The Health Effects Institute

EXECUTIVE SUMMARY

Research Directions to Improve Estimates of Human Exposure and Risk from Diesel Exhaust.
A Special Report of the Diesel Epidemiology Working Group

INTRODUCTION

Diesel engines are used extensively in transportation, especially in heavy-duty applications due to their power, durability, and efficiency. They are more efficient than gasoline engines and emit less carbon dioxide (a greenhouse gas) per unit of work, thus having advantages over gasoline engines in addressing global warming, an issue with increasing importance as the number of vehicle-miles-traveled increases rapidly around the world. Engine manufacturers have significantly lowered the emissions of particles in diesel exhaust over the last decade by improving engine and emission-control technologies. In spite of the many positive attributes of diesel engines, concerns remain about two emissions: nitrogen oxides, which contribute to ozone formation, and particulate matter, which is associated with adverse acute and chronic health effects.

Several state, national, and international agencies have concluded that diesel exhaust is a probable lung carcinogen (see Table 1 in the Diesel Epidemiology Working Group Report). This conclusion implies important public health consequences for the many urban areas (and possibly some rural areas) where diesel vehicles are prevalent and for workers exposed to diesel exhaust in their jobs. Animal models have proven inadequate for obtaining quantitative estimates of the cancer risk diesel emissions pose to the general population. As a result, epidemiologic data from studies of diesel-exposed workers have been the starting point for developing risk models. Numerous studies of diverse design have examined the association between lung cancer risk and diesel exhaust exposure. The difficulty of accurately estimating occupational exposure has limited interpretation of the resulting evidence and its utility for quantitative risk assessment.

In 1998, HEI initiated its Diesel Epidemiology Project, a multifaceted research and assessment effort to (1) develop new research initiatives, including feasibility studies to identify potential new cohorts or to improve exposure assessment methods, and (2) evaluate the strengths and limitations of the published epidemiologic studies available for quantitative risk assessment. As a part of the project, HEI appointed the Diesel Epidemiology Expert Panel to conduct a systematic review of these studies. The Expert Panel reported its findings and recommendations in the 1999 HEI Special Report Diesel Emissions and Lung Cancer: Epidemiology and Quantitative Risk Assessment. They concluded that enhanced exposure and epidemiologic data were needed for quantitative risk assessment and that these data might come from further exploration of existing studies or from new studies. The Expert Panel recommended that HEI consider undertaking a new epidemiologic study after HEI’s feasibility studies were completed and evaluated and after attempts to retrofit improved exposure assessments to existing studies were evaluated for their ability to support quantitative risk assessment.

The Diesel Epidemiology Working Group was formed in the fall of 2000 to
• review reports from 6 diesel feasibility studies funded by HEI to provide information on potential study populations and on exposure assessment methods; and
• consider the results of the feasibility studies and other ongoing research in order to develop a new research agenda to seek better information for quantitative risk assessment of lung cancer and other chronic diseases that may result from exposure to diesel exhaust.

In considering the expectations for a new study, the Working Group recognized that policy makers need risk estimates that are more precise and more certain than those that can be generated from the data now available. Issues related to exposure assessment arise both in designing an epidemiologic study to characterize health effects associated with exposure and in estimating the magnitude of the risk for various populations. In both contexts, characterization of Exposure to diesel exhaust must be sufficiently specific to distinguish its contributions to health effects from those of other sources.

Not only is diesel exhaust a complex mixture of gases and particles, but the particles themselves are a complex mixture; the characteristics depend on many factors including the diesel fuel formulation, combustion conditions in the engine, emission-control technologies, and conditions in the ambient environment into which the exhaust is emitted. Approaches to exposure assessment need to discriminate diesel particles from the many other sources of particles in the complex mixture of particles in air. Current approaches are somewhat nonspecific, using measurements both of particle mass and of marker compounds, such as elemental carbon, that have sources other than diesel emissions. In an epidemiologic study, exposures of participants need to be estimated with as little misclassification as possible. For population exposure assessment, information is needed on typical or average exposures and on the upper tail of the exposure distribution, which carries the greatest risks.

TECHNICAL EVALUATION OF DIESEL FEASIBILITY STUDIES

The 6 feasibility studies described in this report were funded by HEI to provide insight about, first, whether a new retrospective or prospective epidemiologic study could provide data to improve estimates of cancer risk from exposure to diesel exhaust and, second, about whether new methods of exposure analysis would allow us to reevaluate older epidemiologic studies.

