United States
Environmental
Protection Agency
Asthma
Research
Strateg
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Asthma Research Strategy
On the Cover: Asthma is a disease characterized by reversible airway obstruction, chronic
inflammation, and airway remodeling. Susceptibility factors for asthma include the genetic
background and overall health status of a person, as well as lifestyle, socioeconomic status,
residential location, and overall exposure history, especially the potential for exposure to allergic
inducers and nonallergic triggers. The majority of asthma is associated with allergic responses to
common aeroallergens in our indoor and outdoor environment, such as house dust mites,
cockroaches, animal secretions, pollens, and molds. Exacerbation of asthma may occur with
subsequent re-exposure to allergens, or by exposure to a number of nonspecific triggers of lung
inflammation and airway obstruction, such as respiratory viruses, tobacco smoke, or certain air
pollutants.
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Asthma Research Strategy
EPA 600/R-01/061
September 2002
Asthma Research Strategy
Office of Research and Development
U. S. Environmental Protection Agency
Washington, DC 20460
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Asthma Research Strategy
DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved
for publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
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Dear Reader,
The United States Environmental Protection Agency (EPA) is pleased to present
our Asthma Research Strategy. The U.S. Environmental Protection Agency (EPA) is
committed to preventing pollution and reducing risk from environmental health hazards
in communities, homes, workplaces, and ecosystems. According to the 1997 asthma
surveillance estimate from the Centers for Disease Control and Prevention released in
March of 2002, 26.7 million people reported having had physician-diagnosed asthma
during their lifetime. Many recent scientific journal articles and editorials have noted the
increasing rates of asthma, particularly in children, and the need for further study. By
following the goals detailed within the Asthma Research Strategy, EPA scientists will
lead a coordinated research effort to address environmental pollutants that influence the
incidence and severity of asthma. The strategy supplements and expands on other U.S.
agency efforts to better understand this complex disease.
This Asthma Research Strategy identifies and prioritizes the research needed to
provide information to close the gaps in our knowledge and to control environmental
factors that contribute to the disease. It serves to guide the planning of EPA research
efforts, led by the Office of Research and Development (ORD), to address the significant
issues of exposures, effects, risk assessment, and risk management of environmental
pollutants relevant to asthma through the fiscal year 2009.
Pollutants were considered for investigation if they influenced the incidence or
exacerbation of asthma and warranted further study. Four environmental pollutant
classes were identified by EPA scientists: combustion related products, bioaerosols, air
toxics, and pesticides. Additional areas of study detailed in the Strategy are:
susceptibility factors contributing to asthma (e.g., genetics, health status, socioeconomic
status, residence and exposure history, and lifestyle and activity patterns); and risk
assessment and risk management of environmental pollutants relevant to asthma.
Sincerel
Paul Gilman, PhD
Assistant Administrator
Office of Research and Development
U.S. Environmental Protection Agency
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Asthma Research Strategy
AUTHORS AND CONTRIBUTORS
This research strategy was produced by a team of representatives from several laboratories of the U.S.
Environmental Protection Agency (EPA), Office of Research and Development, and the Office of Air and
Radiation.
Hillel S. Koren, Ph.D.—National Health and Environmental Effects Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Bob Axelrad, Ph.D.—Office of Air and Radiation, U.S. Environmental Protection Agency, Washington, DC 20460
Lawrence Folinsbee, Ph.D.—National Center for Environmental Assessment, U.S. Environmental Protection
Agency, Research Triangle Park, NC 27711
Stephen Gavett, Ph.D.—National Health and Environmental Effects Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Bruce Henschel, M.S.—National Risk Management Research Laboratory, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
Laura Kolb, M.P.H.—Office of Air and Radiation, U.S. Environmental Protection Agency, Washington, DC 20460
Suzanne McMaster, Ph.D.—National Health and Environmental Effects Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Lucas Neas, Sc.D.—National Health and Environmental Effects Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Judith Nelson, M.B.A.—Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection
Agency, Washington, DC 20460
William Steen, Ph.D.—National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research
Triangle Park, NC 27711
Kevin Teichman, Ph.D.—Office of Science Policy, U.S. Environmental Protection Agency, Washington, DC 20460
Stephen Vesper, Ph.D.—National Exposure Research Laboratory, U.S. Environmental Protection Agency,
Cincinnati, OH
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Asthma Research Strategy
PEER REVIEW
Peer review is an important component of research strategy development. The peer review history for the
Asthma Research Strategy follows.
ORD Science Council Review
Final Review Date: August 31,2001
Lead Reviewers:
Elaine Z. Francis, Ph.D.—Associate Director for Health, National Center
for Environmental Research, U.S. EPA, Washington, DC
Herman J. Gibb, Ph.D.—Associate Center Director, National Center
for Environmental Assessment, U.S. EPA, Washington, DC
Lester D. Grant, Ph.D.—Acting Associate Director for Health, National
Center for Environmental Assessment, U.S. EPA, Research
Triangle Park, NC
Harold Zenick, Ph.D.—Associate Director for Health, National Health and
Environmental Effects Research Laboratory, U.S. EPA, Research
Triangle Park, NC
External Peer Review:
ASTHMA RESEARCH STRATEGY PEER REVIEW
December 12-13, 2000
Chapel Hill, North Carolina
External Peer Review Panel Members:
Henry Gong, M.D.—Department of Medicine, Rancho Los Amigos National Rehabilitation Center,
Downey, CA
David M. Mannino, M.D.—Air Pollution and Respiratory Health Branch, Centers
for Disease Control and Prevention, Atlanta, GA
James A. Merchant, M.D., Dr.P.H., Dean—College of Public Health,
University of Iowa, Iowa City, IA
Swati Prakash, M.P.H.—Director of Environmental Health and Community-
Based Research Programs, West Harlem Environmental Action,
New York, NY
Peer Review Coordinator:
The review was facilitated by Dr. Robert Menzer—National Center for
Environmental Research, U.S. EPA, Washington, DC
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Asthma Research Strategy
TABLE OF CONTENTS
Executive Summary x
1. Introduction 1
1.1. Factors in the Development of Asthma 1
1.2. Overview of Environmentally-Related Asthma 2
1.3. Preview of ORD Research Approach 3
2. Background 4
2.1. Regulatory Context 4
2.2. Public Health Goals 5
2.2.1. Federal Goals 5
2.2.2. EPA Goals 5
2.3. Linkage to Other Federal Agency Asthma-Environment Research 6
3. Research Needs 7
3.1. Research Area 1: Induction and Exacerbation of Asthma 7
3.2. Research Area 2: Susceptibility Factors 8
4. Research Approach 9
4.1. Research Area 1: Induction and Exacerbation of Asthma 9
4.1.1. Combustion-Related Products 9
4.1.2. Bioaerosols 11
4.1.3. Air Toxics 14
4.1.4. Pesticides 16
4.2. Research Area 2: Susceptibility Factors 18
4.2.1. Genetic Susceptibility 18
4.2.2. Health Status 19
4.2.3. Socioeconomic Status 19
4.2.4. Residence and Exposure History 20
4.2.5. Lifestyle / Activity Patterns 20
4.3. Risk Assessment 21
4.3.1. Asthma Induction Associated with Environmental Exposures 21
4.3.2. Asthma Exacerbation Associated with Environmental Exposures 22
5. Research Prioritization and Timeline 23
5.1. Prioritization Tables 24
5.2. Timeline of Research Activity 26
6. References 29
Appendix A: Abbreviations and Acronyms 31
VII
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Asthma Research Strategy
TABLE OF CONTENTS
(cont'd)
Appendix B: Inventory of Asthma Research 33
Preface to the Appendix 33
Introduction 34
ORD Intramural Asthma Research Program 34
National Center for Environmental Research: Science to Achieve Results
Grants Program 34
EPA Ambient Air Research 35
VIM
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Asthma Research Strategy
LIST OF TABLES
Table 1 Prioritization of the Research Areas 25
Table 2 Induction / Exacerbation 25
Table 3 Susceptibility Factors 26
Table 4 Risk Assessment Prioritization 26
Table 5 Timeline of Research Activity 27
Table B-l ORD Inventory of Intramural Asthma Research Projects 37
Table B-2 EPA/NTEHS Centers of Excellence in Children's Environmental Health
and Disease Prevention Research: Asthma Research Projects 41
Table B-3 ORD/NCER Particulate Matter Research Centers: Asthma Research Projects ...43
Table B-4 Science to Achieve Results (STAR) Grants: Air Pollution Research Projects
on Asthma 44
Table B-5 Targeted Research Centers: Air Pollution Research Projects on Asthma 45
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Executive Summary
Asthma is a complex, multifactorial disease characterized by chronic airway inflammation,
mucus secretion, airway remodeling, and reversible airway obstruction. Both genetic and
environmental factors influence the development and exacerbation of asthma. More than
17 million people in the United States had asthma in 1998, double the incidence in the previous
20 years. Because the increase in asthma incidence cannot be reconciled by changes in
diagnostic categorization or by alterations in the gene pool, associations between asthma and the
environment have attracted increasing attention. Since the Environmental Protection Agency
(EPA) is required to set pollutant standards to protect susceptible populations such as asthmatics,
a coordinated research effort to study environmental pollutants that influence the incidence and
severity of asthma is needed. Therefore, this Asthma Strategy is designed to help plan intramural
and extramural efforts by the Office of Research and Development (ORD) to address the
significant issues of exposures, effects, risk assessment, and risk management of environmental
pollutants relevant to asthma.
The ORD has the expertise to conduct asthma research in the following areas:
(1) induction and exacerbation of asthma; (2) susceptibility factors contributing to asthma; and
(3) risk assessment issues related to induction, exacerbation, and susceptibility. Four classes of
environmental pollutants that may influence the induction and exacerbation of asthma were
identified as needing additional research: (1) combustion-related products (CRPs) formed from
the burning of organic fuels; (2) bioaerosols, including molds and other allergens; (3) air toxics
or hazardous air pollutants, HAPs; and (4) pesticides. Susceptibility factors that may influence
the induction and exacerbation of asthma also were identified. These are (1) genetic
susceptibility, (2) health status, (3) SES, (4) residence and exposure history, and (5) lifestyle and
activity patterns. For each topic, research agenda items were developed to address specific
research needs; within the asthma induction and exacerbation research area, research needs were
listed for exposure, effects, and risk management.
Multiple clinical, epidemiologic, and animal studies suggest that CRPs exacerbate existing
asthma. Exposure research agenda items include assessment of relative exposures from indoor
and outdoor sources and development of exposure models. Effects research agenda items
include examination of CRP-specific asthma outcomes, acute exposure-exacerbation response
relationships, effects on allergen sensitization, and cellular and molecular mechanisms of
asthmatic responses. Finally, risk management studies should include the characterization of
indoor and outdoor sources of CRPs with an emphasis placed on developing models to define
these sources and on the development of appropriate prevention and control approaches and
technologies.
Because bioaerosols, especially fungal allergens, are tremendously important in the
induction and exacerbation of asthma, and because little is known about the degree of exposure
to major asthma-related fungal allergens, further research is needed in this area. Additionally,
there is a need to develop innovative measurement protocols with which to assess the degree of
exposure to fungal allergens. Research concerning the effects of bioaerosols is also needed to
examine the spectrum of fungal sensitivity, to clinically test bronchoprovocation in mold-
sensitive asthmatics, and to examine the adjuvant effects of toxic compounds produced by
bioaerosols. Risk management needs include the development of basic models characterizing the
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Asthma Research Strategy
sources of indoor bioaerosols and of techniques to reduce bioaerosol exposure and the
assessment of technique effectiveness in reducing bioaerosol exposure in outreach programs in
affected communities.
Thirty-three hazardous air pollutants referred to as "air toxics," are recognized as posing the
greatest threat to public health in the largest number of urban areas (Environmental Protection
Agency, 1999). Research agenda items concerning exposure to these toxics include the
monitoring of personal exposures to asthma-associated air toxics; the characterization of the
major sources, pathways, and routes of exposure; and the development of exposure models for
key air toxics. Research agenda items concerning the effects of hazardous air pollutants include
studies of asthma prevalence and respiratory effects in relation to air toxics exposures, definition
of exposure-response relationships for asthma induction and exacerbation, and development of
practical test methods for assessing allergenicity of air toxics. Needed risk management studies
include characterization of emissions from priority indoor and outdoor hazardous air pollutants
sources and development of technologies for reducing emissions from the most important
sources.
Published studies suggest that certain pesticides may affect neurological and immune
function in a manner which may favor the development or exacerbation of asthma. Research is
needed to determine levels of pesticide exposure and usage in populations with different asthma
incidence rates. Immunologic and neurologic mechanisms of responses to pesticides need to be
examined; screening methods to determine pesticide effects on asthma need to be developed; and
the prevalence and severity of asthma associated with exposure to pesticides need to be better
quantified. To better minimize the risks associated with pesticides, improved models of pesticide
emissions, transport, and fate of these emissions in the indoor environment are needed.
Additionally, alternatives for reducing pesticide exposures associated with induction and
exacerbation of asthma need to be developed.
Biological responses to air pollutants in clinical studies of healthy volunteers are
heterogeneous among the population, yet consistent within an individual, suggesting a genetic
basis for responses among healthy individuals and, presumably, asthmatics. Research is needed
to determine the genetic basis of susceptibility to asthma: phenotypic differences in responses of
asthmatics and healthy individuals to environmental pollutants need to be defined, and a DNA
bank of samples associated with phenotypic markers of response in asthmatics and healthy
individuals needs to be established to identify genetic markers of susceptibility. In vitro
approaches and genetically-defined animal model studies can and should be utilized to examine
the effects of specific genes.
Responsiveness to environmental pollutants may depend on the severity of the disease in
asthmatics and the presence of co-morbid conditions. Research agenda items related to health
status include modeling dose-response relationships in asthmatics with a broad range of asthma
severity, examining of the influence of asthma severity and recent respiratory infections on
responses to air pollution episodes, and studying animal models of cardiopulmonary disease to
understand mechanisms of enhanced responses to pollutants.
