Thorium

National Research Council (US) Committee on the Biological Effects of Ionizing Radiations

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National Research Council (US) Committee on the Biological Effects of Ionizing Radiations. Health Risks of Radon and Other Internally Deposited Alpha-Emitters: Beir IV. Washington (DC): National Academies Press (US); 1988.

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Health Risks of Radon and Other Internally Deposited Alpha-Emitters: Beir IV.

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5Thorium

Introduction

Thorium-232 is a primordial element that is distributed throughout the environment. It has a very long physical half-life (1.41 × 10 ¹⁰ yr) and decays by emission of an alpha particle creating a series of radioactive daughters, many of which also emit alpha radiations. One of these daughters is an isotope of radon, ²²⁰Rn, viz., thoron.

The high density and atomic number of thorium led to its use as a contrast agent in medical radiography, as commercially prepared Thorotrast, a 25% colloidal solution of thorium dioxide (ThO₂). Until after the end of World War II, Thorotrast was used extensively as an intravascular contrast agent for cerebral and limb angiography in Europe, the United States, and Japan. It was also injected directly into the spleen for hepatolienography and into abcess cavities in the brain and elsewhere. Direct instillation of Thorotrast into the nasal cavity and paranasal sinuses was also practiced in the past and resulted in a number of epithelial tumors.¹³ Because of Thoro Thorotrast's colloidal characteristics, thorium and its decay products were deposited in body tissues and organs, most frequently in the reticuloendothelial tissues and in bone. Deposition resulted in continuous alpha-particle irradiation throughout life at a low dose rate.

Patients who received alpha-radiation exposure due to radiologically administered Thorotrast in the late 1920s through 1955 have been followed in epidemiological surveys in Germany,⁵¹ Portugal,⁵ Denmark,¹¹ and Japan.³² These studies, described below, demonstrate primarily an excess of liver cancer, including hemangiosarcomas and cholangiosarcomas, and acute myeloid leukemia. This is in contrast to the ²²⁴Ra-exposed patients, discussed in Chapter 4, treated for tuberculosis and ankylosing spondylitis,⁴¹ in whom no significant excess of liver cancer has occurred. The alpha-radiation dosimetry in the liver and bone marrow is complex, and precise quantification of risk in these patients is limited because of the nonuniform distribution of thorium dioxide in these tissues and the possible effects of the colloidal material on cancer risk. Moreover, the dose responsible for induction of neoplasia cannot be distinguished from the wasted radiation after initiation has occurred. Therefore, dose-response relationships are highly uncertain.

Properties and Dosimetry

The long-lived isotope ²³²Th is the parent of a naturally occurring radioactive decay series. The thorium decay series can be considered in two steps: (1) the formation of ²²⁴Ra by the successive decays from ²³²Th, and (2) the decay of ²²⁴Ra and its daughters to stable lead (Figure 5-1). The isotope Ra (half-life, 3.62 days) is an important member of the thorium decay chain; its decay results in the ultimate emission of four alpha particles that release about 26.5 MeV. People with burdens of thorium administered for radiodiagnostic purposes are being irradiated by ²²⁴Ra and its alpha-emitting progeny as a result of its continuous production in vivo from the ²³²Th.³⁸ The radioisotopes in the thorium series and their physical characteristics are listed in Table 5-1.³⁹

Figure 5-1

Formation of ²²⁴Ra by successive decays from ²³²Th. Heavily lined boxes have been drawn around the alpha-particle emitters important to dosimetry. Source: Rundo.

TABLE 5-1

Radioisotopes in the Thorium Series.

Environmental Pathways⁴⁵

Thorium-232 is present in the soil at an average concentration of about 25 Bq/kg (1 Bq = 27 pCi). Because of its very low absorption through the gastrointestinal tract, natural thorium is mainly incorporated into the body by the inhalation of resuspended solid particles at a rate of about 0.1 Bq/yr. The average body content of thorium-232 is about 80 mBq, 60% of which can be found in the skeleton. Associated annual effective dose equivalent is estimated at about 3 µSv (1 Sv = 100 rem). The decay product of ²³²Th, ²²⁸Ra, is much more mobile environmentally, and unlike ²³²Th, ingestion constitutes the major pathway for intake. The annual level is about 15 Bq by ingestion compared to approximately 0.01 Bq from inhalation of the suspended soil particles. Radium-228, on the average, concentrates in bone at a level of about 90 mBq/kg and in soft tissues at about 4 mBq/kg. The decay product of ²²⁸Th, as is true of ²²⁸Ra, is concentrated in bone, with about 80% of the body content of 300 mBq being found in the skeleton.

Radon-220 and its decay products (²¹⁶Po, ²¹²Pb, ²¹²Bi, ²¹²Po, and ²⁰⁸Th) are responsible for an additional annual effective dose equivalent of about 0.22 mSv, 90% of which is a result from indoor exposure. Radon-220 and its decay products are generally present at levels about 10- to 20-fold lower than that of ²²²Ra (from the decay of ²²⁶Ra).

Biological Properties of the Thorium Series

Eight different chemical elements are represented in the thorium series. Three of them (Th, Ra, Po) are represented by two isotopes each (Figure 5-1 and Table 5-1). As the chemical identity of a given atom changes as a result of successive nuclear transformations, it may find itself situated at a metabolically inappropriate site, and there is the possibility that it may translocate. The recoil energy imparted to a nucleus on the emission of an alpha particle of several megaelectronvolts of energy is on the order of 100 keV, far greater than the strength of any chemical bond in the atom.³⁸

