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Bone tumors in Thorotrast patients
ENVIRONMENTAL
RESEARCH
l&88-93
(1979)
Bone Tumors
in Thorotrast W. MAYS
CHARLES Radiobiology
Laboratory,
Patients’
University Utah
of Utah, 84132
Medical
Center,
Salt
Lake
City,
AND HEINZ Kinderpolikliniks
Universitit
Miinchen,
SPIESS Pettenkofer
str 8o, 8 Munich
2, Germany
Received May 1, 1978 Among the Thorotrast patients throughout the world, nine bone sarcomas (six histologically confirmed and three possible) were reported as of 1974. Their appearance times ranged from 16 to 33 years, averaging 26 years after Thorotrast injection. In some countries the population at risk is uncertain, but in Denmark, Germany, and Portugal, about 3000 patients have been followed more than 10 years (45,000 persons years at risk beyond the first 10 years). In these 3000 patients, three to six bone sarcomas have occurred, compared with 0.5 ” case expected naturally. Using the dosimetric results of Rowland and Rundo and assuming that translocating “‘Ra was mainly responsible, the provisional risk coefficient is 55 to 120 bone sarcomas/l@ person rad of average dose to the skeleton without marrow. This risk coefficient is highly tentative because it is based on only three to six bone sarcomas, all reported since 1972. If additional bone sarcomas occur among the living Thorotrast patients, the risk coet?icient could increase appreciably. For comparison, the risk coefficient for long protracted injections of *z4Ra is about 200 bone sarcomas/IO6 person rad, based on 54 cases of bone sarcoma. l
l
l
INTRODUCTION
Marinelli and his disciples showed that in the Thorotrast patients a small but important fraction of the zz4Ra continually escapes from the Thorotrast aggregates and redeposits in bone (Reynolds et al., 1957, Marinelli, 1958; Marinelli and Lucas, 1962). Later, Rowland pointed out that when short-lived zz4Ra is deposited in bone much of its a-particle irradiation is emitted from bone surfaces (see comments by Rowland following the paper by Maletskos et al., 1969). Because of this fact, we have been able to estimate the risk from z3gPu, which also decays to a large extent on bone surfaces, using data on the 54 cases of bone sarcoma which have appeared in some 900 German patients given repeated injections of ‘=Ra (Mays, 1976; Mays et al., 1976; Mays and Spiess, 1978). The Thorotrast patients are particularly valuable in assessing the risk from 23gF’u and other bone surface seekers because several thousand followed patients have been continually irradiated at average skeletal dose rates near the maximum permissible values for radiation workers (0.6 rad/year for 23gPu). Rowland and Rundo (1973) calculated that the typical injection of 25 ml Thorotrast gives an average ’ Supported by U.S. Department of Energy Contract EY-76-C-02-0119 and by EURATOM 218-76-l-B10 D. 88 0013-9351/79/010088-06$0.200/O Copyright @ I979 by Academic Press, Inc. All rights of repmduction in my form reserved.
Contract
BONE TUMORS IN THOROTRAST TABLE BONE TUMORS IN
Tumor We Osteosarcomaa Chondrosarcomaa Fibrosarcoman Osteosarcoma Osteosarcoma Sarcoma Osteosarcoma’ Osteosarcomaa Fibrosarcoma=
Location Femur Humerus Femur Femur Femur Maxilla Tibia Pelvis Ninth thoracic vertebra
Thorotrast injected bnl)
89
PATIENTS
I
THOROTRAST
PATIENTS (1974)
Injection age (sex)
lo-20 lo-20 ? 20 24 60 75 SO-15? 75
Injection to death Wead 33 33 29 29 27 25 16 19 21
Authors van Kaick er a/. (1978) van Kaick er al. (1978) Horta ef al. (1978) Horta ef al. (1978) Horta et al. (1978) Horta ef al. (1978) Altner er a/. (1972) Tsuya ef a/. (1963) %k (1956)
a Tumor diagnosis confirmed histologically.
