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             Five Years of Progress

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                                          EPA 600/R-04/058
                                                July 2004
                                             www.epa.gov
Particulate Matter Research Program
          Five Years of Progress
          U.S. Environmental Protection Agency
           Office of Research and Development
                Washington, DC 20460

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Notice
The information in this document has been subjected to review by the U.S. Environmental Protec-
tion Agency, Office of Research and Development, and has been approved for publication.  Approval
does not signify that the contents reflect the views of the Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation for use.
Abstract

This report summarizes the major accomplishments of the U.S. Environmental Protection Agency's
Particulate Matter (PM) Research Program achieved since 1997. Among the most notable achieve-
ments is that scientists have quantitatively established that exposure to ambient particulate matter
(PM) is associated with morbidity and mortality.  Significant progress has also been made in under-
standing the influence of PM size and composition on unwanted health outcomes, in uncovering the
biological mechanisms which link PM exposure to adverse health outcomes, and in discovering the
human characteristics which increase susceptibility to adverse health outcomes. Additionally, ad-
vances in PM science have provided information about the deposition and fate of particulates in the
respiratory tract as well as about the sources of particulate air pollution and about the atmospheric
processes that influence PM chemistry and transport. These research outcomes provide the basis for
scientifically defensible regulatory actions and support the Agency's ongoing mission of ensuring
that the air in every American community is safe and healthy to breathe.
Particulate Matter Research Program

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Foreword
       With this report, I am proud to present a summary of the major accomplishments achieved
by the U.S. Environmental Protection Agency's Particulate Matter (PM) Research Program since
the promulgation of the National Ambient Air Quality Standards for PM in 1997. Among the
most notable achievements is that Agency scientists and our research partners have quantitatively
established that exposure to ambient PM is associated with morbidity and mortality. We have also
made significant progress in understanding the influence of PM size and composition on unwanted
health outcomes, in uncovering the biological mechanisms which link PM exposure to adverse
health outcomes, and in discovering the human characteristics which increase susceptibility to
adverse health outcomes. Additionally, we have learned important information about the deposition
and fate of particulates in the respiratory tract as well as about the sources of particulate air pollution
and about the atmospheric processes that influence PM chemistry and transport.

       These accomplishments are the product of a successful and ongoing collaborative research
performed by Agency scientists, extramural investigators funded by EPA, and partners such as
the Health Effects Institute (HEI). Other Federal organizations (including the National Institutes
of Health and the Department of Energy) and others participating in the Air Quality Research
Subcommittee of the Federal Committee on Environment and Natural Resources (CENR) have also
made substantial contributions to our efforts to advance PM science.

       The advancements in PM science achieved through these partnerships since 1997 provide a
sound basis for scientifically defensible regulatory actions. Bolstered by these successes and driven
by a sustained commitment to ensuring that the air in every American community is safe and healthy
to breathe, the Agency will continuing our efforts to better understand the complex issues associated
with particulate matter.
                                 Paul Oilman, Ph.D.
                                 Assistant Administrator
                                                               Five Years of Progress

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Contents

Notice	ii
Abstract	ii
Foreword	iii
Contents	iv
Acronyms and Abbreviations	viii
Acknowledgments	x
Introduction	1
  Purpose and Content of this Report	1
    Setting the Stage	2
  Research Planning and Related Activities	4
    The NRC Committee	4
    EPA Research Planning Activities	5
    Grants Focused on PM Research	6
    PM Research Centers	6
    PM Supersites Program	7
    Health Effects Institute	8
    ORD In-House Research	8
    Integration with Other Federal Agencies, the Private Sector, and Other Governmental
    Organizations	9
  Five Years of Progress	10
  References	11
Research Topic 1. Outdoor Measures Versus Actual Human Exposures	13
  Introduction	14
  Key Uncertainties, Objectives, and Special Issues	15
  Major Accomplishments	16
    Longitudinal PM Exposure Studies	16
    Controlled Experiments	18
    The Stochastic Human Exposure and Dose Simulation Model	18
  Programmatic Need and Relevance	19
  Future Directions	20
  References	21
Research Topic 2. Exposures of Susceptible  Subpopulations to Toxic Particulate Matter
Components	23
  Introduction	24
  Key Uncertainties, Objectives, and Special Issues	24
  Major Accomplishments	25
  Programmatic Need and Relevance	26
  Future Directions	27
  References	28
Particulate Matter Research Program

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Research Topic 3. Characterization of Emission Sources	31
  Introduction	32
  Special Issues, Objectives, and Key Uncertainties	33
  Major Accomplishments	33
    NRC Committee Recommendation:  Establish Standard Source-Test Methods for
    Measurement of Particle Size and Chemical Composition	33
    NRC Committee Recommendation:  Characterize Primary Particle Size and
    Composition of Emissions	34
    NRC Committee Recommendation:  Develop New Measurement Methods and Use of Data
    To Characterize Sources of Gas-Phase Ammonia and Semivolatile Organic Vapors	36
    NRC Committee Recommendation:  Translate New Source-Test Procedures and
    Source-Test Data into Comprehensive National Emission Inventories	36
    Additional Research: Evaluation of PM and PM Precursor Control Technology
    Performance	37
  Programmatic Need and Relevance	38
  Future Activities	39
  References	40
Research Topic 4. Air-Quality Model Development and Testing	43
  Introduction	44
  Key Uncertainties and Special Issues	44
  Major Accomplishments	45
    Source-Oriented Models	45
    Receptor-Oriented Models	47
    Atmospheric Chemistry	48
  Programmatic Need and Relevance	49
  Future Directions	50
    Source-Oriented Models	50
    Receptor-Oriented Models	51
    Atmospheric Chemistry	51
  References	52
Research Topic 5. Assessment of Hazardous Particulate Matter Components	55
  Introduction	56
  Key Uncertainties, Objectives, and Special Issues	56
  Major Accomplishments	57
    Physicochemical Attributes of PM	58
     Acid Aerosols	58
     Ultrafine PM (Size, Surface Area, Number)	59
     Fine and Coarse PM	59
    Chemical Properties	60
     Inorganic Constituents	60
     Metals	61
     Organic Constituents and Diesel Exhaust Particles (DEPs)	62
     Biogenic Constituents	63
     Source-Specific Effects	64
  Programmatic Need and Relevance	64
  Future Directions	65
  References	66


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Research Topic 6. Dosimetry: Deposition and Fate of Particles in the Respiratory Tract	71
  Introduction	72
  Key Uncertainties, Objectives, and Special Issues	72
  Major Accomplishments	73
  Programmatic Need and Relevance	75
  Future Directions	76
  References	77
Research Topic 7. Combined Effects of Particulate Matter and Gaseous Pollutants	79
  Introduction	80
  Key Uncertainties, Objectives, and Special Issues	80
  Major Accomplishments	81
    Gaseous Co-Pollutants	81
    Studies on Long-Term Exposure to PM	82
  Programmatic Need and Relevance	85
  Future Directions	86
  References	88
Research Topic 8. Susceptible Subpopulations	91
  Introduction	92
  Key Uncertainties, Objectives, and Special Issues	92
  Major Accomplishments	93
    Ambient PM Exacerbation of Respiratory Disease Conditions	93
    Ambient PM Exacerbation of CVD Conditions	95
    Age-Related At-Risk Population Groups:  The Elderly and Children	96
    Chronic Exposures and Susceptibility	96
  Programmatic Need and Relevance	97
  Future Directions	98
  References	99
Research Topic 9. Mechanisms of Injury	103
  Introduction	104
  Key Uncertainties, Objectives, and Special Issues	105
    PM-induced Inflammation	106
    Effect of PM on Infectivity	106
    PM Affects Autonomic Control of the Heart	107
    PM Alters Cardiac Repolarization	108
    PM Exposure Is Associated with Cardiac Arrythmias and Mis	108
    Interaction Between PM and/or Its Soluble Components and the Heart	109
    PM Exposure Can Affect the Vascular System	110
  Programmatic Need and Relevance	Ill
  Future Directions	Ill
  References	112
Participate Matter Research Program

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Research Topic 10. Analysis and Measurement	115
  Introduction	 116
  Key Uncertainties	 116
  Major Accomplishments	 116
    Statistical Methods	116
     Multi-city Analyses	 116
     Spatial Analytical Methods	117
     "Harvesting"	 117
     Dose-Response/Threshold Issues	117
     Confounding	 118
     Model Specification	118
     Statistical Techniques	118
     Alternative Statistical Techniques	 119
    Measurement Error and Misclassification	 119
     Spatial Error	 119
     Difference Between Ambient Concentration and Exposure	120
    Uncertainties in the Measurement of Ambient Concentrations	120
     Precision	120
     Loss of Semivolatile PM Mass in PM Measurements	121
     Alternate Indicators	121
     Source Category Contributions	121
  Programmatic Need and Relevance	122
  Future Directions	123
  References	124
Research Topic 11. Technical Support—Atmospheric Measurements and Methods	127
  Introduction	128
  Key Uncertainties, Objectives, and Special Issues	129
  Major Accomplishments	130
    FRM Program	130
    Measurement of PM Species	131
    Field Studies	131
    Advanced Measurement Techniques	132
    Network Design and Implementation	133
  Programmatic Need and Relevance	133
  Future Directions	134
  References	135
Appendix A	Al
Appendix B	Bl
Appendix C	Cl
                                                            Five Years of Progress

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Acronyms and Abbreviations
ACS
ANS
AQCD
CAA
CAFO
CAP
CASAC
CENR
CFR
CMAQ
CMB
COH
COPD
CVD
DEP
DMA-APM
EC
ECG
EMEFS
EPA
EPRI
ESFF
ESP
FGD
FRMs
FTIR
GAMs
HEI
HF
HR
HRV
MI
MYP
NAAQS
NanoMOUDI
NARSTO
NCEA
NCER
NE-OPS
NERL
NHEERL
NIEHS
NIH
NIST
American Cancer Society
autonomic nervous system
Air Quality Criteria Document
Clean Air Act
concentrated animal feeding operations
concentrated ambient particle
Clean Air Scientific Advisory Committee
Committee on Environment and Natural Resources
Code of Federal Regulations
Community Multiscale Air Quality
chemical mass balance
coefficient of haze
chronic obstructive pulmonary disease
cardiovascular disease
diesel exhaust particle
differential mobility analyzer-aerosol particle mass analyzer
elemental carbon
el ectrocardi ogram
Eulerian Model Evaluation Field Study
U.S. Environmental Protection Agency
Electric Power Research Institute
electrostatically-enhanced fabric filter
Eastern Supersites Program or electrostatic precipitator
flue gas desulfurization
Federal reference methods
Fourier transform infared
general additive models
Health Effects Institute
high frequency
heart rate
heart rate variability
myocardial infarction
Multi-year Plan
National Ambient Air Quality Standard
Nano Micro-Orifice Uniform Deposit Impactor
North American Research Strategy for Ozone
National Center for Environmental Assessment (EPA)
National Center for Environmental Research (EPA)
Northeast - Oxidant and Particle Study
National Exposure Research Laboratory (EPA)
National Health and Environmental Effects Research Laboratory (EPA)
National Institute of Environmental Health Sciences
National Institutes of Health
National Institute of Standards and Technology
Participate Matter Research Program

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NMMAPS    National Morbidity, Mortality, and Air Pollution Study
NRC         National Research Council
NRMRL     National Risk Management Research Laboratory (EPA)
NYU        New York University
OAQPS      Office of Air Quality, Planning, and Standards (EPA)
OAR        Office of Air and Radiation (EPA)
OC          organic carbon
ORD         Office of Research and Development (EPA)
PAHs        polycyclic aromatic hydrocarbons
PCM        particle composition monitor
PM          particulate matter
PMF         positive matrix factorization
PMx         particulate matter smaller than x symbolmu/im in aerodynamic diameter
RFA         Requests for Applications
ROFA       residual oil fly ash
SAB         Science Advisory Board (EPA)
SAMI       Southern Appalachian Mountains Initiative
SCISSAP     Southern Center for the Integrated Study of Secondary Air Pollutants
SCR         selective catalytic reduction
SDNN       standard deviation of normal to normal
SEM         scanning electron microscope
SHEDS      Stochastic Human Exposure and Dose Simulation
sICAM-1     soluble intercellular adhesion molecule-1
SIP          State Implementation Plan
SMVGEAR  Spars-Matrix, Vectorized Gear Code
SOA         secondary organic aerosol
SOS         Southern Oxidant Study
STAR       Science To Achieve Results
STN         Speciation Trends Network
SVOC       semivolatile organic compound
TEOM       tapered element oscillating microbalance
TOFMS      time-of-flight mass spectrometry
TSP         total suspended particulate
TVA         Tennessee Valley Authority
UCLA       University of California, Los Angeles
VOC         volatile organic compound
XRF         X-ray fluorescence
                                                            Five Years of Progress

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Acknowledgments
       This document was prepared by members of
      the ORD PM Research Management Team and
      by research staff in the PM Research Program.
                    Lead Author

                     Daniel L. Costa
      (National Health and Environmental Effects Research Laboratory)
Participate Matter Research Program

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Contributing Authors:

Jennifer Bland (National Center for Environmental Research)
Janet Burke (National Exposure Research Laboratory)
Robert B. Devlin (National Health and Environmental Effects Research Laboratory)
Edward O. Edney (National Exposure Research Laboratory)
Chris Geron (National Risk Management Research Laboratory)
Barbara S. Glenn (National Center for Environmental Research)
Lester D. Grant (National Center for Environmental Assessment)
D. Bruce Harris (National Risk Management Research Laboratory)
Stacey A. Katz (National Center for Environmental Research)
John Kinsey (National Risk Management Research Laboratory)
Charles Lewis (National Exposure Research Laboratory)
Joellen Lewtas (National Exposure Research Laboratory)
William P. Linak (National Risk Management Research Laboratory)
John P. Meckley (Office of Resources Management and Administration)
C. Andrew Miller (National Risk Management Research Laboratory)
Lucas Neas (National Health and Environmental Effects Research Laboratory)
Gail M. Robarge  ((National Center for Environmental Research)
Shawn Roselle (National Exposure Research Laboratory)
Mary Ross (Office of Air and Radiation, Office of Air Quality Planning and Standards)
Ken Schere (National Exposure Research Laboratory)
Linda S. Sheldon (National Exposure Research Laboratory)
Paul A. Solomon (National Exposure Research Laboratory)
N. Dean Smith (National Risk Management Research Laboratory)
John D. Vandenberg (National Center for Environmental Assessment)
James Vickery (National Exposure Research Laboratory)
Estella Waldman (National Center for Environmental Research)
Timothy H. Watkins (National Exposure Research Laboratory)
Ronald W. Williams (National Exposure Research Laboratory)
William E. Wilson (National Center for Environmental Assessment)
Darrell A. Winner (National Center for Environmental Research)
Joanne Cook of the National Health and Environmental Effects Research Laboratory provided sub-
stantial assistance in preparation of the text and references and in compiling the contributions from
the different authors. This document could not have been generated without her efforts.
                                                             Five Years of Progress

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The air in every American community will be safe



and healthy to breathe. In particular, children, the



  elderly, and people with respiratory ailments will



                 be protected from health risks of



                           breathing polluted air.



                                —EPA Strategic Plan 2000

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Introduction

Purpose and Content of this Report

    3y 1996, evidence had accumulated that suggested day-to-day exposures to ambient
    particulate matter (PM) at or near the level of the then current National Ambient Air Quality
    Standards (NAAQS) were eliciting significant human health effects in the U.S. population,
including hospitalizations and attributable deaths.  This evidence led to the promulgation of PM
NAAQS in 1997 that included new standards for PM smaller than 2.5 um  in aerodynamic diameter
(PM25).1 Uncertainties regarding PM health effects prompted Congress to augment the President's
recommended U.S. Environmental Protection Agency (EPA) budget of $27.8 million for PM
research in 1998 by $22.4 million, and this level of investment in PM research has been largely
maintained since that time.  EPA was charged with accelerating investigations of the role of PM in
air pollution-associated health outcomes and implementing health risk reductions via scientifically
defensible regulatory actions.

Five years of intensive research activity have yielded significant advances in the understanding
of the role of PM in causing health effects.  In general, the advances lie in  three broad areas: (a)
the complex roles of PM attributes and human host factors that contribute  to the health outcomes
and (b) the factors determining public and individual exposures, and (c) the characterization of the
sources and atmospheric processes. A comprehensive national research endeavor was initiated by
EPA in 1998 and currently involves the coordinated efforts of intramural and EPA-funded extramural
investigators, partners, and other federal organizations that function within a scientific framework
of research needs developed by an independent National Academy of Sciences National Research
Council (NRC) committee of experts.

Yet, while much has been learned in this timeframe - the first steps of an ambitious long-range plan
- there remains considerable uncertainty regarding PM-associated health effects. For example,
the research concerning the components and attributes of PM has raised several hypotheses that
may help explain relationships between particles and health and thus require further investigation,
perhaps within the context of source profiling and attribution. With the discovery that many of the
adverse responses to PM exposure appear in individuals who are members of susceptible
subpopulations, futher research is needed on the factors and mechanisms that underlie susceptibility.
And finally, there are uncertainties regarding potential long-term health outcomes - from exposure
measurements to quantifying the extent of possible life-shortening.
'The standard nomenclature is to refer to PM smaller than x |jm in aerodynamic diameter as PMx. The use of PMx
indicates particles between x and y |jm in aerodynamic diameter.
                                                             Five Years of Progress

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The goal of these efforts, of course, is to provide health data appropriate to the review of the NAAQS.
In addition, regulators at the federal and state levels who must implement the NAAQS depend
on predictive and evaluative tools to determine compliance and to develop the needed mitigation
strategies. As the understanding of atmospheric processes and source-to-receptor relationships
improves, these tools are refined with new data and thus are ever-evolving. Research to refine the
databases, reference methods, and atmospheric models that support regulatory needs is crucial to the
mission of the EPA Office of Research and Development (ORD) PM Research Program.

This report is intended to summarize and highlight the salient EPA-funded scientific advances in
PM health, exposure, and implementation research since 1997.  The following discussion is framed
according to the priority research needs noted in the four NRC reports published to date (specifically
the third report,2 which is outlined in a following section) and in the context of the programmatic
and regulatory needs of EPA's Office of Air and Radiation (OAR). To simplify the "Major
Accomplishments" narrative for each research topic, EPA and/or ORD are used to designate the PM
Research Program and only selected prominent or illustrative publications are referenced in the text.
(Appendix A is a complete reference list of publications from EPA-funded research. Appendix B lists
studies funded by EPA partners or other organizations; these studies are also referenced in the report
for continuity or completeness.) Finally, using the state-of-the-art techniques as reported herein, the
envisioned future directions and goals for the specific research topic area research efforts are also
discussed.

Setting the Stage
Episodes of choking air pollution, such as those experienced in Donora, PA, in 1948 and New York
City, NY, in 1962, are extremely rare events in the modern-day U.S. Almost four decades of regulatory
actions and technological advances in emission control have substantially reduced the overt threat of
severe air pollution. However, contaminated  air in the U.S. continues to have widespread effects on
human health and the environment. For example, EPA estimates that current regulations to reduce air
pollution can prevent tens of thousands of premature deaths per year and prevent perhaps hundreds
of thousands of annual hospitalizations for cardiovascular and respiratory illness (1). The monetary
benefits of preventing air-pollution-related premature deaths are estimated to be in the range of $100
billion per year.  The benefits of reducing illness and minimizing the number of lost workdays and the
consequences of restricted activity are estimated to provide an additional savings on the order of $10
billion per year.  However, these cost estimates likely underestimate the true human toll when the costs

 2The fourth and final NRC report on PM research priorities was released as this report was in preparation. Because the
 third and fourth reports were structured around the same 10 priority research areas, as is this report, and because this
 report discusses the accomplishments of the research program prior to the fourth report's completion, this document was
 not modified in response to the final NRC report.

 Participate Matter Research Program

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associated with the loss of quality of life are considered. Underscoring the issue is the fact that these
effects appear to affect certain subgroups more than others, including the elderly, the young, and
those with pre-existing cardiopulmonary problems.  To address these concerns, EPA developed a
Clean Air Goal:

The air in every American community will be safe and healthy to breathe.  In particular, children,
the elderly, and people with respiratory ailments will be protected from health risks of breathing
polluted air.

By the mid-1970s, the air looked cleaner; likewise, conventional epidemiology indicated that the
associated health problems were largely eliminated. However, beginning in the late 1980s and
throughout the 1990s, the novel application of sensitive statistical methods to epidemiological
assessments of daily patterns of air pollution revealed that significant health risks remained, most
notably those associated with ambient PM. Effects on mortality and morbidity were found at lower
concentrations than formerly appreciated.  Most striking was that these effects were observed at
levels at or below the NAAQS for PM10 contemporary with the studies.  Perhaps less surprisingly,
those most affected represented groups who generally might be considered susceptible—the elderly
and those with pre-existing cardiopulmonary disabilities. Moreover, a more  limited study suggested
that chronic PM exposure could potentially shorten life-spans in the general population (2).

Under the Clean Air Act (CAA), PM is one of six major air pollutants for which EPA has established
a NAAQS. The CAA requires periodic review of the scientific basis or "criteria" for these standards
and calls for EPA to lead the preparation of a comprehensive scientific assessment of the state of
the knowledge for each criteria air pollutant.3 The 1996 "Air Quality Criteria for Particulate Matter
Document" (PM AQCD) (2) provided the scientific basis for the current PM NAAQS  set in 1997. At
present, 5 years hence, a revised and updated draft PM AQCD has undergone several reviews by the
Clean Air Scientific Advisory Committee (CASAC) and the public.4 The Fourth External Review
Draft of the PM AQCD (4) was reviewed by CASAC in August 2003; the final revision will be
released in 2004.
3The six criteria air pollutants are carbon monoxide (CO), lead (Pb), nitrogen dioxide (NO2), ozone (O3), PM, and sulfur
dioxide (SO2).
4Due to recent revelations of problems associated with the use of certain widely-used statistical software packages in
a number of published statistical analyses of PM epidemiological data, the fourth draft of the document includes a
discussion of re-analyses of a subset of PM epidemiological studies considered to be of particular relevance to the PM
NAAQS review. Before the revisions to the fourth draft of the PM AQCD were completed, an expert panel assembled
by the Health Effects Institute (HEI) published a peer-reviewed compilation of short communications summarizing
appropriate re-analyses for affected studies addressed in an EPA workshop held November 4-6, 2002. HEI then
completed a report (3) containing the re-analyses, short communications, and commentary by its peer review panel.

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The latest PM AQCD includes discussion of the extensive body of newly available PM research
information that has been published since the publication of the 1996 PM AQCD. This includes
numerous published studies generated by EPA's PM Research Program (both intramural and
extramural components), which, starting in 1998, was rapidly expanded in order to further advance
the scientific bases underlying future PM NAAQS decisions.  The expanded EPA PM Research
Program was initiated as an integrated cross-lab and cross-center effort with high levels of
interaction with OAR and cooperation with other federal agencies, partners, and academia.  With the
development of a Multi-Year Plan (MYP) describing the long-term research priorities, the EPA PM
Research Program is forward-looking and evolving with advances in the science and with the needs
of the regulatory community. Priorities set forth in the MYP are guided by the research needs and
priorities set forth by the NRC Committee on Research Priorities for Airborne Particulate Matter and
the science needs of OAR to set and implement the PM NAAQS.

Research Planning  and Related  Activities

In 1997, the President emphasized urgent concern about PM when the new NAAQS was announced:
"The EPA, in partnership with other federal agencies, will develop a greatly expanded coordinated
interagency PM research program.  The program will contribute to expanding the science associated
with particulate matter health effects, as well as developing improved monitoring methods and
cost-effective mitigation strategies (5)." This directive, coupled with additional funds appropriated
by Congress, charged EPA to refine the assessment of PM health risks and to explore methods to
minimize these risks though monitoring and improved control measures.

The  NRC Committee
To implement this expanded program, Congress asked EPA to arrange for an independent
study  by the National Academy of Sciences through a specially convened NRC panel, the NRC
Committee on Research Priorities for Airborne Particulate Matter (hereafter referred to as the NRC
Committee). The purposes of the NRC Committee study were as follows:  (a) to develop priorities
for a comprehensive PM research plan; (b) to develop an outline for a PM research program that
addressed near- and long-term questions; and (c) to develop a plan to monitor research progress over
the ensuing 5 years. EPA's PM research planning process began immediately following the release
of the 1996 PM AQCD.  A public workshop was held which produced a peer-reviewed document
entitled "Particulate Matter Research Needs for Human Health Risk Assessment To Support Future
Reviews of the National Standards for Particulate Matter" (6).
Particulate Matter Research Program

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Drawing from this document, a preliminary workplan developed by EPA staff, and the panel's broad
range of expertise on the topic, the NRC Committee prepared its initial report in 1998.  It has published
a total of four reports:  "Research Priorities for Airborne Particulate Matter: I.  Immediate Priorities and
a Long-Range Research Portfolio" (7); "II:  Evaluating Research Progress and Updating the Portfolio"
(8); and "III: Early Research Progress" (9); and "IV: Continuing Research Progress" (10).  The fourth
and final report provides an assessment of research progress over the five years of the PM Research
Program and outlines a vision of research priorities and needs meriting attention in coming years.  In
the published reports, the NRC Committee identified important research topic areas and recommended a
multi-year portfolio  and approach to address the highest priority research topics designed to strengthen
and expand the scientific understanding of the links between ambient PM and adverse health effects.  In
its initial report, the NRC Committee did not consider research activities associated with implementing
the NAAQS (11). It has since expanded its review of EPA's PM Research Program to include
implementation-related research in recognition of the close connections between implementation and
health effects.

EPA Research Planning Activities
In 1998, EPA developed an internal draft research strategy that encompassed the NRC Committee's
recommended research priorities. This research strategy also drew from documents and presentations
of a cross-section of groups in both the public and private sector, including other federal organizations
and agencies (e.g., the Committee on Environment and Natural Resources, or CENR, discussed later in
this report); various state agencies; research partners (e.g., HEI);  private groups (e.g., the Electric Power
Research Institute, or EPRI); and  other scientific institutions (e.g., National Institutes of Health, orNIH);
and universities.  The result was the development of a focused, comprehensive, and coordinated program
of PM research spanning the risk  identification/assessment/management paradigm.

This draft strategy was translated  into a working document, the MYP, which could be used for internal
program planning and the evaluation of progress.  The MYP outlines the direction of the program
with long-term and annual  goals;  has associated specific measures of performance, achievement, and
productivity along well-defined pathways; and includes timelines for each long-term goal. Even though
the MYP establishes a strategy, it is used as a living document that is reviewed  quarterly to assess
progress and is revised biannually in the context of OAR regulatory and science program needs. To
oversee coordinated PM research efforts across ORD, across the Agency, and among EPA's partners in
the public and private  sectors,  ORD established the position of National Program Director for PM.  This
person facilitates cooperation and communication about these research activities, both internally and
externally, and is responsible for ensuring that the research program is meeting EPA's science needs
related to PM. EPA's other offices, including the EPA Regional Offices, have also made substantive
contributions to the development  of the MYP, its review, and resource alignments. The MYP also
identifies areas of research that can benefit other EPA research programs to maximize the impact from
each research investment.

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Grants Focused on PM Research
One component of EPA's research strategy is the extramural grants program.  The Science to Achieve
Results (STAR) Program, managed by the National Center for Environmental Research (NCER),
funds research grants in numerous environmental science, engineering, and health disciplines
through a competitive solicitation process and independent peer review.  The program engages the
nation's best scientists and engineers in targeted research that complements EPA's own intramural
research program and those of its partners and other federal agencies.  The focus of the STAR
research program for air has been structured around the priorities identified in the NRC Committee
reports, as well as EPA's PM strategy and MYP.  Requests for Applications (RFAs) are developed
by a team of experts from the ORD labs and OAR to ensure that the research funded will address
high programmatic priorities and be an integral part of the total research program.  In eight years
since  1995, the STAR program has awarded 77 research grants related directly to PM research. The
research generated by way of the STAR Program has significantly expanded the scientific literature
on PM health effects, exposure, emission sources, and atmospheric transformations.

PM Research Centers
In the 1998 EPA Appropriations Bill, Congress directed EPA to establish as many as five PM
university research centers as part of the  expanded ORD PM Research Program. The PM Research
Centers Program began in 1999 with a STAR Program RFA. The RFA was structured around the
research areas identified in the NRC Committee's 1998 report "Research Priorities for Airborne
Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio" (7). Of the 20
applications received, five university PM research centers were selected, and their work is adding
greatly to the body of knowledge related to PM health effects and exposure. While all of the PM
research centers are investigating the health effects of PM,  each has a different focus.  Harvard
University is focusing on urban PM exposure, susceptible populations, and biological mechanisms.
New York University (NYU) work targets specific PM components and size fractions. The
University of Washington's Northwest PM Research Center focuses on the contributions of wood
smoke, agricultural burning, and wildfires to ambient PM.  A consortium of southern California
universities, led by the University of California, Los Angeles (UCLA), is focusing on PM pollution
from mobile sources. The University of Rochester's PM Research Center is working to understand
the behavior and health effects of ultrafine particles.
Particulate Matter Research Program

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In a somewhat unprecedented manner, the ORD in-house PM Research Program is often considered
the sixth PM Research Center of the EPAPM Research Program as a means to prevent redundant
efforts and ensure a coherent approach across the entire program. Over time, the National Program
Director for PM has worked with the extramural PM research center directors to develop productive
liaisons with and between the five PM research centers, emphasizing research communication
and, to the extent possible, collaboration. The PM research center directors and selected staff
meet annually among themselves and with EPA science managers and staff to discuss research
progress, future directions, and organizational  issues. The  extramural PM research centers have
prepared an interim report for the first two and a half years of funded work which was reviewed by a
subcommittee of EPA's Science Advisory Board (SAB) to assess the advantages and shortcomings of
the PM-research-centers concept and the value of cross-center integration (12,13). The report found
favorably for the benefits of the centers to the EPAPM Research Program and for the scientific
value of their integrated efforts. Additionally,  the report made several suggestions for improving
interactions among the centers and with the EPA in-house PM Research Program.

PM Supersites Program
The PM Supersites Program was established as an ambient monitoring research program intended
to address the scientific uncertainties associated with characterization and measurement of fine PM
in the atmosphere. The program was funded primarily by OAR and has benefited from extensive
ORD participation. In the early stages of the program, OAR worked with ORD to develop a PM
"Supersites Conceptual Plan" (http://www.epa.gov/ttn/amtic/files/ambient/
pm25/casac/ssconpl2.pdf) and held a public PM Measurements Research Workshop in Chapel
Hill, NC, on June 22-23, 1998.  The workshop was attended by about 200 members of the
atmospheric, exposure, and health effects research communities. Seven Supersites5 were funded in
the second phase of the program to study advanced ambient monitoring and measurement  methods
and atmospheric  chemistry.  The interactions between OAR,  ORD, and the Supersites Program
participants have provided strong technical guidance to ORD's internal research on ambient
monitoring and atmospheric chemistry and have also enabled the Supersites Program to maintain
focus on the  questions of most importance to OAR and ORD.
5The Supersites are located in Los Angeles and Fresno, CA; Houston, TX; St. Louis, MO; Pittsburgh, PA; Baltimore,
MD; and New York, NY.
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Health Effects Institute
HEI has been a key partner in PM research.  It is an independent, nonprofit corporation chartered in
1980 to provide high quality, impartial, and relevant science on the health effects of environmental
pollutants.  Supported jointly by EPA and industry, HEI has funded over 170 studies and has
published more than 100 research reports and several special reports. Particulate air pollution
is identified as a priority in the HEI Strategic Plan (14), and this public/private partnership has
made significant advances in PM-related research.  HEI has worked closely with the epidemiology
community to solidify its database and analyses of large urban studies (e.g., the National
Morbidity, Mortality, and Air Pollution Study, or NMMAPS), as well as to provide opportunities
for investigations of health (mechanisms), statistics (general additive models, or GAMs, used
in epidemiology), and effects of changing technology (e.g., diesel engines).  An internal EPA
coordination committee facilitates communication  between EPA and HEI concerning research
priorities and direction.  The research supported by HEI is highly relevant to the mission of EPAs
air quality programs and complements EPAs in-house PM Research Program well, especially in the
area of epidemiology.

ORD In-House Research
With the MYP as its guide, the in-house research conducted by ORD and the extramural program
administered by NCER  integrate the diverse capabilities of staff and extramural grantees in health,
exposure, atmospheric, and engineering sciences of the National Health and Environmental Effects
Research Laboratory (NHEERL), the National Risk Management Research  Laboratory (NRMRL),
the National Center for Environmental Assessment (NCEA),  and the National Exposure Research
Laboratory (NERL). The in-house research program balances the long- and short-term needs of the
regulatory program and aims to investigate the health and exposure issues, atmospheric process,
and source-to-receptor relationships that must be understood  in order to set  standards to protect
human health and to develop models, tools, and data for the states and EPA  regions to use in their
development of State Implementation Plans  (SIPs) to meet and enforce the NAAQS. ORD scientists
work closely with OAR to develop monitoring methods (e.g., Federal Reference Methods, or FRMs,
and methods for PM components and precursors) and strategies to acquire not only the mandated
data for implementation and enforcement, but also to provide opportunities  for adjunct health
research to address risk  and accountability questions.
Participate Matter Research Program

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Integration with Other Federal Agencies, the Private Sector, and  Other
Governmental Organizations
The President's call for a greatly expanded and coordinated interagency PM research effort led
to the creation, in 1999, of the Particulate Matter Workgroup, which is administered by the Air
Quality Research Subcommittee of CENR (15). This workgroup, co-chaired by EPA and the
National Institute of Environmental and Health Sciences (NIEHS), meets bi-monthly with a goal
of "enhancing the scientific information base for public policy that protects the public health (of
primary importance) and the environment from harmful effects due to airborne particulate matter."
This goal is to be accomplished by meeting three objectives: (a) "integrate health, exposure,
ecology, atmospheric process, and source characterization research pertaining to particulate matter;"
(b) "coordinate efforts among U.S. federal agencies and, as feasible, the private sector;" and (c)
"address the highest priority research needs first, to inform public policy choices for standard
setting and air quality management." The workgroup is comprised of 22 member agencies (listed
in Appendix C).  The workgroup has completed and recently released its "Strategic Research Plan
for Particulate Matter" (16). This plan will guide the coordinated federal research program over the
next 5 to  10 years. The document outlines the workgroup's current understanding of the PM issue,
identifies selected recent accomplishments in each of its major discipline areas, and identifies key
information gaps within priority research needs.

Integrating the body of national PM research dealing with atmospheric sciences is accomplished
under NARSTO, the multi-stakeholder  entity organized in 1994 to sponsor cooperative public/
private policy-relevant research on tropospheric ozone.6 NARSTO's mission was expanded in 1998
to include ambient PM. Its membership of more than 65 organizations includes all major federal,
state, and provincial governments; private industry; and utility sponsors of atmospheric sciences
research in Canada, Mexico, and the U.S. EPA is a charter member of NARSTO.  Its focus is
PM-source-receptor relationships as understood through the study of emissions characterization,
atmospheric measurement, processes, and modeling. NARSTO research is guided by its "Strategic
Execution Plan," specifically "Part IV:  PM Science Plan," (17). NARSTO recently released an
assessment of PM atmospheric science, "Particulate Matter Science for Policy Makers: A NARSTO
Assessment" (18). The primary purpose of this assessment is to assist policy makers in all three
countries as they implement their national air quality standards for PM.  It presents the latest
understanding of the PM atmospheric phenomena over North America, and, when gaps in knowledge
are identified, recommends additional work to fill them.
Tormerly an acronym for the North American Strategy for Tropospheric Ozone, the term NARSTO has become simply
a wordmark signifying this tri-national, public-private partnership which deals with multiple features of tropospheric
pollution, including ozone and suspended PM.

                                                             Five Years of Progress

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Five  Years of Progress
Because much of the ORD research portfolio and MYP align with the NRC Committee's priority
research topics, this report is also organized in that context.  Each section in this report corresponds
to one of the NRC priority research topics, and the key scientific question posed by the NRC for that
topic is highlighted on the topic's title page. A significant portion of ORD's implementation research
agenda was subsumed by what was referred to as Technical Support in the third NRC Committee
report.  To better describe this part of the agenda, this topic is discussed in the ""Research Topic 11."
Technical Support—Atmospheric Measurements and Methods" section of this report.

The ORD health research program that supports the development of the NAAQS continues to pursue
the unresolved issues  of causality relative to PM characteristics and constituents, but has gradually
shifted perspective to  focus on how PM attributes are linked to their sources.  Because many
constituents of PM appear to have toxicity implications (perhaps as mixtures), source-attributed
PM rather than individual components may better relate to risk and may better target control
strategies.  Meanwhile, topics of growing interest include understanding the role of susceptibility in
PM responses and identifying attributes that may be common across susceptible groups.  Another
area of concern is the  potential for long-term adverse health  outcomes or life shortening as has been
suggested by the recent reassessment of the American Cancer Society (ACS) database. Each of these
issues will be explored by ORD in the next several years.

