by Victoria A. Fisher, M.P.H.
After 20 years of research, results from the landmark Diesel Exhaust in Miners Study were published in March in the Journal of the National Cancer Institute. Findings from two complementary papers, a cohort mortality study and a nested case-control study of lung cancer, provide evidence that exposure to diesel exhaust may cause lung cancer in humans. This is the first report of a significant exposure-response relationship for diesel exposure and lung cancer based on quantitative estimates of historical diesel exposure with adjustment for smoking and other potential confounders. The collaborative effort between NCI and the National Institute for Occupational Safety and Health (NIOSH) was led by Debra T. Silverman, Sc.D., Chief of the Occupational and Environmental Epidemiology Branch (OEEB), and Dr. Michael Attfield, formerly of NIOSH.
Researchers first raised the possibility that diesel exhaust might cause cancer in humans in 1955, after discovering components of diesel exhaust that were known to cause tumors in experimental animals. In 1989, the International Agency for Research on Cancer (IARC) classified diesel exhaust as a “probable” carcinogen based primarily on data from animal studies; data from humans were considered too limited to establish causality. Occupational exposure to diesel exhaust is common among certain groups, including miners, mechanics, transportation workers, and other operators of diesel-powered equipment. Exposure is not limited to workers, however; diesel exhaust is ubiquitous in cities, and people who live near highways, ports, and rail yards may have considerable exposure to diesel exhaust throughout their lives.
Since the 1980s, more than 35 studies have examined the relationship between lung cancer risk and diesel exhaust. Although most of these studies suggested a modest association between diesel exhaust exposure and lung cancer, few quantified exposure levels or adjusted for smoking in their analyses. These limitations of previous studies led Dr. Silverman and her colleagues to conclude that a need existed for further research on the carcinogenicity of diesel exhaust.
“It was vitally important to undertake a large study of diesel exhaust and lung cancer based on a quantitative assessment of historical exposure, taking into account smoking and other potentially relevant factors in order to estimate lung cancer risk,” Dr. Silverman said.
The Diesel Exhaust in Miners Study included four components: (1) an exposure monitoring study conducted from 1998 to 2001 (led by NIOSH), (2) a retrospective exposure assessment (led by NCI), (3) a retrospective cohort mortality study of 12,315 workers at eight non-metal mines (led by NIOSH), and (4) a nested case-control study of lung cancer deaths in the cohort (led by NCI). The researchers chose to investigate exposure to diesel exhaust in underground mines because high levels of diesel exhaust from heavy equipment build up in the enclosed underground mining environment. Non-metal mines (i.e., mines that produce limestone, potash, salt, and trona) were selected to avoid confounding exposures to other potential carcinogens, such as radon.
The researchers characterized current and historical exposures to diesel exhaust, represented by respirable elemental carbon, and estimated personal exposures for each worker in the cohort. They based their estimates on thousands of measurements from exposure surveys at each mining facility, past Mine Safety and Health Administration enforcement surveys, and information from company records and interviews with long-term workers. In addition, the researchers reviewed records of inventories of working diesel equipment at each mine and ventilation data over time. The exposure assessment process is described in five papers published in the Annals of Occupational Hygiene (October 2010 and March 2012).
In the case-control study, the researchers interviewed subjects or next of kin about smoking behavior and other lung cancer risk factors, such as employment in other high-risk occupations and history of nonmalignant respiratory disease. Several DCEG scientists assisted with the case-control study. Jay H. Lubin, Ph.D., senior investigator (now retired) in the Biostatistics Branch (BB), conducted the continuous modeling of exposure data; Nathaniel Rothman, M.D., M.P.H., M.H.S., senior investigator in OEEB, collaborated on the analysis and mechanistic interpretations of the smoking-diesel interaction; CDR Claudine M. Samanic, Ph.D. (OEEB), assisted with the data collection and conduct of the study; and Sholom Wacholder, Ph.D., senior investigator in BB, contributed to the case-control design and analysis. In addition, Aaron E. Blair, Ph.D., M.P.H., a scientist emeritus of OEEB, offered general study guidance.
The cohort study, under the direction of Dr. Attfield, found that the risk of lung cancer among heavily exposed underground workers was five times the risk among workers in the lowest exposure category.
The case-control study, which was led by Dr. Silverman, confirmed the lung cancer findings from the cohort study and had the added strength of smoking histories. After taking smoking and other risk factors into account, the researchers found a threefold risk of lung cancer overall and about a fivefold risk among heavily exposed underground workers. The researchers estimated risk for several exposure metrics, with cumulative diesel exhaust exposure lagged 15 years yielding the strongest gradient in lung cancer risk.
For never smokers and light-to-moderate smokers, the risk of lung cancer death increased with more diesel exhaust exposure. Non-smokers with the highest level of diesel exposure were seven times more likely to die from lung cancer than non-smokers in the lowest exposure category. In contrast, among miners who were heavy smokers, the risk of lung cancer death decreased with increasing levels of exposure.
“Little is known about the interaction of smoking with diesel exhaust,” Dr. Silverman said. “The qualitative interaction we observed has not been reported previously and will require replication.”
The researchers offered possible explanations for the tapering off of risk at high levels of diesel exhaust exposure. Heavy smokers might be more likely to clear diesel exhaust particulate matter from their lungs than non-smokers, a phenomenon that has been reported previously among coal miners who smoke. Carcinogens in diesel exhaust and cigarette smoke also might operate along the same metabolic pathway in the body, competing with each other and saturating the pathway and, thus, diminishing the effects of both components.
The Diesel Exhaust in Miners Study has been described as groundbreaking—not only because of its contribution to science but also because of the scientific and other challenges that the researchers overcame during the 20-year study period. For example, the careful exposure assessment and sophisticated methods development took years. “This study represents an enormous team effort,” Dr. Silverman said. “Many people provided invaluable input during the different stages of the study.”
From the very beginning, the study had high visibility because of its potential impact on regulatory policy, which led to significant legal and political challenges. As early as the mid-1990s, the researchers faced delays resulting from lawsuits from a coalition of companies representing mining industry interests.
“Despite the many challenges throughout the duration of this study, I’m proud to say that we persevered and finally published our findings,” Dr. Silverman said.
Although the researchers studied miners with very high levels of exposure to diesel exhaust, the results may be applicable to other workers with similar levels of diesel exposure and may extend to people living in urban areas with high diesel exhaust levels. Environmental exposures to average respirable elemental carbon levels in the range of 2 to 6 μg/m3 over a lifetime, as is typical in some highly polluted cities, are similar to the cumulative exposures experienced by the underground miners with the lowest exposures in the study. Even underground workers with low exposure levels experienced about a 50 percent increase in lung cancer risk.
The publication of the study results was timely because it preceded reviews by IARC and the NIH National Toxicology Program to reassess the health risks associated with diesel exhaust exposure. In June, IARC announced that it had reclassified diesel exhaust as a Group 1 human carcinogen, a category that IARC uses when sufficient evidence is available indicating that a substance is carcinogenic to humans. The NIH National Toxicology Program will hold a review of diesel exhaust later in 2012.