Lower socioeconomic status (SES) may be correlated with increased exposure to various
indoor allergens and pollutants. Research is needed to examine gradients of SES in relation to
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asthma incidence, severity, and ambient and indoor air pollution levels. Residence and exposure
history, including building factors and residence in highly polluted areas or near point sources of
pollutants, may also be related to asthma incidence and severity. Research is needed to assess the
history of environmental exposure in asthmatics, to develop biomarkers of exposure to
pollutants, to define patterns of asthma prevalence and severity relative to area and point sources
of pollutants, and to quantify building and structural factors relative to asthma incidence.
Additionally, urban or western lifestyle is often correlated with increasing asthma rates.
Consequently, research is needed to assess the factors that may account for this disparity (e.g.,
reduced air exchange in tightly constructed modern buildings, reduction of physical activity, and
increased time spent indoors).
Risk assessment research needs related to asthma induction include improvement of
exposure information for bioaerosols, pesticides, and air toxics in indoor, occupational, and
agricultural settings; development of improved exposure/activity profiles for susceptible
populations; and assessment of asthma induction in an occupational setting for key chemicals of
interest at ambient levels of exposure. Risk assessment research on asthma exacerbation is
needed to develop tools to assess the unique risk of bioaerosols and to determine the relationship
of asthma severity to dose-response relationships for asthma exacerbation by CRPs, air toxics,
and pesticides. To evaluate the risks of mixtures of chemicals, data on exposure to chemical
mixtures in well characterized asthmatics and in validated animal models are required.
Because limited funds make it impossible to address all of the research topics described in
this Asthma Strategy, it was necessary to prioritize the research needs. The following factors
were used in this prioritization: risk-based planning, relevance to EPA's mission, and public
health importance.
Arbitrary scores were assigned for each area for each of the three factors; the scores were
summed; and the relative ranking was determined. Of the three research areas, induction and
exacerbation of asthma received the highest score, followed by susceptibility factors, and then
risk assessment. Within the induction/exacerbation research area, the research topics were
ranked in the following order: CRPs > bioaerosols > air toxics > pesticides. Within the
susceptibility factors research area, the research topics were ranked in the following order:
residence/exposure history > genetic susceptibility > health status > lifestyle/activity >
socioeconomic status. Within the risk assessment research area, the research topics were ranked
in the following order: asthma exacerbation > asthma induction.
The priority scores were used to generate a timeline to show the sequence and relative level
of effort that will be devoted to the research areas and associated topics over an eight year period
[fiscal years (FY) 2001 through 2009], depending on available resources. The timing and level
of effort in this scale are intended to serve as general advisory guidelines indicating how
available resources could efficiently advance scientific knowledge and control environmental
factors that contribute to asthma prevalence and severity. An early peak effort in bioaerosols
research is indicated, followed a year later by maximal efforts in CRPs and air toxics. Research
topics in susceptibility factors peak in FY 2004-05, while risk assessment research, which is
dependent on data from research conducted in the first two research areas, peaks in FY 2005-06
and extends through FY 2009.
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Asthma Research Strategy
1. Introduction
1.1. Factors in the Development of Asthma
Asthma is a disease characterized by reversible airway obstruction, chronic inflammation,
and airway remodeling. The majority of asthma is associated with allergic responses to common
airborne allergens such as house dust mites, pollens, animal dander, and molds. Additionally, the
disease has a definite genetic component. In genetically predisposed individuals, exposure to
allergens can lead to immunologic sensitization (Figure 1). Sensitization involves the production
of antibodies that belong to the immunoglobulin E (IgE) class. Upon re-exposure to allergens,
immediate and delayed (late-phase) responses may occur in a subpopulation of sensitized
individuals. These responses include airway inflammation (characterized by the presence of
inflammatory cells such as eosinophils and activated T-helper lymphocytes) and airway
obstruction that is reversible either spontaneously or with appropriate medication.
Allergen Exposure
Dust Mites, Cockroaches,
Molds, Pollens, Pets,
Allergenic Chemicals
Induction
Genetic
Predisposition
Immunologic
Sensitization
1 (asymptomatic)
ASTHMA
Mild
Moderate
Severe
Death
Susceptibility Factors
Genetics, Health Status,
Lifestyle, Housing,
Socioeconomic Status
Exacerbation
L
Irritants, Promoters
Air Pollution,
Respiratory Viruses,
Tobacco Smoke
Figure 1. Induction of asthma may occur in genetically susceptible individuals upon exposure to common allergens
or certain chemicals. Nonspecific irritants and promoters may facilitate induction through injury and increased
uptake of allergens or by modulating immune responses (dashed arrow). Both allergens and irritants may
exacerbate existing asthma. Inflammation and airway obstruction in asthma are reversible. Consequently, severity
of the disease is variable (double-headed arrows) depending on environmental influences as well as susceptibility
factors as indicated here.
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Asthma Research Strategy
Induction of asthma refers both to the acquisition of immunologic sensitivity to allergens
and the progression to a clinically detectable disease that is indicated by reversible airway
obstruction. Exacerbation of asthma may occur with subsequent re-exposure to allergens or by
exposure to a number of nonspecific triggers of lung inflammation and airway obstruction, such
as respiratory viruses, tobacco smoke, or certain air pollutants. It also has been suggested that
some of these triggers facilitate the induction of asthma by increasing sensitization to allergens.
This may occur via modulation of immune responses or injury to airway epithelium-effects that
allow allergens to penetrate the immune system barrier and to be taken up by antigen-processing
cells.
Susceptibility factors that are indicative of the potential for exposure to allergens and
nonallergic triggers include, not only the genetic component and overall health status, but also
lifestyle, SES, residential location, and overall exposure history.
1.2. Overview of Environmentally-Related Asthma
The prevalence of asthma in the United States has doubled in the last twenty years
(Mannino et al., 1998). More than 17 million people now report having the disease (Centers for
Disease Control and Prevention, 1998). Asthma has increased most rapidly in children less than
14 years old, who also account for the highest overall rates of asthma among the population at
large. Higher rates of asthma are also reported among minorities and inner-city poor populations.
Although asthma-related deaths are infrequent (< 6000 in 1997; Centers for Disease Control and
Prevention, 1998), mortality rates have increased 66% since 1980. Illness associated with asthma
accounts for an estimated 10 million patient visits and 470,000 hospital admissions annually; this
translates to an estimated loss of three million work days and 90 million days of restricted
activity for asthmatics. The costs related to this disease are enormous, with an estimated cost in
the U.S. in 1996 of $14 billion. Trends toward increased prevalence, deaths, and costs of the
disease have also been observed in many other countries. The increase in asthma incidence
cannot be reconciled simply by changes in diagnostic categorization, and it has been too rapid to
be explained by alterations in the gene pool. For these reasons, there has been a growing interest
in the association between the environment and asthma.
Genetic background may determine whether individuals are susceptible to developing
asthma while exposure to various environmental factors may determine the onset and progression
of the disease. Genetic susceptibility, viral and parasitic infections, diet, lifestyle, air pollution,
and allergic status are related to asthma incidence or severity (Koren, 1997). Other studies
suggest that the increased prevalence of allergy and asthma is related to the lowered incidence of
bacterial infections resulting from increased immunizations, decreased numbers of siblings, less
crowding, and overall improvements in hygiene (Romagnini, 2000; Cookson and Moffatt, 1997).
Combined with increased exposure to some allergens, these conditions may lead to an imbalance
between the T-helper lymphocyte subsets responsible for fighting infections (Thl) and those
responsible for promoting allergy (Th2) and may redirect the immune response towards asthma-
related allergens. However, the decrease in infections has occurred since the 1960s while the
increase in asthma is more recent. The levels of exposure due to indoor and outdoor allergens
may have increased, both occupationally and even community-wide. Early childhood exposures
to dust mites, cockroaches, cat secretions, mold spores, and pollen also may have increased. The
recent Institute of Medicine (IOM) report on Indoor Air and Asthma (Institute of Medicine,
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Asthma Research Strategy
2000) found sufficient evidence of a causal relationship or an association between indoor
exposures to house dust mites or environmental tobacco smoke and the development and
exacerbation of asthma. The report also found sufficient evidence of a causal relationship
between indoor exposure to a number of other biogenic allergens (e.g., mold and cockroach) and
the exacerbation of asthma. Other research has looked at lifestyle causes, such as the lack of
time spent outdoors, particularly engaged in vigorous activity. Data have shown that living on a
farm provides protection from asthma; this may mean that most children spend excessive time
indoors which increases their exposure to indoor pollutants. However, none of these factors
alone can be considered the primary cause of the recent increase in asthma prevalence.
Several pollutants cause serious health problems for people with asthma. Increases in
ambient levels of ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), and particulate matter
less than 10 microns aerodynamic diameter (PM10), as well as suspended sulfates, have been
correlated with emergency department visits and hospital admissions for asthma. Brief exposure
to SO2 causes dramatic bronchoconstriction accompanied by shortness of breath and wheezing in
many subjects with asthma while similar exposures cause no effects in healthy subjects.
In addition, indoor exposure to NO2 has been associated with the development or exacerbation of
asthma (Institute of Medicine, 2000). A study performed in Kanawha County, West Virginia
showed an association on a city-wide scale between volatile organic compounds (VOCs) and
other traffic-related pollution and asthma (Ware et al., 1993). Toxicology studies by Gilmour
et al. show that pre-exposure to NO2 can increase the severity of allergen sensitization (Gilmour
et al., 1996) and suggest that common air pollutants might play a role in asthma induction.
While there is no doubt that air pollution exacerbates existing asthma (Koenig, 1999), data
linking air pollution to the incidence of asthma reveal that this relationship is complex and not
simply causal. For example, the dramatically cleaner air that resulted from the shutdown of
many pollutant sources in the former East Germany did not change asthma rates. While eastern
Germans have more bronchitis and wheeze associated with airborne irritants, they also
experience lower rates of asthma and hay fever than western Germans. Additionally, New South
Wales, Australia has high rates of asthma but a relatively clean environment. In most U.S. cities
over the past twenty years, ambient levels of the air pollutants O3, SO2, NO2, and PM10 have
decreased while asthma cases and severity have increased. Finally, the Harvard study of air
pollution and health in six U.S. cities revealed that bronchitis, not asthma, was associated with
increasing air pollution (Dockery et al., 1989). Based on these studies, it seems air pollutants
may play a greater role as an exacerbator of asthma (by increasing sensitization to antigens and
bioaerosols) than as direct causal agents. Although societal and housing factors may be
significant inducers of asthma, a role for air pollutants in the development of asthma cannot be
ruled out. Consequently, additional toxicological and epidemiological research is needed to
clarify the relationships between air pollutants and asthma induction and exacerbation.
1.3. Preview of ORD Research Approach
Conducting research on asthma is consistent with the mission of the EPA to protect public
health and safeguard and improve the natural environment upon which life depends.
Consequently, the EPA ORD is committed to supporting the principles outlined in the Federal
strategy Asthma and the Environment: A Strategy to Protect Children (Asthma Priority Area
Workgroup, 2000). These principles include a commitment to eliminate the disproportionate
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Asthma Research Strategy
impact of asthma on minorities and the poor; to implement effective environmental, medical, and
educational community-based programs and partnerships; to set measurable and consistent goals
for childhood asthma as called for in the Healthy People 2010 program; and to identify and
implement strategies effective in reducing asthma. In addition, the ORD recognizes the need to
address environmentally related aspects of asthma as they apply to adults.
There are several research approaches to the study of asthma which are well within the
scientific capability of the EPA and can provide data to fulfill EPA's mission to protect human
health. Each approach provides a unique type of data needed to understand the environmental
causes of asthma and to effectively manage the risk of exposure to asthma-inducing and/or
exacerbating compounds.
The ORD will focus its asthma
research on three areas: (1) the
induction and exacerbation of
asthma, (2) susceptibility factors
contributing to asthma induction or
exacerbation, and (3) risk
ORD Asthma Research Areas
Induction and exacerbation of asthma
Susceptibility factors contributing to
assessment issues related to asthma induction or exacerbation
induction, exacerbation, and
susceptibility factors. Specific * RlSk assessment
inducing and exacerbating agents to
be studied include bioaerosols,
pesticides, hazardous air pollutants, and combustion-related products. Factors that will be
evaluated for their potential to affect susceptibility include genetics, health status, SES, residence
and exposure history, and lifestyle.
2. Background
2.1. Regulatory Context
Under the Clean Air Act (CAA), the EPA establishes National Ambient Air Quality
Standards (NAAQS) for criteria pollutants (ozone, lead, paniculate matter, sulfur dioxide,
nitrogen oxides, and carbon monoxide). The primary NAAQS are set to protect human health,
including the health of sensitive members of the population such as asthmatics, and are required
to be reevaluated every five years. Therefore, EPA research on the responses of asthmatics
exposed to these air pollutants provides crucial information for the Agency's standard-setting
activities. The EPA also is responsible for regulating major industrial sources of large quantities
of 188 air toxics. Some air toxics (e.g., diisocyanates, anhydrides, metals) are known to cause or
worsen asthma in occupational settings, so data collected at job sites may prove useful to EPA's
regulatory efforts. The CAA also addresses area and mobile sources of air toxics that contribute
or may contribute to asthma prevalence and severity. In addition, the EPA conducts research and
educates the public about indoor air pollutants, such as bioaerosols, that are important in
initiating asthma and in posing recurrent exposure risks to people with asthma. EPA's research
and educational activities are consistent with the recommendations of the recent IOM report on
asthma and indoor air (Institute of Medicine, 2000). This report concluded that several indoor
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Asthma Research Strategy
allergens and pollutants are significant factors in the development and exacerbation of asthma. It
also found that effective mitigation strategies are available and can be employed presently and
that additional research is needed to assess the role of the environment in the development of
asthma, effective interventions to prevent asthma attacks, and the characteristics of a healthy
indoor environment.
