CHRONIC TOXICITY AND ONCOGENICITY INHALATION STUDY WITH VINYL-ACETATEIN THE RAT AND MOUSE

Vinyl acetate was evaluated for chronic toxicity and oncogenicity in m ale and female rats and mice in a 104-week study. Target concentration s were 0, 50, 200, and 600 ppm. The study included interim termination s at approximately 53 and 83 weeks and a group whose exposure was term inated at 70 weeks and allowed a 15-week recovery period. Over the cou rse of the exposures, body weight gain was consistently depressed in a ll 600 ppm groups and in the 200 ppm mice. Except for female rats of t he 600 ppm exposure group, recovery animals showed significant improve ments in weight gain relative to controls. There were no changes in he matological parameters of either species that could be unequivocally r elated to treatment. The only effect noted on clinical chemical parame ters during the study were decreases in blood glucose in the 600 ppm f emales. There were no adverse effects on survival in either species. I ncreases in lung weight were noted in rats and mice primarily in the 6 00 ppm groups. These changes were associated with bronchial exfoliatio n, macrophage accumulation, and fibrous plaques and buds extending int o the airway lumen, and bronchial/bronchiolar epithelial disorganizati on. The most significant histopathological changes were noted in the n asal cavity. In the olfactory epithelium of both rats and mice, the ma in nonneoplastic changes included epithelial atrophy, regenerative eff ects (squamous metaplasia and respiratory metaplasia of olfactory epit helium), basal cell hyperplasia, and epithelial nest-like infolds. No nonneoplastic changes were observed in the respiratory epithelium of r ats, while squamous metaplasia at the naso/maxilloturbinate region was prevalent in mice. Nonneoplastic changes were similar in the recovery groups. Oncogenic responses to vinyl acetate exposure were mainly con fined to the nasal cavity in rats and included endo- and exophytic pap illomas, squamous cell carcinoma, carcinoma in situ in olfactory regio ns, and endophytic papilloma in respiratory regions. Squamous cell car cinomas were also found either in areas normally covered by cuboidal e pithelium or areas of unknown origin. One squamous cell carcinoma was found in the larynx of a rat of the 600 ppm groups. One squamous cell carcinoma was found in the lung of a mouse of the 600 ppm group. The n o-observable-adverse-effect level for all effects was 50 ppm in both s pecies. The tumorigenic response appears to be nonlinear. The nonlinea r dose response and the unique nature of the rodent nasal cavity sugge st that specific risk extrapolation models should be developed for vin yl acetate. (C) 1994 Society of Toxicology.