Non-targeted effects as a paradigm breaking evidence.

The finding that mammalian cells and tissues and whole organisms react differently at high than at low doses of ionizing radiation questions the scientific validity of the linear no-threshold concept for low-dose exposures. Indeed, the classical paradigm of radiobiology was based on the concept that all radiation effects on living matter are due to the direct action of radiation. Meanwhile, the discovery of non-targeted and delayed radiation effects has challenged this concept, and one might ask whether a new paradigm has to be developed to provide more realistic protection against low radiation doses. The present overview summarizes recent findings on the low-dose radiation-induced bystander effect, genomic instability, radiation hypersensitivity, hormesis, radioadaptive and transgenerational responses. For these, some common features can be recognized. Most of these phenomena include (1) intra- and intercellular signaling, involving reactive oxygen species (ROS). This signaling may be transient or persistent, and may involve the release of cytokines (bystander effect, genomic instability) or epigenetic changes (translesional responses), (2) a large variability of responses depending on the type of radiation, genotype (DNA repair capacity) and physiological state of the cells and tissues. Many more parameters are involved in responses at low doses than at high doses, and different pathways are activated. At low doses, non-linear responses are obtained that are not compatible with the LNT concept. At present, more work is needed to identify the essential parameters involved and to provide a basis for proper modelling of low-dose radiation health effects for radiation protection purposes.