Another Confounder in Lung Cancer Occupational Epidemiology — Diesel Engine Fumes

Researchers obviously need to be aware of, and control for, potential and known confounders.  In the context of investigating the etiologies of lung cancer, there is a long list of potential confounding exposures, often ignored in peer-reviewed papers, which focus on one particular outcome of interest.  Just last week, I wrote to emphasize the need to account for potential and known confounding agents, and how this need was particularly strong in studies of weak alleged carcinogens such as crystalline silica.  See Sorting Out Confounded Research – Required by Rule 702.  Yesterday, the World Health Organization (WHO) added another “known” confounder for lung cancer epidemiology:  diesel fume.

According to the International Agency for Research on Cancer (IARC), a division of the WHO, a working group of international experts voted to reclassify diesel engine exhaust as a “Group I” carcinogen.  IARC: Diesel engines exhaust carcinogenic (2012).  This classification means, in IARC parlance, that ” there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity.”  The Group was headed up by Dr. Christopher Portier, who is the director of the National Center for Environmental Health and the Agency for Toxic Substances and Disease Registry at the Centers for Disease Control and Prevention.  Id.

The reclassification removes diesel exhaust from its previous categorization as a Group 2A carcinogen, which is interpreted “as probably carcinogenic to humans.”  Diesel exhaust has been on a high-priority list for re-evaluation since 1998, as result of epidemiologic research from many countries.  The Working Group specifically found that there was sufficient evidence to conclude that diesel exhaust is a cause of lung cancer in humans, and limited evidence to support an association with bladder cancer.  The Group rejected any change in classification of gasoline engine exhaust from its current IARC rating as “possibly carcinogenic to humans. (Group 2B).”

Unlike other IARC Working Group decisions (such as crystalline silica), which were weakened by close votes and significant dissents, the diesel Group’s conclusion was unanimous.  The diesel Group appeared to be impressed by two recent studies of lung cancer in underground miners, released in March 2012.  One study was in a large cohort, conducted by NIOSH, and the other was a nested case-control study, conducted by the National Cancer Institute (NCI).  See Debra T. Silverman, Claudine M. Samanic, Jay H. Lubin, Aaron E. Blair, Patricia A. Stewart , Roel Vermeulen, Joseph B. Coble, Nathaniel Rothman, Patricia L. Schleiff , William D. Travis, Regina G. Ziegler, Sholom Wacholder, Michael D. Attfield, “The Diesel Exhaust in Miners Study: A Nested Case-Control Study of Lung Cancer and Diesel Exhaust,” J. Nat’l Cancer Instit. (2012)(in press and open access); and Michael D. Attfield, Patricia L. Schleiff, Jay H. Lubin, Aaron Blair, Patricia A. Stewart, Roel Vermeulen, Joseph B. Coble, and Debra T. Silverman, “The Diesel Exhaust in Miners Study: A Cohort Mortality Study With Emphasis on Lung Cancer,” J. Nat’l Cancer Instit. (2012)(in press).

According to a story in the New York Times, the IARC Working Group described diesel engine exhaust as “more carcinogenic than secondhand cigarette smoke.”  Donald McNeil, “W.H.O. Declares Diesel Fumes Cause Lung Cancer,” N.Y. Times (June 12, 2012).  The Times also quoted Dr. Debra Silverman, NCI chief of environmental epidemiology, at length.  Dr. Silverman, who was the lead author of the nested case-control study cited by the IARC Press Release, noted that her large study showed that long-term heavy exposure to diesel fumes increased lung cancer risk seven fold. Dr. Silverman described this risk as much greater than that thought to be created by passive smoking, but much smaller than smoking two packs of cigarettes a day.  She stated that “totally” supported the IARC reclassification, and that she believed that governmental agencies would use the IARC analysis as the basis for changing the regulatory classification of diesel exhaust.

Silverman’s nested case-control study appears to have been based upon careful diesel exhaust exposure information, as well as smoking histories.  The study also searched and analyzed for other potential confounders, which might be expected to be involved in underground mining:

“Other potential confounders [ie, duration of cigar smoking; frequency of pipe smoking; environmental tobacco smoke; family history of lung cancer in a first-degree relative; education; body mass index based on usual adult weight and height; leisure time physical activity; diet; estimated cumulative exposure to radon, asbestos, silica, polycyclic aromatic hydrocarbons (PAHs) from non-diesel sources, and respirable dust in the study facility based on air measurement and other data (14)] were evaluated but not included in the final models because they had little or no impact on odds ratios (ie, inclusion of these factors in the final models changed point estimates for diesel exposure by ≤ 10%).”

Silverman, et al., at 4.  The absence of an association between lung cancer and silica exposure is noteworthy in a such a large study of underground miners.

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