dose rate from translocating of an adult.
zz4Ra of about 1 rad/year to the marrow-free
skeleton
BONE TUMORS
Table I shows the bone tumors reported as of 1974 in Thorotrast patients throughout the world. In six cases, the bone sarcomas were contirmed histologically, while three additional cases had clinical or radiographic indications of bone sarcoma, although it was not possible to obtain tissue sections for histological diagnosis. All three of these possible bone sarcomas occurred in Portugal, where most patients die without autopsy because of the local religious customs. Thus, at least six Thorotrast patients have died with confirmed bone sarcomas, and the total number could be nine, or possibly even higher if other bone sarcomas have occurred but have not been reported. If some of the reported bone tumors are radiation induced, and if the risk increases with dose, one might expect the average dosage for the bone tumor cases to be elevated. Indeed, this seems to be true, since the average dosage of 43 ml of Thorotrast for the bone tumor cases is considerably higher than the average intravascular injection of about 23 ml for the Danish patients (estimated from the tabulated data of Faber, 1978), 26 ml for the Portuguese patients (p. 210 of Horta et u/., 1973), 30 ml in German patients dying before 1968, and 22 ml in German patients examined biophysically since 1968 (van Kaick et ul., 1978). The appearance times for the bone tumors averaged 26 years after Thorotrast injection, ranging from 16 to 33 years. Figure 1 shows a tendency for the appearance time of these bone tumors to shorten as the dosage increases. A similar effect has also been observed in the United States radium dial painters (Evans et al., 1969) and in beagles injected with bone-seeking radionuclides (Mays et ul., 1969). OBSERVATION
TIME and IRRADIATION
TIME
In Thorotrast patients, the observation time and the irradiation time both begin at the instant of injection (Fig. 2). But no induced tumors are observed until after a
90
MAYS
AND
SFIESS
EONE TUMOR APPEARANCETIME vs THOROTFIASTGOSAGEII9741 40
00
al
60 ‘ID INJECTED THOROTFWT (ml1
80
IW
FIG. 1. Bone tumor appearance time vs Thorotrast dosage. The appearance times tended to decrease as the injected amount of Thorotrast increased.
“latent” period required for their transformation and growth. In German patients receiving relatively brief irradiation from z24Ra injections, the average appearance time for bone sarcomas is 10 years (Mays and Spiess, 1978). Thus, Thorotrast patients receiving continuous skeletal irradiation from translocating 224Ra are not considered to be at appreciable risk from induced bone sarcomas until at least 10 years after Thorotrast injection. Similarly, the last 10 years of irradiation is considered mainly wasted with respect to inducing an appreciable number of visible bone tumors. THOROTRAST
POPULATION
AT RISK IN DENMARK, GERMANY
PORTUGAL,
AND
In some countries, the number of Thorotrast patients under systematic observation is uncertain, but in Denmark, Portugal, and Germany, follow-up information is available on a combined total of almost 3000 patients living more than 10
OBSERVATION TIME VISIBLE TUMORS
IRRADIATION TIME FIG. 2. Irradiation time and observation time. The irradiation does not instantly produce visible tumors because time is required for the tumors to develop and to enlarge into a recognizable size. Thus, no induced tumors are seen during the first part of the observation time. Similarly, the last part of continuous irradiation is “wasted” with respect to the induction of visible tumors.