Because a dominant objective of the EPA is to examine the effects of environmental
pollutants on susceptible subpopulations (asthmatics constitute 6.4% of the U.S. population), it is
incumbent on the ORD to ensure that carefully collected data is used to reduce the uncertainty in
risk assessment and to set standards that protect asthmatics. Additionally, because asthma
disproportionately affects people of low SES and certain racial and ethnic minorities, research
aimed at understanding asthma induction and exacerbation is consistent with EPA's role in
ensuring environmental justice. In this context, the objective of this strategy is to articulate
important research areas and ORD's capabilities in this arena in order to provide a road map for
ORD's research program development over the next few years. In addition, the research strategy
will aid ORD's coordination and communication with other EPA offices, Federal entities, and
outside groups conducting asthma research.
2.2. Public Health Goals
2.2.1. Federal Goals
At the Federal level, the cabinet-level Presidential Task Force on Environmental Health
Risks and Safety Risks to Children has developed several specific goals related to the Asthma
and the Environment Strategy (Asthma Priority Area Workgroup, 2000). These goals, pursued
through the efforts of multiple Federal Agencies, include the following:
• By the year 2005, the number of households in which children are regularly exposed to
secondhand smoke will be reduced by 15%;
• By the year 2010, asthma hospitalization rates in children will have fallen to no more than
10 hospitalizations per 10,000 people;
• By the year 2010 emergency department visits will be reduced to no more than 46 per
10,000 people;
• By the year 2010, no more than 10% of children with asthma will experience activity
limitations.
2.2.2. EPA Goals
The ultimate goals of the EPA are to prevent new cases of asthma caused by environmental
factors and to reduce the number and severity of attacks experienced by individuals already
diagnosed with asthma. Significant uncertainties and gaps exist in our understanding of
environmental factors contributing to current asthma-related statistics in the U.S. Consequently,
the ORD needs to develop a cross-paradigm research effort. The efforts outlined in this strategy
will provide a substantive foundation to further the federal goals of reducing and mitigating the
consequences and occurrence of asthma and asthma-related illnesses. Working within the EPA
goal of Sound Science, Improved Understanding of Environmental Risk and Greater Innovation
to Address Environmental Problems (Government Performance and Results Act of 1993), the
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Asthma Research Strategy
ORD will develop and apply the best available science to improve understanding of the factors
causing asthma susceptibility, induction, and exacerbation. Additionally, ORD's efforts in this
area will help reduce the reliance on current health risk assessments and assumptions specific to
asthma-related prevalence in U.S. populations. The ORD will focus its attention on identifying
the contributions of chemical and biological sources and on developing a database of mitigation
strategies and exposure and effects information. This robust database subsequently can be used
to assess the risks within specific population sectors and to develop mitigation strategies aimed at
reducing the chemical and biological factors associated with asthma induction and exacerbation.
ORD's cross-paradigm research efforts in this area are unique: both short- and long-term results
of the recommended research will lead directly to intervention strategies aimed at reducing risks
of asthma in the U.S. Asthma research projects currently funded through intra- and extramural
programs within ORD are tabulated in Appendix B.
2.3. Linkage to Other Federal Agency Asthma-Environment Research
A number of Federal entities besides the EPA ORD are active in asthma research. These
include the National Heart Lung and Blood Institute (NHLBI), the National Institute of Allergy
and Infectious Diseases (NIAID), the National Institute of Environmental Health Sciences
(NIEHS), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for
Disease Control's National Center for Environmental Health (CDC/NCEH), and the National
Center for Health Statistics (NCHS). These federal efforts have been summarized (Department
of Health and Human Services, 2000). EPA scientists are already working with some of these
organizations to ensure that EPA research supplements and expands current research efforts into
the causes of asthma, asthma triggers, and effective intervention strategies. The EPA is also
represented in various coordinating bodies that address the subject of asthma. For example, the
ORD is represented in the NIOSH/NORA (National Institute for Occupational Safety and
Heath's National Occupational Research Agenda) partnership team on asthma and chronic
obstructive pulmonary diseases. Most recently, the ORD is supporting an air pollution extension
to the Inner-City Asthma Study (ICAS), a multi-center intervention trial among moderate to
severe asthmatic children in seven cities through an interagency agreement with NIAID and
NIEHS. As part of the air pollution extension to ICAS, researchers in ORD's National Health
and Environmental Effects Research Laboratory (NHEERL) and National Exposure Research
Laboratory (NERL) are evaluating the role of PM and O3 in the daily variation of peak expiratory
flow and respiratory symptoms among asthmatic children. The objectives of these collaborations
are to leverage resources and to enhance other Federal efforts by bringing the expertise and
facilities unique to the EPA. The EPA ORD is the only U.S. organization that has in-house
capabilities for lexicological, clinical, and epidemiological research combined with extensive in-
house capabilities for ambient air and personal exposure measurement.
The ORD can assist the other participants in ICAS in identifying the most appropriate and
cost-effective asthma risk management approaches for the inner city environment and in
designing protocols for intervention studies in order to determine the effectiveness of these risk
management approaches in helping inner-city children. The relationship between these research
topics and those covered by other ORD strategy documents [e.g., Particulate Matter Research
Program (U.S. Environmental Protection Agency, 1996)], Research on Environmental Risks to
Children (U.S. Environmental Protection Agency, 1999)] was an important consideration in the
formation of this document.
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Asthma Research Strategy
3. Research Needs
Research addressing the health effects of specific criteria air pollutants on asthmatic
individuals has been, and will likely remain, an important component of ORD's pollutant-
specific research strategies. However, these pollutant-specific research strategies treat asthma
only tangentially and are not aimed specifically at a full understanding of the health effects of air
pollutants on asthmatics. (For example, ORD's PM research strategy does not address the
genetic basis for differential susceptibility to ambient exposures in asthmatics.) The ORD
research strategy for asthma presented here will provide an integrative framework for scientific
research specifically directed towards improving understanding of the induction and exacerbation
of asthma across the full range of environmental factors without duplicating or replacing research
on specific criteria pollutants that is conducted under ORD's pollutant-specific research
strategies. Based on the unique capabilities of EPA researchers and the opportunity to reduce
scientific uncertainties, this Asthma Research Strategy presents an approach that focuses on the
following areas: 1) induction and exacerbation of asthma in relation to four classes of pollutants;
2) susceptibility factors contributing to asthma; and 3) related risk assessment issues. Within
Research Area 1, the pollutant classes which merit further study are CRPs, bioaerosols, air
toxics, and pesticides. A brief synopsis of these four classes of pollutants and the rationale for
their selection is described below. Thereafter, an introduction to the four areas selected for
additional study as part of Research Area 2, Susceptibility Factors, is provided. Chapter 4
provides details concerning each of the three research areas and highlights suggested research
agenda items.
3.1. Research Area 1: Induction and Exacerbation of Asthma
CRPs are compounds formed by the
Research Area 1: Induction
and Exacerbation of Asthma
Combustion-Related Products
Bioaerosols
Air Toxics
Pesticides
combustion of fossil fuels or by secondary
transformation reactions. Contributing
components include diesel exhaust and criteria
air pollutants such as NO2, O3, ultrafine or fine
particulate matter (PM2 5), and SO2. Current
evidence does not support a significant role for
CRPs (except possibly for diesel exhaust) in the
induction of asthma because ambient levels of
all the criteria air pollutants have generally
declined while asthma prevalence has increased
over the past twenty years. However, the composition of CRPs in the atmosphere has changed
over time with the increasing prevalence of diesel exhaust. Consequently, an interaction of CRPs
with common allergens in the induction of asthma cannot be ruled out. Multiple clinical,
epidemiologic, and animal studies suggest that these pollutants exacerbate existing asthma.
These findings need to be extended to further understanding of interactions with allergens and
exposure response relationships and to develop effective risk management techniques for both
indoor and ambient sources of CRPs.
Bioaerosols include the clinically relevant allergens (e.g., molds, pollens, dust mites, and
pet secretions) that are known to induce asthma in genetically susceptible individuals. For many
bioaerosols, the antigens responsible for sensitization have been characterized. However, almost
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none of the mold allergens have been characterized, despite their widespread distribution and
apparent importance in the induction and exacerbation of asthma.
Air toxics include volatile and semi-volatile organic compounds, some metals, and other
inorganic compounds which were listed in the 1990 amendment to the Clean Air Act. Except for
a few chemicals in occupational settings, little is known about the contribution of air toxics to the
development or worsening of asthma. Research is needed to more accurately assess exposures
and biological effects and to manage the risks associated with individual air toxics or
combinations of compounds, especially those which have been shown to induce or exacerbate
asthma and are included in the list of 33 urban hazardous air pollutants.
Some reports suggest that certain classes of pesticides may be associated with induction or
exacerbation of asthma (O'Malley, 1997). Pesticide exposure may be particularly harmful in
children because their developing immune systems may be more sensitive to pesticide effects.
Epidemiological studies of pesticide exposure levels and asthma prevalence are critically
important in this regard. Increased exposure assessment, investigation of toxicologic effects, and
control strategies for different classes of pesticides are warranted.
3.2. Research Area 2: Susceptibility Factors
As previously stated, asthma is caused by a multitude of factors—none of which is
completely understood. Consequently, the second major area in which additional research is
needed is the area of susceptibility factors. Factors known to contribute to susceptibility are
genetics, gene-environment interactions, health status, and environmental influences.
Environmental influences include SES, residential location, total exposure history, and lifestyle.
Several of these factors, including genetics, SES, and residential location, have been
recommended to be studied in relationship to indoor air quality and asthma (Institute of
Medicine, 2000).
Recent data indicate that responses
of both healthy and asthmatic people to
environmental pollutants is influenced by
genetic background. Identification and
characterization of those genetic
polymorphisms which influence
responsiveness to environmental agents
will provide risk assessment tools with
which to identify people who are
susceptible to these agents
Research Area 2: Susceptibility Factors
• Genetic Susceptibility
• Health Status
• Socio-Economic Status
• Residence and Exposure History
• Lifestyle / Activity Patterns
Research is needed on how asthma severity, age, and the presence of other co-morbid
conditions may alter uptake and deposition of environmental pollutants in the respiratory tract
and how these factors affect the dosimetry of air pollutants and their interactions with asthma.
The relationships between SES and the incidence and severity of asthma in the context of
general air pollution levels needs to be assessed and clarified.
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Residential location relative to area point sources on a small scale and geographic regions
on a larger scale, as well as building age and structure type appear to influence asthma severity
and needs to be studied further. Also, the exposure history of asthmatics to defined allergens and
air pollutants is an important factor in the development of asthma and requires additional study.
Physical activity, time spent indoors, and nutrition influence allergen and air pollution
exposure and effects. The relationship of these factors to subsequent asthma outcomes needs to
be more adequately addressed.
4. Research Approach
The research approach of this strategy tests the general hypothesis that environmental
factors influence the induction and exacerbation of asthma, and that these factors can be
controlled.
4.1. Research Area 1: Induction and Exacerbation of Asthma
4.1.1. Combustion-Related Products
Ambient levels of most CRPs have declined over the past twenty years while asthma
prevalence has increased, suggesting that CRPs are not responsible for the increase in asthma
prevalence. However, recent evidence suggests that both diesel exhaust and environmental
tobacco smoke (ETS) may increase the incidence of asthma, and stronger evidence indicates that
they can exacerbate existing asthma. Indoor air levels of some CRPs may be increasing due to
tighter construction of homes and less ventilation with outdoor air and may be contributing to the
increased prevalence of asthma. Recent human studies suggest that some CRPs, particularly
diesel exhaust, may facilitate allergic sensitization. Hence, a role for CRPs in the induction of
asthma may be implicated (Diaz-Sanchez et al., 1997; Gilmour et al., 1996; Lambert et al.,
1999). There is strong evidence from both human and animal studies that CRPs can exacerbate
existing asthma, but mechanisms for these effects and dose-response relationships are not clearly
defined.
Exposure
While the measurement of ambient air CRPs is extensive, the role of CRPs in asthma-
related problems must be distinguished from other factors. To this end, the monitoring of fine
PM is being expanded to allow better definition of its effects on sensitive populations. The
relationship between indoor and outdoor PM concentrations needs further investigation. The
relationship between exposure to NO2 and asthma severity is not fully understood; however, an
association between NO2 and asthma exacerbation has been shown to exist (Institute of
Medicine, 2000). The time course of asthmatic responses to allergens in relation to CRP
exposure also requires further study as increases in ambient CRP levels may occur minutes,
hours, or days prior to or following acute allergen exposures. Finally, the CRPs in ETS and
diesel exhaust contain toxic low molecular weight compounds that require study, particularly
because these compounds and their metabolites can serve as useful biomarkers of exposure.
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Asthma Research Strategy
Research Agenda Items: CRPs Exposure
• Determine exposures to CRPs from outdoor and indoor sources
• Develop exposure models linking source to exposure and ambient to indoor air
concentrations.
• Determine distributions of peak and mean personal exposure to NO2 and the
relationship between NO2 exposure and asthma.
Effects
Epidemiologic studies should continue to be performed to determine whether acute
exposure to CRPs increases doctors visits, emergency room visits, and hospitalizations. These
studies will improve understanding of the conditions of exposure that lead to asthma
exacerbation. For example, asthma exacerbation may occur following exposure to a single high
exposure or after chronic exposure to lower levels of CRPs. Clinical studies are needed to
determine whether short-term exposure to ambient CRPs leads to an increase in acute
exacerbation of asthma or use of medication and to determine the exposure-response
characteristics. Despite the inverse correlation between CRP levels and asthma prevalence,
CRPs may be important in asthma induction by facilitating sensitization to common allergens.
CRPs such as residual oil fly ash (an emission source surrogate of PM) and NO2 can amplify the
induction of allergic airways responses to dust mite allergen in rats. These types of sensitization
studies should be expanded to examine diesel exhaust and other forms of ambient PM and other
allergens that may be important in urban environments. Similar studies should be carried out in
atopic humans. Previous studies have been conducted to examine the effects of nasal instillation
of diesel exhaust particles on local allergic responses (Diaz-Sanchez et al., 1997). The possibility
that viral infection may further enhance allergic responses following exposure to CRPs could
also be investigated in animal studies or controlled clinical studies. Finally, the cellular and
molecular mechanisms by which CRPs exacerbate airway responsiveness and allergic responses
in animal models or controlled human exposures of asthmatics should be determined.
