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Journal of Occupational & Environmental Medicine:
Original Articles

Chronic Diffuse Interstitial Fibrosis of the Lung in Uranium Miners

Archer, Victor E. MD; Renzetti, Attilio D. MD; Doggett, Reuben S. MD; Jarvis, Joseph Q. MD, MSPH; Colby, Thomas V. MD

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From the Department of Family and Preventive Medicine, Rocky Mountain Center for Occupational and Environmental Health (Dr Archer), Department of Medicine, Division of Respiratory, Critical Care and Occupational (Pulmonary) Medicine (Dr Renzetti), Department of Pathology (Dr Doggett), University of Utah School of Medicine, Salt Lake City, Utah (Dr Archer); the National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo. (Dr Jarvis); and the Department of Pathology, Mayo Clinic-Scottsdale, Scottsdale, Ariz. (Dr Colby).

Address correspondence to: Victor E. Archer, MD, Department of Family and Preventive Medicine, Rocky Mountain Center for Occupational and Environmental Health, University of Utah School of Medicine, Building 512, Salt Lake City, UT 84112.

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Abstract

Many uranium miners have been disabled by and died of pulmonary fibrosis that was not recognized as an occupational disease. A review of animal studies, complications from whole body irradiation, pulmonary function, and mortality studies of uranium miners led us to suspect radiation-induced chronic diffuse interstitial fibrosis in miners who had inhaled excessive radon progeny. A selected group of uranium miners (22) with severe respiratory disease (but no rounded nodules in chest films) were studied. Lung tissue from five disclosed severe diffuse interstitial fibrosis, with"honeycomb lung" in all. Some also had small anthrasilicotic nodules and birefringent crystals. Although quartz crystals probably contributed, we concluded that the predominant injurious agent in these cases was alpha particles from radon progeny. This disease, after a long latent period, usually results in pulmonary hypertension, shortness of breath, and death by cardiopulmonary failure.

Pulmonary function studies in man, lung injury after whole-body irradiation, studies in exposed animals, human mortality studies, and dosimetric considerations have all pointed toward a unique nonmalignant chest disease among US Colorado Plateau uranium miners. This was recognized by the US Congress when it passed the Radiation Exposure Compensation Act, which specified that former uranium miners with specified exposures should be compensated if they had developed bronchogenic cancer or fibrosis of the lung or cor pulmonale related to fibrosis of the lung.1 We have hypothesized that chronic diffuse interstitial fibrosis (DIF) from radiation occurs among uranium miners and may interact with other pulmonary fibrotic agents. DIF is a well-known clinical and pathological entity in man,2,3 although it is known by different names.3-7 DIF is thought to be a common end product of different lung-injuring agents.6-10 In this article we try to demonstrate that radon-progeny inhalation is one of those agents. In connection with federal or state workers' compensation claims, and from clinical studies, we have learned of a substantial number of former uranium miners who are thought to have or have had radiation-induced DIF, with or without interaction with other agents.

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Review

DIF as a result of radiotherapy to the chest has long been known to exist.11 Occupational radiation fibrosis was first reported in 1931 by Belt,12 followed by other reports.13-15 These cases apparently resulted from alpha-emitting radium in dust from fluorescent paint. Radiation-induced DIF in humans has been thought to occur only as a complication of radiotherapy,11 although there were suggestions of nonspecific fibrosis in the lungs of uranium miners,16-19 in whom unusual chest films, symptoms, and loss of pulmonary function were noted. The rate of lung clearance for inhaled dust was found to be reduced among uranium miners.20 Cigarette smoking, silicosis, and radiation were considered as possible causes of these pulmonary findings.

In the 1980s, total-body irradiation began to be used in the treatment of leukemia to destroy diseased bone marrow. It soon became apparent that the lung was nearly as radiosensitive as lymphoid and bone marrow tissues.21 Subacute pneumonitis followed by DIF was found to be the factor that limited the amount of radiation which could be used. Most practitioners have used fractionated doses in the range of 5 to 15 grays (Gy), which still produce lung damage in some patients because of a large variation in individual susceptibility.