BONE
TUMORS
IN
THOROTRAST
TABLE
91
PATIENTS
2
ESTIMATEOFPERSON 0 YEARS ATRISKBEYOND 10 YEARS A~ER~NTRAVASCULAR~NJECTION OFTHOROTRAST
Country Denmark t 1973, Faber) Portugal (1974, Horta) Germany (197.5, van Kaick) Dead before 1968 Examined after 1968 Total
Traced persons living at least IO years after intravascular Thorotrast
Average years from IO years after injection to contact or death
Person year beyond IO years after Thorotrast injection
646 -667=
17 -17*
10,982 -11,339
-87W 802 -2,945
-l@ 18 -15
-8,700 A 14 436 -45,457
l
646 Danish patiehts living 10 yr ] =667. 1012 Danish patients at start ’ Distribution of follow-up times assumed equal in Portugal and Denmark. ’ Calculated assuming a constant number of deaths per year during 28 years in the 1162 traced German Thorotrast patients known to have died between 3 years after injection and 1%8, with average times since injection of 17 years. a [1045 Portuguese patients at start]
years after intravascular injection of Thorotrast (Table 2). The number of persons . years (beyond the first 10 years) totals about 45,000 person years. In other words, the follow-up times of these patients averaged about 15 years beyond the lirst 10 years, or 25 years from injection to the time of death or to the most recent contact. The typical injection of 25 ml of Thorotrast gives an average dose rate to the marrow-free skeleton of about 1 rad/year from translocating 224Ra (Rowland and Rundo 1973). Thus, each year adds another tad, and the 45,000 person years at risk beyond 10 years after injection numerically equals the 45,000 person rad at 10 years before death or latest contact. l
l
l
BONE TUMORS IN DANISH, PORTUGUESE, AND GERMAN THOROTRAST PATIENTS
In the systematically followed Thorotrast populations in Denmark, Portugal, and Germany, the number of reported bone sarcomas is between three (histologically confirmed) and six (confirmed and possible). The expected number is 0.5 case, based on 45,000 person years at risk and a natural incidence rate of 1 bone sarcoma per year/lo5 persons (Doll et al., 1970). Thus, the excess number of cases is between 2.5 and 5.5 cases. Presumably, this excess is due to irradiation. If 0.5 case is the natural expectation for this population, the chance of observing three or more naturally occurring bone sarcomas is less than 2% (p < 0.02). Most of the Thorotrast patients were injected intraarterially for cerebral angiography. VirtuaIly all of their diseases at the time of Thorotrast administration were unrelated to skeletal abnormalities. No bone tumors have been reported among the 829 Portuguese and 1505 German control patients. l
92
MAYS
TENTATIVE
AND
SPIESS
ESTIMATE
OF RISK
Our provisional estimate of the risk coefficient, dose from 224Ra and its daughters, is: =
2.5 to 5.5 bone sarcomas 45,000 person rad l
in terms of average skeletal
55 to 120 bone sarcomas. 106 person rad l
This estimate is highly tentative because it is based on the three to six bone tumors reported since 1972. If additional bone sarcomas occur among the living Thorotrast patients, the risk coefficient could increase appreciably. For comparison, the risk coefficient, extended to long protraction in the German 224Ra patients, is about 200 bone sarcomas/106 person rad of average skeletal dose, based on 54 cases of bone sarcoma (Mays, 1976; Mays et al., 1976; Mays and Spiess, 1978). It may be desirable to make future moditlcations of our tentative risk coefficient for