Lung hyperpermeability and changes in biochemical constituents in bronchoalveolar lavage fluids following X irradiation of the thorax.

Groups of rats were administered different doses of X rays (7.5 and 15 Gy), and the effect on the permeability of their lungs was evaluated during a time frame within which radiation pneumonitis develops. Sham-exposed animals served as controls. End points surveyed included lung weight and increases in the total protein in the lavage fluid. To obtain more detailed information about hyperpermeability and to examine some specific protein changes that occur in the lung's fluid in response to X irradiation, the lavage fluids were subjected to a reverse-phase HPLC technique that resolves 11 fractions quantitatively, including transferrin, albumin, and immunoglobulins derived from blood, as well as eight other protein and nonprotein constituents that appear to be derived from the lung (fractions 1, 2, 6-11). The earliest change following the 7.5-Gy dose was a decrease in fraction 6 at 1 week after exposure. As of Week 5, the lung weight and total protein in the lavage fluid were all normal, while the HPLC analyses revealed significant and equivalent increases in the amount of transferrin, albumin, and immunoglobulins in the lavage fluid; fraction 6 was no longer diminished. At 9 and 13 weeks, hyperpermeability could no longer be detected, while fraction 6 was again decreased at week 13. Fraction 6 was also decreased 1 week after the 15-Gy dose. At 5 weeks, when the weight of the lungs and the total protein in the lavage fluid were elevated, lavage fractions 1, 2, 10, and 11 were all increased, and transferrin, albumin, and immunoglobulins were increased approximately 1500, 1000, and 500%, respectively, and fractions 6 and 9 were decreased. By Week 7, the weight of the lungs returned to control limits, while total protein in the lavage fluid remained elevated. The hyperpermeability was characterized by increases in transferrin and albumin in the lavage fluid, but not immunoglobulins. Fractions 1, 2, 10, and 11 returned to within normal limits, whereas fraction 9 decreased further. Increases in transferrin and albumin were components of a persisting hyperpermeability observed at the last 9-week time point. All other fractions were normal, with the exception of fraction 6, which remained decreased.(ABSTRACT TRUNCATED AT 400 WORDS)

Migratory behaviors of alveolar macrophages during the alveolar clearance of light to heavy burdens of particles.

We investigated the unstimulated and stimulated migratory activities of lavaged alveolar macrophages (AMs) in vitro over the course of alveolar clearance of three different mass lung burdens of microspheres. Our intent was to uncover potentially important relationships between the migratory behaviors of the AM and the retention kinetics of particles. Groups of adult, male Fischer-344 rats were intratracheally instilled with approximately 86 micrograms (low burden, LB), approximately 1 mg (medium burden, MB), or approximately 3.7 mg (high burden, HB) of polystyrene microspheres (2.13 microns diameter), or with carrier vehicle (phosphate buffered saline, PBS) alone. The lung retention kinetics of the particles were determined over an approximately 170 day period. On days 14, approximately 57, and approximately 85, lavaged AMs were assessed for their abilities to migrate through 5-microns pore membranes in response to inactivated rat serum (unstimulated condition) and yeast-activated rat serum (stimulated condition). The retention characteristics of the three burdens could be satisfactorily described by two-component, negative exponential equations. The kinetics of retention of the LB and MB were similar, although some evidence indicated the MB slightly retarded the lung clearance process. Deposition of the HB resulted in more marked prolongations of both the early, more rapid, and the slower, longer term components of alveolar clearance. The unstimulated migration indices of AMs from the particle-instilled lungs were generally not significantly different from those of AMs from PBS-instilled lungs except for a significant increase in the migration indices of LB AMs at the last assay time. The stimulated migration indices of MB and HB AMs were significantly decreased on assay days 14 and approximately 57. On day approximately 85, however, the migration indices of LB, MB, and HB AMs were all increased above the PBS AMs. Comparisons of the frequency distributions of particles in the unstimulated and stimulated AM that migrated to those in corresponding parent AM populations consistently indicated a preferential migration of particle-free AMs and of AMs with lesser loads of microspheres. The overall results of this study suggest that the unstimulated and stimulated migratory activities of particle-laden AMs are depressed in vitro. Our results also suggest that the migratory activities of generally particle-free AMs may be enhanced over a prolonged period of time following the deposition of particles in the lung.