Research Agenda Items: CRPs Effects
• Examine exposure to CRPs (especially fine PM) in relation to asthma outcomes (e.g.,
symptoms, pulmonary function, medication use, doctors visits, ER visits,
hospitalizations, quality of life).
• Determine acute exposure-exacerbation response relationships in clinical and animal
studies.
• Examine whether fine PM or other CRPs enhance sensitization to common
allergens.
• Study cellular and molecular mechanisms of inflammatory and physiological
responses.
Risk Management
The risk management efforts for CRPs should consider both indoor and outdoor CRP
sources (fine PM in particular). As determined by priorities, the ongoing characterization of
CRP emission sources under the PM program could be expanded to provide more complete and
accurate emission factors and source models. For fine PM, this expanded characterization could
also lead to a better understanding of particle size distribution and chemical composition.
Drawing from these refined characterization results, experimental and engineering studies could
be conducted to develop and improve the appropriate control technologies for CRPs.
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Asthma Research Strategy
Outdoor sources of CRPs to be considered include a wide array of stationary sources (e.g.,
industrial and utility boilers, wood and biomass combustion) and mobile sources (e.g., diesel
trucks). Studies of PM should address the characterization and control of both primary PM (i.e.,
PM that is released in the particulate form) and secondary PM (i.e., releases compounds such as
sulfur oxides that can react in the atmosphere to form PM and that, in their unreacted gaseous
form, can independently contribute to asthma symptoms).
Indoor sources of CRPs to be considered include indoor combustion sources, PM
re-suspension, creation of fine PM through indoor air chemistry, and entry from outdoors. These
sources could be characterized through test chamber and test house experiments and associated
modeling studies. Modeling the physical processes involved with the sources and fates of CRPs
(emission mechanisms, deposition/sorption, re-suspension/desorption, etc.) as a function of
source parameters and building parameters (e.g., ventilation) over extended periods would be
useful and could serve as input to the assessment of exposures. This information is required to
effectively design a risk management program that reduces CRPs in indoor air.
Research Agenda Items: CRPs Risk Management
• Continue to characterize the indoor and outdoor sources of selected CRPs,
emphasizing the development of basic models defining these sources.
• From these results, develop appropriate prevention and control approaches and
technologies.
4.1.2. Bioaerosols
Several classes of bioaerosols induce allergic asthma in susceptible individuals. Antigens
from dust mites, cockroaches, pets, and several pollens have been well characterized and are
routinely measured. Bacterial antigens, such as those present in enzyme preparations of Bacillus
subtilis or biopesticides like B. thuringiensis, have also been associated with the induction of
asthma (Pepys, 1992; Bernstein, 1999). Mold growth (including Aspergillus, Penicillium,
Alternaria, and Cladosporium) in damp buildings appears to be an important risk factor for
induction of asthma and other respiratory illnesses (Rylander, 1999; Institute of Medicine, 2000).
Although much attention has focused on inner city populations exposed to high levels of
cockroach allergens, poor housing conditions which promote the growth of molds may pose the
greatest risk of asthma development and exacerbation. However, no federal agency has any
significant research program focusing on the role of fungal allergens in asthma induction and
exacerbation. Therefore, the ORD will concentrate its research efforts on exposure, health
effects, and risk management related to fungal bioaerosols. Research on other bioaerosols (e.g.,
dust mites, cockroaches) should be considered where there is evidence of interactions with other
pollutants (e.g., CRPs, air toxics) causing an increase in the incidence of asthma or exacerbating
asthma symptoms.
Exposure
There are no widely available methods for quantitation of fungal allergens; accordingly,
very few fungal allergens have been identified. Molecular probes specific for fungal allergens
are needed to identify the allergens responsible for health effects. Fungal allergens can then be
biochemically characterized, and quantitative enzyme-linked immunosorbent assays (ELISA) for
these allergens in environmental samples can be developed.
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Asthma Research Strategy
Indoor fungal allergens are probably more significant in asthma induction and exacerbation
than outdoor fungal allergens, especially in damp, poorly-ventilated buildings; however the
relative contributions of each type are unknown. To improve understanding of the factors that
contribute to asthma induction and exacerbation, dampness, carpeting, and air exchange rates
should be compared between homes of asthmatics and healthy individuals. Threshold
concentrations for increased risk of asthma symptoms and hospitalization could then be
established for common fungal allergens. Geographical differences in fungal exposures among
cities and regions may be significant relative to other allergens such as dust mites, cockroaches,
and pollens. Exposure assessments of other bioaerosols, such as cat, dog, rodent, and cockroach
allergens should also be completed, particularly in areas where they appear to significantly
contribute to asthma prevalence and severity and where interactions with other common air
pollutants (such as CRPs and air toxics) may enhance asthmatic symptoms.
Research Agenda Items: Bioaerosol Exposure
• Characterize the degree of exposure to major fungal allergens that have been shown
to induce sensitization and airway obstruction.
• Develop innovative methods and measurement protocols for characterizing and
quantifying bioaerosols identified as major contributors to asthma related
health outcomes.
• Examine building environment factors (e.g., dampness, ventilation) which contribute
to fungal exposure.
• Assess the relative exposures to indoor and outdoor sources of molds.
• Examine the importance of regional differences in fungal exposures as a factor in
the prevalence of asthma.
• Assess the importance of exposure to mold allergens relative to better studied
allergens.
Effects
Exposure assessment, detailed questionnaires, and clinical testing are needed to estimate
the dose of fungal allergen that causes sensitization or exacerbation of asthma symptoms. The
doses of defined bioaerosol antigens which exacerbate clinical symptoms and airway hyper-
responsiveness in sensitized individuals are poorly characterized and likely depend on various
susceptibility factors. Because performance of tasks in school or at the workplace by allergen-
sensitive individuals can be adversely affected by exposure to indoor bioaerosols, new measures
of these effects are needed.
Immunomodulatory agents such as (l->3)-p-D-glucan, a component of mold cell walls, and
mycotoxins, such as those produced by the toxigenic mold species Stachybotrys chartarum, may
promote nonspecific inflammation which contributes to clinical symptoms and allergic
pathophysiology. These adjuvant effects may be studied in appropriate animal models which
respond to fungal allergens with allergic airway diseases characteristic of human asthma.
Although animal models do not replicate all conditions of human asthma, especially with respect
to chronicity of the disease, they are useful for determination of cause-effect and dose-response
relationships between bioaerosol exposure and immune, inflammatory, and physiological
endpoints. Such models are also useful for testing interactions with other allergens, viruses, and
other pollutants. These interactions may be additive, synergistic, or inhibitory. Cellular and
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Asthma Research Strategy
molecular mechanisms of allergic responses to fungal allergens may be determined using whole
animal models and human or animal cell culture systems.
Research Agenda Items: Bioaerosol Effects
• Examine the spectrum of fungal allergen sensitivity in asthmatics in the home and
workplace.
• Carry out allergen bronchoprovocation of clinically-identified mold-sensitive
asthmatics to determine dose-response relationships.
• Examine the adjuvant effects of toxic compounds produced by bioaerosols on
induction and exacerbation of asthma-related responses.
• Examine the interactions of bioaerosols with viruses or environmental agents such as
CRTs.
• Analyze mechanisms of responses with appropriate cell culture or animal models.
Risk Management
Significant testing of bioaerosol risk management techniques has been reported in the
literature. However, to date, even the more promising techniques have provided only modest
clinical benefits for asthmatics, indicating that additional, focused studies are needed to develop
new risk management techniques or to improve the implementation of the existing ones.
Test chamber and test house experiments and associated modeling studies are needed to
more effectively characterize the sources of indoor bioaerosols (including bioaerosols entering
from outdoors). The resulting basic source models would define the physical processes
associated with the source and the fate of the bioaerosols as a function of source parameters and
building parameters (e.g., relative humidity, ventilation rate). This improved understanding of
sources would enable definition of risk management strategies to most effectively reduce
exposure, and the basic source models would serve as input to exposure assessment. The full
range of bioaerosols (i.e., aerosols associated with dust mites, pets, roaches, and fungi) should be
considered in accord with the determined priorities.
Techniques recommended for initial attention include improved building materials,
furnishings, and mechanical system components that are resistant to biological growth;
improved, more durable, or better-verified products (such as mattress encasements or "anti-
allergenic" vacuum cleaners); methods for controlling indoor conditions (such as relative
humidity) that inhibit the growth of fungi, mites, and roaches; improved maintenance techniques;
and improved source treatment measures (such as encapsulation). These source management
techniques warrant primary attention because they offer the potential for significant reductions in
exposure and are not being fully addressed by other investigators.
Risk management techniques involving ventilation and indoor air cleaners/filters would
likely be a secondary research focus. Based on the results from the characterization of exposure
pathways, and, in conjunction with such efforts, studies should be conducted to assess the
performance and effectiveness of ventilation and air cleaning on selected bioaerosols.
Research Agenda Items: Bioaerosol Risk Management
• Develop improved understanding and basic models characterizing the sources of
indoor bioaerosols.
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• Improve, develop, and demonstrate source management techniques to reduce
bioaerosol exposure, such as mold-resistant materials and environmental
controls, and define their effectiveness in outreach programs in affected
communities.
• Assess the effectiveness of improved ventilation and indoor air cleaning and
filtration in reducing bioaerosol exposure.
4.1.3. Air Toxics
The 1990 Clean Air Act Amendments provide the foundation for EPA's air toxics program.
It listed 189 compounds (one was removed so the current number is 188) as hazardous air
pollutants (HAPs) to be regulated. In 1999, 33 HAPs were selected as posing the greatest threat
to public health in the largest number of urban areas (Federal Register, 1999) and 30 compounds
were selected as having the highest impact on asthma and respiratory health (Leikauf et al.,
1995). These compounds were selected based on their ability to induce or exacerbate asthma,
their allergic potential, or their irritant potential. Seven compounds (acetaldehyde, acrolein,
formaldehyde, hydrazine, and cadmium, chromium, and nickel compounds) were selected for
inclusion in both lists (EPA, 1999; Leikauf et al., 1995) and are prime candidates for initial
study. Additionally, six organic acids (three diisocyanates and three acid anhydrides) are known
to cause asthma in occupational settings or are structurally related to such compounds and are
suitable for clinical studies, as is chlorine which is not a known or suspected carcinogen. Both
diesel exhaust and ETS are mixtures of various CRPs and air toxics which may interact to
enhance asthma incidence or severity.
Exposure
One of the most significant problems in the study of air toxics and asthma is the lack of
information on the ambient air concentrations of these compounds (Leikauf et al., 1995). Data
on personal exposures to air toxics are needed to more accurately determine associated risks and
measurements of ambient levels of urban HAPs. An expansion of efforts to fully evaluate key
determinates of exposure to air toxics within urban and occupational settings is of paramount
importance in efforts to understand the relationships between ambient and indoor sources and the
characterization and quantification of major exposure pathways and routes. Exposure research
will focus on addressing major factors contributing to asthma-related illnesses from exposure to
air toxics through better evaluation and characterization of pathways, activity pattern
measurements, and development of quantitative multipathway models for predicting the
contributions from and exposures to air toxics. In addition to industrial area sources, products
such as paints and carpets used in indoor environments may be significant sources of asthma-
associated air toxics. In areas with high asthma prevalence, testing for asthma-related air toxics,
in addition to the previously mentioned compounds, may be warranted.
Research Agenda Items: Air Toxics Exposure
• Monitor personal exposures to asthma-associated air toxics in different
environments.
• Characterize major pathways and routes of exposure to key air toxics, evaluate key
determinants of exposure, and characterize important activities leading to
enhanced exposures in different population sectors (i.e, children, elderly)
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• Characterize sources of asthma-related air toxics, and develop multimedia/
multipathway aggregate exposure and exposure-to-dose models for key air
toxics used in source to dose estimations.
Effects
Quantitative prospective cohort epidemiologic studies with exposure measurements are
needed to determine whether concentrations of air toxics affect asthma rates or severity on a local
or regional basis. Relationships between occupational exposure to air toxics and asthma
incidence and clinical symptoms are still poorly defined. Occupational environment air toxics
measurements would allow definition of exposure-response relationships and relationships
between occupational and environmental exposures. Controlled clinical studies of asthmatic
volunteers exposed to air toxics at levels found in the urban/occupational environment would
also contribute to knowledge of exposure-response relationships. Other epidemiologic studies
could examine whether air toxics facilitate the induction of responses to common allergens.
Air toxics may be directly allergenic or may amplify inflammation and airway hyper-
responsiveness induced by allergens. Animal models can be utilized to develop test methods for
assessing the potential allergenicity of air toxics and to determine whether air toxics increase
sensitization to common allergens. Exacerbation of inflammation and reactivity may also be
examined in allergic or virus-infected animals, and the pathogenetic mechanisms of irritant-
induced asthma can be examined in these models.
Research Agenda Items: Air Toxics Effects
• Conduct studies of asthma prevalence and respiratory effects in relation to air toxics
exposures.
• Define exposure-response relationships for asthma induction/exacerbation using
occupational data and clinical studies.
• Develop practical test methods for assessing the allergenicity of air toxics.
• Determine whether air toxics induce hyper-responsiveness or exacerbate responses
in animal models sensitized to common allergens.
• Study interactive effects of air toxics and CRTs.
Risk Management
Continuing experimental and analytical studies should be conducted to characterize and
model the emissions of air toxics from selected indoor and outdoor sources. Among the outdoor
sources of primary concern are architectural coatings that emit HAPs such as formaldehyde and
acetaldehyde. Indoor sources of concern include building materials, furnishings, interior paints,
consumer products, and office equipment, all of which emit formaldehyde and/or other
compounds of concern to asthmatics. To allow the risk management effort to be focused on
those sources contributing the most to the cumulative exposure, the relationship between indoor
versus outdoor air toxics concentrations and the possible interactions between indoor air
pollutants (e.g., reactions between indoor VOCs and ozone) require further study. Supported by
this characterization work, appropriate experimental and analytical studies should be undertaken
on selected sources in order to develop the technology needed to prevent or reduce emissions of
air toxics. For indoor sources, the initial emphasis should be on pollution prevention measures
(e.g., development of low-emitting materials); for outdoor sources, the focus should be on
pollution prevention measures or on add-on controls, depending upon the source.
