plutonium-dioxide and Lung-Neoplasms

The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

Topics: Adolescent; Adult; Aged; Air Pollutants, Radioactive; Animals; Bone Neoplasms; Cohort Studies; Disease Models, Animal; Dogs; Dose-Response Relationship, Radiation; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasms, Radiation-Induced; Nitrates; Nuclear Reactors; Occupational Exposure; Plutonium; Radionuclide Generators; Registries; Risk Factors; Russia; Young Adult

Accidental exposure by inhalation to alpha-emitting particles from mixed oxide (MOX: uranium and plutonium oxide) fuels is a potential long-term health risk to workers in nuclear fuel fabrication plants. For MOX fuels, the risk of lung cancer development may be different from that assigned to individual components (plutonium, uranium) given different physico-chemical characteristics. The objective of this study was to investigate late effects in rat lungs following inhalation of MOX aerosols of similar particle size containing 2.5 or 7.1% plutonium. Conscious rats were exposed to MOX aerosols and kept for their entire lifespan. Different initial lung burdens (ILBs) were obtained using different amounts of MOX. Lung total alpha activity was determined by external counting and at autopsy for total lung dose calculation. Fixed lung tissue was used for anatomopathological, autoradiographical, and immunohistochemical analyses. Inhalation of MOX at ILBs ranging from 1-20 kBq resulted in lung pathologies (90% of rats) including fibrosis (70%) and malignant lung tumors (45%). High ILBs (4-20 kBq) resulted in reduced survival time (N = 102; p < 0.05) frequently associated with lung fibrosis. Malignant tumor incidence increased linearly with dose (up to 60 Gy) with a risk of 1-1.6% Gy for MOX, similar to results for industrial plutonium oxide alone (1.9% Gy). Staining with antibodies against Surfactant Protein-C, Thyroid Transcription Factor-1, or Oct-4 showed differential labeling of tumor types. In conclusion, late effects following MOX inhalation result in similar risk for development of lung tumors as compared with industrial plutonium oxide.

Topics: Administration, Inhalation; Aerosols; Animals; Body Burden; Dose-Response Relationship, Radiation; Immunohistochemistry; Liver Cirrhosis; Lung; Lung Neoplasms; Male; Plutonium; Rats; Rats, Sprague-Dawley; Time Factors; Uranium Compounds

From the early 1970's to the late 1980's, Pacific Northwest National Laboratory conducted life-span studies in beagle dogs on the biological effects of inhaled plutonium ((238)PuO(2), (239)PuO(2), and Pu[NO(3)](4)) to help predict risks associated with accidental intakes in workers. Years later, the purpose of the present follow-up study was to reassess the dose-response relationship for lung cancer in the PuO(2) dogs compared to controls-with particular focus on the dose-response at relatively low lung doses. A PuO(2) aerosol (2.3 mum activity-median aerodynamic diameter, 1.9 mum geometric standard deviation) was administered to six groups of 20 young (18-mo-old) beagle dogs (10 males and 10 females) by inhalation at six different activity levels, as previously described in Laboratory reports. Control dogs were sham-exposed. In dose level 1, initial pulmonary lung depositions were 130 + or - 48 Bq (3.5 + or - 1.3 nCi), corresponding to 1 Bq g lung tissue (0.029 + or - 0.001 nCi g(-1)). Groups 2 through 6 received initial lung depositions (mean values) of 760, 2,724, 10,345, 37,900, and 200,000 Bq (22, 79, 300, 1,100, and 5,800 nCi) PuO(2), respectively. For each dog, the absorbed dose to lungs was calculated from the initial lung burden and the final lung burden at time of death and lung mass, assuming a single, long-term retention function. Insoluble plutonium oxide exhibited long retention times in the lungs. Increased dose-dependent mortality due to lung cancer (bronchiolar-alveolar carcinoma, adenocarcinoma, and epidermoid carcinoma) and radiation pneumonitis (in the highest exposure group) were observed in dogs exposed to PuO(2). Calculated lung doses ranged from a few cGy (lowest exposure level) to 7,764 cGy in dogs that experienced early deaths from radiation pneumonitis. Data were regrouped by lifetime lung dose and plotted as a function of lung tumor incidence. The lung tumor incidence in controls and zero-dose exposed dogs was 18% (5/28). However, no lung tumors were observed in 16 dogs with the lowest lung doses (8 to 22 cGy, mean 14.4 + or - 7.6 cGy), and only one lung tumor was observed in the next 10 dogs with lung doses ranging from 27 to 48 cGy (mean 37.5 + or - 10.9 cGy). By least-squares analysis, a pure-quadratic function represented the overall dose-response (n = 137, r = 0.96) with no apparent dose-related threshold. Reducing this function to three linear dose-response components, we calculated risk coefficients for each. However, th

Topics: Administration, Inhalation; Aerosols; Alpha Particles; Animals; Body Burden; Carcinogens; Dogs; Dose-Response Relationship, Radiation; Female; Homeostasis; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Plutonium; Risk Assessment; Time Factors

The stochastic effects in the lung of inhaled, insoluble particles of alpha- and beta-emitting particles and low-linear energy transfer (LET) thoracic irradiation were compared in rats using data from previously conducted studies. Male and female F344 rats were exposed briefly by nasal inhalation to relatively insoluble aerosols of CeO(2) or PuO(2) to achieve a range of four lung burdens. The mean lifetime beta doses to the lung were 3.6 + or - 1.3 Gy, 6.8 + or - 1.7 Gy, 12 + or - 4.5 Gy, and 37 + or - 5.9 Gy. The mean lifetime alpha doses to the lung were 0.06 + or - 0.03 Gy, 0.95 + or - 0.46 Gy, 3.7 + or - 1.6 Gy, and 12 + or - 2.4 Gy. Additional rats were exposed to fractionated thoracic doses of x rays given on 10 successive working days. The lifetime doses to the lung were 3.3 Gy, 5.7 Gy, 11 Gy, and 38 Gy. Appropriate sham controls were included in each group and all groups were observed for their life spans. Lung neoplasms were found after all exposures, with the incidence increasing with radiation dose. Rats exposed to PuO(2) had the highest incidence, 94% in the group with a dose of 12 Gy. The incidence in the groups exposed to inhaled CeO(2) or fractionated thoracic x-irradiation was not significantly different. The incidence of lung tumors in the PuO(2) groups was 21 times higher than that of the groups exposed to the lower LET radiations. These results support a radiation-weighting factor of 20, as recommended by ICRP 60.

