Note
PLEURAL MESOTHELIOMA IN THE RAT FOLLOWING EXPOSURE TO 239Pu02 C. L. Sanders" Aklruct-Pleural mesothelioma was an infrequent observation following deposition of 239Pu02in the lung or pleural cavity. Only five tumors were found in 2,105 rats exposed to 239Pu02aerosols in the present study, while four tumors were found in 527 rats that inhaled 239Pu02in previously published lifespan studies. Risk of pleural mesothelioma was not significantly increased by intrapleural injection of 30 kBq 239Pu02. In contrast, a much higher incidence of peritoneal mesothelioma was seen following intraperitoneal injection of 239Pu02due to aggregation of 239Pu02particles on mesothelial surfaces. It was concluded that the lack of 239Pu02aggregation on pleural surfaces is responsible for small numbers of pleural mesothelioma observed following deposition of 239Pu02. Health Phys. 63(6):695-697; 1992 Key words: 239Pu02;lungs, rodent; inhalation; tumor
thymus gland, thoracic lymph nodes, and any grossly appearing abnormal lesions in the thoracic cavity were taken for histopathological and autoradiographic examination. Tissues were fixed in 10% neutral-buffered formalin and 5-6-pm-thick paraffin sections stained with hematoxylin and eosin for light microscopic examination. The number and histological type of pleural mesothelioma were determined. Pleural mesothelioma incidence following inhalation of 239Pu02in the present large lifespan study was compared to mesothelioma incidences in previously published observations in rats iven an intrapleural or intraperitoneal injection of F39Pu02(Sanders 1973, 1976) and to previously published studies with inhaled 239Pu02(Sanders et al. 1976; Sanders and Mahaffey 1981).
INTRODUCTION
RESULTS AND DISCUSSION
THESPATIAL-TEMPORAL dose-distribution pattern from inhaled transuranics greatly influences carcinogenicity in the lung. Aggregation of inhaled 239Pu02promotes pulmonary carcinoma and hemangiosarcoma formation in the rat (Sanders et al. 1988a,b). Likewise, aggregation of intraperitoneally injected submicron-sized 239Pu02 in milky spot regions of the omentum promotes the formation of peritoneal mesothelioma (Sanders 1973). The purpose of this study was to evaluate the role of 239Pu02particle aggregation on the formation of pleural mesothelioma.
A total of six pleural mesotheliomas were observed in 3,157 rats-five tumors in 2,105 rats exposed to 239Pu02(three in rats with depositions ~ 0 . kBq 3 and two in rats with >0.3 kBq) and one tumor in 1,052 sham-exposed control rats (Table 1). Lung doses for rats with pleural mesothelioma were 0.06, 0.32, 0.54, 4.6, and 22 Gy. Survival in rats with pleural mesothelioma was 607 f 199 d as compared to a survival in unexposed controls of 733 f 164; the difference was not statistically significant. Although the incidence of pleural mesothelioma in exposed rats was about 2.5 times greater than in controls, the difference was not significant. All pleural mesotheliomas were considered to have been lethal. One pleural mesothelioma was of the tubulopapillary type and five were of the mixed spindle cell-epithelial cell type. Light and scanning light autoradiographic studies of the lung showed the formation of large pulmonary 239Pu02aggregates associated with pulmonary carcinoma and hemangiosarcoma fonnation. Initially, pleural mesothelial cells are well within the range of alpha particles from inhaled 239Pu02deposited in subpleural alveoli (Sanders et al. 1988b). However, the location of 239Pu02aggregates and the observation that aggregation of 239Pu02particles results in inflammatory and fibrotic responses to these areas, possibly limiting alpha irradiation exposure of the pleura (Sanders et al. 1989), minimizes the irradiation of mesothelial cells.
