Multifactorial induction of epithelial cancers from different respiratory tract segments in animal models is studied by combined treatments with chemical, physical and biological factors. Results of a complex multifactorial study were analyzed. Fourteen groups of hamsters were treated with the following variables: single intralaryngeal instillation of N- methyl-N-nitrosourea (MNU) at 5 weeks of age; 15 weekly instillations of benzo(a)pyrene (BP) adsorbed on ferric oxide (Fe- 0) in saline (or of Fe-0 or saline alone); instillation was either only at the larynx or through the length of the trachea (abrasion of the tracheal epithelium induced reparative hyperplasia and inflammation). The three major determinants of the carcinogenic response were found to be MNU, BP and tracheal wounding, which was a key factor in the induction of carcinomas not only in the trachea but also in the intrapulmonary bronchi. In another hamster study, concurrent intraperitoneal injection of dimethylsulfoxide increased the incidence and severity and decreased the latency of respiratory tumors induced by intratracheal administration of BP/Fe-0 suspensions, more so when DMSO was given with BP, than 5 days after. Binding of BP in the respiratory tract after intratracheal administration of BP/Fe-0 was determined by quantitative autoradiography. In the hamster, it was high in the larynx, trachea and bronchi, and low in the terminal bronchioles. In the rat, binding was high in the trachea, intrapulmonary bronchi and terminal bronchioles, and low in the larynx and extrapulmonary bronchi. Maximum binding was reached within 48-72 hours in hamsters, but only within 3 hours in rats. Silica-induced pulmonary epithelial proliferative lesions were further studied for their pathogenetic relationship to granulomatous cell reaction and to cellular mediators of inflammation, in conjunction with long-term carcinogenesis studies of different forms of silica (quartz, cristobalite, tridymite).