With over three years  of PM25 monitoring data now available from the National Monitoring Network,
there is a pressing need for accelerated implementation-related research (emission measurement
and characterization, regional and local atmospheric modeling for PM, and ambient measurement
methods).  In 2004, EPA is making attainment designations on the basis of monitoring and modeling
data; the tribes, states  and EPA regions must then develop and review requisite SIPs to meet the
current NAAQS. Similarly, the availability of the Supersites Program database for study, methods
development, and validation for important PM constituents (such as organic and elemental carbon,
or OC and EC) will provide valuable information for final SIP implementation.  Thus, the ORD PM
Research Program, with its diverse yet targeted research  agenda, is working to balance cyclic and
tactical needs in order to meet mandated milestones within the context of its strategic MYP.
Particulate Matter Research Program

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References

1.  U.S. Environmental Protection Agency (1999). The benefits and costs of the Clean Air Act: 1990 to 2010
       EPA/410/R-99/001. Washington, DC:  U.S. EPA, Office of Air and Radiation.
2.  U.S. Environmental Protection Agency (1996).  Air quality criteria for paniculate matter.
       EPA/600/P-95/001aF-cF. Research Triangle Park, NC: U.S. EPA, NCEA.
3.  Health Effects Institute.  (2003) "Revised analyses of time-series studies of air pollution and health."
       Special Report. Health Effects Institute Boston, MA.
4.  U.S. Environmental Protection Agency (2003).  Air quality criteria for paniculate matter (fourth external
       review draft). EPA/600/P-99/002aD. Research Triangle Park, NC: U.S. EPA, NCEA.
5.  Clinton, W.J. (1997). "Implementation of revised air quality standards for ozone and particulate matter,"
       62 FR 38421, July 18, 1997.
6.  U.S. Environmental Protection Agency (1998).  Particulate matter research needs for human health risk
       assessment to support future reviews of the National Ambient Air Quality Standards for particulate
       matter. EPA/600/R-97/132F.  Research Triangle Park, NC: U.S. EPA, NCEA.
7. National Research Council (1998). Research Priorities for Airborne Particulate Matter:  I.  Immediate
       Priorities and a Long-Range Research Portfolio. Washington, DC: National Academies Press.
       ISBN 0-309-06094-X.
8.  National Research Council (1999). Research Priorities for Airborne Particulate Matter: II.  Evaluating
       Research Progress and Updating the Portfolio. Washington, DC: National Academies Press.
       ISBN 0-309-06638-7.
9.  National Research Council (2001). Research Priorities for Airborne Particulate Matter: III.  Early
       Research Progress.  Washington, DC: National Academies Press. ISBN 0-309-07337-5.
10. National Research Council (2004). Research Priorities for Airborne Particulate Matter: IV. Continuing
       Research Progress.  Washington, DC: National Academies Press.
11. Samet, J. M., S. L. Zeger, F. Dominici, F. C. Curriero, I. Coursac, D. Dockery, J.  Schwartz and A.
       Zanobetti (2000). National Morbidity, Mortality, and Air Pollution Study. Part II: Morbidity,
       Mortality and Air Pollution in the United States. Research Report 94 (Part 2). Cambridge, MA:
       Health Effects Institute.
12. Lippmann, M., M. Fampton, J.  Schwarz, D. Dockery, R. Schlesinger, P. Koutrakis, J. Froines, A. E.
       Nel, J. Finkelstein, J. Godleski, J. Kaufman, J. Koening, T Larson, D. Luchtel, L.-J.  S. Liu, G.
       Oberdorster, A. Peters, J. Sarnat, C. Sioutas, H. Suh, J. Sullivan, M. Utell, E. Wichmann and J.  T.
       Zelikoff (2003). "The EPA's Particulate Matter (PM) Health Effects  Research Centers Program:
       A Midcourse Report of Status, Progress, and Plans."
       Environ Health Persp lll($): 1074-1092. DOI: 10.1289/ehp.5750.
13. U.S. Environmental Protection Agency (2002). Interim Review of the Particulate Matter (PM) Research
       Centers of the USEPA: An EPA Science Advisory Board Report. Washington, DC: U.S. EPA,
       Science Advisory Board. EPA-SAB-EC-02-008, May 2002.
14. Health Effects Institute (2000).  HEI Strategic Plan for the Health Effects of Air Pollution 2000-2005.
       Cambridge, MA: Health Effects Institute.
15. Committee on Environment and Natural Resources (2002). Strategic Research Plan for Particulate
       Matter. CENR, Air Quality Research Subcommittee, NOAA Aeronomy Laboratory,  Boulder, CO.
16. Committee on Environment and Natural Resources, Air Quality Research Subcommittee (2002).
       Strategic Research Plan for Particulate Matter.
       . Accessed 2004 Feb 3.
17. NARSTO (1997).  Strategic Execution Plan, www.cgenv.com/narsto. Accessed 2004 Feb 3.
18. NARSTO (2003).  Particulate Matter Science for Policy Makers: A NARSTO Assessment.
       www.cgenv.com/narsto.  Accessed 2004 Feb 3.
                                                                 Five Years of Progress

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           A participant in a
PM personal exposure study.

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   Outdoor Measures
         Versus
Actual Human Exposures
     ==
         idividuals?
                 Five Years of Progress

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Introduction

    he epidemiological studies that provided much of the scientific basis for the PM NAAQS of
    1997 indicated that increased risks of mortality and morbidity are associated with ambient PM
    across a wide range of concentrations. A remarkable feature of these studies is the strength
of the concentration-response relationship between data from community monitors and a human
population that spends most of its time indoors. It is almost counterintuitive that monitors
representing the widely distributed PM mass within a given airshed could serve as a surrogate for
individual human exposures given the diversity of lifestyles and activities. Indeed, those found
to be most at risk, including the elderly and individuals with coronary or respiratory disease, are
least likely to be exposed to PM in the outdoor environment, that is measured by ambient monitors.
Additionally, data from early studies suggested that personal PM exposures may differ substantially
from outdoor concentrations due to contributions from indoor sources. Cross-sectional analyses
of previous data also showed weak associations between daily outdoor PM concentrations and
corresponding personal exposures. This disparity was attributed to inter-subject variability and
the limited number of measurements (1-2 days) for any given individual. In 1997, databases that
were fully adequate for relating ambient PM mass  measurements to human exposures did not exist.
The relationship between outdoor PM and the amount that penetrated indoors was only partially
understood, as was the significance of the range of ambient, indoor, and personal sources that
contributed to total personal exposure.

ORD recognized the fundamental need to link outdoor PM to personal exposure early on.
Understanding the source-to-personal exposure component of the risk paradigm became a primary
concern of ORD's PM Research Program.  Specifically, understanding the relationship between PM
measured at community monitors and local outdoor, indoor, and personal exposure concentrations
was considered essential to understanding health risks. Likewise, the effect that human activities
and other factors had on these  relationships required investigation; consequently ORD initiated
research in this area in 1997. Field studies, laboratory studies, and model-development research
have been combined to quantify important relationships and to understand how subpopulations,
regions, seasons, housing type, and human activities affect these relationships.
Participate Matter Research Program

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Key Uncertainties,  Objectives,  and Special  Issues

When the revised NAAQS was promulgated in 1997, these questions about the relationship between PM
measured at ambient sites and personal exposure remained a key area of uncertainty. Thus, understanding
personal exposures to PM provides the critical link between regulatory monitoring of ambient air and
personal health outcomes that is fundamental to the scientific underpinnings of the new NAAQS. The
overall goal of EPA's exposure program has been to develop data and models that characterize and
predict human exposure to PM relative to that measured at ambient sites. Three research objectives were
established with a particular focus on susceptible subpopulations:

   •   To characterize exposure scenarios and to collect data with which to evaluate and quantify the
       relationship between the attributes of exposure (magnitude, frequency, and duration) and ambient
       PM and co-pollutants as measured at community sites for the general and susceptible populations;
   •   To develope exposure models that characterize and predict the exposure (magnitude, frequency,
       and duration) of the general and susceptible populations to PM and co-pollutants relative to that
       measured at ambient sites; and
   •   To use these exposure models to link atmospheric dispersion and lung deposition models in order
       to generate estimates of the source-air-exposure-dose relationships for input into a risk-assessment
       analysis.

Research was conducted in several areas to address these objectives comprehensively. Longitudinal PM
exposure studies were conducted to characterize inter-personal and intra-personal variability in exposure
to PM mass and to describe the relationship between personal exposures and ambient exposure estimates
based on central-site monitoring. Detailed laboratory and field studies were conducted to characterize the
physical and chemical factors that determine the contribution of outdoor PM to indoor concentrations and
personal exposures. The modeling research then was used to develop a conceptual framework and a first-
generation human exposure model for PM mass that could describe both uncertainty and variability of
exposure distributions within the population.

Data collection requirements for this research area were comprehensive, extending from the level of the
community monitor to the  individual. Personal exposure monitoring for PM and co-pollutants was, in
some cases, conducted for as long as 28 days on elderly and cardiopulmonary-compromised participants.
The specialized battery-powered instruments used  were high sensitivity, low burden, lightweight and
quiet. Because of the inherent variability, a large number of studies were required in order to fairly
evaluate the effect of airshed, subpopulation, season, housing type, housing ventilation, and human
activity on the exposure relationships.  This research effort was the result of close collaborations between
EPA intramural and extramural scientists. Data collected to date are under evaluation and are available for
rigorous statistical analysis, as well as for use in the development or verification of exposure models.

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Major Accomplishments
Research in this area has been ongoing since 1997; and much of the research, as projected by the
NRC research portfolio timeline, has been completed.  Data analysis is continuing in an effort
to understand the important factors that influence various cohort exposures in different areas of
the country during different seasons. Through collaborative research partnerships, ORD has
successfully developed the tools and models to reasonably quantify and predict the relationship
between ambient site measurements and personal exposure for PM mass.  The findings from recent
longitudinal PM exposure studies have been critical to the evolution of exposure assessments for PM
mass, which can now be made using high quality data and models.

Longitudinal PM Exposure Studies
Longitudinal PM exposure studies have been conducted in eight U.S. cities (Boston, MA; Los
Angeles, CA; Baltimore, MD; Research Triangle Park, NC;  Seattle, WA; Fresno, CA; New York,
NY;  and Atlanta, GA) over several  seasons (1). These studies are being used to investigate the
influence of aerosol properties from different airsheds and seasons.  Study participants were
monitored over the course of 7-28  days to investigate longitudinal correlations among personal,
indoor, outdoor, and ambient community measurements. The studies included several susceptible
subpopulations, including the elderly and individuals with cardiovascular disease (CVD), chronic
obstructive pulmonary disease (COPD), and asthma. Collectively, these studies generated data from
more than 200 people and their residences over 2500 person-sampling days. More than 15,000
individual PM mass concentration measurements were collected, along with an equivalent amount
of time-activity pattern and indoor PM source data. All of the research groups involved in this
work collaborated closely in the design of field studies and shared similar sampling procedures and
questionnaires in an effort to create compatible data sets.

Emphasis was first placed on defining the relationships between ambient,  outdoor residential, indoor
residential, and personal exposure to PM. Efforts then focused  on identifying and quantifying the
factors that contribute to the observed differences between individuals. Important findings can be
summarized as follows:

   •  Personal exposure/ambient  concentration ratios have substantial intra- and inter-personal
       variability (2, 3, 4, 5).
   •  Stronger personal-outdoor PM correlations exist when longitudinal (repeated measure) data
       are analyzed by individual,  over time. Although the  degree of this association varies by
       individual, the results suggest that, for certain individuals, ambient PM25 concentrations are
       appropriate surrogates for exposures (1,4).


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   •   For pooled analyses that use average exposure concentrations for multiple individuals on
       a single day, longitudinal correlations with the ambient site concentration are high. This
       suggests that for community epidemiological studies, ambient PM concentrations are
       appropriate surrogates for exposures despite concerns to the contrary. Associations were
       strongest for fine particle sulfate, next strongest for PM2 5 mass, and less strong, but still
       significant, for PM10 mass (2, 6, 7).
   •   Correlations between personal exposure and ambient concentrations are high when there is
       limited indoor activity and few indoor sources (2).
   •   Personal exposures to ambient PM are not substantially different for healthy and susceptible
       populations (8).
   •   Some of the interpersonal differences in personal-ambient associations may be due to
       spatial variability in outdoor PM concentrations. Results suggest that for the eastern U.S.,
       outdoor PM concentrations are fairly homogenous. In the Research Triangle Park area in
       North Carolina, outdoor measurements at residences generally ranged from 80 to 120% of
       the ambient measurement at community monitoring sites with very strong correlations (r2 >
       0.9). In Seattle, PM25 mass concentrations showed modest, yet significant, spatial variability
       within a radius of 20 km of monitoring locations (9);  local  PM sources such as mobile
       source and wood burning have been theorized as influencing factors. In Fresno, correlations
       between the ambient monitoring site and an outdoor residential site were relatively weak (r2 <
       0.5), presumably due to nearby mobile sources (2, 10).
   •   A substantial portion of the interpersonal differences in personal-ambient associations
       appears to be due to the varying  effects of outdoor particles on indoor environments.
       Building type and ventilation strongly affect the indoor penetration of ambient PM.
       Because people typically spend more than 90% of their time  indoors, understanding particle
       penetration into buildings is critical to determining exposure  to ambient PM. Until recently,
       particle penetration efficiencies were thought to be constant and were often assumed to be
       100%. Results from current studies show that penetration efficiencies can vary substantially
       by residence and by season. For 30 residences in Seattle, the estimated mean penetration
       efficiency was 56±8% (5,11). In 60 Fresno apartments, the estimated mean was 25±17% in
       the winter and 49±38% in the spring,  demonstrating the substantial effect that differences in
       building ventilation can have over different seasons (3, 10).

Understanding the relationship between concentrations for PM mass and gaseous  co-pollutants
is critical for epidemiological investigations.  Ambient concentrations of PM and its gaseous
co-pollutants are frequently correlated, making it difficult to determine whether observed PM-
health-effect associations are confounded by these gaseous co-pollutants.  Results in Baltimore
demonstrated strong correlations between ambient PM2 5 and ambient gaseous co-pollutant


                                                             Five Years of Progress

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concentrations (i.e., O3, NO2) (12). In contrast, weak correlations were found between personal
PM2 5 exposure and personal exposures to gaseous co-pollutants, suggesting that the gaseous co-
pollutants are unlikely confounders of PM25. Finally, strong correlations existed between personal
exposures to PM25 and ambient concentrations of the co-pollutants, indicating that the gaseous co-
pollutants may serve as appropriate surrogates of personal PM25 exposures in some cities.
Collectively, results from the longitudinal exposure studies have verified that for PM2 5 mass and
sulfate, the ambient monitoring site should serve as an adequate surrogate for exposure to ambient
PM25 mass in community-based epidemiological  studies. Differences between ambient levels and
estimates of personal  exposure should not change the conclusions regarding epidemiology-based
health outcomes.  However, because individuals are typically exposed to lower levels of ambient PM
than would be predicted by community monitors, the strength of the effect may be underestimated.
It is important to note that the conclusions from ORD PM exposure studies are strengthened by the
amount of data that was generated for different regions of the county, different seasons, and different
susceptible populations.

Controlled Experiments
In addition to field studies, carefully controlled laboratory studies have been  conducted to
characterize indoor sources of PM and to identify key parameters that affect the penetration of
ambient PM into indoor environments. In addition to particle size, several environmental factors
were found to influence infiltration.  These factors included building tightness (open or closed
windows,  number and size of wall cracks, etc.), operation of air heating and cooling units, and
outdoor wind speed (13).  These empirical findings carry obvious implications for geographic and
meteorologic determinants of the penetration of ambient PM.  The use of windows or other climate
controls, as well as the quality of construction (resulting in building tightness), should be considered
as interdependent factors.

Other empirical studies have quantified the contribution to indoor PM25 of indoor combustion
sources, including candles (14), incense, and space heaters.  Additionally, as  concerns have arisen
regarding  a potential role for biological sources of PM in causing adverse health effects, ORD has
worked to develop new methods that might aid in the quantification of these biological sources. One
such method was developed to measure the concentration of nonviable bioaerosols such as molds
and spores which are present in indoor environments (15).

The  Stochastic Human  Exposure and Dose Simulation Model
Finally, as part of the  overall and interactive effort to link personal exposure to ambient PM
monitors,  a population exposure model called the Stochastic Human Exposure and Dose Simulation
(SHEDS)  Model has been developed and applied in case studies. Conclusions from these case
studies indicate the following:

Participate Matter  Research Program

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   •   Personal exposure to ambient PM2 5 varies less across a population than direct measures of
       total personal exposure to PM25 (i.e., exposure to non-ambient sources drives variability in
       personal exposure) (16).
   •   The air exchange rate for a given residence is a critical model parameter with a significant
       effect on predicted PM25 exposures.
   •   Model predictions provided exposure results consistent with the measured personal PM2 5
       exposures and the contribution of ambient PM25 to those exposure estimates (based on the
       data from the Raleigh/Chapel Hill, NC, longitudinal exposure study).

An important question concerns the relationship between personal exposure and the sources from
which the constituents derive. The SHEDS-PM Model, a revised version of the basic SHEDS
Model  specifically developed to study exposure to PM, has also been incorporated into a prototype
source-to-dose modeling framework that can be used to analyze the relationships between sources
contributing to PM mass, ambient concentrations, personal exposures, and ultimately to PM dose.
This prototype has been applied in a case study that has demonstrated the ability to link EPA's most
sophisticated air quality model (Community Multiscale Air Quality, or CMAQ, Model) with the
SHEDS-PM Model and a conventional lung deposition model. An epidemiological case study has
also been performed and suggests that the exposures (ambient and total) modeled using the SHEDS-
PM Model can be used as the exposure input to epidemiological models of health outcomes.

Programmatic Need  and Relevance

The association between ambient PM concentrations and health outcomes in the population, in
spite of the fact that people spend more time indoors than out, raises questions regarding exposure-
response relationships.  It is important to gain a fundamental understanding of how these many
factors interact to define individual exposures. Concerns are more significant for potentially
susceptible subpopulations who may spend even more time indoors or who may otherwise alter their
exposures based on their behaviors. Even from the limited studies completed to date, it seems clear
that disease state by itself is unlikely to play a major role in determining total personal exposure to
PM of ambient origin-specifically the PM2 5 fraction.  Individual time-activity profiles, housing,
geographical setting, climate, building construction, and other environmental factors appear to
have more significant influence on personal exposure. Analysis of the results from SHEDS-PM
Model  case studies supports this conclusion. As the research effort continues to examine the role
of specific PM constituents that may be responsible for the associations between ambient PM mass
concentrations and epidemiological health effects, it becomes  even more important to understand the
ability of community-based measurements to accurately reflect exposures to the population.
                                                           Five Years of Progress

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Future Directions

Fine PM mass concentrations in indoor and personal samples appear to correlate reasonably well
on average with ambient measurements.  This reduces the potential for exposure misclassification
when data from only a limited number of ambient PM monitors are available to represent population
exposures in community time-series or long-term, cross-sectional, epidemiological studies of PM.
However, even though the correlations with fine PM are good, the same conclusions regarding
exposure misclassification and the potential for measurement errors may not hold for individual PM
constituents. If, in fact,  the toxicity of PM resides in its matrix or surface constituents (e.g.,  metals, a
speciated organic, or other component), it will be important to ascertain whether the PM components
follow the mass spatial distribution in evaluating PM health effects.  It will also be important to
determine the temporal distribution of these constituents as they may relate to potential  sources
for short-term studies. Additionally, in the context of the still substantial uncertainties regarding
long-term  health effects, longer time-based distributions of potentially causal constituents will be
important in targeting mitigation.
Participate Matter Research  Program

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References

1.  Williams, R., L. Wallace, J. Suggs, G. Evans, J. Creason, R. Highsmith, L. Sheldon, A. Rea, A. Vette, R.
       Zweidinger, K. Leovic, G. Norris, M. Landis, C. Stevens, C. Howard-Reed, T. Conner, C. Rodes,
       P. Lawless, T. Thornburg, L.-J. S. Liu, D. Kalman, J. Kaufman, J. Koenig, T. Larson, T. Lumley,
       L. Sheppard, K. Brown, H. Suh, A. Wheeler, D. Gold, P. Koutrakis and M. Lippmann (2002).
       Preliminary Paniculate Matter Mass Concentrations Associated With Longitudinal Panel Studies.
       EPA/600/R-01/086. Cincinnati, OH: U.S. EPA.
2.  Evans, G., R. Highsmith, L. Sheldon, J. Suggs, R. Williams, R. Zweidinger, J. Creason, D. Walsh, C.
       Rodes and P. Lawless (2000). "The 1999 Fresno particulate matter exposure studies: Comparison of
       community, outdoor, and residential PM mass measurements." JA&WMA 50:  1887-1896.
3.  Williams, R, J. Creason, R. Zweidinger, R. Watts, L. Sheldon and C. Shy (2000). "Indoor, outdoor, and
       personal exposure monitoring of particulate air pollution: The Baltimore elderly epidemiology-
       exposure pilot study." Atmos Environ 34: 4193-4204.
4.  Williams, R., J. Suggs, J. Creason, C. Rodes, P. Lawless, R. Kwok, R. Zweidinger and L. Sheldon (2000).
       "The 1998 Baltimore particulate matter epidemiology-exposure study:  Part 2- personal exposure
       assessment associated with an elderly study population." J Expo Anal Environ Epidemiol 10: 533-543.
5.  Liu, L.-J., C. Slaughter and T. Larson (2002).  "Comparison of light scattering devices and impactors
       for particulate measurements in indoor, outdoor, and personal environments."
       Environ Sci Technol 36: 2977-2986.
6.  Samet, J. M., F. Dominici, F. C. Curriero,  I. Coursac and S. L. Zeger (2000). "Fine particulate air pollution
       and mortality in 20 U.S. cities, 1987-1994." NEnglJMed 343(24): 1742-9.
7.  Landis, M. S., G. Norris, R. W. Williams and J. P. Weinstein (2001).  "Personal exposures to PM25 mass and
       trace elements in Baltimore, Maryland." Atmos Environ  35:  6511-6524.
8.  Allen R., Larson, T, Sheppard, L., Wallace, L. and Liu, L-J S. (2003). Use of Real-time Light Scattering
       Data to Estimate the Contribution of Infiltrated and Indoor-Generated Particles to Indoor Air.
       Environ Sci Tech 37:3484-3492.
9.  Goswami, E., T. Larson, T. Lumley and L.-J. Liu (2002).  "Spatial characteristics of fine particulate matter:
       Identifying representative monitoring locations in Seattle." JA&WMA 52: 324-333.
10. Lawless, P., C. Rodes, G. Evans, L. Sheldon and J. Creason  (2001). "Aerosol concentrations during
       the 1999 Fresno exposure studies as functions of size, season, and meteorology."
       Aerosol Sci Technol 34: 66-74.
11. Lumley, T. and L. Sheppard (2000). "Assessing seasonal confounding and model  selection bias in air
       pollution epidemiology using positive and negative control analyses." Environmetrics 11: 705-717.
12. Sarnat, J. A., J. Schwartz, P. Catalano and H. Suh (2001). "Gaseous pollutants in particulate matter
       epidemiology: Confounders or surrogates?" Environ Health Persp 109: 1053-1061.
13. Mosley, R. B., D. J. Greenwell, L. E. Sparks, Z. Guo, W. G.  Tucker, R. Fortmann and C. Whitfield (2001).
       "Penetration of ambient fine particles into the indoor environment. "Aerosol Sci Technol 34: 127-136.
14. Wasson, S. J., Z. Guo, J. A. McBrian and L. O. Beach (2002). "Lead in candle emissions."
       Sci Total Environ 296: 159-174.
15. Menetrez, M. Y., K. K. Foarde and D. S. Ensor (2001).  "An analytical method for the measurement of
       non-viable bioaemsols" JA&WMA 51: 1436-1442.
16. Burke, J., M. Zufall and H. Ozkaynak (2001). "A population exposure model for particulate matter: Case
       study results for PM2  in Philadelphia, PA." J Expo Anal Environ Epidemiol 11: 470-489.
                                                                Five Years of Progress

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Exposures of Susceptible
     Subpopulations to
 Toxic Particulate Matter
        Components
         w:
    rhat are the exposures
    to biologically important
constituents and specific
characteristics of particulate
matter that cause responses
in potentially susceptible
subpopulations and the general
population?
                       Five Years of Progress

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Introduction

 ^\ esearch Topic 2 extends the Research Topic 1 agenda from mass to potentially toxic
 ^ components of PM. Work efforts are directed at understanding exposures to these agents, as
   \well as evaluating and quantifying the relationship between ambient concentrations and personal
exposures. This research topic was also intended to extend exposure research beyond susceptible
cohorts to the general population. The original intent of the NRC portfolio was that research would be
conducted in this topic area after the toxic components of PM had been identified through toxicological
and epidemiological studies.  Although substantial research has been conducted to understand the
mechanisms of PM toxicity and to identify causal agents, specific toxic agents have not yet been
identified; rather there is evidence that health effects are associated with most of the originally
hypothesized toxic agents. Further, several epidemiological studies are now showing health effects
associated with PM from specific sources rather than focusing on specific components.

A new perspective has been placed on this  area in response to the health research. First, exposure
research on individual PM species has been initiated without waiting for definitive identification of
toxic components. Studies are being performed to investigate exposure relationships for as many of
the hypothesized toxic components as is feasible with current technology. Results of these exposure
studies will then be used to inform health studies.  Second, source apportionment techniques are
being incorporated into exposure research studies  in order to evaluate the ambient-personal exposure
relationship for PM from various sources as well as PM species.

To date, much of the research conducted in this area has been an extension of the longitudinal PM
exposure studies in which additional samples were collected for the measurement of individual species.
Experience gained from the longitudinal  exposure studies provides valuable information for the design
of studies that will specifically address this research topic. Finally,  measurement methods for many PM
components have been refined or developed.  These methods will allow future exposure studies to more
accurately measure the PM constituents of greatest interest.

Key Uncertainties,  Objectives, and Special  Issues

The uncertainties associated with Research Topic 2 are very similar to those of Research Topic 1,
except they apply to individual PM constituents and characteristics and to PM from specific sources.
Fundamental uncertainty is associated with the distributions of exposure to these PM constituents and
with whether susceptible populations are more highly exposed than the general population. A second
uncertainty is the relationship between ambient site measurements and exposure for these constituents.
Three specific objectives are set forth for research in Research Topic 2:
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   •   To estimate exposure distributions of PM constituents, PM characteristics, and PM from
       specific sources;
   •   To determine if ambient measures of PM constituents, PM characteristics, and PM from
       specific sources can be used as appropriate surrogates of personal exposure to estimate health
       effects in epidemiological studies; and
   •   To develop the data and models that will characterize and predict human exposure to PM
       constituents and PM from different sources relative to that measured at ambient sites.

Again, data requirements are very high for this area. Methods must be available that minimize
the burden on study participants, yet are able to measure personal exposures to a range of PM
constituents and characteristics  at low levels. Personal monitoring that is equivalent to monitoring at
a fixed speciation site would be ideal, but this is currently not feasible. However,  several innovative,
sensitive, low-burden methods have been developed and are being used in conjunction with new
models being developed to extend source apportionment techniques to the personal level.
Major Accomplishments
As detailed in the NRC portfolio, work in this topic area was to follow work in Research Topic 1
and to begin after specific toxic constituents were identified. Consistent with the recommended
approach, focused research in this area only began in 2003; nevertheless, noteworthy progress has
already been made in several areas.

Through intramural and extramural collaborations, measurement methods have been developed
and refined to support exposure studies of PM components, characteristics, and PM from specific
sources (1-6).  A moderate-burden, multi-pollutant sampler has been developed for personal
monitoring to measure various PM size fractions and gaseous co-pollutants simultaneously (7,
8). Analytical methods have been refined to quantify elemental carbon (EC) and organic carbon
(OC) more accurately for personal, residential, and ambient samples. EC/OC measurements will
be used for source apportionment both in ambient air and at the personal level. A new assay for
methoxyphenols, as markers of lignin (biomass) combustion, has been developed (9).  If successfully
validated, this marker will enhance the ability to separate the influence of PM from wood smoke
relative to other combustion sources.  Methods for speciating organics associated with PM are being
developed and refined (9).  These methods will enhance the suite of chemicals that can be used
for source apportionment. Finally, an ultrafine ambient PM concentrator has been developed by
placing an ultrafine concentrator and the recently developed Nano Micro-Orifice Uniform Deposit
Impactor (NanoMOUDI) cascade impactor in series. This technology will allow researchers to
conduct chemical analysis on ultrafine particles that can then be used to identify toxic components or
properties and to extend source apportionment methods to ultrafines.

                                                            Five Years  of Progress

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Several new modeling techniques are being developed to evaluate exposure to PM constituents and
PM from various sources. Positive Matrix Factorization (PMF) receptor models have been refined
and are being applied to determine source contributions to indoor air and personal exposure samples
(8). In addition, new models have been developed using data collected in and around Seattle to
determine the influence of PM infiltration factors, seasons, and spatial and temporal variables on
personal exposure to ambient PM (10).  While these models were developed for PM mass, they are
now being extended to EC/OC, speciated organics, and other elements (11).

Many of the samples that were collected as part of the longitudinal PM exposure studies in Research
Topic 1 will be analyzed for chemical constituents including sulfate, nitrate, EC/OC, elements,
and, in some cases, speciated organics.  It is expected that many important findings will result
from both the sample analysis and the subsequent data analysis. Preliminary results have shown
that penetration efficiencies for ultrafines are very low; as a result, indoor-outdoor correlations are
poor (12, 13). In another study, ultrafines, EC, NOx, and CO were measured at several distances
downwind and upwind from a southern California freeway and indicated that a defined "zone of
influence" exists.  Beyond this zone, ultrafine concentrations fall dramatically. Concentrations of
PM (number/volume), EC, CO, and NOx were also found to decrease exponentially with distance
from the freeway (14, 15).

Finally, new studies are being planned and initiated to more fully understand and model exposures
to PM constituents and PM from various sources. For example, field monitoring has been initiated
in 12 southern California communities to determine seasonal profiles of polycyclic aromatic
hydrocarbons (PAHs), aldehydes, and quinones.  These data will be used to elucidate the seasonal
characteristics of PM components, as well as the magnitude and variability in ambient concentrations
as a result of mobile source emissions. Planned studies will be expanded to the general population
in selected metropolitan areas, as well as to selected subpopulations. These studies will draw on the
results from the longitudinal panel studies; in addition, they are expected to use the refined methods
and models that have recently been developed.

Programmatic Need and Relevance

The pursuit of unresolved issues of causality relative to specific PM characteristics and constituents
continues, but has gradually shifted perspective to how PM and its effects are linked to their sources.
Identifying the magnitude and variability of human exposures to PM constituents and characteristics
is an integral part of understanding how PM from differing sources may be linked with adverse
health effects.  Research  Topic 1 results have demonstrated that pooled correlations between ambient
concentrations and exposure are sufficiently strong to justify the use of ambient data as a surrogate
Participate Matter Research  Program

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for exposure in community-based epidemiological studies which evaluate short-term effects of PM25
mass. However, adequate data do not exist to demonstrate the strength of the relationship for PM
constituents, PM characteristics, and PM from specific sources. Results of this research area should
demonstrate whether epidemiological  studies can be used to evaluate health effects for constituents,
to provide models that may be used to improve the exposure estimates for epidemiological studies,
and to provide data for alternative approaches for conducting risk assessments, if needed. Models
generated for PM from specific sources should also be applicable to evaluating the effect of source-
specific mitigation strategies.

Future  Directions

To date, only  a few studies have investigated short-term exposure patterns to selected potential
causal agents and PM from different sources.  As a result, there is insufficient information on the
magnitude and variability of personal exposures to potential causal agents and even less information
on the relationships between personal  exposures to these PM components and measurements taken
at ambient monitoring sites. This lack of data introduces substantial uncertainty into current risk
assessments.  As more data on PM constituents become available from monitoring efforts such as the
PM Speciation Trends Network (STN), more health and epidemiological studies will be conducted
in order to examine the health effects associated with exposure to these constituents. Good exposure
data and models enhance the utility of these studies by refining the personal-exposure-to-source
relationship relative to health outcomes.

The complexity of the PM component issue has recently brought considerable attention to the
advantages of a source-attribution approach to PM personal exposure and health issues.  There
is an added advantage as source  attribution is closely related to the regulatory need for emission
inventory data and community air modeling as part of NAAQS implementation. Emission profiles
and characterization, conducted in parallel with toxicological and panel studies, provide a targeted
strategy with  which to address both sources and source-components that contribute to PM are related
to health  outcomes.  Coordinated exposure assessments provide further refinements that can assist
OAR in its regulation of source emissions. Consequently, ORD-supported programs have begun
to incorporate this conceptual approach in  various panel and epidemiological studies (e.g., 16), as
well as in toxicological studies (17, 18). Several abstracts utilizing these approaches are expected to
appear in 2004; and it is anticipated that a  substantial database will be assembled soon thereafter to
assess the feasibility of this methodology in linking exposure, health, and implementation.
                                                             Five Years of Progress

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References

1. Williams, R., R. Watts, R. Stevens, C. Stone and J. Lewtas (1999).  "Evaluation of a personal air sampler
       for twenty-four hour collection of fine particles and semivolatile organics."
        J Expo Anal Environ Epidemiol 2:  158-166.
2. Chang, M. C., C.  Sioutas, F.R. Cassee and P. B. Fokkens (2001). "Field evaluation of a mobile high-
       capacity particle size classifier (HCPSC) for separate collection of coarse, fine and ultrafine particles."
       JAerosol Sci 32: 139-156.
3. Demokritou, P., I. Kavouras, S. Ferguson and P. Koutrakis (2001).  "Development and laboratory
       performance evaluation of a personal multipollutant sampler for simultaneous measurements of
       particulate and gaseous pollutants." Aerosol Sci Technol 35: 741-752.
4. Chang, M. C., M. Geller, C. Sioutas, P. B. Fokkens and F. Cassee (2002).  "Development and evaluation
       of a compact highly efficient coarse particle concentration for toxicological studies."
        Aerosol Sci  Technol 36: 492-501.
5. Demokritou, P., T. Gupta and P. Koutrakis (2002).  "A high volume apparatus for the condensational
       growth of ultrafine particles for inhalation toxicological studies." Aerosol Sci Technol 36: 1061-1072.
6. Pang, Y., L. Gundel, T. Larson, D. Finn,  L.-J. Liu and C. Claiborn (2002).  "Development and evaluation
       of a personal particulate organic and mass sampler." Environ Sci Technol 36(23): 5205-5210.
7. Sarnat, J. A., P. Koutrakis and H. Suh (2000). "Assessing the relationship between personal particulate and
       gaseous exposures of senior citizens living in Baltimore." JA&WMA  50: 1184-1198.
8. Williams, R., L. Wallace, J. Suggs, G. Evans, J. Creason, R. Highsmith, L. Sheldon, A. Rea, A. Vette,
       R. Zweidinger, K. Leovic, G. Norris, M. Landis, C. Stevens, C. Howard-Reed, T. Conner, C. Rodes,
       P. Lawless, T. Thornburg, L.-J. S. Liu, D. Kalman, J. Kaufman, J. Koenig, T. Larson, T. Lumley,
       L. Sheppard, K. Brown, H. Suh, A.  Wheeler, D. Gold, P. Koutrakis and M. Lippmann (2002).
       Preliminary  Particulate Matter Mass Concentrations Associated With Longitudinal Panel Studies.
       EPA/600/R-01/086. Cincinnati, OH: U.S. EPA.
9. Dills, R., X. Zhu  and D. Kalman (2001).  "Measurement of urinary methoxyphenols and their use for
       biological monitoring of wood smoke exposure." Environ Res 85:  145-158.
10. Lumley, T. and L. Sheppard (2000). "Assessing seasonal confounding and model selection bias in air
       pollution epidemiology using positive and negative control analyses." Environmetrics 11: 705-717.
11. Anderson, M. J., S. L. Miller and J. B. Milford (2001).  "Source apportionment of exposure to toxic
       volatile organic compounds using positive matrix factorization."
        J Expo Anal Environ Epidemiol 11(4): 295-307.
12. Lawless, P., C. Rodes, G. Evans, L. Sheldon and J. Creason (2001). "Aerosol concentrations during
       the 1999 Fresno exposure  studies as functions of size, season, and meteorology."
        Aerosol Sci  Technol 34: 66-74.
13. Vette, A., A. Rea, P. Lawless, C. Rodes, G. Evans, R. Highsmith and L. Sheldon (2001).
       "Characterization of indoor-outdoor aerosol concentration relationships during the Fresno PM
       exposure studies." Aerosol Sci Technol 34: 118-126.
14. Zhu, Y., W. Hinds, S. Kim and C. Sioutas (2002). "Concentration and size distribution of ultrafine
       particles near a major highway." JA&WMA 52: 1032-1042.
15. Zhu, Y, W. Hinds, S. Kim and C. Sioutas (2002). "Study of ultrafine particles near a major highway with
       heavy-duty diesel traffic." Atmos Environ 36:  4323-4335.
16. Laden, F.,  J. Schwartz, F. E. Speizer and D. W. Dockery (2001).  "Air  pollution and mortality:
        A continued follow-up in the Harvard Six Cities  Study [abstract]." Epidemiology 12:881.
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17.  Kodavanti, U. P., R. Hauser, D. C. Christian!, Z. H. Meng, J. McGee, A. Ledbetter, J. Richards and D. L.
       Costa (1998). "Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific
       soluble metals." Toxicol Set 43: 204-212.
18.  Clarke, R. W., B. A. Coull, U. Reinisch, P. Catalano, C. R. Killingsworth, P. Koutrakis, I. Kavouras, J.
       Lawrence, E. G. Lovett, J. M. Wolfson, R. L. Verrier and J. J. Godleski (2000).  "Inhaled concentrated
       ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines."
       Environ Health Persp 108(12): 1179-1187.
                                                                 Five Years  of Progress

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composition, and mass-emission

  mary-particle sources	in the	
      	                   	
the emissions of reactive gai
                         Five Years of Progress

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Introduction

     Unlike most pollutants, ambient PM varies by chemical composition and size with changes in the
     particle formation processes. This leads to significant variability in PM characteristics across
     time and space, across source categories, and across individual sources within a single source
category. Many of the major sources of PM and PM precursor gases are also distinguished by high
spatial and temporal variability in the magnitude of emissions. Determining detailed particle size
and composition for diverse sources, such as wildfires and other uncontrolled burning, concentrated
animal feeding operations (CAFOs), on- and off-road mobile vehicles, and other dispersed sources
generally requires specialized and complex measurement techniques.  Routine measurement methods
are usually unable to provide these data; however, these source types are estimated to be major
contributors to ambient PM2 5 concentrations and exposures.

The significant policy and regulatory implications associated with emission inventories require
that inventory development be led by organizations familiar with the many nuances involved in
incorporating data appropriately into regulatory decisions. Since its inception (even before the
post-1997 period discussed in this report), the EPAPM Research Program, as part of its support
of NAAQS implementation, consulted with OAR to ensure  that its research focused on the areas
of highest priority to regulatory programs. EPA's priorities have focused on source types that are
estimated to make large contributions to ambient PM concentrations but that have high uncertainty
in respect to mass emissions and particle characteristics.  These priorities are directly in line with
those identified by the NRC Committee, as well as by stakeholders in state and regional agencies:
notably, area sources such as uncontrolled burning, residential wood combustion and other sources
of OC and EC including on- and off-road mobile  sources.

These sources are typically much more difficult to characterize than industrial sources that operate
within a relatively narrow band of conditions, are fixed in location, have emission points that are
well defined, and can be sampled using standard EPA methods. The sources of most interest have
few, if any, of these characteristics; they, therefore, exhibit much greater uncertainty in emissions
data. They also present the greatest opportunity for improvement in emission characterization
and inventories. Conversely, the more conventional, stationary point sources are relatively well
characterized, have a significantly lower degree of uncertainty associated with their rate and
composition of emissions, and therefore need less additional research.
Participate Matter Research Program

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Special  Issues,  Objectives,  and Key  Uncertainties

One of the key challenges faced by ORD in the development and performance of its emissions-
characterization research program has been balancing the requirement for an accurate mass
emissions inventory for NAAQS implementation purposes with the equally important need to
improve the available data on chemical speciation, size distributions, and source signatures or
profiles. Source profiles are needed to improve the accuracy of air quality and source-receptor
models that are used as the basis for developing strategies to comply with the PM NAAQS and to
improve the data available for health studies.  In practice, however, the vast majority of inventory
data are generated not by EPA, but rather by state and local agencies that have limited resources
(in terms of both expertise and funding) and which largely rely upon data submitted by regulated
industries.  Because of these limitations, EPA's approach has been to develop models, measurement
approaches, devices, and information that can be used by the states to generate inventory data. In
particular, ORD's research efforts have focused on developing measurements and methods for source
types that are the most difficult to measure and for areas where the existing data are highly uncertain.

Major Accomplishments

At the outset of EPA's PM Research Program, much of the available PM characterization data had
been developed for other purposes, such as the Air Toxics Program, and was therefore focused on
characteristics that were not immediately relevant to PM. The approaches used in these earlier
efforts required adaptation before they could be applied to the specific needs associated with PM.
Specifically, earlier particle characterization focused on inorganic compounds and did not account
for particles formed from organic compounds that were in the vapor phase in the stack but condensed
to form particles at ambient conditions.