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Research Agenda Items: Air Toxics Risk Management
• Characterize emissions from priority indoor and outdoor air toxics sources,
emphasizing the development of basic models defining these sources.
• Develop approaches and technologies for preventing or reducing emissions from the
most important sources.
4.1.4. Pesticides
Pesticide exposures may induce systemic and local reactions, such as irritation of the
respiratory tract and asthma-like reactions in some individuals (O'Malley, 1997). Young
children may be particularly sensitive to the effects of pesticides due to their rapidly developing
nervous and immune systems (Eskenazi et al., 1999). Some adverse reactions to pesticides are
probably nonspecific responses to low molecular weight organic vehicle components (such as
mercaptans). Exposure to carbamate pesticides has been associated with increased incidence of
asthma in Canadian farmers (Senthilselvan et al., 1992). Organophosphates and N-methyl
carbamates inhibit acetylcholinesterase, lead to reduced enzymatic degradation of acetylcholine,
and parasympathetic responses that may include bronchoconstriction. Pyrethrum insecticide may
contain sesquiterpene lactones which have been shown to induce allergic rhinitis and may
exacerbate asthma. Little is known about the specific effects of organochlorine insecticides on
people with asthma.
Exposure
The prevalence of asthma in relation to levels of pesticides encountered outdoors or in
homes has not been established. Considerable difficulties exist, not only in identifying
individuals who have been exposed to pesticides, but also in identifying the pesticides and
exposure levels that may be responsible for observed effects. The concentrations of pesticides in
the air, water, or soil and the duration of exposure may affect both clinical symptoms and the
level of sensitization to common allergens. These relationships between allergen exposure,
pesticide levels, and asthma incidence and clinical symptoms are not well defined. The routes
(ingestion, inhalation, or dermal absorption), as well as the sources (indoor versus outdoor) of
exposure to pesticides, are important factors to consider. Additionally, factors contributing to
children's increased allergen sensitivities/susceptibility resulting from a combination of pesticide
exposure should be better understood.
Where analyses of hospitalizations and emergency room visits for asthma have been
completed, retrospective exposure assessments of pesticide levels in the home may provide
unique opportunities for assessing the types and levels of pesticides associated with asthma
exacerbation. The development of biomarkers of exposure to pesticides in blood or urine
samples may also be useful in this regard.
Research Agenda Items: Pesticide Exposures
• Examine levels of pesticide exposure and usage in geographic regions and
demographic groups with different asthma incidence rates.
• Develop biomarkers for exposure to pesticides.
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Effects
The health effects of pesticide compounds must be segregated from those of the VOCs used
as vehicle components in the formulation of the product. For example, low molecular weight
pesticide compounds may act as haptens, binding to larger proteins and inducing sensitization to
the pesticide. Pesticide exposure may also facilitate sensitization to common allergens by
increasing serum IgE antibodies to these allergens. The increased levels of IgE may serve as a
biomarker of exposure to pesticides, as well as a possible mechanism for increased incidence and
exacerbation of asthma. Some pesticides may also cause dysregulation of the autonomic nervous
system, which may cause direct effects on respiration or modulate immune responses. Animal
toxicology studies can be used as a screening tool to decide which pesticides to examine in
epidemiologic studies. The effects of acute pesticide exposure on airway responsiveness and
allergic inflammation in animal models may also be tested.
Sensitization to common allergens and subsequent induction of asthma may be enhanced
by exposure of infants and children to pesticides. In order to test this hypothesis, epidemiologic
studies can be performed to determine incidence of new asthma in children and corresponding
pesticide exposure levels. Pesticide levels associated with increased incidence will likely vary
depending on the class (organochlorines, carbamates, organophosphates) and mechanism of
action. Studies are being conducted to determine whether acute exposure to pesticides increases
asthmatic symptoms or acute attacks in children. Toxicology studies can also be used to
determine whether fetal or neonatal exposure to various classes of pesticides facilitates induction
of responses to common allergens. Finally, new studies of asthma in workers with high
exposures to pesticides could facilitate understanding of exposure-response relationships and
interactions between occupational and environmental exposures.
Research Agenda Items: Pesticide Effects
• Examine immunologic and neurologic mechanisms of responses to pesticides, and
distinguish from the effects of vehicle compounds.
• Develop methods for screening pesticides for potential to cause or exacerbate asthma
• Determine whether pesticide exposure facilitates induction of asthma or responses to
common allergens.
• Examine asthma prevalence, incidence, and severity associated with exposure to
pesticides.
Risk Management
For any major class of pesticides (e.g., organophosphates, organochlorines, or carbamates)
that becomes linked to the induction or exacerbation of asthma, a detailed source characterization
effort should be conducted involving test chamber and test house experimental studies. This
effort should include computer modeling of the physical processes involved during application of
the pesticide and occurring for an extended period afterwards. The relevant physical processes
include airborne emissions from the wet and dried pesticide film, transformation of the semi-
volatile constituents between the aerosol and gaseous phases, transport to surfaces, deposition (or
sorption) on surfaces, re-suspension (or desorption) from surfaces. This modeling should take
into account pesticide characteristics and building parameters (e.g., ventilation), and should
address both the active ingredients in the pesticide and other constituents (e.g., co-solvents) of
possible concern to asthmatics.
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Drawing upon these improved models for pesticides, a focused study can be undertaken to
develop pollution prevention and other alternatives for reducing indoor pesticide exposure.
Possible examples of such risk management alternatives include definition of the appropriate
ventilation strategy to reduce exposure based on the emission pattern from wet pesticide films;
re-formulations that could result in a lower-emitting product while maintaining pesticide
performance; optimal maintenance/cleaning approaches; integrated pest management,
educational campaigns, usage reduction, and proper use and application.
Research Agenda Items: Pesticide Risk Management
• Develop improved models characterizing the airborne emissions resulting from
pesticide use and the transport and fate of these emissions in the indoor
environment.
• Develop pollution prevention and other alternatives for reducing pesticide exposures
associated with induction and exacerbation of asthma.
4.2. Research Area 2: Susceptibility Factors
4.2.1. Genetic Susceptibility
Previous clinical and epidemiologic studies indicate that responses to environmental
exposures are heterogeneous among individuals. For example, the magnitude of functional and
inflammatory responses to ozone exposures can differ significantly among subjects, while this
trait appears to be consistent for a given individual. These observations suggest that human
susceptibility to environmental insults is influenced by the genetic background of healthy
individuals. It follows that there may also be a genetic basis for differential susceptibility to
ambient exposures in asthmatic patients. The goal of research in this area is to identify and
characterize genetic polymorphisms that influence responsiveness to environmental agents in
order to improve the risk assessment tools used to predict the percentage of the population that is
susceptible to environmental exposures. A critical phase in genetic susceptibility research is
identification of phenotypic differences of asthmatics and healthy individuals by defining the
range of responsiveness to a given exposure under controlled conditions. These phenotypic
differences can then be correlated with the genetic profile of each subject to determine genotypic
differences. To this end, a DNA bank of samples from asthmatic and healthy volunteers in
clinical or epidemiological studies needs to be established. Once this bank is established,
opportunities for conducting genetic analysis experiments will exist.
A "top-down, bottom-up" approach can be used to discover genetic markers of
susceptibility to air pollutants which define differences in responses of asthmatics and healthy
individuals. In this approach, genetic analysis of chromosome regions linked to phenotypic
differences is combined with study of candidate genes associated with asthma. Candidate genes
may be proposed based on clinical or animal toxicology studies. This approach is distinct from
the environmental genome project or the National Health and Nutrition Examination Survey's
(NHANES') genetic retrospective in that phenotypic responses to controlled pollutant exposures
have been identified in subjects studied by ORD investigators. In vitro approaches may also be
used to compare gene expression by airway epithelial cells from asthmatics and healthy humans.
Finally, mutant genetic animal models may be utilized to examine environmental interactions
with defined genetic differences.
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Research Agenda Items: Genetic Susceptibility
• Define differences in responses of asthmatics and healthy individuals to
environmental pollutants as a step towards quantifying genotypes common to
asthmatics.
• Establish DNA bank of samples associated with phenotypic markers of response in
asthmatics and healthy individuals for use in conducting genetic analysis
experiments to identify genetic markers of susceptibility.
• Utilize in vitro studies and animal models to examine effects of specific genes.
4.2.2. Health Status
Responsiveness to environmental pollutants may depend on the severity of disease and
presence of co-morbid conditions. For example, individuals with more severe asthma have
greater decrements in pulmonary function in response to SO2 and O3. Age and the concurrent
presence of other cardiopulmonary diseases can also affect responsiveness. Asthma severity may
alter uptake and deposition of environmental pollutants in the respiratory tract and may
subsequently influence tissue and physiological responses. The objectives of research in this area
are to understand how asthma severity affects dosimetry of air pollutants and subsequent effects
and to determine how age and disease status affect responsiveness. Human studies may be
carried out to explore the effects of asthma severity on dosimetry, and epidemiological studies
can be used to study the responses of mild and severe asthmatics to air pollution episodes.
Finally, animal models of cardiopulmonary disease may be used to examine the effects of
coexposure to allergens and pollutants such as air toxics and CRPs.
Research Agenda Items: Health Status
• Perform dosimetry and dose-response studies on asthmatics with a broad range of
asthma severity with representative compounds.
• Develop mathematical models to understand the effect of asthma severity on
dosimetry of gaseous and particulate air pollutants.
• Examine the influence of asthma severity and recent respiratory infections on
responses to air pollution episodes.
• Study models of cardiopulmonary disease to understand mechanisms of enhanced
responses to pollutants.
4.2.3. Socioeconomic Status
In general, low SES is highly correlated with asthma prevalence and severity but is less
well-correlated with ambient air pollution levels. Low SES, common in inner city populations,
may be indicative of increased exposure to indoor air pollutants such as nitrogen oxides,
bioaerosols, and pesticides, or stationary or mobile sources of CRPs (Northridge et al., 1999).
The relationships between SES and the incidence and severity of asthma need to be clarified.
Gradients of SES may be examined in the context of asthma and air pollution levels. In addition
to its interest from a health perspective, epidemiological studies should be performed to examine
the relationship between SES and asthma prevalence as a social justice issue.
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Research Agenda Items: Socioeconomic Status
• Examine gradients of SES in relation to asthma incidence and severity with
emphasis on their relationship to ambient and indoor air pollution levels.
4.2.4. Residence and Exposure History
The totality of exposure history to defined allergens, air pollutants, pesticides, and other
chemical stressors appears to influence asthma prevalence. Key factors contributing to exposure
history include activity patterns, uptake rates, frequency and duration of the exposures, and
potential dose metrics. Understanding the linkages between these key factors and their
relationship to asthma incidence rate and prevalence is important. Consequently, the exposure
history of asthmatics should be investigated to determine whether asthma prevalence is related to
patterns of exposure to indoor allergens, molds, air toxics, pesticides, and CRPs. Additionally,
biomarkers of exposure to environmental pollutants may be useful in defining the contribution of
individual pollutants to asthma induction.
Residence near area sources of pollutants increases the likelihood of exposure. To assist in
risk assessment, patterns of asthma prevalence and severity should be defined relative to area
sources and geographic regions (e.g., rural versus urban). These studies may also provide insight
into the relative role of indoor versus outdoor pollution. In addition, residential location near
point sources on smaller scales needs to be considered (e.g., proximity to dry cleaners on ground
floor of apartment building or to unventilated garages in housing units). Building age, structural
issues, and multiple-dwelling versus single-family buildings are additional factors which may
influence allergen and environmental pollutant exposures and require further research.
Research Agenda Items: Residence and Exposure History
• Assess environmental exposure history in asthmatic patients.
• Develop biomarkers of exposure to pollutants to assess the potential contribution of
individual pollutants.
• Define patterns of asthma prevalence and severity relative to area and point sources
of pollutants in residential locations.
• Compare existing geographic information system (GIS) data on the location of
sources and their emission inventories to patterns of asthma prevalence and
severity.
• Define the building and structural factors associated with living in an urban
environment that contribute to the high incidence of asthma among inner-city
residents.
4.2.5. Lifestyle / Activity Patterns
Urban or western lifestyle appears to be correlated with increasing asthma rates. However,
the factors that account for the increased rates are not clear. The time, duration, and frequency of
exposures to air pollutants are key factors to be considered when assessing asthma prevalence.
The tight construction of modern buildings reduces ventilation from outside air and may increase
exposures to indoor allergens and exacerbate the effects of indoor air pollutants. Reduction of
physical activity and increased time spent indoors may also be important factors contributing to
higher asthma rates. Exercise and outdoor activity increase ventilation and the inhaled dose of
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Asthma Research Strategy
ambient pollutants and may also promote higher rates of asthma. Specifically, the deposition and
dose of SO2 and particles is increased at higher breathing rates and higher flow rates as is the
depth to which these pollutants penetrate into the lung. Nutritional factors, including vitamin C
intake, also appear to be significant determinants of asthma severity.
Research Agenda Items: Lifestyle /Activity Patterns
• Examine the balance of lifestyle factors, including physical activity, time indoors,
and nutrition, which influence allergen and air pollution exposure and their
relationship to subsequent asthma outcomes.
4.3. Risk Assessment
In addition to advanced research into the factors responsible for the prevalence and
exacerbation of and susceptibility to asthma, risk assessment is a high priority for the ORD. The
following two sections describe specific areas in which additional risk assessment measures are
needed.
