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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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7Transuranic Elements

Introduction

Transuranic elements are members of the actinide series beyond uranium, beginning with neptunium (atomic number 93). The last in the series is element 103 (lawrencium). All are artificially produced in nuclear reactors, accelerators, or explosions of nuclear weapons, and all have several isotopes that emit alpha rays. The energies of the alpha particles emitted from the transuranic elements range from about 5 to well over 8 MeV, with the higher-energy alphas coming largely from the isotopes with the shortest half-lives. Berkelium (element 97), einsteinium (element 99), fermium, mendelevium, nobelium, and lawrencium are produced in such small amounts, mostly for research purposes; and most of the isotopes produced have such short half-lives, a few seconds or minutes, that they are an unlikely health concern. Californium (element 98), a useful neutron radiation source, is available in slightly larger amounts. Neptunium, plutonium, americium, and curium, elements 93 to 96, respectively, are the most abundant and the most extensively used of these man-made actinide series elements. All are produced in nuclear reactors and, because of the alpha-emitting isotopes with very long half-lives, for example, 2.1 × 106 yr for 237Np, 24,400 yr for 239Pu, 458 yr for 241Am, and 17.6 yr for 245Cm, comprise a major radioactive waste disposal concern. Table 7-1 lists the principal transuranic elements which constitute potential health hazards.

TABLE 7-1. Transuranium Nuclides of Potential Biological Significance.

TABLE 7-1

Transuranium Nuclides of Potential Biological Significance.

Plutonium-239 is a constituent of nuclear weapons and, since 5 metric tons were dispersed into the atmosphere and the environment by the nuclear weapons tests of the 1950s and 1960s, trace amounts can be found almost everywhere. Since relatively large amounts are present in nuclear power reactors, the potential release of plutonium in a reactor accident is a concern, although none was released in the Three Mile Island accident and only small amounts were released at Chernobyl.42 Plutonium-238, with a half-life of 86.4 yr, is 280 times more radioactive per unit mass than 239Pu. Because of this high specific activity, it is used as a heat source to power thermoelectric devices used in cardiac pacemakers and space vehicles. The use of very small amounts of 238Pu in pacemakers has not caused concern, but the potential for the reentry and destruction of space vehicles, dispersing kilogram quantities of 238Pu into the environment, is a concern. Americium-241 is a contaminant of plutonium in nuclear weapons and thus has been distributed throughout the environment. Very small amounts have become a dependable source of ionizing radiation required in battery-powered smoke detectors. This use has not caused public health concern. Relatively large quantities of 237Np are produced in fission reactors and, with plutonium, americium, and curium isotopes, must be dealt with as a contaminant in cooling water and as a long-lived component of nuclear reactor waste. For all of the transuranic elements, occupational exposures pose a greater potential for causing detectable health effects than environmental exposures, but there is a greater potential that much larger populations will be exposed to it by environmental exposures, but only to trace amounts. Occupational exposures at nuclear materials production facilities have resulted from inhalation of airborne transuranic elements accidentally released from containment equipment and from entry through wounds occurring in the hands of persons handling these materials in glove boxes.

The biological effects of plutonium and other alpha-emitting transuranic elements, unlike gamma-emitting radionuclides, are primarily dependent upon their entering the body and being deposited in radiosensitive tissues. Further, the presence of transuranic elements in the environment does not necessarily infer their deposition in human tissues. In the following discussion it will be seen that transuranic elements are not readily absorbed from the gastrointestinal tract and are even less readily absorbed through intact skin. If environmental conditions lead to transuranic elements becoming airborne, there is a chance of their being inhaled and deposited in the respiratory tract. Deposition in the respiratory tract represents the highest probability for eventual health effects.

This chapter describes the disposition of transuranic elements that enter the body and the biological effects that may result; it also discusses methods for estimating risks and suggests estimates of risk derived from other sources that might be applied to transuranic elements in human beings. Nearly all of the information on health effects has come from laboratory experiments since there are few human data. However, there are human data to supplement extensive animal data on the distribution of transuranic elements in the tissues of the body. For example, since the beginning of the Manhattan Project in 1943, from 5,000 to 10,000 persons have been employed in positions in the United States involving risk of plutonium exposure. Follow-up of the distribution of plutonium in tissues has been accomplished by obtaining tissue samples at autopsy, or infrequently, from surgical specimens from persons who received such exposure. By 1986, the U.S. Transuranium Registry has collected data from about 200 autopsies on exposed workers whose tissues showed increased concentrations of plutonium.111 Elevated concentrations of plutonium in tissues of the general population are attributed to fallout from atmospheric nuclear weapons testing during the period from 1945 to 1963.119

Since this is not intended as an exhaustive or definitive review of the subject, no attempt is made to ensure comprehensive or specific documentation of the information presented. It is intended, however, that all information can be traced to its source through the literature cited, especially the several reviews and symposia publications from which much of the information was obtained.34,36,41,76,80,117,118,126 Although the committee intended to use only information published in the open literature, reference is made to several recent highly relevant laboratory annual reports.

Routes of Intake and Deposition in the Body

Percutaneous

Because of the relatively short range of alpha particles in tissues, the radiation-sensitive cells of the basal layer of the skin are not irradiated unless the alpha-emitting radionuclides penetrate the stratum corneum or horny layer of the epidermis. The unbroken skin has been shown to be an effective barrier to the penetration of transuranic elements. This has been observed in skin contamination incidents in nuclear industries and in animal experiments.41,46,47,81,82

Insoluble forms such as oxides are easily removed from intact skin by washing. Soluble transuranic compounds, such as nitrates, citrates, chlorides, and complexes with organic solvents, have a greater potential for absorption, even though it is very small. The most common human skin exposures involve plutonium nitrate in nitric acid solutions, plutonium tributylphosphate in carbon tetrachloride, and plutonium in hydrochloric acid. These can be effectively washed from skin with chelating compounds or detergents.

If plutonium, americium, neptunium, or einsteinium is deposited on human or animal skin in a wide range of nitric acid concentrations (0.1 to 10 N) for 1 h, about 5 × 10-4 is absorbed. Americium nitrate in tributylphosphate exhibits nearly a factor of 10 greater percutaneous absorption, about 3 × 10-3.46 While data for transuranic oxides are sparse, one can predict that percutaneous absorption through intact skin would be less than 1 × 10-5 during the first hour after deposition. An approximate 10-fold increase in absorption was seen when soluble transuranic compounds remained on the skin for 3–5 days; over this prolonged time, there was evidence that higher concentrations of nitric-acid-enhanced percutaneous absorption. Under the most extreme conditions, such as plutonium nitrate in 10 N nitric acid for 4 days or americium nitrate in 8 N nitric acid for 3 days, maximum percutaneous absorption was only 2%.

Damage to skin by trauma, wounds, acid, or thermal burns facilitates a more rapid transfer of soluble transuranic compounds into the subcutaneous tissue and blood. Insoluble particles and metal slivers deposited below the level of the epidermis are slowly cleared to regional lymph nodes.

There are three mechanisms for transport of transuranic elements from skin: (1) transfer into the subcutaneous microcirculation and then into the blood and lymphatic systems, (2) transfer onto the skin surface with sudoriferous and sebaceous secretions, and (3) loss from body with desquamation of skin. Autoradiographic studies of cutaneously deposited plutonium, americium, and neptunium show a decreasing concentration with increasing depth in skin, but with focal concentrations of activity in the upper epidermis, hair follicles, sebaceous glands, and microvasculature.47

In the event of accidental occupational exposure to plutonium through skin wounds in the hands and other sites of the body, plutonium may be retained at the wound site and removed by surgery, sloughed from the surface, solubilized and translocated to internal organs, or transported to regional lymph nodes. Wounds penetrating the horny layer of skin lead to more rapid absorption and translocation of soluble transuranic compounds to bone, liver, and other tissues.

The most serious of these accidents, in terms of quantity of activity deposited in the body, involved an explosion that resulted in deposition of a total of 1–5 mCi of 241Am on the face and, by inhalation, in the respiratory tract.12 About 1 mCi remained in the body, mostly in wounds on the face, after initial emergency decontamination. Chelation therapy by intravenous injection of diethylenetriaminepentaacetic acid (DTPA) facilitated the excretion of 900 µCi.

Investigators gave beagle dogs subcutaneous implants of 9.5 µCi 239 PuO2 or 1.3 µCi 239Pu(NO3)4 in their forepaws to mimic hand wounds received by plutonium workers. At 5 and 8 yr following exposure, the injected paws still retained 21 and 16%, respectively, of deposited plutonium; in both cases the highest concentrations of activity were found in regional lymph nodes, with the liver showing the next highest concentration of plutonium. The skeleton retained a greater amount of plutonium from the nitrate than from the dioxide compound.25 Similar results were observed with subcutaneously injected monomeric and polymeric 239Pu in mice, with the monomer behaving like plutonium nitrate and the polymer like plutonium dioxide.44

Gastrointestinal Tract

The gastrointestinal tract, provides a substantial barrier to the uptake of transuranic elements ingested with food or water. Although the fraction absorbed is usually low, continuous ingestion of contaminated food and water may lead to the presence of measurable amounts in the body. Gastrointestinal absorption is also a consideration in assessing the risk from inhaled transuranic elements because of clearance from the lungs to the gastrointestinal tract, but is small compared to direct absorption from the lungs.

The importance of chemical form and oxidation state in the absorption of transuranic elements has been verified in several laboratories. These data have been tabulated by the International Commission on Radiological Protection (ICRP).41 Relatively high concentrations of chlorine in some domestic water supplies could oxidize Pu+4 to Pu+6.52 However, subsequent animal studies failed to provide convincing evidence that changes in valence state for ingested plutonium had a significant effect on gastrointestinal absorption. Fasting may increase the absorption of plutonium by about I order of magnitude. Both calcium- and iron-deficient diets tend to enhance absorption of plutonium.87,112 The absorption of transuranic elements incorporated in food fed to experimental animals may be 2 to 10 times greater than the absorption of chemical forms such as citrate and nitrate.

In adult animals, <0.01% of plutonium and most other transuranic elements is absorbed from the intestines.41 Overall, there is little variation in absorption of plutonium and americium nitrates in adult rats, guinea pigs, or dogs.110 Swine exhibit a greater plutonium absorption than rats or dogs.111 The absorption of 237Np can be increased 10 to 100 times by increasing the mass ingested; however, at occupationally and environmentally relevant levels the absorption is more like that of the other transuranic elements. With few exceptions, the absorption of transuranic compounds from the gastrointestinal tract in adult experimental animals varies over 3 orders of magnitude 10-5 to 10-2 . This led the ICRP41 to adopt values of 0.1 × 10-4 for plutonium oxides and 1 × 10-4 for plutonium nitrate for application to occupational exposures. These values would apply to inhaled material cleared from the respiratory tract to the gastrointestinal tract, as well as to ingested material. For all other plutonium compounds and compounds of all other transuranic elements, including those incorporated in food products and drinking water, the ICRP adopted an absorption factor of 10 × 10-4 for application to exposures of both workers and the public.*

Ingestion of alpha-emitters is not considered a radiological hazard to the gastrointestinal tract since the range of alpha particles is insufficient to penetrate the mucus and intestinal contents and reach the crypt cells.

The neonatal rat and guinea pig absorb about 100 times more plutonium than the adult, while newborn swine absorb 20 times more plutonium than either the newborn rat or guinea pig. In addition to the increased fraction absorbed, a substantial fraction of transuranic elements given in soluble form was retained for several clays within the mucosa of the small bowel.109 The ICRP has adopted an absorption value of 100 × 10-4 for the first year of life in contrast to the value of 10 × 10-4 cited above for all later years.41

Respiratory Tract

Inhalation is probably the most common pathway by which transuranic elements cross the barriers of the body and penetrate into and across living cells. The aerodynamic particle size of the aerosol, which accounts for not only the sizes of particles but also their density and shape, determines the fractional deposition and sites of deposition in the respiratory tract. The subsequent rates and routes of clearance; the translocation to, deposition in, and rate of clearance from other tissues; and the excretion in urine and feces of inhaled transuranic compounds depend on particle size, solubility, density, shape, and other physicochemical characteristics of the aerosol. In this way the physical and radiological properties of the transuranic compound, and the physiological characteristics of the exposed individual determine the amount deposited and thus, the radiation dose rates and total doses delivered to the tissues of the respiratory tract and other organs of the body. Aerodynamic particle diameter is a useful predictive characteristic of an aerosol for the estimation of deposition in regions of the respiratory tract. Several dosimetric models have been developed for describing particle deposition and clearance in the human respiratory tract. These models provide a basis for estimating deposition, distribution, and retention of inhaled radioactive aerosols, taking into account particle size and chemical form of the aerosol. Mathematical models were developed to describe the deposition and clearance of inhaled materials from the several compartments of the nasal passage, the trachea and bronchial tree, the pulmonary parenchyma, and the thoracic lymph nodes. The models, when used for radiation protection purposes, apply to a reference man, a 70-kg male worker. Thus, they can be expected to only approximate the deposition, distribution, and retention of inhaled radionuclides in any given individual.