Of the two isotopes of thorium in the precursors of ²²⁴Ra, the parent of the series, ²³²Th, is the only member of the chain that can exist in vivo in macroscopic quantities. The weight of 1 µCi of ²³²Th is 9.13 g, while the weight of 1 µCi of ²²⁸Th is 1.21 × 10^-9 g. After intravenous injections of such quantities, the concentration of ²²⁸ Th in the blood would be about 6 × 10⁸ atoms/ml, but the concentration of ²³²Th would be about 10¹⁰ times higher. Thorium appears to be held tenaciously at either its site of formation in vivo or its point of entry into the body (other than the bloodstream), regardless of the specific activity of the material. Following intravenous injection, thorium of high specific activity deposits mainly on bone surfaces, from which its release appears to be very slow. In the special case of Thorotrast, in which macroquantities of ²³²Th in colloidal form are injected, it is the physical form that controls its deposition in the cells of the reticuloendothelial system rather than the chemical properties. The colloid aggregates in vivo into clumps as large as 100 µm across, and these aggregates are very stable. The ²²⁸Th that is produced via ²²⁸Ra and ²²⁸Ac in these aggregates does have some mobility, and there is a small loss of activity from thorium deposits. ^38,39

Alpha Dosimetry of Thorium in Humans

Thorotrast was administered as a colloidal form of thorium dioxide; the colloidal particles agglomerate and pose a radiation risk to the reticuloendothelial system in which they are ultimately sequestered. The thorium is ultimately redistributed and produces a nonuniform irradiation. The range of the emitted alpha particles in unit density tissue is approximately 40 to 45 µm, that is, about four or five cell diameters. Microscopic and autoradiographic studies have shown that the colloidal aggregates can range to about 100 µm in diameter, producing a highly nonuniform dose-distribution pattern. Such a distribution is thought to be less biologically effective than a more uniform distribution of the same amount of alpha-particle energy³³ for two reasons. First, some of the alpha-particle energy is expended within the aggregate itself, and thus, that fraction of the radiation dose is unavailable to surrounding cells at risk. Second, the cells closest to the aggregates are subject to multiple alpha-particle traversals of critical targets within the cells. Such over irradiation of sensitive cells at risk increases the likelihood of cell killing or sterilization. To the extent that this occurs, it diminishes the opportunity for the same cells to be transformed later and adds to the overall oncogenic risk. This is illustrated in Figure 5-2, which shows a high-resolution autoradiograph of a Thorotrast aggregate surrounded by dense fibrotic tissue in the human liver.¹³ Quantitative aspects of this exposure situation are discussed in Appendix I and Chapter 4.

Figure 5-2

High-resolution autoradiograph of liver autopsy specimen of a 60-yr-old male who died of hemangioendothelioma in the liver 15 yr after a 75-ml Thorotrast injection for hepatolienography. Magnification, × 1,250; oil immersion.

Radioactivity and, therefore, dose increase with the size of the Thorotrast aggregation. However, this is offset to some extent by alpha-energy absorption within the aggregate. With increasing amounts of Thorotrast injected, an increase in the effective average aggregate diameter and a corresponding decrease in the fraction of alpha-energy emitted by the aggregate are found.⁵⁰ Table 5-2 shows the mean tissue doses in the liver and red bone marrow based on measurements from the German Thorotrast study⁵⁰ and indicates the magnitude of dose modification to tissue afforded by the self-absorption of the alpha particles in thorium dioxide aggregates. For example, in the case of the liver, an increase in the injected quantity of Thorotrast by a factor of 10 is associated with only a fourfold increase in annual radiation dose. The lower uptake of Thorotrast by the bone marrow and the consequent smaller mean aggregate size produced less of an effect.

TABLE 5-2

Mean Annual Alpha-Radiation Dose Following Thorotrast Injection.

Following Thorotrast injection and deposition within the body, a buildup of daughter products proceeds, but it never reaches equilibrium.³⁸ The lack of equilibrium is indicated by the relative excretion rates of ²³²Th and its daughters; thorium is excreted at a slow rate relative to that of radium isotopes.³⁸

Kaul and Noffz²² calculated absorbed doses to the liver, spleen, red bone marrow, lungs, kidneys, and bone for long-term burdens of intravascularly injected Thorotrast. The estimates were performed for typical injection levels of 10, 30, 60, and 100 ml based on best estimates of ²³²Th tissue distribution and steady-state activity ratios between subsequent daughters. The typical tissue distribution of ²³²Th in patients was estimated in the German Thorotrast Study to be as follows: liver, 59%; spleen, 29%; red bone marrow, 9%; calcified bone, 2%; lungs, 0.7%; kidneys, 0.1%.²² The thorium dioxide concentration in regional lymph nodes of the liver and spleen was high, but very low in other lymph nodes in the body.

Correcting for the alpha-particle self-absorption within Thorotrast aggregates, the mean radiation dose to a standard 70-kg man at 30 yr after the intravascular injection of 25 ml of Thorotrast was estimated to be 750 rad to the liver, 2,100 rad to the spleen, 270 rad to the red bone marrow, 60–620 rad into various parts of the lung, and 13 rad to the kidney. Based on the tissue distribution of ²³²Th in Thorotrast-exposed patients and the mean concentration of ²³²Th in various organs of Thorotrast-exposed patients, Figure 5-3 (from the study of Kaul and Noffz²² ) illustrates the mean steady-state alpha-radiation dose rates in the liver, spleen, and red bone marrow. These are plotted against the volume of Thorotrast injected to give values of dose rate for any volume of intravascularly injected Thorotrast between 10 and 100 ml. A typical injection of 25 ml of Thorotrast administered for angiography would result in an estimated dose rate of about 25 rad/yr in the liver and an average of about 16 rad/yr to the endosteal cells of bone.⁵⁰ Dose rates to various parts of bone tissue (bone surface, compact and cancellous bone) were estimated by applying the International Commission on Radiological Protection (ICRP) model¹⁸ on alkaline earth metabolism to the continuous translocation of thorium daughters to bone and to the formation of thorium daughters by decay within bone tissue. The average dose to calcified bone from translocated ²²⁴Ra with its daughters was estimated to be 19 rad at 30 yr after the injection of 25 ml of Thorotrast.

Figure 5-3

Mean alpha-radiation dose rates to the liver, spleen, and red bone marrow verses volume of intravascularly injected Thorotrast. Source: Kaul and Noffz.

