Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust and a cohort mortality study with emphasis on lung cancer.

Two reports published in the Journal present the main results of the Diesel Exhaust in Miners Study (DEMS) (1,2). Although some of the results support the hypothesis that diesel exhaust (DE) exposure increases the risk of lung cancer, some aspects of the results and potential limitations in the DEMS should be taken into consideration in the interpretation of the evidence. In the analysis of continuous exposure variables (1), the hazard ratio for one unit of cumulative DE exposure (one μg/m3-y respirable elemental carbon [REC]) was 1.001 among underground miners and 1.02 (ie, 20-fold higher) among surface miners. Corresponding HRs for one logtransformed unit of average REC intensity were 1.26 and 2.60, respectively. The authors interpret these results as indicating a stronger carcinogenic potential of “aged” DE. In the corresponding analysis of the nested case–control study, however, the risk of lung cancer among surface miners was not consistently increased [Table 4 in (2): a nonstatistically significant dose-dependent decrease in risk was shown for two of the variables]. The DEMS authors interpret these results in the light of the small number of lung cancer cases and the low levels of DE exposure in this group. The reader, however, remains uncertain as to whether surface miners, compared with underground miners, have between twofold and 20-fold higher DE-related risk or no increased risk at all. These results cast doubts on the validity of exposure assessment in the DEMS (3). The anomalous result of a higher overall standardized mortality ratio (SMR) among surface miners than among underground miners in the cohort analysis is attributed to confounding by smoking. No clear evidence, however, is provided to support this interpretation. In the nested case–control study, the distribution of controls by smoking habit [Table 2 in (2)] suggests a lower amount of smoking in surface vs underground miners. Although controls are not representative samples of the two groups of miners, this finding contradicts the hypothesis of tobacco smoking being a stronger confounder for surface miners than for underground miners. More importantly, the odds ratios for tobacco smoking were different in the two groups of miners; whereas the odds ratios in surface workers were consistent with previous studies (4), those in underground miners were much lower. The latter result is hardly credible and puts in question the way information on tobacco smoking was collected and analyzed in the DEMS. The DEMS authors quote a number of previous studies of DE-exposed workers as supporting evidence of their results (5–11). However, the results of some of these studies only weakly support the hypothesis of a causal association [eg, (7)], and several welldesigned studies that did not support the authors’ conclusions were not quoted [see (12) for a detailed review]. More importantly, these previous studies included drivers, machine operators, and railroad workers whose circumstances of DE exposure were closer to those of surface miners than to those of underground miners in the DEMS, for whom there was no clear evidence of an effect of DE exposure. The results reported in the two articles do not match the plan of the statistical analysis outlined in the DEMS protocol (13). One particularly striking example concerns the use of lag in exposure–response analyses. In the study protocol, only a brief mention of lagged analyses is made: “In addition, lagged estimates of exposure will be explored to account for the latent period relating to lung cancer development” [(13), page 21], whereas strong emphasis is given to results of lagged analyses in both articles. The exclusion of miners with less than 5 years of employment and the exclusion of the category at highest exposure in dose– response analyses were not mentioned in the protocol, but the key results of the study are based on these exclusions. This is not to say that data-driven analyses should not be conducted and reported. When a study protocol is prepared, typically on the basis of limited data from a pilot study, it is impossible to figure out all the nuances and complexities of the final data, but to ignore systematically the plans outlined in the protocol is not good practice and may open the door to an arbitrary selection of results. At a minimum, the reports should have distinguished between a priori and a posteriori analyses. The DEMS authors state (2) that exposure to REC in the range of 2–6 μg/m3 over a lifetime would result in cumulative exposures comparable to those of underground miners with low exposures in their study and that these workers had at least a 50% increased lung cancer risk. It is unclear why the authors chose underground miners rather than surface miners for their extrapolation to non–occupational exposure because the latter group experienced circumstances of exposure more similar to that of the population at large than that of the underground miners. More importantly, the exposure reconstruction is subject to substantial uncertainties (3). If historical exposure estimates are systematically underestimated (a plausible scenario given that most available measurements were from recent years), the slope of a dose–response relation would be overestimated, even in case of nondifferential misclassification. The many assumptions involved in the DEMS study design, notably in the exposure reconstruction, and the anomalies in the results of key analyses require a careful interpretation and an in-depth quantitative bias analysis (14), but little along these lines is present in the two articles (1,2). Conclusions of the DEMS authors with respect to DE-related lung cancer risk in underground miners, other exposed workers, and the population at large do not seem to be supported by available results.