NRC Committee Recommendation: Establish Standard  Source-Test
Methods for Measurement of Particle Size and Chemical Composition
In response to this recommendation, ORD has developed new or modified existing measurement
approaches to characterize PM source emissions. These include a state-of-the-art dilution source-
sampling system that can collect and measure both organic and inorganic PM constituents essential
to detailed source chemical profiles.  In addition to hardware development, ORD has also continued
to refine procedures for applications of this instrument.  Similarly, improved analytical methods are
being developed to allow others to search for unique marker compounds that can be used to identify
source types contributing to ambient samples. These efforts have not only generated improved
source emissions data for a limited number of sources, but have also resulted in tools that can be
applied to a broad range of source types. This work has provided a solid technical foundation for
OAR's development of a future dilution-based regulatory measurement method for PM25.


                                                         Five  Years of Progress

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New methods for characterization of exhaust emission from heavy-duty diesel trucks during highway
operation have also been an important ORD effort (1, 2).  These efforts have not only improved
the technologies for mobile-source emission measurement; they have also provided valuable data
concerning how particle emissions and characteristics change with changes in real-world engine
operation. Additional measurements of PM in exhaust plumes have provided data on how these
particle characteristics change as they are diluted with ambient air, thus providing a link between stack
emissions measurements and ambient PM characteristics.

NRC Committee Recommendation:  Characterize  Primary Particle Size and
Composition of Emissions
ORD scientists collected data to improve mass emission factors as well as PM composition and
size information during their work on source testing methods. Using the dilution sampling system
discussed above, ORD investigators generated particle size distributions and chemical composition data
for residential wood combustion, a heavy-duty diesel truck, an industrial oil-fired boiler, an industrial
wood-fired boiler (3), open biomass burning, a hogged wood-waste industrial boiler, a Kraft recovery
boiler, and a smelt tank vent.  In several of these tests, other data were collected to characterize the
performance of pollution controls (residential wood combustion) or other sampling  systems (heavy-
duty diesel trucks). When possible, process data were also collected to allow development of emission
factors and to evaluate variability in PM  characteristics with changes in process parameters.

These tests were designed primarily to evaluate the performance of the dilution sampling system
under different test conditions and to provide samples for detailed analysis with the goal of identifying
unique marker compounds. Even so, the data collected improve the existing source profile data and
are to be included in the Agency's source profile database. In areas in which considerable  research
was being conducted by industry or other research organizations, ORD focused on aspects that are
often overlooked but that are important to OAR or the states. For instance, one of ORD's studies
of emissions from heavy-duty diesel trucks evaluated emissions during engine idling, which can be
important near truck stops when drivers keep their engines running while operating  air conditioners
and other accessories (4). Another test examined the effects of fuel composition on the potential for
emissions of particles containing chlorinated dioxins and furans (5).

In general, ORD's research efforts have gone well beyond simply measuring emission rates and PM
characteristics. A series of tests on residential wood combustion equipment evaluated the ability of
system design features to reduce emissions following several years of operation in private  households
(6) and provided data on mass emissions and organic speciation of the PM emissions as well (7).
These tests generated basic data on emission rates and composition and provided a look at how well
wood stove design features worked after use under real-world conditions.
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Similarly, tests of open biomass burning examined not only emission rates, but also sought to
identify potential marker compounds that could be used in source-receptor models to quantify the
contribution of specific open biomass burning activities to ambient PM concentrations.  ORD's work
has identified different organic marker species associated with different types of biomass ground
cover, which will allow these approaches to be used in various locations where there are disparate
mixes of vegetation cover (8). Several of these tests were conducted in ORD's open-burning test
facility. This approach can be used for a variety of open-burning issues regarding PM and other
air quality research. Even with this facility, it is often more appropriate to conduct testing in the
field, as in a series of agricultural open-burning tests conducted with EPA Region 10 and the State
of Washington.  One advantage of these cooperative testing ventures is that state regulators can be
provided guidance in identifying conditions under which agricultural open-burning may need to be
restricted.

ORD scientists also conducted a series of tests to examine the mechanisms involved in the
generation of PM formed by the combustion of heavy fuel oil and pulverized coal. This work
resulted in the identification of a previously unreported peak in the size distribution of coal-generated
emission PM (9) and demonstrated  a link between combustion system design and characteristics of
particles formed from heavy fuel oil combustion (10). In addition to the particle characterization
work, this research also provided the basis for a collaborative effort to link health effects with
particles from specific sources through a joint research project between NRMRL and NHEERL. The
techniques developed during this collaboration have now been adopted for future direct inhalation
studies of emissions from a broad range of sources with the goal of linking source profiles to ambient
PM toxicological studies in both humans and test  animals.

While the programmatic focus of emission studies generally falls to the in-house program due to
the more immediately applicable nature of the work, significant contributions to this area have also
been achieved by STAR Program grant recipients. To identify unique tracer compounds, researchers
produced numerous research articles characterizing organic compounds generated by the combustion
of different types of biomass under  different conditions (11, 12). These data will be used along with
the emission data from the in-house program to update EPA's database of source chemical profiles
and will therefore be available to other researchers and regulatory agencies.  Together with studies
of biogenic emissions by the ORD in-house program (13), these data improve the accuracy of
atmospheric models of secondary pollutant formation by more accurately quantifying emissions of
PM precursors.  The improved emissions databases will allow these compounds to be appropriately
represented in air quality models, resulting in more accurate predictions of air quality and in
strategies to reduce ambient PM concentrations.
                                                             Five Years of Progress

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ORD also has conducted a series of tests to quantify fugitive dust emissions from construction
activities. These tests have provided improved estimates of these emissions and have provided
guidance to others concerning approaches for measuring these types of fugitive emissions (14).

NRC Committee Recommendation: Develop New Measurement Methods and Use
Data to Characterize Sources of Gas-Phase Ammonia and Semivolatile Organic Vapors
ORD has focused much of its efforts on developing measurement methods that can be used for a
range of different sources and PM constituents and precursors. One example is an open path method
using a Fourier transform infrared (FTIR) system to measure ammonia emissions from hog barns
and lagoons (15, 16)—sources for which traditional stack sampling methods are difficult, if not
impossible, to apply. This approach can be used for other compounds, including methane and other
light organics and can be applied to numerous other sources that do not have discrete stacks. This
open path technique is being considered as an acceptable alternative to existing EPA methods for
these emission estimates.  Ammonia is of particular interest because it has such an intimate role in
PM formation when coupled with acidic vapors, PM emission, or photochemical formation, making
accurate emission inventories critical inputs to air quality models used by states and OAR to develop
and review  SIPs. Thus, the emphasis on ammonia sources has extended to research being conducted
by STAR Program grantees as well. The STAR studies have generally focused on agricultural
activities such as fertilizer application that contribute significantly to overall emission rates (17).

In addition to developing measurement techniques, ORD's research on ammonia emissions has also
studied the most effective parameter to which the emissions can be correlated to improve estimations
for model use.  When developing emission inventories, activity data are  as important as emissions
data; and identifying the parameter that most closely tracks changes in emissions can significantly
improve emission inventories. In the case of swine, animal age (closely correlated with size) and
number were found to be the parameters most closely associated with emissions.

NRC  Committee Recommendation:  Translate New  Source-Test Procedures
and Source-Test Data into Comprehensive National Emission Inventories
Although OAR and state air management agencies are responsible for the development of emission
inventories, ORD's  research has provided significant direct and indirect benefits to the complex
process of estimating national emissions of PM and PM precursors from the wide variety of sources
present across the country. Directly, ORD has provided updated emission factors and improved
speciation and size distribution data. Indirectly, ORD has provided expert guidance to OAR's data
collection and reduction efforts.  The PM implementation research management structure, formally
adopted following NRC Committee recommendations, has ensured that OAR is aware of new
data and methods related to emission rates and characteristics and that ORD is aware of the data
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needs of OAR and, through OAR, and regional, state, and local regulatory agencies. Thus, as new
information is generated it is more quickly incorporated into the inventory development process,
resulting in improved emission inventories and, subsequently, improved air quality models and
implementation strategies.

For the 2002 and subsequent emission inventories prepared by state agencies and OAR, the data
collected using dilution sampling methods will reduce the uncertainty associated with both mass
emissions and the PM10/PM25 split for many source types. These data will also be available for use
by source apportionment modelers and health effects researchers via EPA's SPECIATE Database.
Efforts continue to ensure that source and ambient samples are analyzed using compatible methods
so that these data remain useful for as long a period as possible.

Additional Research:  Evaluation of PM and PM-Precursor Control
Technology Performance
Although control technologies were not addressed by the NRC Committee report, ORD has
evaluated the  performance of technologies to control PM and PM precursors to support the
implementation of regulatory strategies to achieve the NAAQS. ORD has partnered with several
other organizations, including EPRI and the Tennessee Valley Authority (TVA), to leverage resources
and share expertise in the area of advanced PM control technologies.

Research has been conducted and is continuing to evaluate hybrid systems to improve capture of
fine PM from coal-fired power plants. By applying an electric field to a conventional baghouse, an
electrostatically enhanced fabric filter (ESFF) system has been developed that combines the low
pressure drop of an electrostatic precipitator (ESP) and the high collection efficiency of a fabric
filter to improve reduction levels at coal-fired power plants.  The ESFF concept can be retrofit to
plants using an ESP or fabric filter system and provides a cost-effective approach to incremental PM
reductions (18).

Work is also proceeding to address a potential problem associated with the installation of
technologies to reduce emissions of the major PM precursors, SO2 and NOx, from coal-fired
power plants.  In a limited number of cases, installation of wet flue gas desulfurization (FGD) in
combination with selective catalytic reduction (SCR) for NOx control can result in the formation
of visible plumes of acid aerosols, resulting in potentially  high concentrations of acidic PM closely
downwind of plants and in noncompliance with local plume opacity regulations.  A review of current
literature and  available data has been conducted, and measurements at pilot- and  full-scale units are
underway to more accurately quantify the conditions leading to these plumes.
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Programmatic Need  and Relevance
The ORD research efforts invested to inventory and characterize various emission sources are
integral to the Agency's mandate to implement the NAAQS.  As the states prepare their SIPs,
they require a sound knowledge of a spectrum of emission rates associated with the sources
relevant to their airsheds. These data are essential for improving the accuracy of air quality
model predictions that are used to estimate the effects of compliance strategies.  With the 2004
deadlines for OAR's attainment designation for the states and with the initial submission of SIPs
in 2005, ORD, in collaboration with OAR, has made substantial  progress in compiling data on
conventional (industrial) and less conventional (agricultural) emission sources, as well as profiling
characterization in order to promote more accurate airshed emission estimates in the models.  More
accurate and more detailed emissions data for sources with and without controls not only improve
OAR's near-term ability to achieve PM reductions, but also provide the foundation for building the
links between sources and adverse health  effects that may allow  source-specific reductions to reduce
the risks associated with exposure to ambient PM.  In the end, these data are a cornerstone of the
regulatory process and remain a major focus of EPA's PM Research Program.

Work will continue to evaluate the effectiveness and potential side effects of control technology
installation  and operation to ensure that measures taken to reduce ambient PM are not causing
adverse environmental effects in other ways. Future work will examine the  effects of conventional
PM precursor control technologies such as FGD on emissions of other pollutants such as mercury
and will evaluate the effectiveness and applicability of novel approaches such as ESFF and
multipollutant control methods.
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Future Activities

The key areas of concern for ORD's future PM emissions characterization research program lie in
two areas: carbonaceous particles and emissions from dispersed (area and mobile) sources.  In both
areas, ORD's efforts will focus on providing information to quantify the rates and characteristics of
emissions and the variability in those measures. Carbonaceous PM is composed of a large variety
of compounds from a wide range of combustion sources and will make up the majority of ambient
PM following reductions from currently planned control strategies. The role of carbonaceous PM
in other air quality issues, including climate change, persistent organic pollutants,  and air toxics,
provides additional justification for this research direction and results in more cost-effective
research. ORD's current research forms an excellent basis for future progress in this area.
Measuring emissions from dispersed sources remains an area in which improvements in techniques
can significantly improve the accuracy of existing emissions estimates. Emissions from on- and off-
road mobile sources and uncontrolled burning represent significant fractions of current carbonaceous
PM emissions. Improving the accuracy of emissions estimates and speciation data can lead to more
effective controls of those source types and to reduced exposure to carbonaceous PM.
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References

1. Brown, J. E., M. J. Clayton, D. B. Harris and F. G. King, Jr. (2000). "Comparison of the particle
   size distribution of heavy-duty diesel exhaust using a dilution tailpipe sampler and an in-plume
   sampler during on-road operation." JA&WMA 50: 1407-1416.
2. Brown, J. E. (2001). Heavy duty diesel fine par-ticulate matter emissions: Development and
   application of on-road measurement capabilities. EPA/600/R-01/079. Research Triangle Park,
   NC. U.S. EPA,NRMRL.
3. Dayton, D.-P and J. T. Bursey (2001).  Source  sampling fine paniculate matter: Wood-fired
   industrial boiler. EPA/600/R-01/106. Research Triangle Park, NC: U.S. EPA, NRMRL.
4. Broderick, C.-J., H. A. Dwyer, M. Farshchi, D. B. Harris and F. G. King, Jr., (2002). "Effects of
   engine speed and accessory load on idling emissions from heavy-duty diesel trucks."
    J A&WMA  52: 1026-1031.
5. Gullett, B. K., A. Touati and M. D.  Hays (2002).  "PCDD/F, PCB, PAH, and PM emission
   factors for fireplace and woodstove combustion in the San Francisco Bay region."
    Environ Sci Technol  37(9): 1758.
6. Champion, M. and D. R.  Jaasma (1998). Degradation of emissions control performance of wood
   stoves in CrestedButte, CO. EPA-600/R-98-158. Research Triangle Park, NC:
    U. S. EPA, NRMRL.
7. Purvis, C. R., R. C. McCrillis and P. Kariher (2000). "Fine particulate matter  (PM) and organic
   speciation of fireplace emissions." Environ Sci Technol 34: 1653-1658.
8. Hays, M. D., C. Geron, K. J. Linna, N. D. Smith and J. J. Schauer (2002). "Speciation of
   gas-phase and fine particle  emissions from burning of foliar fuels."
    Environ Sci Technol 36:  2281-2295.
9. Linak, W. P., C. A. Miller, W.  S. Seames, J. O. L. Wendt, T. Ishinomori, Y. Endo and S. Miyamae
   (2002).  "On trimodal particle size distributions in fly ash from pulverized coal combustion."
   Proc Comb Inst 29.
10. Linak, W. P., C. A. Miller and J. O.  L. Wendt (2000). "Fine particulate emissions from residual
   fuel oil combustion: Characterization and mechanisms of formation."
    Proc Comb Inst 28: 2651-2658.
11. Simoneit, B. R.  T. (1999).  "A review of biomarker compounds as source indicators and tracers
   for air pollution." Environ Sci Pollu Res 6(3): 159-169.
12. Simoneit, B. R.  T., J. J. Schauer, C. G. Nolte, D. R. Oros, V. O. Elias, M. P. Fraser, W. F.
   Rogge and G. R. Cass (1999). "Levoglucosan, a tracer for cellulose in biomass burning and
   atmospheric particles." Atmos Environ 33(2): 173-182.
13. Geron, C., R. Rasmussen, R. R. Arnts and A. Guenther (2000). "A review and synthesis of
   monoterpene speciation from forests in the United States." Atmos Environ 34: 1761-1781.
14. Muleski, G.  E. and J. C. Cowherd (2001). Particulate emission measurements from controlled
   construction activities. EPA/600/R-01/031.  Research Triangle Park, NC: U.S. EPA, NRMRL.
15. Childers, J. W., E. L. Thompson, Jr., D. B. Harris, D. A. Kirchgessner, M. Clayton, D. F.
   Natschke and W. J. Phillips (2001). "Multi-pollutant concentration measurements around a
   concentrated swine production facility using open-path FTIR  spectrometry."
    AtmosEnviron 35: 1923-1936.
16. Harris, D. B., E. L. J.  Thompson, R. A. Hashmonay, D. A.  Natschke, K. Wagoner and M. G. Yost
   (2001).  "Field evaluation of a method for estimating gaseous fluxes from area sources using
   open-path Fourier transform infrared." Environ Sci Technol 35: 2309-2313.
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17. Goebes, M. D., R. Strader and C. I. Davidson (2003).  "An ammonia emission inventory for
   fertilizer application in the United States." Atmos Environ 37 (18): 2539-2550.
18. Heaphy, R.F., J.D. McCain, L.G. Felix and J.P. Gooch (2001). Pilot-scale testing of an
   electrostatically stimulated pulse-jet fabric filter: Final report for cooperative agreement CR-
   826754-01 (USEPA).  Birmingham, AL: Southern Research Institute.
                                                           Five Years of Progress

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 The CMAQ modeling system contains three types of
   modeling components: a meteorological modeling
 system for the description of atmospheric states and
motions, emission models for man-made and natural
 emissions that are injected into the atmosphere, and
a chemistry-transport modeling system for simulation
           of the chemical transformation and fate.

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      Air-quality Model
Development and Testing
         w;
    rhat are the linkages
    between emission
sources and ambient
concentrations of the biologically
important components of
participate matter?
                        Five Years of Progress

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Introduction

    his research topic focuses on the development and testing of source- and receptor-oriented
    models that characterize the linkages between emission sources and ambient concentrations
    of PM. Source-oriented models use emission-inventory data as input and similarly incorporate
meteorological and atmospheric chemistry processes to provide estimates of ambient PM
concentrations. For these source-oriented models to represent the complex atmospheric chemical
and physical processes credibly, it is essential to understand fundamental atmospheric chemistry and
how various emissions into the atmosphere modulates these processes.  Receptor-oriented models,
on the other hand, use ambient air quality data to arrive at quantitative estimates of the contributions
of the underlying sources to the PM burden.

Understanding the relationships between emission sources and ambient concentrations of PM
requires progress in both source- and receptor-oriented models. Source-oriented models predict
airborne PM concentrations by simulating chemical and physical processes that are coupled with
emissions data. Receptor-oriented models estimate source contribution to airborne PM through
linking emission source  profiles and ambient measurements, but are not predictive. This perceived
weakness of receptor models is balanced by their advantage of not requiring detailed emissions
inventory and meteorological data, which are frequently uncertain or difficult to obtain. Another
advantage and complementary aspect of receptor-oriented modeling is that it provides checks on the
emissions inventories utilized in the source models. Thus, when used together, source- and receptor-
oriented models provide EPA policymakers and states with the data necessary to develop effective
mitigation strategies through predictive and evaluative capabilities.

Key  Uncertainties and  Special Issues

Source-oriented models  for PM are continually being refined.  Models improve as emission
inventory data are expanded and as chemical process models are developed to characterize
and predict atmospheric transformation processes affecting the size distribution and chemical
composition of ambient  PM levels.  Evaluation is, of course, critical to these models if they are to
be used for regulatory purposes and if model performance is to be improved.  Such evaluations rely
upon data as they become available.  By 2004, EPA had accumulated PM25 data (including speciated
data) from its various monitoring sites over the preceding three years, thus making available ambient
data against which these models could be tested and improved. At present, the models appear to
provide accurate estimates of some PM products (e.g., sulfates), but fall short for others (notably
nitrogen compounds such as ammonia and nitrates and organic aerosols).
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Part of the problem with current model estimates of ammonia and nitrates could result from uncertainties
in the emission inventory. One approach to addressing this issue which blends available ambient
measurements with source-oriented model results is "inverse modeling." This approach can be used
to evaluate the expected contribution of specific emmissions if ambient concentrations and other
emmissions are known. In one case, inverse modeling was used to estimate emissions of ammonia and
their contributions to the formation of secondary PM.  While verification is needed before the results
of this inverse technique can be used to adjust the emissions inventories of ammonia, the approach is
promising and may be applied to other forms of PM such as OC. This issue is currently of particular
interest because inventory data showing seasonal ammonia contributions are viewed as critically
important to the utility of the source models in the next round of attainment determinations. Thus, more
work is needed to acquire such emmissions data and to incorporate these data into the existing models
to allow evaluation against the new PM25 monitering.  For organic aerosols, there are also potential
issues related to the emission inventory, including improved accounting for sources of primary OC
like wildfires. In addition, a better understanding of the processes and precursors that affect secondary
organic aerosol formation is needed to improve model performance.

At best, any receptor-oriented model can only approximate the complex physical reality of the emission
source. The uncertainty associated with this situation is best evaluated by examining the degree of
consistency of results from more than one receptor-oriented model and by  comparing results to source-
oriented models. This approach is ongoing in the current EPA PM-receptor modeling-development
program. Receptor-oriented models are also limited in their ability to provide accurate results in
applications in which secondary products are involved. Often such models can identify the presence of
secondary contributions and estimate their magnitudes, but are less successful in determining  the sources
of their precursor emissions. A more satisfactory solution of this problem requires combining a receptor-
oriented model with additional information, such as the atmospheric processes that result in secondary
formation of PM. This is referred to as "hybrid receptor modeling" and is  a frontier research area.
Major Accomplishments
Source-Oriented Models
Predictive air quality models have long been of interest to ORD in its support of OAR activities.  Prior
to 1997, ORD modeling efforts were focused on the issues of acid deposition and oxidants. With the
re-emphasis on PM in 1997 and the realization that atmospheric processes relating to PM were highly
complex and involved multiple pollutants, these models were integrated and updated to provide a basis
for regional and community airshed atmospheric predictions. In 1998, ORD publicly released the initial
version of the CMAQ model. This model was designed to simulate the chemical and physical processes
important to air quality from a "one atmosphere," multi-pollutant approach that included PM, ozone and
photochemical oxidants, acid deposition, visibility, and several  air toxics.
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The aerosol-capable version of the CMAQ model, which was released in June 2002, was designed to provide
an efficient and economical depiction of aerosol dynamics in the atmosphere. It characterizes the atmospheric
PM size subdistributions, called modes (1), and simulates the processes of coagulation, particle growth by
the addition of mass, and new particle formation.  The model also considers both PM25 and PM10 and utilizes
estimates of the primary emissions of oxides of sulfur (SOx), and nitrogen (NOx), ammonia, EC and OC, dust,
and "other species." This underscores the need for improved inventory estimates for ammonia and carbon to
validate and refine the model.  Secondary species concentrations estimated by the model are sulfate, nitrate,
ammonium, water, and secondary organics from precursors of anthropogenic and biogenic origin. Extinction
of visible light by aerosols is represented by two methods: a parametric approximation to Mie extinction
and an empirical  approach based upon field data.  Also included in the CMAQ model are links between
aerosols and gas-phase chemistry, aqueous chemistry (cloud processing of aerosols), size-dependent dry
deposition and plume-in-grid treatments. This model is among the first to attempt to view the atmosphere in
as integrated a fashion as possible with the goal of providing a credible foundation for air quality predictions
that could be relied upon by OAR and state regulators.

The intent of the  CMAQ model is to provide a flexible model that supports new developments by the air
quality modeling community. In this spirit, several researchers funded through STAR Program grants
have contributed  to the current version. Two examples of this are the Sparse-Matrix, Vectorized Gear
Code (SMVGEAR) (2) which numerically solves systems of chemical reactions and ISORROPIA (3) a
computationally efficient but rigorous thermodynamic module that has been incorporated to refine aerosol
predictions.

ORD investigators have performed an initial evaluation of the CMAQ model aerosol component to test
its ability to simulate observed visibility indices and aerosol species concentrations for two summertime
simulation periods (4). The visibility evaluation demonstrated that the CMAQ model reasonably captured
the general spatial and temporal patterns of visibility degradation, including major gradients, maxima, and
minima, but also  showed that it under-predicted visibility degradation (i.e.,  over-predicted visibility). The
speciated aerosol evaluation revealed that the model consistently under-predicted aerosol concentrations of
nitrate, PM25, PM10, and OC. Sulfate was simulated best by the model, followed by PM25, OC, PM10, and
nitrate.

Through collaboration with the Sandia National Laboratories, the processing speed of the CMAQ model
has increased significantly with the 2003 release.  As a result, the model has been used for the first time to
simulate annual PM concentrations over the entire continental US for 2001.  The results of this simulation
were evaluated against observations from the CASTNET, IMPROVE, and STN monitoring networks and
showed that CMAQ performed well in predicting monthly averages of fine particles, sulfates, and nitrates,
but less well in predicting carbonaceous PM concentrations. The results of this evaluation also provided
important insights regarding model performance that will be used to improve future versions of the model.


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In support of the work using the CMAQ model, the STAR Program funded the following research and
development for PM-source-oriented modeling.

   •   The Southern Center for the Integrated Study of Secondary Air Pollutants (SCISSAP)
       developed and evaluated a regional-scale air quality model (URM-1ATM) (6). This model
       played a critical role in the Southern Appalachian Mountains Initiative (SAMI) to address
       specific policy questions, and many of the critical components of the model are now being
       adapted for use in the CMAQ modeling system.  Results indicate that strategies to reduce NOx
       and SO2 simultaneously will be effective in reducing ozone and PM.
   •   The Research Consortium on Ozone and Fine Particle Formation, the Center for Airborne
       Organics, and individual STAR Program grants advanced EPA's understanding of the size
       distribution and chemical composition of PM25 and of the linkages between ozone and PM
       (7). Advances include tools to simulate the sources of particle emission, the modification of
       these primary particles over time in the atmosphere, and the formation of secondary aerosols
       (8, 9). Significant progress has been made in measuring the size and chemical composition
       of single particles using time-of-flight mass  spectrometry (TOFMS) (10, 11), including the
       first attempts at validating advanced air quality models with single-particle TOFMS data (12).
       Parameterizations to simulate secondary organic aerosol (SOA) formation have been, and
       continue to be, a priority research area (13-15).

Receptor-Oriented Models
A principal goal of the EPA PM Research Program over the past several years has been to make
"official," standardized EPA versions of popular receptor models available for state and local
air pollution authorities' use in the next cycle of SIP development (beginning in the 2004-2005
timeframe).  Thus, the focus has been more on model development. The two models that have
received the most attention from EPA are the Chemical Mass Balance (CMB) and the Unmix models.
Both are PC-based software modules, but otherwise are very different. In addition, ORD has
undertaken various case studies in U.S. airsheds of particular interest as examples of how the models
might be used, and, at the same time, to identify errors and inadequacies in the models.

The CMB Model (EPA CMB8.2) is a Microsoft Windows update of widely-used software that has
been supported by EPA for well over a decade. The main goals of the work to update this model are
ease of use and performance stability. Application of the CMB Model requires a library of source
profiles that has been maintained by EPA under the name SPECIATE. The outdated nature of the
SPECIATE profiles is well-recognized, and a major expansion and update of this library began in 2003
under the oversight of a newly formed workgroup that includes both EPA and non-EPA advisors. A
new CMB Model was also completed, externally tested, and documented in 2003.
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The Unmix Model (EPAUnmix2.3) is multivariate in nature and substantially more complicated
than the CMB Model in terms of both its mathematical content and its application. Its appeal is that
external source profiles are not required; instead, they are generated internally from the ambient
data themselves.  A case study representing the first application of this model to an urban airshed
(Phoenix) has recently been completed (16). A noteworthy result was the quantitative estimation of
the separate contributions of diesel and gasoline engines to ambient levels of PM25. The finding that
the gasoline engine contribution appearing larger than the diesel contribution contrasts with most
previously published studies.  In general, the Unmix Model  results compared well with those of a
previous analysis using another advanced receptor model, the PMF Model, which is also multivariate
in nature. The chemical species that were available for this  analysis are the same as those being
collected in EPA's national PM25 STN, which bodes well for the Unmix Model being able to deal
with the vast amount of data being generated by this network.  In  view of the current controversy
over the relative importance of diesel and gasoline engines as sources of PM25, the Phoenix analysis
outcome is an important contribution. The Unmix Model software has recently undergone testing
and evaluation by several independent users and is now available as an EPA-supported tool.

An additional receptor modeling approach based on radiocarbon (14C) measurements has been the
focus of considerable EPA research for several years. Such  measurements allow an estimation of
the fraction of PM25 carbon that is biogenic. The measurements are technologically complex, but
can now be performed in an essentially routine manner.  The method is being applied to samples
collected during major summer field studies over the past few years in Nashville, TN; Atlanta, GA;
Houston, TX; and Tampa, FL (17). A picture is emerging of a surprisingly large PM25 biogenic
fraction, presumably in large part from SOA resulting from the atmospheric transformation of
biogenic volatile organic compounds (VOCs).  This is also generally consistent with recent findings
from the application of EPA's most advanced source model (CMAQ) to the Nashville airshed.
Because this PM25 component is essentially uncontrollable,  any additional results that support this
picture will have significant implications for PM2 5 control strategies.

Atmospheric Chemistry
Efforts are underway in ORD to develop a PM chemistry model for predicting ambient compositions
and concentrations of PM25 containing inorganic salts and acids, liquid water, and organic
compounds. Although the chemistry of inorganic compounds in PM25 is relatively well-established,
the development of PM organic chemistry models has only recently received attention. The first
phase of the EPA program focused on SOA formation. Volatile hydrocarbons, including aromatic
hydrocarbons (key constituents  of automobile exhaust) (18,  19) and biogenic hydrocarbons (20, 21),
undergo atmospheric transformations to form oxidation products that lead to SOA either by forming
new particles or through absorption into pre-existing PM25.
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The overall objective of the laboratory program is to determine the key chemical and physical processes
controlling the yield and chemical composition of the SO A component of PM25 from atmospheric
transformations of aromatic compounds, biogenic hydrocarbons, and atmospherically relevant mixtures
of hydrocarbons.  To address these issues, smog chamber experiments were conducted in which
hydrocarbons were irradiated in the presence of NOx to assess the effect of environmental parameters
such as relative humidity on the yield and chemical composition of SOA.  The hydrocarbon systems
investigated were toluene, />-xylene, 1,3,5-trimethylbenzene, and synthetic automobile exhaust.
The results of the laboratory study clearly demonstrated that aromatic compounds emitted into the
atmosphere contribute to SOA formation through atmospheric transformations that form oxidation
products which are partially absorbed into the organic films on pre-existing PM2 5. The SOA yields were
found to be strongly influenced by the total mass of organic compounds present on PM2 5, but were not
affected significantly by typical  daytime relative humidity.

The laboratory results also demonstrated that SOA compounds from aromatic compounds are far
less effective in taking up liquid water—which contributes to regional haze—than sulfate and nitrate
compounds commonly found in PM25. The SOA chemical composition studies are consistent with the
formation of multi-functional oxygenated compounds, thus providing important tracer compounds for
use in source-receptor relationships. Finally, it was demonstrated that as much as 75% of the SOA from
synthetic automobile exhaust could be explained by the aromatic content of the exhaust.

Programmatic Need  and  Relevance

Source- and receptor-oriented models play central roles in developing, evaluating, and implementing
national air pollution policies and regulations.  To develop and evaluate policy decisions, source-
oriented models can be used to estimate future environmental conditions by assuming alternative control
scenarios. Additionally, receptor-oriented models can provide information on the sources contributing
(both identification of sources and relative contributions) to air pollution problems. This information
allows policymakers to develop  control strategies that effectively target the most significant sources of
air pollution and to better understand the potential near- and long-term effects of their decisions.

In implementing national standards such as the PM NAAQS, source- and receptor-oriented models
provide states with tools to develop SIPs, which are required for regions or areas of the country that EPA
determines are not in compliance with a NAAQS. In preparing  SIPs, source-oriented models are used
to design and evaluate alternative strategies for meeting regulatory requirements and to demonstrate
that SIPs will result in the required environmental outcome.  Receptor-oriented models are used by  SIP
developers to identify the most significant sources contributing to their air pollution problem in order to
develop effectively targeted control strategies.  In addition, receptor modeling provides checks on the
emissions inventories utilized in the source models to develop SIPs and can be used as a tool to evaluate
progress toward reaching attainment.

                                                            Five Years of Progress

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Future Directions

Source- and receptor-modeling tools will continue to provide information for developing effective
risk management policies. Because these modeling tools represent real-world conditions, they
will continue to evolve and be improved as more observational data become available and as our
understanding of the complex atmospheric processes advances.  Some specific areas of future
emphasis for these models are listed in the following sections.

Source-Oriented Models
Development and evaluation of the CMAQ aerosol model is ongoing. Near-term efforts will focus
on improving performance and predicting nitrate and organic particulates.  Work is also underway
to add the nucleation mode to the current version.  The CMAQ model's ability to predict coarse PM
will be enhanced by adding sea salt and road salt to the model. Future work also includes studies of
aerosol processes in fog conditions.

Much of the upcoming effort on the CMAQ model will focus on comparing model results against
data collected during field intensives (i.e., Atlanta  1999 Supersite data; Houston 2000  Southern
Oxidant Study, or SOS, data; 2001 STN data; and  Supersites data).  The ability of the CMAQ model
to predict ambient concentrations at smaller scales (e.g., at the neighborhood scale) will  also be
developed and evaluated. These modeling efforts will provide ambient concentration estimates that
more accurately capture the spatial variability of some pollutants (e.g., certain PM constituents)
and that can be used to improve human exposure estimates. Inverse modeling approaches will also
continue to be explored in an effort to improve emission inventories. The CMAQ model will also
be enhanced to address international transport of PM and to provide air quality forecasts of PM.
Finally, in the longer term, source-oriented models will include mechanisms that treat meteorological
and chemical processes simultaneously (as opposed to using separate mechanisms as in current
models), allowing for more accurate treatment of the real-world interactions between meteorological
and chemical process variables.
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Receptor-Oriented Models
Future receptor modeling work will involve both extending current research and embarking on new
initiatives. Extensions of current research include (a) adding functional enhancements to the Unmix
Model; (b) concluding CMB Model development; (c) comprehensive comparison of radiocarbon
measurements with concurrently measured organic species and with CMAQ model estimates of
SOA; and (d) receptor model applications to additional airsheds with particular focus on the relative
contributions of diesel versus gasoline engine emissions.  New initiatives include (a) bringing the
new PMF receptor model up to the same level of usability and documentation as the CMB and
Unmix models; (b) laboratory and modeling investigation of organic molecular tracers to better
distinguish types of combustion sources; (c) receptor model application to human exposure data; (d)
incorporating back-trajectory analysis and atmospheric process information into receptor modeling
results (i.e., hybrid receptor modeling); and (e) using receptor modeling techniques to check and
improve emission inventories.

Atmospheric Chemistry
Laboratory experiments are now being complemented by computational techniques that use quantum
mechanical calculations to predict thermodynamic properties that influence chemical and physical
reactions in the atmosphere.  Results to date using computational techniques are promising and may
lead to a less resource-intensive means for filling current gaps in atmospheric chemistry and process
research.
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References

1. Binkowski, F. and S. Roselle (2003).  "Models-3/CMAQ model aerosol component. I.  Description."
       JGeophysRes, 108(D6): AAC 3-1-AAC3-18. DOI:10.1029/2001JD001409.
2. Jacobson, M. Z. (1998).  "Improvement of SMVGEARII on vector and scalar machines through absolute
       error tolerance control." Atmos Environ 32(4): 791-796.
3. Nenes, A., S. N. Pandis and C. Pilinis (1998). "ISORROPIA: A new thermodynamic equilibrium model
       for multiphase multicomponent inorganic aerosols." Aquat Geoch 4: 123-152.
4. Mebust, M., B. K. Eder, F.  S. Binkowski and S. Roselle (2003). "Models-3/CMAQ model aerosol
       component. II. Model evaluation." JGeophys Res 108(D6): 4184. DOI: 10.1029/2001JD001410.
5. Gilliland, A., R. Dennis,  S. Roselle, T. Pierce and L. Bender (2001). "Developing the seasonality of NH3
       emissions with an inverse modeling technique." The Scientific World 1(12-82): 356-362.
6. Boylan, J. W., M. T. Odman, J. G. Wilkinson, A. G. Russell, K. G. Doty, W. B. Norris and R. T. McNider
       (2002).  "Development of a comprehensive, multiscale 'One Atmosphere' modeling system:
       Application to the southern Appalachian Mountains." Atmos Environ 36: 3721-3734.
7. Meng, Z. H., D. Dabdub and J. H. Seinfeld (1997). "Chemical coupling between atmospheric ozone and
       particulate matter." Science 111: 116-119.
8. Kleeman, M. J., L. S. Hughes, J. O. Allen and G. R. Cass (1999).  "Source Contributions to the Size
       and Composition Distribution of Atmospheric Particles: Southern California in September 1996."
       Environ Sci Technol 33: 4331-4341.
9. Kleeman, M. J. and G. R. Cass (2001).  "A 3D Eulerian source-oriented model for an externally mixed
       aerosol." Environ Sci Technol 35: 4834-4848.
10. Gard, E. E., M. J. Kleeman, D. S.  Gross, L. S. Hughes, J.  O. Allen, B. D. Morrical, D.  P. Fergenson,
       T. Dienes, M. E. Galli, R. J. Johnson, G. R. Cass and K. A. Prather (1998).  "Direct observation of
       heterogeneous chemistry in the atmosphere." Science 279: 1184 -1187.
11. Hughes, L. S., J. O. Allen, M. J. Kleeman, R. J. Johnson, G. R. Cass, D. S. Gross, E. E. Gard, M. E.
       Galli, B. D. Morrical,  D. P. Fergenson, T. Dienes, C. A. Nobel, D.-Y. Liu, P. J. Silva and K. A. Prather
       (1999).  "The size and composition distribution of atmospheric particles in southern California."
       Environ Sci Technol 33: 3506-3515.
12. Bhave, P. V., M. J. Kleeman, J. O. Allen, L. S. Hughes, K. A. Prather and G. R.  Cass (2002).
       "Evaluation of an air quality model for the size and composition of source-oriented particle classes."
       Environ Sci Technol 36: 2154-2163.
13. Bowman, F., J. Odum, S. N. Pandis and J. H. Seinfeld (1997). "Mathematical model for the formation of
       secondary atmospheric aerosol."Atmos Environ 31: 3921-3931.
14. Ansari, A. S. and S. N. Pandis (1999).  "An analysis of fourmodels predicting the partitioning of semi-
       volatile inorganic aerosol components. "Aerosol Sci Technol 31: 129-153.
15. Pankow, J. F., J. H. Seinfeld, W. E. Asher and G. B. Erdakos (2001).  "Modeling the formation of
       secondary organic aerosol (SOA):  The application of theoretical principles  to measurements obtained
       in the a-pinene-, b-pinene-, sabinene-, D3-carene, and cyclohexene-ozone systems."
       Environ Sci Technol 35: 1164-1172.
16. Lewis, C. W., G. A. Norris, R. C. Henry and T. L. Conner (2003). "Source apportionment of Phoenix
       PM25 aerosol with the unmix receptor model." JA&WMA 53: 325-338.
17. Lemire, K. R., D. T. Allen, G. A. Klouda and C. W. Lewis (2002).  "Fine particulate matter source
       attribution for southeast Texas using 14C/13C ratios."
       JGeophysRes 107(D22): 4613. DOI: 10.1029/2002JD002339.
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18. Forstner, H. J., J. H. Seinfeld and R. C. Flagan (1997).  "Secondary organic aerosol formation from
       the photooxidation of aromatic hydrocarbons: Molecular composition."
        Environ Sci Technol3l: 1345-1358.
19. Odum, J. D., T. P. Jungkam, R. J. Griffin, R. C. Flagan and J. H. Seinfeld (1997).  "The atmospheric
       aerosol-forming potential of whole gasoline vapor." Science 276: 96-99.
20. Griffin, R. J., D. R. Cocker, R. C. Flagan and J. H. Seinfeld (1999). "Organic aerosol formation from the
       oxidation of biogenic hydrocarbons." J Geophys Res 104: 3555-3567.
21. Kamens, R. M. and M. Jaoui (2001). "Modeling aerosol formation from a-pinene and NOx in
       the presence of natural sunlight using gas phase kinetics and gas-particle partitioning theory."
       Environ Sci Technol 35: 1394-1405.
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Assessment of Hazardous
     Participate Matter
        Components
        w:
    rhat is the role of
    physicochemical
characteristics of participate
matter in eliciting adverse health
effects?
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Introduction

      Ambient PM is a complex mix of constituents derived from many sources, both natural
      and anthropogenic.  Hence, the physicochemical composition of PM generally reflects the
      major contributing local and regional sources arising locally as well as regionally.  Within this
framework of source or origin, the nominal PM composition also varies significantly by the size mode
in which it is classified (ultrafine, fine, coarse, and larger) although these three classifications are by no
means homogeneous. Thus, the ambient PM mixture contains particles that can have a wide-range of
physicochemical attributes and likewise can exhibit considerable size heterogeneity.

