Nonlinear dose-response relationship between radon exposure and the risk of lung cancer: evidence from a meta-analysis of published observational studies.

Although radon exposure (RE) has been confirmed to increase the risk of lung cancer (LC), questions remain about the shape of the dose-response relationship between RE and the risk of LC. We carried out a dose-response meta-analysis to investigate and quantify the potential dose-response association between residential and occupational exposure to radon and the risk of LC. All cohort and case-control studies published in English and Chinese on Embase, PubMed, and China National Knowledge Infrastructure (CNKI) digital databases through November 2013 were identified systematically. We extracted effect measures (relative risk, odds ratio, standardized mortality ratio, standardized incidence ratio, or standardized rate ratio) from individual studies to generate pooled results using meta-analysis approaches. We derived meta-analytic estimates using random-effects models taking into account the correlation between estimates. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to carry out a dose-response meta-analysis. Stratified analysis, sensitivity analysis, and assessment of bias were performed in our meta-analysis. Sixty publications fulfilling the inclusion criteria for this meta-analysis were finally included. Occupational RE was associated with LC [risk ratio 1.86, 95% confidence interval (CI)=1.67-2.09; I²=92.2%; 27 prospective studies], for pooled risk estimate of the: standardized mortality ratio [2.00 (95% CI=1.82-2.32)]; standardized incidence ratio [1.45 (95% CI=1.20-1.74)]; relative risk [2.10 (95% CI=1.64-2.69)]. In a subgroup analysis of uranium miners and residents exposed to occupational uranium, the summary risk was 2.23 (95% CI=1.86-2.68) and 1.23 (95% CI=1.05-1.44). The overall meta-analysis showed evidence of a nonlinear association between RE and the risk of LC (P(nonlinearity)<0.014); in addition, the point value of residential radon also improved the results quantitatively, where odds ratios were 1.11 (95% CI=1.07-1.15) and 1.21 (95% CI=1.14-1.29) when the radon concentration was at the point of 100 and 200 Bq/m³ compared with the lowest. For 17 prospective studies with at least three categories of occupational cumulative radon dose, the dose-risk model estimated a risk ratio of 1.26 (95% CI=1.21-1.30) for 100 working level months and 1.51 (95% CI=1.38-1.65) for 200 working level months, respectively. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to alter these results markedly. This meta-analysis shows a nonlinear dose-response association between environmental RE and the risk of LC. This increased risk is particularly apparent when the cumulative exposure to radon is well beyond that resulting from exposure to the recommended limit concentration for a prolonged period of time.