Prominent Dose-Rate Effect and Its Age Dependence of Rat Mammary Carcinogenesis Induced by Continuous Gamma-Ray Exposure

Although the risk of breast cancer after high dose rate radiation exposure has been firmly established, the risk incurred by low dose rates is not well understood. Herein, we provide experimental evidence for dose rate and age dependencies induced by continuous γ-ray irradiation on mammary carcinogenesis. Female rats were subjected to continuous whole-body irradiation i) at 7 weeks of age (denoted adults) at a dose rate of 360 mGy/h (4 Gy total) or ii) at 3 weeks of age (denoted juveniles) or as 7-week-old adults at a dose rate of 6 mGy/h (18 Gy total). Additional rats were acutely irradiated at 13 weeks of age at a dose rate of 30 Gy/h (0.5–4 Gy total). We observed the incidence of mammary tumors by weekly palpation until they were 90 weeks old and following pathological inspection upon autopsy. The tumor incidence rate for each group was characterized by Cox regression analysis. When adult rats were irradiated at 60 mGy/h for a total of 4 Gy, their hazard ratio for mammary carcinoma significantly increased relative to unirradiated controls; however, for adult rats irradiated at 3–24 mGy/h, even though they also received a total of 4 Gy, their hazard ratio for carcinoma incidence did not significantly increase. A larger increase in the incidence rate of carcinoma per dose was found for the juveniles than for the adults irradiated at 6 mGy/h, whereas age did not influence the effect of acute irradiation at 30 Gy/h; a threshold-like dose response was observed for irradiation at 6 mGy/h (threshold, ~2.5 and ~4 Gy for juveniles and adults, respectively). Regarding benign tumors of the mammary gland, a significant increase in their incidence was observed for irradiation down to 6 mGy/h, but not at 3 mGy/h, and there was no evidence of age-dependent induction. Thus, induction of female rat mammary carcinogenesis by continuous γ-ray irradiation was age dependent and drastically increased for adult rats between 24 and 60 mGy/h