Multifactorial hamster respiratory carcinogenesis with interdependent effects of cannula-induced mucosal wounding, saline, ferric oxide, benzo[a]pyrene and N-methyl-N-nitrosourea.

The carcinogenic response induced in the respiratory tract of Syrian golden hamsters by repeated intratracheal instillations of benzo[a]pyrene (BP) adsorbed to ferric oxide (Fe2O3) particles suspended in saline, is shown to result from the interactions of these factors and cannula-induced tracheal wounding. Previous acute studies of intratracheal cannulation (ITC) versus intralaryngeal cannulation (ILC) showed that tracheal cell proliferation increased significantly in ITC-induced mucosal wounds. Only mild increases in intrapulmonary cell proliferation were produced by Fe2O3-saline given by ILC or ITC (Keenan et al., Cancer Res., 49: 1521-1527, 1989). The present chronic studies included the following variables: a single instillation by ILC of N-methyl-N-nitrosourea (MNU) at 5 weeks of age; 15 weekly treatments (beginning at 7 weeks of age) by ILC or ITC alone, or with instillations of saline, or Fe2O3-saline, or BP-Fe2O3-saline; and appropriate controls. Repeated ITC-induced tracheal wounds caused persistent tracheal epithelial hyperplasia, metaplasia and/or atrophy and submucosal fibroplasia during the observation period of 22 to 78 weeks of age (the time of terminal sacrifice). Tracheal cancers (in situ or invasive carcinomas) were seen only in those hamsters which had received repeated ITC and one or both carcinogens. The cancer latency was shortest and the incidence of tracheal (50%) and main-stem bronchial (21%) cancers highest in hamsters given MNU and repeated ITC with BP-Fe2O3-saline. Hamsters given carcinogens by ILC (which induced laryngeal but not tracheal wounds) developed proliferative lesions and cancers of the larynx but no tracheobronchial cancers. These data show the singular importance of repeated ITC-induced intratracheal wounding as an enhancing factor in this respiratory carcinogenesis model. The findings suggest that the mechanism of tumor enhancement involves not only changes in target epithelial cell proliferation, but also alterations in normal epithelial-mesenchymal interactions during tracheal regeneration from repeated chronic submucosal inflammation and mesenchymal repair. In the present experimental model, a single dose of MNU at 5 weeks of age, repeated instilled doses of BP, and tracheal mucosal wounding were each found to be important determinants of the carcinogenic response. Additional effects were observed for instilled Fe2O3 particles, and possibly saline. Interplay of all these factors, as well as of genetic, nutritional, and infectious factors, are considered in relation to risk assessment and prevention.