9CnrV
United States Auqust 2007
Agency mental Pr0teCt'0n EPA/600/R-07/093
Integrated Science Assessment
for Oxides of Nitrogen -
Health Criteria
(First External Review Draft)
-------
EPA/600/R-07/093
August 2007
Integrated Science Assessment
for Oxides of Nitrogen - Health Criteria
National Center for Environmental Assessment-RTP Division
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC
-------
DISCLAIMER
This document is a first external review draft being released for review purposes only and
does not constitute U.S. Environmental Protection Agency policy. Mention of trade names or
commercial products does not constitute endorsement or recommendation for use.
PREFACE
Legislative Requirements
Two sections of the Clean Air Act (CAA) govern the establishment and revision of the
national ambient air quality standards (NAAQS). Section 108 (U.S. Code, 2003a) directs the
Administrator to identify and list "air pollutants" that "in his judgment, may reasonably be
anticipated to endanger public health and welfare" and whose "presence in the ambient air results
from numerous or diverse mobile or stationary sources" and to issue air quality criteria for those
that are listed. Air quality criteria are intended to "accurately reflect the latest scientific
knowledge useful in indicating the kind and extent of identifiable effects on public health or
welfare which may be expected from the presence of [a] pollutant in ambient air."
Section 109 (U.S. Code, 2003b) directs the Administrator to propose and promulgate
"primary" and "secondary" NAAQS for pollutants listed under Section 108. Section 109(b)(1)
defines a primary standard as one "the attainment and maintenance of which in the judgment of
the Administrator, based on such criteria and allowing an adequate margin of safety, are requisite
to protect the public health."1 A secondary standard, as defined in Section 109(b)(2), must
"specify a level of air quality the attainment and maintenance of which, in the judgment of the
Administrator, based on such criteria, is required to protect the public welfare from any known
or anticipated adverse effects associated with the presence of [the] pollutant in the ambient air."2
The requirement that primary standards include an adequate margin of safety was
intended to address uncertainties associated with inconclusive scientific and technical
1 The legislative history of Section 109 indicates that a primary standard is to be set at "the maximum permissible
ambient air level ... which will protect the health of any [sensitive] group of the population" and that, for this
purpose, "reference should be made to a representative sample of persons comprising the sensitive group rather
than to a single person in such a group" [U.S. Senate (1970)].
2 Welfare effects as defined in Section 302(h) [U.S. Code, 2005)] include, but are not limited to, "effects on soils,
water, crops, vegetation, man-made materials, animals, wildlife, weather, visibility and climate, damage to and
deterioration of property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being."
li
-------
information available at the time of standard setting. It was also intended to provide a reasonable
degree of protection against hazards that research has not yet identified. See Lead Industries
Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir 1980), cert, denied, 449 U.S. 1042 (1980);
American Petroleum Institute v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert, denied, 455
U.S. 1034 (1982). Both kinds of uncertainties are components of the risk associated with
pollution at levels below those at which human health effects can be said to occur with
reasonable scientific certainty. Thus, in selecting primary standards that include an adequate
margin of safety, the Administrator is seeking not only to prevent pollution levels that have been
demonstrated to be harmful but also to prevent lower pollutant levels that may pose an
unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree.
In selecting a margin of safety, the U.S. Environmental Protection Agency (EPA)
considers such factors as the nature and severity of the health effects involved, the size of
sensitive population(s) at risk, and the kind and degree of the uncertainties that must be
addressed. The selection of any particular approach to providing an adequate margin of safety is
a policy choice left specifically to the Administrator's judgment. See Lead Industries
Association v. EPA, supra, 647 F.2d at 1161-62.
In setting standards that are "requisite" to protect public health and welfare, as provided
in Section 109(b), EPA's task is to establish standards that are neither more nor less stringent
than necessary for these purposes. In so doing, EPA may not consider the costs of implementing
the standards. See generally Whitman v. American Trucking Associations, 531 U.S. 457, 465-
472 and 475-76 (2001).
Section 109(d)(1) requires that "not later than December 31, 1980, and at 5-year intervals
thereafter, the Administrator shall complete a thorough review of the criteria published under
Section 108 and the national ambient air quality standards and shall make such revisions in such
criteria and standards and promulgate such new standards as may be appropriate ...Section
109(d)(2) requires that an independent scientific review committee "shall complete a review of
the criteria ... and the national primary and secondary ambient air quality standards ... and shall
recommend to the Administrator any new standards and revisions of existing criteria and
standards as may be appropriate ..." Since the early 1980s, this independent review function
has been performed by the Clean Air Scientific Advisory Committee (CAS AC) of EPA's
Science Advisory Board.
in
-------
History of Reviews of the Primary NAAQS for NO2
On April 30, 1971, EPA promulgated identical primary and secondary NAAQS for
nitrogen dioxide (NO2), under Section 109 of the Act, set at 0.053 parts per million (ppm),
annual average (Federal Register, 1971). In 1982, EPA published an Air Quality Criteria
Document (AQCD) for Oxides of Nitrogen (Environmental Protection Agency, 1982), which
updated the scientific criteria upon which the initial N02 standards were based. On February 23,
1984, EPA proposed to retain these standards (Federal Register, 1984). After taking into account
public comments, EPA published the final decision to retain these standards on June 19, 1985
(Federal Register, 1985).
On July 22, 1987, EPA announced that it was undertaking plans to revise the 1982
AQCD for Oxides of Nitrogen (Federal Register, 1987). In November 1991, EPA released an
updated draft AQCD for CASAC and public review and comment (Federal Register, 1991). The
draft document provided a comprehensive assessment of the available scientific and technical
information on heath and welfare effects associated with N02 and other oxides of nitrogen.
CASAC reviewed the document at a meeting held on July 1, 1993, and concluded in a closure
letter to the Administrator that the document "provides a scientifically balanced and defensible
summary of current knowledge of the effects of this pollutant and provides an adequate basis for
EPA to make a decision as to the appropriate NAAQS for N02" (Wolff, 1993).
The EPA also prepared a draft Staff Paper that summarized and integrated the key studies
and scientific evidence contained in the revised AQCD and identified the critical elements to be
considered in the review of the N02 NAAQS. The Staff Paper received external review at a
December 12, 1994, CASAC meeting. CASAC comments and recommendations were reviewed
by EPA staff and incorporated into the final draft of the Staff Paper as appropriate. CASAC
reviewed the final draft of the Staff Paper in June 1995 and responded by written closure letter
(Wolff, 1995). In September of 1995, EPA finalized the document entitled, "Review of the
National Ambient Air Quality Standards for Nitrogen Dioxide Assessment of Scientific and
Technical Information" (U.S. Environmental Protection Agency, 1995).
Based on that review, the Administrator announced her proposed decision not to revise
either the primary or the secondary NAAQS for NO2 (Federal Register, 1995). The decision not
to revise the NO2 NAAQS was finalized after careful evaluation of the comments received on the
iv
-------
proposal. The level for both the existing primary and secondary NAAQS for NO2 is 0.053
annual arithmetic average, calculated as the arithmetic mean of the 1-h NO2 concentrations.
-------
Integrated Science Assessment for Oxides of Nitrogen -
Health Criteria
(First External Review Draft)
1. INTRODUCTION 1-1
2. soi rci: to tissue dosi: 2-1
3. HEALTH EFFECT OF N02 EXPOSURE 3-1
4. SUSCEPTIBLE AND VULNERABLE POPULATIONS 4-1
5. FINDINGS AND CONCLUSIONS 5-1
6. REFERENCES 6-1
vi
-------
Table of Contents
Page
List of Tables x
List of Figures xii
Authors, Contributors, and Reviewers xv
U.S. Environmental Protection Agency Project Team xx
U.S. Environmental Protection Agency Science Advisory Board (SAB)
Staff Office Clean Air Scientific Advisory Committee (CASAC) xxiii
Abbreviations and Acronyms xxvi
1. INTRODUCTION 1-1
1.1 DOCUMENT DEVELOPMENT 1-3
1.2 ORGANIZATION OF THE DOCUMENT 1-5
2. SOURCE TO TISSUE DOSE 2-1
2.1 INTRODUCTION 2-1
2.2 ATMOSPHERIC CHEMISTRY 2-2
2.3 MEASUREMENT METHODS AND ASSOCIATED ISSUES 2-6
2.4 AMBIENT CONCENTRATIONS OF N02 AND ASSOCIATED
OXIDIZED NITROGEN SPECIES AND POLICY RELEVANT
BACKGROUND CONCENTRATIONS 2-7
2.4.1 Ambient Concentrations 2-7
2.4.2 Policy Relevant Background Concentrations Of Nitrogen Dioxide 2-9
2.5 EXPOSURE ISSUES 2-12
2.5.1 Personal Exposures 2-12
2.5.2 Ambient Monitors and Personal Exposures 2-15
2.5.3 NO2 as a Component of Mixtures 2-35
2.6 DOSIMETRY OF INHALED NITROGEN OXIDES 2-40
2.7 INDOOR AND PERSONAL EXPOSURE HEALTH STUDIES 2-41
2.7.1 Recent Indoor Studies of Exposures to Nitrogen Oxides and
Heath Outcomes 2-42
2.7.2 Recent Studies of Personal NOx Exposure 2-48
2.7.3 Summary Indoor and Personal Exposure Studies 2-51
3. INTEGRATED HEALTH EFFECTS OF NO; EXPOSURE 3-1
3.1 POTENTIAL MECHANISMS OF INJURY 3-2
3.2 MORBIDITY ASSOCIATED WITH SHORT-TERM N02 EXPOSURE 3-3
3.2.1 Respiratory Effects Associated with Short-Term NO2 Exposure 3-3
3.2 CARDIOVASCULAR EFFECTS ASSOCIATED WITH SHORT-TERM
NO; EXPOSURE 3-62
3.3 MORTALITY WITH SHORT-TERM EXPOSURE TO NO; 3-80
vii
-------
Table of Contents
(cont'd)
Page
3.3.1 Multicity Studies and Meta-Analyses 3-81
3.3.3 Summary of Effects of Short-Term Exposure to NOx on
Mortality 3-97
3.3.4 Integration of Evidence Related to Mortality and Short-Term
Exposure to N02 3-98
3.4 MORBIDITY ASSOCIATED WITH LONG-TERM N02 EXPOSURE 3-99
3.4.1 Respiratory Effects Associated with Long-Term NO2 Exposure 3-99
3.4.2 Cardiovascular Effects Associated with Long-Term N02
Exposure 3-121
3.4.3 Adverse Birth Outcomes Associated with Long-Term N02
Exposure 3-121
3.4.4 Cancer Incidence Associated with Long-Term N02 Exposure 3-126
3.4.5 Summary of Morbidity Effects Associated with Long-Term
Exposure 3-131
3.5 MORTALITY ASSOCIATED WITH LONG-TERM EXPOSURE 3-131
3.5.1 U.S. Studies on the Long-Term Exposure Effects on Mortality 3-131
3.5.2 European Studies on the Long-Term Exposure Effects on
Mortality 3-135
3.5.3 Estimation of Exposure in Long-Term Exposure Mortality
Studies 3-139
3.5.4 Summary of Risk Estimates for Mortality with Long-Term
Exposure 3-141
3.6 STUDIES OF NO, HONO, AND HNO3 3-143
4. SUSCEPTIBLE AND VULNERABLE POPULATIONS 4-1
4.1 INTRODUCTION 4-1
4.1.1 Preexisting Disease as a Potential Risk Factor 4-1
4.1.2 Age-Related Variations in Susceptibility/Vulnerability 4-3
4.1.3 High-Exposure Groups 4-6
4.1.4 Genetic Factors for Oxidant and Inflammatory Damage from
Air Pollutants 4-8
4.1.5 Vulnerability Related to Socioeconomic Status 4-10
4.2 PUBLIC HEALTH IMPACTS 4-11
4.2.1 Concepts Related to Defining of Adverse Health Effects 4-11
4.2.2 Estimation of Potential Numbers of Persons in At-Risk
Susceptible Population Groups in the United States 4-12
5. FINDINGS AND CONCLUSIONS 5-1
5.1 INTRODUCTION 5-1
5.2 ATMOSPHERIC SCIENCES 5-2
viii
-------
Table of Contents
(cont'd)
Page
5.3 EXPOSURE ASSESSMENT 5-3
5.4 NO; EXPOSURE INDICES 5-5
5.5 HEALTH EFFECTS 5-6
5.5.1 The 1993 AQCD Findings 5-6
5.5.2 New Findings 5-6
5.6 CONCLUSIONS 5-14
6. REFERENCES 6-1
IX
-------
List of Tables
Number Page
2.5-1. Spatial Variability of NO2 in Selected United States Urban Areas 2-52
2.5-2. N02 Concentrations Near Indoor Sources: Short-Term Averages 2-53
2.5-3. NO2 Concentrations Near Indoor Sources: Long-Term Averages 2-54
2.5-4A. The Association Between Personal Exposures and Ambient Concentrations 2-55
2.5-4B. The Association Between Personal Exposures and outdoor Concentrations 2-57
2.5-5. Summary of Regression Models of Personal Exposure to Ambient/
Outdoor NO2 2-60
2.5-6. Indoor/Outdoor Ratio and the Indoor vs. Outdoor Regression Slope 2-63
2.5-7. Correlations (Pearson Correlation Coefficient) Between Ambient NO2 and
Ambient Copollutants 2-65
2.5-8. Pearson Correlation Coefficients between NOx and Traffic-generated
Pollutants 2-66
2.5-9. Correlations (Pearson Correlation Coefficient) Between Ambient NO2
and Personal Copollutants 2-66
2.5-10. Correlations (Pearson Correlation Coefficient) Between Personal NO2
and Ambient Copollutants 2-66
2.5-11. Correlations (Pearson Correlation Coefficient) Between Personal NO2
and Personal Copollutants 2-67
3.2-1. Proposed Mechanisms Whereby NO2 and Respiratory Virus Infections May
Exacerbate Upper and Lower Airway Symptoms 3-150
3.2-2. MultiCity Studies for Respiratory Disease Outcomes and Incremental Changes
in N02 3-151
3.2-3. Effects of Including Copollutants with NO2 in Multipollutant Models 3-152
3.4-1. Associations Between Exposure to Traffic at Home and Asthma History 3-155
3.4-2. Associations Between Measured NO2 and Asthma-Related Outcomes 3-155
4.1. NO2 Exposure Affects Asthmatics 4-14
4.1-1. Effect of Nitrogen Dioxide (20 ppb) on the Risk of Reporting Respiratory
Symptoms and Bronchodilator Use on a Given Day According to GSTM1
or GSTP1 Genotypes Among 151 Asthmatic Children in Mexico City 4-16
4.1-2. Gradation of Individual Responses to Short-Term NO2 Exposure in
Healthy Persons 4-17
x
-------
List of Tables
(cont'd)
Number Page
4.1-3. Gradation of Individual Responses to Short-Term N02 Exposure in Persons
with Impaired Respiratory Systems 4-18
5.5-1. Key Human Health Effects of Exposure to Nitrogen Dioxide—
Clinical Studies 5-16
5.5-2. Summary of Toxicological Effects from NO2 Exposure (LOEL based
on category) 5-17
5.5-3a. Effects of Short-Term NO2 Exposure on Respiratory Outcomes in
the UNITED STATES and Canada 5-18
5.5-3b. Effects of Short-Term NO2 Exposure on Emergency Department
Visits and Hospital Admissions for Respiratory Outcomes in the United States
and Canada 5-22
5.5-3c. Effects of Long-Term NO2 Exposure on Respiratory Outcomes in the United
States and Canada 5-27
XI
-------
List of Figures
Number Page
2.2-1. Schematic diagram of the cycle of reactive nitrogen species in the atmosphere 2-3
2.4-1. Ambient concentrations of NO2 measured at all monitoring sites located within
Metropolitan Statistical Areas in the United States from 2003 through 2005 2-8
2.4-2. Annual mean concentrations of NO2 (ppbv) in surface air over the United States
in the present-day (upper panel) and policy relevant background (middle panel)
MOZART-2 simulations 2-11
2.5-1. Percentage of time people spend in different environments in the United States 2-13
2.5-2. NO2 concentrations measured at 4 m (Van) and at 15 m at NY Department of
Environmental Conservation sites (DEC709406 and DEC709407) 2-20
2.5-3. Distribution of correlation coefficients between personal NO2 exposure
and ambient N02 concentrations, and between personal N02 exposure and
outdoor NO2 concentrations in urban areas 2-26
2.5-4a-d. Correlations of N02 to 03 versus correlations of N02 to CO for Los Angeles,
CA (2001-2005) 2-37
2.5-5. Composite, diurnal variability in 1-h average N02 in urban areas 2-39
2.7-1. Geometric mean symptom rates and 95% confidence intervals for cough
with phlegm during the winter heating period for 388 children grouped
according to estimated amount of NO2 exposure at home and at school 2-45
2.7-2. Proportions (and 95% confidence intervals) of children absent from school
for at least 1 day during the winter heating period grouped according to
estimated amount of NO2 exposure at home and at school (n = 388) 2-46
2.7-3. Data taken from Table 3 in van Strien et al. (2004) 2-47
2.7-4. Mean change in respiratory-tract symptom scores and PEF rates after viral
infection for children in medium and high NO2 exposure tertiles compared
with children in the low exposure tertile 2-49
2.7-5. Mean symptom rates per week (difficulty breathing during the day and night,
and chest tightness at night) plotted against mean maximum nitrogen dioxide
levels (composite of school and home exposure) groups as <20 ppb (n = 12),
20-39 ppb (n = 51), 40-50 ppb (n = 25), 60-79 ppb (n = 18), and 80+ ppb
(n = 68) 2-50
3.2-1. Effect estimates with 95% confidence intervals calculated for both
uncorrected (0) and corrected (~) PEF: change in 5-day mean = lag 0 to
lag 4 days 3-17
xii
-------
List of Figures
(cont'd)
Number Page
3.2-2. Effect estimates with 95% confidence intervals for subjects with both
reported wheezing and a positive skin test only, calculating for both
uncorrected (0) and corrected (~) PEF: change in 5-day man: lag 0 to
lag 4 days 3-18
3.2-3. Results for single- and two-pollutant models: Childhood Asthma Management
Program, November 1993-September 1995 3-24
3.2-4. Results for single- and two-pollutant models: Childhood Asthma Management
Program, November 1993-September 1995 3-25
3.2-5. Odds ratios (95% CI) for associations between cough and 24-h average NO2
concentrations (per 20 ppb) 3-28
3.2-6. Odds ratios (95% CI) for associations between asthma symptoms and 24-h
average NO2 concentrations (per 20 ppb) 3-29
3.2-7. Odds ratios and 95% confidence intervals for associations between asthma
symptoms and 24-h average N02 concentrations (per 20 ppb) from
multipollutant models 3-30
3.2-8 Relative risks (95% CI) for hospital admissions and ED visits for all
respiratory causes with 24-h NO2 concentrations (per 20 ppb) 3-46
3.2-9. Relative Risks (95% CI) for ED visits for asthma per 30-ppb
increase in 1-h peak NO2 3-52
3.2-10. Relative Risk (95% CI) in ED visits for asthma per 20-ppb
increase in 24-h average NO2 3-53
3.2-11. Dose response presentation of data from three studies for asthma ED visits:
(a) Relative risk for an ED visit for asthma in Cincinnati and Cleveland,
OH by quintile of N02. (b) A monotonic increase in Valencia, Spain.
(c) Increased risk in Barcelona, Spain, but no consistent linear trend evident 3-54
3.2-12. Relative risks and 95% confidence intervals for associations between ED
visits and hospital admissions for respiratory diseases and 24-h average NO2
concentrations (per 20 ppb) 3-59
3.2-13. Relative risks (95% CI) for associations between 24-h NO2 exposure
(per 20 ppb) and hospitalizations or emergency department visits for
all cardiovascular diseases (CVD) 3-63
3.2-14. Relative risks (95% CI) for associations between 24-h N02 exposure
(per 20 ppb) and hospitalizations for Ischemic Heart Disease (IHD) 3-66
3.2-15. Relative risks (95% CI) for associations between 24-h N02 exposure
(per 20 ppb) and hospitalizations for myocardial infarction (MI) 3-68
Xlll
-------
List of Figures
(cont'd)
Number Page
3.2-16. Relative risks (95% CI) for associations between 24-h N02 exposure
(per 20 ppb) and hospitalizations for congestive heart failure (CHF) 3-69
3.2-17. Relative risks (95% CI) for associations between 24-h N02 exposure
(per 20 ppb) and hospitalizations for cerebrovascular disease 3-71
3.3-1. Posterior means and 95% posterior intervals of national average estimates
for NO2 effects on total mortality from nonexternal causes at lags 0, 1, and
2 within sets of the 90 cities with pollutant data available 3-82
3.3-2. Shape of the association of total mortality with NO2 over 6 days
(lags 0 through 5) summarized over all cities using a cubic polynomial
distributed lag model 3-86
3.3-3. Combined N02 mortality risk estimates from multicity and meta-analysis
studies. Risk estimates are computed per 20-ppb increase for 24-h average
or 30-ppb increase for 1-h daily maximum NO2 concentrations 3-93
3.4-1. Proportion of 18-year olds with a FEVi below 80% of the predicted value
plotted against the average levels of pollutants from 1994 through 2000 in
the 12 southern California communities of the Children's Health Study 3-101
3.4-2. Effect of individual pollutants on the association of lung function
with asthma 3-112
3.4-3. Odds ratios for within-community bronchitis symptoms associations with
NO2, adjusted for other pollutants in two-pollutant models 3-115
3.4-4. Age-adjusted, nonparametric smoothed relationship between N02 and
mortality from all causes in Oslo, Norway, 1992 through 1995 3-138
3.4-5. Total mortality risk estimates from long-term studies 3-141
xiv
-------
Authors, Contributors, and Reviewers
Authors
Dr. Dennis J. Kotchmar (NOx Team Leader)—National Center for Environmental Assessment
(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Mary Ross (Branch Chief)—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Kathleen Belanger, Yale University, Epidemiology and Public Health, 60 College Street,
New Haven, CT 06510-3210
Dr. James S. Brown—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Douglas Bryant—Cantox Environmental Inc., 1900 Minnesota Court, Mississauga, Ontario
L8S 1P5
Dr. Ila Cote—National Center for Environmental Assessment (B243-01), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Mark Frampton—Strong Memorial Hospital, 601 Elmwood Ave., Box 692, Rochester, NY
14642-8692
Dr. Janneane Gent—Yale University, CPPEE, One Church Street, 6th Floor, New Haven, CT
06510
Dr. Vic Hasselblad—Duke University, 29 Autumn Woods Drive, Durham, NC 27713
Dr. Kazuhiko Ito—New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY
10987
Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Ellen Kirrane—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Thomas Luben—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Andrew Maier—Toxicology Excellence for Risk Assessment, 2300 Montana Avenue,
Suite 409, Cincinnati, OH 45211
August 2007
xv
DRAFT-DO NOT QUOTE OR CITE
-------
Authors, Contributors, and Reviewers
(cont'd)
Authors
(cont'd)
Dr. Qingyu Meng—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Lori White—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Contributors
Dr. Dale Allen, University of Maryland, College Park, MD
Dr. Jeffrey Arnold—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Ms. Louise Camalier, U.S. EPA, OAQPS, Research Triangle Park, NC
Dr. Russell Dickerson, University of Maryland, College Park, MD
Dr. Tina Fan, EOHSI/UMDNJ, Piscataway, NJ
Dr. Arlene Fiore, NOAA/GFDL, Princeton, NJ
Dr. Panos Georgopoulos, EOHSI/UMDNJ, Piscataway, NJ
Dr. Larry Horowitz, NOAA/GFDL, Princeton, NJ
Dr. William Keene, University of Virginia, Charlottesville, VA
Dr. Randall Martin, Dalhousie University, Halifax, Nova Scotia
August 2007
xvi
DRAFT-DO NOT QUOTE OR CITE
-------
Authors, Contributors, and Reviewers
(cont'd)
Contributors
(cont'd)
Dr. Maria Morandi, University of Texas, Houston, TX
Dr. William Munger, Harvard University, Cambridge, MA
Mr. Charles Piety, University of Maryland, College Park, MD
Dr. Sandy Sillman, University of Michigan, Ann Arbor, MI
Dr. Helen Suh, Harvard University, Boston, MA
Ms. Debra Walsh—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Charles Wechsler, EOHSI/UMDNJ, Piscataway, NJ
Dr. Clifford Weisel, EOHSI/UMDNJ, Piscataway, NJ
Dr. Jim Zhang, EOHSI/UMDNJ, Piscataway, NJ
Reviewers
Dr. Tina Bahadori—American Chemistry Council, 1300 Wilson Boulevard, Arlington, VA
22209
Dr. Tim Benner—Office of Science Policy, Office of Research and Development, Washington,
DC 20004
Dr. Daniel Costa—National Program Director for Air, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Robert Devlin—National Health and Environmental Effects Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency, Chapel Hill, NC
Dr. Judy Graham—American Chemistry Council, LRI, 1300 Wilson Boulevard, Arlington, VA
22209
Dr. Stephen Graham—Office of Air and Radiation, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
August 2007
xvii
DRAFT-DO NOT QUOTE OR CITE
-------
Authors, Contributors, and Reviewers
(cont'd)
Reviewers
(cont'd)
Ms. Beth Hassett-Sipple—U.S. Environmental Protection Agency (C504-06), Research Triangle
Park, NC 27711
Dr. Gary Hatch—National Health and Environmental Effects Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
27711
Dr. Scott Jenkins—Office of Air Quality Planning and Standards, U.S. Environmental Protection
Agency (C504-02), Research Triangle Park, NC 27711
Dr. David Kryak—National Exposure Research Laboratory, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. John Langstaff—U.S. Environmental Protection Agency (C504-06), Research Triangle Park,
NC 27711
Dr. Morton Lippmann—NYU School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987
Dr. Thomas Long—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Karen Martin—Office of Air and Radiation, U.S. Environmental Protection Agency
(C504-06), Research Triangle Park, NC 27711
Dr. William McDonnell—William F. McDonnell Consulting, 1207 Hillview Road, Chapel Hill,
NC 27514
Dr. Dave McKee—Office of Air and Radiation/Office of Air Quality Planning and Standards,
U.S. Environmental Protection Agency (C504-06), Research Triangle Park, NC 27711
Dr. Lucas Neas—National Health and Environmental Effects Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency, Chapel Hill, NC 27711
Dr. Russell Owen—National Health and Environmental Effects Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
27711
Dr. Haluk Ozkaynak—National Exposure Research Laboratory, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
August 2007
xviii
DRAFT-DO NOT QUOTE OR CITE
-------
Authors, Contributors, and Reviewers
(cont'd)
Reviewers
(cont'd)
Dr. Jennifer Peel—Colorado State University, 1681 Campus Delivery, Fort Collins, CO 80523-
1681
Mr. Harvey Richmond—Office of Air Quality Planning and Standards/Health and
Environmental Impacts Division, U.S. Environmental Protection Agency (C504-06), Research
Triangle Park, NC 27711
Mr. Joseph Somers—Office of Transportation and Air Quality, U.S. Environmental Protection
Agency, 2000 Traverwood Boulevard, Ann Arbor, MI 48105
Ms. Susan Stone—U.S. Environmental Protection Agency (C504-06), Research Triangle Park,
NC 27711
Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
27711
Dr. Alan Vette—National Exposure Research Laboratory, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. Ron Williams—National Exposure Research Laboratory, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. William Wilson—Office of Research and Development, National Center for Environmental
Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC
27711
August 2007
xix
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency Project Team
for Development of Integrated Scientific Assessment
for Oxides of Nitrogen
Executive Direction
Dr. Ila Cote (Acting Director)—National Center for Environmental Assessment-RTP Division,
(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Scientific Staff
Dr. Dennis Kotchmar (NOx Team Leader)—National Center for Environmental Assessment
(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Jeff Arnold—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. James S. Brown—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Ellen Kirrane—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Tom Long—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Thomas Luben—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Quingyu Meng—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Mary Ross—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
August 2007
xx
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency Project Team
for Development of Integrated Scientific Assessment
for Oxides of Nitrogen
(cont'd)
Scientific Staff
(cont'd)
Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Lori White—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. William Wilson—National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Technical Support Staff
Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment
(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Ms. Christine Searles—Management Analyst, National Center for Environmental Assessment
(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Ms. Debra Walsh—Program Analyst, National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Document Production Staff
Ms. Barbra H. Schwartz—Task Order Manager, Computer Sciences Corporation,
2803 Slater Road, Suite 220, Morrisville, NC 27560
Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland,
11820 Parklawn Drive, Suite 400, Rockville, MD 20852
Mrs. Melissa Cesar—Publication/Graphics Specialist, Computer Sciences Corporation,
2803 Slater Road, Suite 220, Morrisville, NC 27560
August 2007
xxi
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency Project Team
for Development of Integrated Scientific Assessment
for Oxides of Nitrogen
(cont'd)
Document Production Staff
(cont'd)
Mrs. Rebecca Early—Publication/Graphics Specialist, TekSystems, 1201 Edwards Mill Road,
Suite 201, Raleigh, NC 27607
Mr. Eric Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive, Suite
1450, McLean, VA 22102
Ms. Stephanie Harper—Publication/Graphics Specialist, TekSystems, 1201 Edwards Mill Road,
Suite 201, Raleigh, NC 27607
Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland,
11820 Parklawn Drive, Suite 400, Rockville, MD 20852
Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road,
Suite 220, Morrisville, NC 27560
Ms. Molly Windsor—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road,
Suite 220, Morrisville, NC 27560
August 2007
XXll
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency
Science Advisory Board (SAB)
Staff Office Clean Air Scientific Advisory Committee (CASAC)
CASAC NOx and SOx Primary NAAQS Review Panel
Chair
Dr. Rogene Henderson*, Scientist Emeritus, Lovelace Respiratory Research Institute,
Albuquerque, NM
Members
Mr. Ed Avol, Professor, Preventive Medicine, Keck School of Medicine, University of Southern
California, Los Angeles, CA
Dr. John R. Balmes, Professor, Department of Medicine, Division of Occupational and
Environmental Medicine, University of California, San Francisco, CA
Dr. Ellis Cowling*, University Distinguished Professor At-Large, North Carolina State
University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina
State University, Raleigh, NC
Dr. James D. Crapo [M.D.]*, Professor, Department of Medicine, National Jewish Medical and
Research Center, Denver, CO
Dr. Douglas Crawford-Brown*, Director, Carolina Environmental Program; Professor,
Environmental Sciences and Engineering; and Professor, Public Policy, Department of
Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel
Hill, NC
Dr. Terry Gordon, Professor, Environmental Medicine, NYU School of Medicine, Tuxedo, NY
Dr. Dale Hattis, Research Professor, Center for Technology, Environment, and Development,
George Perkins Marsh Institute, Clark University, Worcester, MA
Dr. Patrick Kinney, Associate Professor, Department of Environmental Health Sciences,
Mailman School of Public Health, Columbia University, New York, NY
Dr. Steven Kleeberger, Professor, Laboratory Chief, Laboratory of Respiratory Biology,
NIH/NIEHS, Research Triangle Park, NC
Dr Timothy Larson, Professor, Department of Civil and Environmental Engineering, University
of Washington, Seattle, WA
August 2007
xxm
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency
Science Advisory Board (SAB)
Staff Office Clean Air Scientific Advisory Committee (CASAC)
CASAC NOx and SOx Primary NAAQS Review Panel
(cont'd)
Members
(cont'd)
Dr. Kent Pinkerton, Professor, Regents of the University of California, Center for Health and
the Environment, University of California, Davis, CA
Mr. Richard L. Poirot*, Environmental Analyst, Air Pollution Control Division, Department of
Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT
Dr. Edward Postlethwait, Professor and Chair, Department of Environmental Health Sciences,
School of Public Health, University of Alabama at Birmingham, Birmingham, AL
Dr. Armistead (Ted) Russell*, Georgia Power Distinguished Professor of Environmental
Engineering, Environmental Engineering Group, School of Civil and Environmental
Engineering, Georgia Institute of Technology, Atlanta, GA
Dr. Richard Schlesinger, Associate Dean, Department of Biology, Dyson College, Pace
University, New York, NY
Dr. Christian Seigneur, Vice President, Atmospheric and Environmental Research, Inc., San
Ramon, CA
Dr. Elizabeth A. (Lianne) Sheppard, Research Professor, Biostatistics and Environmental &
Occupational Health Sciences, Public Health and Community Medicine, University of
Washington, Seattle, WA
Dr. Frank Speizer [M.D.]*, Edward Kass Professor of Medicine, Channing Laboratory,
Harvard Medical School, Boston, MA
Dr. George Thurston, Associate Professor, Environmental Medicine, NYU School of Medicine,
New York University, Tuxedo, NY
Dr. James Ultman, Professor, Chemical Engineering, Bioengineering Program, Pennsylvania
State University, University Park, PA
Dr. Ronald Wyzga, Technical Executive, Air Quality Health and Risk, Electric Power Research
Institute, P.O. Box 10412, Palo Alto, CA
August 2007
xxiv
DRAFT-DO NOT QUOTE OR CITE
-------
U.S. Environmental Protection Agency
Science Advisory Board (SAB)
Staff Office Clean Air Scientific Advisory Committee (CASAC)
CASAC NOx and SOx Primary NAAQS Review Panel
(cont'd)
SCIENCE ADVISORY BOARD STAFF
Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W.,
Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov)
(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff
Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington,
DC 20004, Telephone: 202-343-9994)
* Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA
Administrator
August 2007
xxv
DRAFT-DO NOT QUOTE OR CITE
-------
Abbreviations and Acronyms
a
ACP
ACS
ADP
AgNOR
A IRC
AIRE
AM
AMT
APHEA
AQCD
AsNaC>2
ATS
BAL
BC
BHPN
BHR
BMI
BP
Br
BrdU
BRFSS
Cx T
CAA
CAMP
CAPs
CASAC
CC10
CC16
CD4
CD8
CDC
cGMP
CH4
CHD
CHF
CHS
CI
August 2007
alpha
accumulation mode particle
American Cancer Society
adenosine dinucleotide phosphate
argyrophilic nucleolar organizer region
Atherosclerosis Risk in Communities (study)
Acute Infarction Ramipril Efficacy (study)
alveolar macrophage
average medial thickness
Air Pollution on Health: a European Approach (study)
Air Quality Criteria Document
sodium dioxoarsenate
American Thoracic Society
bronchoalveolar lavage
black carbon
A-bis(2-hydroxyl-propyl )nitrosamine
bronchial hyperresponsivity
body mass index
blood pressure
bromine
bromodeoxyuridine
Behavioral Risk Factor Surveillance System
concentration x time; concentration times duration of exposure
Clean Air Act
Childhood Asthma Management Program
concentrated ambient particles
Clean Air Scientific Advisory Committee
Clara cell 10-kDa protein
Clara cell 16-kDa protein
helper T lymphocyte
suppressor T lymphocyte
Centers for Disease Control and Prevention
cyclic guanosine-3',5'-monophosphate
methane
coronary heart disease
congestive heart failure
Children's Health Study
confidence interval
xxvi DRAFT-DO NOT QUOTE OR CITE
-------
CMAQ
CO
CoH
C02
COD
COPD
CVD
A
DEP
DEPcCBP
DLCO
DMA
DMN
DNA
EC
ED
ECG
ECP
ELF
EMECAM
EPA
ER
ETS
EXPOLIS
FEF25-75
FEF75
FEVi
FRM
FVC
GAM
GEE
GIS
GLMM
GM-CSF
GSH
GSSG
GST
H+
HCHO
HF
August 2007
Community Multiscale Air Quality (model)
carbon monoxide
coefficient of haze
carbon dioxide
coefficient of divergence
chronic obstructive pulmonary disease
cardiovascular disease
delta; change in a variable
diesel exhaust particulates
diesel exhaust particulates extract-coated carbon black particles
diffusing capacity of the lung for carbon monoxide
dimethylamine
dimethylnitrosamine
deoxyribonucleic acid
elemental carbon
emergency department
el ectrocardi ography; el ectrocardi ogram
eosinophil cationic protein
epithelial lining fluid
Spanish Multicentre Study on Air Pollution and Mortality
U.S. Environmental Protection Agency
emergency room
environmental tobacco smoke
Air Pollution Exposure Distributions of Adult Urban Populations in
Europe
forced expiratory flow at 25 to 75% of vital capacity
forced expiratory flow at 75% of vital capacity
forced expiratory volume in 1 second
Federal Reference Method
forced vital capacity
Generalized Additive Model(s)
Generalized Estimating Equation(s)
Geographic Information System
Generalized Linear Mixed Model(s)
granulocyte-macrophage colony stimulating factor
glutathione; reduced glutathione
oxidized glutathione
glutathione ^-transferase (e.g., GST Ml, GST PI, GST Tl)
hydrogen ion
formaldehyde
high frequency
xxvii DRAFT-DO NOT QUOTE OR CITE
-------
HNO3 nitric acid
HNO4 pernitric acid
HONO nitrous acid
H2O2 hydrogen peroxide
HR heart rate
HRV heart rate variability
HS hemorrhagic stroke
H2SO4 sulfuric acid
hv solar ultraviolet proton
ICAM-1 intercellular adhesion molecule-1
ICD, ICD9 International Classification of Diseases, Ninth Revision
ICDs implanted cardioverter defibrillators
Ig immunoglobulin (e.g., IgA, IgE, IgG)
IHD ischemic heart disease
IL interleukin (e.g., IL-6, IL-8)
iNOS inducible nitric oxide synthase
IQR interquartile range
IS ischemic stroke
ISA Integrated Science Assessment
ISAAC International Study of Asthma and Allergies in Children
KI potassium iodide
LDH lactate dehydrogenase
LF low frequency
LOESS, LOWESS locally weighted least squares
LT leukotriene (e.g., LTB4, LTC4, LTD4, LTE4)
MI myocardial infarction
MMEF maximal midexpiratory flow
MoOx molybdenum oxide
mRNA messenger ribonucleic acid
MSA metropolitan statistical area
MV motor vehicle emissions
N, n number of observations
NAAQS National Ambient Air Quality Standards
NADPH reduced nicotinamide adenine dinucleotide phosphate
NAL nasal lavage
NAS Normative Aging Study
NCEA-RTP National Center for Environmental Assessment in Research Triangle
Park, NC
NCo.01-0.10 particle number concentration for particle diameter between 10 and
100 nm
NCICAS National Cooperative Inner-City Asthma Study
August 2007
xxviii
DRAFT-DO NOT QUOTE OR CITE
-------
NDMA
A-nitrosodi methyl amine
NK
natural killer (lymphocytes)
NLCS
the Netherlands Cohort Study on Diet and Cancer
NMMAPS
National Morbidity, Mortality, and Air Pollution Study
NMOR
A-nitrosomorpholine
NO
nitric oxide
no2
nitrogen dioxide
no3
nitrate radical
no3
nitrate
NOx
oxides of nitrogen
NOy
sum of NOx and NOz
NOz
oxides of nitrogen and nitrates (difference between NOx and NOy)
n2o5
dinitrogen pentoxide
N/R
not reported
NRC
National Research Council
NSA
nitrosating agent
03
ozone
oc
organic carbon
OH
hydroxyl radical
OR
odds ratio
P,P
probability value
PAARC
French air pollution and chronic respiratory diseases study
PAF
paroxysmal atrial fibrillation
PAH
polycyclic aromatic hydrocarbon
PAN
peroxyacyl nitrate; peroxyacetyl nitrate
Pb
lead
PC
principal components
PCR
polymerase chain reaction
PD20
provocative dose that produces a 20% decrease in FEVi
PD100
provocative dose that produces a 100% increase in sRAW
PEACE
Pollution Effects on Asthmatic Children in Europe (study)
PEF
peak expiratory flow
PEFR
peak expiratory flow rate
PM
particulate matter
PM10
combination of coarse and fine particulate matter
PMio-2.5
coarse particulate matter
PM25
fine particulate matter
PMA
phorbol myri state acetate
PMN
polymorphonuclear leukocytes
ppb
parts per billion
August 2007 xxix DRAFT-DO NOT QUOTE OR CITE
-------
ppm parts per million
PS penalized splines
R intraclass correlation coefficient; proprietary statistical package
r correlation coefficient
rp Pearson's correlation coefficient
rs Spearman's rank correlation coefficient
R2 multiple correlation coefficient
RCS Robust Component Selection (regression model)
r-MSSD square root of the mean of the squared difference between adjacent
normal R-R intervals
ROS reactive oxygen species
RR rate ratio; relative risk
RSV respiratory syncytial virus
SAPALDIA Study of Air Pollution and Lung Diseases in Adults
SCE sister chromatid exchange
SD standard deviation
SDNN standard deviation of normal R-R intervals
SE standard error
SGA small for gestational age
SNPs single nucleotide polymorphisms
S02 sulfur dioxide
SO42" sulfate
S-PLUS general purpose statistics package
sRAW specific airway resistance
STN Speciation Trends Network
TEA triethanol amine
Th2 T-derived helper 2 lymphocyte
TNF tumor necrosis factor (e.g., TNF-a)
TSP total suspended particulates
TWA time-weighted average
TX thromboxane (e.g., TXA2, TXB2)
UFP ultrafine particles; <0.1 |im diameter
VESTA Five (V) Epidemiological Studies on Transport and Asthma
VOCs volatile organic compounds
WHI Women's Health Initiative
WHO World Health Organization
August 2007
XXX
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1. INTRODUCTION
This draft Integrated Science Assessment (ISA) presents a concise synthesis and
evaluation of the most policy-relevant science. It forms the scientific foundation for the review
of the primary (health-based) National Ambient Air Quality Standards (NAAQS) for nitrogen
dioxide (NO2).1 The draft ISA is intended to "accurately reflect the latest scientific knowledge
useful in indicating the kind and extent of identifiable effects on public health which may be
expected from the presence of [a] pollutant in ambient air" (Clean Air Act, Section 108
(42 U.S.C. 7408)).2 Scientific research is incorporated from: atmospheric sciences, air quality
analyses, exposure assessment, dosimetry, controlled human exposure studies, toxicology, and
epidemiology. This document focuses on the gaseous oxides of nitrogen. The draft ISA
contains the key information and judgments formerly found in the Air Quality Criteria Document
(AQCD) for Oxides of Nitrogen. Also, a series of Annexes to the draft ISA provide more details
of the most pertinent scientific literature. The draft ISA and the Annexes, thus serves to update
and revise the information included in the 1993 AQCD document (U.S. Environmental
Protection Agency, 1993).
It will be useful at the outset to distinguish between the definition of "nitrogen oxides" as
it appears in the enabling legislation related to the NAAQS and the definition commonly used in
the air pollution research and management community. In this document, the terms "oxides of
nitrogen" and "nitrogen oxides" refer to all forms of oxidized nitrogen compounds, including
nitric oxide (NO), nitrogen dioxide (N02), and all other oxidized nitrogen-containing compounds
transformed from NO and NO2. This follows usage in the Clean Air Act Section 108(c): "Such
criteria [for oxides of nitrogen] shall include a discussion of nitric and nitrous acids, nitrites,
nitrates, nitrosamines, and other carcinogenic and potentially carcinogenic derivatives of oxides
of nitrogen." By contrast, within the air pollution research and control community, the terms
"oxides of nitrogen" and "nitrogen oxides" are restricted to refer only to the sum of NO and NO2,
and this sum is commonly abbreviated as NOx. The category label used by this community for
1 Information on legislative requirements and history of N02 NAAQS reviews are presented in the Preface.
2 The secondary NAAQS for N02 is being reviewed independently, in conjunction with the review of the secondary
NAAQS for sulfur dioxide (S02). A review of the primary NAAQS for S02 is also underway.
August 2007
1-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
the sum of all forms of oxidized nitrogen compounds including those listed in Section 108(c) is
NOy.
For the current review, multiple species of many nitrogen oxides are considered, as
appropriate and as allowed by the available data. For example, descriptions of the atmospheric
chemistry of nitrogen oxides include both gaseous and particulate species, because a meaningful
analysis would not be possible otherwise. In addition, the health effects of gaseous nitrogen
oxides other than N02 are evaluated when information on these other species is available.
Finally, the possible influence of other atmospheric pollutants on the interpretation of the role of
NO2 in health effects studies is considered, including interactions of NO2 with other pollutants
that co-occur in the environment (e.g., sulfur dioxide [SO2], carbon monoxide [CO], ozone [O3],
particulate matter [PM]). The available database for this draft ISA largely provides information
on the health effects of NO2, with limited information examining other forms of oxides of
nitrogen (e.g., nitrous acid [HONO]).
As discussed in the Draft Integrated Plan for the Review of the Primary NAAQS for
Nitrogen Dioxide (U.S. Environmental Protection Agency, 2007), a series of policy-relevant
questions frames this review of the scientific evidence to provide a scientific basis for a decision
on whether the current primary NAAQS for NO2 (0.053 parts per million (ppm), annual average)
should be retained or revised. The draft ISA focuses on evaluation of the newly available
scientific evidence to best inform consideration of these framing questions, including the
following:
• Has new information altered the scientific support for the occurrence of health effects
following short- and/or long-term exposure to levels of oxides of nitrogen found in the
ambient air?
• What do recent studies focused on the near-roadway environment tell us about health
effects of oxides of nitrogen?
• At what levels of oxides of nitrogen exposure do health effects of concern occur?
• Has new information altered conclusions from previous reviews regarding the plausibility
of adverse health effects caused by exposure to oxides of nitrogen?
• To what extent have important uncertainties identified in the last review been reduced
and/or have new uncertainties emerged?
August 2007
1-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
• What are the air quality relationships between short-term and long-term exposures
to oxides of nitrogen?
1.1 DOCUMENT DEVELOPMENT
The U.S. Environmental Protection Agency formally initiated the current review of the
N02 NAAQS by announcing the commencement of the review in the Federal Register with a call
for information (Federal Register, 2005). In addition to the call for information, publications are
identified through an ongoing literature search process that includes searching MEDLINE and
other databases using as key words the terms: nitrogen oxides, nitrogen dioxide, NO, NOx, NOy,
nitric acid, HNO3, pernitric acid, HNO4, nitrate radical, NO3 , dinitrogen pentoxide, N2O5,
organic nitrates, nitrous acid, HONO or HNO2, peroxyacytyl nitrate, PAN, and total reactive
nitrogen. The search strategy is periodically reexamined and modified to enhance identification
of pertinent published papers. Additional papers are identified for inclusion in the publication
base in several ways. First, EPA staff reviews pre-publication tables of contents for journals in
which relevant papers may be published. Second, expert chapter authors are charged with
independently identifying relevant literature. Finally, additional publications that may be
pertinent are identified by both the public and CASAC during the external review process. The
focus of this ISA is on literature published since the 1993 AQCD for Oxides of Nitrogen. Key
findings and conclusions from the 1993 review are discussed in conjunction with recent findings.
Generally, only information that has undergone scientific peer review and that has been
published (or accepted for publication) in the open literature is considered. The following
sections briefly summarize criteria for selection of studies for this draft ISA.
General Criteria for Study Selection
In assessing the scientific quality and relevance of epidemiological and human or animal
toxicological studies, the following considerations have been taken into account.
• To what extent are the aerometric data, exposure, or dose metrics of adequate quality and
sufficiently representative to serve as credible exposure indicators?
• Were the study populations adequately selected and are they sufficiently well defined to
allow for meaningful comparisons between study groups?
• Are the health endpoint measurements meaningful and reliable?
August 2007
1-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
• Does the study contain unique data such as the documentation of a previously unreported
effect, documentation of the mechanism for an observed effect, or information on
exposure-response relationships?
• Are the statistical analyses appropriate, properly performed, and properly interpreted?
• Are likely covariates (i.e., potential confounders or effect modifiers) adequately
controlled or taken into account in the study design and statistical analysis?
• Are the reported findings internally consistent, biologically plausible, and coherent in
terms of consistency with other known facts?
Consideration of these issues informs our judgments on the relative quality of individual studies
and allows us to focus the assessment on the most pertinent studies.
Criteria for Selecting Epidemiological Studies
In selecting epidemiological studies for this assessment, EPA considered whether a given
study contains information on (1) associations with measured oxides of nitrogen concentrations
using short- or long-term exposures at or near ambient levels of oxides of nitrogen, (2) health
effects of specific oxides of nitrogen species or indicators related to oxides of nitrogen sources
(e.g., motor vehicle emissions, combustion-related particles), (3) health endpoints and
populations not previously extensively researched, (4) multiple pollutant analyses and other
approaches to address issues related to potential confounding and modification of effects, and/or
(5) important methodological issues (e.g., lag of effects, model specifications, thresholds,
mortality displacement) related to interpretation of the health evidence. Among the
epidemiological studies, particular emphasis has been focused on those most relevant to standard
settings in the United States. Specifically, studies conducted in the United States or Canada are
discussed in more detail than those from other geographic regions. Particular emphasis has been
placed on: (A) new multicity studies that employ standardized methodological analyses for
evaluating effects of oxides of nitrogen and that provide overall estimates for effects based on
combined analyses of information pooled across multiple cities, (B) new studies that provide
quantitative effect estimates for populations of interest, and (C) studies that consider oxides of
nitrogen as a component of a complex mixture of air pollutants.
August 2007
1-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Criteria for Selecting Animal and Human Toxicological Studies
Criteria for the selection of research evaluating animal toxicological or controlled human
exposure studies include a focus on those studies conducted at levels within about an order of a
magnitude of ambient NO2 concentrations and those studies that approximate expected human
exposure conditions in terms of concentration and duration. Studies that elucidate mechanisms
of action and/or susceptibility, particularly if the studies were conducted under atmospherically
relevant conditions, are emphasized whenever possible.
The selection of research evaluating controlled human exposures to oxides of nitrogen is
mainly limited to studies in which subjects were exposed to <1 ppm NO2. For these controlled
human exposures, emphasis is placed on studies that (1) investigate potentially susceptible
populations such as asthmatics, particularly studies that compare responses in susceptible
individuals with those in age-matched healthy controls; (2) address issues such as concentration-
response or time-course of responses; (3) investigate exposure to NO2 separately and in
combination with other pollutants such as 03 and S02; (4) include control exposures to filtered
air; and (5) have sufficient statistical power to assess findings.
1.2 ORGANIZATION OF THE DOCUMENT
This draft ISA includes five chapters. This introductory chapter (Chapter 1) presents
background information on the purpose of the document and characterizes how policy-relevant
scientific studies are identified and selected for inclusion in the ISA. Chapter 2 highlights key
concepts or issues relevant to understanding the atmospheric chemistry, sources, exposure and
dosimetry of oxides of nitrogen, following a "source to dose" paradigm. Chapter 3 evaluates and
integrates health information relevant to the review of the primary NAAQS for NO2. In this
chapter, findings from epidemiological controlled human exposure and toxicological studies are
integrated into an assessment of the relationships between exposure to ambient oxides of
nitrogen and health outcomes. This chapter focuses on the strength of epidemiological or
toxicological evidence and the consistency, coherence, and plausibility of the body of evidence
for effects on the respiratory, cardiovascular, or other system. Chapter 4 provides information
relevant to the public health impact of exposure to ambient oxides of nitrogen, including
potential susceptible population groups. Finally, Chapter 5 articulates findings, conclusions
August 2007
1-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
regarding the health evidence and makes recommendations pertinent to exposure and risk
assessments.
In addition, a series of Annexes provide additional details of information in the ISA.
Annex 1 is an introduction and background for the Annex series. In Annex 2, we present
evidence related to the physical and chemical processes controlling the production, destruction,
and levels of reactive nitrogen compounds in the atmosphere, including both oxidized and
reduced species. Annex 3 presents information on environmental concentrations, patterns, and
human exposure to ambient oxides of nitrogen. Annex 4 presents results from toxicological
studies as well as information on dosimetry of oxides of nitrogen. Annex 5 presents results from
controlled human exposure studies, and Annex 6 presents evidence from epidemiological
studies. Annex tables for health studies are generally organized to include information about
(1) concentrations of oxides of nitrogen levels or doses and exposure times, (2) description of
study methods employed, (3) results and comments, and (4) quantitative outcomes for oxides of
nitrogen measures. Annexes 2 and 3 contain additional discussion of information because these
Annexes will be used for other ISAs, such as Oxides of Sulfur (SOx).
August 2007
1-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2. SOURCE TO TISSUE DOSE
This chapter provides basic information about concepts and findings relating to
considerations in atmospheric science, human exposure assessment, and human dosimetry. It is
meant to serve as a prologue for detailed discussions on the evidence on health effects to follow
in Chapters 3 and 4. The order of topics essentially follows that given in the National Research
Council paradigm for integrating air pollutant research (National Research Council, 1998).
2.1 INTRODUCTION
As noted in Chapter 1, the definition of "nitrogen oxides" as it appears in the enabling
legislation related to the NAAQS and the definition commonly used in the air pollution research
and control community differ. In this document, the terms "oxides of nitrogen" and "nitrogen
oxides" refer to all forms of oxidized nitrogen compounds, including nitric oxide (NO), NO2, and
all other oxidized nitrogen-containing compounds transformed from NO and N02.1 In the
Federal Register Notice for the last AQCD for Oxides of Nitrogen (1996), the term "nitrogen
oxides" was used to "describe the sum of NO, NO 2 and other oxides of nitrogen
Nitric oxide and NO2, along with volatile organic compounds (VOCs); anthropogenic and
biogenic hydrocarbons, aldehydes, etc.) and carbon monoxide (CO), are precursors in the
formation of ozone (O3) and photochemical smog. Nitrogen dioxide is an oxidant and can react
to form other photochemical oxidants, including organic nitrates like the peroxyacyl nitrates
(PANs). Nitrogen dioxide can also react with toxic compounds such as polycyclic aromatic
hydrocarbons (PAHs) to form nitro-PAHs, some of which are more toxic than either reactant
alone. Nitrogen dioxide and sulfur dioxide (SO2), another EPA criteria air pollutant, can also be
oxidized to the strong mineral acids nitric acid (HNO3) and sulfuric acid (H2SO4), respectively,
thereby contributing to the acidity of cloud, fog, and rainwater and ambient particles.
1 This follows usage in the Clean Air Act Section 108(c): "Such criteria [for oxides of nitrogen] shall include a
discussion of nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other carcinogenic and potentially
carcinogenic derivatives of oxides of nitrogen." By contrast, within the air pollution research and control
community, the terms "oxides of nitrogen" and "nitrogen oxides" are restricted to refer only to the sum of NO and
N02, and this sum is commonly abbreviated as NOx. The category label used by this community for the sum of all
forms of oxidized nitrogen compounds including those listed in Section 108(c) is NOy.
August 2007
2-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2.2 ATMOSPHERIC CHEMISTRY
The role of NOx in O3 formation was reviewed in Chapter 2 (Section 2.2) of the latest Air
Quality Criteria for Ozone and Related Photochemical Oxidants (2006 AQCD for O3) (U.S.
Environmental Protection Agency, 2006), and has been presented in numerous texts (e.g.,
Seinfeld and Pandis, 1998; Jacob, 1999; Jacobson, 2002). Mechanisms for transporting O3
precursors including NOx, the factors controlling the efficiency of O3 production from NOx,
methods for calculating O3 from its precursors, and methods for measuring NOy were all
reviewed in Section 2.6 of 2006 AQCD for O3. The main points from 2006 AQCD for O3 will
be presented here along with updates based on new material.
The overall chemistry of reactive nitrogen compounds in the atmosphere is summarized
in Figure 2.2-1 and described in greater detail in this document's Annex AX2.2. Nitrogen oxides
are emitted by combustion sources mainly as NO with quantities of N02 typically in the range of
5 to 10% of NO. The major combustion sources of NOx, shown schematically in Figure 2.2-1,
are motor vehicles and electrical utilities, although stationary engines, off-road vehicles, and
industrial facilities also emitNOx. In addition to emissions from fossil fuel combustion, biomass
burning also produces NOx. And apart from these anthropogenic sources, there are also smaller
natural sources which include microbial activity in soils, lightning, and wildfires.
NO and NO2 are often grouped together and given the category label "NOx" because they
are emitted together and can rapidly interconvert as shown in the inner box in Figure 2.2-1.
Nitrogen dioxide reacts with various free radicals in the gas phase and on surfaces in multiphase
processes to form the oxidation products shown in Figure 2.2-1. These products include
inorganic species (shown on the left side of the outer box in Figure 2.2-1) and organic species
(shown on the right side of the outer box in Figure 2.2-1). The oxidized nitrogen species in the
outer box are often collectively termed NOz: thus, NOx + NOz = NOy. The time scale for
reactions of NOx to form products shown in the outer box of Figure 2.2-1 typically ranges from a
few hours during summer to about a day during winter. As a result, morning rush hour
emissions of NOx can be converted almost completely to products by late afternoon during
August 2007
2-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
Long range transport to remote
regions at low temperatures
-NO
hno4^
-^OH
HNO
PANS
HO
hv, OH
NO,
-N2°5^=h.N°3<
hv, M
HONO
PAH
»T
NO
nitro-PAHs
H_0,
MPP
R-C=C-R
NO
MPP
hv
nitrosamines,
-~nitro-phenols,
quinones, etc.
HO
ro!
RO
NO
NO„"
deposition
deposition
emissions
Figure 2.2-1. Schematic diagram of the cycle of reactive nitrogen species in the
atmosphere. MPP refers to multiphase processes, R to an organic
radical, and hv to a solar photon.
warm, sunny conditions. As shown in Figure 2.2-1, different sources emit NOx at different
altitudes. Because the prevailing winds aloft are generally stronger than those at the surface,
emissions from elevated sources can be distributed over a wider area than those emitted at the
surface, and because of the time required for mixing of emissions to the surface, emissions of
NOx from elevated sources will tend to be transformed to the more oxidized NOz products before
they reach the surface.
The concentrations and atmospheric lifetimes of inorganic and organic products from
reactions of NOx vary widely in space and time. Inorganic reaction products include HONO,
HNO3, HNO4, and particulate nitrate (pN03 ). While a broad range of organic nitrogen
compounds are emitted by combustion sources (e.g. nitrosamines and nitro-PAHs), they are also
formed in the atmosphere from reactions of NO and NO2. These include peroxyacyl and
isoprene nitrates, other nitro-PAHs, and the more recently identified nitrated organic compounds
August 2007
2-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
in the quinone family. The largest fractions of the mass of products shown in the outer box of
Figure 2.2-1 are in the form of PAN and HNO3, although other organic nitrates, e.g., isoprene
nitrates and specific biogenic PANs can be important at locations nearer to biogenic sources
(Horowitz et al., 2007; Singh et al., 2007).
In addition to gas-phase reactions, reactions occurring on surfaces or occurring in
multiple phases are important for the formation of HONO and pNC>3 . These reactions can
occur on the surfaces of suspended particles, soil, and buildings and within aqueous media.
The lifetime of PAN is strongly temperature dependent and is stable enough at low temperatures
to be transported long distances before decomposing to release NO2, which can then participate
in O3 formation in these regions remote from the original NOx source. Nitric acid can act
similarly to some extent, but its high solubility and fast deposition rate mean that it is removed
from the atmosphere by uptake on aqueous aerosols and cloud droplets or to the surface faster
than PAN. Characteristic concentrations of many of the oxides of nitrogen species are given in
Annex AX3.2.
As mentioned earlier, NO and N02 are important precursors of 03 formation. However,
because O3 changes in a nonlinear way with the concentrations of its precursors, it is unlike
many other secondarily-formed atmospheric species whose rates of formation vary directly with
emissions of their precursors. At the low NOx concentrations found in most environments
(ranging from remote continental areas to rural and suburban areas downwind of urban centers)
the net production of O3 increases with increasing NOx. At the high NOx concentrations found in
downtown metropolitan areas and especially near busy streets and roadways and in power plant
plumes, net destruction of O3 is initiated with the excess NO found there. In the high NOx
regime, N02 scavenges OH radicals that would otherwise oxidize VOCs to produce peroxy
radicals, which would in turn oxidize NO to NO2. In the low NOx regime, oxidation of VOCs
generates excess free radicals, and hence O3 production varies more nearly directly with NOx.
Between these two regimes, there is a transition zone in which O3 shows only a weak
dependence on NOx concentrations.
Formation ofNitro-PAHs
Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) are produced either by either direct
emissions or by atmospheric reactions. Among combustion sources, diesel emissions have been
August 2007
2-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
identified as the major source of nitro-PAHs in ambient air (Bezabeh et al., 2003; Gibson, 1983;
Schuetzle, 1983; Tokiwa and Ohnishi, 1986). Direct emissions of "nitro-patts" in PM vary with
type of fuel, vehicle maintenance, and ambient conditions (Zielinska et al., 2004). In addition to
being directly emitted, nitro-PAHs can also be formed from both gaseous and heterogeneous
reactions of PAHs with gaseous nitrogen-containing pollutants in the atmosphere, with the
reactions of OH and NO3 radicals with PAHs being the major sources of nitro-PAHs. (Arey
et al., 1986; Arey et al., 1989, 1998; Giancarlo Perrini, 2005; Pitts et al., 1987; Sasaki et al.,
1997; Zielinska et al., 1989; Bamford and Baker, 2003; Reisen and Arey, 2005 and references
therein). Reactions involving OH and NO3 radicals imply that nitro-PAH formation occurs
during both daytime and nighttime in the atmosphere. The major loss process of nitro-PAHs is
photodecomposition (Fan et al., 1996; Feilberg et al., 1999; Feilberg and Nielsen, 2001) with
lifetimes on the order of hours, followed by reactions with OH and NO3 radicals. The reaction
mechanisms for forming and destroying nitro-PAHs in the atmosphere have been described in
Section AX2.2.3.
In ambient particulate organic matter (POM), 2-nitrofluoranthene (2NF) is the dominant
compound, followed by 1-nitropyrene (1NP) and 2-nitropyrene (2NP) (Arey et al., 1989;
Bamford et al., 2003; Reisen and Arey, 2005; Zielinska et al., 1989). 2NF and 2NP are not
directly emitted from primary combustion emissions, but are formed in the atmosphere. 1NP is
generally regarded as a tracer of primary combustion sources, in particular, diesel exhaust. After
formation, nitro-PAHs with low vapor pressures (such as 2NF and 2NP) immediately migrate to
particles under ambient conditions (Fan et al., 1995; Feilberg et al., 1999). More volatile nitro-
PAHs, such as nitronapthalene (NN) remain mainly in the gas phase.
The concentrations for most nitro-PAHs found in ambient air are typically lower than
1 pg/m3, except NNs, 1NP, and 2NF, which can be present at levels up to several tens or
hundreds of pg/m3. These levels are much lower (~2 to -1000 times lower) than their parent
PAHs. However, nitro-PAHs are much more toxic than PAHs (Durant et al., 1996; Grosovsky
et al., 1999; Salmeen et al., 1982; Tokiwa et al., 1998; Tokiwa and Ohnishi, 1986). Moreover,
most nitro-PAHs are present in particles with a mass median diameter of <0.1 |im.
August 2007
2-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2.3 MEASUREMENT METHODS AND ASSOCIATED ISSUES
Nitric oxide is routinely measured using the principle of gas-phase chemiluminescence
induced by the reaction of NO with O3 at low pressure. The Federal Reference Method (FRM)
for N02 makes use of this technique of NO detection with a prerequisite step to reduce the N02
to NO on the surface of a molybdenum oxide (MoOx) substrate heated to between 300 and
400 C. Because the FRM monitor cannot detect NO2, the concentration of NO2 is determined as
the difference between the sample passed over the heated MoOx substrate (the nitrogen oxides
total) and the sample not reduced (the NO). However, the reduction of N02 to NO on the MoOx
substrate is not specific to NO2; hence, the chemiluminescence analyzers are subject to unknown
and varying interferences produced by the presence in the sample of the other oxidized nitrogen
compounds (i.e., NOz compounds shown in the outer box of Figure 2.2-1).
Interference by NOz compounds has long been known (Fehsenfeld et al., 1987; Rodgers
and Davis, 1989; U.S. Environmental Protection Agency, 1993, 2006; Crosley, 1996;
Nunnermacker et al., 1998; Parrish and Fehsenfeld, 2000; McClenny et al., 2002; Dunlea et al.,
2007). These studies have relied on intercomparisons of measurements using the FRM and other
techniques for measuring N02. The sensitivity of the instrument to potential interference by
individual NOz compounds is highly variable and is dependent in part on instrument inlet design
and on the temperature of the reducing substrate, and on the interactions of species with the
reducing substrate. Commercially available NOx monitors have been converted to NOy monitors
by moving the MoOx convertor to interface directly with the sample inlet. Because of losses on
inlet surfaces and differences in the efficiency of reduction of NOz compounds on the heated
MoOx substrate, NOx can not be considered as a universal surrogate for NOy. However, in
settings close to relatively high concentration fresh emissions like those in urban areas during
rush hour, most of the NOy is present as NOx. To the extent that all the major oxidized nitrogen
species can be reduced quantitatively to NO, measurements of NOy should be more reliable than
those for NOx, particularly at typical ambient levels of NO2. Routine measurement reporting of
total NOy rather than of NO and NO2 by subtraction has the additional benefit of characterizing
the entire suite of oxidized nitrogen compounds to which humans are exposed. Reliable
measurements of NOy and NO2, especially at the low concentrations observed in many areas
remote from sources are also crucial for evaluating the performance of three-dimensional,
August 2007
2-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
chemical transport models of oxidant and acid production in the atmosphere (described in
Section AX2.7 of Annex 2).
There are other approaches to measuring N02 that do not suffer from the artifacts
mentioned above. For example, NO2 can be photolytically reduced to NO, with an efficiency of
about 70%. At present, however, this method requires additional development to ensure its cost
effectiveness and reliability for extensive field deployment. The relatively low and variable
conversion efficiency of this technique, for example, means that increased attention to frequent
calibration exercises would be required for routine operation. Optical methods such as those
using differential optical absorption spectroscopy (DOAS) or laser induced fluorescence (LIF)
are also available, as described in Section AX2.8 of Annex AX2. However, these methods are
even more expensive than either the FRM monitors or photolytic reduction technique and require
specialized expertise to operate as well; moreover, the DOAS is an area-integrated rather than a
point-measured technique.
2.4 AMBIENT CONCENTRATIONS OF N02 AND ASSOCIATED
OXIDIZED NITROGEN SPECIES AND POLICY RELEVANT
BACKGROUND CONCENTRATIONS
This section provides a brief summary of information on ambient concentrations of N02
and associated oxidized nitrogen compounds in the United States. It also provides estimates of
Policy Relevant Background Concentrations, i.e., background concentrations used to inform
policy-relevant decisions about the NAAQS.
2.4.1 Ambient Concentrations
Figure 2.4-1 shows ambient concentrations of NO2 measured at all monitoring sites
located within Metropolitan Statistical Areas (MSAs) in the United States from 2003 through
2005. As can be seen from Figure 2.4-1, mean concentrations of N02 are about 15 ppb for
averaging periods ranging from a day to a year, with an interquartile range (IQR) of 10 to
15 ppb. However, the average daily maximum hourly NO2 concentrations are -30 ppb. These
values are about twice as high as the 24-h averages. The highest maximum hourly
concentrations (-200 ppb) are more than a factor of ten higher than the mean hourly or 24-h
concentrations.
August 2007
2-7
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
100
90
80
S" 70
o.
Q.
~ 60
O
'"S 50
<4_>
c
a> 40
o
O 30
20
10
0
.—^201 >jt —^201 *—^129
X
*
o
MAX
99
25
i Mean
1- h max
1- h
24- h
2 week
1-year
Figure 2.4-1.
Ambient concentrations of NO2 measured at all monitoring sites
located within Metropolitan Statistical Areas in the United States
from 2003 through 2005.
Recall from the discussion above that the FRM for N02 is subject to positive interference
by other oxidized nitrogen compounds (NOz), and the degree of interference can be substantial.
In particular, Dunlea et al. (2007) found an average of about 22% of ambient NO2 (~9 to 50 ppb)
measured in Mexico City was due to interference from NOz compounds. Comparable levels of
N02 are found in many locations in the United States. The Dunlea et al. (2007) results were
based on comparison between the chemiluminescent instrument with other (optical) techniques.
The main sources of interference were HNO3 and various organic nitrates. Peak interference of
up to 50% was found during afternoon hours and was associated with O3 and NOz compounds
such as HNO3 and the alkyl and multifunctional alkyl nitrates.
Data for concentrations of NOz constituent species in urban areas in the United States are
sparse. The most comprehensive set of data for any NOz species was obtained for HNO3 as part
of the Children's Health Study for which gas-phase HNO3 was measured at 12 sites in Southern
California from 1994 through 2001 (Alcorn et al., 2004). Levels ranged from <1 ppb to >10 ppb
August 2007
2-8
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
in general, the highest concentrations of HNO3 and the highest ratio of HNO3/NO2 were found
downwind of central Los Angeles in the San Bernadino Valley during summer, as one would
expect for this more oxidized nitrogen product. Measurements of HONO in urban areas are very
limited; however, data from Stutz et al., (2004) and Wang et al., (2006) indicate that levels of
HONO are <1 ppb even under heavily polluted conditions (with the highest levels found during
the night and just after dawn and lowest values found in the afternoon). Several field studies
such as Hayden et al. (2003) in rural Quebec, Williams et al. (1987) near Boulder, CO, and Singh
et al. (2007) in aircraft flights over eastern North America have also found much higher levels of
NOz compounds than NOx in relatively unpolluted rural air.
Calculations with EPA's Community Multiscale Air Quality (CMAQ) modeling system
for the mid-Atlantic region in a domain from Virginia-Southern New Jersey showed that the
highest levels of HNO3 and organic nitrates occur during mid-afternoon, consistent with their
formation by photochemical processes that also produce O3. Model calculations during an O3
episode in July 2002 made for the Maryland State O3 Implementation Plan (SIP) showed episode
averages of the ratio NOz /N02 ranging from 0.26 to 3.6 in rural Virginia, with the highest ratios
in rural areas and lowest ratios in urban centers nearer the sources of fresh NOx emissions. The
capabilities of three-dimensional transport models like CMAQ and issues associated with their
use are presented in Annex Section AX2.7.
2.4.2 Policy Relevant Background Concentrations of Nitrogen Dioxide
Background concentrations of NO2 used for purposes of informing decisions about
NAAQS are referred to as Policy Relevant Background (PRB) concentrations. Policy Relevant
Background concentrations are those concentrations that would occur in the United States in the
absence of anthropogenic emissions in continental North America (defined here as the United
States, Canada, and Mexico). Policy Relevant Background concentrations include contributions
from natural sources everywhere in the world and from anthropogenic sources outside these
three countries. Background levels so defined facilitate separation of pollution levels that can be
controlled by U.S. regulations (or through international agreements with neighboring countries)
from levels that are generally uncontrollable by the United States. The EPA assesses risks to
human health and environmental effects from NO2 levels in excess of PRB concentrations.
August 2007
2-9
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Contributions PRB concentrations include photochemical actions involving natural
emissions of NO, NO2, and reduced nitrogen (NHX) compounds; as well as their long-range
transport from outside North America. Natural sources of N02 and its precursors include
biogenic emissions, wildfires, lightning, and the stratosphere. Biogenic emissions from
agricultural activities are not considered in the formation of PRB concentrations. Discussions of
the sources and estimates of emissions are given in Annex Section AX2.6.2.
Analysis of Policy Relevant Background Contribution to Nitrogen Dioxide Concentrations over
the United States
The MOZART-2 global model of tropospheric chemistry (Horowitz et al., 2003) was
used to diagnose the PRB contribution to NO2 concentrations. The model setup for the present-
day simulation has been published in a series of papers from a recent model intercomparison
(Dentener et al., 2006ab; Shindell et al., 2006; Stevenson et al., 2006; van Noije et al., 2006).
MOZART-2 is driven by National Center for Environmental Prediction meteorological fields
and IIASA 2000 emissions at a horizontal resolution of 1.9° x 1.9° with 28 sigma levels in the
vertical, and it includes gas-phase and aerosol chemistry. Results shown in Figure 2.4-2 are for
the meteorological year 2001. An additional "PRB" simulation was conducted in which
continental North American anthropogenic emissions were set to zero.