MATERIALS AND METHODS A total of 3,157 young adult, female, Wistar rats were exposed, nose-only, to aerosols of high-fired 169Yb203-239P~02 in a lifespan carcinogenesis study (Sanders et al. 1986). Initial lung burden (ILB) was measured in individual rats by whole-body counting for 169Yb.ILB varied from 0.022 f 0.005 kBq to 5.6 f 1.4 kBq (Sanders et al. 1986). The activity median aerodynamic diameter (AMAD) of the aerosol was 1.6 f 0.11 hm (Sanders et al. 1986). The lung, heart, ~
*Washington State University at Tri-Cities and Pacific Northwest Laboratories, Richland, WA 99352. (Manuscriptreceived 21 March 1992; revised manuscript received 15 June 1992, accepted 29 June 1992) 00 1I-9018/92/$3.00/0 Copyright 0 1992 Health Physics Society 695
Health Physics
696
December 1992, Volume 63, Number 6
Table 1. Route of administration and mesothelioma formation in rats following deposition of 2 3 9 P ~ 0All 2. mesotheliomas following inhalation and intrapleural injection are pleural in origin and all mesotheliomas following intraperitoneal injection are peritoneal in origin. Route of administration Inhalation Inhalation In halation Inhalation Inhalation
Deposition of 239Pu02 Number of (kBq) rats 0 1052 0.3 228 0 76 0.007-6.7
Intrapleural injection Intrapleural injection Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection
0 30 0
2.6 13 1 10
Number of mesotheliomas 1
3 2 0
Crude incidence of mesothelioma
(%I
0.095 0.16 0.88 0
527
4
0.75
28 27 108 36 38 34
0
0 3.7 0 5.6
Only one of 27 rats given an intrapleural injection of 30 kBq of submicron-sized 239Pu02developed a pleural mesothelioma (Table 1). Autoradiographs of the lung failed to demonstrate aggregate formation on pleural surfaces but indicated a rapid clearance of particles from the pleural cavity.+ Intrapleurally injected particles are rapidly cleared to thoracic, mediastinal, and hepatic lymph nodes (Rusznyak et al. 1967). Incidences of pleural mesothelioma, as high as 75 %, were observed after intrapleural injection of asbestos fibers (Wagner 1970;Stanton and Wrench 1972). Asbestos fibers, because of their size and shape, would not be easily cleared from the pleural cavity, which would explain their much-greater effectiveness in inducing pleural mesothelioma than 239Pu02particles. Likewise, intraperitoneally injected asbestos and 239Pu02were more effective in inducing peritoneal mesotheliomas. The incidence of peritoneal mesothelioma increased with the increasing amount of injected 239Pu02, from 5.6-26.5% after 2.6-107 kBq depwas osition (Table 1). Intraperitoneally injected 239Pu02 concentrated in focal areas directly upon peritoneal, visceral mesothelium and was as effective as asbestos in inducing mesotheliomas (Sanders 1973). CONCLUSION
It was concluded that aggregation of inhaled 239Pu02 and associated focal pathological changes and lack of aggregation of intrapleurally injected 239Pu02,due to pleural particle clearance, limited alpha irradiation of the pleural mesothelium and subsequent mesothelioma formation. In contrast, a high incidence of peritoneal mesothelioma was seen following intraperitoneally injected 239Pu02(Sanders 1973) and of Personal communication (1976), Sanders, C. Data and notes, Battelle, Pacific Northwest Laboratory, P.O. Box 999, Richland, WA 99352.
1
0 2 4 9
10.5
25.5
Reference Present study Present study Present study Sanders et aI. ( 1976); Sanderes and Mahaffey (1981) Sanders et al. (1976); Sanders and Mahaffey (1981) Sanders (1976) Sanders (1976) Sanders (1973) Sanders (1973) Sanders (1973) Sanders (1973)
pulmonary carcinoma and hemangiosarcoma following inhalation of 239Pu02(Sanders et al. 1988b) due to alveolar particle aggregation, greatly increasing the radiation dose to target cells for tumor induction. REFERENCES Rusznyak, I.; Foldi, M; Szabo, G. Lymphatics and lymph circulation. New York: Pergamon Press; 1967: 484-486. Sanders, C. L. Cocarcinogenesis of 23yPu02with chrysotile asbestos or benzopyrene in the rat abdominal cavity. In: Sanders, C. L.; Busch, R. H.; Ballou, J. E.; Mahlum, D., eds. Radionuclide carcinogenesis, proceedings of the 12th Annual Hanford Biology Symposium. Springfield, VA: NTIS; CONF-720505; 1973: 138-153. Sanders, C. L. Effect