Because only a few airsheds may have a PM character representative of a single source (e.g.,
a smelter), a generic (and simplified) PM is typically depicted in a pie chart defining the gross
composition of each PM size-mode (e.g., sulfate, nitrate, OC, EC, metals etc.) to represent all the
contributing components included in any region or airshed. Therefore, studies that attempt to address
the toxicity of PM for a given size mode may well face complexities that extend beyond the basic
problems of dealing with mixtures. Interaction of size mode and composition provides another
dimension, as does the potential for some particles within a mode or mix to be more toxic than
others. In the bigger picture, assessment of the toxic nature of PM must build upon a fundamental
understanding that exposure to PM constitutes an exposure to a  complex mixture of PM of differing
size and composition that may be chemically or lexicologically  altered by the various gaseous co-
pollutants that coexist in that airshed.

Key Uncertainties,   Objectives,  and Special  Issues

A multitude of epidemiological studies has convincingly shown a positive correlation between the
levels of ambient PM pollution and mortality and morbidity. To date, however, this correlation is
based almost exclusively on a total mass metric—a basis which is somewhat counterintuitive given the
compositional complexities of PM and the deceptively low concentrations of these constituents. Since
the publication of the 1996 PM AQCD, it has been essentially confirmed that PM-related  health effects
are strongly associated with exposure to smaller particles that are largely derived from combustion
processes. The strength of the associations are strongest for PM25, then for PM10, and then total
suspended particulate, or TSP The PM25 fraction is largely the  accumulation mode of ultrafine PM,
combustion byproducts, and secondary  reaction substances.  It stands to reason that the contribution
of any given component within the mix may not be equivalent in value or potency, but may well be
highly dependent on other physicochemical attributes (e.g., co-constituents, specific bioavailability, or
chelates), as well as the health status of the exposed individual.  Evidence collected to date indicates
that the discovery of a uniquely responsible physicochemical attribute of PM is not likely to occur.
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It may be that the sources from which PM derives provide the best achievable linkages to health.
Should sources or PM profiles (including sets of attributes or source attribution) ultimately emerge as
causal indicators for reported effects, regulatory and risk management approaches might be targeted
in a more expedient and economic manner than a mass-based standard.

To develop sound hypotheses on causality and biological plausibility, many researchers have
attempted to integrate the wealth of epidemiological data with the growing body of toxicological
studies to reveal coherence among the findings. In light of the difficulty of separating the
physicochemical attributes of PM that may be of health significance from the mechanisms by
which individual factor(s) may function in the response, a  number of hypotheses have evolved
espousing various PM characteristics as potentially significant contributors to the observed health
effects. At  present, each of the attribute-based hypotheses appears to have a sufficient database to
warrant consideration and further investigation, perhaps with a source-profile focus. As the science
progresses, it is important that any attribute-based hypothesis be critically evaluated and that it
responds to at least the following generic questions:

   •   Are there environmental sources that would lead to exposure to PM with the putative
       constituent(s) or characteristic(s)?
   •   Is there evidence of personal exposure involving PM with that attribute and effect?
   •   Does the putative attribute possess or contribute to a toxic potential?
   •   Is there evidence of an exposure-response relationship, especially at the low concentrations
       found in the ambient environment?
   •   How well does the hypothesis generalize between one PM sample, exposure, or locale and
       another?
Major Accomplishments
Since 1997, empirical toxicological studies have provided important, but limited, evidence indicting
specific PM attributes as being primarily responsible for the cardiopulmonary effects linked to
ambient PM.  In most cases, exposure concentrations in laboratory studies have been substantially
higher than the exposures at which epidemiological studies have found effects.  However, the
use of higher doses in these studies does not negate their value.  First of all, most laboratory
studies are forced to use many fewer test subjects or animals compared to what can be studied
epidemiologically.  Hence, there is not the statistical power to reveal subtle, low-dose responses.
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Additionally, the range of responsiveness of most study models and cohorts is likely much more
narrow than the general population, especially in light of poorly understood host susceptibility
factors.  Thus, most of the toxicology database resides in the "Hazard-Identification" phase of
the risk assessment paradigm. While signifiant uncertainly remain, sufficient coherence between
the toxicological and the epidemiological data has provided a level of "biologic plausibility" to
the epidemiology observation; this, in turn, has opened new avenues for investigation to link PM
properties and constituents that derive from specific sources to health outcomes. The primary PM
properties thought to be related to health effects are discussed in the following text.

Physicochemical Attributes of PM

Acid Aerosols
Because there is relatively little new information on the effects of acid aerosols, the basic
conclusions of the 1996 PM AQCD remain unchanged.  Acid aerosols have repeatedly been
shown to cause little or no pulmonary dysfunction in healthy subjects, although transient slowing
of mucociliary clearance has been observed after short, high-concentration exposures (-1000
ug/m3 for 1 hour). Asthmatics, on the other hand, may experience small, variable decrements in
pulmonary function during acute exposures. Linn and colleagues (2) conducted a study in which
healthy children and children with  allergy or asthma were exposed to sulfuric acid aerosol at lower
concentrations—though still  distinctly higher than typical ambient conditions (100 ug/m3)—for
4 hours. While analysis of the entire group showed no significant effects on symptoms or pulmonary
function, the allergy group did have significant acid-related increases in symptoms.

Analysis of data from Buffalo, New York City, and Philadelphia indicated that fine-mass acid sulfate
was associated with increases in mortality and hospital admissions (3).  Long-term exposures of
animals to acid aerosols, conducted in several studies in the 1980s, did elicit some changes evident
as altered airway secretory cell and epithelial number profiles and some indices of airway function;
but these too were generally mild (e.g., 4). Although pulmonary effects of acid aerosols have been
the subject of extensive research over many years, the cardiovascular effects of acid aerosols have
received little attention. However, anecdotal reports in the personal notes of Amdur (5) from early
studies of human exposure to sulfuric acid and a recent study of acidic residual oil fly ash (ROFA)
PM (which also contains a considerable amount of metal sulfates) suggest the potential for cardiac
function alterations which were perhaps mediated by airway responses. In the latter animal study,
acidic ROFA was found to alter electrocardiogram (ECG) patterns during, but not after, the exposure
(6).  Thus, acid components cannot be dismissed as possible mediators of PM health effects because
so little is known about potential cardiovascular effects. This hypothesis has begun to capture
interest among EPA-funded programs, particularly in  animal studies.
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Ultrafine PM (Size, Surface Area, Number)
The physical attributes of PM-size, surface area, and number-are interrelated, descriptive metrics
of PM. These properties influence PM deposition, penetration, and persistence in the lung, as well
as the potential for systemic transport and the inherent toxicity of the particle itself. While a few
epidemiological studies (e.g., 7) show correlations between health outcomes and ultrafine (<100 nm)
ambient PM, the bulk of the information regarding the toxic potential of ultrafine particulates and the
role of surface area as an alternate health-related PM metric has derived from studies of surrogate
insoluble particles such as mineral oxides (e.g., TiO2) and carbon black (8). These studies have shown
that, when based on an equivalent mass, ultrafine PM can induce more lung injury than fine PM.

More recent studies in rodents appear to support the ultrafine hypothesis, showing that old age and a
compromised or sensitized respiratory tract can increase susceptibility to the inflammatory effects of
ultrafine PM and put the animal at higher risk of oxidative stress-induced lung injury. Results also
show that ultrafine particulate effects can be significantly enhanced by a gaseous co-pollutant such as
ozone (9, 10).

From a measurement standpoint, ultrafine particles pose a special problem because they have such little
mass. They must  be counted using special instruments (e.g., mobility shift analyzers) and may not
be apparent in mass-based environmental monitoring measurements. Ultrafine particles penetrate the
respiratory tract (see Research Topic 6) and deposit widely throughout the airway and lung. However,
given that number rather than mass may drive the toxicity, the disproportionate number getting to the
deep lung may be the key to this exposure.

As with acid aerosols, studies of ultrafine PM have focused largely on effects in the lung; but inhaled
ultrafine particles  may also have the potential to be distributed systemically (as discussed in Research
Topic 9). The potential for such systemic transport may be dependent on particle composition (11,
12). If such transport occurs, ultrafines may have effects that are independent of the effects on the lung.
Recent epidemiological studies evaluating blood viscosity as a correlate of ultrafine exposures have
reported slight increases, raising the prospect of potential cardiovascular implications (7).

Fine and Coarse  PM
As opposed to the ultrafine PM, the association of ambient PM10and PM25 with health outcomes
has garnered much broader research attention. PM10 data collection was mandated by the 1987 PM
NAAQS, and only since 1997 has more widespread  measurement of PM25 been initiated as a prelude
to NAAQS-associated SIP development and implementation.  The fine fraction (PM25) comprises most
of the combustion-related constituents and exhibits a complex and often variable compositional profile.
Fine particles readily penetrate into the airways and  deep respiratory tract. Coarse particles (PM1025)


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are respirable; and, while many are retained within the nose and upper respiratory tract, they can get
into the conducting and some smaller airways. However, most studies suggest minimal effects on
mortality (13-16), perhaps because coarse particles are often of crustal origin

The animal toxicology also shows few effects with crustal particles (17).  Considerable
epidemiological evidence now generally supports the belief that PM25 relates to health effects in the
population better than PM10 or other more typically measured modes (18-20). However,  studies of
several morbidity end points  have recently reported associations with both the fine and coarse PM
fractions (14, 21). It remains to be determined whether end points are differentially responsive to
these size  modes.

A given mass of fine PM has a greater surface area than a comparable mass of coarse PM; likewise,
there is much more surface associated with ultrafines compared to a similar mass of fine PM.  The
effect of size on surface area is exponential.  Thus there is concern that because smaller PM fractions
have a potentially enormous  surface carrying capacity, this factor may relate  to toxicity. As PM
is a complex mixture, the potential role of surface-associated chemicals may  be of considerable
importance. For example,  acute exposure of mice to sulfate-coated fine carbon black was found to
impair alveolar macrophage phagocytosis simply based on the effective dose of sulfate that reached
the macrophages compared to that by breathing a comparable level of sulfate alone (22).

Chemical Properties

Inorganic Constituents
The inorganic constituents of ambient PM derive from either natural or combustion sources. The
crustal or natural constituents of PM are typically silicates that contain surface- and matrix-bound
earthen metals such as calcium, magnesium, aluminum, and iron. As noted previously, most of
these silicates (not being crystalline silica) do not appear to contribute much  toxicity to ambient PM.
Sulfate and nitrate anions derived from combustion or atmospheric processes usually combine with
other constituents in PM (often water-soluble ammonium ions or organic acids, as well as elemental
cations, such as first-row transition metals).  The intrinsic, independent toxicities  of sulfates and
nitrates appear to be rather low, but they may influence the toxicity or bioavailability of other PM
components. Of the cations,  transition metals represent a potential class of causal constituents
for PM-associated health effects that have received considerable attention. Sulfate, nitrate,
ammonium, and metals make up a substantial part of the mass of ambient PM, often with a silicate or
carbonaceous core, layering,  or matrix. The majority of PM-associated metals in fine PM is derived
from stationary or mobile combustion sources; whereas, particle sulfate, nitrate, and ammonium
originate from secondary atmospheric transformation reactions involving SO2, NOx, and biomass
ammonia emissions.

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Metals
Since 1997, in vivo and in vitro studies using emission particles, such as ROFA or soluble transition
metal salts, have contributed substantial new information concerning the health effects of PM-associated
bioavailable metals. The metals of most interest-notably the transition metals of iron, vanadium,
copper, nickel, chromium, cadmium, zinc, and arsenic-are ubiquitous constituents of PM derived from
anthropogenic fossil fuel combustion. Exposure to metals  seems to be widespread, as demonstrated by
studies in autopsy specimens showing dramatic increases in the content of the first-row transition metals
in lung tissues of Mexico City residents since the 1950s consistent with industrialization and pollution
(e.g., 23). Similar studies in North America show metals in the lung tissues of urban dwellers (24)

Although there remain uncertainties concerning the differential effects of one transition metal versus
another, water-soluble or bioavailable metals leached from ROFA or bulk ambient PM clearly elicit
pulminary and cardiac injury in proportion to the concentration of metal in the sample (25, 26).  Other
studies performed in vitro show a similar role for metals (27-29). To date, however, only a few
epidemiological studies have suggested clear role for metals in causing PM health effects (e.g., 29).
The reasons for this apparent discrepancy may relate to the form or bioavailability of the metal or
other confounding factors.  Most of the animal studies which have examined PM-related metal toxicity
involved relatively high dose instillation or inhalation exposure. This raises questions about their
relevance to studies of lower concentration ambient PM. However, studies with  surrogate PM of widely
varying metal content (30-33) and Boston concentrated ambient particles, or CAPs, (22,34) have linked
inflammatory and airway injury markers with specific metal components.

The early years of this PM initiative produced many studies showing that instilled and inhaled ROFA
and related constituent metals are pro-inflammatory (cells,  mediators, and molecular signaling processes
in vivo and in vitro). More recently, inhaled and instilled ROFA and soluble metal components have
been shown to induce cardiac arrhythmias in both healthy and diseased animal models (31, 32, 35) and
to exacerbate the effects of myocardial infarction (MI) in rats (33).  These studies use relatively high
doses or concentrations of PM, but they demonstrate the potential for similar phenomena to occur in
humans.

Of the metal-hypothesis studies relevant to the potential for human health effects, perhaps the most
revealing information emerges from studies conducted with PM extracts from ambient filters from the
Utah Valley. These filters were collected when a steel mill in Utah Valley closed for a labor dispute.
Extracts from the PM ambient filters (containing metals and other soluble constituents) were instilled
into the lungs of humans (36) and  animals (37), as well as tested in vitro (38).  These studies showed
remarkable coherence with epidemiological studies of hospitalization and mortality (e.g., 39, 40) at the
same time and for the same  geographic area of the PM samples that were used in the laboratory studies.
The response patterns in each study paralleled the metal content.

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Furthermore, recent application of novel statistical approaches to the study of source-associated
constituents has shown promise in linking sources with their associated emission profiles (including
metals) to health outcomes in both humans (16) and animals (41). In these studies, metals are often
the elemental markers for specific source types. In summary, metals appear to play a significant role
in determining PM health effects; however, the issue of low dose effects and the variation in PM
metal content and bioavailability remain to be resolved.

Organic Constituents and Diesel Exhaust Particles (DEPs)
Published research concerning the acute (non-cancer) effects of PM-associated OC constituents
is sparse, with the exception of research specifically focused on DEPs. Like metals, organics are
common constituents of combustion-generated PM and are found in ambient PM samples over a
wide geographical range.  OC constituents comprise a substantial portion of the mass of ambient
PM (10 to 60% of the total dry mass) (42). For example, recent studies found that the average
composition of ultrafine aerosols consisted of 40% organic compounds in Houston and 50% in
Southern California (43).

Little is understood about the organic fraction regarding acute PM health effects. In contrast, the
mutagenic (presumptive cancer) effects of ambient PM and evidence of DNA-adducts have been
studied more extensively and have been linked to specific organic fractions (44). Work continues
in this area, but little is directly supported by ORD. Recently, however, a re-evaluation of the ACS
database of 91 U.S. cities indicated that PM was significantly linked to lung cancer outcomes over
the long term (45). This cancer finding is consistent with the potential suggested in the various in
vitro adduct and mutagenesis assays, and it may well renew interest in the carcinogenic potential of
ambient PM as efforts to explore long-term health outcomes expand.

The amount of DEPs in ambient PM can vary substantially from region to region and can be very
high in certain microenvironments.  In Europe, DEPs are considered a major contributor to ambient
PM—as much as 50% in some cases. It is also a concern in the U.S., but it is estimated that DEPs
generally contribute less than 10% to the ambient. (46).  The potential of DEPs to cause cancer has
been well-studied, but its non-cancer health effects remain a puzzle (e.g., 47).  There is, however,
growing human and animal toxicological evidence that DEPs can exacerbate the allergic response to
inhaled antigens (48, 49). EPA-supported research suggests that oxidative stress is a key mechanistic
step in the adjuvant activity of DEPs (48, 50, 51).
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One question that arises is whether the adjuvant effect of DEPs is unique.  It appears that other
emission PM may also have adjuvant-like activity similar to DEPs.  For example, certain transition
metals, such as nickel and vanadium that also induce oxidation have an analogous adjuvant effect in
allergic rodents (52). As toxicological studies continue on other source-specific emissions, as well
as urban CAPs, it will be important to evaluate these immunomodulating effects in the presence of
allergens because this may provide insight into the incidence and severity of allergic rhinitis and
asthma. Abroad perspective of the carcinogenic (especially lung cancer) and non-cancer effects
related to DEP exposure have been discussed in EPA's "Health Assessment Document for Diesel
Engine Exhaust" (53).

The extent to which organic constituents of ambient PM contribute to adverse health effects
identified by current epidemiological studies is not known. Nevertheless, organic constituents
remain of concern in the context of PM health effects due in large part to the contribution of DEPs
to the fine PM fraction and the health effects associated with exposure to these particles.  Other
carbonaceous material exists as EC, which most toxicity studies have shown to be relatively
innocuous unless linked to a co-pollutant such as sulfate (54). However, epidemiology has provided
limited data associating EC with mortality and adverse health on the basis  that EC reflects motor
vehicle contributions to PM (16).

Biogenic Constituents
Recent studies support the conclusion of the 1996 PM AQCD that primary bioaerosols at the
concentrations present in the ambient environment do not likely account for the health effects of
ambient PM.  Ambient PM in urban air contains variable amounts of endotoxin, but the levels
are  typically orders of magnitude less than that needed to induce acute responses.  The in vitro
toxicological  studies that have shown endotoxin associated with ambient PM to be pro-inflammatory,
inducing cytokine expression in human and rat alveolar macrophages, and appear to be dose related
(55, 56).  Further, endotoxin content does appear to vary by size mode. Monn and Becker (57) found
cytokine induction by human monocytes, a characteristic of endotoxin activity, in the coarse size
fraction of outdoor PM, but not in the fine fraction.  Interestingly, while studies in animal models
also require more endotoxin than typically found in ambient PM to induce inflammation, recent
studies suggest endotoxin may have a priming effect on PM-induced inflammatory processes (12,
58). Thus, biogenic material such as endotoxin may play a less direct role that is poorly understood.
It is important to note, however, that virtually all study of so-called biogenics has been limited to
endotoxins and that there  remain  other biologically derived materials associated with molds  and
fungi that are not widely studied.
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Source-Specific Effects
The relationship between mortality, morbidity, and concentrations of source-specific PM is an area
of increasing interest. If health effects can be linked to particular sources of air pollution,  such
information would prove useful for targeting control strategies.  A dramatic example of the effect of
control or mitigation is that of the 1990 coal ban in Dublin and the significant improvement in health
as measured by population death rates. The 70% decrease in ambient black smoke levels achieved
by prohibiting the use of coal in residences and businesses resulted in a 15% decrease in respiratory
deaths and a 10% decrease in cardiovascular deaths (59). These findings are important because while
specific components of the PM mix primarily responsible for effects were not known, there was clearly
an effect.

In an analysis of the data from six U.S. cities, significant associations were found between mortality
and two key sources of pollution—traffic and coal combustion—with the largest specific effect for
the traffic factor (16). Others have found that combustion-related pollutants and sulfates are linked
to cardiovascular mortality (60); still others have found that the fraction of PM10 emissions related to
traffic sources is the primary driver for CVD-related hospital admissions (61).

In a study linked to one of the first Supersites, the relationship of acute cardiovascular conditions with
ambient PM in Atlanta also showed that mobile source contribution appeared to play an important
role (62). Yet another demonstration of the importance of local environmental sources on  air quality
occurred  in the Pacific Northwest, where PM is seasonally dominated by wood smoke. There,
investigators have been able to track the movement of wood smoke PM around the Seattle area as
a step in the development studies of associated health outcomes (63).  In response to the growing
interest in studies which aim to attribute health effects to specific sources, EPA and the PM research
centers held a workshop in the spring  of 2003 to discuss methodologies and approaches for source
apportionment research that can be related to health outcomes.

Programmatic  Need  and Relevance

The toxicological database has provided considerable evidence to  support the hypothesis that certain
physicochemical attributes of particles can be causally linked with regard to the observed health
effects of ambient PM. A single causal attribute may not be found, but may contribute to a complex
mechanism driven by the nature of a given PM and its contributing sources.  The multiple  interactions
that may  elicit a response in a host may make it difficult to identify any single causal component and
may also account for the fact that mass, as the most basic metric, shows the relationships to health
outcomes that it does. As research moves toward source-based linkages with hazardous components,
the contributors to PM adverse health effects can be more appropriately targeted for mitigation.
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Future Directions

Substantial progress has been made since 1997 in regard to PM attributes that seem to play a role
in PM toxicity. At that time, it was clear that acids were a part of the story, but they were obviously
not the sole factor.  "Biologic plausibility" was the mantra of the skeptics who could not conceive of
any component or attribute of PM that was sufficiently toxic or present in sufficient concentration to
elicit the findings revealed by epidemiology. Now there seems to be little doubt that there are indeed
PM-associated effects on human health at ambient levels, and several potential "active" attributes of
PM seem to be involved. The large body of work on PM components has set the stage for a more
comprehensive view of PM,  perhaps ultimately using lexicologically profiled sources as a means to
guide mitigation.

The component-focused research efforts are prepared to be integrated with  the data becoming
available from the speciation monitoring data from the National Monitoring Network.  These
monitoring programs are potential resources for source-attributed ambient PM that can be studied
using a variety of toxicological tools linked to the basic knowledge of component studies and studies
of emission surrogates. The  critical linkages of components and sources and their toxicological
outcomes can be studied with CAPs exposures, using similar study designs either in locales where
CAPs units are established or at sites where speciated monitoring occurs.

When this information is tied to epidemiological and panel studies that will be conducted in the
same areas, it will offer a new opportunity to investigate coherence across disciplines, allowing
complementary, direct hypothesis testing and determination of mechanism. When interwoven, these
approaches should provide considerable insight into the components and sources that can be linked
to PM-associated heath outcomes.
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References

1. Dreher, K. (2000). "Particulate matter physicochemistry and toxicology:  In search of causality—a critical
       perspective." Inhal Toxicol 12(Suppl 3): 45-57.
2. Linn, W. S., H. Gong, Jr., D. A. Shamoo, K. R. Anderson and E. L. Avol (1997). "Chamber exposures of
       children to mixed ozone, sulfur dioxide, and sulfuric acid." Arch Environ Health 52(3): 179-87.
3. Gwynn, R. and G. D. Thurston (1998). "Acidic particulate matter air pollution and daily mortality and
       morbidity in New York City, NY." Epidemiology 9(4): S60.
4. Gearhart, J. M. and R. B. Schlesinger (1989). "Sulfuric acid-induced changes in the physiology and
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19. Schwartz, J., K. L. Timonen and J. Pekkanen (2000).  "Respiratory effects of environmental tobacco
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       1950s and the 1980s." Environ Health Persp 104(6): 630-2.
24. Gallagher, J, J Inmon, S Schlaegle, A Levine, T Rogers, J Scott, F Green, M Schenker, N Menzel,  K
       Whittmaker and K Pinkerton (2003). "Health effects indicators in human lungs in relation to particle
       concentration and metal content," Particulate Matter: Atmospheric Sciences, Exposure and the  Fourth
       Colloquium on PM and Human Health, March 31-April 4, 2003, Pittsburgh, PA.
25. Ohio, A. J., Z. H. Meng, G. E. Hatch and D. L. Costa (1997). "Luminol-enhanced chemiluminescence
       after in vitro exposures of rat alveolar macrophages to oil fly ash is metal dependent."
       Inhal Toxicol 9: 255-271.
26. Costa, D. L. and K. L. Dreher (1999). "What do we need to know about airborne particles to make
       effective risk management decisions?" Human Ecol Risk Assess 5(3): 481-492.
27. Dye, J., K. B. Adler, J. H. Richards and K. L. Dreher (1997).  "Epithelial injury induced by exposure to
       residual oil fly ash particles: Role of reactive oxygen species."
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28. Samet, J. M., L. M. Graves, J. Quay, L. A. Dailey, R. B. Devlin, A. J. Ohio, W. Wu, P. A. Bromberg and
       W. Reed (1998). "Activation of MAPKs in human bronchial epithelial cells exposed to metals."
       Am JPhysiol 275(3 Pt 1): L551-558.
29. Samet, J. M., A. J. Ohio, D. L. Costa and M. C. Madden (2000).  "Increased expression of
       cyclooxygenase 2 mediates oil fly ash-induced lung injury." Exp Lung Res 26: 57-69.
30. Costa (1998). "Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific
       soluble metals." Toxicol Sci 43: 204-212.
31. Campen, M. J., D. L. Costa and W.  P. Watkinson (2000). "Cardiac and thermoregulatory toxicity of
       residual oil fly ash in cardiopulmonary-compromised rats." Inhal Toxicol  12: 7-22.
32. Watkinson, W. P., M. J. Campen, J.  P. Nolan and D. L. Costa (2001). "Cardiovascular and systemic
       responses to inhaled pollutants in rodents: Effects of ozone and particulate matter."
       Environ Health Persp 109: 539-546.
33. Wellenius, G. A., P. H. N. Saldiva, J. R. F. Batalha, G.  G. Krishna Murthy, B. A. Coull, R. L. Verrier and
       J. J. Godleski (2002). "Electrocardiographic changes during exposure to residual oil fly ash (ROFA)
       particles in a rat model of myocardial infarction." Toxicol Sci 66: 327-335.
34. Saldiva, P. H. N., R. W. Clarke, B. A. Coull, R. C. Stearns, J. Lawrence, G. G. Krishna Murthy, E. Diaz,
       P. Koutrakis, H. Suh, A. Tsuda and J. J. Godleski (2002).  "Lung inflamation induced by concentrated
       ambient air particles is related to particle composition." Am J Respir Crit Care Med 165: 1610-1617.
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35. Watkinson, W. P., M. J. Campen and D. L. Costa (1998). "Cardiac arrhythmia induction after exposure to
       residual oil fly ash particles in the pulmonary hypertensive rat." Toxicol Sci 41: 209-216.
36. Ohio, A. J. and R.  B. Devlin (2001). "Inflammatory lung injury after bronchial instillation of air pollution
       particles"AmJRespirCritCareMed 164(4): 704-708.
37. Dye, J. A., J. R. Lehmann, J. K. McGee, D. W. Winsett, A.  D. Ledbetter, J. I. Everitt, A. J. Ohio and D. L.
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       with epidemiological studies in Utah Valley residents." Environ Health Persp 109(Suppl 3): 395-403.
38. Frampton, M. W., A. J. Ohio, J. M. Samet, J. L. Carson, J. D. Carter and R. B. Devlin (1999). "Effects
       of aqueous extracts of PM10 filters from the Utah valley on human airway epithelial cells."
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39. Pope, C. A., 3rd (1989).  "Respiratory disease associated with community air pollution and a steel mill,
       Utah Valley." Am J Public Health 79(5): 623-8.
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       pollution" Am Heart J 138: 890-899.
41. Clarke, R. W., B. A. Coull,  U. Reinisch, P. Catalano, C. R. Killingsworth, P. Koutrakis, I. Kavouras,
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       composition of atmospheric ultrafine particles." Philos  Trans R Soc LondA 358: 2581-2592.
44. Lewtas, J., D. Walsh, R. Williams  and L. Dobias (1997). "Air pollution exposure-DNA adduct dosimetry
       in humans and rodents: Evidence for non-linearity at high doses." Mutat Res 378(1-2): 51-63.
45. Pope, C. A. I., R. T Burnett, M. J. Thun, E. E.  Calle, D. Krewski, K. Ito and G. D. Thurston (2002).
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46. Christoforou, C. S., L. G. Salmon, M. P. Hannigan, P. A. Solomon and G. R. Cass (2000).  "Trends in fine
       particle concentration and chemical composition in southern California." JA&WMA 50: 43-53.
47. Mauderly, J.  L. (2001).  "Diesel emissions: Is  more health  research still needed?" Toxicol Sci 62(1): 6-9.
48. Nel, A., D. Diaz-Sanchez and N. Li (2001).  "The role of particulate pollutants in pulmonary
       inflammation and asthma:  Evidence for the involvement of organic chemicals and oxidative stress."
       Curr Opin Pulm Med 7: 20-26.
49. DeMarini, D.M., L.R. Brooks,  S.H. Warren, T. Kobayashi,  M.I. Gilmour and P. Singh, (2004).
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       exhaust particles." Environ Health Persp in press. DOI: 10.1289/ehp.6578.
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       and A. E. Nel (2002). "Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust
       particles in a murine model for ovalbumin  sensitization." JImmunol 168: 2560-2567.
51. Li, N., M. Venkatesan, A. Miguel, R. Kaplan, C. Gujuluva, J. Alam and A. Nel (2000). "Induction of
       heme oxygenase-1 expression  in macrophages by diesel exhaust particle chemicals and quinones via
       the antioxidant-responsive  element" J Immunol 165: 3393-3401.
52. Lambert, A. L.,  M. J. Selgrade and M. I. Gilmour (2000). "Enhanced allergic sensitization by residual oil
       fly ash particles is mediated by soluble metal constituents." Toxicol Appl Pharmacol 165: 84-93.
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53.  U.S. Environmental Protection Agency (2002). Health Assessment Document for Diesel Engine Exhaust.
       EPA/600/8-90/057F. Washington, DC: U.S. EPA, NCEA.
54.  Clarke, R. W., J. M. Antonini, D. R. Hemenway, R. Frank, S. R. Kleeberger and G. J. Jakab (2000).
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       macrophage function." Inhal Toxicol 12(3): 169-86.
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       expression from alveolar macrophages treated with urban air particles." Exp Lung Res 22(5): 577-92.
56.  Becker, S., J. M. Soukup and J. E. Gallagher (2002).  "Differential particulate air pollution induced
       oxidant stress in human granulocytes, monocytes  and alveolar macrophages."
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57.  Monn, C. and S. Becker (1999). "Cytotoxicity and induction of proinflammatory cytokines from
       human monocytes exposed to fine (PM25) and coarse particles (PM10 25) in outdoor and indoor air."
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58.  Imrich, A., Y. Y. Ning, H. Koziel, B. Coull and L. Kobzik (1999). "Lipopolysaccharide priming amplifies
       lung macrophage tumor necrosis factor production in response to air particles."
        Toxicol Appl Pharmacol 159(2): 117-124.
59.  Clancy, L., P. Goodman, H. Sinclair and D. W. Dockery (2002). "Effect of air-pollution control on death
       rates in Dublin, Ireland: An intervention study." Lancet 360(9341): 1210-1214.
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       Phoenix, 1995-1997." Environ Health Persp 108:  347-353.
61.  Janssen, N. A. H., J. Schwartz, A. Zanobetti and H. Suh (2002). "Air conditioning and source-specific
       particles as modifiers of the effect of PM10 on hospital admissions for heart and lung disease."
       Environ Health Persp 110: 43-49.
62.  Tolbert, P. E.,  M. Klein, K. B. Metzger, J. Peel, W. D.  Flanders, K. Todd, J. A. Mulholland, P. B. Ryan and
       H. Frumkin (2000). "Interim results of the study of particulate s and health in Atlanta (SOPHIA)."
       J Expo Anal Environ Epidemiol 10(5):  446-460.
63.  Sheppard, L.,  D. Levy and H. Checkoway  (2001). "Correcting for the effects of location and atmospheric
       conditions on air pollution exposures in a case-crossover study."
        J Expo Anal Environ Epidemiol 11: 86-96.
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Dosimetry:  Deposition and
   Fate of Particles in the
       Respiratory Tract
          w
      are the deposition
    patterns and fate of
particles in the respiratory
tract of individuals belonging
to presumed susceptible
subpopulations?
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Introduction

    he most scientifically defensible relevant exposure measure for toxicity and health-risk
    assessment of PM is the actual dose deposition of particles in the respiratory tract and the
    subsequent retention and translocation of the deposited particles. However, accurate assessment of
dose to the lung (and notably to a target within the lung) can be a formidable task because dose varies
widely, changing with the physicochemical properties of particles themselves as well as with individual
human factors such as breathing patterns and lung morphology. Moreover, the latter factors vary with age,
gender, and the presence of lung disease.  The presence of other pollutants also may alter the physiology
of breathing. Therefore, dose information obtained from one particular subject group generally cannot
always be extrapolated to other groups. Furthermore, deposition within the lung is not uniform, but varies
markedly along the respiratory pathway and among different compartmental regions of the lungs.  Thus,
there is marked local heterogeneity of dose within the lung.  In fact, the heterogeneity of dose distribution
within the lung and the local enhancement can be even more  exaggerated in subjects with obstructive
lung diseases such as asthma and COPD.  Because the translocation and removal processes of deposited
particles are usually impaired in such patients, an excessive tissue burden at local sites for a prolonged
period of time is a likely formula for tissue injury, disease, or other eventual adverse health outcomes.
Along with exposure parameters, the internal dose is a critical factor for linking ambient air with health
outcomes and for determining individual or population health risks to PM.

Key Uncertainties,  Objectives,  and Special Issues

Research on PM dosimetry has focused primarily on total lung deposition, but there has been less
emphasis on tracheobronchial versus alveolar lung subdivisions. Most of these data have been acquired
with spherical and uniformly sized particles in healthy young adult men under normal breathing
conditions.  While little is known about the effects of age, gender, and pre-existing lung disease, even less
is known about local dose enhancement within the lung, particularly for subjects with obstructive airway
disease. Data for respiratory deposition of real ambient heterogeneous aerosols are virtually non-existent.
Particle dose is expressed by mass of particles, regardless of particle size, shape, chemical composition,
and other particle properties that may form a  more relevant dose metric to examine observed or potential
health effects. In both controlled exposure and epidemiological studies, dose assessment is generally
neglected because there is no straightforward way to use what is known in the context of observational
or panel epidemiological studies. As animal toxicology becomes increasingly important in addressing
chronic exposure, susceptibility, causality, and composition-specific effects on the lung, the links across
species (especially those with impaired lungs) remain general and are of limited quantitative use in the risk
assessment paradigm. This lack of information makes it difficult to extrapolate toxicological data from
animals to humans and underscorees the importance of improved information on comparative dosimeter.
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Major Accomplishments
ORD has made significant progress in several key areas of respiratory tract dosimetry: (a)
development of a novel and non-invasive experimental method that allows the measurement of
detailed regional deposition dose of inhaled particles in humans; (b) measurement of total and detailed
regional deposition of fine- and coarse-mode particles in different subject groups under varying
inhalation conditions; (c) measurement of respiratory dose of ultrafine particles in men and women;
(d) development of a three-dimensional computer simulation model for assessing micro-dosimetry in
the respiratory airways; and (e) initiation of rodent to human simulation models to mimic deposition
profiles from rodents to humans.

The new method for determination of deposition profiles in humans is based upon the notion that
a single inhalation of aerosol distributed throughout the tidal volume is  equivalent to a series of
inhalations of small volumes containing aerosol. To apply this method, the tidal volume typically
is divided into 10 compartments of equal volume. Aerosol is injected as a series of small volumes
during inhalation such that the series distributes within the lung.  During exhalation, the distribution
of the recovered aerosol can be used to calculate the deposition efficiency and deposition fraction in
each of 10 compartments using software developed by ORD. Because the bolus aerosol method does
not require radiolabeled aerosols, the  method may be applied to a broad spectrum of subject groups,
including both healthy persons and persons with lung disease.  The method also allows repeated
measurements in the same individuals without concerns of a potential health hazard from radioactivity.
The method has been thoroughly tested and validated and has been successfully used for a variety of
subjects who would be expected to have different deposition profiles. ORD's experimental dosimetry
system is the only system in the world capable of such precise characterization of deposition behavior
in human studies without attendant risks from radiolabeled aerosols (1,2).

Research conducted by ORD can now provide total as well as detailed regional deposition data for
fine and coarse particles in four different subject groups:  young adults,  old adults, asthmatic subjects,
and subjects with COPD (3). Men and women were studied in each group (4).  Deposition dose was
assessed with a variety of breathing conditions mimicking sleep, resting, and mild exercise conditions.
The collective data sets are unique in  their quality, size, and  scope; and  they provide the most accurate
dose information that  can be readily used for risk assessment of inhaled PM in healthy and diseased
subjects (5, 6).
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The hypothesis that ultrafine PM may be responsible for the observed association of health effects
with ambient PM prompted ORD investigators to evaluate this unique portion of the PM spectrum.
Data have been collected to determine total fractional deposition, as well as a more detailed 10-
compartment regional deposition profile in adult men and women (7). This study was the first
published report  on the distribution of ultrafines within the lung. Somewhat surprisingly and in
a manner not fully  consistent with the predictions of some published models, the ultrafine PM
distributed along the respiratory tract in a pattern much like that of coarse PM:  bronchial airway
deposition was most prominent, especially for the smallest ultrafine  PM (< 20 nm). The pattern
showed that, while some particles make their way to the deep lung, the majority appear to be
removed higher in the respiratory tree.

ORD used data from empirical studies to develop and validate an advanced three-dimensional
computer simulation model for tracking inhaled particles within the  respiratory airways (8). By
doing so, the exact location of particle deposition can be identified; and deposition dose can be
assessed at microscopic local airway regions. This state-of-the-art technique allows respiratory dose
to be estimated at specific tissue locations. The three-dimensional computer modeling of the human
respiratory tract (9) was awarded the 1997 Smithsonian Award for Medicine.

