Is residual confounding a reasonable explanation for the apparent protective effects of beta-carotene found in epidemiologic studies of lung cancer in smokers?

The results of three randomized trials of beta-carotene supplementation for the prevention of lung cancer among smokers are in contradiction to a large body of epidemiologic evidence for the reduction of risk of lung cancer among smokers with higher intake and/or higher serum levels of beta-carotene. Complicating this issue are widely noted negative associations between tobacco use and intake or serum levels of beta-carotene. Although observational studies attempt to control for reported smoking histories, the accuracy of self-reported smoking is uncertain; correlations as low as 0.5 between reported and true smoking exposure are not inconsistent with studies of biomarkers of cigarette exposure. The authors developed a simple statistical model for random errors in reported smoking (relative to true tobacco exposure) and assumed a modest (inverse) relation between true tobacco exposure and serum beta-carotene. Calculations from this model, combined with a model for lung cancer contemplated by Doll and Peto (J Epidemiol Community Health 1978;78:303-13), suggest that biases in assessment of smoking exposure between smokers with low versus high beta-carotene intake may plausibly explain much or all of the observed protective effect of high beta-carotene levels. Appropriate cohort studies of lung cancer in smokers, utilizing biomarkers of smoking, are needed and are presently ongoing.