Topics: Administration, Inhalation; Aerosols; Alpha Particles; Animals; Beta Particles; Body Burden; Cerium; Cerium Radioisotopes; Dose-Response Relationship, Radiation; Female; Lung; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred F344; Stochastic Processes; X-Rays

Determination of radiation protection guidelines for persons working with plutonium has been complicated by limited human data on the biological behavior and subsequent health effects from internally deposited plutonium. One solution has been the use of animal models to predict likely health effects in humans. To compare the relationships between plutonium inhalation and lung fibrosis and lung cancer, data from life-span studies of beagle dogs given a single exposure to either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide(239PuO2) were analyzed. Estimates of the cumulative hazard of lung fibrosis and lung cancer after exposure to either were generated. The hazard of lung fibrosis was not consistent with a linear no-threshold model, although the magnitude of the threshold differed by radionuclide. In dogs given 239PuO2,the best model of lung fibrosis incorporated a linear dose response function; a linear-quadratic dose-response function fit the data better in dogs given 238PuO2. At any given cumulative dose, the lung fibrosis hazard was greater for dogs given 238PuO2. In dogs given 238PuO2, with or without covariates, aquadratic dose-response function for lung cancer hazard fit better than a linear no-threshold model. In dogs given 239PuO2, models of lung cancer with the dose-response function as the sole predictor variable were consistent with a linear no-threshold model; however, a quadratic dose-response function with a cell-killing term fit better. These findings have implications for radiation protection because, while lung cancer hazard was dependent on cumulative dose, regardless of isotope, the lung fibrosis hazard depended on both cumulative dose and isotope.

Topics: Administration, Inhalation; Animals; Dogs; Dose-Response Relationship, Radiation; Female; Fibrosis; Life Expectancy; Lung Neoplasms; Male; Plutonium; Probability; Radiation Dosage; Risk Assessment; Time Factors

Determination of radiation protection guidelines for persons working with plutonium has been complicated by limited human data on the biological behavior and subsequent health effects from internally deposited plutonium. One solution has been the use of animal models to predict likely health effects in humans. To compare the relationships between plutonium inhalation and lung fibrosis and lung cancer, data from life-span studies of beagle dogs given a single exposure to either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide (239PuO2) were analyzed. Estimates of the cumulative hazard of lung fibrosis and lung cancer after exposure to either were generated. The hazard of lung fibrosis was not consistent with a linear no-threshold model, although the magnitude of the threshold differed by radionuclide. In dogs given 239PuO2, the best model of lung fibrosis incorporated a linear dose-response function; a linear-quadratic dose-response function fit the data better in dogs given 238PuO2. At any given cumulative dose, the lung fibrosis hazard was greater for dogs given 238PuO2. In dogs given 238PuO2, with or without covariates, a quadratic dose-response function for lung cancer hazard fit better than a linear no-threshold model. In dogs given 239PuO2, models of lung cancer with the dose-response function as the sole predictor variable were consistent with a linear no-threshold model; however, a quadratic dose-response function with a cell-killing term fit better. These findings have implications for radiation protection because, while lung cancer hazard was dependent on cumulative dose, regardless of isotope, the lung fibrosis hazard depended on both cumulative dose and isotope.

Topics: Animals; Dogs; Dose-Response Relationship, Radiation; Incidence; Inhalation Exposure; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Pulmonary Fibrosis

Beagle dogs inhaled graded exposure levels of insoluble plutonium dioxide ((239)PuO(2)) aerosols in one of three monodisperse particle sizes at the Lovelace Respiratory Research Institute (LRRI) to study the life-span health effects of different degrees of alpha-particle dose non-uniformity in the lung. The primary noncarcinogenic effects seen were lymphopenia, atrophy and fibrosis of the thoracic lymph nodes, and radiation pneumonitis and pulmonary fibrosis. Radiation pneumonitis/ pulmonary fibrosis occurred from 105 days to more than 11 years after exposure, with the lowest associated alpha-particle dose being 5.9 Gy. The primary carcinogenic effects also occurred almost exclusively in the lung because of the short range of the alpha-particle emissions. The earliest lung cancer was observed at 1086 days after the inhalation exposure. The most common type seen was papillary adenocarcinoma followed by bronchioloalveolar carcinoma. These lung cancer results indicate that a more uniform distribution of alpha-particle dose within the lung has an equal or possibly greater risk of neoplasia than less uniform distributions of alpha-particle dose. The results are consistent with a linear relationship between dose and response, but these data do not directly address the response expected at low dose levels. No primary tumors were found in the tracheobronchial and mediastinal lymph nodes despite the high alpha-particle radiation doses to these lymph nodes, and no cases of leukemia were observed.

Topics: Absorption; Animals; Dogs; Dose-Response Relationship, Radiation; Female; Hematology; Inhalation Exposure; Lung Neoplasms; Male; Particle Size; Plutonium; Pulmonary Fibrosis; Radiation Dosage; Radiation Pneumonitis; Radiometry; Risk Assessment; Tissue Distribution

To compare the incidence of each lung tumour type after inhalation exposure of rats to either NpO(2) or industrial PuO(2) aerosols, which have a similar size.. Male Sprague-Dawley rats were exposed once and followed during their whole life span. At the end of their life, the whole lungs were fixed, embedded and cut into thin sections for histological analysis. The presence of tumours was evaluated on three distinct levels of the lobes for phenotype determination to establish dose-effect relationships.. In the range of lung doses studied (0.05 to more than 50 Gy), the general trend was an increased frequency of all types of tumours after inhalation exposure to neptunium compared with plutonium. The linearity of the lower part of the dose-effect relationships for all malignant lung tumours leads to the conclusion that NpO(2) is 3.3-fold more carcinogenic than PuO(2).. According to a linear extrapolation of the data on malignant lung tumour incidence collected among all studies reported on actinide oxide carcinogenesis, the risk of lung tumour appears to vary over a factor of about 10 depending on the nature and/or size of the aerosol. This variation has to be taken into account for a realistic assessment of tumour risk.

