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Within 1 yr after localized irradiation of a hind limb with single (1756 rads) or fractionated (4650 rads in 3 wk) x-ray doses, radiation-induced osteosarcomas were observed in four of nine single-dose rabbits and two of 11 fractionated-dose rabbits. Tumors were observed in the proximal tibia in five cases and the distal femur in one case. In terms of production of osteoid or osseous tissue, three tumors were well differentiated, one slightly differentiated, and two (spindle-cell tumors) undifferentiated. This report summarizes the Tc-99m pyrophosphate (TcPPi) imaging and autoradiographic, radiographic, and histologic studies of these osteosarcomas. The four differentiated osteosarcomas were detected 1--2.5 mo earlier by TcPPi imaging than by radiography, whereas the two undifferentiated tumors were suspected 2 wk or 3.5 mo earlier radiographically. Autoradiograms showed TcPPi localization in bone produced by differentiated osteosarcomas, and in regions of reactive bone resorption and formation peripheral to tumors. The results support a recommendation for combined radiographic and scintigraphic techniques for the early detection of osteosarcomas.

Thirty-nine adult male Beagles received either fast neutron or photon irradiation to the right thorax to determine the relative biological effectiveness (RBE) of fast neutrons on normal pulmonary tissue. The right anterior abdomen was included in the field of radiation. Twenty-four dogs (six/group) received fast neutrons with an average energy of 15 MeV to total doses of 1000, 1500, 2250 or 3375 rad in four fractions per week for six weeks. Fifteen dogs received 3000, 4500 or 6750 rad of photons (five/group) in an identical fractionation pattern. All neutron irradiated dogs receiving 3375 and 2250 rad and one receiving 1500 rad developed clinical signs of pancreatic, hepatic and gastrointestinal disturbances. The liver enzymes of these dogs became elevated and they died or were euthanatized in extremis 47-367 days after irradiation. Only one 6750 rad photon dog developed similar signs and died 708 days post-irradiation. Five neutron and 10 photon exposed dogs died of other causes. Neutron-induced lesions in the stomach and duodenum included hemorrhages, erosions, ulcerations and fibrosis. Ulcers perforated the GI tract of five dogs. Pancreatic lesions included degranulation and necrosis of acinar cells, fibrosis ans atrophy. Islet cells were not obviously damaged. All lesions were associated with degenerative and occlusive vascular changes. The RBE of fast neutrons, assessed by clinical signs, gross and microscopic pathology, is approximately 3-4.5 for pancreas and about 4.5 for pylorus and duodenum.

One hundred fifty-one beagle dogs were irradiated with either photons or fast neutrons (15 MeV) to one of three dose-limiting normal tissues--spinal cord, lung, or brain. The radiation was given in four fractions per week for 5 weeks (spinal cord), 6 weeks (lung), or 7 weeks (brain) to total doses encompassing those given clinically for cancer management. To date, no nonirradiated dogs or photon-irradiated dogs have developed any neoplasms. Seven dogs receiving fast neutrons have developed 9 neoplasms within the irradiated field. Of the neutron-irradiated dogs at risk, the incidence of neoplasia was 15%. The latent period for radiation-induced cancers has varied from 1 to 4 1/2 years at this time in the study.

Quantitative Tc-99m pyrophosphate bone imaging was carried out in locally irradiated and control areas of New Zealand albino rabbits to determine the potential role of bone imaging in assessing the time course of radiation effects in bone and surrounding tissues. In vitro Tc-99m tissue assays, and serial radiographs. from the irradiated and contralateral limbs were obtained at regular intervals over the first 12 mo following irradiation for comparison with quantitative results from the camera studies. The autoradiographic localization of TcPPi was also studied in the x-irradiated and contralateral bones of the rabbits. The results show that TcPPi bone imaging is a sensitive in vivo indicator of early radiation effects upon vasculature and bone remodeling. The findings suggest that the quantitative bone-imaging technique may be useful in the evaluation of the effects of treatment modalities on the skeleton.

Thirty-nine adult male purebred beagles received either fast neutron or photon irradiation to the right thorax to determine the effects on pulmonary tissue. The right half of the liver was included in the field of radiation. Twenty-four dogs (six/group) received fast neutrons with a mean energy of 15 MeV to total doses of 1000, 1500, 2250, or 3375 rads in four fractions per week for 6 weeks. Fifteen dogs received 3000, 4500, or 6750 total rads of photons (five dogs/group) in an identical fractionation pattern. All neutron-irradiated dogs receiving 3375 and 2250 rads and one receiving 1500 rads developed clinical signs, hepatic enzyme, and bilirubin elevations, and the dogs died or were euthanized in extremis on postirradiation day 47-291. Signs of liver injury, other than enzyme changes, have not developed to date (1200-1300 days) in the remaining dogs, except in one 6750-rad photon dog that died of hepatic failure on postirradiation day 708. At necropsy, the irradiated right lobes of the liver were atrophic and the nonirradiated left lobes underwent compensatory hypertrophy. Hepatic arterioles and bile ducts were injured in every dog, but no obstructive lesions were observed in hepatic veins. Portal fibroplasia, bile retention, and proliferation of bile ductules was common; the latter two changes also occurred in the nonirradiated lobes. No qualitative differences were observed between hepatic lesions in neutron- versus photon-irradiated dogs. The relative biological effectiveness of fast neutrons for liver damage appears to be no less than 4.5.

Autoradiographs were prepared from tissues of rats sacrificed 10 minutes after injection of biologically active 125I-labeled parathyroid hormone. No radioactivity was seen in intestine and muscle. Deposition in liver was diffuse showing some sinusoidal concentrations. Depostion in kidney was high and, nearly all activity appeared in selected tubules (presumably proximal tubules) in the outer third of the cortex. Specific localization was also seen in bone particularly in the cellular layers of periosteum and endosteum adjacent to bony matrix and to some extent in osteocytes.

Recent improvements in radiation therapy of some malignancies in lower abdominal sites are leading to a prolongation of life in persons of child-bearing age. These successes require an evaluation of the possible undersirable consequences of the unavoidable gonadal irradiation that occurs in these cases. A review of radiobiological data from experimental animal studies and retrospective clinical studies suggests that in most instances human gonadal exposures in both sexes are insufficient to cause permanent sterility, because the exposures are fractionated and the total gonadal dose is much less than 600 rads. As a consequence, return of fertility must be anticipated, and the worrison questions of radiation-induced genetic damage in subsequent pregnancies must be addressed. This review did not substantiate this fear, because no case reports could be found of malformed infants among the progeny of previously irradiated parents. Some experimental studies suggest that radiation-damaged spermatogonia are self-destructive, but any evidence for this phenomenon in the ovary is nonexistent. We suggest that the difference between fact and theory here may be the mathematical result of the interplay of low probability for occurrences and the few patients who until now have survived long enough for study.

Histologic and tracer techniques were used to investigate and document alterations in bone pathophysiology subsequent to irradiation of the left hind limb of rabbits. Numerous time-dependent changes were observed. Among these were an inflammatory response shortly after irradiation, and an increase in the remodeling of cortical bone, which peaked between 3 and 6 mo after irradiation. The changes in bone remodeling correlated with changes in vascular patency in a manner consistent with the hypothesis that radiation damage in mature bone is mediated primarily through alterations in the fine vasculature. The findings of this study provide important information on the time course of changes in bone pathophysiology following regional irradiation. They are used in the second of this series of papers to help establish which mechanisms are responsible for postirradiation alterations in the localization of Tc-99m pyrophosphate in these rabbits.