Both the steady-state activity ratio of thorium daughters to ²³²Th and the self-absorption of alpha particles in ²³²ThO₂ aggregates are important for estimating the absorbed dose in tissues due to Thorotrast. Gamma rays from ²²⁸Ac, ²¹²Pb, and ²⁰⁸Tl and alpha rays from ²³²Th and ²²⁸Th emitted from autopsy samples make it possible to estimate the steady-state activity ratio of thorium daughters to ²³²Th. The steady-state activity ratio of ²²⁸Th to ²³²Th can be determined from an alpha-ray energy spectrum and that of ²²⁴Ra to ²²⁸Th and ²²⁸Ra can be determined from a gamma-ray energy spectrum.²¹ For estimation of average absorbed dose in an organ, the distribution of Thorotrast aggregate sizes must be assumed. Examination of Thorotrast-exposed patients and results of laboratory animal experiments demonstrate that the concentration of Thorotrast throughout the liver varies considerably, perhaps by a factor of 100 in Thorotrast-exposed patients.¹²^,¹³ Large paravascular injections, together with the heterogeneous distribution in the liver, may be sources of error for the calculation of the tissue dose to the organs of the reticuloendothelial system. Moreover, the estimated tissue dose is dependent on the total injected volume of Thorotrast, the gross organ distribution of the ²³²Th and its daughter products, the average size of the ThO₂ aggregates, and the alpha-particle self-absorption within the aggregates. At the cellular level, there may be dose rate differences up to a factor of 10,000. Currently, only estimates of the mean organ dose are available.

Kato et al.²⁰ estimated the absorbed dose in the liver, spleen, and bone marrow in 30 Japanese Thorotrast-exposed patients who died of liver cancer, liver cirrhosis, and other Thorotrast-associated conditions. In the liver, a mean dose rate of 36 rad/yr and a total absorbed dose of 939 rad was calculated; for the spleen the doses were 200 rad/yr and 5,760 rad, respectively; for the bone marrow the doses were 99 rad/yr and 3,087 rad, respectively. For the Japanese patients with hepatic tumors,²⁰ the mean latent period was 31 yr, the mean absorbed dose in the liver was 939 rad (range, 145–3,234 rad), self-absorption was 0.5, body weight was 50–60 kg, and liver weight was 1,200 g.

Kaul and Noffz²² estimated the mean dose rates in West German patients based on a 25-ml intravascular injection of Thorotrast in a 70-kg person, to be as follows: liver, 25 rad/yr; spleen, 70 rad/yr; bone marrow, 9 rad/yr; endosteal layer in bone, 16 rad/yr; main pulmonary bronchi, 13 rad/yr, and kidneys, 0.4 rad/yr. The calculations assume the ²¹²Bi activity equals the ²¹²Pb activity in all tissues; if the kidney concentrates ²¹²Bi from the blood plasma, then the kidney dose rate could be much higher than 0.4 rad/yr. The high dose rate to the endosteal layer in bone is due to the thorium dioxide in adjacent bone marrow and translocation of ²²⁴Ra from deposits in the reticuloendothelial system to bone surfaces. For the West German patients, the mean latent period was 30 yr, the mean absorbed dose in the liver was 824 rad (range, 384–1,391 rad), the self-absorption was 0.15–0.48, the body weight was about 70 kg, and the liver weight was about 1,800 g. The mean absorbed dose in the liver in the Japanese data was 14% higher than that in the German data, in part, because of the less massive livers in the Japanese patients.²⁰

Animal Studies

Liver and Spleen Tumors

Several animal studies provide a better understanding of the carcinogenic potency of Thorotrast in humans. Early reports discussed whether, in addition to radiation, a foreign body effect or the chemical properties of Thorotrast should be taken into consideration as potential causal factors in tumor induction. Bensted² examined the effects of zirconium dioxide aquasol (Zirconotrast) and conventional and ²³⁰Th-enriched Thorotrast in mice, and found no clear evidence of an increased incidence of Thorotrast-specific tumors compared with Zirconotrast. Faber⁶ injected rabbits with various amounts of ²³⁰Th-enriched Thorotrast and found a shortened latency period for hemangioendotheliomas when compared with that caused by commercial Thorotrast. Riedel et al.³⁵^,³⁶ examined the distribution of colloidal thorium, zirconium, and hafnium dioxides and found that the organ distribution of Thorotrast and the kinetics of thorium daughters demonstrated comparable biological behavior in mice, rats, dogs, rabbits, and humans. The other colloids studied failed to show any significantly different effects due to their distribution from those of the thorium dioxide sol.

The investigations by Wesch et al.⁵⁴^,⁵⁵ are of particular interest since their objectives were to test for a dose response for carcinogenesis and to determine whether a foreign body effect was involved. In these experiments, ²³²Th was enriched with different fractions of ²³⁰Th to allow variation in dose rate for constant volumes of Thorotrast injected or varying volumes for a constant burden of radioactivity. They found that the frequency of liver and spleen tumors following a single injection of Thorotrast followed a linear dependence on radiation dose rate, but was not correlated with the volume of Thorotrast injected. At a constant dose rate, an increase in the volume of Thorotrast did not increase the tumor risk but did decrease the mean latent period. For a constant activity injected, a factor of 10 increase in the mass injected resulted in further life-shortening. A linear dose-response relationship for liver cancer was found; I(D) = 3.3 + 0.79D, where I(D) is the crude incidence (I) of all liver tumors and D is the dose rate. The correlation between dose and incidence was 0.97. The value of I at D = 0 did not differ from the observed control incidence of 2.7%.

In later studies, Wesch et al.⁵⁶ studied rats injected with Zirconotrast (colloidal ZrO₂) in which ²²⁸Th was incorporated. The liver cell carcinomas, intrahepatic bile duct carcinomas, and hemangiosarcomas induced were similar to Thorotrast tumors in humans. The number of hepatic or splenic tumors increased by a factor of 15 compared to controls; the frequency was dose rate dependent but did not correlate with the number of injected particles. The inactive colloid (without ²²⁸Th) did not induce primary hepatic or splenic tumors in excess, nor did it increase the tumor incidence at a constant dose rate.

