Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part I: Mammary gland and digestive tract

Abstract

While epidemiological data are available for the dose and dose-rate effectiveness factor (DDREF) for human populations, animal models have contributed significantly to providing quantitative data with mechanistic insights. The aim of the current review is to compile both the in vitro experiments with reference to the dose-rate effects of DNA damage and repair, and the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. In particular, the review focuses especially on the results pertaining to underlying biological mechanisms and discusses their possible involvement in the process of radiation-induced carcinogenesis. Because the concept of adverse outcome pathway (AOP) together with the key events has been considered as a clue to estimate radiation risks at low doses and low dose-rates, the review scrutinized the dose-rate dependency of the key events related to carcinogenesis, which enables us to unify the underlying critical mechanisms to establish a connection between animal experimental studies with human epidemiological studies.

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 .…”