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Four subgroups of a colony of 50 mice were housed in environmental chambers supplied by particle- and pollutant-filtered air. The animals were exposed to 0.35 ppm ozone and / or simulated high altitude (380 mm Hg) for four weeks, with exposure 41/2 hours / day and 5 days/week. Lung elastin area and alveolar wall area were quantitated by computer assisted image analysis of paraffin embedded sections stained with aldehyde fuchsin and metanil yellow. Compared to the controls, the combination of ozone and simulated high altitude resulted in a 54.5% increase in lung elastin area (p < 0.005), and simulated high altitude by itself increased elastin area by 19.6% (p < 0.05). Simulated high altitude with and without ozone exposure also increased alveolar wall area (24.8%, p < 0.01; and 9.7%, NS, respectively). Ozone exposure alone had a reverse effect: a 16.1% decrease in elastin area (p < 0.1), and a 6.5% decrease in alveolar wall area (NS). Since an intact lung scaffolding is required for full restoration of injured alveolar epithelium and since intact lung elastin is critical for proper lung compliance, the results suggest that ozone exposure at high altitude is most likely to have an adverse effect on lung structure and function.

In defining the adverse effects of ambient levels of ozone on the human lung, research has tended to emphasize direct cause and effect responses. However, disease is generally multicausative and the lung has relatively few ways to respond to injury. Moreover, all adult lungs have some disease. Thus, pathogenesis is more appropriately addressed by asking "What role does the agent in question play in the causation, promotion, facilitation, and/or exacerbation of disease that is present?" Our recent studies of the lungs of 107 ostensibly healthy youths between 14 and 25 years of age (violent death cases in Los Angeles County) add suggestive evidence to epidemiologic and experimental data indicating that air pollution is adversely affecting the human lung. We found 80% of the youths with some degree of presumably subclinical Centriacinar Region disease and, in 27%, the Centriacinar Region disease was severe and extensive. Centriacinar Region disease has been linked to infectious organisms, cigarette smoke, ozone, mineral dusts, and other noxious agents. Recently, a mild form of Centriacinar Region disease has been produced in primates exposed to a level of ozone (0.15 ppm) that is frequently exceeded in Los Angeles. Since there is suggestive evidence that air pollution in Los Angeles increases the rate of decline of lung function, we suspect that there has also been an increase in the rate of structural decline, manifest in part by accentuated Centriacinar Region disease. The health significance of Centriacinar Region disease is just beginning to be appreciated. At the very least, reserve depletion reflected in the Centriacinar Region disease implies some reduction in lung performance and some increase in susceptibility to disease in general. At worst, the unexpected severity of the Centriacinar Region disease may be a bellwether for an impending rise in clinically manifested lung disease for the general population. An urgent research need is the monitoring of health through inventories of the functional and structural units of the human lung, with special emphasis on subpopulations of cell societies of the lung. The feasibility of applying image analysis for large volume objective quantitations has been demonstrated and should be implemented. Multicity studies, in cooperation with Offices of the Medical Examiner-Coroner and autopsy services in general, can help meet the critical need for increased sensitivity in the monitoring of the public health in a changing environment.

A total of 24 tissue sections from the lungs of 8 vineyard workers with silicate pneumoconiosis were searched for 10 m fibrous and platy particulates, identified earlier as primarily mica phyllosilicates. The purpose of the study was to augment the very limited data available on the range of physical fiber lengths and the light microscopic characteristics of 10 m phyllosilicates that reach human respiratory tissues. Brightly birefringent crystals having an estimated length longer than 10 m were measured using a calibrated reticule eyepiece. Of 148 particulates confirmed as 10 m in length, 137 were fibrous (aspect ratio 3) and 11 were platy forms, with the largest plate measuring 37 m x 28 m. Mean length of the fibers was 19 m, with several as long as 35 m. Mean width was 2.6 m and mean aspect ratio was 8.9. Most of the 10 m fibrous particles were rodlike or fibroplaty, the latter with irregular contours and nonuniform diameters. The majority of the 10 m fibers, and all but one of the 7 fibers 35 m in length, were apparently recent deposits since they were found in respiratory tissues showing macrophage response but little or no fibrosis. Dissolution and short axis fragmentation of 10 m fibers was frequent. Long axis fragmentation (splintering) of 10 m platy particulates was also frequent and appeared to be a mechanism for in vivo generation of 10 m fibers. While the findings pertain to vineyard workers exposed to exceptionally high levels of phyllosilicates, the atmosphere of a rural area was involved. Moreover, community atmospheres may at times contain high levels of phyllosilicates due to industrial and vehicular emissions, construction and agricultural activities, and natural events such as dust storms. Personal and local exposures to commercial products containing silicates are additional considerations. Pertinently, everyone's lung contains on average billions of particulates and millions of fibers that are largely phyllosilicates. The 5 m fibers warrant special attention in view of their recognized fibrogenic potential, the uncertainty about their collection as part of PM-10 monitoring, and the poorly defined pathogenesis of most fibrosing lung diseases. Moreover, there are data indicating that PM-10 monitoring does not include all 10 m fibrous and platy particulates that reach respiratory tissues, whether particulate measurement is by physical or aerodynamically equivalent diameter (AED). It would seem prudent to collect particulates of all sizes that are present in the ambient air, to measure them according to physical as well as AED size, and to evaluate their chemical, physical, and pathobiologic properties.

