Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC^1638N/+ Mice

Purpose There are uncertainties associated with the prediction of colorectal cancer (CRC) risk from highly energetic heavy ion (HZE) radiation. We undertook a comprehensive assessment of intestinal and colonic tumorigenesis induced after exposure to high linear energy transfer (high-LET) HZE radiation spanning a range of doses and LET in a CRC mouse model and compared the results with the effects of low-LET γ radiation. Methods and Materials Male and female APC^1638N/+ mice (n=20 mice per group) were whole-body exposed to sham-radiation, γ rays, ¹²C, ²⁸Si, or ⁵⁶Fe radiation. For the >1 Gy HZE dose, we used γ-ray equitoxic doses calculated using relative biological effectiveness (RBE) determined previously. The mice were euthanized 150 days after irradiation, and intestinal and colon tumor frequency was scored. Results The highest number of tumors was observed after ²⁸Si, followed by ⁵⁶Fe and ¹²C radiation, and tumorigenesis showed a male preponderance, especially after ²⁸Si. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses, suggesting either radiation-induced elimination of target cells or tumorigenesis reaching a saturation point at higher doses. Calculation of RBE for intestinal and colon tumorigenesis showed the highest value with ²⁸Si, and lower doses showed greater RBE relative to higher doses. Conclusions We have demonstrated that the RBE of heavy ion radiation-induced intestinal and colon tumorigenesis is related to ion energy, LET, gender, and peak RBE is observed at an LET of 69 keV/μm. Our study has implications for understanding risk to astronauts undertaking long duration space missions.