For inhalation of an aerosol with an activity median aerodynamic diameter (AMAD) of 1 µm, according to the ICRP model (based largely on experiments with nonradioactive aerosols in human subjects), 30% of the particles are deposited in the nasal passages, 8% in the trachea and bronchial tree, and 25% in the pulmonary parenchyma, for a total deposition in the respiratory tract of 63% of the amount inhaled. The amount exhaled, not deposited, is 37%. These deposition fractions will vary with particle size and the breathing rate and volume.39 The ICRP has devised metabolic models to describe the retention and translocation of transuranic compounds from these sites of deposition, based largely on data from experimental animals. The following summarizes this information for several transuranic compounds.

Following deposition in the lungs, particles are quickly phagocytized by alveolar macrophages. The attenuated cytoplasm of type I alveolar epithelial cells may also phagocytize particles.95 Up to 1% of particles, including transuranic oxides, deposited in the lung may also be taken up by tracheobronchial and bronchiolar epithelia.13 Particles penetrating the respiratory epithelium may be phagocytized in interstitial areas and, if insoluble, eventually cleared to regional lymph nodes of the thoracic cavity. Since relatively soluble transuranic compounds, such as nitrates, citrates, and the oxides of americium and curium, are rapidly cleared into the blood, only small fractions are cleared to lymph nodes. However, plutonium inhaled as relatively insoluble plutonium oxide particles is very slowly cleared into the blood. Thus, within a few hours after inhalation, about half of inhaled 239PuO2 deposited in the alveoli can be removed from experimental animal lungs by multiple lavage,71,92 with most particles having been phagocytized by pulmonary macrophages. This phagocytosis of plutonium particles may facilitate their transport from the lungs by the mucociliary epithelium and possibly contributes to their transport to lymphatic tissues.

The distribution of transuranic elements within the lungs is relatively uniform after inhalation, more uniform for the most soluble forms. Following the initial clearance process and especially the absorption of the more transportable material by the blood circulating through the lungs, the distribution within the lungs becomes much less uniform. The material retained in the lungs for long times is localized primarily in bronchiolar, alveolar, and lymphatic structures of the lung parenchyma, frequently in regions of fibrosis and scar tissue.24 This pattern appears to be consistent among all experimental animals studied, and while there are few observations, there is no evidence to the contrary for human lungs.

Respiratory tract clearance of inhaled plutonium in human accidental exposure cases is similar to that seen in PuO2 studies with large animals (dog,5,70 sheep,108 baboon,8 burro,108 and rhesus monkey50 ) with half-times for three exponential phases of approximately 1, 30, and 300 to over 1,500 days, respectively.124 The second phase is not always distinguishable. Early clearance of plutonium is from the nasal passages and upper tracheobronchial regions, while clearance with longer half-times is from the bronchiolar and alveolar or pulmonary regions. High fecal to urine 239Pu ratios (between 50 and 500), indicative of a high insolubility, are observed in humans for long periods following inhalation of 239PuO2. A large fraction, as much as 50%, of inhaled and deposited insoluble 239PuO2 and up to about 25% of 238PuO2 may eventually be transported to the thoracic lymph nodes of dogs.83

In contrast to 239PuO2, inhaled 241Am and 244Cm dioxides, as well as plutonium nitrates, in humans and animals are relatively soluble, with about half of the amounts deposited in the bronchiolar and alveolar regions cleared with a half-life of 10 to 40 days and the remainder cleared with half-lives generally ranging from 200 to 500 days. Less than 1% of these relatively soluble transuranic compounds deposit in thoracic lymph nodes.6

While plutonium oxide particles are generally quite insoluble in the respiratory tract, there are some exceptions. For example, it has been demonstrated in several animal species that the conditions under which plutonium is oxidized may affect the fate of particles deposited in the respiratory tract.5 Electron micrographs suggest that plutonium particles oxidized at high temperatures have less surface area than those oxidized at much lower temperatures and, thus, could have lower dissolution rates in body fluids. This was verified in studies in which plutonium oxide particles formed at high temperatures (over 1,000°C) tended to have lower translocation rates from the lungs than plutonium oxidized in air at ambient temperatures or calcined at relatively low temperatures. Also, alveolar clearance and translocation of 238PuO2 to other tissues such as liver and bone are nearly always more rapid than those for comparably prepared 239 PuO2.5,6,83 Plutonium-238 is 280 times more radioactive than an equal mass of 239Pu. Radiolysis may cause these high-specific-activity 238PuO2 particles to fragment within the lungs, greatly increasing the surface area of the 238Pu particles, and thus their dissolution rate.

Nanometer-diameter plutonium oxide particles have been found to be cleared from the respiratory tract very rapidly and appear to be excreted in the urine as particles.105 If transuranic elements are inhaled simultaneously with other materials, their disposition may depend on how the transuranic element is combined with the other material in the aerosol. For example, calcining 239PuO2 with a relatively large amount of sodium, potassium, calcium, aluminum, or uranium increases the solubility of 239Pu in the lung.3,106 Increasing the ratio of plutonium to sodium in laser-vaporized aerosols of PuO2-UO 2 and sodium from 0 to 1:1 and to > 1:10 increased the rate of clearance from the lungs and translocation to extrapulmonary tissues from 0.5 to 5.0 and 24%, respectively.58 After inhalation of an aerosol of 239PuO2 and 244CmO2 calcined as a mixture, both plutonium and curium remained in the lung somewhat longer than when calcined and inhaled separately.101 The translocation of curium to extrapulmonary tissues was largely prevented by incorporation into the much greater mass of the PuO2 matrix. However, in rats the rate of alveolar clearance and translocation of 169Yb and 239Pu inhaled as an oxide, prepared by calcining 169Yb mixed with 239Pu, were not significantly different from the rates of clearance and translocation of 169Yb2O3 or 239PuO 2 inhaled separately.102

The high rate of accumulation of inhaled insoluble plutonium in lymph nodes has stimulated considerable interest. Lymph nodes draining the lungs attain concentrations of inhaled plutonium many times higher than those of any other tissue. The particles are preferentially localized along sinusoids in the paracortical area and in medullary cords and less so in the lymphoid germinal centers.40 More than 10% of 239PuO2 deposited in the alveoli was taken up by thoracic lymph nodes of dogs by 1 yr postexposure, increasing to 15% by 2 yr and 30 to 50% by 5 to 15 yr. Accumulation of inhaled 238PuO2 in thoracic lymph nodes was less than 239PuO2; it reached a maximum of 20 to 24% and gradually declined to <10% after 10 to 15 yr.83 No significant differences in uptake by thoracic lymph nodes were noted for monodisperse 239PuO2 at AMAD values of 0.72, 1.4, and 2.8 µm.32 Less than 1% of alveolar-deposited 238(NO3)4, 239Pu(NO3)4, 241Am oxide, or 244Cm oxide was found in thoracic lymph nodes of dogs at >1 yr postexposure.2123,64 Uptake of inhaled 239PuO2 in lymph nodes of baboons appears to be similar to that in lymph nodes of beagle dogs.8

Liver and Bone

In addition to the respiratory tract, a considerable research effort has focused on the deposition and retention of transuranic elements in liver and bone. Animal experiments and analysis of human tissues confirm that liver and skeleton are the principal receptors of transuranic elements that enter the blood. The distribution of transuranic elements between these two tissues varies depending on the form of the transuranic element taken into the body. Concentrations of fallout plutonium in human liver and bone range between about 0.5 and 1.5 pCi/kg. In most cases the concentrations are higher in liver,18 but higher concentrations in bone have been reported.45 Although the skeleton is about 4 times the mass of the liver, the liver is generally found to contain as much or more of the total plutonium in the body than is in the skeleton. Following occupational exposures to plutonium, depositions in the liver range from being about equal to about twice those in the skeleton.

Transuranic elements within the liver are uniformly distributed throughout the hepatic epithelium only for a short time after intravenous injection. At long times after injection and following other routes of intake, transuranic elements localize in the phagocytic lining cells of the sinusoids, the Kuppfer cells of the reticuloendothelial system.

In the skeleton transuranic elements tend to concentrate on trabecular and cortical bone surfaces, with the endosteal cells being the principal recipients of emitted alpha radiation. Transuranic elements may be found in bone marrow soon after intravenous injection, but the levels decrease as the levels in the circulating blood decrease. At long times after exposure, slightly increasing amounts may be seen in bone marrow, possibly resulting from redistribution of transuranic elements by bone resorption processes.

Over 20 cases of accidental exposure to 241Am, mostly by inhalation, have been reported in the literature, with total body burdens ranging from 10 nCi to 25 µCi.127 The depositions in skeleton generally exceeded those in lung. However, the distribution of 241Am in one accidental inhalation exposure case treated with DTPA at about 1 yr postexposure was as follows: 41% of body burden in lung, 47% in liver, and 12% in bone.31 This suggests that DTPA selectively enhances the excretion of systemic americium and is consistent with the results from animal experiments that show that DTPA is ineffective in removing transuranic elements from lungs.6 In six accidental human exposures to curium oxide, retention and excretion were similar to those expected for soluble plutonium compounds.86

While deposition of transuranic elements in liver and bone are qualitatively similar among mammalian species, there are quantitative differences. There are also differences in retention, especially in the liver. The initial fraction of injected 241Am and 244Cm found in rat liver was three times that of injected 239Pu, although clearance from the liver was rapid in all cases.104 Deposition and retention of neptunium in liver appears to be appreciably less than those in bone, but most of the experiments were done with rats which have been shown to lose actinides from their livers much more rapidly than other species, including man.116 In studies of dogs,83 following the inhalation of 239PuO2, up to about 20% may accumulate in liver (over 1% of the body content) but only 2%a accumulates in skeleton (less than 1% of the body content after 15 yr. However, in dogs that inhaled 238 PuO2 or 239Pu(NO3)4, liver and skeleton accumulated comparable fractions of the amount deposited after 6 yr (20%) and had comparable fractions of the body content (about 40 to 45%).30,83 After intravenous injection as a citrate, dog liver accumulated about 30% of plutonium, 50% of americium, and 35% of curium after 1 week.54 The retention half-time for both plutonium and americium in dog liver is about 10 yr. In rats, a large fraction of the plutonium is lost through bile secretion.9 Less 239Pu was taken up by liver and bone in monkeys than in dogs following inhalation of 239Pu(NO3)4, with the liver retention time being much less in monkeys than in dogs.15 In cynomolgus monkeys about 16% of the initial lung burden of 241AmO2 was was taken up by the liver and 8% by the skeleton, with the retention half-time for 241Am in liver being considerably shorter than that in the liver of the dog.65 After the first week postexposure, 241Am excreted in the feces was eliminated mostly from the liver.20

The ICRP, after reviewing all the experimental data and the results from human autopsies, concluded that the liver can be considered to receive about 30% and the skeleton about 50% of the amount of plutonium that enters the blood, with retention half-times of 20 yr and 50 yr, respectively. The same applies to americium and curium, except that the retention times in liver may be less. For californium, berkelium, and einsteinium, deposition was taken to be 25% in liver and 65% in skeleton. For neptunium liver deposition was taken to be about 15% and skeleton deposition is about 65%.41

Health Effects Studies in Animals

Tissues of interest with respect to potential health effects following intake of a transuranic element are lungs, liver, bone, bone marrow, and lymph nodes, and to a lesser degree thyroid gland, gonads, and kidney. By far the greatest emphasis has been placed on lungs and bone since these two tissues have been the predominant sites of neoplasia in experimental animals.

Life-span studies in animals for the purpose of examining the carcinogenicity of orally or percutaneously deposited transuranic compounds have not attracted much interest because of the very low rate of absorption of transuranic compounds. No completed life-span study of transuranic compounds taken into the body by any route has indicated a significant increase of gastrointestinal tract tumors.

Respiratory Tract

Inhalation of comparatively large amounts of transuranic compounds in experimental animals results in radiation pneumonitis and fibrosis with histological features similar to those observed after external radiotherapy.19,24 Respiratory insufficiency, caused by diffuse fibrosis in the lungs and characterized by increased respiratory rate, decreased arterial oxygen, and increased carbon dioxide, can lead to death within a month or 2 after deposition of 1 to 2 µCi/g of lung tissue of alpha-emitting transuranic elements in rodents, dogs, and primates.38 An initial lung deposition of 200 nCi of 239PuO2 in rats, which is in the range that yields a maximum response, leads to a replacement of 12% of the lung volume with fibrotic tissue at about 1.5 yr after exposure.