The effects of ambient levels of NO2 on the spleens of adult and newborn Swiss Webster (S/W) mice were determined. Spleens were evaluated by the following criteria: (1) spleen weight, expressed as a percent of the body weight (% spleen weight), (2) size of the spleen lymphoid nodules as determined by computed image analysis, (3) spleen cell counts, and (4) histopathologic evaluation. Data for NO2-exposed animals were compared with data for control animals that inhaled filtered air. Totals of 217 control and 217 NO2-exposed animals were studied. After 6 wk of exposure to NO2 at ambient levels (0.35 ± 0.05 ppm), the following significant changes were observed in the spleens of exposed mice: (1) increase in % spleen weight (p <0.0025), (2) increase in size of spleen lymphoid nodules (p <0.01), (3) smaller increase in spleen cell number per given weight increment of spleen as determined by correlation coefficients (p < 0.0125) and linear regression analysis of spleen cell counts, and (4) an apparently greater predominance of red cells in the red pulp. It is concluded that inhalation of N02 is associated with quantifiable spleen changes, which may prove to be useful indicators for assessing effects of inhaled NO2.

Fifty-three lung cancers with a pathologic diagnosis of bronchiolo-alveolar carcinoma were reviewed, particular attention being paid to the validity of the diagnosis and prognosis. Twenty-one cases were acceptable as primary lung tumors on the basis of complete necropsy study (nine cases), long-term survival following operation without recurrence (eight cases), and recurrent disease with unusually long survival times (four cases). Origin of these tumors from bronchiolar mucosa could not be proved. Contrariwise it is likely that an occasional tumor with characteristics of the terminal bronchiolar type may arise from the mucosa of small bronchi. The most consistent pattern believed to represent a bronchiologenic proliferation is the “fibroelastic” form; an associated elastica proliferation or condensation was found. Scar cancers of the classical type, i.e., central scar and peripherally oriented carcinoma, offer reassurance that the tumors are primary in the lung; their peripheral location implies that the mucosal type proliferation arises in a bronchiole. (A fibroelastic pattern was seen in some of the scar cancers in this series.) Contiguity of tumor and bronchiolar mucosa favors a primary origin for the tumor, but is not a conclusive finding at this time. A spectrum of bronchiologenic proliferation was noted, ranging from benign hyperplasia to infiltrating and destructive adenocarcinoma. Tumor growth along alveolar walls is interpreted as a superficial spreading phenomenon (“epiphytic” growth). Invasion, as opposed to superficial spread, is not always obvious with ordinary stains, but can be identified readily by elastic stains. Predominantly mucinous “epiphytic” adenocarcinomas are the ones most likely to be mimicked by metastatic cancer. Unfavorable histologic features are the presence of destructive-type invasion, intra-alveolar tumor cell clusters, multifocal tumor, blood vessel invasion, and lymph node metastases. There is a strong suggestion that scar cancers and tumors of the fibroelastic type are more amenable to resection as a group. The routine use of elastic stains will probably identify scar cancers of the condensation type that otherwise might be missed.

A method has been developed for detection of altered lung capillary permeability and epithelial cell damage by low levels of nitrogen dioxide. Leakage of tritiated serum, injected intravenously before or at intervals after NO2 exposure, was detected by scintillation counting of dialyzed pulmonary lavage fluid. In experiments with mice, elevated readings were obtained for those exposed to continuous low levels of NO2. Determinations were also made of plasma levels and lung tissue content. Although good reproducibility and significant differences were not achieved in respect to the accumulation of reabsorbed serum and its large degradation products in lung tissue, evidence (including data from ultrastructural autoradiography) was found that serves to encourage further exploration. The results of the lavage fluid study by itself warrant strong consideration of the methodology as a highly sensitive and biologically meaningful indicator of adverse air pollutant levels.