TOXICOLOGY AND CARCINOGENESIS STUDIES OF OZONE AND OZONE 4-(N-NITROSOMETHYLAMINO)-1-(3-PYRIDYL)-1-BUTANONE IN FISCHER-344 N RATS/

The purpose of this study was to evaluate the toxicity and potential c arcinogenicity or cocarcinogenicity of ozone exposure in rats. Fischer -344/N (F-344/N) rats were exposed 6 hr/day, 5 days/wk, to 0, 0.12, 0. 5, or 1.0 ppm ozone by inhalation for 2-yr and lifetime exposures. The cocarcinogenicity study included subcutaneous administration of 0, 0. 1, or 1.0 mg/kg body weight of 4-(N-nitrosomethylamino)-1-(3-pyridyl)- 1-butanone (NNK) and inhalation of 0 or 0.5 ppm ozone to male rats. NN K was administered by subcutaneous injections 3 times per week for the first 20 wk with ozone inhalation exposure. The ozone inhalation expo sure was for 2 yr (104 wk), including the first 20 wk of NNK treatment and continuing for 84 wk after the last NNK injection. Ozone exposure caused a concentration-related increase in inflammation of the centri acinar region of the lung. There was also increased fibrosis and an ex tension of the bronchiolar epithelium in these centriacinar regions to involve the proximal alveoli. There was no increased incidence of neo plasms at any site, including the lung, that was associated with ozone exposure. Rats administered 1.0 mg/kg body weight NNK alone had an in creased incidence of bronchiolar/alveolar neoplasms, but this effect w as not enhanced by ozone exposure. Ozone exposure for 2 yr and lifetim e was associated with site-specific toxic alterations in the nasal pas sage and lung similar to those previously described for short-term exp osures. While there was significant attenuation of the pulmonary lesio ns as compared to short-term exposures, lesions persisted in the lifet ime study and there was evidence of a mild progressive fibrosis. We co nclude that under the conditions of these studies: (a) ozone exposure is not carcinogenic to either male or female F-344/N rats, (b) ozone d oes not enhance the incidence of pulmonary neoplasms in F-344/N rats e xposed to a known pulmonary carcinogen (NNK), and (c) mild site-specif ic toxic lesions characteristic of ozone exposure persist in the nasal passage and lung throughout the lifetime of the rat with continued oz one exposure.