Thorotrast-induced bone sarcomas. For example, if only the last 5 years of irradiation is considered wasted, the number of person rad from translocating 224Rawould be about 61,000, and the corresponding risk coefficient would be 40 to 90 bone sarcomas/lo6 person rad, based on 1974 data. If the skeletal irradiation from 232Th, 22’Ra, and 22*Th is important and is expressed in biologically equivalent units of 224Ra dose, this could decrease the risk coefftcient. We have used the dosimetry of Rowland and Rundo (1973), but other dosimetric models, such as by Dudley (1978) and by Kaul and Noffz (1978) could yield somewhat different results. l
l
l
DISCUSSION
It is not our purpose to give tinal results, but to show that the Thorotrast experience is of direct relevance to the question of plutonium risk to bone at presently permissible dose rates. Only during the last few years have a statistically significant number of bone sarcomas been reported among the Thorotrast patients, and based on this trend, additional bone sarcomas are expected. If reliable estimates of the full risk are to be obtained, it is essential that the Thorotrast studies continue with adequate long-range funding to insure their successful completion. With respect to late-appearing cancers, these studies have just recently entered their most important phase. REFERENCES 1. Altner, P. C., Simmons, D. J., Lucas, H. F., and Cummins, H. (1972). Osteogenic sarcoma in a patient injected with Thorotrast. J. Eone Joint Swg. 54-A, 670-675. 2. Doll, R., Muir, C., and Waterhouse, H. (1970). Cancer incidence in five continents. International Union Against Cancer, Springer-Verlag, Berlin/New York. 3. Dudley, R. A. (1978). Bone irradiation in Thorotrast cases: Results of measurements at IAEA. Health Phys., 35, 103- 112. 4. Evans, R. D., Keane, A. T., Kolenkow, R. J., Neal, W. R., and Shanahan, M. M. (1%9). Radiogenic tumors in the radium and mesothorium cases studied at M.I.T. in “Delayed Effects of Bone-Seeking Radionuclides” (C. W. Mays, W. S. S, Jee, R. D. Lloyd, B. J. Stover, J. H. Dougherty, and G. N. Taylor, Eds.), pp. 157-194. Univ. of Utah Press, Salt Lake City, Utah. 5. Faber, M. (1978). Malignancies in Danish Thorotrast patients. He&h t’hys. 35, 153- 158. 6. Horta, J., Motta, L., and Tavares, M. H. (1973). Epidemiological follow-up studies of the Portuguese Thorotrast series. in “Rise Report 294. Proceedings of the Third International Meeting
BONE TUMORS IN TEOROTRAST
7. 8. 9. 10.
11.
PATIENTS
93
on the Toxicity of Thorotrast,” (M. Faber, Ed.), pp. 193-211. Danish Atomic Energy Commission, Copenhagen. Horta, J., Horta, M. E., Motta, L. C., and Tavares, M. H. (1978). Malignancies in Portuguese Thorosrast patients. He&i P!rys., 35, 13?-151. van Kaick, G., Muth, H., Lorenz, D., and Kaul, A. (1978). Malignancies in German Thorotrast patients and estimated tissue dose. Heahh Phys., 35, 127- 136. Kaul, A. and Noffz, W. (1978). Tissue dose in Thorotrast patients. He~ifh Phys. 35, 113-121. Maletskos, C. J., Keane, A. T., Telles, N. C., and Evans, R. D. (1%9). Retention and absorption of zz4Ra and z3aTh and some dosimetric consequences of Zz4Rain human beings. In “Delayed Effects of Bone-Seeking Radionuclides” (C. W. Mays, W. S. S. Jee, R. D. Lloyd, B. J. Stover, J. H. Dougherty, and G. N. Taylor, Eds.). pp. 29-49. Univ. of Utah Press, Salt Lake City, Utah. Marinehi, L. D. (1958). Radioactivity and the human skeleton. The Janeway lecture. Amer. J. Roentgenok
80, 129-739.