of transuranics in pulmonary lymph nodes of rodents. In: Ballou, J. E., ed. Radiation and the lymphatic system, proceedings of the 14th Annual Hanford Biology Symposium. Springfield, VA: NTIS; CONF740930; 1976: 225-229. Sanders, C. L.; Dagle, G. E.; Cannon, W. C.; Craig, D. K.; Powers, G. J.; Meier, D. M. Inhalation carcinogenesis of high-fired 23yPu02 in rats. Radiat. Res. 68:349-360; 1976. Sanders, C. L.; Lauhala, K. E.; McDonald, K. E. Scanning electron microscopy of lung following alpha irradiation. Scanning Microscopy 3: 907-9 18; 1989. Sanders, C. L.; Mahaffey, J. A. Inhalation carcinogenesis of repeated exposures to high-fired 239Pu02in rats. Health Phys. 4 1~629-644;198 1. Sanders, C. L.; McDonald, K. E.; Killand, B. W.; Mahaffey, J. A.; Cannon, W. C. Low-level lifespan studies with inhaled 239Pu02in rats. In: Thompson, R. C.; Mahaffey, J. A., ed. Life-span radiation effects studies in animals: What can they tell us? Proceedings of the 22nd Annual Hanford Life Sciences Symposium. Springfield, VA: NTIS; CONF-830951; 1986: 429-449. Sanders, C. L.; McDonald, K. E.; Lauhala, K. E. Promotion of pulmonary carcinogenesis by plutonium particle aggregation following inhalation of 239Pu02.Radiat. Res. 116: 393-405; 1988a. Sanders, C. L.; McDonald, K. E.; Lauhala, K. E. SEM auto-
Pleural mesothelioma in a rat from exposure to 239Pu02 0 C. L. SANDERS
691
pleural injection of asbestos and silica. In: Nattesheim, P.; Hanna, M. G., Jr.; Deatherage, J. W., eds. Morphology of experimental respiratory carcinogenesis, proceedingsof the AEC Symposium Series 2 1. Springfield, VA: NTIS; CONF700501; 1970: 347-358.
radiography:Aggregation of inhaled 239Pu02. Int. J. Radiat. Biol. 54:115-121; 1988b. Stanton, M. F.; Wrench, C. Mechanisms of mesothelioma induction with asbestos and fibrous glass. J. Natl. Cancer Inst. 48:797-821; 1972. Wagner, J. C. The pathogenesis of tumors following intra-
..
,
PLEURAL MESOTHELIOMA IN THE RAT FOLLOWING EXPOSURE TO 239Pu02 C. L. Sanders" Aklruct-Pleural mesothelioma was an infrequent observation following deposition of 239Pu02in the lung or pleural cavity. Only five tumors were found in 2,105 rats exposed to 239Pu02aerosols in the present study, while four tumors were found in 527 rats that inhaled 239Pu02in previously published lifespan studies. Risk of pleural mesothelioma was not significantly increased by intrapleural injection of 30 kBq 239Pu02. In contrast, a much higher incidence of peritoneal mesothelioma was seen following intraperitoneal injection of 239Pu02due to aggregation of 239Pu02particles on mesothelial surfaces. It was concluded that the lack of 239Pu02aggregation on pleural surfaces is responsible for small numbers of pleural mesothelioma observed following deposition of 239Pu02. Health Phys. 63(6):695-697; 1992 Key words: 239Pu02;lungs, rodent; inhalation; tumor
thymus gland, thoracic lymph nodes, and any grossly appearing abnormal lesions in the thoracic cavity were taken for histopathological and autoradiographic examination. Tissues were fixed in 10% neutral-buffered formalin and 5-6-pm-thick paraffin sections stained with hematoxylin and eosin for light microscopic examination. The number and histological type of pleural mesothelioma were determined. Pleural mesothelioma incidence following inhalation of 239Pu02in the present large lifespan study was compared to mesothelioma incidences in previously published observations in rats iven an intrapleural or intraperitoneal injection of F39Pu02(Sanders 1973, 1976) and to previously published studies with inhaled 239Pu02(Sanders et al. 1976; Sanders and Mahaffey 1981).
INTRODUCTION
RESULTS AND DISCUSSION
THESPATIAL-TEMPORAL dose-distribution pattern from inhaled transuranics greatly influences carcinogenicity in the lung. Aggregation of inhaled 239Pu02promotes pulmonary carcinoma and hemangiosarcoma formation in the rat (Sanders et al. 1988a,b). Likewise, aggregation of intraperitoneally injected submicron-sized 239Pu02 in milky spot regions of the omentum promotes the formation of peritoneal mesothelioma (Sanders 1973). The purpose of this study was to evaluate the role of 239Pu02particle aggregation on the formation of pleural mesothelioma.
