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Background: Lung cancer was noted to be increased in cigarette smoking miners and nonminers. Carcinogen particulates deposit differentially in the central, middle, and peripheral zones of the bronchial tree depending on the size of the particle. The object of this study was to evaluate the incidence of tumors; their cell types; and the relationship of particulate size to their position in the bronchial tree., Methods: Tumor position in the bronchial tree was studied for a cohort of 467 uranium miners and 311 nonminers with lung cancer., Results: An examination of all histologic subtypes showed that the proportion of lung cancers in the central zone was significantly greater in miners than in nonminers presumably due to the deposition of radon decay products attached to the silica dust particles. The higher percentage of central tumors in the miners was primarily due to the distribution of a greater proportion of squamous cell and small-cell tumors. The ratio of 0.75 for the central to middle and peripheral location for adenocarcinomas was much lower than for squamous cell and small-cell carcinomas with ratios of 1.4 and 7.3, respectively. In the mining cohort, there were ten times as many small-cell tumors in the central area as in the middle and peripheral regions, whereas, for the nonminers there were only five times as as many centrally located small-cell tumors as middle and peripheral (chi square is 7.0 degrees, P < 0.01). These data suggest that radon may be deposited preferentially to the central region of the lungs in uranium miners., Conclusions: Based on our observations of the differential positions of lung tumors in the bronchial tree for miners and nonminers and previous studies by others regarding size-dependent deposition of particulates in the bronchial tree, it is concluded that inhaled dust, radon, and cigarette smoke combine to form large particulates that deposit in the central bronchial tree. Filtered cigarette smoke or other small carcinogens from smaller particulates that deposit more peripherally.

The purpose of this study was to analyze the histological distribution of polymerase chain reaction (PCR)-amplified hantaviral cDNA in three cases of fatal hantaviral infection that occurred 2 years ago in Long Island, NY. The three otherwise healthy patients had a rapid death characterized by fever and pulmonary failure and were identified from the autopsy files at University Hospital, Stony Brook. Six autopsy controls with either no pulmonary disease (three) or fatal pneumonitis of known etiology (three) were also studied. PCR-amplified hantaviral cDNA was detected in the lung tissue of the three cases and none of the six controls using the reverse transcriptase in situ PCR technique. In the positive cases, viral RNA was detected in approximately 20% of pneumocytes and alveolar endothelial cells as determined with a consensus and Four Corners-specific primer pair. Infected endothelial cells were identified in a wide variety of other sites, but at rates much lower than in the lungs. The selective localization of the viral RNA in many pneumocytes and pulmonary endothelial cells using a highly sensitive PCR-based test demonstrates a correlation between direct viral infection in the lung and the disease process.

The carcinogenic response to the combined and separate exposures to formaldehyde (HCHO) and hydrochloric acid (HCl) was investigated in male inbred SD rats. The rats were exposed to gaseous HCHO, 14 ppm, and HCl, 10 ppm, in two experiments. In one experiment the gases were premixed at high concentrations before being diluted in the exposure chamber air to maximize the formation of the carcinogen bis(chloromethyl)ether (BCME). In the second experiment exposure was repeated to HCl and HCHO premixed at high concentrations, and not premixed (to minimize BCME formation), as well as to HCHO alone and HCl alone. The second experiment is being reported on at an interim stage. HCHO alone induced squamous carcinomas of the nasal cavity as did the combined exposures to HCHO and HCl. No carcinogenic response was observed with HCl alone. HCHO accounted for most, if not all, of the carcinogenic activity of the mixture of HCHO-HCl.

The comparative carcinogenicity of dimethylcarbamoyl chloride (DMCC) was studies in male, Syrian Golden Hamsters by inhalation. Hamsters were exposed to 1ppm and the exposure periods were 6 hours per day, 5 days per week for the lifetime of the animals. Fifty-one percent of the hamsters developed carcinomas of the nasal tract. Morphologically, all of these tumors were classified as squamous cell carcinomas. In comparing the response of rats and hamsters at 1 ppm DMCC, the rat seems to show increased sensitivity and the percentage of tumor yield is almost doubled, with the tumors appearing much earlier in rats than in hamsters. However, the remarkable tumor yield in both species indicates the potent carcinogenic effects of DMCC.

The remaining tissue of the tracheobronchial tree from 210 men who died from lung cancer was studied to compare the histologic alterations leading to further sites of primary cancer. These men were uranium miners matched with nonminers for age and smoking habits. In the examination of a total of 28,928 cross-sections carcinoma in situ was found in 96% of the miners and in 92% of the nonminers. The number of slides from miners showing degree 2 or 3 atypia in areas of carcinoma in situ was about double the number found from the nonminers. Although the difference was not statistically significant, 32% of the miners had at least one section showing early primary invasive carcinoma compared with 22% of the nonminers. The data indicate that the synergistic effect of the exposure to uranium dust along with cigarette smoking increases the risk of lung cancer and that in addition to a main tumor mass, other sites of tissue alterations leading to tumor development are frequently already present in the lung.

