The effects of styrene on lung cells in female mice and rats.

Styrene has been shown to cause an increase in the incidence of lung tumors in CD-1 mice following chronic exposure at 40 and 160 ppm, whereas no treatment-related increase in tumors in any organ was seen in rats chronically exposed to up to 1000 ppm styrene. So far most of the mechanistic studies have been performed with male animals. The aim of the present study was to further elucidate the target cell population in mouse lungs exposed to styrene, and to investigate possible differential in vivo effects (e.g., glutathione depletion, increased lipid peroxidation, and oxidative DNA damage). Groups of female CD-1 mice were exposed to styrene at concentrations of 0, 172 or 688 mg/m3 (0, 40 or 160 ppm) for 6 h per day on 1 day, 5 consecutive days or for 20 days during a 4 week period. Groups of female Crl:CD rats were exposed to styrene at concentrations of 0, 688 or 2150 mg/m3 (0, 160 or 500 ppm) for a single 6 h period or for 6 h per day on 5 consecutive days. No signs of lung toxicity were observed in rats. The cytology of cells in lung lavage fluid provided no signs of an inflammatory response in either rats or mice. In mice, both exposure levels caused decreased CC16 protein concentrations in lung lavage fluid after 1 and 5 exposures and in mouse blood serum throughout the study, suggesting that styrene may cause destruction of Clara cells in mice. Degenerative lesions in mouse Clara cells (vacuolar cell degeneration, cell necrosis) were revealed by electronmicroscopy. After 5 and 20 exposures of mice at 160 ppm, cellular crowding, expressed as an irregular epithelial lining and indicative of a very early hyperplasia was noted. Although a depletion of glutathione was noted in mouse lung homogenates after 20 exposures, there was no evidence of oxidative stress as indicated by unchanged concentrations of 8-OH-deoxyguanosine. Malondialdehyde, an indicator of lipid peroxidation, was slightly increased in mice after 1 exposure at 160 ppm only.

Chronic pulmonary effects of respirable methylene diphenyl diisocyanate (MDI) aerosol in rats: combination of findings from two bioassays.

Two independent bioassays are available which have examined the potential carcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate (MDI) following long-term inhalation exposure in rats. These studies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the histopathological findings. This paper presents a definitive overview ofthe pulmonary toxicity of MDI developed following a thorough review of both investigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was conducted by an independent reviewing pathologist. This included the re-examination of the original lung slides, supported by an analysis of the exposure regimens, the results of which were used to develop an accurate profile of the doses received by the animals in the two studies. Histopathological findings were then combined with this information to give an overall dose-response curve for both studies as a whole. The range of total inhalation exposures to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m3. Major pulmonary effects included increased lung weights together with bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicating a very similar qualitative response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the studies were considered as a whole a reasonable overall dose-response relationship was apparent for major lung lesions. Lung tumours (in low incidences) only occurred at the highest dose level in both studies (17,575 and 17,728 mgh/m3). For inflammatory and other non-neoplastic pulmonary changes, the lowest dose examined (559 mgh/m3) was regarded as a no-observed-adverse-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for human risk assessment of MDI.

Different patterns of kidney toxicity after subacute administration of Na-nitrilotriacetic acid and Fe-nitrilotriacetic acid to Wistar rats.

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrilotriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract. In contrast to FeNTA, Na3NTA requires high dose levels to produce tumors. The aim of this study was to compare the effects of Na3NTA and FeNTA on cellular proliferation, histopathology, lipid peroxidation, and 8-OH-2'-deoxyguanosine levels in the kidneys as well as on the urinary excretion of Ca, Fe, and Zn. For evaluation of DNA synthesis both compounds were administered for 1 or 4 weeks to 14-week-old male Wistar rats at a tumor causing dose, Na3NTA via the diet at 150 ppm and 20,000 ppm (approximately 9 and approximately 1000 mg/kg/day) and FeNTA i.p. at 25 mg/kg/day. An osmotic minipump, containing 20 mg/ml BrdU, was implanted subcutaneously 7 days before necropsy. Na3NTA showed nearly no effect on DNA replication after 1 week but a strong reaction after 4 weeks. The increase was 10- to 18-fold in different renal compartments. The enhancement of proliferation in the proximal tubules was nearly twice that in the distal tubules. In contrast, FeNTA caused DNA replication during the first week, and this was restricted to the proximal tubules. After 4 weeks there was an 18-fold increase in the outer stripe and no effect in the inner stripe of the outer medulla. The data presented give evidence to the assumption that both substances increase cell proliferation as a compensatory mechanism, causing different pattern of tubular proliferation in terms of time course and affected cell types. Both Na3NTA at 20,000 ppm and FeNTA led to increased lipid peroxidation, whereas increased levels of 8-OH-2'-deoxyguanosine were observed only after treatment with FeNTA. Urinary excretion of Zn was increased 30-fold after administration of 20,000 ppm Na3NTA but only 2-fold after administration of FeNTA. Urinary excretion of Ca and Fe remained unchanged after treatment with either Na3NTA and FeNTA. These results show that the Na3NTA-related proliferative effects are not mediated by an internal formation of FeNTA.

