The Health Effects Institute

RFA 98-1: Characterization of Exposure to and
Health Effects of Particulate Matter

Contents:
Background
Overview
RFA 98-1A: Characterizing exposure to Particulate Matter
RFA 98-1B: Health effects of Particles: Dosimetry and pathophysiologic changes related to Particle Size and Composition
Overall Program Goals and Time Frame
References
Application Process and Deadlines
Evaluation Process

BACKGROUND

Particulate matter (PM) comes from many sources and varies in size, chemical composition, and other physical, chemical, and biological properties depending on the sources of the particles and the changes they undergo in the atmosphere. Recently, the U.S. Environmental Protection Agency (EPA) promulgated new National Ambient Air Quality Standards (NAAQS) for PM. In addition to retaining the current 24-hour and yearly standards for PM10, EPA added new 24-hour and yearly standards for PM2.5 (Federal Register 1997). The decision to introduce standards regulating the levels of fine particles was based on "comparisons between fine and coarse particles [suggesting] that fine particles are a better surrogate for those particle components linked to mortality and morbidity effects at levels below the current standards" (U.S. Environmental Protection Agency 1996b). To the extent possible, efforts to control the levels of particles should focus on the sources of particles associated with health effects.

Compliance with NAAQSs is based on measurements of PM10 taken at defined outdoor monitoring sites in the United States. The epidemiologic studies that show an association between increased levels of particulate air pollution and increases in morbidity and mortality have relied on these ambient measurements as surrogates for personal exposure. However, the assumption that ambient exposure data are an adequate surrogate for personal exposure to PM has not yet been validated. To do so, we must understand better how the data for ambient particle levels relate to personal exposure, which involves varying amounts of time outdoors for individual members of the population.

Although the association between increased levels of PM and increased morbidity and mortality observed in epidemiologic studies is relatively consistent, toxicologic studies to corroborate these findings have only recently begun. After inhalation, the particles that deposit in the respiratory tract (dose) and their ultimate fate depend on many parameters or attributes of both the particles and the subjects inhaling them. Determining the dose and fate of inhaled particles is important for linking exposure information to health effects, extrapolating findings across species, and investigating mechanisms of effects in the body.

Preliminary results from studies with animal models of human diseases have shown that exposure to particles may produce alterations in cardiac function (Godleski et al. 1997) and pulmonary inflammation (Killingsworth et al. 1997; Kodavanti et al. 1997). However, additional animal and human studies need to be conducted to confirm these findings and determine whether the effects could result from exposure to environmentally relevant levels of particles, to understand the characteristics and components of the particles responsible, and to investigate the sequence of events that might lead to morbidity and mortality.

OVERVIEW OF RFA 98-1

Current research being conducted by HEI and other organizations is addressing some of the critical exposure and health effects questions about PM (a summary of HEI's research efforts is provided in the Strategic Plan Update, available by sending an E-mail to: pubs@healtheffects.org). Nevertheless, to provide a substantial body of information to contribute to the next EPA review of the NAAQSs for PM, which will begin in 1999, many key questions remain to be addressed. After considering research plans from other institutions, HEI has selected a focused set of research topics. The goals for HEI's targeted and highly coordinated effort are described in three sections.

CHARACTERIZING EXPOSURE TO PARTICULATE MATTER

Although a large body of epidemiologic research suggests that exposure to ambient particulate air pollution (PM10 and PM2.5) may cause both acute and chronic health effects, lack of information on a number of key aspects of exposure to particles complicates interpreting this research, assessing human risk, and designing preventive control strategies.

Most epidemiologic studies of the acute health effects of PM have used measurements of PM taken at stationary monitoring sites as surrogate values of personal exposure, and analyzed the morbidity and mortality data for a given population in relation to that estimate of PM exposure (U.S. Environmental Protection Agency 1996a). However, so far, there are insufficient data to confirm the assumption that ambient particle levels can be used as indicators of personal exposure. Exposure data have been collected to evaluate the relationship between PM concentrations in different microenvironments (indoors and outdoors) and ambient PM concentrations (measured at centrally located monitors) and how these relate to personal exposure. For the most part, however, these studies were not designed to address directly the uncertainties in the epidemiologic studies (e.g., temporal variation). Few of the studies have dealt with other pollutants whose levels vary spatially and temporally with the levels of PM.

