Health Risks of Radon and Other Internally Deposited Alpha-Emitters BEIR IV (1988) / Chapter Skim
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7 Transuranic Elements
7 Transuranic Elements
Pages 303-366
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From page 303... ...
Table 7-1 lists the principal transuranic elements which constitute potential health hazards.
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From page 304... ...
2a Einsteinium 252Es 0.5 6.7 UIncludes energy of fission fragments, neutrons, and gamma rays. 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 l950s and 1960s, trace amounts can be found almost everywhere.
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From page 305... ...
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.
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From page 306... ...
This has been observed in skin contamination incidents in nuclear industries and in animal experiments.4' 46 47 8~ 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.
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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)
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From page 308... ...
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 ICRP4t to adopt values of 0.1 x 10-4 for plutonium oxides and 1 x 10-4 for plutonium nitrate for application to occupational exposures.
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From page 309... ...
The subsequent rates and routes of clearance; the transIocation 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 physicoche~cal 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 *
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From page 310... ...
The attenuated cytoplasm of type alveolar epithelial cells may also phagocytize particles.95 Up to loo of particles, including transuranic oxides, deposited in the Jung may also be taken up by tracheobronchial and bronchiolar epithelia.l3 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 tra~suranic 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.
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From page 311... ...
Less than l$to 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,
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For example, calcining 239PuO2 with a relatively large amount of sodium, potassium, calcium, aluminum, or uranium increases the solubility of 239Pu in the lung.3 306 Increasing the ratio of plutonium to sodium in laser-vaporized aerosols of PuO2-UO2 and sodium from 0 to 1:1 and to > 1:10 increased the rate of clearance from the lungs and transIocation to extrapulmonary tissues from O.S to 5.0 and 24~o, respectively.53 After inhalation of an aerosol of 239 PuO2 and 244CmO2 calcined as a mixture, both plutonium and curium remained in the lung somewhat longer than when caTcined and inhaled separately.~°i The transiocation 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 transIocation of i69Yb and 239 Pu inhaled as an oxide, prepared by calcining i69Yb mixed with 239 Pu, were not significantly different from the rates of clearance and transIocation of i69Yb2O3 or 239 PuO2 inhaled separately.~02 The high rate of accumulation of inhaled insoluble plutonium in lymph nodes has stimulated considerable interest.
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Accumulation of inhaled 238PuO2 in thoracic lymph nodes was less than 239PuO2; it reached a maximum of 20 to 24~o and gradually declined to |
From page 314... ...
However, the distribution of 241Am in one accidental inhalation exposure case treated with DTPA at about 1 yr postexposure was as follows: 41~o of body burden in lung, 47~o in liver, and 12% in bone.3i 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.
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From page 315... ...
For neptunium liver deposition was taken to be about 15%0 and skeleton deposition is about 65%.4i 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, gas nads, 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.
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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.
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From page 317... ...
They reflect nonspecific hepatic or skeletal changes and are more significant in dogs 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 239Pu02,83 116 exposed to 238Pu02,83 and 105 exposed to inhaled 239Pu(NO3~4;23 there were also 66 unexposed control dogs.
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From page 318... ...
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 red to the lung for 238 Pu 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 Jung tumors have been observed in this incomplete study were 30 to 120 red to the lung for dogs that inhaled 239PuO2 and 100 red to the lung in dogs that inhaled 238 PuO2; the tumors occurred after 166 to 175 months and after 134 months, respectively.
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From page 319... ...
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 ejects of inhaled transuranic compounds in rats.40 Spontaneous lung tumors are rare in control rats, occurring in |
From page 320... ...
Pleural mesotheliomas have also been seen in rats and dogs 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.
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From page 321... ...
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 inhaled238PuO2, 239PuO2, or24iAmO2.5666 Intravenous injections of highly radioactive 238 Pu microspheres retained in the capillaries of the lungs resulted in very few Jung 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.
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From page 322... ...
The liver retains transuranic elements with long biological halftimes in some species, resulting in substantial radiation doses to liver over a normal life span. I.iver tumors have been observed in some lifespan studies of inhaled radionuclides in dogs and Chinese hamsters.
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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.
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Inhalation of monodisperse 1.5-,llm particles did not cause a bone tumor rate different from that of inhalation of monodisperse 3.~,um particles.66 Bone tumors were seen at skeletal doses ranging from 50 to 480 red in dogs exposed to polydisperse 238 PuO2.83 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.
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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.
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From page 326... ...
of about 20 when compared to x rays in the production of dicentric aberrations in lymphocytes.~4 Chromosome aberrations have been quantified in blood lymphocytes obtained from monkeys that have inhaled 239PuO2 and 239Pu(NO3~; significant results were seen only at cumulative lung doses of >1,000 rad.~7 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.
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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.
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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 I,os 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.~23 No increased risks attributable to plutonium exposure have been noted in this cohort.