4.3.1. Asthma Induction Associated with Environmental Exposures
To assess the risk of asthma induction, human exposure studies, epidemiology studies,
occupational studies, and animal toxicology studies must be utilized. Animal toxicology studies
must be extrapolated to human health effects and compared to human equivalent exposures to
complete the risk assessment cycle and provide the basis for risk assessment. The development
of an assessment approach would be similar for CRPs, bioaerosols, pesticides, or air toxics. The
pattern, timing, and quantification of exposures is likely to be a key issue in determining risk for
asthma induction from environmental chemicals or combinations of environmental chemicals
and biological factors. An understanding of temporal factors such as the frequency and duration
of exposure and the timing of exposures with respect to age and time of day and season is
required to assess exposure risks. Additionally, a determination also must be made as to whether
induction and/or resensitization occurs as a result of a few high level exposures, numerous low
level exposures, or both types of exposures.
Another major issue central to assessing the risk of asthma induction is the prevalence of
phenotypes and genotypes that are susceptible to induction as it is likely that a combination of
genetic susceptibility and environmental exposure is required for induction. Methods for
combining susceptibility with exposure information need to be developed to assess the risk for
induction. Since adequate human exposure-response information is presently lacking for many
chemical and biological agents of concern, it will be necessary to utilize validated animal-to-
human extrapolation models to develop dose response assessments as well as to utilize
epidemiological studies to identify key inducers and cofactors.
The induction of asthma generally requires genetic susceptibility, appropriate timing,
exposure to susceptibility-enhancing or adjuvant chemicals (e.g., diesel exhaust particles), and
adequate exposure to an inducer or combination of inducers. Activity and associated ventilation
rates determine bulk flow of gases and particles and influence the extent and pattern of particle
deposition. Because environmental levels vary during the day, the juxtaposition of activity and
exposure may play an important role in induction. Consequently, simultaneous exposure/activity
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information in a susceptible population, preferably across age, would be useful for risk
assessment.
Occupational studies may provide a good model for a simplified risk assessment of
induction for the following reasons: exposure information can be provided for the workplace
(likely the primary source of exposure); activity can be observed and ventilation monitored or
estimated; the duration of exposure can be adequately characterized (both cumulative and acute);
internal dose or effect surrogates can be developed; whether or not new workers were naive to
exposure could be determined; and, with ongoing development of tools to evaluate human
genetic characteristics, the contribution of genetics could be evaluated. These types of studies
may be especially useful in assessing the effects of air toxics. In addition, information on the
presence of cofactors such as other environmental chemicals, smoking habit, and infectious
respiratory disease would likely be available. Furthermore, specific challenges can be
administered to determine if an individual in whom asthma has been induced is indeed sensitive
to chemicals that are present in the workplace. In similar fashion, the occupational environment
also provides a setting for the evaluation of biomarkers of exposure, effect, or susceptibility that
would be useful for validation of laboratory animal models by providing data to establish the
degree of human homology. If satisfactory risk estimates could be developed under such a
scenario, it could serve as a model for other assessment formulations in places where information
may be less abundant.
Research Agenda Items: Asthma Induction
• Improve exposure information for bioaerosols, pesticides, and toxics in focused
areas of concern (e.g., indoors, occupational, and agricultural settings).
• Develop improved exposure/activity profiles for susceptible populations (e.g.,
children of asthmatic parents).
• Examine induction of asthma in an occupational setting for key chemicals of
ambient interest.
4.3.2. Asthma Exacerbation Associated with Environmental Exposures
Bioaerosols
In order to assess the risk of exacerbation of asthma due to exposure to specific agents, the
prevalence of the sensitivity to this agent must be known. This information is likely to be
location specific (the quantitatively predominant allergens in a specific region are more likely to
be the most significant triggers) or perhaps occupation-specific; whereas, dose-response
relationships are likely to have a high degree of variability. Furthermore, asthma exacerbation by
specific stimuli typically involves both an early phase (0-3 hours) and a late phase (4-10 hours).
The late phase may occur in combination with an early phase, may occur in isolation, or may not
occur to any significant degree. The likelihood of occurrence of an early phase, late phase, or the
combination is poorly understood and complicates the assessment of the risk posed by specific
stimuli. A dose-response assessment for a specific stimulus (e.g., Stachybotrys or platinum salts)
is only valid for people who are responsive to that stimulus. Additionally, certain non-exposure
factors (such as humidity, ventilation systems and their operation) in indoor environments can
contribute to the problems caused by bioaerosols. In light of these complicating factors, tools
need to be developed that can aid in assessing the risk posed by biological agents. Risk
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Asthma Research Strategy
assessment for exacerbation of asthma by biological agents would only be feasible for the most
common allergens causing asthma (e.g., dust mite, cockroaches).
Combustion-Related Products, Pesticides, and Air Toxics
The risk assessment approach for asthma exacerbation will likely be simpler in the case of
the non-specific stimuli CRPs, pesticides, and air toxics as compared to that for specific
bioaerosols. Although the extent of exposure to agents such as SO2 and O3 is well quantified, the
breadth of this information in the temporal and spatial domains is limited. For other chemicals,
limited dose-response information exists, but the range of doses and the variability of sensitivity
among asthmatics to these chemicals is poorly understood. The use of exposure models needs to
be expanded to provide estimates of exposure to chemicals for which less extensive data is
available. Assessments of combined exposures are also needed in order to assess modifications
of dose-response relationships to one chemical by prior, simultaneous, or subsequent exposure to
another. Studies controlling for the influence of exercise and cold air on ventilation rates must
also be conducted to assess the risk of exposure to specific and non-specific agents. Risk
assessment studies for CRPs, pesticides, and air toxics should include the use of activity diaries
to better understand the relative contribution of indoor and outdoor agents.
Another factor that must be taken into account in estimating risk of exacerbation of asthma
for both specific and non-specific stimuli is the severity of the disease. Little information exists
on the variability of response to environmental chemicals across the spectrum of asthma severity.
In some cases, environmental exposures, particularly to specific biologic agents, can be life
threatening. To assess the risk of life threatening responses to environmental chemicals, much
better dose-response information is needed.
Research Agenda Items: Asthma Exacerbation
• Develop risk assessment tools to assess risk of bioaerosols.
• Clarify the relationship of asthma severity to dose-response for asthma exacerbation
by CRPs, Toxics, and Pesticides.
• Collect better data on population exposure and the prevalence of sensitivity.
• Evaluate the risks of mixtures of chemicals using data on exposure to mixtures
(simultaneous or sequential) in well characterized asthmatics and in validated
animal models.
5. Research Prioritization and Timeline
The research topics identified in this strategy are broad in scope. In anticipation of funding
limitations, the following decision-making criteria were used to set research priorities:
Risk-Based Planning: Research that addresses an element of the risk assessment
paradigm and is designed to reduce the greatest uncertainties is
of the highest priority.
Scientific Excellence: The quality of the science selected for support is of critical
importance to both the regulatory application of the resulting
information and the overall credibility of the Agency.
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Programmatic Relevance:
Research Coordination:
Capabilities and
Capacities:
Sequence of Research:
The degree to which a research project addresses a specific
statutory requirement will be an important ranking factor.
It is important to determine whether research that will provide
equivalent or complementary information is underway or
planned elsewhere. A high priority will be given to projects
that leverage resources within or outside the Agency.
The likelihood that research can be implemented within a
reasonable period of time using existing facilities, expertise,
and available resources will be considered when ranking
competing projects. This criterion applies to work conducted
intramurally, as well as in situations where EPA expertise is
needed to oversee the completion of work conducted through a
cooperative agreement, contract, or grant.
The value of some research, regardless of its priority ranking on
other criteria, is dependent upon the completion of other work.
Research that is dependent upon completion of otherwise
equally ranked work will receive a lower priority. Such time
dependency requires that periodic review of progress is made in
order to move to the next stage.
5.1. Prioritization Tables
Since this is a research strategy document rather than a research plan, research areas that
have been outlined in this document, rather than specific research plans, have been prioritized.
This prioritization will be useful in evaluating research proposals written in response to future
RFAs (request for applications). Because EPA's mission differs from that of other public health
agencies, prioritization decisions made here will depend most significantly on two of the listed
criteria: risk-based planning and programmatic relevance. The potential of proposed research to
promote human health also will be a strong determinant of assigned priority.
In Tables 1-4, scores were assigned for each research area (Table 1) and topic (Tables 2-4)
relative to risk-based planning, programmatic relevance, and public health importance. The
scores range from + to +++, signifying a range from lowest to highest importance. The scores
were summed to indicate the overall importance of the research area or topic. These scores do
not indicate quantitative differences among area/topics, but allow discrimination of rank
importance, which is indicated in the last line of each table. These overall rankings informed the
scientific discussions about individual asthma research proposals reviewed by the Asthma
Research Strategy Team and were used in the final decision process to grade these proposals.
The first step was to assess the relative priority of the three research areas discussed in this
document: induction and exacerbation, susceptibility factors, and risk assessment. This
approach is shown in Table 1. The scores range from + to +++ signifying a range from lowest to
highest in terms of importance of each of the three criteria. The scores reflect the need for data in
these research areas and the importance of the risk assessment. Taking these criteria into
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account, the importance of the three research areas is as follows: (1) Induction/Exacerbation,
(2) Susceptibility Factors, and (3) Risk Assessment.
TABLE 1. PRIORITIZATION OF THE RESEARCH AREAS
Criteria
Induction /
Exacerbation
Susceptibility Factors Risk Assessment
Public Health Importance
EPA Mission
Risk-Based Planning
Score
Ranking
Table 2 describes the prioritization process as applied to research topics under the
induction/exacerbation research area. Prioritization ranks the research topics as (1) CRPs,
(2) Bioaerosols, (3) Air Toxics, and (4) Pesticides. CRPs ranked first because of their relevance
to EPA's mission and the need for risk assessment data. Bioaerosols on the other hand scored
high in terms of the public health importance. Both air toxics and pesticides were judged to be of
less importance with respect to asthma-related public health importance.
TABLE 2. INDUCTION / EXACERBATION
Criteria
CRPs
Bioaerosols
Air Toxics
Pesticides
Public Health Importance
EPA Mission
Risk-Based Planning
Score
Ranking
7
1
6
2
5
3
4
4
CRPs = Combustion-Related Products
Table 3 describes the prioritization of research topics under the susceptibility factors
research area as (1) Residence and Exposure history, (2) Genetic Susceptibility, (3) Health
Status, (4) Lifestyle and Activity Patterns, and (5) Socioeconomic Status. Residence and
exposure history ranked highest because of the relatively high programmatic relevance and the
need for data for risk assessment overlaid by the fact that it is an important public health issue.
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TABLE 3. SUSCEPTIBILITY FACTORS
Criteria
Genetic
Susceptibility
Health
Status
Socio-
conomic
Status
Residence/
Exposure
History
Lifestyle/
Activity
Pattern
Public Health Importance
EPA Mission
Risk-Based Planning
Score
Ranking
7
2
6
3
4
5
8
1
5
4
Table 4 describes the prioritization process as applied to research topics induction and
exacerbation of asthma under the risk assessment research area. Because very few pollutants are
thought to be responsible for the induction of asthma, they are not perceived as a critical public
health issue. In contrast, many pollutants are known to exacerbate asthma and, therefore, are a
public health threat. As a result, risk assessment for exacerbation of asthma by environmental
pollutants ranked higher than risk assessment for induction of asthma.
TABLE 4. RISK ASSESSMENT PRIORITIZATION
Criteria
Induction
Exacerbation
Public Health Importance
EPA Mission
Risk-Based Planning
Score
Ranking
6
1
5.2. Timeline of Research Activity
The preceding prioritization tables were used to project the sequence and level of effort
devoted to the research areas and associated topics (Table 5). The numbers in this timeline
indicate the relative level of effort proposed in FY 2001-2009 for each of the research topics
within the research areas, with 1 representing the lowest level of effort and 8 representing the
highest. These levels, and the total level of effort for each research topic and for each fiscal year,
represent arbitrary units. This scale is not intended to be a precise tool for dictating research
activity and distribution of resources, but rather is intended as a general guideline indicating how
available resources can most efficiently advance scientific knowledge and control environmental
factors contributing to asthma prevalence and severity.
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TABLE 5. TIMELINE OF RESEARCH ACTIVITY
CRPs
Bioaerosols
Air Toxics
Pesticides
Induction/Exacerbation
Total
Genetic Susceptibility
Health/Disease Status
Socioeconomic Status
Residence, Exp. History
Lifestyle/ Activity Pattern
Susceptibility
Factors Total
Induction
Exacerbation
Risk Assessment
Total
Total Effort
FY01
3
2
1
6
1
1
2
0
8
FY02
3
8
1
12
o
J
2
2
7
0
19
FY03
7
8
4
1
20
4
2
1
4
11
2
4
6
37
FY04
7
6
4
2
19
3
4
2
5
2
16
3
5
8
43
FY05
5
4
3
3
15
3
4
2
4
3
16
5
6
11
42
FY06
6
4
4
3
17
3
3
2
4
2
14
5
5
10
41
FY07
6
4
3
1
14
2
3
1
4
2
12
4
5
9
35
FY08 FY09
4 2
2
1
7 2
2 2
1
2
1
6 2
3 3
3 3
6 6
19 10
Total
43
38
21
10
112
23
19
8
26
10
86
25
31
56
254
The total level of effort for each research topic is consistent with the ranking of the topics
in the prioritization tables. Similarly, the total effort for each research area is consistent with the
ranking of the areas in Table 1. The level of effort for the research topics in each fiscal year
follows a logical sequence in which an early peak effort on bioaerosols (FY 2002-03) is followed
by maximal efforts in CRPs and air toxics a year later. Research on susceptibility factors
generally peak in FY 2004-05. Since risk assessment research is dependent on data from
research conducted in the first two research areas, the level of effort in this area peaks in FY
2005-06 and extends through FY 2009. These guidelines for research funding should provide a
balanced and equitable sharing of resources and will facilitate an understanding of how
environmental factors contribute to the development and exacerbation of asthma.
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Ind. Med. 21:587-593.
Romagnini, S. (2000) The role of lymphocytes in allergic disease. J. Allergy Clin. Immunol. 105: 399-408.
Rylander, R.; Etzel, R. (1999) Workshop on children's health and indoor mold exposure. Environ. Health Perspect.