Topics: Actinoid Series Elements; Aerosols; Animals; Dose-Response Relationship, Radiation; Lung; Lung Neoplasms; Male; Neptunium; Oxides; Phenotype; Plutonium; Radiation Dosage; Rats; Rats, Sprague-Dawley; Risk Factors; Time Factors

Radiation-induced pulmonary carcinogenesis was compared in female Wistar rats following either inhalation exposure to alpha-emitting (239)PuO(2) aerosols, whole-body or thoracic X-ray irradiation. Dose-dependent survival reduction was correlated with increased malignant lung tumors at doses over 0.45 Gy, reaching the maximum incidence of 90% at 6.6-8.5 Gy in (239)Pu-exposed rats. While the differential dose responses for each histopathological type of tumors were noted, almost 70-80% were carcinomas among all of the primary tumors from (239)Pu-exposed rats. As the dose response curves for lung carcinomas were compared, the slope of the fit linear equation and the calculated relative effectiveness for 50% incidence of lung carcinomas were approximately 11-times as high in (239)Pu-exposure as those of thoracic X-irradiation. The numbers of tumor lesions distributed in the lung per tumor-bearing animal were about 2-fold more in (239)Pu-exposed rats, while the proportions of their histopathological types were similar between (239)Pu-exposure and X-irradiation. These results indicate that the magnitudes of the relative effectiveness or risk for pulmonary carcinogenesis are greater in (239)Pu-exposure than X-irradiation, and that radiation-induced lung tumors appear to originate mostly from the same target epithelial cells.

Topics: Adenoma; Animals; Carcinoma; Computer Simulation; Dose-Response Relationship, Radiation; Female; Inhalation Exposure; Lung Neoplasms; Models, Biological; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Radiometry; Rats; Survival Rate; Whole-Body Irradiation; X-Rays

Immunohistochemical examinations were performed on rat pulmonary tumors induced by inhalation exposures to 239PuO2 aerosols, or by X-ray-irradiation to identify and compare cellular origins or, in turn, target cells at risk for radiation carcinogenesis. Both plutonium-induced and X-ray-induced pulmonary tumors appeared to occur from the lower respiratory tract epithelium through bronchioles into alveoli, and were histopathologically diagnosed as adenoma, adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma. Immunohistochemical staining of neoplastic lesions using rabbit polyclonal antibodies to rat surfactant apoprotein A specific for alveolar type II pneumocytes, and Clara cell antigen specific for nonciliated bronchiolar Clara cells, showed that most of the adenomatous and adenocarcinomatous lesions from plutonium-exposed or X-irradiated rats were positive for either or both antigens, while, in contrast, adenosquamous and squamous lesions were mostly negative for both antigens. Even though there were some differences in the proportions and distributions of immunoreactive cells between plutonium- and X-ray-induced tumors and among neoplastic lesions, the results indicate that radiation-induced pulmonary adenomas and adenocarcinomas mostly originate from either alveolar type II pneumocytes or bronchiolar Clara cells, while adenosquamous and squamous carcinomas may be derived from the other epithelial cell components, or might have lost specific antigenicity during their transforming differentiation.

Topics: Administration, Inhalation; Aerosols; Animals; Female; Immunohistochemistry; Lung Neoplasms; Plutonium; Radiation Injuries; Rats; X-Rays

Sequential examinations were done on the pulmonary cytokinetics and pulmonary lesions in rats after inhalation exposure to (239)PuO(2) aerosols to investigate the pathogenesis of lung tumors. Total cell yields of lavaged bronchoalveolar cells as well as the estimated numbers of pulmonary alveolar macrophages were significantly reduced from 1 to 3 months after exposure but recovered thereafter to the control levels. The proportions of multinucleated or micronucleated pulmonary alveolar macrophages increased significantly in lavaged cells from 1 month, and the increase was sustained up to 18 months after exposure. Both tumor necrosis factor and nitric oxide were shown to be differentially released from stimulated cultures of pulmonary alveolar macrophages during the period from 6 to 18 months after exposure. The labeling indices of alveolar and bronchiolar epithelial cells treated with 5-bromo-2'-deoxyuridine increased significantly in lungs from 3 months and were sustained up to 18 months after exposure. Histopathological examinations revealed that after the early inflammation, hyperplasia and metaplasia of the lining of the bronchioloalveolar epithelium were predominant from 3 to 6 months, while adenomatous or adenocarcinomatous lesions appeared and developed from 12 months after exposure. The appearance of primary lung tumors, almost all of which were adenomas and adenocarcinomas, was found in the dose range of 1 to 2 Gy from 12 months after exposures. These results indicate that the pathogenetic process initiated by early cellular damage and alterations associated with inflammation is followed by the proliferative and metaplastic lesions of pulmonary epithelium, leading to the appearance and development of pulmonary neoplasms from 1 year after the inhalation exposures in rats that received a minimum lung dose of more than 1 Gy.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Bronchoalveolar Lavage Fluid; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; DNA Replication; Epithelial Cells; Female; Hyperplasia; Inflammation; Lung; Lung Neoplasms; Macrophages, Alveolar; Metaplasia; Neoplasms, Radiation-Induced; Nitric Oxide; Plutonium; Radiation Injuries, Experimental; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

We investigated mutations of the Tp53 tumor suppressor gene (formerly known as p53) in the lung tumors induced in rats after inhalation of plutonium dioxide ((239)PuO(2)) aerosols. Exons 5, 6, 7 and 8 of the Tp53 gene were examined for mutations by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified fragments and direct sequencing analysis. Almost all the mutations were guanine (G) to adenine (A) transitions and were distributed in exons 5 and 6. The Tp53 mutations occurred in lung tumors of various phenotypes and levels of immunohistochemical staining of Tp53 nuclear protein. These results indicate that the Tp53 mutations are not associated with tumor phenotype and nuclear accumulation of Tp53 protein, and that the G to A transition could be a common point mutation in the lung tumors seen after the inhalation of plutonium dioxide. The point mutations in the Tp53 gene seem to play a role in the development of lung tumors in rats after inhalation exposures to plutonium dioxide.

Topics: Animals; Female; Genes, p53; Lung Neoplasms; Mutation; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Wistar

Dose responses were compared among primary lung tumors and their histological types induced by a single inhalation exposure of female Wistar strain rats to submicron-size and polydispersed aerosols of plutonium dioxide (239PuO2). While the primary lung tumors were found only in 2.3% of the unexposed control animals, the frequency of all the primary lung tumors in the exposed animals was 44% at the mean lung dose of 0.71 Gy, and increased sharply at the doses of 1.5 Gy or more, reaching the maximum of 97% at 5.4 Gy, and the dose responses around at 1.0 Gy were different between benign and malignant lung tumors. Almost all the pulmonary tumors in the exposed animals were classified into epithelial types such as adenomas, adenocarcinomas, adenosquamous carcinomas, and squamous cell carcinomas. The dose responses were different between these tumor types as shown by the peak incidence of adenomas at 0.71 Gy, adenocarcinomas at 2.9 Gy, adenosquamous and squamous cell carcinomas at 5.4-8.5 Gy, respectively. As the magnitudes of neoplastic lesions in pulmonary carcinomas were expressed by histological scores, metaplasias and adenomatous lesions most frequently appeared at doses of 1.5 Gy, while the appearance and increase of carcinomatous lesions differed in the dose ranges as shown by the peak incidence of adenocarcinomatous lesions at 2.9 Gy, and adenosquamous or squamous lesions at 5.4-6.6 Gy. These results indicate a differential dose response of pulmonary carcinogenesis in which metaplasias and benign adenomas were induced at lower doses (< 1.0 Gy), whereas malignant carcinomas were induced at relatively higher doses (> 1.5 Gy). Together with the increase of carcinomatous lesions at higher doses, the intranuclear p53 protein accumulation was detectable, but only in a few percentages of malignant carcinomas.