Ambient particles vary in composition and physical characteristics depending on their source. Because strategies to reduce particulate emissions need to target relevant sources, further research is needed to understand how particles from different sources affect personal exposure as well as the relative toxicity of different types of particles. The relationships between and among ambient levels, microenvironmental levels, and personal exposure and dose of PM need clarification; and epidemiologic studies need to be designed in which personal exposure information (coupled with time-activity information) is used to assess health risk. In addition, because personal exposure is in many cases dominated by time spent indoors, we need to characterize indoor particles and understand how outdoor particles contribute to the indoor mixture.

EXPOSURE OBJECTIVES

The main objective of RFA 98-1A is to characterize personal exposure to particles in different indoor and outdoor microenvironments, and in geographic locations that differ in types and sources of particles, topography, and climate; and to apply better characterization to improve exposure estimates in epidemiologic studies. Studies to address this objective should determine particle characteristics (e.g., concentration, size, and composition) and describe the relation between personal exposure and the measures of exposure that are typically used in epidemiologic time-series studies. This goal includes addressing questions about similarities or differences in the levels and characteristics of particles in various microenvironments, how outdoor particles contribute to indoor particle levels, and individual activities and activity patterns that influence personal exposure and resulting dose. HEI encourages investigators to pursue studies designed to characterize personal exposure for defined population subgroups selected on the basis of their presumed susceptibility to particles.

Studies should include the following attributes:

In addition, HEI encourages multidisciplinary applications that link exposure studies with:

RFA 98-1B. HEALTH EFFECTS OF PARTICLES: DOSIMETRY AND PATHOPHYSIOLOGIC CHANGES RELATED TO PARTICLE SIZE AND COMPOSITION

Recent population-based epidemiologic studies carried out in several different communities indicate a relatively consistent association between increases in morbidity and mortality and short-term increases in ambient particulate air pollution (for a review, see U.S. Environmental Protection Agency 1996a). These findings relate to both total mortality and mortality from cardiovascular and respiratory diseases separately, and to both daily fluctuations in mortality and chronic effects measured across different communities with different ambient concentrations of particles. Similar associations have been found for rates of hospital admissions for respiratory and cardiovascular diseases for subjects over age 65.

These epidemiologic results, although reproducible, have been subject to intense debate for a variety of reasons, including questions about which analytic approaches are most appropriate to use, uncertainties in how exposure was assessed in people at risk, and the lack of a specific biologic mechanism to explain the observed association. Recently, toxicologic studies have been undertaken to attempt to replicate this association between health effects and exposure to particles in compromised animals, to evaluate the sensitivity of various animal models of human disease, to investigate mechanisms by which a short-term increase in particle levels might cause morbidity and mortality, and to understand which particle characteristics or components might be associated with the adverse effects. For example, preliminary results from a study with dogs have suggested that exposure via inhalation to concentrated ambient particles at levels not much in excess of those in polluted environmental settings produces electrocardiographic changes that are considered to be an indicator of life-threatening cardiac arrhythmias (Godleski et al. 1997). This study raises questions as to whether these findings can be extrapolated to and reproduced in free-living people. Other potential effects of particles, such as increased vulnerability to respiratory infections, increased frequency and severity of asthma attacks, and pathophysiologic changes in the lung, also need further investigation in animal and human studies.

In addition to questions about mechanisms by which relatively low levels of particles may cause adverse health effects, questions about dosimetry need to be addressed. It is not clear how measurements of particle exposure (usually in units of mass per volume of air) taken at central monitoring sites, or even personal exposure measurements, might be related to the dose of particles deposited in the respiratory tract in individuals with different activity patterns and physiologic parameters. Although attempts have been made to model particle deposition and clearance as a function of particle size, many uncertainties remain about the actual dose of particles in the lung and their persistence, whether particle components are biologically available, and the roles of different types of cells in clearing particles from the lungs.

HEALTH EFFECTS OBJECTIVES

HEI's goal in requesting proposals under RFA 98-1B is to fund a targeted, coordinated set of studies that will elucidate:

In order to provide the spectrum of information needed, and ultimately to relate the results to humans, HEI is seeking a combination of approaches including epidemiologic studies and laboratory exposure studies with animals and humans. In order to understand which particles may be responsible for health effects, HEI is interested in studies using:

All epidemiologic and laboratory exposure studies should include detailed analyses of size, biological composition (e.g., endotoxins, pollens, bacteria, allergens, spores), and chemical composition of particles. Inhalation is the preferred route of exposure in animal and human studies.

