To evaluate the lifetime carcinogenic hazards of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60 Co γ rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies, after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas, hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with increased early onset and lifetime cancer risk.

To evaluate the lifetime health effects of exposure to ionizing radiation during development, 1,680 beagles received wholebody exposures to 60 Co γ rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days after breeding, or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. There was no significant effect of irradiation on mean survival times in any groups. In 1,343 dogs allowed to live out their life span, chronic renal disease was a common cause of mortality, and irradiation in the late fetal or juvenile periods potentiated this disease, resulting in increased mortality due to renal failure. This was consistent with earlier findings of the high radiosensitivity of the kidney in the perinatal period. Hypothyroidism associated with atrophic thyroiditis was decreased by irradiation, a finding contrary to expectation and not easily explained. Diabetes mellitus was increased by irradiation in the mid- and late gestation and juvenile periods, a finding which is intriguing based on early reports of a similar finding in atomic bomb survivors. Though convulsive seizures were a common cause of mortality in the dogs, there was no evidence for increased risk associated with prenatal irradiation as has been reported in humans. Genetic analyses indicated that renal disease, hypothyroidism, diabetes mellitus and convulsive seizures all had a heritable component, but that this did not influence or bias the radiation responses evaluated.

To evaluate the lifetime hazards of exposure to ionizing radiation, 1,680 beagles received whole-body exposures to 60 Co γ rays or sham exposures during development. Eight groups of 120 dogs each received mean doses of 16-18 or 81-88 cGy at 8, 28 or 55 days of gestation, or at 2 days after birth. One group of 120 dogs received a mean of 83 cGy at 70 days of age and one group of 240 dogs received a mean of 81 cGy at 365 days of age. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. Irradiated dogs had a decreased risk for hypothyroidism, a finding that was surprising and not easily explained. Of the 1,343 life-span dogs, those exposed as neonates at 2 days of age or as juveniles at 70 days of age had evidence for an increased risk for thyroid follicular cell neoplasia. Hypothyroid dogs had a significantly increased risk for thyroid neoplasia, including greater risk for carcinomas, but no evidence of a greater sensitivity to radiation-induced tumors. In dogs with normal thyroid function irradiated at 2 or 70 days of age there was increased risk for benign and malignant follicular cell neoplasms, including multiple neoplasms. No difference between sexes was noted. These findings related to age sensitivity in the dog were consistent with the high risk for radiogenic thyroid neoplasia in humans after exposure during early childhood.

Beagle dogs that were part of a life span study of the effects of low-level ionizing radiation during development were evaluated for the incidence of skin neoplasia and solar dermatosis. A total of 991 dogs up to 14 years of age were examined. The dogs were housed in gravel-based, outdoor pens with doghouses in a high-altitude, high-sunshine level environment. Solar dermatosis was restricted to the sparsely haired, nonpigmented abdominal skin. Skin neoplasms were either removed surgically or found at necropsy. Solar dermatosis was diagnosed in 363 of the 991 dogs, an incidence of 36.6%. There were 175 hemangiomas, hemangiosarcomas, or squamous cell carcinomas of the skin in the 991 dogs. Of these, 129 tumors occurred in dogs with, and only 46 in dogs without, solar dermatosis. Of the dogs with solar dermatosis, 93 (26%) had at least one of the three tumor types, compared to only 44 (7%) of dogs without solar dermatosis. Thirty-two dogs had multiple tumor types and solar dermatosis, compared to only two dogs with multiple tumor types and no solar dermatosis. There was a highly significant correlation (P < 0.001) between the occurrence of these tumor types and solar dermatosis in the unpigmented abdominal skin. This correlation was strongest for the malignant neoplasms. Whole-body γ-radiation exposures were delivered at one of three prenatal or three postnatal ages up to 1 year of age. There appeared to be an increased risk for hemangiosarcomas and squamous cell carcinomas in dogs with solar dermatosis and given γ-ray exposures at 1 year of age. This suggests an interaction between exposures to ionizing and ultraviolet radiation.

As part of a long-term study of the effects of irradiation during development, prenatal and early neonatal mortality were evaluated for beagles exposed in utero at 8 days postcoitus (dpc), 28 dpc, 55 dpc, or 2 days postpartum. Mean doses used were 0, 0.16, or 0.83 Gy. A decrease in whelping rates was observed for female breeders irradiated at 8 dpc. There was a significant decrease in litter sizes from female breeders irradiated at 8 and 28 dpc. Both of these findings are indicative of increased embryonic mortality. There was a significant decrease in the percentage of females born after exposures given at 28 dpc, indicating a differential radiosensitivity by sex. A significant increase in early neonatal mortality up to 14 days of age was observed for beagles exposed 8 or 28 dpc, again with an excess mortality in females.

Thymic explant cultures were used to study the radiosensitivity of nonlymphoid thymic components in dogs. Thymic fragments from fetal (50 days gestation), new born, and juvenile (70 days old) dogs were irradiated in vitro at 0, 0.5, 1, 2, or 4 Gy prior to culture. Colonies were classified as epithelial, spindle, or mixed cell type, and colony numbers were counted and diameters measured. Radiation caused a significant dose-related decrease in the number of spindle cell colonies from all ages. There was a corresponding, but smaller, dose-related increase in the number of epithelial colonies. The diameter of spindle cell colonies also decreased with dose, and this was accompanied by a reduction in cell density. While epithelial colony diameters did not change consistently with dose, there was an overall reduction in cell density in these colonies. This was more severe in the fetal than in the juvenile cultures. These results indicate that the putative mesenchymal (spindle cell) components of the thymus are significantly more radiosensitive than the epithelium at all ages and that fetal epithelium is more sensitive than epithelium from postnatal animals. This suggests that radiation-induced thymic epithelial defects reported after prenatal irradiation could be due to a combination of direct epithelial injury and defective inductive interaction between epithelium and the more radiosensitive mesenchyme.