We first examine the role of PRB in contributing to NO2 concentrations in surface air.
Figure 2.4-2 shows the annual mean N02 concentrations in surface air in the base case
simulation (top panel) and the PRB simulation (middle panel), along with the percentage
contribution of the background to the total base case NO2 (bottom panel). Maximum
concentrations in the base case simulation occur along the Ohio River Valley and in the
Los Angeles basin. While present-day concentrations are often above 5 ppbv, PRB is less than
300 pptv over most of the continental United States, and less than 100 pptv in the eastern United
States. The distribution of PRB (middle panel of Figure 2.4-2) largely reflects the distribution of
soil NO emissions, with some local enhancements due to biomass burning such as in western
Montana. In the northeastern United States, where present-day NO2 concentrations are highest,
PRB contributes <1% to the total. Thus, it appears that PRB levels of N02 are much smaller
than observed levels.
August 2007
2-10
DRAFT-DO NOT QUOTE OR CITE
-------
Total
50°N
45°N
40°N
35°N
30°N
25°N
120°W ioo°w aa°w
< 50 290 530 770 1010 1250
Figure 2.4-2. Annual mean concentrations of NO2 (ppbv) in surface air over the United
States in the present-day (upper panel) and policy relevant background
(middle panel) MOZART-2 simulations. The bottom panel shows the
percentage contribution of the background to the present-day
concentrations. See text in Annex Section AX2.9 for details.
August 2007 2-11 DRAFT-DO NOT QUOTE OR CITE
I20°W
ea°w
105 125
Percent Background Contribution
50°N
45° N
40°N
35°N
30°N
25°N
Background
ioo°w
S0°N
45°N
40°N
35°N
30°N
25°N
iao°w
100°W
-------
1 2.5 EXPOSURE ISSUES
2
3 2.5.1 Personal Exposures
4
5 2.5.1.1 General Concepts
6 Human exposure to an airborne pollutant consists of contact between the human and the
7 pollutant at a specific concentration for a specified period of time. People spend various
8 amounts of time in different microenvironments (Figure 2.5-1) characterized by different
9 pollutant concentrations. The figure represents a composite average across the United States
10 across all age groups. Different cohorts, e.g., the elderly might be expected to exhibit different
11 activity patterns. The integrated exposure of a person to a given pollutant is the sum of the
12 exposures over all time intervals for all microenvironments in which the individual spent time.
13 Therefore, the personal exposure concentration to a pollutant, such as NO2, can be
14 represented by the following equation:
16 where ET is the time-weighted average personal exposure concentration over a certain period of
17 time, n is the total number of microenvironments that a person encounters,/ is the fraction of
19 microenvironment during the time fraction,/. The exposure a person experiences can be
20 characterized as an instantaneous exposure, a peak exposure such as might occur during cooking,
21 an average exposure, or an integrated exposure over all environments a person encounters.
22 These distinctions are important because health effects caused by long-term low-level exposures
23 may differ from those caused by short-term peak exposures.
24 An individual's total exposure (ET) can also be represented by the following equation:
15
¦%= 2 Cifi
i-1
(2.5-1)
18 time spent in the ith microenvironment, and Ct is the average concentration in the ith
27
25
26
subject to the constraint
August 2007
2-12
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
NHAPS - Nation, Percentage Time Spent
Total n = 9,196
IN A RESIDENCE (68.7%
TOTAL TIME SPENT
INDOORS (86.9%)
r~ OUTDOORS (7.6%)
IN A VEHICLE (5.5%)
OFFICE-FACTORY 15.4%)
OTHER INDOOR LOCATION (11%)
BAR-RESTAURANT (1.8%)
Figure 2.5-1.
Percentage of time people spend in different environments in the
United States.
Source: Klepeis et al. (2001).
In the case where microenvironmental exposures occur mainly in one microenvironment,
Equation 2.5-2 may be approximated by
ET=Ea + Ena = {y + (l-y)\Pa/(a + k)]}Ca + Ena = aCa + £
na
(2.5-4)
where y is the fraction of time people spend outdoors, and a is the ratio of a person's exposure to
a pollutant of ambient origin to the pollutant's ambient concentration. Other symbols have the
same definitions in Equation 2.5-2 and 2.5-3. If microenvironmental concentrations are
considered, then Equation 2.5-4 can be recast as
Cme = Ca + Cna =[Pa /{a + k)\Ca + S/[V(a + k)] ^ 5_5^
where Cme is the concentration in a microenvironment; Ca and C„a are the contributions to Cme
from ambient and nonambient sources; S is the microenvironmental source strength; V is the
volume of the microenvironment, and the symbols in brackets have the same meaning as in
Equation 2.5-4.
August 2007
2-13
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Microenvironments in which people are exposed to air pollutants such as NO2 typically
include residential indoor environments, other indoor locations, near-traffic outdoor
environments, other outdoor locations, and in vehicles as shown in Figure 2.5-1. Indoor
combustion sources such as gas stoves and space heaters need to be considered when evaluating
exposures to NO2. Exposure misclassification may result when total human exposure is not
disaggregated between various microenvironments, and this may obscure the true relationship
between ambient air pollutant exposures and health outcomes.
In a given microenvironment, the ambient component of a person's microenvironmental
exposure to a pollutant is determined by the following physical factors.
• Ambient concentration
• The air exchange rate
• The pollutant specific penetration coefficient
• The pollutant specific decay rate
• The fraction of time an individual spends in the microenvironment
These factors are in turn determined by the following exposure factors (see Annex AX3.5).
• Environmental conditions, such as weather and season
• Dwelling conditions, such as the location of the house which determines
proximity to sources and geographical features that can modify transport from
sources; the amount of natural ventilation (e.g., open windows and doors, and the
"draftiness" of the dwelling) and ventilation system (e.g., filtration efficiency and
operation cycle)
• Personal activities, (e.g., the time spent cooking or commuting)
• Socioeconomic status, (e.g., the level of education and the income level)
• Demographic factors (e.g., age and gender)
• Indoor sources and sinks of a pollutant
• Microenvironmental line and point sources (e.g., lawn equipment)
In general, the relationship between personal exposures and ambient concentrations can
be modified by microenvironments in the following ways: (1) during infiltration, ambient
pollutants can be lost through chemical and physical loss processes, and therefore, the ambient
August 2007
2-14
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
component of a pollutant's concentration in a microenvironment is not the same as its ambient
concentration but the product of the ambient concentration and the infiltration factor (Finf or a if
people spend 100% of their time indoors) and (2) exposure to nonambient, microenvironmental
sources.
In practice, it is extremely difficult to characterize community exposures by
measurements of each individual's personal exposures. Instead, the distribution of personal
exposures in a community, or the population exposure, is characterized by extrapolating
measurements of personal exposure using various techniques or by stochastic, deterministic or
hybrid exposure modeling approaches such as APEX, SHEDS, and MENTOR (see AX3.7 for a
description of modeling methods). Variations in community-level personal exposures are
determined by cross-community variations in ambient pollutant concentrations and the physical
and exposure factors mentioned above. These factors also determine the strength of the
association between population exposure to NO2 of ambient origin and ambient NO2
concentrations.
2.5.2 Ambient Monitors and Personal Exposures
Of major concern is the ability of NO2 measured by ambient monitors to serve as a good
indicator of personal exposure to NO2 of ambient origin. The key question is what errors are
associated with using N02 measured by ambient monitors as a surrogate for personal exposure to
ambient NO2 in epidemiological studies. There are three aspects of this issue: (1) ambient and
personal sampling issues; (2) the spatial variability of ambient NO2 concentrations; (3) the
associations between ambient concentrations and personal exposures as influenced by exposure
factors, e.g., indoor sources and sinks, and the time people spend indoors and outdoors. These
issues are treated individually in the following subsections.
2.5.2.1 Ambient and Personal Sampling Issues
Personal exposures in human exposure and panel studies of NO2 health effects are
monitored by passive samplers. Their performance is evaluated by comparison to the
chemiluminescence monitoring method. Some form of evaluation is crucial for determining
measurement errors associated with exposure estimates. However, measurements of NO2 are
subject to artifacts both at the ambient level and at the personal level. As discussed above in
Section 2.3, measurements of ambient NO2 are themselves subject to variable interference
August 2007
2-15
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
caused by other NOy compounds, in particular PANs, organic nitrates, pN03 , and HONO and
hno3.
The most widely used passive samplers are Palmes tubes (Palmes et al., 1976),
Yanagisawa badges (Yanagisawa and Nishimura, 1982), Ogawa samplers (Ogawa and
Company, http://www.ogawausa.com) and radial diffusive samplers (Cocheo et al., 1996). The
theories behind and applications of Palmes Tubes and Yanagisawa badges have been described
in the last AQCD for Oxides of Nitrogen (U.S. Environmental Protection Agency, 1993).
Descriptions of the rest of the commercialized samplers will be presented in detail in Annex
Section AX3.3. Briefly, after penetrating into a passive sampler governed by Fick's law,
environmental NO2 is fixed by the adsorbent (Krupa and Legge, 2000). The sorbent can be
either physically sorptive (e.g., active carbon) or chemisorptive (e.g., triethanolamine [TEA], KI,
and arsenate sodium oxide [AsNa02]); passive samplers for NO2 are chemisorptive, i.e., a
reagent coated on a support (e.g., metal mesh, filter) chemically reacts with and captures NO2.
The sorbent is extracted and analyzed for one or more reactive derivatives; the mass of NO2
collected is derived from the concentration of the derivative(s) based on the stoichiometry of the
reaction.
The effect of environmental conditions (e.g., temperature, wind speed, humidity) on the
performance of passive samplers is a concern when used for residential indoor, outdoor, and
personal exposure studies, because of sampling rates that deviate from ideal and can vary
through the sampling period. Overall, field test results of passive sampler performance are not
consistent, and they have not been extensively studied over a wide range of concentrations, wind
velocities, temperatures and relative humidities (Varshney and Singh, 2003).
Another concern for passive sampling is interference from other pollutants. Interference
from other NOy species can contribute to NO2 exposure monitoring errors, but the kinetics and
stoichiometry of interferent compound reactions have not been well established, especially for
passive samplers. In the U.K., an NO2 monitoring plan using a cost-effective, simpler tube-type
passive sampler has been proposed and implemented countrywide. However, in a comparison of
N02 concentrations measured outdoors by the passive samplers with those measured by the
chemiluminescence method, NO2 concentrations measured by the passive samplers were -30%
higher than those measured by the chemiluminescence method (Campbell et al., 1994).
August 2007
2-16
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Although the majority of studies indicate that passive samplers have very good precision,
generally within 5% (Gair et al., 1991; Gair and Penkett, 1995; Plaisance et al., 2004; Kirby
et al., 2001), field evaluation studies showed that the overall average N02 concentrations
calculated from diffusion tube measurements were likely to be within 10% of chemiluminescent
measurement data (Bush et al., 2001; Mukerjee et al., 2004). As mentioned before, TEA-based
diffusive sampling methods tend to overestimate NO2 concentrations in field comparisons with
chemiluminescence analyzers (Campbell et al., 1994). This could be due in part to chemical
reactions between O3 and NO occurring in the diffusion tube, or differential sensitivity to other
forms of NOy, such as HONO, PAN, and HNO3, between the passive samplers and the
chemiluminescence analyzers (Gair et al., 1991). Due to spatial and temporal variability of NO
and N02 concentrations, especially at roadsides where NO concentrations are relatively high and
when sufficient O3 is present for interconversion between the species, the lack of agreement
between the passive samplers and ambient monitors can represent differences in sampler
response (Heal et al., 1999; Cox, 2003).
A third aspect of passive sampler performance is that, compared with ambient
chemiluminescence monitors, passive samplers give relatively longer time averaged
concentrations (from days to weeks). Consequently, diffusive samplers including those used for
NO2 monitoring provide integrated but not high time-resolution concentration measurements.
Hourly fluctuations in NO2 concentrations may be important to the evaluation of exposure-health
effects relationships, and continuous monitors, such as the chemiluminescent monitors, remain
the only approach for estimating short-term peak exposures.
2.5.2.2 Spatial Variability
2.5.2.2.1 Spatial Variability of Ambient NO2 Concentrations
Summary statistics for the spatial variability in several urban areas across the United
States are shown in Table 2.5-1. These areas were chosen because they are the major urban
areas with at least five monitors operating from 2003 to 2005. Values in parentheses below the
city name indicate the number of monitoring sites in that particular city. The second column
shows the mean concentration across all sites and the range in means at individual sites. The
third column gives the range of Pearson correlation coefficients between individual site pairs in
the urban area. The fourth column shows the 90th percentile absolute difference in
August 2007
2-17
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
concentrations between site pairs. The fifth column gives the coefficient of divergence (COD),
an indication of the variability across the monitoring sites in each city; a COD value of 0
indicates there are no differences between concentrations at paired sites (spatial homogeneity),
while a COD value approaching 1 indicates extreme spatially heterogeneity.
As can be seen from the table, mean concentrations at individual sites vary by factors of
1.5 to 6 in the MS As examined. The sites in New York City tend to be the most highly
correlated and show the highest mean levels, reflecting their proximity to traffic, as evidenced by
the highest mean concentration of all the entries. They are also located closer to each other than
sites in western cities. Correlations between individual site pairs range from slightly negative to
highly positive in all of the urban areas except for New York City. However, correlation
coefficients are not sufficient for describing spatial variability as concentrations at two sites may
be highly correlated but show differences in levels. Thus, the range in mean concentrations is
given. Even in New York City, the spread in mean concentrations is about 40% of the citywide
mean (12/29). The relative spread in mean concentrations is larger in the other urban areas
shown in Table 2.5-1. As might be expected, the 90th percentile concentration ranges are even
larger than the ranges in the means.
The same statistics as shown in Table 2.5-1 have been used to describe the spatial
variability of fine particulate matter (PM2.5) (U.S. Environmental Protection Agency, 2004; Pinto
et al., 2005) and O3 (U.S. Environmental Protection Agency, 2006). However, because of
relative sparseness in data coverage for N02, spatial variability in all cities that were considered
for PM2.5 and O3 could not be considered. Thus, the number of cities included here is much
smaller than for either O3 (24 urban areas) or PM2.5 (27 urban areas). Even in those cities where
there were monitors for all three pollutants, data may not have been collected at the same
locations, and even if they were, there will be different responses to local sources. For example,
concentrations of NO2 collected near traffic will be highest in an urban area, but concentrations
of O3 will tend to be lowest there because of titration by NO forming NO2. However, some
general observations can still be made. Mean concentrations of NO2 at individual monitoring
sites are not as highly variable as for 03 but are more highly variable than PM2.5. Lower bounds
on intersite correlation coefficients for PM2.5 and for O3 tend to be much higher than NO2 in the
same areas shown in Table 2.5-1. CODs for PM2.5 are much lower than for O3, whereas CODs
for NO2 tend to be the largest among these three pollutants.
August 2007
2-18
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2.5.2.2.2 Small-Scale Vertical Variability
Inlets to instruments for monitoring gas phase criteria pollutants can be located from 3 to
15 m above ground level (CFR 58, Appendix E, 2002). Depending on the pollutant, either there
can be positive, negative, or no vertical gradient from the surface to the monitor inlet. Positive
gradients (i.e., concentrations increase with height) result when pollutants are formed over large
areas by atmospheric photochemical reactions (i.e., secondary pollutants such as 03) and
destroyed by deposition to the surface or by reaction with pollutants emitted near the surface.
Pollutants that are emitted by sources at or just above ground level show negative vertical
gradients. Pollutants with area sources (widely dispersed surface sources) and that have minimal
deposition velocities show little or no vertical gradient. Restrepo et al. (2004) compared data for
criteria pollutants collected at fixed monitoring sites at 15 m above the surface on a school
rooftop to those measured by a van whose inlet was 4 m above the surface at monitoring sites in
the South Bronx during two sampling periods in November and December 2001. They found
that CO, S02, and N02 showed negative vertical gradients, whereas 03 showed a positive
vertical gradient and PM2.5 showed no significant vertical gradient. As shown in Figure 2.5-2,
N02 mixing ratios obtained at 4 m (mean -74 ppb) were about a factor of 2.5 higher than at 15 m
(mean -30 ppb). Because tail pipe emissions occur at lower heights, NO2 values could have
been much higher nearer to the surface and the underestimation of N02 values by monitoring at
15 m even larger. Restrepo et al. (2004) noted that the use of the N02 data obtained by the
stationary monitors underestimates human exposures to N02 in the South Bronx. This situation
is not unique to the South Bronx and could arise in other large urban areas in the United States
with populations of similar demographic and socioeconomic characteristics.
Thus, weak associations might be found between concentrations at ambient monitors and
other outdoor locations and between concentrations in indoor microenvironments and personal
exposures in part because of the spatial (horizontal and vertical) variability in NO2. As
mentioned earlier, there are far fewer monitors for NO2 than for O3 or PM2.5. Consequently, NO2
ambient monitors may be less representative of community or personal exposures than are
ambient monitors O3 or PM2.5 for their respective exposures.
August 2007
2-19
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
0.12
0.1
0.08
a. 0.06
£L
0.04
0.02
u
~
~
~
1 J \
~
~
t *
\ f\
f
•
*
1 r
\ \ ~ T
~ Va \
\
~ / \ ] I1 h.
V V A / S a
v \ \/\ \ /\
\ 1 li ~ 1 \ 1 \
^ vT .
~ \r \/
_ ~ ~
¦'v ^
r \ a
\/
t
\
1
¦
^ ^ ^
s\\ N\\ N\\" n\\" n\\"
<$>N c?>N C?N c?N c?N c^N e?N c?N
-4— Van — «- -DEC709406 DEC709407
Figure 2.5-2.
N02 concentrations measured at 4 m (Van) and at 15 m at NY
Department of Environmental Conservation sites (DEC709406 and
DEC709407).
Source: Restrepo et al. (2004).
2.5.2.3 Relationships of Personal Exposure and Ambient Concentration
2.5.2.3.1 Indoor Sources and Sinks of NO2 and Associated Pollutants
Indoor sources and indoor air chemistry of N02 are important, because they influence the
indoor NO2 concentrations to which humans are exposed and alter the association between
personal exposures and ambient concentrations.
Penetration of outdoor NO2 and combustion in various forms are the major sources of
N02 to indoor environments, e.g., homes, schools, restaurants, and theaters. As might be
expected, indoor concentrations of N02 in the absence of combustion sources are determined by
the infiltration of outdoor NO2 (Spengler et al., 1994; Weschler and Shields, 1994; Levy et al.,
1998b), with potentially significant indoor contributions from chemical reactions of NO in
August 2007
2-20
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
exhaled breath with O3 (see AX3.4.2 for sample calculations). Indoor sources of nitrogen oxides
have been characterized in several reviews, namely the last AQCD for Oxides of Nitrogen (U.S.
Environmental Protection Agency, 1993); the Review of the Health Risks Associated with
Nitrogen Dioxide and Sulfur Dioxide in Indoor Air for Health Canada (Brauer et al., 2002); and
the Staff Recommendations for revision of the NO2 Standard in California (California Air
Resources Board, 2006). Mechanisms by which nitrogen oxides are produced in the combustion
zones of indoor sources were reviewed in the last AQCD for Oxides of Nitrogen (U.S.
Environmental Protection Agency, 1993) and will not be repeated here. Sources of ambient NO2
are reviewed in AX2.6. It should also be noted that indoor sources can affect ambient NO2
levels, particularly in areas in which atmospheric mixing is limited, such as in valleys.
Combustion of fossil fuels and biomass is the major primary source of nitrogen oxides.
Combustion of fossil fuels occurs in appliances used for cooking, heating, and drying clothes,
e.g., oil furnaces, kerosene space heaters, coal stoves. Motor vehicles and various types of
generators in structures attached to living areas also contribute NO2 to indoor environments.
Indoor sources of N02 from biomass include wood burning fireplaces and wood stoves and
tobacco.
A large number of studies, as described in the reviews cited above, have all noted the
importance of gas cooking appliances as sources of NO2 emissions. Depending on geographical
location, season, other sources of NO2, length of monitoring period, and household
characteristics, homes with gas cooking appliances have approximately 50% to over 400%
higher NO2 concentrations than homes with electric cooking appliances (Gilbert et al., 2006; Lee
et al., 2000; Garcia-Algar et al., 2003; Raw et al., 2004; Leaderer et al., 1986; Garcia-Algar,
2003). Gas cooking appliances remain significantly associated with indoor NO2 concentrations
after adjusting for several potential confounders including season, type of community,
socioeconomic status, use of extractor fans, household smoking, and type of heating (Garcia-
Algar et al., 2004; Garrett, 1999). Homes with gas appliances with pilot lights emit more NO2
resulting in NO2 concentrations -10 ppb higher than in homes with gas appliances with
electronic ignition (Spengler et al., 1994; Lee et al., 1998). Secondary heating appliances are
additional sources of NO2 in indoor environments, particularly if the appliances are unvented or
inadequately vented. As heating costs increase, the use of these secondary heating appliances
tends to increase.
August 2007
2-21
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Gas heaters, particularly when unvented or inadequately vented, produce high levels of
indoor NO2 (Kodoma et al., 2002). Results summarized by Brauer et al. (2001) indicate that
concentrations of N02 in homes with unvented gas hot water heaters were 10 to 21 ppb higher
than in homes with vented heaters, which in turn, had NO2 concentrations 7.5 to 38 ppb higher
than homes without gas hot water heaters.
Table 2.5-2 shows short-term average (i.e., minutes to hours) concentrations of NO2 in
homes with combustion sources (mainly gas fired), and Table 2.5-3 shows long-term average
(i.e., 24 h to 2 weeks) concentrations of NO2 in homes with mainly gas combustion sources.
As can be seen from Tables 2.5-2 and 2.5-3, shorter-term average concentrations tend to
be much higher than longer-term averages. As Triche et al. (2005) indicated, the 90th percentile
concentrations can be substantially greater than the medians, even for 2-week samples. This
finding illustrates the high variability of indoor NO2 found among homes, reflecting differences
in ventilation of emissions from sources, air exchange rates, the size of rooms, etc. The
concentrations for short averaging periods that are listed in Table 2.5-2 correspond to about 10 to
30 ppb on a 24-h average basis. As can be seen from inspection of Table 2.5-3, these sources
would contribute significantly to the longer-term averages reported there if operated on a similar
schedule on a daily basis. This implies that measurements made with long averaging periods
may not capture the nature of the diurnal pattern of indoor concentrations of NO2 in homes with
strong indoor sources, a problem that becomes more evident as ambient NO2 levels decrease
with more efficient controls on outdoor sources.
The contribution of NO2 from combustion of biomass fuels has not been studied as
extensively as that from gas. A main conclusion from the 1993 AQCD for Oxides of Nitrogen
was that properly vented wood stoves and fireplaces would make only minor contributions to
indoor N02 levels and several studies conclude that using wood burning appliances does not
increase indoor NO2 concentrations (Levesque et al., 2001; Triche et al., 2005).
Other indoor combustion sources of NO2 are candle burning and smoking. In a study of
students living in Copenhagen, Sorensen et al. (2005) found that personal exposures to NO2 were
significantly associated with time exposed to burning candles in addition to other sources (data
not reported). Results of studies relating NO2 concentrations and exposures to environmental
tobacco smoke (ETS) have been mixed. Several studies found positive associations between
August 2007
2-22
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
NO2 levels and ETS (e.g., Linaker et al., 1996; Farrow et al., 1997; Aim et al., 1998; Levy, 1998;
Monn et al., 1998; Cyrys et al., 2000; Lee et al., 2000; Garcia-Algar, 2004) whereas others have
not (Madany et al., 1993; Hackney et al., 1992; Kawamoto et al., 1993).
Some copollutants could be generated from indoor combustion sources along with NO2.
Spicer et al. (1993) compared the measured increase in HONO in a test house resulting from
direct emissions of HONO from a gas range and from production by surface reactions of NO2.
They found that emissions from the gas range could account for -84% of the measured increase
in HONO. In a study of Southern California homes (Lee et al., 2002), indoor levels of NO2 and
HONO were positively associated with the presence of gas ranges.
Rogge et al. (1993) reported that most of the particle mass emitted from a vented natural
gas space heater and a hot water heater was in the form of organic compounds. About 26% of
the mass could be ascribed to single organic compounds, the majority of which were PAHs, oxy-
PAHs, aza arenes, and thia arenes. Brown et al. (2004) characterized emissions of NO2,
formaldehyde (HCHO), carbon monoxide (CO) and a number of hydrocarbons, aldehydes, and
acids from unvented gas heaters in a chamber study in Australia. They found highly variable
concentrations of these pollutants depending on the model of heater and operating conditions.
Concentrations of NO2 in their room-sized test chamber ranged from 180 to 810 ppb; HCHO
ranged from <10 to 2100 ppb; CO ranged from ~1 to 18 ppm along with smaller amounts of
PM2.5 and hydrocarbons, aldehydes, and acids.
Chemistry in indoor settings can be both a source and a sink for N02 (Weschler and
Shields, 1997). NO2 is produced by reactions of NO with O3 or peroxy radicals, while NO2 is
removed by gas phase reactions with O3 and assorted free radicals and by surface-promoted
hydrolysis and reduction reactions. The concentration of indoor NO2 also affects the
decomposition of PAN. Each of these processes is discussed below.
Indoor NO can be oxidized to NO2 by reacting with O3 or peroxy radicals. The latter are
generated by indoor air chemistry involving O3 and unsaturated hydrocarbons such as terpenes
found in air fresheners and other household products (Sawar et al., 2002a,b; Nazaroff and
Weschler, 2004; Carslaw, 2007).
At an indoor O3 concentration of 10 ppb and an indoor NO concentration that is
significantly smaller than that of O3, the half-life of NO is 2.5 min (using kinetic data contained
in Jet Propulsion Laboratory, 2006). This reaction is sufficiently fast to compete with even
August 2007
2-23
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
relatively fast air exchange rates. Hence, the amount of NO2 produced from NO tends to be
limited by the amount of O3 available (Weschler et al., 1994).
N02 reacts with 03 to produce nitrate radicals (N03). To date, there have been no indoor
measurements of the concentration of NO3 radicals in indoor settings. Modeling studies by
Nazaroff and Cass (1986), Weschler et al. (1992), Sarwar et al. (2002b), and Carslaw et al.
(2007) estimate indoor NO3 radical concentrations in the range of 0.01 to 5 parts per trillion
(ppt), depending on the indoor levels of 03 and N02. Once formed, N03 can oxidize organic
compounds by either adding to an unsaturated carbon bond or abstracting a hydrogen atom
(Wayne et al., 1991). In certain indoor settings, the nitrate radical may be a more important
indoor oxidant than either O3 or the hydroxyl radical (Nazaroff and Weschler, 2004; Wayne
et al., 1991). Thus, N03 radicals and the products of N03 radical chemistry may be meaningful
confounders in NO2 exposure studies.
Reactions between NO2 and various free radicals can be an indoor source of organo-
nitrates, analogous to the chain-terminating reactions observed in photochemical smog
(Weschler and Shields, 1997). Additionally, based on laboratory measurements and
measurements in outdoor air (Finlayson-Pitts and Pitts, 2000), one would anticipate thatN02, in
the presence of trace amounts of HNO3, can react with PAHs sorbed onto indoor surfaces to
produce mono- and dinitro-PAHs. Nitrogen dioxide can also be reduced on certain surfaces,
forming NO. Spicer et al. (1989) found that as much as 15% of the NO2 removed on various
indoor surfaces was reemitted as NO. Weschler and Shields (1996) found that the amount of
NO2 removed by charcoal filters used in buildings were almost equally matched by the amount
of NO subsequently emitted by the same filters.
Nitrogen dioxide can also be converted to HONO indoors through air chemistry. As
noted earlier in this chapter, HONO occurs in the atmosphere mainly through multiphase
processes involving NO2. Nitrous acid has been observed to form on surfaces containing
partially oxidized aromatic structures (Stemmler et al., 2006) and on soot particles (Aumann
et al., 1998). Indoors, surface-to-volume ratios are much larger than outdoors, and the surface-
mediated hydrolysis of N02 is a major indoor source of HONO (Brauer et al., 1990; Febo and
Perrino, 1991; Spicer et al., 1993; Brauer et al., 1993; Spengler et al., 1993; Wainman et al.,
2001; Lee et al., 2002). Lee et al. (2002) reported average indoor HONO levels were about 6
times higher than outdoor levels (4.6 versus 0.8 ppb). Indoor HONO concentrations averaged
August 2007
2-24
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
17% of indoor NO2 concentrations, and the two were strongly correlated. Indoor HONO levels
were higher in homes with humidifiers compared to homes without humidifiers (5.9 versus 2.6
ppb). This last observation is consistent with the studies of Brauer et al. (1993) and Wainman
et al. (2001), indicating that the production rate of HONO from NO2 surface reactions is larger at
higher relative humidities. Spicer et al. (1993) reported that an equilibrium between adsorption
of HONO from the gas range (or other indoor combustion sources) and HONO produced by
surface reactions determines the relative importance of these processes in producing HONO in
indoor air.
2.5.2.3.2 Associations among Ambient and Outdoor Concentrations and Personal
Exposures
Results of studies showing associations between ambient concentrations and personal
exposures are shown in Table 2.5-4A and results of studies showing associations between
outdoor concentrations and personal exposures are shown in Table 2.5-4B. Figure 2.5-3
summarizes these correlation coefficients with box-whisker plots.
The association between personal N02 exposure and ambient and outdoor N02
concentrations varies from poor to good as shown in Tables 2.5-4A and B, with stronger
associations generally found when outdoor rather than ambient concentrations are used. This
situation arises in part because outdoor measurements are generally made much closer to study
participants' homes than are measurements of ambient N02 concentrations (cf. Section 2.5.2.2).
Associations between ambient concentrations and personal exposures were not stratified
by the presence of indoor sources, except in Aim et al. (1998) and Sarnat et al. (2006). The
strength of the association between personal exposures and ambient and/or outdoor
concentrations for a population is determined by variations in indoor or other local sources, air
exchange rate, penetration, and decay rate of N02 in different microenvironments and the time
people spend in different microenvironments with different NO2 concentrations. Aim et al.
(1998) indicated that the association between personal exposure and outdoor concentration was
stronger than the correlation between personal exposure and central site concentration. Kim
et al. (2006) pointed out that the association was not improved using the ambient sampler closest
August 2007
2-25
DRAFT-DO NOT QUOTE OR CITE
-------
c
0
O
it
o
o
c
o
ro
a)
i_
o
o
0.4 -
-0.2
N = 26
N = 23
Personal vs. Ambient Personal vs. Outdoor
Figure 2.5-3.
Distribution of correlation coefficients between personal N02
exposure and ambient NO2 concentrations, and between personal NO2
exposure and outdoor N02 concentrations in urban areas. (Note:
Data presented here are rp and rs, and a square root was taken of R2
when necessary; N is the number of case studies examined.)
1 to a home. Home ventilation is another important factor modifying the personal-ambient
2 relationships; one would expect to observe the strongest associations for subjects spending time
3 indoors with open windows. Aim et al. (1998) and Kodama et al. (2002) observed the
4 association between personal exposure and ambient concentration became stronger during the
5 summer than the winter. However, Sarnat et al. (2006) reported that R2 values decreased from
6 0.34 for a low ventilation population to 0.16 for a high ventilation population in the summer, and
7 from 0.47 to 0.34 in the fall.
8 The association between personal exposure and ambient concentration is complicated and
9 is determined by many factors. Exposure misclassification might occur if a single factor, such as
August 2007
2-26
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
season or ventilation status, is used as an exposure indicator. Higher personal to ambient
correlation has been found for subjects living in rural areas and lower correlation with subjects
living in urban areas (Rojas-Bracho et al., 2002; Aim et al., 1998). Spengler et al. (1994) also
observed that the relationship between personal exposure and outdoor concentration was highest
in areas with lower ambient NO2 levels (R2 = 0.47) and lowest in areas with higher ambient NO2
levels (R2 = 0.33). This might reflect the highly heterogeneous distribution or the effect of local
sources of N02 in an urban area, and personal activities are more diverse in an urban area.
However, it is also possible that indoor sources could explain more personal exposure when
ambient concentrations become lower and more homogeneously distributed.
When there is little or no contribution from indoor sources, ambient concentrations
primarily determine exposure; however, if there are indoor sources, the importance of outdoor
levels in determining personal exposures decreases. The association between ambient
concentrations and personal exposures strengthens after controlling for indoor sources.
Raaschou-Nielsen et al. (1997), Spengler et al. (1994), and Gauvin et al. (2001) reported that R2
values increased by 10 to 40% after controlling for indoor sources, such as gas appliances and
ETS.
The correlation coefficient between personal exposures and ambient concentrations has
different meanings for different study designs. There are three types of correlations generated
from different study designs: longitudinal, "pooled," and daily-average correlations.
Longitudinal correlations are calculated when data from a study includes measurements over
multiple days for each subject (longitudinal study design). Longitudinal correlations describe the
temporal relationship between daily personal NO2 exposure or microenvironment concentration
and daily ambient NO2 concentration for each individual subject. The longitudinal correlation
coefficient may differ for each subject. The distribution of correlations across a population could
be obtained with this type of data. Pooled correlations are calculated when a study involves one
or only a few measurements per subject and when different subjects are studied on subsequent
days. Pooled correlations combine individual subject/individual day data for the calculation of
correlations. Pooled correlations describe the relationship between daily personal N02 exposure
and daily ambient NO2 concentration across all subjects in the study. Daily-average correlations
are calculated by averaging exposure across subjects for each day. Daily-average correlations
then describe the relationship between the daily average exposure and daily ambient NO2
August 2007
2-27
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
concentration (U.S. Environmental Protection Agency, 2004). The type of correlation analysis
can have a substantial effect on the value of the resultant correlation coefficient. Mage et al.
(1999) showed that very low correlations between personal exposure and ambient concentrations
could be obtained when people with very different non-ambient exposures are pooled, even
though their individual longitudinal correlations are high. Most studies, (employing both cross-
sectional and longitudinal study designs) examined in the current review showed that ambient
N02 is associated with personal N02 exposure, however, the strength of the association varied
considerably.
2.5.2.3.3 Ambient Contribution to Personal NO2 Exposure
Another aspect of the relationship of personal NO2 exposure and ambient NO2 is the
contribution of ambient NO2 to personal exposures. The infiltration factor (/•',„/) and alpha (a)
are the keys to evaluate personal NO2 exposure of ambient origin. As defined in Equations 2.5-2
through 2.5-5, the infiltration factor (/•',„/) of NO2, the physical meaning of which is the fraction
of ambient N02 found in the indoor environment, is determined by the N02 penetration
coefficient (P), air exchange rate (a), and the N02 decay rate (k). Alpha (a) is a function of Finf
and the fraction of time people spend outdoors (y), and the physical meaning of a is the ratio of
personal ambient exposure concentration to ambient concentration, in the absence of exposures
to non-ambient sources (i.e., when Ena = 0).
The values for a and F^/can be calculated physically through Equations 2.5-2 through
2.5-5, if P, k, a, and >' are known. However, the values of P and k for NO2 are rarely reported,
and in most mass balance modeling work, P is assumed to equal 1 and k is assumed to equal
0.99 h_1, (Yamanaka, 1984; Yang et al., 2004; Dimitroulopoulou et al., 2001; Kulkarni et al.,
2002). It is well known that P and k are dependent on a large number of indoor parameters, such
as temperature, relative humidity, surface properties, surface-to-volume ratio, the turbulence of
airflow, building type and coexisting pollutants (Lee et al., 1996; Cotterill et al., 1997; Monn
et al., 1998; Garcia-Algar et al., 2003; Sorensen et al., 2005; Zota et al., 2005). As a result, using
a fixed value, as mentioned above, would either over- or underestimate the true a or Finf. It
should also be pointed out that both P and k are functions of the complicated mass transfer
processes that occur on indoor surfaces, and therefore, are associated with air exchange rate,
August 2007
2-28
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
which has an impact on the turbulence of indoor airflows. However, the relationship between P,
k, and a has not been thoroughly investigated.
Alternatively, the ratio of personal exposure to ambient concentration can be regarded as
a in the absence of indoor or nonambient sources. Only a few studies have reported the value
and distribution of the ratio of personal N02 exposure to ambient N02 concentration, and even
fewer studies reported the value and distribution of a based on sophisticated study designs.
Rojas-Bracho et al. (2002) reported the median personal/outdoor ratio was 0.64 (with an IQR of
0.45), but the authors reported that a was overestimated by this ratio because of indoor sources.
The random component superposition (RCS) model is an alternative way to calculate Finf
or a using observed ambient and personal exposure concentrations (Ott et al., 2000). The RCS
statistical model (shown in Equation 2.5-2 through 2.5-5) uses the slope of the regression line of
personal concentration on the ambient NO2 concentration to estimate the population averaged
attenuation factor and means and distributions of ambient and nonambient contributions to
personal NO2 concentrations (the intercept of the regression is the averaged nonambient
contribution to personal exposure) (U.S. Environmental Protection Agency, 2004). As shown in
Table 2.5-5, a calculated by the RCS model ranges from 0.3 to 0.6. Similarly, as shown in Table
2.5-6, Fin ranges from 0.4 to 0.7.
The RCS model calculates ambient contributions to indoor concentrations and personal
exposures based on the statistical inferences of regression analysis. However, personal-outdoor
regressions could be affected by extreme values (outliers either on the x or the >' axis). Another
limitation of the RCS model is that this model is not designed to estimate ambient and
nonambient contributions for individuals, in part because the use of a single value for a does not
account for the large home-to-home variations in actual air exchange rates and penetration and
decay rates of NO2. In the RCS model, a is also determined by the selection of the predictor.
Using residential outdoor NO2 concentrations as the model predictor might give a different
estimate of a than using ambient NO2 because of the spatial variability of NO2 mentioned early
in this section.
Personal exposure levels in most of the studies considered here were lower than the
corresponding outdoor or ambient levels. In the presence of local sources (indoor or local traffic
sources not accounted for by the ambient monitor), personal exposure levels could be higher than
outdoor or ambient levels (Spengler et al., 1994, 1996; Nakai et al., 1995; Linn et al., 1996;
August 2007
2-29
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Raaschou-Nielsen et al., 1997; Aim et al., 1998; Levy et al., 1998; Monn et al., 1998; Liard et al.,
1999; Kramer et al., 2000; Linaker et al., 2000; Mukala et al., 2000; Gauvin et al., 2001; Moon
et al., 2001; Rotko et al., 2001; Sarnat et al., 2001, 2005, 2006; Kodama et al., 2002; Mosqueron
et al., 2002; Ramirez-Aguilar et al., 2002; Rojas-Bracho et al., 2002; Lai et al., 2004; Nerriere
et al., 2005; Sorensen et al., 2005; Kim et al., 2006).
Nerriere et al. (2005) investigated factors determining the discrepancies between personal
exposure and ambient levels in the Genotox ER study in France (Grenoble, Paris, Rouen, and
Strasbourg). The authors reported that factors affecting the concentration discrepancies between
personal exposure and corresponding ambient monitoring site concentrations were season, city
and land use dependent. During the winter, city and land use account for 31% of the variation of
the discrepancy, and during the summer, 54% of the variation in the discrepancy can be
explained by these factors. When using the ambient site to represent ambient levels, the largest
difference between ambient and personal exposure was found at the "proximity to traffic" site,
while the smallest difference was found at the "background" site. When using urban background
site as ambient level, the largest difference was observed at the "industry" site, and the smallest
difference was observed at the background site, which reflected the heterogeneous distribution of
NO2 in an urban area. During winter, differences between ambient site and personal exposure
concentrations were larger than those in the summer.
In summary, NO2 is monitored at far fewer sites than either O3 or PM. Significant spatial
variations in ambient N02 concentrations were observed in urban areas. Measurements of N02
are subject to artifacts both at the ambient level and at the personal level. Personal exposure to
ambient and outdoor NO2 is determined by many factors as listed in Section 2.5.1 and mentioned
previously in Section 2.5.2. These factors all help determine the contribution of ambient NO2 to
personal exposures. Personal activities determine when, where, and how people are exposed to
NO2. The variations of these physical and exposure factors determine the strength of the
association between personal exposure and ambient concentrations both longitudinally and cross-
sectionally. In the absence of indoor and local sources, personal exposures to NO2 are between
the ambient level and the indoor level. However, personal exposures could be much higher than
either indoor or outdoor concentrations in the presence of these sources. A number of studies
found that personal NO2 was associated with ambient NO2, but the strength of the association
ranged from poor to good.
August 2007
2-30
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Some researchers concluded that ambient NO2 may be a reasonable proxy for personal
exposures, while others noted that caution must be exercised if ambient NO2 is used as a
surrogate for personal exposure. Reasons for the differences in study results are not clear, but
are related in large measure to differences in study design, to the spatial heterogeneity of NO2 in
study areas, to indoor sources, to the seasonal and geographic variability in the infiltration of
ambient NO2, and to differences in the time spent in different microenvironments. Measurement
artifacts at the ambient level and differences in analytical measurement capabilities among
different groups could also have contributed to the mixed results. The collective variability in all
of the above parameters, in general, contributes to exposure misclassification errors in air
pollution-health outcome studies.
The association between community average exposures and ambient concentrations is
more directly relevant to epidemiological studies, in which ambient concentrations are used as a
surrogate for community exposure. Liard et al. (1999) conducted an exposure study for office
workers and children in Paris. Three 4-day averaged measurements were conducted for both
adults and children, and personal N02 exposures were measured at the same time for each study
participant. The authors reported that the population-averaged exposure during each
measurement fluctuated with the ambient concentration, with an rs of 1, although the correlation
coefficient based on individual measurements was low (Table 2.5-4A). The findings in this
study support the assumption in time-series epidemiological studies that ambient concentrations
are a reasonable surrogate for community average exposures. Monn et al. (1998) and Monn
(2001) reported personal NO2 exposures obtained in the SAPALDIA study (eight study centers
in Switzerland). In each study location, personal exposures for NO2 were measured
simultaneously for all participants, as well as the residential outdoor concentrations (Table
2.5-4B). Monn (2001) observed a strong association between the average personal exposures in
each study location and corresponding average outdoor concentrations with an R2 of 0.965. As
pointed out by the author, in an analysis of individual single exposure and outdoor concentration
data, personal versus outdoor R2 was less than 0.3 (Monn et al., 1998). The results of Monn
(2001) imply that long-term averaged ambient concentrations are a good surrogate for population
exposures.
August 2007
2-31
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2.5.2.4 Exposure Measurement Error in Epidemiological Studies: N02
In many air pollution epidemiological studies, especially time-series studies with
administrative data on mortality and hospitalization outcomes, data from central ambient
monitoring sites generally are used as the estimate of exposure. Personal exposures of individual
study subjects generally are not directly measured in epidemiological studies. Routinely
collected ambient monitor data, though readily available and convenient, may not represent true
personal exposure, which includes both ambient and nonambient (i.e., indoor) source exposures.
Also, personal exposure measurements may or may not be subject to the same artifacts as the
ambient measurements. Therefore, they may not be measuring the same quantities. Zeka and
Schwartz (2004) state that each pollutant, as measured at a central site in each city, is a surrogate
for exposure to the same pollutant in personal exposure measurements.
In considering exposure error, it should be noted that total personal exposure can be
partitioned into two types of sources, ambient and nonambient. Sheppard (2005) notes that
nonambient source exposures typically vary across individuals, but the community averages do
not vary across communities. In addition, nonambient exposures are not likely to have strong
temporal correlations. In contrast, ambient concentrations across individuals should be highly
correlated, as they tend to vary over time similarly for everyone because of changes in source
generation, weather, and season. The independence of ambient and nonambient exposure
sources has important implication. Sheppard et al. (2005) observes that when ambient and
nonambient sources are independent, exposure variation due to nonambient source exposures
behaves like Berkson measurement error (i.e., statistically independent from the observed
variable) and does not bias the effect estimates.
A simulation study by Sheppard et al. (2005) also considered attenuation of the risk based
on personal behavior, their microenvironment, and qualities of the pollutant in time-series
studies. Of particular interest is their finding that significant variation in nonambient exposure or
in ambient source exposure that is independent of ambient concentration does not further bias the
effect estimate. In other words, risk estimates were not further attenuated in time-series studies
even when the correlations between personal exposures and ambient concentrations were weak.
In the case of NO2, there are exposures to nonambient indoor sources to consider.
Exposures to nonambient sources are largely independent of ambient exposures for a number of
sources such as exposures associated with cooking or smoking. However, the relationship
August 2007
2-32
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
between exposure to some nonambient sources and to ambient concentrations may not be
entirely straightforward. If the indoor source strength is driven by outdoor parameters that also
determine ambient levels, then exposures to these sources could be associated with ambient
concentrations. For example, use of natural gas or other fuels for heating varies with outdoor
temperatures and are a source of nonambient exposures to NO2. Of course, the contribution to
personal exposures from indoor heating depends to a large extent on how efficiently the
emissions are vented. Ambient levels will also vary with emissions from local facilities, such as
power plants, that respond to changes in temperature. Indoor sources could also be affecting
ambient levels. This situation is found in many areas where there can be trapping of emissions
within topographic features. Again, the contribution of the nonambient sources depends largely
on how efficiently the emissions are vented.
Other complications for NO2 in the relationship between personal exposures and ambient
concentrations include expected strong seasonal variation of personal behaviors and building
ventilation practices that can modify exposure. Also, there may be potential differential errors
based on different measurement techniques for ambient and personal measurement. In addition,
the relationship may be affected by temperature (e.g., high temperature may increase air
conditioning use, which may reduce NO2 penetration indoors), further complicating the role of
temperature as a confounder of NO2 health effects. It should be noted that the pattern of
exposure misclassification error and influence of confounders may differ across the outcomes of
interest as well as in susceptible populations and by study design. For example, those who may
be suffering from chronic cardiovascular or respiratory conditions may be in a more protective
environment (i.e., with less exposure to both NO2 and its confounders such as temperature and
PM) than those who are healthy.
As discussed thoroughly in the 2004 PM AQCD (Section 8.4.5), the resulting exposure
measurement error and its effect on the estimates of relative risk must be considered to include
both Berkson type and classical-type error (i.e., statistically independent of the true variable).
Errors of the classical type arise when a quantity is measured by some device and repeated
measurements vary around the true value. Error of the Berkson type is involved when a group's
average is assigned to each individual suiting the group's characteristics. The group's average is
thus the "measured value," that is the value that enters the analysis, and the individual latent
value is the "true value" (Heid et al., 2004)
August 2007
2-33
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
In theory, there are three components to exposure measurement error in time-series
studies as described by Zeger et al. (2000): (1) the use of average population rather than
individual exposure data, (2) the difference between average personal ambient exposure and
ambient concentrations at central monitoring sites, and (3) the difference between true and
measured ambient concentrations. The first error component, having aggregate rather than
individual exposure data, is a Berkson measurement error, which in a simple linear model
increases the standard error, but does not bias the risk estimate. The second error component
resulting from the difference between average personal ambient exposure and outdoor ambient
concentration level has the greatest potential to introduce bias. If the error is of a fixed amount
(i.e., absolute differences do not change with increasing concentrations), there is no bias.
However, if the error is not a fixed difference, this error will likely attenuate the N02 risk
estimate, as personal NO2 exposures are generally lower than ambient NO2 concentrations in
homes without sources while they are higher in homes with sources. The third error component,
the instrument measurement error in the ambient levels, is referred to as nondifferential
measurement error and, while unlikely to cause substantial bias, can lead to a bias toward
the null.
Sheppard (2005) stated that the time-series design is an ecologic study design and, thus,
suffers from loss of information (i.e., sources of variation) in the analysis. In air pollution
studies, it only uses information about the ambient concentrations, which represent only a
fraction of the total personal exposure variation over time and individuals in a population. Thus,
there is less power in time-series studies than there would be if the time-series design could use
all the exposure variation in the population. Sheppard concluded that the size of the populations
that can be feasibly studied in time-series studies, even with the lower exposure variation from
using only ambient concentration data, overwhelms the benefits of using total personal exposure
on a subset of the population in a feasible panel study. Relative to panel studies, time-series
studies are immensely more powerful, because they can consider all the events over time in
entire populations.
Interpretation of the results observed in epidemiological studies using N02 measurements
from ambient monitoring sites needs to consider the impact of exposure measurement error.
Results from a simulation study by Sheppard et al. (2005) seem to suggest that effect estimates
were not further biased in time-series studies even when the correlations between personal
August 2007
2-34
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
exposures and ambient concentrations were weak. Zeger et al. (2000) indicated that realistic
models for estimating air pollution health effects have elements of both classical and Berkson
error models, which generally lead to effect estimates biased toward the null. However, they
also noted that when a pollutant with no health effect is correlated with at least one pollutant
having a nonzero effect, regression coefficients can be biased away from the null; that is,
positive associations can be observed.
2.5.3 N02 as a Component of Mixtures
2.5.3.1 Correlations between Ambient NO2 and Ambient Copollutants
Confounding of NO2 health effects is often examined at the ambient level, as ambient
concentrations are generally used to reflect exposures in epidemiological studies. The majority
of studies examining pollutant associations in the ambient environment have focused on ambient
NO2, PM2.5 (and its components), and CO, with fewer studies reporting the relationship between
ambient NO2 and ambient O3 or SO2.
Data were compiled from EPA's Air Quality System and a number of exposure studies.
Correlations between ambient concentrations of N02 and other pollutants, PM2.5 (and its
components where available), CO, O3, and SO2 are summarized in Table 2.5-7. Mean values of
paired, site-wise correlations are shown. As can be seen from the table, NO2 is moderately
correlated with PM2.5 (range: 0.37 to 0.78) and with CO (0.41 to 0.76) in suburban and urban
areas. At locations such as Riverside, CA, associations between ambient N02 and ambient CO
concentrations (both largely traffic-related pollutants) are much lower, likely as the result of
other sources of both CO and NO2 increasing in importance in moving away from the urban
core. These sources include oxidation of CH4 and other biogenic compounds, residential wood
burning and prescribed and wild land fires for CO and soil emissions, lightning, and residential
wood burning and wild land fires for NO2. In urban areas, the ambient NO2-CO correlations
vary widely. The strongest correlations are seen between NO2 and elemental carbon. Note that
the results of Hochadel et al. (2006) for PM2.5 optical absorbance have been interpreted in terms
of elemental carbon (EC). Correlations between ambient N02 and ambient 03 are mainly
negative, owing to the chemical relation between the two, with again considerable variability in
the observed correlations. Only one study (Sarnat et al., 2001) examined associations between
August 2007
2-35
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
ambient NO2 and ambient SO2 concentrations, and it showed a negative correlation during
winter. This analysis needs to be extended to other cities.
Figures 2.5-4a-d show seasonal plots of correlations between N02 and 03 versus
correlations between NO2 and CO. As can be seen from the figures, NO2 is positively correlated
with CO during all seasons at all sites. However, the sign of the correlation of NO2 with O3
varies with season, ranging from negative during winter to slightly positive during summer.
There are at least two main factors contributing to the observed seasonal behavior. Ozone and
radicals correlated with it tend to be higher during the summer, thereby tending to increase the
ratio of NO2 to NO. Nitrogen oxide compounds formed by further the oxidation of NOx are also
expected to be correlated with O3 and increased summertime photochemical activity. Because
some of these additionally oxidized nitrogen compounds create a positive artifact in the FRM for
NOz, they may also tend to increase the correlation of NO2 with O3 during the warmer months.
A number of case studies show similar correlations between ambient NO2 and other
pollutants presented above. Particulate and gaseous copollutants data were analyzed at 10 sites
in St. Louis Regional Air Pollution Study dataset (1975-1977) by Kim et al. (2005). This study
examined the spatial variability in source contributions to PM2.5 Table 2.5-8 shows correlations
between NOx and traffic pollutants measured in ambient air.
Leaded gasoline was in use at the time, making Pb and Br good markers for motor
vehicle exhaust. Motor vehicle emissions are the main anthropogenic source of CO in urban
areas. However, outside of urban areas and away from sources burning fossil fuels, biomass
burning and the oxidation of biogenic hydrocarbons, in particular isoprene and methane, can
represent the major source of CO. In general, biogenic emissions of precursors to CO formation
or CO from biomass burning can cause the relationship between CO and motor vehicles to break
down.
In the Restrepo et al. (2004) study, NO2 behaved as if traffic was its main source, as NO2
behaved similarly to CO and PM2.5, i.e., their concentrations decreased with height. Ozone
showed the opposite vertical gradient, i.e., its concentration increased with height. Seaton and
Dennekamp (2003) suggested that N02 may be a surrogate for ultrafine particles, in particular
August 2007
2-36
DRAFT-DO NOT QUOTE OR CITE
-------
o
CM
O
Winter
— 1-
Summer
0.8'
0.6'
0,4'
0.2-
—i 1 1—
I -0.8 -0.6 -0.4 -0.2 0 0.2 04 0.6 0.8
-0.2 ¦
-0.4 ¦
-0.6 ¦
-0.8-
¦ -1'
:A\>
0.8-
0.6-
0 4-
0.2-
~* * *
~ ~ ~ ~
1 1 1 1 u
4. 1 1
-0.2
-0.4 ¦
-0.6 ¦
-0.8-
N0Z: CO
Spring
N02: CO
Fall
0.8-
0 8-
0 6-
0.6-
0 4-
0.4-
CO
O
0.2-
co
0
0 2-
~ ~~ A
~ \ #
(N
O
1 -08 -06 -04 -02
V ot 0* |B
N
O
1 -0.8 -0.6 -0.4 -0.2
0.2 0.4 *0.6 fi.e
z
-0 2 ¦
Z
-0 2 ¦
-0.4 ¦
-0.4 ¦
~ ~
-0.6 "
-0.6 ¦
-0.8-
-0.8-
N02: CO
N02: CO
Figure 2.5-4a-d. Correlations of NO2 to O3 versus correlations of NO2 to CO for Los
Angeles, CA (2001-2005).
1 for particle number concentrations. The results from the measurements made at a background
2 site in Aberdeen city over the course of 6 months showed very high correlation between the
3 number concentration of particles less than 100 nm in diameter and NO2. The correlation
4 between N02 and the particle number concentration (r = 0.89) was much higher than that
5 between NO2 and PM2.5
August 2007
2-37
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
(r = 0.55) and that between NO2 and PM10 (r = 0.45). A time-series mortality study (Wichmann
et al., 2000; re-analysis by Stolzel et al., 2003) conducted in Erfurt, Germany, measured and
analyzed ultrafine particle number and mass concentrations as well as N02. Unlike Seaton and
Dennekamp's data, in this data set, the correlation between NO2 and various number
concentration indices were not much stronger than those between PM2.5 and number
concentration indices or those between PM10 and number concentration indices. For example,
the correlation between NC0.oi-o.io (particle number concentration for particle diameter between
10 and 100 nm) and NO2, PM2.5, and PM10 were 0.66, 0.61, and 0.61, respectively.
2.5.3.2 Correlations of Personal and Ambient NO2 and Personal and Ambient
Copollutants
Correlations between ambient concentrations of N02 and personal copollutants, PM2.5
(and its components where available), CO, O3, and SO2 are summarized in Table 2.5-9.
Correlations between personal concentrations of NO2 and ambient copollutants, PM2.5 (and its
components where available), CO, O3, and SO2 are summarized in Table 2.5-10, and correlations
between personal N02 concentrations and personal copollutant concentrations are shown in
Table 2.5-11.
Most studies examined above show that personal NO2 concentrations are significantly
correlated with either ambient or personal level PM2.5 or other combustion generated pollutants,
e.g., CO and EC.
As might be expected from a pollutant having a major traffic source, the diurnal cycle of
NO2 in typical urban areas is characterized by traffic emissions, with peaks in emissions
occurring during morning and evening rush hour traffic. Motor vehicle emissions consist mainly
of NO, with only about 10% of primary emissions in the form of NO2. The diurnal pattern of
NO and N02 concentrations are also strongly influenced by the diurnal variation in the mixing
layer height. Thus, during the morning rush hour when mixing layer heights are still low, traffic
produces a peak in NO and NO2 concentrations. As the mixing layer height increases during the
day, dilution of emissions occurs, and NO and NO2 are converted to NOz. During the afternoon
rush hour, mixing layer heights are often still at, or are near, their daily maximum values
resulting in dilution of traffic emissions through a larger volume than in the morning. Starting
near sunset, the mixing layer height drops and conversion of NO to NO2 occurs without
subsequent photolysis of NO2 recreating NO.
August 2007
2-38
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
The composite diurnal variability of NO2 in selected urban areas with multiple sites
(New York, NY; Atlanta, GA; Baton Rouge, LA; Chicago, IL; Houston, TX; Riverside, CA; and
Los Angeles, CA) is shown in Figure 2.5-5. Figure 2.5-5 shows that lowest hourly median
concentrations are typically found at around midday and that highest hourly median
concentrations are found either in the early morning or in mid-evening. Median values range by
about a factor of two from about 13 ppb to about 25 ppb. However, individual hourly
concentrations can be considerably higher than these typical median values, and hourly N02
concentrations of >0.10 ppm can be found at any time of day.
E
o.
a
c
o
+3
ra
u.
c
0)
o
c
o
o
0.20-
0.19-
0.18-
0.17
0.16
0.15
0.14
0.13
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
X X X
xx*
5*
ill
tt 4 M
p
i 111 p 11 1 111 1 1 111 1 111 1 p 1 1 111 1 111 1 111 1 111 1 1111 1 11
0123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hour
Figure 2.5-5
Composite, diurnal variability in 1-h average NO2 in urban areas.
Values shown are averages from 2003 through 2005. Boxes define the
interquartile range, and the whiskers the 5th and 95th percentile
values. Asterisks denote individual values above the 95th percentile.
Information concerning the seasonal variability of ambient NO2 concentrations is given
in the Section AX3.3. NO2 levels are highest during the cooler months of the year and still show
positive correlations with CO. Mean NO2 levels are lowest during the summer months, though
of course, there can be large positive excursions associated with the development of high-
August 2007
2-39
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
pressure systems. In this regard, NO2 behaves as a primary pollutant, although there is no good
reason to suspect strong seasonal variations in its emissions.
2.6 DOSIMETRY OF INHALED NITROGEN OXIDES
This section provides a brief overview of N02 dosimetry and updates information
provided in the 1993 AQCD for Oxides of Nitrogen. A more extensive discussion of NO2
dosimetry appears in Annex 4. Nitrogen dioxide, classified as a reactive gas, interacts with
surfactants, antioxidants, and other compounds in the epithelial lining fluid (ELF). The
compounds thought to be responsible for adverse pulmonary effects of inhaled N02 are the
reaction products themselves or the metabolites of these products in the ELF.
Acute NO2 uptake in the lower respiratory tract is thought to be rate-limited by chemical
reactions of NO2 with ELF constituents rather than by gas solubility in the ELF (Postlethwait and
Bidani, 1990). Postlethwait and Bidani (1994) concluded that the reaction between N02 and
water does not significantly contribute to the absorption of inhaled NO2. Rather, uptake is a
first-order process for NO2 concentrations of <10 ppm, is aqueous substrate-dependent, and is
saturable. Postlethwait et al. (1991) reported that inhaled NO2 (<10 ppm) does not penetrate the
ELF to reach underlying sites and suggested that cytotoxicity may be due to N02 reactants
formed in the ELF. Related to the balance between reaction product formation and removal, it
was further suggested that cellular responses may be nonlinear with greater responses being
possible at low levels of NO2 uptake versus higher levels of uptake.
Ascorbate and glutathione (GSH) are the primary N02 absorption substrates in rat ELF
(Postlethwait et al., 1995). Velsor and Postlethwait (1997) investigated the mechanisms of acute
epithelial injury from NO2 exposure. Membrane oxidation was not a simple monotonic function
of GSH and ascorbic acid levels. The maximal levels of membrane oxidation were observed at
low antioxidant levels versus null or high antioxidant levels. Glutathione and ascorbic acid-
related membrane oxidation were superoxide and hydrogen peroxide dependent, respectively.
The authors suggested that increased absorption of NO2 occurred at the higher antioxidant
concentrations, but little secondary oxidation of the membrane occurred because the reactive
species (e.g., superoxide and hydrogen peroxide) generated during absorption were quenched. A
lower rate of N02 absorption occurred at the low antioxidant concentrations, but oxidants were
not quenched and so were available to interact with the cell membrane. Illustrating the complex
August 2007
2-40
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
interaction of antioxidants, some studies suggest that MVoxidized GSH may be again reduced
by uric acid and/or ascorbic acid (Kelly et al., 1996; Kelly and Tetley, 1997).
Very limited work related to the quantification of N02 uptake has been reported since the
1993 AQCD for Oxides of Nitrogen. In both humans and animals, the uptake of NO2 uptake by
the upper respiratory tract decreases with increasing ventilator rates. This causes a greater
proportion of inhaled NO2 to be delivered to the lower respiratory tract. In humans, the
breathing pattern shifts from nasal to oronasal during exercise relative to rest. Since the nasal
passages absorb more inhaled NO2 than the mouth, exercise (with respect to the resting state)
delivers a disproportionately greater quantity of the inhaled mass to the pulmonary region of the
lung, where the NO2 is readily absorbed. Bauer et al. (1986) reported a statistically significant
increase in uptake from 72% during rest to 87% during exercise in a group of 15 asthmatic
adults. The minute ventilation also increased from 8.1 L/min during rest to 30.4 L/min during
exercise. Hence, exercise increased the dose rate of NO2 by 5-fold in these subjects. Similar
results have been reported for beagle dogs where the dose rate of NO2 was 3-fold greater for the
dogs during exercise than rest (Kleinman and Mautz, 1991).
2.7 INDOOR AND PERSONAL EXPOSURE HEALTH STUDIES
At the time of the 1993 AQCD for Oxides of Nitrogen, many of the available health
effects studies consisted predominately of indoor NO2 exposure studies. Although indoor
sources in these studies include both gas-fueled cooking and heating appliances, in most of the
older studies the focus was primarily on cooking stoves. Indoor studies evaluated in the 1993
AQCD for Oxides of Nitrogen include Neas et al. (1991), Dijkstra et al. (1990), Ekwo et al.
(1983), Ware et al. (1984), Melia et al. (1977, 1979, 1982a,b, 1990), and Keller et al. (1979a,b).
Indoor studies examining children 2 years old or younger include Samet et al. (1993, 1992),
Ogston et al. (1985), and Margolis et al. (1992). Available outdoor studies with ambient N02
measures include Dockery et al. (1989), Braun-Fahrlaender et al. (1992), Schwartz (1989),
Schwartz et al. (1991), Schwartz and Zeger (1990), and Vedal et al. (1987). Although there was
some evidence suggesting that increased NO2 exposure was associated with increased respiratory
symptoms in children aged 5 to 12 years, the main conclusion was that there was insufficient
epidemiological evidence for an association between short-term exposure and health effects.
August 2007
2-41
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2.7.1 Recent Indoor Studies of Exposures to Nitrogen Oxides and Heath
Outcomes
These studies consist of NO2 exposures that may differ from ambient exposure in relation
to pattern, levels, and associated copollutants (see Annex Table AX6.1 for details). Samet and
Bell (2004) state that, while "evidence from studies of outdoor air pollution cannot readily
isolate an effect of NO2 because of its contribution to the formation of secondary particles and
ozone, observational studies of exposure indoors can test hypothesis related to NO2 specifically
although confounding by combustion sources in the home is a concern." Thus, indoor NO2
sources are not likely confounded by other ambient pollutants such as PM, 03, CO, and S02.
Most of the studies conducted since 1993 have taken place in Australia and attempted to
capture indoor exposures (with passive diffusion badges) from both cooking and heating sources
in homes and schools (Pilotto et al., 1997a, 2004; Garrett et al., 1998; Smith et al., 2000).
Several indoor exposure studies have also been conducted in Europe (Farrow et al., 1997; Simoni
et al., 2002, 2004), one in Singapore (Ng et al., 2001), and one cohort study in the United States
(Belanger et al., 2006; van Strien et al., 2004). The key results from these studies are
summarized in the Annex Table AX6.1. These include one key intervention study (Pilotto et al.,
2004) that provides strong evidence of a detrimental effect of exposure to indoor levels of N02.
Pilotto et al. (2004) conducted a randomized intervention study of respiratory symptoms
of asthmatic children in Australia before and after selective replacement of unflued gas heaters in
schools. In the study, 18 schools using unflued gas heaters were randomly allocated to have an
electric heater (n = 4) or a flued gas heater (n = 4) installed or to retain their original heaters
(n = 10). Changes to the heating systems were disguised as routine maintenance to prevent bias
in reporting of symptoms. Children were eligible for the study if they had physician-diagnosed
asthma and no unflued heater in their homes. For the 114 children enrolled, symptoms were
recorded daily and reported in fortnightly telephone interviews during 12 weeks in the winter.
Passive diffusion badges were used to measure NO2 exposure in classrooms (6 h/day) and in the
children's homes. Schools in the intervention group (with new heaters) averaged with overall
means (SD) of 15.5 (6.6) ppb NO2, while control schools (with unflued heaters) averaged
47.0 (26.8) ppb. Exposure to N02 in the children's homes was quite variable but with similar
mean levels. Levels at homes for the intervention group were 13.7 (19.3) ppb, and 14.6
(21.5) ppb for the control group. Children attending intervention schools had significant
August 2007
2-42
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
reductions in several symptoms: difficulty breathing during the day (rate ratio [RR] = 0.41
[95% CI: 0.07, 0.98]) and at night (RR = 0.32 [95% CI: 0.14, 0.69]); chest tightness during the
day (RR = 0.45 [95% CI: 0.25, 0.81]) and at night (RR= 0.59 [95% CI: 0.28, 1.29]); and
asthma attacks during the day (RR = 0.39 [95% CI: 0.17, 0.93]).
Samet and Bell (2004) state that Pilotto et al. (2004) provides persuasive evidence of an
association between exposure to NO2 from in-class heaters and the respiratory health of children
with asthma and further that the study provides evidence from an intervention and, thus, avoids
some potential limitations at observational studies. The two groups of children studied had
similar baseline characteristics. In addition, the concentrations in the home environment were
similar for the two groups, implying that exposure at school was likely to be the primary
determinant of a difference in indoor N02 exposure between the two groups. Samet and Utell
(1990) concluded that, the "absence of significant differences between the groups for lung
function tests and bronchial responsiveness are consistent with the majority of chamber study
results."
In an earlier study of the health effects of unflued gas heaters on wintertime respiratory
symptoms of 388 Australian schoolchildren, Pilotto et al. (1997a) measured NO2 in
41 classrooms in 8 schools, with half using unflued gas heaters and half using electric heat.
Although similar methods were used to measure NO2 levels (passive diffusion badge monitors
exposed for 6 h at a time), there were three major differences between this study and the 2003
study: (1) the 1997 study was not a randomized trial, (2) enrollment was not restricted to
asthmatic children, and (3) enrollment was not restricted to children from homes without unflued
gas heaters. In Pilotto et al. (1997a), only children from nonsmoking homes were enrolled and a
subset of children (n = 121) living in homes with unflued gas heaters were given badges to be
used at home. Symptoms were recorded daily by each child's parents. Children were classified
into low- and high-exposure groups based on their measured exposure at school, their measured
exposure at home (if they lived in homes with unflued gas heaters), or their reported use of
electric heat at home. Maximum hourly concentration in these classrooms each day over
2 weeks of hourly monitoring were highly correlated with their corresponding 6-h concentrations
measured over the same 2 weeks (r = 0.85). Hourly peaks of NO2 of the order of >80 ppb were
associated with 6-h average levels of approximately >40 ppb. They inferred that children in
classrooms with gas heaters that had 6-h average levels of >40 ppb were experiencing
August 2007
2-43
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
approximately 4-fold or higher 1-h peaks of exposure than the NO2 levels experienced by
children who had no gas exposure (6-h average levels of 20 ppb). The importance of this study
is that it examines the effect of repeated peaks over time as have been used in toxicological
infectivity studies (e.g., Miller et al., 1987).
Pilotto et al. (1997a) report that during the winter heating season, children in the high
exposure category (NO2 > 40 ppb) had higher rates of sore throat, colds, and absenteeism than all
other children. In models adjusted for personal risk factors including asthma, allergies, and
geographic area, classroom NO2 level and school absence were significantly associated (odds
ratio [OR] = 1.92 [95% CI: 1.13, 3.25]). Increased likelihood of individual respiratory
symptoms was not significantly associated with classroom level of NO2 (e.g., cough with
phlegm: adjusted OR = 1.28 (95% CI: 0.76,2.15). Dose-response relationships are illustrated
in Figure 2.7-1 for symptom rates for cough and in Figure 2.7-2 for school absence. Pilotto et al.
(1997b) notes that this study "provides evidence that short-term exposure to the peak levels of
NO2 produced by unflued gas appliances affects respiratory health and that the significant dose-
response relationship seen with increasing N02 exposure strengthens the evidence for a cause-
effect relationship."
One recent birth cohort study in the United States measured indoor exposure to NO2
(Belanger et al., 2006; van Strien et al., 2004). Families were eligible for this study if they had a
child with physician-diagnosed asthma (asthmatic sibling) and a newborn infant (birth cohort
subject). N02 levels were measured using Palmes tubes left in the homes for 2 weeks. Higher
levels of NO2 were measured in homes with gas stoves (mean [SD], 26 [18] ppb) than in homes
with electric ranges (9 [9] ppb). Children living in multifamily homes were exposed to more
NO2 (23 [17] ppb) than children in single-family homes (10 [12] ppb). The authors examined
associations between N02 concentrations and respiratory symptoms experienced by the
asthmatic sibling in the month prior to sampling (Belanger et al., 2005). For children living in
multifamily homes, each 20-ppb increase in NO2 concentration increased the likelihood of any
wheeze or chest tightness (OR for wheeze = 1.52 [95% CI: 1.04, 2.21]; OR for chest
tightness = 1.61 [95% CI: 1.04, 2.49]) as well as increasing the risk of suffering additional days
of symptoms. No significant associations were found between level of NO2 and symptoms for
children living in single-family homes. The authors suggested that the low levels of exposure
may have been responsible for the lack of association observed in single-family homes. In these
August 2007
2-44
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
£ 0.12
0.10
0.08
0.06
0.04
0.02
o
0.00
<40
n=105
i r
Intermed
n=39
40-60
n=46
60-80
n=12
n r
80-100
n=94
>100
n=92
Nitrogen dioxide, ppb
Figure 2.7-1. Geometric mean symptom rates and 95% confidence intervals for
cough with phlegm during the winter heating period for 388 children
grouped according to estimated amount of NO2 exposure at home and
at school. Group means and trends (p = 0.02) estimated from mixed
models allowing for correlation between children within classrooms
(unadjusted for confounding).
Source: Pilotto et al. (1997a).
same families, van Strien et al. (2004) compared the measured NO2 concentrations with
respiratory symptoms experienced by the birth cohort infants during the first year of life.
Although wheeze was not associated with NO2 concentration, persistent cough was associated
with increasing N02 concentration in a dose-response relationship as shown in Figure 2.7-3
(van Strien et al., 2004).
An important consideration in the evaluation of these study results is that NOx is part of a
complex mixture of chemicals emitted from unvented gas heaters. In addition to NO and NO2,
indoor combustion sources such as unvented gas heaters emit other pollutants that are present in
the fuel or are formed during combustion. The major products from the combustion of natural
gas are carbon dioxide (CO2) and CO followed by HCHO with smaller amounts of other
oxidized organic compounds in the gas phase. In a study of pollutants emitted by unvented gas
heaters, Brown et al. (2004) found that CO in a room test chamber ranged from 1 to 18 ppm for
August 2007
2-45
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
0.10
0.08
.m 0.06
0.04
0.02
0.00
i r
Intermed
n=39
1 T
80-100
n=94
1 1
>100
n=92
<40
n=105
40-60
n=46
60-80
n=12
Nitrogen dioxide, ppb
Figure 2.7-2. Proportions (and 95% confidence intervals) of children absent from
school for at least 1 day during the winter heating period grouped
according to estimated amount of NO2 exposure at home and at school
(n = 388). Group means and trend (p < 0.001) estimated from
Generalized (binomial) Linear Mixed Models (GLMM) allowing for
correlation between children with classrooms (unadjusted for
confounding).