TYPES OF STUDIES AND ENDPOINTS OF INTEREST

(1) Epidemiologic Studies of Cardiorespiratory Function and Other Relevant Endpoints

These studies would seek to determine whether the subclinical changes seen in preliminary animal studies involving exposure to concentrated ambient particles occur in people exposed to particles under real-world conditions. The studies also would compare effects in different geographic regions with different ambient particulate concentrations. In addition, they would measure personal exposure and activity patterns that also could be used to decrease uncertainties in exposure estimates in the time-series epidemiologic studies (as sought in RFA 98-1A). Such studies should

HEI encourages applicants to propose collaborative efforts with investigators applying to characterize exposures as described above in RFA 98-1A. In addition, HEI will work with the funded investigators to maximize similarities in study design and in endpoints measured so as to enhance the comparability of results among studies conducted at different locations with different types of particles and patterns of copollutants.

(2) Controlled-Exposure Studies with Humans to Investigate Cardiorespiratory and Other Endpoints Related to the Effects Seen in Animal Studies

Controlled-exposure studies with humans could measure a broader variety of endpoints than are feasible in field studies. If subclinical effects occur in "nonsusceptible" individuals at some level of exposure to particles, and in susceptible individuals at lower levels of exposure, it is likely that these effects would be detectable in a relatively small number of subjects. Once the effects are identified, they would be useful in beginning to define the biologic mechanisms involved. These studies might also help characterize the dose-response relationship, or include exposures to particles combined with other pollutants to identify possible interactions.

Because the ECG effects seen in preliminary results from studies with dogs are potentially very serious in humans, and because the pathogenic mechanisms are not understood, it is important to proceed carefully in exposing people to concentrated ambient or other particles. This would mean conducting initial experiments with normal subjects at relatively low levels of exposure, and then proceeding to higher concentrations. Potentially susceptible subjects could then be studied at low concentrations and later at increased levels. Exposure can be progressively increased through exercise, higher concentrations of particles, and longer durations.

(3) Animal Studies to Attempt to Replicate, Further Explore, and Extend Preliminary Findings of Particle Exposure Effects on Cardiac and Respiratory Functions and of Changes in Other Pathophysiologic Processes That May Be Associated with Increased Morbidity and Mortality

These studies might have the following aims:

(4) Studies with Animals and Humans to Characterize the Distribution and Dose of Inhaled Particles and Particle Components in the Respiratory Tract

The results of these studies would allow dose and distribution information to be compared across species. For example, histopathologic and chemical characterization of the types of particles deposited in the respiratory tract and measurements of the fates of particle constituents would be applicable approaches.

Please note that applications to this RFA can propose a combination of approaches. For example, dosimetry studies could be combined with health effects studies, or an investigator may want to conduct field studies first and then use a subset of that study population in a controlled-exposure study. HEI is not interested in applications using only in vitro methods; however, applications that include in vitro experiments in combination with animal or human health effects studies would be considered.

OVERALL PROGRAM GOALS AND TIME FRAME

A large component of the research program to be funded under RFA 98-1 is intended to provide results for the next review of the NAAQS for PM. In order to produce and integrate information over the next two years to contribute to that review, HEI has developed a framework for research that will coordinate the exposure and health effects objectives described above. This set of studies would likely include:

HEI also wants to coordinate its research program with existing exposure studies by EPA and other organizations, and would welcome applications that are integrated with ongoing exposure assessment efforts. Investigators planning studies at certain geographic sites are urged to discuss their plans with other investigators who have research under way or soon to be initiated in that same area so that new studies can build on and complement others (e.g., in Baltimore, Phoenix, and elsewhere).

The framework described above calls for integrating exposure assessment and health effects studies around particular sites. Some integration must be planned during the application phase, and HEI is counting on interested scientists to contact colleagues with different types of expertise at other institutions to discuss possible collaborations. Related applications may be submitted as (1) a composite application (e.g., exposure and epidemiology in one application) that represents more than one institution but has one principal investigator, or (2) separate but coordinated applications from two or more institutions. Some investigators may want to submit applications for multi-center studies at two or more sites. To meet its programmatic goals, HEI may fund one multi-site study, several single-site studies, or a combination. Further integration of studies will be done after applications have been selected for funding.

Because of the short time frame for this research, applicants should be prepared to work with HEI's Research Committee and scientific staff, and with other investigators, in the summer of 1998 to develop protocols for their studies that are well coordinated with related studies, and to start their research at full effort immediately. The goal of the coordinated approach is to maximize similarities in study design and endpoints to be measured so as to enhance the ability to compare results from studies conducted at different locations, with different types of particles, and with different subject populations. Rather than specifying particular protocols in this RFA, HEI is relying on applicants to develop interesting and unique approaches, and then will work with investigators to mold the funded studies into a highly coordinated program.

