diesel exhaust exposure, as based on job classification codes. They used two ... able from: http://pubs.healtheffects.org/view.php?id=7 1999. 7. Pronk A, Coble J, ...
Correspondence Diesel Motor Exhaust and Lung Cancer: Additional Perspectives To the Editor: Olsson and coworkers (1) pooled data from 11 lung cancer casecontrol studies from Europe and Canada, yielding a population of approximately 13,300 cases plus approximately 16,300 control subjects (w 81% men; median age, 64 yr), and they examined diesel exhaust exposure, as based on job classification codes. They used two exposure levels (low ¼ 1, high ¼ 4), and these were multiplied by job duration to get quartiles of cumulative exposure. The authors reported “a small consistent association between occupational exposure to [diesel motor exhaust] DME and lung cancer” (highest exposure quartile vs. unexposed; odds ratio, 1.31; 95% confidence interval, 1.19–1.43) and concluded “our results suggest that DME exposure may contribute to the current lung cancer burden.” We believe additional context and perspective are helpful here, noting that a number of careful analyses conclude that available data do not quantitatively link occupational DME exposure to increases in lung cancer (2, 3). For example, in a much larger cohort study (4) (w 55,000 railroad workers), the authors concluded: “Although we originally reported that lung cancer risk increased with increasing years of work in diesel-exposed jobs, subsequent reanalyses of these data, with adjustment for attained age, indicated decreased risk with more years worked.” Likewise, an exposure–response trend is not apparent for occupations with widely differing DME exposures (e.g., underground miners vs. truckers) (2, 5). An expert panel that reviewed a body of occupational data (6) concluded that the epidemiologic data were not consistent with a steadily increasing cumulative DME exposure being associated with increasing lung cancer risk. They noted that many studies suffered from inadequate exposure assessment, incomplete adjustment for smoking, unmeasured confounding variables (e.g., other job category differences), and latency periods being too short. The study by Olsson and colleagues (1) is also subject to interpretational caveats. DME exposure was inferred, and no actual DME concentrations were considered. The authors assigned miners the same exposure level as railway and road vehicle loaders, seemingly at odds with what is known about relative exposure (7). The job exposure matrix did not allow for changes in diesel engine technology over time. There was adjustment for smoking, but age at smoking initiation seems not to have been considered. Interestingly, they did not find an exposure–response trend in “neversmokers” or in women. Odds ratios decreased when smoking adjustments were made, and it is possible that corrections for smoking were incomplete. It is unclear how the authors allowed for sufficient latency between DME exposure and lung cancer, which is estimated to have a latency period of 15 or more years. Finally, dramatic improvements in diesel engine technology since 1998 have reduced DME emissions by about 100-fold. New ultra-clean on-highway and nonroad diesel vehicles available today are equivalent to the best natural gas and gasoline vehicles (8). Author Disclosure: W.B.B. and T.W.H. are both employed by Navistar, Inc.
William B. Bunn, M.D. Thomas W. Hesterberg, Ph.D. Navistar Warrenville, Illinois
References 1. Olsson AC, Gustavsson P, Kromhout H, Peters S, Vermeulen R, Bru¨ske I, Pesch B, Siemiatycki J, Pintos J, Bru¨ning T, et al. Exposure to diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada. Am J Respir Crit Care Med. 2011;183: 941–948. 2. Hesterberg TW, Bunn W, Chase GR, Valberg PA, Slavin TJ, Lapin CA, Hart GA. A critical assessment of studies on the carcinogenic potential of diesel exhaust. Crit Rev Toxicol 2006;36:727–776. 3. Gamble J. Lung cancer and diesel exhaust: acritical review of the occupational epidemiology literature. Crit Rev Toxicol 2010;40:189–244. 4. Garshick E, Laden F, Hart JE, Rosner B, Smith TJ, Dockery DW, Speizer FE. Lung cancer in railroad workers exposed to diesel exhaust. Environ Health Perspect 2004;112:1539–1543. 5. Valberg PA, Watson AY. Comparative mutagenic dose of ambient diesel engine exhaust. Inhal Toxicol 1999;11:215–228. 6. Health Effects Institute. Diesel emissions and lung cancer: epidemiology and quantitative risk assessment. (Accessed 7/20/2011.) Available from: http://pubs.healtheffects.org/view.php?id¼7 1999. 7. Pronk A, Coble J, Stewart PA. Occupational exposure to diesel engine exhaust: a literature review. J Expo Sci Environ Epidemiol 2009;19: 443–457. 8. Hesterberg TW, Lapin CA, Bunn WB. A comparison of emissions from vehicles fueled with diesel or compressed natural gas. Environ Sci Technol 2008;42:6437–6445.