The Working Group evaluated the following reports on possible new cohorts for investigation:

• Cancer Risk from Diesel Emissions Exposure in Central and Eastern Europe: A Feasibility Study, Paolo Boffeta and colleagues, International Agency for Research on Cancer, Lyon, France

• Cancer Risk from Diesel Exhaust Exposure in the Canadian Railroad Industry: A Feasibility Study, Murray Finkelstein and Dave Verma, McMaster University, Hamilton, Ontario, Canada

• Quantitative Assessment of Lung Cancer Risk from Diesel Exhaust Exposure in the US Trucking Industry: A Feasibility Study, Eric Garshick and colleagues, Channing Laboratory, Brigham and Women’s Hospital, Boston MA, USA

These well-executed studies evaluated the following cohorts: (1) a diverse set of historical cohorts of workers exposed to diesel emissions, including miners and bus or railroad transport company workers, in Russia and several Eastern European countries; (2) Canadian railroad workers; and (3) US truckers. The results of the studies illustrated the difficulties epidemiologic researchers face in finding suitable populations for study—populations with (a) adequate exposure data available, (b) exposures in a range likely to be informative and relevant to ambient levels, (c) data available on potential confounding and modifying factors, and (d) offering sufficiently large sample sizes. Each of the cohort studies had strengths and limitations, but for all of them accuracy of exposure assessment was a problem. The Working Group believes that full studies of these cohorts would probably add to the evidence regarding the carcinogenicity of diesel exhaust. However, it concluded that such studies could not be justified for the purpose of generating substantially accurate exposure-response relations, which the Working Group believes should be the goal of future epidemiologic studies of diesel exhaust.

The Working Group evaluated the following exposure assessment reports:

• Measurement of Diesel Aerosol Exposure: A Feasibility Study, David Kittelson and colleagues, University of Minnesota, Minneapolis, Minnesota

• Measuring Diesel Emissions Exposure in Underground Mines: A Feasibility Study, Barbara Zielinska and colleagues, Desert Research Institute, Reno, Nevada

• Real-World Particulate Matter and Gaseous Emissions from Motor Vehicles in a Highway Tunnel, Alan Gertler and colleagues, Desert Research Institute, Reno, Nevada

The feasibility studies addressing methods for exposure assessment and characterization of diesel particles are complementary to the proposals of new populations to be investigated because improved exposure assessment methods are needed to reduce misclassification of exposure and enhance precision in epidemiologic studies. The findings confirm that we still lack sufficiently specific methods for characterizing exposures to diesel exhaust. The Working Group agrees with the investigators that elemental carbon may be a useful indicator of occupational exposure to diesel exhaust in settings where diesel exhaust is the dominant source of particulate emissions. However, additional surrogates should be explored because elemental carbon as the only marker lacks the sensitivity and specificity necessary as a signature for ambient exposure, which includes elemental carbon from other combustion sources. Improved surrogates for diesel exhaust exposure might be used to enhance exposure assessment for past studies, to strengthen future epidemiologic studies, and to assess population exposure.

The Working Group also found that considerations of statistical power in the feasibility studies did not address quantification of risk to the degree of precision necessary for quantitative risk assessment. The calculations also did not acknowledge the uncertainty that arises from using estimated exposure values.

RESEARCH RECOMMENDATIONS

Because many agencies have concluded that diesel particles are a probable human carcinogen, the emphasis in risk assessment has shifted to quantifying the burden of lung cancer and other diseases associated with exposure to diesel emissions. This shift requires quantitative estimates of the relation between disease risk and the level and conditions of exposure. Epidemiologic studies of diesel-exposed populations can provide the risk estimates with the needed precision only if (a) populations with exposures relevant to the general population are studied, (b) exposures are accurately estimated, (c) data are available on potential confounding factors, and (d) sufficient data are accrued during follow-up. Thus, there are serious problems in improving knowledge regarding both exposure and response to diesel emissions. Nonetheless, the insights from these feasibility studies suggest areas for future investigation.

The Working Group does not recommend initiating a new cohort study of any of the proposed populations at this time; the high probable cost and continuing methodologic and data challenges make it difficult to predict that such a study would substantially improve quantitative estimates of risk. To meet these challenges, the Working Group has identified activities that could enhance risk assessments over the next 1 to 2 years (short-term activities), 3 to 10 years (medium-term activities), and 10 to 20 years (long-term activities).