Beagle dogs were given a single, whole-body γ-radiation exposure at various stages during ocular development and were evaluated for the presence of ocular lesions. Dogs were exposed during middle or late pregnancy at 28 or 55 days postcoitus (dpc) or as neonates at 2 days postpartum (dpp). Mean whole-body and ocular doses ranged from 1.0 to 3.8 Gy. Dogs were sacrificed and ocular lesions were evaluated at 70 days, 2 years, or 4 years of age. Retinal dysplasias and atrophy were the most striking lesions related to radiation exposure. These lesions were bilateral and focal to diffuse in nature, and they increased in severity with increasing radiation dose. The stage of development at irradiation had a marked effect on the distribution of retinal lesions, with the most severe changes being present in that portion of the retina undergoing differentiation at the time of the insult. In dogs sacrificed at 70 days of age the lesions were primarily dysplasias consisting of ectopic nuclear aggregates in the photoreceptor layer, retinal folds, and retinal rosettes. With increasing age (up to 4 years), there appeared to be progression of the extent of the clinically evident lesions, and there was a change in the nature of the lesions from dysplasia to atrophy. This was accompanied by marked attenuation of the retinal vasculature.

Canine kidneys were biopsied at 2-week intervals from 3 to 13 weeks after a single 15-Gy dose of intraoperatively delivered 6 MeV electrons to determine the pathogenesis and dose-limiting tissue for radiation nephropathy. The data suggest that the dose and time after irradiation determine the dose-limiting tissue. The early functional survival of canine kidneys appeared to be dependent on parenchymal cell killing. Histologic changes in epithelial cells were seen as early as 3 weeks after irradiation. The parenchyma decreased to 50% of the preirradiation volume by 9 weeks but repopulated to near normal by 11 weeks. A second wave of depopulation, possibly due to perivascular fibrosis, was evident at 13 weeks. Previous investigators have demonstrated progressively extensive changes in renal vessels after irradiation. In this study, permanent vascular damage was seen at 3 weeks; however, most early changes in vessel walls proved to be temporary and probably resulted from atrophic vasoconstriction following parenchymal depopulation. Vessel dimensions returned to near normal as the parenchyma repopulated; however, a "histohematic barrier" created by progressively increasing perivascular fibrosis may cause a reduction in oxygen and nutrient support of the parenchyma and permanent loss of renal function.

Chinese hamsters (LF random bred) were injected intraperitoneally with a range of levels of ${}^{144}{\rm Ce}-{}^{144}{\rm Pr}$ citrate. After the injection they either had no further treatment or were partially hepatectomized at either 20 days before injection or 20 or 200 days after injection. Control hamsters were subjected to a similar surgical schedule. The average radiation dose to the liver at sacrifice ranged from 15 to 110 Gy and produced from 0.44 to 3.40 metaphase chromosomal aberrations per liver cell. Thus aberration frequency was very high when liver tumors were observed. Of the 330 animals injected with ${}^{144}{\rm Ce}$ , 109 developed primary neoplasms in the liver while no liver tumors were observed in 97 control animals. When animals with similar survival and total lifetime dose to the liver were compared, partial hepatectomy performed 20 or 200 days after ${}^{144}{\rm Ce}$ injection significantly increased liver tumor incidence. Partial hepatectomy before ${}^{144}{\rm Ce}$ injection had no effect. Enhanced cell division from partial hepatectomy plays a role in the induction of liver neoplasms following low-dose-rate β-γ exposure from the radioisotope ${}^{144}{\rm Ce}$ .

Beagle dogs were exposed by inhalation to ${}^{144}{\rm Ce}$ in fused aluminosilicate particles, a relatively insoluble, inert carrier material. The radioactive particles deposited in the deep lung resulted in chronic irradiation of the pulmonary and adjacent thoracic tissues. Dogs exposed to high levels of ${}^{144}{\rm Ce}$ in fused aluminosilicate particles received more than 25,000 rad to lung by 3 yr after exposure. They developed a severe and persistent lymphopenia, and their remaining peripheral lymphocytes showed a decreased ability to respond to plant mitogens in vitro. The lymphopenia and the functional defect in the remaining lymphocytes suggested that an immunologic suppression existed in these dogs. Many lymphocytes were being killed in vivo by the radiation but another population was present that was viable in vivo but died when placed in vitro, accounting for at least part of the reduction in response to plant mitogens. No plasma factor was found that could account for the reduced lymphocyte transformation. The ${}^{144}{\rm Ce}\text{-exposed}$ dogs developed a high incidence of primary pulmonary hemangiosarcomas between 1 and 5 yr after exposure. This suggests that carcinogenesis after intrapulmonary deposition of radionuclides may result from a combination of the direct carcinogenic effect and the immunosuppressive effect of the irradiation.