Source: Pilotto et al. (1997a).
NO2 ranging from 100 to 300 ppb; corresponding levels of HCHO were highly variable, ranging
from <10 ppb to a few hundred ppb (with an outlier at >2 ppm).
PM in the sub-micrometer size range is also produced during natural gas combustion.
Ristovski et al. (2000) concluded that particulate mass emissions from natural gas heaters are
low but that natural gas heaters are larger sources of organic compounds, such as HCHO. They
also measured emission rates for individual particles, which are expected to be present mainly in
the ultrafine size range, but concluded that these rates are low and they could not detect an
increase in particle number from one of the two model heaters tested. However, Rogge et al.
(1993) found that at least 22% of the fine particle mass emitted by natural gas heaters consists of
PAHs, oxy-PAHs, and aza-and thia-arenes. They also identified emissions of speciated alkanes,
n-alkanoic acids, polycyclic aromatic ketones, and quinones. However, these accounted for only
about another 4% of the fine PM emitted. Although the rates of emission of PM are low and are
August 2007
2-46
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
a. persistent cough
<5 5-10 10-17 >17
N02 concentration quartile (ppb)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
b. shortnes
i
s of breat
i
1
h
<
1
1
<5 5-10 10-17 >17
N02 concentration quartile (ppb)
Figure 2.7-3. Data taken from Table 3 in van Strien et al. (2004). Adjusted
association of increasing indoor NO2 concentration with number of
days with persistent cough (panel a) or shortness of breath (panel b)
for 762 infants during the first year of life. Relative risks from
Poisson regression analyses adjusted for confounders.
not likely to affect PM levels, their PAH content indicates that natural gas combustion could be a
significant source of PAHs in indoor environments.
Overall, the recent studies build upon the evidence available from personal and indoor
exposure studies in the 1993 AQCD, showing consistent evidence of respiratory effects with
exposure to NO2. These studies can serve as a bridge between epidemiological studies and
controlled human exposure studies, as noted above, and provide some evidence of coherence for
respiratory effects. As is true for NOx in the ambient air, indoor NOx concentrations may be
correlated with a mixture of other pollutants. The major products of combustion of natural gas
include CO2 and CO, followed by HCHO, with smaller amounts of other oxidized organic
compounds in the gas phase and sub-micrometer PM whose major identifiable components are
PAHs, possibly complicating the interpretation of associations between health effects and indoor
NO2 levels.
August 2007
2-47
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2.7.2 Recent Studies of Personal NOx Exposure
Several studies collected personal exposure data for NO2. Personal exposure to NO2 and
the severity of virus-induced asthma (Chauhan et al., 2003), including risk of airflow obstruction
(Linaker et al., 2000) was studied in a group of 114 asthmatic children in England. Children
were supplied with Palmes diffusion tubes, which they clipped to their clothing during the day
and placed in the bedroom at night. Tubes were changed every week for the duration of the
13-month study period. Nasal aspirates were obtained and analyzed for a variety of respiratory-
illness causing viruses (Chauhan et al., 2003). The authors found significant increases in the
4 point symptom severity score associated with exposure to NO2 levels greater than 14 |ig/m3
(7.4 ppb) in the week preceding any viral infection (score increase of 0.6 [95% CI: 0.01, 1.18])
or respiratory syncytial virus alone (score increase of 2.1 [95% CI: 0.52, 3.81]). Chauhan
et al. 2003 also found a significant reduction in PEF associated with exposure greater than 14
|ig/m3 (by 12 L/min [95% CI: -23.6, -0.80]). Exploration of the relationship between PEF and
NO2 showed that the risk of a PEF episode (as diagnosed by a clinician's review of each child's
PEF data) beginning within a week of a upper respiratory infection was significantly associated
with exposure to N02 greater than 28 |ig/m3 (14.9 ppb) (RR =1.9 [95% CI: 1.1, 3.4]) (Linaker
et al., 2000). See Figure 2.7-4. Thus, high personal NO2 exposure in the week before an upper
respiratory infection was associated with either increased severity of lower-respiratory-tract
symptoms or reduction of PEF for all virus types together and for two of the common respiratory
viruses, C picornavirus and RSV, individually.
Nitschke et al. (2006) used passive diffusion badges for measuring NO2 exposures in 6-h
increments at home and school for 174 asthmatic children in Australia. School and home
measurements were based on 3 consecutive days of sampling. The maximum of 9 days of
sampling (for 6 h each day) N02 value was selected as the representative daily exposure for
dose-response analyses. Children kept a daily record of respiratory symptoms for the 12-week
study period. Significant associations were found between the maximum NO2 level at school or
home and respiratory symptom rates (see Annex Table AX 6-1). The dose response relationship
is illustrated in Figure 2.7-5.
In a cross-sectional survey of 344 children in Australia, Ponsonby et al. (2001) used
passive gas samplers to measure personal exposure to NO2. Personal badges were pinned to a
child's clothing at the end of each school day and removed when the child arrived at school the
August 2007
2-48
DRAFT-DO NOT QUOTE OR CITE
-------
a>
c
o
o
to
£
d>
V)
E
o
a
E
>•
w
30-,
2-5-
20-
1-5-
£ 10-
0-5-
c
E
3,
a>
ra
c
re
.c
o
c
re
CD
0-
20 ¦
15-
10 -
5 -
-5-
-10-
-15-
-20-
Lower respiratory-tract score
N02 exposure
~ 7-5-14 pg/m3
¦ >i4Mg/m3
p=005
I
PEF rate
.4^
p=001
p=0 04
&
Virus
Figure 2.7-4.
Mean change in respiratory-tract symptom scores and PEF rates after
viral infection for children in medium and high NO2 exposure tertiles
compared with children in the low exposure tertile.
Source: Chauhan et al. (2003).
August 2007
2-49
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
0.6
J£
0>
a>
5
i_
0)
Q.
CD
*•>
ro
i_
E
o
Q.
E
>
(/>
E
ro
0)
0.5
0.4
0.3
0.2
0.1
i i i i i i i
20 40 60 80 100 120 140
Mean (composite school & home) nitrogen dioxide, ppb
D-d Day difficulty breathing
Night difficulty breathing
¦—¦ Night chest tightness
Figure 2.7-5. Mean symptom rates per week (difficulty breathing during the day
and night, and chest tightness at night) plotted against mean
maximum nitrogen dioxide levels (composite of school and home
exposure) groups as <20 ppb (n = 12), 20-39 ppb (n = 51), 40-50 ppb
(n = 25), 60-79 ppb (n = 18), and 80+ ppb (n = 68).
Source: Nitschke et at. (2006).
next day. School exposures were measured with passive samplers placed in each child's
classroom. Sampling took place for 2 consecutive days. Mean (SD) personal exposure was
10.4 (11.1) ppb and mean total NO2 exposure (personal plus schoolroom) was 10.1 (8.6) ppb.
Of the health outcomes measured (recent wheeze, asthma ever, lung function measured when
NO2 sampling stopped), only the FEVi/FVC ratio following cold air challenge was significantly
associated with NO2 levels measured with the personal badges (-0.12 [95% CI: -0.23, -0.01])
per 1 ppb increase in personal exposure).
In Finland, Mukula et al. (1999, 2000) studied 162 preschool-age children. Mukula et al.
(2000) used passive monitors exposed for 1-week periods over the course of 13 weeks both
indoors, outdoors, and on the clothing of preschool children attending 8 day care centers in
Helsinki. The only significant association between NO2 measured personally and symptoms was
for cough during the winter (relative risk [RR] = 1.86 [95% CI: 1.15, 3.02] for NO2 at levels
August 2007
2-50
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
above 27.5 |ig/m3 [14.5 ppb]). Similar results were obtained when data were analyzed
unstratified by season, but including a factor for season (RR = 1.52 [95% CI: 1.00, 2.31] for
N02 at levels above 27.5 |ig/m3 [14.5 ppb], Mukala et al., 1999).
2.7.3 Summary Indoor and Personal Exposure Studies
Overall, the recent studies build upon the evidence available from personal and indoor
exposure studies in the 1993 AQCD, showing consistent evidence of respiratory effects with
exposure to NO2. There is convincing evidence for a direct effect of NO2 exposure on
respiratory health from the randomized intervention study by Pilotto et al. (2003) and from other
studies enrolling asthmatic children (Pilotto et al., 1997; Nitschke et al., 2006; Smith et al., 2000;
Belanger et al., 2006). From indoor and personal exposure studies, effects observed in these
studies all occurred at ambient levels and are relatively unconfounded by copollutants found in
ambient air that make unambiguous interpretation of many of the health effects studies of
ambient exposure problematic. Chauhan et al. (2003) shows an association between increased
personal exposure to N02 and the severity of virus-induced asthma exacerbations in children.
The study design reduced potential bias from misclassification of other pollutant exposure or
health outcomes. As is true for NO2 in the ambient air, indoor NO2 concentrations may be
correlated with a mixture of other pollutants, as the major products of combustion of natural gas
includes C02, CO, and HCHO, along with smaller amounts of other oxidized organic compounds
in the gas phase and sub-micrometer PM, particularly PAHs, thus complicating the interpretation
of associations between health effects and indoor NO2 levels. Nonetheless, the findings of these
recent indoor and personal exposure studies, combined with studies available in the previous
AQCD, provide strong evidence that N02 exposure is associated with respiratory effects. These
studies can serve as a bridge between epidemiological studies and controlled human exposure
studies, as noted above, and provide some evidence of coherence for respiratory effects.
August 2007
2-51
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-1. SPATIAL VARIABILITY OF NOz IN SELECTED UNITED STATES
URBAN AREAS
r P90 (ppb) COD
0.77-0.90 7- 19 0.08-0.23
0.22-0.89 7-24 0.15 -0.59
-0.05 -0.83 10-39 0.13 -0.66
0.31 -0.80 6-20 0.13 -0.47
0.01 -0.90 8-32 0.08-0.51
0.03 -0.84 10-40 0.14-0.70
Mean
Concentration (ppb)
New York, NY
29
(5)
(25 - 37)
Atlanta, GA
11
(5)
(5-16)
Chicago, IL
22
(7)
(6-30)
Houston, TX
13
(7)
(7-18)
Los Angeles, CA
25
(14)
(14-33)
Riverside, CA
21
(9)
(5-32)
August 2007
2-52
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-2. N02 CONCENTRATIONS NEAR INDOOR SOURCES:
SHORT-TERM AVERAGES
Avg
Concentration (ppb)
Peak
Concentration (ppb)
Comment
Reference
191 kitchen,
195 living room,
184 bedroom
375 kitchen,
401 living room,
421 bedroom
Cooked full meal with use of gas
stove and range for
2 h and 20 min; 7 h TWA
Fortman et al.
(2001)
400 kitchen,
living room,
bedroom
673 bedroom
Automatic oven cleaning of gas
stove. Avgs are over the entire
cycle.
Fortman et al.
(2001)
90 (low setting),
350 (med setting),
360 (high setting)
N/R
Natural gas unvented fireplace, 0.5 h
TWA in main living area of house
(177 m3).
Duttonetal. (2001)
N/R
1000
Room concentration with kerosene
heater operating for 46 min.
Girman et al. (1982)
N/R
1500
Room concentration with gas heater
operating for 10 min.
Girman et al. (1982)
180 to 650
N/R
Calculated steady-state concentration
from specific unvented gas space
heaters operating in a 1400 ft2 house,
1.0 h"1 for air exchange rate.
Girman et al. (1982)
N/R = not reported
TWA = time-weighted avg
1 Unvented are not permitted in many areas such as California.
August 2007
2-53
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-3. N02 CONCENTRATIONS NEAR INDOOR SOURCES:
LONG-TERM AVERAGES
Avg Concentration (ppb)
Comment
Reference
30 to 33
22
6 to 11
Gas stoves with pilot lights
Gas stoves without pilot lights
Electric ranges
Study conducted in 517 homes in Boston, values
represent 2-wk avgs
Lee etal. (1998)
55 (Median)
41 (90th %-ile)
80 (90th %-ile)
84 (90th %-ile)
147 (90th %-ile)
52 (90th %-ile)
Gas space heaters
No indoor combustion source
Fireplaces
Kerosene heaters
Gas space heaters
Wood stoves
All values represent 2-wk avgs in living rooms
Triche et al.
(2005)
18
19
15
Bedrooms
Living rooms
Outdoors
Almost all homes had gas stoves. Values
represent 2-wk avgs
Zipprich et al.
(2002)
August 2007
2-54
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-4A. I ll I ASSOCIATION BETWEEN PERSONAL EXPOSURES
AND AMBIENT CONCENTRATIONS
Study
Study Design Association Variable
Location
Season
rp, rs, or R2
Linn et al.
(1996)
Longitudinal, Southern California, Personal vs. central
269 School Children,
fall, winter, and spring 1992-1994,
24-h avg, 1-wk consecutive measurement
for each season for each child.
Pooled
Pooled
0.63 (rp)
(n = 107)
Aim et al.
(1998)
Longitudinal, Helsinki, Personal vs. central
246 children aged 3-6 yrs old,
winter and spring of 1991,
1-wk averaged sample for each person, ~ , , ,
. , .r , . r , Personal vs. central
6 consecutive wks in the winter and
7 consecutive wks in the spring.
Downtown
Suburban
Spring
Spring
0.64 (rp),p< 0.001
(Sample size was not
reported.)
0.78 (rp),p< 0.001
(Sample size was not
reported.)
Personal vs. central
Downtown
Winter
-0.06 (rp), p > 0.05
(Sample size was not
reported.)
Personal vs. central
Suburban
Winter
0.32 (rp), p > 0.05
(Sample size was not
reported.)
Personal vs. central
Downtown
(electric stove
home)
Pooled
0.42 (rp), p < 0.01
(Sample size was not
reported.)
Personal vs. central
Downtown (gas
stove home)
Pooled
0.16 (rp),p> 0.01
(Sample size was not
reported.)
Personal vs. central
Suburban
(electric stove
home)
Pooled
0.55 (rp),p< 0.001
(Sample size was not
reported.)
Personal vs. central
Downtown
(nonsmoking
home)
Pooled
0.47 (rp),p< 0.001
(Sample size was not
reported.)
Personal vs. central
Downtown
(smoking home)
Pooled
0.23 (rp), p > 0.01
(Sample size was not
reported.)
Personal vs. central
Suburban
(nonsmoking
home)
Pooled
0.53 (rp),p< 0.001
(Sample size was not
reported.)
Personal vs. central
Suburban
(smoking home)
Pooled
0.52 (rp),p< 0.001
(Sample size was not
reported.)
Personal vs. central
Pooled
Pooled
0.37 (R2)
(n = 24)
August 2007
2-55
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-4A (cont'd). Till ASSOCIATION BETWEEN PERSONAL EXPOSURES
AND AMBIENT CONCENTRATIONS
Study
Study Design
Association
Variable
Location
Season
, orRz
Liard et al. Daily avg/cross-sectional, Paris,
(1999) 55 adults and 39 children,
May-June 1996, three 4-day avg measurements for each person,
during each measurement session, all subjects were measured at
the same time.
Gauvin Daily avg/cross-sectional, three French metropolitan areas,
et al. 73 children,
(2001) April-June 1998 in Grenoble, May-June 1998 in Toulouse, and
June-October 1998 in Paris,
one 48-h avg measurement for each child, all children in the
same city were measured on the same day.
Kim et al. Longitudinal, Toronto,
(2006) 28 adults with coronary artery disease,
Aug 1999 to Nov 2001,
1 day/wk, 24-h avg, for a maximum of 10 wks for each person.
Adults vs. central Urban
Children vs.
central
Urban
Personal vs. Urban
central (Grenoble)
Personal vs. Urban
central (Toulouse)
Personal vs. Urban
central (Paris)
Personal vs. Urban
central (subject
wise)
Summer
Summer
Pooled
Pooled
Pooled
Pooled
0.41 (R2),
p< 0.0001
(Sample size was
not reported.)
0.17 (R2),
p = 0.0004
(Sample size was
not reported.)
0.01 (R2)
(Sample size was
not reported.)
0.04 (R2)
(Sample size was
not reported.)
0.02 (R2)
(Sample size was
not reported.)
-0.36 to 0.94 (rs)
with a median of
0.57
(15 subjects)
Sarnat et Longitudinal, Baltimore,
al. (2001) 56 seniors, schoolchildren, and people with COPD,
summer of 1998 and winter of 1999,
14 of 56 subjects participated in both sampling seasons; all
subjects were monitored for 12 consecutive days (24-h avg
samples) in each of the one or two seasons, with the exception of
children who were measured for 8 consecutive days during the
Personal vs.
central (subject
wise)
Urban
Summer
Winter
-0.45 to 0.85 (rs)
with a median of
0.05*
(24 subjects)
-0.6 to 0.75 (rs)
with a median of
0.05*
(45 subjects)
Sarnat
et al.
(2005)
Sarnat
et al.
(2006)
Longitudinal, Boston,
43 seniors and schoolchildren,
summer of 1999 and winter of 2000,
Similar study design as Sarnat et al. (2001).
Personal vs.
central (subject
wise)
Urban
Summer
Winter
Longitudinal, Steubenville,
15 senior subjects,
summer and fall of 2000,
two consecutive 24-h samples were collected for each subject for
each wk, 23 wks total
Personal vs.
central
Urban
Summer
Fall
-0.25 to 0.5 (rs)
with a median of
0.3*
(Sample size was
not reported in
the text.). Slope
= 0.19,0.08-0.30
-0.5 to 0.9 (rB)
with a median of
0.4*
(Sample size was
not reported in
the text.) Slope
= -0.03,
-0.21-0.15
0.14 (R2)
(n = 122),
p < 0.05
0.43 (R2),
p < 0.05
(n = 138)
* Values were estimated from figures in the original paper.
August 2007
2-56
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-4B. I ll I ASSOCIATION BETWEEN PERSONAL EXPOSURES
AND OUTDOOR CONCENTRATIONS
Association
Study Study Design Variable Location Season rp, rs, orR2
Kramer et al.
(2000)
West Germany,
191 children.
March and Sept 1996,
two 1-wk averaged measurements for each child
in each mo.
Personal vs.
outdoor
Personal vs.
outdoor
Pooled
Urban
Pooled
Pooled
0.37 (rp)
(n = 281)
0.06 (rp)
(n= 182)
Rojas-Bracho
et al. (2002)
Santiago,
20 children,
winters of 1998 and 1999,
five 24-h avg samples for 5 consecutive days for
each child.
Personal vs.
outdoor
Urban
Winter
0.27 (R2)
(n = 87)
Raaschou-
Nielsen et al.
(1997)
Copenhagen and rural areas,
204 children,
Oct 1994, April, May, and June 1995,
two 1-wk avg measurements for each child in
each mo.
Personal vs.
outdoor
Personal vs.
outdoor
Urban
Rural
Pooled
Pooled
0.15 (R2)
(n = 97)
0.35 (R2)
(n = 99)
Aim et al. (1998)
Helsinki,
246 children aged 3-6 yrs old,
winter and spring of 1991,
1-wk averaged sample for each person for 6
consecutive wks in the winter and 7 consecutive
wks in the spring.
Personal vs.
outdoor
Personal vs.
outdoor
Downtown
Suburban
Winter
Winter
0.46 (rp)
(Sample
size was not
reported.)
0.49 (rp)
(Sample
size was not
reported.)
Personal vs.
outdoor
Downtown
Spring
0.80 (rp)
(Sample
size was not
reported.)
Personal vs.
outdoor
Suburban
Spring
0.82 (rp)
(Sample
size was not
reported.)
Personal vs.
outdoor
Downtown
(electric
stove
home)
Pooled
0.55 (rp)
(Sample
size was not
reported.)
Personal vs.
outdoor
Downtown
(gas stove
home)
Pooled
0.59 (rp)
(Sample
size was not
reported.)
Personal vs.
outdoor
Suburban
(electric
stove
home)
Pooled
0.63 (rp)
(Sample
size was not
reported.)
August 2007
2-57
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-4B (cont'd). Till ASSOCIATION BETWEEN PERSONAL EXPOSURES
AND OUTDOOR CONCENTRATIONS
Study
Study Design
Association
Variable Location Season
rp, rs, or R
Almetal. (1998)
(cont'd)
Personal vs. outdoor Downtown Pooled
(nonsmoking
home)
Personal vs. outdoor Downtown Pooled
(smoking
home)
Personal vs. outdoor Suburban Pooled
(nonsmoking
home)
Personal vs. outdoor Suburban Pooled
(smoking
home)
Personal vs. outdoor Pooled Pooled
Monn et al. Geneva, Basel, Lugano, Aarau,
(1998) Wald, Payerne, Montana, and
Davos (SAPALDIA study,
Switzerland),
140 subjects,
Dec 1993 to Dec 1994,
each home was monitored for 3
periods of 1 mo; in the 1 st wk of
each period, personal, indoor
rand outdoor levels were
measured, and in the next 3
consecutive wks, only outdoor
levels were measured (1-wk
averaged measurement).
Levy et al. (1998) 18 cities across 15 countries,
568 adults,
Feb or March 1996,
one 2-day avg measurement for
each person, all people were
measured on the same winter
day.
Personal vs. outdoor Pooled
Pooled
Personal vs. outdoor Urban
Winter
0.73 (rp)
(Sample size was not
reported.)
0.51 (rp)
(Sample size was not
reported.)
0.59 (rp)
(Sample size was not
reported.)
0.46 (rp)
(Sample size was not
reported.)
0.86 (R2)
(n = 23)
0.33 (R2)
(n= 1,494)
0.57 (r„)
(n = 546)
August 2007
2-58
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-4B (cont'd). Till ASSOCIATION BETWEEN PERSONAL EXPOSURES
AND OUTDOOR CONCENTRATIONS
Study
Study Design
Association Variable Location
Season
rp, r„ or R
Kodamaetal. Tokyo,
(2002) 150 junior-high school
students and their family
members,
Feb 24-26, Jun 2-4, July 13-
15, and Oct 14-16 in 1998 and
Jan 26-28 in 1999,
3-day avg, personal exposures
were monitored on the same
day.
Spengler et al. Los Angeles Basin,
(1994) probability-based sample, 70
subjects,
May 1987 to May 1988,
each participant was
monitored during each of 8
cycles (48-h avg sampling
period) throughout the yr in
the microenvironmental
component of the study.
Linaker et al. Southampton,
(2000) 114 asthmatic children,
Oct 1994 to Dec 1995,
13 mos (1-wk avgs) for each
child.
Personal vs. outdoor
Personal vs. outdoor
Personal vs. outdoor
Personal vs. outdoor
(overall measurements
across children and
time)
Personal vs. outdoor
(subject-wise)
Urban
Urban
Pooled
Summer
Winter
Pooled
Pooled
Pooled,
urban, no
major
indoor
sources
By person Pooled
0.24 (rp)
(Sample size
was not
reported.)
0.08 (rp)
(Sample size
was not
reported.)
0.48 (R2)
(Sample size
was not
reported.)
Not
significant
(Sample size
was not
reported.)
-0.77 to
0.68 and
median
-0.02 (rp)
(Sample size
was not
reported.)
Lai et al. (2004)
Oxford,
50 adults,
Dec 1998 to Feb 2000,
one 48-h avg measurement
per person.
Personal vs. outdoor
Urban
Pooled
0.41 (rp)
(Sample size
was not
reported.)
* Values were estimated from figures in the original paper.
August 2007
2-59
DRAFT-DO NOT QUOTE OR CITE
-------
&
CJQ
c
to
o
o
<1
TABLE 2.5-5. SUMMARY OF REGRESSION MODELS OF PERSONAL EXPOSURE TO AMBIENT/OUTDOOR NQ2
Study
Location
Season
Model Type
Slope (SE)
Intercept / ppb
W
to
On
O
O
O
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
Rojas-Bracho
et al. (2002)
Aim et al.
(1998)
Monn et al.
(1998)
Levy et al.
(1998)
Spengler et al.
(1994)
Santiago, Winter
20 children,
winters of 1998 and 1999,
five, 24-h avg samples on consecutive days
for each child.
Helsinki, Winter +
246 children aged 3-6 yrs, Spring
winter and spring of 1991,
1-wk averaged sample for each person, 6
consecutive wks in the winter and 7
consecutive wks in the spring.
Geneva, Basle, Lugano, Aarau, Wald, All
Payerne, Montana, and Davos
(SAPALDIA study, Switzerland),
140 subjects,
Dec 1993 to Dec 1994,
each home was monitored for 3 periods of
1 mo; in the 1st wk of each period,
personal, indoor rand outdoor levels were
measured, and in the next 3 consecutive
wks, only outdoor levels were measured
(1-wk averaged measurement).
18 cities across 15 countries, Winter
568 adults,
Feb or March 1996,
One, 48-h avg measurement for each
person, all people were measured on the
same day.
Los Angeles Basin, All
probability-based sample, 70 subjects,
May 1987 to May 1988,
in the microenvironmental component of
the study, each participant was monitored
for 48 hours during each of 8 sampling
cycles throughout the yr.
Personal vs. outdoor (n = 87)
0.33 (0.05)
7.2
0.27
Population vs. outdoor (n = 23)
0.4
4.7
0.86
Personal (all subjects) vs.
outdoor (n= 1,494)
Personal (no smokers and gas
cooking) vs. outdoor (n = 943)
0.45
0.38
7.2
7.2
0.33
0.27
Personal vs. outdoor (n = 546)
0.49
14.5
Personal vs. outdoor
0.56
15.8
0.51
-------
TABLE 2.5-5 (cont'd). SUMMARY OF REGRESSION MODELS OF PERSONAL EXPOSURE TO
AMBIENT/OUTDOOR NQ2
Study
Location
Season
Model Type
Slope (SE)
Intercept / ppb
R2
Sorensen et al.
Copenhagen,
All
Personal vs. outdoor (n = 73)
0.60 (0.07)
—
—
(2005)
30 subjects (20-33 yrs old) in each
measurement campaign,
(>8 °C)
Personal vs. outdoor (n = 35)
0.68 (0.09)
—
—
fall 1999, and winter, spring and summer
(<8 °C)
Personal vs. outdoor (n = 38)
0.32(0.13)
—
—
of 2000,
four measurement campaigns in 1 yr; each
campaign lasted 5 wks with 6 subjects each
wk; one 48-h avg N02 measurement for
each subject.
Sorensen et al.
Copenhagen,
All
Personal vs. central (n = 66)
0.56 (0.09)
—
—
(2005)
30 subjects (20-33 yrs old) in each
measurement campaign,
fall 1999, and winter, spring and summer
of 2000,
four measurement campaigns in 1 yr; each
campaign lasted 5 wks with 6 subjects each
wk; one 48-h avg N02 measurement for
each subject.
-------
&
CJQ
c
to
o
o
<1
TABLE 2.5-5 (cont'd). SUMMARY OF REGRESSION MODELS OF PERSONAL EXPOSURE TO
AMBIENT/OUTDOOR N02
to
On
to
H
6
o
2
o
H
o
c
o
H
W
O
V
o
l-H
H
ffl
Study
Location
Season
Model Type
Slope (SE)
Intercept / ppb
R2
Aim et al.
Helsinki,
Winter +
Population vs. central (n = 24)
0.3
5.0
0.37
(1998)
246 children aged 3-6 yrs,
winter and spring of 1991,
1-wk averaged sample for each person,
6 consecutive wks in the winter and
7 consecutive wks in the spring.
Spring
Sarnat et al.
Baltimore,
Summer
Personal vs. central (n = 225 for
0.04*
9.5
—
(2001)
56 seniors, Schoolchildren, and people
with COPD,
summer of 1998 and winter of 1999,
14 of 56 subjects participated in both
sampling seasons; all subjects were
monitored for 12 consecutive days (24-h
avg sample) in each of the one or two
24 subjects)
seasons, with the exception of children
Winter
Personal vs. central (n = 487 for
-0.05*
18.2
—
who were measured for 8 consecutive days
45 subjects)
during the summer.
Sarnat et al.
Boston,
Summer
Personal vs. central (n = 341)
0.19
—
—
(2005)
43 seniors and schoolchildren,
summer of 1999 and winter of 2000,
Similar study design as Sarnat et al., 2001.
Winter
Personal vs. central (n = 298)
-0.03*
Sarnat et al.
Steubenville,
Summer
Personal vs. central (n = 122)
0.25 (0.06)
—
0.14
(2006)
15 senior subjects,
Fall
Personal vs. central (n= 138)
0.49 (0.05)
_
0.43
summer and fall of 2000,
two consecutive 24-h samples were
collected for each subject for each wk,
23 wks total.
*Not significant at the 5% level.
-------
&
CJQ
c
to
o
o
<1
TABLE 2.5-6. INDOOR/OUTDOOR RATIO AND THE INDOOR VS. OUTDOOR REGRESSION SLOPE
to
On
LtJ
H
6
o
2
o
H
O
c
o
H
W
O
o
HH
H
W
Regression Format
Indoor
Study
Description
Season
or Ratio
Characteristics
Finf
Comments
Mosqueron et al.
Paris,
Overall study
Residential indoor vs.
Cooking
0.26
The overall R2 is 0.14,
(2002)
62 Paris office workers,
seasons
ambient and using gas
(n = 62)
and ambient N02 and
Dec 1999 to Sept 2000,
cooking
indoor cooking account
48-h residential indoor,
for 0.07 each
workplace, outdoor, and personal
Office indoor vs. ambient
None
0.56
The overall R2 is 0.24,
exposure were measured.
and floor height
(n = 62)
partial R2 for ambient and
floor height were 0.18 and
0.06, respectively
Lee et al. (1999)
Hong Kong,
Overall study
Indoor vs. outdoor
—
0.59
R2 was 0.59. The slopes
14 public places with mechanical
seasons
(n= 14)
for NO and NOx were
ventilation systems,
1.11 and 1.04 respectively
Oct 1996 to March 1997,
Teflon bags were used to collect
indoor and outdoor NO and N02
during peak hours.
Monnetal. (1997)
Switzerland,
Overall study
Indoor/outdoor ratio
Without gas
o
4--
O
<1
17 homes across Switzerland,
seasons
cooking
(n = 26)
winter 1994 to summer 1995,
48- to 72-h indoor, outdoor and
personal N02 were measured.
Lee et al. (1995)
Boston area,
Summer
Indoor/outdoor ratio
Electric stove
0.77
Homes with gas stove and
517 residential homes,
homes
(bedroom)
gas stove with pilot light
Nov 1984 to Oct 1986,
(Sample size
have an I/O ratio > 1, but
2-wk averaged indoor (kitchen,
was not
the values were not
living room, and bedroom) and
reported)
reported
outdoor N02 were measured.
-------
&
CJQ
c
to
o
o
<1
TABLE 2.5-6 (cont'd). INDOOR/OUTDOOR RATIO AND THE INDOOR VS. OUTDOOR REGRESSION SLOPE
Study
Description
Season
Regression Format
or Ratio
Indoor
Characteristics
inf
Comments
to
On
o
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
Garrett et al. (1999) The Latrobe Valley, Victoria,
Australia,
80 homes,
March-April 1994, and Jan-Feb,
1995,
4-day averaged indoor (bedroom,
living room, and kitchen) and
outdoor N02 was monitored.
Overall study
seasons
Indoor/outdoor ratio
No major indoor 0.8
sources (major sources (n= 15)
were gas stove, vented
gas heater, and
smoking)
The ratio increased to
1.3, to 1.8, and to 2.2 for
homes with one, two and
three major indoor
sources.
Monnetal. (1998)
Spengler et al.
(1994)
Geneva, Basle, Lugano, Aarau, Overall study
Wald, Payerne, Montana, and seasons
Davos (SAPALDIA study,
Switzerland),
140 subjects,
Dec 1993 to Dec 1994,
each home was monitored for 3
periods of 1 mo; in the 1st wk of
each period, personal, indoor rand
outdoor levels were measured,
and in the next 3 consecutive
wks, only outdoor levels were
measured (1-wk averaged
measurement).
Los Angeles Basin, Overall study
probability-based sample, 70 seasons
subjects,
May 1987 to May 1988,
48-h averaged, in the
microenvironmental component
of the study, each participant was
monitored during each of eight
sampling cycles throughout the
yr.
Residential indoor vs.
residential outdoor
All homes
Homes without
smokers and gas-
cooking
0.47 R2 was 0.37.
(n= 1544)
0.40 R2 was 0.33.
(n = 968)
Residential indoor vs. Gas range with pilot 0.49
residential outdoor light (n=314)
Gas range without pilot 0.4
light (n = 148)
Electric stove
0.4
(n = 170)
R was 0.44.
R was 0.39.
R was 0.41.
-------
TABLE 2.5-7. CORRELATIONS (PEARSON CORRELATION COEFFICIENT)
BETWEEN AMBIENT NOz AND AMBIENT COPOLLUTANTS
Study (ambient)
Location
PM,
CO
Os
SO,
This Assessment Los Angeles
0.49 (u3), 0.56 (s)
This Assessment
Riverside, CA
This Assessment Chicago
This Assessment
Kim et al. (2006)
New York City
Toronto
Sarnat et al. (2006) Steubenville, OH
(autumn)
Sarnat etal.
(2006)
Connell et al.
(2005)
Steubenville, OH
(summer)
Steubenville, OH
Kim et al. (2005) St. Louis (RAPS)
Sarnat et al.
(2001)4
Sarnat et al. (2001)
Hochadel et al.
(2006)
Arx et al. (2004)
Cyrys et al. (2003)
Mosqueron et al.
(2002)
Rojas-Bracho et al.
(2002)
Baltimore, MD
(summer)
Baltimore, MD
(winter)
21 European cities
Ehrfurt, Germany
Paris
Santiago, Chile
0.49 (s)
0.58 (u)
0.44
0.78 (0.70 for
sulfate, 0.82 for
EC)
0.00
(0.1 for sulfate,
0.24 for EC)
0.50
0.37
0.75
Ruhr area, Germany 0.41, (0.93 for
EC )
0.75
0.50
0.69
0.77
0.59 (u),
0.64 (s)
0.43 (u),
0.41 (s),
0.15 (r)
0.53 (u),
0.46 (s)
0.46 (u)
0.72
0.641
0.75
0.76
0.74
-0.29 (u),
-0.11 (s)
0.045 (u),
0.10 (s),
-0.31 (r)
-0.20 (u)
0.06 (u)
0.02
not significant
-0.71
-0.17
'Value with respect to NOx.
2Inferred based on EC as dominant contributor to PM2 5 absorbance.
3u: urban; s: suburban; and r: rural
4Spearman correlation coefficient was reported
August 2007
2-65
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-8. PEARSON CORRELATION COEFFICIENTS BETWEEN NOx AND
TRAFFIC-GENERATED POLLUTANTS
NOx: PM2 5 (MV component)
0.48 < r < 0.751
0.48 < r < 0.752
NOx: CO
0.30 < r < 0.771
0.54 < r < 0.772
NOx: Pb
0.42 < r < 0.761
0.48 < r < 0.762
NOx: Br
0.55 < r < 0.731
0.58 < r < 0.732
N02: EC3 0.93
N02: EC4 0.82 autumn, 0.24 summer
'St. Louis RAPS (Kim et al., 2006), all sites
2St. Louis RAPS (Kim et al., 2006), all sites with upwind background site removed
3Ruhr Valley (Hochadel et al., 2006)
4Steubenville, OH (Sarnat et al., 2006)
TABLE 2.5-9. CORRELATIONS (PEARSON CORRELATION COEFFICIENT)
BETWEEN AMBIENT NOz AND PERSONAL COPOLLUTANTS
Study
Location
PM,, Sulfate
EC
Ultrafine particle
Sarnat et al.
(2006)
Sarnat et al.
(2006)
Vinzents
et al. (2005)
Steubenville, Fall
0.71 0.52
Steubenville, Summer 0.00 0.1 not
significant
Copenhagen — —
0.70 —
0.26 —
0.49 (R ) explained by ambient N02
and ambient temperature
TABLE 2.5-10. CORRELATIONS (PEARSON CORRELATION COEFFICIENT)
BETWEEN PERSONAL NOz AND AMBIENT COPOLLUTANTS
Study
Location
PM,
Sulfate
EC
PM,
CO
Sarnat et al. (2006) Steubenville, Fall 0.46
Sarnat et al. (2006) Steubenville, Summer 0.00
0.35
0.1
not significant
0.57
0.17
Kim et al. (2006)
Toronto
Roias-Bracho et al. Santiago
(2002)
0.30
0.65
0.20
0.39
August 2007 2-66 DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 2.5-11. CORRELATIONS (PEARSON CORRELATION COEFFICIENT)
BETWEEN PERSONAL NOz AND PERSONAL COPOLLUTANTS
Study
Location
pm25
CO
VOCs
HONO
Kim et al. (2006)
Toronto
0.41
0.12
—
Modig et al. (2004)
Umea
"
"
0.06 for 1,
3-butadiene; and 0.10
for benzene
"
Mosqueron et al.
(2002)
Paris
0.12 but not
significant
—
—
—
Jarvis et al. (2005)
21 European
cities
—
—
—
0.77 for indoor N02
and indoor HONO
Lee et al. (2002)
—
—
—
—
0.51 for indoor N02
and indoor HONO
Lai et al. (2004)
Oxford
-0.1
0.3
0.11 forTVOCs
—
August 2007
2-67
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3. INTEGRATED HEALTH EFFECTS OF
no2 EXPOSURE
This chapter integrates epidemiological, human clinical, and toxicological evidence for
adverse health effects associated with exposure to NO2, alone or in combination with other
pollutants. The body of epidemiological and experimental evidence is evaluated for strength,
consistency, coherence, and plausibility. Judgments are made about the extent to which causal
inferences can be made on the observed associations between health effects and exposure to
oxides of nitrogen. The focus is on studies conducted at environmentally relevant
concentrations, i.e., primarily studies that identify effects associated with N02 levels <5 ppm.
The evaluations of those studies incorporate the science and conclusions from the 1993 AQCD
for Oxides of Nitrogen. More detailed information is summarized in the Annexes, highlighting
key study findings. The chapter first presents a brief overview of the toxicological evidence for
potential mechanisms of injury. Morbidity and mortality associated with short-term exposures to
NO2 are presented next, followed by morbidity and mortality associated with long-term
exposures. The chapter concludes with discussions of the limited literature on health effects
associated with other oxides of nitrogen, including NO, HONO, and HNO3.
Issues relevant to the evaluation of epidemiological study findings were discussed in
previous documents, particularly in the AQCDs for PM (U.S. Environmental Protection Agency,
2004) and O3 (U.S. Environmental Protection Agency, 2006). These include the influence of
model specification on study findings, the evaluation of lag periods used in epidemiological
analyses, and general considerations regarding confounding or effect modification. In evaluating
NO2 epidemiological studies, the consideration of measurement and exposure errors are of
particular relevance. Chapter 2 describes the extent and significance of the positive artifacts
from other oxidized nitrogen compounds in the FRM-reported NO2 values found in standard
regulatory networks. Because nearly all epidemiological studies use FRM-reported NO2 as the
population exposure estimates, these estimates represent the effects of other oxidized nitrogen
compounds in addition to NO2.
In the 1993 AQCD for Oxides of Nitrogen, human clinical evidence indicated thatN02
caused decrements in lung function, particularly increased airways resistance in healthy subjects
August 2007
3-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
with exposures of >2.0 ppm for 2 h. Other studies showed increased airways responsiveness in
healthy subjects at concentrations of >1 ppm for 1 h. Asthmatics and COPD patients
demonstrated increased decrements in lung function that were dependent on exposure conditions.
However, concentration-response relationships were not observed for changes in lung function,
airways responsiveness, or symptoms, and no association was apparent between lung function
responses and respiratory symptoms. Epidemiological evidence was somewhat mixed for the
effects of N02 exposure on lower respiratory symptoms and disease, but supportive for effects in
children aged 5 to 12 years. However, at the time, data were inadequate to determine a
quantitative relationship between estimates of exposure and symptoms. There was similarly
insufficient epidemiological evidence regarding the long- or short-term effects of NO2 on
pulmonary function. Animal toxicology studies evaluated in the 1993 AQCD identified
biochemical and cellular mechanisms whereby NO2 induces effects. The ability of NO2 to
modulate host defenses and enhance susceptibility to bacterial and viral disease was attributed to
alterations in alveolar macrophage (AM) structure, function, and metabolic activity. Animal
infectivity models also demonstrated decreased resistance to bacterial infections associated with
NO2 exposure. Analysis of exposure regimens showed the dependence of effects on the
concentration and duration and the exposure profile, rather than the cumulative product of
concentration times duration of exposure (C x T).
3.1 POTENTIAL MECHANISMS OF INJURY
The effects of N02 on respiratory tract function account for most of the currently
available literature relevant to this evaluation of the effects of gaseous NOx, and the evidence
includes a variety of endpoints ranging from biochemical effects to morphological and functional
changes. Limited relevant data are available for effects of other gaseous oxides of nitrogen, such
as NO and HNO3 vapor. This evidence is briefly discussed in Section 3.7 with further details
available in Annex Chapters 4, 5, and 6.
Biochemical studies on the effects of NO2 on the lung focus on the possible
mechanism(s) of toxicity and/or on detection of indicators of tissue and cellular damage. The
biochemical effects observed in the respiratory tract after N02 exposure include chemical
alteration of lipids, amino acids, proteins, and enzymes and changes in oxidant/antioxidant
homeostasis. Membrane polyunsaturated fatty acids and thiol groups are the main biochemical
August 2007
3-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
targets for NO2 exposure: data available in the 1993 AQCD indicated that NO2 induces lipid
peroxidation and changes in lipid content of cell membranes. These effects appear to occur at
concentrations as low as 0.04 ppm. Another likely mechanism involves the oxidation of water-
soluble low-molecular-weight reducing substances and proteins, resulting in enzyme dysfunction
that manifests itself as toxicity (Freeman and Mudd, 1981). Mechanisms of respiratory tract
toxicity may relate to NO2 metabolites or reaction products resulting in local pH changes or to
direct damage to target cells via reactive metabolites. The underlying mechanisms are complex,
because their effects may occur directly through the action of nitrogen or oxygen radicals
generated via MVmediated chemical reactions or may be secondary to release of reactive
oxygen species (ROS) by leukocytes responding to local irritation caused by cell damage. For a
detailed description of mechanism studies, see Annex Chapter 4.
3.2 MORBIDITY ASSOCIATED WITH SHORT-TERM N02
EXPOSURE
3.2.1 Respiratory Effects Associated with Short-Term NO2 Exposure
3.2.1.1 Lung Host Defenses and Immunity
Lung host defenses are sensitive to NO2 exposure, with numerous measures of such
effects observed at concentrations of <1 ppm. According to Chauhan et al. (2003), potential
mechanisms include "direct effects on the upper and lower airways by ciliary dyskinesis (Carson
et al., 1993), epithelial damage (Devalia et al., 1993a), increases in pro-inflammatory mediators
and cytokines (Devalia et al., 1993b), rises in IgE concentration (Siegel et al., 1997), and
interaction with allergens (Tunnicliffe et al., 1994), or indirectly through impairment of
bronchial immunity (Sandstrom et al., 1992)." Table 3.2-1 summarizes a range of proposed
mechanisms by which exposure to N02 in conjunction with viral infections may exacerbate
upper and lower airways symptoms (Chauhan et al., 1998). A major concern has been the
potential for NO2 exposure to enhance susceptibility to, or the severity of, illness resulting from
respiratory infections and asthma, especially in children. The following discussion focuses on
studies published since the 1993 AQCD and conducted at near-ambient exposure concentrations.
August 2007
3-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
One new epidemiological field study (Chauhan et al., 2003) discussed in Section 2.7
provided evidence that increased personal exposure to NO2 worsens virus-associated symptoms
and lung function in children with asthma. Personal exposure concentrations were low, with
medians for the exposure quartiles ranging from 2.6 to 10.9 ppb. These concentrations are at
least 2 orders of magnitude lower than the lowest concentrations demonstrated to have
measurable effects on airways inflammation in association with allergen challenge in clinical
studies. Differences that can influence the interaction of N02 and infectious agents include
exercise (Illing et al., 1980), the presence of 03 (Ehrlich et al., 1977; Gardner, 1980; Gardner
et al., 1982; Graham et al., 1987), and elevated temperatures (Gardner et al., 1982).
Several clinical studies have attempted to address the question of whether NO2 exposures
impaired host defenses and/or increased susceptibility to infection and produced mixed results
(Rehn et al., 1982; Goings et al., 1989; Rubinstein et al., 1991; Sandstrom et al.1990, 1991,
1992a,b; Devlin 1992, 1999; Frampton et al., 2002: from Samet and Bell, 2004, review) (see the
1993 AQCD for details of older studies and Annex Table AX5-1 for additional details on newer
studies). One approach has been to examine the effects of in vivo N02 exposure on the function
of AMs obtained by bronchoalveolar lavage, including the susceptibility of these cells to viral
infection in vitro. Two studies since 1993 involved 2.0-ppm NO2 exposures for 4 or 6 h with
intermittent exercise and found no effect on AM inactivation of influenza virus either
immediately or 18 h after exposure (Azadniv et al., 1998; Devlin et al., 1999). However, the
Devlin et al. (1999) study found reduced AM phagocytic capacity after N02 exposure,
suggesting a reduced ability to clear inhaled bacteria or other infectious agents. Frampton et al.
(2002) examined NO2 effects on viral infectivity of airways epithelial cells. Subjects were
exposed to air, or 0.6- or 1.5-ppm NO2 for 3 h, and bronchoscopy was performed 3.5 h after
exposure. Epithelial cells were harvested from the airways by brushing and then challenged in
vitro with influenza virus and respiratory syncytial virus (RSV). NO2 exposure did not alter viral
infectivity, but appeared to enhance epithelial cell injury in response to infection with RSV
(p = 0.024). Similar results were seen with influenza virus. These findings suggest that prior
exposure to N02 may increase the susceptibility of the respiratory epithelium to injury by
subsequent viral challenge. Over all results from clinical studies are equivocal but suggestive of
the potential for NO2 effects.
August 2007
3-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Animal studies provide clearer evidence that host defense system components such as
mucociliary transport and AMs (see Annex Tables AX.4.3 and 4.4) are targets for inhaled NO2.
Animal studies further show that N02 can impair the respiratory host defense system sufficiently
to render the host more susceptible to respiratory infections (See Annex Table 4.5). Ciliated
epithelial cells involved in mucociliary transport in the conducting airways exhibit
morphological changes atNC>2 concentration as low as 0.5 ppm with 7 months of exposure
(Yamamoto and Takahashi, 1984). However, mucociliary clearance is not affected by N02
exposure as low as 3 ppm. In a 1994 study, exposure of guinea pigs to 5640- or 16,920-|ig/m3
(3 or 9 ppm) NO2 6 h/day, 6 days/week for 2 weeks resulted in concentration-dependent
decreases in ciliary activity of 12 and 30% of control values at NO2 concentrations of
5640 |ig/m3 (3 ppm) and 16,920 |ig/m3 (9 ppm), respectively (Ohashi et al., 1994). These
concentration-dependent decreases are accompanied by a concentration-dependent increase in
eosinophil accumulation on the epithelium and submucosal connective tissue layer of the nasal
mucosa. For foreign agents such as some bacteria and viruses that deposit below the mucociliary
region in the gas-exchange region of the lung, AMs primarily provide host defenses by acting to
remove or kill viable particles, remove nonviable particles, and process and present antigens to
lymphocytes for antibody production. AMs are one of the sensitive targets for NO2, as
evidenced by in vivo acute and long-term animal exposures and in vitro studies (see Annex
Table AX4.4 for details of studies related to each of these morphological or functional
parameters in exposed animals). The susceptibility to bacterial and viral pulmonary infections in
animals also increases with NO2 exposures of as low as 0.5 ppm. No new studies published
since 1993 were identified that evaluated this endpoint. Annex Table AX4.5 summarizes the
effects of NO2 exposure and infectious agents in animal studies as compiled in the 1993 AQCD
for Oxides of Nitrogen. It is important to note that the 1993 AQCD provides evidence that the
host's response to inhaled NO2 can be significantly influenced by the duration and temporal
patterns of exposure. This is important in considering continuous versus intermittent exposures
and attempting to understanding observed differences in reported results.
In summary, the evidence for altered host defense is coherent across disciplines and
plausible. Taken as a whole, however, the body evidence lacks consistency and robustness. The
epidemiologic, clinical, and animal data provide supportive evidence of impaired host-defense
systems and increased risk of susceptibility to both viral and bacterial infections. In particular,
August 2007
3-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
the Pilotto et al. (2004) and the Chauhan et al. (2003) studies add to the weight of evidence
produced since the last AQCD. Their findings indicate that exposure to NO2 before the start of a
respiratory infection is associated with an increase in respiratory symptoms and exacerbation of
asthma. These effects are reported to occur at levels near and below the current NAAQS. These
indoor/personal NCVexposure studies all were controlled for some variable associated with
ambient NO2 exposure; however, confounding with ultrafine emissions remains a concern.
Clinical Studies on Host Defense and Immunity
Clinical studies have attempted to address the question of whether N02 exposure
increases susceptibility to infection. Goings et al. (1989) exposed healthy volunteers to either
1- to 3 ppm NO2 or to air for 2 h/day for 3 consecutive days. A live, genetically engineered
influenza A vaccine virus was administered intranasally to all subjects after exposure on day 2.
Infection was determined by virus recovery from nasal washings, a 4-fold or greater increase in
antibody titer, or both. The findings of this study were inconclusive, in part, because of
limitations in sample size. In addition, the attenuated, cold-adapted virus used in the study was
incapable of infecting the lower respiratory tract, where NO2 may have the most important
impact on host defense.
There is evidence from both animal and human studies that exposure to NO2 may alter
lymphocyte subsets in the lung and possibly in the blood. Lymphocytes, particularly T cells and
NK cells, play a key role in the innate immune system and host defense against respiratory
viruses. Sandstrom et al. (1990, 1991) observed a significant, dose-related increase in
lymphocytes and mast cells recovered by bronchoalveolar lavage (BAL) 24-h after a 20-min
exposure to NO2 at 2.25 to 5.5 ppm. Rubinstein et al. (1991) found that a series of 4 daily, 2-h
exposures to 0.60 ppm NO2 resulted in a small increase in NK cells recovered by BAL. In
contrast, repeated exposures to 1.5- or 4 ppm NO2 for 20 min every second day on six occasions
resulted in decreased CD16+56+ (NK cells) and CD19+ cells (B lymphocytes) in BAL fluid, 24-h
after the final exposure (Sandstrom et al., 1992a,b). No effects were seen on polymorphonuclear
leukocytes (PMN) or total lymphocyte numbers. Solomon et al. (2000) found a decrease in
CD4+ T lymphocytes in BAL fluid 18-h after 4 daily, 4-h exposures to 2.0 ppm NO2. Azadniv
et al. (1998) observed a small but significant reduction in CD8+ T lymphocytes in peripheral
blood, but not BAL, 18-h following single 6-h exposures to 2.0 ppm NO2. Frampton et al.
August 2007
3-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
(2002) found small increases in BAL lymphocytes and decreases in blood lymphocytes with
exposures to 0.6 and 1.5 ppm NO2 for 3 h.
The observed effects on lymphocyte responses, as described above, have not been
consistent among studies. Differing exposure protocols and small numbers of subjects among
these studies may explain the varying and conflicting findings. Furthermore, the clinical
significance of transient, small changes in lymphocyte subsets is unclear. It is possible that the
inflammatory response to N02 exposure involves both lymphocytes and PMNs, with lymphocyte
responses occurring transiently and at lower concentrations and PMN responses predominating
at higher concentrations or more prolonged exposures. The airways lymphocyte responses do
not provide convincing evidence of impairment in host defense.
One study found that 20-min exposures to N02 at 1.5 to 3.5 ppm transiently reduced
airways mucociliary activity, assessed by fiberoptic bronchoscopy (Helleday et al., 1995).
Reduced mucus clearance would be expected to increase susceptibility to infection by reducing
the removal rate of microorganisms from airways. However, the study was weakened by a lack
of a true air control exposure as well as by the absence of randomization and blinding. As a
clarification, Helleday et al. (1995) did not measure mucus clearance rates directly using
radiolabeled particles; rather they utilized an optical technique to characterize ciliary activity.
Rehn et al. (1982) examined the effect of NO2 exposure on mucociliary clearance of a
radiolabeled Teflon aerosol. After a 1-h exposure to either 0.27- or 1.06-ppm (500 or
2000 |ig/m3) N02, there were no changes in airways clearance rates.
Another approach has been to examine the effects of in vivo NO2 exposure on the
function of AMs obtained by bronchoalveolar lavage, including the susceptibility of these cells
to viral infection in vitro. Several NO2 exposure scenarios, including continuous low-level
exposure or intermittent peak exposures have been examined (Frampton et al., 1989). AMs
obtained by BAL 3.5-h after a 3-h continuous exposure to 0.60 ppm NO2 tended to inactivate
influenza virus in vitro less effectively than cells collected after air exposure. The effect was
observed in cells from 4 of the 9 subjects studied; AMs from these 4 subjects increased release of
interleukin-1 (IL-1) after exposure to N02, whereas cells from the remaining 5 subjects
decreased release of IL-1 following exposure. However, two subsequent studies (Azadniv et al.,
1998; Devlin et al., 1999) involving 2.0 ppm NO2 exposures for 4 or 6 h, with intermittent
exercise, found no effect on AM inactivation of influenza virus either immediately or 18-h after
August 2007
3-7
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
exposure. However, the Devlin et al. (1999) study found reduced AM phagocytic capacity after
NO2 exposure, suggesting a reduced ability to clear inhaled bacteria or other infectious agents.
Frampton et al. (2002) examined N02 effects on viral infectivity of airways epithelial
cells. Subjects were exposed to air, or 0.6- or 1.5-ppm NO2 for 3 h, and bronchoscopy was
performed 3.5-h after exposure. Epithelial cells were harvested from the airways by brushing
and then challenged in vitro with influenza virus and respiratory syncytial virus (RSV). NO2
exposure did not alter viral infectivity, but appeared to enhance epithelial cell injury in response
to infection with RSV (p = 0.024). A similar nonsignificant change was seen with influenza
virus. These findings suggest that prior exposure to NO2 may increase the susceptibility of the
respiratory epithelium to injury by subsequent viral challenge.
Toxicological Studies on Host Defense and Immunity
Mucociliary Clearance
Substances capable of disrupting or impairing mucociliary clearance can result in an
excess accumulation of cellular secretions, increased acute bacterial and viral infections, chronic
bronchitis, and prolonged pulmonary complications (Schlesinger et al., 1987). The respiratory
tract often responds to irritants by increasing mucus secretion. Ideally, this would enhance the
capture of harmful substances to be removed to the upper respiratory tract through the action of
the ciliated epithelium. The ciliated epithelial cells lining the respiratory tract (tracheobronchial
region) can respond to insults by changing cilia beat frequency, cessation of beating, and/or
development of abnormal forms of cilia. With even greater exposures, loss of cilia and ciliated
epithelial cells can be found in animals exposed to NO2, and a description of such
histopathologic changes can be found in the Section 3.2.1.1 on morphological changes.
Changes in the functional impairment of mucociliary clearance are observed at high
concentrations of N02 (>5.0 ppm) (Giordano and Morrow, 1972; Kita and Omichi, 1974). At
lower exposures (2 h/day for 2, 7, and 14 days to 564- and 1880-|ig/m3 [0.3 and 1.0 ppm] N02),
the mucociliary clearance of inhaled tracer particles deposited in the tracheobronchial tree of
rabbits was not altered (Schlesinger et al., 1987). Vollmuth et al. (1986) studied the clearance of
strontium-85-radiolabelled polystyrene latex spheres from the lungs of rabbits following a single
2-h exposure to NO2 at 564, 1880, 5640, or 18,800 |ig/m3 (0.3, 1.0, 3.0, or 10.0 ppm). An
acceleration in clearance occurred immediately after exposure to the two lowest N02
August 2007
3-8
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
concentrations; a similar effect was found by Schlesinger and Gearhart (1987). At the higher
levels of NO2, acceleration in clearance was not evident until midway through the 14-day
postexposure period. Repeated exposure for 14 days (2 h/day) to 1880- or 18,800-|ig/m3 (1.0 or
10.0 ppm) NO2 produced a response similar to a single exposure at the same concentration.
Exposure of guinea pigs to 5640- or 16,920-|ig/m3 (3 or 9 ppm) NO2 6 h/day,
6 days/week for 2 weeks resulted in concentration-dependent decreases in ciliary activity of 12
and 30% of control values atN02 concentrations of 5640 |ig/m3 (3 ppm) and 16,920 |ig/m3
(9 ppm), respectively, (Ohashi et al., 1994) accompanied by concentration-dependent increase in
eosinophil accumulation on the epithelium and submucosal connective tissue layer of the nasal
mucosa. Morphological changes (i.e., compound cilia, cytoplasmic vacuolization, sloughing)
were observed only in the nose of animals in the high-concentration group.
Effects on AMs and Mast Cells
The effectiveness of AMs depends on the type, number, and viability of the cells. To
perform their primary function of detoxifying and/or clearing the lung of infectious and
noninfectious particles, AMs must maintain an intact membrane, mobility, and phagocytic
activity, and have functioning enzyme systems as well as secrete cellular mediators that recruit
and activate inflammatory cells in the lungs (Fels and Cohn, 1986). AMs are one of the sensitive
targets for NO2, as evidenced by in vivo acute and long-term animal exposures and in vitro
studies, and there are studies (see Annex Table AX4.4) related to each of these morphological or
functional parameters in exposed animals.
Structural changes, including the loss of surface processes, appearance of fenestrae, bleb
formation, and denuded surface areas, have been observed in AMs isolated from mice
continuously exposed to 3760-|ig/m3 (2.0 ppm) NO2 or to 940-|ig/m3 (0.5 ppm) NO2
continuously with a 1-h peak to 3760 |ig/m3 (2.0 ppm) for 5 days/week. The AMs showed
distinctive morphological changes after 21 weeks of exposure that would be expected to interfere
with cellular functions such as chemotaxis and phagocytosis (Aranyi et al., 1976). Continuous
exposure to lower NO2 concentrations, i.e., to 940 |ig/m3 (0.5 ppm) continuous or to 1.8 |ig/m3
(0.1 ppm) continuous with a 3-h peak to 1880 |ig/m3 (1.0 ppm) for periods up to 24 weeks, did
not result in any significant morphological or biochemical changes.
Mochitate et al. (1986) reported a significant increase in the total number of AMs isolated
from rats during 10 days of exposure to 7520-|ig/m3 (4.0 ppm) NO2, but the number of PMNs
August 2007
3-9
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
did not increase. The AMs from exposed animals also exhibited increased metabolic activity, as
measured by the activities of glucose-6-phosphate dehydrogenase, glutathione peroxidase, and
pyruvate kinase. The AMs also showed increased rates of synthesis of protein and DNA. All
responses peaked on day 4 and returned to control levels by the day 10. Increased numbers and
metabolic activity of AMs would be expected to have a positive influence on host defenses.
However, AMs are rich in proteolytic enzymes and increased numbers could result in some
tissue destruction when the enzymes are released. Schlesinger (1987a,b) found no significant
changes in the number or the viability of AMs in BAL fluid from rabbits exposed to 564- or
1880-|ig/m3 (0.3 or 1.0 ppm) NO2, 2 h/day for 13 days. Although there were no effects on the
numbers of AMs that phagocytosed latex spheres, 2 days of exposure to 564 |ig/m3 (0.3 ppm)
decreased the phagocytic capacity (i.e., number of spheres phagocytosed per cell). The higher
level of NO2 increased phagocytosis, whereas longer exposures had no effect. In rats,
continuous exposure at 7520-|ig/m3 (4.0 ppm) or 15,000-|ig/m3 (8.0 ppm) NO2 for 10 days
significantly increased the number of AMs in the BAL fluid, with the increase becoming
significant by the fifth day of exposure. Viability of these isolated cells decreased on day 1 and
remained depressed throughout exposure. However, phagocytic activity of AMs was
significantly depressed (after 5 days of exposure to 15,000 |ig/m3 [8.0 ppm] and 7 days of
exposure to 7520 |ig/m3 [4.0 ppm]), but returned to the control value at 10 days of exposure
(Suzuki et al., 1986). There may be a species difference in responsiveness, because Lefkowitz
et al. (1986) did not observe a depression in phagocytosis in mice exposed for 7 days to
9400-|ig/m3 (5.0 ppm) NO2.
Suzuki et al. (1986) proposed that the inhibition of phagocytosis might be due to NO2
effects on membrane lipid peroxidation. Studies by Dowell et al. (1971) and Goldstein et al.
(1977) add support to this hypothesis. Acute exposure to 5640 to 7520 |ig/m3 (3.0 to 4.0 ppm)
caused swelling of AMs (Dowell et al., 1971) and increased agglutination of AMs with
concanavalin A (Goldstein et al., 1977), suggesting damage to membrane functions.
NO2 exposure appears to decrease the ability of rat AMs to produce superoxide anion,
which may limit antibacterial activity (Amoruso et al., 1981). Amoruso et al. (1981) presented
evidence of such an effect atNC>2 concentrations ranging from 1.3 to 17.0 ppm. The duration of
the NO2 exposure was not given; all exposures were expressed in terms of parts per million x h
(ppm-h). A 50% decrease of superoxide anion production began after exposure to
August 2007
3-10
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
54,700-|ig/m3-h (29.1 ppm-h) NO2. Suzuki et al. (1986) reported a marked decrease in the
ability of rat AMs to produce superoxide anion following a 10-day exposure to either 7520- or
15,000-|ig/m3 (4.0 or 8.0 ppm) N02. At the highest concentration, the effect was significant
each day, but at the lower concentration, the depression was significant only on exposure days 3,
5, and 10. Superoxide production in AMs from rat BAL fluid, stimulated by phorbol myristate
acetate (PMA), was decreased after 0.5 days of exposure to 940-|ig/m3 (0.5 ppm) NO2 and
continued to be depressed after 1, 5, and 10 days of exposure (Robison et al., 1993).
Kumae and Arakawa (2006) compared the female offspring of Brown-Norway rats that
were exposed continuously to NO2 at 376, 940, or 3760 |ig/m3 (0.2, 0.5, or 2.0 ppm) during
breeding and gestation and up through 12 weeks of age to female offspring who were exposed
continuously to 376, 940, or 3760 |ig/m3 (0.2, 0.5, or 2.0 ppm) only during the weanling period
(from weeks 5 to 12). The ROS generation from AMs was significantly suppressed in the
940- and 3760-|ig/m3 (0.5 and 2.0 ppm) MVexposed weanling animals; no change in ROS-
generating capability was observed in the embryonic-exposed animals compared to the air
controls.
The AMs obtained by BAL from baboons exposed to 3760-|ig/m3 (2.0 ppm) NO2 for
8 h/day, 5 days/week for 6 months had impaired responsiveness to migration inhibitory factor
produced by sensitized lymphocytes (Green and Schneider, 1978). This substance affects the
behavior of AMs by inhibiting free migration, which in turn, interferes with AM functional
capacity. In addition, the random mobility of AMs was significantly depressed in rabbits
following a 2 h/day exposure for 13 days to NO2 at 564 |ig/m3 (0.3 ppm) but not at 1880 |ig/m3
(1.0 ppm) (Schlesinger, 1987b).
Mast cells also play an important role in modulating lung inflammatory responses. IgE-
mediated histamine release from lung mast cells was significantly increased in guinea pigs, but
not rats, exposed to 7520-|ig/m3 (4.0 ppm) NO2, 24 h/day for 12 weeks (Fujimaki and Nohara,
1994). No effect of NO2 on histamine release was observed at the lower concentrations of 1880-
or 3760-|ig/m3 (1 or 2 ppm) NO2.
Several newer studies provide information on the concentration at which effects on the
recruitment and infiltration of PMNs into the lung occur following NO2 exposure. When
Robison et al. (1993) exposed rats to 0 or 0.5-ppm NO2, 8 h/day, 5 days/week for 0.5, 1, 5, or
10 days, no effects were observed on neutrophil, lymphocyte, or macrophage/monocyte levels or
August 2007
3-11
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
cell population percentages in BAL. Results, therefore, suggest no significant influx of
inflammatory cells into lung airways and alveolar spaces. In rats exposed to 0 or 1.2-ppm NO2,
there were no significant differences in cell viability and percentages of pulmonary AMs or
PMNs between animals exposed to 1.2-ppm NO2 and nonexposed controls (Bermudez, 2001).
However, when Pagani et al. (1994) exposed rats to NO2 at 0, 5, or 10 ppm, 24-h or 24 h/day for
7 days, exposure to 10 ppm caused maximal influx of PMN at 24 h, but no influx was observed
after 7 days of exposure. Likewise, no significant changes in lymphocyte counts were observed.
Humoral Immunity and Response to Challenge Agents
As noted by U.S. Environmental Protection Agency (1993), it is most relevant to assess
the effects of inhaled compounds on cell-mediated and antibody responses in the lung itself,
because this is the primary site of defense against respiratory infections. However, because of
technical obstacles, many older studies have assessed the responses in inhaled pollutants or N02
in the spleen or peripheral blood. These studies are more difficult to interpret in terms of
enhanced risk of respiratory infections. Some studies suggest little effect, whereas others
suggest suppression or activation, depending not only on concentration but also on length of
exposure, species tested, and specific endpoints measured. Annex Table AX4.3 summarizes the
various humoral and cell-mediated effects seen in animals exposed to NO2.
Interaction with Infectious Microorganisms
Suppression of host defense mechanisms by NO2 as described in the studies above would
be expected to result in an increased incidence and severity of pulmonary infections (Miller
et al., 1987, Gardner et al., 1979; Coffin and Gardner, 1972). Various experimental approaches
have been employed using animals in an effort to determine the overall functional efficiency of
the host's pulmonary defenses following NO2 exposure. In the most commonly used infectivity
model, animals are exposed to either NO2 or filtered air and the treatment groups are combined
and exposed briefly to an aerosol of a viable agent, such as Streptococcus spp., Klebsiella
pneumoniae, Diplococcus pneumoniae, or influenza virus and mortality rates are determined
(Ehrlich, 1966; Henry et al., 1970; Coffin and Gardner, 1972; Ehrlich et al., 1979; Gardner,
1982). Although the endpoint is mortality, this experimental test is considered a sensitive
indicator of the depression of the defense mechanisms and is a commonly used assay for
assessing immunotoxicity.
August 2007
3-12
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Annex Table AX4.5 summarizes the effects of NO2 exposure and infectious agents in
animal studies as compiled in the 1993 AQCD for Oxides of Nitrogen. No new studies
published since 1993 were identified that evaluated this endpoint. The susceptibility to bacterial
and viral pulmonary infections in animals increases with NO2 exposure. After acute exposure,
the lowest observed concentration that increased lung susceptibility to bacterial infections was
3750-|ig/m3 (2 ppm) NO2 in a 3-h exposure study with mice (Ehrlich et al., 1977; Ehrlich, 1980).
Acute (17 h) exposures to greater than 4250-|ig/m3 (2.3 ppm) N02 also decreased pulmonary
bactericidal activity in mice (Goldstein et al., 1974). Long-term exposure studies have
demonstrated that NO2 exposure reduces the efficiency of defense against infections at
concentrations as low as 940 |ig/m3 (0.5 ppm). Mice challenged with influenza A/PR/8 virus
after continuous exposure for 39 days had increased mortality (Ito, 1971); a 6-month exposure
to the same NO2 concentration likewise resulted in increased bacterial-induced mortality in mice
(Ehrlich and Henry, 1968). Gardner et al. (1977a,b) also reported an increase in mortality with
increasing length of exposure in mice exposed to NO2 from 940 to 52,640 |ig/m3 (0.5 to
28 ppm).
The influence of a wide variety of exposure regimens has been evaluated using the
infectivity model (Annex Table AX4.5). For example, the effect of varying durations of
continuous exposure on the mortality of mice exposed to NO2 was determined for varying
durations of time (Gardner et al., 1977b). When the product of C x T was held constant, the
relationship between concentration and time produced significantly different mortality responses.
Concentration had more influence than duration on the outcome. A more complete discussion of
the C x T relationship issues for NO2 is summarized in a later section. The effect of continuous
versus intermittent exposure to NO2 followed by bacterial challenge has been studied (Ehrlich
and Henry, 1968; Gardner et al., 1979); results suggest that fluctuating levels may ultimately be
as toxic as sustained higher levels (Gardner et al., 1979). Extensive investigations have also
been made on the response to airborne infections in mice breathing spike exposures to NO2
superimposed on a lower continuous background level of NO2, which simulates the pattern
(although not the N02 concentrations) of exposure in the urban environment in the United States
(Gardner 1980; Gardner et al., 1982; Graham et al., 1987). The pattern of exposure determined
the response and that the response was found not to be predictable based on a simple C x T
relationship. Miller et al. (1987) further investigated the effects of chronic exposure to NO2
August 2007
3-13
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
spikes on murine antibacterial lung defenses using a spike-to-baseline ratio of 4:1, which is not
uncommon in the urban environment in the United States. Mice were exposed 23 h/day,
7 days/week for 1 year to a baseline of 376 |ig/m3 (0.2 ppm) or to this baseline level on which
was superimposed a 1-h spike of 1500-|ig/m3 (0.8 ppm) NO2, twice a day, 5 days/week. There
was significantly greater mortality in mice exposed to peak plus baseline compared to baseline-
exposed animals.
A dose-related decrease in pulmonary antibacterial defenses occurs from N02 exposure.
Decreases in antibacterial defenses occurred at concentrations ranging from 7520-|ig/m3
(4.0 ppm) NO2 for Staphylococcus aureus to 37,500-|ig/m3 (20 ppm) NO2 for Proteus mirabilis
(Jakab, 1987).
Differences in species susceptibility to N02 or to a pathogen may play a role in the
enhancement of mortality seen in experimental animals. Additional factors can influence the
interaction of and infectious agents such as exercise (Illing et al., 1980), the presence of O3
(Ehrlich et al., 1977; Gardner, 1980; Gardner et al., 1982; Graham et al., 1987), or elevated
temperatures (Gardner et al., 1982). Table 3.2-1 summarizes a range of proposed mechanisms
by which exposure to NO2 in conjunction with viral infections may exacerbate upper and lower
airways symptoms (Chauhan et al., 1998).
3.2.1.2 Effects of Short-Term NO2 Exposure on Lung Function
Epidemiological Studies of Lung Function
Spirometry (FEVi)—Children
Reliable, repeatable measurement of lung function in children presents special
challenges. The method that seems to produce the most accurate results is spirometry, but
because it requires special equipment and trained testers, it is not generally used for large-scale
studies. Of the three studies reviewed here that did use spirometry (Hoek and Brunekreef, 1994;
Linn et al., 1996; Timonen et al., 2002), all conducted repeat lung function measurements in
schoolchildren. All found significant associations between small decrements in lung function
and increases in ambient NO2 levels. Hoek and Brunekreef (1994) enrolled 1,079 children in the
Netherlands to examine the effects of low-level winter air pollution on FVC, FEVi, MMEF, and
PEF. A significant effect was found only for the PEF measure: the mean (over all subjects)
August 2007
3-14
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
slope (SE) was a reduction of 52 mL/s (95% CI: 21, 83) for 20-ppb increase in the previous
day's NO2. The authors do not give mean values for lung function measurements, so it is not
possible to calculate what percentage of PEF this decrement represents. Linn et al. (1996)
examined 269 Los Angeles-area schoolchildren and short-term air pollution exposures. The
authors found statistically significant associations between previous-day 24-h NO2
concentrations and FVC the next morning (mean decline of 8 mL [95% CI: 2, 14] per 20-ppb
increase in N02), and current-day 24-h N02 concentrations and morning to evening changes in
FEVi (mean decline of 8 mL [95% CI: 2, 14] per 20-ppb increase in NO2). Timonen et al.
