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Silica and Lung Cancer: When Is Enough Evidence Enough?

Stayner, Leslie

doi: 10.1097/01.ede.0000249538.78415.58

From the University of Illinois at Chicago School of Public Health, Chicago, IL.

Correspondence: Leslie Stayner, Division of Epidemiology and Biostatistics, University of Illinois at Chicago School of Public Health (M/C 923), 1603 West Taylor Street, Room 971, Chicago, IL 60612. E-mail:

The case–control study presented in this issue of Epidemiology by Cassidy et al1 provides striking evidence of an association between occupational exposure to crystalline silica and lung cancer. The study not only demonstrated an overall positive association, but also very strong evidence for an exposure–response relationship. These findings are not themselves very surprising or novel given that similar findings have been reported in numerous previous studies. What makes these findings most remarkable is that they come from a population-based case–control study. This study design has rarely been capable of demonstrating convincing evidence for associations for exposures to occupational carcinogens due to low power and poor exposure classification stemming from their reliance on self-reported exposures. These studies have been of particularly limited use in demonstrating exposure–response relationships. In large part the success of this study is due to the unusually detailed questionnaires on work histories that were used. In addition to collecting complete work histories, the study included “specialized questionnaires” for specific jobs designed to yield additional information on silica and the 69 other occupational exposures. The study's exposure assessment was clearly also enhanced by the detailed review by a group of industrial hygiene experts. Overall this study, along with the work of Siemiatycki,2 provides a model for how population-based studies can be useful for studying occupational exposures and diseases.

The authors are somewhat circumspect in their conclusions as most epidemiologists are prone to be. They state that, “Overall, these results are consistent with a causal interpretation of the association between exposure to silica and lung cancer.” However, this tentativeness in their conclusions may be too restrained. After all, the International Agency for Research on Cancer (IARC),3 the National Institute for Occupational Safety and Health (NIOSH),4 and the National Toxicology Program (NTP)5 have all concluded that exposure to respirable crystalline silica is a known human carcinogen. (IARC and NIOSH qualified this conclusion as being carcinogenic in occupational settings.) The authors note that, despite these pronouncements by authoritative organizations, some authors have disagreed with these conclusions6 and that a controversy still persists because not all studies have been consistent in observing an association or an exposure–response relationship or have adequately controlled for potential confounding exposures. However, how credible are these arguments against a causal interpretation?

Although most epidemiologic studies have observed a positive association between exposures to crystalline silica and lung cancer,7 there have been some notable exceptions. For example, studies of coal miners who are exposed to crystalline silica have not generally demonstrated an increased lung cancer risk,8,9 which may be explained by the coating of silica in mines by clay. It is likely, as noted by IARC, that the carcinogenicity of crystalline silica “may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biologic activity.”3 In fact, the situation with silica may be viewed as quite analogous to that for asbestos, which has also not been consistently associated with an increased risk of lung cancer in all studies. For example, asbestos exposure has not generally been observed to be associated with an excess risk of lung cancer in studies of mechanics involved in asbestos brake repair.10

Evidence for an exposure–response relationship between silica and lung cancer has been observed in most, but not all, of the studies that have been able to quantify exposure. This pattern is not unusual in occupational epidemiology in which studies often fail to find a relationship simply because of the lack of adequate exposure information or because some studies have very low exposures. Steenland et al11 have demonstrated strong evidence for an exposure–response relationship between crystalline silica and lung cancer risk in a pooled analysis of 10 cohort studies of occupationally exposed workers. The study by Cassidy et al1 in this journal provides further evidence for an exposure–response relationship.

Of course, potential uncontrolled confounding by risk factors for lung cancer is an argument that can never be fully dismissed in epidemiologic studies. Of particular concern in occupational cohort studies is the difficulty in adequately controlling for confounding by cigarette smoking. Several of the cohort studies that adjusted for smoking have demonstrated an excess of lung cancer, although the control for smoking in many of these studies was less than optimal. The results of the article by Cassidy et al1 presented in this journal appear to have been well controlled for smoking and other workplace exposures. It is quite implausible that residual confounding by smoking or other risk factors for lung cancer in this and other studies could explain the observed excess of lung cancer in the wide variety of populations and study designs that have been used. Also, it is generally considered very unlikely that confounding by smoking could explain the positive exposure–response relationships observed in these studies, which largely rely on comparisons between workers with similar socioeconomic backgrounds.

Have we reached a point at which there is enough evidence to conclude that, at least under some circumstances, exposure to crystalline silica is causally associated with an increased risk of lung cancer? This is a difficult question for epidemiologists to answer given the admonitions of many authors such as Rothman and Greenland12 that it is impossible to absolutely prove anything in epidemiology, or for that matter in any observational science. Nonetheless, pragmatically speaking, I think we all have become comfortable with accepting certain hypotheses as causal, eg, the hypothesis that cigarette smoking and asbestos are causal risk factors for lung cancer. The question is really whether or not as a scientific community we have reached the “tipping point” for concluding that the evidence for a causal relationship between silica and the risk of lung cancer is compelling. I personally believe that the answer to this question is “yes,” but a few may still disagree, as was the case until recently with smoking.

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LESLIE STAYNER is Professor of Epidemiology and Director of Epidemiology and Biostatistics at the University of Illinois at Chicago, School of Public Health. He previously worked for the National Institute for Occupational Safety and Health where he conducted research on numerous occupational carcinogens, including asbestos, cadmium, chromium, dinitrotoluene, diesel exhaust, ethylene oxide, formaldehyde, and silica, and on methods for risk assessment.

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© 2007 Lippincott Williams & Wilkins, Inc.