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ToxSci Advance Access published online on June 22, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh203
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received April 6, 2004
Accepted June 11, 2004

Carcinogenicity

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

Joe L. Mauderly 1*, Andrew P. Gigliotti 1, Edward B. Barr 1, William E. Bechtold 1, Steven A. Belinsky 1, Fletcher F. Hahn 1, Charles A. Hobbs 1, Thomas H. March 1, Steven K. Seilkop 2, Gregory L. Finch 3

1 Lovelace Respiratory Research Institute, Albuquerque, NM
2 SKS Consulting Services, Siler City, NC
3 Pfizer, Groton, CT

* To whom correspondence should be addressed. E-mail: jmauderl{at}lrri.org.


  Abstract

An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-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 = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m3 , or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the 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 = 14%; LS = 6%; and C = 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 = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.

Keywords: Lung cancer, nasal cancer, tumors, neoplasia, cigarette smoke, inhalation, rats
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