RFA 98-3: Epidemiologic Investigations of Human Populations Exposed to Diesel Engine Emissions: Feasibility Studies
(Spring 1998 Research Agenda)
Introduction Background Overview of the HEI Diesel Epidemiology Project
Feasibility Studies Application Guidelines References
Application Process and Deadlines Evaluation Process
INTRODUCTION
The expanding worldwide use of diesel vehicles and the uncertain effect of their emissions on human health has focused attention on risk assessments of diesel engine exhaust. At the present time, there is uncertainty about using existing toxicologic or epidemiologic data for quantitative cancer risk assessments of diesel emissions. Moreover, emissions have changed substantially over the last decade because of new fuels, engine designs, and emissions control technology. Thus, new data are needed to better inform regulators and policymakers as to the risks of exposure to emissions from today's diesel engines, especially in ambient settings. The Health Effects Institute (HEI) has initiated a Diesel Epidemiology Project to address this need and, as part of that Project, plans to support epidemiologic studies of the health effects of diesel emissions beginning in 2000. We are therefore issuing this Request for Applications (RFA) for feasibility studies relevant to that research.
BACKGROUND
DIESEL ENGINE EMISSIONS
Diesel engines are an important part of the world's transportation and industrial infrastructure, and their use may expand in the future. Durability and energy efficiency account for their dominant use in heavy-duty applications – i.e., trucks, buses, construction and farm equipment, locomotives, and ships. Also, diesel engines emit less carbon dioxide (a greenhouse gas) per unit of work done than do their gasoline-powered counterparts. In Europe, where fuel prices are three- to four-times higher than in the United States, and concern for climate change is strong, 20% to 50% of the new light-duty passenger fleet is powered by diesel engines. In the United States, advanced-technology diesel engines have been proposed as key elements in the nations's energy conservation strategy (e.g., the fuel-efficient car of the Partnership for a New Generation of Vehicles) and may see use in sport utility vehicles.
Despite their advantages, conventional diesel engines contribute to air pollution in occupational and ambient settings. Compared to gasoline engines, they emit more particulate matter than gasoline engines per unit of fuel burned, and more oxides of nitrogen, which contribute to the formation of ground-level ozone. The particulate emissions are of special concern, because the particles are readily respirable (90% by mass are less than 1 µm), and the chemicals adsorbed onto their surfaces include many known or suspected mutagens and carcinogens. (In this discussion, the term "diesel particulate matter" refers to the solid elemental carbon particles plus the adsorbed organic and inorganic chemicals.)
In the United States and Europe, decisions are being made about how to regulate diesel engine emissions and whether advanced-technology diesel engines represent the best engine designs for the future. These decisions are difficult because at the present time there is uncertainty about using either the available toxicologic or epidemiologic data to develop quantitative risk assessments for diesel exhaust. Moreover, diesel emissions have changed both qualitatively and quantitatively over the last decade and are expected to change in the future. Thus, there is a need for new scientific data on the risks of exposure to diesel engines in use today.
RISK ESTIMATES OF DIESEL ENGINE EMISSIONS
Numerous toxicologic and epidemiologic studies have examined the potential for diesel emissions to cause or contribute to the development of cancer and other diseases (HEI 1995; California EPA 1998; U.S. EPA 1998). Attempts have been made to use the results of these studies to estimate the risk of lung cancer due to exposure to the concentrations of diesel emissions found in occupational and ambient settings. Studies clearly demonstrate that prolonged exposures to extremely high concentrations of diesel emissions produce lung tumors in rats and that the carbonaceous particles, not the adsorbed chemicals, are the likely cause of tumors in this species. These studies and others focused on the response of the rat lung to high doses of inhaled, poorly soluble, nonfibrous particles have raised questions about the relevance of the current rat model for risk assessments of such materials, because lung tumors in the animals are observed only following exposure to levels of particles that cause significant impairment in particle clearance (the so-called particle overload phenomenon). The inflammation, epithelial cell hyperplasia, and metaplasia associated with this impairment are thought to be related to the development of neoplasms in this species.