SHORT-TERM ACTIVITIES

Proposed short-term activities largely relate to improving exposure assessment, including the possibility of defining a signature that is characteristic of diesel emissions. Additional recommendations address certain design issues that would enhance any new epidemiologic studies. The Working Group proposes the following specific activities related to exposure assessment:

• Convening a workshop to plan approaches for exploring emissions and monitoring data to identify signatures of diesel exhaust that would enable measurement in ambient exposures. Contemporary techniques for data exploration could be applied to the substantial exposure data sets in existence or under development by HEI and other organizations. An anticipated product would be a list of available data and potentially informative approaches for analysis. HEI intends to follow the workshop with a research initiative to conduct analyses of existing and emerging data sets to identify a diesel signature.
• Characterizing diesel particles in HEI studies in a standard way in both laboratory and population contexts.
• Taking advantage of the US Environmental Protection Agency’s Supersites and speciation sites by additional targeted data collection and analyses to develop a regional characterization of organic compounds associated with particulate matter.
• With full consideration of uncertainty, calculating sample sizes needed for future epidemiologic studies to characterize exposure-risk relations. The Working Group suggests that HEI take the lead in developing these calculations, a task to be accomplished using simulation methods or other approaches.

MEDIUM-TERM ACTIVITIES

The Working Group’s recommendations for activities that would produce results in 3 to 10 years are based in part on the likely existence of new epidemiologic studies and anticipated advances in understanding the molecular and cellular biology of lung cancer. They also build on the results anticipated from the proposed short-term activities. The Working Group recommends:

• Continuing to evaluate opportunities to enhance exposure assessment approaches, including, for example, analysis of filters from special monitoring initiatives (eg, Supersites and the speciation network) and single-particle analysis based on mass spectroscopy.
• Evaluating opportunities to apply new approaches for assessing diesel signatures in epidemiologic studies in progress.
• Assessing possible biomarkers for lung cancers related to diesel emissions exposure.
• Conducting further research directed at effects of diesel exhaust exposure other than cancer.

LONG-TERM ACTIVITIES

In making recommendations for activities that will produce results beyond 10 years, the Working Group assumes that quantitative risk assessment will remain central in managing potential risks of diesel emissions. The Working Group recommends:

• Designing and implementing population surveillance instruments for exposure to diesel exhaust using validated source signatures. Surveillance strategies might also include modeling ambient air data and biomarkers.
• Periodically performing source-signature characterization to track changes in emissions as engine and emission-control technologies and fuels evolve. This might be accomplished with periodic tunnel studies or laboratory studies.
• Undertaking further laboratory and population-based studies on risk of lung cancer or other diseases, possibly using biomarkers of dose and exploring gene-environment interactions.

Although the Working Group does not recommend undertaking a major new epidemiologic study at present, it may be appropriate to implement a new study as research methods evolve for both exposure and outcome assessment. The Working Group does not foresee a waning of interest in the possible adverse effects of diesel exhaust and their quantitative relations with exposure. Methodologic challenges to conducting such a study include obtaining complete and accurate exposure assessment, identifying an exposure marker or set of markers that is a specific signature for diesel exhaust (and likely to reflect diesel emissions in the future), maintaining sufficiently complete follow-up over a 25-year period, and measuring other critical exposures and confounding factors. Diesel emissions are being reduced and modified as a result of changes in engine and emission-control technologies; consequently, it is not clear that the exposures and outcomes measured in a prospective study started today would have relevance for the exposures and health effects present 25 years from today. Over time, we anticipate improved methods for exposure assessment and for use of biomarkers, a focus of our proposed short-term and medium-term research agendas. With better research tools, it may become feasible to carry out more informative epidemiologic studies in the future, although future researchers may still face the challenges of continuously changing technology and emissions.

SUMMARY

As emphasis has shifted toward quantifying the potential burden of lung cancer associated with diesel exhaust, HEI has evaluated the available epidemiologic evidence and sought ways to enhance these data. It has convened expert panels and carried out workshops for this purpose. The feasibility studies discussed in this report were one outcome of this process. The findings of these studies contribute to our understanding of the potential for epidemiologic research to quantify disease risks associated with diesel emissions. On the basis of reviewing these studies, the Working Group has recommended a series of short-term, medium-term, and long-term research activities. The Working Group does not recommend proceeding with full studies of the populations considered in the feasibility studies, largely because of concern about the ability of investigators to estimate past exposures with sufficient certainty. Because concern for the public health consequences of diesel exposure is likely to continue, HEI might consider establishing populations for prospective observation so that exposure assessment with sufficient validity could be implemented. The activities recommended by the Working Group should enhance epidemiologic studies in progress and planning for future research.

The Health Effects Institute

EXECUTIVE SUMMARY

Research Directions to Improve Estimates of Human Exposure and Risk from Diesel Exhaust. A Special Report of the Diesel Epidemiology Working Group

INTRODUCTION

Research Directions to Improve Estimates of Human Exposure and Risk from Diesel Exhaust.
A Special Report of the Diesel Epidemiology Working Group