Topics: Administration, Inhalation; Animals; Dose-Response Relationship, Radiation; Female; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Wistar; Tumor Suppressor Protein p53

Combined analyses of data on 260 life-span beagle dogs that inhaled 238PuO2 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets.

Topics: Administration, Inhalation; Animals; Bone Neoplasms; Data Interpretation, Statistical; Dogs; Dose-Response Relationship, Radiation; Female; Linear Models; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Models, Statistical; Neoplasms, Radiation-Induced; Plutonium; Proportional Hazards Models; Risk Factors

Beagle dogs exposed to 238PuO2 aerosols (136 dogs, 13-22 per group, mean initial lung depositions of 0.0, 0.13, 0.68, 3.1, 13, 52 and 210 kBq) were observed throughout life to determine tissues at risk and dose-effect relationships. The pulmonary retention of 238Pu was represented by the sum of two exponentially decreasing components of the initial lung deposition; about 84% cleared with a 174-day half-time; the half-time of the remainder was 908 days. The average percentages of final body burden found in lung, skeleton, liver and thoracic lymph nodes in the 30 longest-surviving dogs (mean survival 14 years) were 1, 46, 42 and 6%, respectively. Of 116 beagles exposed to plutonium, 34 (29%) developed bone tumors, 31 (27%) developed lung tumors, and 8 (7%) developed liver tumors. Although lungs accumulated a higher average radiation dose than skeleton, more deaths were due to bone tumors than to lung tumors. Deterministic effects included radiation pneumonitis, osteodystrophy, hepatic nodular hyperplasia, lymphopenia, neutropenia and sclerosing tracheobronchial lymphadenitis. Hypoadrenocorticism was also observed in a few dogs. Increased serum alanine aminotransferase, indicative of liver damage, was observed in groups with > or =3.1 kBq initial lung deposition. Estimates of cumulative tissue dose in a human exposed to airborne 238PuO2 for 50 years at a rate of one annual limit on intake each year were derived based on a comparison of the data on metabolism for humans and beagles. The 50-year dose estimates for humans are an order of magnitude lower than doses at which increased incidence of neoplasia was observed in these dogs, whereas the projected doses to humans from 50-year exposure at the annual limit of intake are of similar magnitude to those at which deterministic effects were seen in the beagles.

Topics: Addison Disease; Administration, Inhalation; Animals; Bone Neoplasms; Dogs; Dose-Response Relationship, Radiation; Female; Hematologic Diseases; Humans; Liver Neoplasms; Lung; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Plutonium; Radiation Injuries, Experimental; Radiation Pneumonitis; Risk; Tissue Distribution

This study was conducted to determine the biological effects of inhaled 238PuO2 over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of 238PuO2 to achieve graded levels of initial lung burden (ILB). The aerosols also contained 169Yb to provide a gamma-ray-emitting label for the 238Pu inhaled by each dog. Excreta were collected periodically over each dog's life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest alpha-particle doses, ranging from 0.16-68 Gy for the lung, 0.08-8.7 Gy for the skeleton and 0.18-19 for the liver. At death all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. Bone tumors found in 93 dogs were the most common cause of death. Lung tumors found in 46 dogs were the second most common cause of death. Liver tumors, which were found in 20 dogs but were the cause of death in only two dogs, occurred later than the tumors in bone and lung. Tumors in these three organs often occurred in the same animal and were competing causes of death. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to 238PuO2.

Topics: Administration, Inhalation; Alpha Particles; Animals; Body Burden; Bone Neoplasms; Dogs; Dose-Response Relationship, Radiation; Female; Gamma Rays; Longevity; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Osteosarcoma; Plutonium; Proportional Hazards Models; Radiation Injuries, Experimental; Reference Values; Regression Analysis; Respiration; Sex Characteristics; Time Factors; Tissue Distribution

Pulmonary carcinogenesis was compared in female F344 and Wistar rats after inhalation of high-fired 239PuO2. Plutonium particle aggregation, as determined by quantitative light and scanning electron microscopic autoradiography, was greater for the F344 strain than for the Wistar strain. The median survival times were similar in control and low-dose (0.8-1.0 Gy) groups of both strains, but were significantly decreased in the high-dose (34-37 Gy) groups of both strains. Squamous metaplasia was not found in control or low-dose groups of either strain, but was found in 62-65% of high-dose groups of both strains. Adenomatous metaplasia was considerably higher in control and low-dose groups of F344 rats than in Wistar rats. A total of 87 lung tumors were found in 140 exposed F344 rats and 46 lung tumors in 176 exposed Wistar rats. The incidence of lung tumors in F344 rats was 1.7% in controls, 20% in the low-dose group and 82% in the high-dose group. The incidence of lung tumors in Wistar rats was 0.1% in controls, nil in the low-dose group and 68% in the high-dose group. About half of all lung tumors in both strains were considered to be the primary cause of death. The median survival times of rats of both strains in the high-dose groups that died with lung tumors were greater compared with rats in these groups that died without lung tumors. In contrast, these differences did not occur among rats in the low-dose groups. The absolute risk was 1900 lung tumors per 10(4) Rat-Gy for F344 rats receiving low doses and nil for Wistar rats receiving low doses, but about 210 lung tumors per 10(4) Rat-Gy for high-dose groups of both strains. The adenomatous tumor phenotype predominated in the F344 strain, while the squamous tumor phenotype predominated in the Wistar strain. Risk of squamous tumors was similar for both strains. Overall, the F344 strain appears to be more "sensitive" than the Wistar strain to formation of lung tumors at low to moderate doses from inhaled 239PuO2 due mostly to an increased incidence of adenomatous phenotype tumors.