107(suppl. 3): 465-468.
Senthilselvan, A.; McDuffie, H. H.; Dosman, J. A. (1992) Association of asthma with use of pesticides. Results of a
cross-sectional survey of farmers. Am. Rev. Respir. Dis. 146: 884-887.
U.S. Environmental Protection Agency. (1996) Paniculate matter research program strategy. Research Triangle
Park, NC: Office of Research and Development; report no. NHEERL-MS-97-019; October. Available at:
www.epa.gov/ORD.resplans.matter.pdf.
29
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Asthma Research Strategy
U. S. Environmental Protection Agency. (1999) Strategy for research on environmental risks to children.
Washington, DC: Office of Research and Development, National Center for Environmental Assessment.
Available at: www.epa.gov/ncea/childab.htm.
Ware, J. H.; Spengler, J. D.; Neas, L. M; Samet, J. M; Wagner, G. R.; Coultas, D.; Ozkaynak, H.; Schwab, M.
(1993) Respiratory and irritant health effects of ambient volatile organic compounds: the Kanawha County
health study. Am. J. Epidemiol. 137: 1287-1301.
30
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Asthma Research Strategy
Appendix A
CAA
CDC/NCEH
CRP
ELISA
EPA
ETS
FY
GIS
HAP
ICAS
IgE
IOM
NAAQS
NCHS
NERL
NHANES
NHEERL
NHLBI
NIAID
NIEHS
NIOSH/NORA
NO2
03
ORD
PM
PM
PM
RFAs
SES
SO2
VOCs
10
2.5
Abbreviations and Acronyms
Clean Air Act
Centers for Disease Control and Prevention's National Center for
Environmental Health
Combustion related product
Enzyme-linked immunosorbent assays
Environmental Protection Agency
Environmental tobacco smoke
Fiscal year
Geographic information system
Hazardous air pollutant
Inner-City Asthma Study
Immunoglobulin E
Institute of Medicine
National Ambient Air Quality Standards
National Center for Health Statistics
National Exposure Research Laboratory
National Health and Nutrition Examination Survey
National Health and Environmental Effects Research Laboratory
National Heart Lung and Blood Institute
National Institute of Allergy and Infectious Diseases
National Institute of Environmental Health Sciences
National Institute for Occupational Safety and Heath"s National Occupational
Research Agenda
Nitrogen dioxide
Ozone
Office of Research and Development
Particulate matter
Particulate matter with an aerodynamic diameter < 10 //m
Particulate matter with an aerodynamic diameter < 2.5 //m
Request for Applications
Socioeconomic status
Sulfur dioxide
Volatile organic compounds
31
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-------
Asthma Research Strategy
Appendix B
U.S. Environmental Protection Agency
Office of Research and Development
Inventory of Asthma Research
Preface to the Appendix
This inventory is a compilation of the asthma research currently funded through intra- and
extramural programs within the U.S. Environmental Protection Agency's (EPA) Office of
Research and Development (ORD). It was prepared by the Asthma Research Strategy
Workgroup and represents the collective efforts of ORD's National Health and Environmental
Effects Research Laboratory (NHEERL), National Exposure Research Laboratory (NERL),
National Risk Management Research Laboratory (NRMRL), National Center for Environmental
Research (NCER), and the National Center for Environmental Assessment (NCEA).
A number of other Federal entities are active in asthma research, including the National
Heart Lung and Blood Institute (NHLBI), the National Institute of Allergy and Infectious
Diseases (NIAID), the National Institute of Environmental Health Sciences (NIEHS), the Agency
for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and
Prevention's National Center for Environmental Health (CDC/NCEH), and the National Center
for Health Statistics (NCHS). These federal efforts have been summarized in the Inventory of
Federal Asthma Activities prepared by the Federal Liaison Group on Asthma. Scientists from the
EPA are already working with some of these organizations to ensure that EPA research
supplements and expands current research efforts into the causes of asthma, asthma triggers, and
effective intervention strategies. Additionally, the EPA is represented on various coordinating
bodies that address the subject of asthma to enhance other Federal efforts by bringing the
expertise and facilities unique to the EPA to previously-initiated asthma research.
This inventory is organized by the source of funding: specific intramural research projects
are presented first, followed by extramural research grants and fellowships funded through the
program Science to Achieve Results (STAR) and, lastly, by other ORD research on ambient air
pollutants that takes into consideration health risks to sensitive subpopulations with asthma.
33
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Asthma Research Strategy
Introduction
Conducting research on asthma is consistent with the mission of the EPA to protect public
health and safeguard the natural environment—air, water, and land—upon which life depends.
The EPA ORD is committed to supporting the principles outlined in the Federal strategy:
(1) eliminating the disproportionate impact of asthma on minorities and the poor; (2) increasing
reliance on community-based programs and partnerships to successfully implement effective
environmental, medical, and educational programs; (3) setting measurable and consistent goals
for childhood asthma as set forth in the Healthy People 2010 program; and (4) identifying
strategies that are effective in reducing asthma so they may be implemented. In addition, the
ORD recognizes the need to address environmentally related aspects of asthma as they apply to
adults.
The following asthma research to be conducted by the ORD focuses on the three primary
areas identified in the Asthma Research Strategy: (1) induction and exacerbation of asthma,
(2) susceptibility factors contributing to asthma induction or exacerbation, and (3) risk
assessment. Specific agents studied will include bioaerosols, pesticides, hazardous air pollutants
and combustion related products. Factors to be evaluated for their influence on susceptibility
include genetic susceptibility, health status, socio-economic status, residence and exposure
history, and lifestyle.
ORD Intramural Asthma Research Program
The three national laboratories (NHEERL, NERL, NRMRL) and the NCEA within the
ORD are undertaking an intramural asthma research program (see Table B-l) to characterize the
role of various environmental factors (e.g., molds and gaseous and particulate pollutants) in
asthma and to better understand the mechanisms of allergic sensitization and asthma
exacerbation. The general hypothesis is that environmental factors influence asthma onset and
exacerbation and that these factors can be controlled. The program will also assess the relative
role these pollutants play in the indoor versus outdoor environments and study the efficacy of
various intervention protocols. Several projects address adult populations as part of
epidemiological studies and in controlled clinical exposure studies. Children are specifically
targeted in various epidemiology studies around the U.S. The ORD is a partner in the Inner City
Asthma Study (ICAS), a multi-center intervention trial among moderate to severe asthmatic
children in seven cities, through an Interagency Agreement with two NIH institutes, the National
Institute of Allergy and Infectious Diseases and the National Institute for Environmental Health
Sciences.
National Center for Environmental Research: Science to Achieve Results Grants Program
The mission of the NCER within the ORD is to stimulate the research community to
provide high quality, innovative ideas and solutions to protect human health and the
environment. The NCER program, Science to Achieve Results (STAR), funds research grants
and fellowships in environmental science and engineering.
In 1998, NCER began a five-year partnership with the National Institute of Environmental
Health Sciences (NIEHS) and the Centers for Disease Control and Prevention (CDC) to sponsor
35
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Asthma Research Strategy
eight Centers for Children's Environmental Health and Disease Prevention Research (see Table
B-2). The centers have undertaken multi-disciplinary basic and applied research in combination
with community-based prevention research. These efforts support studies on the causes and
mechanisms for children's disorders having an environmental etiology, including asthma and
respiratory illnesses. One program investigates how exposures to environmental pollutants and
allergens exacerbate asthma and relate to other lung diseases in children living in the inner city,
while another is studying causes of airway disease in children from rural communities. Research
on effective neighborhood and household interventions to reduce risks of asthma is also an
important focus of the centers' program. In addition to the centers' grants, NCER, in partnership
with NIEHS, is supporting two environmental justice grants to develop effective community-
based environmental interventions to help combat asthma in the urban environment.
Another major priority for the STAR program has been research related to particulate
matter air pollution. Particulate matter (PM) is the general term used for a mixture of solid
particles and liquid droplets found in the air. Particulate matter exists in a wide range of sizes
(from fine to coarse) and originates from many different stationary and mobile sources, as well as
from natural sources. Fine particles can accumulate in the respiratory system and are associated
with numerous health effects including the aggravation of asthma. In recognition of this
potential public health problem, NCER awarded five-year funding to five university-based PM
Research Centers which are undertaking integrated programs of health research (see Table B-3).
Exposure studies are being conducted to better understand and characterize personal exposures to
PM (e.g., size and composition of PM, indoor air versus outdoor air contribution). Controlled
clinical studies in humans and animal toxicology studies will help identify the constituents or
properties of PM that are most responsible for human health effects and help explain how these
effects occur. The research centers also are developing dosimetry models that take into account
the amount of PM deposited into the lungs of exposed individuals. This will help elucidate the
relationship between personal exposure to PM and the health responses of sensitive populations,
such as those with asthma. In addition, epidemiological studies are underway to examine the
health effects of PM exposure in susceptible subpopulations.
In addition, the STAR program has awarded a number of individual grants to investigators
examining environmental influences on asthma (see Table B-4). Examples range from the
relationship between exposure to PM and exacerbation of asthma to effective means of
controlling dust mites, a cause of asthma in susceptible individuals. For more information on the
NCER grants programs, visit the web site: http://es.epa.gov/ncerqa/.
EPA Ambient Air Research
The EPA is funding three research centers to conduct ambient air research on the induction
and exacerbation of asthma in the population (see Table B-5). Specific studies include effects of
PM on childhood asthma and the induction of airway inflammation, mechanisms of
environmental lung diseases, and the effects of air toxics on people with preexisting respiratory
problems including asthma.
The EPA is conducting a risk analysis for PM as part of the National Ambient Air Quality
Standards (NAAQS) review. As part of the total risk assessment, the review includes a look at
hospital admissions for respiratory causes and the risk of asthma symptoms for children exposed
36
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Asthma Research Strategy
to ambient particulate matter. The EPA also anticipates conducting a risk assessment for the
ozone NAAQS review, which will include looking at the increased risk of childhood asthma at
higher ambient ozone levels.
In addition, the EPA is conducting research on sulfur dioxide (SO2), a suspected asthma
trigger. As announced in the Federal Register on January 9, 2001, the EPA plans to propose an
integrated monitoring strategy to revise the minimum requirements for ambient monitoring in
compliance with the SO2 NAAQS. The EPA also intends to issue SO2 monitoring guidelines to
assist state and local air pollution control agencies in evaluating their networks and the
appropriateness of revising such networks to better address the issue of short-term (five minutes)
peaks of SO2 that have been shown to cause breathing difficulty in sensitive people with asthma.
Finally, the EPA is seeking support and participation from the states and industry to develop
plans for collecting additional five-minute air quality monitoring data. This effort is expected to
take about two years including planning, coordination, data collection, and analysis and to
provide important new information on the likelihood and nature of five-minute peak SO2
concentrations that may occur around various types of industrial facilities. The monitoring
information will help inform decisions in the next periodic review of the SO2 NAAQS.
Healthy People 2010 Objectives:
24-2 Hospitalizations for asthma
24-3 Hospital emergency department visits for asthma
24-7 Appropriate asthma care
EPA Contacts:
Mary Smith, OECA/ORE/AED, representative for EPA asthma programs and interagency
committees
Jim Raub, ORD/NCEA/NCEA-RTP, representative for ORD asthma research strategy
and tracking
37
-------
-------
TABLE B-l. ORD INVENTORY OF INTRAMURAL ASTHMA RESEARCH PROJECTS
00
CD
Project Title
1. Develop test methods to access the potential
allergenicity of environmental contaminants
2. Characterization of the allergenicity of Stachybotrys
chartarum and other molds in the indoor
environment and risks to children
3. Influence of environmental factors on allergic
sensitization to dust mite allergy
4. Enhancement of allergic responses in mice by
paniculate matter
5. Interactions of paniculate matter air pollution with
lung sensory nerves
6. Neurophysiology links between sensory irritation
and cardiac function
7. Effect of allergen challenge on surfactant function
and oxygen saturation
8. Use of induced sputum to determine differences in
response of normal and asthmatic subjects
9. Exposure of asthmatics to concentrated ambient
particles (CAPS)
10. Differences in gene expression between cells from
normal and asthmatic subjects
11. Exacerbation of asthma by paniculate matter
12. National Children's Study
OMIS
Task
No.1
126
126
126
131
131
131
131
115
115
115
1434
Status
Active
Active
Active
Active
Pending
postdoc
Active
Active
Active
Active
Active
Active
Pending
start-up
Lab/Center2
NHEERL
NHEERL
NERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
NHEERL
Investigators
Selgrade, MJ
Selgrade, MJ;
Ward, M
Vesper, S
Gilmour, I
Gavett, S
Gavett, S
Costa, D
Wiester, MJ
Devlin, R
Kehrl, H
Devlin, R
Neas, L
Mendola, P
Project Period
1998-2002
1999-2001
1999-2002
X
3
a
So
TO
a
S
s-
2
TO*
^
-------
TABLE B-l (cont'd). ORD INVENTORY OF INTRAMURAL ASTHMA RESEARCH PROJECTS
Project Title
13. Effects of short-term ozone exposure upon asthma
status
14. Long-term ozone exposure and incidence of
asthma in adults
15. Long-term exposure to air pollutants and incidence of
respiratory disease in children
16. Short-term exposure to ozone and rates of
hospitalization
17. A pilot home asthma intervention study in Boston
public housing
18. Characterization of indoor VOC/air toxics
emissions from sources controlled by internal
diffusion
19. Ability to reduce indoor exposure to VOC air
toxics from photocopiers through judicious
selection of toner
20. Development of guidance to reduce the exposure
of children with respiratory problems to airborne
irritants while in school ("Buy Clean")
21. Performance of ozone generators sold as indoor
air cleaners, and the potential role of ozone in
creating air toxics through indoor air chemistry
22. Home design and operation to reduce exposure of
occupants to fine PM infiltrating from outdoors
OMIS
Task
No.1
391
391
391
391
5542
5543
3848
6381
4910
9744
2127
Status
Completed
Completed
Active
Active
Completed
Active
Active
Active
Active
Active
Lab/Center2
NHEERL
NHEERL
NHEERL
NHEERL
NRMRL
NRMRL
NRMRL
NRMRL
NRMRL
NRMRL
Investigators
McDonnell, W
McDonnell, W
McDonnell, W
McDonnell, W
Howard, B
Chang, J
Henschel, DB
Henschel, DB
Mason, M
Mosley, R
Project Period
1999-2002
1999-2002
2000-2002
X
!•
3
a
1998-2003 ^
S
a
3
s-
03
1997-2002 g
J?