In order to facilitate the rapid implementation of studies, HEI is planning to purchase or otherwise make available two or three particle concentrators to successful applicants to RFA 98-1 who are interested in conducting human or animal studies with concentrated ambient particles. The criteria that will be used to decide whether or not a study that proposes to use an ambient particle concentrator will be funded include (1) experience and expertise on the team of investigators in conducting chamber studies involving particle exposure, and in monitoring exposure to and characterizing particles; (2) the nature and concentration of the ambient particulate mixture at the location of the applicant's laboratory; (3) merit of the study aims and design; (4) applicant's description of how the concentrator will be used, how its performance will be evaluated, and the types of analyses that will be conducted to characterize the particles; and (5) adequacy of the available laboratory space for installing an ambient particle concentrator. HEI is still developing plans for acquiring particle concentrators, but intends to have them available for installation in August 1998. Applicants should indicate their interest in using one of HEI's particle concentrators in their Letters of Intent and include in their applications detailed information relevant to the evaluation criteria listed above for potential recipients of particle concentrators. Investigators desiring more information about HEI's plans for providing particle concentrators should call Dr. Jane Warren at HEI (617) 876-6700.

Studies funded under RFA 98-1 will start in the summer of 1998. Investigators conducting research designed to be incorporated into the next PM criteria document will be required to submit comprehensive reports on their studies by December 31, 1999, so that they can be reviewed by HEI's Review Committee and published by June 30, 2000. HEI expects most studies will be designed to provide information in this short time frame, and as appropriate, may include a second phase to extend the work for an additional year or two. A few studies designed to provide information only in a longer term (three or more years) may also be funded.

HEI intends to fund three to five exposure characterization studies, two or three epidemiologic sensitivity analyses, and six to ten health effects studies (including epidemiology, controlled human exposure, and animal studies). These will include a mix of large and small studies. The number funded in each category will depend in part on the quality of the applications and on how broad study objectives are. HEI has available between $5 and $7 million for research funded under this set of RFAs.

REFERENCES

Federal Register. 1997. Environmental Protection Agency: National Ambient Air Quality Standards for Particulate Matter; Final Rule. July 18, 1997. 40 CFR Part 50, pp. 1-54.

Godleski JJ, Lovett EG, Sioutas C, Killingsworth CR, Krishna Murthy GG, Hatch V, Wolfson JM, Ferguson ST, Koutrakis P, Verrier RL. 1992. Impact of inhaled concentrated ambient air particles on canine electrocardiographic patterns (abstract). Thirteenth HEI Annual Conference, May 4-6, 1997, Annapolis, MD. Health Effects Institute, Cambridge, MA.

Killingsworth CR, Alessandrini F, Krishna Murthy GG, Catalano PJ, Paulauskis JD, Godleski JJ. 1997. Inflammation, chemokine expression, and death in monocrotaline-treated rats following fuel oil fly ash inhalation. Inhalation Toxicol 9:541–565.

Kodavanti UP, Jaskot RH, Costa DL, Dreher KL. 1997. Pulmonary proinflammatory gene induction following acute exposure to residual oil fly ash: Roles of particle-associated metals. Inhalation Toxicol 9:679–701.

U.S. Environmental Protection Agency. 1996a. Air Quality Criteria for Particulate Matter, Vol. III. EPA/600/P-95/001cF. Office of Research and Development, Washington, DC.

U.S. Environmental Protection Agency. 1996b. Review of the National Ambient Air Quality Standards for Particulate Matter: Policy Assessment of Scientific and Technical Information. OAQPS Staff Paper. EPA-452\R-96-013, July 1996. Office of Air Quality Planning and Standards, Research Triangle Park, NC.

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.

Deadline for Letters of Intent: The Letter of Intent should be received no later than WEDNESDAY, FEBRUARY 18, 1998 at the following address:

Ms. Francine Marmenout
Administrative Assistant
Health Effects Institute
955 Massachusetts Avenue
Cambridge, MA 02139
Tel: (617) 876-6700

FULL APPLICATION

Investigators are asked to prepare a full application will be sent the appropriate application forms to be completed. Inquiries regarding application and evaluation procedures may be directed to Dr. Jane Warren or Dr. Maria Costantini. 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 98-1 must either reach the office of the Health Effects Institute by WEDNESDAY, APRIL 1, 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 emission 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.

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 evaluated applications according to the following criteria:

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.

Home | About HEI | What's New? | Newsletter | HEI International | Publications
Research | Funding | Meetings | Contact HEI | Links | Search | Site Map
Copyright © 2010 Health Effects Institute. Please send comments to webmaster@healtheffects.org