Topics: Aerosols; Animals; Carcinoma; Dose-Response Relationship, Radiation; Epithelium; Female; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred F344; Rats, Wistar; Sarcoma, Experimental

A life-span study indicated that plutonium activity in the thoracic lymph nodes is a contributor to development of lymphopenia in beagles exposed to 239PuO2. Significant lymphopenia was found in 67 (58%) beagles given a single nose-only exposure to 239PuO2 to result in mean initial lung depositions ranging from 0.69 to 213.3 kBq. Lymphoid atrophy and sclerosis of the thoracic lymph nodes and lymphopenia were observed in exposure-level groups with initial lung depositions > or = 2.5 kBq. Those dogs with final plutonium concentrations in the thoracic lymph nodes > or = 0.4 kBq/g and dose rates > or = 0.01 Gy/day developed lymphopenia. Marked differences existed between chronically lymphopenic dogs and intermittently lymphopenic dogs with regard to initial lung deposition, time to lymphopenic events and absolute lymphocyte concentrations. Linear regression analysis revealed moderate correlation between reduction in lymphocyte values and initial lung deposition, in both magnitude and time of appearance after exposure. Cumulative dose and dose rate appeared to act together to produce initial effects on lymphocyte populations, while dose rate alone appeared to be responsible for the maintenance and subsequent cycles of lymphopenia seen over the life span. No primary tumors were associated with the thoracic lymph nodes in this study, although 70% of the lymphopenic dogs developed lung tumors.

Topics: Administration, Inhalation; Animals; Dogs; Female; Longevity; Lung Neoplasms; Lymph Nodes; Lymphocytes; Lymphopenia; Male; Neoplasms, Radiation-Induced; Plutonium; Severity of Illness Index

The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.

Topics: Adenocarcinoma; Aerosols; Amino Acid Sequence; Animals; Blotting, Southern; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; DNA Primers; DNA, Neoplasm; Exons; Female; Genes, p53; Glutamine; Immunohistochemistry; Lung Neoplasms; Lysine; Molecular Sequence Data; Mutagenesis; Neoplasms, Radiation-Induced; Plutonium; Point Mutation; Polymerase Chain Reaction; Rats; Rats, Inbred F344; Tumor Suppressor Protein p53

To study the long-term biological effects of repeated inhalation exposure to 239PuO2, 84-day-old rats were exposed to aerosols of 239PuO2 to re-establish desired 239Pu lung burdens of 26, 80 or 250 Bq every other month for 1 year (seven exposures). Other rats were exposed once at 84 or 450 days of age to achieve desired initial lung burdens of 30, 90, 280 or 850 Bq. The incidences of lung tumors were not significantly different (Fisher's exact test; P > 0.05) in groups of rats with similar lifetime mean alpha-particle doses to the lungs of 0.90 +/- 0.39 to 4.4 +/- 1.8 (+/- SD) Gy, whether exposed once or repeatedly. Among rats with mean alpha-particle doses of 12 +/- 2.4 to 10 +/- 2.1 Gy to the lungs after single or repeated exposures, respectively, the crude incidence of lung tumors was significantly less (Fisher's exact test; P < 0.05) in the rats exposed repeatedly. Times to death of rats with lung tumors were compared among groups with similar alpha-particle doses to the lungs after single or repeated exposure to 239PuO2. Those that died with lung tumors after repeated exposures died at times similar to (Mantel-Cox statistic; P > 0.05) or later than (Mantel-Cox statistic; P < 0.05) those for 84-day-old rats exposed once. The risk of lung tumors in rats per unit dose to the lungs was less in the rats exposed repeatedly than in those exposed once. It was concluded that alpha-particle doses to the lung of rats exposed repeatedly to aerosols of 239PuO2 were not more carcinogenic and possibly were less carcinogenic than the dose after a single inhalation exposure when rats with similar lifetime alpha-particle doses to the lungs were compared. The relative biological effectiveness in rats of the alpha-particle dose to the lungs from inhaled 239PuO2 relative to beta-particle doses to the lungs from inhaled 144CeO2 was 21 +/- 3.

Topics: Administration, Inhalation; Aerosols; Alpha Particles; Animals; Beta Particles; Body Burden; Body Weight; Female; Lung Neoplasms; Male; Metabolic Clearance Rate; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Rats; Rats, Inbred F344; Sex Factors

Female Wistar strain rats were exposed to a single inhalation of a submicron-size aerosol of high-fired 239PuO2 to investigate pulmonary carcinogenesis during lifespan periods. The absorbed lung doses of the exposed animals ranged from 0.6 to 12 Gy and were well correlated with the initial lung deposition (ILD) of 0.1 to 2.3 kBq. Survival and induction of primary lung tumors in 116 exposed rats were compared with those in 56 untreated control rats in respect to lung doses received. Mean survival time was greatly reduced, and the cumulative incidence of total lung tumors was markedly increased to 90-100% in rats that received more than 4 Gy, whereas of the controls only one animal (1.8%) died of primary lung tumors. Primary but benign adenomas were present in exposed animals given 1.0 Gy or less, and the incidence of adenomas was 22-25% at 4-5 Gy, but decreased sharply to 3-5% at 6-8 Gy. In contrast, no malignant carcinomas, including adenocarcinomas, adenosquamous carcinomas and squamous cell carcinomas, developed at a dose of less than 1.0 Gy, whereas they were present in 75% or more of the rats given 4-10 Gy, but only in 55% at 12 Gy. Although there were no clear differences in the dose and time required for induction among the carcinoma types, all tended to develop in earlier periods after inhalation than adenomas. Despite the limited number of exposed animals that received lower doses, results suggest that malignant lung carcinomas are highly and early induced and have a different dose-effect relationship than benign adenomas at doses of more than 1 Gy after inhalation exposure to 239PuO2.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Female; Incidence; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Wistar

Female, young adult, Wistar rats were given a single inhalation exposure to a submicron sized aerosol of high-fired 239PuO2 and observed during their lifespan for primary lung tumours. Rats were distributed among sham-control (n = 1052) and exposed (n = 2105) groups. Survival was significantly reduced only in rats with lung doses > 30 Gy. A total of 99 primary lung tumours were found, of which 92% were malignant and 80% were carcinomas. Of malignant lung tumours, 49 were squamous cell carcinoma, 23 adenocarcinoma, nine hemangiosarcoma, seven adenosquamous carcinoma, and three fibrosarcoma. One adenocarcinoma was found in controls and only four adenomas were seen in the exposed rat at lung doses < 1.5 Gy. The lowest doses at which lung tumours appeared in exposed rats were 1.5 Gy for squamous cell carcinoma, 3.1 Gy for adenocarcinoma. 4.1 Gy for hemangiosarcoma, and about 9 Gy for adenosquamous carcinoma and fibrosarcoma. Pulmonary squamous metaplasia was not seen in controls and was first seen in exposed rats only at lung doses > 1 Gy. Primary lung tumours were the presumed cause of death (fatal) in 60% of rats with malignant lung tumours; causes of death were equally distributed among all tumour types and doses. The incidence of all lung tumours was 0.095% in control rats, 0.21% in 1877 rats with lung doses < 1 Gy, and 41% in 228 rats with doses > 1 Gy. Lung tumour incidence increased in a linear manner from 6.9% at 2.3 Gy to an incidence of 64-88% at 16-44 Gy. Absolute malignant lung tumour risk averaged 270 lung tumours per 10(4) rat-Gy above a lung dose of 1 Gy. All types of malignant lung tumours induced by inhaled 239PuO2 exhibited a threshold at a lung dose > 1 Gy.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Female; Fibrosarcoma; Hemangiosarcoma; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Radiation Injuries, Experimental; Rats; Rats, Wistar; Survival Analysis