(2002) enrolled 33 Finnish children with chronic respiratory symptoms to study the effects of
exercise-induced lung function changes and ambient air pollution. No significant effects were
observed for lung function changes due to exercise, but significant associations were observed
for level of NO2 lagged by 2 days and baseline FVC (mean decline of 21 mL [95% CI: -29, -12]
for 20-ppb N02) and FEVi (mean decline of 20 mL [95% CI: -26, -13] for 20-ppb N02).
Supervised Peak Flow Meter Measurements—Children
Other studies conducted supervised lung function measurements in schoolchildren using
peak flow devices (Scarlett et al., 1996; Peacock et al., 2003; Steerenberg et al., 2001). Scarlett
et al. (1996) used portable peak flow meters to measure lung function in 154 pupils in a school in
southern England. No significant associations were found between level of ambient N02 and
FEV0.75, FVC, or the ratio of FEV0.75 to FVC. They also reported that lung function of children
with current wheeze (n = 14) was not differentially affected. In a second study by the same
group of investigators, Peacock et al. (2003) measured peak flow rates for 177 children in three
schools in southern England. Although no significant associations were found between level of
NO2 and peak flow, there was a significant association for peak flow decrements of 20% or more
with N02 lagged by 2 days or averaged over the previous 4 days. For all children, the OR
(95% CI) for each 20-ppb increase in N02 was 1.91 (95% CI: 1.52, 2.76) and 2.32 (95% CI:
1.00, 5.50) for a 2-day lag and 1 to 4 day lag, respectively. Odds ratios (OR) were similar for a
subset of 43 children with current wheeze (as determined by a questionnaire administered to
parents) (OR= 1.70 [95% CI: 1.00, 2.86] and OR = 2.81 [95% CI: 0.98, 8.06], for a 2-day lag
and 1 to 4 day lag, respectively). Steerenberg et al. (2001) enrolled 82 children (38 urban,
44 suburban) in the Netherlands and collected supervised peak flow measurements at their
August 2007
3-15
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
schools. Significant inverse associations were found between PEF and NO2: each 20-ppb
increase in NO2 lagged by 1 day was associated with a 3.1% decrease in PEF. Ward et al. (2002)
studied the effects of air pollutants on PEF on a panel of 162 nine-year-old children in England
for winter and summer periods and reported no significant associations between NO2 and lung
functions or symptoms.
Home-Use Peak Flow Meter Measurements—Children
Reliable data are notoriously difficult to come by using portable peak flow measuring
devices (for example, see Wensley and Silverman, 2001). This may help explain why, in
contrast to studies with supervised measurements, none of the nine studies using home peak flow
measurements reported any significant associations with ambient NO2 (Roemer et al., 1998
[2,010 children in the PEACE study in Europe]; Roemer et al., 1999 [a subset of 1,621 children
from the PEACE study with chronic respiratory symptoms]; Mortimer et al., 2002
[846 asthmatic children from the NCICAS]; Van der Zee et al., 1999 [633 children in the
Netherlands]; Timonen and Pekkanen, 1997 [169 children including asth3matics in Finland];
Ranzi et al., 2004 [118 children, some with asthma, in the Italian AIRE study]; Segala et al.,
1998 and Just et al., 2002 [over 80 asthmatic children in Paris]; Delfino et al., 2003a
[22 asthmatic children in southern California]).
Ward et al. (2000) examined the effect of correcting peak flow for nonlinear errors on
NO2 effects estimates in a panel study of 147 (47% female) 9-year olds. The correction resulted
in a small increase in the group mean PEF (1.1 L-min '), For the entire panel, NO2 effect
estimates were all corrected in the positive direction with a narrowing of the 95% confidence
interval, and all but the result for 0-day lag were decreased in absolute size by up to 73% (effect
estimate for NO2 lagged 3 days corrected from -0.56 to —0.15% per 10 ppb). When only the
symptomatic/atopic children (i.e., reported wheezing and positive skin test) were considered, the
estimates for associations with 5-day average NO2 decreased in size from —2.53% to -0.90% per
10 ppb. In addition, lag 0 became significant with an increase in magnitude from —0.51% to
-1.22%) per 10 ppb. Figures 3.2-1 and 3.2-2 illustrate the results for the whole panel and the
symptomatic/atopic children, respectively. The authors concluded that correction for PEF meter
measurements resulted in small but important shifts in the direction and size of effect estimates
August 2007
3-16
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
o
<>
I
0
I
3
I
5-day Mean
Pollulant lag days
Figure 3.2-1. Effect estimates with 95% confidence intervals calculated for both
uncorrected (0) and corrected (~) PEF: change in 5-day mean = lag 0 to
lag 4 days.
Source: Ward et al. (2000).
and probable interpretation of results. The effects of correction were, however, not consistent
across pollutants or lags and could not be easily predicted (Ward et al., 2000).
Spirometry (FEVi)—Adults
Spirometry was used in a large cross-sectional study in Switzerland (Schindler et al.,
2001). A subset of 3,912 lifetime nonsmoking adults participated in the spirometric lung
function measurements in the SAPALDIA study (Study of Air Pollution and Lung Diseases in
Adults). Significant inverse relationships were found between increases in NO2 and decreases in
FVC (by 2.74% [95% CI: 0.83, 4.62]) and FEVi (by 2.52% [95% CI: 0.49, 4.55]) for a 20-ppb
increase in N02 on the same day as the examination. FEF25-75 (forced expiratory flow at 25% to
75% of FVC) was found to decrease by 6.73% (95% CI: 0.038, 13.31) for each 20-ppb increase
August 2007
3-17
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
0)
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
measurements to examine the effects of winter air pollution on lung function (Silkoff et al.,
2005). Subjects were enrolled in one of two winters (n = 16 and 18 per winter panel). The
authors observed no adverse effects of ambient air pollution on lung function for the first winter,
but in the second winter did see a significant decrease in morning PEF associated with same day
and previous day NO2 level (quantitative results not provided).
Home-Use Peak Flow Meter Measurements—Adults
Of the studies reviewed that employed portable peak flow meters for subject-measured
lung function, none reported significant associations with N02 levels (van der Zee et al., 2000
[489 adults in the Netherlands]; Higgins et al., 1995 [153 adults in the UK including COPD and
asthma patients]; Park et al., 2005a [64 asthmatic adults in Korea]; Hiltermann et al., 1998
[60 asthmatic adults in the Netherlands]; Harre et al., 1997 [40 adults with COPD in New
Zealand]; Forsberg et al., 1998 [38 adult asthmatics in Sweden]; and Higgins et al., 2000
[35 adults in the UK with COPD or asthma]).
Clinical Studies of Lung Function
Healthy Adults
Studies examining responses of healthy volunteers to acute exposure to NO2 have
generally failed to show alterations in lung mechanics such as airways resistance (Hackney et al.,
1978; Kerr et al., 1979; Linn et al., 1985a; Mohsenin, 1987a, 1988; Frampton et al., 1991; Kim
et al., 1991; Morrow et al., 1992; Rasmussen et al., 1992; Vagaggini et al., 1996; Azadniv et al.,
1998; Devlin et al., 1999). Exposures ranging from 75 minutes to 5 h at concentrations up to
4.0-ppm NO2 did not alter pulmonary function. Bylin et al. (1985) found increased airways
resistance after a 20-min exposure to 0.25-ppm NO2 and decreased airways resistance after a
20-min exposure to 0.5-ppm N02, but no change in airways responsiveness to aerosolized
histamine challenge in the same subjects. These effects have not been confirmed in other
laboratories.
Few human clinical studies of NO2 have included elderly subjects. Morrow et al. (1992)
studied the responses of 20 healthy volunteers, 13 smokers, and 7 nonsmokers, of mean age
61 years, following exposure to 0.3-ppm NO2 for 4 h with light exercise. There was no
significant change in lung function related to NO2 exposure for the group as a whole. However,
August 2007
3-19
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
the 13 smokers experienced a slight decrease in FEVi during exposure, and their responses were
significantly different from the 7 nonsmokers (% change in FEVi at end of exposure:
-2.25 versus +1.25%, p = 0.01). The post-hoc analysis and small numbers of subjects,
especially in the nonsmoking group, limits the interpretation of these findings.
The controlled studies reviewed in O3 AQCD (U.S. Environmental Protection Agency,
2006) generally reported only small pulmonary function changes after combined exposures of
N02 or HNO3 with 03, regardless of whether the interactive effects were potentiating or additive.
Hazucha et al. (1994) found that preexposure of healthy women to 0.6-ppm NO2 for 2 h
enhanced spirometric responses and methacholine airways responsiveness induced by a
subsequent 2-h exposure to 0.3-ppm O3, with intermittent exercise. Following a 1-h exposure
with heavy exercise, Adams et al. (1987) found no differences between spirometric responses to
0.3-ppm O3 and the combination of 0.6-ppm NO2 + 0.3-ppm O3. However, the increase in
airways resistance was significantly less for NO2 + O3 than for O3 alone.
Gong et al. (2005) studied 6 healthy elderly subjects (mean age 68 years) and 18 patients
with COPD (mean age 71 years), all exposed to: (a) air, (b) 0.4-ppm N02, (c) -200 |ig/m3
concentrated ambient fine particles (CAPs), and (d) CAPs + NO2. Exposures were for 2-h with
exercise for 15 min of each half hour. CAPs exposure was associated with small reductions in
mid-expiratory flow rates on spirometry, and reductions in oxygen saturation, but there were no
effects of N02 on lung function, oxygen saturation, or sputum inflammatory cells. However, the
exposures were not fully randomized or blinded, and most of the NO2 exposures took place
months after completion of the CAPs and air exposures. In addition, the small number of healthy
subjects severely limits the statistical power for this group.
Chronic Obstructive Pulmonary Disease Patients
Few studies have examined responses to N02 in subjects with chronic obstructive
pulmonary disease (COPD). Hackney et al. (1978) found no lung function effects of exposure to
0.3-ppm NO2 for 4-h with intermittent exercise in smokers with symptoms and reduced FEVi.
In a group of 22 subjects with moderate COPD, Linn et al. (1985b) found no pulmonary effects
of 1-h exposures to 0.5-, 1.0-, or 2.0-ppm NO2 with 30 min of exercise.
In a study by Morrow et al. (1992), 20 subjects with COPD were exposed for 4-h to
0.3-ppm NO2 in an environmental chamber, with intermittent exercise. Progressive decrements
August 2007
3-20
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
in forced vital capacity (FVC) occurred during the exposure, becoming statistically significant
only at the end of the exposure. The decrements in FVC occurred without changes in flow rates.
These changes in lung function were typical of the "restrictive" pattern seen with 03 rather than
the obstructive changes described by some studies of NO2 exposure in asthmatics.
Gong et al. (2005) exposed 6 elderly healthy adults and 10 COPD patients to four
separate atmospheres: (a) air, (b) 0.4-ppm NO2, (c) ~200-|ig/m3 CAPs, or (d) CAPs + NO2. As
noted above, there were no significant effects of N02 in either the healthy or the COPD subjects.
Asthmatic Individuals
Kleinman et al. (1983) evaluated the response of lightly exercising asthmatic subjects to
inhalation of 0.2-ppm NO2 for 2 h, during which resting minute ventilation doubled. Forced
expiratory flows and airways resistance were not altered by the NO2 exposure. Bauer et al.
(1986) studied the effects of mouthpiece exposure to 0.3-ppm N02 for 30 min (20 min at rest
followed by 10 min of exercise at -40 L/min) in 15 asthmatics. At this level, NO2 inhalation
produced significant decrements in forced expiratory flow rates after exercise, but not at rest.
Jorres and Magnussen (1991) found no effects on lung function in 11 patients with mild asthma
exposed to 0.25-ppm N02 for 30-min, including 10-min of exercise. However, small reductions
in FEVi were observed following 1-ppm NO2 exposure for 3-h with intermittent exercise in
12 mild asthmatics. Koenig et al. (1994) found no pulmonary function effects of exposure to
0.3-ppm NO2 in combination with 0.12-ppm O3, with or without sulfuric acid (H2SO4)
(70 |ig/m3) or HNO3 (0.05 ppm), in 22 adolescents with mild asthma. However, 6 additional
subjects dropped out of the study citing uncomfortable respiratory symptoms.
Jenkins et al. (1999) examined FEVi decrements and airways responsiveness to allergen
in a group of mild, atopic asthmatics. The subjects were exposed during rest for 6 h to filtered
air, NO2 (200 ppb), O3 (100 ppb), or NO2 (200 ppb) + O3 (100 ppb). The subjects were also
exposed for 3 h to N02 (400 ppb), 03 (200 ppb), or N02 (400 ppb) + 03 (200 ppb) to provide
doses identical to those in the 6-h protocols (i.e., equal C x T). Immediately following the 3-h
exposure, but not after the 6-h exposure, there were significant decrements in FEVi following
O3 and NO2 + O3 exposures.
August 2007
3-21
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Summary
Epidemiological studies using data from supervised lung function measurements or
spirometry report small decrements in lung function (Hoek and Brunekreef, 1994; Linn et al.,
1996; Schindler et al., 2001) or peak flow meters (Peacock et al., 2003). Each 20-ppb increase in
same-day NO2 concentration was associated with FVC deficits of 0.3% (Linn et al., 1996) to
2.7% (Schindler et al., 2001). No significant associations were reported in any studies using
unsupervised, self-administered peak flow measurements with portable devices.
Clinical studies have not provided compelling evidence of NO2 effects on pulmonary
function. Acute exposures of young, healthy volunteers to NO2 at levels as high as 4.0 ppm do
not alter lung function as measured by spirometry or airways resistance. The small number of
studies of COPD patients prevents any conclusions about effects on pulmonary function. The
Morrow et al. (1992) study, performed in Rochester, NY, suggested restrictive type effects of
0.3-ppm NO2 exposure for 4 h. However, three other studies, performed in Southern California
at similar exposure concentrations, found no effects. The contrasting findings in these studies
may, in part, reflect the difference in duration of exposure or the differing levels of background
ambient air pollution to which the subjects were exposed chronically, as there were much lower
background levels in Rochester, NY than in Southern California. For asthmatics, the effects of
N02 on pulmonary function have also been inconsistent at exposure concentrations of less than
1-ppm N02. Overall, clinical studies have failed to show effects of N02 on pulmonary function
at exposure concentrations relevant to ambient exposures. However, highly variable findings in
COPD and asthmatic patients suggest that some individuals may be particularly susceptible to
NO2 effects.
3.2.1.3 Respiratory Symptoms
Since the 1993 AQCD, results have been published from several single-city and multicity
studies, including three large longitudinal studies in urban areas covering the continental United
States and southern Ontario: the Harvard Six Cities study (Six Cities; Schwartz et al., 1994), the
National Cooperative Inner-City Asthma Study (NCICAS; Mortimer et al., 2002), and the
Childhood Asthma Management Program (CAMP; Schildcrout et al., 2006). Because of similar
analytic techniques (i.e., multistaged modeling and generalized estimating equations [GEE]), one
strength of all three of these studies is that, as Schildcrout et al. (2006) stated, they could each be
considered as a meta-analysis of "large, within-city panel studies" without some of the
August 2007
3-22
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
limitations associated with meta-analyses, e.g., "between-study heterogeneity and obvious
publication bias."
The report from the Six Cities study includes 1,844 schoolchildren who were followed
for 1 year (Schwartz et al., 1994). Symptoms (in 13 categories, analyzed as cough, lower or
upper respiratory symptoms), were recorded daily. Cities included Watertown (MA), Baltimore,
Kingston-Harriman (TN), Steubenville, Topeka, and Portage (WI). In Mortimer et al. (2002),
864 asthmatic children were followed daily for four 2-week periods over the course of 9 months.
The eight NCICAS cities were New York City (Bronx, E. Harlem), Baltimore, Washington
(DC), Cleveland, Detroit, St Louis, and Chicago. Morning and evening asthma symptoms
(analyzed as none versus any) and peak flow were recorded. Schildcrout et al. (2006) reported
on 990 asthmatic children living within 50 miles of one of 31 NO2 monitors located in eight
North American cities (Boston, Baltimore, Toronto, St. Louis, Denver, Albuquerque, San Diego,
and Seattle). Symptoms (analyzed as none versus any per day) and rescue medication use
(analyzed as number of uses per day) were recorded daily for 2 months. All three studies found
significant associations between level of N02 exposure and risk of respiratory symptoms in
children (Schwartz et al., 1994), and in particular, asthmatic children (Mortimer et al., 2002;
Schildcrout et al., 2006).
In Schwartz et al. (1994), a significant association was found between a 4-day mean of
NO2 exposure and incidence of cough among all children in single-pollutant models: the odds
ratio (OR) was reported for each 10-ppb increase in N02 as OR = 1.27 (95% CI: 1.04, 1.56)
(given in Annex Table AX6.2 for a 20-ppb increase). Cough incidence was not significantly
associated with NO2 on the previous day. The local nonparametric smooth of the 4-day mean
concentration showed increased (p = 0.01) cough incidence up to approximately the mean
concentration (-13 ppb), after which no further increase was observed. The significant
association between cough and 4-day mean NO2 remained unchanged in models that included
O3, but was attenuated and lost significance in two-pollutant models including PM10 (OR for
10-ppb increase in N02= 1.17 [95% CI: 0.94, 1.46]) or S02 (OR for N02 = 1.19 [95% CI: 0.95,
1.51]).
In Mortimer et al. (2002), the greatest effect of the pollutants studied for morning
symptoms was for a 6-day moving average. For increased N02, the risk of any asthma
symptoms (cough, wheeze, shortness of breath) among the asthmatic children in the NCICAS
August 2007
3-23
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
was somewhat higher than for the healthy children in the Six Cities study: OR = 1.48 (95% CI:
1.02, 2.16). Effects were attenuated in multipollutant models that included O3 (OR for 20-ppb
increase in N02 = 1.40 [95% CI: 0.93, 2.09]), 03 and S02 (OR for N02 = 1.31 [95% CI: 0.87,
2.09]), or 03, S02, andPMio(ORforN02= 1.45 [95% CI: 0.63, 3.34]).
In the CAMP study (Shildcrout et al., 2006), the strongest association between N02 and
increased risk of cough was found for a 2-day lag: each 20-ppb increase in N02 occurring 2 days
before measurement increased risk of cough (OR = 1.09 [95% CI: 1.03, 1.15]). Two-pollutant
models including CO, PM10, or S02 produced similar results . (See Figure 3.2-3.) Further,
increased N02 exposure was associated with increased use of rescue medication in the CAMP
study, with the strongest association for a 2-day lag, both for single- and multipollutant models
(e.g., for an increase of 20-ppb N02 in the single-pollutant model, the RR for increased inhaler
usage was 1.05 (95% CI: 1.01,1.09). (See Figure 3.2-4.)
Two 3-month-long panel studies recruited asthmatic children from the one outpatient
clinic in Paris: one study followed 84 children in the fall of 1992 (Segala et al., 1998), and the
other followed 82 children during the winter of 1996 (Just et al., 2002). GEE in logistic
regression analyses found significant associations between respiratory symptoms and level of
N02 and are shown in Annex Table AX6.2 for each 20-ppb increase in N02. No multipollutant
models were shown.
In metropolitan Sydney, 148 children with a history of wheeze were followed for
11 months (Jalaludin et al., 2004). Daily symptoms, medication use, and doctor visits were
examined. In regression models using GEE, significant associations were found between
increased likelihood of wet cough and each 8.2-ppb increase in N02 (OR = 1.05 [95% CI: 1.00,
1.10]). The authors report that estimates did not change in multipollutant models including O3 or
PM10. Ward et al. (2002) examined respiratory symptoms in a panel of 162 children in the
United Kingdom.
No significant associations were reported for the winter period, but a significant
association was reported for the summer period for cough and N02 (lag 0; OR = 1.09 [95% CI:
1.17, 1.01]).
For adults, most studies examining associations between ambient N02 pollution and
respiratory symptoms were conducted in Europe. Various studies have enrolled older adults
August 2007
3-24
DRAFT-DO NOT QUOTE OR CITE
-------
Asthma Symptoms
Nitrogen dioxide
Lag 0
Lag 1
Lag 2
3-day moving sum
1.00
0.97 —
1.06
1.13
1.04
—~—
1.10
1j
1.01
D3
1.09
—~-
1.04
—~-
¦1.07
1.15
Nitrogen dioxide and PM10
Lag 0
Lag 1
Lag 2
3-day moving sum
1.13
1.11
1.15
1.07
T
T
0.75
0.85
0.95 1.05
Odds Ratio
1.15
1.25
Figure 3.2-3. Results for single- and two-pollutant models: Childhood Asthma
Management Program, November 1993-September 1995. Odds ratios for
daily asthma symptoms associated with shifts in within-subject
concentrations.
Source: Schildcrout et al. (2006).
August 2007
3-25
DRAFT-DO NOT QUOTE OR CITE
-------
Rescue Inhaler Uses
Nitrogen dioxide
Lag 0
Lag 1
Lag 2
3-day moving sum
Nitrogen dioxide and PM10
Lag 0
Lag 1
Lag 2
3-day moving sum
0.75
0.85
0.95 1.05
Rate Ratio
1.15
1.25
Figure 3.2-4. Results for single- and two-pollutant models: Childhood Asthma
Management Program, November 1993-September 1995. Odds ratios for
daily rescue inhaler use associated with shifts in within-subject
concentrations. All city-specific estimates of pollutant effects were
included in calculations of study-wide effects except nitrogen dioxide in
Seattle, Washington. Horizontal lines represent the 95% confidence
interval (with limits specified at ends).
Source: Schildcrout et al. (2006).
1 (van der Zee et al., 2000; Harre et al., 1997; Silkoff et al., 2005), nonsmoking adults (Segala
2 et al., 2004), patients with COPD (Higgins et al., 1995; Desqueyroux et al., 2002), bronchial
3 hyperresponsiveness (Boezen et al., 1998), or asthma (Hiltermann et al., 1998; Forsberg et al.,
4 1998; von Klot et al., 2002). Associations were found between NO2 and either respiratory
5 symptoms or inhaler use in a number studies (van der Zee et al., 2000; Harre et al., 1997; Silkoff
August 2007
3-26
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
et al., 2005; Segala et al., 2004; Hiltermann et al., 1998), but not in all studies (Desqueyroux
et al., 2002; von Klot et al., 2002).
Summary Analysis Methodology of Respiratory Symptom Studies
Of the ambient exposure studies reviewed above, it is striking that the studies using
generalized estimating equations (GEE) in the analysis also report significant associations
between daily exposure to NO2 and respiratory effects (see list of these studies in Annex
Table AX6.2). It is possible that the development of the GEE extension to generalized linear
models (GLM) for analysis of longitudinal data (Liang and Zeger, 1986) and subsequent
availability of GEE in statistical analysis packages permitted a much more accurate estimate of
within-subjects variability in repeated-measures designs. This may explain, in part, why so
many of the studies using GEE in the analysis show associations between daily exposure and
symptoms, while other studies using alternative methods to estimate (and perhaps overestimate)
autocorrelation do not (e.g., Roemer et al., 1998 and the PEACE study). Among the studies
using GEE, with the exception of Mortimer et al. (2002) where the strongest association was
with a mean of the previous 6 days, studies enrolling asthmatics, children or adults, found
significant associations between ambient N02 exposure and respiratory symptoms for lags of
0, 1, or 2 days (see Annex Table AX6.2). Interestingly, for the three studies enrolling healthy
subjects (Schwartz et al., 1994; Pino et al., 2004; Segala et al., 2004) significant associations are
only found for longer lag times (of 4 to 6 days). All significant associations between ambient
NO2 and respiratory symptoms occurred in locations with 24-h average NO2 levels below the
annual EPA standard of 53 ppb.
Odds ratios and 95% confidence limits for associations with cough and asthma symptoms
in children are presented in Figures 3.2-5 and 3.2-6, respectively. These figures are called forest
plots, and the area of the square denoting the odds ratio is the proportional to the weight of the
study. When combined in a random effect meta-analysis, the results for cough showed a
significant association with NO2 exposure (OR = 1.09 [95% CI: 1.05, 1.24]; p value in test for
heterogeneity = 0.110). For asthma symptoms, the combined odds ratio from a meta-analyses
was 1.14, (95%) CI: 1.05, 1.24), and the test for heterogeneity had a p value of 0.055. The
effects used in the analysis were selected as follows. Those studies having 0 lag were preferred
to 1-day lags and moving averages, longer single-day lags were not included; if a study had both
August 2007
3-27
DRAFT-DO NOT QUOTE OR CITE
-------
Schwartz et al, 1994 -
Schwartz et al, 1994* -
Schwartz et al, 1994 -
Jalaludin et al 2002* -
Jalaludin et al 2002 -
Just etal 2002 -
Just et al 2002 -
Just et al 2002 -
von Klot et al 2002 -
von Klot et al 2002* -
Just et al 2002* -
Just et al 2002 -
Just et al 2002 -
B
1 1 1—
1 1.5 2 2.5
odds ratio for cough in std units
~r
3
~i—r
3.5 4
~l—I
4.5 5
Figure 3.2-5. Odds ratios (95% CI) for associations between cough and 24-h average
NO2 concentrations (per 20 ppb).
Schwartz et al. (1994): incidence; lags: 1-4 day moving average 0, and 1.
Jalaludin et al. (2002): prevalence; dry cough, wet cough; lags 0, 0, 0.
Just et al. (2002): prevalence; nocturnal cough; lags 0, 0-2, 0-4 day
moving average. Vot Klot et al. (2002): prevalence; cough; lags 1-5 day
moving average, 0. Just et al. (2002): incidence; nocturnal cough; lags 0,
0-2, 0-4. The effects used in the meta-analysis are denoted by *.
1 incidence and prevalence, then the incidence effect was to be used; and "dry cough" was
2 preferred to "wet cough."
3 The results of multipollutant analyses for the three U.S. multicity studies are presented in
4 Figure 3.2-7. Associations with NO2 were generally robust to adjustment for copollutants, as
5 stated previously. Odds ratios were often unchanged with the addition of copollutants, though
August 2007
3-28
DRAFT-DO NOT QUOTE OR CITE
-------
Mortimer et al, 2002* -
Schildcrout et al, 2006* -
Schildcrout et al, 2006 -
Schildcrout et al, 2006 -
Delfino et al 2002* -
Just et al 2002 -
Just et al 2002
Just et al 2002* -
Just etal 2002 -
Just et al 2002 -
Just etal 2002 -
Segala et al 1998* -
Segala et al 1998
I
T
"I 1—I—I
1 1.5 2 2.5 3 3.5 4 4.5 5
odds ratio for asthma symptoms in std units
Figure 3.2-6. Odds ratios (95% CI) for associations between asthma symptoms and
24-h average N02 concentrations (per 20 ppb).
Mortimer et al. (2002): prevalence; lag: 1-6 day moving average.
Schildcrout et al. (2006): prevalence; lags 0,1, 3 day moving average.
Delfino et al. (2002): prevalence; lag 0. Just et al. (2002): prevalence;
lags 0, 0-2, 0-4; incidence; lags 0, 0-2, 0-4. Segala et al. (1998): incidence;
lags 0,1. The effects used in the meta-analysis are denoted by *.
1 reductions in magnitude are apparent in certain models, such as with adjustment for SO2 in the
2 Six Cities study results (Schwartz et al., 2004).
3
4 School Absence
5 The few studies available that used school absence as a health endpoint did not find a
6 significant association with increased levels of ambient NO2 (Gilliland et al., 2001; Rondeau
August 2007
3-29
DRAFT-DO NOT QUOTE OR CITE
-------
Odds Ratio
0.6 1.0 1.4 1.8 2.2 2.6 3.0 3.4
Studv Locations AvaTime Pollutants
Schwartz etal. (1994) 6 cities, US 24-h N02
no2 + pm10
no2 + o3
no2 + so2
c
1 1
lough Incidence
• 6-11 years
0 5-12 years
¦ 4-9 years
~ 9-17 years
Schildcrout et al. (2006) 8 North American cities 24-h N02
N02 + CO
no2 + pm10
no2 + so2
Asthma Symptoms
•-
•-
24-h N02
no2 + CO
no2 + pm,0
no2 + so2
» Rescue Inhaler Use
•
»
Mortimer et al. (2002) 8 cities, US 4-h N02
no2 + o3
N02 + 03 + S02
N02+ 03 + S02 + PM10
Morning % PEFR
¦
¦
¦
Figure 3.2-7. Odds ratios and 95% confidence intervals for associations between
asthma symptoms and 24-h average NO2 concentrations (per 20 ppb)
from multipollutant models. Details about effects from the top of the
figure to the bottom entries are: Mortimer et al. (2002): prevalence; lag:
1-6 day moving average. Schildcrout et al. (2006): prevalence; lags 0,1, 3
day moving average. Delfino et al. (2002): prevalence; lag 0. Just et al.
(2002): prevalence; lags 0, 0-2, 0-4; incidence; lags 0, 0-2, 0-4. Segala
et al. (1998): incidence; lags 0,1.
1 et al., 2005; Park et al., 2002). As part of the Children's Health Study, Gilliland et al. (2001)
2 examined school absence among 2,081 schoolchildren in 12 communities in Southern California
3 and found significant associations between 20-ppb increases in O3 and respiratory illness related
4 absences, but no association in single-pollutant models with NO2 or PMi0. Annual mean daily
5 N02 in the 12 communities ranged from 5 to 45 ppb. Park et al. (2002) studied school
6 absenteeism in an elementary school in Seoul, Korea, and found significant risks associated with
7 increases of PM10 (RR = 1.06 [95% CI: 1.04, 1.09] for each 42.1-|ig/m3 increase), SO2
8 (RR = 1.09 [95% CI: 1.07, 1.12] for each 5.68-ppb increase), and 03 (RR= 1.08 [95% CI: 1.06,
August 2007
3-30
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
1.11 ] for each 15,94-ppb increase) but none with NO2 (although there is a suggestion of an
association with an RR of 1.02 (95% CI: 0.99, 1.04) for each 14.51-ppb increase).
Summary
Taken together, these studies indicate that short-term exposure to N02 is associated with
respiratory symptoms in children and adults. For children, the results of new multicity studies
provide substantial support for associations with respiratory symptoms, particularly in asthmatic
children. In adults, the recent studies link short-term NO2 exposure with various respiratory
symptoms or medication use, but the findings are not always consistent.
3.2.1.4 Airways Inflammation
Epidemiological Studies of Airways Inflammation
A number of studies have examined biological markers for inflammation (exhaled NO
and inflammatory nasal lavage [NAL] markers [Steerenberg et al., 2001, 2003]; exhaled NO
[Adamkiewicz et al., 2004]) and lung damage (urinary Clara cell protein CC16 [Timonen et al.,
2004]). Steerenberg et al. (2001) studied 126 schoolchildren from urban and suburban
communities in the Netherlands. Sampling of exhaled air and NAL fluid was performed seven
times, once per week over the course of 2 months. On average, the ambient NO2 levels were
1.5 times higher and ambient NO levels 7.8 times higher in the urban compared to suburban
community. Compared to children in the suburban community, urban children had significantly
greater levels of inflammatory NAL markers (IL-8, urea, uric acid, albumin) but not greater
levels of exhaled NO. However, within the urban group, a concentration-response relationship
was seen. For increases of 20 ppb in NO2 lagged by 1 or 3 days, exhaled NO increased
significantly by 6.4 to 8.8 ppb. Exhaled NO also increased for suburban children versus
comparable increases in N02, but not significantly. Another study by Steerenberg et al. (2003)
of 119 schoolchildren in the Netherlands found associations between ambient NO2 and level of
exhaled NO, but quantitative regression results are not given. The authors concluded from their
data that an established, ongoing inflammatory response to pollen was not exacerbated by
subsequent exposure to high levels of air pollution or pollen Steerenberg et al., (2003).
Adamkiewicz et al. (2004) studied 29 elderly adults in Steubenville and found significant
August 2007
3-31
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
associations between increased exhaled NO and increased daily levels of PM2.5, but no
association was found with ambient NO2.
Timonen et al. (2004) collected biweekly urine samples for 6 months from 131 adults
with coronary heart disease living in Amsterdam, Helsinki, and Erfurt, Germany. Estimates
using data from all three communities showed significant associations between urinary levels of
Clara cell protein CC16 (a marker for lung damage) with elevations in daily PM2.5 concentration,
but not ambient N02. In Helsinki, however, there was a significant association between a
10-|ig/m3 increase in NO2 lagged by 3 days and a 9.2% increase (95% CI: 0.1, 18.3) in
ln(CC16). Interestingly, the correlation between NO2 and PM2.5 was lower in Helsinki (r = 0.35)
compared to this correlation in Amsterdam (r = 0.49) or Erfurt (r = 0.82).
Bernard et al. (1998) examined personal exposure to N02 and its effect on plasma
antioxidants in a group of 107 healthy adults in Montpellier, France. Subjects wore passive
monitors for 14 days. When subjects were divided into two exposure groups (above and below
40 |ig/m3 [21.3 ppb]), those in the high-exposure group had significantly lower plasma
P-carotene levels. This difference was even greater when analysis was stratified by dietary
P-carotene intake: exposure to >40-|ig/m3 NO2 had the largest effect on plasma P-carotene level
among subjects who ate <4 mg/day P-carotene (p < 0.005). No other pollutants were included in
this study.
Clinical Studies of Airways Inflammation
Healthy Adults
Helleday et al. (1994) performed BAL before and 24 h after exposure to 3.5-ppm NO2 for
20 min, with 15 min of light exercise in 8 smokers and 8 nonsmokers. The recovery of PMNs in
the bronchial portion of BAL was slightly increased in the nonsmokers, while only the alveolar
portion showed increased PMN numbers in smokers. A significant weakness of this study was
the failure to include a true air exposure with a randomized, double-blind design.
The 1993 AQCD for Oxides of Nitrogen cited preliminary findings from two studies
showing modest airways inflammation, as indicated by increased PMN numbers in BAL fluid
after exposure to 2.0-ppm NO2 for 4 to 6-h with intermittent exercise. Both of those studies have
now been published in complete form Azadniv et al. (1998); Devlin et al. (1999), and additional
August 2007
3-32
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
studies summarized below provided a clearer picture of the airways inflammatory response to
NO2 exposure.
Healthy volunteers exposed to 2.0-ppm N02 for 6-h with intermittent exercise (Azadniv
et al., 1998) showed a slight increase in the percentage of PMNs obtained in BAL fluid 18-h
after exposure (air, 2.2 ± 0.3%; NO2, 3.1 ± 0.4%). In a separate group of subjects exposed using
the same protocol but assessed immediately after exposure Gavras et al., (1994), no effects were
found in AM phenotype or expression of the cell adhesion molecule CD1 lb or receptors for IgG.
Blomberg et al. (1997) reported that 4-h exposures to 2.0-ppm NO2 resulted in an increase in
IL-8 and PMNs in the proximal airways of healthy subjects, although no changes were seen in
bronchial biopsies. This group also studied the effects of repeated 4-h exposures to 2-ppm NO2
on 4 consecutive days, with BAL, bronchial biopsies, and BAL fluid antioxidant levels assessed
1.5-h after the last exposure Blomberg et al., (1999). The bronchial wash fraction of BAL fluid
showed a 2-fold increase in PMNs and a 1.5-fold increase in myeloperoxidase, indicating
persistent mild airways inflammation with repeated NO2 exposure.
Devlin et al. (1999) exposed 8 healthy nonsmokers to 2.0-ppm NO2 for 4-h with
intermittent exercise. BAL performed the following morning showed a 3.1-fold increase in
PMNs recovered in the bronchial fraction, indicating small airways inflammation. These
investigators also observed a reduction in AM phagocytosis and superoxide production,
indicating possible adverse effects on host defense.
Pathmanathan et al. (2003) conducted four repeated daily exposures of healthy subjects to
4-ppm NO2 or air for 4 h, with intermittent exercise. Exposures were randomized and separated
by 3 weeks. Bronchoscopy and bronchial biopsies were performed 1-h after the last exposure.
Immunohistochemistry of the respiratory epithelium showed increased expression of IL-5, IL-10,
and IL-13, as well as intercellular adhesion molecule-1 (ICAM-1). These interleukins are
upregulated in Th2 inflammatory responses, which are characteristic of allergic inflammation.
The findings suggest repeated NO2 exposures may drive the airways inflammatory response
toward a Th2 or allergic-type response. Unfortunately, the report provided no data on
inflammatory cell responses in the epithelium or on cells or cytokines in BAL fluid. Thus, the
findings cannot be considered conclusive regarding allergic inflammation. Furthermore, the
exposure concentrations of 4 ppm are considerably higher than ambient outdoor concentrations.
August 2007
3-33
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Recent studies provide evidence for airways inflammatory effects at concentrations
<2.0 ppm. Frampton et al. (2002) examined NO2 concentration responses in 21 healthy
nonsmokers. Subjects were exposed to air or 0.6- or 1.5-ppm N02 for 3 h, with intermittent
exercise, with exposures separated by at least 3 weeks. BAL was performed 3.5-h after
exposure. PMN numbers in the bronchial lavage fraction increased slightly (<3-fold) but
significantly (p = 0.0003) after exposure to 1.5-ppm NO2; no increase was evident at 0.6-ppm
N02. Lymphocyte numbers increased in the bronchial lavage fraction after 0.6-ppm N02, but
not 1.5 ppm. CD4+ T lymphocyte numbers increased in the alveolar lavage fraction, and
lymphocytes decreased in blood. These findings suggest a lymphocytic airways inflammatory
response to 0.6-ppm NO2, which changes to a mild neutrophilic response at 1.5-ppm NO2.
.Torres et al. (1995) found that 3-h exposures to 1-ppm N02 with intermittent exercise
altered levels of eicosanoids, but not inflammatory cells, in BAL fluid collected 1-h after
exposure. Eicosanoids are chemical mediators of the inflammatory response; their increase in
BAL fluid in this study suggests inflammation. The absence of an increase in PMN numbers
may reflect the timing of bronchoscopy (1 h after exposure). The peak influx of PMNs may
occur several hours after exposure, as it does following O3 exposure.
The studies summarized in this section provide evidence for airways inflammation at
NO2 concentrations of <2.0 ppm; separately analyzing the bronchial fraction of BAL appears to
increase the sensitivity for detecting airways inflammatory effects of NO2 exposure. The onset
of inflammatory responses in healthy subjects appears to be between 100 and 200 ppm-min, i.e.,
1 ppm for 2 to 3 h.
Toxicological Studies of Airways Inflammation
Numerous studies demonstrate changes in protein and enzyme levels in the lung
following inhalation of NO2 (see Annex Table AX4.2). These observations reflect the ability of
N02 to cause lung inflammation associated with concomitant infiltration of serum protein,
enzymes, and inflammatory cells. However, interpretation of the array of changes observed may
also reflect other factors. For example, NO2 exposure may induce differentiation of some cell
populations in response to damage-induced tissue remodeling. Thus, some changes in lung
enzyme activity and protein content may reflect changes in cell types, rather than the direct
effects of NO2 on protein infiltration. Furthermore, some direct effects of NO2 on enzymes are
August 2007
3-34
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
possible because NO2 can oxidize certain reducible amino acids or side chains of proteins in
aqueous solution (Freeman and Mudd, 1981).
Increased BAL fluid protein levels have been observed at low concentrations of N02.
Exposure to 752-|ig/m3 (0.4 ppm) NO2 continuously for 1 week resulted in increases in BAL
protein in vitamin c-deficient guinea pigs (Sherwin and Carlson, 1973). A slight increase in
albumin, indicating a mild degree of injury to the pulmonary capillary membrane, was observed
in mice exposed to 9400-|ig/m3 (5.0 ppm) N02, 6 h/day for 6 days Rose et al., (1989). Guinea
pigs demonstrated significantly increased lactate dehydrogenase (LDH) content of the lower
lobes of the lung following exposure to 3760-|ig/m3 (2.0 ppm) NO2 for 1, 2, or 3 weeks Sherwin
et al., (1972). However, in rats, increases in LDH in BAL fluid were noted at exposure to 1880
to 9400-|ig/m3 (1.0 to 5.0 ppm) N02, 7-h/day, 5-days/week for 2.7 weeks, but values returned to
control levels after 15 weeks of exposure while histological changes persisted (Gregory et al.,
1983).
Numerous studies in rats and mice published since the 1993 AQCD for Oxides of
Nitrogen have investigated the ability of N02 to induce protein level changes consistent with
inflammation. Muller et al. (1994) exposed rats to 0, 0.8-, 5-, or 10-ppm NO2 continuously for 1
or 3 days and reported that BAL protein content significantly increased in a concentration- and
exposure duration-dependent manner, with the change becoming significant at 5 ppm for 3 days
and at 10 ppm for > 1 day of exposure. Pagani et al. (1994) exposed rats to 0, 9-, or 18-mg/m3 (0,
5, or 10 ppm) NO2, 24 h or 24-h/day for 7 days. In their study, protein content in BAL fluid
increased significantly only after 24 h of exposure to 10-ppm NO2.
Overall, these newer studies suggest that markers of inflammation measured in BAL fluid
such as total protein content and content of markers of cell membrane permeability (e.g., LDH)
increase only at or above 5-ppm exposure. Based on the new studies, rats and mice appear to
respond in a similar fashion.
It has also been reported that protein content changes in BAL fluid can be dependent on
dietary antioxidant status, further clouding the interpretation of such effects. NO2 exposure
increases the protein content of BAL fluid in vitamin C-deficient guinea pigs at N02 levels as
low as 1880 |ig/m3 (1.0 ppm) after a 72-h exposure, but a 1-week exposure to 752 |ig/m3
(0.4 ppm) did not increase protein levels (Selgrade et al., 1981). The results of this 1-week
exposure apparently conflict with those of Sherwin and Carlson (1973), who found increased
August 2007
3-35
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
protein content of BAL fluid from vitamin C-deficient guinea pigs exposed to 752-|ig/m3
(0.4 ppm) NO2 for 1 week. Differences in exposure techniques, protein measurement methods,
and/or degree of vitamin C deficiencies may explain the difference between the two studies.
Hatch et al. (1986) found that the NCVinduced increase in BAL protein in vitamin C-deficient
guinea pigs was accompanied by an increase in lung content of nonprotein sulfhydryls and
ascorbic acid and a decrease in vitamin E content. The increased susceptibility to NO2 was
observed when lung vitamin C was reduced (by diet) to levels <50% of normal.
Summary
Recent epidemiological studies provide some evidence that short-term exposure to NO2
can result in inflammatory responses in the airways, but the findings are not consistently
positive. The controlled human exposure studies summarized in this section provide evidence
for airways inflammation atN02 concentrations of <2.0 ppm; separately analyzing the bronchial
fraction of BAL appears to increase the sensitivity for detecting airways inflammatory effects of
NO2 exposure. The onset of inflammatory responses in healthy subjects appears to be between
100 and 200 ppm-min, i.e., 1 ppm for 2 to 3 h. Biological markers of inflammation are reported
in antioxidant-deficient laboratory animals with exposures to 0.4-ppm N02. Normal animals do
not respond until exposed to much higher levels, i.e., 5-ppm NO2. Together, the available
evidence indicates that short-term exposure to NO2 may result in airways inflammation
particularly among the more susceptible, such as those with antioxidant deficiencies.
3.3.1.5 Airways Hyperresponsiveness
Clinical Studies of Airways Responsiveness
Inhaled pollutants such as NO2 may have direct effects on lung function, or they may
enhance the inherent responsiveness of the airways to challenge with a bronchoconstricting
agent. Several drugs and other stimuli that cause bronchoconstriction have been used in
challenge testing, including the cholinergic drugs methacholine and carbachol, as well as
histamine, hypertonic saline, cold air, and SO2. Challenge with "specific" allergens is
considered in asthmatics.
Asthmatics are generally much more sensitive to nonspecific bronchoconstricting agents
than non-asthmatics, and airways challenge testing is used as a diagnostic test in asthma. There
August 2007
3-36
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
is a wide range of airways responsiveness in healthy people, and responsiveness is influenced by
many factors, including medications, cigarette smoke, pollutants, respiratory infections,
occupational exposures, and respiratory irritants. Standards for airways challenge testing have
been developed for the clinical laboratory (American Thoracic Society, 2000a). However,
variations in methods for administering the bronchoconstricting agents may substantially affect
the results (Cockcroft et al., 2005).
Increases in nonspecific airways responsiveness in response to pollutant exposure mean
that the pollutant causes the airways to be more sensitive to other stimuli, and in asthmatics, is
one indicator of increased severity of disease. In addition, increases in airways responsiveness
are correlated with worsened asthma control, and effective treatment often reduces airways
responsiveness.
Nonspecific Responsiveness in Healthy Adults
Several observations indicate thatN02 exposures in the range of 1.5 to 2.0 ppm cause
small but significant increases in airways responsiveness in healthy subjects. Mohsenin (1988)
found that a 1-h exposure to 2-ppm NO2 increased responsiveness to methacholine, as measured
by changes in specific airways conductance, without directly affecting lung function.
Furthermore, pretreatment with ascorbic acid prevented the MVinduced increase in airways
responsiveness (Mohsenin, 1987a). A mild increase in responsiveness to carbachol was
observed following a 3-h exposure to 1.5-ppm NO2, but not to intermittent peaks of 2.0 ppm
(Frampton et al. 1991). Thus, the lower threshold concentration of NO2 for causing increases
in nonspecific airways responsiveness in healthy subjects appears to be in the 1- to 2-ppm range.
Nonspecific Responsiveness in Asthmatic Individuals
The 1993 AQCD for Oxides of Nitrogen reported results from some early studies that
suggested that NO2 might enhance subsequent responsiveness to challenge by
bronchoconstricting agents. This increase in airways responsiveness in asthmatics has been
observed in some, but not all studies, at relatively low N02 concentrations within the range of
0.2 to 0.3 ppm. Appearing in Tables 15-9 and 15-10 of the 1993 AQCD (U.S. Environmental
Protection Agency, 1993), the meta-analysis by Folinsbee (1992) also provided suggestive
evidence of increased airways responsiveness in asthmatics exposed to NO2 concentrations of as
August 2007
3-37
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
low as 0.1 ppm for 1 hour during rest. However, numerous studies had not reported independent
effects of NO2 on lung function in asthmatic individuals.
Roger et al. (1990), in a comprehensive, concentration-response experiment, were unable
to confirm the results of a pilot study suggesting airways responses occur in asthmatic subjects.
Twenty-one male asthmatics exposed to NO2 at 0.15, 0.30, or 0.60 ppm for 75 min did not
experience significant effects on lung function or airways responsiveness compared with air
exposure. Bylin et al. (1985) found significantly increased bronchial responsiveness to histamine
challenge compared with sham exposure in 8 atopic asthmatics exposed to 0.30-ppm NO2 for
20 min. Five of 8 asthmatics demonstrated increased reactivity, while 3 subjects showed no
change, as assessed by specific airways resistance. Mohsenin (1987b) reported enhanced
responsiveness to methacholine in 8 asthmatic subjects exposed to 0.50-ppm N02 at rest for 1 h;
airways responsiveness was measured by partial expiratory flow rates at 40% vital capacity,
which may have increased the sensitivity for detecting small changes in airways responsiveness.
Jorres and Magnussen (1991) found no effects on lung function or methacholine responsiveness
in 11 patients with mild asthma exposed to 0.25-ppm N02 for 30 min with 10 min of exercise.
Strand et al. (1996) performed a series of studies in mild asthmatics exposed to 0.26 ppm for
30 min and found increased responsiveness to histamine as well as to allergen challenge (see
below).
The effects of NO2 exposure on SCVinduced bronchoconstriction have been examined,
but with inconsistent results. Jorres and Magnussen (1990) found an increase in airways
responsiveness to SO2 in asthmatic subjects following exposure to 0.25-ppm NO2 for 30 min at
rest, yet Rubinstein et al. (1990) found no change in responsiveness to SO2 inhalation following
exposure of asthmatics to 0.30-ppm NO2 for 30 min with 20 min of exercise.
The inconsistent results of these studies have not been satisfactorily explained. It is
evident that a wide range of responses occurs among asthmatics exposed to NO2. This variation
may in part reflect differences in subjects and exposure protocols: mouthpiece versus chamber,
obstructed versus non-obstructed asthmatics, sedentary versus exercise, and varying use of
medication(s) among subjects. Identification of factors that predispose to N02 responsiveness
requires further investigation. These studies have typically involved volunteers with mild
asthma; data are needed from more severely affected asthmatics who may be more susceptible.
Overall, there is only suggestive evidence that short-term exposures to NO2 at outdoor ambient
August 2007
3-38
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
concentrations (<0.25 ppm) significantly alter lung function or nonspecific airways
responsiveness in most people with mild asthma. However, it remains possible that more severe
asthmatics, or individuals with particular sensitivity to N02 airways effects, would experience
reductions in lung function or increased airways responsiveness when exercising outdoors at
NO2 concentrations of <0.25 ppm. Furthermore, outdoor levels influence indoor concentrations,
which may reach peak levels that are clinically important for some adults and children with
asthma.
Allergen Responsiveness in Asthmatic Individuals
In asthmatics, inhalation of an allergen to which an individual is sensitized can cause
bronchoconstriction and increased allergic airways inflammation, and this an important cause of
asthma exacerbations. Aerosolized allergens can be used in controlled airways challenge testing
in the laboratory, either clinically to identify specific allergens to which the individual is
responsive or in research to investigate the pathogenesis of the airways allergic response or the
effectiveness of treatments. The degree of responsiveness is a function of the concentration of
inhaled allergen, the degree of sensitization as measured by the level of allergen-specific
immunoglobulin E, and the degree of nonspecific airways responsiveness (Cockcroft and Davis,
2006).
It is difficult to predict the level of responsiveness to an allergen, and rarely, severe
bronchoconstriction can occur with inhalation of very low concentrations of allergen. Allergen
challenge testing, therefore, involves greater risk than nonspecific airways challenge with drugs
such as methacholine. Asthmatics may experience both an "early" response, with declines in
lung function within minutes after the challenge, and a "late" response, with a decline in lung
function hours after the exposure. The early response primarily reflects release of histamine and
other mediators by airways mast cells; the late response reflects enhanced airways inflammation
and mucous production. Responses to allergen challenge are typically measured as changes in
pulmonary function, such as declines in FEVi. However, the airways inflammatory response can
also be assessed using BAL, induced sputum, or exhaled breath condensate.
The potential for NO2 exposure to enhance responsiveness to allergen challenge in
asthmatics deserves special mention. Several recent studies, summarized in Annex Table AX5.3,
have reported that low-level exposures to NO2, both at rest and with exercise, enhance the
response to specific allergen challenge in mild asthmatics.
August 2007
3-39
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Tunnicliffe et al. (1994) exposed 8 subjects with mild asthma to 0.1- or 0.4-ppm NO2 for
1-h at rest and reported that 0.4-ppm NO2 exposure slightly increased responsiveness to a fixed
dose of allergen during both the early and late phases of the response. In two U.K. studies
(Devalia et al., 1994; Rusznak et al., 1996), exposure to the combination of 0.4-ppm NO2 and
0.2-ppm SO2 increased responsiveness to subsequent allergen challenge in mild atopic
asthmatics, whereas, neither pollutant alone altered allergen responsiveness.
A series of studies from the Karolinska Institute in Sweden have explored airways
responses to allergen challenge in asthmatics. Strand et al. (1997) demonstrated that single
30-min exposures to 0.26-ppm NO2 increased the late phase response to allergen challenge 4-h
after exposure. In a separate study (Strand et al., 1998), 4 daily repeated exposures to 0.26-ppm
N02 for 30 min increased both the early and late-phase responses to allergen. Barck et al. (2002)
used the same exposure and challenge protocol in the earlier Strand studies (0.26 ppm for 30
min, with allergen challenge 4-h after exposure), and performed BAL 19-h after exposure to
determine NO2 effects on the inflammatory response to allergen challenge. NO2 (0.26 ppm for
30 min) followed by allergen caused increases in the BAL recovery of PMN and eosinophil
cationic protein (ECP), with reduced volume of BAL fluid and reduced cell viability, compared
with air followed by allergen. ECP is released by degranulating eosinophils, is toxic to
respiratory epithelial cells, and is thought to play a role in the pathogenesis of airways injury in
asthma. These findings indicate that NO2 enhanced the airways inflammatory response to
allergen. Subsequently, Barck et al. (2005a) exposed 18 mild asthmatics to air or N02 for 15
min on day 1, followed by two 15-min exposures separated by 1-h on day 2, with allergen
challenge after exposures on both days 1 and 2. Sputum was induced before exposure on day
1 and after exposures (morning of day 3). NO2 + allergen, compared to air + allergen, treatment
resulted in increased levels of ECP in both sputum and blood and increased myeloperoxidase
levels in blood. A separate study examined NO2 effects on nasal responses to nasal allergen
challenge (Barck et al., 2005b). Single 30-min exposures to 0.26-ppm NO2 did not enhance
nasal allergen responses. All exposures in the Karolinska Institute studies (Barck et al., 2002,
2005a; Strand et al., 1997, 1998) used subjects at rest. These studies utilized an adequate
number of subjects, included air control exposures, randomized exposure order, and separated
exposures by at least 2 weeks. Together, they appear to demonstrate convincingly effects of
quite brief exposures to 0.26 ppm on allergen responsiveness in asthmatics. The level of
August 2007
3-40
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
confidence in the findings from the Karolinska Institute would be further increased with
confirmation from other laboratories. However, the findings may shed some light on the variable
results in earlier studies of N02 effects on nonspecific airways responsiveness. It is possible that
some prior studies may have been variably confounded by environmental allergen exposure,
increasing the variability in subject responses to NO2 and perhaps explaining some of the
inconsistent findings.
Several studies have been conducted using longer N02 exposures. Wang et al. (1995a,b,
1999) found that more intense (0.4 ppm) and prolonged (6 h) NO2 exposures enhanced allergen
responsiveness in the nasal mucosa in subjects with allergic rhinitis. Jenkins et al. (1999)
examined FEVi decrements and airways responsiveness to allergen in a group of mild, atopic
asthmatics. The subjects were exposed for 3-h to N02 (400 ppb), 03 (200 ppb), and N02
(400 ppb) + O3 (200 ppb). The subjects were also exposed for 6-h to produce exposure
concentrations that would provide identical doses to the 3-h protocols (i.e., equivalent C x T).
Significant increases in airways responsiveness to allergen occurred following all the 3-h
exposures, but not following the 6-h exposures.
Lastly, one study examined the effects on allergen responsiveness of exposure to traffic
exhaust in a tunnel (Svartengren et al., 2000). Twenty mild asthmatics sat in a stationary vehicle
within a busy tunnel for 30 min. Allergen challenge was performed 4-h later. The control
exposure was in a hotel room in a suburban area with low air pollution levels. Exposures were
separated by 4 weeks and the order was randomized. Median N02 levels in the vehicle were
313 |ig/m3 or 0.166 ppm, PM10 levels were 170 |ig/m3, and PM2.5 levels were 95 |ig/m3. Median
NO2 levels outside the hotel were 11 |ig/m3. Subjects in the tunnel experienced increased cough,
and also reported awareness of noise and odors. More importantly, there was a greater allergen-
induced increase in specific airways resistance after the tunnel exposure than after the control
exposure (44% versus 31% respectively). Thoracic gas volume was also increased to a greater
degree after the tunnel exposure, suggesting increased gas trapping within the lung. These
findings were most pronounced in the subjects exposed to the highest levels of NO2. This study
suggests that exposure to traffic exhaust, and particularly the N02 component, increases allergen
responsiveness in asthmatics, and the results fit well with the findings in studies of clinical
exposures of NO2 (Barck et al., 2002, 2005a). However, it was not possible to blind the
exposures, and the control exposure (hotel room, presumably quiet and relaxed) was not well
August 2007
3-41
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
matched to the experimental exposure (vehicle, noisy, odorous). It remains possible that factors
other than NO2 contributed to, or were responsible for, the observed differences in allergen
responsiveness.
These recent studies involving allergen challenge suggest that NO2 may enhance the
sensitivity to allergen-induced decrements in lung function, and increase the allergen-induced
airways inflammatory response. Enhancement of allergic responses in asthmatics occurs at
exposure levels more than an order of magnitude lower than those associated with airways
inflammation in healthy subjects. The dosimetry difference is even greater when considering
that the allergen challenge studies were generally performed at rest, while the airways
inflammation studies in healthy subjects were performed with intermittent exercise.
Enhancement of allergen responses has been found at exposures as low as 8 ppm-min, i.e.,
0.26 ppm for 30 min. Additional work is needed to understand more completely the exposure-
response characteristics of NO2 effects on allergen responses, as well as the effects of exercise,
relationship to the severity of asthma, the role of asthma medications, and other clinical factors.
Additional animal and in vitro studies are needed to establish the precise mechanisms involved.
Toxicological Studies of Airways Responsiveness
The 1993 AQCD found airways responsiveness to be a key health response to NO2
exposure. Although the mechanisms are not fully known, many studies have demonstrated the
ability of NO2 exposure to increase bronchial sensitivity to various challenge agents.
Acute exposures of Brown-Norway rats to NO2 at a concentration of 9400 |ig/m3 (5 ppm)
for 3-h resulted in increased specific immune response to house dust mite allergen and increased
immune-mediated pulmonary inflammation (Gilmour et al., 1996). Higher levels of antigen-
specific serum IgE, local IgA, IgG, and IgE were observed when rats were exposed to NO2 after
both the immunization and challenge phase, but not after either the immunization or challenge
phase alone. Increases in the number of inflammatory cells in the lungs and lymphocyte
responsiveness to house dust mite allergen in the spleen and mediastinal lymph node were
observed. The authors concluded that this increased immune responsiveness to house dust mite
allergen may be the result of the increased permeability of the lung caused by NO2 exposure,
enhancing translocation of the antigen to local lymph nodes and circulation to other sites in the
body.
August 2007
3-42
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
A delayed bronchial response, seen as increased respiration rate (tachypnea), occurred in
N02-exposed, Candida albicans-sensitized guinea pigs 15 to 42-h after a challenge dose of
C. albicans (Kitabatake et al., 1995). Guinea pigs were given an intraperitoneal injection of
C. albicans, followed by a second injection 4 weeks later. Two weeks after the second injection,
the animals were given an inhalation exposure of killed C. albicans. Animals were also exposed
4 h/day to 8955-|ig/m3 (4.76 ppm) NO2 from the same day as the first injection of C. albicans for
a total of 30 exposures (5 days/week).
Pulmonary function (lung resistance, dynamic compliance) was not affected in
N02-exposed rabbits immunized intraperitoneally within 24-h of birth until 3 months of age to
either Alternaria tenuis or house dust mite antigen. The rabbits were given intraperitoneal
injections once weekly for 1 month, and then every 2 weeks thereafter, and exposed to
7520-|ig/m3 (4 ppm) NO2 for 2-h daily (Douglas et al., 1994).
Kobayashi and Miura (1995) studied the concentration- and time-dependency of airways
hyperresponsiveness to inhaled histamine aerosol in guinea pigs exposed subchronically to NO2.
In one experiment, guinea pigs were exposed by inhalation to 0, 113, 940, or 7520-|ig/m3
(0, 0.06, 0.5, or 4.0 ppm) NO2, 24 h/day for 6 or 12 weeks. Immediately following the last
exposure, airways hyperresponsiveness was assessed by measurement of specific airways
resistance as a function of increasing concentrations of histamine aerosol. Animals exposed to
7520-|ig/m3 (4 ppm) NO2 for 6 weeks exhibited increased airways response to inhaled histamine
aerosol; airways response at 12 weeks was not determined. No effects were observed at the
lower exposure levels. In another experiment conducted in this study (Kobayashi and Miura,
1995), guinea pigs were exposed by inhalation to 0, 1880-, 3760-, or 7520-|ig/m3 (0, 1.0, 2.0, or
4.0 ppm) NO2, 24 h/day for 6 or 12 weeks, and the airways hyperresponsiveness was determined.
Increased hyperresponsiveness to inhaled histamine was observed in animals exposed to
7520 |ig/m3 (4 ppm) for 6 weeks; 3760 |ig/m3 (2 ppm) for 6 and 12 weeks; and 1880 |ig/m3
(1 ppm) for 12 weeks only. The results also showed that at 1880- or 3760-|ig/m3 (1 or 2 ppm)
NO2, airways hyperresponsiveness developed to a higher degree with the passage of time.
Therefore, a higher concentration of N02 induces airways hyperresponsiveness faster than a
lower concentration. When the specific airways resistance was compared to values determined
1 week prior to initiation of the NO2 exposure, values were increased in the 3760- and
August 2007
3-43
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
7520-|ig/m3 (2.0 and 4.0 ppm) animals at 12 weeks only. Specific airways resistance was also
increased to a higher degree with the passage of time.
Summary
Exposure to N02 enhances the inherent responsiveness of the airways to subsequent
specific and nonspecific challenges. Hyperresponsiveness to a challenge agent is typically
characterized by bronchoconstriction subsequent to NO2 compared to clean air exposure.
Subchronic exposures (6 to 12 weeks) of animals to NO2 (1 to 4 ppm) increases responsiveness
to nonspecific challenge. Healthy humans exposed to N02 in the range of 1.5 to 2.0 ppm for a
few hours also develop small but significant increases in nonspecific airways responsiveness.
There is limited evidence that asthmatics may experience increased airways responsiveness to
nonspecific challenge following exposure to between 0.2- and 0.3-ppm NO2 for 30 min. A meta-
analysis of four studies provided suggestive evidence of increased airways responsiveness in
asthmatics exposed to 0.1-ppm NO2 for 1 h. Data supporting increased airways responsiveness
to specific allergen challenges following NO2 exposure is more compelling. Bronchoconstriction
following an allergen challenge occurs in asthmatics exposed during rest to 0.26-ppm NO2 for 30
min relative to clean air. However, inflammatory responses to allergen challenge in asthmatics
may be a more sensitive endpoint and have been reported subsequent to exposure at 0.26-ppm
NO2 for 30 min. These inflammatory responses to the allergen challenge were not accompanied
by any changes in pulmonary function or subjective symptoms. Increased immune-mediated
pulmonary inflammation also occurs in rats exposed to house dust mite allergen following
exposure to 5-ppm N02 for 3 h. Overall, studies involving allergen challenge suggest that N02
exposure increases the allergen-induced airways inflammatory response and may also enhance
the sensitivity to allergen-induced decrements in lung function.
3.2.1.6 Hospital Admissions and Emergency Department Visits for Respiratory
Outcomes
Total respiratory causes for emergency department (ED) visits typically include asthma,
COPD (including pneumonia, bronchitis, and emphysema), upper and lower respiratory
infections such as influenza, and other minor categories. Morbidities that result in ED visits are
closely related to, but are generally less severe than, those that result in unscheduled hospital
admissions. In many cases, acute health problems are successfully treated in the ED; however, a
August 2007
3-44
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
subset of more severe cases that present initially to the ED may require hospital admission and
are then classified as hospital admissions. ED visits represent an important acute outcome that
may be affected by N02 exposures.
Many studies have been published in the past decade that examined temporal associations
between NO2 exposures and ED visits and hospital admissions for respiratory diseases. Asthma
visits typically dominate the daily incidence counts. Chronic bronchitis and emphysema often
are combined to define COPD, which is a prominent diagnosis among older adults with lung
disease.
3.3.1.6.1 All Respiratory Outcomes (ICD9: 460-519)
Overall, the majority of studies that have examined all respiratory outcomes as a single
group have focused on hospital admission data. Those studies are summarized here, along with a
single study of ED visits and all respiratory outcomes.
Two multicity studies that combine the effects of ambient air pollution (including NO2)
in several cities and describe similar response rates and respiratory health outcomes as measured
by increased hospital admissions are available (Barnett et al., 2005); (Simpson et al., 2005a).
These studies are summarized in Table 3.2-2.
Barnett et al. (2005) used a case-crossover method to study ambient air pollution effects
on respiratory hospital admissions of children (age groups 0, 1 to 4, and 5 to 14 years) in
multiple cities in both Australia and New Zealand during the study period 1998-2001. For NO2
the interquartile ranges for 1-h and 24-h NO2 were 9.0 and 5.1 ppb, respectively. No significant
associations were reported between N02 and hospital admission for infants or children 1 to 4
years old in these cities. For all respiratory admissions among children 1 to 4 years, a 2.8%
(95% CI: 0.7, 4.9) increase was found for a 9-ppb increment in the daily maximum 1-h
concentration of NO2, and for children aged 5 tol4 years the same increase in NO2 resulted in a
4.7%) increase in admission for all respiratory disease (95%> CI: 1.6, 7.9) both lagged 0 to 1 day
(Barnett et al., 2005). Multipollutant models in the study showed that the results for NO2 were
often independent of the effects of other pollutants, although some impact caused by particles
and SO2 could not be separated from those found for NO2. For respiratory admissions in the
5- to 14-year age group, a significant association with PMi0 disappeared after adjusting for N02,
indicating that this result could not be separated from that for NO2. However, the association
with NO2 remained after adjusting for PMi0.
August 2007
3-45
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
In a multicity study of all hospitalizations for respiratory disease (ICD9 460 to 519) for
people ages >65 years, Simpson et al. (2005a) examined the response to a change in the
maximum daily 1-h concentration equivalent to the average IQR of the four cities (54.5 ppb).
The calculated relative risk (RR, expressed per ppb) (1.0027 [95% CI: 1.0015, 1.0039] lag 0 to
1) was small, but statistically significant. The authors present results from three statistical
models that produced similar results overall for the four cities. Perth generally experienced
much lower 1-h maximum concentrations of N02 than the other Australian cities.
In their analysis of two-pollutant models, Simpson et al. (2005a) reported that
concentrations of NO2 and particulate matter (PM10) may be associated with similar outcomes or
effects. There was clear evidence of heterogeneity of response across different cities within
similar age groups to the same pollutant mixtures. For respiratory hospitalization the city that
provided the greatest source of heterogeneity, Perth, was the same in each of the three statistical
model approaches applied. Simpson et al. (2005a) suggest that a possible source of variation of
response could lie in the population characteristics (age, structure, etc.) that differentiate one
urban population from another. They concluded that it might not be reasonable to generalize
health outcomes in response to pollutants experienced in one urban location to another location.
Several North American studies have examined ED visits and hospital admissions for all
respiratory causes and ambient NO2 concentrations (Linn et al., 2000; Peel et al., 2005; Luginaah
et al., 2005; Fung et al., 2006). These studies have generally focused on adults and the elderly.
(See Figure 3.2-8.)
Among adults (>30 years of age) living in a large area of Los Angeles, Linn et al. (2000)
noted seasonal associations between NO2 levels (mean 24-h average NO2: 34 ppb) and the
frequency of hospitalization for all pulmonary disease. Though associations were positive for
each of the four seasons, the associations for autumn and winter were markedly higher. It was
noted that these single-pollutant results could not be distinguished from effects related to
copollutants PM10 and CO (Linn et al., 2000).
Peel et al. (2005) examined ED visits for all respiratory causes among all ages in relation
to ambient N02 concentrations in Atlanta, GA; they found a 1.6% (95% CI: 0.6, 2.7) increase in
respiratory ED visits associated with a 20-ppb increase in 1-h maximum NO2 concentrations.
August 2007
3-46
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
Reference
location
age
other
lag
Linn et al., 2000
Los Angeles, CA
>30
Spring 24-h avg
0-1
Linn et al., 2000
Los Angeles, CA
>30
Summer 24-h avg
0-1
Linn et al., 2000
Los Angeles, CA
>30
Autumn 24-h avg
0-1
Linn et al., 2000
Los Angeles, CA
>30
Winter 24-h avg
0-1
Peel et al., 2005
Atlanta, GA
all ages
1-h max
0-2
Fung et al., 2006
Vancouver, Canada
65+
24-h avg
0
Fung et al., 2006
Vancouver, Canada
65+
24-h avg
0-3
Luginaah et al., 2005
Windsor, Canada
all ages
females 1-h max
1
Luginaah et al., 2005
Windsor, Canada
all ages
males 1-h max
1
Luginaah etal., 2005
Windsor, Canada
0-14
females 1-h max
2
Luginaah et al., 2005
Windsor, Canada
0-14
males 1-h max
2
Luginaah et al., 2005
Windsor, Canada
65+
females 1-h max
1
Luginaah etal., 2005
Windsor, Canada
65+
males 1-h max
1
I
!
B
B
1 I l l l l l l l ll II II I
.5 .6 .7 .8 .9 1 1.1 1.2 1.3 1.4 1.51.61.71.81.9 2
Relative Risk Per Standard Unit
Figure 3.2-8 Relative risks (95% CI) for hospital admissions and ED visits for all
respiratory causes with 24-h NO2 concentrations (per 20 ppb).
In Vancouver, Fung et al. (2006) used time-series analysis, the method of Dewanji and
Moolgavkar (2000), and case-crossover analysis of all respiratory hospitalizations for adults aged
65 and older. All three methods showed positive associations between incremental changes in
N02 of 5.43 ppb (IQR) from a mean concentration of 16.83 ppb. Using a time-series analysis
Fung et al. (2006) reported a RR of 1.018 ([95% CI: 1.003, 1.034] lag 0) while the case-
crossover analysis showed a significant change in the relative rate of 1.028 ([95% CI: 1.010,
1.04] lag 0). These represented percent changes of 1.8% and 2.8% respectively. The Dewanji
and Moolgavkar model did not produce a statistically significant association between N02 and
hospitalization for the IQR of 5.43 ppb (RR = 1.012 [95% CI: 0.997, 1.027] lag 0)]. Results of
multipollutant models were not given, but there were strong correlations of NO2 with CO
(r = 0.74), SO2, PM10, and PM10-2.5 (Fung et al., 2006).
In the Windsor/Detroit border area of Canada, Luginaah et al. (2005) noted a positive
trend between an incremental change in NO2 of 16 ppb (mean 1-h maximum: 38.9 ppb) and
August 2007
3-47
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
respiratory admissions. These authors used two approaches that included both time-series and
case-crossover analyses segregated by sex. Though associations for females in each of the age
groups examined were positive, the authors found only one statistically significant association in
females aged 0 to 14 years that identified an increased percent of hospitalization of 18.9% using
the case-crossover analysis (RR = 1.189 [95% CI: 1.002, 1.411] lag 2). In this study, CO and
NO2 were correlated (r = 0.38) and thought to represent motor vehicle emissions.
Studies from Europe on associations with respiratory hospitalization were conducted in
London, Paris, and in Drammen, Norway. A detailed analysis of respiratory hospitalization by
age group and by seasonal temperature was carried out in London using the APHEA protocol
(Ponce de Leon et al., 1996). In this study, significant positive relative risks were reported for all
ages and for children (0 to 14 year olds), but the presence of 03 during summer months may
have also contributed to a change in the rate of hospitalization. Respiratory hospitalizations for
adults (15 to 64 years) examined separately were not statistically significantly increased. The
increased hospitalization rates were based on an incremental change for NO2 of 27 ppb (similar
to the difference of the 90th and 10th percentiles of the annual concentration) and an annual
mean 24-h concentration of 37.3 ppb in London.
In Paris, France (mean 24-h average NO2 of 23.6 ppb), Dab et al. (1996) determined that
there was no statistically significant association between admissions for all respiratory causes
combined based on an incremental change of 52.35 ppb, though the estimates were positive.
In Drammen, Norway, Oftedal et al. (2003) reported associations between respiratory
hospitalizations and NO2. Oftedal et al. (2003) reported that both NO2 and benzene were
associated with an increase in hospital admission for all respiratory disease. In a single-pollutant
model, the relative rate of hospitalization for all respiratory disease increased based on an
increment of 11 -ppb N02 (RR = 1.060 [95% CI: 1.017, 1.105] lag 3 days). This finding was
robust, since in two-pollutant models NO2 remained associated with a significant increase in
admissions after adjusting for PM10 (RR = 1.063 [95% CI: 1.008, 1.120]) or for benzene
concentration (RR = 1.046 [95% CI: 1.002, 1.091]). Other studies outside the United States
found positive outcomes (Llorca et al., 2005; Braga et al., 2001; Wong et al., 1999).
