Alveolar epithelial hyperplasia was present in “most treated mice with adenomas” and was not observed in controls (incidence data not reported, no further information provided). See adenoma incidence data in Table 2-8 (Evidence pertaining to carcinogenic effects in animals exposed to naphthalene).

"RESULTS

Pulmonary Tumor Bioassay

Table 1 presents results on the prevalence of pulmonary adenomas in control and treated animals for all chemicals tested via inhalation exposure for 6 mo. Treatment-related mortality was observed in the 20 and 50 ppm 1,2-dibromoethane (first study) and 500 ppm vinyl chloride (first study, both sexes) groups of strain A/J animals. Significant increases in the frequency (tumors per mouse) and incidence (tumors per tumor-bearing mouse lung) of adenoma formation during the testing period were observed with animals exposed to Cc!rbon disulfide, 1,2-dibromoethane (two studies), ethylene oxide (two studies), nitrogen dioxide, and vinyl chloride (two studies). Specifically, exposure of mice to 300 pm carbon disulfide resulted in a small, but statistically significant (p < 0.05), increase in the frequency of adenoma formation. The results of the two studies with 1,2-dibromoethane indicated a concentration-related increase in the frequency of adenoma formation. These later results were significant and reproducible at 50 ppm. All animals in the first study responded with slightly more tumors than their counterparts in the second study. The results of the two studies with ethylene oxide indicated a small, but statistically significant (p < 0.05), increase in the frequency and incidence of adenoma formation. The results of the two studies with 1,2-dibromoethane indicated a concentration-related increase in the frequency and incidence of adenoma formation. These latter results were significant and reproducible at 50 ppm. All animals in the first study responded with slightly more tumors than their counterparts in the second study. The results of the two studies with ethylene oxide indicated a small, but statistically significant (p < 0.05), increase in the frequency and incidence of adenoma formation. The exposure of mice to naphthalene did not cause any significant change in tumor frequency, but did show a significant increase in tumor incidence following treatment at 10 and 30 ppm. Mice exposed to nitrogen dioxide showed a small, but statistically significant (p < 0.05), increase in tumor frequency and incidence. The results of the two studies with vinyl chloride indicated a concentration-related increase in frequency and incidence of adenoma formation. The response was significant and reproducible and was observed in both sexes. The male mice exposed to 50 ppm in the first study developed significantly more tumors than the female mice (p < 0.001) exposed to the same concentration in both studies. The female mic~ exposed to 50 ppm in the second study developed slightly, but statistically significant (p < 0.05), more tumors than similar female mice in the first study (controls were not statistically different). The results of the studies showing little or no change in frequency and incidence of adenoma formation following the regimen of chemical exposure (6 hid, 5 d/wk, for 6 mo) were further compared with the pooled, negative control response from all experiments. Animals exposed to carbon disulfide (300 ppm) or to ethylene oxide (70 to 200 ppm) showed a significant increase in a mean tumor frequency, even though the increases were relatively small compared to vinyl chloride and 1,2-dibromoethane. Similarly, 200 ppm ethylene oxide (first study) exposure resulted in a significant tumor incidence when compared to the pooled, negative control response. Exposure to naphthalene was without significant effect on tumor frequency, but was significant when the incidence of tumor formation was compared with the pooled, negative control response. The frequencies of adenoma formation from the negative control animals exposed to conditioned air are also presented in Table 1. The mean tumor count among the 30 female mice tested in the first study with 1,2-dibromoethane indicated a statistically significant (p < 0.05) increase from that observed in all studies. The mean tumor counts from the other studies did not differ significantly from each other. The incidence of tumor formation was different in the negative control mice in the naphthalene and first 1,2-dibromoethane studies. The incidence of tumor formation from the other studies did not differ significantly from each other. The frequency and incidence of adenoma formation from positive control animals given a single intraperitoneal injection of urethane (1000 mg/kg) is summarized in Table 2. Data are presented by study group for both male and female mice surviving through the 26-wk holding period. The positive control mice from the first study with ethylene oxide showed a significantly lower frequency of adenoma formation than the mice from studies with other chemicals, even though there was 100% tumor incidence. The tumor frequencies observed in positive control animals from other experiments were not significantly different from one another.

Histopathologic Evaluation of Lung Adenomas

Histopathological examination of lungs from animals used in these studies revealed multiple alveolar adenomas in treated animals and single alveolar adenomas in untreated animals. The alveolar adenomas were morphologically similar in nearly all mice and consisted of large cuboidal or columnar epithelial cells supported by a sparse fibroblastic stroma and arranged in poorly defined acinar structures with papillary formations. An adenoma in a control mouse from the first vinyl chloride study had a primarily solid pattern of growth with uniform polygonal-shaped cells arranged in small clusters separated by capillaries. There was no apparent difference in the occurrence of pattern of anatomic distribution of alveolar adenomas occurring in urethane-treated mice and treated mice of each study group examined. Alveolar epithelial hyperplasia was observed in lungs examined from treated and positive control (urethane) animals and consisted of focal proliferation of cubiodal cells comprising the alveolar epithelium but without effacement of normal alveolar architecture. This lesion may precede the development of the alveolar adenoma; it was present in the lungs of most treated mice with adenomas and was not observed in examined control lungs. Several changes in the lungs of mice treated with 1,2-dibromoethane clearly distinguished them from others examined. A single bronchiolar adenoma with a prominent papillary pattern was observed, consisting of tall columnar epithelial cells. In each of the 1,2-dibromoethane-treated mice examined, multifocal hyperplasia and cellular atypia of the bronchiolar epithelium were observed. These changes consisted of focal stratification of bronchiolar epithelial cells or small papillary formations protruding into the bronchiolar lumens and occasional cells with enlarged hyperchromatic nuclei. Minimal chronic inflammation accompanied these changes and was characterized by a few widely scattered mononuclear cells in the bronchiolar lamina propria. In addition, alveolar epithelial hyperplasia in 1,2-dibromoethanetreated mice was frequently parabronchiolar in location and affected alveoli that abut the bronchiolar walls. In summary, there were no apparent differences in pattern of distribution or morphologic appearance of alveolar adenomas occurring in urethane-treated mice and mice treated with ethylene oxide, vinyl chloride, or 1,2-dibromoethane. Bronchiolar epithelial hyperplasia and cellular atypia occurred only in 1,2-dibromoethane-treated mice, and one mouse had a bronchiolar adenoma. No carcinomas were observed in the tissues examined."

Female A/J Mice