Radiation risk to low fluences of alpha particles may be greater than we thought

Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the international Commission on Ra diation Protection (ICRP) and the United States National Council on Radiati on Protection and Measurements (NCRP) have recommended that estimates of ca ncer risk for low dose exposure be extrapolated from higher doses by using a linear, no-threshold model. This recommendation is based on the dogma tha t the DNA of the nucleus is the main target for radiation-induced genotoxic ity and, as fewer cells are directly damaged, the deleterious effects of ra diation proportionally decline. In this paper, we used a precision microbea m to target an exact fraction (either 100% or less than or equal to 20%) of the cells in a confluent population and irradiated their nuclei with exact ly one a particle each. We found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to t he response. In fact, irradiation of 10% of a confluent mammalian cell popu lation with a single a particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. Th is effect was significantly eliminated in cells pretreated with a 1 mM dose of octanol, which inhibits gap junction-mediated intercellular communicati on, or in cells carrying a dominant negative connexin 43 vector. The data i mply that the relevant target for radiation mutagenesis is larger than an i ndividual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimates for low dose, high linear-energy-tra nsfer (LET) radiation exposure.