From the Authors: We thank the Journal for the opportunity to respond to the letter by Hesterberg and Bunn concerning our article. Hesterberg and Bunn provide “additional perspectives” on our findings and suggest that our study was subject to interpretational caveats. We appreciate the additional perspectives provided, but take issue with the suggestion that our study was wrongly interpreted. Based on the Health Effects Institute special report from 1999, Hesterberg and Bunn argue that many studies on DME and lung cancer suffer from inadequate exposure assessment, incomplete adjustment for smoking, unmeasured confounding variables, and latency periods being too short (1). While we agree that many previously conducted studies had such limitations, we believe that our study addressed many of these issues and therefore is an important contribution to the body of evidence on DME exposure and lung cancer risk. To overcome inadequate exposure assessment in previous studies, limiting exposure–response analyses, we estimated DME exposure semiquantitatively and independently from the case-control studies by assigning jobs no, low, or high exposure to DME. Indeed, miners and railway and road vehicle loaders were both grouped in the high-exposure category. This does not assume that they have the same exposure level, but merely reflects that both occupations have significantly higher DME exposures than, for instance, drivers whose DME exposure was classified as low. Based on this classification, we demonstrated a clear association with duration of exposure among subjects in both the low and in the high exposure groups and with measures of cumulative exposure. Our exposure classification will have suffered from a certain amount of error, as would every exposure assessment method. However, measurement error would have been nondifferential, as exposure assignment was done independently of case/control status. In most scenarios, such a nondifferential and independent misclassification of subjects would have led to an underestimation of risk but would not have introduced a false positive finding.
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To address potential confounding by smoking, all studies in SYNERGY have collected detailed data on individual smoking history. In our study, adjustment for cigarette pack-years and time-since-quitting provided the model that fitted the data best. Moreover, Leffondre´ and colleagues have noted that after adjustment for these two variables, age-at-initiation does not independently contribute to lung cancer risk (3). Adding age-at–cigarette initiation in the model resulted in an OR of 1.29 (95% CI, 1.18– 1.41) for the highest quartile of cumulative DME exposure among all subjects. Hesterberg and Bunn also noted that we did not observe a statistically significant exposure–response trend among never-smokers and women. As indicated in our paper, this is most likely the result of relatively small sub-sample sizes. However, the lung cancer risks in the highest cumulative exposure category in never-smokers (OR, 1.26; 95% CI, 0.90–1.78) and in women (OR, 1.58; 95% CI, 0.96–2.59) support our overall results. Regarding other potential confounding, the SYNERGY study has complete lifetime occupational history, which allowed us to adjust for ever-employment in previous or subsequent jobs entailing exposure to known lung carcinogens (4, 5). This concerned 12% of cases and 8% of controls. Further, analyses without these subjects did not change the overall results, and we therefore believe that unmeasured occupational confounding was not an important issue in our analyses. Since DME exposure represents a mixture of compounds, which could consist of tumor initiators and promoters and/or progressors, we were reluctant to specify a priori a certain latency period (6). Nevertheless, upon the suggestion of a 15-year latency period for the carcinogenicity of DME, we repeated our analyses with a 15-year lag. Results were very similar to our un-lagged results; for example, the OR for the highest quartile of cumulative DME exposure among all subjects was 1.29 (95% CI, 1.17–1.41), with P value , 0.001 for trend test. Hesterberg and Bunn cite the study by Garshick and coworkers (2) as being more informative given the larger size of the cohort. This perspective is misleading, as the power of a study mostly