Light microscopy, morphometry, and cytokinetic techniques were used to examine the dynamics of plutonium-induced pulmonary proliferative lesions and neoplasms in rats at several intervals to 450 days after inhalation exposure to aerosols of 239PuO2. Maximal increases in alveolar and bronchiolar epithelial cell labeling were seen at 30 days; decreasing subsequently, the levels remained elevated above control indices. Focal proliferative epithelial lesions developed in the lung by 180 days and before the onset of pulmonary neoplasms. Pulmonary neoplasms, predominantly adenocarcinomas and squamous cell carcinomas, were initially observed at 308 days. The proliferative lesions progressed through a succession of morphological changes leading to the development of neoplasms. The volume density (fraction) and epithelial surface area of foci of alveolar epithelial hyperplasia increased progressively between 180 and 450 days after exposure, in contrast to the other proliferative lesions. We conclude that plutonium-induced pulmonary neoplasms develop through a succession of focal proliferative lesions that represent developmental preneoplastic lesions. Progressive increases in volume and epithelial surface area of the alveolar epithelial hyperplasias suggest that they may be more at risk for neoplastic transformation than the other histological types of proliferative foci.

Topics: Adenocarcinoma; Administration, Inhalation; Animals; Carcinoma, Squamous Cell; Cell Cycle; Female; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred F344

Spatial-temporal dose-distribution patterns in the lung continually change following inhalation of radionuclides. Lung clearance, microdosimetry, and radiation dose were examined in female Wistar rats exposed to high-fired 169Yb2O3-239PuO2 aerosols. Whole-body counting for 169Yb at 14 d postexposure provided an accurate (r = 0.99) estimate of 239Pu lung content. Alpha irradiation of tracheal epithelium was at least 50 times less than for bronchiolar epithelium due principally to preferential retention of 239PuO2 in peribronchiolar alveoli as compared to other alveolar regions. The formation of large aggregates (> 25 particles) increased linearly with initial lung burden starting at 0.4 kBq; mean dose rate to these focal alveolar regions was 120 Gy d-1. Concentration of 239PuO2 in pulmonary macrophages and in aggregates, along with the limited penetration of alpha particles in tissue, resulted in a highly nonhomogeneous dose distribution pattern. Alveolar clearance was best represented by a biphasic clearance curve comprised of a rapid early phase (80% initial lung burden) and a slow late phase (20% initial lung burden). Studies with intratracheally instilled 237PuO2-239PuO2 and with inhaled 239PuO2 showed that alveolar clearance was inversely proportional to initial lung burden. A single clearance function was derived from experimentally determined clearance curves for inhaled 239PuO2 that was used to accurately estimate lung dose at all initial lung burden levels. Lung doses were calculated for 2,105 exposed lifespan rats based on individually determined initial lung burden, survival time, and individually computed clearance function.

Topics: Administration, Inhalation; Aerosols; Animals; Female; Life Expectancy; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Wistar

We investigated the modifying effects of preexisting, bleomycin-induced pulmonary fibrosis on the deposition, retention, and biological effects of inhaled 239PuO2 in the rat. Among rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kilogram body mass were similar whether or not pulmonary fibrosis was present. However, clearance of 239Pu from the lungs was significantly decreased in the rats with preexisting pulmonary fibrosis. The incidence of lung lesions (epithelial hyperplasia, diffuse macrophage increases and aggregation, and loose and dense connective tissue) was significantly greater among rats with preexisting pulmonary fibrosis than among the exposed controls. Rats with preexisting fibrosis had shorter life spans than 239PuO2-exposed control rats. When groups of rats with similar alpha doses to the lungs were compared, the incidences of neoplastic lesions in the lung, the times to death of rats with lung neoplasms, and the risk of lung tumors per unit of alpha dose to the lungs in rats with or without pulmonary fibrosis were similar. The results of this study suggest that humans with uncomplicated pulmonary fibrosis may not be more sensitive to the carcinogenic effects of inhaled 239PuO2 than are individuals with normal lungs, assuming that the total alpha doses to the lungs are similar.

Topics: Administration, Inhalation; Animals; Bleomycin; Female; Lung; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Plutonium; Pulmonary Fibrosis; Rats; Rats, Inbred F344

The modifying effects of pre-existing pulmonary emphysema on the deposition, distribution, retention and effects of inhaled 239PuO2 in the rat were investigated. The presence of emphysema in the rats was documented by morphometric and respiratory function measurements. For rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kg body mass were lower in rats with emphysema than in those without emphysema; however, the retention of 239Pu over time was similar in both groups. The distribution of 239Pu particles in the lungs of rats with emphysema tended to be more random than in the lungs of control rats. The life span, and incidences of non-neoplastic and neoplastic lesions in the lung, and risk of lung tumours per unit of alpha dose to the lungs in the rats with emphysema were similar to or less than in the control rats, when groups with similar initial lung burdens of 239Pu were compared. The results of this study suggest that humans with uncomplicated pulmonary emphysema are not necessarily more sensitive to the carcinogenic effects of inhaled 239PuO2 than individuals with normal lungs.

Topics: Administration, Inhalation; Animals; Body Weight; Female; Lung; Lung Neoplasms; Male; Plutonium; Pulmonary Emphysema; Rats; Rats, Inbred F344; Respiration; Survival Rate; Tissue Distribution

Data from epidemiological studies of humans exposed to potentially harmful substances are usually analyzed using methods that account for the dependence of risks on time-related factors such as age and follow-up period. Recently developed statistical procedures allow modeling of the age-specific risks as a function of dose as well as factors such as age at exposure, time since exposure, exposure duration, and dose rate. These procedures potentially allow more rigorous inferences and clearer understanding of the patterns of risk observed in epidemiological studies than has been available in the past. Statistical procedures that consider time-related factors can also be applied to laboratory animal data, providing information that is useful for the problems involved in extrapolating from animal studies to humans. By applying such procedures to data on exposure to the same substance in different species (including humans) or to different substances in the same species, better understanding of the relationship of risks across species and across substances can be achieved. In addition, such statistical procedures allow appropriate treatment of exposure that is accumulated over time and lead to improved understanding of patterns of risk over time. The approach is illustrated using data from a lifespan study of beagle dogs exposed to inhaled Pu.

