Chronic Inhalation Exposure to Mainstream Cigarette Smoke Increases Lung and Nasal Tumor Incidence in Rats

An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for researchoncarcinogenicmechanisms,smokecomposition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n 5 81 to 178/gender) were exposed whole-body 6h/day,5days/weekforupto30monthstosmokefrom1R3research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m 3 , or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated bylightmicroscopy.Aslightreductionofsurvivalsuggestedthatthe HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS 5 14%; LS 5 6%; and C 5 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS 5 6%, LS 5 0.3%, C 5 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.