Alveolar deposition of 0.1 µCi/g of lung of 239PuO2 in dogs may lead to respiratory failure within 10 months. It is characterized by pulmonary edema, severe vascular damage, fibrinous accumulations in bronchioles and alveoli, and pulmonary fibrosis. Alveolar deposition of about 0.05 µCi/g of lung induced pulmonary fibrosis, bronchioloalveolar hyperplasia and metaplasia, alveolar histiocytic proliferation, pleural fibrosis, and early tumor formation within 5 yr after exposure. In comparable studies with inhaled 238Pu oxides, these lung lesions were found to be more closely related to total cumulative radiation lung dose than to dose rate.40 Inhaled PuO2 particles in dog lung are associated with areas of pulmonary fibrosis, as is the case in the rat and the Syrian hamster. Migration of particles over time results in focal concentrations of the particles in peripheral regions of the lungs.

A more homogeneous spatial-temporal dose distribution pattern was seen in the lungs of baboons than in the lungs of dogs or rats following inhalation of 239PuO2, leading to a more diffuse interstitial pneumonitis and fibrosis at high doses.60 The acute mortality doses for baboons with inhaled 239PuO2 were similar to those seen in dogs.8 The lesions in the baboon lung were described as more homogeneous than those in dogs and consisted of interstitial pneumonitis with fibrosis rich in elastic fibers, hyalinized arteries, and intense proliferation of type II alveolar epithelial cells and foci of giant cell interstitial pneumonia.

At levels below those that cause acute radiation pneumonitis, chronic alpha irradiation produces a progressive interstitial fibrosis. Both pneumonitis and fibrosis interfere with respiratory function by increasing the barrier distance in alveolar septal interstitial tissue to the diffusion of gases. The nadir of the pneumonitis reaction is typically seen at 60–200 days after the deposition of transuranic elements. After about 200 days, the acute pneumonitis either repairs or slowly progresses to a chronic inflammatory condition associated with interstitial fibrosis. The terminal phase of radiation pneumonitis/fibrosis is characterized by an increased respiratory rate, depressed carbon dioxide consumption, decreased CO diffusion, and decreased pulmonary compliance.24

Pulmonary fibrosis from inhaled PuO2 particles is seen most frequently at sites of particle concentration in subpleural regions. Epidermoid carcinoma and adenocarcinoma in rats and bronchioloalveolar carcinoma in dogs, usually preceded by associated metaplastic changes, often arise from these areas of intense fibrosis. The origin and mode of development of these tumors closely parallel the development of certain lung carcinomas in the human lung periphery that can be traced to old peripheral tubercular or trauma-induced scars.55 Metaplastic lesions occupy only a small part of the lung volume when compared with tumor volume. Yet, cell turnover times for adenomatous metaplasia, adenocarcinoma, squamous cell metaplasia, and squamous cell carcinoma of the rat following inhalation of PuO2 were similar.90 Induction of nasal or paranasal tumors has not been seen in any experimental animal or human population exposed to transuranic elements by inhalation or any other route, nor have induced primary tumors been seen in the oral-pharyngeal cavity, larynx, or trachea.

Clinical pathological changes following exposure to transuranic elements reflect the quantities deposited and the amounts of cellular damage or induction of primary tumors in extrapulmonary organs, particularly the liver and bone. These changes are dose related and usually occur late in the animal's life span. They reflect nonspecific hepatic or skeletal changes and are more significant in clogs inhaling soluble than insoluble transuranic compounds.85

The biological effects of inhaled plutonium have been studied for 30 yr in over 1,000 beagle dogs. At the Pacific Northwest Laboratory this included 116 exposed to 239PuO2,83 116 exposed to 238PuO2,83 and 105 exposed to inhaled 239Pu(NO3)4;23 there were also 66 unexposed control dogs. The aerosols were polydispersed with an AMAD of 2.3 µm for 239PuO2 and 1.8 µm for 238PuO2. A total of 172 of these dogs were alive as of September 30, 1986. Deaths from radiation pneumonitis resulted from high doses of inhaled 239Pu compounds (~0.5 µCi/kg or 50 nCi/g of lung and a total lung dose of about 4,000 rad), but not from comparable levels of 238PuO2, which clears the lungs more rapidly.

Of 98 deaths that occurred 3 to 15 yr after exposure to 239PuO2, there were 48 lung cancers. There were three bone tumors, all in the lowest two dose groups, which resulted in an uncertain relationship between bone tumor formation and plutonium exposure. Other tumors in the exposed animals were also seen among the controls. Of 72 deaths that occurred 3 to 12.5 yr after exposure to 238PuO2, 4 were related to lung tumors and 33 to bone tumors (13 of the dogs also had lung tumors unrelated to death).83 Of 38 deaths that occurred 3 to 9 yr after exposure to 239Pu(NO3)4, 4 were related to lung tumors (2 also had radiation pneumonitis) and 21 to bone tumors (11 of the dogs also had lung tumors unrelated to death).23 There is a high probability that these deaths were attributed to the plutonium exposures. The relationship of other causes of death to plutonium exposures is very uncertain. For example, a number of dogs had malignant lymphoma, but they were distributed among both control and plutonium-exposed animals. Further analysis of morbidity and mortality in these dogs would be premature until the experiments are completed. As a preliminary estimate, the risk of developing a lung tumor ranged from about 450 to 650 lung tumors/106 tad to the lung for 238Pu and 239Pu, but time and competing causes of death, that is, radiation pneumonitis and bone cancer, were not adequately accounted for.84 The lowest lung doses at which lung tumors have been observed in this incomplete study were 30 to 120 rad to the lung for dogs that inhaled 239PuO2 and 100 rad to the lung in dogs that inhaled 238PuO2; the tumors occurred after 166 to 175 months and after 134 months, respectively. Because of the number of lung tumors in unexposed control dogs (4/20, or 25%) and the limited number of dogs receiving each dose, it may not be possible to evaluate the lung-tumor risk at doses approaching those in human exposure cases or at doses comparable to the limits for occupational exposure.39

Another major life-span inhalation study in dogs is in progress at the Inhalation Toxicology Research Institute with largely monodisperse 238PuO2 and 239PuO2 aerosols with AMADs of 0.75, 1.5, or 3.0 µm.75 Initial lung burdens in 576 dogs ranged from 0.0002 to 2 µCi/kg of body weight with 12 dogs in each dose and particle-size group and a total of 96 unexposed control dogs. An initial lung burden of 0.00023 µCi/kg of body weight in a dog is approximately equivalent to 0.016 µCi of plutonium in the lungs of a 70-kg human.

A total of 61 of 72 young adults dogs exposed to 1.5-µm and 64 of 72 dogs exposed to 3.0-µm 238PuO2 were dead after 11 to 13 yr. Osteosarcoma of the skeleton was the most commonly observed tumor in over half the animals; few primary lung tumors were present.68 Of 216 dogs exposed to 239PuO2, 135 were dead after 8 to 10 yr. Radiation pneumonitis and pulmonary fibrosis were the causes of death in the highest dose groups, and lung carcinoma was the most frequent cause of death and the only fatal cancers in dogs at lower dose levels.73 No clear pattern of death based on particle size of inhaled plutonium has been seen from available data. Studies of immature (3-month-old) or aged (8- to 10-yr-old) dogs exposed to monodisperse 239PuO2 have not yet indicated significant differences in lung-tumor induction as a function of age at exposure.74 Dogs exposed repeatedly by inhalation to 239PuO2 at levels high enough to cause fatal pulmonary pneumonitis and fibrosis died after about the same cumulative radiation dose to the lung as those exposed only once to the aerosol.26

The bronchioloalveolar junction appears to be the site of lung tumor formation following inhalation of plutonium compounds. Lung tumors arise from peripheral areas of the lung, typically in proximity to areas of interstitial fibrosis or from small cavities communicating with bronchioles. The cells of origin are considered to be undifferentiated, nonciliated precursor epithelial cells, with various phenotypes developing in tumor cells giving different histological patterns. These were classified as bronchioloalveolar carcinoma, combined epidermoid and adenocarcinoma, adenocarcinoma, epidermoid carcinoma, and mixed sarcoma and carcinoma. Multiple tumors are frequently present in the same lung, occasionally with more than one histological type.24

A large body of experimental data exists for carcinogenic effects of inhaled transuranic compounds in rats.40 Spontaneous lung tumors are rare in control rats, occurring in <0.1% of unexposed Wistar rats and up to 1–2% in other strains, such as in Fischer rats. Among the inhaled alpha-emitters shown to induce lung tumors in rats are 238Pu, 239Pu, 241Am, 244Cm, and 253Es. A statistically significant increase in lung tumors was seen in experimental animals at alpha-particle lung doses above 10 rad.

In most life-span studies of inhaled transuranic elements in rats, average doses are calculated for groups of animals that inhaled roughly the same amounts of radionuclides. Since large variability could occur within a dose group, it was probable that induced lung tumors in a group would be skewed to the individual rats given the highest doses. A recent life-span study of inhaled 239PuO2 with 3,192 rats (including 1,058 sham-exposed controls) at individually measured initial lung deposition levels ranging from about 0.5 to 180 nCi, indicates a possible threshold dose of 100–200 rad to the lungs for lung-tumor formation.103 This result contrasts with the appearance of tumors at doses as low as 10 rad in an earlier study.99 Both studies were carried out in young, adult, female, SPF, Wistar rats. Possible, as yet undetected, genetic differences, as well as improved dosimetry at the lower dose levels, may account for these differences in lung-tumor response between the two groups studied in the same laboratory. Also, the incidence of premalignant metaplastic lesions (squamous cell and adenomatous lesions) in the lung was significantly increased only at doses exceeding 100–200 rad.103 Even though the analyses are incomplete, it could be concluded that the tumor response over the dose range addressed in this study was nonlinear.

Experimentally induced mesotheliomas have been described in rats following intraperitoneal instillation of 239PuO2 with morphogenesis sequelae similar to those observed for intraperitoneally instilled chrysotile asbestos. Pleural mesotheliomas have also been seen in rats and clogs following inhalation of transuranic elements.24

In rats, most of the nasal, laryngeal, tracheal, bronchial, and bronchiolar branches of the respiratory tract are lined by pseudostratified, ciliated and mucus-secreting goblet, and columnar epithelial cells, all of which, along with the alveolar epithelium, are relatively radioresistant. Respiratory epithelium has a relatively large capacity to repair sublethal radiation damage. The important progenitor cells in renewing bronchiolo-bronchial epithelium may be small mucus-containing cells rather than basal cells. These cells differentiate and proliferate during regeneration and preneoplastic, metaplastic renewal. The probable target cell for carcinoma formation in the rat lung is the peripheral terminal bronchiolar epithelium, possibly the nonciliated Clara cell. The alveolar endothelial cell is the target cell for hemangiosarcoma formation, the fibroblast for fibrosarcoma formation, and the pleural mesothelial cell for mesothelioma formation.24

Mice appear to be less susceptible to PuO2-induced lung tumors than do rats.51 Pulmonary fibrosis was increased at >6 months after an initial alveolar deposition of >4 Bq. There was also a decrease in total lung cellularity; the latter was partially compensated for by hyperplasia in less affected areas of the lung. Plutonium dioxide particles were markedly concentrated within fibrotic nodules in the lungs. In the mouse, most spontaneous lung tumors are either papillary adenomas or adenocarcinomas consisting of either cuboidal alveolar cells or columnar bronchiolar cells which occur multicentrically in the periphery of the lung late in life. The highest lung-tumor incidence was seen with the smallest 239PuO2 particle size, indicating that the most homogeneous dose-distribution pattern is the most carcinogenic.51

Protraction of 239PuO2 inhalation exposures in mice (bimonthly intervals for 1 yr to lung burdens of 0.5, 2.5, or 12.5 nCi) resulted in a greater incidence of pulmonary adenoma and adenocarcinoma than was observed with a similar radiation dose delivered after a single inhalation exposure.57 Protraction in mice was calculated to increase the volume of exposed lung by threefold as compared to a single exposure. In contrast, protraction of 239PuO2 exposure in Syrian hamsters56 or rats97 had no significant effect on lung-tumor incidence. However, the Syrian golden hamster appears to be resistant to the induction of lung tumors from inhaled radionuclides, although the hamster lung is relatively sensitive to lung-tumor induction by intratracheally instilled 210Po in saline.53 Although there are substantial spatial-temporal dose-distribution pattern differences for alpha irradiation from intratracheally instilled 210Po as compared to inhaled PuO2, this does not adequately explain the relatively few lung tumors induced in hamsters with comparable or higher doses of inhaled 238PuO2 and 239PuO2. Hamsters exposed to radon and radon decay products were also resistant to lung-tumor induction. Only two lung tumors were seen in 600 hamsters following inhalation of PuO2, and these occurred only at lung doses of >1,000 rad.94 No malignant lung tumors were seen in about 1,000 hamsters exposed to inhaled 238PuO2, 239PuO2, or 241AmO2.56,66 Intravenous injections of highly radioactive 238Pu microspheres retained in the capillaries of the lungs resulted in very few lung tumors in hamsters.4

