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Epidemiologic Research on Health Effects of Long-Term Exposure to Ambient Particulate Matter and Other Air Pollutants

The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications for a prospective observational study of cardiovascular disease initiation and progression associated with long-term exposure to ambient particulate matter and other air pollutants in a population-based sample.

Prospective epidemiological studies are needed to extend the knowledge gained from previous studies that identified an increased risk of cardiopulmonary and cardiovascular mortality and hospitalizations in older individuals, as well as decreased development of lung function among school-aged children. The EPA is soliciting proposals to recruit a new adult cohort for a multisite, prospective, population-based observational study of adults designed to determine the long-term effects of particulate matter constituents and copollutants on the natural history of cardiovascular disease, including indicators of subclinical disease, clinical disease incidence, mortality, and the assessment of physiological parameters indicative of the progression of disease.

Particulate matter has been linked to serious respiratory and cardiovascular disease. Important health outcomes shown to be associated with exposure to ambient particulate matter include premature mortality, aggravation of respiratory and heart disease (as indicated by increased hospital admissions and emergency room visits, school absences, lost work days, and restricted-activity days), aggravated asthma, acute respiratory symptoms, chronic bronchitis, decreased lung function, and increased risk of myocardial infarction. This request for applications invites applications for prospective epidemiology studies using validated measures of subclinical disease to study the natural history of cardiovascular disease associated with long-term exposure to ambient particulate matter and copollutants.

Long-term exposure to ambient airborne particulate matter is associated with increased mortality, with the mortality risk most strongly related to ambient concentrations of sulfates and fine particles less than 2.5 micrometers in diameter. In addition to mortality, particulate matter with an aerodynamic diameter of less than 10 micrometers, 2.5-10 micrometers, or less than 2.5 micrometers is associated with a reduction in lung function development among school-aged children. The health effects also are associated with other air pollutants including nitrogen dioxide, ozone, and inorganic acid vapor. The identification of those health end points that are associated with specific particulate matter constituents and other pollutant types is a current EPA research priority.

New prospective studies are needed that incorporate newer particulate matter concentration measurements and technologies to study more diverse study populations. These studies will need to directly address design and analytical issues such as 1) the collection of data on individual-level risk factors and personal exposure factors, 2) adjustment for simultaneous exposure to gaseous and other copollutants, and 3) the spatial correlation of mortality and pollution levels.

Whether or not long-term particle exposure plays a role in the initiation or progression of chronic conditions such as atherosclerosis, diabetes, chronic obstructive pulmonary disease, chronic bronchitis, and asthma is a critical research question. Two validated, reproducible measures that have been used by other researchers to follow the subclinical progression of atherosclerosis are measurement of coronary calcification by computed tomography and ultrasound measurement of the common carotid artery. These measures predict the risk of adverse clinical events and are associated with well-established risk factors for cardiovascular disease.

Prospective studies using outcome measures such as these would significantly advance our understanding of the contribution of ambient air pollution to the development of chronic disease. In addition, there is little current understanding of whether individual attributes such as age, the presence of disease or risk factors for disease, residential location (inner city, suburban, rural), education level, or race/ethnicity place individuals at higher risk (effect modifiers). This research will be important in identifying populations that are particularly susceptible to the adverse effects of long-term exposure to ambient particulate matter.

The EPA's P[M.sub.2.5] Chemical Speciation Trends Network (or STN) was established by regulation and is a companion network to the mass-based Federal Reference Method network implemented in support of the P[M.sub.2.5] national ambient air quality standard. The EPA established the STN to provide nationally consistent speciated P[M.sub.2.5] data for the assessment of trends at representative sites in urban areas across the United States. As part of a routine monitoring program, the STN quantifies mass concentrations and P[M.sub.2.5] constituents, including numerous trace elements, ions (sulfate, nitrate, sodium, potassium, ammonium), elemental carbon, and organic carbon.

The STN began operation in late 1999, and there are currently a total of 54 STN sites. As of this writing, data in the STN goes through approximately October 2002, and there are at least a year's worth of data for about 36 of the 54 STN sites. To assist in the development of proposals in response to this RFA, a spreadsheet titled "P[M.sub.2.5] Urban Speciation Monitors" can be found on the EPA's Office of Research and Development/National Center for Environmental Research website at http://es.epa.gov/ncer/rfa/current/ 2003_pm_epi-monitors.html.