Topics: Administration, Inhalation; Animals; Dogs; Female; Humans; Lung; Lung Neoplasms; Male; Models, Statistical; Neoplasms, Radiation-Induced; Plutonium; Risk; Species Specificity; Time Factors

The goal of this study is to show the relationship of inhaled Pu particle distribution and alveolar-bronchiolar target-cell response with respect to the formation of pulmonary carcinoma. The proliferation of type 2 alveolar epithelium and nonciliated bronchiolar epithelium appears critical in the induction of lung tumors associated from inhaled 239PuO2. Female, Wistar rats were either sham-exposed (40 rats) or given a single inhalation to 169Yb-239PuO2 (99 rats, ILB, 3.9 +/- 1.2 kBq) and examined at 20 time intervals from 1 day to 700 days postexposure for Pu particle distribution in airways by SEM quantitative autoradiography and for cell labeling with tritiated thymidine. Initially, deposited Pu particles were rapidly cleared from the surface of the trachea, bronchi, and bronchioles within a few days. Thereafter, about 5 times more alpha track exposure to the bronchiolar epithelium was delivered from Pu particles found in peribronchiolar alveoli than from Pu particles being cleared from bronchiolar surfaces. Exposure of bronchiolar epithelium at later times was due mostly to the formation of peribronchiolar Pu particle aggregates. A maximal increase in labeled alveolar wall cells was seen at 60 days after exposure, decreasing gradually to control levels by 400 days. Cell labeling in focal alveolar regions of Pu aggregation was about 5 fold higher. Increased bronchiolar epithelium labeling appeared in two phases. The first phase was seen 15 days after exposure, associated with initial deposition and clearance of Pu particles. The second phase slowly reached a maximum at 250 days and was associated with peribronchiolar Pu aggregate formation. The temporal-spatial dose-distribution pattern for inhaled Pu particles is an important aspect of Pu-induced pulmonary carcinogenesis.

Topics: Administration, Inhalation; Animals; Autoradiography; Bronchi; Epithelium; Female; Lung; Lung Neoplasms; Mucous Membrane; Neoplasms, Radiation-Induced; Plutonium; Pulmonary Alveoli; Rats; Rats, Inbred Strains; Tissue Distribution; Trachea

Promotion of lung tumor formation from inhaled 239PuO2 in rats may be associated with aggregation of plutonium particles near bronchioles. The relationship of plutonium particle aggregation in the lung and the development of lung tumors after inhalation of 239PuO2 was studied in 664 life span rats with mean lung doses ranging from 0.35 to 20 Gy. Plutonium particle concentration and aggregation were determined from autoradiographic sections of the left lung lobe. The increase in particles/cm2 and mean number of particles per aggregate up to 20 Gy were directly proportional to lung dose. Aggregates with greater than 25 particles increased linearly with dose from 0.2% at 1.4 Gy to 8.2% at 20 Gy, in a pattern similar to increasing severity of pulmonary fibrosis and incidence of lung tumors. Lung tumor incidence increased from about 6% at 1.4 Gy to 83% at 8 Gy; no further increase in lung tumors was seen at doses greater than 8 Gy. Maximum lung tumor incidence at 8 Gy corresponded to a particle concentration of 130/cm2 and four particles/aggregate with 4% of aggregates having greater than 25 particles. Aggregation of inhaled plutonium particles in clusters of greater than 25 particles resulted in daily doses of only a few centigray to focal tissue regions containing clustered particles, yet these doses appeared sufficient to cause pulmonary fibrosis and promotion of pulmonary carcinogenesis.

Topics: Administration, Inhalation; Animals; Female; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms

Multistage models of cancer induction have been accepted in chemical and radiation carcinogenesis for many years. Most models assume that both initiating and promoting events are required for greatest expression of tumor incidence. The sequence of events is important in determining the shape of the dose-response curve. A total of 1058 female, SPF, Wistar, sham-exposed rats and 2134 rats given a single inhalation to 169Yb, 239PuO2 are being studied for lung tumor formation in a life-span study. Histopathological analyses have been completed on 1149 rats. Similar dose-response curves are seen for pulmonary fibrosis pulmonary metaplasia and lung tumor formation. Lung tumor incidences were: 0.6% (0 Gy), 0.5% (0.06 Gy), 0% (0.11 Gy), 0% (0.23 Gy), 4.5% (0.46 Gy), 0% (0.84 Gy), 13.8% (1.9 Gy), 18.6% (3.5 Gy), 72.5% (7.4 Gy), and 84.9% (15 Gy). The dose lung-tumor curve was best fit by a quadratic function and was not well fit by a linear function. It is proposed that the low-dose portion of the quadratic curve represents promotion event(s) due to increasing 239PuO2 particle clustering in subpleural regions, leading to a cellular evolution of focally intense inflammation, fibrosis, epithelial metaplasia and carcinoma formation. A defined, practical threshold dose may be useful with respect to setting radiation protection guidelines for lung tumor induction.

Topics: Administration, Inhalation; Animals; Female; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Rats; Rats, Inbred Strains

Our current experiments were designed to show whether 12 months' exposure to cigarette smoke enhances the incidence of lung tumours in mice that had previously inhaled 239PuO2. These periods of smoke exposure are almost complete. After death their lungs will be cleared and any nodules found will be sectioned for histopathology. This paper reports the results of two preliminary experiments conducted earlier. The first study showed that mice could tolerate the proposed smoking regime for 3 months, with no sign of ill health in any animal throughout. The major difference found was a reduced growth rate in both smoke- and sham-exposed mice relative to that of cage controls. After 3 months of treatment, histopathology and morphometry of lung sections found only slight smoke-induced changes. These included a reduced proportion of alveolar space and an increased number of pulmonary alveolar macrophages (PAM) per unit area. Bronchopulmonary lavage showed that the PAM from smoke-exposed mice were larger than those from sham-exposed or control mice and that an increased proportion of cells were binucleate. All mice in the second study were initially exposed to 239PuO2, then subsequently divided into three treatment groups as above. Cigarette smoke exposure was shown to inhibit the removal of 239Pu from the lung whilst sham exposure had no effect. Smoke exposure also produced an increase and sham exposure a decrease in lung weights relative to those of cage controls. The latter was probably as a result of their lower growth rate. In our current experiments it is likely that the group receiving 239PuO2, then smoke, will receive a higher radiation dose to lung than those receiving 239PuO2 only. Any increased tumour incidence found will be considered in conjunction with this evidence.

