Low dose and dose rate effects on radiation mutagenesis, teratogenesis and carcinogenesis

Complete text of publication follows. Low dose and dose rate effectiveness is one of the most important subject to study for the risk of radiations in humans. In the present study, analyses were made at various dose rates (0.04 to 1, 189 mGy/min) for our data on radiation induced cancer, malformation and mutation in mice after the germ-line, in utero or postnatal exposure and also for the direct effects of radiation on human thyroid tissues maintained in SCID mice. Exposure of young adult mice to high dose γ-rays (6.8 Gy) at high dose rate induced high incidence of tumors in various organs. However, the incidences of leukaemia, skin tumors and hepatomas decreased strikingly by lowering the dose rate (DDREF; 20-45). DDREF of leukaemia was 1.8-2.5 at lower doses (0.4 and 2.0 Gy). Dose rate effects were observed in all the other tumors (DDREF; 2-4) except breast tumor. In utero exposure to X-rays, 60Co γ-rays, 252Cf neutron, and 3H water resulted in the significant increase of somatic (coat color) mutations, malformations and tumors in PTHTF1 mice at dose range from 0.1 to 1.0 Gy, and significant reduction of these defects was observed by low dose rate exposure (DDREF; 3- 20). Furthermore, significant increases of leukemia, skin cancer and lung tumor were observed in the offspring of mice exposed to X-rays and γ-rays at spermatogonial stage at high dose rate, but there was no increase of these tumors in the offspring after low dose rate exposure, showing an apparent dose rate effect or protracted dose effect, as in the case in specific locus mutation. In contrast, double-strand break repair deficient SCID mice showed extremely high sensitivity to both high and low dose rate γ-rays for the induction of leukemia, fetal death and malformation, and there were no dose rate effects in the incidences of these defects, while dose rate effect was apparent in wild-type mice. This indicates that double-strand break repair is a major cause of dose rate effectiveness in radiation induced fetal death, malformation and leukemia. We have established a novel biotechnology to maintain normal human organs/tissues for a long period (3 years) in the improved SCID mice which are defective of T-cell and B-cell function and can not reject human tissues. Consecutive exposure of human thyroid tissues to X-rays and 137Cs γ-rays at high dose rate resulted in significant yields of p53 and c-kit mutations in the human thyroid tissues in addition to morphological and functional disorder. However, no mutations have been induced by low dose rate ?-ray exposure, showing an apparent dose rate effects, i.e., high repairing ability in the human thyroid tissue. (Supported by MEXT Japan, Mitsubishi Foundation, Princess Takamatsu Cancer Research Foundation, Research for the Future-JSPS, and Japan Space Forum).