A total of six pleural mesotheliomas were observed in 3,157 rats-five tumors in 2,105 rats exposed to 239Pu02(three in rats with depositions ~ 0 . kBq 3 and two in rats with >0.3 kBq) and one tumor in 1,052 sham-exposed control rats (Table 1). Lung doses for rats with pleural mesothelioma were 0.06, 0.32, 0.54, 4.6, and 22 Gy. Survival in rats with pleural mesothelioma was 607 f 199 d as compared to a survival in unexposed controls of 733 f 164; the difference was not statistically significant. Although the incidence of pleural mesothelioma in exposed rats was about 2.5 times greater than in controls, the difference was not significant. All pleural mesotheliomas were considered to have been lethal. One pleural mesothelioma was of the tubulopapillary type and five were of the mixed spindle cell-epithelial cell type. Light and scanning light autoradiographic studies of the lung showed the formation of large pulmonary 239Pu02aggregates associated with pulmonary carcinoma and hemangiosarcoma fonnation. Initially, pleural mesothelial cells are well within the range of alpha particles from inhaled 239Pu02deposited in subpleural alveoli (Sanders et al. 1988b). However, the location of 239Pu02aggregates and the observation that aggregation of 239Pu02particles results in inflammatory and fibrotic responses to these areas, possibly limiting alpha irradiation exposure of the pleura (Sanders et al. 1989), minimizes the irradiation of mesothelial cells.
MATERIALS AND METHODS A total of 3,157 young adult, female, Wistar rats were exposed, nose-only, to aerosols of high-fired 169Yb203-239P~02 in a lifespan carcinogenesis study (Sanders et al. 1986). Initial lung burden (ILB) was measured in individual rats by whole-body counting for 169Yb.ILB varied from 0.022 f 0.005 kBq to 5.6 f 1.4 kBq (Sanders et al. 1986). The activity median aerodynamic diameter (AMAD) of the aerosol was 1.6 f 0.11 hm (Sanders et al. 1986). The lung, heart, ~
*Washington State University at Tri-Cities and Pacific Northwest Laboratories, Richland, WA 99352. (Manuscriptreceived 21 March 1992; revised manuscript received 15 June 1992, accepted 29 June 1992) 00 1I-9018/92/$3.00/0 Copyright 0 1992 Health Physics Society 695
Health Physics
696
December 1992, Volume 63, Number 6
Table 1. Route of administration and mesothelioma formation in rats following deposition of 2 3 9 P ~ 0All 2. mesotheliomas following inhalation and intrapleural injection are pleural in origin and all mesotheliomas following intraperitoneal injection are peritoneal in origin. Route of administration Inhalation Inhalation In halation Inhalation Inhalation
Deposition of 239Pu02 Number of (kBq) rats 0 1052 0.3 228 0 76 0.007-6.7
Intrapleural injection Intrapleural injection Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection
0 30 0
2.6 13 1 10
Number of mesotheliomas 1
3 2 0
Crude incidence of mesothelioma
(%I
0.095 0.16 0.88 0
527
4
0.75
28 27 108 36 38 34
0
0 3.7 0 5.6
Only one of 27 rats given an intrapleural injection of 30 kBq of submicron-sized 239Pu02developed a pleural mesothelioma (Table 1). Autoradiographs of the lung failed to demonstrate aggregate formation on pleural surfaces but indicated a rapid clearance of particles from the pleural cavity.+ Intrapleurally injected particles are rapidly cleared to thoracic, mediastinal, and hepatic lymph nodes (Rusznyak et al. 1967). Incidences of pleural mesothelioma, as high as 75 %, were observed after intrapleural injection of asbestos fibers (Wagner 1970;Stanton and Wrench 1972). Asbestos fibers, because of their size and shape, would not be easily cleared from the pleural cavity, which would explain their much-greater effectiveness in inducing pleural mesothelioma than 239Pu02particles. Likewise, intraperitoneally injected asbestos and 239Pu02were more effective in inducing peritoneal mesotheliomas. The incidence of peritoneal mesothelioma increased with the increasing amount of injected 239Pu02, from 5.6-26.5% after 2.6-107 kBq depwas osition (Table 1). Intraperitoneally injected 239Pu02 concentrated in focal areas directly upon peritoneal, visceral mesothelium and was as effective as asbestos in inducing mesotheliomas (Sanders 1973). CONCLUSION
It was concluded that aggregation of inhaled 239Pu02 and associated focal pathological changes and lack of aggregation of intrapleurally injected 239Pu02,due to pleural particle clearance, limited alpha irradiation of the pleural mesothelium and subsequent mesothelioma formation. In contrast, a high incidence of peritoneal mesothelioma was seen following intraperitoneally injected 239Pu02(Sanders 1973) and of Personal communication (1976), Sanders, C. Data and notes, Battelle, Pacific Northwest Laboratory, P.O. Box 999, Richland, WA 99352.