3.2.1.6.2 Asthma (ICD9: 493)
In North America, the most recent studies to investigate for evidence of an association
between ambient concentrations of NO2 and hospitalizations or ED visits were conducted by
August 2007
3-48
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Linn et al. (2000); Lin et al. (2003, 2004); Jaffe et al. (2003); Peel et al. (2005); and Tolbert
et al. (2000). Mean concentrations of NO2 in studies of hospitalizations and ED visits for asthma
in North America varied from city to city. The mean daily concentrations were relatively low in
Canada, recorded at 25.24 ppb (SD 9.04) in Toronto, ON from 1981 to 1993, and 18.65 ppb (SD
5.59) in Vancouver, BC from 1987 to 1991. In Atlanta, GA between 1993 and 1995, the mean
of the daily 1-h maximum concentration was 81.7 ppb (SD 53.8) (Tolbert et al., 2000) but
decreased between 1993 and 2000 to 45.9 ppb (SD 17.3) (Peel et al., 2005). During studies
carried out between 1991 and 1996, the mean of the 24-h average NO2 concentration in
Cincinnati was 50 ppb (SD 15) and 48 ppb (SD 16) in Cleveland (Jaffe et al., 2003).
Surprisingly, the lowest concentrations were reported by Linn et al (2000), who calculated the
overall mean in Los Angeles, CA from 1992 to 1995 to be 3.4 ppb (SE 1.3).
Linn et al. (2000) found significant increases (1.14% [95% CI: 0.9, 1.9]) in hospital
admissions for asthma with a 10 ppb change in the 24-h average concentration of NO2 in
Los Angeles (mean 24-h NO2: 34 ppb). When seasonal differences in hospitalization frequency
were examined, higher rates of hospitalization for asthma in Los Angeles were found for the
cooler months of autumn (1.9% [95% CI: 1.1, 2.7]), and winter (2.8% [95% CI: 2.7, 2.9]) based
on a 10 ppb change in the concentration of NO2 (Linn et al., 2000).
Lin et al. examined the data for hospital admissions due to asthma in the Canadian cities
of Toronto (Linn et al., 2003) and Vancouver (Linn et al., 2004). Lin et al. (2004) studied
gaseous air pollutants and 3,822 asthma hospitalizations (2,368 boys, 1,454 girls) among
children 6 to 12 years of age with low household income in Vancouver, Canada between 1987
and 1998. NO2 levels were derived from 30 monitoring stations. Exposures to NO2 were found
to be significantly and positively associated with asthma hospitalization for males in the low
socioeconomic group but not in the high socioeconomic group. This effect did not persist among
females. Lin et al. (2003) conducted a case-crossover analysis of the effect of short-term
exposure to gaseous pollution on 7,319 asthma hospitalizations (4,629 boys, 2,690 girls) in
children in Toronto between 1980 and 1994. NO2 concentrations measured from four
monitoring stations were positively associated with asthma admissions in both sexes. The effects
of NO2 on asthma hospitalization remained after adjustment for PM. Differences in the results of
these two studies might be attributed to differences in the study designs.
August 2007
3-49
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
A study in Paris showed an association for hospitalization for asthma based on both the
mean 24-h average concentration and the maximum daily 1-h concentration of NO2 (mean
38.6 ppb) Dab et al., (1996). For the 24-h N02 concentration, the estimate was 17.5%
(RR = 1.175 [95% CI: 1.059, 1.304] lag 0 to 1); while for a similar incremental change in the
1-h maximum concentration of NO2, the increase in admissions for asthma was 8.1%
(RR = 1.081 [95% CI: 1.019, 1.148] lag 0 to 1).
In Atlanta, GA, Peel et al. (2005) examined various respiratory ED visits in relation to
pollutant levels from 1 January 1993 to 31 August 2000. The pollutants and metrics for this
analysis were selected a priori based on current hypotheses regarding potentially causal
pollutants and components with a focus on PM aspects (Albritton and Greenbaum, 1998;
Schlesinger, 2000) as well as useful models for primary traffic related pollutants. The mean
daily count of asthma ED visits for asthma was 39.0 ± 20.5 over the entire study period. Results
for the a priori single-pollutant models examining a 3-day moving average (lag 0, 1, and 2) of
NO2 showed a small but not statistically significant associations with asthma visits (RR = 1.014
[95% CI: 0.997, 1.030) for all age groups. In secondary analysis of patients ages 2 to 18 years, a
20-ppb increase in the day 5 lag of the NO2 concentration yielded an RR of 1.027 (95% CI:
1.005, 1.000).
Wade et al. (2006) examined the effects of instrument precision and spatial variability on
assessment of the temporal variation of ambient air pollution (including NO2) in Atlanta. The
use of calculated instrument data yielded an estimate of instrument imprecision equal to 20% of
the temporal variation for NOx and PM2.5 mass and 10% of O3 and CO. The spatial variability
was approximately 80% of the temporal variation for NOx. Population-weighted uncertainty in
primary pollutant levels because of instrument imprecision and spatial variation was found to be
60 to 70%) of the temporal variation. Note that these ambient air pollutant error estimates have
not been incorporated into the health risk models by Peel et al., (2005) and are expected to
appear in a later publication.
Jaffe et al. (2003) examined the effects of ambient pollutants during the summer months
(June through August) on the daily number of ED visits for asthma among Medicaid recipients
aged 5 to 34 years from 1 July 1991 to 30 June 1996 in Cincinnati and Cleveland. The percent
change in ED visits for asthma as the primary diagnosis per 10-ppb increase in 24-h average NO2
August 2007
3-50
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
concentration was 6% (95% CI: -1,13) in Cincinnati and 4% (95% CI: -1, 8) in Cleveland,
with an overall percent increase in ED visits of 3% (95% CI: -1, 7).
A number of studies outside of North America have examined the association between
NO2 and hospitalization or ED visits for asthma. Barnett et al., (2005) examined specific
respiratory disease outcomes and did not find associations between incremental changes in NO2
concentration and respiratory admissions for asthma among children 1 to 4 years old. The
largest association found in this study was a 6.0% increase in asthma admissions in the 5- to
14-year age group related to a 5.1-ppb increase in 24-h NO2, with evidence of a seasonal impact
that resulted in larger increases in admissions during the warm season. When the same groups
were examined for the effect of a 9.0-ppb change in the maximum 1-h concentration of NO2,
there were no significant associations between N02 and hospitalization for asthma.
Tenias et al. (1998) used the APHEA design and analysis approach in Valencia, Spain, to
examine the association between hospital ED visits for asthma among patients over 14 years old
and air pollution for the period 1 January 1993 to 31 December 1995, yielding 734 cases. The
mean 24-h N02 level was 57.7 |ig/m3 and the mean 1-h N02 level was 100.1 |ig/m3. There were
7.6% and 3.7% increases in ED visits associated with the 24-h average NO2 concentration at lag
0 (1.076 [95% CI: 1.020, 1.134]) and the 1-h maximum NO2 concentration (1.037 [95% CI:
1.008, 1.066]), respectively. Examination of single- and two-pollutant models shows that the
addition 03, smoke, or S02 into the model results in little variation in the N02 effect estimates,
thus diminishing the effect of confounding on the NO2 effect estimates.
Castellsague et al. (1995) examined the association between hospital emergency visits for
asthma and air pollutants during the winter and summer months from 1985 to 1989 in Barcelona,
Spain for the 14 to 65 year age group. Barcelona traffic density on working day shows little
variability during the year, suggesting a steady emission of vehicle exhaust, which is the main
source of NO2 in the city. There were 460 summer asthma visits and 452 winter visits. Mean
NO2 levels averaged 104.0 |ig/m3 (95th percentile =183 |ig/m3) during the summer, and
100.8 |ig/m3 (95th percentile =153 |ig/m3) during the winter. The increase in asthma visits for a
25-|ig/m3 increase of current day levels of NO2 was 4.5% (95% CI: 0.9, 8.1) in summer and
5.6%) (95%) CI: 1.1, 10.4) in winter. A cumulative measure of NO2 yielded a slightly stronger
association.
August 2007
3-51
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
A time-series analysis in Sydney examined respiratory outcomes in children and adults,
but reported no association between changes in NO2 (24-h average) for asthma admissions
(Morgan et al., 1998a). For children aged 1 to 14, a 5.3% increase in hospital admissions for
asthma ([95% CI: 1.1, 9.7] lag 0) was associated with the daily 1-h maximum value based on
15-ppb incremental change. This association with the 1-h maximum daily concentration
remained robust in a multiple pollutant model (5.95% [95% CI: 1.11,11.02] lag 0) which was
only marginally different from the single-pollutant model (Morgan et al., 1998a). The
association with adults also was positive, but not statistically significant.
Studies of ED visits for asthma have been reported from cities in Europe including
London (Atkinson et al., 1999a,b; Hajat et al., 1999); Belfast (Thompson et al., 2001); Valencia,
Barcelona, and Madrid, Spain (Tenias et al., 1998; Galan et al., 2003; Castellsague et al., 1995);
Turin, Italy (Migliaretti et al., 2004, 2005); Marseille, France (Boutin-Forzano et al., 2004); and
Amsterdam and Rotterdam (Schouten et al., 1996). Sunyer et al. (1997) have described a meta-
analysis of several cities under the umbrella of the APHEA protocol (Katsouyanni et al., 1996).
Additional cities where associations between ED visits for asthma and ambient concentrations of
NO2 have been examined include Melbourne, Brisbane and Perth, Australia (Erbas et al., 2005;
Hinwood et al., 2006), and Sao Paulo, Brazil (Farhat et al., 2005).
Figures 3.2-9 and 3.2-10 show the percent increases (and 95% confidence limits) in visits
to the ED for asthma associated with daily NO2 1-h peaks and 24-h averages for each study,
respectively. Meta-analysis and meta-regression were used to summarize these results. The
results of meta-regression show that the percent increases did not vary significantly for adults
versus children, the sampling time of NO2, or the daily NO2 concentration for each sampling
time. The lags presented in the figures vary depending on reported results. Most studies
reported effect estimates from a short lag period (i.e., 0 to 2 days).
Figure 3.2-11 provides three examples of dose response relationships for the effect
estimates of asthma visits to the ED and NO2 concentrations. Jaffe et al. (2003) found a positive
association between ambient NO2 and asthma ED visits among Medicaid-enrolled asthmatics in
two urban cities in Ohio. When a concentration-response relationship was examined by quintile
of NO2 concentration, risk decreased in the second quintile and increased monotonically in the
third and fourth quintiles in Cleveland, but were less smooth in Cincinnati. The lack of
consistency in results may be due to the uncontrolled interaction effects of copollutants,
August 2007
3-52
DRAFT-DO NOT QUOTE OR CITE
-------
Reference
location
age other
lag
Jaffe et al, 2003
Cincinnati
5-34
1
Jaffe et al, 2003
Cleveland
5-34
1
Sunyeretal, 1997
4 European cities <14
0-1
Sunyeretal, 1997
4 European cities
15-64
0-1
Boutin-Forzano et al, 2004
Marseille
3-49
1
Migliaretti et al, 2004
Turin
4-15
0
Boutin-Forzano et al, 2004
Marseille
3-49
0
Thompson et al, 2001
Belfast
children
0
Galan et al, 2003
Madrid
All
1
Galan et al, 2003
Madrid
All
0
Migliaretti et al, 2004
Turin
<4
0
Tenias et al, 1998
Valencia
14+
0
Farhat et al, 2005
SSo Paulo
<13
2d MA "
T
i—i—i—i—i—i—i—r
1 1.1 1.2 1.3 1.4 1.5 1.61.7
.7 .8 .9
Relative Risk Per Standard Unit
Figure 3.2-9. Relative Risks (95% CI) for ED visits for asthma per 30-ppb increase in
1-h peak N()2.
Reference
location
age
Tolbert et al, 2000
Atlanta
all
Tolbert et al, 2000
Atlanta
<16
Peel et al, 2005
Atlanta
2 to 18
Erbas et al, 2005
Melbourne - eastern
1 to 15
Erbas et al, 2005
Melbourne - inner
1 to 15
Erbas et al, 2005
Melbourne - southern
1 to 15
Erbas et al, 2005
Melbourne - western
1 to 15
Stieb etal, 1996
Saint John, NB,Canada
All ages
Sunyeret al. 1997
4 Eurpean Cities
15 to 64
Sunyer et al, 1997
4 European cities
<14
Castellsague et al,1995
Barcelona - summer
>14
Tenias et al, 1998
Valencia
>14
Castellsague et al,1995
Barcelona - winter
>14
Atkinson et al, 1999
London
15 to 64
Atkinson et al, 1999
London
Oto 14
Hajatetal, 1999
London
0-14
Hajatetal, 1999
London
15-64
Hajatetal, 1999
London
65+
lag
other
1993-98 0-2
1993-95 0-2
0
0
0
0
2
0
0-1
0
0
0
0
0
1
0
2
n i i i i i i i [
.7 .8 .9 1 1.1 1.2 1.3 1.4 1.5
Relative Risk Per Standard Unit
Figure 3.2-10. Relative Risk (95% CI) in ED visits for asthma per 20-ppb increase in
24-h average NO2.
August 2007
3-53
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
1.5
1.4
1.3
.* 1-2
(A
> 1.1
>
TO
o 1.0
0.9
0.8
0.7 -| 1 1 1 1 1
0 20 40 60 80 100
24-h average N02
Figure 3.2-11. Dose response presentation of data from three studies for asthma ED
visits: (a) Relative risk for an ED visit for asthma in Cincinnati and
Cleveland, OH by quintile of N02. (b) A monotonic increase in Valencia,
Spain, (c) Increased risk in Barcelona, Spain, but no consistent linear
trend evident.
Source: (a) Jaffe et al., 2003; (b) Tenias et al., 1998; (c) Castellsague et al., 1995.
uncontrolled confounding by variables such as pollen and influenza epidemics, and incomplete
data. Tenias et al. (1998) reported a positive and significant association between ambient NO2
and ED visits in Valencia's Hospital Clinic Universitari from 1994-1995. Castellsague et al.
(1995) found a small but significant association of N02 and ED visits due to asthma in
Barcelona. Specifically, the adjusted risk estimates of asthma visits for each quartile of NO2
showed increased risks in each quartile, although the increase was not monotonic. Increased
trends were apparent in both summer and winter for the second quartile, suggesting that if any
threshold level exists, it may be quite low.
COPD (ICD9: 490-496)
Studies examining COPD outcomes have focused on hospital admission data, including
multicity studies in the United States (Moolgavkar, 2000), Europe (Anderson et al., 1997) and
- • —• Castellsague summer
» Castellsague winter
- — ^ Jaffe - Cincinnati
Jaffe - Cleveland
• Tenias
August 2007
3-54
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Australia (Simpson et al., 2005a), and single-city studies in Canada (Yang et al., 2005), Europe
(Dab et al., 1996), and Australia (Morgan et al., 1998).
Moolgavkar (2003) reported statistically significant associations between N02 and COPD
admissions in two U.S. counties, with approximately 2% increases in Cook County, IL and Los
Angeles County, CA associated with a 10-ppm increase in NO2. Multipollutant models adjusted
for PM10 and PM2.5 attenuated these estimates slightly, though they remained statistically
significant.
Anderson et al. (1997) examined COPD admissions in six European cities with mean
24-h average and daily 1-h maximum NO2 concentrations ranging from 22 to 35 ppb and 33.5 to
51.3 ppb, respectively. Admissions in Amsterdam, Barcelona, London, Paris, and Rotterdam
during different periods from 1977 to 1991 were analyzed for association with N02 by season
(warm or cool) or for the entire year and using an incremental change of 26 ppb for either the
daily 1-h maximum or the 24-h average concentration. The APHEA protocol (time series) was
employed in data analysis. The authors reported associations between hospital admissions for
COPD and 24-h average N02 during the warm season (RR = 1.03 [95% CI: 1.00, 1.06] lag 1)
and 1-h maximum NO2 (RR= 1.02 [95% CI: 1.00, 1.05] lag 1). Significant risks for
hospitalization for obstructive respiratory diseases were found year round for both the 24-h
average and the daily 1-h maximum value for NO2 (Anderson et al., 1997). No multipollutant
models were described for this meta-analysis, but black smoke, O3, and SO2 all appeared to be
responsible for an increased frequency of admissions. The authors reported some heterogeneity
of association between cities. When the authors investigated individual cities, only London, with
a 26-ppb increase in NO2 was clearly significantly positive on its own for increased hospital
admissions for COPD. Amsterdam showed no association between NO2 and COPD admissions.
Simpson et al. (2005a) report small but statistically significant associations between
incremental changes in NO2 and COPD among patients >65 years using hospitalization data
from four Australian cities (0.3% increase [95% CI: 0.15, 0.39). The analysis of admissions in
Sydney, Melbourne, Brisbane, and Perth sought to compare three modeling approaches for
outcomes including generalized additive models (GAM), GLM and a penalized spline model.
The authors found significant heterogeneity of response among results in different cities.
In a time-series study in Vancouver, an area with low pollution concentrations (24-h
mean NO2 of 17.03 ppb), Yang et al. (2005) reported associations between NO2 and hospital
August 2007
3-55
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
admissions for COPD in patients >65 years for both the lag 1 day (RR = 1.05; 95% CI: 1.01,
1.09) and 7-day extended lag period (RR =1.11 [95% CI: 1.04, 1.20]). Yang et al. (2005)
reported thatN02 was the strongest predictor of hospital admissions for COPD in single-
pollutant models; however, in two-pollutant models with either PMio or CO, the effect of NO2
was attenuated and lost significance.
A time-series analysis in Sydney, Australia, examined respiratory outcomes in children
and adults, but generally failed to show an association between changes in N02 (24-h average)
for increased hospital admissions among COPD patients >65 years (Morgan et al., 1998a).
Similarly, a study in Paris, France, of COPD and related obstructive respiratory disease found
that NO2 was not statistically significantly associated with increased hospital admissions (Dab
et al., 1996).
Multipollutant Modeling Results
Several studies of the relationship between ambient NO2 concentrations and ED visits
evaluated copollutant models (Sunyer et al., 1997; Atkinson et al., 1999b; Galan et al., 2003).
Individual models including NO2 and black smoke (Sunyer et al., 1997; Atkinson et al., 1999b),
S02 (Sunyer et al., 1997; Atkinson et al., 1999b; Galan et al., 2003), CO (Atkinson et al., 1999b),
PM10 (Atkinson et al., 1999b; Galan et al., 2003), or O3 (Atkinson et al., 1999b) did not produce
effect estimates that were significantly different than those produced when using the single-
pollutant model.
Respiratory ED visit and hospital admission studies observed consistent N02 risk
estimates with the inclusion of SO2, O3, and PM constituents (Burnett et al., 1997b, 1999; Lee
et al., 2006). In one of these studies (Burnett et al., 1997), the effect of NO2 was adjusted for
SO42 and coefficient of haze (CoH). With the addition of SO42 in the model, the risk estimate
for N02 on respiratory hospitalizations remained relatively stable; however, the inclusion of the
CoH term in the model yielded an attenuated risk estimate.
In field studies, power to assess independent NO2 effects may be limited by small sample
sizes and short follow-up times. Yet, the NO2 effect was not as robust to the addition of
copollutants in multipollutant models, with a few exceptions. For example, in Schwartz et al.
(1994), the significant association between cough and 4-day mean NO2 remained unchanged in
models that included O3 but was attenuated and lost significance in two-pollutant models
August 2007
3-56
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
including PMio or SO2. In Mortimer et al. (2002), effects were attenuated in multipollutant
models that included O3; O3 and SO2; or O3, SO2, and PMi0. In Schildcrout et al. (2006), each
20-ppb increase in N02 increased risk of cough (OR 1.09 [95% CI: 1.03, 1.15). This result was
unchanged in two-pollutant models with CO, PM10, or SO2.
Multipollutant regression analyses indicated thatN02 risk estimates, in general, were not
sensitive to the inclusion of copollutants, including CO and SO2. There is limited evidence that
PM10 or other ambient particle constituents do have an effect on N02 risk estimates. These
results suggest that the effect of NO2 on respiratory health outcomes appears to be robust and
independent of the effects of other gaseous copollutants but that ambient particles may confound
NO2 effects on health.
Summary
Overall, there is strong evidence that increased ED visits and hospital admissions for
respiratory causes, including asthma and COPD, are associated with ambient concentrations of
NO2. Still, it is important to note that there uncertainty remains regarding the role of NO2 as a
surrogate for other pollutants, which could confound results presented in this section. In nearly
all of these studies, there was evidence of correlations between N02 and CO and PM measures.
Some authors found statistically significant associations between asthma ED visits or hospital
admissions and NO2 in single-pollutant models and subsequently examined these associations in
two- or multipollutant models. In Sao Paulo, asthma remained strongly associated with NO2
after adjustment for PM10 and SO2, but not when CO was included in the model (Farhat et al.,
2005). In Madrid, significant association with N02 remained after adjustment for S02 but not
PM10 (Galan et al., 2003). Similarly, in Turin, adjustment for total suspended particulate (TSP)-
attenuated effects of NO2 (Migliaretti et al., 2004) demonstrating that the responses to individual
pollutant species were not independent. In a meta-analysis of four cities in the APHEA project,
N02 remained associated with asthma for adults after adjustment for the effects of black smoke
(Sunyer et al., 1997). In associations between ED visits to hospitals and NO2, Atkinson et al.
(1999a) found that effects of NO2 remained after adjustment for SO2, CO, PM10, or black smoke.
August 2007
3-57
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
3.2.1.8 Integration of Evidence and Biological Plausibility for Associations between
NO2 Exposure and Respiratory Health Effects
Taken together, recent studies provide strong evidence that NO2 is associated with a
range of respiratory effects, from biochemical effects or biological markers of inflammation to
hospitalization for respiratory diseases. This conclusion is based on findings from numerous
new epidemiological studies, including multipollutant studies that control for the effects of other
pollutants, and is supported by evidence from toxicological and controlled human exposure
studies.
The body of evidence from epidemiological studies has grown substantially since the
1993 AQCD. The strongest new epidemiological evidence is for associations with increased ED
visits and hospital admissions for respiratory causes, especially asthma and COPD, with ambient
concentrations of NO2. In nearly all of these studies, there were high correlations between
ambient measures of N02 and CO and PM. The effect estimates for N02 were robust after the
inclusion of CO and PM in multipollutant models, as shown in Figure 3.2-12. Looking within
the new epidemiological findings, there is evidence of coherence for respiratory effects in the
associations between short-term NO2 exposure and respiratory symptoms and ED visits or
hospital admissions for respiratory diseases, particularly asthma. Recent studies reporting
associations between indoor and personal exposure to NO2 and respiratory symptoms or lung
function provide key support for epidemiological findings of associations with ambient NO2
concentrations (e.g., Pilotto et al., 2004). In particular, an intervention study (Pilotto et al., 2004)
provides strong evidence of a detrimental effect of exposure to NO2.
Evidence from experimental studies provides plausibility for effects on the respiratory
system with NO2 exposure. Toxicological studies have shown that lung host defenses, including
mucociliary clearance and AM and other immune cell functions, are sensitive to NO2 exposure,
with numerous measures of such effects observed at concentrations below 1 ppm. These are
potential mechanisms underlying more frank effects observed in epidemiological studies, such as
hospital admissions or ED visits for respiratory diseases, including asthma, COPD, or respiratory
infections. A recent epidemiological study (Chauhan et al., 2003) provided evidence that
increased personal exposures to NO2 worsen virus-associated symptoms and lung function in
August 2007
3-58
DRAFT-DO NOT QUOTE OR CITE
-------
Study
Locations
Sunyeretal, (1997) Barcelona,
Helsinki, Paris,
London
Atkinson et al, (1999b) London
Galan et al. (2003) Madrid
Lee et ai. (2002) Seoul, Korea
Avg Time Pollutants
24-h N02
N02 + BS
N02 + S02
N02
N02 + BS
1-h N02
N02 + S02
N02 + CO
NO2 + PM10
NOj + BS
no2 + o3
24-h NO,
NOj + S02
N02 + PM10
24-h N02
no2 + pm10
no2 + S02
N02 + °3
no2 + CO
no2+o3 + co + pm10+so2
0.9
Burnett et al. (1997b) Toronto, ON
1-h
N02+
no2+
no2
no2+pm10
NOj + PM25
no2 + 03 + S02
O3 + SO2+PMf0
°3 + S02+ PM2 5
Burnett et al. (1999) Toronto, ON
24-h
NO,
N02+ 03 + S02+ PM10
N02+ o3 + so2+pm25
N02+ 03 + S02+ pm1025
1.0
Relative risk
1.1 1.2 1.3
1.4
1.5
Asthma
o <15 years
• 15-54 years
¦ 0-14 years
~ All ages
All Respiratory
Q (SE > 3)
d (SE > 3)
~ (SE a 2)
~ (SE 2 3)
Respiratory Infection
Figure 3.2-12.
Relative risks and 95% confidence intervals for associations between ED
visits and hospital admissions for respiratory diseases and 24-h average
NO2 concentrations (per 20 ppb).
1 children with asthma. The limited evidence from controlled human exposure studies indicates
2 that N02 may increase susceptibility to injury by subsequent viral challenge.
3 Controlled human exposure studies provide strong evidence for airways responsiveness
4 with short-term exposure to NO;; however, they do not provide compelling evidence for other
5 respiratory effects, such as changes in lung function or subjective respiratory symptoms.
August 2007
3-59
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Biological markers of inflammation are reported in antioxidant-deficient laboratory animals with
exposures to 0.4-ppm NO2. Normal animals do not respond until exposed to much higher levels,
i.e., 5-ppm N02. Recent epidemiological studies provide somewhat mixed evidence on short-
term exposure to NO2 and inflammatory responses in the airways. The controlled human
exposure studies provide evidence for airways inflammation atNC>2 concentrations of <2.0 ppm;
the onset of inflammatory responses in healthy subjects appears to be between 100 and
200 ppm-min, i.e., 1 ppm for 2 to 3 h.
The biochemical effects observed in the respiratory tract following exposure to NO2
include chemical alteration of lipids, amino acids, proteins, enzymes, and changes in
oxidant/antioxidant homeostasis, with membrane polyunsaturated fatty acids and thiol groups as
the main biochemical targets for N02 exposure. However, the biological implications of such
alterations are unclear.
Asthma is the respiratory illness for which most evidence is available. The following
section provides further integrative discussion with a particular focus on the epidemiological and
experimental study findings relevant to asthmatics.
Integration with a Focus on Asthma
Asthmatic Children
There is strong evidence from epidemiological studies for an association between N02
exposure and children's hospital admissions, ED visits, and calls to doctors for asthma. This
evidence came from large longitudinal studies, panel studies, and time-series studies. NO2
exposure is associated with aggravation of asthma effects that include symptoms, medication
use, and lung function. Effects of N02 on asthma were most evident with cumulative lag of 2 to
6 days, rather than same-day levels of NO2. Time-series studies also demonstrated a relationship
in children between hospital admissions or ED visits for asthma and NO2 exposure, even after
correcting for PM and CO concentrations.
As discussed in Section 3.2.1.3, large, longitudinal cohort studies in the United States,
Canada and Europe have reported significant associations between level of NO2 and risk of
respiratory symptoms in children, particularly asthmatic children. A number of recent panel
studies of asthmatic children have also generally reported significant associations between
respiratory symptoms and N02 exposure. The effects were observed with lag periods ranging
August 2007
3-60
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
from 2 days to a 6-day moving average for NO2, suggesting that NO2 may not only be directly
triggering asthma attache, but may also be acting indirectly as a primer for subsequent antigen
exposure.
Important evidence is also available from epidemiological studies of indoor NO2
exposures. A number of recent studies show associations with wheeze, chest tightness, and
length of symptoms (Belanger et al., 2006); respiratory symptom rates (Nitschke et al., 2006);
school absences (Pilotto et al., 1997a); respiratory symptoms, likelihood of chest tightness, and
asthma attacks (Smith et al., 2000); and severity of virus-induced asthma (Chauhan et al., 2003).
However, several studies (Mukala et al., 1999, 2000; Farrow et al., 1997) evaluating younger
children found no association between indoor NO2 and respiratory symptoms.
Human clinical studies of the health effects of N02 have not been conducted on children;
however, toxicological studies provide strong biological plausibility of the effects of NO2
exposure on asthma exacerbation in children. Several endpoints in these studies point to
mechanisms by which NO2 can produce these adverse health effects. These mechanisms include
reduced mucociliary clearance, AM function, such as depressed phagocytic activity and altered
humoral- and cell-mediated immunity. NO2 effects on AMs at levels as low as 1.0 ppm are
especially relevant to effects seen with asthmatics. This exposure causes decreased bactericidal
activity, reduced cell viability, disruption of membrane integrity and reduced cell number. These
are all mechanisms that can provide biological plausibility for the NO2 effects in asthmatic
children observed in epidemiological studies. Chauhan et al. (2003) have reviewed potential
mechanisms by which NO2 exacerbates asthma in the presence of viral infections. They include
"direct effects on the upper and lower airways by ciliary dyskinesis, epithelial damage, increases
in pro-inflammatory mediators and cytokines, rises in IgE concentration, and interactions with
allergens, or indirectly through impairment of bronchial immunity."
As stated above, asthma is a chronic inflammatory disorder. Animal studies provide
strong evidence that NO2 can produce inflammation and lung permeability changes. One
limitation of this work is that effects on markers of inflammation, such as BAL fluid levels of
total protein and lactate dehydrogenase, and recruitment or proliferation of leukocytes, occur
only at exposure levels of >5 ppm. Studies conducted at these higher exposure concentrations
may elicit mechanisms of action and effects that do not occur at near-ambient levels of NO2.
August 2007
3-61
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Asthmatic Adults
One of the key health effects of concern at near-ambient concentrations of N02 is
increases in airways responsiveness of asthmatic individuals after short-term exposures.
Epidemiological studies show a strong association between NO2 exposures and asthma
symptoms in adult asthmatics. Outdoor NO2 studies in Europe found an increased risk of
shortness of breath (Hiltermann et al., 1998); prevalence for wheeze, phlegm, cough, and
breathing problems upon waking (Von Klot et al., 2002); and severe asthma symptoms (Forsberg
et al., 1998) associated with NO2 levels. Several indoor NO2 exposure studies have shown
associations, as well. Endpoints include likelihood of cough (Smith et al., 2000) and rescue
medication use (Ng et al., 2001).
Controlled human exposure studies are limited to acute, fully reversible functional and/or
symptomatic responses and are further limited to exposures of only mild asthmatics. Increased
airways responsiveness, the most sensitive indicator of response, occurred with resting exposures
of 0.2 to 0.5-ppm N02. Other studies showed an absence of effects on airways responsiveness at
much higher concentrations, up to 4 ppm. Lung function effects are variable and inconsistent;
however, there is little evidence for effects at <0.25 ppm. There is no obvious explanation for
the apparent lack of concentration-response relationship; therefore, the findings do not provide
clear quantitative conclusions about the health effects of short-term exposures to N02. Effects at
lower levels are seen in the epidemiological studies described above.
3.2 CARDIOVASCULAR EFFECTS ASSOCIATED WITH SHORT-
TERM N02 EXPOSURE
3.2.2.1 Studies of Hospital Admissions and Emergency Department Visits for
Cardiovascular Disease (CVD)
Our current review includes approximately 40 studies published since 1992 that address
the effect of NOx exposure on hospitalizations or ED visits for CVD. No studies were reviewed
that linked CVD hospital admissions or emergency visits with exposure to NOx prior to the
release of the document in 1993. Cases of CVD are typically identified using ICD codes
recorded on hospital discharge records. However, counts of hospital or ED admissions are also
used. Studies of ED visits include cases that are less severe than those that have been
documented to require hospitalization via discharge records and these studies are clearly
August 2007
3-62
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
distinguished in the annex tables. All CVD diagnoses or selected diagnoses for diseases or
disease grouping such as myocardial infarction (MI), ischemic heart disease (IHD), congestive
heart failure (CHF), angina pectoris, cardiac arrhythmia, cerebrovascular diseases, or stroke are
outcomes considered in the analyses.
All CVD (ICD9 390-459)
All studies of the association of hospitalizations or ED visits are positive and most
confidence limits exclude the null value, with the exception of the lag 1 results for the elderly
reported by Jalaludin et al., 2006. Results from these studies are summarized in Figure 3.2-13.
However, findings from multicity studies conducted in Spain (Ballester et al., 2006) and
Australia (Barnett et al., 2006) indicate weak associations in single-pollutant models, which are
attenuated in multipollutant models. Analyses from a study conducted in Los Angeles and Cook
Counties (Moolgavkar et al., 2003), also show an increase in hospital admissions for CVD
associated with NO2 that was diminished in multipollutant models. Associations were also
diminished with the use of increasingly stringent convergence criteria applied for subsequent
reanalyses (Moolgavkar, 2003). Another large multiyear study conducted in Los Angeles
County reports a small increase in CVD admissions, but authors could not distinguish
independent effects of specific pollutants (Linn et al., 2000).
Pekkanen et al. (2000) reports an association between plasma fibrinogen, a risk factor and
possible biomarker for cardiovascular disease, and NO2 (See Section 3.1.2.3). In addition,
findings from controlled human exposure and animal studies may provide limited biological
plausibility and mechanistic evidence for the epidemiology findings. These studies evaluated
cardiovascular endpoints such as blood pressure, cardiac output and hematological parameters
(Folinsbee et al., 1978; Linn et al., 1985b; Posin et al., 1978; Frampton et al., 2002; Suzuki et al.,
1981, 1984; Mersch et al., 1973; Kunimoto et al., 1984; Takano et al., 2004).
Heart Disease (ICD9 390-429)
Some investigators distinguish heart diseases from diseases of the cerebrovascular
system, involving blood vessels supplying blood to the brain, in their research. Findings from
studies conducted in Canada and the Detroit area report positive associations of heart disease
with NO2 that are diminished in two-pollutant models (Fung et al., 2005; Burnett et al., 1997a,
1999).
August 2007
3-63
DRAFT-DO NOT QUOTE OR CITE
-------
Reference
Metzger et al, 2004
Metzger et al, 2004
Linn et al, 2000
Moolgavkar et al, 2003
Moolgavkar et a I, 2003
Schwartz, 1997
Barnett et al, 2006
Jalaludin et al, 2006
Jalaludin et al, 2006
Jalaludin et al, 2006
Hinwood et al, 2006
Wong et al, 1999
location
Atlanta
Atlanta
Los Angeles
Los Angeles
Los Angeles
Tucson, AZ
Australia & N2
Sydney, Australia
Sydney, Australia
Sydney, Australia
Perth, Australia
Hong Kong, China
age other lag
All ages 0
All ages ER visits 0
>30 o
All ages o
All ages 1
65+ 0
65+ 0-1
65+ cool season 0
65+ warm season 0
1
1
65+ ER visits
Not
reported
65+
Pantazopoulou et al 1995 Athens, Greece
Pantazopoulou et al 1995 Athens, Greece
Ballester et al 2006
Chan et al, 2006
Chang et al, 2005
Yang et al 2004
Yang et al 2004
Atkinson et al, 1999
Atkinson et al, 1999
Poloniecki et al, 1997
Spain
Taipei, Taiwan
Taipei. Taiwan
Kaohsiung, Taiwan
Kaohsiung Taiwan
London, UK
London, UK
London, UK
All winter
All summer
All ages
All ages 1
All ages 0-2
All ages Temp < 25°C 0-2
All ages Temp > 25°C 0-2
65+ 0
0-64 0
All ages 0
0-1
not stated •
not stated •
0-1
1
1 II I I I I I I I II II I
.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1,81.9 22,12.22.3
Relative Risk Per Standard Unit
Figure 3.2-13.
Relative risks (95% CI) for associations between 24-h NO2 exposure (per
20 ppb) and hospitalizations or emergency department visits for all
cardiovascular diseases (CVD). Primary author and year of publication,
city, stratification variable(s), and lag are listed. Results for lags 0 or 1
are presented, as available.
1 However, findings from several European and Australian multicity studies indicate robust
2 associations between NO2 and hospitalization for heart disease (Von Klot et al., 2005; Barnett
3 et al., 2006; Simpson et al., 2005a). Von Klot et al. analyzed prospective cohort data from five
4 European cities (Augsburg, Barcelona, Helsinki, Rome, and Stockholm) to determine if
5 readmissions for cardiac-related disorders were associated with ambient NO2 level. The range in
6 24-h NO2 level was 15.8 to 26 ppb in the five cities studied. Von Klot reports a 3.2% (95% CI:
7 1.4, 5.1) increase in re-admissions among cardiac patients, which was independent of the effect
August 2007
3-64
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
of PMio and O3 in two-pollutant models. A 20-ppb increase in 24-h average NO2 level was
associated (RR =1.14 (95% CI: 1.08, 1.21) with an increase in hospital admissions among the
elderly in five cities in Australia and New Zealand (Barnett et al., 2006). Daily maximum N02
level was associated with a similar increase in hospitalizations (2.8% (95% CI: 1.38, 4.26) per
increase of 9.3-ppb NO2) among the elderly of Sydney, Australia (Jalaludin et al., 2006). Daily
1-h maximum NO2 level was associated with increases in hospitalizations among the elderly
(RR: 1.06 [95%> CI: 1.03, 1.08] per 30-ppb increase in N02) (Simpson et al., 2005a). Increases
in admissions were also reported for all ages (Jalaludin et al., 2006; Simpson et al., 2005a). An
earlier study also yielded positive results with an increase of 20 ppb in the 24-h average NO2
level associated with a RR of 1.09 (95%> CI: 1.06, 1.14) increase in cardiac admissions among
all ages and similar increase among the elderly (Morgan et al., 1998a). Results were diminished
slightly when the 1-h maximum NO2 level was used (Morgan et al., 1998a).
Some results remained robust in two-pollutant models (Simpson et al., 2005a; Morgan
et al., 1998a) while results reported in other studies were attenuated by the inclusion of CO in
multipollutant models (Jalaludin et al., 2006; Barnett et al., 2006). Two Asian case crossover
studies (Chang et al., 2005; Yang et al., 2004) report increases in cardiac disease that are robust
in multipollutant models. However, the effects reported by Yang et al. were orders of magnitude
above results reported in other studies (Yang et al., 2006). A time-series analysis conducted in
Hong Kong reported small associations that were not robust in multipollutant models (Wong
et al., 1999).
Arrhythmia (ICD9 427)
Arrhythmia is variation from the normal heart rhythm. Ventricular arrhythmias cause
most sudden cardiac deaths while atrial fibrillation or supraventricular arrhythmia, the most
common type of arrhythmia, is not a direct threat to life (Dockery et al., 2005). However, risk
factors for atrial fibrillation include hypertension, coronary artery disease and COPD and atrial
fibrillation is associated with increased risk of stroke.
Hospital or ED admissions for arrhythmia were inconsistently associated with increases
in ambient NO2 level. Some studies report positive associations (Rich et al., 2006a; Mann et al.,
2002; Barnett et al., 2006) while others report null associations (Metzger et al., 2004; Lippmann
et al., 2000; reanalysis Ito, 2003, 2004). Studies of heart rate variability (HRV) and implanted
August 2007
3-65
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
cardioverter defibrillators provide limited evidence to support a possible association between
arrhythmias and NO2 or ambient pollution levels (See Section 3.1.2.3).
Ischemic Heart Disease (IHD) ICD9 410-414
Some studies further delineate cardiac disease by using groupings of specific conditions
such as IHD, which includes acute MI, previous MI, angina pectoris, and other chronic IHD.
Figure 3.2-14 summarizes studies that include hospitalization for IHD as an outcome. Two U.S.
studies report associations of IHD hospitalizations or ED visits with ambient NO2 level (Mann
et al., 2002; Metzger et al., 2004), while another reports no association (Lippmann et al., 2000;
reanalysis Ito, 2003, 2004). The study by Mann et al. (2002) was novel, because exposures were
assigned based on proximity to the monitoring station and results were pooled across air basins.
Independent NO2 effects were not distinguished in these studies, however (Mann et al., 2002;
Metzger et al., 2004).
Reference
location
Metzger et al, 2004 Atlanta
Ito et al, 2004
Detroit, Ml
Mann et al, 2000 Los Angeles
>1,2006
Simpson et al, 2005 Australia
Not
stated
age other lag
Any 0
elderly 1992-1994 0
40+
65+ 0-1
Any 1
Jalaludin et al, 2006 Sydney, Australia 65+ ER visit
Lee et al. 2003 Seoul, Korea 64+
Not
stated
-B-
B
n 1 1 1 r~
.9 1 1.1 1.2 1.3
Relative Risk Per Standard Unit
1.4
Figure 3.2-14.
Relative risks (95% CI) for associations between 24-h NO2 exposure (per
20 ppb) and hospitalizations for Ischemic Heart Disease (IHD). Primary
author and year of publication, city, stratification variable(s), and lag are
listed. Results for lags 0 or 1 are presented, as available.
August 2007
3-66
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
A European study conducted in Helsinki reports an association of NO with both
hospitalization and ED visits for IHD while no association with NO2 was observed (Ponka and
Virtanen, 1996). In a multicity study in Europe, a 4.2-ppb increase N02 was associated with an
increase in readmission for angina pectoris (ICD9 411,413) among cardiac patients (von Klot
et al., 2005). O3 may have been contributed to this observed effect, however (von Klot et al.,
2005). Small associations of IHD admissions with incremental increases in NO2 have been
observed in Australian populations (Barnett et al., 2006; Jalaludin et al., 2006; Simpson et al.,
2005a). In a study with populations from seven cities in Australia, Barnett et al., (2006) found
that there was no association between NO2 and IHD admissions for the age group 25 to 64 years.
For persons 65 years and older an increase of 2.5% ([95% CI: 1.0, 4.1] lag 0 to 1) in IHD
hospital admissions per 5.1-ppb increase in N02 was reported. A study of four Australian cities
reported a 1-ppb change in the daily maximum 1-h concentration of NO2 was associated with a
0.17%) change in hospitalization for IHD ([95%> CI: 0.07, 0.27] lag 0) among the elderly. In a
single-city study of Sydney, Jalaludin et al. (2006) reported a 2.11%> ([95%> CI: 0.34, 3.01] lag 0)
change in the rate of hospitalization of patients 65 years and older per 9.3-ppb increase in daily
maximum 1-h concentration of NO2. A seasonal effect of NO2 on hospitalization for IHD was
observed (Jalaludin et al., 2006). However, the effect of NO2 was diminished when it was
modeled with CO (Jalaludin et al., 2006).
Wong et al. (1999) reported no association between IHD admissions and 24-h average
N02 concentration in Hong Kong (Wong et al., 1999). A Korean study reported an 8%> increase
in hospitalization for IHD during all seasons (RR = 1.08 [95%> CI: 1.036, 1.14] lag 5) per
14.6-ppb increase in 24-h concentration of NO2 (Lee et al., 2003a). The relative risk increased
dramatically for those >64 years of age in the summer months to 25%> for the same incremental
change (RR= 1.25 [95%> CI: 1.11, 1.41] lag 5). The effect ofN02 remained robust in
two-pollutant models with PM10 (RR = 1.09 [95%> CI: 1.02, 1.16] lag 5) but not with CO.
Hospital Admissions for Myocardial Infarction (MI) (ICD9 410)
Key studies of hospital admissions for MI are summarized in Figure 3.2-15. Positive
associations of emergency admissions for MI and increases in ambient NO2 level were reported
in Boston (Zanobetti and Schwartz, 2006) and Southern California (Linn et al., 2000; Mann
et al., 2002). Zanobetti and Schwartz report an increase of 10.21%> (3.82-15.61%), lag 0) in
August 2007
3-67
DRAFT-DO NOT QUOTE OR CITE
-------
Reference
location
Zanobetti
& Schwartz 2006
Boston
Mann et al, 2000 Los Angeles, CA 40+
age other lag
65+ 0-1
Linn et al, 2000
Barnettet al, 2006
Los Angeles, CA 30+
Australia
65+
& New Zealand
D'lppoliti et al, 2003 Rome, Italy 18+
Lanki et al, 2006 Europe 35+
von Klot et al, 2005 Europe 35+
not stated -
0
0-1
1
1
0
-B
~i 1 1 1—
.9 1 1.1 1.2
Relative Risk Per Standard Unit
1.3
Figure 3.2-15.
Relative risks (95% CI) for associations between 24-h NO2 exposure
(per 20 ppb) and hospitalizations for myocardial infarction (MI).
Primary author and year of publication, city, stratification variable(s),
and lag are listed. Results for lags 0 or 1 are presented as available.
1 emergency MI admissions per 16.8-ppb incremental increase in 24-h average NO2 among the
2 elderly. NO2, black carbon (BC), and CO were correlated during the warm season making it
3 difficult to distinguish the effect of N02 (Zanobetti and Schwartz, 2006). Linn et al. reported a
4 1.1% ([95% CI: 0.6, 1.6%], lag 0) increase in admissions for MI per 10-ppb increase inN02 and
5 Mann et al. reported a 2.04% ([95% CI: 1.05, 3.02%], lag 0-1) increase per 10-ppb increase in
6 NO2 in Southern California. Again, NO2 and CO were highly correlated making it difficult to
7 distinguish an independent effect of N02. Pooled results from two European multicity studies
8 are not consistent. Von Klot et al. report a 2.8% RR of 1.10 (95% CI: 1.01, 1.21) increase in MI
9 admissions and Lanki et al. reports a null effect (lag 1). One single-city study in Italy
10 (D'lppoliti et al., 2003) found positive significant associations between 24-h average NO2 level
August 2007
3-68
DRAFT-DO NOT QUOTE OR CITE
-------
1 and admission for MI. D'Ippoliti observed a 2.6% (95% CI: 0.2, 5.2%) increase with a 20-ppb
2 increase in NO2.
3
4 Congestive Heart Failure (CHF) (ICD9 428)
5 Studies of hospital admissions and ED visits for CHF have produced mixed results
6 (Figure 3.2-16). A seven city study conducted in the US among the elderly found positive
7 associations in Los Angeles (RR: = 1.32 [1.21, 1.43]), Chicago (RR: = 1.37 [1.14, 1.61]) and
8 NewYork(RR: = 1.14 [1.04, 1.28]) per 20-ppb increase in NO2 (Morris et al., 1995). Estimates
9 were close to the null value in Philadelphia, Detroit, Houston, and Milwaukee and only the
10 estimate for New York remained significant in multi-pollutant models (Morris et al., 1995).
Reference
location
age
other
lag
Metzger et al, 2004
Atlanta, GA
All ages
0-2
Morris et al, 1995
Chicago, IL
65+
0
Ito, 2004
Detroit, Ml
elderly
1992-1994
0
Morris et al, 1995
Detroit, Ml
65+
0
Morris et al, 1995
Houston, TX
65+
0
Linn et al. 2000
Los Angeles, CA
30+
0
Mann et al, 2000
Los Angeles, CA
40+
not
stated
Morris et al, 1995
Los Angeles, CA
65+
0
Morris etal, 1995
Milwaukee, Wl
65+
0
Morris et al, 1995
New York, NY
65+
0
Morris et al, 1995
Philadelphia, PA
65+
0
Wellenius et al, 2005
Pittsburgh, PA
65+
not
stated
Barnett et al, 2006
Australia
65+
0-1
B
B
-3-
T
~T
1.1
\
1.2
1 1.1 1.2 1.3 1
Relative Risk Per Standard Unit
1^
1.5
n
1.6
Figure 3.2-16.
Relative risks (95% CI) for associations between 24-h NO2 exposure (per
20 ppb) and hospitalizations for congestive heart failure (CHF). Primary
author and year of publication, city, stratification variable(s), and lag are
listed. Results for lags 0 or 1 are presented as available.
August 2007
3-69
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
A more recent study of an elderly population conducted in Pittsburgh and Allegheny
County reported a OR = 1.08 increase in CHF admissions with a 20-ppb increase in NO2
(Wellenius et al., 2005). The result for N02 was not affected by PMi0 but was diminished in a
two-pollutant model containing CO. A 6.9% (OR =1.3 [95% CI: 1.09, 1.55], lag 0) increase in
CHF admissions was observed in a seven city Australian study (pooled results) per 20-ppb
increase in 24-h average NO2 concentration among the elderly (Barnett et al., 2006).
Hospital Admissions for Stroke and Cerebrovascular Disease (ICD9 430-448)
Cerebrovascular diseases include ICD9 codes 430-448 and may be more narrowly
defined to capture ischemic stroke (IS) (ICD9 433-435) and hemorrhagic stroke (HS) (ICD9
430). Studies that have evaluated the association between all cerebrovascular disease and
ambient NO2 concentration are summarized in Figure 3.2-17. Results from these studies are
inconsistent. The largest study described in the figure, conducted by Linn et al. (2000), did not
find an effect for NO2 on cerebrovascular disease admission (Linn et al., 2000). However, these
authors report an increase in hospitalizations of 2.7% (95% CI: 2.6, 2.8) for occlusive stroke
during the winter months (year round effect also observed). Wellenius et al. (2005) found a
2.94% increase in IS admissions per 11.93% increase in 24-h average N02 level (multipollutant
models were not examined) (Wellenius et al., 2005). In a Canadian study, Villeneuve et al.
(2006) reported an association between NO2 exposure and IS during the winter months, among
the elderly (OR = 1.26 [95% CI: 1.09, 1.46], lag 3).
Results from Europe are also inconsistent with Ponka and Virtanen (1996) reporting null
results and Ballester et al. (2001) reporting a 1.15 ([95% CI: 1.02, 1.29], lag 4) increase in
cerebrovascular admissions per 20-ppb increase in 24-h NO2 level. No association was found in
Sydney between daily 1-h maximum NO2 concentration and cerebrovascular disease (Jalaludin
et al., 2006). No associations between air pollutants and stroke were reported in a multicity
study conducted in Australia and New Zealand (Barnett et al., 2006). Investigations of N02
cerebrovascular disease and stroke have been conducted in populations in Asia (Chan et al.,
2006; Tsai et al., 2003). An increase in 24-h average concentration NO2 of 20 ppb resulted in
increased risk of hospitalization (OR = 1.67 [95% CI: 1.48, 1.87] lag 0 to 2) in Taiwan (Tsai
et al., 2003). The associations were stronger on warm days. Using multipollutant models that
were adjusted for PM10, CO, O3, and SO2, Tsai et al. (2003) found the association between NO2
and IS as well as PIH remained significant (p < 0.01). By contrast, a study by Chan et al. in
August 2007
3-70
DRAFT-DO NOT QUOTE OR CITE
-------
Reference
I to, 2004
Linn et al, 2000
Jalaludin et al, 2006
Wong et al, 1999
Tsai et al, 2003
Tsai et al, 2003
location
Detroit, Ml
Los Angeles >30
Sydney, Australia 65+
Hong Kong
age other lag
elderly 1992-1994 0
0
ER visit
65+
Ponka and Virtanen, 1996 Helsinki, Finland All ages
Ba Hester et a I 2001
Chan et al, 2006
Spain
Taipei, Taiwan
All ages
All ages
1
0-1
Kaohsiung, China All ages >20°C 0-2
Kaohsiung, China All ages <20°C 0-2
~
1 I I I I I I I F I I
.7 .8 .9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7
Relative Risk Per Standard Unit
Figure 3.2-17. Relative risks (95% CI) for associations between 24-h NO2 exposure (per
20 ppb) and hospitalizations for cerebrovascular disease. Primary author
and year of publication, city, stratification variable(s), and lag are listed.
Results for lags 0 or 1 are presented as available.
1 Taiwan, failed to demonstrate statistically significant associations between NO2 and rates of
2 hospital admissions for cerebrovascular disease, stroke (IS or HS) (Chan et al., 2006).
3
4 Vaso-occlusion in Sickle Cell
5 A recent study evaluated the association of pain in Sickle Cell patients, which is thought
6 to be caused by vaso-occlusion, with air pollution (Yallop et al., 2007). A time series analysis
7 was performed to link daily hospital admissions for acute pain among sickle cell patients with
8 daily air pollution levels in London using the cross correlation function. No association was
9 reported for N02. However, Yallop et al. observed an association (CCF = -0.063, lag 0) for NO,
10 CO, and03.
August 2007
3-71
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Multipollutant Modeling Results
The majority of studies of CVD hospital and ED admissions reported results from
multipollutant models. Since results from multipollutant models in single-city studies are
generally less stable because of smaller sample sizes, results for multicity studies are discussed
in this section. Burnett et al. (1997a) report robust estimates for cardiac disease hospital
admissions and N02, whereas the observed association for cardiac hospitalizations and PM were
explained by gaseous pollutants. In another multicity study conducted in the same area,
associations of NO2 with cardiac disease were not attenuated when CO, SO2, and PM variables
were included in the models (Burnett et al., 1999). Relative risks for NO2 with CHF were
diminished in multipollutant models used in a multicity study including six U.S. cities (Morris
et al., 1995). Wellenius et al. (2005a) did not report multipollutant results for a study of
ischemic and HS. In this study, only ischemic stroke was associated with NO2 exposure.
Investigators conducting a multicity study in Australia observed a different effect with
the N02 association, with CVD weakening after inclusion of CO in the model (Barnett et al.,
2006). The authors hypothesized that NO2 is a good surrogate for PM, which may explain the
observed effect of NO2 on admissions for CVD (Barnett et al., 2006). Results from another
multicity study in Australia are similar with authors suggesting that NO2 effects on cardiac
disease and IHD may be confounded by PM (Simpson et al., 2005b). Multicity studies from
Europe are inconsistent with regard to the results of multipollutant models. Von Klot et al.
reported that the effect of NO2 on MI, angina, and cardiac disease was independent of PM10 and
O3 (von Klot et al., 2005), while Ballester et al. (2006) reported that the effect of NO2 on cardiac
disease was diminished in two-pollutant models. Copollutant model results for NO2 were not
reported for a third multicity study in Europe (Lanki et al., 2006).
Results from multipollutant models have been inconsistent in large multicenter studies
that have evaluated the effect NO2 on hospital and ED visits for CVD. In general, investigators
acknowledge the limitations of multipollutant models to tease out independent contributions of
individual and highly correlated pollutants. In addition, most researchers generally acknowledge
the possibility that observed effects on the cardiovascular system are related to traffic pollutants.
See Table 3.2-3 for the effects of including a copollutant with NO2 in multipollutant models.
August 2007
3-72
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3.2.2.2 Heart Rate Variability, Repolarization, Arrhythmia, and Other Measures
Cardiovascular Function Associated with Short-Term NO2 Exposure
Heart Rate Variability
HRV, a measure of the beat-to-beat change in heart rate (HR), is a reflection of the
overall autonomic control of the heart. It is hypothesized that increased air pollution levels may
stimulate the autonomic nervous system and lead to an imbalance of cardiac autonomic control
characterized by sympathetic activation unopposed by parasympathetic control (Liao et al., 2004;
Brook et al., 2004). Such an imbalance of cardiac autonomic control may predispose susceptible
people to greater risk of ventricular arrhythmias and consequent cardiac deaths (Liao et al., 2004;
Brook et al., 2004). HRV has been studied most frequently in coronary artery disease
populations, particularly in the post-MI population. Lower time domain as well as frequency
domain variables (i.e., reduced HRV) are associated with an increase in cardiac and all-cause
mortality among this susceptible population. Those variables most closely correlated with
parasympathetic tone appear to have the strongest predictive value in heart disease populations.
Specifically, acute changes in RR-variability temporally precede and are predictive of increased
long-term risk for the occurrence of ischemic sudden death and/or precipitating ventricular
arrhythmias in individuals with established heart disease (for example, see La Rovere et al.,
2003). However, acute changes in HRV parameters do not necessarily occur immediately prior
to sudden fatal ventricular arrhythmias (Waxman et al., 1994). HRV itself is not the causative
agent, nor has it been implied to be a causative agent in any of the studies performed to date.
Altered HRV, including changes in HRV associated with exposure to criteria pollutants, may be
a marker for enhanced risk.
The potentially adverse effects of air pollutants on cardiac autonomic control were
examined in a large population-based study, among the first in this field. Liao et al. (2004)
investigated short-term associations between ambient pollutants and cardiac autonomic control
from the fourth cohort examination (1996 to 1998) of the population-based Atherosclerosis Risk
in Communities (ARIC) Study. PM10, N02, and other gaseous air pollutants were examined in
this study. PM10 (24-h average) and NO2 exposures (24-h average) 1 day prior to the randomly
allocated examination date were used. The mean (SD) NO2 level was 21 (8) ppb. They
calculated 5-min HRV indices between 8:30 a.m. and 12:30 p.m. and used logarithmically-
transformed data on high-frequency (0.15 to 0.40 Hz) and low-frequency (0.04 to 0.15 Hz)
August 2007
3-73
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
power, standard deviation of normal R-R intervals (SDNN), and mean HR. The effective sample
sizes for NO2 and PM10 were 4,390 and 4,899, respectively, from three U.S. study centers in
North Carolina, Minnesota, and Mississippi. PMi0 concentrations measured 1 day prior to the
HRV measurements were inversely associated with both frequency- and time-domain HRV
indices. Ambient NO2 concentrations were inversely associated with high-frequency power and
SDNN. In single-pollutant models, a 20-ppb increase in ambient NO2 was associated with a
5% reduction (95% CI: 0.7, 9.2), in mean SDNN. Consistently more pronounced associations
were suggested between PM10 and HRV among persons with a history of hypertension.
The Liao et al. (2004) findings were cross-sectionally derived from a population-based
sample and reflect the short-term effects of air pollution on HRV. When the regression
coefficients for each individual pollutant model were compared, the effects for PMi0 were
considerably larger than the effects for gaseous pollutants such as NO2. Because of the
population-based sample, this study is more generalizable than other smaller panel studies. The
findings are suggestive of short-term effects of air pollutants, including NO2, on HRV at the
population level.
Various measures of HRV have been examined in relation to daily levels of ambient air
pollution in other studies (Chan et al., 2005; Wheeler et al., 2006; Holguin et al., 2003;
Luttmann-Gibson et al., 2006; Schwartz et al., 2005). Chan et al. (2005) recruited 83 patients
from the cardiology section of a hospital in Taiwan. Patients included 39 with coronary heart
disease (CHD) and 44 with more than one risk factor for CHD. The authors reported finding
significant associations between increases in NO2 and decline in SDNN (NO2 lagged 4 to 8 h)
and LF (NO2 lagged 5 or 7 h) (see Annex Table AX6.4.1 for quantitative results). There were no
significant associations for r-MSSD or HF and NO2. None of the other pollutants tested (PM10,
CO, S02, 03) were significantly associated with any of the HRV measured. Wheeler et al.
(2006) examined HRV and ambient air pollution in Atlanta in 12 patients who had an MI from
3 to 12 months prior to enrollment and 18 COPD patients. The results in the two patient groups
were quite different: increasing concentration of NO2 in the previous 4-h significantly reduced
SDNN in MI patients and significantly increased SDNN in COPD patients (see Annex Table
AX6.10). Similar significant associations were seen with increases in 4-h ambient PM25. The
PM2.5 concentrations were moderately correlated with NO2 levels (r = 0.4).
August 2007
3-74
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
In contrast, Holguin et al. (2003) PM2.5 concentrations were moderately correlated with
NO2 levels (v = 0.04) in 34 elderly adults in Mexico City and found no significant associations
with increases in N02, but did find significant effects of PM2.5 on HF, particularly among
hypertensive subjects. Similarly, Luttmann-Gibson et al. (2006) also found significant effects of
PM2.5 and S04 on HRV measured in a panel of 32 senior adults in Steubenville, OH, but
observed no effect of increasing NO2. Likewise, Schwartz et al. (2005) found significant effects
of increases in PM2.5 on measures of HRV, while no associations with N02 were observed. A
population-based study of air pollutants and HRV was conducted in Boston, MA on 497 men
from the VA Normative Aging Study (NAS) (Park et al., 2005b). The mean (SD) 24-h
average NO2 concentration was 22.7 (6.2) ppb. Associations with HRV outcomes were observed
with a 4-h moving average of 03 and PM2.5 concentrations, but not with N02.
Repolarization Changes
In addition to the role played by the autonomic nervous system in arrhythmogenic
conditions, myocardial vulnerability and repolarization abnormalities are believed to be key
factors contributing to the mechanism of such diseases. Measures of repolarization include QT
duration, T-wave complexity, variability of T-wave complexity, and T-wave amplitude. A
prospective panel study, conducted in East Germany, analyzed 12 repeat ECG recordings for
56 males with IHD (Henneberger et al., 2005). Ambient air pollutants measured at fixed
monitoring sites were used to assign individual exposures for 0 to 5, 5 to 11, 12 to 17, 18 to 23,
0 to 23 h and for 2 to 5 days prior to the EEG. Pollutants considered were ultrafine particles
(UFP), accumulation mode particle (ACP), PM2.5, elemental carbon (EC), organic carbon (OC),
SO2, NO2, NO, and CO. Associations were observed between (1) QT duration and EC and OC;
(2) T-wave amplitude and UFP, ACP and PM2.5; and (3) T-wave complexity and PM10, EC, and
OC. NO (r = 0.83) and NO2 (0.76) were highly correlated with UFP but were not associated
with repolarization abnormalities.
Arrhythmias Recorded on Implanted Defibrillators
Implanted cardioverter defibrillators (ICDs) are often used in cardiac patients to detect
life-threatening arrhythmias. Among patients with ICDs in eastern Massachusetts, increases in
ambient NO2 was significantly associated with defibrillator discharges (Peters et al., 2000) and
ventricular arrhythmias (Dockery et al., 2005; Rich et al., 2005), but not with paroxysmal atrial
August 2007
3-75
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
fibrillation (PAF) episodes (Rich et al., 2006a). In a pilot study, Peters et al. (2000) abstracted
device records for 3 years for each of 100 patients with ICDs. Defibrillator discharge events
were positively associated with the previous day and 5-day mean N02 concentrations: each
20-ppb increase in the previous day's NO2 level was associated with an increased risk of a
discharge event (OR = 1.55 [95% CI: 1.05, 2.29]) (see Annex Table AX6.4.2 for the increase
associated with a 20-ppb increase in NO2).
Two separate analyses of the same cohort of patients examined the association between
air pollution and the incidence of ventricular arrhythmias (Dockery et al., 2005; Rich et al.,
2005). A total of 203 patients with ICDs who lived within 25 miles of the ambient monitoring
site in Boston were monitored. Data included a total of 635 person-years of follow-up or an
average of 3.1 years per subject. The median (IQR) 48-h average N02 concentration was
22.7 (7.7) ppb. In the analysis by Dockery et al. (2005), positive associations were observed
between ventricular arrhythmias within 3 days of a prior event and a 2-day mean of several air
pollutants including PM2.5, BC, NO2, CO, and SO2. Rich et al. (2005, 2006a) examined
associations between ambient air pollution levels and two other cardiac endpoints recorded by
the ICDs, namely ventricular arrhythmias (Rich et al., 2005) and PAF episodes (Rich et al.,
2006a). In single-pollutant models, each 20-ppb increase in the mean NO2 level over the
previous 2 days was associated with an increased likelihood of ventricular arrhythmia, OR = 1.54
(95% CI: 1.11, 2.18). The association withN02 was not significant in two pollutant models
with PM2.5, but remained marginally significant in models with 03 (2.0-ppb increase in 24-h
moving average NO2 was associated with an OR =1.36 [95% CI: 1.00, 1.80]). There was a
strong association between an increase of NO2 (by 20 ppb) and ventricular arrhythmia in the
presence of ventricular arrhythmia within the previous 72 h (OR = 2.09 [95% CI: 1.26, 3.51]).
No association was found between N02 levels and PAF (Rich et al., 2006b).
Plasma Fibrinogen, Biomarker for Cardiovascular Disease
Epidemiological Studies
In a large cross-sectional study of 7,205 office workers in London, Pekkanen et al. (2000)
collected blood samples and analyzed the association between plasma fibrinogen, a risk factor
for CVD, and ambient levels of air pollution. In models adjusting for weather and demographic
and socioeconomic factors, there was an increased likelihood of blood levels of fibrinogen
August 2007
3-76
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
>3.19 g/1 (90th percentile) for each 20-ppb increase in NO2 lagged by 3 days (OR =1.14 [95%
CI: 1.03, 1.25]). The correlation between daily NO2 and other traffic-related pollutants were
high: daily levels of black smoke (r = 0.75), PMi0 (r = 0.76), S02 (r = 0.62), CO (r = 0.81). The
authors suggest that the increased concentrations of fibrinogen, a mediator of cardiovascular
morbidity and mortality, may be an indicator of inflammatory reactions caused by air pollution.
Pekkanen et al. (2002) enrolled a panel of 45 adults with coronary heart disease in order
to examine associations between heart function as measured by risk of ST-segment depression
and particulate pollution. Level of particulate and gaseous pollutants, including NO2, lagged by
2 days was found to have the strongest effect on risk of ST-segment depression during mild
exercise tests (OR= 14.1 [95% CI: 3.0, 65.4] for ST-segment depression of >0.1mV with a
20-ppb increase in N02 lagged by 2 days). A large (n = 863) cross-sectional study of resting
heart rate (HR) of adults in France found significant associations between elevated levels of NO2
within 8-h of measurement and resting HR of >75 beats per minute (bpm) (OR = 2.7 [95% CI:
1.2, 5.4] for resting HR >75 bpm for each 20-ppb increase in NO2) (Ruidivets et al., 2005).
Controlled Human Exposure and Animal Studies
Folinsbee et al. (1978) studied three groups of 5 healthy males exposed to 0.62-ppm N02
for 2 h. The groups differed by duration of exercise during exposure: 15, 30, or 60 min. In
addition to pulmonary function, outcome measures included indirect calorimetry, cardiac output
using the CO2 rebreathing technique, blood pressure, HR, and diffusing capacity of the lung for
carbon monoxide (DLCO). There were no significant effects for the individual groups, or for the
15 subjects analyzed together. However, the small number of subjects in each group limited
statistical power.
Drechsler-Parks (1995) assessed changes in cardiac output using noninvasive impedance
cardiography. Eight older adults (56 to 85 years of age) were exposed to 0.60-ppm N02,
0.45-ppm O3, and the combination of 0.60-ppm NO2 + 0.45-ppm O3 for 2-h with intermittent
exercise. The exercise-induced increase in cardiac output was smaller with the NO2 + O3
exposures than with the filtered air or O3 exposures alone. There were no significant differences
in minute ventilation, HR, or cardiac stroke volume, although the mean stroke volume was lower
for N02 + 03 than for air. The author speculated that chemical interactions between 03 and N02
August 2007
3-77
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
at the level of the epithelial lining fluid led to the production of nitrite, leading to vasodilatation,
with reduced cardiac preload and cardiac output. This study has not been repeated.
One previous study (Linn et al., 1985a) reported small but statistically significant
reductions in blood pressure after exposure to 4-ppm NO2 for 75 min, a finding consistent with
systemic vasodilatation in response to the exposure. However, many subsequent studies at
concentrations generally less than 4 ppm have not reported changes in blood pressure in response
to N02 exposure.
There is also evidence that NO2 exposure may affect circulating red blood cells. Posin
et al. (1978) exposed 10 healthy males to 1- or 2-ppm NO2 for 2.5 to 3.0-h daily for 2 days.
Blood obtained immediately after the second exposure showed a reduced hemoglobin and
hematocrit (N02: 41.96 ± 2.75; sham exposure: 43.18 ± 2.83, p = 0.001) and reduced red blood
cell acetyl cholinesterase levels. However, the control air exposures were not identical to and
concurrent with the NO2 exposures, a potential flaw in the study design.
In the study by Frampton et al. (2002), healthy subjects were exposed to air or 0.6- or
1.5-ppm N02 for 3-h with intermittent exercise, and blood was obtained 3.5-h after exposure.
There was a significant, concentration-related reduction in hematocrit and hemoglobin in both
males and females, confirming the findings of Posin et al. (1978). These studies suggest that
NO2 exposure in the range of 1- to 2-ppm for a few hours is sufficient to alter the red blood cell
membrane. The reductions in blood hemoglobin were not sufficiently large to result in health
effects for these healthy subjects. However, in the Frampton study, the reduction in hemoglobin
represented the equivalent of about 200 mL of blood loss for a 70-kg male. This could
conceivably have adverse cardiovascular consequences for someone with significant underlying
lung disease, heart disease, or anemia.
These few studies suggest systemic effects of N02 exposure at concentrations below
2.0 ppm, but the observations require confirmation. The results on the effect of NO2 on various
hematological parameters in animals are inconsistent and thus, provide little biological
plausibility for the epidemiology findings. There have also been reported changes in the red
blood cell membranes of experimental animals following N02 exposure. Red blood cell
D-2,3-diphosphoglycerate was reportedly increased in guinea pigs following exposure to
0.36-ppm NO2 for 1 week (Mersch et al., 1973). An increase in red blood cell sialic acid,
indicative of a younger population of red blood cells, was reported in rats exposed to 4.0-ppm
August 2007
3-78
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
NO2 continuously for 1 to 10 days (Kunimoto et al., 1984). However, in another study, exposure
to the same concentration of NO2 resulted in a decrease in red blood cells (Mochitate and Miura,
1984). A more recent study (Takano et al., 2004) using an obese rat strain found changes in
blood triglycerides, high-density lipoprotein cholesterol (HDL), and HDL/total cholesterol ratios
with a 24-week exposure to 0.16-ppm NO2.
In the only study conducted below 5-ppm NO2 that evaluated methemoglobin formation,
Nakajima and Kusumoto (1968) reported that, in mice exposed to 0.8-ppm N02 for 5 days, the
amount of methemoglobin was not increased. This is in contrast to some (but not all) in vitro
and high concentrations of NO2 in vivo studies, which have found methemoglobin effects
(U.S. Environmental Protection Agency, 1993).
3.2.2.3 Integration for Effects of Short-Term N02 Exposure on Cardiovascular Outcomes
Cardiac rhythm disorders are the leading cause of hospital admissions for CVD in the
United States (Henneberger et al., 2005). Results from a Boston area study of ventricular
arrhythmias indicate an association of arrhythmia with short-term exposure to ambient (Peters
et al., 2000; Dockery et al., 2005; Rich et al., 2005; see also Annex Table AX2.6.4-1). However,
arrhythmias were also associated with PM exposure and high correlations among ambient
pollutants were reported. A study of repolarization changes and air pollution also points to PM
as a possible causative agent (Henneberger et al., 2005). Results from studies of HRV are also
inconclusive with regard to the effect of NO2 on the cardiovascular system (Liao et al., 2004;
Chan et al., 2005; Wheeler et al., 2006; Holguin et al., 2003; Luttmann-Gibson et al., 2006;
Schwartz et al., 2005).
Numerous studies have shown an association between NO2 exposure and hospital or ED
admissions for CVD including IHD, MI, CFH, cardiac disease not involving the peripheral
circulation, and cerebrovascular disease. Both incremental changes in daily 1-h maximum
concentrations and 24-h averages of N02 are associated with IHD admissions worldwide.
Associations between hospital admissions for MI and ambient NO2 are reported in both the
United States and Europe. Associations between ambient NO2 and CHF were found in several
U.S. cities and in an Australian multicity meta-analysis. Studies of ambient NO2 and other
cardiac disease or cerebrovascular disease are fewer and provide less consistent results.
However, evidence from multipollutant models is inconsistent and does not suggest that the
effects of NO2 are robust when adjusted for other traffic-related pollutants.
August 2007
3-79
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
A small number of controlled human exposure studies have evaluated cardiovascular
responses to NO2 exposure. Typically, the studies utilize short exposure durations and small
numbers of subjects, resulting in poor characterization of N02 concentration-response and, thus,
are of limited value in providing corroborating evidence for the epidemiological findings. Early
work (Folinsbee et al., 1978) using exposures of 0.62 ppm for 2-h found no changes in HR and
cardiac output in healthy males. Another early study (Linn et al., 1985a) demonstrated
reductions in blood pressure (BP) following an exposure of 4-ppm N02 for 75 min. A more
recent study (Gong et al., 2005) demonstrated reductions in diastolic BP following a 2-h
exposure to 0.4-ppm NO2. Another cardiovascular endpoint affected by NO2 is circulating red
blood cells. Posin et al. (1978) found reduced hemoglobin, hematocrit, and RBC
acetylcholinesterase levels following exposures to 1- or 2-ppm N02 for 2.5 to 3-h daily for 2
days. This was confirmed in a study (Frampton et al., 2002) exposing healthy subjects to 0.6 and
1.5 ppm for 3-h with intermittent exercise. These alterations in hemoglobin and hematocrit do
not pose a risk to healthy individuals, but could account for the observed cardiovascular
morbidity and mortality in individuals with underlying IHD, CHF, and other heart and lung
disease.