Epidemiologic studies are generally consistent in observing a small to moderate excess relative risk of lung cancer in workers who were exposed to emissions from older, uncontrolled diesel engines (Cohen and Higgins 1995). However, using these data to estimate the magnitude of the cancer risk is limited because:
No epidemiologic study has included quantitative measurements of the past exposures of the study subjects. Their exposure to diesel exhaust has been characterized largely in terms of job titles or duration of employment in a particular job or industry, rather than by direct measurements of diesel exhaust constituents. Although this approach is not unusual in occupational epidemiology and may support "hazard identification," it poses a major limitation in developing quantitative estimates of risk.
The emissions from diesel engines being manufactured today differ substantially from emissions of the 1960's and 1970's that have been associated with increased lung cancer risk.
OVERVIEW OF THE HEI DIESEL EPIDEMIOLOGY PROJECT
The HEI Diesel Epidemiology Project has been designed to develop new information to support quantitative estimates of the potential health risks associated with ambient exposure to diesel engine emissions in today's general population. The Project has two components:
Review by an Expert Panel consisting of statisticians, epidemiologists, and industrial hygienists of the existing epidemiologic studies of workers exposed to diesel engine emissions in order to identify key information needed to improve quantitative risk assessment.
Support by HEI of new research designed to improve the epidemiologic data on which cancer risk assessments of diesel emissions can be based.
THE EXPERT PANEL
The goals of the Expert Panel are to (1) review the data that form the basis of the current attempts to make quantitative risk assessments for diesel exhaust; (2) identity sources of uncertainty and data gaps; (3) make recommendations as to the value of extending or conducting further analyses of existing data sets, and (4) make recommendations as to areas of new research and the criteria to be contained in new studies that would improve quantitative risk assessment. The Panel is expected to issue its report in the fall of 1998.
NEW EPIDEMIOLOGIC RESEARCH
Previous epidemiologic studies provide information about the cancer risks of occupational exposures of workers, mostly males, to relatively high concentrations of diesel emissions from uncontrolled engines. New information is needed to develop reliable estimates of the risks of exposure to ambient concentrations of emissions from diesel engines that represent the mixture of technologies and fuels in use today. This information is needed for occupational cohorts and, to the extent that studies are feasible, for the general population and for potentially susceptible subpopulations such as women and children, whose risk from exposure to diesel exhaust has not been studied.
Most research on diesel engine emissions has been directed toward its potential carcinogenicity, but the direct effects of combustion-generated particles on the airways and cardiovascular system may contribute not only to cancer but to diseases such as asthma and heart disease. Although these are important public health issues, the number of outcomes that can be measured in a single study is limited. HEI therefore anticipates that its new epidemiologic research will continue to focus mainly on cancer risks; however, a study may collect information on other health effects such as cardiovascular disease, chronic obstructive pulmonary disease, and asthma when this effort does not compromise the study's major goal.
The new epidemiologic research will be developed over the next two years as follows:
Research Strategy Workshop: Late 1998
The Expert Panel will issue its report at a public workshop that will include investigators currently conducting or planning epidemiologic studies of the risks of exposure to diesel emissions and HEI-funded investigators who will conduct the newly selected feasibility studies. This workshop is intended to inform the HEI, potential sponsors, and other interested parties as to the design and preliminary findings of studies in this area.
Feasibility Studies: 1998-1999
During the planning stages for new research, preliminary work will be necessary to identify appropriate cohorts, confirm access to records, determine the range of exposures, and validate exposure assessment techniques. This Request for Applications (RFA 98-3) describes HEI's objectives for feasibility studies to support the design of the full-scale epidemiologic research described below.
Full-Scale Study: 2000 –
HEI plans to support either a single full-scale study or a coordinated set of studies targeted toward understanding the magnitude of the cancer risks associated with ambient exposure to the emissions of diesel engines, particularly those used in motor vehicles. Emphasis will be placed on studies that can provide information on the dose-response relation between exposure to diesel emissions and lung cancer. However, HEI would welcome research designs that would also allow the assessment of other end points as well. The design of the full study or set of studies will be guided by the recommendations of the Expert Panel and the results of other investigations, including the feasibility studies that are the focus of this RFA. In anticipation that adequate funding can be obtained from appropriate government and industrial sponsors, HEI plans to issue a Request for Applications in 1999 and to have the research under way in the year 2000.
