Models of cancer - Tobacco Smoke

BrooklynDodger reminds the reader that the importance of mechanistic models is whether they suggest that high dose cancer risks persist at substantially lower exposure levels.

The best human example is tobacco smoke. Given the current close to consensus that environmental tobacco smoke causes cancer, it would appear that high to low dose persistance of risk exists for at least this carcinogen. For smokers, the risk is visible confirmed to the general population. For ETS exposed it's a risk compare to no ETS exposed lung cancer. This might be a 100 fold range of risk against at 1000 fold range of exposure.

Carcinogens are frequently dichotomized in two dichotomies: genotoxic and non-genotoxic; initiators and promoters. Genotoxicity is generally considered equivalent to initiation, and to have no threshold. There may be other mechanisms of initiation other than genotoxicity, receptor based, which also lack a threshold.

Promotors are imagined not to operate by a genotoxic mechanism - the metaphor is irritation or toxicity such as to promote cell proliferation. In turn, irritation is imagined to have a threshold.

So, here it's suggested the tobacco smoke is mostly a promoter. So, what carcinogenic insult is it promoting? The investigators suggest that it's promoting itself, but the environment contains many other lung carcinogens - diesel, silica for two ubiquitants.

The investigators conclude promotion is the primary mechanism for tobacco smoke. Since tobacco smoke has not threshold, then promotion may have no threshold either, in the only human systems in which it's been tested.

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Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1171-81.

Multistage carcinogenesis and lung cancer mortality in three cohorts.

Hazelton WD, Clements MS, Moolgavkar SH.


Fred Hutchinson Cancer Research Center, Public Health Sciences Division, M2-B500, 1100 Fairview Avenue North, Box 19024, Seattle, WA 98109-1024, USA. hazelton@fhcrc.org

Experimental evidence indicates that tobacco smoke acts both as an initiator and a promoter in lung carcinogenesis. We used the two-stage clonal expansion model incorporating the ideas of initiation, promotion, and malignant conversion to analyze lung cancer mortality in three large cohorts, the British Doctors' cohort and the two American Cancer Society cohorts, to determine how smoking habits influence age-specific lung cancer rates via these mechanisms. Likelihood ratio tests indicate that smoking-related promotion is the dominant model mechanism associated with lung cancer mortality in all cohorts. Smoking-related initiation is less important than promotion but interacts synergistically with it. Although no information on ex-smokers is available in these data, the model with estimated variables can be used to project risks among ex-smokers. These projected risks are in good agreement with the risk among ex-smokers derived from other studies. We present 10-year projected risks for current and former smokers adjusted for competing causes of mortality. The importance of smoking duration on lung cancer risk in these cohorts is a direct consequence of promotion. Intervention and treatment strategies should focus on promotion as the primary etiologic mechanism in lung carcinogenesis.