DIF in irradiated humans is not always preceded by pneumonitis; it may progress for at least 14 years and often results in death.22-24 Although pulmonary fibrosis induced by internal alpha particles (as in miners) might differ from that induced by external irradiation, the animal data reviewed below indicate no qualitative, but possibly quantitative, differences.

In addition to the well-known excess of lung cancer among uranium miners resulting from radon progeny,25 many of these workers in the United States have been disabled and have died as a result of nonmalignant respiratory diseases (NMRD).26-28 Most uranium miners with NMRD who have applied for state workers' compensation have not been awarded payments because their chest films did not have the characteristics of advanced silicosis, and occupational DIF was not considered to be a mining-associated disease by clinicians or workers' compensation tribunals. Since most uranium miners who died of NMRD had smoked and had been exposed to some silica dust, death certificate diagnoses of chronic obstructive pulmonary disease, pneumoconiosis, silicosis, emphysema, chronic bronchitis, and cor pulmonale have been common. Some of these diagnoses have been correct, of course, but others may represent cases of DIF.

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Radiobiology

The bulk of the injury from the ionizing radiation in uranium mines comes as alpha radiation from radon progeny decaying in or adjacent to lung tissue.25 The radon progeny are inhaled by miners along with other mine dust. As they pass through tissue, alpha particles create ion pairs by dissociating water molecules into hydroxyl and oxygen radicals. These extremely reactive ions cause injury to all types of biological molecules that they encounter. In addition, alpha particles that pass through cell nuclei injure DNA, resulting in chromosome aberrations and translocations29 that may inhibit cell reproduction or cause cancer or cell death. In addition, radiation damage to cell membranes and blood vessels may result in edema and cell death. Insufficient cell reproduction may be instrumental in the delayed fibrosis of lung tissue seen after irradiation. While there is injury to all cell types, the fibrous and leukocytic infiltration seen around blood vessels, along with the loss of vascularity in fibrous areas, suggests that damage to the intima of capillaries and arterioles is the sentinel event in radiation DIF,22-24,30-33 but injury to alveolar epithelium may also be important. Some investigators, however, contend that pulmonary immunocompetent cells respond to radiation injury by release of inflammatory mediators, or that an autoimmune reaction may be initiated, either of which may lead to progressive fibrosis.34-38 All of the above-mentioned mechanisms may play a role, but the final common pathway is a disturbance in collagen metabolism.39-40 This leads to an imbalance in the rates of synthesis and degradation of collagen.

Because of the DNA injury mechanism, it is likely that all exposures to alpha particles result in some lung injury that is not fully reparable. However, there appears to be a threshold for clinical DIF after x-irradiation in the neighborhood of 4 to 7 sieverts (sv) when all lung tissue is irradiated.22,33,41,42 To compare this threshold with uranium miner exposures, we must convert work-level months (WLM) to Sv, which is an uncertain procedure. A rough approximation may be obtained by equating 1000 WLM to 7 Gy of average dose to bronchial epithelium.43 However, the average dose to alveolar walls is about one tenth of this,44 and the Quality Factor for alpha particles is between 10 and 25,29,45 so we use an intermediate value of 17. Therefore, (7 Gy÷ 10) × 17 = 11.9 Sv. Thus 1000 WLM would represent approximately 12 Sv to the lung parenchyma. Despite the uncertainties in this conversion, 1000 WLM appears to be well above the value thought to be a threshold for radiation DIF in man, so many of the more highly exposed uranium miners (some of whom received as much as 15,000 WLM) would be expected to exhibit DIF. The conversion of WLM to Sv does not allow for the low dose rate (protraction) of occupational exposure to radon progeny. However, evidence from fibrosis induction by alpha particles and neutrons in animals offers evidence that no reduction of effect comes from protraction of dose.22,46

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Animal Experiments and Radiation Fibrosis

External chest irradiation (1-50 Sv) of mice, rats, rabbits, and dogs resulted in the loss of capillary bed, thickening of alveolar membranes, collagen deposits in interalveolar septa, pulmonary hypertension, and depression of several measures of pulmonary function at doses as low as 4.5 Sv, after following up the animals for periods as long as 4 years.47-53