The Diesel Epidemiology Project will proceed according to the following schedule:
Spring 1998
Expert Panel starts work
HEI issues RFA 98-3 for feasibility studies (May)
Summer 1998
Expert Panel continues work
Applications for RFA 98-3 due (July 30)
Fall/Winter 1998
Selection of feasibility studies (September)
Expert Panel issues report
Research Strategy Workshop
Feasibility studies start (December)
1999
Review progress of feasibility studies
Issue RFA for full-scale study (assuming adequate funds available)
2000
Applications for full studies due
Application review and study negotiations
Full study (or studies) start
RFA 98-3. EPIDEMIOLOGIC INVESTIGATIONS OF HUMAN POPULATIONS EXPOSED TO DIESEL ENGINE EMISSIONS: FEASIBILITY STUDIES
Epidemiologic studies can make unique contributions to understanding environmental risks because they evaluate the effects of environmental pollutants in humans under relevant exposure conditions. However, studying the health effects of single sources of air pollution is challenging because: (1) People are continuously exposed to multiple pollutants from diverse sources. (2) There is often a long time-lag between environmental exposures and the clinical appearance of diseases such as cancer. (3) Investigators need to conduct expensive long-term prospective studies or make retrospective estimates of exposure, which increases the likelihood of exposure misclassification. (4) The changing nature of diesel emissions over the last decade raises questions about the relevance of data derived prior to 1990 for assessing risk to emissions from current model diesel engines. (5) Confounding factors, such as cigarette smoking (the major cause of lung cancer) need to be carefully controlled.
For these reasons, HEI's planning for new research will include exploration of multiple approaches to exposure assessment. HEI's goal in issuing RFA 98-3 is to support feasibility studies for investigators who (1) have access to appropriate study populations but require some funding to demonstrate their suitability for a full epidemiologic study; (2) have already developed methods for measuring exposure to diesel emissions but need to assess their performance in relevant environments; (3) have information on how the characteristics of diesel emissions and the levels of exposure have changed over time in work sites or in the general environment, and/or (4) need funding to develop strategies for linking current measurements of diesel emissions with past exposures.
The objective of RFA 98-3 is to determine the feasibility of studies designed to provide information on the dose-response relation between human cancer risk and long-term exposure to diesel emissions. Applicants must propose studies that involve human populations and/or quantitative exposure estimates, addressing one or both of the following Specific Aims:
(1) Identify study populations exposed to diesel emissions that could provide reasonably precise estimates of small to moderate excesses of lung cancer or chronic nonmalignant cardiorespiratory disease.
Such populations should have had sufficient duration of exposure and follow-up time to allow the induction of cancer or other chronic diseases. Populations of particular interest are those with a range of exposures to diesel exhaust that include the levels reported in ambient settings (1 -10 µg particulate matter/m3) and the low range f occupational environments(10 - 200 µg/m3), although populations with more intense exposures may also be included. Potentially susceptible subpopulations such as women and children are also of interest. The proposed studies should:
Describe a population or populations exposed to diesel emissions in either occupational or ambient environments and the rationale for their selection.
Confirm access to medical and job history records.
Assess records to identify health outcomes.
Applicants should provide evidence that the proposed cohorts have the characteristics necessary for a full study. For example, the cohort should be large enough to provide sufficient cases of lung cancer for a study of adequate power and the exposure period should be long enough to allow for the induction of lung cancer. Applicants should also consider the impact of measurement error on the precision of any risk estimates.
Investigators submitting proposals under Specific Aim (1) do not need to propose detailed exposure measurement strategies (see Specific Aim 2). They should, however, discuss what information they have on the following issues for their cohort study and what information they expect to gain in their feasibility study.
Sources of exposure to diesel emissions (engine types, models, and age).
Information on diesel fuel formulation.
Possible confounding exposures such as cigarette smoke, environmental tobacco smoke, gasoline engine exhaust, and other chemicals.
Methods being considered for characterizing exposures.
The distribution of exposures in the proposed population.
Changes in exposure levels over time.
The impact of past and projected changes in technology and diesel fuel formulation (and, thus, exposures to diesel engine exhaust) over time.
(2) Develop an exposure assessment strategy with two related components: (a) validation of measurement techniques, and (b) development of approaches for using data generated by these techniques to make quantitative estimates of retrospective exposures to diesel engine emissions. Proposals may address either or both of these components.