Taylor et al.⁴³ examined the liver carcinogenicity of ²⁴¹Am and Thorotrast in mice and found that at comparable doses, in rad, of ²⁴¹Am and Thorotrast it was approximately equal. The toxicity ratio (²⁴¹Am/Thorotrast) for liver cancer induction approximated 1.2, with a range of 0.6–1.6. This further suggests that nonradiation factors of Thorotrast were not significant in liver tumor induction.

Brooks et al.³ injected hamsters with Thorotrast and found that the chromosome aberration frequency in liver cells increased linearly as a function of time and radiation dose. The slope of the dose-response relationship was estimated to be 0.56 aberrations/cell/Gy. This slope can be compared to the value of 0.48 aberrations/cell/Gy observed with injected ²³⁹Pu citrate. The data suggest that the dose distribution, chemical effects, or particle loading in the liver do not increase the frequency of chromosome aberrations induced by Thorotrast above that predicted for the more homogeneously distributed alpha radiation from ²³⁹Pu citrate. This provides some evidence that the data from Thorotrast-exposed patients may not overestimate the risk for primary liver damage from internally deposited alpha-emitting radionuclides.

Wegener and Hasenöhrl⁵³ examined rats injected intravenously with different quantities and different alpha doses of Thorotrast. The total frequency of liver and spleen tumors in animals receiving ²³⁰ Th-enriched Thorotrast was dependent on the dose given. The relationship between dose and effect was almost linear. The volume of injected Thorotrast, given a constant dose rate, had only a slight influence on the number of tumors induced.

The experimental evidence from studies on laboratory animals suggests that Thorotrast-induced tumors appear to arise in large measure from the effects of radiation, and that the carcinogenic effect may not be directly related to the physical presence of the particulate material in the tissues, to the chemical properties of thorium, or to the fibrotic tissue formed by cells killed by the radiation. Tissue destruction of significance does not precede the development of liver neoplasia in rats and mice, even when the radiation dose is very high.³⁶

Fibroblast proliferation may occur at injection sites in the subcutaneous tissues in a large proportion of Thorotrast-induced tumors in rats, and this may suggest that neoplasia could develop in those animals that have a vigorous inflammatory reaction to the presence of Thorotrast. However, no difference has been found in the incidence of hepatic tumors in a comparison in mice and rats of the late effects of Thorotrast and the nonradioactive colloidal contrast medium Zirconotrast.²^,⁵⁶ Studies on the effects of radioactive colloidal gold in laboratory animals demonstrated that it was not necessarily the colloidal state of the material that rendered it carcinogenic for the liver. Whereas a number of investigations have emphasized the possible role of cirrhosis and related biochemical factors in the livers of Thorotrast-exposed patients, no recent experimental evidence is available to indicate induction of liver damage and cirrhosis in rats and mice following the administration of Thorotrast.¹²

Bone Tumors

For ²²⁸Th, the tissues that are of importance in the neoplastic response in bone are the osteogenic tissues at the surface of bones and possibly in or near zones of endochondral bone formation, especially endosteal tissue.⁴ Mays et al.²⁶ found that ²²⁸Th is 8 times as effective as ²²⁶Ra for the induction of osteosarcomas from injected bone-seeking alpha-emitting radionuclides in beagle dogs. The higher effectiveness of ²²⁸Th is apparently due to the surface deposition of the thorium closer to the osteogenic tissue, in contrast to the distribution of the radium isotope throughout the bone tissue volume.

Studies of the bones of beagle dogs receiving single intravenous injections of ²²⁸Th have shown that the histopathological changes preceding the development of osteosarcomas are similar to those caused by ²³⁹Pu and ²²⁶Ra and those in radium-bearing humans. High radiation doses altered the vasculature and circulation and caused bone necrosis, bone resorption, reduced bone formation, and marrow fibrosis.¹⁹^,²⁶

Lloyd et al.²⁴ determined toxicity ratios for bone sarcoma induction at low dose rates and at low total doses in life-span observations of beagles, injected as young adults, for incorporated ²²⁸Th relative to that for ²²⁶Ra. For equal incidence of bone sarcoma, ²²⁸Th was about 8.5 ± 2.3 times as effective as ²²⁶Ra on the basis of cumulative average skeletal dose at 1 yr after death. ²²⁸Th was about 9.1 ± 2.5 times as effective as ²²⁶Ra when skeletal doses were compared at the time of death.

Human Studies

The studies in humans are almost all done following administration of Thorotrast. When Thorotrast is injected intravenously, the particles are taken up by the macrophages of the reticuloendothelial system; and the organs that show the greatest concentrations of aggregates of crystals are the liver, spleen, bone marrow, and lymph nodes. Hematological studies of Thorotrast-exposed patients demonstrated that it is common to find anemia, with an increase in the early forms of the myeloid series.⁵² Because of Thorotrast deposition in the bone marrow, destruction of erythropoietic and myelopoietic tissues and the subsequent appearance of circulating immature blood cells would be expected.

The use of Thorotrast for hepatolienography and angiography in order to examine the reticuloendothelial system resulted in the induction of primary sarcomas, carcinomas, and mixed neoplasms in the liver.⁵² Since hepatic carcinomas are associated with other pathologic conditions of the liver, for example, cirrhosis, and since in some of these patients Thorotrast was administered to diagnose and evaluate liver disease, it is difficult to assess the role of precancerous conditions that may have existed at the time of the administration of Thorotrast and the extent to which the radioactive colloid may have accelerated the induction of malignancy.