is driven by the number of cases and prevalence of exposure. We note that our analyses were based on more than 5,600 exposed lung cancer cases, compared with less than 3,400 in the study by Garshick and colleagues. More important, however, is that both studies had ample power to address low risks of DME and that both studies reported an overall increased risk of lung cancer among exposed subjects. Garshick and coworkers attributed the fact that no association with duration was found to a “Healthy Worker Effect,” to which our study would have been less prone, given that we had complete occupational histories. In summary, we observed a positive exposure–response association between lung cancer risk and intensity of DME exposure as well as for duration of exposure, and also after adjustment for smoking and exposure to other occupational lung carcinogens. As Hesterberg and Bunn have pointed out, diesel engine technology has changed since the 1990s. Most of our cases were recruited between 1990 and 2000, and as such our results pertain to DME exposures that would have occurred mostly prior to the 1990s. However, many old diesel engines are still in use, notably in less-developed countries, but also in Europe and North America (7). Finally, given that mechanisms and specific constituents in DME responsible for the putative increase in lung cancer risk are unknown, it is difficult to estimate what the health effect of newer diesel engines might be. This will need to be addressed in future studies. Author Disclosure: H.K. has received an industry-sponsored grant from the Industrial Minerals Association. S.P., P.G., I.B., J.S., B.P., and T.B. have received industry-sponsored grants from EUROBITUME, Deutscher Asphaltverband, Concawe, Zentralverband des deutschen Dachdeckerhandwerks and Aksys, and Industrieverband Bitumen-, Dach-, and Dichtungsbahnen. None of the other
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authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Ann Olsson, Ph.D. International Agency for Research on Cancer Lyon, France and Karolinska Institutet Stockholm, Sweden Roel Vermeulen, Ph.D. Hans Kromhout, Ph.D. Susan Peters, M.Sc. Institute for Risk Assessment Sciences Utrecht, The Netherlands Per Gustavsson, M.D., Ph.D. Karolinska Institutet Stockholm, Sweden Irene Brüske, M.D., Ph.D. Deutsches Forschungszentrum fu¨r Gesundheit und Umwelt Neuherberg, Germany Jack Siemiatycki, Ph.D. University of Montreal Montreal, Quebec, Canada Beate Pesch, Ph.D. Thomas Brüning, M.D., Ph.D. Ruhr-Universita¨t Bochum Bochum, Germany Kurt Straif, M.D., Ph.D. International Agency for Research on Cancer Lyon, France ON BEHALF OF THE SYNERGY GROUP References 1. Health Effects Institute. Diesel emissions and lung cancer: epidemiology and quantitative risk assessment. Special reports 1999 (accessed 2011 January 25). Available from: http://pubs.healtheffects.org/view.php?id¼7 2. Garshick E, Laden F, Hart JE, Rosner B, Smith TJ, Dockary DW, Speizer FE. Lung cancer in railroad workers exposed to diesel exhaust. Environ Health Perspect 2004;112:1539–1543. 3. Leffondre K, Abrahamowicz M, Siemiatycki J, Rachet B. Modeling smoking history: a comparison of different approaches. Am J Epidemiol 2002;156:813–823. 4. Mirabelli D, Chiusolo M, Calisti R, Massacesi S, Richiardi L, Nesti M, Merletti F. [Database of occupations and industrial activities that involve the risk of pulmonary tumors.] Epidemiol Prev 2001;25:215–221. 5. Ahrens W, Merletti F. A standard tool for the analysis of occupational lung cancer in epidemiologic studies. Int J Occup Environ Health 1998;4:236–240. 6. Bostrom CE, Gerde P, Hanberg A, Jernstrom B, Johansson C, Kyrklund T, Rannug A, Tornqvist M, Victorin K, Westerholm R. Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air. Environ Health Perspect 2002;110:451–488. 7. Awofeso N. Generator diesel exhaust: a major hazard to health and the environment in Nigeria. Am J Respir Crit Care Med (In press)
Shock and Pulmonary Edema Secondary to Severe Acute Hypercapnic Acidosis To the Editor: Manzanares and colleagues propose hypercapnic acidosis as the mechanism for a life-threatening complication of mechanical ventilation (1). Obstruction of the expiratory ventilator limb may, however, have led to catastrophic multi-organ dysfunction by an alternative mechanism. Excessive hyperinflation with positive pressure
