Fifth Warren K. Sinclair Keynote Address: Issues in Quantifying the Effects of Low-Level Radiation

Abstract

Health risks from exposure to high doses of ionizing radiation are well characterized from epidemiological studies. Uncertainty and controversy remain for extension of these risks to the low doses and low dose rates of particular relevance in the workplace, in medical diagnostics and screening, and from background radiations. In order to make such extrapolations, a number of concepts have been developed for radiation protection, partly on the basis of assumed processes in the mechanisms of radiation carcinogenesis. Included amongst these are the assumptions of a linear no-threshold dose response and simple scaling factors for dose rate and radiation quality. With a progressive reduction in recommended dose limits over the past half century, these approaches have had considerable success in protecting humans. But do they go far enough or, conversely, are they overprotective? Four selected underlying aspects are considered. It is concluded that (1) even the lowest dose of radiation has the capability to cause complex DNA damage that can lead to a variety of permanent cellular changes; (2) the unique clustered characteristics of radiation damage, even at very low doses, enable it to stand out above the much larger quantity of endogenous DNA damage; (3) although a chromosome aberration may represent the rate-limiting initiating event for carcinogenesis, as is often assumed, direct evidence is still lacking; and (4) the extensive influence that dicentric aberrations have had on guiding extrapolations for radiation protection may be substantially misleading. Finally, some comments are offered on aspects that lie outside the current paradigm.

Dependence and independence of survival parameters on linear energy transfer in cells and tissues

“…It is now generally accepted that high-LET radiation induces complex clustered damage to DNA, particularly complex double-stranded breaks (DSBs) [22–25], which are less repairable by either non-homologous end-joining or the homologous recombination pathway [26]. Throughout this paper, ‘clustered damage’ to DNA is intended to refer only to damage at the nanometer level of the DNA molecule, mostly extending over not more than one or two helical turns of the DNA, in accordance with the original usage of the term in the references cited.…”

Biological Consequences and Health Risks of Low-Level Exposure to Ionizing Radiation: Commentary on the Workshop

“…Over the past three decades, experimental data in cultured cells, tissues, and animals have established that cells may detect and react very sensitively to various intracellular changes, such as pH, and extracellular environmental influences, even to single energy deposition events (Zamboglou et al 1981;Feinendegen et al 1984;Goodhead 2009). Up-regulation of existing physiological defenses and protections has been quantified in various cell systems.…”

DNA end resection is needed for the repair of complex lesions in G1-phase human cells

“…Radiation track structure simulation analysis suggests that complex DSBs are induced by IR and their frequency increases by increasing the radiation ionization density (linear energy transfer, LET). 1 Recent molecular data shows that more severe, clustered DSBs are more difficult to repair and may be responsible for the formation of chromosomal aberrations and other late effects. 2 Eukaryotic cells have evolved different mechanisms of DSB repair, and the pathway choice is influenced by cell cycle stage, chromatin structure, and damage complexity.…”