In light of recent findings on cardiac and systemic effects  of PM, extramural researchers have
attempted to address the potential translocation of PM from the lung after exposure. The studies of
deposition and toxicokinetics conducted in rodents  complement and extend the perspective of the
human studies and  theoretical deposition models developed in-house (10, 11). These ORD studies in
animal models focused on overall corporal clearance rather than mucociliary clearance per se.  Two
of the studies conducted under the auspices of the Rochester PM Research Center addressed overall
clearance of ultrafine PM from the lung. Somewhat surprisingly, it was found that size alone did not
dictate the translocation of similarly-sized ultrafine surrogate particles.  Rather, their composition
appeared to be determinant. Significant quantities of 14carbon-labeled ultrafine PM translocated to
the liver directly from the lung after exposure while the majority of 192iridium particles were rapidly
cleared tracheobronchially with only minute quantities measured in  extrapulmonary tissues (12, 13).
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The Rochester PM Research Center also examined deposition by PM size using controlled human
exposures. In a small study of healthy and asthmatic humans, total respiratory deposition of inhaled
ultrafine surrogate particles was higher compared to fine particles among healthy individuals and
increased with exercise and among subjects with asthma (14). Other STAR Program researchers
studied nasal deposition of fine and coarse polystyrene surrogate particles using anesthetized rats
as compared to a nasal mold.  Deposition fraction varied by flow rate, direction, and particle size;
and comparison between the animal model and the nasal cast was favorable (15-18). Efforts using
experimental data and physical concepts to develop models of particle deposition as a function of
age are currently under development (19). These studies with ultrafine PM may have significant
implications for the anticipated increase in diesel- and other carbon-based ultrafine PM.

Programmatic  Need  and Relevance

The goal of linking exposure to dose to effect remains a key objective of the ORD PM Research
Program. This goal is especially applicable to the assessment of susceptible groups. Significant
findings in the ORD PM Research Program indicate that enhanced dose under otherwise typical
exposure conditions may occur in individuals who have pre-existing cardiopulmonary disease.
Hotspots occur in the normal as well as the diseased lung due to a variety of aerodynamic factors.
Hence, exposure-dose relationships must be fully understood in  order to address issues of variability
in healthy and diseased individuals.  Salient advances in the program since 1997 include the
following:

   •   The respiratory dose of inhaled PM is distributed unevenly within the lung, and the actual
       dose at local airway regions can be many times greater than the overall lung dose. The
       situation is particularly pronounced in patients with obstructive airway disease in whom
       regional lung deposition is even more highly localized.
   •   Respiratory dose is very comparable between young and old adults. Therefore, relative dose
       itself may not be a factor of concern for healthy elderly subjects.
   •   Although overall respiratory dose is comparable between men and women in general,
       women tend to receive a relatively larger dose in the upper airway regions. This may lead
       to somewhat different responses to inhaled PM in men and women; i.e., more upper airway
       irritancy in women.
   •   Ultrafine and coarse PM generally deposit in the same regions of the respiratory tract.
   •   Preliminary data suggests that some particles may, as a function of size and composition,
       migrate from the lung to organs and tissues.
   •   Risk assessment based on overall  lung deposition dose alone may significantly underestimate
       potential risk of exposure to ambient PM, especially in diseased individuals.
                                                           Five Years of Progress

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Future Directions

Dosimetry research is beginning to emphasize lung deposition differences in potentially susceptible
populations and in experimental animals.  Currently, ORD has curtailed much of its experimental
program in humans, but is planning additional work in animal models—both healthy and diseased—
to support the development of predictive within-lung dose-models.  Although there are limitations
to the simulation of real-world situations,  some work is proceeding in this area with STAR Program
support while mathematical models and computer simulations are being developed to provide
insights into dose distribution within the lung for a variety of subject groups. Modeling will be
useful for identifying those who will be more susceptible and for determining which particular
anatomic regions within the lung are most susceptible to injuries.
Participate Matter Research Program

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       epithelium to extrapulmonary organs." J Toxicol Environ Health 65(20): 1513-1530.
13. Oberdorster, G., Z. Sharp, V. Atudorei, A. Elder, R. Gelein, A. Lunts, W. Kreyling and C. Cox
       (2002). "Extrapulmonary translocation of ultrafine carbon particles following whole-body
       inhalation exposure of rats." J Toxicol Environ Health A 65(20):  1531-1543.
14. Frampton, M. W. (2001).  "Systemic and cardiovascular effects of airway injury and
       inflammation:  Ultrafine particle exposure in humans."
       Environ Health Persp 109(Suppl 4): 529-32.
15. Kelly, J. T.,  C. M. Bobbitt and B. Asgharian (2001). "/« vivo measurement of fine and coarse
       aerosol deposition in the nasal airways of female Long-Evans rats."
       Toxicol Sci 64(2): 253-258.
16. Kelly, J. T.,  J. S. Kimbell and B. Asgharian (2001). "Deposition of fine and coarse aerosols in a
       rat nasal  mold." Inhal Toxicol 13(7): 577-588.
17. Kelly, J. T.,  E. W. Tewksbury, B. A. Wong and B. Asgharian (2002).  "Nasal and lung deposition
       of fine and coarse particles in rats" Ann Occup Hyg 46(Suppl 1): 346-349.
18. Asgharian, B., J. T. Kelly and E. W. Tewksbury (2003).  "Respiratory deposition and inhalability
       of monodisperse aerosols in Long Evan rats." Toxicol Sci 71: 104-111.
19. Phalen, R. F. and M. J. Oldham (2001). "Methods for modeling particle deposition as a function
       of age" Respir Physiol 128(1):  119-130.

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 Combined Effects of
Particulate  Matter and
  Gaseous Pollutants
          How can the effects of
          participate matter be
       disentangled from the effects of
       other pollutants? How can the
       effects of long-term exposure
       to particulate matter and other
       pollutants be better understood?
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Introduction

    Air pollution is a complex mix of primary and secondary pollutants, the latter of which are
    generated by atmospheric transformation. While these pollutants are commonly linked to
    anthropogenic activities involving, among others, combustion of fossil fuels, there are various
biogenic sources that significantly complicate the atmospheric chemistry.  Under the CAA, air quality
standards are set for individual criteria pollutants. However, ambient PM coexists with other air
pollutants and, although PM often remains significantly associated with health endpoints in models that
include the gaseous co-pollutants, the influence or role of the co-pollutants in these outcomes is not
fully understood. It is often difficult to fully segregate the influence of individual pollutants and assess
interactions; thus, the integration of observational and empirical approaches will greatly aid in the
assessment of individual versus mixture risks. In addition, such work will also aid in the evaluation of
the control strategies.

Our current knowledge of long-term PM effects is based on a small number of epidemiological studies
that compare differences in the survival of well-characterized cohorts of human subjects with air
pollution levels in their cities of residence. Such longitudinal studies are much less common than
short-term time-series studies of PM due to the difficulty and expense of enrolling and  maintaining
follow-up of cohorts. However, as the National Monitoring Network is being revised and information
is becoming available from EPA's Supersites Program and STN, the timing is right to develop both
retrospective and prospective studies of mortality, disease initiation and progression that may be
associated with long-term exposure to ambient PM mass, PM components, and co-pollutants.

Key Uncertainties,  Objectives, and Special Issues

The 1996 PM AQCD concluded that PM, alone or in combination with other pollutants, was associated
with a range of adverse health effects.  A key  uncertainty concerned the relationship between PM
and co-pollutants with respect to these adverse effects, especially where PM and the co-pollutants
were related to the same source types.  HEI-funded re-analyses of data from time-series studies on
mortality indicated that the results were little  influenced by changes in statistical modeling strategies
or control for weather variables, but that it could sometimes be difficult to distinguish the effects
of PM from other combustion-related gaseous pollutants in data from a single city (1).  The NRC
Committee noted that a significant amount of epidemiological work has attempted to address this issue.
However, the NRC Committee maintained that additional controlled human exposure research and
toxicological studies were needed on the role of PM and gases in causing health effects, both alone and
in combination,  and on whether co-exposure to gases influences PM toxicity and vice versa (2).
At the time the 1996 PM AQCD was published, three epidemiological studies of long-term exposure
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to PM had been published in the peer-reviewed literature.  Two of these studies were geographically
broad in scope: the Harvard Six-Cities Adult Cohort Study (3) and the ACS Cohort Study (4). The
third study, the Seventh Day Adventist Health Study on Smog (5), focused solely on California. The
first two studies reported significant associations between risk of premature mortality and long-term
exposure to PM25.  While the California study did not find significant associations of mortality with
TSP, there was a trend for respiratory cancer. These studies have been pivotal in recognizing the
potential importance of long-term exposure to PM.  At the same time, questions have been raised
about these cohort  studies, bringing up such issues as their ability to address potential confounders or
effect modifiers and difficulty of retrospectively assessing exposures to pollutants using contemporary
ambient monitoring data (2, 6).
Major Accomplishments
In the last five years, much of what has been learned regarding PM co-pollutant effects, confounding,
and long-term risks to PM has emerged from the extramural epidemiological work conducted under
the STAR, PM research center, and HEI programs.  "The EPAs Paniculate Matter (PM) Health Effects
Research Centers Program: AMidcourse Report of Status, Progress, and Plans" provides a cohesive
overview of the studies addressing co-pollutant and chronic issues (7). The advances reported are
complemented by recent re-analysis efforts supported by HEI that replicated and conducted sensitivity
analyses of the original results from the Harvard Six-Cities Adult Cohort Study and the ACS Cohort
Study (8).

Gaseous Co-Pollutants
The NMMAPS, sponsored by HEI, included analyses of PM10 relationships with mortality in 90 U.S.
cities with additional, more detailed analyses being conducted in a subset of the 20 largest U.S. cities
(9). A uniform methodology was used to evaluate the relationship between mortality and PM10 for the
different cities, and the results were synthesized to provide a combined estimate of effects across the
cities. One key objective of the NMMAPS analysis was to characterize the effects of PM10 and each
of the gaseous co-pollutants, alone and in combination.  This assessment yielded the important finding
that exposure to higher levels of ambient PM10 was associated with increased daily mortality rates
in the 90-city analyses, and this association was not confounded by the presence of the gaseous co-
pollutants (9).1 Using an  alternative method, Schwartz (11) conducted a series of multi-city
analyses from 10 U.S. cities for which daily PM monitoring data were available and found consistent
'In further analysis of data from the 90 U.S. cities, NMMAPS investigators discovered that the default parameters within
the software package commonly used for time-series epidemiological studies do not assure convergence of its iterative
estimation procedure and can provide biased estimates of regression coefficients and standard errors (refer to Research
Topic 10). Re-analysis of the data with more stringent parameters resulted in a smaller risk estimate, but the effect
remained statistically significant; and previously drawn conclusions regarding the link between PM10 and mortality were
still supported (10).

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PM10-mortality associations and O3, CO, or SO2.  Panel studies have also begun to focus on
teasing out the effects of gaseous co-pollutants as illustrated by recent cardiac studies conducted in
Baltimore that included the assessment of gaseous co-pollutants (12). The analyses to assess the
effects of co-pollutants have just begun and are being applied to other populations (e.g., Fresno, CA).

Recognizing the need to address the issue of co-pollutants in controlled exposure studies, ORD
has initiated multiple investigations through both its intramural and extramural programs. Human
studies examining the effects of CAPs exposure in different population groups have also examined
ozone, NO2, and SO2, as well as several different components of PM (13). Analyses to segregate
potential co-pollutant effects are still underway. Similarly, a number of the PM research centers and
STAR Program grantees have research in progress to examine the health effects of CAPs and co-
pollutants in various animal models of disease and susceptibility. To date, the bulk of the data derive
from surrogate PM, products of fresh combustion, or combinations of various ROFA exposures.

One study in particular, Kodavanti et al. (14), used various ROFA samples to assess the linkages
between health outcomes and ROFA composition. Specific metals display region-specific roles
in the lung. On the other hand, studies nearly completed, but as yet unpublished, indicate that the
effects of the PM component and the irritant gas component (SO2) had quite distinctive regional
effects.  Studies with CAPs in animal models are ongoing.  Some of these exposure studies are brief
single exposures, while others are seasonal in design.  In all cases, every effort is being made to link
the responses with  composition to provide potential source associations. Results of these studies are
expected to begin appearing in the peer-reviewed literature within the next two to three years.

Studies on  Long-Term  Exposure to PM
Two critical studies have been carefully re-analyzed by independent researchers to address several
concerns regarding confounding and potential bias (8). The HEI re-analysis project confirmed the
results of the Harvard Six-Cities Adult Cohort and ACS studies with minor adjustments in their
mortality estimates. Since the conclusion of HEI's re-analysis project, the cohorts from three
longitudinal studies on PM have been extended by the original investigators to include additional
years of follow up  and alternative exposure measures.

Pope et  al. (15)  extended the original ACS study by eight years and replicated the findings of
increased cardiopulmonary mortality risk, but in addition, reported a significant association with
mortality from lung cancer. Although not yet published, Harvard researchers have presented findings
from an additional  9 years  of follow up (1990-1998) of participants in the Harvard Six-Cities Adult
Cohort Study.  Survival analyses of all-cause mortality showed that life expectancy continues to be
reduced in the more polluted cities where the mortality risk ratios are the same as those observed
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in the original study.  In addition, the follow-up analyses showed that the relative risk for deaths
decreased in the two cities reporting decreases in air pollution levels (16). Additionally, in the
recently updated Seventh Day Adventist Health Study on Smog, investigators-using airport visibility
data to estimate exposure to PM2 5-reported increases in mortality associated with increments in
PM25 (17) that are consistent with other reports. Early methodological criticisms of these studies
have been largely resolved, and the updated results support the concerns regarding an association
between long-term exposures to PM and decreased survival (18).

Long-term exposure to PM is not only a concern for premature mortality, but for morbidity as well.
Studies of chronic effects of PM exposure on the respiratory health of children have been conducted
by two of the PM research centers.  The Harvard Twenty-Four Cities Study assessed respiratory
health and particle exposures of 13,364  fourth- and fifth-grade schoolchildren in the U.S. and
Canada between 1988 and 1991.  The University of Southern California Children's Health Study
has similarly assessed respiratory health and particle exposures of approximately 4,000 fourth- and
fifth- grade schoolchildren in 12 communities in Southern California. Recent results from  this  latter
study associated PM2 5 with slower growth of lung function in children residing in communities
with higher than average annual PM25. The slow growth appears to be nonrecoverable, and children
moving to these areas also experienced slowed growth in lung function (19).

These results stimulated the Harvard and UCLA PM research  centers to plan for follow-up pooled
analyses of the cohorts of children from the Harvard Twenty-Four Cities Study and the University
of Southern California Children's Health Study. The former study would address effects of
PM attributed to power plants, while the latter would focus on PM attributed to mobile sources.
Similarly, an ORD study of respiratory health in 3000  El Paso schoolchildren has been ongoing since
2000. This study  assesses the effects of PM and gaseous co-pollutants (including VOCs) associated
with local industry and traffic density. These data are currently being analyzed, and publications are
anticipated over the next several years.

In response to the NRC Committee recommendations to begin to address long-term health effects
of PM, EPA held a workshop in 1999 that  explored ways to augment existing cohort studies to
investigate links between long-term exposure to pollutants and cardiovascular morbidity and
mortality.  ORD is now funding several  investigators to conduct retrospective studies using existing
cohort data for such analyses. The cohorts include participants in the Nurses' Health Study and the
Seventh Day Adventist Health Study on Smog.
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Long-term toxicological studies in rodents have recently been initiated in an attempt to focus on
the specific vulnerability of putative susceptible models and the linkages with PM composition and
sources.  ORD has conducted and published studies with ROFAfor as long as 16 weeks; ongoing are
three studies of intermittent CAPs exposure extending from 6 to 13 seasonal weeks in both normal
healthy and cardiac-compromised (hypertensive) rats. The ROFA exposures induced subtle but
reversible effects on blood fibrinogen and small changes in lung pathology which were highly dose
and time dependent (20, 21).  Perhaps most striking is the effect of the inhaled ROFA on cardiac
tissue pathology, suggestive of developing injury and disease. The surprising  aspect is that this
type of lesion was most prominent in the healthy rats, not the compromised hypertensive rat, for
reasons that are not clear (21). The data from the CAPs studies are currently undergoing analysis,
but preliminary findings suggest that the daily exposure, not the cumulative (over the extended time
period studied), challenge is the most important determinant of effect. The most notable outcomes
thus far have been in measurements of blood fibrinogen, a finding consistent with reports in humans
(13, 22).

Plans are in discussion by the NYU PM Research Center for a subchronic PM25 exposure study
using normal and susceptible mice.  The animal models include those with both targeted mutations
of the genes apolipoprotein E and the low density lipoprotein receptor and those with only the
targeted mutation of the gene for apolipoprotein E.  The study will use New York City CAPs and
will monitor cardiac and respiratory function. While studies of this type are inherently difficult
to conduct and are dependent upon the models being studied, it is expected that these studies will
provide data that will be of importance to health assessments during the next few years.
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Programmatic Need  and Relevance

Epidemiological studies have played a critical role in previous reviews of the health-based PM
NAAQS and will likely continue to do so in the ongoing PM NAAQS review. Distinguishing the
effects of one pollutant from another, as well as understanding interactions between co-pollutants in
producing effects, has been a key area of uncertainty in previous PM NAAQS decisions. Reducing
this uncertainty will help EPA better assess risks associated with PM and other pollutants, estimate
health benefits from reducing pollutant emissions, and establish the most effective and efficient
NAAQS for the protection of human health

While many studies have been published on effects associated with short-term exposures, the
recurring concern has been that fewer studies have assessed long-term exposures. In addition,
little toxicological research has studied chronic exposures to ambient particles. In establishing
NAAQS for fine particles,  EPA determined that it was appropriate to rely on the annual standard
as the "controlling" standard in order to reduce both short-term and long-term PM concentrations.
The level of the annual PM25 NAAQS was based on the results of both short-term and long-term
exposures studies with greater emphasis on the results for the more numerous short-term studies.
Further understanding of the role that PM and other pollutants may play in the development of
disease and increased mortality risk, as well as of potential mechanisms for these effects, will assist
in future decisions regarding long-term PM NAAQS.
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Future Directions

The Agency has solicited proposals and expects to provide funding to recruit a new cohort in order
to extend the knowledge gained from the earlier longitudinal studies.  The solicitation requested
proposals for prospective studies of CVD and respiratory disease endpoints in relation to PM.
Outcomes of interest will include hospital admissions for CVD and respiratory disease, as well
as other validated subclinical measures of the progression of CVD. The studies will evaluate
alternative PM exposure metrics (mass, components, sources, and temporal patterns), the effect
of PM in combination with gaseous co-pollutants, and effects on potentially susceptible groups.
The new study will be able to use ambient monitoring data on PM25 collected since 1999 as well
as speciation site data on PM constituents.  The RFA was developed in consultation with NIEHS;
the  National Heart, Lung, and Blood Institute; and the National Institute of Allergy and Infectious
Disease.

Intramurally, EPA is collaborating with other programs, such as the National Health and Nutrition
Examination Survey, to assess links between long-term PM exposure and health. These plans have
been well-coordinated with the extramural program's efforts to develop the RFA for a longitudinal
epidemiological study.

Animal studies are being planned to follow from the studies discussed previously. Recently there
was a suggestion made to coordinate a multi-lab summer CAPs study standardizing the animal
model and exposure design. The goal is to ascertain differences in the toxicity of regional PM.
There may be a hiatus in the Research Triangle Park-ORD effort while the data from previous
studies are evaluated and while the CAPs exposure system in the new Research Triangle Park facility
is being installed and up-fitted.

This topic, perhaps more than many other research priority identified by the NRC Committee, is in
its relative infancy. While the epidemiological literature continues to address the extent to which PM
causes health effects independent of other pollutants, controlled exposure studies have just started
to analyze this question. Similarly, given the complexity, expense, and duration of longitudinal
epidemiological studies of PM health effects, coupled with the historic lack of fine PM monitoring
data and adequate biomarkers, it is not surprising that such studies are only now coming into
existence.
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Analogous problems exist with long-term animal studies, which at present are likely to be limited
to seasonal studies due to the practical limits of working with animals and compromised cohorts.
One key is the linkage to the contributing sources of PM. Thus, there is a critical dependency
on monitoring and analytic data collected with an eye to source apportionment analyses. The
development of the National Monitoring Network will be essential to many of the planned
epidemiological studies, and it is anticipated that animal studies will likewise attempt to use this rich
database to assess hypothesis of causality and susceptibility.
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References

1. Kelsall, J. E., J. M. Samet, S. L. Zeger and J. Xu (1997). "Air pollution and mortality in Philadelphia,
        1974-1988." AmJEpidemiol 146: 750-762.
2. National Research Council  (2001). Research Priorities for Airborne Paniculate Matter:  III.  Early
       Research Progress. Washington, DC: National Academies Press.  ISBN 0-309-07337-5.
3. Dockery, D. W., C. A. Pope, 3rd, X. Xu, J. D. Spengler, J. H. Ware, M. E. Fay, B. G. Ferris, Jr. and F. E.
        Speizer (1993). "An association between air pollution and mortality in six U.S. cities."
        NEnglJMed329(24):  1753-9.
4. Pope, C. A., 3rd, M. J. Thun, M. M. Namboodiri, D. W. Dockery, J. S. Evans, F. E. Speizer and C. W.
       Heath, Jr. (1995).  "Particulate air pollution as a predictor of mortality in a prospective study of U.S.
       adults." AmJRespir Crit Care Med 151(3 Pt 1):  669-74.
5. Abbey, D. E., P. K. Mills, F. F. Petersen and W. L. Beeson (1991). "Long-term ambient concentrations
       of total suspended particulates and oxidants as related to incidence of chronic disease in California
        Seventh-Day Adventists" Environ Health Persp 94: 43-50.
6. National Research Council (1999).  Research Priorities for Airborne Particulate Matter: II.  Evaluating
       Research Progress and Updating the Portfolio. Washington, DC: National Academies Press.
       ISBN 0-309-06638-7.
7. Lippmann, M., M. Fampton, J. Schwarz, D. Dockery, R. Schlesinger, P. Koutrakis, J. Froines, A. E. Nel,  J.
       Finkelstein, J. Godleski,  J. Kaufman, J. Koening, T. Larson, D. Luchtel, L.-J. S. Liu,  G. Oberdorster,
       A. Peters, J. Sarnat, C. Sioutas, H. Suh, J. Sullivan, M. Utell, E. Wichmann and J. T. Zelikoff (2003).
       "The EPA's Particulate Matter (PM) Health Effects Research Centers Program: A Midcourse Report
       of Status, Progress, and Plans." Environ Health Persp 111(8): 1074-1092. DOI: 10.1289/ehp.5750.
8. Krewski, D., R. T. Burnett, M. S. Goldberg, K. Hoover, J. Siemiatycki, M. Jerret, M. Abrahamowicz and
       W. H. While (2000). Reanalysis of the Harvard Six Cities Study and the American Cancer Society
       Study of Particulate Pollution and Mortality.  Special report of the Institute's Particle Epidemiology
       Reanalysis Project. Cambridge,  MA: Health Effects Institute.
9. Samet, J. M., F. Dominici, F. C. Curriero, I. Coursac and S. L. Zeger (2000). "Fine particulate air pollution
       and mortality in 20 U.S.  cities, 1987-1994." NEnglJMed 343(24): 1742-9.
10. Dominici, F., A. McDermott, S. L. Zeger and J. M. Samet (2002). "On the use of generalized additive
       models in time series of air pollution and health." Am J Epidemiol 156(3): 193-203.
11. Schwartz, J. (2000).  "Assessing confounding, effect modification, and thresholds in the association
       between ambient particles and daily deaths." Environ Health Persp 108(6): 563-568.
12. Liao, D., J. Creason, C. Shy, R. Williams, R. Watts and R. Zweidinger (1999).  "Daily variation of
       particulate air pollution and poor cardiac autonomic control in the elderly."
        Environ Health Persp 107: 521-525.
13. Ohio, A. J., C. Kim and R. B. Devlin (2000).  "Concentrated ambient air particles induce mild pulmonary
       inflammation in healthy human volunteers." Am JRespir Crit Care Med 162(3  Pt 1): 981-988.
14. Kodavanti, U. P., R. Hauser,  D. C. Christiani, Z. H. Meng, J. McGee, A. Ledbetter, J. Richards and D. L.
       Costa (1998). "Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific
       soluble metals." Toxicol Sci 43: 204-212.
15. Pope, C. A. I., R. T. Burnett, M. J. Thun, E. E. Calle, D. Krewski, K. Ito and G. D. Thurston (2002).
       "Lung cancer, cardiopulmonary mortality and long-term exposure to fine particulate air pollution."
       JAmMedAssoc2Vl: 1132-1141.
16. Laden, F., J. Schwartz, F. E.  Speizer  and D. W. Dockery (2001).  "Air pollution and mortality:
        A continued follow-up in the Harvard Six Cities Study [abstract]." Epidemiology 12:881.
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17. McDonnell, W. R, N. Nishino-Ishikawa, F. F. Petersen, L. H. Chen and D. E. Abbey (2000).
       "Relationships of mortality with the fine and coarse fractions of long- term ambient PM10
       concentrations in nonsmokers." JExpo Anal Environ Epidemiol 10(5): 427-436.
18. Bates, D. V. (2000).  "Lines that connect: Assessing the causality inference in the case of particulate
       pollution." Environ Health Persp 108(2): 91-2.
19. Avol, E. L., W. J. Gauderman, S. M. Tan, S. J. London and J. M. Peters (2001).  "Respiratory effects of
       relocating to areas of differing air pollution levels."AmJRespir Crit Care Med 164(11): 2067-72.
20. Kodavanti, U. P., M. C. J. Schladweiler, A. D. Ledbetter, R. Hauser, D. C. Christiani, J.  M. Samet, J.
       McGee, J. H. Richards and D. L. Costa (2002). "Pulmonary and systemic effects of zinc-containing
       emission particles in three rat strains:  Multiple exposure scenarios." Toxicol Sci 70: 73-85.
21. Kodavanti, U. P., C. Moyer, A. D. Ledbetter, M. C. Schladweiler, D. L. Costa, R. Hauser, D. C. Christiani
       and A. Nyska (2003). "Inhaled environmental combustion particles cause myocardial injury in the
       Wistar Kyoto rat." Toxicol Sci 71(2): 237-245.
22. Peters, A., A. Boring, H. E. Wichmann and W. Koenig (1997).  "Increased plasma viscosity during an air
       pollution episode: A link to mortality?" Lancet 349:  1582-1587.
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   Susceptible
Subpopulations
  w;
    rhat subpopulations are
    at an increased risk of
adverse health outcomes from
particulate matter?
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Introduction

    ime-series epidemiological studies associating mortality and hospital admissions with daily
    ambient PM concentrations suggest that responses to PM predominate in certain subpopulations,
    as denned by age and pre-existing disease. Observational studies conducted in the early 1990s
funded by EPA, HEI, and other sponsors have shown that people older than 65 years have higher
mortality risks associated with PM exposure than the population as a whole. Likewise, individuals
with pre-existing CVD or respiratory disease (including COPD and pulmonary infection) show
similar or higher risk of PM-related mortality and morbidity. Asthmatics, especially children,
also have been identified as a potential susceptible subpopulation based on their diary records,
hospitalization, school absenteeism, and use-frequency of bronchodilators that associate with
ambient PM levels. There is even limited evidence of prenatal effects of PM (and perhaps co-
pollutants) on cardiac development and mortality in the first two years of life and perhaps of further
suppression of lung growth during childhood.

Clearly,  there is sufficient evidence to conclude that certain groups are likely to be more sensitive
or responsive to PM than others.  Genetic variability may influence the distribution of sensitivity,
but there may be physiological susceptibility factors common to the groups that may indicate a
higher risk potential. Thus, while the first step is to identify susceptible groups within the general
population for inclusion into the overall risk assessment paradigm, characterizing the risk factors that
underlie susceptibility may be most the most fruitful revelation in the long run.

Key  Uncertainties,  Objectives,  and  Special Issues

The 1997 NAAQS decision recognized the supportive evidence for greater risk in susceptible
subpopulations. The early findings that supported the decision have since been replicated in many
more observational studies. While the elderly and the very young may be somewhat more sensitive
than the population in cross-section, those with impaired cardiovascular and respiratory systems
appear to be at greatest risk for PM mortality and morbidity. Indeed, because these disease "entities"
often involve both organ systems  (by virtue of their physiological interdependence), it may be
difficult to segregate organ-specific risk with standard epidemiological methods.  Hence,  clinical
studies in human volunteers and novel animal models of disease have begun detailed examinations
of the biochemical and physiological mechanisms of PM-associated risks. When combined
with panel studies, it appears that the strong PM associations with the presence of pre-existing
cardiopulmonary disease have been affirmed.  What is left to explore is the "how" and "why."
As noted previously, the CAA requires the protection of susceptible  groups.  As the evidence
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accrues, it appears that susceptibility may be at the hub of the entire issue, at least with regard to
acute effects.  How susceptibility is related to long-term or chronic effects is virtually unexplored.
However, regarding the issue of susceptibility in the context of the numbers of people affected, even
a small percentage reduction in PM levels could translate to a large number of avoided cases.

In 1997, there were 3,475,000 U.S. hospital discharges for respiratory diseases: 38% for pneumonia,
14% for asthma, 13% for chronic bronchitis, 8% for acute bronchitis, and the remainder (27%)
not specified (1).  Of the 195,943 deaths recorded as caused by respiratory diseases, 44% resulted
from acute infections, 10% for emphysema and bronchitis, 3% for asthma,  and 42% for unspecified
COPD (2). This point is even more marked among the subpopulation with CVD.  For the same
year, 1997, there were about 4,188,000 U.S. hospital discharges with heart  disease as the primary
diagnosis (1). Among these, about 2,090,000 (50%) were for ischemic heart disease; 756,000 (18%)
for MI or heart attack (a subcategory of ischemic heart disease); 957,000 (23%) for congestive
heart failure; and 635,000 (15%) for cardiac dysrhythmias.  Deaths from heart disease in 1997 were
726,974 (2). As there were about four times as many CVD deaths when compared to those due to
respiratory disease, the CVD group is clearly at higher risk of mortality overall. Moreover, there are
many more people with CVD—many with a silent condition that usually goes undiagnosed until a
cardiovascular event.  Thus, despite the fact that the respiratory and CVD risks reported in several
studies have been about equal, PM-CVD interactions are likely to outnumber the PM-respiratory
events. Given these numbers, the societal economic and personal costs of PM effects to those who
may  be susceptible due to an underlying disease are substantial.
Major Accomplishments
Ambient PM Exacerbation of Respiratory Disease Conditions
Many time-series studies have shown that pre-existent chronic lung diseases as a group (but
especially COPD) constitutes a risk factor for mortality associated with PM exposure (3). Studies
with humans that might reveal more specific data have been limited by ethical exclusions of severely
diseased individuals and by the absence of valid physiological indicators of subclinical disease
(parallel to the function of ECGs in cardiac disease). Measures of blood-gas saturation and lung
function do not appear to be sufficiently revealing or sensitive to mild physiological changes in those
with moderate clinical disease.

On the other hand, subjects with moderate COPD and asthma have been exposed to inert aerosols
in controlled human exposure studies to assess the distribution of PM within the lung (4). It is now
clear that any disease  that involves the airways elicits a heterogeneously distributed deposition of
PM within the lung, as discussed in Research Topic 6. This study and subsequent models (5) have
shown up to 10-fold higher than normal deposition at airway bifurcations where the creation of

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"hotspots" may well have biological implications, especially if the individual already has diminished
function or other disability due to the underlying disease. Thus, the dosimetry of PM within the
lung must be considered an important element of the susceptibility paradigm with almost any
cardiopulmonary disease condition.

There are several reports of associations between short-term fluctuations in ambient PM and day-to-
day frequency of respiratory illnesses (6). In most cases, notably in pre-teen children, assessments
have found exacerbation of pre-existing respiratory illness and related symptoms rather than de novo
acute respiratory infections (7).  The use of inhalers has also been shown to increase in many young
asthmatics in response to air pollution in general and PM in particular.

A study of children in East Germany found that the prevalence of nonasthmatic respiratory symptoms
including bronchitis, otitis media, frequent colds, and febrile infections declined between two
periods in the 1990s when ambient air pollution levels declined (8).  Others have observed that
acute respiratory infections associated with PM exposure in elderly subjects with cardiopulmonary
disease appear to result in complications of the underlying cardiac disorder and require subsequent
hospitalization (9).  Animals exposed to surrogate PM have not consistently exhibited vulnerability to
infections, but altered lung phagocyte function has been reported (10,  11). Thus, while there appears
to be a strong likelihood that infections  may be worsened by exposure to PM, general statements
regarding interaction of PM with response to infectious agents are difficult to validate due to the
unique attributes of various infectious agents and the variability of the immune status of the  host.

Researchers have designed experimental studies to elucidate aspects of the underlying biology
of lung diseases that may lead to heightened sensitivity to PM (notwithstanding the dose issue
noted previously).  Apart from the functional linkages with the cardiac system for maintenance of
adequate gas exchange and fluid balance, inflammation in the diseased respiratory tract (airways and
alveoli) could also play a key role.  Studies in animals genetically or exogenously altered to  induce
inflammation show that such animals may become intrinsically more responsive to surrogate or
concentrated ambient PM (12-15). Existing basic biological data are sufficient to hypothesize that
exudated fluids in airspaces may either interact differently with deposited PM to augment injury (e.g.,
to generate oxidants)(16, 17) or to predispose the lung (18) to enhance a response to a stereotypic
PM stimulus through otherwise normal  pathways.  Less appreciated is the loss of reserve (functional
or biochemical) when the susceptible individual is incapable of sufficient compensation (e.g.,
antioxidant responses)(19). Any of these or related mechanisms may contribute to susceptibility and
may be one common factor that can be attributable to other susceptible groups. Understanding these
factors will ultimately aid in addressing the true risk of susceptible groups to PM.
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Ambient PM Exacerbation of CVD Conditions
Exacerbation of heart disease has been associated in time-series studies not only with ambient
PM, but also with other combustion-related ambient pollutants  such as CO and NO2.  It remains
unclear whether the combustion gases in this context are acting as surrogates for PM or as additional
predictors.  A number of studies using creative approaches and  surrogate exposures have provided
additional evidence of direct cardiac effects in humans exposed to air pollution. For example, recent
panel studies of human subjects with CVD have shown correlations between air pollution levels,
notably levels of PM, and the frequency of intervention discharges of implanted cardiac defibrillators
as well as elicitation of ST-segment depression during repeated exercise tests (20).

Analogously, Pope et al. (21) have noted altered autonomic control of cardiac function [in the form
of reduced heart rate (HR) variability (HRV)] over a wide age-range of healthy subjects when they
were introduced into an airport lounge with active smokers.  Evidence of vascular narrowing with
exposure to CAPs has also been reported suggesting parallel cardiovascular responses in human
clinical studies (22). Collectively, these and previous studies that have shown ambient PM-induced
alterations in cardiac physiology in human subjects (20, 23, 24) and that are complemented by
animal studies (12, 25-27) provide evidence that there are significant cardiac responses to PM.
Moreover, changes in plasma viscosity (28) and other factors involved in clotting function (29)
provide a plausible sequence of events that could culminate in sudden cardiac events in some
individuals.

The recent HEI report on an epidemiological study in Montreal provides interesting new information
regarding the types of medical conditions that potentially predispose individuals to  increased
risk for PM-associated mortality (30). Investigators linked immediate and underlying clinical
conditions recorded on the death certificate with indices of ambient PM (TSP; PM10; estimated
PM25; coefficient of haze, or COH; sulfates; and extinction coefficients) lagged for  0 to 4 days.  The
results supported previous findings identifying those with pre-existing cardiopulmonary conditions
at increased risk for ambient PM effects and implicated another possible risk factor, diabetes (which
involves  cardiovascular complications as it progresses) as a potential susceptibility  condition.
Zanobetti and Schwartz (31) have found more directly that those with diabetes are at increased
risk; presumably, this finding is related to the cardiac and vascular complications associated with
this disease. At the present time, diabetes is being investigated as a mediator of PM-related risk in
epidemiological studies; parallel work is proceeding in animal models to segregate  the underlying
mode of action.
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Age-Related At-Risk Population Groups:  The  Elderly and Children
The very young and the very old have been identified among those most affected by PM air pollution.
As noted previously, a major factor in increased susceptibility to air pollution is the presence of a pre-
existing illness as discussed by Zanobetti et al. (9). The effect of PM pollution on mortality and acute
morbidity is well-documented in time-series studies:  risk increases gradually above the age of 45 and
continues to increase more steeply after 65 years. It is well known that cardiopulmonary diseases are
more common to the elderly and are the major cause  of death in older age groups.

While panel studies of PM morbidity have tended to  focus on healthy people in retirement homes
(23) and while chamber studies with elderly volunteers exposed to concentrated ambient PM (32) are
even more restrictive regarding health exclusion criteria, these studies have shown subtle alterations
of autonomic control of cardiac function (i.e., slight depression of HRV) and small changes in blood
clotting factors.  Though small, these changes are considered clinically significant based on studies of
risk in cardiac patients and studies of CVD progression in the general population. The HRV changes
contrast with the lack of similar physiological changes in healthy young people (29) who surprisingly
have more consistent changes in  the clotting factors.  The biological significance of these results
and their reproducibility remain to be explained but are the subject of continuing human and animal
studies.

Chronic Exposures  and  Susceptibility
Susceptibility to health outcomes from long-term or lifetime exposures is poorly understood. Three
longitudinal studies (two with partial funding by the EPA) have  shown elevated mortality risk from
chronic PM exposure (refer to Research Topic 7), but these studies were not able to reliably separate
the effects of gaseous co-pollutants and other risk factors from PM.  Over the long term, innate
differences in metabolism or other mechanisms may  affect the likelihood of progressive deterioration
or disease (COPD,  CVD, or lung cancer).  Uncertainties remain regarding the extent to which
progression is a product of total cumulative or repeated episodes or patterns of PM exposures and to
what degree disease or other risk factors add to or complicate the magnitude of response.

Regarding potential lung developmental effects of PM, there exist both experimental and
epidemiological data that, though limited, suggest the early post-neonatal period of lung development
is a time of high susceptibility for lung damage by environmental toxicants. In experimental animals,
for example, elevated neonatal susceptibility to lung-targeted toxicants has been reported at doses
"well below the no-effects level for adults" (33). Furthermore, acute injury to the lung during early
postnatal development may impair or retard normal repair, growth, and maturation. These and other
results in animals appear to agree at least qualitatively with the recent findings  for young children
living in the Los Angeles area where both oxidants and high levels of PM prevail (34).
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These and other types of health effects in children are emerging as potentially important issues that
were not appreciated in 1997. Unfortunately, relatively little is known about the relationship of
PM to these and other serious health endpoints (low birth weight, preterm birth, neonatal and infant
mortality, emergency hospital admissions, and mortality in older children). The recent report (35)
linking CO exposures of mothers in Los Angeles with fetal cardiac defects raises concerns about
PM, which was inconclusively linked in the study. Similarly, little is yet known  about involvement
of PM exposure in the progression from less serious childhood conditions, such as asthma and
respiratory symptoms, to more serious disease endpoints later in life.