Available published data do not indicate that inhaled transuranic elements are associated with as high an incidence of respiratory carcinoma in nonhuman primates as that seen in rats and dogs. Although the study is not completed, there have been a few lung tumors in baboons more than 10 yr after inhalation of 239PuO2. These were generally small lesions associated with regions of severe radiation pneumonitis. One baboon died because of a large epidermoid carcinoma at 2,528 days postexposure.8 A single pulmonary fibrosarcoma has been found in a rhesus monkey 9 yr after inhalation of 239PuO2.33

None of the results of the many animal experiments with inhaled transuranic elements have suggested an enhanced risk when the material is deposited in the form of discrete particles (hot particles) rather than dispersed throughout the tissue. The experimental results tend to support the concept that, at relevant levels of occupational and environmental exposures, a slightly greater risk may be associated with alpha-emitting transuranic elements dispersed throughout a tissue than concentrated in a few particles. An explanation for this observation is that the few cells containing or adjacent to the particles are more likely to receive killing doses than transforming doses of radiation, whereas the opposite would occur with a more diffuse distribution of the radioactivity among a much larger population of cells.40,78

The risk of cancer formation in the lungs or elsewhere following exposure to multiple or combined agents, including radionuclides, is poorly understood. Combined interactions may behave in an antagonistic, independent, additive, or synergistic manner. Cigarette smoking and alpha-irradiation interactions in uranium miners are examined in Appendix VII. Cigarette smoke depressed lung clearance of inhaled 239PuO2 in rats and dogs,28,29 but the effect on pulmonary carcinogenesis has not been studied. An additive tumor response was seen in rats that showed induction of abdominal sarcomas following intraperitoneal injection of 239PuO2 and benzo(a)pyrene (BaP), a common carcinogenic hydrocarbon in cigarette smoke.93 Intratracheally instilled BaP appeared to act synergistically with inhaled 239PuO2 in causing lung cancer in rats.63 Studies of the possible interaction of plutonium with other inhaled toxic substances such as asbestos, urethan, cadmium oxide, beryllium oxide, and nitrogen dioxide have produced results that are equivocal with respect to enhancing plutonium lung-cancer risks.

Liver

Hepatocytes and the biliary epithelium are relatively radioresistant, although as a whole organ the liver is moderately radiosensitive. Early hepatocyte injury is not due to depressed hepatocyte proliferation since cell turnover in the intact liver is low. Chromosome damage in hepatocytes persists for long periods of time following irradiation and is seen only when hepatocytes are stimulated to proliferate, as by partial hepatectomy.

The liver retains transuranic elements with long biological half-times in some species, resulting in substantial radiation doses to liver over a normal life span. Liver tumors have been observed in some life-span studies of inhaled radionuclides in dogs and Chinese hamsters. The incidence of liver tumors in Chinese hamsters injected with 239 Pu was 39–47% at liver doses of 1,400–4,500 rad and 26–32% at 270–720 rad; liver tumor incidence was similar for injected 239Pu citrate and 239PuO2-labeled particles.16 Intraperitoneally injected 241Am citrate in deer and grasshopper mice resulted in an increased liver-tumor incidence; grasshopper mice were more sensitive than deer mice to tumor formation.61 The longer life spans for these cricetid rodents than for the laboratory mouse or rat and the higher retention rate of transuranic elements in liver combined to give a relatively high liver-tumor yield. Liver-tumor risks were calculated to be 765 tumors/10 6 mice/rad to the liver for deer mice and 1,390 tumors/106 mice/rad to the liver for grasshopper mice.

Liver-tumor risk is much less following injection of transuranic compounds in rats or dogs and even rarer following inhalation exposure. The rapid loss of transuranic activity from the liver of rats may explain the low liver-tumor rates seen in this species. A significant increase in liver tumors has not been observed in life-span studies of beagle dogs that have inhaled any plutonium compound. However, bile duct carcinoma and a lesser number of sarcomas and fibrosarcomas have occurred in beagle dogs given 239Pu or 241Am citrate intravenously.115 The primary tumors occurred after long latent periods and thus were seen only in the dogs that received doses of plutonium and americium that were sufficiently low to allow a long life span. Radiation doses to the liver of dogs that developed tumors were as low as 10 rad. There were 9 bile duct carcinomas and 2 hepatic cell carcinomas in 219 dogs given plutonium and 11 bile duct carcinomas and 3 hepatic cell carcinomas in 128 dogs given americium. The fact that liver tumors are rarely induced by inhaled transuranic elements in experimental animals does not negate a potential liver-tumor risk in humans.

Bone

The initial deposition of transuranic elements on bone surfaces is uneven. For example, in the femur of the dog the relative distribution of injected 239Pu is 1.0 for the periosteum, 1.2 for haversian canals, 1.5 for epiphyseal areas, 2.6 for endosteal areas, and 3.0 for metaphyseal areas.43 In humans, the ratio of periosteal to endosteal surface area is 8:100, which implies that, based on area, the endosteum is the most likely site of malignant change. Plutonium is deposited at higher concentrations in the vertebrae than in long bones. The amount and type of a transuranic elements on the bone surface, its residence time on the bone surface during which it is irradiating osteoblasts, the number of osteoblasts exposed to alpha particles, osteoblast migration and proliferation rate, and bone remodeling by osteoclastic and osteoblastic activities all alter the spatial-temporal dose-distribution pattern in bone and influence subsequent bone-tumor formation.

High doses of transuranic elements deposited in bone can result in pathological fractures, most frequently in the ribs.79 A moderate but generalized osteoporosis is seen along with cortical thickening in the long bones. Growth stunting is seen in long bones of young animals given >3 µCi 239Pu/kg.

A significantly increased incidence of bone tumors was estimated at 0.38%/rad to the bone in beagle dogs, 0.10%/rad to the bone in mice, and 0.06%/rad to the bone in rats following intravenous administration of 239Pu citrate.62 Spontaneous bone tumors occur so rarely in the rat that they cannot be taken into account.30 In mice, the monomeric form of 239Pu is about twice as effective as the polymeric form in producing bone sarcomas.91 The St. Bernard dog is about 5 times more sensitive than the beagle dog to 239Pu-induced bone sarcoma formation, but also has a higher spontaneous incidence.114

Inhaled 238PuO2 and 239Pu(NO3)4 but not 239PuO2, are potent inducers of bone tumors in dogs. After 15 yr postexposure, the skeletons of dogs had taken up only 1% of the initial alveolar-deposited 239Pu from inhaled 239PuO2, in contrast to 20% of initially deposited 238 Pu from inhaled 238PuO2 after 12 yr39 and 25% of 239Pu from inhaled 239Pu(NO3)4 after 9 yr.23 Twelve years after inhalation of 238PuO2 , a total of 31 dogs had osteosarcomas of 116 exposed dogs at cumulative skeletal doses ranging from 50 to 480 rad; 13 of the tumors originated in the vertebrae.83 After 11 to 13 yr, bone sarcoma was the primary cause of death in 84 dogs; an initial lung burden of 0.02 µCi of 238Pu/kg of body weight is the lowest dose at which fatal bone sarcoma has occurred in this, as yet, incomplete study.68 Skeletal radiation doses for these dogs have not been reported. Inhalation of monodisperse 1.5-µm particles did not cause a bone tumor rate different from that of inhalation of monodisperse 3.0-µm particles.66 Bone tumors were seen at skeletal doses ranging from 50 to 480 rad in dogs exposed to polydisperse 238PuO2.83 Bone tumors are not caused by inhaled insoluble 239PuO2 because of its long retention time in respiratory tract tissues and low rate of translocation to bone.

Inhaled transuranic elements are not as carcinogenic in bones of rats as in those of dogs. The fractionation of inhaled 244CmO2 over 10 exposures at 3-week intervals, starting at 70 days of age, resulted in an increase in the bone-tumor incidence of 27%, compared with 12% in rats given a single exposure at that age.98 Intratracheal instillation of 253EsCl3 appeared to cause a higher bone-tumor incidence than that observed with inhaled 253Es(NO3)3.10,11 Intratracheally instilled 239Pu sodium triacetate resulted in a higher bone-tumor incidence (20%) than that observed with inhaled Es(NO3)3 (4%). Inhaled air-oxidized 239PuO2,96 high-fired 238PuO2,100 and single or protracted high-fired 238PuO2 97,99 in rats and inhaled high-fired 238PuO2 and 239PuO2 in hamsters94 did not induce bone tumors.

Bone Marrow

Although radiation leukemogenesis occurs in humans and experimental animals after and irradiation with x rays and gamma rays, it is not a significant finding after the internal deposition of alpha-emitting transuranic compounds, which concentrate more in bone than in bone marrow. The evidence from either experimental or epidemiological studies that plutonium or any other transuranic compound can induce leukemia is scanty.120 Myeloid leukemia has been induced in CBA mice following injection of 239Pu, but with a much greater yield of osteosarcoma.35 Currently, on the basis of the experimental animal studies, no case can be made that transuranic elements are leukemogenic.

Lymphocytes and Lymph Nodes

The hematological effects of transuranic element deposition reflect irradiation of hematopoietic tissue associated with organs that concentrate transuranic elements, as well as direct irradiation of blood cells circulating through the lung, liver, and lymph nodes. Leukopenia occurs after inhalation of relatively large quantities of transuranic elements, for example, after inhalation of 4 to 10 µCi of 241Am in dogs.49 However, a reduction in the absolute number of lymphocytes in the circulating blood is the most sensitive hematological response to the deposition of transuranic elements in the respiratory tract. This has been an especially notable observation in dogs exposed to PuO2. The time of onset and the degree of lymphocytopenia is dose-related following inhalation of plutonium dioxide.89 Lymphocytopenia can be detected after pulmonary depositions of >0.7 nCi of PuO2/g of lung. In contrast, the minimum lung burden required to produce a significant lymphocytopenia in dogs inhaling 239Pu(NO3)4 was 2 nCi/g of lung. A lung deposition of >500 nCi of 239PuO2 is required to cause a mean lymphocyte reduction of 50% in rats,88 while a significant lymphocytopenia is seen in the rhesus monkey only at lung burdens of 900 to 1,800 µCi.15 Lymphadenitis and replacement of parenchymal cells with scar tissue are common findings in regional lymph nodes nearest sites containing PuO2 in dogs. A significant risk of primary tumors in lymph nodes containing very low to high concentrations of plutonium has not been demonstrated in rats, dogs, or humans.

Lymphocytes are among the most radiosensitive cells in the body, while reticular cells that act as a source of regeneration lymphocytes in lymph nodes along with macrophages, plasma cells, and antigen-stimulated lymphocytes are radioresistant. Alpha particles exhibit a relative biological effectiveness (RBE) of about 20 when compared to x rays in the production of dicentric aberrations in lymphocytes.14 Chromosome aberrations have been quantified in blood lymphocytes obtained from monkeys that have inhaled 239PuO2 and 239Pu(NO3)4; significant results were seen only at cumulative lung doses of >1,000 rad.17,50 This suggests that the chromosome aberration frequency of lymphocytes of the monkey is an insensitive indicator of transuranic damage in the lung.

Other Tissues

The deposition of inhaled or injected plutonium compounds in tissues other than lung, lymph nodes, liver, and bone is relatively small. In the relatively small mass of the mammary tissue of rats plutonium increased the incidence of mammary tumors;59 however, it is not reported in other species. Damage to spermatogenic elements was observed at 5 months in rabbits injected with plutonium at testicular doses of 735 rem.48

Electrolyte imbalances, including hyperkalemia, hyponitremia, and hypochloremia, have been seen in dogs exposed to 238PuO2-labeled aerosols.83 These changes have been associated with hypoadrenocorticism (Addison's disease) in six dogs following inhalation of >4.5 nCi PuO2/g of lung. The pathogenesis of the syndrome is not known.

Relatively high concentrations of americium were observed in the thyroids of beagle dogs.107 Autoradiography showed that the 241Am deposited primarily in the interfollicular areas. No adverse effects on thyroid function or on the incidence of thyroid disease were observed.

Effects in these other tissues are generally accompanied by much more severe effects in lung, lymph nodes, liver, or bone.