Study proposals should address all of the following questions:

1) Does long-term exposure to ambient particulate matter increase the risk of cardiovascular disease incidence or progression?

2) Is annual change in the value of specific physiologic parameters or increased incidence of intermediate subclinical and clinical outcomes associated with long-term exposure to particulate matter?

3) Are these adverse health end points differentially associated with specific chemical constituents, size fractions, or sources of ambient particulate matter? and

4) What are the most relevant methodologies and exposure metrics for estimating the adverse health effects of long-term exposure to ambient particulate matter?

The EPA is particularly interested in proposals that specifically address all of the elements described below.

Health end points. The EPA is interested in proposals focusing primarily on the evaluation of the annual change in indicators of cardiovascular disease progression in adults. Other outcome measures, including lung function decline, incidence of hospitalizations, and mortality, are of secondary interest.

Study protocols that include repeated measurements of validated, state-of-the-art, noninvasive subclinical health outcomes are desired. Repeated measures should be of sufficient precision and sensitivity to demonstrate progression of cardiovascular disease in individuals. Outcomes that are objective predictors of clinically relevant health end points and that are associated with well-established risk factors for the clinical end points are of highest interest.

A study design with sufficient power to detect an association between long-term exposure to ambient particulate matter and a biologically relevant change in the physiologic variables under study over a 3- to 4-year observation period is desired. The EPA does not expect that the studies will have adequate power to detect an association of exposure measures with the incidence of clinically diagnosed adverse events (e.g., hospitalizations) over this same time period. However, proposals that are sufficiently powered to detect an association between long-term exposure to ambient particulate matter and the incidence of clinically recognized cardiovascular or respiratory disease over a 10-year time period are preferred.

Confounding. Study designs or statistical strategies to control for potential confounding by other major determinants of cardiovascular disease, such as smoking, diet, exercise, and socioeconomic status, are preferred. If general unrestricted study populations are selected, they should be large enough and diverse enough to permit careful adjustment for individual-level characteristics that may confound the relationship between health end points and pollution levels. Questionnaire assessment of certain potential confounders, such as smoking status, should be validated by the collection of biologic samples in a subset of individuals.

Effect modification. The EPA is interested in proposals with study populations that are large enough and diverse enough to examine individual-level characteristics that have been shown to modify the relationship between health end points and air pollutants. Research objectives that include hypotheses to address individual susceptibility are desired.

Exposure gradients. Study populations with an adequate range of average annual ambient concentrations of airborne particulate matter are preferred. The EPA is interested in both regional (e.g., transported sulfates and nitrates, gradients related to specific home heating fuels such as residual fuel oil and wood) and local (e.g., intra-urban concentration gradients from mobile sources) gradients in ambient concentrations. The EPA anticipates that individuals from multiple geographic regions will be selected to meet this interest. The research narrative should describe why study locations were selected and the extent to which the use of federal, state, and local monitoring systems and data was considered.

Particulate matter constituents and copollutants. In addition to inhalable particulate matter (P[M.sub.10]), the EPA prefers studies that consider other specific chemical constituents and size fractions of ambient particulate matter and copollutants. The EPA is interested in the study of fine particles (P[M.sub.2.5]) as well as alternative exposure metrics for particulate matter, including the chemical composition of particles and source apportionment. Various temporal patterns of exposure should be considered, including measures of cumulative exposure.

Exposure misclassification. Proposals should include the use of geographic information systems or other methods to estimate ambient concentration at each subject's residence using pollutant measurements taken at central monitoring sites. Successful proposals will include the identification and analysis of factors that affect personal exposure to ambient air pollution. These factors may include local, personal, or household factors. Validation studies using indoor or personal monitors should not make up more than 10-20% of the project's total budget.

Analytic issues. The EPA anticipates that the use or development of sophisticated analytical tools will be necessary to disentangle the individual contribution of particulate matter components and copollutants, account for spatial clustering and autocorrelation, and address other analytical complexities.

The project period for this solicitation shall be a total of 10 years with two study phases. It is anticipated that a total of approximately $30 million will be awarded, depending on the availability of funds. The EPA seeks the most cost-effective proposals that utilize funding of up to $3-4 million per year for the first five years and $1-2 million per year for the second five years. Requests for EPA funding exceeding $30 million will not be considered.