Many Thorotrast-exposed patients have been reported to have hepatocellular and cholangiocellular carcinoma of the liver.⁴ While histologically similar, these neoplasms were classified as hepatosarcomas, hemangioepitheliomas, endothelial cell sarcomas, and hemangioendotheliomas. On the basis of the limited clinical and experimental material available, it has been suggested that the hemangioendotheliomas may very well be almost a Thorotrast-specific tumor.¹

There are five epidemiological follow-up studies of Thorotrast-exposed patients, namely, the German Thorotrast study,⁴⁶^–⁵¹ the Japanese Thorotrast cases,²⁰^,²¹^,²⁹^–³² the Thorotrast-exposed patients in Portugal,¹^,⁵^,¹⁷ the Danish Thorotrast study,⁶^–¹¹ and the American study.¹⁴

The German Thorotrast Study

The German Thorotrast study⁴⁶^–⁵¹ now consists of a follow-up of 5,159 Thorotrast-exposed patients and 5,151 controls followed since 1933 and 1935, respectively. The Thorotrast-exposed patients underwent diagnostic x-ray examination during the period 1930 to 1951; these were primarily intravascular injections of x-ray contrast medium for cerebral angiography and angiography of the lower and upper limbs. There were 2,334 Thorotrast-exposed patients and 1,912 control patients who survived 3 yr or more after treatment and could be traced. Follow-up to 1984 has been performed on 894 Thorotrast-exposed patients and 662 control patients; 1,964 Thorotrast-exposed patients and 1,409 control patients have died.

The causes of death in the latter group are listed in Table 5-3.⁵¹ Most evident in the Thorotrast-exposed patients was 347 cases of liver cancer, compared with 2 cases in the control group; the liver tumors were carcinomas, primarily cholangiocellular and hemangiosarcomas. Cirrhosis was present in many of the patients with liver tumors. The shortest latency period was 16 yr, and some now range to latency intervals of more than 40 yr. The accumulated alpha-radiation tissue dose to the liver is estimated to range from 200 to 1,500 rad.⁵⁰

TABLE 5-3

The German Thorotrast Study: Causes of Death in Examined and Nonexamined Patients (Combined).

Myeloproliferative disorders occurred in 35 Thorotrast-exposed patients and 3 controls; the diseases included acute myeloid leukemia and erythroleukemia, monocytic leukemia, and chronic myeloid leukemia. The shortest latency interval for leukemia was 5 yr. The estimated accumulated dose to the red bone marrow is estimated to range from 50 to 400 rad. Non-Hodgkins lymphoma occurred in 16 Thorotrast-exposed patients and in 7 controls. Only four bone sarcomas have appeared in the 2,334 Thorotrast-exposed patients; the accumulated dose to the bone surface was estimated to be about 200–470 rad. Bone marrow failure due to aplastic anemia, agranulocytosis, or thrombocytopenia occurred in 20 Thorotrast-exposed patients and in 1 control patient; it is possible that some aplastic anemias were misdiagnosed aleukemic leukemias.

The results of the German Thorotrast study,⁵¹ when compared with those of the Portuguese,⁵ Danish,¹¹ and Japanese³² studies, show similar excess rates of liver cancers and leukemia.²⁷^,²⁸ Dose-effect relationships for liver cancers and leukemias have been observed in the West German study (Figure 5-4).⁵¹ However, the influence of the dose rate to bone marrow on the leukemia incidence cannot, as yet, be established. The cumulative incidence of liver cancers and leukemias plotted against time after Thorotrast injection (Figure 5-4) assumes an average volume of 25 ml of Thorotrast per injection, which corresponds to a tissue dose rate of 25 rad/yr in the liver and 9 rad/yr in the bone marrow. Leukemias appeared 5 yr after injection and continued to increase subsequently, while liver cancers did not appear until almost 20 yr after injection and then increased very rapidly. The proportion of cumulative leukemia incidence to cumulative liver cancer incidence is 1.2 to 12% by 40 yr, or 1 to 10. Time after injection is an important factor in the incidence of liver cancers but is much less so in the case of leukemias.

Figure 5-4

The German Thorotrast study. Cumulative incidence of liver tumors (solid line) and leukemia (dotted line) in examined and nonexamined patients (n = 2,135). Source: van Kaick et al.

Figure 5-5 illustrates the cumulative incidence of liver tumors in examined German Thorotrast-exposed patients with different liver dose rates.⁵⁰ Three groups of patients were studied: those receiving more than 20 ml of Thorotrast (dose rate, approximately 30 rad/yr), those receiving approximately 11–20 ml (dose rate, approximately 18 rad/yr), and those receiving less than 10 ml (dose rate, approximately 10 rad/yr). The dose and dose rate dependence are indicated in Figure 5-5, both with the shortening of the latent interval with increasing dose and dose rate and with the increased frequency of liver cancers in these patients with increasing dose and dose rate. In this study, the cumulative incidence of liver tumors was not influenced by the age at injection.

Figure 5-5

The German Thorotrast study. Cumulative incidence of liver tumors in examined Thorotrast-treated patients with different liver dose rates. Source: van Kaick et al.

There is an apparent lack of excess lung cancers in Thorotrast-exposed patients, (46 [2.3%] observed versus 40 [2.8%] in controls), even though the bronchi are exposed to chronic alpha radiation from ²²⁰Rn, which is exhaled with the breath. Initial estimates of the accumulated radiation dose to the bronchial airways of these patients suggested doses as high as 1,000 rad, based on the injection of 1 µCi of ²³²Th and about 45 ml of Thorotrast deposited in the reticuloendothelial system.¹⁵ At this dose level it might be expected that as many as 50 excess lung cancers might occur in the Thorotrast-exposed patients surveyed; however, no excess occurred. Reevaluation of lung doses¹⁶ by using a Weibel model and calculating doses for bronchial stem cells at generation-specific depths resulted in a decrease in the mean bronchial dose estimates by a factor of 4.3 and in the segmental bronchi dose estimates by a factor of 3.3; this brings the estimates of excess lung cancer in Thorotrast-exposed patients closer to the level observed in the control group.