Programmatic Need and Relevance
Studies of PM generally focus on its attributes or exposure issues. However, the collective
and accumulating evidence indicates that not everyone is similarly affected by PM.  There are
subpopulations, generally described in the context of overall health, who appear  to be susceptible
and who may in fact statistically drive much or most of the overall population response.  Identifying
these populations and, more importantly, identifying the host characteristics that contribute
to heightened risk are vital to ultimately protecting those at risk by minimizing exposure and
recommending ways to minimize personal risk.

While there is some appreciation of the factors that may contribute to acute PM risk, evidence is
needed to segregate which subpopulations may be more prone to adverse health risk with chronic
exposure.  As EPA moves toward the next cycle  of the NAAQS review, this information will help
support the quantification of risk for the most susceptible subpopulations.
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Future Directions

Host variability is undoubtedly an important factor in determining the response profile of a
population exposed to PM. Studies to date suggest that certain subpopulations are indeed more
acutely responsive to PM, perhaps due to differences in lung deposition (either in terms of dose
and/or intrapulmonary distribution) or to other biological aspects of the cardiopulmonary system or
disease. EPA will emphasize the characterization of susceptible groups in extramurally supported
epidemiological studies of health effects stemming from long-term PM exposure.

The role of innate host attributes of risk grounded in one's genetic code is largely unknown, but
potentially of great importance. Changes in these attributes with age or the presence of deteriorated
cardiopulmonary function contribute further to risk, but these changes are likely to be studied only
in population-based analyses. Research needs to focus on individual risk and on the elements
that define or underlie that risk. Both clinically based and field studies of humans will help focus
attention on potential factors, but it is animal-based study that will permit specific hypothesis testing
to define mechanisms.
EPA is currently expanding its knowledge base in the area of studies of susceptibility with both
human clinical and animal disease and/or genetic model studies.  As the mechanisms of action of
cardiorespiratory response become more clear, these mechanisms can be investigated in potentially
sensitive subpopulations and animal models.  Similarly, the role of loss of reserve or compensatory
response has not been adequately studied.  Chronic disease and the process of aging erodes reserve
and lowers the threshold for toxicity or response. Thus, emphasis in EPA studies will be placed on
both wings of the response paradigm-induction and recovery.
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References

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2.  Hoyert, D. L., K. D. Kochanek and S. L. Murphy (1999). "Deaths: Final data for 1997."
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3.  Samet, J. M., F. Dominici, F. C. Curriero, I. Coursac and S. L. Zeger (2000). "Fine particulate air
      pollution and mortality in 20 U.S. cities, 1987-1994." N EnglJ Med 343(24): 1742-9.
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5.  Segal, R. A., T. B. Martonen, C. S. Kim and M. Shearer (2002).  "Computer simulations
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6.  Linn, W. S., Y. Szlachcic, H. Gong, Jr.,  P. L. Kinney and K. T. Berhane (2000). "Air pollution
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       Environ Health Persp 108(5): 427-534.
7.  Pekkanen, J., S. T. Remes, T. Husman, M. Lindberg, M. Kajosaari, A.  Koivikko and L. Soininen
      (1997).  "Prevalence of asthma symptoms in video and written questionnaires among
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8.  Heinrich, J., B. Hoelscher and H. E. Wichmann (2000). "Decline of ambient air pollution and
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9.  Zanobetti, A.,  J. Schwartz and D. Gold  (2000).  "Are there sensitive subgroups for the effects of
      airborne particles?" Environ Health Persp 108(9): 841-5.
10. Clarke, R. W., J. M. Antonini, D. R. Hemenway, R. Frank, S. R. Kleeberger and G. J. Jakab
      (2000).  "Inhaled particle-bound sulfate: Effects on pulmonary inflammatory responses and
      alveolar macrophage function." Inhal Toxicol 12(3): 169-86.
11. Gilmour, M.  I. and H. S. Koren (2002).  "Interaction of inhaled particles with the immune
      system." In Particle-Lung Interactions. P. Gehr and J. Heyder, eds. New York,
      Marcel Dekker, Inc.
12. Clarke, R. W., P. J. Catalano, P. Koutrakis, G. G. Murthy, C. Sioutas, J. Paulauskis, B. Coull,
      S. Ferguson and J. J. Godleski (1999).  "Urban air particulate inhalation alters pulmonary
      function and induces pulmonary inflammation in a rodent model of chronic bronchitis."
      Inhal Toxicol 11(8): 637-656.
13. Goldsmith, C. A., K. Hamada, Y. Ning, G. Qin, P. Catalano, G. G. Krishna Murthy, J. Lawrence
      and L. Kobzik (1999). "Effects of environmental aerosols on airway hyperresponsiveness in
      a murine model of asthma." Inhal Toxicol 11: 981-998.
14. Goldsmith, C. A., C. Frevert, A. Imrich, C. Sioutas and L. Kobzik (1997). "Alveolar
      macrophage interaction with air pollution particulates."
       Environ Health Persp 105(Suppl 5): 1191-1195.
15. Hamada, K., C. A. Goldsmith and L. Kobzik (1999). "Increased airway hyperresponsiveness
      and inflammation in a juvenile mouse model of asthma exposed to air-pollutant aerosol."
      J Toxicol Environ Health A 58(3): 129-143.
16. Costa, D. L. and K. L. Dreher (1997).  "Bioavailable transition metals mediate injury to the
      cardiopulmonary system of healthy and compromosed animal models."
       Environ Health Persp 105(Suppl. 5): 1053-1060.
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17. Ohio, A. 1, Z. H. Meng, G. E. Hatch and D. L. Costa (1997). "Luminol-enhanced
       chemiluminescence after in vitro exposures of rat alveolar macrophages to oil fly ash is metal
       dependent." Inhal Toxicol 9: 255-271.
18. Undem, B. J. and M. J. Carr (2002).  "The role of nerves in asthma."
        Curr Allergy Asthma Rep 2(2): 159-65.
19. Kodavanti, U. P. and D. L. Costa (2001). "Rodent models of susceptibility: What is their place
       in inhalation toxicology?" Respir Physiol 128: 57-70.
20. Peters, A., E. Liu, R. L. Verrier, J. Schwartz, D. R. Gold, M. Mittleman, J. Baliff, J. A. Oh, G.
       Allen, K. Monahan and D. W. Dockery (2000). "Air pollution and incidence of cardiac
       arrhythmia." Epidemiology 11(1): 11-17.
21. Pope, C. A. L, R. L. Verrier, E. G. Lovett, A. C. Larson, M. E. Raizenne, R. E. Kanner, J.
       Schwartz, G. M. Villegas, D. R. Gold and D. W. Dockery (1999).  "Heart rate variability
       associated with particulate air pollution." Am Heart J 138: 890-899.
22. Brook, R.  D., J. R. Brook, B. Urch, R. Vincent, S. Rajagopalan and F. Silverman (2002).
       "Inhalation of fine parti culate air pollution and ozone causes acute arterial vasoconstriction in
       healthy adults."  Circulation 105(13): 1534-6.
23. Liao, D., J. Creason, C. Shy, R. Williams, R. Watts and R.  Zweidinger (1999). "Daily
       variation of parti culate air pollution and poor cardiac autonomic control in the elderly."
       Environ Health Persp 107: 521-525.
24. Gold, D. R., A. Litonjua, J. Schwartz, E. Lovett, A. Larson, B. Nearing, G. Allen, M.
       Verrier, R. Cherry and R. Verrier (2000). "Ambient pollution and heart rate variability."
       Circulation 101(11): 1267-73.
25. Watkinson, W. P., M. J. Campen and D. L. Costa (1998). "Cardiac arrhythmia induction
       after exposure to residual oil fly ash particles in the pulmonary hypertensive rat."
       Toxicol Sci 41: 209-216.
26. Kodavanti, U. P., M. C. J. Schladweiler, A. Ledbetter, W. P. Watkinson, M. J. Campen, D.
       W. Winsett, J. R. Richards, K. Crissman, G. E. Hatch and D. L. Costa (2000).  "The
       spontaneously hypertensive rat as a  model  of human cardiovascular disease: Evidence of
       exacerbated cardiopulmonary injury and oxidative stress from inhaled emission particulate
       matter." ToxicolApplPharmacol 164: 250-263.
27. Wellenius, G. A., P. H. N.  Saldiva, J. R. R Batalha, G. G. Krishna Murthy, B. A. Coull, R. L.
       Verrier and J. J.  Godleski (2002).  "Electrocardiographic changes during exposure to residual
       oil fly ash (ROFA) Particles in a rat  model  of myocardial infarction."
        Toxicol Sci 66: 327-335.
28. Peters, A., A. Doring, H. E. Wichmann and W. Koenig (1997). "Increased plasma viscosity
       during  an air pollution episode: A link to mortality?" Lancet 349:  1582-1587.
29. Ghio, A. J., C. Kim and R. B. Devlin (2000).  "Concentrated ambient air particles induce mild
       pulmonary inflammation in healthy  human volunteers."
        Am J Respir Crit Care Med 162(3 Pt 1): 981-988.
30. Goldberg, M. S., J.  C. Bailar, 3rd, R. T. Burnett, J. R. Brook, R. Tamblyn, Y. Bonvalot, P. Ernst,
       K. M. Flegel, R. K. Singh and M. F. Valois (2000). Identifying subgroups of the general
       population that may be susceptible to short-term increases in particulate air pollution:  A
       time-series study in Montreal, Quebec.  Research Report 97 (pp. 7-13; discussion,  pp. 115-
       120). Cambridge, MA: Health Effects Institute.
31. Zanobetti, A. and J. Schwartz (2001).  "Are diabetics more susceptible to the health effects of
       airborne particles?" Am J Respir Crit Care Med 164(5): 831-3.
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32.  Devlin, R. B., A. J. Ohio, H. Kehrl, G. Sanders and W. Cascio (2003).  "Exposure of humans to
       concentrated ambient air pollution particles (CAPS) results in decreased heart rate variability
       in elderly but not young volunteers." Eur Respir J40: 76-80.
33.  Plopper, C. G. and M. V. Fanucchi (2000). "Do urban environmental pollutants exacerbate
       childhood lung diseases?" Environ Health Persp 108(6): A252-3.
34.  Gauderman, W. J., R. McConnell, F. Gilliland, S. London, D. Thomas, E. Avol, H. Vora, K.
       Berhane, E. B. Rappaport, F. Lurmann, H. G. Margolis and J. Peters (2000). "Association
       between air pollution and lung function growth in  southern California children."
       Am JRespir Crit Care Med 162(4 Pt 1): 1383-90.
35.  Ritz, B., F. Yu, S. Fruin, G.  Chapa, G. M. Shaw and J. A. Harris (2002). "Ambient air pollution
       and risk of birth defects in Southern California." Am J Epidemiol 155(1): 17-25.
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Mechanisms
    of Injury
      What are the underlying
      mechanisms (local
pulmonary and systemic) that
can explain the epidemiological
findings of mortality/morbidity
associated with exposure to
ambient particulate matter?
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Introduction
    he recommendations for changes in the 1997 PM10 and PM25 NAAQS were primarily based on
    a large and coherent epidemiological database of significant associations between ambient air
    PM concentrations and excess mortality and morbidity. Although the 1996 PM AQCD
provided some information that lent biological plausibility to causal links between PM and health
effects, evidence from controlled human and animal exposure studies was largely unavailable at that
time. Based on this information gap, the NRC Committee placed a high priority on gaining a better
understanding of the biological plausibility and mechanisms of PM-associated health outcomes.
Since that time, significant progress has been made in identifying pathophysiological processes
in humans and animals exposed to various PM. These processes can provide insight into the
mechanisms by which PM may exert its effects.
Several mechanistic pathways by which PM could cause adverse health effects have been
investigated.  Some of them are quite complex and involve interaction between several organs or
tissues (e.g., lung, heart, vascular system, autonomic nervous system). The figure below highlights
the complexity and interdependency of some of these pathways.
      Potential PM Effects on the Cardiovascular System
                            Ambient PM
       Pulmonary Reflexes
        Autonomic Nervous
             System
      Conduction/Repolarization
          I           I
     Heart Rate     Cardiac Rhythm
            Cardiac
           Disruption
           Pulmonary Inflammation
                                             Systemic Inflammation
                                           Endothelial Cell
                                             Dysfunction
                            Platelet
                           Activation
                 Plaque Rupture
Sudden
Cardiac
 Death
Thrombosis
                        Clotting
                        Factors
Viscosity
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The primary portal of entry for PM air pollution is the lung, and PM interactions with respiratory
epithelium and alveolar macrophages likely mediate a wide range of pulmonary effects.  These
include lung injury, inflammation, and changes in resistance to infection or sensitivity to allergens.
PM or its reaction products may also stimulate airway sensory nerves, leading to changes in lung
function and autonomic tone.  However, PM likely exerts many systemic effects, with perhaps the
most significant from a health effect standpoint being those on the cardiovascular system.

There are several mechanisms by which PM may directly or indirectly affect the cardiovascular
system.  Potential neural mechanisms involve the autonomic nervous system (ANS) via direct
pulmonary irritant reflexes or reflexes activated during pulmonary inflammation that would
ultimately influence cardiac function. Ultrafine or soluble PM components may enter pulmonary
capillary blood and be rapidly transported to extrapulmonary tissues, such as heart, liver, and bone
marrow tissues, with either direct or indirect effects on organ function.  Some of these effects could
include changes in ion channel function in myocardial cells, ischemic responses of the myocardium,
systemic responses including inflammation which can trigger endothelial cell dysfunction, and
triggering thrombosis via alterations in the coagulation and clotting cascade.

It should also be remembered that PM is a complex mixture of many different components, and it is
possible that different components may stimulate different mechanistic pathways or interact in other
ways to alter response thresholds (e.g., endotoxins and other PM constituents).  Thus, exposure to
PM may result in one or more pathways being activated depending on the chemical and physical
makeup of the PM.

Key Uncertainties,  Objectives,  and  Special  Issues

Historically, most air pollutants studied by EPA have had the respiratory system as their primary, if
not only, target. However, PM, unlike other criteria pollutants, has been associated with significant
acute mortality. Thus, different mechanisms likely underlie the pathophysiological events which
lead to PM-induced mortality; and these events do not seem to be confined to the respiratory system.
A key challenge facing EPA was the development of expertise in areas not traditionally related to
air pollution research, particularly in the areas of cardiac and vascular biology.  To help address
these needs, EPA has sponsored or co-sponsored two workshops designed to bring cardiovascular
researchers together with respiratory toxicologists who perform PM research. EPA has also focused
a part of its STAR grants program on attracting researchers with cardiovascular expertise into the
PM research community. In addition, ORD researchers, as well as PM research centers funded by
ORD, have initiated collaborations with cardiovascular researchers.
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PM-induced Inflammation
Airway injury and inflammation are well-known consequences of toxic inhalation exposures.
The presence or absence of an inflammatory response is an important issue for several reasons:
Inflammation may induce systemic effects, including an acute phase response with increased blood
viscosity and coagulability, which have been linked to increased risk for MI in patients with severe
coronary artery disease. In chronic respiratory diseases, such as asthma and COPD, inflammation
is a key pathophysiological feature. Chronic, repeated inflammatory challenges of the airways may
result in structural changes in the lung that can lead to irreversible lung disease. Thus, inflammation
may be involved in both acute and chronic effects. Furthermore, systemic inflammation is known
to contribute to a number of diseases, including CVD and diabetes. A number of EPA studies have
shown that instillation or inhalation of particles causes pulmonary inflammation and epithelial injury.
Many of these studies were conducted to characterize the effects of metallic PM components and
are described in the section of Research Topic 5; examples of additional studies are presented in the
following text.

Exposure of healthy young humans to Chapel Hill CAPs causes mild pulmonary inflammation as
evidenced by increased numbers of neutrophils present in bronchoalveolar lavage fluid (1). Healthy
humans exposed to Los Angeles CAPs or to  carbonaceous ultrafine particles provide evidence for
effects on systemic markers of inflammation and leukocyte recruitment. These studies indicate
increased blood levels of soluble intercellular adhesion molecule-1 (sICAM-1), a transmembrane
protein which is expressed on leukocytes and endothelial cells and which plays an important role in
monocyte recruitment to atherosclerotic lesions and inflamed airways (2).  These human studies were
complemented by animal studies in which healthy dogs exposed to Boston CAPs showed increases
in neutrophils in bronchoalveolar lavage fluid and in circulating blood neutrophils (3). However,
rodent studies have not been consistent in their responses to CAPs from Research Triangle Park (4)
and from New York City (5); minor changes occurred in both healthy and compromised animals.

Effect  of PM on Infectivity
Epidemiological studies have demonstrated that infection, especially pneumonia, contributes
substantially to the increased morbidity and mortality among elderly individuals following exposure
to PM. This suggests that inhaled PM can act as an immunosuppressive factor that undermines the
pulmonary immune responses of normal host.  For example, exposure of bacterially infected rats to
New York City CAPs altered both pulmonary and systemic immunity and exacerbated the infection
process in a time-dependent manner (6).  Streptococcus pneumoniae-infected  rats exposed to PM
also demonstrated increased burdens of pulmonary bacteria,  numbers of circulating white blood
cells, numbers of pneumococcal-associated lung lesions,  and incidence of bacteremia compared to
air-exposed, infected control rats.  In addition, PM from various sources has been shown to induce
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apoptosis in alveolar macrophages, which can lead to decreased phagocytic defenses in the lung.
These findings suggest that PM exposure may affect the host immune response during pulmonary
infection and may help explain epidemiological observations.

PM Affects Autonomic Control of the Heart
There is growing clinical and epidemiological evidence that ambient air pollution can precipitate
acute cardiac events, such as angina pectoris, cardiac arrhythmias, and MI.  A number of EPA
studies have demonstrated that inhaled particles can affect the heart through the ANS. Direct input
from the lungs to the ANS via pulmonary afferent fibers can affect both HR and HRV. The heart is
under the constant influence of both sympathetic and parasympathetic innervation from the ANS,
and monitoring changes in HR and HRV can provide insight into the balance between those two
arms of the ANS. During recent decades, a large clinical database has developed that describes a
significant relationship between autonomic dysfunction and sudden cardiac death. One measure of
this dysfunction, low HRV, has been implicated as a predictor of increased cardiac morbidity and
mortality.

Several independent epidemiological panel studies of elderly volunteers (some of whom have CVD
or pulmonary disease) have reported associations between PM concentrations and various measures
of HR and HRV (7-9). Although there are some differences among these studies, they generally
report a negative association between PM levels and standard deviation of normal-to-normal beat
intervals (SDNN), a measure of HRV found by the Framingham Heart Study to be associated with a
higher risk of death. Increases in PM have also been associated with decreases in HRV in the high
frequency (HF) range, which is a reflection of parasympathetic modulation of the heart. Thus, taken
as a whole, evidence from panel studies indicates that PM can directly affect the ANS in such as way
as to alter HR and HRV.

The reported associations between PM levels and changes in HRV in the panel studies have been
confirmed in controlled exposure studies. Healthy elderly volunteers exposed to Chapel Hill CAPs
experienced a decrease in the HF component of HRV while no change was observed following
exposure of these subjects to clean air (10).  A positive association between PM and HR has also
been reported in healthy rats (11); elevated HR is known to be associated with hypertension,
coronary heart disease, and death. In related animal studies, alterations in HRV have been reported
in healthy dogs exposed to Boston CAPs (12).  Additionally, in similar rodent studies, a model of
severe lung inflammation developed increased HR following exposure to urban PM (13).
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       As a caution, however, it should be noted that lowered HRV has primarily been used as a predictor
       of subsequent increased mortality and morbidity. It is not yet clear whether a single reversible acute
       change in HRV places a person more at risk for an immediate adverse cardiac event. Additionally, it is
       not yet known whether changes in HRV associated with exposure to PM represent an independent risk
       or are just a marker of exposure.

       PM Alters  Cardiac Repolarization
       PM has also been shown to induce changes in conductance and repolarization of the heart. Duration
       and morphology  of repolarization (the cellular events which occur between heartbeats) may reflect
       subtle changes in myocardial substrate and vulnerability to PM. There is considerable evidence linking
       changes in various parameters of cardiac repolarization (e.g., T wave morphology, QT and T wave
       variability, T wave alternans, and changes in ST segment height) to the risk of sudden death. Humans
       exposed to ultrafine carbon particles have shown altered repolarization, as indicated by the corrected
       QT interval on the cardiogram; and this effect persisted to at least 21  hours after exposure (2, 14).
       Rodent models of susceptibility (monocrotaline-injected or spontaneously hypertensive rats) exposed to
       ROFA showed exacerbated ST segment depression, a factor which reflects  T wave morphology during
       repolarization and which has been useful in diagnosing patients with  ischemic heart disease (15, 16).

       Likewise, ambient particles cause exaggerated changes in ST segment elevation in dogs subjected to
       a controlled occlusion of a coronary artery (12). In contrast to reduced HRV, which may not represent
       an adverse effect, PM-induced changes  in cardiac repolarization are clearly of clinical concern in
       susceptible populations.  Augmenting this concern is recent data from prolonged episodic exposures
       of otherwise healthy rats to ROFA for 16 weeks (17). Damage to heart tissues of these rats after
       prolonged exposures would be consistent with conduction abnormalities.

       PM Exposure Is Associated with Cardiac Arrythmias and Mis
       While PM-induced changes associated with repolarization, conductance, HRV, and HR have the
       potential to progress to malignant arrhythmias, there is now evidence from both human and animal
       studies that PM exposure may be linked to severe events directly associated with sudden cardiac death.
       A recent  epidemiological study of patients with implanted cardiac defibrillators reported associations
       between PM and increased defibrillators discharges, which occur when patients experience significant
       cardiac arrhythmias (18).  Presumably, some of these patients would  have suffered a life-threatening
       event had they not had implanted defibrillators. A second study reported that the risk for MI onset
       increased in association with PM levels in the 2 hours preceding the MI (19).
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PM exposure has been linked with arrhythmia and even death in several toxicological studies.
Changes in ECG patterns were reported in dogs exposed to CAPs (12) and rats exposed to urban
PM from Ottawa (20). Old rats exposed to New York City CAPs showed a significant increase in
the frequency of supraventricular arrhythmias (21, 22). Increased arrhythmia was observed in rats
exposed to ROFA or ambient PM; rat models of cardiorespiratory disease showed the most severe
changes (23, 15).  If an animal model of cardiovascular susceptibility was used, exposure to ROFA
resulted in a nearly 50%  mortality rate (24, 25).

Taken as a whole,  these studies provide convincing evidence that PM exposure can affect critical
cardiac events, resulting  in altered ECG profiles, arrhythmias, and even death. However, it should
also be noted that  not all  studies have been able to observe these effects (5, 26). Additional work is
needed to  confirm these findings.

Interaction Between  PM and/or Its Soluble Components and the Heart
In addition to affecting the ANS via the lung, it is also possible that PM or its components could
directly attack the myocardium.  There is substantial evidence that chronic exposure to fibers
encountered in the workplace (e.g., asbestos) results in deposition of fibers in organs other than the
lung.  Some recent ORD studies have suggested that ultrafine PM may exit the lung and deposit in
other organs such  as the liver and heart (27). So far, these studies have used sources of particles
not naturally found in the air (e.g., pure carbon, silver colloid, latex); and not all of the studies are
positive (28). Consequently, it is not yet clear to what extent PM actually leaves the lung or whether,
if it does leave the lung, to what extent PM interacts directly with the heart.

There is, however, some  evidence of direct changes in the myocardium following PM exposure.
Rats exposed to ROFA, which is comprised mostly of soluble transition metals, have increased pro-
inflammatory cytokine expression in the heart (24). In another study, heart tissue obtained from
dogs living in highly polluted Mexico City revealed greater cardiac inflammation and myocyte death
compared to hearts obtained from dogs living in areas with low air pollution. In the same study,
substantial deposits of PM could be seen throughout the myocardium in the Mexico City dogs (29).
In vitro studies ongoing at EPA are showing that soluble PM components can directly affect the
beating frequency of cardiac cells as well as their ability to communicate with one another. Though
preliminary, these observations point to a need for additional work to better define PM-induced
effects on  myocardial tissue.
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PM Exposure Can Affect the Vascular System
Acute coronary events frequently occur as a result of thrombus formation in the site of a ruptured
atherosclerotic plaque. Increased levels of clotting and coagulation factors, platelet aggregability,
and blood viscosity, together with reduced fibrinolytic activity (ability to dissolve clots) and
endothelial cell dysfunction, can promote a pro-coagulant state which could potentially contribute
to thrombus formation. C reactive protein, a marker of systemic inflammation which correlates
with some cardiac events, has been positively associated with PM in panel studies (30). Some panel
studies also report associations between PM and enhanced blood viscosity or increased fibrinogen,
a known risk factor for ischemic heart disease (31). Controlled human and animal exposure studies
have also reported that exposure to CAPs (in humans) or ROFA (in animals) results in increased
levels of blood fibrinogen (32, 33).

Animals exposed to New York CAPs have increased numbers of blood platelets and neutrophils
(11). Increased platelets create a more thrombogenic environment, which is even further exacerbated
by the presence of pro-inflammatory neutrophils. However, similar changes were not observed
with Research Triangle Park CAPs (4). Several ongoing human and animal studies are measuring
selected vascular markers of coagulation, clotting, and acute phase response. Preliminary findings
thus far do not present a clear pattern. Some studies are reporting PM-induced increases in clotting
and coagulation factors and vascular inflammatory cells that suggest PM may alter the coagulation
pathways which may trigger cardiovascular events. However, similar studies have  not observed
these changes. Additional studies will be needed to determine which of these changes, if any, are
caused by exposure to ambient PM.

Endothelial cell dysfunction may contribute to myocardial ischemia in some susceptible populations.
The vascular endothelium secretes multiple factors that control vascular tone, modulate platelet
activity, and influence thrombogenesis. A current EPA study is observing endothelial cell
dysfunction in humans exposed to CAPs as measured by dilation of the brachial artery and is
confirming an earlier study published by Canadian scientists (34). This vasoconstriction could be
caused by an increase in circulating endothelin-1, a protein that has been reported to be increased
in rats exposed to PM (35). In vitro studies using endothelial  cells show that metals associated
with PM emissions activate several genes that alter cell function, activating them to produce
inflammogenic mediators that may represent an early part of a clotting event.

Collectively, it appears that PM can affect the vascular system by creating a more thrombogenic
environment.  However, additional studies are needed to determine the exact pathways and
mechanisms by which these changes are caused.
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Programmatic Need and  Relevance

There are several complex pathways by which PM may be exerting its effects. Because PM is a
complex mixture exhibiting many different chemical and physical properties, it is likely that more
than one pathway is activated depending on the individual properties of specific PM samples and
perhaps on the health status or genetic make-up of the host. Results reported from panel studies,
controlled human exposure studies, and animal toxicological studies, though small in number, are
generally coherent with the epidemiological findings of associations between PM and increased
mortality or hospital admissions for CVD.  Furthermore, they add support to specific hypotheses
regarding the possible mechanisms by which PM exposure may be linked with adverse cardiac
outcomes. Defining a credible mechanism or mode of action will enhance the assessment of risk
both qualitatively and quantitatively.  Because cardiac events represent the number one killer of U.S.
adults, findings that link PM and cardiac events are of tremendous importance.

Future  Directions

Five years ago, a description of PM health effects would typically include a caveat that the
underlying biological mechanisms were largely unknown. As summarized previously, the scientific
literature is now rapidly expanding with hypotheses concerning plausible mechanistic pathways by
which PM could cause adverse effects. However,  research is still far from clearly explaining the
pathways by which very small concentrations of inhaled ambient PM can produce the cardiovascular
and pulmonary changes that can contribute to increased mortality/morbidity. Therefore, research
on the adverse cardiovascular effects  of PM needs to be expanded, particularly among individuals
with CVD. Based on existing epidemiological and experimental data, mechanistic considerations
should focus on alterations in the autonomic nervous system; ischemic responses in the myocardium;
chemical effects on ion channel function in myocardial cells; and inflammatory responses triggering
endothelial dysfunction, atherosclerosis,  and thrombosis.  ORD, through its intramural and
extramural programs, will be focusing specifically on these early and primary  events to separate the
effects of PM among other stressors.  The roles of pre-existing disease and other features bearing on
susceptibility are likely to be key to the health observations.
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References
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2. Frampton, M. W. (2001). "Systemic and cardiovascular effects of airway injury and inflammation: Ultrafme particle
        exposure in humans." Environ Health Persp 109(Suppl 4): 529-32.
3. Clarke, R. W., P. Catalano, B. Coull, P. Koutrakis, G. G. Krishna Murthy, T. Rice and J. J. Godleski (2000). "Age-
        related responses in rats to concentrated urban air particles (CAPs)." Inhal Toxicol 12(1): 73-84.
4. Kodavanti, U. P., R. Mebane, A. Ledbetter, T. Krantz, J. McGee, M. Jackson, L. Walsh, H. Milliard, B.-Y. Chen, J.
        Richards and D. L. Costa (2000).  "Variable pulmonary responses from exposure to concentrated ambient air
        particles in a rat model of bronchitis." Toxicol Sci 54: 441-451.
5. Gordon, T., C. Nadziejko, L. C. Chen and R. Schlesinger (2000).  Effects of concentrated ambient particles in rats
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6. Zelikoff, J. T., C. Nadziejko, K. Fang, T. Gordon, C. Premdass and M. D. Cohen (1999). "Short-term low-dose
        inhalation of ambient paniculate matter exacerbates ongoing pneumococcal infections in Streptococcus
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        Health, R. Phalen and Y. Bell, eds., 8-94 to 8-101.
7. Liao, D., J. Creason, C. Shy, R. Williams, R. Watts and R. Zweidinger (1999). "Daily variation of paniculate air
        pollution and poor cardiac autonomic control in the elderly." Environ Health Persp 107: 521-525.
8. Pope, C. A. L, R. L. Verrier, E. G. Lovett, A. C. Larson, M. E. Raizenne, R. E. Kanner, J. Schwartz, G. M. Villegas,
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        Am Heart J 13%: S90-S99.
9. Gold, D. R., A. Litonjua, J. Schwartz, E. Lovett, A. Larson, B. Nearing, G. Allen, M. Verrier, R. Cherry and R.
        Verrier (2000). "The relationship between paniculate pollution and heart rate variability."
        Circulation 101(11): 1267-1273.
10. Devlin, R. B., A. J.  Ohio, H. Kehrl,  G. Sanders and W. Cascio (2003). "Exposure of humans to concentrated
        ambient air pollution particles (CAPS) results in decreased heart rate variability in elderly but not young
        volunteers." Eur Respir J40: 76-80.
11. Gordon, T.,  C. Nadziejko, R. Schlesinger and L. C. Chen (1998). "Pulmonary and cardiovascular effects of acute
        exposure to concentrated ambient particles in rats." Toxicol Lett 96-97: 285-288.
12. Godleski, J. J., R. L. Verrier, P. Koutrakis and P. Catalano (2000). Mechanisms of Morbidity and Mortality from
        Exposure to Ambient Air Particles. Research Report 91. Cambridge, MA: Health Effects Institute.
13. Watkinson,  W. P., M. J. Campen, K. L. Dreher, W.-Y Su, U. P. Kodavanti, J. W. Highfill and D. L. Costa (2000).
        "Thermoregulatory effects following exposure to paniculate matter in healthy and cardiopulmonary-
        compromised rats." J Therm Biol 25: 131-137.
14. Zareba, W, A. Nomuraand J. P. Couderc (2001).  "Cardiovascular effects of air pollution:  What to measure in
        ECG?" Environ Health Persp 109 (Suppl 4): 533-538.
15. Kodavanti, U. P., M. C. J. Schladweiler, A. Ledbetter, W. P. Watkinson, M. J. Campen, D. W. Winsett, J. R. Richards,
        K. Crissman, G. E. Hatch and D. L. Costa (2000).  "The spontaneously hypertensive rat as a model of human
        cardiovascular disease: Evidence of exacerbated cardiopulmonary injury and oxidative stress from inhaled
        emission paniculate matter." ToxicolAppl Pharmacol 164: 250-263.
16. Campen, M. J., J. P. Nolan, M. C. J. Schladweiler, U. P. Kodavanti, D. L. Costa and W. P. Watkinson (2002).
        "Cardiac and thermoregulatory effects of instilled paniculate matter-associated transition metals in healthy and
        cardiopulmonary-compromisedrats.  Part A." J Toxicol Environ Health 65: 1615-1631.
17. Kodavanti, U. P., C. Moyer, A. D. Ledbetter, M. C. Schladweiler, D. L. Costa, R. Hauser, D. C. Christiani and A.
        Nyska (2003).  "Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat."
        Toxicol Sci 71(2): 237-245.
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18. Peters, A., E. Liu, R. L. Verrier, J. Schwartz, D. R. Gold, M. Mittleman, J. Baliff, J. A. Oh, G. Allen, K. Monahan
        and D. W. Dockery (2000). "Air pollution and incidence of cardiac arrhythmia." Epidemiology 11(1): 11-17.
19. Peters, A., D. W. Dockery, J. E. Muller, M. D. Murray and M. Mittleman (2001). "Increased paniculate air pollution
        and the triggering of myocardial infarction."  Circulation 103: 2810-2815.
20. Watkinson, W. P., M. J. Campen, J. P. Nolan, U. P. Kodavanti, K. L. Dreher, W.-Y. Su, J. W. Highfill and D. L. Costa
        (2000). "Cardiovascular effects following exposure to paniculate matter in healthy and cardiopulmonary-
        compromised rats." In Relationships Between Acute and Chronic Effects of Air Pollution. U. Heinrich and
        U. Mohr, eds. Washington, ILSI Press: 447-463.
21. Utell, L. M. J., M. W. Frampton, W. Zareba, R. B. Devlin and W. E. Cascio (2002). "Cardiovascular effects
        associated with air pollution: Potential mechanisms and methods of testing." Inhal Toxicol 14(12): 1231-1247.
22. Nadziejko, C., K. Fang, E. Nadziejko,  S. P. Narciso, M. Zhong and L. C.  Chen (2002). "Immediate effects
        of paniculate air pollutants on heart rate and  respiratory rate in hypertensive rats."
         Cardiovasc Toxicol 2(4): 245-252.
23. Watkinson, W. P., M. J. Campen and D. L. Costa (1998).  "Cardiac arrhythmia induction after exposure to residual
        oil fly ash particles in the pulmonary hypertensive rat." Toxicol Sci 41: 209-216.
24. Killingsworth, C. R., F. Alessandrini, G. C. Krishna Murty, P. J. Catalano, J.D. Paulauskis and J. J. Godleski (1997).
        "Inflammation, chemokine expression, and death in monocrotaline-treated rats following fuel coal fly ash
        inhalation." Inhal Toxicol 9: 541-565.
25. Kodavanti, U. P., M. C. Jackson, A. D. Ledbetter, J. R. Richards, S. Y. Gardner, W. P. Watkinson, M. J. Campen and
        D. L. Costa (1999). "Lung injury from intratracheal  and inhalation exposures to residual oil fly ash in a rat
        model of monocrotaline-induced pulmonary hypertension." J Toxicol Environ Health 57: 101-121.
26. Muggenburg, B. A., L. Tilley and F. H. Green (2000).  "Animal models of cardiac disease: Potential usefulness for
        studying health effects of inhaled particles." Inhal Toxicol 12(9): 901-925.
27. Oberdorster, G., Z. Sharp, V. Atudorei, A. Elder, R. Gelein, A. Lunts, W. Kreyling and C. Cox (2002).
        "Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats."
        J Toxicol Environ Health A 65(20): 1531-1543.
28. Kreyling, W. G., M. Semmler, F. Erbe, P. Mayer, S. Takenaka, H. Schulz, G.  Oberdorster and A. Ziesenis (2002).
        "Ultrafine insoluble iridium particles are negligibly translocated from lung epithelium to extrapulmonary
        organs." J Toxicol Environ Health 65(20):  1513-1530.
29. Calderon-Garciduenas, L., T. M. Gambling, H. Acuna, R. Garcia, N. Osnaya, S. Monroy, A. Villarreal-Calderon, J.
        Carson, H.  S. Koren and R. B. Devlin (2001). "Canines as sentinel species for assessing chronic exposures to
        air pollutants: Part 2.  Cardiac pathology." Toxicol Sci 61(2): 356-367.
30. Peters, A., M. Frohlich, A. Doring, T. Immervoll,  H. E. Wichmann, W. L. Hutchinson, M. B. Pepys and W. Koenig
        (2001). "Paniculate air pollution is associated with an acute phase response in men; results from the MONICA-
        Augsburg Study." Eur Heart.722(14): 1198-204.
31. Peters, A., A. Doring, H. E. Wichmann and W. Koenig (1997). "Increased plasma viscosity during an air pollution
        episode: A link to mortality T Lancet 3 49: 1582-1587.
32. Gardner, S. Y, J. R. Lehmann and D. L. Costa (2000). "Oil fly ash-induced elevations of plasma fibrinogen in rats."
        Toxicol Sci  57: 175-180.
33. Ohio, A. J., C. Kim and R. B. Devlin (2000). "Concentrated ambient air particles induce mild pulmonary
        inflammation in healthy human volunteers." Am JRespir Crit Care Med 162(3 Pt 1): 981-988.
34. Brook, R. D., J.  R. Brook, B. Urch, R.  Vincent, S. Rajagopalan and F. Silverman (2002). "Inhalation
        of fine paniculate air pollution and ozone causes acute arterial vasoconstriction in healthy adults."
        Circulation 105(13): 1534-6.
35. Vincent, R., P. Kumarathasan, P. Goegan, S. G. Bjarnason, J. Guenette, D. Berube, I. Y. Adamson, S. Desjardins, R.
        T. Burnett, F. J. Miller andB. Battistini (2001). Inhalation Toxicology of Urban Ambient Particulate Matter:
        Acute Cardiovascular Effects in Rats.  Research Report 104. Cambridge, MA: Health Effects Institute.
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    Analysis
         and
Measurement
     To what extent does
     the choice of statistical
  methods in the analysis of
  data from epidemiological
  studies influence estimates of
  health risks from exposures to
  particulate matter? Can existing
  methods be improved? What
  is the effect of measurement
  error and misclassification on
  estimates of the association
  between air pollution and
  health?
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Introduction

    he statistical association between ambient concentrations of PM and health outcomes (mortality
    and morbidity) provides evidence that exposure to ambient PM may have an adverse effect on
    human health. However, sophisticated statistical techniques are required to identify the effects
of PM in the presence of many other causes of mortality and morbidity. Thus, concerns have
arisen over the reliability of the statistical models and possible effects of measurement error or
misclassification on estimates of health risks.
Key Uncertainties
Current epidemiological research finds that per 10 ug/m3 increase in ambient PM concentrations,
there are excess risks of mortality of a few tenths of a percent to a few percent in the general
population. Obtaining statistical significance on this scale places stringent demands on statistical
analysis techniques.  Sophisticated models are required to control for mortality associated with
season, temperature, epidemics, etc. Understandably, concerns exist regarding a variety of statistical
and exposure classification issues.
Major Accomplishments
Statistical Methods
In 1998, EPA and the National Research Center for Statistics and the Environment at the University
of Washington organized a Workshop on Particulate Methodology to explore issues related to
analysis and measurement. As discussed in following text, significant progress has been made in
addressing many of the statistical issues emphasized in the workshop report (1).