A set of special instructions on how applicants should apply for a National Center for Environmental Research grant is found at http://es.epa. gov/ncer/rfa/forms/ ("Standard Instructions for Submitting a STAR Application"). The necessary forms for submitting an application will be found on this website. The deadline for receipt of applications is 24 July 2003. Complete information on this announcement is located at http://es.epa. gov/ncer/rfa/current/2003_pm_epi.html.

Contact: Barbara Glenn, 202-564-6319, e-mail: [e-mail]; Gail Robarge, 202-564-8301, e-mail: [e-mail]; or Stacey Katz, 202-564-8201, e-mail: [e-mail] (e-mail inquiries are preferred). Reference: 2003-STAR-F1

Microbial Risk in Drinking Water 

The Centers for Disease Control and Prevention (CDC) has estimated that there are more than 200 million cases of acute gastrointestinal illness per year in the United States. Household intervention epidemiological studies have suggested that 10-40% of gastrointestinal illness may be associated with drinking water. If only a small fraction of annual gastrointestinal illness is caused by exposure to pathogens in drinking water, millions of cases of these illnesses may be associated with drinking water each year. This rate is substantially greater than the U.S. Environmental Protection Agency's (EPA) current estimates of illness caused by individual pathogens.

Many waterborne illnesses will be reduced substantially by the EPA's regulatory efforts to treat for pathogens originating in the source water. However, there is still much uncertainty regarding the etiology of waterborne diseases and the extent to which waterborne disease incidence may still exist. Uncertainties result from both variable characteristics of pathogens and problems with distribution systems.

Methodologies, analytical tools, and data are needed to help in estimating the extent of gastrointestinal illness attributable to drinking water in populations served by community water and to determine its chief causes. In this regard, methodologies for improving the sensitivity of recognizing risk that is attributable to drinking water are especially needed.

The EPA, as part of its Science to Achieve Results (STAR) program, is seeking applications proposing innovative approaches for estimating microbial risk. Proposed approaches, tools, and data should contribute to providing a better understanding of the magnitude, and, if feasible, the etiology of microbial risk in drinking water.

Research is being solicited in two distinct areas of research: 1) development of indices or classification schemes, or actual risk characterizations based on data collection and analysis, that indicate relative degrees of potential risk from pathogens in source water, pathogen passage through treatment barriers, or vulnerability of a distribution system to pathogen intrusion or growth; and 2) epidemiological studies of groundwater- or surface water--based systems that generate data to indicate attributable risk from pathogens in distribution systems. Examples of research in either of the above two areas may involve characterizations of relative risk from different causes or characterization of risk associated with one cause such as vulnerability in distribution systems.

It is anticipated that a total of approximately $6 million will be awarded, depending on the availability of funds, with approximately $3 million to be awarded to proposals responsive to each of the two research areas. The EPA anticipates funding approximately 5-8 awards total under this request for applications. The projected award per grant is as follows:

1) Up to $200,000 per year total costs, with a duration of 2-3 years, for proposals responsive to the first research area (development of indices or classification schemes to characterize microbial risk). Requests for amounts in excess of a total of $600,000, including direct and indirect costs, will not be considered. Approximately 4-6 awards will be made in this research area.

2) Up to $600,000 per year total costs, for up to 3 years, for proposals responsive to the second research area (epidemiological investigations). Requests for amounts in excess of a total of $1.8 million, including direct and indirect costs, will not be considered. Approximately 1-2 awards will be made in this research area.

The standard instructions for submitting a STAR application, including the necessary forms, can be found on the National Center for Environmental Research website at http://es.epa.gov/ncer/ rfa/forms/. The deadline for receipt of applications is 10 July 2003. Complete information on this announcement is available at http://es.epa. gov/ncer/rfa/current/2003_microbial.html.

Contact: Cynthia Nolt-Helms, 202-5646763, e-mail: [e-mail] (e-mail inquiries are preferred). Reference: 2003-STAR-H1 for research area 1 (development of indices or classification schemes to characterize microbial risk); 2003-STAR-H2 for research area 2 (epidemiological investigations)