The Portuguese Thorotrast Study

The epidemiological study of Thorotrast-exposed patients in Portugal¹^,⁵^,¹⁷ represents a 30-yr follow-up of about 2,500 patients exposed mainly between 1929 and 1955 and approximately 2,000 controls. Some 60% of the patients were given Thorotrast for cerebral angiography; the remainder were given Thorotrast for reasons that included limb arteriography and venography, aortography, hepatosplenography, and examination of the paranasal sinuses. By the end of 1976, 955 of the 1,244 traced Thorotrast-exposed patients and 656 of the control cases had died; 137 of the patients died from malignant tumors, 87 of which were primary liver cancers. Of the 32 liver cancers with confirmed histological classification, 18 were hemangioendotheliomas and 4 were biliary duct carcinomas. There were eight carcinomas of the stomach, five carcinomas of the lung, two carcinomas of the larynx, and five primary bone tumors. A total of 23 patients died of blood disorders (12 from leukemias, mostly acute and myeloid) and 27 died of cirrhosis of the liver. There was only 1 case of liver cancer in the 656 deaths in the control group, no cases of leukemia, and 6 cases of liver cirrhosis. Analysis of the data has shown that the number of observed deaths from malignancies—liver, bone, bronchus, larynx, and leukemias—and from liver cirrhosis in the Thorotrast-exposed patients was significantly higher than the expected corresponding numbers in the general Portuguese population.

The majority of the liver tumors were hemangioendotheliomas, one-third were cholangiocarcinomas, two were hepatomas, and one was reticulosarcoma. There were four cases of multicentric tumors of the reticuloendothelial organs, including the liver. Estimates of the amount of Thorotrast sol injected into the patients who had died ranged from 18.0 to 38.9 ml, with an average of about 26 ml. The latency periods varied with the main causes of death. The highest average latent periods were found among those who died from malignancies (greater than 27 yr); for liver cancers, the range was 29–34 yr; for leukemias it was about 20 yr.⁵^,¹⁷

The Japanese Thorotrast Study

An epidemiological study is being conducted in Japan of 282 patients who were given Thorotrast for angiography and hepatolienography during World War II.²⁰^,²¹^,²⁹^–³² Their follow-up now extends to 38–46 yr post-Thorotrast administration. The amount of Thorotrast injected intravascularly in 159 cases ranged from 1.0 to 139 ml (0.02 to 2.78 µCi); the mean injection volume per patient was 17.1 ml (0.3 µCi). In the 261 cases with intravascular injection, there have been 50 cases of liver cancer, 4 cases of blood disease, 3 cases of lung cancer, 1 case of osteosarcoma, 22 other malignant tumors, and 16 cases of liver cirrhosis. These data are summarized together with the data on the non-Thorotrast-exposed control group in Table 5-4. The mortality rates due to hepatic and other malignant tumors, blood diseases, and cirrhosis of the liver and the overall mortality rate were significantly higher in the group treated with Thorotrast intravascularly than in the controls. Figure 5-6 shows the cumulative indices of malignant hepatic tumors, liver cirrhosis, and blood disease. The first case of liver cancer occurred 21 yr after Thorotrast injection, and the number increased rapidly thereafter, reaching 15% of the total number of cases at 40 yr postinjection. Deaths due to liver cirrhosis and blood diseases were first observed at 18 and 16 yr after injection, respectively, and increased to 5.6 and 1.3%, respectively, of the total number of cases at 38 and 36 yr postinjection. These observations concerning malignant hepatic tumors, liver cirrhosis, and blood diseases are in accord with the findings of the German Thorotrast study.⁴⁹^,⁵⁰

TABLE 5-4

The Japanese Thorotrast Study: Causes of Death in Intravascular Thorotrast Group and in Controls.

Figure 5-6

The Japanese Thorotrast study. Duration from Thorotrast administration to death due to hepatic malignant tumors, liver cirrhosis, and blood diseases in the group exposed to Thorotrast intravascularly. Source: Mori et al.

In the Japanese Thorotrast study,³¹ the absorbed dose rate in the liver, spleen, and bone marrow was estimated for 71 autopsy cases of Thorotrast-treated patients who died from cholangiocarcinoma, hemangioendothelioma, liver cell carcinoma, liver cirrhosis, and blood and other diseases. The mean dose rate in the liver, spleen, and bone marrow, classified by cause of death, was estimated to be 22.2–34.7, 67.8–137.8, and 15.9–36.6 rad/yr, respectively. Mean latent periods for the different causes of deaths in patients exposed to Thorotrast (liver cancers, liver cirrhosis, and blood diseases) ranged from about 30–37 years and decreased with increasing dose rate.²¹

Cumulative indices of malignant hepatic tumors, liver cirrhosis, and blood diseases reached 19.2, 6.1, and 1.5%, respectively (Figure 5-6), of the total number of patients exposed to Thorotrast intravascularly at 43 yr after injection. This is in accord with those values reported in the West German Thorotrast study.⁵¹

Of the 21 patients given Thorotrast nonintravascularly, 6 were alive, 14 were dead, and 1 was untraceable. The causes of death were 1 carcinoma of the pancreas, 2 liver cirrhoses, 10 other diseases, and 1 accident. No significant relationship was found between the causes of death and Thorotrast injection when compared with controls.

In the patients exposed to Thorotrast intravascularly, the dose rates to the liver estimated in 96 cases ranged from 2 to 69 rad/yr; the mean absorbed dose was 919.6 rad (standard deviation [SD], 409.0 rad) for 67 malignant hepatic tumors, 958.6 rad (SD, 251.6 rad) for 8 liver cirrhoses, and 757.3 rad (SD, 334.5 rad) for 21 other tumors and diseases. The dose rates to the spleen, estimated in 82 cases, ranged from 8 to 743 rad/yr. The dose rates to the bone marrow in 63 cases ranged from 1 to 157 rad/yr.