12. Marinelli, L. D., and Lucas. H. F.. Jr. (1%2). Translocation of thorium daughters to bone. In “Some Aspects of Internal Irradiation” (T. F. Dougherty, W. S. S. Jee, C. W. Mays, and B. J. Stover, Eds.), pp. 499-Sl6. Pergamon, Oxford. 13. Mays, C. W., Dougherty. T. F., Taylor, G. N., Lloyd, R. D., Stover, B. J., Jee, W. S. S., Christensen, W. R., Dougherty, J. H., and Atherton, D. R. (1%9). Radiation-induced bone cancer in beagles. In “Delayed Effects of Bone-Seeking Radionuclides” (C. W. Mays, W. S. S. Jee, R. D. Lloyd, B. J. Stover, J. H. Dougherty, and G. N. Taylor, Eds.), pp. 387-408, Univ. of Utah Press, Salt Lake City, Utah. 14. Mays, C. W. (1976). Estimated risk from 239Puto human bone, liver, and lung. Zn “Biological and Environmental Effects of Low Level Radiation” (M. Lewis, Ed.), Vol. II, pp. 373-384. IAEA, Vienna. 15. Mays, C. W., Spiess, H., Taylor, G. N., Lloyd, R. D., Jee, W. S. S., McFarland, S. S., Taysum, D. H., Brammer, T. W., Brammer, D., and Pollard, T. A. (1976). Estimated risk to human bone from z39Pu. In “The Health Effects of Plutonium and Radium” (W. S. S. Jee, Ed.), pp. 343362. J. W. Press, Anatomy Department, University of Utah, Salt Lake City, Utah. 16. Mays, C. W., and Spiess, H. (1978). Bone sarcoma risk to man from **4Ra, *Z6Ra, and z39Pu. Iri “Biological Effects of Ra-224” (W. A. MulIer and H. G. Ebert, Eds.), pp. 168-179, Martizus Nijhoff Medical Division, The Hague/Boston. 17. Reynolds, J. C., Gustafson, P. F., and Marinelli, L. D. (1957). Retention and elimination of radium isotopes produced by the decay of thorium parents within the body: Calculations and comparison with experimental findings. Argonne National Laboratory Report ANL-5689, pp. l-43. 18. Rowland, R. E., and Rundo, J, (1973). The skeletal dose from ‘**Ra following intravascular administration of Thorotrast. In “Rise Report 294. Proceedings of the Third International Meeting on the Toxicity of Thorotrast” (M. Faber, Ed.), pp. 95-103. Danish Atomic Energy Commission, Copenhagen. 19. Tsuya, A., Tanaka, T., Mori, T., Hashizumi, T., and Kato, Y. (1%3). Four cases of Thorotrast injury and estimation of absorbed tissue dose in critical organs. Japan. J. Radiar. Res. 4, 126-145. 20. &k, F. (1956). Trvale poskozeni organismu thorotrastem. Universitas Carolina Medica, Supplementum 2/1956, Sessio secunda facultatis medicae scientifica, pp. 254-258. [In Czech with summary in English.]
RESEARCH
l&88-93
(1979)
Bone Tumors
in Thorotrast W. MAYS
CHARLES Radiobiology
Laboratory,
Patients’
University Utah
of Utah, 84132
Medical
Center,
Salt
Lake
City,
AND HEINZ Kinderpolikliniks
Universitit
Miinchen,
SPIESS Pettenkofer
str 8o, 8 Munich
2, Germany
Received May 1, 1978 Among the Thorotrast patients throughout the world, nine bone sarcomas (six histologically confirmed and three possible) were reported as of 1974. Their appearance times ranged from 16 to 33 years, averaging 26 years after Thorotrast injection. In some countries the population at risk is uncertain, but in Denmark, Germany, and Portugal, about 3000 patients have been followed more than 10 years (45,000 persons years at risk beyond the first 10 years). In these 3000 patients, three to six bone sarcomas have occurred, compared with 0.5 ” case expected naturally. Using the dosimetric results of Rowland and Rundo and assuming that translocating “‘Ra was mainly responsible, the provisional risk coefficient is 55 to 120 bone sarcomas/l@ person rad of average dose to the skeleton without marrow. This risk coefficient is highly tentative because it is based on only three to six bone sarcomas, all reported since 1972. If additional bone sarcomas occur among the living Thorotrast patients, the risk coet?icient could increase appreciably. For comparison, the risk coefficient for long protracted injections of *z4Ra is about 200 bone sarcomas/IO6 person rad, based on 54 cases of bone sarcoma. l
l
l
INTRODUCTION