Intratracheal injection of samples of naturally occurring and man-made mineral fibres into guinea pigs showed that while long fibre samples produced marked fibrosis, short fibre specimens produced only a macrophage reaction. In most cases the long fibre samples were administered in smaller doses than the short. The samples tested were crocidolite asbestos, a synthetic fluoramphibole and two specimens of glass fibre with different mean diameters. With all the minerals tested some short fibres, but not long fibres, were transported to the hilar lymph nodes. In some instances the numbers of short fibres found in these nodes appeared to be much higher than would be expected from the percentage of short fibres in the original sample, and it is suggested that this may be due to the breakdown of long fibres within the lung.

A range of acute studies were performed with chloromethyl methyl either (CMME) and bis(chloromethyl)ether (BCME), including 14-day LC50's following single seven-hour inhalation exposures. The LC50's for CMME were 55 ppm for rats and 65 ppm for hamsters. The LC50's for BCME were 7 ppm for both species. All animals showed characteristic changes of acute irritation of the respiratory tract manifested by congestion, edema, and hemorrhage. Severe shortening of life span was seen in 30-day exposures of rats to CMME and in all studies with BCME. Incidences of mucosal changes, including atypia, were generally increased in a dose-related manner in both species. The carcinogenicity of BCME in these range finding experiments was demonstrated by a skin cancer in a rat after three exposures and a nasal tumor in a hamster after one exposure to 1 ppm BCME.

Inhalation exposure experiments with the direct-acting alkylating agent epichlorohydrin (ECH) were done on noninbred male Sprague-Dawley rats. Single 6-hour exposure to ECH and follow-up for 14 days showed the median lethal concentration to be about 360 ppm. Further inhalation experiments were done with 6-hour exposure 5 days/week. A short-term 30-exposure regimen with 100 ppm ECH produced malignant squamous cell carcinomas of the nasal cavity in 15 of 140 rats and respiratory tract papillomas in 3 rats. Among 100 rats, lifetime exposure to 30 ppm yielded 1 malignant squamous carcinoma of the nasal cavity plus 1 nasal papilloma. No nasal or respiratory tract tumors were produced by lifetime exposure of 100 rats to 10 ppm. As controls, 100 air-treated and 50 untreated rats were used. A dose-rate effect was observed for ECH inasmuch as 30-day exposure to 100 ppm (3,000 ppm-days) produced 15 cancers in comparison to the 1 cancer from the lifetime exposure to 30 ppm (8,700 ppm-days) and no cancers from lifetime exposure to 10 ppm (2,500 ppm-days).

Concentrations of 0.25 and 0.5 mug/ml calcium chromate (CaCrO4-2H2O)dissolved in Dulbecco's medium were found to alter the growth behavior of BHK21 cells in culture. Treated cells grew as shortened fibroblasts and in random orientation. The changes detected during the first two weeks of culture in the presence of the metal became more pronounced as the number of growth passages increased. In addition to the alterations noted above, chromate-treated cells grew into large clusters in Methocel (an alternative technique to the agar suspension system), while untreated cells underwent, at most, only one or two divisions in Methocel. These alterations in growth properties were irreversible and persisted after removal of the treated cells from chromate-containing medium, suggesting that a heritable change had occurred as opposed to a transient, chromate-dependent alteration of cell growth. This experimental observation suggests that chromate salts and perhaps salts of other metals can transform BHK21 cells in vitro or can select for spontaneously transformed cells.

Tissue samples from lung cancer patients who had worked at a copper smelter and from controls were collected and classified by a panel of pathologists: 38% of the cancers were found to be adenocarcinomas, compared to 12% among the controls, a statistically significant difference (p less than 0.05). The predominance of adenocarcinomas was associated with arsenic exposure. This finding is not consistent with Kreyberg's hypothesis that small-cell undifferentiated and epidermoid carcinomas are the only type that increase in response to inhaled carcinogens [1962].

Rats and hamsters were exposed to 0.1 ppm bis(chloromethyl)ether (BCME) six hours per day, five days per week throughout their lifetime. Additional groups of rats were given 10, 20, 40, 60, 80, and 100 exposures to 0.1 ppm BCME and then held until death. Forty cancers originating in the respiratory tract were found in the 200 rats involved in these studies. These included 14 cancers of the lung and 26 cancers of the nasal cavity. They occurred in dose-related fashion. A single undifferentiated carcinoma of the lung was seen in a hamster.

Rats and hamsters were exposed to 1 ppm of chloromethyl methyl ether six hours per day, five days per week, throughout their lifetime. Mortality and weight gain of the exposed animals paralleled that of the control animals. Malignant tumors of the respiratory tract were found in two rats. These were a squamous cell carcinoma of the lung with blood vessel invasion and an esthesloneuroepithelioma originating in the olfactory epithelium and invading the forebrain. One hamster was found to have an adenocarcinoma of the lung and another, a squamous papilloma of the trachea. A single exposed rat had a pituitary tumor of primitive cell type that may well have been coincidental.