Extensive animal studies have been done using inhaled radon progeny as the source of alpha particles.54,55 These experiments were mainly designed to study lung cancer induction, but considerable pulmonary fibrosis was also observed. Changes that are related to fibrosis54-62 are summarized in Table 1. Some of the experiments may have had too short a follow-up period (or the animals died too soon) to demonstrate much fibrosis, but most did demonstrate substantial amounts of pulmonary fibrosis along with lung cancers. In some, like the experiments of Kushneva,56 the exposures over 6000 WLM of Chameaud et al,58,59 and the dog experiments by the Department of Energy,55 the doses were high enough that many of the animals were killed by pulmonary fibrosis before tumors developed. In rats, trace amounts of fibrosis were seen at less than 600 WLM,55 a trace to small amounts were seen at 1000 WLM, and increasing amounts were seen at up to 10,000 WLM.55 The same types of pathology changes noted above for external irradiation were noted in these experiments. In the Hanford Department of Energy experiments, cigarette smoke appears to have contributed little to fibrosis, either alone or in combination with other agents. Uranium ore (with siliceous dust) in the amount used contributed little fibrosis by itself but may have been synergistic with radiation. In these studies, little effort was made to measure pulmonary function or to seek a threshold for fibrosis. At two years into the experiment, the exposed Hanford dogs were reported to have a respiratory rate nearly twice that of controls, and other lung changes were noted.61,62

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Interaction of Radiation, Crystalline Silica Dust, and Smoking

Smoking is not generally considered to be a cause of fibrosis as seen in chest films,63,64 although a small effect has been reported65,66 and a little fibrosis from smoking was seen at autopsy and in animal studies.55,61,67-69 However, smoking does appear to enhance the action of other fibrogenic agents.70-71 In animal studies, the fibrosis from siliceous dust was enhanced by ionizing radiation, whether from external sources72 or internal sources.55,56,73,74 One study seemed to suggest no interaction,75 and another suggested inhibition by radiation.76 These two studies, however, appear to have been too short in duration to detect an interaction.

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Cardio-Respiratory Studies in Man

Comprehensive respiratory physiologic studies were performed by Trapp et al18 on 34 working uranium miners selected because of their high cumulative radiation exposure (mean of 1142 WLM). Of these workers, 19 had normal chest films, 13 had bilateral widespread nodular densities without the conglomeration typical of simple silicosis, and the remaining two had densities characteristic of DIF. All subjects had the following studies: complete spirometry; total lung capacity and its subdivisions by both closed-circuit helium method and by body plethysmography; plus single breath nitrogen and carbon monoxide, gas exchange, and arterial blood gases at rest, during, and after unsteady-state exercise; and radioactive xenon. In addition, four of the subjects (three with normal chest films and one with DIF) underwent cardiac catheterization.

The results of these studies demonstrated the presence of relatively mild airway obstruction, pulmonary overinflation, decrease in pulmonary compliance, reduced oxygen saturation after exercise and an increase in physiologic dead space. The degree of physiologic abnormality was more severe in those miners with evidence of silicosis or DIF than in those with normal chest films, but there was no qualitative difference in the results of the two groups. Only 20 of these subjects had smoked cigarettes, and findings in these 20 did not differ from those of the nonsmokers. All four subjects who had cardiac catheterization had pulmonary hypertension during exercise, and in two of these subjects pulmonary arterial wedge pressure was also elevated. These findings were interpreted as indicative of a widespread pathologic process, probably fibrotic in nature and located so as to impair function at the bronchiolar and arteriolar levels. Although the relative roles of free silica (quartz) and inhaled radioactivity could not be clearly distinguished, it was suggested that the alpha radiation from radon progeny attached to dust in uranium mines probably enhanced the fibrogenic effect of quartz dust in the lung to produce these changes.