1
0 2 4 9
10.5
25.5
Reference Present study Present study Present study Sanders et aI. ( 1976); Sanderes and Mahaffey (1981) Sanders et al. (1976); Sanders and Mahaffey (1981) Sanders (1976) Sanders (1976) Sanders (1973) Sanders (1973) Sanders (1973) Sanders (1973)
pulmonary carcinoma and hemangiosarcoma following inhalation of 239Pu02(Sanders et al. 1988b) due to alveolar particle aggregation, greatly increasing the radiation dose to target cells for tumor induction. REFERENCES Rusznyak, I.; Foldi, M; Szabo, G. Lymphatics and lymph circulation. New York: Pergamon Press; 1967: 484-486. Sanders, C. L. Cocarcinogenesis of 23yPu02with chrysotile asbestos or benzopyrene in the rat abdominal cavity. In: Sanders, C. L.; Busch, R. H.; Ballou, J. E.; Mahlum, D., eds. Radionuclide carcinogenesis, proceedings of the 12th Annual Hanford Biology Symposium. Springfield, VA: NTIS; CONF-720505; 1973: 138-153. Sanders, C. L. Effect of transuranics in pulmonary lymph nodes of rodents. In: Ballou, J. E., ed. Radiation and the lymphatic system, proceedings of the 14th Annual Hanford Biology Symposium. Springfield, VA: NTIS; CONF740930; 1976: 225-229. Sanders, C. L.; Dagle, G. E.; Cannon, W. C.; Craig, D. K.; Powers, G. J.; Meier, D. M. Inhalation carcinogenesis of high-fired 23yPu02 in rats. Radiat. Res. 68:349-360; 1976. Sanders, C. L.; Lauhala, K. E.; McDonald, K. E. Scanning electron microscopy of lung following alpha irradiation. Scanning Microscopy 3: 907-9 18; 1989. Sanders, C. L.; Mahaffey, J. A. Inhalation carcinogenesis of repeated exposures to high-fired 239Pu02in rats. Health Phys. 4 1~629-644;198 1. Sanders, C. L.; McDonald, K. E.; Killand, B. W.; Mahaffey, J. A.; Cannon, W. C. Low-level lifespan studies with inhaled 239Pu02in rats. In: Thompson, R. C.; Mahaffey, J. A., ed. Life-span radiation effects studies in animals: What can they tell us? Proceedings of the 22nd Annual Hanford Life Sciences Symposium. Springfield, VA: NTIS; CONF-830951; 1986: 429-449. Sanders, C. L.; McDonald, K. E.; Lauhala, K. E. Promotion of pulmonary carcinogenesis by plutonium particle aggregation following inhalation of 239Pu02.Radiat. Res. 116: 393-405; 1988a. Sanders, C. L.; McDonald, K. E.; Lauhala, K. E. SEM auto-
Pleural mesothelioma in a rat from exposure to 239Pu02 0 C. L. SANDERS
691
pleural injection of asbestos and silica. In: Nattesheim, P.; Hanna, M. G., Jr.; Deatherage, J. W., eds. Morphology of experimental respiratory carcinogenesis, proceedingsof the AEC Symposium Series 2 1. Springfield, VA: NTIS; CONF700501; 1970: 347-358.
radiography:Aggregation of inhaled 239Pu02. Int. J. Radiat. Biol. 54:115-121; 1988b. Stanton, M. F.; Wrench, C. Mechanisms of mesothelioma induction with asbestos and fibrous glass. J. Natl. Cancer Inst. 48:797-821; 1972. Wagner, J. C. The pathogenesis of tumors following intra-
..
,