There are limited experimental data on the effects of ambient NO2 on the heart. Two
early studies (Suzuki et al., 1981, 1984) showed reductions in PaC>2 at 4 ppm for 3 months and
reduced HR at 1.2 and 4 ppm for 1 month. Data on the effects of NO2 on hematological
endpoints are inconsistent; however, two early studies (Mersch et al., 1973; Kunimoto et al.,
1984) found changes in RBC membranes and sialic acid. A more recent study (Takano et al.,
2004) using an obese rat strain found changes in blood triglycerides, HDL, and HDL/total
cholesterol ratios with a 24-week exposure to 0.16-ppm NO2. These studies may provide limited
biological plausibility and mechanistic evidence for an effect on the cardiovascular system.
3.3 MORTALITY WITH SHORT-TERM EXPOSURE TO N02
Since the 1993 AQCD, a number of studies, mostly using time-series analyses, reported
short-term mortality risk estimates for NOx, in most cases, (see Annex Table AX6.7). There
was no epidemiological study reviewed in the 1993 AQCD that examined the mortality effects of
ambient NOx. However, since most of these studies' original focus or hypothesis was on PM, a
quantitative interpretation of the NOx mortality risk estimates requires caution.
August 2007
3-80
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3.3.1 Multicity Studies and Meta-Analyses
In reviewing the range of mortality risk estimates, multicity studies provide the most
useful information because they analyze multiple cities data in a consistent method, avoiding
potential publication bias. Risk estimates from multicity studies are also usually reported for
consistent lag days, further reducing potential bias caused by choosing the "best" lag in
individual studies. There have been several multicity studies from the United States, Canada,
and Europe. Meta-analysis studies also provide useful information on describing heterogeneity
of risk estimates across studies, but unlike multicity studies, the heterogeneity of risk estimates
seen in meta-analysis may also reflect the variation in analytical approaches across studies.
Multicity studies and meta-analyses are reviewed in the following section, and effect estimates
from these studies are summarized. Discussion will focus on the studies that were not affected
by GAM with convergence issues (Dominici et al., 2002; Ramsay et al., 2003) unless otherwise
noted when the studies raise relevant issues.
3.3.1.1 United States Largest 90 Cities Study
The time-series analysis of the largest 90 U.S. cities (Samet et al., 2000; reanalysis
Dominici et al., 2003) in the National Morbidity, Mortality, and Air Pollution Study (NMMAPS)
is by far the largest multicity study conducted to date to investigate the mortality effects of air
pollution, but its primary interest was PM (i.e., PMio). It should also be noted that, according to
the table of mean pollution levels in the original report (Samet et al., 2000), NO2 was not
measured in 32 of the 90 cities. The analysis in the original report used GAMs with default
convergence criteria and Dominici et al. (2003) reanalyzed the data using GAM with stringent
convergence criteria as well as using GLM. It should be noted that this model's adjustment for
weather effects employs more terms than other time-series studies in the literature, suggesting
that the model adjusts for potential confounders more aggressively than the models in other
studies. PM10 and 03 (in summer) appeared to be more strongly associated with mortality than
the other gaseous pollutants. Regarding NO2, SO2, and CO, the authors stated, "The results did
not indicate associations of these pollutants with total mortality." However, it should be noted
that, as with PM10, NO2, SO2, and CO, each showed the strongest association at lag 1 day (for
03, it was lag 0 day), and as with PMi0, addition of other copollutants in the model at lag 1 day
hardly affected the mortality risk estimates of these gaseous pollutants. Figure 3.3-1 shows the
August 2007
3-81
DRAFT-DO NOT QUOTE OR CITE
-------
sj
Q-
Q.
°§
*1
°-c
*8
?§
oO
.Ea>
a>c3
OlCD
c i-
(T3U
6"
1.0
0.5
-0.5
-1.0
Lag 0
Lag 1
¦ ¦ •
Lag 2
¦ f
¦ V
•
M
* •
• i i * •
f
X
•
f
¦
I
JR
•
•
" ~ * t
¦ rn ¦
H
m
n
til
ft
M
i
•
¦
[
4
ABCDEABCDEABCDE
Models
Figure 3.3-1. Posterior means and 95% posterior intervals of national average
estimates for N02 effects on total mortality from nonexternal causes at
lags 0,1, and 2 within sets of the 90 cities with pollutant data available.
Models A = \<)2 alone; B = \G2 + PMi0; C = N02 + PM10 + 03; D = N02
+ PMio + S02; E = S02 + PM„, + CO.
Source: Dominici et al. (2003).
1 total mortality risk estimates for N02 from Dominici et al, (2003). The N02 risk estimates in the
2 multipollutant models were about the same or larger. Thus, these results do not indicate that the
3 N02-mortality association was confounded by PMio or other pollutants (and vice versa).
4 3.3.1.2 Canadian Multicity Studies
5 There have been four Canadian multicity studies: (1) analysis of gaseous pollutants in
6 11 cities from 1980 to 1991 (Burnett et al., 1998); (2) analysis of PM2 5, PMi0-2.5, and gaseous
7 pollutants in 8 cities from 1986 to 1996 (Burnett et al., 2000); (3) analysis of PM2 5, PMi0.2.5, and
8 gaseous pollutants in 12 cities from 1981 to 1999 (Burnett et al., 2004); and, (4) analysis of N02,
9 NO, PM2.5 and its selected components, PMi0.2.5, PM]0, as well as an examination of correlation
August 2007
3-82
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
between these pollutants and selected traffic-related species including VOCs and PAHs with
between 1984 and 2000 (Brook et al., 2007). Since the first two studies were affected by the
GAM issue (only the PM indices were reanalyzed for the second study in Burnett and Goldberg,
2003), and the third study is most extensive both in terms of the length and coverage of cities, the
discussion will focus on the third study.
Total (nonaccidental), cardiovascular, and respiratory mortality were analyzed in the
Burnett et al. (2004) study. Daily 24-h average as well as 1-h max values were analyzed for all
the gaseous pollutants and CoH. For PM2.5, PM10-2.5, PM10, CoH, SO2, and CO, the strongest
mortality association was found at lag 1, whereas for NO2, it was the 3-day moving average
(i.e., average of 0-, 1-, and 2-day lags), and for O3, it was the 2-day moving average. Of the
single- day lag estimates for N02, lag 1-day showed the strongest associations, which is
consistent with the NMMAPS result. The 24-h average values showed stronger associations than
the 1-h max values for all the gaseous pollutants and CoH except for O3. The pooled NO2
mortality risk estimate in a single-pollutant model (for all available days) was 2.0% (95% CI:
1.1, 2.9) per 20-ppb increase in the 3-day moving average of N02. N02 was most strongly
correlated with CoH (r = 0.60), followed by PM2.5 (r = 0.48). However, the MVmortality
association was insensitive to adjustment for these or any of other pollutants in the two-pollutant
models. For example, the NO2 mortality risk estimate with CoH in the model was 2.6% (95%
CI: 1.3, 3.9) per 20-ppb increase in the 3-day moving average of NO2. The model with O3
resulted in the largest reduction in the N02 risk estimate, 1.8% (95% CI: 0.9, 2.7). For the data
subset for days when PM2.5 data were available (every 6th day), the NO2 risk estimate was 2.4%
(95%) CI: 0.7, 4.1) and 3.1% (95% CI: 1.2, 5.1) per 20-ppb increase in 1-day lagN02, without
and with PM2.5 in the model, respectively. The risk estimates for cardiovascular (2.0% [95% CI:
0.5, 3.5]) and respiratory deaths (2.1% [95% CI: -0.2, 4.4] per 20-ppb increase in the 3-day
moving average) were similar to that for total mortality. In their sensitivity analysis, larger risk
estimates were observed for warmer months. Older age groups also showed larger risk
estimates.
The results from the above 12-city study appear to be similar to those from the 8-city
study (Burnett et al., 2000) in that MVmortality associations were stronger than those for the
associations between the size-fractionated PM indices and mortality, and simultaneous inclusion
of NO2 and the size-fractionated PM indices in the regression model resulted in reductions in the
August 2007
3-83
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
PM risk estimates. However, Burnett et al. (2004) mentioned, in their discussion section, results
from additional data collection and analysis in which daily PM2.5 was collected in 11 of the
12 cities between 1998 and 2000. In that analysis, simultaneous inclusion of the PM2.5 and N02
in the model resulted in a considerable reduction of the NO2 risk estimates. Thus, while the NO2
risk estimates were not sensitive to adjustment for the PM indices collected every-6th-day, it was
sensitive to adjustment for the daily PM2.5. Burnett et al. (2004) discussed that reducing
combustion would result in public health benefits because N02 or its products originate from
combustion sources but cautioned that they could not implicate NO2 as a specific causal
pollutant.
Brook et al. (2007) further examined data from ten Canadian cities with a special focus
on the N02 and the role of other traffic-related air pollutants. Again, N02 showed the strongest
associations with mortality among the pollutants examined including NO, and none of the other
pollutants substantially reduced N02 risk estimates in multi-pollutant models. The analysis also
confirmed the 2004 Burnett et al. study result that NO2 risk estimate was larger in the warm
season. Generally, NO showed stronger correlation with the primary VOCs (e.g., benzene,
toluene, xylenes, etc.) than NO2 or PM2.5. NO2 was more strongly correlated with the organic
compounds than it is with the PM mass indices or trace metals in PM25. Brook et al. concluded
that the strong NO2 effects seen in Canadian cities could be a result of it being the best indicator,
among the pollutants monitored, of fresh combustion as well as photochemically processed
urban air.
In summarizing the Canadian multicity studies, NO2 was most consistently associated
with mortality among the air pollutants examined, especially in warm season. Adjustments for
PM indices and its components did not reduce NO2 risk estimates. NO2 was also shown to be
associated with organic compounds that are indicative of combustion products (traffic-related air
pollution) and photochemical reactions
3.3.1.3 Air Pollution and Health: A European Approach (APHEA) Studies
The first report (Touloumi et al., 1997) on NO2 and O3 effects on mortality from the Air
Pollution and Health: a European Approach (APHEA1) project included six cities (Athens,
Barcelona, Paris, Lyon, Koln, and London). The data were analyzed by each center separately
following a standardized methodology, but the lag for the "best" model was allowed to vary in
these cities from 0 to 3 days. A 30-ppb increase in 1-h max NO2 was associated with a 1.5%
August 2007
3-84
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
(95% CI: 1.0, 2.0) increased risk in nonaccidental mortality. There was a tendency for larger
effects of NO2 in cities with higher levels of black smoke. The pooled estimate for NO2 was
almost halved when black smoke was included in the model. The author suggested that the N02
effects on mortality could have been confounded by other "vehicle-derived pollutants." Zmirou
et al. (1998) analyzed (broad) cause-specific mortality (cardiovascular and respiratory causes) in
ten European cities including the four cities (Barcelona, Paris, Lyon, and London) for which NO2
was available, but they reported that "N02 did not show consistent relationships" with these
mortality categories.
One of the extended APHEA2 project studies (Katsouyanni et al., 2001; reanalysis, 2003)
analyzed data from 29 European cities and reported risk estimates for PM10 and not for NO2, but
found that the cities with higher N02 levels tended to have larger PMi0 risk estimates.
Furthermore, simultaneous inclusion of PM10 and NO2 reduced the PM10 risk estimate by half.
An analysis of the elderly mortality in the same 28 cities (Aga et al., 2003) also found a similar
effect modification of PM by NO2. Thus, combined with the Touloumi et al. study result
described above, PM and N02 risk estimates in these European cities may be reflecting the
health effects of the same air pollution source and/or effect modifiers of each other.
Samoli et al. (2005) investigated the concentration-response relationship between NO2
and total nonaccidental mortality in nine of the APHEA2 cities where medians were >110 |ig/m3
(57 ppb) and the third quartiles were >130 |ig/m3 (68 ppb). Two methods, the nonparametric
meta-smooth method and the parametric cubic spline method, were applied to estimate the shape
of the concentration-response relationship. Both methods suggested a monotonic increase in the
relationship, and the investigators concluded that the linear model was adequate to describe the
N02-mortality relationship.
In another APHEA2 study, Samoli et al. (2006) analyzed 29 APHEA2 cities to estimate
NO2 associations for total, cardiovascular, and respiratory deaths. Unlike the APHEA1 method,
the average of lags 0 and 1 days were chosen a priori to avoid potential bias with the "best" lag
approach. In addition, to estimate multiday effects, a cubic polynomial distributed lag with lags
up to 5 days before deaths was used. The figure for the total mortality risk estimates in the fitted
distributed lag model is shown in Figure 3.3-2, which suggests multiday effects. The strongest
association shown at lag 1 day is also consistent with the results from NMMAPS and Canadian
multicity studies. The estimated increase in total deaths was 1.7% (95% CI: 1.3, 2.2) per 30-ppb
August 2007
3-85
DRAFT-DO NOT QUOTE OR CITE
-------
0.3-
0
LO
CO
0
o
c
0.2-
0.1-
0.0-
-0.1
0
Day lag
Figure 3.3-2. Shape of the association of total mortality with NO2 over 6 days (lags 0
through 5) summarized over all cities using a cubic polynomial
distributed lag model. The percent increase is for 10-jig/m3 increase in
the 1-h maxima of NO2.
Source: Samoli et al. (2006).
1 increase in 1-h max N02. The risk estimates for cardiovascular and respiratory deaths were
2 2.3% (95% CI: 1.7, 3.0) and 2.2% (95% CI: 1.0, 3.4) per 30-ppb increase, respectively. The
3 estimates using the distributed lag models were higher than those for the average of 0- and 1-day
4 lags by 23%, 22%, and 45% for total, cardiovascular, and respiratory mortality, respectively.
5 However, such a pattern was not consistently clear on the city-to-city basis (in 17 out of
6 29 cities, this was the case). Samoli et al. presented the shape of the association of total and
7 respiratory mortality (they mentioned that the shape for the cardiovascular mortality was similar
8 to that for total mortality) using the cubic polynomial distributed lag model. In the two-pollutant
9 models with black smoke, PMi0, S02, and 03, the risk estimates for total and cardiovascular
10 mortality were not affected. The largest reduction in the NO2 risk estimate for total mortality
August 2007
3-86
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
was for the model with SO2, reducing the estimate to 1.5% (95% CI: 1.0, 2.0). For respiratory
mortality, only the risk estimate with SO2 was substantially reduced (by -50%). In a second-
stage analysis, the city-specific effect estimates were regressed on potential effect modifiers by
weighted regression, with weights inversely proportional to their city-specific variances. For
total and cardiovascular mortality, the geographical area (defined as western, southern, and
central eastern European cities) was the most important effect modifier (estimates were lower in
eastern cities), followed by the smoking prevalence (N02 risk estimates were higher in cities
with a lower prevalence of smoking). For cardiovascular mortality, the cities with higher natural
gas consumption had higher NO2 risk estimates. The authors concluded that the results showed
effects of NO2 on mortality, but that the role of NO2 as a surrogate of other unmeasured
pollutants could not be completely ruled out.
In summarizing the series of APHEA studies, the NO2 risk estimates were somewhat
sensitive to the inclusion of PM in the model in the APHEA1 (six cities), but not in the analysis
of a larger set in the APHEA2 (29 cities). The fact that PM risk estimates tend to be higher in
the cities with higher N02, and vice-versa, appears to suggest that the mortality risk estimates for
NO2 and PM share the same source type(s) in these European cities. An examination of the
concentration-response function in nine cities suggested no evidence of threshold. Multiday
lagged effects were suggested.
3.3.1.4 The Netherlands Study
While the Netherlands studies for the 1986 to 1994 data (Hoek et al. 2000 and 2001;
reanalysis in Hoek, 2003) are not multicity studies and the Netherlands data were also analyzed
as part of APHEA2 (Samoli et al., 2006), the results from the reanalysis (Hoek, 2003) are
discussed here, because the database comes from a large population (14.8 million for the entire
country) and a more extensive analysis was conducted than in the multicity studies. PM10, black
smoke, O3, NO2, SO2, CO, sulfate (SO42 ), and nitrate (NO3 ) were analyzed at lags 0, 1, and
2 days and the average of lags 0-6 days. PMi0, S042 , and N03 had less than 1/3 of the
available days for other pollutants. All the pollutants were associated with total mortality, and
for single-day models, lag 1 day showed strongest associations for all the pollutants. The N02
risk estimate in a single-pollutant model was 1.9% (95% CI: 1.2, 2.7) per 20-ppb increase in
1-day lag 24-h average NO2, and 1.5% (95% CI: 0.7, 2.4) per 20-ppb increase in the average of
August 2007
3-87
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
0-6 day 24-h average NO2. NO2 was most highly correlated with black smoke (r = 0.87), and the
simultaneous inclusion of NO2 and black smoke reduced both pollutants' risk estimates (NO2
risk estimate = 0.8% [95% CI: -0.5, 2.1] per 20-ppb increase in the average of 0-6 day NO2).
PM10 was less correlated with NO2 (r = 0.62), and the simultaneous inclusion of these pollutants
resulted in an increase in the NO2 risk estimate. Cause-specific analysis showed larger risk
estimates for COPD (6.1% [95% CI: 2.7, 9.7] per 20-ppb increase in the average of 0-6 day
daily average N02) and pneumonia (11.5% [95% CI: 6.7, 16.5]) deaths, but because essentially
all of the pollutants showed larger risk estimates for these subcategories, it is difficult to interpret
these estimates as effects of NO2 alone. Likewise, the analysis of more specific cardiovascular
mortality categories (Hoek et al., 2001; reanalysis in Hoek, 2003) showed larger NO2 risk
estimates than that for the overall cardiovascular mortality, but again, since the same pattern was
seen for other pollutants as well, it is difficult to interpret these cause-specific risk estimates as
due to NO2 alone.
3.3.1.5 Other European Multicity Studies
There are also other European multicity studies, conducted in eight Italian cities (Biggeri
et al., 2005), nine French cities (Le Tertre et al., 2002) and seven Spanish cities (Saez et al.,
2002). The studies by Le Tertre et al. (2002) and Saez et al. (2002) were conducted using GAM
methods with the default convergence setting.
Biggeri et al. (2005) analyzed eight Italian cities (Turin, Milan, Verona, Ravenna,
Bologna, Florence, Rome, and Palermo) from 1990 to 1999. Only single-pollutant models were
examined in this study. The NO2 risk estimates were 3.6% (95% CI: 2.3, 5.0), 5.1% (95% CI:
3.0, 7.3), and 5.6% (95% CI: 0.2, 11.2) per 20-ppb increase in the average of 0- and 1-day lag
24-h average NO2, for total, cardiovascular, and respiratory deaths, respectively. Since all the
pollutants showed positive associations with these mortality categories, and the correlation
among the pollutants were not presented, it is not clear how much of the observed associations
are shared or confounded. The mortality risk estimates were not heterogeneous across cities for
all the gaseous pollutants.
The French nine cities study examined black smoke, SO2, NO2, and O3 by generally
following the APHEA protocol but using GAM and the average of lags 0 and 1 day for
combined estimates. All four pollutants were positively associated with mortality outcomes,
August 2007
3-88
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
with a 50-|ig/m3 (26 ppb) increase in pollutants being associated with an increase of 2.7 to 3.8%
in total mortality. The study did not report description of correlation among the pollutants or
conduct multipollutant models; therefore, it is difficult to assess the potential extent of
confounding among these pollutants. The NO2 risk estimates were reported to be homogeneous
across cities.
The Spanish Multi-center Study on Air Pollution and Mortality (whose Spanish acronym
is EMECAM) published a study with a focus on PM indices (PM10, TSP, and black smoke) and
SO2 in 12 cities (Ballester et al., 2002) and a study that focused on O3 and NO2 in seven cities
(Saez et al., 2002). These studies followed the APHEA protocol but using the GAM approach.
The Ballester et al. study did not consider NO2, and, while the Saez et al. study did consider
S02 and CO in the multipollutant model, they did not consider PM indices. Thus, the extent of
correlation between NO2 and PM indices, or the extent of possible confounding between these
pollutants is not known. The Saez et al. (2002) study reported that NO2 was positively
associated with total and cardiovascular mortality in the model with all the gaseous pollutants
included simultaneously. The N02 risk estimates were reported to be heterogeneous across the
cities.
3.3.1.6 Australian Four Cities Study
Simpson et al. (2005b) analyzed data from four Australian cities (Brisbane, Melbourne,
Perth, and Sydney) using methods similar to the APHEA2 approach. They also examined
sensitivity of results to three statistical models: (1) GAM with a single nonparametric smoother
(to adjust for temporal trends) and parametric smoothers to adjust for other covariates and using
stringent convergence criteria as implemented in the statistical package, Splus; (2) GLM with
natural splines; and (3) GAM with a penalized spline algorithm in conjunction with multiple
smoothing parameter estimation by generalized cross-validation, which avoids the back-fitting
issues, as implemented in the statistical package, R. Associations between mortality and N02,
O3, and nephelometer readings were examined at single day lag 0, 1,2, and 3 days and using the
average of 0- and 1-day lags. Among the three pollutants, correlation was strongest between
NO2 and nephelometer readings, ranging from (r ~ up to 0.62 among the four cities). Of the
three pollutants, N02 showed the largest mortality risk estimates per inter-quartile-range. The
authors state that the results using the three statistical methods "yield similar results," although
the figure of the results for the three methods appear to show some 20% difference in risk
August 2007
3-89
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
estimates between the smallest (the GLM approach) and the largest (the GAM with R). The
authors presented numerical results from the GAM/Splus approach. The estimated risk for
30-ppb increase in 1-h maximum increase of the average of 0- and 1-day lag N02 was 3.4%
(95% CI: 1.1, 5.7), 4.3% (95% CI: 0.9, 7.8), and 11.4% (95% CI: 3.5, 19.9) for total,
cardiovascular, and respiratory deaths, respectively. The NO2 risk estimates were not sensitive
to the addition of nephelometer readings (3.1% [95% CI: 0.3, 5.9]) or O3 (3.67% [95% CI: 1.2,
6.2]) in the two-pollutant models for total mortality, but the nephelometer risk estimate was
greatly reduced in the model with NO2.
Multipollutant Modeling Results
The results from multipollutant models in the multicity studies (i.e., NMMAPS, Canadian
12 cities, APHEA2, and Australian 4 cities studies) suggest that NO2 mortality risk estimates
were generally not sensitive to the inclusion of copollutant(s) (mostly PM indices) in the models.
The Netherlands study (Hoek et al., 2003), with a large population database, showed a reduction
in NO2 mortality risk estimates when black smoke was included in the model. Examining this
issue in single-city studies is more difficult because of generally wider confidence intervals
owing to smaller sample size. Also, many of the available single-city studies that presented
multipollutant model results were those that used GAM analyses with default convergence
criteria. Furthermore, because a large majority of these single-city studies focused on PM (and
less frequently, O3), very few studies examined multipollutant models with NO2 and other
gaseous pollutants and the combinations of copollutants examined were not usually consistent
across studies. Thus, a systematic evaluation of the multipollutant results from single-city
studies is limited, and we only briefly summarize these results qualitatively, with focus on larger
cities below.
The single-city analyses that examined NO2 and PM indices together and did not find
major reductions (i.e., more than 50% reduction in excess risk estimates) in N02 risk estimates
include analyses of data from Cook County, IL, with PM10 (Moolgavkar, 2003; GAM analysis);
Los Angeles, CA, with PM2.5 (Moolgavkar, 2003; GAM analysis); Maricopa County, AZ, with
PM10 (Moolgavkar, 2000; GAM analysis); and, Vancouver, Canada, with PM10 (Vedal et al.,
2003). The single-city studies that analyzed N02 and PM indices together and did find major
reductions in NO2 risk estimates include analyses of data from Philadelphia, PA, with TSP
August 2007
3-90
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
(Kelsall et al., 1997; GAM analysis); Santa Clara County, CA, with PM2.5 and N03 (Fairley,
1999 with GAM; reanalysis, 2003); Mexico City with PM2.5 (Borja-Aburto et al., 1998); Sydney,
Australia, with bsp (Morgan et al., 1998). Thus, it is difficult to find a consistent pattern of
evidence of confounding with PM from these single-city results. It is also possible that the
constituents of PM (e.g., relative contribution of traffic-related pollution to PM mass) vary from
city to city and hence correlations of PM with NO2 vary, contributing to apparently inconsistent
results.
A fewer single-city studies examined multipollutant models with NO2 and other gaseous
pollutants. Those that examined NO2 and O3 simultaneously and did not find major reductions in
NO2 risk estimates include analyses of data from Los Angeles, CA (Kinney and Ozkaynak,
1991); Philadelphia, PA (Kelsall et al., 1997; GAM analysis); Philadelphia, PA (Lipfert et al.,
2000b); London, England (Bremner et al., 1999). The studies in which adding O3 did reduce
NO2 risk estimates include analyses of data from Barcelona, Spain (Saez et al., 2002, asthma
mortality); and Sydney, Australia (Morgan et al., 1998). In Toronto data (Burnett et al., 1998),
including both CO and N02 reduced the N02 risk estimate; however, in the Canadian 12-cities
study, the combined NO2 risk estimate was not sensitive to inclusions of CO. In the analyses of
data from Philadelphia, PA (Kelsall et al., 1997; GAM analysis); Vancouver, Canada (Vedal
et al., 2003); and London, England (Bremner et al., 1999), two-pollutant models with SO2 did
not reduce N02 risk estimates, whereas in the analyses of Seoul, Korea (Kwon et al., 2001) and
Hong Kong, China (Wong et al., 2001), adding SO2 in the model did reduce NO2 risk estimates.
Again, the results from these single-city studies are too limited to allow a consistent pattern to
emerge.
In summary, because of the lack of consistency in the way multipollutants were examined
(e.g., lags examined, combination of pollutants examined, model specification) and because of
the limited statistical power in individual cities, it is difficult to extract information that help
elucidate a pattern of confounding between NO2 and other pollutants from these single-city
studies. Therefore, the multipollutant results from multicity studies provide more useful
information on this issue. As noted before, the results from the multicity studies from the United
States, Canada, and Europe generally suggest that NO2 mortality risk estimates are not very
sensitive to the addition of copollutants. However, this does not resolve the issue of surrogacy
August 2007
3-91
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
and its interpretation is also complicated by the possible influence of varying extent of exposure
characterization error across multiple pollutants.
3.3.1.7 Meta-analyses of N02 Mortality Studies
Stieb et al. (2002) reviewed time-series mortality studies published between 1985 and
2000, and conducted meta-analysis to estimate combined effects for each of PMio, CO, NO2, O3,
and SO2. Since many of the studies reviewed in that analysis were affected by the GAM
convergence issue, Stieb et al. (2003) updated the estimates by separating the GAM versus non-
GAM studies and by single- versus multipollutant models. There were more GAM estimates
than non-GAM estimates for all the pollutants except SO2. For NO2, there were 11 estimates
from single-pollutant models and only 3 estimates from multipollutant models. The lags and
multiday averaging used in these estimates varied. The combined estimate for total mortality
was 0.8% (95% CI: 0.2, 1.5) per 20-ppb increase in the daily average N02 from the single-
pollutant models, and 0.4% (95% CI: -0.2, 1.1). Note that, although the estimate from the
multipollutant models was smaller than that from the single-pollutant models, the number of the
studies for the multipollutant models was small (three), also, the data extraction procedure of this
meta-analysis for the multipollutant models was to extract from each study the multipollutant
model that resulted in the greatest reduction in risk estimate compared with that observed in
single-pollutant models. It should also be noted that all the multicity studies whose combined
estimates have been discussed above were published after this meta-analysis.
3.3.1.8 Summary of Risk Estimates for Mortality from Short-Term N02 Exposure
Studies
Figure 3.3-3 shows combined estimates for total mortality per the standardized
increments (20 ppb for 24-h average or 30 ppb for daily 1-h maximum) from the multicity
studies and meta-analysis discussed above. The estimates from single-pollutant models range
from 0.5 (the NMMAPS study) to 3.6 (the Italian 8 cities study) percent. The heterogeneity of
estimates in these studies may be due to several factors including the differences in: (1) model
specification, (2) averaging/lag time, (3) NO2 levels, and (4) effect modifying factors.
Interestingly, the Canadian 12-city study showed combined risk estimates (average of 0-1 day or
single 1-day lag) about 4 times larger than that for the U.S. estimate, despite the fact that the
range of Canadian NO2 (10 to 26 ppb) was somewhat lower than that for the U.S. data (9 to
August 2007
3-92
DRAFT-DO NOT QUOTE OR CITE
-------
Percent excess mortality
0 2 4 6
U.S. 90 cities study (Dominici et al., 2003)
24-hr average, lag 1 day -
with PM10 and SO2 -
Canadian 12 cities study (Burnett et al., 2004)
24-hr average, average of lag 0-2 days -
with O3 -
24-hr average, lag 1 day (every-6th-day) -
with PM2.5 _
European 30 cities study (Samoli et al., 2006)
1-hr daily max.average of lag 0-1 days "
with SO2 -
Italian 8 cities study (Biggeri et al., 2005)
24-hr average,average of lag 0-1 days
The Netherlands study (Hoek. 2003)
24-hr average, lag 1 day -
average of lag 0-6 days -
with black smoke -
Australian 4 cities study (Simpson et al., 2005)
1-hr daily max,average of lag 0-1 days -
with fine particles by nephelometer -
Meta-analysis (Stieb et al., 2003)
24-hr average, lag and multi-day averages mixed
with co-pollutants that showed largest reduction
-e-
0 NO2 alone
O with ct>pallutant
Figure 3.3-3. Combined NO2 mortality risk estimates from multicity and meta-analysis
studies. Risk estimates are computed per 20-ppb increase for 24-h
average or 30-ppb increase for 1-h daily maximum NO2 concentrations.
For multipollutant models, results from the models that resulted in the
greatest reduction in NO2 risk estimates are shown.
1 39 ppb for the 10%-trirnmed data). In fact, the NMMAPS estimate is the smallest among the
2 multicities studies. Since a similar pattern (i.e., the NMMAPS estimate being the smallest
August 2007
3-93
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
among multicities study) was seen for PMio mortality risk estimates (U.S. Environmental
Protection Agency, 2004), it is possible that this may be due to the difference in model
specifications. The NMMAPS study used more smoothing terms (two terms for temperature
[same-day and average of lag 1 to 3] and two terms for dewpoint [same-day and average of lag
1 to 3]) and more degrees of freedom for the smoothing terms (up to 6) than other studies, which
usually include up to two smoothing terms for weather variables.
The multipollutant models in these studies generally did not alter N02 risk estimates,
except for the Netherlands study. The meta-analysis by Stieb et al. (2003) shows a smaller
combined risk estimate for the multipollutant models than that for single-pollutant models, but
since these are not from the same set of studies (11 studies for single-pollutant models and
3 studies for multipollutant models), it is not clear how much of the difference was due to the
addition of copollutants. Thus, the evidence of confounding, in the sense of instability of risk
estimates in multipollutant models, is not clear from these studies. The difference in risk
estimates due to lag/averaging time also was not clear from these studies.
In the Canadian study, the estimate for the 3-day average (2.0%) and that for 1-day lag
(2.4%, though this was based on every-6th-day data, to match with PM2.5 data) were similar in
magnitude. In the Netherlands study, the estimate for the 1-day lag (1.9%) and that for the
average of 0 to 6 days (1.5%) were not very different. In the Samoli et al. (2006) study, they
examined a polynomial distributed lag, and reported that the combined risk estimate for total
mortality was 23% larger (45% larger for respiratory mortality) than that for the average of
0- and 1-day lags. However, such a pattern was not consistently clear on the city-to-city basis.
Thus, while the risk estimates for multiday effects may be larger than the single-day or 1- to
2-day average risk estimates, the evidence so far indicates that the magnitude of such multiday
risk estimates are not much bigger than the 1-or 2-day average estimates. Among the 1-day risk
estimates, the association at 1-day lag was generally the strongest in these multicity studies.
In summary, the range of NO2 total mortality risk estimates is 0.5 to 3.6% per 20-ppb
increase in the 24-h average NO2 (or 30-ppb increase in the daily 1-h maximum). The risk
estimates are generally insensitive to the inclusion of copollutants. Multiday effects have been
suggested, but their magnitude, when expressed per the same increment, is not very different
from those for 1-or 2-day average exposure indices. A few studies examined association
August 2007
3-94
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
between cause-specific mortality and NO2. While NO2 risk estimates for some specific causes
were found to be larger than for all-cause mortality, such a pattern was not unique to NO2.
3.3.1.9 Cause-Specific Mortality from Short-Term Exposure to N02
Risk estimates for specific causes of death would be useful in evaluating consistency of
the association with causal inference. However, comparing relative size of risk estimates across
categories of different mean daily counts (e.g., all-cause versus respiratory) requires caution
when the "best lag" estimates are chosen from several lags. This is because the range of risk
estimates for the smaller daily mean counts are expected to be larger due to larger standard error
of estimates, and the "best lag" choice would result in a larger bias for the category with smaller
mean counts. Thus, it would be more appropriate to compare risk estimates across different
cause-specific categories using the same lag (unless there is a strong indication that lag structure
of associations would be different among the different causes).
Several multicity studies provided risk estimates for broad cause-specific categories
(typically all-cause, cardiovascular, and respiratory) using consistent lags/averaging for broad
specific causes. In the Canadian 12-city study (Burnett et al., 2004), the NO2 excess risk
estimates for all-cause, cardiopulmonary, and respiratory mortality were 2.0% (95% CI: 1.1,
2.9), 2.0% (95% CI: 0.5, 3.53), and 2.1% (95% CI: -0.2, 4.4) per 20-ppb increase in the
average of 0 to 2 day lags of 24-h average NO2, respectively, suggesting no difference in risk
estimates among these categories. In the Samoli et al. (2006) APHEA2 analysis of 30 European
cities, estimated increases in all-cause, cardiovascular, and respiratory deaths were 1.7%
(95% CI: 1.3, 2.2), 2.3% (95% CI: 0.7, 3.0), and 2.2% (95% CI: 1.0, 3.4) per 30-ppb increase
in the average of 0- and 1-day lag daily 1-h max NO2, respectively. In Biggeri et al. (2005)
analysis of eight Italian cities, the NO2 risk estimates for all-cause, cardiovascular, and
respiratory mortality were 3.6% (95% CI: 2.3, 5.0), 5.1% (95% CI: 3.0, 7.3), and 5.6% (95%
CI: 0.2, 11.2), respectively, per 20-ppb increase in the average of 0- and 1-day lags of 24-h
average NO2. In the Australian four-city study (Simpson et al., 2005b), the risk estimates for all-
cause, cardiovascular, and respiratory mortality were 3.4% (95% CI: 1.1, 5.7), 4.3% (95% CI:
0.9, 7.8), and 11.4% (95% CI: 3.5, 19.9), respectively, per 20-ppb increase in the average of
0- and 1-day lags of 24-h average N02. In the Netherlands study, the risk estimates for all-cause
(2.6%) [95% CI: 1.2, 4.0] per 20-ppb increase in the average of 0 through 6 day lags of daily
August 2007
3-95
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
24-h average NO2) and cardiovascular (2.7% [95% CI: 0.7, 4.7]) deaths were similar, but those
for COPD (10.4% [95% CI: 4.5, 16.7]) and pneumonia (19.9% [95% CI: 11.5, 29.0]) were
much larger. These results suggest that, with some exceptions, the risk estimates for
cardiovascular and respiratory causes are larger than that for all-cause mortality. However, it
should be noted that this pattern was not unique to NO2—other pollutants often showed similar
patterns. There are numerous single-city studies (see the annex table) that also examined broad
specific causes (cardiovascular and respiratory), but the patterns are not always consistent, likely
due to smaller sample size, or the lags reported were not consistent across the specific causes
examined.
Some of the single-city studies examined more specific causes within cardiovascular or
respiratory causes. In the Netherlands study (Hoek et al., 2001; reanalysis Hoek, 2003), the risk
estimates for heart failure (7.6% [95% CI: 1.4, 14.2] per the average of 0- through 6-day lags of
24-h average NO2) and cerebrovascular disease were larger than those for total cardiovascular
(2.7%) [95%> CI: 0.7, 4.7]) causes. However, such a pattern was seen for PM10, CO, and SO2 as
well. In the Goldberg et al. (2003) analysis of Montreal data, the risk estimates for the death
with underlying cause of CHF and those deaths classified as having CHF 1 year before death
(through the universal insurance plan) were compared. They did not find associations between
air pollution and those with underlying cause of CHF, but they found associations between some
of the air pollutants examined (i.e., CoH, SO2, NO2) and the deaths that were classified as having
CHF 1 year before death. Again, the association with the specific cause of death was not unique
to NO2. This pattern of association between multiple pollutants, including but not specific to
NO2, and specific causes of deaths were seen for asthma mortality (Saez et al., 1999), mortality
in a cohort with COPD (Garcia-Aymerich et al., 2000; Sunyer and Basagana, 2001), mortality in
a cohort with severe asthma (Sunyer et al., 2002), infant mortality (Loomis et al., 1999),
intrauterine mortality (Pereira et al., 1998), and mortality in a cohort of patients with CHF
(Kwon et al., 2001). While NO2 may have contributed to these associations as part of the
mixture of pollutants or as a surrogate index, these studies cannot be used to evaluate specificity
of N02 effects on these specific causes of death.
In summary, both broad specific (cardiovascular and respiratory) and more specific
causes/categories of death have been shown to be associated with NO2. However, since other
August 2007
3-96
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
pollutants also showed similar associations with these causes or categories, it is difficult to
discuss consistency with causal inference that is specific to NO2.
3.3.3 Summary of Effects of Short-Term Exposure to NOx on Mortality
Range of mortality risk estimates: In the short-term studies, the range of NO2 total
mortality risk estimates is 0.5 to 3.6% per 20-ppb increase in the 24-h average NO2 (or 30-ppb
increase in the daily 1-h maximum). Various lag/averaging days and distributed lags do not
appear to alter the estimates substantially.
Confounding: In the large multicity time-series studies, the NO2 risk estimates were
generally insensitive to the inclusion of copollutants in the models. In that sense, strong
evidence of confounding is not indicated in the short-term studies' results.
NO2 (or NOx) as a surrogate marker: The issue of NO2 being a surrogate marker of
another pollutant or for a pollution type is probably the most important one in interpreting NO2
risk estimates, but currently available information is not sufficient to establish quantitative
characterization of such surrogacy. N02 has been suggested to be a surrogate marker of traffic-
related air pollution, ultrafine particles, fine particles, and weather conditions. The fact that NO2
plays a critical role in the photochemical reactions that produce other potentially harmful
pollutants make it difficult to treat NO2 simply as a surrogate marker or confounder. More
characterization of the surrogate marker is needed from different geographic locations.
Increasingly available PM speciation data may help this effort.
Concentration-response function: One multicity time-series study (Samoli et al., 2006)
examined this issue. There was no indication of a threshold, and the concentration-response
curves were consistent with linear hypothesis.
Effect modification: Only few studies in the short-term effects studies examined possible
effect modifiers. The APHEA2 time-series analysis found that the most important effect
modifier was the geographical area (eastern cities had lower NO2 risk estimates than western or
southern cities). For respiratory mortality, cities with high median PMi0 showed higher risk
estimates. The Canadian 12 cities study reported that the risk estimate was higher in summer
than in winter. Older age groups also showed larger risk estimates.
Sensitivity of risk estimates to model specification: Most time-series studies examined
the sensitivity of risk estimates to alternative model specifications by changing the degrees of
August 2007
3-97
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
freedom for smoothing terms to adjust for temporal trends and weather effects, and the changes
in risk estimates were typically not substantial (i.e., <30%). However, these studies did not
apply qualitatively different alternative models (i.e., different number of smoothing terms) that
are found across studies. One study using the NMMAPS data did find that varying degrees of
freedom for temporal adjustment made a 2-fold change in the PM mortality risk estimate.
Similar attempts should be made to examine sensitivity of risk estimates to qualitatively different
weather model specifications.
3.3.4 Integration of Evidence Related to Mortality and Short-Term
Exposure to NO2
In evaluating the risk estimates for mortality, the main focus is on multicity studies and
meta-analyses. These studies of short-term mortality effects include the NMMAPS, Canadian
multi-cities studies, APHEA, Italian 8 cities study, the Netherlands study, the Australian 4 cities
study, and the Stieb et al. (2002, 2003) meta-analyses. The largest U.S. study of 90 cities
showed a MVmortality association with a total mortality risk estimate at lag 1 of 0.25% per
10 ppb or 0.50%) per 20 ppb. A Canadian 12-city study (Burnett et al., 2004) showed an N02
mortality risk estimate of 2.0% per 20-ppb increase in the 3-day moving average of NO2. These
acute mortality studies are described in detail in Annex Table AX6.7 and summarized in Figure
3.3-3. The range of NO2 total mortality risk estimates is 0.5 to 3.6%> per 20-ppb increase in the
24-h average of N02 (or 30-ppb increase in the daily 1-h maximum).
As stated above, controlled human exposure studies, by necessity, are limited to acute,
fully reversible functional and/or symptomatic responses in healthy or mildly asthmatic subjects.
Animal studies have not used mortality as an endpoint in acute exposure studies. However, a
number of animal studies (described in Section 2.3) have shown biochemical, lung host defense,
permeability, and inflammation effects with acute exposures that may provide limited biological
plausibility for mortality in susceptible individuals. A 5-ppm NO2 exposure for 24 h in rats
caused increases in blood and lung total GSH and a similar exposure resulted in impairment of
alveolar surface tension of surfactant phospholipids due to altered fatty acid content. A fairly
large body of literature describes the effects of NO2 on lung host defenses at low exposures.
However, most of these effects are seen only with subchronic or chronic exposure, and therefore,
do not correlate well with the short lag times evidenced in the epidemiological studies. Acute
exposures to <5ppm NO2 show increased BAL protein, increased epithelial cell proliferation,
August 2007
3-98
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
increased neutrophils, and decreased pulmonary eosinophils; however, these effects, similarly,
do not correlate well with the short lag times in mortality studies.
3.4 MORBIDITY ASSOCIATED WITH LONG-TERM N02 EXPOSURE
3.4.1 Respiratory Effects Associated with Long-Term N02 Exposure
3.4.1.1 Lung Function Growth
Epidemiologic Studies
Studies of lung function demonstrate some of the strongest effects of chronic exposure to
NO2. Six studies are listed in Annex Table AX6.6-1, three from the United States and three from
Europe. Three of the studies involved lung function in children and three report lung function
studies in adults.
The Children's Health Study (CHS) in California is a longitudinal cohort study designed
to investigate the effect of chronic exposure to several air contaminates (including NO2) on
respiratory health in children. Twelve California communities were selected based on historical
data indicating different levels of specific pollutants. In each community, monitoring sites were
set up to measure NO2, O3, and PM10 hourly and average PM2.5 and acid vapor every 2 weeks.
Children were recruited though local schools in grades 4, 7, and 10. Questionnaires were
distributed though the schools and answered with parental help. Lung function was measured for
each child using portable equipment at the school. The study followed children for 10 years,
with annual questionnaires and lung function measurement.
In 2004, Gauderman reported results for 8-year follow up of the children enrolled in
grade 4 (n = 1759). Exposure to N02 was significantly associated with deficits in lung growth
over the 8-year period. The difference in FVC for children exposed to the lowest versus the
highest levels of N02 (34.6 ppb) was-95.0 mL. (95% CI: -189.4 to-0.6). ForFEVithe
difference was 101.4 mL (95% CI: -165.5 to -38.4) and for MMEF the difference was
-221.0 mL/s (95% CI: -377.6, -44.4). Results were similar for boys and girls and among
children who did not have a history of asthma. These deficits in growth of lung function resulted
in clinically significant differences in FEVi at age 18. The study had the following important
characteristics: it was prospective; exposure and outcome data were collected in a consistent
August 2007
3-99
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
manner over the duration of the study; and confounding by SES was controlled in the models and
by selecting communities similar in demographic characteristics at the outset. In addition, the
N02 concentration associated with deficits in lung growth was 34.6 ppb (39.0 ppb highest mean
-4.4 ppb lowest mean), a level below the current standard. Similar results were reported for acid
vapor (resulting primarily from photochemical conversions of NOx to HNO3), with a difference
in FVC of 105.2 mL (95% CI: -105.2, -15.9); FEVi 105.8 (95% CI: -168.8, -42.7); and
MMEF -165.0 (95% CI: -344.8, -14.7). These results are depicted in Figure 3.4-1. The
authors concluded that the effects of NO2 could not be distinguished from the effects of particles
(PM2.5 and PM10). NO2 was strongly correlated with these other contaminants (0.79, and 0.67,
respectively). For example, exposure to the highest versus the lowest PM2.5 concentrations was
associated with a difference in FEVi of -79.7 mL (95% CI: -153.0, -6.4). The effects on
growth in lung function in this study cannot be attributed to O3. O3 was not correlated with NO2
(-0.11), and no significant effects of O3 were detected (difference in FEVi -22.8 (95% CI:
-122.3, 76.6).
Gauderman et al. (2007) has reported results of an 8-year follow-up on 3,677 children
who participated in the CHS in California. Briefly, this study recruited schoolchildren in
12 California communities with differing levels of air pollution. Each child had lung function
measurements taken at school each year for 8 years. Children living <500 m from a freeway
(n = 440) had significant deficits in lung growth over the 8-year follow-up compared to children
who lived at least 1500 m from a freeway. The difference in FVC was -63 mL (-131 to 5); the
difference in FEVi ~81 mL (-143 to -18); and the difference in MMEF -127 mL/s (-243 to
-11). This study did not attempt to measure specific pollutants near freeways or to estimate
exposure to specific pollutants for study subjects. Thus, while the study presents important
findings with respect to traffic pollution and respiratory health in children, it does not provide
evidence that N02 is responsible for these deficits in lung growth.
Avol et al. (2001) studied the effect of relocating to areas of differing air pollution levels
in 110 10-year-old children who were participating in the CHS. As a group, subjects who had
moved to areas of lower PM10 showed increased growth in lung function and the same
relationship was observed for NO2. In general, the authors focused on associations with PM,
where larger and significant effects were observed; associations were reported with N02, but
they did not reach statistical significance.
August 2007
3-100
DRAFT-DO NOT QUOTE OR CITE
-------
CD
10 r
ro
> 8
"O
<1)
I 6
'°.
Hi 25
- ~LB
R = 0.04
P = 0.89
~ UP
SD
~ ML
~ RV
~ AT
~SM ~ LM
~ AL
~LE
LN
-r-
35
—
45
—i—
55
¦LA
-1—
65
03 from 10 a.m. to 6 p.m. (ppb)
75
R = 0.66
P = 0.02
PM10 (lJg/m3)
R = 0.75
P = 0.005
LA
LU
li.
~ UP
R = 0 69
P = 0.01
RV ~
LM SM ~
~ ~
R = 0.74
P = 0.006
_ ~LM
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
Acid Vapor (ppb)
Elemental Carbon (pg/m3)
Figure 3.4-1. Proportion of 18-year olds with a FEVi below 80% of the predicted value
plotted against the average levels of pollutants from 1994 through 2000 in
the 12 southern California communities of the Children's Health Study.
AL = Alpine: AT = Atascadero; LA = Lake Arrowhead: LB = Long Beach; LE = Lake Elsinore: LM = Lompoc;
LN = Lancaster; ML = Mira Loma; RV = Riverside; SD = San Dimas; SM = Santa Maria: UP = Upland
Source: Derived from Gauderman et al. (2004).
August 2007
3-101
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Overall, the studies discussed above are substantiated by cross sectional studies that
examined effects of exposure to NO2 on lung function. Peters (1999) reported the initial results
from the CHS. This was a cross-sectional analysis of lung function tests conducted on
3,293 children in the first year of the study. Both NO2 and PM10 were associated with decreases
in FVC, FEVi, and MMEF. O3 was associated with decreases in MMEF and PEFR. For all
pollutants, the decreases were only significant for girls.
In the United States, a study was conducted of students attending the University of
California (Berkeley) who had been lifelong residents of the Los Angeles or San Francisco areas
(Tager, 2005). Using geocoded address histories, a lifetime exposure to air pollution was
constructed for each student. Increasing lifetime exposure to NO2 was associated with decreased
FEF75 and FEF25-75. Controlling for 03 in the models, however, substantially reduced the effect
of N02.
In Germany, Moseler (1994) measured NO2 outside the homes of 467 children, including
106 who had physician-diagnosed asthma. Five of six lung function parameters were reduced
among asthmatic children exposed to N02 at concentrations >21 ppb. No significant reductions
in lung function were detected among children without asthma.
The SAPALDIA (Study of Air Pollution and Lung Diseases in Adults) study
(Ackermann-Liebrich, 1997) compared 9,651 adults (age 18 to 60) in eight different regions in
Switzerland. Significant associations of NO2, SO2, and PM10 with FEVi and FVC were found
with a 10-|ig/m3 increase in annual average exposure. Due to the high correlations between N02
and the other pollutants (SO2 = 0.86, PM10 = 0.91), it was difficult to assess the effect of a
specific pollutant. A random subsample of 560 adults from SAPALDIA recorded personal
measurements of NO2 and measurements of NO2 outside their homes (Schindler, 1998). Using
the personal and home measurements of N02, similar associations were reported between N02
with FEVi and FVC.
Goss et al. (2004) examined the relationship of ambient pollutants on individuals with
cystic fibrosis using the Cystic Fibrosis Foundation National Patient Registry in 1999 and 2000.
Exposure was assessed by linking air pollution values from the Aerometric Information Retrieval
System with the patient's home zip code. Associations were reported between PM and
exacerbations or lung function changes, but no clear associations were found for NO2, SO2, O3,
August 2007
3-102
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
and CO. The odds of patients with cystic fibrosis having two or more pulmonary exacerbations
during 2000 per 10 ppb N02 is 0.98 (95% CI: 0.91, 1.01).
Toxicology Studies
A limited number of animal studies, especially those using spikes of N02, have shown
decrements in vital capacity and lung distensibility, which may provide biological plausibility for
these lung function findings. NO2 concentrations in many urban areas of the United States and
elsewhere consist of spikes superimposed on a relatively constant background level. Miller et al.
(1987) evaluated this urban pattern of N02 exposure in mice using continuous 7 days/week,
23 h/day exposures to 0.2-ppm NO2 with twice daily (5 days/week) 1-h spike exposures to
0.8-ppm NO2 for 32 and 52 weeks. Mice exposed to clean air and to the constant background
concentration of 0.2-ppm NO2 served as controls. Vital capacity tended to be lower (p = 0.054)
in mice exposed to N02 with diurnal spikes than in mice exposed to air. Lung distensibility,
measured as respiratory system compliance, also tended to be lower in mice exposed to diurnal
spikes of NO2 compared with constant NO2 exposure or air exposure. These changes suggest
that <52 weeks of low-level NO2 exposure with diurnal spikes may produce a subtle decrease in
lung distensibility, although part of this loss in compliance may be a reflection of the reduced
vital capacity. Vital capacity appeared to remain suppressed for at least 30 days after exposure.
Lung morphology in these mice was evaluated only by light microscopy (a relatively insensitive
method) and showed no exposure-related lesions. The decrease in lung distensibility suggested
by this study is consistent with the thickening of collagen fibrils in monkeys (Bils, 1976) and the
increase in lung collagen synthesis rates of rats (Last et al., 1983) after exposure to higher levels
of N02.
Tepper et al. (1993) exposed rats to 0.5-ppm NO2, 22 h/day, 7 days/week, with a 2-h
spike of 1.5-ppm N02, 5 days/week for up to 78 weeks. No effects on pulmonary function were
observed between 1 and 52 weeks of exposure. However, after 78 weeks of exposure, flow at
25% forced vital capacity was decreased, perhaps indicating airways obstruction. A significant
decrease in the frequency of breathing was also observed at 78 weeks that was paralleled by a
trend toward increased expiratory resistance and expiratory time. Taken together, these results
suggest that few, if any, significant effects were seen that suggest incipient lung degeneration.
August 2007
3-103
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
The age sensitivity to exposure to diurnal spikes of NO2 was studied by Stevens et al.
(1988), who exposed 1-day- and 7-week-old rats to continuous baselines of 0.5-, 1.0-, and
2.0-ppm N02 with twice daily 1-h spikes at three times these baseline concentrations for 1, 3, or
7 weeks. In neonatal rats, vital capacity and respiratory system compliance increased following
3 weeks, but not 6 weeks, of exposure to the 1.0- and 2.0-ppm NO2 baselines with spikes. In
young adult rats, respiratory system compliance decreased following 6 weeks of exposure, and
body weight decreased following 3 and 6 weeks of exposure to the 2-ppm baseline with spike.
In the young adult rats, pulmonary function changes returned to normal values 3 weeks after
exposure ceased. A correlated morphometric study (Chang et al., 1986) is summarized in
Section 3.4.1.2 below.
Lafuma et al. (1987) exposed 12-week-old hamsters with and without laboratory-induced
(elastase) emphysema to 2.0-ppm NO2, 8 h/day, 5 days/week for 8 weeks. Vital capacity and
pulmonary compliance were not affected by NO2 exposure.
There were no effects on pulmonary function (lung resistance, dynamic compliance) in
N02-exposed rabbits that were immunized intraperitoneally within 24-h of birth until 3 months
of age to either Alternaria tenuis or house dust mite antigen. The rabbits were given
intraperitoneal injections once weekly for 1 month, and then every 2 weeks thereafter and
exposed to 4-ppm NO2 for 2-h daily (Douglas et al., 1994).
3.4.1.2 Morphological Effects
Animal toxicology studies demonstrate morphological changes to the respiratory tract
from exposure to N02 that may provide further biological plausibility for the decrements in lung
function growth observed in epidemiological studies discussed above. The centriacinar region is
most sensitive to NO2 and is where injury is first noted. This region includes the terminal
conducting airways (terminal bronchioles), respiratory bronchioles, and adjacent alveolar ducts
and alveoli. The upper respiratory tract (i.e., nasal cavity) does not appear to be much affected
by NO2 exposure. Within the centriacinar region, cell injury occurs in the ciliated cells of the
bronchiolar epithelium and the type 1 cells of the alveolar epithelium, which are then replaced
with nonciliated bronchiolar (Clara) cells and type II cells, respectively. Permanent alterations
resembling emphysema-like disease may result from chronic exposure.
There is a large degree of interspecies variability in responsiveness to NO2; this is clearly
evident from those few early studies where different species were exposed under identical
August 2007
3-104
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
conditions (Wagner et al., 1965; Furiosi et al., 1973; Azoulay-Dupuis et al., 1983). This
variability may be due to dosimetric differences in effective dose of NO2 reaching target sites,
but other species differences may play a role. Guinea pigs, hamsters, and monkeys all appear to
be more severely affected morphologically by equivalent exposure to NO2 than are rats, the most
commonly used experimental animal. However, in most cases, similar types of histological
lesions are produced when similar effective concentrations are used.
Time Course
Several investigators have studied the temporal progression of early events due to N02
exposure in the rat (e.g., Freeman et al., 1966, 1968, 1972; Stephens et al., 1971, 1972; Evans
etal., 1972, 1973a,b, 1974, 1975, 1976, 1977; Cabral-Anderson etal., 1977; Rombout et al.,
1986) and guinea-pig (Sherwin et al., 1973). These studies observed increased AM aggregation,
desquamation of type I cells and ciliated bronchiolar cells, and accumulation of fibrin in small
airways as the earliest alterations resulting from exposure to NO2. These alterations were seen
within 24 to 72-h of exposure to N02 concentrations of >2.0 ppm. However, repair of injured
tissue and replacement of destroyed cells begins within 24 to 48-h of continuous exposure. The
new cells in the bronchiolar are derived from nonciliated bronchiolar (Clara) cells, whereas in
the alveoli, the damaged type I cells are replaced with type II cells. One feature of the new cells
is that they are relatively resistant to effects of continued NO2 exposure.
The time course of alveolar lesions was also investigated by Kubota et al. (1987) in rats
continuously exposed to 0.04- to 4.0-ppm N02, 24 h/day for up to 27 months. One phase, which
lasted for 9 to 18 months of exposure, consisted of a decrease in number and an increase in cell
volume of type 1 epithelium, an increase in the number and volume of type II cells, and an
increase in the relative ratio of type II to type I cells. A second phase, between 18 to 27 months
of exposure, showed some recovery of the alveolar epithelium, but the total volume of interstitial
tissue decreased, while collagen fibers in the interstitium increased. These findings indicate that
some lesions, i.e., epithelial changes, tend to resolve, at least partially, with continued chronic
exposure to low concentrations and to resolve rapidly during postexposure periods. At 0.4 ppm,
the authors reported that the lesion typically was milder and its initiation delayed, compared to
the higher concentration. At 0.4 and 4.0 ppm, morphometric increases in the mean alveolar
thickness of the air-blood tissue barrier in the rats were also observed. According to the authors,
August 2007
3-105
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
these interstitial changes were considered to be progressive and leading to fibrosis, rather than
resolving as do epithelial changes.
In a more recent study, Barth et al., (1994a) evaluated cell proliferation at three different
levels (bronchial, bronchiolar epithelium, and type II cells) in the lungs of rats exposed to 0, 0.8-,
5-, or 10-ppm NO2, 24 h/day for 1 or 3 days. The highest rate of cell proliferation occurred in
the bronchiolar epithelium. Cell proliferation was increased in type II cells after exposure to
5-ppm N02 for 3 days and 10-ppm N02 for 1 or 3 days. In the bronchiolar epithelium, cell
proliferation was increased at 0.8 ppm and above for both 1 and 3 days. Increased cell
proliferation (AgNOR-number only) in the bronchial epithelium was observed in animals
exposed to 10 ppm for 3 days.
Rats were also exposed continuously to N02 at 0, 5, 10, or 20 ppm continuously for 3 or
25 days (Barth et al., 1994b, 1995; Barth and Muller, 1999). The highest proliferative activity
was in the respiratory bronchiolar epithelium (Barth et al., 1994b; Barth and Muller, 1999).
After 3 days of exposure, cell proliferation in the bronchiolar epithelium was increased 3-fold in
the 5-ppm exposure group and remained elevated at the same level in the next two higher-
concentration groups. The bronchial epithelium showed a different pattern, with a dose-
dependent increase in the 10- and 20-ppm exposure groups. After 25 days, cell proliferation
levels were increased in both the bronchiolar and bronchial epithelium in the 10- and 20-ppm
groups. The increase was dose-dependent and there was no significant difference in the levels
between the two tissues.
Pulmonary tissue damage, vascular alterations, Clara cell proliferation, and tissue-
specific localization of N02 effects were all found to be both exposure duration- and
concentration-dependent (Barth et al., 1995; Barth and Muller, 1999). After 3 days of exposure,
there were histopathological changes extending from slight interstitial edema after exposure to
5 ppm, to epithelial necrosis and interstitial inflammatory infiltration after exposure to 10 ppm,
and an additional intra-alveolar edema after 20 ppm. Clara cells from the lungs of all
N02-exposed groups lost the apical intraluminal projections, and the damaged epithelium was
covered by a layer of CC10 reactive material. These changes in Clara cells were not observed
after 25 days of exposure. Exposure for 25 days to 10- and 20-ppm NO2 resulted in a dose-linear
increase of cell proliferation in the bronchial and bronchiolar epithelium. Double labeling of
August 2007
3-106
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CC10 and BrdU showed that cell proliferation was restricted to Clara cells, an indication of the
progenitor role of Clara cells in oxidative stress injury in the lung tissue.
Morphometry studies showed that alveolar circumference was increased and alveolar
surface density was decreased after an exposure to 20 ppm after 3 days and to 10 and 20 ppm
after 25 days (Barth et al., 1994b, 1995). No significant alveolar changes were observed in the
5-ppm exposure groups. The average medial thickness (AMT) of the pulmonary arteries was
decreased in the 5-ppm group at both 3 and 25 days; AMT was increased in the 10-ppm group
after 25 days and in the 37,600-|ig/m3 (20 ppm) group after 3 and 25 days (Barth et al., 1994b,
1995). The AMT and alveolar density were negatively correlated (coefficient of correlation:
-0.56), suggesting that pulmonary tissue damage and vascular alterations are closely related
(Barth et al., 1995). These high exposure studies undoubtedly initiate mechanisms of injury that
do not occur at more relevant near-ambient exposures, so little insight can be gained with these
histopathology and morphometry studies in animals regarding these epidemiological findings.
Effects of NO2 as a Function of Exposure Pattern
Few morphological studies have been designed to evaluate modifying factors to NO2
exposures, such as the exposure duration and concentration relationship, short-term peaks in
concentration, or cycles of exposure and postexposure.
The relative roles of concentration and time in response to subchronic exposure have
been investigated by Rombout et al. (1986). Rats were exposed from 0.53 to 10.6 ppm for up to
28 days; or to 10.2 ppm for either a single 6-h exposure, 6 h/day for 28 days, or 24 h/day for
28 days. Exposure concentration played a more important role in inducing lung epithelial cell
lesions than did exposure duration provided C x T was constant. The effect of concentration was
stronger with intermittent exposure than with continuous exposure.
Few studies have examined ambient N02 patterns consisting of a low baseline level with
transient spikes of NO2, as exists in the environment. However, in some cases, there was no
group at the baseline exposure, preventing evaluation of the contribution of peaks to the
responses. Gregory et al. (1983) exposed rats (14 to 16 weeks old) for 7 h/day, 5 days/week for
up to 15 weeks to N02 at 1.0 or 5.0 or 1.0 ppm with two 1.5-h spikes of 5.0 ppm per day. After
15 weeks of exposure, histopathologic changes were minimal, with focal hyperinflation and
August 2007
3-107
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
areas of subpleural accumulation of macrophages found in some of the animals exposed either to
the baseline of 5.0 ppm or to 1.0 ppm with the 5.0-ppm spikes.
Port et al. (1977) observed dilated respiratory bronchioles and alveolar ducts in mice
exposed to 0.1-ppm NO2 with daily 2-h peaks to 1.0 ppm for 6 months. Miller et al. (1987)
found no morphological effects in mice exposed for 1 year, although host defense functional
changes were noted (see Section 4.3.2).
Changes in the proximal alveolar and terminal bronchiolar regions in response to
exposure to baseline NO2 concentration plus NO2 spikes were also investigated in the rat. Crapo
et al. (1984) and Chang et al. (1986) exposed rats for 6 weeks to a baseline concentration of
0.5- or 2.0-ppm NO2, 23 h/day for 7 days/week, onto which were superimposed two daily 30-
min spikes of three times the baseline concentration for 5 days/week. Morphometric analyses
showed increases in the volumes of the type 2 epithelium, surface area of type II cells, interstitial
matrix, and AMs; no changes were seen in the volume of fibroblasts at the lower concentration.
Most of the changes were also noted at the higher exposure level, and in some cases, the change
was greater than that at the lower level (i.e., increase in type 1 and type 2 epithelial volume). At
both levels of exposure, the increase in the volume of type II cells and interstitial fibroblasts
were not accompanied by significant changes in their numbers, but the number of AMs
decreased. At the highest exposure, the number of type I cells decreased and their average
surface area increased. Generally, there was a spreading and hypertrophy of type II cells. A
correlation between decreased compliance (Stevens et al., 1988) and thickening of the alveolar
interstitium was found (see Section 3.3.1.1 for details of the pulmonary function portion of the
study). Examination of the terminal bronchiolar region revealed no effects at the lower exposure
level. At the higher level, there was a 19% decrease in ciliated cells per unit area of the
epithelial basement membrane and a reduction in the mean ciliated surface area. The size of the
dome protrusions of nonciliated bronchiolar (Clara) cells was decreased, giving the bronchial
epithelium a flattened appearance, but there was no change in the number of cells.
Factors Affecting Susceptibility to Morphological Changes
Susceptibility to morphological effects may be influenced by many factors, such as age,
compromised lung function, and acute infections. Age of the animal at the time of exposure may
be responsible for some of the variability in morphological response seen in the same species
exposed to comparable concentrations.
August 2007
3-108
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
It appears that neonates, prior to weaning, are relatively resistant to NO2, and that
responsiveness then increases (Stevens et al., 1978). Furthermore, the responsiveness of mature
animals appears to decline somewhat with age, until an increase in responsiveness occurs at
some point in senescence. However, the morphological response to NO2 in animals of different
ages involves similarities in the cell types affected and in the nature of the damage incurred.
Age-related differences occur in the extent of damage and in the time required for repair, the
latter taking longer in older animals. The reasons for age differences in susceptibility are not
known but may involve toxicokinetic and toxicodynamic differences during different growth
phases.
Kyono and Kawai (1982) exposed rats at 1, 3, 12, and 21 months of age continuously for
1 month to 0.11-, 0.46-, 2.8-, or 8.8-ppm N02. Light and electron microscopic analyses were
used, and various morphometric parameters were assessed, including arithmetic mean thickness
of the air-blood barrier and the volume density of various alveolar wall components. Because
these investigators were interested in the effect of the overall gas-exchange area, they
deliberately excluded the centriacinar alveolar region, site of main damage. Analysis of
individual results was complex, but depending upon the animal's age and the specified endpoint,
exposure levels as low as 0.11 ppm changed specific morphometric parameters. There was a
trend towards a concentration-dependent increase in air-blood barrier thickness in all age groups,
with evidence of age-related differences in response. At any concentration, the response of this
endpoint decreased in rats from 1 to 12 months old, but increased again in 21-month-old animals.
Type I and II cells showed various degrees of response, depending on both age at onset of
exposure and exposure concentration. The response of each lung component did not always
show a simple concentration-dependent increase or decrease, but suggested a multiphasic
reaction pattern.
Kyono and Kawai (1982) may not have used the most susceptible animal model.
Azoulay-Dupuis et al. (1983) investigated the species and age-related susceptibility to
morphological changes by exposing both rats and guinea pigs aged 5 to >60 days old to 2.0 and
10 ppm for 3 days. There was no mortality in the rats; however, mortality increased with
increasing age in guinea pigs exposed to 10 ppm. In both species, older animals showed greater
effects of exposure than did neonates. Rats at all ages and guinea pigs less than 45 days old were
not affected. The 45-day-old guinea pigs showed thickening of alveolar walls, alveolar edema,
August 2007
3-109
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
and inflammation; animals older than 45 days showed similar, but more frequent, alterations that
seemed to increase with age. Adults also had focal loss of cilia in bronchioli.
Age-related responsiveness to an urban pattern of N02 was evaluated by Chang et al.
(1986, 1988) using 1-day- or 6-week-old rats exposed for 6 weeks to a baseline of 0.5-ppm NO2
for 23 h/day, 7 days/week, with two 1-h spikes (given in the morning and afternoon) of 1.5 ppm
5 days/week. Electron microscopic morphometric analysis of the proximal alveolar regions
showed an increase in the surface density of the alveolar basement membrane in the older
animals that was not seen in the younger animals. Although both age groups responded in a
generally similar manner, the 6-week-old rats seemed to be generally more susceptible to injury
than were the 1-day-olds, as the 6-week old animals had more variables that were significantly
different from their control group. There was no qualitative evidence of morphological injury in
the terminal bronchioles of the younger rats, but there was a 19% increase in the average ciliated
cell surface that was not evident in the older rats. In addition, there was a 13% increase in the
mean luminal surface area of Clara cells in the younger versus control animals of the same age.
Pulmonary function was also altered in similarly exposed rats (Stevens et al., 1988) (see Section
3.3.1.1). Interpretation of the neonatal effects is difficult. Assuming that rats prior to weaning
are more resistant to NO2 (Stevens et al., 1978) (see below), effects observed after a 6-week
exposure from birth may have resulted from the last 3 weeks of exposure, as the first 3 weeks
may constitute a more resistant period. In contrast, effects observed in young adults probably
reflect the impact of the entire 6-week exposure. These findings may parallel the effects
observed in the CHS studies reviewed above, identifying school-age children as vulnerable to the
effects of NO2.
Few studies have been conducted on effects in individuals with preexisting respiratory
disease with exposure to environmental levels of N02. These studies include animals with
laboratory-induced emphysema or infections. Morphometric analyses of lungs from normal and
elastase-induced emphysematous hamsters (2 months old) that had been exposed to 2.0-ppm
NO2 for 8 h/day, 5 days/week, for 8 weeks, indicated that emphysematous lesions were
exacerbated by N02 (i.e., N02 increased pulmonary volume and decreased internal alveolar
surface area) (Lafuma et al. (1987). The investigators suggested that these results may imply a
role for N02 in enhancing pre-existing emphysema. A study by Fenters et al. (1973) also
reported that acute infectious (influenza) lung disease enhanced the morphological effects of
August 2007
3-110
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
NO2 in squirrel monkeys when these animals were exposed continuously to 1.0-ppm NO2 for 16
months.
3.4.1.3 Asthma Prevalence and Incidence—Children
Among the studies reporting results from the United States in regard to asthma
prevalence incidence associated with NO2 exposure, several publications from the CHS in
California report results. Gauderman et al., 2005 conducted a study of children randomly
selected from the CHS with exposure measured at children's homes. Although only 208 were
enrolled, exposure to N02 was strongly associated with both lifetime history of asthma, and
asthma medications use. Gauderman et al. (2005) measured ambient NO2 with Palmes tubes
attached at the subjects' homes at the roofline eaves, signposts, or rain gutters at an approximate
height of 2 m above the ground. Samples were deployed for 2-week periods in both summer and
fall. Traffic-related pollutants were characterized by 3 metrics: (1) proximity of home to
freeway, (2) average number of vehicles within 150 meters, and (3) model-based estimates.
Yearly average NO2 levels within the 10 communities ranged from 12.9 to 51.5 ppb. The
average NO2 concentration measured at home was associated with asthma prevalence (OR =8.33
[95% CI: 1.15, 59.87] per 20 ppb) with similar results by season and when taking into account
several potential confounders. Tables 3.4-1 and 3.4-2 show associations with several indicators
of traffic-related air pollution and asthma. In each community measured, NO2 was more strongly
correlated with estimates of freeway-related pollution than with non-freeway-related pollution.
In a related CHS study, McConnell et al. (2006) studied the relationship of proximity to major
roads and asthma and found a positive relationship.
Further evaluation of exposure estimation was done in this cohort of schoolchildren
(Molitor et al., 2007). Several models of interurban air pollution exposure were used to classify
and predict FVC in an integrated Bayesian modeling framework, using three interurban
predictors: distance to a freeway; traffic density; and predicted average N02 exposure from the
California line source dispersion (CALINE4) model. Results suggested that the inclusion of
residual spatial terms can reduce uncertainty in the prediction of exposures and associated health
effects (Molitor et al., 2007).
Islam et al. (2007) studied whether lung function is associated with new onset asthma and
whether this relationship varies by exposure to ambient air pollutants by examining a cohort of
2,057 fourth-grade children who were asthma- and wheeze-free at the start of the CHS and
August 2007
3-111
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
followed them for 8 years. A hierarchal model was used to evaluate the effect of individual air
pollutants (NO2, PM10, PM2.5, and acid vapor, O3, EC, and OC) on the association of lung
function with asthma as shown in Figure 3.4-2. The loss of the protective effect from better lung
function can be appreciated from these graphs. PM indicators were significantly related, and
NO2 was marginally significant (p = 0.06). This study shows that better airflow, characterized
by higher FEF25-75 and FEVi during childhood was associated with decreased risk of new onset
asthma during adolescence. However, exposure to high levels of ambient pollutants (N02 and
others) attenuated this protective association of lung function on asthma occurrence.
Brauer et al. (2007) assessed the development of asthmatic/allergic symptoms and respiratory
infections during the first 4 years of life in a birth cohort study (n = 4.000, but the number of
participants decreased over the study to -3500) in the Netherlands. The mean N02 concentration
was 13.1 ppb. Air pollution concentrations at the home address at birth were calculated by a
model combining air pollution measurements with a Geographic Information System (GIS).