Surveys of pulmonary function of active uranium miners have been reported, including forced vital capacity (FVC), forced expiratory volume in 1 second(FEV1)/FVC ratio, and maximum mid-expiratory flow or peak flow. With stratification by age, other hard-rock mining (OHR), and cigarette smoking, and using partial correlation coefficients among 2349 men, it was found that the FEV1 and FEV1/FVC ratios were significantly lower among those who had high cumulative exposure to radon progeny than among those with lower exposure.17,77 There was little association of these changes with years of OHR. The radon progeny exposure of the group ranged from 1 to 15,000 WLM, with a mean of 870 WLM. This study was done prior to the development of modern analytical methods,78,79 but it considered all important variables and groups were large enough that individual differences could be averaged out. Therefore it is unlikely that observed differences were spurious findings. The minimal association found with OHR quartz dust exposure suggests that the changes found were not all due to the quartz exposure. These findings are considered to be consistent with the earlier findings of shortness of breath (SOB), persistent cough, and emphysema among this group of uranium miners.16

Two chest disease studies were done in a group of uranium miners with mean exposures of approximately 111 WLM.78-80 Among the 477 men examined, there were 30 with rounded, 6 with linear/irregular, and 3 with reticulonodular opacities, all of which were small. Those men with the longest periods of exposure had increased SOB, low FEV, and a higher frequency of x-ray opacities. Considering the low WLM in these studies, radiation-induced DIF would be expected to be rare or absent. A third study in the same mining area suggested an ethnic difference in NMRD between Native American and other miners.81

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Mortality Studies of Uranium Miners

Most mortality studies of uranium miners have concentrated on lung cancer, but a few have also analyzed NMRD.26-28 Most of the reports have come from the most highly exposed study group, those who did the early mining on the Colorado Plateau. An early report noted that 80 deaths among white miners were from NMRD other than tuberculosis vs 24.9 expected.26 The strongest and most consistent associations were between WLM and deaths by both lung cancer and NMRD. Although age was not considered in this analysis (except for the calculation of the expected rates), there was a strong exposure-response relationship. Age adjustment reduced the exposure-response slope but did not alter the relationship(V.E.A., unpublished data, 1977). There was also a strong association between years after start of underground uranium mining and NMRD, just as there was with lung cancer, implying long latent periods. In a special analysis,26 it was found that the relationship between the frequency of deaths due to lung cancer and to NMRD was the same in persons with earlier x-ray pneumoconiosis as in those with earlier normal chest films. This suggested that the common factor between the excess lung cancer and excess NMRD deaths was radiation and that simple silicosis was just incidental. This conclusion was strengthened by the observation that there was no correlation between the level of radon progeny and the level of silica dust in these mines during the 1950s and early 1960s.82

Follow-up of the Colorado Plateau cohort of white miners through 1977 noted 83 non-infective NMRD deaths observed vs 16.6 expected.27 No breakdown by WLM or smoking was done. In a subsequent report on the nonsmokers from this study group,83 it was noted that there were 8 NMRD deaths observed vs 0.7 expected.

In a recent analysis of the non-white miners in the Colorado Plateau cohort,84 it was noted that there were 20 deaths due to"pneumoconiosis" vs 7.7 expected (standard mortality rate [SMR] of 2.3). Most of this excess appears to be due to pulmonary fibrosis or silicosis, as this group of Navajos smoked little.

An unusual fibrotic condition was noted in 80 Canadian uranium miners in the Elliot Lake, Ontario, region.19 This is probably the disease that was noted on 11 death certificates as "silicosis and chronic interstitial pneumonia," giving an SMR of 514 in a report on Ontario uranium miners.85 A subsequent report on a larger group from this area reported an SMR of 111 for NMRD for uranium miners.86 The magnitude of radon-progeny exposure to men with this diagnosis was not given, nor was the description adequate for one to be certain it was DIF.

Although the above review suggests that DIF in uranium miners is present, is at least partly due to radiation, and was most often found among the more highly exposed subjects, it is not conclusive. A demonstration of the disease in individuals is necessary. This we do below with 22 selected cases. This study supplements the epidemiologic studies with respect to etiology, clinical features, and pathology.