Multi-city Analyses
Time-series analyses were initially conducted on a single location selected primarily on the basis of
data availability. New techniques have been proposed for combining results from several  studies;
and studies of more formal, multi-city designs have  been conducted.  NMMAPS was a pioneering
effort that used a sampling frame defined by U.S. counties (2). The 90 largest urban areas (by
population) were selected, and the daily mortality data for 1987-1994 were analyzed using a
common statistical protocol to evaluate associations with PM and other pollutants. In the  multi-city
approach, the potential selection bias of only a single or a few locations is avoided. Additionally,
publication bias from reporting only positive results is avoided because results are reported for all
cities selected for the multi-city study.
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Spatial Analytical Methods
In the analysis of data from studies that examine the association between city-specific mortality and
long-term average pollutant concentrations, an important issue is whether observations of individual
subjects are independent or correlated.  Spatial correlation in mortality can result from social and
physical environments of residents of the same city. Air pollution can be spatially autocorrelated
as a result of broad regional patterns stemming from source and dispersion patterns.  In a recent
re-analysis of data from a study that examined associations between mortality and fine-particle and
sulfate concentrations in 154 cities throughout the U.S., new methods were developed and applied to
allow for the presence of spatial autocorrelation in the data (2).

"Harvesting"
"Harvesting", in the context of time-series mortality studies, refers to the question of whether deaths
from air pollution occur in people who are highly susceptible and near death (and who die a few
days earlier because of air pollution than they otherwise would have) or whether air pollution leads
to the death of people who are not otherwise near death.  Many studies have identified associations
between daily mortality and air quality variables measured at the time of or a few days before
deaths, but until recently it has not been possible to fully  address the issue of "harvesting".  A
newly developed methodology-the constrained, distributed lag model-makes it feasible to better
understand the time course  of deaths related to air pollution exposures (3).  Recent studies using this
technique suggest that, at most, only a small fraction of the deaths associated with air pollution in
daily time-series studies can be attributed to short term mortality displacement (4, 5). Several other
analytical approaches have  also been proposed to address "harvesting" (6). The various approaches
have been applied to several locations and  provide little evidence for "harvesting". However, these
approaches need to be tested on additional  data sets and refined to better quantify the degree of life-
shortening associated with PM and other pollutants.

Dose-Response/Threshold Issues
There has been considerable controversy over the question of whether there is a threshold value
below which PM exposure is not harmful and whether the dose-response (or exposure-response)
relationship is linear. To date, studies of PM health effects suggest a no-threshold, linear dose-
response relationship. If there are thresholds for the effects of PM  on deaths or hospital admissions,
health effects may be overstated.  A new methodology has been developed that allows smoothed
dose-response curves from multiple locations to be combined, and  its effectiveness has been
demonstrated using simulation studies (4).  Analysis of daily deaths in 10 U.S. cities showed
no deviation from linearity  down to the lowest exposure concentrations (7) when statistical
methodologies to incorporate heterogeneity across cities were used (8).
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        Confounding
        In attempting to set policy based on epidemiological results, there is always the concern that another,
        unmeasured indicator highly correlated with the measured indicator is responsible for all or some
        of the observed relationship. In PM epidemiology, gaseous co-pollutants (CO, NO2, SO2, O3) are
        considered potential confounders.  This possibility has frequently been investigated by including
        a PM indicator and one or more gaseous co-pollutants in a multiple pollutant model. Progress has
        been made in understanding how one pollutant can yield an association with health effects, even
        though the health effects are caused by a second pollutant (9). The dependence of this effect on the
        correlation coefficient between the pollutants, the relative toxicity, and the error in each indicator has
        been investigated (10).  A hierarchical model to assess the confounding effect of gaseous co-pollutants
        for both morbidity and mortality in multi-city studies has been developed and applied to examine the
        association between PM10 and daily deaths (2). The results of this analysis suggest that associations
        were not confounded by gaseous air pollutants.

        Model Specification
        While there has been general agreement among epidemiologists and biostatisticians on how to
        formulate  models for time-series analyses, there are many possibilities for smoothing functions
        to account for the relationships of health effects with temperature, humidity, and season.  Several
        studies have investigated the sensitivity of estimated health risks to variations in smoothing function,
        including Bayesian approaches which compare thousands of possible models (11).  Other studies have
        investigated the possible confounding effects of epidemics and the relationship of temperature and
        humidity with mortality to guide selection of lags and functions for use in smoothing (12-14).

        Statistical Techniques
        The application of the time series has been facilitated by recent advances in computer hardware and
        by the development of statistical software that appropriately accounts for the data structure of the daily
        time series. Nonparametric smoothing techniques have facilitated accounting for health outcomes
        associated with temperature, humidity, and season. However, epidemiologists and biostatisticians
        have recently recognized two problems.  When nonparametric smoothing is used in GAMs, the
        default iteration criteria are not adequate to ensure convergence. In addition, an approximation used
        to estimate the standard error yields values that are too low.  As a result, the default GAM technique
        frequently predicted too high an estimate of risk and too low a standard error.
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To address this issue, ORD invited authors of papers relevant to the PM standard-setting process to
re-analyze their data using more stringent GAM convergence criteria and also using only parametric
smoothing functions which permit exact calculation of standard error. The workshop was held
November 4-6, 2002, and led to a substantial clarification of the potential  effects of problems in the
use of GAM. Two new statistical techniques were presented which avoid the problems with GAM.
The workshop also featured a discussion of model selection and sensitivity analysis. The results
of the re-analyses were peer-reviewed by an HEI committee and was recently published as an HEI
report (15).  The existence of a statistical link between exposure to ambient PM and health outcomes
remains valid.

Alternative Statistical Techniques
The Poisson log-link approach to time-series analysis  is popular and has proven useful. However,
a number of alternative approaches have been developed. A very promising approach is the case-
crossover technique, which, by design, avoids some of the smoothing problems encountered in
the Poisson approach but appears to give comparable health risks for PM (16, 17). A number of
methodological papers have examined the potential for bias and confounding in this approach
and developed new statistical methods to overcome these problems (18-20). Another alternative
approach applies additive mixed models to the relationship between air pollution and health (21).
The mixed model approach does not have the shortcomings of the GAM because it provides
accurate standard errors and does not use back-fitting. This approach can provide smoothed dose
response curves against multiple predictors for Poisson data. It is currently being applied to the re-
examination of the association between PM10 and hospital admissions.

Measurement Error and  Misclassification
Measurement error and misclassification refer to a variety of errors  arising from the use of ambient
concentrations measurements as an indicator of exposure.

Spatial Error
An error or bias may be introduced into the estimated  health risk if the measured ambient
concentration value, either from one site or the average of values from several sites, is not
representative of the community-wide average.  The spatial correlation between PM10, gaseous
pollutants, and weather parameters has been investigated in the north-central U.S. (22). In ongoing
work, PM2 5 and PM10_2 5 values from the National Monitoring Network are being used to investigate
the spatial variability of PM25 and PM10 25 in cities across the U.S. In other studies, the spatial
variability of chemical components and source category  contributions are being examined. PM2 5
and sulfate appear to be reasonably uniform in many cities.  However, PM10 25, other chemical
species, and some source categories may not be so uniformly distributed.
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Difference Between Ambient Concentration and Exposure
Total personal exposure is composed of two major components: ambient exposure (due to
exposure to ambient PM while outdoors and to ambient PM which has infiltrated indoors while
indoors) and non-ambient exposure (due to exposure to PM from indoor and personal sources).
Ambient exposure is attenuated relative to ambient concentration (i.e., the concentration of
ambient PM indoors is less than ambient PM outdoors). For epidemiological studies using ambient
concentrations as an exposure indicator, ambient exposure is usually the exposure of interest.
However, in some situations, the non-ambient exposure may be important or the association of non-
ambient exposure with health outcomes may be  studied. The ambient concentration and the total
personal exposure may be measured, but ambient and non-ambient exposure must be estimated using
other information.

As discussed under Research Topics 1 and 2, EPA has an extensive program devoted to studying the
relationships between ambient concentration, total personal exposure, ambient exposure, and non-
ambient exposure. Work in progress suggests that, as long as non-ambient exposure is independent
of ambient concentration, values of the health risk associated with ambient concentration (C) and
values of the health risk associated with ambient exposure (A) will not be changed by inclusion of
health effects due to non-ambient exposure in the health-outcome time series.  However, C will be
biased low compared to A by the ratio ambient exposure/ambient concentration; i.e., C = ambient
exposure/ambient concentration or A/C. A/C will give  the reduction in health risk that would be
expected from a reduction in ambient concentration.  Therefore, it is a parameter of interest to local
public health officials.  However, C will differ from city to city because of differences in building
characteristics and time spent outdoors.

Uncertainties in the Measurement of Ambient Concentrations

Precision
The FRMs for PM, as discussed in "Research Topic 11," provide a precise measurement of the mass
of PM remaining on a filter after equilibration. However, because there is no standard measurement
method for suspended PM, it is not possible to measure accuracy except in terms of the precision
with which a candidate sampler  agrees with a reference sampler.
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Loss of Semivolatile PM Mass in PM Measurements
Semivolatile PM includes ammonium nitrate and semivolatile organic compounds (SVOCs) that
exist in the particulate phase in the atmosphere but evaporate from filters during sampling and
storage. EPA has supported the development of monitors with the potential for batch and continuous
measurements of both the semivolatile and nonvolatile components of PM (23). These monitors,
other continuous monitors, and the FRM have been intercompared for a 2-year period in Salt Lake
City, UT, and for episodic periods in other cities (24). These studies have provided new information
on the amount of semivolatile components lost by the FRM and by other continuous monitors at
various sites in the U.S. and on the seasonal variations and sources of semivolatile PM (25). This
program also led to the development of a technique for artifact-free measurement of nonvolatile and
semivolatile OC that could be used in the EPA speciation network.  Currently, measurement of OC
mass is influenced by positive artifacts (due to absorption of organic vapor by the quartz filter) and
by negative artifacts (due to the evaporation of semivolatile OC).

Alternate Indicators
EPA is conducting additional  studies to develop monitors for other parameters and to use alternate
indicators in epidemiological  studies. Among these efforts is EPAs support of the Rochester PM
Research Center, which emphasizes health effects associated with exposure to ultrafine particles.
However, there  are currently no convenient ways to measure an indicator of ultrafine particles.
EPA has supported the development of a monitor, the electrical aerosol detector, that may serve as
an indicator of the amount of ultrafine PM deposited in the lung (26).  In addition, the long-term
monitoring studies supported by EPA in Phoenix provide adequate information for conducting
epidemiological studies with  several alternate indicators, including PM: 0 and PM2 5 measured by
tapered element oscillating microbalance (TEOM)  and filters (27).

Source Category Contributions
EPA scientists are currently using time series of source category contributions from EPA studies in
Phoenix, AZ, and Philadelphia, PA, as exposure indicators in epidemiological analyses.
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       Programmatic  Need and Relevance

       Epidemiological studies have played a critical role in previous PM NAAQS reviews and will likely
       do so in the future. Quantitative assessments of risk and health benefits assessments have relied
       upon the concentration-response functions from epidemiological studies.  Further exploration of
       methodological issues in the epidemiological analyses is expected to result in better assessment of
       these functions and reduce uncertainty in findings.
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Future Directions

New techniques for statistical analysis and model selection presented at the November 2002 EPA
GAM workshop will be used in further epidemiological analyses and should lead to better scientific
understanding and public acceptance of epidemiological results.  EPA scientists participated in the
PM Research Center workshop to compare source category estimates derived from different receptor
models using a common data set and to use a time series of source category contributions as alternate
indicators of exposure.  In this regard, measurements of speciated PM at national PM monitoring
sites in several cities will provide the basis for epidemiological studies capable of providing
information concerning the time structure of health responses to PM exposure.

New techniques for measuring ultrafine PM and semivolatile as well as nonvolatile PM mass will
be improved and can add to the existing data for epidemiological studies.  Epidemiological studies
in individual cities with low spatial variation of PM concentration and that cover a range of climatic
conditions (temperature, relative humidity, seasonality) will be very useful in sorting out the relative
effects of pollution and weather factors.  Exposure studies, in conjunction with measurements of
health outcomes, will permit investigation of associations  of health effects with ambient and non-
ambient exposure as well as with ambient concentration and total personal exposure. Statistical
simulations will be used to quantitatively investigate the effect of spatial variability on health risk
estimates. The addition of city-specific data for key model inputs (i.e., housing characteristics
and human activity patterns) will permit analysis of city-to-city variability in the ratio of ambient
exposure to ambient concentration and in the amount of non-ambient exposure.
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        References
        1.  Cox, L. H. (2000). "Statistical issues in the study of air pollution involving airborne particulate
               matter." Environmetrics 11: 611-626.
        2.  Samet, J. M., A. J. Ohio, D. L. Costa and M. C. Madden (2000).  "Increased expression of
               cyclooxygenase 2 mediates oil fly ash-induced lung injury." Exp Lung Res 26: 57-69.
        3.  Zanobetti, A., M.  P. Wand, J. Schwartz and L. M. Ryan (2000). "Generalized additive distributed
               lag models: Quantifying mortality displacement." Biostatistics 1(3): 279-292.
        4.  Schwartz, J. (2000). "Assessing confounding, effect modification, and thresholds in the association
               between ambient particles and daily deaths." Environ Health Persp 108(6): 563-568.
        5.  Schwartz, J. (2001). "Is there harvesting in the association of airborne particles with daily deaths
               and hospital admissions?" Epidemiology 12(1): 55-61.
        6.  Zeger, S. L., F. Dominici and J. Samet (1999). "Harvesting-resistant estimates of air pollution
               effects on mortality." Epidemiology 10(2): 171-175.
        7.  Schwartz, J. and A. Zanobetti (2000).  "Using meta-smoothing to estimate dose-response
               trends across multiple studies with application  to air pollution and daily death."
               Epidemiology 11(6): 666-672.
        8.  Schwartz, J., F. Ballester, M. Saez, S. Perez-Hoyos, J. Bellido, K. Cambra, F. Arribas, A. Canada,
               M. J. Perez-Boillos and J.  Sunyer (2001).  "The concentration-response relation between air
               pollution and daily deaths." Environ Health Persp 109: 1001-1006.
        9.  Long, C. M., H. H. Suh, L. Kobzik, P. J. Catalano, Y. Y. Ning and P. Koutrakis (2001). "A pilot
               investigation of the relative toxicity of indoor and outdoor fine particles: In vitro effects of
               endotoxin and other particulate properties." Environ Health Persp 109(10): 1019-1026.
        10. Carrothers, T. J. and J. S. Evans (2000).  "Assessing the impact of differential measurement error
               on estimates of fine particle mortality." JA&WMA 50:  65-74.
        11. Clyde, M. (2000).  "Model uncertainty and health effect studies for particulate matter."
               Environmetrics 11: 745-763.
        12. Braga, A. L., A. Zanobetti and J. Schwartz (2000). "Do respiratory epidemics confound the
               association between air pollution and daily deaths?" Eur Respir J 16: 723-728.
        13. Braga, A. L., A. Zanobetti and J. Schwartz (2001). "The time course of weather related deaths."
               Epidemiology 12: 662-667.
        14. Braga, A. L., A. Zanobetti and J. Schwartz (2002). "The effect of weather on respiratory
               cardiovascular deaths in 12 U.S. counties." Environ Health Persp 110(9): 859-864.
        15. Health Effects Institute. (2003) Revised analyses of the National Morbidity, Mortality, and
               Air Pollution Study (NMMAPS), part II. In: Revised analyses of time-series studies of
               air pollution and health.  Special report. Boston, MA: Health Effects Institute; pp. 9-72.
               Available: http://www.healtheffects.org/Pubs/TimeSeries.pdffl2 May, 2004].
        16. Neas, L. M., J. Schwartz and D. Dockery (1999).  "A case-crossover analysis of air pollution and
               mortality in Philadelphia." Environ Health Persp 107(8): 629-631.
        17. Bateson, T.  and J. Schwartz (2001). "Selection bias  and confounding in case-crossover analyses
               of environmental time series data." Epidemiology 12: 654-661.
        18. Lumley, T. and D. Levy (2000). "Bias in the case-crossover design:  Implications for studies of
               air pollution." Environmetrics 11: 689-704.
        19. Levy, D., T. Lumley, L. Sheppard, J. Kaufman and H. Checkoway (2001).  "Referent selection in
               case-crossover analyses of acute health effects  of air pollution." Epidemiology 12: 186-192.
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20.  Sheppard, L., D. Levy and H. Checkoway (2001).  "Correcting for the effects of location and
       atmospheric conditions on air pollution exposures in a case-crossover study."
       J Expo Anal Environ Epidemiol 11: 86-96.
21.  Coull, B. A., J. Schwartz and M. P. Wand (2001). "Respiratory health and air pollution:
       Additive mixed model analyses." Biostatistics 2: 337-349.
22.  Ito, K., G. D. Thurston, A. Nadas and M. Lippmann (2001). "Monitor-to-monitor temporal
       correlation of air pollution and weather variables in the North-Central U.S."
       J Expo Anal Environ Epidemiol 11(1): 21-32.
23.  Pang, Y, Y.  Ren, F. Obeidi, R. Hastings, D. J. Eatough and W. E. Wilson (2001). "Semi-volatile
       species in PM25: Comparison of integrated continuous samplers for PM25 research or
       monitoring." JA&WMA 51: 25-36.
24.  Obeidi, F. and D. J. Eatough (2002). "Continuous measurement of semi-volatile fine particulate
       mass in Provo, UT." AerosolSci Technol 36:  191-203.
25.  Long, C. M., H. H. Suh, P. J.  Catalano and P. Koutrakis (2001). "Using time- and size-resolved
       particulate  data to quantify indoor penetration and deposition behavior."
       Environ Sci Technol 35(10): 2089-2099.
26.  Woo, K. S.,  R. Chen, D. Y. H. Pui and W. E. Wilson (2001). "Use of continuous measurements of
       integral aerosol parameters to estimate particle surace area." Aerosol Sci Technol 34: 57-64.
27.  Kegler, S. R., W. E. Wilson and A. H. Marcus (2001).  "PMp intermodal (PM25-PMj) mass, and
       the soil component of PM25 in Phoenix, AZ, 1995-96." Aerosol Sci Technol 15:  914-920.
                                                           Five Years of Progress
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  «BB«»    I    •     |
  Technical
      What are the
      concentrations of PM
and PM components in the
ambient atmosphere and how
do they vary over time and
space?
                    Five Years of Progress

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Introduction

    Atmospheric PM, comprising solid and liquid particles suspended in air, has both natural (earthen
    or biogenic) and anthropogenic sources. Ambient PM is either emitted directly into the air as
    primary particles or is formed through chemical reactions among mixed gas phase materials
and sunlight while drifting through the atmosphere. The resulting distribution of ambient PM
includes particles that may span five to six orders of magnitude in size and exhibit a wide diversity
of chemical and physical properties. The major chemical components of fine PM (PM25) are sulfate,
nitrate, ammonium, carbonaceous  material (OC, composed itself of hundreds of organic compounds,
and EC or black carbont).  Coarse  PM (PM10_25) is composed of primarily crustal material (typically
oxides or salts of elements found in dirt; e.g., Fe, Ca, Si, Al).

Measurement of atmospheric PM is fundamental  for evaluating and managing air quality. It serves
multiple purposes, from providing key inputs to health effects research to understanding atmospheric
processes and chemistry, relating PM observed at a monitoring site to its sources, and supporting
NAAQS implementation. EPAs research to support atmospheric PM measurement can be broken
down into five areas:

   (1) Federal Reference Method  (FRM) Program
      •   Produces reference methods as metric of air pollution related to health effects
      •   Revises and improves reference methods
      •   Evaluates alternatives for equivalency to reference methods

   (2) Measurement of PM  species
      •   Develops, improves, evaluates, and inter-compares methods to measure PM species
      •   Provides basic PM species and source information

   (3) Field Studies
      •   Provides national leadership and coordination for broad scale field measurement
          campaigns

   (4) Advanced Measurement Techniques
      •   Maintains state of the art measurement capability for measuring particles

   (5) Network Design and  Implementation
      •   Provides a major  supportive role to  OAR in monitoring strategy development and
          implementation, including network  evolution and application of new technology
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By virtue of its complex nature, no single measurement method can both collect and analyze PM;
thus, measurement of atmospheric PM is accomplished via a number of measurement and analysis
methods. Historically, PM has been collected on filters with subsequent chemical analysis in the
laboratory.  Many of these PM collection methods are less than optimal because they are time-
consuming, provide limited temporal data, and are prone to interferences or biases that create
uncertainty in the measurement.  Because they are also expensive, spatial coverage of sampling is
generally restricted. Recent developments in continuous and semi-continuous methods provide
considerable improvements in temporal resolution of PM concentrations (1-3).  Single particle
mass spectrometers, also recently developed, provide continuous composition by size.  At present,
however, these methods are mostly qualitative; detailed quantification requires additional co-located
measurements of PM by size using integrated filter measurements or impactors.  EPA is cooperating
with many other organizations, both public and private, to perform research to improve collection
and analysis methods that produce the measured values observed in PM monitoring networks, such
as EPAs National Monitoring Network.

Key Uncertainties,  Objectives,  and Special  Issues

The FRMs for PM2 5 and PM10 are based on collecting PM on filters over 24-hr sampling periods to
measure PM mass in ambient air (40 CFR Parts 50-53, 58). However,  gas-solid phase partitioning,
which is affected by a number of environmental variables, as well as the collection process itself,
results in significant uncertainty in the measurement of PM mass, even by the FRMs.  In addition,
sample handling, storage, and equilibration of filters introduce errors into the measurement.  Filter
collection also limits most speciated sampling to a l-in-3 or l-in-6 day sampling schedule, thus
greatly limiting temporal evaluations of the nature of PM concentrations, which have been shown to
have considerable diurnal variation.

The collection and analysis of PM components is fraught with problems due to the complex nature
of aerosols. While some compounds like ammonium sulfate are stable (nonvolatile), others such as
ammonium nitrate and a large fraction of the organic material exist in both the gas and aerosol phase
under normal ambient conditions. Collection of these species is difficult, and biases arise when
PM is collected using traditional filter-based methods.  Improved methods have been developed for
nitrate, but the collection of OC remains problematic (4-6).  Measurements of OC is particularly
difficult because it is composed of hundreds or even thousands of species of which only about 15-
20% have been identified and quantified.

The semivolatile nature of many of the organic compounds also makes collection difficult (4, 7).
Aside from difficulties associated with the collection of PM, the analytical methods are problematic,
especially for carbonaceous material, which can be divided into two categories:  OC and EC.

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Separating carbonaceous material into OC and EC is often done as a first cut at better understanding
PM composition. Methods for measuring OC and EC exist and have been widely used, but the
methods differ substantially in their results, especially for EC.  In fact, recent comparisons of the
two methods being used in EPA's National Monitoring Network, IMPROVE and the PM25 STN,
indicate a difference by a factor of two in EC values (8). Efforts are underway to better understand
the relationships between measurements taken using these two methods.

Advances have been made in PM measurement techniques, but much remains to be done to bring
newer techniques into wider application.  Continuous and semi-continuous methods for PM mass
(fine, coarse, and PM10) and its major components of PM are emerging. While some of these
methods are commercially available, the uncertainties in their measured values are still unknown
and greatly limit their use. Advanced methods for measuring the chemical composition and physical
properties of single particles also are emerging (9). However, many of the single-particle methods
are qualitative; and, like many advanced techniques, their operation is subject to problems and
requires highly trained personnel.

Finally, a major shortcoming in our understanding of the uncertainties associated with PM
measurements is the lack of appropriate reference standards and standard reference materials.  While
precision can be obtained for the overall measurements (collection and analysis) by co-locating
multiple samplers, the accuracy of these measurements is unknown (5).  To date, the best approach
to evaluation has been looking at equivalency to other methods.
Major Accomplishments
Several major accomplishments in the technology used to measure PM have been achieved over
the last five years, many in coordination with OAR and the greater scientific community. These are
summarized in following text using the five broad areas of the EPA atmospheric PM measurement
research outlined in the introduction to this section.

FRM Program
EPA developed and evaluated the FRM for PM2 5 (10).  This method is being used in the National
Monitoring Network to measure PM2 5 mass concentrations for comparison to the PM2 5 NAAQS
levels. With the potential for a PM coarse particle standard and in cooperation with the Los
Angeles Supersites project (refer to the following Field Studies section), EPA has developed a
continuous coarse particle sampler (11). This sampler will be evaluated by EPA as a possible FRM
or equivalent.  EPA has also evaluated numerous methods submitted by organizations outside
EPA for reference and equivalency to the FRM.  Since 1997, ORD has evaluated and approved 10
applications for PM10 reference method designations, 10 applications for PM25 reference method
designations, and four applications for PM25 equivalent method designations.

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Measurement of PM Species
EPA has established the PM2 5 STN and was the first to evaluate the newly developed chemical
speciation samplers prior to their implementation in the National Monitoring Network (12, 13).
Results suggested areas for modifications to the samplers, and many of these were implemented and
confirmed in a second intercomparison study in conjunction with the first of EPA's PM Supersites
projects in Atlanta, GA (2) (refer to the following Field Studies section). The IMPROVE and STN
analysis methods for determining concentrations of OC and EC on quartz fiber filters have been
compared, and the results of this study have led to the current STN analysis protocol (8). EPA
has performed and continues to perform research to improve the understanding of the differences
between these two national networks.

EPA, in conjunction with the National Institute of Standards and Technology (NIST), has established
the PM25 Organic Working Group to conduct inter-laboratory trials that will allow the comparison
of measurements for various organic species among the participants (PM Supersites, PM research
centers, and other investigators); the establishment of consensus reference values for organic species
in PM standard reference materials; and the development of calibration and reference standards
for the analysis of organic compounds in atmospheric PM with an emphasis on important source
apportionment tracers for sources potentially related to adverse health effects (14). The project is in
Phase II with about 20 laboratories participating nationwide.

Researchers funded by ORD through the STAR Program significantly contributed to the ability
to measure PM species, as well as to evaluate the FRM.  Progress involved either continuous and
semi-continuous monitor development (e.g. 15-18) or the evaluation and improvement of collection
techniques (e.g. 19-25).

Field Studies
EPA established a regionally based ambient monitoring program known as the PM Supersites
Program to provide critical information and data to better understand atmospheric processes and
source-receptor relationships and to support health effects and exposure research. The program has
also provided a mechanism to test and compare advanced measurement methods. Phase I of the
Supersites Program included studies in Atlanta, GA, and Fresno, CA. Phase II includes studies in
New York, NY; Baltimore, MD; Pittsburgh, PA; St. Louis, MO; Houston, TX;  and Fresno and Los
Angeles, Ca.  Initiated by ORD and the head of the CAS AC Fine Particles  Subcommittee, the five
eastern PM Supersites projects were organized into a uniform intensive sampling program (July
2001-January 2002) with over 20 other studies coordinated to form what has become known as the
Eastern Supersites Program (ESP).
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The database from these intensives is being compiled and will include all aerometric data collected
in the U.S. for a 13-month period beginning June 28, 2001. This will be the largest air quality
database ever established and will be used by EPA and others to evaluate national and regional air
quality models.  The data gathering phase of PM Supersites Program will end in 2004 when data
from each Supersite project will be submitted to two databases: the NARSTO Permanent Data
Archive and the Supersite Integrated Relational Database. The data analysis phase was initiated in
2003 and will continue through 2005.

EPA has also participated in studies conducted by  the SOS in the southeastern U.S.,  specifically
in Atlanta, Nashville, and Houston. Novel methods were used for sample collection, followed by
advanced extraction and analysis techniques to determine concentrations of organic  aerosols and
SVOCs. EPA personnel conducted the measurements at these locations. In addition to the SOS
studies, a major STAR Program grant supported field measurements in Philadelphia during 1998,
1999, and 2000 through the Northeast Oxidant and Particle Study (NE-OPS) campaign.

Advanced Measurement Techniques
EPA established a state-of-the-art organic analysis laboratory, scanning electron microscope (SEM)
laboratory, and trace elements x-ray fluorescence (XRF) laboratory.  These laboratories are used
for methods development and evaluation, and they support other programs by providing advanced
chemical analyses.  The SEM laboratory has developed state-of-the-art methods for  the chemical
and morphological analysis of single particles on filters. These results have been used in studies to
apportion the measured  PM observed at a receptor site back to its sources (26-28).

A number of advanced measurement methods were compared during the Atlanta Supersites Project
(1-3, 9, 29). Results indicate reasonable agreement among methods measuring the same parameter
for most species with highly trained personnel operating many of these instruments. The Atlanta
Supersites Project has resulted in nearly 25 publications; 15 of which are included in a special issue
of the Journal of Geophysical Research - Atmospheres (2).

The STAR Program-funded Southern Center for the Integrated Study of Secondary Air Pollutants
(SCISSAP) developed and field-tested several instruments: (a) Particle Composition Monitor (PCM)
and related laboratory analytical techniques for measuring the mass and composition of PM25 as well
as its precursor compounds using the filter-denuder technique; (b) Differential Mobility Analyzer-
Aerosol Particle Mass Analyzer (DMA-APM) for in situ measurements of particle mass as a function
of mobility (i.e., size); and (c) a system for quantifying in situ concentrations of oxygenated VOCs.
The key SCISSAP findings point toward a regionally distributed source of fine particles and indicate
that over 60% of the PM2 5 mass is comprised of sulfate and organic compounds. The DMA-APS
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instrument provides a precise and accurate technique for measuring particle density. Observations in
Atlanta show two distinct types of particles: the "low density" particles have densities similar to DEPs,
and the "high density" particles are consistent with particles consisting primarily of OC and sulfates
(30). Investigators participated in several field studies, including the 1999 SOS Nashville/Middle
Tennessee Ozone Study, the 2000 Texas Air Quality Study, and the Atlanta Supersite Program (31, 32).

Through STAR Program grants, ORD has invested in the development of real-time single particle
measurement techniques. Advances include development of the aerosol mass spectrometer that can
quantify in real time the amount of size- and composition-resolved PAHs  (33); development of an
instrument capable of distinguishing PM25 constituents such as OC, EC, and inorganic compounds in
the ultrafine sizes (34); improvement of methods to speciate volatile and reacting compounds in single
particles by on-line laser desorption ionization mass spectrometry (35, 36); development of real-time
chemical analysis of organic aerosols using a thermal desorption particle beam mass spectrometer (37);
and improvement of methods to quantify single-particle field measurements (38-40).

Network Design and  Implementation
ORD's atmospheric measurements research has made substantial contributions to the development of
the new "National Ambient Air Monitoring Strategy" recently released by the Office of Air Quality,
Planning, and Standards (OAQPS) for external review (41).

Programmatic Need and Relevance

Measurement methods including collection and analysis methods are critical to understanding the
accumulation of PM in air, linking pollutants at monitoring sites back to their sources, developing
control strategies for minimizing pollution levels, and understanding health and welfare effects of
PM and other pollutants. No method will perfectly measure the concentration of PM in air, so there
is a critical need to determine the accuracy with which methods estimate concentrations. Much of
the work conducted by EPA is designed to  develop methods and evaluate their uncertainty, a task
which is hampered by the lack of reference standards. At best, precision and equivalency is obtained
by comparison to other methods that also are prone to undefined uncertainties. PM25 and PM10 mass
are currently the indicators for NAAQS. Consequently, defining the uncertainty associated with
these measures is critical because areas that exceed the standards will be required to develop plans
for reducing pollution levels in the affected areas. The promulgation of a coarse particle standard
(i.e., particles measuring between 10 and 2.5 microns) is expected within the next 2 years, and the
uncertainty with these methods will also need to be established.  Future research will continue to define
and minimize uncertainty in the measurements by developing standards and by improving methods for
collection and analysis of PM.
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Future Directions

OC and EC, organic aerosols species, and SVOCs make up 20-70% of the mass of PM25 nearly
everywhere in the country at all times. However, to date, EPA has been unable to collect the
organic fraction of the aerosol without significant bias (positive and negative); and the uncertainties
associated with its measurement, including collection and analysis, are often undefined or very
large. For example, of the four chemical speciation monitors evaluated for the National Monitoring
Network, the measurement of OC had an estimated uncertainty of more than 30% based on a
comparison of the methods used. For EC, the uncertainty estimate rose to 200% depending on the
analysis method. This uncertainty is still just a measure of comparability of very similar methods
while the uncertainty associated with how well we determined what was actually in the air is
undefined and may  be off by a significant amount. The uncertainties for measuring mass, sulfate,
nitrate, and trace metals range from 10-20%, but the accuracy relative to a reference standard is still
unknown, as is how well the reported data represent what is actually present in air.

While the development and improvement of methods to measure speciated PM are of utmost
importance to EPA's National Monitoring Network program, this program will also require continued
support for measuring PM mass. As mentioned previously, a coarse PM NAAQS is expected to be
promulgated in the  next 2 years and will need an FRM.  Additionally, the states, which carry out
the monitoring of PM, are extremely interested in replacing labor-intensive, filter-based monitoring
methods with continuous methods.

Given these issues,  future EPA efforts will continue to emphasize improving collection and analysis
methods for OC and EC; continuing to develop, improve, and evaluate continuous methods for all
major components of PM; and developing and evaluating methods for the measurement of coarse
particles. Many of  these evaluations will occur in conjunction with EPA's PM Supersites Program
and throughout ORD to help ensure compatible measurements with emissions estimates and health
and exposure studies. EPA will continue to provide direction to the states and local and tribal
communities and will continue to support the National Monitoring Network to ensure that these
networks obtain data that are defensible and  of known uncertainty. EPA will continue to coordinate
with other federal agencies, either directly or through various air quality subcommittees, such as
CENR, NARSTO, and others, as well as the  private sector. EPA's role in future years will be to lead
PM methods research both in direction and products.
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References