00
-------
TABLE B-l (cont'd). ORD INVENTORY OF INTRAMURAL ASTHMA RESEARCH PROJECTS
Project Title
23. Characterization of indoor fine PM emission
sources
24. Impact of home construction, operation, and
furnishings on occupant exposure to gaseous
combustion-related pollutants (CRPs) infiltrating
from outdoors
25. Effectiveness of air cleaners for reducing risk from
indoor pollutants
26. Source characterization and risk management options
to reduce airborne exposure to Stachybotrys chartarum
and other microbiologicals
27. Risk management options for indoor
microbiologicals
28. Development and demonstration of improved
methods for sampling and analysis of fine indoor
bioaerosols, and assessment of the extent to
which indoor bioaerosols infiltrate from outdoors
29. Validation of improved methods for sampling and
analysis of fine indoor bioaerosols for use as a
protocol for the National Children's Study
30. Risk assessment and risk management for indoor
mold
31. Ambient PM exposure and respiratory health in
four Chinese cities
OMIS
Task
No.1
5547
11191
9746
6171
6382
9748
80201
Status
Active
Pending
start-up
Pending
start-up
Active
Pending
start-up
Active
Pending
start-up
Active
Active
Lab/Center2 Investigators
NRMRL Quo, Z
NRMRL Mosley, R
NRMRL Sparks, L
NRMRL Menetrez, M
NRMRL Menetrez, M
NRMRL Menetrez, M
NRMRL Menetrez, M
NERL Vesper, S
NCEA-WA
NHEERL
NRMRL
NCEA-RTP Chapman, R
Project Period
1999-2002
2002-2003
2001-2003
1999-2003
2001-2002
2001-2002
2002-2003
1999-2001
So
1
a-
I
I
-------
TABLE B-l (cont'd). ORD INVENTORY OF INTRAMURAL ASTHMA RESEARCH PROJECTS
Project Title
32. Effect of endogenous nitric oxide production on
ozone exposure dosimetry and response in
asthmatic subjects
OMIS
Task
No.1
Status Lab/Center2 Investigators
Active NCEA-RTP Raub, J
UNC/CEMLB
Project Period
1998-2001
1 ORD Management Information System (OMIS)
2 Key to ORD Laboratories and Centers: NHEERL = National Health and Environmental Effects Research Laboratory; NERL = National
Exposure Research Laboratory; NRMRL = National Risk Management Research Laboratory; NCEA = National Center for Environmental
Assessment.
So
1
a-
I
I
-------
TABLE B-2. EPA/NIEHS CENTERS OF EXCELLENCE IN CHILDREN'S ENVIRONMENTAL HEALTH AND DISEASE
PREVENTION RESEARCH: Asthma Research Projects1
Project Title
EPA
Grant
Status
Center
Investigators/Institutions
Project
Period
1. Asthma in children: a community-based
intervention project
2. Children's susceptibility to air pollution
3. Children's exposure to environmental tobacco
smoke: changes in allergic response
4. Multi-component intervention study of
asthma in children from rural communities
5. Mechanisms that initiate, promote, and
£ resolve grain dust/LPS- induced inflammation
6. Role of RSV infection and endotoxin in
airway inflammation
7. A model to study the development of
persistent environmental airway disease
8. A community-based intervention to reduce
environmental triggers for asthma among
children
9. Indoor and outdoor air contaminant exposures
and asthma aggravation among children
10. Chemokines in the pathogenesis of asthma
R826708
R826708
R826708
R826711
R826711
R826711
R826711
R826710
Active
Active
Active
Active
Active
Active
Active
Active
R826710 Active
R826710 Active
Children's Environmental
Health Center
Children's Environmental
Health Center
Children's Environmental
Health Center
Airway Disease in Children
from Rural Communities
Airway Disease in Children
from Rural Communities
Airway Disease in Children
from Rural Communities
Airway Disease in Children
from Rural Communities
Michigan Center for the
Environment and Children's
Health
Michigan Center for the
Environment and Children's
Health
Michigan Center for the
Environment and Children's
Health
Gong, H; Jones, C; McConnell, R 1998-2002
(University of Southern California)
Gong, H; Jones, C; McConnell, R 1998-2002
(University of Southern California)
Gong, H; Jones, C; McConnell, R 1998-2002
(University of Southern California)
Schwartz, D; Merchant, J 1998-2002
(University of Iowa)
Schwartz, D; Merchant, J 1998-2002
(University of Iowa)
Schwartz, D; Merchant, J 1998-2002
(University of Iowa)
Schwartz, D; Merchant, J 1998-2002
(University of Iowa)
Israel, B; Parker, E 1998-2002
(University of Michigan)
Israel, B; Parker, E 1998-2002
(University of Michigan)
Israel, B; Parker, E 1998-2002
(University of Michigan)
So
1
a-
I
I
-------
TABLE B-2 (cont'd). EPA/NIEHS CENTERS OF EXCELLENCE IN CHILDREN'S ENVIRONMENTAL HEALTH AND
DISEASE PREVENTION RESEARCH: Asthma Research Projects1
Project Title
EPA
Grant
Status
Center
Investigators/Institutions
Project
Period
11. A randomized, controlled trial of home
exposure control in asthma
12. The relationship of airborne pollutants and
allergens to asthma morbidity
13. Mechanisms of particulate-induced allergic
asthma
14. Genetic mechanisms of susceptibility to
inhaled pollutants
15. Community-based intervention: reducing
risks of asthma
16. Research on asthma: prenatal and postnatal
environmental exposure
17. Research project on growth and development
18. The epidemiological investigation of the
effects of pesticide exposure on
neurodevelopment, growth, and respiratory
health of farmworker children
R826724 Active
R826724 Active
R826724 Active
R826724 Active
R827027
R827027
R827027
R826709
Active
Active
Active
Active
The Johns Hopkins University Center
for the Asthmatic Child in the Urban
Environment
The Johns Hopkins University Center
for the Asthmatic Child in the Urban
Environment
The Johns Hopkins University Center
for the Asthmatic Child in the Urban
Environment
The Johns Hopkins University Center
for the Asthmatic Child in the Urban
Environment
Columbia Center for Children's
Environmental Health
Columbia Center for Children's
Environmental Health
Columbia Center for Children's
Environmental Health
Center for Research on the Exposures
and Health of Farm Worker Children
in California
Eggleston, P 1998-2002
(Johns Hopkins University)
Eggleston, P 1998-2002
(Johns Hopkins University)
Eggleston, P 1998-2002
(Johns Hopkins University)
Eggleston, P 1998-2002
(Johns Hopkins University)
Perera, F 1998-2002
(Columbia University)
Perera, F 1998-2002
(Columbia University)
Perera, F 1998-2002
(Columbia University)
Eskenazi, B 1998-2002
(University of California
at Berkeley)
ORD Management Information System (OMIS) No. 4924.
So
1
a-
I
I
-------
-ti.
Ol
TABLE B-3. ORD/NCER PARTICIPATE MATTER RESEARCH CENTERS: Asthma Research Projects1
EPA Project
Project Title Grant Status Center Investigators/Institutions2 Period
1. Asthma exacerbation study: PM enhancement of
the antigen-specific IgE response
2. Allergic inflammation study: adjuvant effects of
PAH and redox-active quinones in PM
3. Airborne PM and quinone study: reaction with
tissue nucleophiles
4. Comprehensive exposure and health effect
assessment in susceptible subpopulations
5. Ultrafine particle: characterization, health effects,
and pathophysiological mechanisms: clinical
studies
6. Ultrafine particle: characterization, health effects,
and pathophysiological mechanisms: in vitro
mechanisms
7. A prospective study of asthma susceptibility to
PM: epidemiologic investigations of key PM
components and biomarkers of effects
8. Ambient particle effects: exposure, susceptibility,
and mechanisms
R827352 Active
R827352 Active
R827352 Active
R827355 Active
Southern California Center
for Airborne Paniculate
Matter
Southern California Center
for Airborne Paniculate
Matter
Southern California Center
for Airborne Paniculate
Matter
Northwest Research Center
for Paniculate Air Pollution
and Health
R827354 Active Rochester PM Center
(U. of Rochester; CIT;
UCR; GSF- NRCEH; RTI;
SUNY at Buffalo; UNM)
R827354 Active Rochester PM Center
R827351 Active
New York University PM
Center
R827353 Active Harvard PM Center
Froines, JR; Colome, SD; Turco, RP 1999-2004
(UCLA, UCI, and UCR; CIT; USC,
RLAMC)
Froines, JR; Colome, SD; Turco, RP 1999-2004
(UCLA, UCI, and UCR; CIT; USC,
RLAMC)
Froines, JR; Colome, SD; Turco, RP 1999-2004
(UCLA, UCI, and UCR; CIT; USC,
RLAMC)
Koenig, JQ; Liu, L-J; Covert, DS; 1999-2004
Claiborn, C
(University of Washington;
Washington State University)
Utell, M; Frampton, M 1999-2004
(University of Rochester)
Finkelstein, J 1999-2004
Thurston, GD; Reibman, J 1999-2004
(New York University)
Koutrakis, P; Godleski, JJ; 1999-2004
Schwartz, J et al.
(Harvard University)
So
1
a-
I
I
1 ORD Management Information System (OMIS) No. 6044
2 Key to Institutions: UCLA = University of California at Los Angeles, UCI = University of California at Irvine, UCR = University of California at Riverside,
CIT = California Institute of Technology, USC = University of Southern California, RLAMC = Rancho Los Amigos Medical Center,GSF-NRCEH =
GSF- National Research Center for Environment and Health (Neuherberg, Germany), RTI = Research Triangle Institute, SUNY = State University of New
York, UNM = University of New Mexico.
-------
TABLE B-4. SCIENCE TO ACHIEVE RESULTS (STAR) GRANTS: Air Pollution Research Projects on Asthma
o>
Project Title
1 . Paniculate air pollution and initiation of
EPA
Grant
R826779
OMIS
Task
No.1
4918
Status
Active
Institutions
Harvard University
Investigators
Kobzik, L; Koutrakis, P;
Project
Period
1998-2001
asthma
2. Mechanisms of age-dependent ozone
induced airway dysfunction
3. School-based study of complex
environmental exposures and related health
effects in children: Part A-exposure
4. Health effects of HAPs among inner urban
school children
5. Human health effects of exposure to
ultrafme particles
6. Airborne paniculate matter-induced lung
inflammation
7.
8.
Effects of inhaled ultrafine particles on
asthma
Ultrafine particles in urban and respiratory
health among children with respiratory
symptoms
9. Factors controlling the dust mite
population in the indoor environment
10. Effect of ammonium bisulfate and carbon
black particles inhaled alone and in
combination on airway reactivity in
sensitized brown Norway rats
1 1 . Acidic PM and daily human mortality in
three U.S. cities
12. Cellular mechanisms of pulmonary
inflammation by environmental particles
R827447 5625 Active Harvard School of Public
Health
R825813 2310 Active University of Minnesota
R826789 4917 Active School of Public Health,
University of Minnesota
R826781 4918 Active University of Rochester
School of Medicine and
Dentistry
R826782 4918 Active University of Texas,
Houston Health Science
Center
R826785 4918 Active Lovelace Respiratory
Research Institute
R825265 1021 Active Harvard University
R825250 1255 Completed Wright State University
11-30-00
R826778 4918 Completed Lovelace Respiratory
4-30-01 Research Institute
R825264 1021 Completed New York University
11-17-00 School of Medicine
R824790 Completed Harvard School of Public
9-30-99 Health
Shore, S; Gonzalez-Flecha, B
Shore, S
1999-2002
Sexton, K; Adgate, J; Greaves, 1998-2001
I; Church, T; Ramachandran, G
Greaves, I; Sexton, K; 1998-2001
Church, T; Adgate, J
Frampton, M; Utell, M; 1998-2001
Oberdorster, G; Marder, V;
Zareba, W
Holian, A; Morandi, MT; 1998-2001
Parsley, E
Bice, DE; Redman, TK; Nikula, 1998-2001
KJ; Barr, EB; Cheng, YS
Schwartz, J 1996-1999
Arlian, LG 1997-2000
Benson, JM; Cheng, Y-S; 1998-2001
Powell, QH; Bice, DE;
Barrett, EG
Thurston, G; Ito, K; Gwynn, 1996-2000
RC; Lall, R; Lippmann, M
Kobzik, L; Shore, S; Godleski, J 1996-1999
So
1
a-
I
I
-------
TABLE B-5. TARGETED RESEARCH CENTERS: Air Pollution Research Projects on Asthma
Project Title
EPA
Grant
OMIS
Task
No.1 Status
Institution
Investigators
Project
Period
1. Acute exposure to paniculate air pollution R824702 2307 Active
and childhood asthma
2. Asthma-related projects: particle-induced R824702 2307 Active
lung inflammation; effects of diesel particles
on development of allergic asthma; role of
SP-A and SP-D; mechanism of NO2 toxicity
3. Effects of urban air toxics in an elderly 2087 Active
population of asthmatics
4. Health effects of environmental pollutants R828112 1235 Active
and mechanism of disease
National Jewish Medical
and Research Center
National Jewish Medical
and Research Center
Mickey Leland National
Urban Air Toxics
Research Center
Health Effects Institute
Mason, R; Rabonovitch, 1998-2002
N; Worthen, S; Gelfand,
E.; White, C.
Mason, R; Rabonovitch, 1998-2002
N; Worthen, S; Gelfand,
E.; White, C.
Campion, R 2001-2004
Greenbaum, D 2000-2005
1 ORD Management Information System (OMIS).
I
X
I
3
a
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September 2002
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