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Material and Methods

Approximately 400 active, deceased, or ex-uranium miners were referred to the authors for evaluation of lung disease (both fibrosis and lung cancer) and for evaluation of magnitude of radiation exposure between 1970 and 1992, in connection with special studies or with applications for state or federal compensation. Many of those miners with lung cancer also had evidence of pulmonary fibrosis but were rejected for this study. There were 102 miners who were considered as possibly having lung fibrosis. One was excluded because of asbestos exposure, two because of tuberculosis, and 32 because of rounded or conglomerate lesions suggesting silicosis (because of workers' compensation implications, we excluded those who were likely to be diagnosed clinically as having silicosis). One worker was rejected because tissue samples indicated acute diffuse alveolar damage, even though chest films met our criteria. Of the remaining miners, only 20 met our criteria of having chest films exhibiting diffuse, linear or reticular, fibronodular opacities in both lower lung fields, with no rounded nodules or significant coalescence. We accepted one worker who had died suddenly without having had a chest x-ray but whose tissue at autopsy indicated DIF (case 9). Another worker who had some small rounded nodules but whose autopsy indicated DIF as well as silicotic nodules (case 1) was accepted. Data on the 22 miners accepted are given in Table 2. Although 9 cases had an autopsy or open-wedge biopsy, lung tissue could be obtained for our review in only 5 cases. These are the first 5 cases discussed inTable 2 and the only cases discussed inTable 3. Information from the pathology report on the other 4 autopsied cases is included in Table 2. Lung tissue slides were studied by two of the authors (R.S.D., T.V.C.). Their findings are described below and summarized in Table 3. These 5 are considered to be representative of the other 17 inTable 2 and of many of the highly exposed uranium miners who have died of NMRD, as noted in the mortality studies. Blood gas analyses were done rarely and pulmonary function tests (PFTs) were done on most workers, but few miners had chest films that were available because most hospitals destroy them after a few years. Therefore, most of our chest film information is from reports by examining radiologists, and the International Labor Organization (ILO) classification could not be used. Judging by those that we have seen, we think that all the severe cases would have had opacities classed as s, t, or u, with profusion of 2/2, 2/3, or 3/3 in most sectors.

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Table 3
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Pulmonary radiation exposure to radon progeny while mining was estimated by multiplying the average working level (WL) in each year by the months exposed in a mine and adding the WLM obtained for each year to obtain an overall WLM. Measurements were not always available for each year, so interpolations and estimates were sometimes necessary. Exposure to quartz dust is ubiquitous in underground hard-rock mines and has been recognized as a hazard since the 1930s. The early silicosis risks had largely been controlled by wet drilling and mine ventilation since the late 1940s, although small isolated mines sometimes neglected these controls. During the 1960s, Utah and Colorado uranium mines (where most of our 22 subjects worked) averaged about 4 million particles of dust per cubic foot (MP-PCF) of dust.82 The threshold limit value in use during that period was 5.5 MPPCF for 40% free silica, which is in the range encountered by our subjects. Individual exposures to free silica are unknown.

Five to nine slides were reviewed on each of the first 5 cases(Table 2). The histologic pattern and distribution of fibrotic changes within the lungs were classified according to morphologic schemes given in the literature.7,87-90 If the area of fibrosis occupied more than three low-power fields per slide (2.5 × objective and 15× wide-field eyepiece), it was "severe" (+++); less than one low-power field per slide was "slight" (+); and areas with intermediate fibrosis were"moderate" (++).

The same technique was used to semi-quantitatively determine the number of anthrasilicotic nodules in the lung slides. Rare, widely scattered nodules per microscopic slide were "rare" (+); slides containing more than ten nodules per 5 fields were "frequent" (+++); and slides containing an intermediate number were (++). Those cases designated as +++ sometimes contained up to 6 nodules in a single field, and the nodules were sometimes aggregated into small confluent masses.

