FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM

Abstract

Inhalation exposure of rats to 600 ppm vinyl acetate monomer produced nasal papillomas, squamous-cell carcinomas, and carcinoma in situ in rats. These tumors had a very long latency to onset, appearing only at terminal sacrifice. Nonneoplastic lesions were largely confined to the olfactory regions lining the dorsal meatus and mainly consisted of epithelial degeneration and basal-cell hyperplasia. The no-observed-adverse-effect level (NOAEL) for these effects was 50 ppm. Vinyl acetate is metabolized by nasal carboxylesterase to acetaldehyde, a DNA-protein cross-linking agent, and acetic acid, a cytotoxicant. Both vinyl acetate and acetaldehyde are clastogenic. These observations support the notion that multiple stages are likely involved in the mechanism of vinyl acetate carcinogenesis. The purpose of these experiments was to study the role of induced cell proliferation in the early changes in nasal epithelium that lead to cancer. Rats were exposed to 0, 50, 200, 600, or 1000 ppm vinyl acetate for 1, 5, or 20 exposures and killed 18 h after the last exposure for evaluation of nasal epithelial cell proliferation. In respiratory epithelium, cell proliferation rates were elevated after a single exposure, but returned to control levels after 5 and 20 exposures. In olfactory epithelium, cell proliferation rates also increased after an initial exposure and subsided after 5 exposures but then rebounded with a second wave of proliferation following 20 exposures. Histopathological changes were largely confined to the olfactory epithelium. The NOAEL for all effects was 200 ppm. These results demonstrate the capability for distinctly different responses between respiratory and olfactory epithelium. The complex nature of the responses further suggests a role for cellular and biochemical adaptation in the toxic responses to vinyl acetate exposure.