Human Epidemiological Studies

Persons residing in the Northern Hemisphere have been exposed to very low levels of 239Pu from atmospheric nuclear weapons testing in the 1950s and 1960s and to 238Pu from an accidental disintegration of power sources after aborted spaceflights. However, the levels of plutonium and other transuranic elements deposited in the general population are well below those that might cause detectable health effects. Persons working with nuclear material have also been exposed to transuranic elements. But these, too, have been relatively small exposures; only a few accident victims received relatively high exposures. Since the beginning of the Manhattan Project in 1943, from 5,000 to 10,000 persons have been employed in positions in the United States involving risk of plutonium exposure. In a survey of 203 U.S. government contractor personnel who incurred internal deposition of plutonium between 1957 and 1970, 131 cases were contaminated by inhalation, 48 through wounds in the skin, 8 by both routes, and 16 through an unidentified route.123

Studies of employees of Rocky Flats Nuclear Weapons Plant and Los Alamos National Laboratory have been reported.1,2,121123,125 The most extensive report on the Rocky Flats employees was a mortality study of a cohort of 5,413 white males who were employed there for at least 2 yr and followed through 1979.125 Individual radiation exposures were documented from health physics records based on periodic urine bioassays for plutonium and annual summaries of film badge readings for external radiation (gamma, neutron, beta, and x rays). Because systemic depositions of less than 2 nCi of plutonium are not measured reliably, only those workers with exposures of > 2 nCi were considered exposed. Follow-up investigations identified the status of 98.9% of the cohort and located the death certificates for 99.9% of the deceased. Mortality from specific causes was evaluated in two ways. First, standardized mortality ratios were used to compare the observed deaths among the entire cohort versus the expected deaths based on U.S. rates. Second, the authors compared exposed with monitored unexposed workers (unmonitored workers were excluded) by stratifying on age and calendar period of death.

Analyses were also conducted separately by 2-, 5-, and 10-year periods of latency from the date that a worker reached 2 nCi of plutonium exposure or 1 rem of external radiation exposure.

The average external dose for the entire cohort was 4.13 rem, and the average plutonium burden was 1.75 nCi. Approximately 25% of the cohort was exposed to both 2 nCi or more and 1 rem or more. The mortality experience of the entire cohort was less than that expected based on U.S. mortality rates, with a standardized mortality ratio of 62 for all causes of death and 71 for all causes of cancer. The only significant excess risk was for the category of benign and unspecified neoplasms, with a standardized mortality ratio of 376.

To minimize biases, such as the healthy worker effect, comparisons of exposed to unexposed workers within the cohort were carried out. After plutonium exposure was lagged for 5 yr, total mortality and all lymphopoietic malignancy rates were slightly elevated.

No significant linearly increasing dose-response trends in risk with plutonium dose were found with a 2-, 5-, or 10-yr induction period for any causes of death or total mortality. Nevertheless, the authors concluded that this study suggested that plutonium-burdened individuals may experience increased risk of lymphopoietic neoplasms. This increased risk was based on four deaths, one each from lymphosarcoma/reticulosarcoma, non-Hodgkin's lymphoma, multiple myeloma, and myeloid leukemia (the last two are not usually categorized as lymphopoietic neoplasms). Lymphopoietic neoplasms have not been a common observation in the many studies of thousands of experimental animals treated with plutonium over a wide range of doses. The analysis showed no elevated risks for cancer of the tissues that show the highest concentration of plutonium in human autopsy cases and experimental animals, for example, lung, bone, and liver.

A smaller cohort of 26 former Los Alamos workers with the highest known plutonium concentrations at that facility in its early period of operation has been followed for 37 yr and repeatedly evaluated medically.123 No increased risks attributable to plutonium exposure have been noted in this cohort. An investigation of cancer incidence among Los Alamos workers employed from 1969 through 1978 found no significant excess risks.2

Risk Estimates

The limited human epidemiological studies of transuranic element deposition fail to demonstrate any unequivocal association of exposure with cancer formation at any anatomical location. Although clearly identified in experimental animals given plutonium, no significant lung-, bone-, or liver-cancer risk has been found in plutonium workers exposed 30 yr ago or more. Thus, these limited epidemiological studies do not indicate a cancer risk appreciably higher than that estimated from previous calculations made by United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) or the Committee on the Biological Effects of Ionizing Radiations (BEIR). In the absence of adequate human epidemiological data, cancer risk for transuranic elements is usually estimated on the basis of human studies of other alpha-emitting radionuclides (e.g., uranium miners exposed to radon and its progeny, radium-dial painters, patients undergoing treatment with radium, or thorotrast-exposed patients) and of low linear energy transfer (LET) radiation exposures.

Lung Cancer

In this report, risk estimates for lung cancer resulting from exposure to radon and radon daughters were obtained from analyses of data on occupationally exposed miners. The BEIR III Committee77 also used human data to estimate risks from low-LET radiation. Data on humans exposed to transuranic elements are far too limited to permit useful quantification of risks. These data have shown no unequivocal evidence of risk resulting from such exposure, but these negative findings possibly resulted from small sample sizes and the limited magnitude of the exposures.

In the absence of directly relevant human data, there are at least two approaches that can be used to estimate risks. The first involves the use of estimated lifetime risks obtained from laboratory animal experiments. Difficulties with this approach relate to the many differences between animals and humans, including differences in histological types of cancers, differences in confounding exposures (e.g., smoking), differences in spontaneous risks, and differences in life span. The second approach involves expressing risks obtained from humans exposed to alpha radiation from radon decay products or to low-LET x and gamma radiation in terms of dose (or dose equivalent) to the lung or other relevant tissues, and then applying these risk estimates to the doses resulting from exposure to high-LET alpha radiation from transuranic elements. A difficulty with this approach is that there may be characteristics of specific exposures that are not fully reflected in a single dose estimate but that may affect resulting health effect risks. In particular, risks may depend on the specific cells of the lung that are irradiated. This may be quite different for transuranic element exposure than for exposure to radon decay products or low-LET radiation. In a report by the ICRP,40 both approaches were utilized and the results were compared.

In Chapter 2 of this report, a model for estimating risks resulting from radon exposure was provided, based on analyses of data from four groups of miners. This model allows estimation of the lifetime risk resulting from exposure, expressed in working-level months (WLM), at any particular period in a lifetime. Risks resulting from exposures received during different periods of time throughout life can be summed to obtain an overall risk estimate for any specified sequence of exposures. The model specifically incorporates observed patterns of risk over time in miners, and also uses life-table methods to account for attrition of the population from death for reasons unrelated to radiation exposure.

A possible approach for estimating risks of exposure to inhaled transuranic elements would be to apply the model developed for radon exposure. This would require, as a minimum, conversion of the WLM to an appropriate measure of dose to the lung and would also require determination of the dose and its distribution over time resulting from any transuranic element exposure for which risk estimates were desired. Before such an approach can be applied, its validity needs to be confirmed by evaluating available laboratory animal data. Instances in which experiments involving both radon decay products and transuranic element exposure have been conducted in the same animal species are especially relevant for this purpose.

To evaluate the adequacy of the BEIR IV (Chapter 2, this volume) radon model for predicting risks in animals exposed to transuranics elements, data from relevant experiments need to be analyzed by methods that are comparable to those employed in analyzing data from epidemiological cohorts. In particular, it is not adequate to base analyses only on the proportion of animals that have developed lung tumors. Instead, the pattern of risk over time needs to be explicitly examined by modeling risk as a function of the exposure history as well as factors such as age at risk, age at exposure, and time since exposure. Such an approach allows explicit consideration of the time distribution of dose and also minimizes problems related to competing risks from bone tumors or other diseases resulting from the exposure.

The particular findings observed in the analyses of miners described in Chapter 2 of this volume with respect to the effect of age at exposure, time since exposure, and age at risk need to be checked using available laboratory animal data. Such patterns could be compared for different species and for the radionuclide involved in the exposure, whether it is radon or various transuranic elements. It must be recognized, however, that there are difficulties in examining time-related effects in animals in the same manner as in humans. These difficulties are related to the short life span, small numbers of animals (especially in canine laboratory experiments), and the lack of adequate data on time of occurrence in instances in which lung tumors are incidental findings and not the cause of death. Finally, it is unclear whether lung cancers induced in man by inhaled transuranic elements would occur in the lung periphery, as in rats and dogs, or in the bronchi, a tumor location rarely found in experimental animal studies with inhaled transuranic elements but a frequent site of cancer in human lungs.

It is also important to conduct analyses that allow quantitative comparison of risks resulting from different types of exposure in the same species. A method of analysis is needed that accounts for competing risks as well as different temporal and spatial patterns of dose. This can be accomplished by modeling the age- or time-specific relative risk as a function of the estimated cumulative dose to lungs. Such analyses could be useful for comparing risks due to radon with those due to exposures to various transuranic elements and might indicate ways in which the BEIR IV radon model (Chapter 2, this volume) would need to be modified to predict risks from transuranic element exposure.

In addition, analyses could be conducted that allow quantitative comparison of risks resulting from similar types of exposure, but in different animal species. Such comparisons should provide insights that are relevant to the use of laboratory, animal data for estimating risks in humans. Comparisons of this type have been made and have generally been based on the proportion of animals that developed tumors. This approach may not be adequate if competing risks differ substantially in the species being compared; certainly, competing risks in humans are quite different from those in experimental animals. Another approach for making such comparisons is to examine the hazard or risk per unit of time. This hazard could be expressed either as a relative or absolute excess, and could also be used to estimate the probability of developing a lung tumor by time t, given survival to time t. Time might be expressed as a fraction of life span that would be similar for the species being compared. The choice of a measurement of risk that will provide the best comparison across species and thus be most appropriate for the extrapolation of risks from animals to man is required. Appropriate analyses of available experimental data could provide insights with regard to this issue.

Since the above methods have not yet been applied to experimental animal data for inhaled radionuclides, it is necessary to rely on risk estimates obtained by other methods, such as those used by the ICRP.40 The available data on lung-tumor induction by alpha-and beta-gamma-emitters were nearly all from worldwide rat studies. The studies were conducted under different protocols and were complicated by varying methods of dose estimation, exposure (inhalation or intubation), and diagnosis of malignant tumors. While other factors were not constant (e.g., age at exposure), the lack of data on time and cause of death for individual animals precluded the use of much better models that incorporate this information. Because of these deficiencies, a data-selection scheme was devised, and the probit and weighted linear models were selected as two possible models to describe the available dose-response data, recognizing that both were probably inappropriate. Both the linear and probit models gave a reasonable description of the alpha-emitter dose-response data, while neither model was useful in mimicking the extremely variable beta-gamma-emitter data over the range of observed doses.

Risk estimates based on the Mantel-Bryan procedure were stated by the ICRP40 in terms of the dose that causes 1 cancer/million animals. These estimates were 52, 14, 40, and 1,190 mrad to the lung for soluble alpha-, insoluble alpha-, all alpha-, and beta-gamma-emitting radionuclides, respectively. In contrast, an extrapolation of the linear model used by the ICRP40 gave a dose estimate of about 3 mrad to the lung for all alpha-emitters, about 13 times higher than that resulting from use of the Mantel-Bryan procedure.

The risk estimate provided in this report (BEIR IV) from analyses of miners exposed to radon and radon daughters is 350 lung-cancer deaths/million persons/WLM. If expressed per rad, using a nominal value of 0.5 tad/per WLM, this estimate would be 700 cancer deaths/million person-tad and would be equivalent to a dose of 1.4 mrad causing 1 cancer/million persons. The estimated risk based on human radon data is within about a factor of 2 of the estimate obtained through linear extrapolation from animals exposed to transuranic elements but is considerably larger than the estimates obtained by using the Mantel-Bryan procedure. However, it should be recalled that the Committee's estimate for radon projects that most of the cancers occur in smokers. For nonsmokers, the risks are about a factor of 10 less.

Bone Cancer

Extensive human data on bone cancer from alpha irradiation are available from studies of about 1,700 people exposed to radium from 1910 to 1930 with a follow-up period of more than 55 yr; 54 bone cancers and 27 cancers of the paranasal sinuses and mastoids were found in this group by 1974.77 Also, a large number of experimental animal studies with radium and other alpha-emitting radionuclides including transuranic elements have produced substantial data on bone cancer.

Data from several studies on the effect of internal deposition of two isotopes of radium and two isotopes of plutonium on bone-cancer death rates have been collected and summarized by the committee in an easily compared form. Annex 7A describes the 15 different data sets of quantities: n, the number of bone cancer deaths; N, the number of individuals; D, the total cumulative dose to the skeleton received by these individuals; and T, the total animal- or person-years of observation of the individuals by dose group within each study. These summary statistics are often available in the published papers that describe each study and are the minimum needed for each of 5 to 10 well-spaced dose-rate groups within each study. It is also necessary to assume that the dose rate is roughly constant over time and over animals within each dose-rate group. The summary of the radium-dial painter data contained only three broad dose-rate groups. Because of this, the analyses included here are intended more as examples of the proposed methodology than as definitive results.