Hypertensive-type structural changes were semi-quantitatively graded by assessing the degree of abnormal thickening of the arterial intima and/or media. The thickening was due exclusively to an increase in fibrous tissue within the intimal layer and an increase in smooth muscle forming the medial layer. For each layer, the increase in thickness was graded as "slight,""moderate," and "severe." Lesions were classed as "Grade-1" if there was slight thickening of the medial layer and the intimal layer appeared normal. Lesions exhibiting moderate concentric medial thickening and none to slight intimal thickening were "Grade-2." Lesions exhibiting concomitant moderate concentric medial and intimal thickening were "Grade-3." A standard polarization microscopy technique was used to visualize birefringent crystalline material within the lung tissue.

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Pathology

The five cases with tissue (Table 3) manifested a pattern of DIF with honeycombing (usual interstitial pneumonia pattern).4,7,87-90 In addition, anthrasilicotic nodules were present in four. Most were 0.1 to 2 mm in diameter, but in case 1, some were larger than 2 mm. Some of these changes are illustrated in Figures 1 and 2. In case 5, there was interstitial fibrosis and honeycombing but not anthrasilicotic nodules. Occasional birefringent particles were found in the nodules of three cases. Vascular changes characterized by intimal proliferation and medial hypertrophy were variably present in all five cases (reflecting pulmonary hypertension). These changes were confined exclusively to arterioles that ranged from 200-500 microns and were not limited to areas near nodules or scarring. Few small arteries (100-500 µm) were seen in scarred areas, as is usual in interstitial fibrosis.91-93 Histologic changes in the airways, manifesting primarily as a chronic bronchiolitis with or without associated lymphoid follicles ("follicular bronchiolitis") or pneumonia and bronchiectasis, were also seen in all five cases. No giant cells, central necrosis of nodules, granulomas, or tumors were seen in any of the five cases.

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Case no. 3 exhibited copious numbers of macrophages laden with intracytoplasmic coarse brown-black particles, as seen in siderosis.94-96 The pigment origin is unknown. Cases no. 1 and 3 also had scattered macrophages containing yellow to brown-black finely granular pigment similar to that seen in smokers.97-98

Cases no. 5 and 11, with no anthrasilicotic nodules, may represent pure radiation fibrosis. Their pathology, except for the nodules, appeared to be the same as that of the others. Case no. 1, with a clinical diagnosis of simple silicosis, differed from the others only in size of anthrasilicotic nodules.

It is likely that no cases with pure silicosis are present in our study material, but their pathology is well known. In stage I or II cases, the tissue between nodules is relatively normal and interstitial fibrosis is minor. In terminal cases, nodules are large and coalescent; there is often architectural distortion of the lungs, and "honeycomb lung" is rare.93

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Clinical Aspects

Clinical and demographic data on all 22 cases is given inTable 2. Seven cases were 50 years of age or less when they first sought medical care for SOB. Radiation exposure of the 22 averaged 1612 WLM. This was higher than the mean WLM of 1142 in the Trapp et al study,18 in which high WLM was a criterion for selection. Four of the 22 had never smoked, and five others were minimal smokers. These minimal smokers were Navajo Indians who smoked only on social occasions (1-5 cigarettes/week) and probably never inhaled the smoke directly. Seven had worked in OHR mines before underground uranium mining. The first symptom for all but one was SOB on exertion. The first symptom in the one exception was sudden death. The SOB seemed to be our of proportion to the "mild" changes seen in chest films and PFTs at this time. When there was a cough or fibronodular changes in the chest film, clinicians usually thought they were dealing with chronic bronchitis or early silicosis.

The chest films of 12 cases showed diffuse linear opacities without nodulation. The rest were fibronodular. These changes were most prominent in the lower lobes and were bilateral. When nodularity was noted, it was sometimes described as "fine," or as 1-3 mm in size; none were described as rounded. This is due to the fact that subjects thought to have silicotic nodules were screened out (unless autopsied). Some had localized scaring elsewhere in the lung fields. Some PFTs showed evidence of both obstructive and restrictive disease, but others were noted as having only one or the other. A positive tuberculin test was found in 5 cases, who were treated with isoniazid even though no acid-fast bacilli were found. No improvement resulted.