Topics: Animals; Cocarcinogenesis; Lung Neoplasms; Mice; Neoplasms, Radiation-Induced; Plutonium; Smoking

Three-dimensional dose-rate/time/response surfaces for chronic exposure to carcinogens, toxicants, and ionizing radiation dramatically clarify the separate and interactive roles of competing risks. The three dimensions are average dose rate, exposure time, and risk. An illustration with computer graphics shows the contributions with the passage of time of the competing risks of death from radiation pneumonitis/fibrosis, lung cancer, and natural aging consequent to the inhalation of plutonium-239 dioxide by beagles. These relationships are further evaluated by mathematical stripping with three-dimensional illustrations that graphically show the resultant separate contribution of each fatal effect. Radiation pneumonitis predominates at high dose rates and lung cancer at intermediate dose rates. Low dose rates result in spontaneous deaths from natural aging, yielding a type of practical threshold for lung cancer induction. Risk assessment is benefited by the insights that become apparent with these three-dimensional models. The improved conceptualization afforded by them contributes to the planning and evaluation of epidemiological analyses and experimental studies involving chronic exposure to toxicants.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Life Expectancy; Lung Neoplasms; Models, Biological; Neoplasms, Radiation-Induced; Plutonium; Risk

To determine the long-term biological effects of protracted alpha irradiation of the lung, 84-day-old C57BL/6J mice were repeatedly exposed by inhalation to aerosols of 239PuO2 every other month for up to six exposures in 10 months to reestablish lung burdens of 20, 90, or 460 Bq. Other mice were exposed only once when either 84 or 460 days of age to achieve desired initial lung burdens of 20, 90, 460, or 2300 Bq. Suitable control groups were maintained. Groups of mice with similar cumulative alpha doses to the lung had 3.4 to 4.4 times greater incidence of pulmonary tumors (adenomas and adenocarcinomas) when the dose to the lung was protracted by the repeated inhalation exposures compared to mice that received a single inhalation exposure. Excess pulmonary tumors per unit dose to the lung were also greater in groups of repeatedly exposed mice compared to those exposed only once. Repeatedly exposed mice also died earlier with pulmonary tumors than did those exposed once. It appears that protraction of an alpha dose to lungs increases the carcinogenic risk of inhaled 239PuO2 in mice.

Topics: Administration, Inhalation; Aerosols; Alpha Particles; Animals; Female; Lung; Lung Neoplasms; Mice; Mice, Inbred C57BL; Models, Biological; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Radiation Injuries, Experimental

A pulmonary fibrosarcoma of bronchial origin was discovered in a Rhesus monkey that died of pulmonary fibrosis 9 years after inhalation of plutonium-239 dioxide and with a radiation dose to lung of 1400 rad (14 Gy). It grew around the major bronchus of the right cardiac lung lobe and extended into the bronchial lumen and into surrounding pulmonary parenchyma. It also readily invaded muscular pulmonary arteries, resulting in infarction and scarring in the right cardiac lobe. Despite this aggressive growth, the tumor did not metastasize. The primary cause of death was severe pulmonary fibrosis involving the alveolar septa and and perivascular and peribronchial interstitium. Bullous or pericitrical emphysema was prominent. The initial lung burden of plutonium in this monkey was 270 nCi (10 kBq) which is equivalent to approximately 500 times the maximum permissible lung burden for man on a radioactivity per unit body weight basis. The time-dose relationship for survival is consistent with that of dogs and baboons that inhaled plutonium dioxide and died with lung tumors.

Topics: Administration, Inhalation; Animals; Fibrosarcoma; Lung Neoplasms; Macaca mulatta; Male; Neoplasms, Radiation-Induced; Plutonium

This study describes the effect of intratracheal instillations (2 X 5 mg) of benzo(a)pyrene (B(a)P) on lung carcinogenesis in rats which had previously inhaled different levels of 239 plutonium oxide (220, 630, 6300 Bq, initial lung burden). Survival decreased with increasing PuO2 exposure and additional B(a)P exposure. The incidence of malignant lung tumours, adjusted for differences in survival, increased in a dose-related fashion with PuO2 dose and was elevated in the presence of additional B(a)P exposure. A multiplicative relative risk model was found to describe reasonably well the observed joint effect. The practical implications of these findings are discussed.

Topics: Administration, Intranasal; Animals; Benzo(a)pyrene; Benzopyrenes; Cocarcinogenesis; Drug Synergism; Lung Neoplasms; Male; Plutonium; Rats; Rats, Inbred Strains; Risk

Syrian hamsters, Fischer rats and Beagle dogs inhaled monodisperse aerosols of PuO2 and were sacrificed during the first 16 days after exposure. The microscopic distribution of radiation dose and tissue-at-risk to alpha irradiation around individual particles in lung was studied using autoradiographs of lung tissue sections. The dose distributions in dogs and rats were more diffuse than in hamsters. A slightly greater tumor incidence was calculated for rats and dogs than for hamsters on the basis of dose distribution using the same dose-effect model for all three species. The small differences in tumor incidence predicted on this basis do not explain the extremely large differences in tumor incidences observed in these species after inhalation of PuO2.

Topics: Aerosols; Alpha Particles; Animals; Cricetinae; Dogs; Lung; Lung Neoplasms; Male; Mesocricetus; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Rats; Rats, Inbred F344; Species Specificity

Topics: Alpha Particles; Animals; Ascorbic Acid; Female; Lung Neoplasms; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred F344; Time Factors

Syrian hamsters were exposed to various levels of aerosolized 239PuO2 particles to attain a range of initial lung burdens (medians ranged from 40 to 144 nCi). They were allowed to live without sacrifice and had gross and microscopic tissue examinations at death. Over a range of median lung doses from 4-12 000 rad there was an average 2 per cent incidence of malignant tumours (adenocarcinomas) and 9 per cent incidence of total tumours (primarily adenomas). Some of these results are consistent with those from other laboratories using plutonium oxide aerosols but they represent considerably lower lung tumour incidences than previously observed in this laboratory using aerosols of 238PuO2-ZrO2 particles.

Topics: Animals; Cricetinae; Dose-Response Relationship, Radiation; Female; Lung Neoplasms; Male; Mesocricetus; Neoplasms, Radiation-Induced; Plutonium; Sex Factors; Zirconium

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Dose-Response Relationship, Radiation; Female; Hemangiosarcoma; Lung Neoplasms; Mesothelioma; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Inbred Strains; Sarcoma, Experimental; Time Factors