Modeling low-dose radiation-induced acute myeloid leukemia in male CBA/H mice
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ORIGINAL ARTICLE
Modeling low‑dose radiation‑induced acute myeloid leukemia in male CBA/H mice Sjors Stouten1,2 · Sjoerd Verduyn Lunel2 · Rosemary Finnon3 · Christophe Badie3 · Fieke Dekkers1,2 Received: 5 June 2020 / Accepted: 1 November 2020 © The Author(s) 2020
Abstract The effect of low-dose ionizing radiation exposure on leukemia incidence remains poorly understood. Possible dose-response curves for various forms of leukemia are largely based on cohorts of atomic bomb survivors. Animal studies can contribute to an improved understanding of radiation-induced acute myeloid leukemia (rAML) in humans. In male CBA/H mice, incidence of rAML can be described by a two-hit model involving a radiation-induced deletion with Sfpi1 gene copy loss and a point mutation in the remaining Sfpi1 allele. In the present study (historical) mouse data were used and these processes were translated into a mathematical model to study photon-induced low-dose AML incidence in male CBA/H mice following acute exposure. Numerical model solutions for low-dose rAML incidence and diagnosis times could respectively be approximated with a model linear-quadratic in radiation dose and a normal cumulative distribution function. Interestingly, the low-dose incidence was found to be proportional to the modeled number of cells carrying the Sfpi1 deletion present per mouse following exposure. After making only model-derived high-dose rAML estimates available to extrapolate from, the linear-quadratic model could be used to approximate low-dose rAML incidence calculated with our mouse model. The accuracy in estimating low-dose rAML incidence when extrapolating from a linear model using a low-dose effectiveness factor was found to depend on whether a data transformation was used in the curve fitting procedure. Keywords Low-dose · Acute myeloid leukemia · CBA mice · Mathematical modeling · Ionizing radiation exposure · LDEF
Introduction Many epidemiological studies have been conducted to elucidate the relationship between low-dose (LD) ionizing radiation (IR) exposure and leukemia incidence (Hsu et al. 2013; Preston et al. 1994; Pearce et al. 2012; Laurier et al. 2017). For radiological protection it is important to reliably quantify possible LD risks, to develop health and safety policies concerning IR exposure related to occupational hazards and public health. Data analyses of the Japanese atomic bomb * Sjors Stouten [email protected] 1
Netherlands National Institute for Public Health and the Environment, Bilthoven, The Netherlands
2
Mathematical Institute, Utrecht University, Utrecht 3508 TA, The Netherlands
3
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot, OX11 ORQ, UK
survivors life-span study showed that both a linear-quadratic (LQ) and a preferred purely quadratic model can describe acute myeloid leukemia (AML) risk over a wide dose range (Preston et al. 1994; Richardson et al. 2009; Hsu et al. 2013). Different do
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