Alveolar macrophage-particle relationships during lung clearance.

Retention kinetics for insoluble particles that deposit in the lung oftentimes resemble a multicomponent process during alveolar clearance, with each component appearing to follow simple first-order kinetics. Inasmuch as alveolar macrophages (AM) are thought to play an important role in particle removal from the lung, a study was undertaken to examine particle-AM relationships during the clearance of particles to obtain information on potential AM mechanisms that could provide the underlying bases for the lung retention kinetics of the particles. Adult, Fischer 344 rats were intratracheally instilled with 1.6 x 10(7) (approximately 86 micrograms) polystyrene microspheres (approximately 2 microns diam). On Days 7, 14, 57, 85, and 176 thereafter, subgroups were killed, their lungs were lavaged, recovered cells (greater than 95% AM) were counted, the frequency distribution of the particles among the AM was determined (e.g., zero, 1 to 2, 3 to 4 particles/AM), and the total numbers of particles lavaged were estimated. The lavaged lungs were solubilized, and unlavaged particles were also counted. The sums of the lavaged and unlavaged particles were used to estimate retained lung burdens at each postinstillation time. The lung retention data followed a pattern consistent with the sum of two negative exponential components, i.e., an earlier, more rapid component and a slower, longer term component. The rates at which the AM disappeared from a given particle category also were biphasic for AM that contained up to 14 microspheres. The rates of both the earlier and longer term components of such disappearance were found to increase with increasing AM burdens. Over an AM burden range of 1 to 10 microspheres, the proportion of AM that disappeared via rapid components also increased as the particle burden defining an AM category increased. At higher particle burdens, the proportion of AM that disappeared by an early component appeared to markedly diminish; an early component for AM disappearance was no longer resolvable for AM that contained greater than 15 microspheres. The net effect of these phenomena was that retained lung burdens over time became progressively contained in AM with lesser burdens of particles. The results from this study suggest that the rate(s) of translocation of particle-containing AM from the lung during lung clearance may be related to their individual particulate burdens. These findings, however, are also consistent with a gradual redistribution of particles among the lung's AM population over time concurrent with AM removal from the lung. Regardless, the biphasic nature of the lung retention data qualitatively was generally evident for particle-containing AM as well.

Plutonium and lung cancer.

The National Plutonium Workers Study surveys workers at three major U.S. Department of Energy facilities who were exposed to Pu and other radioactive substances. The purpose of the study is to measure adverse health effects, if any, which arise from exposure. Most exposures occur from inhalation of highly insoluble forms of plutonium oxide, and from animal studies, lung cancer is the most likely outcome. To date, the studies have shown that lung cancer mortality among highly exposed persons is surprisingly low when compared to national averages.

Mortality among plutonium and other radiation workers at a plutonium weapons facility.

Mortality among 5,413 white males who were employed for at least two years at a plutonium weapons facility was investigated to measure risks from exposures to low levels of plutonium and external radiation. When compared with US death rates, fewer deaths than expected were found for all causes of death, all cancers, and lung cancer. No bone cancer was observed. An excess of brain tumors was found for the cohort in general. Elevated rate ratios for all causes of death and all lymphopoietic neoplasms were found when employees with plutonium body burdens greater than or equal to 2 nCi were compared with those with body burdens less than 2 nCi, while accounting for age, calendar period, and induction time. Increased rate ratios were also found for esophageal, stomach, colon, and prostate cancers, and for lymphosarcomas and reticulum cell sarcomas. No elevated rate ratios were noted for bone and liver cancers. When employees with cumulative exposures greater than or equal to 1 rem were compared with those with exposures less than 1 rem, elevated rate ratios were found for myeloid leukemia, lymphosarcoma and reticulum cell sarcoma, liver neoplasms, and unspecified brain tumors. No overall dose-response relationships were found for plutonium or external radiation exposures. Standardized rate ratios increased, however, as plutonium body burden levels increased for all causes, all cancers, and digestive cancers at five years induction time. Standardized rate ratios also increased as external radiation exposure categories increased for all lymphopoietic cancers and unspecified brain tumors for a two-year induction period. With the exception of analyses of combined categories of death, and perhaps of lung cancer, confidence limits were wide, indicating limited precision. Nevertheless, these findings suggest that increased risks for several types of cancers cannot be ruled out at this time for individuals with plutonium body burdens of greater than or equal to 2 nCi. Plutonium-burdened individuals should continue to be studied in future years.