Factors that influence health risk behaviors among tanning salon patrons.

A principal components analysis identified the immediate convenience of indoor tanning (i.e., relaxation, perceived attractiveness of tans) as a major factor that motivates people to visit commercial tanning salons frequently and continually. Long-term considerations, such as price, socializing, and perceived health, also emerged as a motivating factor that was related to tanning frequency. Furthermore, almost half of the participants mentioned that regulations restricting indoor tanning would not make them more cautious in their tanning behavior. Findings confirm several other studies indicating that knowledge of the danger of UV exposure may have little influence on actual tanning behavior. Suggestions for alternative approaches that focus on the perceived attractiveness of tanned skin rather than the susceptibility of frequent tanners to skin cancer are discussed.

Chemically induced pulmonary mucoepidermoid carcinoma in a female Wistar rat.

A case of a mucoepidermoid carcinoma, conventionally classified as an adenosquamous carcinoma, is described. The tumour bearing rat was exposed to a mixture of a pyrolized pitch condensate rich in polycyclic aromatic hydrocarbons and carbon black particles by inhalation for 10 months. The neoplasm was examined by conventional histopathologic procedures and by immunohistochemical detection of intermediate filaments. Morphologically, the tumour consisted of two components. The centre of the neoplasm was predominantly of adenocarcinomatous tissue and this was surrounded by keratinized squamous epithelium. The predominantly adenocarcinomatous component had a characteristic structural pattern consisting of one or a few layers of squamous epithelium covered by a continuous layer of mature goblet cells. The flattened cells were recognizable as squamous cells on the light microscopic level only after immunohistochemical staining with cytokeratin antibodies. Goblet cells and extracellular mucin were intensely positive for the PAS-reagent. This mucoepidermoid carcinoma in the rat was morphologically similar to those described in man. It is still unclear whether pulmonary mucoepidermoid carcinomas of humans originate from the bronchial epithelium or bronchial glands. It is most probable that the mucoepidermoid carcinoma of a rat described in this communication occurred by metaplasia in a carcinoma of bronchiolo-alveolar origin.

Neoplastic lung lesions in rat after chronic exposure to crystalline silica.

Groups of 100 SPF Fischer-344 rats were exposed 6 h a day, 5 d a week for 24 months to crystalline silica (1 mg center dot m-3, DQ 12 quartz) or titanium dioxide (5 mg center dot m-3) or air only. The animals were kept without further exposure for an additional 1.5 months. In the group exposed to crystalline silica a significantly increased incidence of 20 primary lung tumors was observed among 19 animals. The distribution of tumor types consisted of 3 adenomas, 11 adenocarcinomas, 4 benign cystic keratinizing squamous-cell tumors, 1 adenosquamous carcinoma, and 1 squamous-cell carcinoma. There were also 13 nodular hyperplasia lesions, which were interpreted to be borderline cases of adenomas. Approximately half of the adenoid tumors and all of the nodular hyperplasia lesions were characterized by moderate central fibrosis. The principal nonneoplastic findings in the silica-exposed group were lipoproteinosis, inflammation, epithelial hyperplasia, and fibrosis. The results can be considered significant due to the increased lung tumor incidence at a relatively low exposure level.

Morphological comparison between benign keratinizing cystic squamous cell tumours of the lung and squamous lesions of the skin in rats.

Approximately 700 cases of keratinizing cystic squamous lung lesions in rats were investigated by light microscopy in order to clarify the nomenclature and classification of these lesions. The structure of benign keratinizing cystic squamous cell tumours of the lung was compared to that of cystic squamous lesions in the skin of rats, with consideration of data from the literature. We conclude that the reviewed keratinizing cystic squamous cell lesions of the lung are true neoplasms and that the growth pattern of these cystic lesions is inconsistent with that of a simple cyst. In the development of squamous lung cancer, a continuum of proliferation from exaggerated metaplasia through benign cystic tumours to invasive squamous cell carcinomas can be observed.

Surface-wrinkling maculopathy as a potential complication of trabeculectomy: a case report.

We report a case of "crinkled cellophane maculopathy" which developed during the first few days following an uneventful trabeculectomy in a high myopic patient with primary open-angle glaucoma. We suggest pathogenic mechanisms that may have induced such premacular lesions, emphasizing the patient's high myopia combined with a postoperative inflammatory reaction.