The Uneven Irradiation of a Target Cell and Its Dynamic Movement Can Mathematically Explain Incubation Period for the Induction of Cancer by Internally Deposited Radionuclides

Abstract

Irradiation from internally deposited radionuclides induces malignant tumors. Ingested radionuclides accumulate in specific organs, which are irradiated over a lifelong period. Our aim is to elucidate why the development of malignant tumors requires long-term internal exposure, on the order of decades, despite the fact that irradiation is continuous over this period. Three major factors are considered to be responsible for the long incubation time in carcinogenesis caused by internally deposited alpha-emitters: uneven distribution of radionuclides, limited range of irradiation, and dynamic movement of tumor precursor cells. We hypothesized that target cells susceptible to malignant transformation may undergo one event by alpha particles and may then migrate outside of the range of alpha particles, thereby avoiding immediate induction of successive additional events that would lead to cell death or neoplastic changes. Based on this hypothesis, we further proposed a mathematical model to predict the relationship between dose rate and incubation period of tumors induced by internally deposited alpha-emitters. The function was non-linear and included terms of both direct and indirect radiation effects. It well fitted both human Th-ICC cases and rat Pu-induced lung cancer, suggesting that indirect radiation effects are independent from dose rate. The significance of parameters of the model is discussed.

Introduction and Overview

“…Once radioactive materials are ingested, they are not evenly distributed throughout the body, but become enriched in specific organs dependent on their chemical and physical properties, and the target organs are heavily exposed. Even in an organ, the distribution of radionuclides and irradiation at the microscopic level is not homogeneous [6]. In addition, deposited radionuclides form a much more complicated exposure profile than in external exposure, due to physical radioactive decay, biological excretion of radioactive materials [7], and dynamic remodeling of the organ [8].…”

Hepatic and Perihepatic Involvement in Pneumokonioses and Other Mineral-Induced Diseases

“…The mechanisms causing the marked delay between thorium dioxide injection and manifestation of liver cancer have not been fully elucidated. One model proposed that target cells susceptible to malignant transformation may undergo one event by alpha particles and may then migrate outside of the range of alpha particles, thereby avoiding immediate induction of successive additional events for neoplastic change (Yamamoto et al 2010). Thorium dioxide is also transported within organs via migration of macrophages that have ingested the Thorotrast particles (Goto et al 2002), microdistribution therefore being markedly influenced by the migration dynamics of phagocytosing cells.…”

Radiation pathology: From thorotrast to the future beyond radioresistance

“…In this equation, dose rate but not total dose is crucial to determining the incubation period of cancers induced by internal exposure. From this equation, we discovered a need to consider the contribution of the indirect effect proportional to dose rate to internal radiation carcinogensis …”