All but three of the cases were disabled by their pulmonary problems (two were still mining when examined, and one died suddenly without seeking medical help). The time between "first doctor visit for SOB" and death (1-12 years) was characterized in most cases by progressive SOB until supplemental oxygen was required and by repeated pneumonia with antibiotic treatments. Several had cardiac arrhythmias or syncope; several died suddenly, implying ventricular fibrillation; but only 3 of the 22 had evidence of chronic heart failure. Two had spontaneous pneumothoraces shortly before death. A diagnosis of DIF was made on 6 of the 22 during life. Evidence of cor pulmonale was noted in all nine of the autopsy/biopsy cases and in six of the others. Presumably all had some emphysema, but it was mentioned clinically in only 11 cases, and lung tissue was not preserved in a manner that would permit its determination from the examined tissue. Barrel chest and/or finger clubbing was noted in only 5 of 22 cases, presumably because the periods of cardiac or pulmonary decompensation were short. Six of the 22 were considered by clinicians to have silicosis, but none of them had chest films characteristic of advanced or end-stage silicosis, although two did have a little nodular coalescence seen in chest films, and some had small silicotic nodules in lung tissue or lymph nodes. Although only half of the subjects were noted to have a chronic cough, all five of the lung specimens we studied had evidence of bronchial disease. All 14 of the deceased cases died in acute cardiopulmonary failure. Death was usually triggered by pneumonia or cardiac arrhythmias (presumably from right heart strain).

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Comment

Except for anthrasilicotic nodules, the histomorphologic changes present in all the examined lungs are remarkably similar to the changes observed in the lungs of Syrian golden hamsters that were exposed to radon and radon daughters plus uranium ore dust and diesel exhaust fumes, and in beagle dogs that, in addition to radon and radon daughters, were exposed to uranium ore dust with or without cigarette smoke.61 The hamsters exposed to radon, radon progeny, and uranium ore dust and diesel fumes developed intra-alveolar accumulation of pigmented macrophages, bronchial squamous metaplasia, alveolar epithelial cell injury, bronchitis and bronchiolitis, and chronic interstitial pneumonitis combined with alveolar septal fibrosis. The dogs exposed to radon, radon daughters, uranium ore dust, and cigarette smoke developed accumulation of pigmented macrophages within alveolar spaces, chronic bronchitis with bronchial squamous metaplasia, vesicular emphysema, and pleural fibrous thickening.

The existence of nodules in our autopsy cases may have been over-emphasized because in routine autopsies the pathologist usually tries to take samples from the sites with most severe disease. Fibrous nodules seen in our patients resembled those described in rats and dogs exposed to a combination of radon progeny and quartz dust. Similar circumscribed nodules are seen in silicosis, but they usually contain abundant quartz crystals.99,100 Although polarized birefringent crystals are not specific for quartz, the paucity of them seen in the present study suggests that silica was not the major pathogen in these cases. The similarity of the animal pathology to that of our miners, however, suggests that both represent an interaction of radiation and silica.

There are many known causes of DIF,16,17 including ionizing radiation, some medical drugs and some industrial dusts.6-10 Several pneumoconioses often have an element of interstitial fibrosis, but 30% to 40% of cases have no known cause.2-10 It is estimated that those with unknown cause have a prevalence of 3 to 6 cases/100,000 person-years (PY) in the United Kingdom.2,5,6 The prevalence was reported to be between 5 and 29/100,000 PY in the United States.9,101,102 The incidence for all men over 18 years of age was 16.4/100,000 PY in Bernalillo County, New Mexico.9 This estimate may be artificially high because of migration by elderly individuals seeking a healthier climate. In the study the disease was found primarily in the elderly-the median age was 69 years, with only four cases under age 55. In the present study, by contrast, the median age was 54 years with only one case over age 69 at diagnosis. Because of this age difference, and "expected" number of compare with our mining group would be about 3 or 4/100,000, similar to that found in the United Kingdom.

