Inverse dose protraction effects of low-LET radiation: Evidence and significance

Biological effects of ionizing radiation vary not merely with total dose but also with temporal dose distribution. Sparing dose protraction effects, in which dose protraction reduces effects of radiation have widely been accepted and generally assumed in radiation protection, particularly for stochastic effects (e.g., solid cancer). In contrast, inverse dose protraction effects (IDPEs) in which dose protraction enhances radiation effects have not been well recognized, nor comprehensively reviewed. Here, we review the current knowledge on IDPEs of low linear energy transfer (LET) radiation. To the best of our knowledge, since 1952, 157 biology, epidemiology or clinical papers have reported IDPEs following external or internal low-LET irradiation with photons (X-rays, γ-rays), β-rays, electrons, protons or helium ions. IDPEs of low-LET radiation have been described for biochemical changes in cell-free macromolecules (DNA, proteins or lipids), DNA damage responses in bacteria and yeasts, DNA damage, cytogenetic changes, neoplastic transformation and cell death in mammalian cell cultures of human, rodent or bovine origin, mutagenesis in silkworms, cytogenetic changes, induction of cancer (solid tumors and leukemia) and non-cancer effects (male sterility, cataracts and diseases of the circulatory system), tumor inactivation and survival in non-human mammals (rodents, rabbits, dogs and pigs), and induction of cancer and non-cancer effects (skin changes and diseases of the circulatory system) in humans. In contrast to a growing body of phenomenological evidence for manifestations of IDPEs, there is limited knowledge on mechanistic underpinnings, but proposed mechanisms involve cell cycle-dependent resensitization and low dose hyper-radiosensitivity. These necessitate continued studies for further mechanistic developments and assessment of implications of scientific evidence for radiation protection (e.g., in terms of a dose rate effectiveness factor).