Marinelli and his disciples showed that in the Thorotrast patients a small but important fraction of the zz4Ra continually escapes from the Thorotrast aggregates and redeposits in bone (Reynolds et al., 1957, Marinelli, 1958; Marinelli and Lucas, 1962). Later, Rowland pointed out that when short-lived zz4Ra is deposited in bone much of its a-particle irradiation is emitted from bone surfaces (see comments by Rowland following the paper by Maletskos et al., 1969). Because of this fact, we have been able to estimate the risk from z3gPu, which also decays to a large extent on bone surfaces, using data on the 54 cases of bone sarcoma which have appeared in some 900 German patients given repeated injections of ‘=Ra (Mays, 1976; Mays et al., 1976; Mays and Spiess, 1978). The Thorotrast patients are particularly valuable in assessing the risk from 23gF’u and other bone surface seekers because several thousand followed patients have been continually irradiated at average skeletal dose rates near the maximum permissible values for radiation workers (0.6 rad/year for 23gPu). Rowland and Rundo (1973) calculated that the typical injection of 25 ml Thorotrast gives an average ’ Supported by U.S. Department of Energy Contract EY-76-C-02-0119 and by EURATOM 218-76-l-B10 D. 88 0013-9351/79/010088-06$0.200/O Copyright @ I979 by Academic Press, Inc. All rights of repmduction in my form reserved.
Contract
BONE TUMORS IN THOROTRAST TABLE BONE TUMORS IN
Tumor We Osteosarcomaa Chondrosarcomaa Fibrosarcoman Osteosarcoma Osteosarcoma Sarcoma Osteosarcoma’ Osteosarcomaa Fibrosarcoma=
Location Femur Humerus Femur Femur Femur Maxilla Tibia Pelvis Ninth thoracic vertebra
Thorotrast injected bnl)
89
PATIENTS
I
THOROTRAST
PATIENTS (1974)
Injection age (sex)
lo-20 lo-20 ? 20 24 60 75 SO-15? 75
Injection to death Wead 33 33 29 29 27 25 16 19 21
Authors van Kaick er a/. (1978) van Kaick er al. (1978) Horta ef al. (1978) Horta ef al. (1978) Horta et al. (1978) Horta ef al. (1978) Altner er a/. (1972) Tsuya ef a/. (1963) %k (1956)
a Tumor diagnosis confirmed histologically.
dose rate from translocating of an adult.
zz4Ra of about 1 rad/year to the marrow-free
skeleton
BONE TUMORS
Table I shows the bone tumors reported as of 1974 in Thorotrast patients throughout the world. In six cases, the bone sarcomas were contirmed histologically, while three additional cases had clinical or radiographic indications of bone sarcoma, although it was not possible to obtain tissue sections for histological diagnosis. All three of these possible bone sarcomas occurred in Portugal, where most patients die without autopsy because of the local religious customs. Thus, at least six Thorotrast patients have died with confirmed bone sarcomas, and the total number could be nine, or possibly even higher if other bone sarcomas have occurred but have not been reported. If some of the reported bone tumors are radiation induced, and if the risk increases with dose, one might expect the average dosage for the bone tumor cases to be elevated. Indeed, this seems to be true, since the average dosage of 43 ml of Thorotrast for the bone tumor cases is considerably higher than the average intravascular injection of about 23 ml for the Danish patients (estimated from the tabulated data of Faber, 1978), 26 ml for the Portuguese patients (p. 210 of Horta et u/., 1973), 30 ml in German patients dying before 1968, and 22 ml in German patients examined biophysically since 1968 (van Kaick et ul., 1978). The appearance times for the bone tumors averaged 26 years after Thorotrast injection, ranging from 16 to 33 years. Figure 1 shows a tendency for the appearance time of these bone tumors to shorten as the dosage increases. A similar effect has also been observed in the United States radium dial painters (Evans et al., 1969) and in beagles injected with bone-seeking radionuclides (Mays et ul., 1969). OBSERVATION
TIME and IRRADIATION
TIME
In Thorotrast patients, the observation time and the irradiation time both begin at the instant of injection (Fig. 2). But no induced tumors are observed until after a
90
MAYS
AND
SFIESS
EONE TUMOR APPEARANCETIME vs THOROTFIASTGOSAGEII9741 40
00
al
60 ‘ID INJECTED THOROTFWT (ml1
80
IW
FIG. 1. Bone tumor appearance time vs Thorotrast dosage. The appearance times tended to decrease as the injected amount of Thorotrast increased.