Although our cases were collected in an anecdotal manner, the fact that most of them belonged to white or Navajo study groups of uranium miners27,28 enables us to make estimates for DIF among uranium miners. Nineteen were members of the combined study group of 4126 followed up for about 95,000 PY. This gives an estimate of 20/100,000 PY for the total group. If we exclude all those with fewer than 1000 WLM exposure, we have 14 cases among 4336 PY among Navajos, and approximately 20,000 PY among whites, for a combined rate of 57/100,000 PY. Excluding cases no. 2 and 3 (cases that might be attributed to siderosis or to rheumatoid arthritis) would reduce it to 49/100,000 PY. Although these numbers are imprecise and are much higher than "expected" as estimated above, they are minimal estimates because we have not attempted to identify all cases of DIF appearing in the two study groups, and the 137 excess NMRD deaths (12 Navajo, and 125 whites) (R.J. Roscoe, MS, unpublished data, 1995) suggest that there are many more DIF cases in the cohorts.

There was evidence of DIF in all of our cases, and evidence of cor pulmonale in most. The importance of these items is evident from the fact that only about 35% of patients diagnosed with cor pulmonale survive for a year after diagnosis,103 and few DIF patients survive more than 5 years after diagnosis.6 The short survival is probably due to the fact that the SOB increases slowly and can be compensated for by several means. It is usually only when the limits of this compensation are reached, with suddenly worsening symptoms, that medical help is sought.

In many of the cases, the chest disease was not simple DIF. Seven of the autopsy cases had nodules reflecting exposure to silica dust as well as DIF. Many had chronic changes in bronchi with productive cough and emphysema, but none had the extensive bronchitic changes with severe emphysema usually seen in end-stage COPD, and none had the progressive massive fibrosis or distortion of lung architecture usually seen in end-stage silicosis. Non-smokers and minimal smokers were well represented in this group of 22 cases, so smoking could not be an important factor. The observed anthrasilicotic nodules, siderosis, and bronchitic and cigarette-related changes were not dominant, so they were either coincidental or were reflecting an interaction between two or more etiologic aspects, the most important of which was apparently ionizing radiation.

On the basis of pulmonary function and pathology studies of both animals and man, it appears that the basic lesions of DIF among uranium miners are injury to alveolar epithelium and capillary endothelium throughout the lung parenchyma, accompanied by fibrosis of the interalveolar septa, loss of capillary bed, and chronic inflammation of the bronchioles and small bronchi. This is followed by hypertensive changes in arterioles. These changes are progressive long after exposure stops, as might be expected from radiation injury, which causes delayed death and nonreplacement of cells. It results in bilateral diffuse linear or reticular opacities in chest films, which may not appear until several years after exposure and are most evident in the lower lung fields. Quartz dust may alter the opacities to fibronodular types. Much of this change may not be evident on ordinary chest films, as suggested in the study of Trapp et al18 and by the findings in asbestosis (a very similar disease), in which standard chest films may miss as many as 50% of men with asbestosis.104-107 These fibrotic changes are followed by pulmonary hypertension and cor pulmonale. There is some loss in diffusion capacity, some loss of lung capacity, and some loss of ventilatory capacity, but none of these are marked until late in the disease. Diagnosis may depend on high-resolution computed tomography scan, exercise testing, determining pulmonary artery blood pressure, or open-wedge biopsy.

One of the authors (V.E.A.) has been in contact with the physicians of uranium miners for forty years. Some of their observations related to NMRD may be of interest: that future lung cancer could be predicted in uranium miners by a simple PFT (both lung cancer and NMRD are frequent among the most highly exposed); that x-ray therapy of a miner's lung cancer may quickly result in respiratory failure; that the lungs may expand poorly to fill the space after lobectomy for cancer; and dismay that "Stage I or II silicosis" could cause respiratory failure and death. The term "uranium miner's lung" was coined for the peculiar NMRD observed among the miners.

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Acknowledgments

The authors are grateful to the many clinics, hospitals, and pathologists who have kindly submitted records and tissue slides for our review. We are especially grateful to Jonathan M. Samet, MD, and to Joel B. Bechtel, MD, for their thoughtful reviews and excellent comments on the manuscript.

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References

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