In a Japanese series of 120 autopsy cases of patients who died of Thorotrast-associated conditions, there were reported²³ 36 cases of cholangiocarcinoma, 25 cases of angiosarcoma, 10 cases of hepatocellular carcinoma, and 4 cases of multiple hepatic malignancies. The latent periods were as follows: cholangiocarcinoma, mean, 34.1 ± 6.6 yr (range, 23–45 yr); angiosarcoma, mean, 36.4 ± 5.4 yr (range, 27–49 yr); hepatocellular carcinoma, mean, 35.3 ± 5.8 yr (range, 23–41 yr). No unusual histological features were recorded in liver cancers in the Thorotrast- and non-Thorotrast-exposed patients. The coexistence of two or three different malignant neoplasms of the liver was found in 4 (5.3%) of the 75 Thorotrast-induced hepatic malignancies. In 55 Japanese patients who received Thorotrast intravascularly 29–50 yr previously, significant dose-dependent changes were found both in the appearance of Howell-Jolly bodies in the erythrocytes, which increased significantly with thorium body burden, as was an increase in osmotic resistance of erythrocytes with an increase in thorium deposition.⁴²

The Danish Thorotrast Study

A follow-up study of Danish neurosurgical patients injected with Thorotrast during the years 1935–1946,⁶^–¹¹ was begun a few years after the cessation of the radiological use of Thorotrast. The control population used is derived from the Danish Cancer Registry. The malignant tumors found in excess in 1979 were as follows: cancers of the digestive tract, 71 observed versus 21 expected; liver tumors, 50 versus 0.75; lung cancers, 14 versus 7.5; and leukemias 14 versus 1.6. In the 1986 report of results to the end of 1983,¹¹ 1,169 patients had died and 150 were alive. Cancer types have shown little difference over time, and only liver tumors and leukemias show great divergence from expected rates. Liver tumors were the largest single cause of death from 1980 to 1983. There have been 93 liver cancers versus 0.89 expected, and 23 leukemias versus 3.12 expected. There also appeared to be an excess of lung cancer (19 observed versus 9.1 expected). This apparent difference is unexplained.

The American Thorotrast Study

Falk et al.¹⁴ carried out a preliminary epidemiological investigation of Thorotrast-exposed patients in the United States covering the years 1964–1974 and found 26 cases of Thorotrast-induced hepatic angiosarcoma. All patients had undergone either hepatolienography or cerebral angiography. This hepatic tumor incidence was still increasing in the early 1970s, and a larger proportion of the more recent cases had undergone relatively low-dose Thorotrast radiological procedures and prolonged latent periods, ranging from 19.8 to 28.0 yr, and 1 case was as long as 40 yr.

Other Human Studies

Toohey et al.⁴⁴ have measured the activity of thorium daughters (²²⁸ Ac, ²¹²Pb, ²¹²Bi) in vivo in studies of the health effects of thorium exposure on 133 former workers in a thorium refinery; in addition, the exhalation rate of ²²⁰Rn (from ²²⁴Ra) was determined for each subject. The values observed were elevated and appeared to be representative of the given individual only. No correlation was made concerning health outcomes.

Xing-an et al.⁵⁷ have examined exhaled thoron activity and ²²⁸Th lung burden in 20 miners inhaling thorium dust in iron mines; the ²²⁸Th lung burden was approximately four times higher than that in nonexposed controls. The thoron concentrations in the breath of miners were 3 to 4 times higher than those in controls. They also found that the ²²⁸Th body burden in 20 persons living in a high-background area (Dong-anling region) was 3 times greater than that in controls. No health effects were examined.

Estimation of Excess Risk Following Thorotrast Administration

The primary sources for determining the risks for tumor induction after exposure to thorium are the epidemiological studies of Thorotrast-exposed patients. Although these can now provide estimates for the risks of liver cancer and possibly leukemia, these risk estimates are applicable only to intravascular Thorotrast-exposure. Animal studies indicate that it is primarily the alpha radiation from ²³²ThO₂ that causes the tumors. Other forms of thorium would be subject to different pharmacodynamics, and thus, the dose distribution and health effects would be different.

In order to calculate the risk of dying by liver cancer after Thorotrast injection, it is necessary to know the size of the Thorotrast population cohort, the average dose to the liver per year, the number of persons dead at time t, the number of liver cancers at time t, and finally the number of liver cancers in the control group at time t. In addition, it is necessary to assume a death rate at time t (to estimate total liver cancers when the entire cohort is dead) and latent period.

Both the German and the Japanese Thorotrast cases have been followed for about 40 yr, and in the Portuguese study, results are available as of 1976, at which time those cases had been followed for about 30 yr. Table 5-5 lists the information from these three studies needed to make approximate estimates of the liver-cancer risk.

TABLE 5-5

Liver Cancer Data from Thorotrast Studies.

The major assumptions in this calculation are (1) the rate at which the study group is dying (which determines the total lifetime of the study) and (2) the latency period. Figures 5-3 and 5-5 appear to provide evidence that the latent period is about 20 yr. Estimation of the rate of dying is more difficult from the information available. The rate is expected to increase with age, and the simple linear model following liver-cancer deaths should be a rough approximation to what will actually occur. An example calculation of the risk is given in the box entitled ''Example Risk Estimate for Liver Cancer in the German Thorotrast Study."

Using these assumptions, excess lifetime risks have been calculated for liver cancer for the three different Thorotrast studies, namely, the German, the Japanese, and the Portuguese studies. These risks are shown in Table 5-6.

TABLE 5-6

Estimated Liver Cancer Risks from Thorotrast.

An assumption of a shorter latent period, for example 10 yr as in the Biological Effects of Ionizing Radiation (BEIR) III report,³⁴ will reduce these risk values because the effective dose will have increased due to the longer time at risk. A 10-yr assumed latent period will reduce the risk estimates by about one third. The 1980 BEIR III report³⁴ based its projections on an assumed minimal latent period of 10 yr and observed mortality to the end of life for the total population in the three studies still alive and at risk; it estimated approximately 300 excess liver cancers/10⁶ person-rad of alpha radiation to the liver.

It must be remembered that these estimates are for Thorotrast, not thorium. The dosimetry of thorium in other forms will likely be quite different from the dose distributions associated with Thorotrast aggregates, and the risk values will also be different.

EXAMPLE RISK ESTIMATE FOR LIVER CANCER IN THE GERMAN THOROTRAST STUDY

Assumptions:

1.

Total death rate after 20 yr parallels liver-cancer death rate and is linear during the last 20 yr.

2.

The latency period is 20 yr.

