Early cell proliferative and cytotoxic effects of phenacetin on rat nasal mucosa

The oral analgesic drug phenacetin is known to cause nasal and renal tumors in rats when fed in the diet for 2 years at 1.25 or 2.5%. Long-term exposure to chemicals at cytotoxic concentrations may lead to tumor formation secondary to chronic restorative cell proliferation. In the present experiments, cell proliferative and cytotoxic effects on the nasal mucosa were examined after short-term phenacetin administration. One week of daily gavage treatment of rats with phenacetin at doses comparable to those used in oncogenicity studies resulted in dose-related increases in DNA synthesis in both respiratory and olfactory mucosa. The increase in respiratory mucosa was due to inflammatory cells in the lamina propria and not proliferation of the respiratory epithelial cells. This observation demonstrates a potentially serious artifact in analytical approaches to DNA synthesis using tissue homogenates. One or two weeks of daily phenacetin treatment resulted in degenerative changes in the olfactory epithelium and necrosis of Bowman's glands. These changes were associated with increases in cell proliferation only in the olfactory epithelium. Two-week daily gavage treatment of rats with phenacetin at 100, 625, or 1250 mg/kg/day increased olfactory epithelial cell replication 62.4, 174, or 763%, respectively. The dose-response relationship for cell proliferation was similar to that of nasal tumor formation. These data suggest that the primary site of phenacetin toxicity within the nose is the olfactory mucosa, with restorative cell proliferation being confined to the epithelial cell layer. The data indicated that early cell proliferative responses may be important in the genesis of nasal tumors and that cell proliferation data may be useful for setting dose levels for oncogenicity studies.