title: Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats.
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/m(3), 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.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA. jmauderl@lrri.org
authors.forename: Joe L
authors.initials: JL
authors.lastname: Mauderly
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Gigliotti
authors.forename: Edward B
authors.initials: EB
authors.lastname: Barr
authors.forename: William E
authors.initials: WE
authors.lastname: Bechtold
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Fletcher F
authors.initials: FF
authors.lastname: Hahn
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hobbs
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Steven K
authors.initials: SK
authors.lastname: Seilkop
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Finch
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003062:Codon / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D011905:Genes, ras / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology*; D008297:Male; D009093:Mucus / Q000378:metabolism; D009297:Nasal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009669:Nose Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012906:Smoke / Q000032:analysis*; D012907:Smoking / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D003062:Codon; D012906:Smoke