Of Mice [and rats] and Men exposed to cigarette smoke

BrooklynDodger(s) request indulgence for a possible reposting. The Dodger(s) intend a posting on effects of silica exposure at 15 mg/M3, and also on the controversy over titanium dioxide and carbon black carcinogenicity. It's important to establish how resistent rats and mice are to particle carcinogenesis in the bioassay, and why that's important for risk assessment.

The goal is to parallelogramate exposures, man to mouse, epidemiology to bioassay.

Remarkably, it turns out that until 2004, there was not sufficient NTP evidence that cigarette smoke caused cancer in animals. Reproducibly, cigarette smoke caused cancer in hamsters, but larynx not lung cancer. Rats and mice were marginal. But, NTP requires two species. Without human evidence [imagine 1953], cigarettes would not have been "reasonably anticipated."

In the current climate, cigarettes would have been permitted to go into commerce [were they an industrial product] and might have been advocated as a lower toxicity alternative to cigars and pipes.

In 2004, and 2005, bioassays were finally published showing an association between cigarette smoke exposure and lung cancer in rats and mice. BrooklynDodger(s) note the effect level is about 200 mg/M3. Remember that number when people denigrate the bioassay of titanium dioxide at that level, or call 5 mg/M3 a "high" exposure to diesel particulate.

Second, the Dodger(s) notes the 30 month exposure of the rats or the "lifetime" exposure of the mouse. The Ramazzini Institute scientists have been criticized for lifetime exposure, rather than the standard 24 month [and industry advocated 18 month] in the US.

Next time we have an argument about unrealistic exposure levels, remember the cigarette studies.

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Mauderly, J. L.; Gigliotti, A. P.; Barr, E. B.; Bechtold, W. E.; Belinsky, S. A.; Hahn, F. F.; Hobbs, C. A.; March, T. H.; Seilkop, S. K., and Finch, G. L.

Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats. Toxicol Sci. 2004 Oct; 81(2):280-92.

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.

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Hutt, J. A.; Vuillemenot, B. R.; Barr, E. B.; Grimes, M. J.; Hahn, F. F.; Hobbs, C. H.; March, T. H.; Gigliotti, A. P.; Seilkop, S. K.; Finch, G. L.; Mauderly, J. L., and Belinsky, S. A.

Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways.

Carcinogenesis. 2005 Nov; 26(11):1999-2009.

Abstract: Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.

Hecht, S.S. (2005)

Carcinogenicity studies of inhaled cigarette smoke in laboratory animals: old and new. Carcinogenesis 26, 1488-92.

Abstract: A new study demonstrates that lifetime whole-body exposure of B6C3F1 mice to high doses of cigarette smoke robustly increases lung cancer incidence compared with sham exposed animals. This is the first study to demonstrate a strong effect of inhaled cigarette smoke on lung cancer in an animal model. This commentary attempts to put the new results in perspective with the existing literature on cigarette smoke inhalation studies in animals and discusses strengths, limitations and possible applications of available models.