Meta-analyses of published epidemiological studies, 1979-2006, point to open causal questions in silica-silicosis-lung cancer research.

BACKGROUND AND OBJECTIVES: Following up on a previous meta-analysis of lung cancer risk in individuals without silicosis, we provide more detailed results of silica associated lung cancer risk in both silicotics and non-silicotics. The objective was to examine in depth whether current data allows to answer the pressing question "does silica cause lung cancer in the absence of silicosis"? METHODS: We updated earlier meta-analyses of silicosis and lung cancer and compared the results with our 2009 meta-analysis of risks in individuals without silicosis. We performed fixed (FE) and random (RE) effects meta-analyses, calculated heterogeneity statistics, stratified the study material, performed sensitivity analyses with modified study results and meta-regressions to detect effect modification. RESULTS: In silicotics, lung cancer risks were found to be doubled in 38 studies (FE: RR = 2.1; 95% CI = 2.0-2.3). In non-silicotics, eight studies without smoking adjustment suggested marginally elevated risks (FE: RR = 1.2; 95% CI = 1.1-1.3; RE: RR = 1.2; 95% CI =1.0-1.4) but three studies which were controlled for smoking showed null results (FE and RE: RR = 1.0; 95% CI = 0.8-1.3). Heterogeneity was substantial but could be linked to study characteristics, like sector of industry, and other second-level data in meta-regression. As no excess was observe dfor other smoking-related effects in studies ofllung cancer among non-silicotics, smoking was not considered to be an important confounder or modifier. CONCLUSIONn: Our meta-analyses further substantiate evidence of a strong association between silicosis and lung cancer. However, questions remain regarding lung cancer caused by silica in non-silicotics. Ideally, future investigations should consider the entire exposure-response range between silica exposure, silicosis development and lung cancer occurrence, and analyze data in terms of processes taking intermediate confounding into account.

Is exposure to silica associated with lung cancer in the absence of silicosis? A meta-analytical approach to an important public health question.

OBJECTIVE: This report investigates epidemiologically whether exposure to silica is associated with lung cancer risks in individuals without silicosis. METHODS: We searched the PubMed reference data base from 1966 through 1/2007 for reports of lung cancer in silica-exposed persons without and with silicosis. To explore heterogeneity between studies, a multi-stage strategy was employed. First, fixed-effect summaries (FES) and corresponding 95% confidence intervals (CI) for various combinations of studies were calculated, weighting individual results by their precision. The homogeneity of the contributing results was examined using chi(2) statistics. Where there was evidence of substantial heterogeneity, the CI around the FES was increased to take account of the between-study variability. Random-effect summaries and their CI for identical combinations of studies were also computed. Meta regression was used to explore interactions with covariates. To draw comparisons, parallel analyses were performed for non-silicotics and for silicotics. RESULTS: The persistence of a significant link between silicosis and lung cancer since the characterisation in 1997 of silica as a human carcinogen [our estimates of lung cancer relative risks (RR) exceeded unity in each of 38 eligible studies of silicotics published until 1/2007, averaging 2.1 in analyses based on both fixed and random effect models (95% CI = (2.0-2.3) and (1.9-2.3), respectively)] does not resolve our study question, namely whether exposure to silica levels below those required to induce silicosis are carcinogenic. Importantly, our detailed examination of 11 studies of lung cancer in silica-exposed individuals without silicosis included only three with data allowing adjustment for smoking habits. They yielded a pooled RR estimate of 1.0 [95% CI = (0.8-1.3)]. The other eight studies, with no adjustment for smoking habits, suggested a marginally elevated risk of lung cancer [RR = 1.2; 95% CI (1.1-1.4)], but with significant heterogeneity between studies (P approximately 0.05). CONCLUSIONS: Necessary further research should concentrate on silica exposures both above and below those that induce silicosis, so that the shape of the exposure-response relationship may be identified, with adjustments for likely confounding factors including silicosis. Time-dependent information on silicosis and on silica dust is required as well as the application of methods like G-estimation to answer the important public health question: Is silicosis a necessary condition for the elevation of silica-associated lung cancer risks?