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LUNG CANCER In this report, risk estimates for Jung cancer resulting from exposure to radon and radon daughters were obtained from analyses of data on occupationally exposed miners. The BEIR Ill Committees also used human data to estimate risks from low-LET radiation.
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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.
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From page 331... ...
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.
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From page 332... ...
Risk estimates based on the Mantel-Bryan procedure were stated by the [CRP40 in terms of the dose that causes 1 cancer/m~lion animals. These estimates were 52, 14, 40, and 1,190 mrad to the Jung for soluble alpha-, insoluble alpha-, all alpha-, and beta-gamma emitting radionuclides, respectively.
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From page 333... ...
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.
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From page 334... ...
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-red received beyond a latency period of relatively little increased risk. The 95~o confidence interval includes the range from 80 to 1,100 bone-cancer deaths/million person-red.
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From page 335... ...
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)
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From page 336... ...
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.
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Therefore, estimates of risk for transuranic elements cannot be derived from human epidern~ological studies. Although risk estimates have been derived from experimental animals studies, they cannot readily be extrapolated to human.
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1976. Recent animal studies on the deposition, retention and translocation of plutonium and other transuranic compounds.
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1978. Deposition, translocation, and effects of transuranic particles inhaled by experimental animals.
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1980. Biological Effects of Inhaled Radionuclides.
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1982. Induction of lung tumors in mice following the inhalation of 239PuO2.
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1982. Risk estimates for liver.
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1984. Retention of 239 Pu in the mouse lung and estimation of consequence dose following inhalation of sized 239PUO2.
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Dosimetry and response in rat pulmonary epithelium following inhalation of 239PuO2.
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1983. Inhaled transuranics in rodents.
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1980. Absorption of actinide elements from the gastrointestinal tract of rats, guinea pigs and dogs.
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1985. A 37-year medical followup of Manhattan project plutonium workers.
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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.
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This section gives a brief description of all the data the comrn~ttee used to obtain the bone-cancer risk estimate for plutonium deposition. The endpoint in all studies considered here is bone cancer.
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We did not use data in beagles exposed to 239 Pu aerosols since no osteosarcomas were observed in these animals. The absence of bone sarcomas in these beagles is due to the lower specific activity of 239Pu, which id not cause a fragmentation of the aerosol particles, resulting in virtually no delivered dose to the skeleton.
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From page 351... ...
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 anunal-days of observation, and D is the sum of the cumulative doses in reds up to death, or time of last contact of each individual in the dose group. A simple linear-effect mode} is used to relate the dependence of n on N
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(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 ~ and ~ are estimated by a Poisson regression analysis, which also produces approximate standard errors for these estimates.
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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.
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. Table 7A-2 presents the estimates of the parameter A, their estimated standard errors, the estimate of a, and the likelihood ratio goodness of fit statistics, with their degrees of freedom.
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SUMMARY STATISTICS FOR EACH STUDY As discussed by DuMouche] and Harris, each of the separate dose-response studies is summarized by a single number, together with its estimated standard error.
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From page 356... ...
and Harrist then provide final estimates and standard deviations for each of the bid values, including those for which no corresponding Yij value is available. The crux of the Bayesian analysis is the specification of the prior distributions for a!
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(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 pi.)
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From page 358... ...
The only important feature is that the standard deviation of a2 - Ct3 is 0.1, and the standard deviations of all other linear combinations of ai are assumed to be very large. Any other prior distributions of pi that have these features lead to almost exactly the same results.
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From page 359... ...
(7A-7) If one uses the assumed normality of the prior distributions of A, the above probabilities can be used to derive the means and covariance matrix of A
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From page 360... ...
The corresponding values of b and V are given in Table 7A-5. ~ , PRIOR DISTRIBUTION FOR Cr r~' ~ ~ ~ v ~ he value of ~ determines how reliable the interspecies extrapolation is expected to be.
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From page 361... ...
Therefore, this prior distribution for a is used in the Bayesian analysis. RESULTS OF THE BAYESIAN ANALYSIS Having defined the quantities Y
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From page 362... ...
Note that the uncertainty ratios >0.975/~0.025 for the potencies of plutonium are greater than those for radium, since no direct data on the ejects of plutonium in man have yet been incorporated into the analysis. 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 analysm of those data.
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From page 363... ...
for those exposed to 238 Pu and 239Pu, respectively. Since the previous analysis concluded that ~ is probably less than 1, human bone-cancer death/thousand person-red of plutonium exposure, there cannot be much further information in these data.
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CONCLUSION AND SUMMARY Data from several studies on the effect of internal deposition of two isotopes of radium and two isotopes of plutonium on bonecancer 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
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From page 365... ...
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.
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From page 366... ...
The 95~o confidence interval includes the range from about 80 to 1100 bone cancer deaths per million person red. These risks are 5 to 10 times larger than the estimated risks for 2269228 Ra ~ humus, but the interval of uncertainty determined here is considered to be realistic.
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