“latent” period required for their transformation and growth. In German patients receiving relatively brief irradiation from z24Ra injections, the average appearance time for bone sarcomas is 10 years (Mays and Spiess, 1978). Thus, Thorotrast patients receiving continuous skeletal irradiation from translocating 224Ra are not considered to be at appreciable risk from induced bone sarcomas until at least 10 years after Thorotrast injection. Similarly, the last 10 years of irradiation is considered mainly wasted with respect to inducing an appreciable number of visible bone tumors. THOROTRAST
POPULATION
AT RISK IN DENMARK, GERMANY
PORTUGAL,
AND
In some countries, the number of Thorotrast patients under systematic observation is uncertain, but in Denmark, Portugal, and Germany, follow-up information is available on a combined total of almost 3000 patients living more than 10
OBSERVATION TIME VISIBLE TUMORS
IRRADIATION TIME FIG. 2. Irradiation time and observation time. The irradiation does not instantly produce visible tumors because time is required for the tumors to develop and to enlarge into a recognizable size. Thus, no induced tumors are seen during the first part of the observation time. Similarly, the last part of continuous irradiation is “wasted” with respect to the induction of visible tumors.
BONE
TUMORS
IN
THOROTRAST
TABLE
91
PATIENTS
2
ESTIMATEOFPERSON 0 YEARS ATRISKBEYOND 10 YEARS A~ER~NTRAVASCULAR~NJECTION OFTHOROTRAST
Country Denmark t 1973, Faber) Portugal (1974, Horta) Germany (197.5, van Kaick) Dead before 1968 Examined after 1968 Total
Traced persons living at least IO years after intravascular Thorotrast
Average years from IO years after injection to contact or death
Person year beyond IO years after Thorotrast injection
646 -667=
17 -17*
10,982 -11,339
-87W 802 -2,945
-l@ 18 -15
-8,700 A 14 436 -45,457
l
646 Danish patiehts living 10 yr ] =667. 1012 Danish patients at start ’ Distribution of follow-up times assumed equal in Portugal and Denmark. ’ Calculated assuming a constant number of deaths per year during 28 years in the 1162 traced German Thorotrast patients known to have died between 3 years after injection and 1%8, with average times since injection of 17 years. a [1045 Portuguese patients at start]
years after intravascular injection of Thorotrast (Table 2). The number of persons . years (beyond the first 10 years) totals about 45,000 person years. In other words, the follow-up times of these patients averaged about 15 years beyond the lirst 10 years, or 25 years from injection to the time of death or to the most recent contact. The typical injection of 25 ml of Thorotrast gives an average dose rate to the marrow-free skeleton of about 1 rad/year from translocating 224Ra (Rowland and Rundo 1973). Thus, each year adds another tad, and the 45,000 person years at risk beyond 10 years after injection numerically equals the 45,000 person rad at 10 years before death or latest contact. l
l
l
BONE TUMORS IN DANISH, PORTUGUESE, AND GERMAN THOROTRAST PATIENTS
In the systematically followed Thorotrast populations in Denmark, Portugal, and Germany, the number of reported bone sarcomas is between three (histologically confirmed) and six (confirmed and possible). The expected number is 0.5 case, based on 45,000 person years at risk and a natural incidence rate of 1 bone sarcoma per year/lo5 persons (Doll et al., 1970). Thus, the excess number of cases is between 2.5 and 5.5 cases. Presumably, this excess is due to irradiation. If 0.5 case is the natural expectation for this population, the chance of observing three or more naturally occurring bone sarcomas is less than 2% (p < 0.02). Most of the Thorotrast patients were injected intraarterially for cerebral angiography. VirtuaIly all of their diseases at the time of Thorotrast administration were unrelated to skeletal abnormalities. No bone tumors have been reported among the 829 Portuguese and 1505 German control patients. l