Mortality among workers at the Pantex weapons facility.

We compared total and cause-specific mortality for workers at the Pantex nuclear weapons assembly facility employed between 1951 and 31 December 1978 with expected mortality based on U.S. death rates. We observed significantly fewer deaths than expected from all causes of death, all cancers, digestive cancers, lung cancer, arteriosclerotic heart disease, and digestive diseases. There were no causes of death which occurred significantly more frequently than expected. Analyses of worker mortality by duration of employment, time since first employment, and radiation exposure greater than 1.00 rem produced similar results. We found no evidence that mortality from any cause of death was increased as a result of employment at Pantex.

A melanoma case-control study at the Los Alamos National Laboratory.

We conducted a melanoma case-control study at the Los Alamos National Laboratory to investigate whether related occupational exposures or personal characteristics of employees could be identified. This study was prompted by a recent report from the Lawrence Livermore National Laboratory that melanoma was much more frequent than expected among employees and that persons suffering from melanoma more often worked as chemists. Our investigation did not uncover an association with plutonium body burden, cumulative external radiation exposure, or employment as a chemist or a physicist. The major finding was that cases were more educated than controls. Melanoma risk was 2.11 among college-educated employees and increased to 3.17 among those with graduate degrees (Mantel-extension linear trend probability = 0.038). This finding is consistent with the often reported increased melanoma incidence among persons of higher social class. It points to personal characteristics, particular to persons of higher educational attainment, as risk factors for melanoma at the Los Alamos National Laboratory.

An update of epidemiologic studies of plutonium workers.

Retrospective and prospective epidemiologic studies are being conducted as part of a national survey of plutonium workers at four Department of Energy facilities (Los Alamos, NM; Rocky Flats, CO; Mound Laboratory, OH; and Savannah River, SC). A preliminary analysis of mortality was done for all white males who have worked at the Rocky Flats Plant during the period 1952-79. The 452 observed deaths were significantly fewer than the 831 expected for all causes. The 107 deaths due to all malignant neoplasms were also significantly fewer than the 167 expected from these diseases. Expected deaths were derived from age and calendar-specific death rates for U.S. white males. Deaths reported for benign and unspecified neoplasms numbered eight versus an expected two, a significant elevation. These tumors, all intracranial, are the subject of a case-control study to be reported later. Subdividing the cohort on the basis of plutonium exposures and external radiation exposures results in similar overall findings. The benign and unspecified neoplasms, however, were not significantly high in the plutonium-exposed group.

Malignant melanoma incidence at the Los Alamos National Laboratory.

In an analysis of melanoma incidence for 1969 to 1978 among 11 308 workers at the Los Alamos National Laboratory in New Mexico 6 cases were detected in the total cohort, in which 5.69 cases would be expected (standardised incidence ratio [SIR] = 105; 90% confidence interval [CI] = 51,198) on the basis of incidence rates for the State of New Mexico, specific for age, sex, and ethnic origin. Among the White non-Hispanic men, 3 cases were detected, whereas 4.4 would be expected. The associated SIR of 68 (90% CI = 23, 163) does not suggest excess melanoma incidence in this subcohort. A direct comparison with Statewide incidence rates gave similar results. These results do not agree with the threefold excess of malignant melanoma incidence found among White male employees at the Lawrence Livermore National Laboratory.