The most important information gap that limits the use of existing epidemiologic studies for quantitative risk assessment is the absence of quantitative exposure information. Future studies must provide data that are suitable for estimating dose-response relations. Historical exposure estimates need to be linked to direct measurements and to health outcomes. A comprehensive exposure assessment strategy needs to consider the exposure metric, the techniques available for measuring constituents of diesel emissions, the ability to relate exposure measurements to specific environments, the time relation between exposure to diesel emissions and the development of cancer, the time of introduction of diesel engines into the proposed study setting, the changes in diesel emissions over time, and the mix of old and new technologies at the study site.
a) Validation of measurement techniques. Because direct measurements of one or more of the components of diesel engine emissions will be essential, it is critical that the methods used to make these measurements be tested and evaluated in the field before they are applied in a full-scale study. Applicants should therefore discuss:
The proposed method(s) and instrumentation for sampling and analyzing components of diesel emissions.
Settings in which these methods have been applied and the types of diesel engines and fuels used in these settings.
Accuracy, sensitivity, and reproducibility of the methods as previously used.
Sources of interference, including cigarette smoke, non-diesel combustion emissions, and other particles.
Measurement error.
Any available pilot data.
Proposed locations for environmental and occupational measurements.
Number of samples required to yield satisfactory statistical results for exposures ranging from 1 to 1,000 µg particulate matter/m3.
HEI primarily seeks studies that will apply reasonably well-established techniques for exposure assessment. These may include biological markers of exposure if the proposed markers have been validated and appear likely to reduce exposure misclassification. Whatever methods are proposed for the feasibility study, applicants should show how they can be linked ultimately to an exposure assessment strategy for a full-scale epidemiologic study (see Specific Aim 2.b). If future studies demonstrate a positive association between exposure to diesel emissions and cancer, it will be important to know what constituents in diesel emissions are responsible. Although applicants may quantify exposure to diesel emissions using a single component such as particulate matter as an exposure metric, they are encouraged to obtain information on chemical components that are suspect from a health standpoint.
(b) Proposal of approaches for developing quantitative estimates of long-term exposure to diesel emissions. A primary goal of the full study will be to elucidate the exposure-response relation between diesel emissions and lung cancer and possibly other chronic diseases. Applicants should therefore discuss:
Proposed approaches for linking direct measurements of diesel emissions to retrospective exposure estimates with regard to cohorts or individuals.
Data sources for historical records, such as work assignment records and ambient monitoring data.
How changes in the nature of exposure and work practices over time will be handled in the exposure assessment.
Validation techniques to be used.
The impact of reducing exposure misclassification.
How exposure modeling will be done to provide realistic quantitative estimates for individual study participants.
Strengths and limitations of the proposed approaches.
APPLICATION GUIDELINES
The full-scale epidemiologic study or studies that HEI plans to support in the year 2000 will be a multi-disciplinary effort requiring the collaboration of epidemiologists, statisticians, and exposure assessment experts. Potential applicants for the full studies will be encouraged to develop multi-disciplinary teams, and such teams may also apply for funding under RFA 98-3. The feasibility studies, however, are not required to be collaborative efforts and may instead focus on only one of the specific aims described above. Investigators whose feasibility studies have particularly promising cohorts or methods for exposure estimation will be assisted by HEI to develop collaborations for the full-scale study.
Please note that RFA 98-3 seeks applications from investigators whose methods for measuring exposure to diesel emission that have already been tested and validated. The development of new exposure methodologies will not be supported through this RFA but may be supported by HEI under a different funding mechanism. Interested investigators should contact HEI for additional information.
Applicants need to discuss how they will address the fact that today's diesel fleet on the highway is a mix of old and new technologies, each having a poorly documented set of emission characteristics. Given the durability of diesel engines, a constantly changing mix of engines can be expected to persist into the future. Settings with engines of exclusively new technology may not exist; if so, they may not have existed long enough to manifest their health effects. Even the characterization of the emissions from the new technology engines presents a moving target because the technology continues to advance and diesel fuels are being reformulated. Applicants proposing to study occupational settings should discuss how the emissions from the engines used in these environments compares with the engine emissions to which much of the general public is exposed, e.g., on highways and in cities.
In anticipation that adequate funds will be available, HEI plans to issue an RFA for a full-scale epidemiologic study (or a coordinated set of studies) in 1999. The feasibility studies funded under RFA 98-3 are expected to provide results that will inform the development of applications for the full study. HEI will therefore evaluate and implement the feasibility study applications by late 1998; the studies will begin in December 1998 and run for one year. The Institute plans to support three to five studies under RFA 98-3 and has between $800,000 and $1,000,000 available for this research.
