Low Doses of Ionizing Radiation: The Relationship between Damage Induction and Biological Benefit Contradicts Validity of the LNT-Hypothesis

L. Feinendegen, Morgan Lecture (Brookhaven National Laboratory)

Absorption of ionizing radiation in biological tissue generates energy deposition (track) events stochastically interacting with constituent atoms and molecules and always also creating bursts of reactive oxygen species (ROS). These ROS are quite similar to those ROS that arise abundantly and constantly by normal oxidative metabolism. ROS effects from either source need attention when assessing radiation-induced alterations in biological structure and function. Endogenous ROS alone induce about 106 DNA oxyadducts per cell per day compared to about 5 x 10-3 total DNA damage per average cell per day from background radiation exposure (1 mGy low-LET radiation per year). At this background level, the corresponding ratio of probabilities of endogenous versus radiogenic DNA double strand breaks (DSBs) per cell per day is about 103 with some 25 - 40 % of low-LET caused radiogenic DNA-DSBs being of the multi-damage-site type. Radiogenic DNA damage increases in proportion to absorbed dose over a certain dose range. The probability of a low-dose induced DSB per oncogenic stem cell to bring it into a lethal cancer is about 10-12. By evolution, tissues possess physiological mechanisms of protection against an array of potentially toxic agents, externally from the environment and endogenously from metabolism, mainly against the abundantly and constantly produced ROS. Ad hoc protection operates at a level that is genetically determined. Following small to moderate perturbation of cell-tissue homeostasis by a toxic impact, adaptive responses develop with a delay and may last from hours to weeks, even months, and aim at protecting the system against renewed insults. Protective responses encompass defense by scavenging mechanisms, DNA repair, damage removal largely by apoptosis and immune responses, as well as changes in cell proliferation. Gene expressions are altered correspondingly Acute low-dose irradiation below about 0.2 Gy not only disturbs cell-tissue homeostasis but also initiates various forms of adaptived protection that appears with a delay of hours and may last from less than a day to months. The balance between damage production and adaptive protection favors protection at low doses and damage at high doses. The low-dose induced protection appears to function against accumulation of DNA damage mainly from endogenous sources, such as ROS. Bystander effects from high-dosed cells to non-irradiated neighboring cells appear to induce both damage and protection. With respect to oncogenesis, a model using microdosimetry and based on the above dual response pattern at low doses and dose rates is consistent with published non-linear epidemiological and experimental data and, thus, contradicts the linear-no-threshold dose-risk hypothesis for radiation-induced cancer. The LNT hypothesis should be abandoned and be replaced by a hypothesis that is scientifically justified and causes less unreasonable fear and unnecessary expenditure.

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