plutonium-dioxide and Osteosarcoma

Plutonium-238 (238Pu) has a half-life of about 87.7 y and thus a higher specific activity than 239Pu. It is used in radioisotope thermoelectric generators and is a substantial source of plutonium alpha-radiation in spent nuclear fuels. Early animal studies demonstrated differences in the biokinetics of inhaled oxides of 238Pu and 239Pu with 238Pu having a substantially more rapid translocation from the lungs to the systemic organs, particularly the skeleton. This resulted in the predominant occurrence of skeletal cancers in animals exposed to 238Pu oxides but lung cancers in those with exposures to 239Pu oxides. The anatomical distribution of osteogenic sarcomas seen in animal studies was similar to that observed with 239Pu and also in plutonium workers but differed from naturally occurring tumors. The in vivo "solubility" of 238Pu has been associated with the relative amounts of 238Pu/239Pu in the particles and calcination temperatures during the preparation of the dioxides. There is experimental evidence of in vivo 238Pu particle fragmentation attributed to nuclear recoil during radioactive decay. The resulting conversion of microparticles to nanoparticles may alter their interactions with macrophages and transport across epithelial barriers. There are few documented cases of human exposures, but the biokinetics appeared to depend on the chemical and physical nature of the aerosols. Robust human biokinetic and dosimetric models have not been developed, due in part to the lack of data. With the acceleration of nuclear technologies and the greater demand for reprocessing and/or disposal of spent nuclear fuels, the potential for human exposure to 238Pu will likely increase in the future.

Topics: Aerosols; Animals; Bone Neoplasms; Endocytosis; Health Physics; Humans; Intestinal Absorption; Lung; Neoplasms, Radiation-Induced; Nuclear Reactors; Occupational Exposure; Osteosarcoma; Plutonium; Radiometry

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

Dose-response relationships observed in laboratory animals can be used to identify possible human risk factors and may also be used in a quantitative manner when human data are not available. This paper presents an analysis of the dose dependency of osteosarcoma incidence in beagle dogs given a single inhalation exposure to a monodisperse aerosol of 238PuO2. We were particularly interested in comparing the predicted risks that were based on average bone dose with those based on endosteal cell dose and in evaluating the advantages of using a more biologically relevant cell-specific dose in risk estimation. The endosteal cell dose was calculated using the method of Marshall et al. (Health Phys. 35, 91-101, 1978), as extended to account for exposure by inhalation. The relationship between dose and time to tumor was analyzed by the proportional hazards regression model. The probability of developing osteosarcoma was strongly dependent on dose for dogs receiving low doses, but this was not true for dogs receiving high doses. The predicted risk based on endosteal cell dose was not consistently higher or lower than the risk based on average bone dose at various times after exposure, because the relationship between these two doses was not linear with respect to time. Also, as a result of the nonlinear relationship between these two doses, the risk estimated based on endosteal cell dose would not be a fixed factor of that based on the average dose. Random errors in the measured initial lung burden had a relatively large impact on the predicted risk based on endosteal cell dose, and the difference between the estimated risk of developing osteosarcoma based on endosteal cell dose and that based on average bone dose is likely to be within the error margins of the estimated risks.

Topics: Administration, Inhalation; Animals; Bone and Bones; Dogs; Incidence; Neoplasms, Radiation-Induced; Osteosarcoma; Plutonium; Radiation Dosage; Risk

Primary liver tumors developed in Beagle dogs exposed by inhalation to aerosols of 238PuO2. Initial deposition of 238PuO2 in the respiratory tract was followed by translocation of a portion of the 238Pu to the liver and skeleton, which resulted in a large dose commitment and tumor risk to all three tissues. In a population of 144 dogs exposed to 238PuO2, 112 dogs died or were killed 4000 days after 238Pu exposure, 100 dogs had osteosarcoma, and 28 dogs had lung cancers. At increasing times after exposure, however, liver lesions have become more pronounced. Ten primary liver tumors in nine animals were diagnosed in the dogs dying before 4000 days after exposure. An additional five primary liver tumors in three dogs occurred in 9 animals killed after 4000 days after exposure. The majority of these tumors have been fibrosarcomas. The liver tumors were usually not the cause of death, and rarely metastasized. The occurrence of liver tumors in this study indicates that 238Pu is an effective hepatic carcinogen. Liver carcinogenesis is assuming an increasing importance in this study at late times after inhalation exposure. These results suggest that the liver may be an important organ at risk for the development of neoplasia in humans at time periods long after inhalation of 238Pu.

Topics: Administration, Inhalation; Aerosols; Animals; Bile Duct Neoplasms; Cystadenoma; Dogs; Drug Residues; Fibroma; Fibrosarcoma; Liver; Liver Neoplasms, Experimental; Lung; Mast-Cell Sarcoma; Osteosarcoma; Plutonium