Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part II: Hematopoietic system, lung and liver

Abstract

While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner.

Low-Dose Non-Targeted Effects and Mitochondrial Control

“…Several excellent recent reviews [369][370][371] give a detailed account of the key events of LDR effects in animal models. Prolonged life times of mice after chronic low-dose rate IR exposure could be observed [372,373].…”

Human–mouse comparison of the multistage nature of radiation carcinogenesis in a mathematical model

“…Ionizing radiation has a relatively simple mechanism of action, in which the ionization and excitation of water and biomolecules lead to oxidation and strand breaks in DNA and, thereby, mutations generated via repair of that damage by error-prone cellular machinery; when such a mutation occurs in a cancer driver gene, that mutation may represent a step forward in the formation of cancer, which generally requires the accumulation of a certain number of driver mutations. [4][5][6] This simple pathway is regarded as the major route to carcinogenesis induced by low-linear energy transfer (LET; i.e., sparsely ionizing) radiations like γ rays, albeit other mechanisms have also been postulated, [5][6][7][8][9] especially regarding chronic exposure to high-LET (i.e., densely ionizing) radiations. 10 In addition, ionizing radiation is a physical entity that can be accurately measured as the absorbed energy in target tissues and cells, unlike chemical substances, which are subjected to sometimes complex toxicokinetics and metabolic processes.…”

“…The present study used this approach with studies of cancer risk from exposure to ionizing radiation. Ionizing radiation has a relatively simple mechanism of action, in which the ionization and excitation of water and biomolecules lead to oxidation and strand breaks in DNA and, thereby, mutations generated via repair of that damage by error‐prone cellular machinery; when such a mutation occurs in a cancer driver gene, that mutation may represent a step forward in the formation of cancer, which generally requires the accumulation of a certain number of driver mutations 4–6 . This simple pathway is regarded as the major route to carcinogenesis induced by low‐linear energy transfer (LET; i.e., sparsely ionizing) radiations like γ rays, albeit other mechanisms have also been postulated, 5–9 especially regarding chronic exposure to high‐LET (i.e., densely ionizing) radiations 10 .…”