Late Effects After Incorporation of the Short-lived Alpha-emitters 224Ra and 227Th in Mice

Abstract

224Ra (half-life 3.64 days) or 227Th (half-life 18.7 days) were intraperitoneally injected in 3–4 week old NMRI mice. The spontaneous osteosarcoma incidence was about 1% in females and 0% in males. The distribution of 224Ra within the skeleton showed the highest concentration in the long bones, somewhat lower values in the vertebral column, increasing towards the lower part. Single injections of 224Ra with activities between 1 and 100 μCi/kg, corresponding to mean skeletal doses (m.s.d.) of 30–3000 rad resulted in an osteosarcoma incidence of 7% in females at the lowest activity applied and reached a maximum of 22% at higher activities, whereas in males the maximum was 8.5%. Single injections of 227Th with activities between 0.1 and 50 μCi/kg of 227Th (corresponding to m.s.d. of 20–10,000 rad) produced an osteosarcoma incidence of 3% at the lowest activity applied and a maximum incidence of 60% at 5 μCi/kg corresponding to 1000 rad. Dose protraction by fractionated application of 224Ra with individual injections of 0.5 or 1.5 or 4.5 μCi/kg twice weekly and treatment periods of 4, 12, 24 and 36 weeks reaching total doses of 12 μCi/kg (m.s.d. 360 rad), 36 μCi/kg (m.s.d. 1080 rad) and 72 μCi/kg (m.s.d. 2160 rad) resulted in an increased osteosarcoma incidence with protraction time and total dose. In this series the highest osteosarcoma incidence (more than 9(1%′0) was observed after a protraction of 36 μCi/kg (m.s.d. 1080 rad) over 36 weeks. After single injection of 224Ra or 227Th in the higher dose range the head bones represented the main location of the osteosarcoma. In addition an increased occurrence of ossifying fibromas of the jaws was observed in the higher dose groups. Fractionated application of 224Rad did not increase the tumor risk of the head bones. After 50 μCi/kg of 227Th (m.s.d. 10,000 rad) bone necrosis preceded the appearance of bone tumors. A somewhat earlier occurrence of leukemia was seen in certain groups after single injection of 227Th and one group of fractionated application of 224Ra.