Assumed cohort average annual death rate = 1964/20 = 98.2 deaths/yr

Estimated remaining mean time to death of cohort = (2,334 - 1,964)/98.2 = 4 years

Total expected number of liver cancers = 347[(20+4)]/20 = 416

Person-rad-wasted dose = 25(56,016 × 25) = 1,380,950

Total excess number of liver cancers = 416 - (2/1,409) × 2,334 = 413

Risk per 10⁶ person-rad = 413/1,380,950 = 300/10⁶ person-rad

Faber⁶^,⁸^,⁹ estimated the excess rate of liver cancer in adults as 4.2 cases/year/10⁶ person-rad. For a 40-yr follow-up, this would correspond to about 170 cases/10⁶ person-rad. Such estimates, however, are not based on modeling the pattern of risk over time and must be considered provisional until more complete data are available.

Deaths from leukemia in the Thorotrast surveys in Germany, Portugal, and Denmark are in excess of the national rates of death from leukemia. Two categories of malignant disease exist, namely, (1) malignant disease originating in the bone marrow, that is, leukemia (including acute myeloid and chronic myeloid leukemia), multiple myeloma, and hemangiosarcoma confined to the bone marrow; and (2) malignant disease arising in the lymphoid tissues, that is, malignant disease that includes thymoma, reticulosarcoma, and acute lymphoid leukemia. By 1978, the total of the former category in the combined surveys exceeded 40 cases, which is a combined rate of about 12 cases/1,000 persons.²⁷ The expected number of cases would depend on the age distribution of the population of Thorotrast-exposed patients. If an expected value of 2/1,000 patients is assumed, the excess due to Thorotrast would be 10/1,000.²⁷^,²⁸ The average dose to bone marrow was about 150–200 rad.²⁷ This would result in an estimated lifetime linear risk coefficient of 50–60 excess leukemia cases/10⁶ person-rad.²⁷

In the second category, a total of 11 cases have been recorded,²⁷ which is a combined incidence rate of about 3/1,000 patients. If the expected rate were 1.5/1,000, this excess would be significant. However, no risk coefficient can be estimated since diseases as uncommon as those listed are difficult to distinguish in national registries, and there are no reliable data on the dose to the lymphoid tissues in the Thorotrast-exposed patients.²⁷

Mole²⁸ reported that by 1979, of 3,772 Thorotrast-exposed patients in the German, Danish, and Portuguese Thorotrast surveys, 26 died from bone marrow failure, that is, 6.9/1,000. If the expected control value were approximately 1.6/1,000 and the bone marrow dose is taken as 270 rad over 30 yr for a 25-ml injection, then a lifetime linear risk coefficient of 20 excess cases/10⁶ person-rad can be estimated. However, the risk coefficient may be nearer to 30/10⁶ person-rad since the deaths in the Danish subjects occurred at 7–24 yr (mean, 16 yr)⁴ and in the Portuguese subjects at 8–37 yr (mean, 25 yr)⁵ after Thorotrast administration.

Mays and Spiess²⁵ have estimated the risk of bone-tumor induction in Thorotrast-exposed patients. In Germany, Portugal, and Denmark, 3,000 patients followed for more than 10 yr had contributed about 45,000 person-yr at risk beyond the first 10 yr by 1979; 3–6 bone sarcomas had occurred, compared with 0.5 expected cases. Rowland and Rundo³⁷ have calculated that a typical intravascular injection of 25 ml of Thorotrast gave an average dose rate from translocated ²²⁴Ra of about 1 rad/yr to the marrow-free skeleton of an adult. Assuming that translocated ²²⁴Ra is the source of exposure, the risk coefficient estimated is 55–120 excess bone sarcomas/10⁶ person-rad (average dose to the skeleton without bone marrow). For comparison, the risk coefficient for protracted injections of ²²⁴Ra is estimated to be about 200 excess bone sarcomas/10 ⁶ person-rad, based on 54 cases of bone sarcoma.²⁵ The effect of age at the time of Thorotrast administration on the induction of neoplasia is poorly understood; patients receiving Thorotrast at younger ages appear to have an excess of bone sarcomas, whereas patients receiving Thorotrast at older ages do not.²⁵

Liver tumors arising from hepatic parenchymal or bile duct cells, or hemangioendotheliomas, have not been recorded in excess in humans exposed to external low linear energy transfer radiations, although leukemia is commonly induced from such exposures.³⁴ This is in contrast to the Thorotrast-exposed patients where the linear risk coefficient for liver tumors is considerably higher than that for leukemia.²⁷^,²⁸ This may be due, in part, to the practice of averaging the dose in the liver; local deposits of Thorotrast provide sufficiently high local alpha-radiation doses to induce cycles of necrosis and regeneration. While radiation plays an important role, it has been suggested that it may be only the hepatocellular tumors and not the hemangioendotheliomas that are associated with cycles of liver necrosis and regeneration in the absence of radiation.⁶

The wide local variation of Thorotrast dose distribution in the liver also occurs in the bone marrow, lymph nodes, and spleen; Mole²⁷^,²⁸ speculated that local radiation levels from Thorotrast deposits are much greater than dose averages throughout the tissue and that this could be responsible for the high incidence of leukemias in Thorotrast-exposed patients, and perhaps also for the apparent excess of multiple myeloma and lymph node neoplasms. The inhomogeneous radiation produced by alpha-emitters and the nonuniform and patchy anatomic distribution of Thorotrast complicate any attempt to calculate radiation dosage to the tissues of these patients. Correlation with histopathological findings based on terminal burdens is difficult, since the uneven and irregular distribution with increasing aggregation and flocculation of Thorotrast granules and migration and redistribution of thorium constantly change the levels of radiation dose. Further, some of the decay products of the complicated thorium series are soluble, translocate, and are bone seekers. Thus, average dose to the tissues may be an inappropriate parameter, and calculations based on terminal burdens do not necessarily represent the radiation dose that may be responsible for initiating malignant processes.

In summary, the combined epidemiological studies of Thorotrast-exposed patients provide estimates for the cancer risks and are listed in Table 5-7.

TABLE 5-7

Lifetime Excess Cancer Risks from Thorotrast.

The extent to which these risk numbers apply to other thorium radionuclides in other forms is unknown.

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Bookshelf ID: NBK218130

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