Cocarcinogenic and tumor promoting properties of asbestos and other minerals in tracheobronchial epithelium

Abstract

Epidemiologic and experimental studies document a synergistic effect of asbestos and smoking in the induction of bronchogenic carcinoma. Whereas the increased risk of these cancers in nonsmoking asbestos workers is 4-fold or less in comparison to nonsmokers in the general population, individuals who smoke and are exposed to asbestos occupationally have a 80-90 fold increased risk. The observations summarized above provide substantial insight into the interactions between asbestos and chemical carcinogens in cigarette smoke at the cellular level (Fig. 8). On the one hand, asbestos fibers and other particulates appear to act as condensation nuclei for PAH in the occupational setting or environment. They then facilitate the transfer of these chemical carcinogens into target cells, i.e., those destined to develop into tumor cells. As a result, the adduct formation of PAH to DNA is encouraged, an event linked intrinsically to initiation of transformation. Alternatively, asbestos appears to enhance and modulate the further development of initiated cells to neoplastic cells by a process resembling tumor promotion in mouse skin. In this regard, the most dramatic example illustrating the importance of asbestos in two-stage carcinogenesis is an experiment by Topping and Nettesheim. These investigators inserted the PAH, 7,12-dimethyl-benz(a)anthracene (DMBA) into the lumen of rat trachea which then were implanted on syngeneic animals. Subsequently, chrysotile asbestos was introduced, and grafts were removed for histology when palpable tumors occurred. At non-tumorigenic (i.e., initiating) amounts of DMBA, asbestos promoted the development of malignancies, although two neoplasms were observed with use of asbestos alone. Asbestos was not carcinogenic at these amounts, but a low incidence (5%) of squamous cell carcinoma was observed with use of chrysotile alone at much higher concentrations. These results suggest that asbestos is a weak carcinogen, but more importantly a promoter of carcinogenesis in the respiratory tract. Studies in this laboratory show striking effects of asbestos fibers on cell proliferation and differentiation although these responses appear to occur also after exposure of tracheobronchial cells to nonasbestos fibers including fiberglass.