92
MAYS
TENTATIVE
AND
SPIESS
ESTIMATE
OF RISK
Our provisional estimate of the risk coefficient, dose from 224Ra and its daughters, is: =
2.5 to 5.5 bone sarcomas 45,000 person rad l
in terms of average skeletal
55 to 120 bone sarcomas. 106 person rad l
This estimate is highly tentative because it is based on the three to six bone tumors reported since 1972. If additional bone sarcomas occur among the living Thorotrast patients, the risk coefficient could increase appreciably. For comparison, the risk coefficient, extended to long protraction in the German 224Ra patients, is about 200 bone sarcomas/106 person rad of average skeletal dose, based on 54 cases of bone sarcoma (Mays, 1976; Mays et al., 1976; Mays and Spiess, 1978). It may be desirable to make future moditlcations of our tentative risk coefficient for Thorotrast-induced bone sarcomas. For example, if only the last 5 years of irradiation is considered wasted, the number of person rad from translocating 224Rawould be about 61,000, and the corresponding risk coefficient would be 40 to 90 bone sarcomas/lo6 person rad, based on 1974 data. If the skeletal irradiation from 232Th, 22’Ra, and 22*Th is important and is expressed in biologically equivalent units of 224Ra dose, this could decrease the risk coefftcient. We have used the dosimetry of Rowland and Rundo (1973), but other dosimetric models, such as by Dudley (1978) and by Kaul and Noffz (1978) could yield somewhat different results. l
l
l
DISCUSSION
It is not our purpose to give tinal results, but to show that the Thorotrast experience is of direct relevance to the question of plutonium risk to bone at presently permissible dose rates. Only during the last few years have a statistically significant number of bone sarcomas been reported among the Thorotrast patients, and based on this trend, additional bone sarcomas are expected. If reliable estimates of the full risk are to be obtained, it is essential that the Thorotrast studies continue with adequate long-range funding to insure their successful completion. With respect to late-appearing cancers, these studies have just recently entered their most important phase. REFERENCES 1. Altner, P. C., Simmons, D. J., Lucas, H. F., and Cummins, H. (1972). Osteogenic sarcoma in a patient injected with Thorotrast. J. Eone Joint Swg. 54-A, 670-675. 2. Doll, R., Muir, C., and Waterhouse, H. (1970). Cancer incidence in five continents. International Union Against Cancer, Springer-Verlag, Berlin/New York. 3. Dudley, R. A. (1978). Bone irradiation in Thorotrast cases: Results of measurements at IAEA. Health Phys., 35, 103- 112. 4. Evans, R. D., Keane, A. T., Kolenkow, R. J., Neal, W. R., and Shanahan, M. M. (1%9). Radiogenic tumors in the radium and mesothorium cases studied at M.I.T. in “Delayed Effects of Bone-Seeking Radionuclides” (C. W. Mays, W. S. S, Jee, R. D. Lloyd, B. J. Stover, J. H. Dougherty, and G. N. Taylor, Eds.), pp. 157-194. Univ. of Utah Press, Salt Lake City, Utah. 5. Faber, M. (1978). Malignancies in Danish Thorotrast patients. He&h t’hys. 35, 153- 158. 6. Horta, J., Motta, L., and Tavares, M. H. (1973). Epidemiological follow-up studies of the Portuguese Thorotrast series. in “Rise Report 294. Proceedings of the Third International Meeting
BONE TUMORS IN TEOROTRAST
7. 8. 9. 10.
11.
PATIENTS
93
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