The committee has applied a Bayesian methodology developed by DuMouchel and Harris27 to estimate the bone-cancer risk in humans due to exposure to plutonium (see Annex 7A). Using the summary data tables, the committee fitted a linear dose-response model to the data from each study. This produced an estimate of the bone cancers per rad observed in each study, with an estimate of the within-study sampling variation attached to each slope. This approach allows the use of a Bayesian components of variance model to estimate how ratios of slopes from different studies differ by more than can be explained by the within-study sampling variation. However, there are indications that there may be no hope of extrapolating dose-response slopes more accurately than to a factor of 2 or 4. This would be true even if very good data on the effects of other isotopes on human bone-cancer rates and of plutonium on several animal systems were available. This question cannot be settled without gathering more data from other combinations of isotopes that act on biological systems. The Bayesian methodology employed here allows quantification and adjustment for prior uncertainty that is impossible to achieve when an approach to statistical inference based on frequencies is used.

In this regard, it is necessary to consider how each of the studies fits into the matrix of other studies already performed so that analyses of all the studies can be most informative. For example, one crucial hole in the array of studies available was that there were no measures of the effect of radium on bone cancer in rats. This gap prevented the analysis from making effective use of the several plutonium studies on rats. Similarly, the fact that all the radium studies on beagle dogs used the injected mode of dose administration, while most of the plutonium studies on beagles used inhalation as the mode of dose administration, introduced a prior uncertainty that lessened the accuracy of the analysis.

To summarize the tentative conclusions of the Bayesian analysis presented here, the potency of plutonium deposition in human bone is estimated to be 300 bone-cancer deaths/million person-tad received beyond a latency period of relatively little increased risk. The 95% confidence interval includes the range from 80 to 1,100 bone-cancer deaths/million person-tad. These values are 5 to 10 times higher than the corresponding estimates of the effects of two isotopes of radium. The chief contribution of this analysis is that it provides a more realistic appraisal of the interval of uncertainty.

Finally, published data on a few humans injected with plutonium were reanalyzed and integrated into the larger analysis. The analysis showed that these data are too meager to provide any important information on the bone-cancer effects of plutonium deposition.

Liver Cancer

Although liver tumors have not been associated with any human exposures to transuranic elements, they have occurred in populations given Thorotrast (colloidal 232ThO2) as a contrast medium in diagnostic radiology (see Chapter 5). Liver cancers have also been observed in experimental animal studies of transuranic elements, particularly those in which the animals were given transuranic compounds by intravenous injection. Because liver cancers appear to have a long latency period, the only animals at risk are those that have not succumbed to lung and bone cancers (which have a strong association with exposure to transuranic elements) or died of other causes.

Studies of dogs given alpha-emitting transuranic elements by intravenous injection have led to estimates of liver-cancer mortality risk in dogs of 920/million rad.72 In Chapter 5, a risk estimate is derived for internally deposited Thorotrast of 260–300 fatal liver cancers/million person-rad. This suggests that either the effective dose from Thorotrast aggregates is less than the calculated value or that dogs may be about 3 times more sensitive to radiation-induced liver cancer than Thorotrast-exposed patients. Since there are no human data for transuranic elements and an acceptable method has not been developed for extrapolating the results from animal experiments to humans, it might be possible to apply the same risk estimate to transuranic elements in liver. Before this is done, careful consideration should be given to the differences between Thorotrast aggregates and deposits of transuranic elements, as well as to the uncertainties that are involved.

Other Tissues

Among tissues irradiated by transuranic elements deposited in the body, only lymph nodes that drain regions containing deposits of transuranic particles are likely to receive radiation doses approaching or exceeding those received by lungs, liver, and bone. In spite of the large radiation doses received by thoracic, abdominal, and regional lymph nodes in thousands of experimental animals, there is little evidence of primary neoplasia. A few lymphatic vessel tumors and hemangiosarcomas have been observed in lymph nodes. Lymph nodes are relatively resistant to radiation carcinogenesis, and the committee has not attempted to derive a risk estimate for lymphatic tissue.

Risk estimates for transuranic elements are frequently applied to cancers known to originate in other tissues following irradiation from other sources such as external gamma and x radiation. For example, a risk of 400 leukemia deaths/million/rad of alpha radiation to the bone marrow and 400 deaths due to gastrointestinal tract cancer/million/rad of alpha radiation have been estimated for exposures to transuranic elements.4 These tumors have not been identified as likely causes of death in animal experiments with transuranic elements or observed following human exposures. Thus, the validity of such risk estimates for transuranic element exposures is highly uncertain. In applying these or other risk estimates to transuranic elements, however, the most uncertainty may be in the calculation of the doses to the tissues. Dose calculations that may be appropriate for radiation protection purposes, for example, those by the ICRP39 may be entirely misleading for projecting risks of cancer mortality from transuranic element exposures.

Summary

The transuranic elements, which are produced in nuclear reactors, accelerators, and explosions of nuclear weapons and which are characterized by a predominance of isotopes emitting alpha radiations with energies ranging from 5 to over 8 MeV, are dominated quantitatively by plutonium, neptunium, and americium. The transuranic elements are not readily absorbed from the skin (<5 × 10-4). Absorption of transuranic compounds from the gastrointestinal tract at less than 1 × 10-4 may be increased to a level of 1 × 10-3 if incorporated into food products. Because of the short range of alpha radiation in tissues, the alpha-emitting transuranic elements are not a health concern unless they enter the body and deposit in radiation-sensitive tissues through wounds or the respiratory tract.

Insoluble transuranic compounds, primarily plutonium dioxide, are avidly retained in the lungs and the thoracic lymph nodes. Other plutonium compounds and essentially all compounds of other transuranic elements are more mobile when taken into the body through the respiratory tract or through wounds and are deposited in bone, liver, and, to a lesser extent, other tissues. Transuranic elements deposited in lungs, lymph nodes, bone, and liver are generally retained for a long time, frequently with half-times of many months or years. Distribution of transuranic elements within the tissues may be diffuse at first, but they often accumulate or form aggregates within cells or cellular structures. Particles and aggregates of transuranic elements, possibly mobilized by macrophages, may be deposited eventually in lymphatic or fibrotic tissues. In lungs, transuranic elements tend to accumulate in bronchiolar-alveolar and lymphatic structures in the parenchyma, frequently in regions of fibrosis. Transuranic particles are preferentially localized in paracortical and medullary regions of lymph nodes, which are also associated with fibrotic tissue. In liver transuranic elements localize in reticuloendothelial cells and in bone, primarily on the endosteal surfaces.

It is clear that transuranic elements are not homogeneously distributed throughout the body or throughout the tissues in which they are deposited. Further, since the range of alpha radiation in tissues is short, less than 100 µm, tissues in which they are deposited will be very nonuniformly irradiated. Only under conditions of very high deposition would more than a few percentage of the total cells in a tissue be exposed to alpha radiations, and many of these would receive doses more likely to kill than initiate neoplastic transformation. Thus, it is likely that, under most conditions, only a very small fraction of the alpha energy would be available for cancer induction. Nevertheless, the association of cancers in lungs, bone, and liver with the deposition of transuranic elements in these tissues in several animal species under experimental conditions but has not been demonstrated in several thousand human beings who have been accidentally exposed predominantly to low levels of transuranic elements.

Therefore, estimates of risk for transuranic elements cannot be derived from human epidemiological studies. Although risk estimates have been derived from experimental animals studies, they cannot readily be extrapolated to human. Until problems associated with this extrapolation are resolved, the only acceptable alternative is to apply risk estimates derived from studies of human populations exposed to other alpha-emitting radionuclides. For lung cancer the risk estimate is 700 lung-cancer deaths/million person-tad, based on the estimate for radon and its progeny. This value is about one-third larger than those that can be derived from current incomplete studies of plutonium in dogs. For bone cancer, the risk estimate is 80 to 1,100 bone cancer deaths/million person-rad from Bayesian analysis of human radium and animal transuranic and radium data. For liver, the risk estimate is 300 cancer deaths/million person-tad, based on human Thorotrast data. In applying these risk estimates to transuranic elements, their origin as well as the great uncertainties associated with their calculation should be remembered.

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Annex 7A. A Bayesian Methodology for Combining Radiation Studies

Introduction

This study reviews and integrates several other studies in which the effect of high linear energy transfer (LET) radiation on the risk of bone cancer has been measured. The methods used are very similar to those described by DuMouchel and Harris.1 The general goal is to enable the quantitative use of the results of animal studies for the estimation of human cancer risks from exposure to ionizing radiation, especially plutonium. The choice of bone cancer as an endpoint and of plutonium as the source of exposure for this study was made partially because of its inherent interest and because of issues of data availability and suitability.

Data Sets Used

Since very little data exist on the long-term effects of plutonium deposition in humans, for purposes of risk estimation it becomes necessary to use data from different animal species exposed to different isotopes and chemical forms of plutonium and other internal alpha-emitters. Animal studies have been designed and carried out at several laboratories in various countries over the last few decades in an attempt to fill this information gap. In addition, it was anticipated that an epidemiological follow-up study of the radium-dial painters could provide a calibration point that could be used to scale the bone-cancer risk observed in animals exposed to internal alpha-emitters, yielding a calibrated bone-cancer risk estimate for humans exposed to plutonium. However, until now no formal statistical methods for integrating the data from all these studies have been proposed or applied in the literature. The problem is that the many different studies whose results need to be combined into a ''meta-analysis" have differing data collection designs, differing sample sizes, and thus, differing probable sampling errors. Most importantly, they have differing degrees of relevance to the problem of estimating the risk from plutonium deposition in humans.

This section gives a brief description of all the data the committee used to obtain the bone-cancer risk estimate for plutonium deposition. The endpoint in all studies considered here is bone cancer. The data sets were obtained from different publications or, if unpublished, directly from the investigators. For some experiments, information on skeletal dose and survival time after exposure for each individual or individual animal was available. For other studies, only rough summary statistics for groups of individuals could be obtained. This inhomogeneity of available data posed some difficulties for the data analysis.

A total of 15 sets of data were assembled, reanalyzed as individual data sets, and then integrated into one meta-analysis. These 15 data sets came from fewer than 15 studies, because we separated data according to the isotope of radium or plutonium involved, even though in some studies they were published together. Table 7A-1 lists the biological system, the isotope, and the source of data for each of the 15 data sets.

TABLE 7A-1. Data Sets Used.

TABLE 7A-1

Data Sets Used.

A large group of data came from the studies with beagles at the University of Utah7 and the Inhalation Toxicology Research Institute (ITRI) of the Lovelace Biomedical and Environmental Research Institute in Albuquerque.2 These data are available in detail. The Utah studies included in this analysis used beagles injected with 239Pu, 228Ra, and 226Ra. For most of the animals, we were able to obtain the mean skeletal dose from published reports.7 For a few beagles, this information was not available. In these cases, we approximated the dose by scaling injected doses to that of other beagles with similar injected activities. The report7 listed amount of injected activities, time to death, and cause of death for all dead beagles. For most beagles that were still alive at the data reporting date; the report listed the cumulative dose up to this point, and the time since injection.

Identical information was available for the inhalation studies with beagles at ITRI.2 We used the data on beagles exposed to 238PuO 2 (1.5 µm [AMAD]) and 238PuO2 activity median aerodynamic diameter (3.0 µm AMAD) monodisperse aerosols. We did not use data in beagles exposed to 239Pu aerosols since no osteosarcomas were observed in these animals. The absence of bone sarcomas in these beagles is clue to the lower specific activity of 239Pu, which did not cause a fragmentation of the aerosol particles, resulting in virtually no delivered dose to the skeleton.

From the Pacific Northwest Laboratory (PNL), we used data (J. Park, personal communication) on beagles exposed to 238PuO2 aerosols. Individual skeletal doses, survival time, and cause of death were also available for each animal in this study.

From Table 6 in ICRP Publication 31 from the International Commission on Radiological Protection (ICRP),3 we obtained summary statistics on studies of rats exposed to 239Pu citrate, 239Pu ammonium pentacarbonate, 239Pu nitrate, 238Pu nitrate, and 238PuO2. Additional dose information on the 238PuO2 study was provided by C. L. Sanders (personal communication).

The data on the 226Ra- and 228Ra-dial painters were provided by R. Schlenker (personal communication). We used tabular information on the 226Ra/228Ra dose ratio, approximate dose rates, number of osteosarcomas, and number of person-years of follow-up. Only the data with a large or small 226Ra to 228Ra cumulative-dose ratio were used for this analysis.

The limited information on 238Pu and 239Pu in man was taken from reports by Rowland and Durbin.4,5 We used survival time since exposure and cumulative alpha-ray doses to bone for all plutonium injection cases who lived more than 5 yr after injection. As discussed later in this annex, the limited nature of these data required that they be handled differently than the other data sets.