Questions regarding RFA 98-3 should be directed to:
Dr. Kathleen M. Nauss
Health Effects Institute
955 Massachusetts Avenue
Cambridge, MA 02139
Tel: 617-876-6700
e-mail: knauss@healtheffects.org
REFERENCES
Cohen AJ, Higgins, MWP. 1995. Health effects of diesel exhaust: Epidemiology. In: Diesel Exhaust: A Critical Analysis of Emissions, Exposure, and Health Effects (A Special Report of the Institute's Diesel Working Group) pp. 125–137. Health Effects Institute, Cambridge, MA.
California Environmental Protection Agency.1998. Health Risk Assessment for Diesel Exhaust. Public and Scientific Review Panel Review Draft. Office of Environmental Health Hazard Assessment, Sacramento, CA.
Health Effects Institute. 1995. Diesel Exhaust: A Critical Analysis of Emissions, Exposure, and Health Effects (A Special Report of the Institute's Diesel Working Group). Health Effects Institute, Cambridge, MA.
U.S. Environmental Protection Agency. 1998. Health Assessment Document for Diesel Emission. SAB Review Draft. EPA/600/8-90/057C. Office of Research and Development, Washington, D.C.
APPLICATION PROCESS AND DEADLINES
LETTER OF INTENT
Prospective applicants are asked to submit a one-page Letter of Intent, which should include a synopsis of the project indicating the specific goals, the general approach to be used, and identification of all participating institutions. Confidential or proprietary information on methodologic details should not be included in the Letter of Intent.
HEI requests Letters of Intent in order to organize the application review process. The Letter of Intent is not binding. In some instances, HEI may advise the applicant that the work described in the Letter of Intent does not appear to address objectives of the RFA. Please note in your letter of intent that you received this RFA over the web site so that we will know that you did not get the printed book which contains the forms for a full application (see below).
Deadline for Letters of Intent: The Letter of Intent should be received no later than TUESDAY, JUNE 30, 1998 at the following address:
Ms. Francine Marmenout
Administrative Assistant
Health Effects Institute
955 Massachusetts Avenue
Cambridge, MA 02139
Tel: (617) 876-6700FULL APPLICATION
Investigators who are asked to prepare a full application should note in their Letter of Intent (see above) that they received this information from the web site and do not have the printed book. Inquiries regarding application and evaluation procedures may be directed to Dr. Kathleen Nauss. If two applications are interdependent or closely related, they should be appropriately cross-referenced in the project plan.
Twenty-five copies of each application are needed by HEI for the review process.
Deadline for Applications: Applications for RFA 98-3 must either reach the office of the Health Effects Institute by THURSDAY, JULY 30, 1998 or be sent by air delivery service postmarked by that date. Applications not meeting these conditions will not be considered.
EVALUATION PROCESS
HEI is committed to facilitating research on the health effects of air pollutants from automotive emissions and other sources by encouraging applications from researchers with skills and methods in various disciplines, including those not conventionally associated with this field. Procedures and criteria for evaluation of applications have been designed with these goals in mind.
Applications received will be evaluated by HEI in a two-stage process: an external review followed by an internal review.
EXTERNAL REVIEW
Applications undergo a competitive evaluation of their scientific merit by an ad hoc panel of scientists selected for their expertise in relevant areas. The panel will evaluate applications according to the following general criteria in addition to the specific guidelines given in the RFA:
Relevance of the proposed research to the objectives of the RFA;
Scientific merit of the research design, approaches, methodology, analytical methods, and statistical procedures;
Personnel and facilities; including
Experience and competence of the principal investigator and scientific staff
Adequacy of effort on the project by scientific and technical staff
Adequacy of facilities; and
Reasonableness of the proposed cost.
The proposals ranked most highly by the review panel may be additionally reviewed for evaluation of the experimental design and analytical methods by a statistician.
INTERNAL REVIEW
The internal review conducted by the HEI Research Committee generally focuses on the applications ranked highly by the external review panel. The review is intended to ensure that the studies funded constitute a coherent program addressing the objectives of the Institute. The Research Committee makes recommendations regarding funding of studies to the Institute's Board of Directors, which makes the final decision.
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