1.  Solomon, P. A., K. Baumann, E. S. Edgerton, R. Tanner, D. Eatough, W. Modey, H. Maring, D.
       Savoie, S. Natarajan, M. B. Meyer and G. Norris (2003). "Comparison of integrated samplers
       for mass and composition during the 1999 Atlanta-Supersites Project."
       JGeophysRes(10S)D7: 8423.  DOT 10.1029/2001JD001218.
2.  Solomon, P. A., W.  Chameides, R. W. Weber, A. Middlebrook, C. S. Kiang, A. G. Russell, A.
       Butler, B.  Turpin, D. Mikel, R. Scheffe, E. Cowling, E. Edgerton, J. S. John, J. Jansen, P.
       McMurry, S. Hering and T. Bahadori (2003). "Overview of the 1999 Atlanta Supersites
       Project." JGeopfrysRes(lOS)D7: 8413. DOT: 10.1029/2001JD001458.
3.  Weber, R., D. Orsini, Y. Duan, K. Baumann, C. S. Kiang, W. Chameides, Y. N. Lee, F. Brechtel,
       P. Klotz, P. Jongejan, H. ten Brink, S. Slanina, C. B. Boring, Z. Genfa, P.  Dasgupta, S.
       Hering, M. Stolzenburg, D. D. Butcher, E. Edgerton, B. Harstell, P. Solomon and R. Tanner
       (2003). "Intercomparison of near real-time monitors of PM25 of nitrate and sulfate at the
       Environmental Protection Agency Atlanta Supersite."
       JGeophysRes 108(D7): 8421.  DOT: 10.1029/2001JD001220.
4.  Turpin, B. J., P. Saxena and E. Andrews (2000). "Measuring and simulating particulate organics in
       the atmosphere: Problems and prospects." AtmosEnviron 34: 2983-3013.
5.  Fehsenfeld, F., D. Hastie, C. Chow, and P. A. Solomon (2002). "Gas and Particle Measurements,
       Chapter 4" (Final External Review Draft). In NARSTO Particulate Matter Science
       Assessment. McMurry, P., Shepherd, M., and Vickery, J. eds.  Pasco, WA: NARSTO.
6.  Committee on Environment and Natural Resources, Air Quality Research Subcommittee (2002).
       Strategic Research Plan for Particulate Matter.
       . Accessed 2004 Feb 3.
7.  Lewtas, L., Y. Pang, d. Booth, S. Reimer, D. J. Eatough and L. A. Gundel (2001).  "Comparison
       of sampling methods for semi-volatile organic carbon associated with PM25."
       Aerosol Sci Technol 34:39-42.
8.  Norris, G. A., E. M. Birch, C. W. Lewis, M. P. Tolocka and P. A.  Solomon (2003). "Comparison of
       particulate organic and elemental carbon measurements made with the IMPROVE and NIOSH
       Method 5040 Protocols." Aerosol Sci Technol, submitted.
9.  Middlebrook, A., D. Murphy, S.-H. Lee, D. S. Thomson, K. A. Prather, R. J. Wenzel, D.-Y Liu,
       D. J. Phares, K. P.  Rhoads, A. S. Wexler, M. V. Johnston, J. L. Jimenez, T. J. Jayne, D. R.
       Worsnop, I. Yourshaw, J. H. Seinfeld and R. C. Flagan (2003). "A comparison of particles
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11. Misra, C., M. Geller, P. Shah, C. Sioutas and P. Solomon (2001). "Development and Evaluation
       of a Continuous Coarse (PM10 - PM25) Particle Monitor." JA&WMA 51:  1309-1317.
12. Solomon, P. A., W. Mitchell, D. B. Gemmill, M. P. Tolocka, G. A. Norris, R. W. Wiener, S.
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13. Tolocka, M. P., P. A. Solomon, W. Mitchell, G. A. Norris, D. B. Gemmill, R. W. Wiener, R.
       W. Vanderpool, J. B. Homolya and J. Rice (2001). "East versus West in the US: Chemical
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       Aerosol Sci Technol (Special Issue for PM2000) 34(1): 88-96.
14. National Institutes of Standards and Technology (2002). Intercomparison Program for Organic
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16. Babich, P., P. Wang, G. Allen, C. Sioutas and P. Koutrakis (2000).  "Development and evaluation
       of a continuous ambient PM25 mass monitor." Aerosol Sci Technol 32(4): 309-324.
17. Eatough, D. J., N. L. Eatough, E Obeidi, P. Pang, W. Modey and R. Long (2001). "Continuous
       determination of PM25 mass, including semi-volatile species." Aerosol Sci Technol 34: 1-8.
18. Kidwell, C. B. and J. M. Ondov (2001). "Development and evaluation of a prototype system
       for collecting sub-hourly ambient aerosol for chemical analysis."
       Aerosol Sci Technol 35(1): 596-601.
19. Kidwell, C. B., J. M. Ondov, C. Sioutas and P. Koutrakis (1998). "Ambient aerosol
       concentration by condensation and virtual impaction for collection and chemical analysis."
       JAerosol Sci 29(S1): S1039-S1040.
20. Ding, Y, Y. Pang, D. J. Eatough, N. L. Eatough and R. L. Tanner (2002). "High-volume
       diffusion denuder sampler for the routine monitoring of fine particulate matter: II.  Field
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21. Pang, Y, N. L. Eatough, W. K. Modey and D. J. Eatough (2002). "Evaluation of the RAMS
       continuous monitor for determination of PM25 mass including semi-volatile material in
       Philadelphia, PA"JA&WMA 52(5): 563-572.
22. Kavouras, I.  G., S. T. Ferguson, J. Wolfson and P. Koutrakis (2000).  "Development and
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23. Kavouras, I.  G. and P. Koutrakis (2001).  "Use of polyurethane foam as the impaction substrate/
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24. Sioutas, C., P. Koutrakis, P. Y. Wang, P. Babich and J. M. Wolfson (1999). "Experimental
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25. Ding, Y. and P. Koutrakis (2000). "Development of a dichotomous slit nozzle virtual impactor."
       JAerosol Sci 31(12): 1421-1431.
26. Conner, T., G. Norris, M. Landis and R. Williams (2001). "Individual particle analysis of
       indoor, outdoor, and personal samples from the 1998 Baltimore retirement home study."
       AtmosEnviron 35: 3935-3946.
27. Mamane, Y, R. D. Willis and T. L. Conner (2001).  "Evaluation of computer-controlled
       scanning electron microscopy applied to an ambient urban aerosol sample."
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28. Willis, R. D., W. D. Ellenson and T. L. Conner (2001). "Monitoring and source apportionment
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29. Lim, H.-J. and B. J. Turpin (2003). "Semicontinuous aerosol carbon measurements:
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30.  McMurry, P. H., X. Wang, K. Park and K. Ehara (2002). "The relationship between mass
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34.  Mallina, R., A. Wexler, K. Rhoads and M. Johnston (2000).  "High speed particle beam
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 Appendix
      A
EPA-Funded Studies
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Abbey, D. E., R. J. Burchette, S. F. Knutsen, W. F. McDonnell, M. D. Lebowitz and P. L. Enright
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       Scattering Data To Estimate the Contribution of Infiltrated and Indoor-Generated Particles to
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Ansari, A. S. and S. N. Pandis  (2000b). "Water absorption by secondary organic aerosol and its
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       continuous ambient PM25 mass monitor." Aerosol Sci Technol 32(4): 309-324.
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Bahrmann, C. P. and V. K. Saxena (1998). "The influence of air mass history on black carbon
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Godleski, J. 1, R. W. Clarke, B. A. Coull, P. H. N. Saldiva, N. F. Jiang, J. Lawrence and P. Koutrakis
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Goldsmith, C. A., Y. Ning, G. Qin, A. Imrich, J. Lawrence, G. G. Murthy, P. J. Catalano and L.
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Goswami, E., T. Larson, T. Lumley and L.-J. Liu (2002). "Spatial characteristics of fine particulate
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Griffin, R. I, D. Dabdub, M. J. Kleeman, M. P. Fraser, G. R. Cass and J. H. Seinfeld (2002b).
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Guo, Z., R. Mosley, S. Wasson, R. Fortmann and J. McBrian (2000b). "Interference of SF6 tracer gas
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      2000: Particulate Matter and Health - The Scientific Basis for Regulatory Decision Making,
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Guo, Z., R. B. Mosley, S. J. Wasson, R.  C. Fortmann and J. A. McBrian (2001). "Dissociation of
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Gwynn, R.  C. and G. D. Thurston  (2001). "The burden of air pollution: Impacts among racial
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Gwynn, R.  C.,  R. T. Burnett and G. D. Thurston (2000). "A time-series analysis of acidic
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Harris, D. B. and F. B. King (2000). "Comparison of the particle size distribution of heavy-duty diesel
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Harris, D. B., King, F.G., Jr., Brown, E. J. (1998). "Development of on-road emission factors for
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Harris, D. B., E. L. J. Thompson, R. A. Hashmonay, D. A. Natschke, K. Wagoner and M. G. Yost
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Harris, D. B., R. C. Shores, J. A. Walker, C. A. Vogel, D. A. Natschke and K. Wagoner (200Ic).
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Hashmonay, R. A. and D. B. Harris (2001). "Particulate matter measurements using open-path Fourier
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Hattis, D., A. Russ, R. Goble, P. Banati  and M. Chu (2001). "Human inter-individual variability in
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Hays, M. D., C. Geron, K. J. Linna, N. D. Smith and J. J. Schauer (2002). "Speciation of gas-phase and
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Heaphy, R.F., J.D. McCain, L.G. Felix,  and J.P Gooch (2001). Pilot-scale testing of an electrostatically
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Hosiokangas, J., J. Ruuskanen and J. Pekkanen (1999).  "Effects of soil dust episodes and mixed fuel
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Howard-Reed, C., A. Rea, M. Zufall, J.  Burke, R. Williams, J. Suggs, D. Walsh,  R. Kwok and L.
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Huang, Y T., A. J. Ghio, E. Nozik-Grayck and C. A. Piantadosi (2001).  "Vascular release of nonheme
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Huang, Y. C., J. Soukup, S. Harder and S. Becker (2003). "Mitochondrial oxidant production by a
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Huffman, G. P., F. E. Huggins, R. E. Huggins, W. P. Linak and C. A. Miller (1999). "XAFS
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Huffman, G. P., F. E. Huggins, N. Shah, R. Huggins, W. P. Linak, C. A. Miller, R. J. Pugmire, H. L.
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Hughes, L.  S., J. O. Allen, M. J. Kleeman, R. J. Johnson, G. R. Cass, D. S. Gross, E. E. Gard, M. E.
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Jacobson, M. Z. (1997). "Numerical techniques to solve condensational and dissolutional growth
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Jacobson, M. Z. (1998). "Improvement of SMVGEARII on vector and scalar machines through
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Jacobson, M. Z. (1999). "Studying the effects of calcium and magnesium on size-distributed nitrate
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Janssen, N. A. H., J. Schwartz, A.  Zanobetti and H. Suh (2002). "Air conditioning and source-
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Jaoui, M. and R. M. Kamens (2001). "Mass balance of gaseous and particulate products analysis
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Jaques, P. A. and C. S. Kim (2000). "Measurement of total lung deposition of inhaled ultrafine
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Kreyling, W. G., M. Semmler, F. Erbe, P. Mayer, S. Takenaka, H. Schulz, G. Oberdorster and A.
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Levy, J. I, E. A. Houseman, L. Ryan, D. Richardson and J. D. Spengler (2000). "Particle
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Linak, W. P., C. A. Miller, J. O. L. Wendt and K. Dreher (1999b). "Fine particulate from residual fuel
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       exposure for children's health." Environ Health Persp 108(3): 457-462.
Pope, C. A., 3rd, D. J. Eatough, D. R. Gold, Y. Pang,  K. R. Nielsen, P. Nath, R. L. Verrier and R. E.
       Kanner (2001). "Acute exposure to environmental tobacco smoke and heart rate variability."
       Environ Health Persp 109(7): 711 -716.
Pope, C. A. I, R. T. Burnett, M. J. Thun, E. E.  Calle,  D. Krewski, K. Ito and G.  D.  Thurston (2002).
       "Lung cancer, cardiopulmonary mortality and long-term exposure to fine particulate air
       pollution." JAm MedAssoc 287: 1132-1141.

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Prahalad, A. K., J. M. Soukup, J. Inmon, R. Willis, A. J. Ohio, S. Becker and J. E. Gallagher (1999a).
       "Ambient air particles: Effects on cellular oxidant radical generation in relation to particulate
       elemental chemistry." ToxicolApplPharmacol 158(2): 81-91.
Prahalad, A. K., D. K. Manchester, I. C. Hsu, J. Inmon and J. E. Gallagher (1999b).
       "Human placental microsomal activation and DNA adduction by air pollutants."
       Bull Environ Contam Toxicol 62(1): 93-100.
Prahalad, A. K., J. M. Soukup, J. Inmon, R. Willis, A. J. Ghio, S. Becker, J. M. Samet, A. J. Ghio
       and M. C. Madden (1999c). "Induction of cyclooxygenase 2 expression in rats exposed to
       residual oil fly ash." Exp Lung Res 26: 57-69.
Prahalad, A. K., J. Inmon, A. J. Ghio and J. E. Gallagher (2000). "Enhancement of 2'-
       deoxyguanosine hydroxylation and DNA damage by coal and oil fly ash in relation to
       particulate metal content and availability." Chem Res Toxicol 13(10): 1011-1019.
Prahalad, A. K., J. Inmon, L. A. Dailey, M. C. Madden, A. J. Ghio and J. E. Gallagher (2001). "Air
       pollution particles mediated oxidative DNA base damage in a cell free system and in human
       airway epithelial cells in relation to particulate metal content and bioreactivity."
       Chem Res Toxicol 14(7): 879-887.
Pun, B. K., R. J.  Griffin, C. Seigneur and J. H. Seinfeld (2002). "Secondary organic aerosol: II.
       Thermodynamic model for gas/particle partitioning of molecular constituents."
       JGeophysRes 107(Part 17, Sect.4): AAC 4. DOI: 10.1029/2001JD000542.
Purvis, C. R., R.  C. McCrillis and P. Kariher (2000). "Fine particulate matter (PM) and organic
       speciation of fireplace emissions." Environ Sci Technol 34: 1653-1658.
Qian, Z., R. S. Chapman, q. Tian, Y. Chen, P. Lio and J.  Zhang (2000). "Effects of air pollution on
       children's respiratory health in three Chinese cities." Arch Environ Health 55: 126-133.
Qian, Z., J. Zhang, F. Wei, W. Wilson and R. S. Chapman (2001). "Long-term ambient air
       pollution levels in four Chinese cities:  Inter-city and intra-city concentration gradients for
       epidemiological studies." J Expo Anal Environ Epidemiol 11: 341-351.
Qian, J., C. L. DeForest and R. E. Miller (2003). "Time-resolved step-scan  FT-IR spectroscopy:
       Applications to the in situ, real-time analysis of aqueous and organic aerosols."
       Anal Chem, in press.
Quay, J. L., W. Reed, J. Samet and R. B. Devlin (1998). "Air pollution particles induce IL-6 gene
       expression in human airway epithelial cells viaNF-kappaB activation."
       Am JRespir CellMolBiol 19(1): 98-106.
Quintana, P., J. Valenzia, R. Delfino and L.-J. Liu (2001). "Monitoring of 1-minute personal
       particulate matter exposures in relation to voice-recorded time-activity data."
       Environ Res 87: 199-213.
Rahman, Q., J. Norwood and G. E. Hatch (1997). "Evidence that exposure  of particulate air
       pollutants to human and rat alveolar macrophages leads to  differential oxidative response."
       Biochem Biophys Res Commun 240: 668-672.
Rea, A., M. Zufall, R. Williams, C. Reed and L. Sheldon (2001). "The influence of human activity
       patterns on personal PM exposure: a comparative analysis  of filter-based and continuous
       particle measurements." JA&WMA 51: 1271-1279.
Reibman, J., Y. Hsu, L.  C. Chen, W. Choy, A. Talbot, W. C. Su and T. Gordon (2002). "Size-fractions
       of ambient particulate matter induce granulocyte macrophage colony-stimulating factor in
       human bronchial epithelial cells by mitogen-activated protein kinase pathways."
       Am JRespir CellMol5/0/27(4): 455-462.


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Richter, H. and J. B. Howard (2000). "Formation of poly cyclic aromatic hydrocarbons and their
       growth to soot - A review of chemical reaction pathways."
       Prog Energy and Combust Sci 26: 565-608.
Riesenfeld, E., D. Chalupa, F. R. Gibb, G. Oberdorster, R. Gelein, P. E. Morrow, M. J. Utell and
       M. W. Frampton (2000). "Ultrafine particle concentrations in a hospital."
       Inhal Toxicol 12(Suppl. 2): 83-94.
Rodes, C., P. Lawless, G. Evans, L. Sheldon, R. Williams, A. Vette, J. Creason and D. Walsh (2001).
       "The relationships between personal PM exposures for elderly populations and indoor and
       outdoor concentrations for three retirement center scenarios."
       J Expo Anal Environ Epidemiol 11:  103-116.
Rosati, J. A., J. S. Brown, T. M. Peters, D. Leith and C. S. Kim (2002). "A poly disperse aerosol
       inhalation system for use in human inhalation studies." J Aerosol Sci 33:  1433-1446.
Sal diva, P. H. N., R. W. Clarke, B. A. Coull, R. C. Stearns, J. Lawrence, G. G. Krishna Murthy, E.
       Diaz, P. Koutrakis, H. Suh, A. Tsuda and J. J. Godleski (2002). "Lung inflamation induced
       by concentrated ambient air particles is related to particle composition."
       Am JRespir Crit Care Med 165: 1610-1617.
Samet, J. M., L. M. Graves, J. Quay, L. A. Dailey, R. B. Devlin, A. J. Ghio, W. Wu, P. A. Bromberg
       and W. Reed (1998). "Activation of MAPKs in human bronchial epithelial cells exposed to
       metals." AmJPhysiol 275(3 Pt 1): L551-558.
Samet, J. M., R. Silbajoris, W. Wu and L. M. Graves (1999). "Tyrosine phosphatases as targets in
       metal-induced signaling in human airway epithelial cells."
       Am JRespir CellMolBiol 21(3): 357-364.
Samet, J. M., F. Dominici, F. C. Curriero, I. Coursac and S. L. Zeger (2000a). "Fine particulate air
       pollution and mortality in 20 U.S. cities, 1987-1994." NEnglJMed343(24): 1742-9.
Samet, J. M., A. J. Ghio,  D. L. Costa and M. C. Madden (2000b). "Increased expression of
       cyclooxygenase 2 mediates oil  fly ash-induced lung injury." Exp Lung Res 26: 57-69.
Samet, J. M., R. Silbajoris, T. Huang and I. Jaspers (2002). "Transcription factor activation following
       exposure of an intact lung preparation to metallic particulate matter."
       Environ Health Persp  110(10): 985-990.
Samet, J. M., L. M. Graaves and W. Wu (2003). "Mechanisms of Zn-induced signal initiation
       through the epidermal growth factor receptor." Toxicol ApplPharmacol 191(1):  86-93
Sarnat, J. A., P. Koutrakis and H. Suh (2000). "Assessing the relationship between personal
       particulate and gaseous exposures of senior citizens living in Baltimore."
       JA&WMA50: 1184-1198.
Sarnet, J. A., J. Schwartz, P.  Catalano and H. Suh (2001). "Gaseous pollutants in particulate matter
       epidemiology:  Confounders or surrogates?" Environ Health Persp 109: 1053-1061.
Savov, J. D., S. H. Gavett, D. M. Brass, D. L. Costa and D. A. Schwartz (2002). "Neutrophils play
       a critical role in the development of LPS-induced airway disease."
       Am JPhysiol: Lung CellMolPhysiol 283(5 part 1): L952-962.
Schauer, J. J., M. M. Shafer, N. D. Smith and M. D. Hays  (1999). "Chemical analysis of fine
       particulate matter for source reconciliation: The next step." Paper presented at the AAAR
       1999 Annual Meeting, Tacoma, WA, October 11-15, 1999.
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Schelegle, E. S., L. J. Gershwin, L. A. Miller, M. V. Fanucchi, L. S. van Winkle, J. P. Gerriets,
       W. F. Walby, A. M. Omlor, A. R. Buckpitt, B. K. Tarkington, V. J. Wong, J. P. load, K. E.
       Pinkerton, R. Wu, M. J. Evans, D. M. Hyde and C. G. Plopper (2001). "Allergic asthma
       induced in Rhesus monkeys by house dust mite (Dermatophagiodes farinae)."
       Am J Pathol 158(1): 333-341.
Schlesinger, R. B. (2000). "Properties of ambient PM responsible for human health effects:
       Coherence between epidemiology and toxicology." Inhal Toxicol 12(Suppl 1): 23-25.
Schroeter, J. D., J. S. Fleming, D. Hwang and T. B. Martonen (2002). "A computer model of lung
       morphology to analyze SPECT images." ComputMedImaging Graph 26(4): 237-46.
Schwartz, J. (2000). "Assessing confounding, effect modification, and thresholds in  the association
       between ambient particles and daily deaths." Environ Health Persp 108(6): 563-568.
Schwartz, J. (2001). "Is there harvesting in the association of airborne particles with daily deaths and
       hospital admissions?" Epidemiology 12(1): 55-61.
Schwartz, J. (2002). "The use of epidemiology in environmental risk assessment."
       JHuman Ecol Risk Assess  8(6): 1253-1265.
Schwartz, J. and L. M. Neas (2000). "Fine particles are more strongly associated than coarse
       particles with acute respiratory health effects in schoolchildren." Epidemiology 11(1): 6-10.
Schwartz, J. and A. Zanobetti (2000). "Using meta-smoothing to estimate dose-response
       trends across multiple studies with application to air pollution and daily death."
       Epidemiology 11(6): 666-672.
Schwartz, J., K. L. Timonen and J.  Pekkanen (2000). "Respiratory effects of environmental tobacco
       smoke in a panel study of asthmatic and symptomatic children."
       Am JRespir Crit Care Med 161(3 Pt 1): 802-6.
Schwartz, J., F. Ballester, M. Saez,  S. Perez-Hoyos, J. Bellido, K. Cambra, F. Arribas, A. Canada,
       M. J. Perez-Boillos and J. Sunyer (2001). "The concentration-response relation between air
       pollution and daily deaths." Environ Health Persp 109: 1001-1006.
Sedman, C. B. (1999). "Controlling emissions from fuel and waste combustion."
       Chem Engin 95(1): 82-88.
Segal, R. A., T. B. Martonen and C. S. Kim (2000). "Comparison of computer simulations of total
       lung deposition to human subject data in healthy test subjects." JA&WMA 50(7): 1262-1268.
Segal, R. A., T. B. Martonen, C. S.  Kim and M. Shearer (2002). "Computer simulations of particle
       deposition in the lungs of chronic obstructive pulmonary disease patients."
       Inhal Toxicol 14(7): 705-720.
Seinfeld, J. H., G. B. Erdakos, W. E. Asher and J. F. Pankow (2001). "Modeling the  formation of
       secondary organic aerosol (SOA). The predicted effects of relative humidity on aerosol
       formation in the a-pinene-, b-pinene-, sabinene-, D3-carene, and cyclohexene-ozone
       systems." Environ Sci Technol 35:1806-1817.
Selgrade, M. J. K. (2000). "Air pollution and respiratory disease: Extrapolating from animal models
       to human health effects." Immunopharmacology 48(3): 319-324.
Selgrade, M. J. K. (2002). "Applying pulmonary immunotoxicity data to risk assessment." In
       Pulmonary Immunotoxicology. M. Cohen, J. T. Zelikoff and R. B. Schleschinger, eds.
       Norwell, MA, Kluwer Academic.
Shen, S., Y. Zhu, P. Jaques and C. Sioutas (2002). "Evaluation of the SMPS-APS system as a
       continuous monitor for measuring PM25 and PM10 and coarse (PM25_10) concentrations."
       Atmos Environ 36(24): 3939-3950.


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Sheppard, L. and D. Damian (2000). "Estimating short-term PM effects accounting for surrogate
       exposure measurements from ambient monitors." Environmetrics 11: 675-687.
Sheppard, L. and J. Kaufman (2000). "Sorting out the role of air pollutants in asthma initiation."
       Epidemiology 11: 100-101.
Sheppard, L. and T. Lumley (2000). "Comments on 'Combining evidence on air pollution and daily
       mortality from the 20 largest U.S. cities: A hierarchical modeling strategy'" by Francesca
       Dominici, Jonathan M.  Samet and Scott L. Zeger." JRSS B 163: 297.
Sheppard, L., D. Levy and H. Checkoway (2001). "Correcting for the effects of location and
       atmospheric conditions on air pollution exposures in a case-crossover study."
       J Expo Anal Environ Epidemiol 11: 86-96.
Shoji, T., F. E. Huggins, G. Huffman, W. P. Linak and C. A. Miller (2000). "XAFS spectroscopy
       analysis of selected elements in fine paniculate matter derived from coal combustion."
       Energy Fuels 16(2): 325-329. DOT: 10.1021/ef010200b.
Shores, R. C., J. Walker, S. Kimbrough, R. B. McCulloch, M. O. Rodgers and J. R. Pearson (2000).
       "Measurement of ammonia emissions from EPAs instrumented vehicle." Paper presented at
       the 10th CRC On-Road Vehicle Emissions Workshop, San Diego, CA, March 27-29, 2000.
Shukla, A., C. Timblin, K. BeruBe, T. Gordon, W. McKinney, K. Driscoll, P. Vacek and B. T.
       Mossman (2000). "Inhaled particulate matter causes expression of nuclear factor (NF)-
       kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro''
       AmJRespir CellMol5/0/23(2): 182-187.
Silbajoris, R., A. J. Ghio, J. M. Samet, R. Jaskot, K. L. Dreher and L. E. Brighton (2000). "/« vivo
       and in vitro correlation of pulmonary MAP kinase activation following metallic exposure."
       Inhal Toxicol 12(6): 453-468.
Simoneit, B. R. T. (1999). "A review of biomarker compounds as source indicators and tracers for air
       pollution." Environ Sci Pollu Res 6(3): 159-169.
Simoneit, B. R. T., J. J. Schauer, C. G. Nolte, D. R. Oros, V. O. Elias, M. P. Fraser, W. F. Rogge  and
       G. R. Cass  (1999). "Levoglucosan, a tracer for cellulose in biomass burning and atmospheric
       particles." Atmos Environ 33(2): 173-182.
Simoneit, B. R. T., W. F. Rogge, Q.-Y. Lang  and R. Jaffe (2000). "Molecular characterization of
       smoke from campfire burning of pine wood (Pinus elliottii)" Chemosphere 2(1): 107-122.
Simoneit, B. R. T., D. R. Oros and V. O. Elias (2000). "Molecular tracers for smoke from charring/
       burning of chitin biopolymer." Chemosphere 2(1):  101-105.
Singer, C. F., B. Ghorishi and C. B.  Sedman (2001). "Lime based multi-pollutant sorbents."
       Paper presented at the US EPA/DOE/EPR1 Combined Power Plant Air Pollutant Control
       Symposium: The Mega Symposium., Chicago, IL, August 20-23, 2001.
Singh, M., P. Jaques and C. Sioutas (2002). "Size distribution and diurnal characteristics of particle-
       bound metals in source and receptor sites of the Los Angeles Basin."
       Atmos Environ 36(10): 1675-1689.
Sioutas, C., E. Abt, J. K. Wolfson and P. Koutrakis (1999). "Evaluation of the measurement
       performance of the scanning mobility particle sizer and aerodynamic particle sizer."
       Aerosol Sci Technol?,Q(l}: 84-92.
Sioutas, C., P. Koutrakis, P. Y. Wang, P. Babich and J. M. Wolfson (1999). "Experimental
       investigation of pressure drop with particle loading in Nuclepore filters."
       Aerosol Sci Technol 30( 1): 71 -83.
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Sioutas, C., S. Kim, M. Chang, L. Terrell and H. Gong (2000). "Field Evaluation of a Modified
       DataRAM MIE Scattering Monitor for Real-Time PM25 Mass Concentration Measurements."
       AtmosEnviron 34: 4829-4838.
Smith, N. D., C. D. Geron, K. J. Linna and M. D. Hays (2000). "Biomarkers for open burning
       of foliar fuels." Paper presented at the AAAR 2000 Annual Meeting, St. Louis, MO,
       November 6-10, 2000.
Smith, K. R., S. Kim, J. J. Recendez, C. Sioutas and K. E. Pinkerton (2002a). "Health effects of
       concentrated  California particulate matter in rats." Toxicologist 66(1-S): 359-360.
Smith, K. R., D. L. Uyeminanami, U. P. Kodavanti, J. D. Crapo, L.-Y. Chang and K. E. Pinkerton
       (2002b). "Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant."
       Free Radio Biol Med 3 3 (8): 1106-1114.
Solomon, P. A., W. Mitchell, D. B. Gemmill, M. P. Tolocka, G. A. Norris, R. W. Wiener, S. Eberly,
       J. Rice, J. Homolya, R. Scheffe, R. W. Vanderpool, R. Murdoch, S. Natarajan and E.
       Hardison (2000). Evaluation ofPM25 chemical speciation samplers for use in the U.S. EPA
       nationalPM25 Chemical Speciation Network. EPA-454/R-01-005 (NTIS PB#2001-105814).
       Research Triangle Park, NC: U.S. EPA, ORD.
Solomon, P. A., M. P. Tolocka, G. Norris and M. Landis (2001). "Chemical analysis methods for
       atmospheric aerosol components." In Aerosol Measurement: Principles, Techniques, and
       Application, Second Edition. P. Barren and K. Willeke, eds. John Wiley & Sons, Inc.,
       New York, NY.
Solomon, P. A., K. Baumann, E. S. Edgerton, R. Tanner, D. Eatough, W. Modey, H. Maring, D.
       Savoie, S. Natarajan, M. B. Meyer and G. Norris (2003a). "Comparison of integrated
       samplers for mass and composition during the 1999 Atlanta-Supersites Project."
       JGeophysRes(\QS)T>l: 8423. DOI 10.1029/2001JD001218.
Solomon, P. A., W. Chameides, R. W. Weber, A. Middlebrook, C. S. Kiang, A. G. Russell, A. Butler,
       B. Turpin, D. Mikel, R. Scheffe, E. Cowling, E. Edgerton, J. S. John, J. Jansen, P. McMurry,
       S. Hering and T. Bahadori (2003b). "Overview of the 1999 Atlanta Supersites Project."
       JGeophysRes(\QS)Tn\ 8413. DOI: 10.1029/2001JD001458.
Song, X. H., P. K. Hopke, D. P. Fergenson and K. A. Prather (1999).  "Classification of
       single particles analyzed by ATOFMS using an artificial neural network, ART-2A."
       Anal Chem 71(4): 860-865.
Soukup, J. M. and S. Becker (2001). "Human alveolar macrophage responses to air pollution
       particulates are associated with insoluble components of coarse material, including
       particulate endotoxin." ToxicolApplPharmacol 171(1): 20-26.
Soukup, J. M., A. J. Ghio and S. Becker (2000). "Soluble components of Utah Valley particulate
       pollution alter alveolar macrophage function in vivo and in vitro''
       Inhal Toxicol 12(5): 401-414.
Sparks, L. E., R. B. Mosley, Z. Guo and D. J. Greenwell (2000). "Deposition rates of particles
       indoors as a function of particle diameter." Poster presented at PM 2000: Particulate
       Matter and Health - The Scientific Basis for Regulatory Decision Making, Charleston, SC,
       January 25-28, 2000.
Spencer, R. M., J. D. Schroeter and T. B. Martonen (2001). "Computer simulations of lung airway
       structures using data-driven surface modeling techniques." Comput Biol Med'31(6): 499-511.
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Srivastava, R. K., D. S. McRae and M. T. Odman (2001). "Simulation of a reacting pollutant puff
       using an adaptive grid algorithm." J Geophys Res 106(D20): 24245-24258.
Stehr, J., R. R. Dickerson, K. A. Hallock-Waters, B. G. Doddridge and D. Kirk (2000).
       "Observations of NOx,  CO and SO2 and the origin of reactive nitrogen to the eastern United
       States." J Geophys Res 105: 3553-3563.
Stonehuerner, J., I. Jaspers, S. Nierkens and R. B. Devlin (2000). "Changes in gene expression in
       NHBE cells exposed to transition metals." Toxicologist 54: 1503.
Strader, R., F. Lurmann and S. N. Pandis. (1999). "Evaluation of secondary organic aerosol
       formation in winter." Atmos Environ 33: 4849-4863.
Stringer, B. and L. Kobzik (1998). "Environmental particulate-mediated cytokine production in lung
       epithelial cells (A549): role of preexisting inflammation and oxidant stress."
       J Toxicol Environ Health ,4 5 5 (1): 31 -44.
Stringer, B., A. Imrich and L. Kobzik (1996). "Lung epithelial cell (A549) interaction with
       unopsonized environmental particulates: quantitation of particle-specific binding and IL-8
       production." Exp Lung Res 22(5): 495-508.
Su, W. Y, R. H. Jaskot, J.  Richards, A. R. Abramson, W. Woessner, W. H. Yu and K. L. Dreher
       (2000a). "Induction of pulmonary matrilysin expression by combustion and ambient air
       particles." Am JPhysiol:  Lung CellMol Physiol (279): L152-L160.
Su, W. Y, J. H. Jaskot and K. L. Dreher (2000b). "Particulate matter induction of pulmonary
       gelatinase A, gelatinase B, and tissue inhibitor of metalloproteinase expression."
       Inhal Toxicol 12(2): 105-119.
Sullivan, J., N. Ishikawa, L. Sheppard, L. Siscovick, H. Checkoway and J. Kaufman (2003).
       "Exposure to ambient fine particulate matter and primary cardiac arrest in individuals with
       and without clinically recognized heart disease." Am JEpidemiol 157: 501-509.
Sun, L., J. V. Zidek, N. D. Le and H. Ozkaynak (2000). "Interpolating Vancouver's daily ambient
       PM10 field." Environmetrics 11(6): 651-663.
Sun, G., K. Crissman, J. Norwood, J. Richards, R. Slade and G. E. Hatch (2001). "Oxidative
       interactions of synthetic lung epithelial lining fluid with metal-containing particulate matter."
       Am JPhysiol: Lung Cell Mol Physiol (281): L807-L815.
Thornburg, J., D. S. Ensor, C. E.  Rhodes, P. A. Lawless, L. E. Sparks and R. B. Mosley (2000).
       "Physical factors influencing indoor-outdoor ratios calculated using a complete IAQ model."
       Paper presented at PM2000: Particulate Matter and Health - The Scientific Basis for
       Regulatory Decision Making,  Charleston,  SC, January 25-28, 2000.
Thornburg, J. W., D. S. Ensor,  C. E. Rhodes, P. A. Lawless, L. E. Sparks and R.  B. Mosley (2001).
       "Penetration of particles into buildings and associated physical factors, part I: Model
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Thurston, G. D., K. Ito and R.  C. Gwynn (1998). "Racial variations in the associations of acid air
       pollution with daily hospital admissions and mortality."
       Am JRespir Crit Care Med 157: A511.
Thurston, G. D., K. Ito, R. Lall and W. Wilson (2000). "Influence of PM components in associations
       with Philadelphia,  PA mortality and hospital admissions."
       Am JRespir Crit Care Med 161: A25.
Tiittanen, P., K. L. Timonen, J. Ruuskanen, A. Mirme and J. Pekkanen (1999). "Fine particulate
       air pollution, resuspended road dust and respiratory health among symptomatic children."
       Eur Respir J13 (2): 266-273.

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Timblin, C., K. BeruBe, A. Churg, K. Driscoll, T. Gordon, D. Hemenway, E. Walsh, A. B. Cummins,
       P. Vacek and B. Mossman (1998). "Ambient particulate matter causes activation of the c-jun
       kinase/stress-activated protein kinase cascade and DNA synthesis in lung epithelial cells."
       Cancer Res 58(20): 4543-4547.
Timonen, K. L. and J. Pekkanen (1997). "Air pollution and respiratory health among children with
       asthmatic or cough symptoms." Am JRespir Crit CareMed 156(2 Pt 1): 546-452.
Tobias, H. J. and P. J. Ziemann (1999). "Compound identification in organic aerosols using
       temperature-programmed thermal desorption particle beam mass spectrometry."
       AnalChem 71: 3428-3435.
Tobias, H. J. and P. J. Ziemann (2000). "Thermal desorption mass spectrometric analysis of organic
       aerosol formed from reactions of 1-tetradecene and O3 in the presence of alcohols and
       carboxylic acids." Environ Sci Technol 34: 2105-2115.
Tobias, H. J., K. S. Docherty, D. E. Beving and P. J. Ziemann (2000a). "Effect of relative humidity
       on the chemical composition of secondary organic aerosol formed from reactions of 1-
       tetradecene and O3." Environ Sci Technol 34: 2116-2125.
Tobias, H. J., P. M. Kooiman, K. S. Docherty and P. J. Ziemann (2000b).  "Real-time chemical
       analysis of organic aerosols using a thermal desorption particle beam mass spectrometer."
       Aerosol Sci Technol?,?,: 170-190.
Tolocka, M. P., P. A. Solomon, W.  Mitchell, G. A. Norris, D. B. Gemmill, R. W. Wiener, R. W.
       Vanderpool, J. B. Homolya and J. Rice (2001). "East versus West in the US: Chemical
       characteristics of PM25 during the Winter of 1999."
       Aerosol Sci Technol (Special Issue for PM2000) 34(1): 88-96.
Trenga, C., P. Williams and J. Koenig (2001). "Dietary antioxidants and ozone-induced bronchial
       hyperresponsiveness in adults with asthma." Arch Environ Health 56: 242-249.
Tsuda, A., R. A. Rogers, P. E. Hydon and J. P. Butler (2002). "Chaotic mixing deep in the lung."
       Proc NatlAcadSci USA 99(15): 10173-10178.
Tucker, W.  G. (1997). "Particulate matter sources, emissions, and control options—USA." Paper
       presented at the 5th US-Dutch International Symposium on Air Pollution in the 21st Century:
       Priority Issues and Policy Trends, Noordwijk, The Netherlands, April 13-17.
Tucker, W.  G. (1998). "An overview of PM25 control strategies." Paper presented at the Conference
       on Air Quality: Mercury, Trace Elements, and Particulate Matter., McLean, VA.
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              Appendix
                     B
          Studies Funded by EPA
            Partners and Others
This bibliography lists the research publications supported
by EPA partners, industry, or other governmental and non-
 governmental organizations that are cited in the report.
                              Five Years of Progress

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Abbey, D. E., P. K. Mills, F. F. Petersen and W. L. Beeson (1991). "Long-term ambient
       concentrations of total suspended particulates and oxidants as related to incidence of chronic
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Anderson, M. J., S. L. Miller and J. B. Milford (2001). "Source apportionment of exposure to toxic
       volatile organic compounds using positive matrix factorization."
       JExpo Anal Environ Epidemiol 11(4): 295-307.
Avol, E. L., W. J. Gauderman, S. M. Tan, S. J. London and J. M. Peters (2001). "Respiratory effects
       of relocating to areas of differing air pollution levels."
       Am JRespir Crit Care Med 164(11):  2067-72.
Bates, D. V. (2000). "Lines that connect: Assessing the causality inference in the case of particulate
       pollution:' Environ Health Persp 108(2): 91-2.
Brook, R. D., J. R. Brook, B. Urch, R. Vincent, S. Rajagopalan and F.  Silverman (2002). "Inhalation
       of fine parti culate air pollution and ozone causes  acute arterial  vasoconstriction in healthy
       adults." Circulation 105(13): 1534-6.
Cass, G. R., L. S. Hughes, P. Bhave, M. J. Kleeman, J. O. Allen and L. G. Salmon (2000). "The
       chemical composition of atmospheric ultrafine particles."
       Philos TransRSocLondA 358: 2581-2592.
Clarke, R. W., J. M. Antonini, D. R. Hemenway, R. Frank,  S. R. Kleeberger and G. J. Jakab (2000).
       "Inhaled particle-bound sulfate: Effects on pulmonary inflammatory responses and alveolar
       macrophage function." Inhal Toxicol 12(3): 169-86.
Committee on Environment and Natural Resources, Air Quality Research Subcommittee (2002).
       Strategic Research Plan for Particulate Matter.
       . Accessed 2004 Feb 3.
       Committee on Environment and Natural Resources (2002).
Dockery, D. W., C. A. Pope, 3rd, X. Xu, J. D. Spengler, J. H. Ware, M. E. Fay, B. G. Ferris, Jr. and
       F. E. Speizer (1993). "An association  between air pollution and mortality in six U.S. cities."
       NEnglJMed 329(24): 1753-9.
Dominici, F., A. McDermott, S. L. Zeger and J. M. Samet (2002). "On the use of generalized
       additive models in time series of air pollution and health." Am  J Epidemiol 156(3): 193-203.
Fehsenfeld, F., D. Hastie, C. Chow, and P. A.  Solomon (2002). "Gas and Particle Measurements,
       Chapter 4" (Final External Review Draft). In NARSTO P articulate Matter Science
       Assessment. McMurry, P., Shepherd, M., and Vickery, J. eds. Pasco, WA: NARSTO.
Fortoul, T. L,  L. S. Osorio, A. T. Tovar, D. Salazar, M. E. Castilla and  G. Olaiz-Fernandez (1996).
       "Metals in lung tissue from autopsy cases in Mexico City residents: comparison of cases
       from the 1950s and the 1980s." Environ Health Persp 104(6):  630-2.
Gauderman, W. J., R.  McConnell, F. Gilliland, S. London, D. Thomas, E. Avol, H. Vora, K. Berhane,
       E. B. Rappaport, F. Lurmann, H. G. Margolis and J. Peters (2000). "Association between air
       pollution and lung function growth in southern California children."
       Am JRespir Crit Care Med 162(4 Pt  1): 1383-90.
Gearhart, J. M. and R. B. Schlesinger (1989). "Sulfuric acid-induced changes in the physiology and
       structure of the tracheobronchial airways." Environ Health Persp 79: 127-36.
Godleski, J. J., R. L. Verrier, P. Koutrakis and P. Catalano (2000). Mechanisms of Morbidity and
       Mortality from Exposure to Ambient Air Particles. Research Report 91. Cambridge, MA:
       Health Effects Institute.
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Gold, D. R., A. I. Damokosh, C. A. Pope, 3rd, D. W. Dockery, W. F. McDonnell, P. Serrano, A. Retama
       and M. Castillejos (1999). "Particulate and ozone pollutant effects on the respiratory function of
       children in southwest Mexico City." Epidemiology 10(1): 8-16.
Goldberg, M. S., J. C. Bailar, 3rd, R. T. Burnett, J. R. Brook, R. Tamblyn, Y. Bonvalot, P. Ernst, K. M.
       Flegel, R. K. Singh and M. F. Valois (2000). Identifying subgroups of the general population that
       may be susceptible to short-term increases in paniculate air pollution:  A time-series study in
       Montreal, Quebec. Research Report 97 (pp. 7-13; discussion, pp. 115-120). Cambridge, MA:
       Health Effects Institute.
Gordon, T., C. Nadziejko, R. Schlesinger and L. C. Chen (1998). "Pulmonary and cardiovascular effects
       of acute exposure to concentrated ambient particles in rats." Toxicol Lett 96-97: 285-288.
Gordon, T., C. Nadziejko, L. C. Chen and R. Schlesinger (2000). Effects of concentrated ambient
       particles in rats and hamsters: an exploratory study. Research Report 93. Cambridge, MA:
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                Appendix
               CENR Air Quality
            Research Subcommittee
               Particulate Matter
                   Workgroup
This appendix lists members of the CENR Air Quality Research
Subcommittee Particulate Matter Workgroup, a federal coalition
 of agencies and departments with vested research efforts and
         interest in air quality as it relates to PM.
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Department of Agriculture
   •  Agricultural Research Service
   •  Cooperative State Research, Education, and Extension Service
   •  Forest Service
   •  Natural Resources Conservation Service

Department of Commerce
   •  National Institute of Standards and Technology
   •  National Oceanic and Atmospheric Administration

Department of Defense

Department of Energy

Department of Health and Human Services
   •  Centers for Disease Control and Prevention
   •  National Institutes of Health

Department of Housing and Urban Development
Particulate Matter Research Program

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Department of the Interior
   •  Geological Survey
   •  National Park Service

Department of State

Department of Transportation
   •  Federal Aviation Administration
   •  Federal Highway Administration

Environmental Protection Agency

National Aeronautics and Space Administration

National Science Foundation

Office of Management and Budget

Office of Science and Technology Policy

Tennessee Valley Authority
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LJniled Stages
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