Separate Analyses of Each Data Set

Statistical Model

For comparative purposes, it is necessary to perform parallel analyses of the data from each of the studies. Because data from the different studies are often only available in summarized form, the choice of analysis method is somewhat restricted. The data from each study are aggregated by dose group. In each study, all individuals within a given dose group are assumed to have been exposed to approximately the same dose rate (rads per day), which is assumed to be approximately constant over the period of Observation of each individual. For each dose group in each study, four totals are collected: N is the number of individuals in the dose group, n is the number of deaths from bone cancer, T is the total person-days or animal-days of observation, and D is the sum of the cumulative doses in rads up to death, or time of last contact of each individual in the dose group.

A simple linear-effect model is used to relate the dependence of n on N, T, and D. For each individual, the hazard rate for bone-cancer death is assumed to be approximately equal to λ D / T, where the dose rate is set at D / T for each member of the group, and the parameter λ is the potency of the particular isotope when applied to the particular biological system and is measured in cancers per rad. Within each dose group, the number of cancer deaths, n, would then be approximately distributed as a Poisson variable with expectation:

Image img00101.jpg

The quantities λ and τ are possibly different for each experiment. The time period τ is the latency of bone sarcomas for a particular isotope within the given biological system and is measured in years. The fraction (1 - τ N / T) represents the approximate proportion of the years at risk, T, which fell before the beginning of the minimum latency period. Thus, the effective total dose to the dose group is D times this proportion, which is then multiplied by λ to produce the expected number of cancer deaths. (In all of the species considered here, the natural mortality rate from bone cancer is very low and will be assumed to be zero.)

For each experiment, the values of λ and τ are estimated by a Poisson regression analysis, which also produces approximate standard errors for these estimates. Although this statistical model is presumably only an approximation to reality, it is possible to compute a measure of goodness of fit of the model by comparing the observed and fitted cancer counts by using the usual likelihood ratio or Pearson chi-squared statistics. If there are K dose groups in an experiment, the chi-squared value has K – 2 degrees of freedom. Unfortunately, in most of thee studies under consideration there were too few observed bone-cancer deaths to give the test of fit much power.

Adequacy of the Model

It is very unlikely that such a simple model holds exactly in each of the biological systems under consideration. The dose effect may not be linear in some or all species, the proper concept of latency is certainly more complicated than Equation 7A-1 indicates, metabolic differences between species produce different retention times and patterns of deposition, and the age-specific susceptibility to bone cancer may differ between species, among many other possibilities. However, the available data and the available scientific theory do not permit use of a more detailed statistical model. The chief merit of the proposed model is that it allows an assessment of how consistent is a natural and simple measure of carcinogenic potency, namely, the cancers-per tad for each combination of an isotope acting on a biological system. Similarly, it is clear that bone-cancer deaths never appear immediately after exposure, so it is necessary to make some adjustment for latency. The model in Equation 7A-1 is simple, yet it is about as realistic as possible, given that only N, n, T, and D are available for each dose group. Use of this model does not deny that the mechanisms of carcinogenesis are different for different species; on the contrary, comparisons of estimated values of λ provide a way of assessing the magnitudes and patterns of these differences.

The model assumes that each individual receives a constant dose rate during the period of observation. This is a reasonable assumption in studies in which the dose comes from a one-time internal deposition of isotopes with long half-lives and clearance times. All the animal experiments were of this type.

The proper model to use for the radium-dial painter data is especially uncertain. It is noteworthy that Rowland et al.6 report that a quadratic-exponential model fits these data much better than does a linear-effects model. However, the versions of the linear-effects model that Rowland et al.6 fit differed in several respects from that which we proposed above in Equation 7A-l, so the question of appropriateness of our model is still unanswered until the radium-dial painter data can be analyzed in greater detail. (The data on the radium-dial painters have only three very broad dose groups, and are too broad for the assumptions of our analysis.) With these caveats in mind, the radium-dial painter data are included in the analysis.

Analysis of the data on the effects of plutonium in man is even more problematic. These data, presented and described by Rowland and Durbin,4,5 consists of records on 18 individuals who were injected with one of the two isotopes of plutonium under consideration. Since none of these individuals has so far contracted bone cancer, the data by themselves can only provide a rough upper bound on the potency of internal deposition of plutonium in human bone. In addition, one statistical approximation that occurs in our methodology for combining the results of many studies requires that each included study have some bone-cancer cases. Therefore, the data on plutonium in man is not included in the initial analysis in which all studies are summarized. Instead, those data are used at a later stage of the analysis (see below).

The assumption that each individual in a dose group received exactly the average dose given to individuals in the group is not critical to the analysis. If individual doses were available, the analysis would gain estimating power. So long as there are at least five or six well-spaced dose groups, the loss of power is not appreciable.

The model also assumes that the minimum latency period, τ, is approximately independent of the dose level. There is some evidence of this based on examination of the data from the radium-dial painters, where the first cancers begin appearing at about the same time lag after the first exposure, regardless of the level of exposure.

Results of the Individual Analyses

Poisson regressions were performed on 13 of the data sets discussed earlier in this annex (excluding only the data on plutonium in man). Table 7A-2 presents the estimates of the parameter λ, their estimated standard errors, the estimate of τ, and the likelihood ratio goodness of fit statistics, with their degrees of freedom.

TABLE 7A-2. Results of Individual Analyses.

TABLE 7A-2

Results of Individual Analyses.

The Bayesian Model Combining All Studies

The reanalysis of the individual data sets are only a necessary preliminary step to the real goal of providing a unified method of interpreting the entire ensemble of studies. To do this, a Bayesian framework, developed in detail by DuMouchel and Harris,1 is applied. In that report they introduced a theoretical model and illustrated it with an extensive analysis combining 37 different studies on the carcinogenic and mutagenic potency of 10 different polyaromatic hydrocarbons in five different biological systems. The present analysis of radiation-induced bone-cancer studies follows closely the model of the earlier study. Readers interested in the theoretical development of the Bayesian model for combining studies should refer to that paper and its accompanying-discussion.

Components of Variation

The principal goal of the model is to impose a formal theoretical structure on the previously ill-defined problem of interspecies extrapolation. In this. effort, three ideas are central. First, there is a crucial distinction between the error of measurement within each dose-response study and the error of imperfect relevance among the studies. Second, the uncertain relevance between experiments can be formalized by reference to a hypothetical superpopulation model that generates all the experimental data. Relevance is then roughly quantifiable by the fit of the data to the underlying model. Third, the available biological and physical information about species differences, characteristics of isotopes, disease mechanisms, and the like enters the analysis in the form of prior assumptions about the parameters of the underlying model relating the experiments.

Summary Statistics for Each Study

As discussed by DuMouchel and Harris,1 each of the separate dose-response studies is summarized by a single number, together with its estimated standard error. This number is the natural logarithm of the estimated dose-response slope. The slope was denoted by λ in the previous section; we now define θ = log λ. Let y denote the estimate of θ from a particular study. The standard error of y, denoted by c, is taken to be the coefficient of variation of the estimate of λ. That is, θ is log λ, y is the estimate of θ from a single experiment and equals the log (estimate of λ), and c is the estimate of the standard error of y and equals (standard error of estimate of λ)/(estimate of λ). The values of y and c for each of the separate studies can be computed directly from the first two columns of Table 7A-2. They are shown in Table 7A-3.

TABLE 7A-3. Summaries of the Individual Studies.

TABLE 7A-3

Summaries of the Individual Studies.

Formal Model

Let y i j be the estimated log slope as taken from the ith row and jth column of Table 7A-3, which is assumed to be an unbiased estimate of θ i j , the true log slope for the particular animal system-isotope combination. Conditional on θ ij , yij is assumed to be normally distributed with standard deviation c ij. Formally:

Image img00102.jpg

The values of θ have normal prior distributions that are independent, conditional on the values of further parameters:

Image img00103.jpg

Finally, the parameters α i , γ j , and σ all have prior distributions as discussed below. The specification of these prior distributions, together with the values of y and c given in Table 7A-3, completes the specification of the formal Bayesian model. Equations given by DuMouchel and Harris1 then provide final estimates and standard deviations for each of the θ i j values, including those for which no corresponding y i j value is available.

The crux of the Bayesian analysis is the specification of the prior distributions for α, γ, and σ. In order to do this, it is necessary to have a good understanding of the meanings of these parameters and their conceptual role in the analysis. These parameters, which are only used to specify the prior distribution of the θ i j term, the parameters of direct interest, are called hyperparameters.

Interpretation of the Hyperparameters

The prior mean of θ i j , the log of the slope of bone-cancer risk versus dose, is, by Equation 7A-3, the sum of an average for the ith biological system, α i , and an effect due to the jth isotope, γ j . This additive model translates to a multiplicative model on the original scale. This means that the prior expectation is that the ratio of the carcinogenic potency of any two isotopes is preserved across species. The hyperparameter σ measures how well the actual θ i j values conform to this prior expectation. A belief that σ is very near zero implies a belief that the relative potency of isotopes is almost exactly the same for every species. Larger values of σ imply more probability that some of the species systems have isotope-specific reactions to radiation.

The fact that the mean value of each θ ij has an additive representation implies that we cannot identify a priori which biological system is most likely to exhibit a distinctive reaction to any particular isotope. The specific values of α i measure the sensitivity of the ith biological system to the average isotope, while the specific values of the γ j measure the average potency of the jth isotope across biological systems.

Prior Distributions used in the Analyses

Differences between Biological Systems

The values of α1, α2, α3, α4, respectively, represent the average log potency of the isotopes being considered, when dose is measured as rads to the skeleton, in the four biological systems. Except for the data now being analyzed, there is very little knowledge about these quantities. Therefore, it seems appropriate to choose prior distributions for the α1 term that are very broad. These parameters are all assumed to have identical normal distributions, with a mean of 0 and a standard deviation of 10. (Note that all of the values of y are between -4 and +2. This shows that the data are much more precise than the assumed marginal prior distributions of α i .) Although there is little prior information about the individual α i , a predominant fact concerning them is that two of the four biological systems are in the beagle, the only difference being the mode of administration of the dose. As discussed above in this annex, the studies varied as to whether the dose was delivered by ingestion, injection, and inhalation. The inhalation method is a quite different pathway to the skeleton than is either ingestion or injection. The ingestion and injection experiments are designed to be as comparable as possible, and theoretically, their bone-cancer effects should be the same if the dose to the skeleton is the same. However, considering the difficulty in determining dose to the skeleton, metabolic differences, and other differences between the two groups of beagles, one cannot rule out the possibility that all of these differences result in a systematic difference in the estimated potency of all isotopes. This possibility will be described by following the prior probability statement:

Image img00104.jpg

This states that there is only a 5% probability that the ratio of average potencies (tumors per tad to the skeleton) from the two modes of administration is greater than e 0.2 in favor of either mode. In terms of the assumption of normal distributions, this translates to an assumption that the standard deviation of α2 - α3 is 0.1. Since the variances of each α i have been assumed to equal 100, this implies that the covariance of α2 and α3 is 99.995. To summarize, the prior distributions of the α i are assumed to be normal with means of 0 and covariance matrix:

100000
010099.9950
099.9951000
000100

The fact that the variances and covariances are chosen to be exactly 100 and 99.995 is not crucial here. The only important feature is that the standard deviation of α2 - α3 is 0.1, and the standard deviations of all other linear combinations of α i are assumed to be very large. Any other prior distributions of α i that have these features lead to almost exactly the same results.

Differences between Isotopes

Next, the prior distributions of γ j are considered. These distributions represent the average differences (across species), on a log scale, of the potencies of the four isotopes under consideration. Here there is some scientific knowledge. If one really believed "a rad is a rad is a rad," then one would assume that every γ j = 0. However, the possibility that the different isotopes have different potencies per rad to the skeleton will be assumed here. The hyperparameters γ1 and γ2 correspond to the isotopes 226Ra and 228Ra, respectively. The latter isotope has a much shorter half-life, a different decay chain with daughters that emit different radiations of different energies, and this may interact with the phenomenon of carcinogenesis in unpredictable ways. It is barely possible that either of the two radium isotopes is as much as twice as potent as the other. This will be stated probabilistically as:

Image img00105.jpg

Similarly, γ3 and γ4 correspond to the isotopes 238Pu and 239Pu, respectively. These two isotopes each have very long half-lives, and it is harder to find a rationale for the possibility of a consistent difference between these two isotopes. Accordingly, a ratio of potencies of 1.5 is barely possible here. Probabilistically,

Image img00106.jpg

Finally, compare the potencies of radium and plutonium. Here there is also scientific knowledge. Because it is known that plutonium concentrates more in the outer layers of bone cells than does radium, and because osteosarcomas also tend to originate in these layers of cells, the same dose to the skeleton of plutonium will tend to produce more tumors in all species than will radium. The relative potency of either isotope of plutonium to either isotope of radium is judged to be almost surely greater than 1 but less than 10. Probabilistically,

Image img00107.jpg

If one uses the assumed normality of the prior distributions of γ j , the above probabilities can be used to derive the means and covariance matrix of γ j . The means are (-0.25 log 10, -0.25 log 10, 0.25 log 10, 0.25 log 10). The prior covariance matrix for the γ j is:

0.1660.1060.00.0
0.1060.1660.00.0
0.00.00.1660.145
0.00.00.1450.166

Using the terminology of DuMouchel and Harris,1 the values of Y, C, X, b, and V are now specified for the Bayesian analysis. The values of Y, C, and X are given in Table 7A-4.

