The main objective of this research is to determine the toxic and carcinogenic effects on the rat tracheal mucociliary epithelium of two major pollutants in the environment, namely, formaldehyde (HCHO) and benzo(a)pyrene (Bap) when these agents are delivered separately or in various repeat combinations directly to the mucosa in our newly-developed, open-ended, flow-through tracheal implant system (FTTI). This experimental system permits unlimited numbers of uniform exposures of gases, liquids or solids directly to the target tissue. Our working hypothesis is that repetitive exposure to low doses of hazardous agents may be far more carcinogenic in experimental systems than exposure to acutely toxic high doses, and that repetitive exposure to combinations of these agents will better reflect the actual contribution they make to the development of cancers in the respiratory tract in the human situation. To test possible roles of HCHO in carcinogenesis, HCHO aerosols and Bap solutions will be given in various combinations, namely, Bap followed by HCHO in a classical initiation-promotion scheme; Bap and HCHO given intermittently close together to test for co-carcinogenesis, and HCHO given before Bap to test the impact of increasing cell proliferation and squamous metaplasia on subsequent Bap-induced neoplasia. The number of tumor induction sites appearing in the FTTI during and following exposure to these regimens will be quantitated using an in vivo-in vitro approach developed by us in which the number of cell populations with altered growth control, an early marker of potentially tumorigenic cells, can be quantitated. Tumor development in the tracheal mucosa will primarily be followed by diagnosis of the cytopathology of the cells exfoliating into the lumens of the FTTI. The stages of carcinogenesis will be classified by criteria (mild, moderate, marked atypia, carcinoma, etc.) conventionally used for human sputum cytopathology. The cytopathology will be verified by periodic sampling of the exposed tracheas for histopathology. These experiments should clearly demonstrate the role, if any, of HCHO in respiratory carcinogenesis. These studies should also demonstrate the potential of this experimental system for determining the toxic and carcinogenic effects of other hazardous agents on the respiratory system.
| Cosma, G N; Jamasbi, R; Marchok, A C (1988) Growth inhibition and DNA damage induced by benzo[a]pyrene and formaldehyde in primary cultures of rat tracheal epithelial cells. Mutat Res 201:161-8 |
| Cosma, G N; Wilhite, A S; Marchok, A C (1988) The detection of DNA-protein cross-links in rat tracheal implants exposed in vivo to benzo[a]pyrene and formaldehyde. Cancer Lett 42:13-21 |
| Cosma, G N; Marchok, A C (1988) Benzo[a]pyrene- and formaldehyde-induced DNA damage and repair in rat tracheal epithelial cells. Toxicology 51:309-20 |
| Marchok, A C; Martin, D H (1987) Sequential appearance of anchorage independence, uncontrolled nuclear division and tumorigenicity in 7,12-dimethylbenz(a)anthracene-exposed rat tracheal epithelial cells. Cancer Res 47:3446-50 |
| Cosma, G N; Marchok, A C (1987) The induction of growth-altered cell populations (tumor-initiation sites) in rat tracheal implants exposed to benzo[a]pyrene and formaldehyde. Carcinogenesis 8:1951-3 |
