IR in hematopoietic system is leukomogenesis.…”

Half-century archives of occupational medical data on French nuclear workers: a dusty warehouse or gold mine for epidemiological research?

“…Until the 1960s only high cholesterol values were recorded. Routine recording started only after 1973, with the first major publications on total cholesterol as a cardiovascular risk factor (22)(23)(24)(25). For workers hired later than 1970 the completeness rose highly, except, once again for HDL cholesterol (Figure 1).…”

“…Considering that blood count parameters in our sample have almost 100 % completeness and availability over time, it would be relatively easy to evaluate the effects of low-dose ionising radiation on blood counts (23,24). Diastolic and systolic blood pressure can also be analysed in relation to internal uranium dose received before retirement.…”