This exposure model was validated. The association between exposure and health outcomes was
analyzed by multiple logistic regression in the adjustment for confounding variables. The
interquartile range in increase in NO2 was 10.6 |ig/m3.
Wheeze, doctor-diagnosed asthma, and flu and serious colds were associated with air
pollutants (considered traffic-related: NO2, PM2.5, soot); for example, NO2 was associated with
doctor-diagnosed asthma (OR = 1.28 [95% CI: 1.04, 1.56) for a cumulative lifetime indicator.
Jerrett (2007) comments on this study that (1) the effects are larger and more consistent than in
participants of the same study at age 2; (2) these effects suggest that onset and persistence of
respiratory disease formation begins at an early age and continues; and (3) the more sophisticated
method for exposure assessment used based on spatially and temporally representative field
measurements and land use regression is capable of capturing small area variations in traffic
pollutants. Importantly, this study is one of the few assessing disease incidence in the same
manner as the CHS discussed above.
Kim et al. (2004a) reported positive associations for girls to both NO2 and NOx in the San
Francisco bay area. They studied 1,109 students (grades 3 to 5) at 10 school sites for bronchitis
symptoms and asthma in relation to ambient pollutant levels to include NO, NO2, and NOx
measured at the school site. Mean levels ranged for schools from 33 to 69 ppb for NOx; 19 to 31
August 2007
3-112
DRAFT-DO NOT QUOTE OR CITE
-------
1.80-
1.50
1.20
!§ 0.50'
0.60'
0.30
0.00
I
1.80-
1.50"
1.20"
§= 0.50-
0.60"
0.30"
0.00"
1.80-
1.50-
1.20"
* 0.50-
R2 = 0.42
P = 0.01
~ LM AT
BM* —
W*AL
LG LN
10
R2 = 0.24
P = 0.06
~ LE
~ SD
~ LB
~ UP
~ RV
1.80-
1.50"
1.20"
* 0.50-
0.60-
0.30"
15 20
PM25(mgm/m3)
25
-i
30
0.00
R2 = 0.28
P = 0.04
4 LM AT
LG
VSM_
~ ~'~LN
~ UP
~ SD RV
*LE
~ LB
10
.ML
UP
~
~ AL .
~ LG ~LN
1.80"
1.50*
1.20"
^ 0.50"
0.60"
0.30"
20
R2 = 0.24
P = 0.06
30 40 50
PM10(mgm/m3)
60
70
UP
ML ~
~ SO
AL *LB
—i i 1 i i ; 1 1
0 5 10 15 20 25 30 35 40
N02(ppb)
R2 = 0.20
P = 0.08
0.00-
0
-1 1 i
4 6 8
Acid Vapor(ppb)
10
—i
12
~ UP
~ ML
~ SD
1.80-
1.50-
1.20"
0.501
0.60
0.301
R2 = 0.27
P = 0.05
~ UP
~ ML
1.80'
1.50
1.20'
§= 0.50'
0.60'
0.30
0.00
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Elemental Carbon(mgm/mi)
R2 = 0.08
P = 0.64
I.00-
~ SD
~LM A^4LEj:RV-
7al a ~lb
LG ~LN
0
—r-
10
4 6 8
Organic Carbon(mgm/ms)
—\—
12
14
—i—
35
—i—
45
—i—
55
-1
65
Ozone 10-6(ppb/m2)
Figure 3.4-2. Effect of individual pollutants on the association of lung function with
asthma.
Source: Islam et al. (2007).
August 2007
3-113
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
for NO2; and 11 to 38 ppb for NO. NOx and NO2 measurements at school sites away from traffic
were similar to levels measured at the regional site. They found associations between traffic-
related pollutants and asthma and bronchitis symptoms, which is consistent with previous reports
of traffic and respiratory outcomes. Some U.S. studies had previously shown inconsistent
results, possibly due to exposure misclassification as the studies used only a single fixed site.
The higher effect estimates with black carbon, NOx, and NO compared with NO2 and PM2.5
suggest that primary or fresh traffic emissions may play an etiologic role in these relationships
and that while NOx and NO may serve as indicators of traffic exposures, they may also act as
etiologic agents themselves.
Millstein et al. (2004) studied the effects of ambient air pollutants on asthma medication
use and wheezing among 2,034 fourth-grade schoolchildren from the CHS. Included in the
pollutants examined were NO2 and HNO3. They observed that monthly average pollutant levels
produced primarily by photochemistry (i.e., O3, HNO3, and acetic acid) were associated with
asthma medication use among children with asthma—especially among children who spent more
than the calculated median time outdoors. The March-August OR for HNO3 (IQR 1.64 ppb) was
1.62 (95% CI: 0.94, 2.80) and for N02 (IQR 5.74 ppb) was 0.96 (95% CI: 0.68, 1.37).
Other studies (see Annex Table AX6.2) have investigated asthma prevalence in children
associated with NO2 exposure. Although several of these studies have reported positive
associations, the large number of comparisons made and the limited number of positive results
do not suggest a strong relationship between chronic N02 exposure and asthma. Exposure in
these studies varied, but medians were often greater than 20 ppb. Most of the studies did not
report correlations of NO2 exposure with other air pollutants; therefore, it is not possible to
determine whether some of these associations were related to other air contaminants.
Annex Table AX6.6-2 lists several studies from Europe where the International Study of
Asthma and Allergies in Children (ISAAC) protocol was used. Children were interviewed in
school and results of the questionnaire were compared with air pollution measurements in their
communities. These studies included thousands of children in several European countries and
Taiwan, and all but one were negative. In Austria (Studnicka, 1997) the highest level of
exposure (14.7- to 17.0-ppb NO2) was associated with increased risk of asthma.
Two studies (Shima and Adachi, 2000; Kim et al., 2004a) reported positive associations
for girls, but negative associations for boys. It is difficult to interpret these studies since the level
August 2007
3-114
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
of exposure did not vary by gender. The children surveyed were 9 to 11 years old. In this age
range, asthma is more common among girls, perhaps due to hormonal influences, while asthma
is more common in boys at younger ages.
3.4.1.4 Respiratory Symptoms
Although a large number of studies have investigated effects of chronic exposure to NO2
on respiratory symptoms, the validity of these studies is uncertain. More appropriately,
symptoms should be compared to acute exposures. In some of these studies, a symptom (e.g.
wheeze) may be used as a surrogate for disease that is difficult to define or diagnose, (e.g.
asthma). This confusion between acute and chronic symptoms or acute and chronic exposure
may explain some of the inconsistency in results of these studies.
Annex Table AX6.6-3 lists nine studies, most of which report some positive associations
with N02 exposure and symptoms, but all report a large number of negative results. Only one of
these studies (Peters et al., 1999) reported an association of NO2 exposure with wheeze, and in
boys. This was despite the fact that wheeze was investigated in a large number of studies,
including several studies that included thousands of children.
McConnell et al. (2003) studied the relationship between bronchitis symptoms and
pollutants in the CHS. Symptoms assessed yearly by questionnaire from 1996 to 1999 were
associated with the yearly variability for the pollutants for NO2 (OR = 1.071 ppb [95% CI: 1.02,
1.13). In two-pollutant models, the effects of yearly variation in NO2 were only modestly
reduced by adjusting for other pollutants except for OC and NO2. (See Figure 3.4-3).
McConnell et al. (2006) evaluated whether the association of exposure to air pollution
with annual prevalence of chronic cough, phlegm production, or bronchitis was modified by dog
or cat ownership indicators or allergen and endotoxin exposure. Subjects consisted of
475 children from the CHS. Among children owning a dog, there was strong association
between bronchitis symptoms and all pollutants studied. Odds ratio for N02 were 1.49 (95% CI:
1.14, 1.95), indicating that dog ownership may worsen the relationship between air pollution and
respiratory symptoms in asthmatic children.
Cough and difficulty breathing were more commonly reported in association with NO2
exposure. Interestingly, both Garrett et al., 1999 and Hirsch et al., 1999 report positive
associations between NO2 exposure and symptoms when symptoms are less common. Garrett
August 2007
3-115
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.5 -1
n
1.4 -
Q.
Q.
1 3 -
*
0
1,2 -
(U
a:
1.1 -
V)
"O
u
1.U "
0
0.9 -
Risk of Bronchitic Symptoms as a Function
of Yearly Deviation in N02
L_L_L_LJ__LJ_J—j.
o*
&
—I—
O
&
o
Adjustment Air Pollutants
Figure 3.4-3. Odds ratios for within-community bronchitis symptoms associations with
N02, adjusted for other pollutants in two-pollutant models.
Source: McConnell et al. (2003).
indicates a positive associations only during the summer months and Hirsch reports a significant
association with cough, particularly cough among non-atopic children.
Three studies (Mukala et al., 1999; van Strien et al., 2004; Nitschke et al., 2006)
compared exposure to N02 measured by personal monitors, or monitors in the home, with
respiratory symptoms. Mukala et al. (1999) reported a significant association of the highest level
of weekly NO2 exposure and cough. Both cough and shortness of breath were reported by
van Strien et al. (2004) associated with measured home exposure to NO2 among infants. This
relationship appeared to be dose dependent. Nitschke et al. (2006) reported difficulty breathing
and chest tightness in asthmatic children that was associated with 10-ppb increases in NO2
measured in school classrooms. Further discussion of these studies was provided earlier in
Section 6.2.
Two studies of infants were conducted in Germany and the Netherlands using the same
exposure protocol (Gehring et al., 2002; Brauer et al., 2002). In Munich, 1,756 infants were
enrolled and followed for 2 years. Outcomes of interest were asthma, bronchitis, and respiratory
August 2007
3-116
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
symptoms including wheeze, cough, and nasal symptoms. To determine exposure, 40 measuring
sites were selected in Munich, including sites along main roads, side streets and background
sites. At each site, N02 was measured four times (once in each season) for 14 days using Palmes
tubes. Regression modeling was used to relate annual average pollutant concentrations to a set
of predictor variables (i.e., traffic density, heavy vehicle density, household density, population
density) obtained from GIS. The percentage of variability explained by the model (R2) was
0.62 for N02. Using geocoded birth addresses, values for the predictor variables were obtained
for each child, and the model was used to assign an estimate of NO2 exposure. At 1 year of age,
an increase of 8.5 |ig/m3 of NO2 was associated with cough (OR = 1.40 [95% CI: 1.12, 1.75])
and dry cough at night (OR = 1.36 [95% CI: 1.07, 1.74]). NO2 exposure was not associated
with wheeze, bronchitis, or respiratory infections. Estimated PM2.5 exposure was also associated
with cough and dry cough at night, with nearly identical odds ratios.
In the Netherlands (Brauer et al., 2002), the same protocol was used to estimate NO2
exposure in a birth cohort of 3,730 infants. However, these study subjects lived in many
different communities from rural areas to large cities in northern, central and western parts of the
Netherlands. Forty sites were selected to represent different exposures and measurements were
taken as in the Gehring et al. (2002) study. In this study, ear, nose, and throat infections
(OR= 1.16 [95%> CI: 1.00, 1.34]) and physician-diagnosed flu (OR = 1.11 [95%> CI: 1.00,
1.23]) were marginally significant. The association of NO2 of with dry cough at night could not
be replicated, nor was N02 associated with asthma, wheeze, bronchitis, or eczema.
In both of these studies, the 40 monitoring sites set up to measure NO2 also measured
PM2.5 with Harvard Impactors. Estimates of NO2 and PM2.5 were highly correlated in Braurer
et al., correlation = 0.97). The correlation was not reported in Gehring et al.; however, the
similarity of odds ratios for each pollutant suggests that the estimated exposures were also highly
correlated. Thus, a major limitation of these studies is the inability to distinguish the effects of
different pollutants.
In a study of 3,946 Munich schoolchildren, Nicolai et al. (2003) assessed traffic exposure
using two different methods. First, all street segments within 50 m of each child's home were
identified and the average daily traffic counts were totaled. Second, a model was constructed
based on measurement of NO2 at 34 sites throughout the city using traffic counts and street
characteristics (R2 = 0.77). The model was then used to estimate NO2 exposure at each child's
August 2007
3-117
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
home address. When traffic counts of < 50m were used as an exposure variable, a significant
association was found with current asthma (OR = 1.79 [95% CI: 1.05, 3.05]), wheeze
(OR = 1.66 [95% CI: 1.07, 2.57]), and cough (OR = 1.62 [95% CI: 1.16, 2.27]). Similar results
were found when modeled NO2 exposure was substituted as the exposure variable (current
asthma OR = 1.65 [95% CI: 0.94, 2.90], wheeze OR = 1.58 [95% CI: 1.05, 2.48], cough
OR = 1.60 [95% CI: 1.14, 2.23]). Asthma, wheeze, and cough were also associated with
estimated exposures to soot and benzene derived from models, suggesting that some component
of traffic pollution is increasing risk of respiratory conditions in children, but making it difficult
to determine whether NO2 is the cause of these conditions.
3.4.1.5 Integration of Evidence on Long-Term NO2 Exposure and Respiratory Illness
and Lung Function Decrements
There is strong evidence for the increased occurrence of respiratory illness in children
associated with long-term exposures to NO2. An earlier U.S. Environmental Protection Agency
meta-analysis of indoor NO2 studies supported an effect of estimated exposure to NO2 on
respiratory symptoms and disease in children ages 5 to 12. A similar relationship was not seen
with infants and younger children ages 0 to 2. Recent evidence from cohort studies from
California, examining NO2 exposure in children over an 8-year period, demonstrated deficits in
lung function growth. Deficits in lung function growth is a known risk factor for chronic
respiratory disease and possibly for premature mortality in later life stages. Lung growth
continues from early development through early adulthood, reaches a plateau, and then
eventually declines with advancing age. Dockery and Brunekreef (1996) have hypothesized that
the risk for chronic respiratory disease is associated with maximum lung size, the length of time
the lung size has been at the plateau, and the rate of decline of lung function. Therefore,
exposures to NO2 in childhood may reduce maximum lung size by limiting lung growth and
subsequently increase the risk in adulthood for chronic respiratory disease.
Animal toxicological studies provide biological plausibility for the observed increased
incidence of respiratory illness among children. A number of defense system components such
as AMs and the humoral and cell-mediated immune system have been demonstrated to be targets
for inhaled NO2. The animal studies described above show that NO2 exposure impairs the host
defense system, causing animals to be more susceptible to respiratory infections. Morphological
changes are elicited in ciliated epithelial cells at NO2 concentrations as low as 0.5 ppm for
August 2007
3-118
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
7 months; however, early studies showed that mucociliary clearance is not affected by exposures
<5 ppm. A more recent study in guinea pigs showed a concentration-dependent decrease in
ciliary activity at 3-ppm N02.
A second line of defense in the lung, the AMs, are affected by NO2 in a concentration-
and species-dependent manner with both acute and chronic exposures. Mechanisms whereby
NO2 affects AM function include membrane lipid peroxidation, decreased ability to produce
superoxide anion, inhibition of migration, and decreased phagocytic activity. Decreases in
bactericidal and phagocytic activities are likely related to increased susceptibility to pulmonary
infections. More recent studies have confirmed that AMs are a primary target for NO2 at
exposure levels <1 ppm.
Humoral and cell-mediated immune systems comprise a third line of defense that has
been shown to be suppressed by NO2 exposure. The use of animal infectivity studies provides
key biological plausibility evidence for the effects of NO2 on respiratory morbidity and
mortality. For these studies, the animals are exposed to NO2, followed by exposure to an aerosol
containing the infectious agent. This body of work shows that N02 decreases intrapulmonary
bactericidal activity in mice in a concentration-dependent manner, with no concurrent changes to
mucociliary clearance.
Thus, strong evidence indicates that the reduced efficacy of lung defense systems is an
important mechanism for the observed increase in incidence and severity of respiratory
infections. Overall, the N02 toxicological literature suggests a linear concentration-response
relationship that exists in an exposure range of 0.5 to >5 ppm and mortality resulting from
pulmonary infection. NO2 exposure reduces the efficiency of defense against infections at
concentrations as low as 0.5 ppm. The exposure protocol is important, with concentration being
more important than duration of exposure and with peak exposures being important in the overall
response. The effect of concentration is stronger with intermittent exposure than with continuous
exposure. Repeated exposures of low levels of NO2 are necessary for many respiratory effects.
The animal toxicological studies also demonstrate differences in species sensitivity to NO2 and
differences in responses to the microbes used for the infectivity tests. Animal to human
extrapolation is limited by a poor understanding of the quantitative relationship between NO2
concentrations and effective doses between animals and humans. However, animals and humans
August 2007
3-119
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
share many host defense components, making the infectivity model useful for understanding the
mechanisms whereby NO2 elicits adverse respiratory health effects.
The 1993 AQCD for Oxides of Nitrogen stated that an increase of reported respiratory
symptoms in some epidemiology studies may be an indication of the ability of the respiratory
host-defense mechanism to either overcome an infection or to limit its severity. NO2 may affect
the immune system in such a way that one or several aspects of the immune system do not
function at a level sufficient to limit the extent or occurrence of infection.
Toxicological and human clinical studies demonstrating altered host defenses provide
plausibility for the observed increase in frequency and severity of respiratory symptoms and/or
infections in humans. Increased severity or rate of respiratory illness may result from altered
host defenses in an N02 exposed lung subsequently infected with an infectious microorganism.
Although the host defense system reacts both very specifically and generally to the challenge, the
overall response in humans is expressed as a generalized demonstration of signs and symptoms
that may be associated with a site such as the lower respiratory tract and also may be reported or
objectively discerned as a general outcome such as a chest cold, cough, or an incident of asthma
or bronchitis (U.S. Environmental Protection Agency, 1993).
Other important biochemical mechanisms examined in animals may provide biological
plausibility for chronic effects of NO2 observed in epidemiology studies. The main biochemical
targets of NO2 exposure appear to be antioxidants, membrane polyunsaturated fatty acids, and
thiol groups. N02 effects include changes in oxidant/antioxidant homeostasis and chemical
alterations of lipids and proteins. Lipid peroxidation has been observed atN02 exposures as low
as 0.04 ppm (for 9-months) and at exposures of 1.2 ppm for 1 week, suggesting lower effect
thresholds with longer durations of exposure. Other studies show decreases in the formation of
key arachidonic acid metabolites in AMs following N02 exposures of 0.5 ppm. N02 has also
been shown to increase collagen synthesis rates at concentrations as low as 0.5 ppm. This could
indicate increases in total lung collagen, which are associated with pulmonary fibrosis.
Morphological effects following chronic N02 exposures have been identified in animal studies
that link to these increases in collagen synthesis and may provide plausibility for the deficits in
lung function growth described in epidemiological studies.
August 2007
3-120
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3.4.2 Cardiovascular Effects Associated with Long-Term N02 Exposure
Limited toxicology data exist on the effect of NO2 on the heart. Alterations in vagal
responses have been shown to occur in rats exposed to 10-ppm NO2 for 24 h; however, exposure
to 0.4-ppm N02 for 4 weeks revealed no change (Tsubone and Suzuki, 1984). N02-induced
effects on cardiac performance are suggested by a significant reduction in Pa02 in rats exposed
to 4.0-ppm NO2 for 3 months. When exposure was decreased to 0.4-ppm NO2 over the same
exposure period, PaC>2 was not affected (Suzuki et al., 1981). In addition, a reduction in HR has
been shown in mice exposed to both 1.2 and 4.0-ppm N02 for 1 month (Suzuki et al., 1984).
Whether these effects are the direct result of NO2 exposure or secondary responses to lung
edema and changes in blood hemoglobin content is not known (U.S. Environmental Protection
Agency, 1993). A more recent study (Takano et al., 2004) using an obese rat strain found
changes in blood triglycerides, HDL, and HDL/total cholesterol ratios with a 24-week exposure
to 0.16-ppm NO2.
No effect on hematocrit and hemoglobin have been reported in squirrel monkeys exposed
to 1.0-ppm NO2 for 16 months (Fenters et al., 1973) or in dogs exposed to <5.0-ppm NO2 for
18 months (Wagner et al., 1965). There was, however, polycythemia and an increased ratio of
PMNs to lymphocytes in rats exposed to 2.0 +1.0 ppm NO2 for 14 months (Furiosi et al., 1973).
No additional studies were found in the literature since the 1993 AQCD for Oxides of Nitrogen.
3.4.3 Adverse Birth Outcomes Associated with Long-Term NO2 Exposure
The effects of maternal exposure during pregnancy to air pollution have been examined
by several investigators in recent years (2000 through 2006). The most common endpoints
studied are low birth weight, preterm delivery, and measures of intrauterine growth (e.g., small
for gestational age [SGA]). Generally, these studies have used routinely collected air pollution
data and birth certificates from a given area for their analysis.
The reliability and validity of birth certificate data has been recently reviewed
(DiGiuseppe et al., 2002). The authors found that specific variables had different degrees of
reliability. Variables rated the most reliable included birth weight, maternal age, race, and
insurance status. Gestational age, parity, and delivery type (vaginal versus cesarean) were
reasonably reliable, while obstetrical complications and personal exposures, e.g., smoking and
alcohol consumption, were not.
August 2007
3-121
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Mothers who have a low birth weight or preterm infant are at high risk to have an adverse
outcome in a subsequent pregnancy. Similarly, mothers who have a normal infant are at low risk
for an adverse outcome in the next pregnancy. Statistically, births to the same mother are not
independent observations. As most women in the United States have two or more births and
these births often occur within a few years, birth certificate data, which include several years of
observations, have a very large number of non-independent observations. None of the studies
reviewed considered this problem, and all analyzed births as independent events. For studies
using only 1 (or at most 2) years of birth certificates, the effects are small; for studies using
several years of birth certificates, the variance estimates would be reduced.
While most studies analyzed average NO2 exposure for the whole pregnancy, many also
considered exposure during specific trimesters or other time periods. Fetal growth, for example,
is much more variable during the third trimester. Thus, studies of fetal growth might anticipate
that exposure during the third trimester would have the greatest likelihood of an association, as is
true for the effect of maternal smoking during pregnancy. However, growth can also be affected
through placentation, which occurs in the first trimester. Similarly, preterm delivery might be
expected to be related to exposure early in pregnancy affecting placentation, or through acute
effects occurring just before delivery.
Of the three studies conducted in the United States, one (Bell et al., 2007) reported a
significant decrease in birthweight associated with exposure to NO2 among mothers in
Connecticut and Massachusetts. The two studies conducted in California did not find
associations between NO2 exposure with any adverse birth outcome (Ritz et al., 2000; Salam
et al., 2005). Differences in these studies that may have contributed to the differences in results
include the following: sample size; average NO2 concentration; and different pollution mixtures.
The results reported by Bell et al. (2007) had the largest sample size and therefore greater power
to assess small increases in risk. The two California studies reported higher mean concentrations
of NO, but also strong correlations of NO2 exposure with PM mass and CO.
Annex Table AX6.5-1 lists seven studies that investigated the relationship of ambient
N02 exposure with birth weight. Since low birth weight may result from either inadequate
growth in utero or delivery before the usual 40 weeks of gestation, three of the authors only
considered low birth weight (<2500 g) in full-term deliveries (>37 weeks), the other four
controlled for gestational age in the analysis. When correlations with other pollutants were
August 2007
3-122
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
reported in these studies, they ranged from 0.5 to 0.8. All of these studies reported strong effects
for other pollutants.
Lee et al. (2003) reported a significant association between N02 and low birth weight,
and the association was only for exposure in the second trimester. It is difficult to hypothesize
any biological mechanism relating NO2 exposure and fetal growth specifically in the second
trimester. Bell et al. (2007) reported an increased risk of low birth weight with NO2 exposure
averaged over pregnancy (OR = 1.027 [95% CI: 1.002, 1.051]) and a deficit in birthweight
specific to the first trimester. In addition, the deficit in birthweight appeared to be greater among
black mothers (-12.7 g per IQR increase in N02 [95% CI: -18.0, -7.5]) than for white mothers
(-8.3 g per IQR increase in NO2 [95% CI: -10.4, -6.3]).
Six studies investigated N02 exposure related to preterm delivery (Annex Table
AX6.5.2). Three reported positive associations (Bobak, 2000; Maroziene et al., 2002; Leem
et al., 2006) and three reported no association (Liu et al., 2003; Ritz et al., 2000; Hansen et al.,
2006). Among the studies reporting an association, two (Bobak, 2000; Leem et al., 2006)
reported significant associations for both the first trimester and the third trimester of pregnancy.
The third (Maroziene et al., 2002) reported significant increases in risk for exposure in the first
trimester and averaged over all of pregnancy. In two (Bobak, 2000; Leem et al., 2006) of the
positive studies, NO2 exposure was correlated with SO2 exposure (r = 0.54, 0.61 for the two
studies); the third study did not report correlations.
Three studies (see details in Annex Table AX6.5-3) specifically investigated fetal growth
by comparing birth weight for gestational age with national standards. Two of these studies
reported associations of small for gestational age with NO2 exposure. Mannes et al. (2004)
determined increased risk for exposure in trimesters 2 and 3, while Liu et al. (2003) reported
risks associated only with NO2 exposure in the first month of pregnancy. In all three studies,
NO2 exposure was correlated with CO exposure (r = 0.69, 0.57, 0.72 in the three studies).
Reproductive and Developmental Effects of NO2 Exposure in Animal Studies
Only a few studies have investigated the effects of NO2 on reproduction and development
of N02. Exposure to 1.0-ppm N02 for 7 h/day, 5 days/week for 21 days, resulted in no
alterations in spermatogenesis, germinal cells, or interstitial cells of the testes of 6 rats (Kripke
and Sherwin, 1984). Similarly, breeding studies by Shalamberidze and Tsereteli (1971) found
August 2007
3-123
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
that long-term NO2 exposure had no effect on fertility. However, there was a statistically
significant decrease in litter size and neonatal weight when male and female rats exposed to
1.3-ppm N02, 12 h/day for 3 months were bred. In utero death due to N02 exposure resulted in
smaller litter sizes, but no direct teratogenic effects were observed in the offspring. In fact, after
several weeks, MVexposed litters approached weights similar to those of controls.
Following inhalation exposure of pregnant Wistar rats to 0.5- and 5.3-ppm NO2 for
6 h/day throughout gestation (21 days), maternal toxic effects and developmental disturbances in
the progeny were reported (Tabacova et al., 1984; Balabaeva and Tabacova, 1985; Tabacova and
Balabaeva, 1988). Maternal weight gain during gestation was significantly reduced at 5.3 ppm,
with findings of pathological changes, e.g., desquamative bronchitis and bronchiolitis in the
lung, mild parenchymal dystrophy and reduction of glycogen in the liver, and blood stasis and
inflammatory reaction in the placenta. At gross examination, the placentas of the high-dose
dams were smaller in size than those of control rats. A marked increase of lipid peroxides was
found in maternal lungs and particularly in the placenta at both exposure levels by the end of
gestation (Balabaeva and Tabacova, 1985). Disturbances in the prenatal development of the
progeny were registered, such as 2- to 4-fold increase in late post-implantation lethality at 0.5
and 5.3 ppm, respectively, as well as reduced fetal weight at term and stunted growth at 5.3 ppm.
These effects were significantly related to the content of lipid peroxides in the placenta, which
was suggestive of a pathogenetic role of placental damage. Teratogenic effects were not
observed, but dose-dependent morphological signs of embryotoxicity and retarded intrauterine
development, such as generalized edema, subcutaneous hematoma, retarded ossification, and
skeletal aberrations, were found at both exposure levels.
In a developmental neurotoxicity study, Wistar rats were exposed by inhalation to 0-,
0.025-, 0.05-, 0.5-, or 5.3-ppm N02 during gestational days 0 through 21. It is unclear whether
the study was conducted at two separate times. Maternal toxicity was not reported. Viability
and physical development (i.e., incisor eruption and eye opening) were significantly affected in
the group exposed only to 5.3 ppm. There was a concentration-dependent change in
neurobehavioral endpoints, including disturbances in early neuromotor development, including
coordination deficits, retarded locomotor development, and decreased activity and reactivity.
Statistical significance was observed in some or all of the endpoints at the time point(s)
measured in the 0.05-, 0.5-, and 5.3-ppm exposure groups.
August 2007
3-124
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Di Giovanni et al. (1994) investigated whether in utero exposure of rats to NO2 changed
ultrasonic vocalization, a behavioral response indicator of the development of emotionality.
Pregnant Wistar female rats were exposed by inhalation to 0, 1.5-, and 3-ppm N02 from day 0 to
20 of gestation. Dam weight gain, pregnancy length, litter size at birth, number of dams giving
birth, and postnatal mortality were unaffected by NO2. There was a significant decrease in the
duration of ultrasonic signals elicited by the removal of the pups from the nest in the 10-day and
15-day-old male pups in the 3-ppm N02-exposed group. No other parameters of ultrasonic
emission, or of motor activity, were significantly affected in these prenatally exposed pups.
Since prenatal exposure to NO2 did not significantly influence the rate of calling, the authors
concluded that this decrease in the duration of ultrasounds in the 3-ppm NO2 exposed group does
not necessarily indicate altered emotionality, and the biological significance of these findings
remains to be determined.
3.4.3.1 Integration and Biological Plausibility for Reproductive and Developmental
Effects
Integration of epidemiological and toxicological findings is limited by the dearth of
studies in both disciplines. In epidemiological studies of birth outcomes, generally, birth
certificate data were compared to NO2 measured by routine monitoring. Only a small number of
studies looked at low birth weight or preterm delivery. Of the seven studies that examined
associations between low birth weight and ambient NO2, only two reported a significant
association (Bell et al., 2007; Lee et al., 2003). Two studies of fetal growth reported associations
of small for gestational age with NO2 exposure. Overall, exposure in the third trimester may
have the strongest association with evaluating effects on fetal growth. In evaluations of preterm
delivery, three studies reported positive associations and three studies reported no association.
Exposure early and late in the pregnancy may be associated more strongly with effects on
preterm delivery. These results are confounded by prior pregnancy history (i.e., multiple births
to the same mother are not independent observations), smoking, and poor quality of birth
certificate data.
The small body of toxicological literature examining the effects of N02 on birth
outcomes is somewhat inconclusive, but NO2 does not appear to be a reproductive toxicant. One
early study found a decrease in litter size and neonatal weight when male and female rats were
exposed to 1.3 ppm for 3 months and then bred. Earlier studies suggested that exposures of
August 2007
3-125
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
<10 ppm did not induce mutagenesis in rats. The few toxicological studies discussed that
evaluated the effects of NO2 on reproduction and development show that NO2 at ~5 ppm
throughout gestation reduced maternal weight gain. A 5-ppm exposure resulted in smaller
placentas, increased maternal lipid peroxides, increased late post-implantation mortality,
embryotoxicity, and retarded intrauterine development. Gestational exposure to 3-ppm NO2
caused a decrease in duration, but not rate, of ultrasonic vocalization in pups.
In summary, epidemiological evidence is not strong for associations between N02
exposure and grown retardation; however, some evidence is accumulating for effects on preterm
delivery. Similarly, scant animal evidence supports a weak association between NO2 exposure
and adverse birth outcomes and provides little mechanistic information or biological plausibility
for the epidemiology findings.
3.4.4 Cancer Incidence Associated with Long-Term NO2 Exposure
Two studies (see Annex Table AX6.5-6) have investigated the relationship between NO2
exposure and lung cancer and reported positive associations. Although this literature review has
concentrated on studies that measured exposure to NO2, modeled exposures will be considered
for cancer studies. This is necessary because the relevant exposure period for lung cancer may
be 30 years or more.
Nyberg et al. (2000) reported results of a case control study of 1,043 men age 40 to
75 years with lung cancer and 2,364 controls in Stockholm County. They mapped residence
addresses to a GIS database indicating 4,300 traffic-related line sources and 500 point sources of
NO2 exposure. Exposure was derived from a model validated by comparison to actual
measurements of N02 at six sites. Exposure to N02 at 10 |ig/m3 was associated with an OR of
1.10 (95% CI: 0.97, 1.23). Exposure to the 90th percentile (>29.26 |ig/m3) of NO2 was
associated with an OR of 1.44 (95% CI: 1.05, 1.99).
Very similar results were reported in a Norwegian study (Nafstad et al., 2003). The study
population is a cohort of 16,209 men who enrolled in a study of cardiovascular disease in 1972.
The Norwegian cancer registry identified 422 incident cases of lung cancer. Exposure data was
modeled based on residence, estimating exposure for each person in each year from 1974 to
1998. Each 10 |ig/m3 of NO2 was associated with an OR of 1.08 (95% CI: 1.02, 1.15). Cancer
August 2007
3-126
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
incidence with exposure of >30 |ig/m3 was associated with an OR of 1.36 (95% CI: 1.01, 1.83);
however, controlling for SO2 exposure did appreciably change the effect estimates for NO2.
What is particularly striking in these two studies is the similarity in the estimate of effect.
Despite the fact that these two studies were conducted by different investigators, in different
countries, using different study designs and different methods for modeling exposure, the odds
ratios and confidence intervals for exposure per 10 |ig/m3 and above 30 |ig/m3 are virtually
identical.
Animal and In Vitro Carcinogenicity and Genotoxicity Studies
There is no clear evidence that NO2 acts as a complete carcinogen. No studies were
found on NO2 using classical carcinogenesis whole-animal bioassays. Of the existing studies
that have evaluated the carcinogenic and cocarcinogenic potential of NO2, results are often
unclear or conflicting. Witschi et al. (1988) critically reviewed some of the important theoretical
issues in interpreting these types of studies. NO2 does appear to act as a tumor promoter at the
site of contact (i.e., in the respiratory tract from inhalation exposure), possibly due to its ability to
produce cellular damage and, thus, promote regenerative cell proliferation. This hypothesis is
supported by observed hyperplasia of the lung epithelium from N02 exposure (see Lung
Morphology section, U.S. Environmental Protection Agency, 1993), which is a common
response to lung injury, and enhancement of endogenous retrovirus expression (Roy-Burman
et al., 1982). However, these findings were considered by U.S. Environmental Protection
Agency (1993) to be inconclusive.
When studied using in vivo assays, no inductions of recessive lethal mutations were
observed in Drosophila exposed to NO2 (Inoue et al., 1981; Victorin et al., 1990). NO2 does not
increase chromosomal aberrations in lymphocytes and spermatocytes or micronuclei in bone
marrow cells (Gooch et al., 1977; Victorin et al., 1990). No increased stimulation of poly(ADP-
ribose)synthetase activity (an indicator of DNA repair, suggesting possible DNA damage) was
reported in AMs recovered from BAL of rats continuously exposed to 1.2-ppm NO2 for 3 days
(Bermudez, 2001).
NO2 has been shown to be positive when tested for genotoxicity in in vitro assays (see
Annex Table AX4.8). N02 is mutagenic in bacteria and in plants. In cell cultures, three studies
August 2007
3-127
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
showed chromosomal aberrations, SCE, and DNA single-strand breaks. However, a fourth study
(Isomura et al., 1984) concluded that NO, but not NO2, was mutagenic in hamster cells.
Coexposure Studies with NO2 and Known Carcinogens
Rats were injected with jV-bis(2-hydroxy-propyl)nitrosamine (BHPN) and continuously
exposed to 0.04, 0.4, or 4.0-ppm NO2 for 17 months. Although the data indicated five times as
many lung adenomas or adenocarcinomas in the rats injected with BHPN and exposed to 4-ppm
NO2 (5/40 compared to 1/10), the results failed to achieve statistical significance (Ichinose et al.,
1991). In a later study, Ichinose and Sagai (1992) reported increased lung tumors in rats injected
with BHPN, followed the next day by either clean air (0%), 0.05-ppm O3 (8.3%), 0.05-ppm
O3 + 0.4-ppm NO2 (13.9%) or 0.4-ppm NO2 + 1 mg/m3 H2S04-aerosol (8.3%) for 13 months,
and then maintained for another 11 months until study termination. Exposure to NO2 was
continuous, while the exposures to 03 and H2S04-aerosol were intermittent (exposure for
10 h/day). The increased lung tumors from combined exposure of O3 and NO2 were statistically
significant.
Ohyama et al. (1999) coexposed rats to diesel exhaust particulates (DEP) extract-coated
carbon black particles (DEPcCBP) once a week for 4 weeks by intratracheal instillation and to
either 6-ppm NO2, 4-ppm SO2, or 6-ppm NO2 + 4-ppm SO2 16 h/day for 8 months, and
thereafter exposed to clean air for 8 months. Alveolar adenomas were increased in animals
exposed to DEPcCBP and either NO2 and/or SO2 compared to animals in the DEPcCBP-only
group and to controls. The incidences of lung tumors for the NO2, SO2, and NO2 and/or SO2
groups were 6/24 (25%), 4/30 (13%), and 3/28 (11%), respectively. No alveolar adenomas were
observed in animals exposed to DEPcCBP alone or in the controls. Increased alveolar
hyperplasia was elevated in all groups compared to controls. In addition, DNA adducts, as
determined by 32P- postlabelling, was observed in the 2/3 animals exposed to both DEPcCBP
and either N02 and/or S02, but not in animals exposed to DEPcCBP alone or controls. The
authors concluded that the cellular damage induced by NO2 and/or SO2 may have resulted in
increased cellular permeability of the DEPcCBP particles into the cells.
Studies in Animals with Spontaneously High Tumor Rates
Three studies evaluated tumor response in strains with high tumor rates. The frequency
and incidence of spontaneously occurring pulmonary adenomas was increased in strain A/J mice
August 2007
3-128
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
(with spontaneously high tumor rates) after exposure to 10.0-ppm NO2 for 6 h/day, 5 days/week
for 6 months (Adkins et al., 1986). These small, but statistically significant, increases were only
detectable when the control response from nine groups (n = 400) were pooled. Exposure to 1.0-
and 5.0-ppm NO2 had no effect. In contrast, Richters and Damji (1990) found that an
intermittent exposure to 0.25-ppm NO2 for up to 26 weeks decreased the progression of a
spontaneous T cell lymphoma in AKR/cum mice and increased survival rates. The investigators
attribute this effect to an N02-induced decrease in the proliferation of T cell subpopulation in the
spleen (especially T-helper/inducer CD+ lymphocytes), that produce growth factors for the
lymphoma. A study by Wagner et al. (1965) suggested that NO2 may accelerate the production
of tumors in CAFl/Jax mice (a strain that has spontaneously high pulmonary tumor rates) after
continuous exposure to 5.0-ppm N02. After 12 months of exposure, 7/10 mice in the exposed
group had tumors, compared to 4/10 in the controls. No differences in tumor production were
observed after 14 and 16 months of exposure. A statistical evaluation of the data was not
presented.
Facilitation of Metastases
Whether N02 facilitates metastases has been the subject of several experiments by
Richters and Kuraitis (1981, 1983), Richters and Richters (1983), and Richters et al. (1985).
Mice were exposed to several concentrations and durations of N02 and were injected
intravenously with a cultured-derived melanoma cell line (B16) after exposure, and subsequent
tumors in the lung were counted. Although some of the experiments showed an increased
number of lung tumors, statistical methods were inappropriate. Furthermore, the experimental
technique used in these studies probably did not evaluate metastases formation, as the term is
generally understood, but more correctly, colonization of the lung by tumor cells.
Production of N-Nitroso Compounds and other Nitro Derivatives
Because of evidence that NO2 could produce NO2 and NO3 in the blood and the fact
that NO2 is known to react with amines to produce animal carcinogens (nitrosamines), the
possibility that NO2 could produce cancer via nitrosamine formation has been investigated. Iqbal
et al. (1980) were the first to demonstrate a linear time- and concentration-dependent relationship
between the amount of N-nitrosomorpholine (NMOR, an animal carcinogen) found in whole-
mouse homogenates after the mice were gavaged with 2 mg of morpholine (an exogenous amine
August 2007
3-129
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
that is rapidly nitrosated) and exposure to 15.0- to 50.0-ppm NO2 for between 1 and 4 h. In a
follow-up study at more environmentally relevant exposures, Iqbal et al. (1981) used
dimethylamine (DMA), an amine that is slowly nitrosated to dimethylnitrosamine (DMN). They
reported a concentration-related increase in biosynthesis of DMN atNC>2 concentrations as low
as 0.1 ppm; however, the rate was significantly greater at concentrations above 10.0-ppm NO2.
Increased length of exposure also increased DMN formation between 0.5 and 2 h, but synthesis
of DMN was less after 3 or 4 h of exposure than after 0.5 h.
Mirvish et al. (1981) concluded that the results of Iqbal et al. (1980) were technically
flawed, but they found that in vivo exposure to NO2 could produce a nitrosating agent (NSA)
that would nitrosate morpholine only when morpholine was added in vitro. Further experiments
showed that the NSA was localized in the skin (Mirvish et al., 1983) and that mouse skin
cholesterol was a likely NSA (Mirvish et al., 1986). It has also been reported that only very
lipid-soluble amines, which can penetrate the skin, would be available to the NSA. Compounds
such as morpholine, which are not lipid-soluble, could only react with NO2 when painted directly
on the skin (Mirvish et al., 1988). Iqbal (1984), responding to the Mirvish et al. (1981)
criticisms, verified their earlier (Iqbal et al., 1980) studies.
The relative significance of N02 from N02 compared with other N02 sources such as
food, tobacco, and NO3 -reducing oral bacteria is uncertain. Nitrosamines have not been
detected in tissues of animals exposed by inhalation to N02 unless precursors to nitrosamines
and/or inhibitors of nitrosamine metabolism are coadministered. Rubenchik et al. (1995) could
not detect jV-nitrosodimethylamine (NDMA) in tissues of mice exposed to 7.5 to 8.5 mg/m3 NO2
for 1 h. NDMA was found in tissues, however, if mice were simultaneously given oral doses of
amidopyrine and 4-methylpyrazole, an inhibitor of NDMA metabolism. Nevertheless, the main
source of NO2 in the body is formed endogenously, and food is also a contributing source of
nitrite (from nitrate conversion).
3.4.4.1 Integration and Biological Plausibility for Cancer Incidence
In summary, two epidemiological studies conducted in Europe showed an association
between long-term N02 exposure and cancer incidence, with OR at 10-|ig/m3 N02, ranging from
1.10 to 1.08. Animal studies have provided no clear evidence that NO2 acts as a carcinogen.
The 1993 AQCD for Oxides of Nitrogendeemed findings of hyperplasia of lung epithelium from
August 2007
3-130
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
NO2 exposure as inconclusive, though NO2 does appear to act as a tumor promoter at the site of
contact. There are no in vivo studies that suggest that NO2 causes teratogenesis or malignant
tumors. Only very high exposure studies, i.e., levels not relevant to ambient N02 levels,
demonstrate increased chromosomal aberrations and mutations in in vitro studies.
3.4.5 Summary of Morbidity Effects Associated with Long-Term Exposure
This section has presented epidemiological and toxicological studies evaluating
decrements in lung function, asthma prevalence, respiratory symptoms, and morphological
damage associated with long-term NO2 exposures. It has further presented limited evidence of
cardiovascular effects, adverse birth outcomes, and cancer incidence linked to long-term NO2
exposure. Toxicological studies characterizing altered lung host defenses provide convincing
biological plausibility for many of the respiratory effects observed in epidemiological studies,
especially the decrements in lung function observed in the cohort studies. Epidemiology
evidence is less clear for effects of long-term NO2 exposure on adverse birth outcomes and
cancer incidence. Animal studies do not provide mechanistic information to support these
observational findings. Some toxicological studies have demonstrated an effect of NO2 exposure
on cardiovascular endpoints; however, whether these effects are the direct result of NO2
exposure or secondary responses to lung edema and changes in blood hemoglobin content are not
known. Parallel findings have been reported in the epidemiological literature for short-term
exposures only.
3.5 MORTALITY ASSOCIATED WITH LONG-TERM EXPOSURE
There have been several studies that examined mortality associations with long-term
exposure to air pollution, including NO2. They all used Cox-proportional hazards regression
models with adjustment for potential confounders. The U.S. studies tended to focus on effects of
PM, while the European studies tended to investigate the influence of traffic-related air pollution.
3.5.1 U.S. Studies on the Long-Term Exposure Effects on Mortality
Dockery et al. (1993) conducted a prospective cohort study to study the effects of air
pollution with main focus on PM components in six U.S. cities, which were chosen based on the
levels of air pollution (with Portage, WI being the least polluted and Steubenville, OH, the most
August 2007
3-131
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
polluted). Cox proportional hazards regression was conducted with data from a 14-to-16-year
mortality follow-up of 8,111 adults in the six cities, adjusting for smoking, sex, occupational
exposures, etc. Fine particles were the strongest predictor of mortality, but N02 was not
analyzed in their study. Krewski et al. (2000) conducted sensitivity analysis of the Harvard Six
Cities study and examined associations between gaseous pollutants (i.e., O3, NO2, SO2, CO) and
mortality. NO2 showed risk estimates similar to those for PM2.5 per "low to high" range
increment with total (1.15 [95% CI: 1.04, 1.27] per 10-ppb increase), cardiopulmonary (1.17
[95% CI: 1.02, 1.34]), and lung cancer (1.09 [95% CI: 0.76, 1.57]) deaths; however, in this
dataset N02 was highly correlated with PM2.5 (r = 0.78), S042 (r = 0.78), and S02 (r = 0.84).
Pope et al. (1995) examined PM effects on mortality using the American Cancer Society
(ACS) cohort. Air pollution data from 151 U.S. metropolitan areas in 1980 were linked with
individual risk factors on 552,138 adults who resided in these areas when enrolled in the study in
1982. Mortality was followed up until 1989. As with the Harvard Six Cities Study, the main
hypothesis of this study was focused on fine particles and SO42 , and gaseous pollutants were not
analyzed. Krewski et al. (2000) examined association between gaseous pollutants (means by
season) and mortality in the Pope et al. (1995) study dataset. NO2 showed weak but negative
associations with total and cardiopulmonary deaths using either seasonal means. An extended
study of the ACS cohort doubled the follow-up time (to 1998) and tripled the number of deaths
compared to the original study (Pope et al., 2002). In addition to PM2.5, all the gaseous
pollutants were examined. SO2 was associated with all the mortality outcomes (including all
other cause of deaths), but NO2 showed no associations with the mortality outcomes (RR = 1.00
[95% CI: 0.98, 1.02] per 10-ppb increase in multi-year average NO2).
Miller et al. (2007) studied 65,893 postmenopausal women between the ages of 50 and
79 years without previous cardiovascular disease in 36 U.S. metropolitan areas from 1994 to
1998. They examined the association between one or more fatal or nonfatal cardiovascular
events and the women's exposure to air pollutants. Subject's exposures to air pollution were
estimated by assigning the annual mean levels of air pollutants in 2000 measured at the nearest
monitor to the location of residence based on its five-digit ZIP Code centroid. Thus, the
exposure estimate in this study is spatially more resolved than those in the Harvard Six Cities or
the ACS cohort study. A total of 1,816 women had one or more fatal or nonfatal cardiovascular
events, including 261 deaths from cardiovascular causes. The main focus of the study was
August 2007
3-132
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
PM2.5, but the overall CVD events (but not results for death events only) using all the
copollutants (PMio, PM10-2.5, SO2, NO2, CO, and O3) in both single- and multipollutant models
were presented. The results for the data with non-missing exposure data were included
(N = 28,402 subjects resulting in 879 CVD events) are described here. In the single-pollutant
model results, PM2.5 showed the strongest associations with the CVD events by far among the
pollutants (hazard ratio = 1.24 [95% CI: 1.04, 1.48] per 10-|ig/m3 increase in annual average),
followed by S02 (HR = 1.07 [95% CI: 0.95, 1.20] per 5-ppb increase in the annual average).
NO2 did not show association with the overall CVD events (HR = 0.98 [95% CI: 0.89, 1.08] per
10-ppb increase in the annual average). In the multipollutant model (apparently, all the
pollutants were included in the model), the PM^/s association with the overall CVD events was
even stronger and the estimate larger (1.53 [95% CI: 1.21, 1.94]), and the association with S02
also became stronger and the estimate larger (HR =1.13 [95% CI: 0.98, 1.30]). NO2 became
negatively associated with the overall CVD events (HR = 0.82 [95% CI: 0.70, 0.95]).
Correlations among these pollutants were not described, and therefore it is not possible to
estimate the extent of confounding among these pollutants in these associations, but it is clear
that PM2.5 was the best predictor of the CVD events.
Lipfert et al. (2000a) conducted an analysis of a national cohort of-70,000 male U.S.
military veterans who were diagnosed as hypertensive in the mid 1970s and were followed up for
about 21 years (up to 1996). This cohort was 35% black and 81% had been smokers at one time.
TSP, PM10, CO, O3, NO2, SO2, SO42 , PM2.5, and coarse particles were considered. The county
of residence at the time of entry to the study was used to estimate exposures. Pollution levels
were averaged by year and county. Four exposure periods (1960-74, 1975-81, 1982-88, and
1989-96) were defined, and deaths during each of the three most recent exposure periods were
considered. Lipfert et al. noted that the pollution risk estimates were sensitive to the regression
model specification, exposure periods, and the inclusion of ecological and individual variables.
The authors reported that indications of concurrent mortality risks were found for NO2 (the
estimate was not given with confidence bands) and peak O3. Their subsequent analysis (Lipfert
et al., 2003) reported that the air pollution-mortality associations were not sensitive to the
adjustment for blood pressure. Lipfert et al. (2006a) also examined associations between traffic
density and mortality in the same cohort, whose follow-up period was extended to 2001. The
county-level traffic density was derived by dividing vehicle-km traveled by the county land area.
August 2007
3-133
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Because of the wide range of the traffic density variable, log-transformed traffic density was
used in their analysis. They reported that traffic density was a better predictor of mortality than
ambient air pollution variables, with the possible exception of 03. The log-transformed traffic
density variable was moderately correlated with NO2 (r = 0.48) and PM2.5 (r = 0.50) in this data
set. For the 1989 to 1996 data period (the period that showed generally the strongest
associations with exposure variables among the four periods), the estimated mortality relative
risk for N02 was 1.025 (95% CI: 0.983, 1.068) per 10-ppb increase in a single-pollutant model.
The two-pollutant model with the traffic density variable reduced NO2 risk estimates to 0.996
(95% CI: 0.954, 1.040). Interestingly, as the investigators pointed out, the risk estimates due to
traffic density did not vary appreciably across these four periods. They speculated that other
environmental factors such as particles from tire, traffic noise, spatial gradients in socioeconomic
status, etc., might have been involved. Lipfert et al. (2006b) further extended analysis of the
veteran's cohort data to include the U.S. Environmental Protection Agency's Speciation Trends
Network (STN) data, which collected chemical components of PM2.5. They analyzed the STN
data for year 2002, again using county-level averages. As in the previous Lipfert et al. (2006a)
study, traffic density was the most important predictor of mortality, but associations were also
seen for elemental carbon, vanadium, N03 , and nickel. N02, 03, and PMi0 also showed
positive but weaker associations. The risk estimate for NO2 was 1.043 (95% CI: 0.967, 1.125)
per 10-ppb increase in a single-pollutant model. Multi-pollutant model results were not
presented for NO2.
Abbey et al. (1999) investigated associations between long-term ambient concentrations
of PM10, O3, NO2, SO2, and CO (1973 to 1992) and mortality (1977 to 1992) in a cohort of
6,338 nonsmoking California Seventh-day Adventists. Monthly indices of ambient air pollutant
concentrations at 348 monitoring stations throughout California were interpolated to zip code
centroids according to home or work location histories of study participants, cumulated, and then
averaged over time. They reported associations between PM10 and total mortality for males and
non-malignant respiratory mortality for both sexes. NO2 was not associated with all-cause,
cardiopulmonary, or respiratory mortality for either sex. Lung cancer mortality showed large
risk estimates for most of the pollutants in either or both sexes, but the number of lung cancer
deaths in this cohort was very small (12 for female and 18 for male) and therefore it is difficult to
interpret these estimates.
August 2007
3-134
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
The U.S. studies mentioned above have differences in study population characteristics
and geographic unit of averaging for pollution exposure estimates, and therefore the results
cannot be directly compared. The ACS and Women's Health Initiative (WHI) cohort studies
found no associations with NO2, but in the veterans study, NO2 was among the pollutants that
showed associations with mortality, though traffic density showed the strongest association. The
geographic resolution of air pollution exposure estimation varied across these studies: the
Metropolitan Statistical Area (MSA)-level averaging in the ACS study; county-level averaging
in the veterans' study; and assigning the nearest monitor's annual average to the ZIP code
centroid. Traffic density and other pollutants that showed mortality associations in the veterans
study, including elemental carbon, nickel, and vanadium and NO2 (but not O3 or NO3 ), are more
localized pollutants, and therefore, using county-level aggregation, rather than MSA-level, may
have resulted in smaller exposure misclassification. However, in the WHI cohort study, despite
its finer resolution of exposure estimation, NO2 (which is presumably more locally impacted than
PM2.5) was not associated with cardiovascular events. It should also be noted that there are
generally fewer N02 monitors than PM2.5 monitors in U.S. cities (nationwide, N02 has the
smallest number of monitors among the Criteria pollutants except lead). Therefore, even when
the spatial resolution for exposure estimates is high in the study design, the fewer available
monitors for NO2 compared to other pollutants, may result in compromised exposure estimation
for N02. Thus, there is uncertainty regarding how the scale of aggregation affects the analyses
that utilize cross-sectional comparisons.
3.5.2 European Studies on the Long-Term Exposure Effects on Mortality
In contrast to the U.S. studies described above, the European studies described below,
have more spatially resolved exposure estimates, because their hypotheses or study aims
involved mortality effects of traffic-related air pollution. One study from France used a design
similar to the Harvard Six Cities study or ACS in that it was not intended to study of traffic-
related air pollution, and the exposure estimate was not done on an individual basis.
Hoek et al. (2002) investigated a random sample of 5,000 subjects from the Netherlands
Cohort Study on Diet and Cancer (NLCS) ages 55 to 69 from 1986 to 1994. Long-term exposure
to traffic-related air pollutants (black smoke and NO2) was estimated using 1986 home
addresses. Exposure was estimated with the measured regional and urban background
August 2007
3-135
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
concentration and an indicator variable for living near major roads. Cardiopulmonary mortality
was associated with living near a major road (RR = 1.95 [95% CI: 1.09, 3.52]) and less strongly
with the estimated air pollution levels (e.g., for N02, RR = 1.32 [95% CI: 0.88, 1.98] per 10-ppb
increase). The risk estimate for living near a major road was 1.41 (95% CI: 0.94, 2.12) for total
mortality. For estimated NO2 (incorporating both background and local impact), the RR was
1.15 (95%) CI: 0.60, 2.23) per 10 ppb). Because theN02 exposure estimates were modeled,
interpretation of their risk estimates is not straightforward. However, these results do suggest
that NO2, as a marker of traffic-related air pollution, was associated with these mortality
outcomes.
Filleul et al. (2005) investigated long-term effects of air pollution on mortality in 14,284
adults who resided in 24 areas from seven French cities when enrolled in the PAARC survey (for
air pollution and chronic respiratory diseases) in 1974. Daily measurements of SO2, TSP, black
smoke, NO2, and NO were made in 24 areas for 3 years (1974 through 76). Cox-proportional
hazards models adjusted for smoking, educational level, BMI, and occupational exposure.
Models were run before and after exclusion of six area monitors influenced by local traffic as
determined by the NO/NO2 ratio of >3. Before exclusion of the six areas, none of the air
pollutants were associated with mortality outcomes. After exclusion of these areas, analyses
showed associations between total mortality and TSP, black smoke, NO2, and NO. The
estimated N02 risks were 1.28 (95% CI: 1.07, 1.55), 1.58 (95% CI: 1.07, 2.33), and 2.12
(95%) CI: 1.11, 4.03) per 10-ppb increase in N02 mean over the study period for total,
cardiopulmonary, and lung cancer mortality, respectively. From these results, the authors noted
that inclusion of air monitoring data from stations directly influenced by local traffic could
overestimate the mean population exposure and bias the results. This point raises a concern for
N02 exposure estimates used in other studies (e.g., ACS) in which the average of available
monitors was used to represent the exposure of each city's entire population.
Nafstad et al. (2004) investigated the association between mortality and long-term air
pollution exposure in a cohort of Norwegian men followed from 1972/1973 through 1998.
Nafstad et al. also presented the result for lung cancer deaths only in their earlier (Nafstad et al.,
2003) analysis discussed in Section 3.3.4, but their 2004 study includes more mortality
categories and is therefore described here. Data from 16,209 men 40 to 49 years of age living in
Oslo, Norway, in 1972 and 1973 were linked with data from the Norwegian Death Register and
August 2007
3-136
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
with estimates of average yearly air pollution levels at the participants' home addresses from
1974 to 1998. PM was not considered in this study because measurement methods changed
during the study period. NOx, rather than N02, was used. Exposure estimates for NOx and S02
were constructed using models based on subjects' addresses and emission data for industry,
heating, and traffic and measured concentrations. Addresses linked to 50 of the busiest streets
were given an additional exposure based on estimates of annual average daily traffic. The
adjusted risk estimate for total mortality was 1.08 [95% CI: 1.06, 1.11] for a 10-|ig/m3 increase
in the estimated exposure to NOx. Corresponding mortality risk estimates for respiratory causes
other than lung cancer was 1.16 (95% CI: 1.06, 1.26); for lung cancer, 1.11 (95% CI: 1.03,
1.19); and for ischemic heart diseases, 1.08 (95% CI: 1.03, 1.12). SO2 did not show similar
associations. The risk estimates presented for categorical levels of these pollutants showed
mostly monotonic exposure-response relationships for NOx, but not for SO2. The authors noted
that the SO2 levels were reduced by a factor of 7 during the study period, whereas NOx did not
show any clear downward trends. These results are suggestive of the effects of traffic-related air
pollution on long-term mortality, but NOx likely represented the combined effects of that source,
possibly including PM, which could not be analyzed in this study. Nyberg et al. (2000), a case-
control study of 1,043 men aged 40 to 75 with lung cancer and 2,364 controls in Stockholm
County, reported similar results to this study. They mapped residence addresses to a GIS
database indicating 4,300 traffic-related line sources and 500 point sources of NO2 exposure.
Exposure was derived from a model validated by comparison to actual measurements of N02 at
six sites. Exposure to NO2 at 10 |ig/m3 was associated with an OR of 1.10 (95% CI: 0.97 1.23).
Exposure to the 90th percentile (>29.26 |ig/m3) of N02 was associated with an OR of 1.44 (95%
CI: 1.05, 1.99).
Naess et al. (2007) investigated the concentration-response relationships between air
pollution (i.e., NO2, PM10, PM2.5) and cause-specific mortality using all the inhabitants of Oslo,
Norway, aged 51 to 90 years on January 1, 1992 (n = 143,842), with follow-up of deaths from
1992 to 1998. An air dispersion model was used to estimate the air pollution levels for 1992
through 1995 in all 470 administrative neighborhoods. Correlations among these pollutants were
high (ranged 0.88 to 0.95), but they were not correlated with education and occupation (less than
0.05). All causes of deaths were associated with all indicators of air pollution for both sexes and
both age groups. The investigators reported that the effects appeared to increase at NO2 levels
August 2007
3-137
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
higher than 40 |ig/m3 (21 ppb) in the younger age (51 to 70 years) group and with a linear effect
in the interval of 20 to 60 |ig/m3 (10 to 31 ppb) for the older age group (see Figure 3.4-4).
However, they also noted that a similar pattern was found for both PM2.5 and PMi0. Thus, the
apparent threshold effect was not unique to NO2. NO2 risk estimates for all-cause mortality were
presented only in a figure. Associations between these pollutants and cardiovascular causes,
lung cancer, and COPD were also found in both age groups and sexes. The effect estimates were
particularly larger for COPD deaths. The findings are generally consistent with those from
Nafstad et al. (2003 and 2004) studies, in which a smaller number of male-only subjects were
analyzed. Unlike the 2004 Nafstad study, the Naess et al. study (2007) did not adjust for
smoking or physical activities. While NO2 effects were suggested, the high correlation among
the PM indices and N02 or NOx makes it difficult to ascribe these associations to N02/NOx
alone.
Ages 51-70 years
All causes
Ages 71-90 years
Nitrogen dioxide (|.ig/m}) Nitrogen dioxide {(jg/m )
Figure 3.4-4. Age-adjusted, nonparametric smoothed relationship between NO2 and
mortality from all causes in Oslo, Norway, 1992 through 1995.
Source: Naess et al. (2007).
Gehring et al. (2006) investigated the relationship between long-term exposure to air
pollution originating from traffic and industrial sources and total and cause-specific mortality in
a cohort of women living in North Rhine-Westphalia, Germany. The area includes the Ruhr
region, one of Europe's largest industrial areas. Approximately 4,800 women (age 50 to
August 2007
3-138
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
59 years) were followed for vital status and migration. Exposure to air pollution was estimated
by GIS models using the distance to major roads, NO2, and PM10 (estimated from 0.71 x TSP,
based on available PMi0 and TSP data in the area) concentrations from air monitoring station
data. Cardiopulmonary mortality was associated with living within a 50-m radius of a major
road (RR = 1.70 [95% CI: 1.02, 2.81]), N02 (RR = 1.72 [95% CI: 1.28, 2.29] per 10-ppb
increase in annual average), and PM10 (RR = 1.34 [95% CI: 1.06, 1.71] per 7-|ig/m3 increase in
annual average). Exposure to N02 was also associated with all-cause mortality (1.21 [95% CI:
1.03, 1.42] per 10 ppb). NO2 was generally more strongly associated with mortality than the
indicator for living near a major road (within versus beyond a 50-m radius) or PMi0.
3.5.3 Estimation of Exposure in Long-Term Exposure Mortality Studies
The long-term exposure mortality studies described above can be categorized into two
types based on the way exposure estimates were made: (1) studies in which the community
average values were assigned to all the subjects in that community; (2) studies in which
individual subject's exposure was estimated based on spatial modeling using emission and
concentration data. The first type is what Kunzli and Tager (1997) called "semi-individual"
study in which the information on potential confounders are collected and adjusted for on an
individual basis, but the air pollution exposure estimate was done on an ecologic basis. The
Harvard Six Cities study, the ACS study, and the French PAARC study are of this type. The
studies that used the latter type of approach are mostly studies that attempted to investigate the
effects of traffic-related pollutants. In the Abbey et al. (1999) Seventh-day Adventist study,
individual exposure estimates were made through interpolation of ambient monitors because a
relatively large number of monitors (348) were available within California, but unlike the
European studies, they did not attempt to address specifically the influence of traffic-related
exposures.
The Filleul et al. (2005) French seven cities (24 areas) study found that associations
between N02 and mortality outcomes were found only after exclusions of six area monitors that
were highly influenced by local traffic. This raises a question about potential exposure errors
associated with NO2 or NOx in the semi-individual studies. In order for the population average
exposure estimate to be representative in a semi-ecologic study, the data from locally impacted
N02 monitors may cause exposure error or, at the least, monitor selection criteria need to be
August 2007
3-139
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
consistent across cities (even if those who live near the source are the ones who are adversely
affected). It is not clear; to what extent such exposure error affected other semi-individual
studies. Unlike regional air pollutants (e.g., SO42 and PM2.5) in the eastern United States in
warm seasons when its major constituent is SO42 ) whose levels are generally uniform within the
scale of the metropolitan area, the within-city variation for more locally impacted pollutants such
as NO2, SO2, and CO are likely to be larger and, therefore, are more likely to have larger
exposure errors in the semi-individual studies. The smaller number of monitors available for
NO2 in the United States may make the relative error worse for NO2 compared to other
pollutants. In the Krewski et al. (2000) sensitivity analysis of the Harvard Six Cities study, NO2
was associated with total and cardiopulmonary deaths. However, NO2 was highly correlated
with PM2.5, SO42 , and SO2 in this data set, and combined with the relatively small number of
cities studied, it is difficult to interpret the risk estimates. In Krewski et al.'s sensitivity analysis
of the 1995 ACS study, or in the Pope et al.'s (2002) extended ACS study, NO2 was not
associated with deaths.
In the Hoek et al. study (2002), the indicator of living near a major road was a better
predictor of mortality than the estimated NO2 exposures. In the Gehring et al. study (2006) of
the North Rhine-Westphalia, Germany, the estimated NO2 was a better predictor of total and
cardiopulmonary mortality than the indicator of living near a major road. Comparing the results
for the indicators of living near a major road (categorical) and the estimated N02 or NOx
exposures (continuous) is not straightforward, but it is possible that, depending on the presence
of other combustion sources (e.g., the North Rhine-Westphalia area included highly industrial
areas), NO2 may represent more than traffic-related pollution.
The second type of studies discussed above, which estimated individual exposures, may
provide more accurate exposure estimates than the semi-individual studies. However, because
they generally involve modeling with such information as traffic volume and other emission
estimates in addition to monitored concentrations, additional uncertainties may be introduced.
Thus, validity and comparability of various methods may need to be examined. In addition,
because the review process, such as this, ultimately needs to link the relationship between the
concentration measured at the community monitors and the health effects, interpreting the risk
estimates based on individual-level exposures will require an additional step to translate the
difference. In addition, the studies with estimated individual exposures will need to deal with
August 2007
3-140
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
within-city spatial confounding with socioeconomic conditions. While most of these studies
adjusted for the socioeconomic variables, residual confounding is always a concern. Finally, a
more accurate exposure estimate does not solve the problem of the surrogate role that N02 may
play. Most of these studies do acknowledge this issue and generally treat NO2 as a surrogate
marker, but the extent of such surrogacy and confounding with other traffic- or combustion-
related pollutant is not clear at this point.
3.5.4 Summary of Risk Estimates for Mortality with Long-Term Exposure
Figure 3.4-5 summarizes the NO2 risk estimates for total mortality from the studies
reviewed above. The risk estimates are grouped to those that used ecologic-level exposure
estimates and those that used individual exposure estimates, but because of the small number of
studies listed, no systematic pattern is apparent. Not all of these studies presented correlation
between NO2 and other pollutants, but those that did present some high correlation coefficients.
For example, in the Harvard Six Cities study, the correlation between NO2 and PM2.5 was 0.78.
In the French study, the correlation between N02 and black smoke was 0.72. In the
German study, the correlation between NO2 and PM10 was 0.8 for the 5-year averages.
Therefore, interpretation of the estimates requires additional caution. The risk estimates for total
mortality ranged from 0 to 1.28 per 10-ppb increase in annual or longer averages of NO2. The
risk estimates for more specific categories were often larger than these, but such associations
were often not specific to NO2, or not consistent across studies.
In the long-term studies, those that did report correlation among pollutants suggest that
NO2 was highly correlated with PM indices to the extent (r ~ 0.8) that results from multipollutant
models would be meaningless.
Available information on long-term mortality NO2 risk estimates for more specific causes
is also limited. Among the studies with larger number of subjects, the ACS study (Pope et al.,
2002) examined cardiopulmonary and lung cancer deaths, but as with the all-cause deaths, they
were not associated with N02. In the Naess et al. (2007) analysis of all inhabitants of Oslo,
Norway, age 51 to 90, NO2 risk estimates for COPD were higher than those for other causes, but
the same pattern was seen for PM2.5 and PMi0. In the Gehring et al. (2006) study in North
Rhine-Westphalia, Germany, NO2 risk estimates for cardiopulmonary mortality were larger than
August 2007
3-141
DRAFT-DO NOT QUOTE OR CITE
-------
Relative risk per 10 ppb NO2
0.5 1 0 1.5 2.0 2.5
1
Studies wiith ecologic exposure estimates
Seventh-day Adventist (Abbey et al., 1999)
Male "
-f-
Female
-*
Harvard six cities (Krewski et al., 2000) -
—•—
ACS (Pope et al., 2002) -
i
~
Veterans' cohort study (Lipfert et al., 2006b)
French PAAC survey (Filleul et al., 2005) -
•
Studies w
ith individual exposure estimates
The Netherlands NLCS (Hoeh et al., 2002) -
—a
North Rhine-Westphalia, Germany; female
¦
{Gehring et al., 2006)
Figure 3.4-5. Total mortality risk estimates from long-term studies. The original
estimate for the Norwegian study was estimated for NOx. Conversion of
N02 = 0.35 x NOx was used.
August 2007
3-142
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
those for all-cause mortality, but, again, the same pattern was seen for PMi0. Thus, higher risk
estimates seen for specific causes of deaths were not specific to NO2 in these studies.
In long-term studies, different geographic scales were used to estimate air pollution
exposure estimates across studies. Since the relative strength of association with health
outcomes among various air pollutant indices may be affected by the spatial distribution of the
pollutants (i.e., regional versus local), the numbers of monitors available, and the scale of
aggregation in the study design, it is not clear how these factors affected the apparent difference
in results.
3.6 STUDIES OF NO, HONO, AND HNO3
As discussed earlier in Chapter 3, the family of NOx contains many other chemicals
besides NO2. Of these, chemicals of interest from a toxicology standpoint include nitric oxide
(NO) and HNO3. Most of the data is on NO, with many of the studies using high concentrations.
Only the lower concentration studies (i.e., studies that tested concentrations within an order or
two of magnitude above environmental levels) have been included in this update.
Nitric Oxide (NO)
Endogenous Formation of NO
Compared with NO2, the toxicity database on NO is small. A confounding factor with
the toxicity studies on NO is that it is often difficult to obtain pure NO in air without some
contamination with NO2.
Endogenous NO is formed in cells from the amino acid L-arginine by at least three
different oxygen-utilizing NO synthetases. Endogenous NO is involved in intracellular signaling
in the nervous system, mediation of vasodilation in both systemic and pulmonary circulation, and
mediation of cytotoxicity and host defense reactions in the immune system (Garthwaite, 1991;
Barinaga, 1991; Moncada et al., 1991, 1992; Snyder and Bredt, 1992). There are two basic
actions of endogenous NO. It is involved in a variety of actions at low concentrations (pico-
nanomolar) within nerve and endothelial cells via activation of guanylate cyclase (Ignarro,
1989). The other action of endogenous NO involves high concentrations (nano- to micromolar)
and is formed during induction of enzymes triggered by exposure of cells to bacterial toxins or to
August 2007
3-143
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
growth-regulating factors (cytokinins). The inducible nitric oxide synthetase (iNOS) formation
occurs especially in macrophages and neutrophil leukocytes and is important for the killing of
bacteria and parasites and possibly also for cytostasis in antitumor reactions (Hibbs et al., 1988;
Ignarro, 1989; Moncada et al., 1991, 1992).
Effects of NO on Pulmonary Function, Morphology, and Host Lung Defense Function
Murphy et al. (1964) found that respiratory function was not affected in guinea pigs
exposed to NO at 19,600 |ig/m3 (16 ppm) or 61,300 |ig/m3 (50 ppm) for 4 h. Guinea pigs
exposed to 6130-|ig/m3 (5 ppm) NO for 30 min, twice a week for 7 weeks showed increased
airways responsiveness to acetylcholine. Reversal of methacholine-induced bronchoconstriction
by NO has been reported in guinea pigs at 6130 |ig/m3 (5 ppm) (Dupuy et al., 1992), while in
rabbits, full reversal of methacholine-induced bronchoconstriction was seen at 98,100 |ig/m3
(80 ppm) (Hogman et al., 1993). This action is in contrast to N02 as described above, which
sensitizes the lung to bronchoconstriction following irritant and allergen challenge.
Holt et al. (1979) found grossly emphysematous lungs in NO-exposed mice, whereas
comparable exposures to NO2 resulted in only airspace enlargement. In the study by Azoulay
et al. (1981), rats exposed continuously to 3760-|ig/m3 (2 ppm) NO for 6-h to 6 weeks were
found to have significant enlargement of the airspaces and destruction of alveolar septa.
Results from a recent study (Mercer et al. (1995) suggest that the pattern of injury
produced by NO may differ from NO2, as well as being more potent in introducing certain
changes in lung morphology. In this study, male rats were exposed to either NO or NO2 at
0.5 ppm with twice daily 1-h spikes of 1.5 ppm for 9 weeks. The number of pores of Kohn and
detached alveolar septa were evaluated by electron microscopy, using stereological procedures
for the study of lung structure that involved morphometric analyses of electron micrographs.
