Inverse dose protraction effects of high-LET radiation: evidence and significance

Biological effects of ionizing radiation vary with radiation quality, which is often expressed as the amount of energy deposited per unit length, i.e., linear energy transfer (LET). For acute irradiation, high-LET radiation generally produces greater biological effects than low-LET radiation, but little knowledge exists as to how dose protraction modifies effects. In this regard, inverse dose protraction effects (IDPEs) are phenomena in which dose protraction enhances effects, contrasting sparing dose protraction effects in which dose protraction reduces effects. Here, we review the current knowledge on IDPEs of high-LET radiation. To the best of our knowledge, since 1967, 80 biology or epidemiology papers have reported IDPEs following external or internal high-LET irradiation with neutrons, deuterons, α-particles, light ions, or heavy ions. IDPEs of high-LET radiation have been described for biochemical changes in cell-free macromolecules, neoplastic transformation, cell death, DNA damage responses and gene expression changes in mammalian cell cultures of human or rodent origin, gene mutations, cytogenetic changes, cancer, non-cancer effects (e.g., testicular effects, cataracts, cardiovascular diseases) and life shortening in non-human mammals (rodents and dogs), and induction of lung cancer and bone tumors in humans. For external irradiation of mammalian cells in vitro and mammals in vivo, IDPEs of low- and high-LET radiation have been reported for radiation doses spanning in excess of three or four orders of magnitude in slightly different ranges, and for radiation dose rates both spanning over six orders of magnitude in different ranges. IDPEs of high-LET radiation in humans have been reported following internal exposure, but not external exposure. Manifestations and mechanisms of IDPEs of high-LET radiation are far less understood than those of low-LET radiation, warranting further studies that will be pivotal to assess the implications for radiation protection.