TABLE 7A-4. Values of Y, C, and X .

TABLE 7A-4

Values of Y, C, and X .

The values of C in Table 7A-4 are estimated standard errors. They would be squared and then represented as a diagonal matrix to conform to the notation of DuMouchel and Harris.1 The first four columns of X identify the four biological systems, while the last four columns of X identify the four isotopes. The corresponding values of b and V are given in Table 7A-5.

TABLE 7A-5. Values of b and V .

TABLE 7A-5

Values of b and V .

Prior Distribution for σ

The value of σ determines how reliable the interspecies extrapolation is expected to be. From Equation 7A-3 each log potency, θ ij , has prior mean α i + γ j and prior standard deviation σ. For any two biological systems, i and i', and any two isotopes, j and j', the linear combination Δ = θ i j - θ i' j - θ i j' + θ i' j' = log (λ i j i'j )/(λ i j' i'j' ), is assumed to be normally distributed with mean of 0 and a standard deviation of 2σ, conditional on σ. The interpretation of Δ is that eΔ is the ratio by which the extrapolation of potency fails when the isotopes j and j' are compared for the pair of biological systems i and i', if individual potencies were perfectly measured. We judge that this extrapolation is highly unlikely to fail by more than a factor of 10. Probabilistically,

Image img00108.jpg

Now, conditional on σ:

Image img00109.jpg

where Φ is the standard normal distribution function. Therefore,

Image img00110.jpg

where E{} refers to the expectation with respect to the prior distribution of σ. If we assume that, a priori, σ takes each of the 10 values 0.05, 0.15, . . ., 0.95 with a probability of one-tenth, then expectation in Equation 7A-10 is, in fact, about 0.06, which is in agreement with the subjective-assessment of Ρ(| Δ | > log 10). Therefore, this prior distribution for σ is used in the Bayesian analysis.

Results of the Bayesian Analysis

Having defined the quantities Y, C, X, b, V, and the prior distribution of σ it is now straightforward to use the procedures given by DuMouchel and Harris1 to compute the posterior distributions of σ and θ ij . When this is done, the posterior distribution of σ is π(σ |Y), given by:

σ=0.050.150.250.350.450.550.650.750.850.95
π(σ |Y)=0.2410.2120.1660.1220.0870.0620.0430.0300.0210.015

Thus, although the prior distribution of σ was approximately uniform over the interval (0,1), the posterior mean of σ is 0.25 and Ρ(| σ < 0.5 | Y) = 0.83. Roughly, this analysis suggests that σ is about half as large as was supposed a priori. Extrapolation on the basis of the comparison of two isotopes on each of two species is likely to be off by a factor of 3 to 5 rather than by a factor of 10. The posterior probability that a new extrapolation will be off by a factor of 10 or more is Ρ(| Δ | > log 10 | Y) = 0.18, down from the value of 0.06 computed from the prior distribution.

Table 7A-6 displays information on the posterior distributions of the potencies of each of the four isotopes in man. The last three lines of Table 7A-6 show the medians and 95% confidence limits of the potency, in bone cancers per 1,000 rad to the skeleton, of each of the isotopes. These limits were computed by resuming that the posterior distributions of θ (= log λ) are Gaussian, as is approximately true. Note that the uncertainty ratios λ0.9750.025 for the potencies of plutonium are greater than those for radium, since no direct data on the effects of plutonium in man have yet been incorporated into the analysis.

TABLE 7A-6. Summary of Posterior Distributions after Combining Studies.

TABLE 7A-6

Summary of Posterior Distributions after Combining Studies.

Using the Data on Human Exposure to Plutonium

The posterior distribution for the effects of plutonium on man resulting from the Bayesian analysis described above in which the data from Rowland and Durbin4,5 were not used, is now used as the prior distribution for the analysis of those data. This second analysis proceeds as a Bayesian update by using the Poisson likelihood function of the data, namely

Image img00111.jpg

where D = (D 1, D 2, . . .) and T = (T 1, T 2, . . .) are, respectively, the doses (in thousands of rads) and observation times (in years) for the individuals included in the studies. Each individual is considered as a group of size N = 1, and since no bone cancers were observed in these individuals, every n = 0. The value τ = 5 yr was used as the latency parameter for this analysis. When the values of D, T, and τ are substituted into the above formula for L (λ), it becomes:

Image img00112.jpg

Under our model, the expected, number of bone-cancer deaths among the individuals in the studies by Rowland and Durbin4,5 would be 0.449λ and 0.324λ for those exposed to 238Pu and 239Pu, respectively. Since the previous analysis concluded that λ is probably less than 1, human bone-cancer death/thousand person-rad of plutonium exposure, there cannot be much further information in these data.

The previous analysis approximated the distribution of λ by a log-normal distribution. However, in order to combine this distribution with the exponential likelihood function given above, it is convenient to use a gamma-distribution approximation. For a given mean and variance of λ, the gamma distribution with the same first two moments as the log-normal distribution will be Considered equivalent to it. The gamma density is:

Image img00113.jpg

where c > 0 and d > 0 are parameters determining the mean and variance of λ, and k(c,d) is a normalizing constant ensuring that the density integrates to unity over the range λ > 0. The mean of λ is c/d, while the variance of λ is c/d 2. When the distributions from Table 7A-6 are converted from log-normal to gamma representations, the resulting values of c and d are shown in Table 7A-7.

TABLE 7A-7. Converting from Log Normal to Gamma Distributions.

TABLE 7A-7

Converting from Log Normal to Gamma Distributions.

If λ has the G(λ; c,d) density, the values of c and d have a simple interpretation. Bayesian probability intervals for λ then coincide numerically with the frequentist confidence intervals which would result if c cancers were observed in a population exposed to a total of d (times 1,000) rad (outside the latent period). Thus, the conclusions reached by this Bayesian analysis of the data in Table 7A-3, excluding the data on plutonium in man, are numerically very similar to those that might be reached by a non-Bayesian statistician who had observed 1.9 (i.e., about 2) bone-cancer deaths in a human population exposed to a total of 4,700 person-rad from plutonium exposure.

The G(λ; c,d) prior distribution is mathematically convenient because it is easily updated: On observation of n cancers in a population exposed to a total of d' cumulative (latency-adjusted) thousands of rad, the posterior density of λ is G(λ; c + n, d +d'). In incorporating the data from Rowland and Durbin,4,5 the values of n are 0 for both isotopes, while d'. = 0.449 for 238Pu, and d' = 0.324 for 239Pu. The posterior gamma densities are therefore G(λ; 1.9, 5.1) for 238 Pu and G(λ; 1.9, 5.0) for 239Pu. The mean values of λ then become 0.370 and 0.379, respectively. If the gamma distributions are converted back to the log-normal distributions with the same mean and variance, the percentiles of λ are as given in Table 7A-8. As can be seen by comparing the results given in Table 7A-8 with those in Table 7A-6, the use of the human plutonium data has very little effect on the distribution of λ.

TABLE 7A-8. Percentiles of λ.

TABLE 7A-8

Percentiles of λ.

Conclusion and Summary

Data from several studies on the effect of internal deposition of two isotopes of radium and two isotopes of plutonium on bone-cancer death rates have been collected and summarized in an easily compared form. The 15 different data tables of the quantities n, the number of bone-cancer deaths; N, the number of individuals; D, the total cumulative dose to the skeleton received by these individuals; and T, the total animal or person-years of observation of the individuals, by doze group, within each study were described. These summary statistics are often available in the published papers that describe each study, and they are the bare minimum needed to make any cross-study meta-analysis possible. The values n, N, D, and T are needed for each of 5 to 10 well-spaced dose-rate groups within each study. It is also necessary to assume that the dose rate is roughly constant over time and over animals within each dose-rate group. The summary of the radium-dial painter data that were available within the time frame of this analysis contained only three broad dose-rate groups. With more detailed data, the analysis could be improved.

Using these summary data tables, a linear-effects dose-response model was fitted to the data from each study. This produced an estimate of the bone cancers per rad observed in each study, with an estimate of the within-study sampling variation attached to each slope. This allowed the use of a Bayesian components of variance model to estimate by how much ratios of slopes from different studies differ more than could be explained by the within-study sampling variation. The posterior distribution of the parameter σ showed that, although the variation in the ratios of estimated slopes for different isotopes deposited in the same species could possibly be explained purely by within-study sampling errors, making extrapolation across species and isotopes potentially accurate, the fact that the value σ = log 2 also had nonnegligible probability means that there may be no hope of extrapolating dose-response slopes more accurately than by a factor of 2 or 4, even if very good data on the effects of other isotopes on human bone-cancer rates and of plutonium on several animal systems are available. The question cannot be settled without gathering more data from other combinations of isotopes that act on biological systems.

In this regard, it would be greatly advisable for researchers to consider how their proposed studies fit into the matrix of other studies already performed, so that meta-analysis of all the studies can be most informative. For example, one crucial hole in the array of studies available was that there were no measures of the effect of radium on bone cancer in rats. This prevented the analysis from making effective use of the several plutonium studies on rats. Similarly, the fact that all the radium studies on beagles used the injection mode of dose administration, while most of the plutonium studies on beagles used the inhalation mode of administration, introduced a prior uncertainty, which lessened the accuracy of the Bayesian analysis.

The Bayesian methodology illustrated here allows a quantification and adjustment for prior uncertainty which is impossible to achieve by using the frequentist approach to statistical inference. The particular prior distributions of the hyperparameters {α1}, (γj}, and σ that were used in the analyses were intended to make use of as much scientific information as possible, in addition to the information contained in the data under analysis.

In summary, the Bayesian analysis presented here gives an estimate of the risk of bone cancer due to internally deposited plutonium of about 300 cancer deaths per million person-rad for dose received beyond the latency period of very small increased risk. The 95% confidence interval includes the range from about 80 to 1100 bone cancer deaths per million person-rad. These risks are 5 to 10 times larger than the estimated risks for 226,228 Ra in humans, but the interval of uncertainty determined here is considered to be realistic.

Finally, the published data on a few humans injected with plutonium were reanalyzed and integrated into the larger analysis. It was determined that these data are too meager to provide any important information on the bone-cancer effects of plutonium deposition.

References

1.
DuMouchel, W. H., and J. E. Harris. 1983. Bayes methods for combining results of cancer studies in humans and other species, with discussion. J. Am. Stat. Assoc. 78:293–315.
2.
Inhalation Toxicology Research Institute (ITRI). 1985. Annual Report LMF-114. Albuquerque, N.M.: Lovelace Biomedical and Environmental Research Institute.
3.
International Commission on Radiological Protection (ICRP). 1976. Biological Effects of Inhaled Radionuclides. ICRP Publication 31. Oxford: Pergamon Press.
4.
Rowland, R. E., and P. W. Durbin. 1976. Survival, causes of death, and estimated tissue doses in a group of human beings injected with plutonium and radium. Salt Lake City: University of Utah Medical Center: The J.W. Press.
5.
Rowland, R. E., and P. W. Durbin. 1978. The plutonium cases: An update to 1977. Oral presentation at the Scientific Group Meeting on Long-term Effects of Radium and Thorium in Man, Geneva: World Health Organisation. (A summary can be found in pp. 138–141 in Radiological and Environmental Research Division Annual Report, ANL-78-65, Part II, Argonne, Ill., Argonne National Laboratory, 1978.)
6.
Rowland, R. E., A. F. Stehney, and H. F. Lucas, Jr. 1987. Dose-response relationships for female radium dial workers. Radiat. Res. 76:368–383. [PubMed: 287126]
7.
University of Utah, Radiobiology Division. 1983. Research in Radiobiology. Radiobiology Division Annual Report C00-119-258. Salt Lake City: University of Utah School of Medicine.

Footnotes

*

These are revised from those used to calculate annual limits on intake by the ICRP.41 The f 1 values (fraction transferred to blood) used were 0.1 × 10-4 for plutonium oxides; 1 × 10-4 for nitrates and other plutonium compounds; 5 × 10-4 for all americium, curium, and californium compounds; and 100 × 10-4 for neptunium compounds.

Copyright © 1988 by the National Academy of Sciences.
Bookshelf ID: NBK218114

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