The average number of pores per lung for the NO group exceeded by approximately 2.5 times
the mean number for the N02 groups, which was more than 10 times that for controls. The mean
number of detached septa per lung was significantly higher for the NO group (mean 117) than
the NO2 group (mean 20) or the controls (mean 4). There was also a statistically significant
30% reduction in interstitial cells in the NO group, but no significant differences in the other
parenchymal cell types were observed between the controls and the NO- or N02-exposed groups.
Lastly, the thickness of the interstitial space was reduced for the NO group (mean 0.24 |im
August 2007
3-144
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
versus 0.32 jam for controls) but not for the NO2 group (mean 0.29 |im), and epithelial cell
thickness did not differ between the groups.
In a subsequent study, Mercer et al. (1999) exposed rats continuously 22 h/day to 0,
2454, or 7362-|ig/m3 (0, 2, or 6 ppm) NO for 6 weeks. The surface density of the alveolar
basement membrane and the average thickness of the type II alveolar epithelium, although
reduced, did not differ statistically from control animals. Morphometric analysis showed that a
significant greater fraction of the alveolar surface was covered by type II cells in the lungs from
both NO exposure groups. There was a 52% increase in the number of type II cells per surface
area of basement membrane in the 7362-|ig/m3 (6 ppm) NO-exposed animals, as well as an
approximate 3-fold increase in the number of AMs in the airspaces of rat lungs. The mean
number of AMs in the airspaces of lungs from the 2454-|ig/m3 (2 ppm) NO-exposed animals was
elevated but not statistically different from controls. Inhaled NO produced significant
sequestration of platelets in the pulmonary capillaries, as determined from transmission electron
micrographs. The volume density of platelets in the pulmonary capillaries was increased
approximately 2-fold in the NO-exposed groups. Although present in higher numbers, the
platelets did not demonstrate morphologic features of activation such as large, irregular profiles.
Under scanning electron microscopy, fenestrae were found to be distributed throughout the gas-
exchange region of the lungs. Unlike the results of Mercer et al. (1995), there were no
statistically significant differences in the number of lung fenestrae between control and NO-
exposed lungs, as determined by both serial-section counts and scanning electron microscopy.
Thus, it appears that inhaled NO produces a pattern of injury similar to that of NO2, at least in
this regard.
Two studies reported the effects of NO on host defense function of the lungs. Mice
exposed to 12,270-|ig/m3 (10 ppm) NO for 2 h/day, 5 days/week for 30 weeks (Holt et al., 1979)
developed immunological alterations that are difficult to interpret due to the duration dependence
of some of the responses (e.g., an enhancement of the humoral immune response to sheep red
blood cells was seen at 10 weeks, but this was not evident at the end of the exposure series). In
the study by Azoulay et al. (1981), mice exposed continuously to 3760-|ig/m3 (2.0 ppm) NO for
6-h to 4 weeks did not show any effect on resistance to infection induced by a bacterial aerosol
administered after each NO exposure. Although the data are limited, NO does not appear to have
the same effect on parameters related to host immune defense as NO2.
August 2007
3-145
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Metabolic Effects in the Lung and Other Tissues
NO has a higher affinity for heme-bound iron than does CO. This affinity leads to the
formation of methemoglobin and the stimulation of guanylate cyclase. NO stimulates guanylate
cyclase in vitro, resulting in smooth muscle relaxation and vasodilation (Katsuki et al., 1977;
Ignarro, 1989; Moncada et al., 1991). This activation pathway via guanylate cyclase is probably
involved in the vasodilation observed in the pulmonary circulation and the acute bronchodilator
effect from inhaled NO. The initial pulmonary vasodilation that occurs during NO inhalation
does not appear to be maintained chronically. Pulmonary cGMP, iNOS, mRNA, and TNF-a
were increased in the lungs of rats after a 1-h exposure to 7362-|ig/m3 (6 ppm) NO, but
decreased to control values after 1-day and 1-week exposure periods (Brady et. al., 1998). Lipid
peroxidation (measured as malonyl dialdehyde) was decreased at all time points.
It is unclear whether other effects might be exerted from ambient NO via the pathway
involving guanylate cyclase. Since NO is rapidly inactivated by hemoglobin, internal organs
other than the lungs are unlikely to be affected directly by cGMP-mediated vasodilator influence
from ambient concentrations of NO.
Methemoglobin formation from inhaled NO, via the formation of nitrosylhemoglobin
(Oda et al., 1975, 1979, 1980a,b; Case et al., 1979; Nakajima et al., 1980) and subsequent
oxidation with oxygen, has been well-characterized (Kon et al., 1977; Chiodi and Mohler, 1985).
Levels of reduced glutathione in the lung are not changed in mice exposed to NO
concentrations of 12,300 to 25,800 |ig/m3 (10 to 21 ppm) for 3-h daily for 7 days (Watanabe
et al., 1980).
The cytotoxic effects of NO may be explained by the possible mechanism of NO reacting
with thiol-associated iron in enzymes and eventually displacing the iron (Hibbs et al., 1988;
Weinberg, 1992). Other effects of NO with iron and various enzymes and nucleic acids are
listed in Annex AX4.6.
Effects of Short-Term NO Exposure
Research on the role of endogenous NO as a mediator of vascular tone continues to be
active. NO inhalation is used in clinical settings or therapeutically to treat pulmonary
hypertension due to its effects on vascular tone in the pulmonary vascular bed. It is possible that
NO2 could influence airways or pulmonary vascular availability of NO, with consequences for
the regulation of pulmonary vascular function. Ponka and Virtenen (1996) report an association
August 2007
3-146
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
of hospital and ED admissions with NO. Other studies summarized below were experimental in
design.
The effects of inhaled NO are limited to the pulmonary vasculature presumably due to
rapid removal of NO from the circulation arising from reactions with hemoglobin. Although
many studies have used concentrations that are not relevant to environmental levels of air
pollution and were not designed to evaluate the effects of ambient exposures, changes in
pulmonary vascular resistance do occur at concentrations as low as 10 ppm following acute
exposure in pigs (Alving et al., 1993; Holopainen et al., 1999) and 5 ppm in sheep (Fratacci
et al., 1991; Ichinose et al., 1995; DeMarco, et al., 1996). In addition, Jiang et al (2002) reported
in a rodent model of chronic pulmonary hypertension that showed that inhaled NO
concentrations ranging from 0.1 to 2.0 ppm reduced mean pulmonary arterial pressure, while no
such changes were observed in control rats (i.e., normal hypertensive). Thus, changes in
vascular tone from inhaled NO occur in the 5-ppm range, although effects may also be present at
lower concentrations in sensitized animals.
Formation of methemoglobin, via the formation of nitrosylhemoglobin (Oda et al., 1975,
1979, 1980a,b; Case et al., 1979; Nakajima et al., 1980) and subsequent oxidation with oxygen
has been well-described (Kon et al., 1977; Chiodi and Mohler, 1985). Methemoglobin in mice
increased exponentially with the NO concentration, from 24,500 to 98,100 |ig/m3 (20 to
80 ppm); levels rapidly decreased after cessation of exposure, with a half-time of only a few
minutes (Oda et al.,1980b). Exposure of mice to 2940-|ig/m3 (2.4 ppm) NO for 23 to 29 months
resulted in nitrosylhemoglobin levels at 0.01%, while the maximal methemoglobin level was
0.3% (Oda et al., 1980b). Exposure to 12,300-|ig/m3 (10 ppm) NO2 for 6.5 months resulted in
nitrosylhemoglobin level of 0.13% and methemoglobin level of 0.2% (Oda et al., 1976). Rats
exposed to 2450 |ig/m3 (2 ppm) continuously for 6 weeks showed no detectable methemoglobin
(Azoulay et al., 1977). In humans, the ability to reduce methemoglobin varies genetically and is
lower in infants, complicating direct extrapolation of effect levels to human health risk
assessment.
The ability of NO to react with iron-containing enzymes has additional ramifications
beyond methemoglobin. Mice exposed to NO at 11,070 |ig/m3 (9 ppm) for 16-h had decreased
iron transferrin (Case et al., 1979). When exposed to 12,300 |ig/m3 (10 ppm) for 6.5 months,
leukocyte count and proportion of PMN cells were increased (Oda et al., 1976). Red blood cell
August 2007
3-147
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
morphology, spleen weight, and bilirubin were also affected. A slight increase in hemolysis was
seen in mice exposed to 2940 |ig/m3 (2.4 ppm) of NO (Oda et al., 1980a).
Nitrous Acid (HONO)
Two indoor nitrous acid studies were identified that examine health effects and HONO
exposure. One of these was van Strien et al. (2004) discussed above, and the other is Jarvis et al.
(2006). In England, Jarvis et al. (2005) studied 276 adults and related respiratory symptoms and
lung function to home levels of NO2 and HONO as well as outdoor NO2 levels. The median
indoor HONO level was 3.10 ppb (IQR2.05 to 5.09) and 12.76 ppb forN02 indoors and
13.83-ppb NO2 outdoors. The prevalence of wheeze was higher in individuals in the highest
quartile HONO concentration where 33.3% reported wheeze in the previous 12 months versus
those in the lowest concentration quartile where 25.5% reported wheeze. No significant
relationships for N02 were noted. An increase in 1 ppb in indoor HONO was associated with a
decrease in FEVi, percentages predicted (-0.96% [95% CI: -1.82, -0.09). After adjustment for
NO2 measures, the association of HONO with low lung function persisted. In the van Strien
et al. (2004) study of infants in the United States, NO2 and HONO were moderately correlated
(r = 0.40) with higher correlations in homes during autumn and winter (r = 0.83). The highest
nitrous acid level was 4.2 ppb. Nitrous acid exposure was not independently associated with
respiratory symptoms.
There have also been controlled human exposure studies evaluating the effects of nitrous
acid. Beckett et al. (1995) exposed 11 mild asthmatics to air or 0.65 ppm HONO for 3 h,
including three 20-min exercise periods. Spirometry and symptoms were measured during and
immediately following exposure. HONO caused a small increase in irritant respiratory
symptoms, and a 3% decline in FVC, relative to air exposure. FEVi was not significantly
affected. Rasmussen et al. (1995) exposed 15 healthy nonsmokers to air, 0.077, and 0.395-ppm
HONO for 3.5-h including a single 10-min exercise period. HONO caused concentration-related
increases in epithelial cells in eye tear fluid, suggesting eye conjunctival irritation. Specific
airways conductance (the inverse of airways resistance) decreased 10% after HONO and
2% after air. There were no significant effects on FEVi or airways responsiveness.
August 2007
3-148
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Nitric Acid (HNO3)
As discussed in Section 3.4.1, recent reports from the Childrens' Health Study in
Southern California have reported associations between decreased lung function growth and acid
vapor (results primarily from photochemical conversions of oxides of nitrogen to HNO3 vapor).
Significant associations were reported for long-term exposure to acid vapor with decrements in
measures of lung function, though similar associations were reported with N02 and measures of
PM (Gauderman et al., 2004).
Very few toxicological studies have been conducted with HNO3, even though it exists in
ambient air generally as a water-soluble vapor. The few studies available have examined the
histological response to instilled HN03 (usually 1%). This procedure was used to develop
models of bronchiolitis obliterans in various animal species, including dogs, rabbits, and rats
(Totten and Moran, 1961; Greenberg et al., 1971; Gardiner and Schanker, 1976; Mink et al.,
1984). The World Health Organization (WHO, 1997) considered these studies to be informative
for the design of inhalation studies but of questionable relevancy to understanding the pulmonary
response to pure HNO3 vapor. Based on the limited data available, HNO3 appears to affect some
respiratory tract parameters in a fashion that is qualitatively similar to NO2.
In a study by Abraham et al. (1982), normal sheep and allergic sheep (i.e., having airways
responses similar to those occurring in humans with allergic airways disease) were exposed to
4120-|ig/m3 (1.6 ppm) HNO3 vapor for 4-h using a "head-only" chamber. There was decreased
specific pulmonary flow resistance in both groups of sheep, indicating no bronchoconstriction.
The allergic, but not the normal, sheep showed increased airways reactivity to carbachol, both
immediately and 24-h after HNO3 exposure. Exposure of rabbits to HNO3 concentrations of 50,
150, or 450 |ig/m3 (0.02, 0.06, or 0.17 ppm), 4 h/day, 3 days/week for 4 weeks caused no overt
pathology in conducting airways, and airways epithelium was normal in all exposure groups
(Schlesinger et al., 1994). Stimulated superoxide production, however, was reduced in
pulmonary macrophages at all exposure levels. Nadziejko et al. (1992) exposed rats to HNO3
vapor for either a single 4-h exposure period to 1000-|ig/m3 (0.39 ppm) HN03 vapor or 4 h/day
for 4 days to 250-|ig/m3 (0.1 ppm) HNO3 vapor. There were no changes in cell populations in
the BAL fluid from rats under either exposure condition. HNO3 vapor, under either exposure
condition, did not affect zymosan-stimulated respiratory burst activity when pulmonary
macrophages were cultured overnight in order to prevent spontaneous respiratory burst activity.
August 2007
3-149
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
However, when measured using freshly isolated macrophages, both spontaneous and PMA-
stimulated respiratory burst activity was decreased in pulmonary macrophages from rats exposed
to 250-|ig/m3 (0.1 ppm) HN03 vapor for 4 days; results from the single 4-h exposure to
1000-|ig/m3 (0.39 ppm) HNO3 vapor were not reported. Lavage fluid protein content was not
affected, but lavage fluid elastase inhibitor capacity was increased in both exposure groups. It is
not known whether this increase was caused by enhanced production of an elastase inhibitor
within the lung or due to increased permeability and leakage of elastase inhibitor from the
plasma into the lung lining layer.
Sindhu et al. (1998) reported no effects on lung polyamine metabolism in rats exposed to
50-|ig/m3 (0.02 ppm) HNO3 4 h/day, 3 days/week for 40 weeks. No other endpoints were
evaluated.
August 2007
3-150
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 3.2-1. PROPOSED MECHANISMS WHEREBY NOz AND RESPIRATORY
VIRUS INFECTIONS MAY EXACERBATE UPPER AND LOWER
AIRWAY SYMPTOMS
Proposed Mechanisms
Upper Airways
Epithelium
i Ciliary beat frequency
t Epithelial permeability
i Nasal filtering of inhaled allergen and increased penetration to lower
airway
t Conditional of inspire air, low temperature/humidity, bronchospasm
Lower Airways
Epithelium
(as in upper airways)
Cytokines
i Epithelial-derived IL-8
t Macrophage-derived IL-lb
Inflammatory cells
Mast cells
t Mast cell tryptase
Lymphocytes
t Neutrophils
t Total lymphocytes
t NK lymphocytes
i T-helper/T-cytotoxic cell ratio
Inflammatory mediators
t Free radicals, proteases, TXA2, TXB2, LTB4
Allergens
t Penetrance due to ciliostasis
1 PD20 FEVi
t Antigen-specific IgE
Peripheral blood
i Total macrophages
i B and NK lymphocytes
i Total lymphocytes
Source: Chauhanetal. (1998).
August 2007
3-151
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 3.2-2. MULTICITY STUDIES FOR RESPIRATORY DISEASE OUTCOMES AND INCREMENTAL CHANGES
INNOz
95% Confidence
Reference NO2 (ppb)1 Interval
Location
Effect
Age
24-h avg
(Range of
Means Across
Cities)
1-h Max
(Range of Means
Across Cities)
%Change
Normalized
to 10 ppb2
Lower
Upper
Lag
ANALYSES
Barnett et al.
(2005)
Respiratory
0
7.0, 11.5
6.1
-2.0
14.3
0,1
Barnett et al.
(2005)
Respiratory
1 to 4
7.0, 11.5
4.7
-1.6
11.2
0,1
Barnett et al.
(2005)
Respiratory
1 to 4
15.7, 23.2
3.1
0.8
5.4
0,1
Barnett et al.
(2005)
Respiratory
5 to 14
7.0, 11.5
11.4
3.3
19.8
0,1
Barnett et al.
(2005)
Respiratory
5 to 14
15.7, 23.2
5.2
1.8
8.8
0,1
Simpson et al.
(2005a)
Respiratory
>65
16.3, 24.1
3.0
1.5
3.9
0,1
1 Conversion from ng/m3 to ppb: ^ 1.91
2 In order to normalize values for percentage change into a standard unit of 10 ppb, the inverse of the increments identified by the author were
multiplied by 10
-------
&
CJQ
c
to
o
o
<1
TABLE 3.2-3. EFFECTS OF INCLUDING COPOLLUTANTS WITH N02 IN MULTIPOLLUTANT MODELS
Reference, Study
Location and
Period
Statistical Analysis
N02 Averaging
Time and
Mean Levels
(PPb)
Correlation (r) with Other Pollutants
PMin PM,
PM,
SO, CO
03
Standardized* Percent Excess Risk
(95% CI)
Samet et al.
Original two-stage
24-h avg:
0.53
NR
NR
0.51
0.64
0.02
Total Mortality:
(2000)
analytic approach
11.0-39.4
N02 alone: 0.50% [0.10, 0.90]
(Reanalysis
that pooled data
NO2 + PM10: 0.60% [-0.10, 1.40]
Dominici et al.
from multiple
N02 + PM10 + 03: 0.64% [-0.20, 1.60]
(2003)) 90 cities,
locations using
N02 + PM10 + S02: 0.50% [-0.40, 1.40]
United States
GAM, reanalysis
N02 + PM10 + CO: 0.54% [-0.36, 1.44]
1987-1994
with GAM with
more stringent
criteria and with
GLM with natural
cubic splines
Sunyer et al.
Poisson regression,
24-h avg:
NR
NR
NR
NR
NR
NR
Asthma:
(1997) Multi-
GEE; followed
Barcelona:
N02 alone, <15 yrs: 1.5% [0.2, 2.6]
city, Europe
APHEA protocol
27.56 Helsinki:
NO2 + BS, <15yrs: 1.4% [-1.8, 4.7]
(Barcelona,
18.2 London:
N02 + S02, <15 yrs: 1.3% [-0.5, 3.2]
Helsinki, Paris,
35.88 Paris:
N02 alone, 15-64 yrs: 1.5% [0.3, 2.7]
London) 1986-
21.84
N02 + BS, 15-64 yrs: 3.4% [1.0, 5.9]
1992
Atkinson et al.
Poisson regression,
1-hmax: 50.3
NR
NR
NR
NR
NR
NR
Asthma among 0-14 year olds:
(1999b) London,
followed APHEA
(17.0)
N02 alone: 7.4% [3.6, 11.3]
United Kingdom,
protocol
N02 + S02: 4.8% [0.3, 9.4]
1/92-12/94
NO2 + CO: 6.9% [3.0, 11.0]
NO2 + PM10: 5.8% [1.6, 10.1]
NO2 + BS: 6.9% [3.0, 11.0]
N02 + 03: 8.0% [4.2, 12.0]
Galan et al.
Poisson Regression
24-h avg: 34.89
0.76
NR
NR
0.61
NR
-0.21
Asthma:
(2003) Madrid,
with (1) APHEA
(9.36)
N02 alone: 6.7% [2.6, 11.1]
Spain 1995-1998
protocol, and (2)
N02 + S02: 6.3% [0.8, 12.1]
GAM with strict
N02 + PM10: 0.2% [- 5.8, 6.3]
criteria
LtJ
H
6
o
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
-------
&
CJQ
c
to
o
o
<1
TABLE 3.2-3 (cont'd). EFFECTS OF INCLUDING COPOLLUTANTS WITH NQ2 IN MULTIPOLLUTANT MODELS
Correlation (r) with Other Pollutants
Reference, Study
Location and
Period
Statistical
Analysis
N02 Averaging
Time and
Mean Levels
(PPb)
PMii
PM,
PMii
SO, CO
03
Standardized* Percent Excess Risk
(95% CI)
o
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
McConnell et al.
(2003), Southern
California, United
States 1993-1999
Nafstad et al.
(2003), Oslo,
Norway
1972-1999
Burnett et al.
(1997b) Toronto,
ON, Canada
Burnett et al.
(1999) Toronto,
ON, Canada
1980-1994
Three-stage
regression to
yield a logistic
mixed-effects
model
24-havg: 19.4
(11.3)
0.2
0.54
-0.22
NR NR 0.59
Cox-proportional 24-h avg (NOx): NR
hazard regression 5.6
NR
NR
0.63 NR NR
Poisson
regression, GEE,
GAM
Poisson
regression
1-h max: 38.5
0.61
NR
NR
0.46 0.25 0.07
24-havg: 25.2
(9.1)
0.52
0.5
0.38
0.54 0.55 -0.03
Asthma:
N02 Alone: 7.4%
N02 + 03: 5.9%
NO2 + PM10: 6.7%
N02 + PM25: 5.5%
NO2 + PM10-2.5: 8.2%
Lung Cancer Incidence:
NOx alone: 34.4% [7.9, 71.2]
NOx+ S02: 44.3% [12.0, 82.9]
Other Cancer Incidence:
NOx alone: 7.9% [-3.8, 25.1]
NOx + S02: 20.6% [3.9, 39.3]
All respiratory hospital admissions:
N02 alone: 25.2% [13.2, 38.2]
N02 + PM10: 22.1% [t = 2.85]
N02 + O3+ S02: 15.5% [t = 2.45]
N02 + 03+ S02 + PM10: 15.5% [t = 1.77]
Respiratory infection:
N02 alone: 3.7% [SE >3]
NO2 + SO2 + O3 + PM10: 3.3% [SE >3]
N02 + S02 + 03 +PM25: 3.2% [SE >2]
N02 + S02 + 03 +PM10.25: 3.6% [SE >3]
-------
&
CJQ
c
to
o
o
<1
3.2-3 (cont'd). EFFECTS OF INCLUDING COPOLLUTANTS WITH NQ2 IN MULTIPOLLUTANT MODELS
Reference,
N02 Averaging
Correlation (r) with Other Pollutants
Study Location
Statistical
Time and Mean
Standardized* Percent Excess Risk
and Period
Analysis
Levels (ppb)
PMio PM2.5 PM10-2.5 SO2
CO
O3
(95% CI)
Lee et al. (2002)
Poisson
24-h avg: 31.5
0.74 NR NR 0.72
0.79
-0.07
Asthma:
Seoul, Korea
regression,
(10.3)
N02 alone: 21.1% [13.9, 28.4]
12/1/1997-
GAM
N02 + PM10: 18.2% [9.7, 26.9]
12/31/1999
N02 + S02: 28.4% [15.4, 41.7]
N02 + 03: 19.7% [12.5, 28.4]
NO2 + CO: 16.8% [4.1, 31.3]
N02 + 03 +CO + PM10 + S02: 13.7%
[0.3,28.7]
Schwartz et al.
Logistic
24-h avg: 13.3
0.36 0.35 NR 0.51
NR
-0.28
Cough Incidence:
(1994), Six
regression,
N02 alone: 61.3% [8.2, 143.4]
cities, United
subsequent
NO2 + PM10: 36.9% [-11.6, 113.2]
States 1984-
analysis
NO2 + O3: 61.3% [8.2, 140.3]
1988
using GAM
N02 + S02: 18.8% [11.6, 69.0]
Mortimer et al.
Linear mixed
4-havg: 32
NR NR NR NR
NR
0.29
Morning %PEFR
(2002) Eight
effects
N02 alone: 48% [2, 116]
urban areas,
models and
NO2 + O3: 40% [-7, 109]
United States
GEE
N02 + 03+ S02: 31% [-13, 109]
1993
N02 + 03 + S02 + PM10: 45% [- 37,
234]
Schildcrout
Logistic and
24-h avg: 17.8-26.0
0.26, NR NR 0.23,
0.63,
0.04,
Asthma symptoms:
et al. (2006)
Poisson
0.64 0.68
0.92
0.47
N02 alone: 4.0% [1.0, 7.0]
Eight North
regression
N02 + CO: 4.0% [0.0, 8.0]
American Cities
with GEE
NO2 + PM10: 4.0% [0.0, 7.0]
1993-1995
N02 + S02: 4.0% [-1.0, 8.0]
Rescue Inhaler Use:
N02 alone: 3.0% [1.0, 5.0]
N02 + CO: 4.0% [0.0, 7.0]
N02 + PM10: 2.0% [0.0, 5.0]
N02 + S02: 3.0% [-2.0, 5.0]
H
6
o
2
o
H
O
c
o
H
ffl
o
o
HH
H
W
* 24-h avg N02 standardized to 20-ppb increment; 1-h max N02 standardized to 30-ppb increment
NR: Not Reported
-------
TABLE 3.4-1. ASSOCIATIONS BETWEEN EXPOSURE TO TRAFFIC AT HOME
AND ASTHMA HISTORY
Exposure Metric
Odds Ratio per IQR OR* (95% CI)
Distance to freeway
1.89(1.19-3.02)
Traffic volume within 150 meters
1.45 (0.73-2.91)
Model-based pollution from:
Freeways
2.22(1.36-3.63)
Other roads
1.00 (0.75-1.33)
Freeways and other roads
1.40 (0.86-2.27)
*Odds ratio per change of 1IQR. For distance to freeway, OR for the 25th percentile compared with the 75th percentile (i.e.,
living closer compared with farther from the freeway). For remaining traffic variables, OR for the 75th percentile compared
with the 25th percentile. All models were adjusted for sex, race, Hispanic ethnicity, cohort, and community.
Source: Gaudermann et al. (2005).
TABLE 3.4-2. ASSOCIATIONS BETWEEN MEASURED NOz AND ASTHMA-
RELATED OUTCOMES (N = 208)
Outcome
No.
Measured N02
OR* (95% CI)
Distance to Freeway
OR* (95% CI)
Model-based Pollution
From Freeways OR*
(95% CI)
Lifetime history
of asthma
31
1.83 (1.04-3.21)
1.89(1.19-3.02)
2.22(1.36-3.63)
Recent wheezef
43
1.72 (1.07-2.77)
1.59 (1.06-2.36)
1.70 (1.12-2.58)
Recent wheeze
with exercise f
25
2.01 (1.08-3.72)
2.57 (1.50-4.38)
2.56 (1.50-4.38)
Current asthma
medication use
26
2.19 (1.20-4.01)
2.04 (1.25-3.31)
1.92(1.18-3.12)
*Odds ratio per change of 1 IQR in exposure (see footnotes to Table 3.4-1).
fWithin the last 12 months.
Source: Gaudermann et al. (2005).
August 2007
3-156
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4. SUSCEPTIBLE AND VULNERABLE POPULATIONS
4.1 INTRODUCTION
The previous AQCD for Oxides of Nitrogen (1993) identified certain groups within the
population that may be more susceptible to the effects of N02 exposure, including persons with
preexisting respiratory disease, children, and the elderly. Many other factors such as gender,
nutritional status, smoking, and genetic variability also may contribute to the differential effects
of environmental pollutants, including NOx.
The reasons for paying special attention to these groups were that (1) they may be
affected by lower levels of NO2 than the general populations or that (2) the impact of an effect
may be greater for these groups. Finally, epidemiological studies reviewed in the previous
AQCD for Oxides of Nitrogen identified children aged 5 to 12 years as a potentially susceptible
subpopulation for increases in N02 respiratory morbidity.
In the current document, we will focus on the susceptibility of subpopulations with
preexisting asthma and cardiovascular disease, age-related susceptibility and vulnerability, high-
exposure occupational groups, and genetic factors.
4.1.1 Preexisting Disease as a Potential Risk Factor
A recent report of the National Research Council (NRC) emphasized the need to evaluate
the effect of air pollution on susceptible groups including those with respiratory illnesses and
cardiovascular disease (CVD) (NRC, 2004). Generally, chronic obstructive pulmonary disease
(COPD), conduction disorders, congestive heart failure (CHF), diabetes, and myocardial
infarction (MI) are conditions believed to put persons at greater risk of adverse events associated
with air pollution. In addition, epidemiological evidence indicates that persons with bronchial
hyperresponsivness (BHR) as determined by methacholine provocation may be at greater risk of
symptoms, such as phlegm and lower respiratory symptoms, than subjects without BHR (Boezen
et al., 1998). Several researchers have investigated the effect of air pollution among potentially
sensitive groups with preexisting medical conditions. Asthmatics are known to be one of the
most N02-responsive subgroups in the population; the evidence related to asthmatics is discussed
in further detail below.
August 2007
4-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Asthmatics
Airways hyperresponsiveness in asthmatics to both nonspecific chemical and physical
stimuli and to specific allergens appears to be the most sensitive indicator of response to NO2.
Responsiveness is determined using a challenge agent, which causes an abnormal degree of
constriction of the airways as a result of smooth muscle contraction. This response ranges from
mild to severe (spanning orders of magnitude) and is often accompanied by production of
sputum, cough, wheezing, shortness of breath, and chest tightness. Though some asthmatics do
not have this bronchoconstrictor response and some nonasthmatic individuals do (Pattenmore
et al., 1990), increased airways responsiveness is correlated with asthma symptoms and
increased asthma medication usage. Clinical studies have reported increased airways
responsiveness to allergen challenge in asthmatics following exposure to 0.26-ppm NO2 for
30 min during rest (Barck et al., 2002; Strand et al., 1996, 1998).
Epidemiological studies have reported associations with a range of health outcomes with
both short-term and long-term N02 exposure in asthmatics; Table 4.1 highlights some of the
findings for asthmatics discussed in Chapter 3. The results reported in these studies generally
report a positive excess risk for asthmatics associated with NO2. The recent evidence
strengthens conclusions drawn in the 1993 AQCD for Oxides of Nitrogen that asthmatics are
likely more susceptible to effects from N02 exposures than the general public.
Persons with Cardiovascular Diseases
Epidemiological studies consistently have demonstrated an association between ambient
levels of air pollutants and daily hospital admissions, and CVD emergency department (ED)
visits. Recent epidemiological studies also have shown that persons with preexisting
cardiopulmonary conditions are at increased risk for adverse cardiac health events associated
with ambient N02 concentrations (Peel et al., 2006; Mann et al., 2002; D'Ippoliti et al., 2003;
von Klot et al., 2005). Peel et al. (2006) reported evidence of effect modification by co-morbid
hypertension and diabetes for the association of ED visits for arrhythmia associated with NOx
exposure. In another study, a statistically significant positive relationship was found between
N02 concentrations and hospitalizations for ischemic heart disease (IHD) among those with prior
diagnoses of CHF and arrhythmia (Mann et al., 2002). The authors speculated, however that the
vulnerability of the secondary CHF group may be due to differential diagnoses in this group
(Mann et al., 2002). Modification of the association between N02 and MI by conduction
August 2007
4-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
disorders was observed in another study (D'Ippoliti et al., 2003). Though there is limited
evidence from clinical or toxicological studies on potential susceptibility in those with CVDs, the
epidemiological evidence suggests that these individuals may be more sensitive to effects of N02
exposure.
4.1.2 Age-Related Variations in Susceptibility/Vulnerability
Children and elders often are both considered at increase risks from air pollution,
compared to the general population. The American Academy of Pediatrics (2004) notes that
children and infants are among the most susceptible to many air pollutants, including NO2.
Eighty percent of alveoli are formed postnatally and changes in the lung continue through
adolescence; the developing lung is highly susceptible to damage from exposure to
environmental toxicants (Dietert et al., 2000). Children also have increased vulnerability as they
spend more time outdoors, are highly active, and have high minute ventilation, which
collectively increase their dose (Plunkett et al., 1992; Wiley et al., 1991a,b). In addition to
children, the elderly are frequently classified as being particularly susceptible to air pollution.
The basis of the increased sensitivity in the elderly is not known, but one hypothesis is that it
may be related to changes in the respiratory tract lining fluid antioxidant defense network (Kelly
et al., 2003). Also, the generally declining health status of many elders may increase their risks
to air pollution induced effects.
While evidence is limited for age-specific associations between NO2 and acute
respiratory ED visits, there is stronger evidence of the association between ambient NO2
concentrations and hospital admissions for children and older adults. Peel et al. (2005) and
Atkinson et al. (1999b) each found that the percent increase in ED visits for asthma among
children was twice that found for subjects of all ages. Specifically, Peel et al. (2005) found that
asthma ED visits among children (2 to 18 years) increased by 2.7% in response to a 20-ppb
increase in the 1-h maximum NO2 concentration, while the increase for all ages was 1.4%.
Similarly, Atkinson et al. (1999b) reported an 8.97% increase in ED visits for asthma among
children aged 0 to 14 years associated with a 36-ppb increase in the 1-h maximum NO2
concentration, while the increase for adults aged 15 to 64 and all ages together were 4.44% and
4.37%), respectively. Two additional studies (Sunyer et al., 1997; Migliaretti et al., 2005) found
no difference in the rates of ED visits associated with NO2 concentrations for children <15 years
August 2007
4-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
and adults aged 15 to 64 years. Migliaretti et al. (2005) found that a 5.2-ppb increase in NO2 was
associated with a 7.7% increase in ED visits for asthma for participants over 64 years of age,
while the same increment was associated with a 2.4% increase among participants of all ages.
Atkinson et al. (1999b) evaluated the effect of a 36-ppb increase in NO2 on ED visits for all
respiratory causes and found percent increases to be higher among children (1 to 14 years,
2.17%)) and the elderly (>65 years, 3.65%>) compared to adults aged 15 to 64 (1.87%).
A number of studies investigated the association between ambient N02 levels and
hospital admissions for all respiratory causes stratified by age group (Luginaah et al., 2005;
Schouten et al., 1996; Ponce de Leon et al., 1996; Atkinson et al., 1999a; Prescott et al., 1998;
Fusco et al., 2001; Braga et al., 2001; Wong et al., 1999). Of the six studies that evaluated the
elderly population, four found that the percent increase in hospital admissions for all respiratory
causes associated with ambient NO2 concentrations was higher for the elderly age group
(>65 years) compared with the adult age group (Schouten et al., 1996; Ponce de Leon et al.,
1996; Atkinson et al., 1999a; Prescott et al., 1998). Luginaah et al. (2005) and Wong et al.
(1999) found no statistically significant difference in the elderly and adult age groups. Braga
et al. (2001) only included subjects aged 0 to 19 years, but further stratified to find the largest
percent increase in hospital admissions associated with NO2 concentrations in the 0 to 2 age
group (9.4%). Fusco et al. (2001) reported a larger increase in hospital admissions for all
respiratory diseases among children compared with subjects of all ages (4.0% and 2.5%,
respectively). The difference persisted when hospital admissions were limited to asthma only.
Likewise, Fusco et al. (2001) reported a larger increase in hospital admission for asthma among
children compared with subjects of all ages (10.7% and 4.6%, respectively). Hinwood et al.
(2006), Atkinson et al. (1999a), and Anderson et al. (1998) also found larger increases in hospital
admissions for asthma among children (0 to 14 years) and the elderly (>65 years) compared to
subjects of all ages, though the increases reported in these studies were more modest in
magnitude than that reported by Fusco et al. (2001).
In elderly populations, associations between N02 and hospitalizations or ED visits for
CVD, including stroke, have been observed in several multicity studies (Barnett et al., 2006;
Simpson et al., 2005; Wellenius et al., 2005; Morris et al., 1995). However, some results were
inconsistent across cities (Morris et al., 1995), and investigators could not distinguish the effect
of N02 from the effect of other traffic-related pollutants such as CO and particulate matter (PM).
August 2007
4-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Reductions in blood hemoglobin (-10%) have been reported in healthy subjects following
exposure to NO2 (1 to 2 ppm) for a few hours during intermittent exercise (Frampton et al.,
2002). The consequence of this hemoglobin reduction in individuals with significant underlying
lung disease, heart disease, or anemia has not been evaluated, but the reductions could lead to
adverse cardiovascular consequences.
Many field studies focused on the effect of NO2 on the respiratory health of children,
while fewer field studies compared the effect of N02 in adults and other age groups. In general,
children and adults experienced decrements in lung function associated with short-term ambient
NO2 exposures (see Section 3.2.1.2 for more details). Importantly, a number of long-term
exposures studies suggest effects in children - impaired lung function growth, increased
respiratory symptoms and infections, and onset of asthma (see Table 4.1 and Section 3.4.1.1).
Several mortality studies have investigated age-related differences in NO2 effects.
Among the studies that observed positive associations between NO2 and mortality, a comparison
of all age or <64 years of age MVmortality risk estimates to that of the >65 years of age
indicates that, in general, the elderly population is more susceptible to N02 effects (Biggeri et al.,
2005; Burnett et al., 2004). One study (Simpson et al., 2005) found no difference in increases in
CVD mortality associated with NO2 concentrations between all ages and those participants
>65 years of age.
Collectively, there is supporting evidence of age-related differences in susceptibility to
NO2 health effects. Elders (>65 years of age) appears to be at increased risk of MVrelated
hospitalizations. Asthmatic children (<18 years of age) are likely to experience other adverse
respiratory health outcomes with increased NO2 exposure e.g. airways hyperresponsivness often
accompanied by production of sputum, cough, wheezing, shortness of breath, chest tightness,
and increased use of asthma medication. Toxicological evidence available in the 1993 AQCD
also provided evidence for age-related differences in MVinduced lung injury. Neonates, prior
to weaning, appeared to be relatively resistant to effects of NO2. However, responsiveness
increased in young animals following weaning, appeared to decline in mature animals, then an
increase in responsiveness occurred at some point in senescence. Additionally, new evidence
since the 1993 AQCD raises concerns for increased severity and frequency of respiratory
infections, decreased lung function growth, increased onset of asthma and allergy, increase
hospital and ED visits for asthmatic children.
August 2007
4-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4.1.3 High-Exposure Groups
Lee et al. (2000) reported that NO2 concentration in heavy traffic (-60 ppb) can be over
twice that of a residential outdoor level (-26 ppb) in North America. Westerdahl et al. (2005)
reported on-road N02 concentrations in Los Angeles ranging from 40 to 70 ppb on freeways,
compared to 20 to 40 ppb on residential or arterial roads. People in traffic can potentially
experience high concentrations of NO2 as a result of the high air exchange rates for vehicles.
Park et al. (1998) observed that the air exchange in cars varied from 1 to 3 times per hour, with
windows closed and no mechanical ventilation, to 36 to 47 times per hour, with windows closed
and the fan set on fresh air. These results imply that the NO2 concentration inside a vehicle
could rapidly approach those outside the vehicle during commuting. It follows that people with
occupations that require them to be in or close to traffic or roadways (i.e. bus and taxi drivers,
highway patrol officers) could be differentially exposed to N02 and, therefore, should be
considered a susceptible population.
While driving, concentrations for personal exposure in a vehicle cabin could be
substantially higher than ambient concentrations measured nearby. Sabin et al. (2005) reported
that N02 concentrations in the cabins of school buses in Los Angeles ranged from 24 to 120 ppb,
which were typically factors of 2 to 3 (maximum, 5) higher than at ambient monitors in the area.
Lewne et al. (2006) reported work hour exposures to NO2 for taxi drivers (25.1 ppb), bus drivers
(31.4 ppb), and truck drivers (35.6 ppb). These levels were 1.8, 2.7, and 2.8 times ambient
concentrations. Riediker et al. (2003) studied the exposure to N02 inside patrol cars. The
authors found that the mean and maximum NO2 concentrations in a patrol car were 41.7 and
548.5 ppb compared to 30.4 and 69.5 ppb for the ambient sites. These studies suggest that
people in traffic can be exposed to much higher levels of NO2 than are obtained at ambient
monitoring sites. Due to the high peak exposures while driving, total personal exposure could be
underestimated if exposures while commuting are not considered; and sometimes exposure in
traffic can dominate personal exposure to NO2 (Lee et al., 2000; Son et al., 2004). Variations in
traffic-related exposure could be attributed to time spent in traffic, type of vehicle, and distance
from major roads (Sabin et al., 2005; Son et al., 2004; Chan et al., 1999). Sabin et al. (2005)
reported that the intrusion of the vehicle's own exhaust into the passenger cabin is another NO2
source contributing to personal exposure while commuting but that the fraction of air inside the
August 2007
4-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
cabin from a vehicle's own exhaust was small, ranging from 0.02 to 0.28%, increasing with the
age of the vehicle (CARB, 2007).
Distance to major roadways could be another factor affecting indoor and outdoor N02
concentration, and personal NO2 exposure. Many studies show that outdoor NO2 levels are
strongly associated with distance from major roads (i.e., the closer to a major road, the higher the
NO2 concentration) (Gilbert et al., 2005; Roorda-Knape et al., 1998; Lai and Patil, 2001;
Kodama et al., 2002; Gonzales et al., 2005; Cotterill and Kingham, 1997; Nakai et al., 1995).
Meteorological factors (wind direction and wind speed) and traffic density are also important in
interpreting measured NO2 concentrations (Gilbert et al., 2005; Roorda-Knape et al., 1998;
Rotko et al., 2001; Aim et al., 1998; Singer et al., 2004; Nakai et al., 1995). Singer et al. (2004)
reported results of the East Bay Children's Respiratory Health Study. The authors found that
NO2 concentrations increased with decreasing downwind distance for school and neighborhood
sites within 350 m downwind of a freeway, and schools located upwind or far downwind of
freeways were generally indistinguishable from one another and regional pollution levels.
Most studies show that indoor N02 is correlated with outdoor N02 and is also a function
of distance to traffic, traffic density, and meteorological parameters. For example,
Roorda-Knape et al. (1998) reported thatN02 concentrations in classrooms were significantly
correlated with car and total traffic density (r = 0.68), percentage of time downwind (r = 0.88)
and distance of the school from the roadway (r = -0.83).
Personal exposure is associated with traffic density and proximity to traffic, although
personal exposure is also influenced by indoor sources. Aim et al. (1998) reported that NO2
exposures was higher for the children living in the downtown (13.9 ppb) than in the suburban
area (9.2 ppb, p = 0.0001) of Helsinki. Within the urban area of Helsinki, Rotko et al. (2001)
observed that the NO2 exposure was significantly associated with traffic volume near homes.
The average exposure level of 138 subjects having low or moderate traffic near their homes was
12.3 ppb, while the level was 15.8 ppb for the 38 subjects having high traffic volume near home.
Gauvin et al. (2001) reported the ratio of traffic density to distance from a roadway was one of
the significant interpreters of personal exposure in Grenoble, Toulouse, and Paris. After
controlling indoor source impacts on personal exposure, Kodama et al. (2002) and Nakai et al.
(1995) observed that personal exposure decreased with increasing distance from residence home
to major road.
August 2007
4-7
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Although traffic is a major source of ambient NO2, industrial point sources are also
contributors to ambient NO2. However, no published reports were found to address the effect of
those sources on population exposure within the United States. Nerriere et al. (2005) measured
personal exposures to fine PM (PM2.5), PM10, and NO2 in traffic dominated, urban background
and industrial settings in Paris, Grenoble, Rouen, and Strasbourg, France. They always found
highest ambient concentrations and personal exposures close to traffic. In some cases, traffic
urban background concentrations of N02 were higher than in the industrial zone. However, PM
levels and personal exposures tended to be higher in the industrial area than in the traffic-
dominated area. It should be remembered that there can be high traffic emissions in industrial
zones, such as in the Ship Channel in Houston, TX. In rural areas where traffic is sparse, other
sources could dominate. Martin et al. (2003) found pulses of N02 release from agricultural areas
occur following rainfall. Other rural contributors to NO2 include wildfires and residential wood
burning.
4.1.4 Genetic Factors for Oxidant and Inflammatory Damage from Air
Pollutants
A consensus now exists among epidemiologists that genetic factors related to health
outcomes and ambient pollutant exposures merit serious consideration (Kauffmann et al., 2004;
Gilliland et al., 1999). Several criteria must be satisfied in selecting and establishing useful links
between polymorphisms in candidate genes and adverse respiratory effects. First, the product of
the candidate gene must be significantly involved in the pathogenesis of the adverse effect of
interest, often a complex trait with many determinants. Second, polymorphisms in the gene must
produce a functional change in either the protein product or in the level of expression of the
protein. Third, in epidemiological studies, the issue of confounding by other environmental
exposures must be carefully considered.
Several glutathione s-transferase (GST) families have common, functionally important
polymorphic alleles that significantly affect host defense function in the lung (e.g., homozygosity
for the null allele at the GSTM1 and GSTT1 loci, and homozygosity for the A105G allele at the
GSTP1 locus). GST genes are inducible by oxidative stress. Exposure to radicals and oxidants
in air pollution induces decreases in GSH that increase transcription of GSTs. Individuals with
genotypes that result in enzymes with reduced or absent peroxide activity are likely to have
reduced oxidant defenses and increased susceptibility to inhaled oxidants and radicals.
August 2007
4-8
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Romieu et al. (2006) investigated the relationships between common polymorphisms in
two genes involved in response to oxidative stress (i.e., GSTM1 and GSTP1) and both
respiratory symptoms and lung function in response to 03, N02, and PMi0 among 151 asthmatic
children. The children were genotyped using polymerase chain reaction (PCR) methods and
followed from October 1998 to April 2000. After adjusting for asthma severity, temperature,
environmental tobacco smoke, chronological time and supplementation group, children with the
GSTM1 null polymorphism were more likely to report difficulty breathing in response to 03 than
GSTM1 positive children. Children with the GSTP1 Val/Val genotype were more likely to
experience breathing difficulty and bronchodilator use in response to O3 compared with children
with the GSTP1 Ile/Ile and Ile/Val genotypes. This pattern was consistent for O3 exposure over
various numbers of lag days. Table 4.1-1 shows the results for the effect of a 20-ppb exposure to
NO2 on respiratory symptom according to genetic polymorphisms of GSTM1 and GSTP1. A
small increase in breathing difficulty was observed with a 20-ppb increase in ambient NO2 levels
for all of the genotype groups across various numbers of lag days, though none of these
associations was statistically significant. This suggests that ambient N02 concentrations may
affect breathing in children regardless of their GSTM1 or GSTP1 genotypes. In contrast to O3,
the GSTM1 positive and GSTP1 Ile/Ile and Ile/Val genotype children were more likely to
experience cough and bronchodilator use in response to NO2 than GSTM1 null and GSTP11
Val/Val children. Contrary to expectations, a 20-ppb increase in ambient NO2 concentrations
was associated with a decrease in bronchodilator use among GSTP1 Val/Val genotype children.
A few studies of genotypes and respiratory health or general air pollution also have been
conducted. Lee et al. (2004) studied ninth grade schoolchildren with asthma in Taiwan for a
gene-environmental interaction between GSTP1105 genotypes and outdoor pollution. While
noting mean N02 levels of 41.2 ppb from 1994 to 2001, they examined general district air
pollution levels of low, moderate, and high in the analysis and reported results suggested of such
an interaction of asthma, genotype and air pollution. Gilliland et al. (2002) examined effects of
GSTM1, GSTT1, and GSTP1 genotypes and acute respiratory illness, specifically respiratory
illness related absences from school. The goal was to examine potential susceptibilities on this
basis, but not specifically air pollutants. They concluded that fourth grade school children who
inherited a GSTP1 Vail 05 variant allele had a decreased risk of respiratory illness related school
absence, indicating that GSTP1 genotype influences the risk and/or severity of acute respiratory
August 2007
4-9
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
infections in school-aged children. Gauderman et al. (2007) described a methodology that uses
principal components (PC) analysis computed on single nucleotide polymorphisms (SNP)
markers for testing association between a disease and a candidate gene. As an example, they
evaluated subjects in the children's health study (CHS) looking at chronic bronchitis symptoms.
The authors observed stronger evidence of an association using the PC approach (p = 0.044) than
using either a genotype-based (p = 0.13) or haplotype-based (p = 0.052) approach. This
methodology may be applied to relationships in this and other databases to evaluate aspects of air
pollutants such as NO2. Khoury et al. (2005) states that while genomics is still in its infancy,
opportunities exist for developing, testing, and applying the tools of genomics to public health
research with possible environmental causes.
In summary, N02-related genetic effects have been presented primarily by Romieu et al.
(2006) and indicate that asthmatic children with GSTM1 null and GSTP1 Val/Val genotypes
appear to be more susceptible to developing respiratory symptoms related to O3, but not NO2,
concentrations. It was suggested that ambient NO2 concentrations may affect breathing in
children regardless of their GSTM1 or GSTP1 genotypes. In contrast to 03, the GSTM1 positive
and GSTP1 Ile/Ile and Ile/Val genotype children were more likely to experience cough and
bronchodilator use in response to NO2 than GSTM1 null and GSTP11 Val/Val children.
Contrary to expectations, a 20-ppb increase in ambient NO2 concentrations was associated with a
decrease in bronchodilator use among GSTP1 Val/Val genotype children. Understanding a basis
for susceptibility to asthma, will facilitate improve the precision of future studies of air pollution
and health.
4.1.5 Vulnerability Related to Socioeconomic Status
Finally, it is possible that individuals with lower socioeconomic status be more
vulnerable to the effects of exposure to NO2. There are a range of potential factors that would
cause increased vulnerability, including reduced access to health care or living in areas with
increased emissions, such as near major sources or roadways. However, the evidence
specifically related to vulnerability is sparse. In one new study, Clougherty et al. (2007)
evaluated the synergistic effects of traffic related air pollutants, including NO2, and the
synergistic effects between social and physical factors in asthma, e.g. stress, violence. The
authors reported an elevated risk of asthma with a 4.3 ppb increase in NO2 exposure solely
August 2007
4-10
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
among children with above-median exposure to violence in their neighborhoods, an indicator of
lower socioeconomic status.
4.2 PUBLIC HEALTH IMPACTS
Exposure to ambient NOx (primarily N02 studied) is associated with a variety of health
outcomes. In protecting public health, a distinction must be made between health effects that are
considered "adverse" and those that are not. What constitutes an adverse health effect varies for
different population groups, with some changes in healthy individuals not being viewed as
adverse but those of similar type and magnitude in other susceptible individuals with preexisting
disease being seen as adverse.
4.2.1 Concepts Related to Defining of Adverse Health Effects
The American Thoracic Society (ATS) published an official statement on "What
Constitutes an Adverse Health Effect of Air Pollution?" (ATS, 2000b). This statement updated
guidance for defining adverse respiratory health effects published 15 years earlier (ATS, 1985).
The 2000 update takes into account (1) new investigative approaches used to identify the effects
of air pollution; (2) increased focus on quality of life measures more sophisticated considerations
of risks, particularly to susceptible groups; and (3) exposure to air pollution that increases the
risk of an adverse effect to the entire population is viewed as adverse, even though it may not
increase the risk of any identifiable individual to an unacceptable level. For example, if the risk
distribution for asthmatics is shifted toward increased risks, this is considered adverse even if
this shift does not result in clinically observable effects at the lower end of the distribution,
because individuals within the population would have diminished reserve function.
Reflecting new investigative approaches, the ATS statement also describes the potential
usefulness of research into the genetic basis for disease, including responses to environmental
agents that provide insights into the mechanistic basis for susceptibility and provide markers of
risk status. Likewise, biomarkers that are indicators of exposure, effect, or susceptibility may
someday be useful in defining the point at which one or an array of responses should be
considered an adverse effect.
In an attempt to provide information useful in helping to define adverse health effects
associated with ambient NO2 exposure by describing the gradation of severity and adversity of
August 2007
4-11
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
respiratory related NO2 effects, and those definitions are presented here as Tables 4.1-2 and
4.1-3. The severity of effects described in those tables and the approaches taken to define their
relative adversity are adapted from the ATS statements (ATS, 1985, 2000).
As assessed in detail in earlier chapters of this document and briefly recapitulated in
preceding sections of this chapter, exposures to a range of NO2 concentrations have been
reported to be associated with increasing severity of several categories of health effects.
4.2.2 Estimation of Potential Numbers of Persons in At-Risk Susceptible
Population Groups in the United States
4.2.2.1 Asthma
A recent CDC report (CDC, 2005) on the prevalence of asthma in the United States,
states that the burden of asthma has increased over the past two decades. It is known that a
complex set of factors influence asthma; it is not clear what factors are driving this increase in
prevalence. In 1982, roughly 4% of people younger than 18 years old had asthma. Asthma is
the most prevalent chronic disease among children, and is the number one reason for school
absences. By 1994, this rate had increased to almost 7%, or approximately five million people
under the age of 18. Furthermore, from 1982 through 1994, the overall annual age-adjusted
prevalence rate of asthma for people younger than 18 years old increased by 72%. In 2005,
approximately 22.2 million (or 7.7% of the population) currently had asthma. The incidence was
higher among children (8.9% of children) compared to adults (7.2% of adults.) Prevalence also
is higher among certain ethnic or racial groups, such as Puerto Ricans, American Indians, Alaska
Natives, and African Americans. The asthma prevalence rate for black Americans in 1992 was
just under 6%, representing almost two million people with asthma. The prevalence rate among
white was about 5%, which translates to approximately 12 million people. Gender and age is
also a determinant of prevalence, with adult females having a 40% higher prevalence rate than
adult males, and boys having a 30% higher rate than girls. Additionally a recent study,
Clougherty et al. (2007) evaluated the synergistic effects of traffic relate air pollutants, including
NO2, and the synergistic effects between social and physical factors in asthma, e.g. stress,
violence. The difference in prevalence among races may be related to differences in such things
as socioeconomic status, living conditions, diet, and allergen exposures.
August 2007
4-12
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4.2.2.2 Heart Disease and Stroke
Heart disease is the leading cause of death in the United States, while death from stroke
ranks third. Survey results published by Centers for Disease Control and Prevention (CDC,
2007 a,b) provide estimates of the prevalence of persons living with heart disease and stroke.
The data used for the analyses was from the 2005 Behavioral Risk Factor Surveillance System
(BRFSS). A random selection of the civilian population aged 18 years or more (n = 356,112)
participated in the survey. Participants were asked if a doctor or other health professional had
ever told them that they had a "heart attack, also called a myocardial infarction," "angina or
coronary heart disease," or "stroke." Differences in prevalence were assessed by age,
race/ethnicity/ sex, education, and state or territory of residence. Approximately 6.5%
(13.6 million people, based on Census 2000 data) of respondents reported a history of MI, angina
or coronary heart disease (CHD). Men reported a higher prevalence of heart disease than
women, and prevalence increased with age. Heart disease decreased with higher education, and
American Indians/Alaska natives and multiracial persons had substantially higher prevalence of
history of heart disease. The prevalence of heart disease also varied depending on state of
residence, with persons from West Virginia reporting the highest prevalence of heart disease.
Approximately 2.6% of participants reported a history of stroke (approximately 5.4 million
people, based on census 2000 data). Again, the prevalence of stroke increased with age, male
gender, and lower educational attainment. American Indians and Alaska natives reported a
higher prevalence of stroke. In addition, residents for southern state reported a higher prevalence
of history of stroke. Approximately 35 million people (12.4%) are above the age of 65 in the
United States (Census 2000). Together, American Indians, Alaska Natives, and multiracial
persons represent approximately 7.2 million people (2.5% of the U.S. population).
August 2007
4-13
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 4.1. NQ2 EXPOSURE AFFECTS ASTHMATICS
An intervention study (Pilotto et al., 2004) of respiratory symptoms of asthmatic children in
Australia resulted in reductions in several symptoms (difficulty in breathing during the day and
at night, chest tightness during the day and at night, and asthma attacks during the day) related
to reduction in N02 exposure from in-class heaters. Information on other heater emissions,
such as ultrafine particles, was not reported.
Birth cohort studies in the United Sates (Belanger et al., 2006; Van Strein et al., 2004) and
Europe (Brauer et al., 2007) relate NO2 concentrations to increased respiratory symptoms,
infections, and asthma in the very young.
In England, Chauhan et al. (2003) and Linaker et al. (2000) studied personal NO2 exposure and
found NO2 exposure in the week before an upper respiratory infection was associated with
either increased severity of lower-respiratory-tract symptoms, or reduction of PEF for all virus
types together, and for two of the common viruses, RSV and a picorna virus, individually.
Nitschke et al. (2006) reported difficulty breathing and chest tightness associated with 10 ppb
increases in NO2 measured in school classrooms. Lung function tests were performed at the
beginning and at the end of the study period, and the authors observed personal NO2 exposures
related in a dose-response manner for reported symptoms in asthmatics.
United States multicity studies of ambient NO2 exposure examined respiratory symptoms in
asthmatics (Mortimer et al., 2002; Schildcrout et al., 2006). In the NCICAS (Mortimer et al.,
2002) the greatest effect was seen for morning symptoms (cough, wheeze, shortness of breath)
for a 6-day-morning average. In multi-pollutant models, the NO2 effect was attenuated though
remained positive, for O3, SO2, and combined coarse and fine particulate matter (PM10). In the
CAMP study (Schildcrout et al., 2006), the strongest association between NO2 and increased
risk of cough and increased use of rescue medication was found for a 2-day lag, which was not
attenuated, in two-pollutant models for CO, PM10, or SO2. Single city panel studies in the Los
Angeles area are supportive of these associations for asthmatics (Ostro et al., 2001; Delfino
et al., 2002, 2003a,b). Segala et al. (1998) and Just et al. (2002), in Paris both found positive
relationships to NO2 exposure and symptoms in asthmatics.
Few studies of the impact of NO2 on respiratory symptoms of adult asthmatics are available.
These find positive associations for NO2 exposure and respiratory symptoms in European
studies (Hiltermann et al., 1998; Von Klot et al., 2002; and Forseberg et al., 1998).
The associations between ambient concentrations of NO2 and ER visits for asthma in the United
States are positive (Jaffe et al., 2003; Peel et al., 2005; Tolbert et al., 2000). Studies conducted
outside the United States (Castlellsague et al., 1995; Sunyer et al., 1997; Atkinson et al.,
1999a,b; Tenias et al., 1998; Erbas et al., 2005) found similar results. A concentration response
for NO2 and asthma ER visits is indicated in these studies (Jaffe et al., 2003; Tenias et al., 1998;
Castellsague et al., 1995).
August 2007
4-14
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 4.1 (cont'd). NQ2 EXPOSURE AFFECTS ASTHMATICS
In relation to long-term exposure, Moseler (1994) examined a cohort in Germany and reported
decrements in lung function parameters related to NO2 exposure measures in a group of
physician-diagnosed asthmatic children.
The relationship between long-term NO2 exposure and asthma prevalence and incidence has
been examined in several studies. In the CHS, Gauderman et al. (2005) report a positive
relationship. Further, Islam et al. (2007) studied the CHS cohort to determine whether lung
function is associated with new onset asthma. A positive relationship was seen for N02
exposure, which was marginally significant while indications for PM were significant. In a
separate cohort in the Netherlands, Brauer et al. (2007) provide confirming evidence for this
relationship.
Acute mortality related to asthma was examined in Barcelona, Spain (Saez et al., 1999; Sunyer
et al., 2002). In the study by Sunyer et al. (2002), severe asthmatics with more than one asthma
emergency visit were found to have the strongest mortality associations with N02.
August 2007
4-15
DRAFT-DO NOT QUOTE OR CITE
-------
&
CJQ
c
to
o
o
<1
TABLE 4.1-1. EFFECT OF NITROGEN DIOXIDE (20 PPB) ON THE RISK OF REPORTING RESPIRATORY
SYMPTOMS AND BRONCHODILATOR USE ON A GIVEN DAY ACCORDING TO GSTM1 OR GSTP1 GENOTYPES
AMONG 151 ASTHMATIC CHILDREN IN MEXICO CITY
GSTM1 positive
OR (95% CI)
GSTM1 null
OR (95% CI)
GSTP1 Ile/Ile Ile/Val
OR (95% CI)
GSTP1 Val/Val
OR (95% CI)
On
O
O
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
Cough
N021 day lag
N02 2 day avg
N02 6 day avg
Difficulty breathing
N021 day lag
N02 2 day avg
N02 6 day avg
Bronchodilator use
N021 day lag
N02 2 day avg
N02 6 day avg
1.03 (1.00, 1.06)
1.05 (1.01, 1.09)
1.12(1.07, 1.17)
1.04 (0.98, 1.10)
1.03 (0.97, 1.10)
1.07 (0.98, 1.17)
1.02 (0.99, 1.05)
1.03 (1.00, 1.07)
1.06(1.01, 1.11)
1.01 (0.97, 1.05)
1.00 (0.96, 1.05)
1.06 (1.00, 1.13)
1.01 (0.95, 1.07)
1.02 (0.95, 1.10)
1.02 (0.93, 1.12)
0.97 (0.94, 1.00)
0.96 (0.93, 1.00)
0.96 (0.91, 1.00)
1.04(1.01, 1.07)
1.05 (1.02, 1.09)
1.12(1.07, 1.17)
1.03 (0.98, 1.07)
1.03 (0.98, 1.09)
1.06 (0.99, 1.13)
1.02 (0.99, 1.05)
1.03 (0.99, 1.06)
1.05 (1.01, 1.09)
1.00 (0.96,
0.99 (0.95,
1.05 (0.99,
1.03 (0.94,
1.04 (0.93,
1.04 (0.90,
0.96 (0.93,
0.96 (0.92,
0.96 (0.90,
1.03)
1.04)
1.12)
1.13)
1.16)
1.20)
1.00)
1.00)
1.01)
ORs are calculated using GEE models for logistic regression adjusting for asthma severity, previous day temperature, environmental tobacco smoke exposure, chronological time, and
supplementation group. Changes in symptoms are shown for an increase of 20 ppb in 1 h nitrogen dioxide (N02) maximum over different averages.
Source: Romieu et al. (2006).
-------
TABLE 4.1-2. GRADATION OF INDIVIDUAL RESPONSES TO SHORT-TERM NOz
EXPOSURE IN HEALTHY PERSONS3
Symptomatic
Response
Normal
Mild
Moderate
Severe
Cough
Infrequent cough Cough with deep
breath
Frequent
spontaneous cough
Persistent
uncontrollable cough
Chest pain
None
Discomfort just
noticeable on
exercise or
deep breath
Marked discomfort
on exercise or deep
breath
Severe discomfort
on exercise or
deep breath
Duration of response None
<4 h
>4 hbut <24 h
>24 h
Functional Response
None
Small
Moderate
Large
FEVi
Within normal
range (± 3%)
Decrements of
3 to <10%
Decrements of
>10 but <20%
Decrements of
>20%
Nonspecific
bronchial
responsiveness
Within normal
range
Increases of <100% Increases of <300% Increases of >300%
Duration of response None
<4 h
>4 hbut <24 h
>24 h
Impact of Responses
Normal
Normal
Mild
Moderate
Interference with
normal activity
None
None
A few sensitive
individuals choose
to limit activity
Many sensitive
individuals choose
to limit activity
An increase in nonspecific bronchial responsiveness of 100% is equivalent to a 50% decrease in PD20 or PD100.
August 2007
4-17
DRAFT-DO NOT QUOTE OR CITE
-------
TABLE 4.1-3. GRADATION OF INDIVIDUAL RESPONSES TO SHORT-TERM NOz
EXPOSURE IN PERSONS WITH IMPAIRED RESPIRATORY SYSTEMS
Symptomatic
Response
Normal
Mild
Moderate
Severe
Wheeze
None
With otherwise
normal breathing
With shortness of
breath
Persistent with
shortness of breath
Cough
Infrequent
cough
Cough with deep
breath
Frequent
spontaneous cough
Persistent
uncontrollable cough
Chest pain
None
Discomfort just
noticeable on
exercise or deep
breath
Marked discomfort
on exercise or deep
breath
Severe discomfort
on exercise or deep
breath
Duration of response
None
<4 h
>4 h, but <24 h
>24 h
Functional
Response
None
Small
Moderate
Large
FEVi change
Nonspecific
bronchial
responsiveness
Decrements of
<3%
Within normal
range
Decrements of
3 to <10%
Increases of <100%
Decrements of
>10 but <20%
Increases of <300%
Decrements of
>20%
Increases of >300%
Airways resistance
(SRaw)
Within normal
range (± 20%)
SRaw increased
<100%
SRaw increased up
to 200% or up to
15 cmH20-s
SRaw increased
>200% or more than
15 cmH20-s
Duration of response
None
<4 h
>4 hbut <24 h
>24 h
Impact of
Responses
Normal
Mild
Moderate
Severe
Interference with
normal activity
None
Few individuals
choose to limit
activity
Many individuals
choose to limit
activity
Most individuals
choose to limit
activity
Medical treatment
No change
Normal medication
as needed
Increased frequency
of medication use or
additional
medication
Physician or
emergency room
visit
An increase in nonspecific bronchial responsiveness of 100% is equivalent to a 50% decrease in PD20 or PD100.
August 2007
4-18
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
5. FINDINGS AND CONCLUSIONS
5.1 INTRODUCTION
The previous chapters have presented the most policy-relevant science, integrated across
disciplines, as it pertains to oxides of nitrogen. The goal of this chapter is to summarize key
findings and draw conclusions from this information. Sections of this chapter are as follows:
(1) this introduction, (2) atmospheric sciences, (3) exposure assessment, (4) NO2 exposure
indices, (5) a summary of health effects, and (6) conclusions.
It will be useful at the outset to distinguish between the definitions of "nitrogen oxides"
as it appears in the enabling legislation related to the NAAQS and the definition commonly used
in the air pollution research and management community. In this document, the terms "oxides of
nitrogen" and "nitrogen oxides" refer to all forms of oxidized nitrogen compounds, including
NO, N02, and all other oxidized nitrogen-containing compounds transformed from NO and N02.
This follows usage in the Clean Air Act Section 108(c): "Such criteria [for oxides of nitrogen]
shall include a discussion of nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other
carcinogenic and potentially carcinogenic derivatives of oxides of nitrogen." By contrast, within
the air pollution research and control community, the terms "oxides of nitrogen" and "nitrogen
oxides" are restricted to refer only to the sum of NO and NO2, and this sum is commonly
abbreviated as NOx. The category label used by this community for the sum of all forms of
oxidized nitrogen compounds including those listed in Section 108(c) is NOy.
For the current review, multiple species of many nitrogen oxides are considered as
appropriate and as allowed by the available data. For example, descriptions of the atmospheric
chemistry of nitrogen oxides include both gaseous and particulate species, because a meaningful
analysis would not be possible otherwise. In addition, the health effects of gaseous nitrogen
oxides other than N02 are evaluated when information on these other species is available.
Finally, the possible influence of other atmospheric pollutants on the interpretation of the role of
NO2 in health effects studies is considered, including interactions of NO2 with other pollutants
that co-occur in the environment (e.g., SO2, CO, O3, particulate matter). The available database
for this draft ISA largely provides information on the health effects of N02, with limited
information examining other forms of oxides of nitrogen (e.g., HONO). Thus, the review
August 2007
5-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
examines a large NO2 database along with other studies of other gaseous oxides of nitrogen, as
available.
5.2 ATMOSPHERIC SCIENCES
Atmospheric sciences and exposure assessment are key elements in the causal chain
linking pollutant sources to health effects. Atmospheric chemical processes involving NO2 result
in the formation of photochemical oxidants such as O3 and PAN and precursors to acid aerosol
formation such as the strong acid, mutagenic nitro-PAHs and other potentially toxic compounds.
Key findings related to measuring such compounds are listed below.
• The current method of determining ambient NOx (i.e., NO + N02) and then reporting
N02 concentrations by subtraction of NO is subject to interference by NOx oxidation
products (NOz), chiefly HNO3 and PAN at levels that are largely uncharacterized and
highly variable. Limited evidence suggests that these compounds result in an
overestimate of NO2 levels by roughly 20 to 25% at typical ambient levels. Smaller
errors are estimated to occur in measurements taken nearer to strong NOx sources since
most of the mass emitted as NOx would not yet have been further oxidized to NOz.
Relatively larger errors, then, appear in locations more distant from strong local NOx
sources.
• Techniques for measuring NO2 more selectively than the FRM generally involve
expensive and complex systems. As an example, NO2 could be photolytically reduced to
NO before detection by chemiluminescence in existing networks to eliminate the NOz
interference; however, this technique requires further development to ensure its reliability
and cost effectiveness for extensive field deployment.
• A measurement of total oxidized nitrogen compounds, i.e., the sum of NO, NO2, and all
their reaction products, defined as NOy, would provide a more physically meaningful
measurement of oxidized nitrogen than do measurements of NOx and N02 as reported
currently.
• Existing NOx monitors could be converted to NOy monitors with relatively
straightforward modifications. However, NOy monitors can be subject to relatively
minor positive artifacts from particulate nitrate compounds, and, like the FRM NOx
August 2007
5-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
monitors, to positive interference by reduced nitrogen compounds if the converter
temperature is not carefully controlled.
• Because motor vehicles are a large source of urban NO2, ambient NO2 generally behaves
much like a traffic-generated pollutant in urban areas. It is associated with other traffic-
generated pollutants such as CO at ambient levels and shows spatial and temporal
variability consistent with other traffic-generated pollutants.
• Nitro-PAHs, which are responsible for most of the mutagenicity associated with ambient
PAH samples and other potentially toxic compounds are emitted both directly from
automobile tailpipes and by other NOx sources and also are formed secondarily from
atmospheric reactions of NO2.
• Annual average concentrations of NO2 (-15 ppb) are well below the level of the current
NAAQS (53 ppb). However, daily maximum 1-h average concentrations can be greater
than 100 ppb in a few locations, such as those heavily influenced by traffic.
• Policy Relevant Background Concentrations of NO2 are much lower than average
ambient concentrations and are typically less than 0.1 ppb over most of the United States,
with highest values found in agricultural areas.
• Measurements of NOy have the additional benefit of characterizing the entire suite of
oxidized nitrogen compounds in ambient air to which people are exposed.
5.3 EXPOSURE ASSESSMENT
In assessing human exposures to N02, recall that people are exposed to the entire suite of
oxidized nitrogen compounds that are characterized by NOy and not just to N02 or NOx. The
amount of time a person spends in different microenvironments and the infiltration
characteristics of these microenvironments are strong determinants of the association between
ambient NO2 concentrations and human exposures. In addition to ambient NO2, people are also
exposed to N02 produced by indoor sources such as gas stoves, to N02 and other products of
indoor air reactions, and to NO2 in vehicles while commuting. Key findings related to assessing
NO2 exposures are listed below.
• Spatially, NO2 is highly variable in urban areas, potentially leading to exposure error
resulting from either a lack of correlation or differences in levels between a central
August 2007
5-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
monitoring site and the community average. Intersite correlations for NO2 concentrations
range from slightly negative to highly positive. The range of spatial variation in NO2
concentrations is similar to that for 03, but larger than that of PM2.5. Twenty-four-hour
concentration differences between individual paired sites in an MSA can be larger than
the annual means at these sites.
• Rooftop NO2 measurements, particularly in inner cities, likely underestimate levels
occurring at or near the earth's surface closer to the vehicle emitters.
• Methods for measuring personal NO2 generally correlate well with ambient methods in
collocated samples, but they tend to be biased high relative to reported ambient
measurements and are subject to artifacts.
• In the absence of indoor sources, indoor NO2 levels are about one-half those found
outdoors. In the presence of indoor sources, particularly unvented combustion sources,
NO2 levels can be much higher than reported ambient concentrations.
• Alpha (a), the fraction of the ambient NO2 concentration that contributes to a person's
exposure to ambient NO2 ranged from -0.3 to -0.6 in studies where examined.
• Indoor exposures to NO2 are accompanied by exposures to other products of indoor
combustion and to products of NO2 chemistry occurring indoors and outdoors, such as
HONO.
• The evidence relating ambient levels to personal exposures is mixed. Most of the
longitudinal studies examined found that ambient levels of NO2 were reliable proxies of
personal exposures to N02. However, a number of studies found no significant
associations between ambient and personal levels of NO2. The differences in study
results are related in large measure to differences in study design, to the spatial
heterogeneity of NO2 in study areas, to the presence of indoor sources, to seasonal and
geographic differences in the infiltration of ambient N02, and to differences in the time
spent in different microenvironments. Measurement artifacts and differences in
analytical measurement capabilities could also have contributed to the mixed results.
• The collective variability in all of the above parameters, in general, contributes to
exposure misclassification errors in air pollution-health outcome studies.
• A few European studies in which community averages of personal exposures were
compared to either ambient or outdoor concentrations support the assumption that
August 2007
5-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
ambient concentrations are a reasonable surrogate for community average exposures in
epidemiological studies.
The available data are limited, but suggest that the regulatory ambient monitors provide
reasonable proxies for personal exposures to NO2. At the same time, variable, positive artifacts
associated with measuring NO2 using the Federal Reference Method severely limit its ability to
serve as a precise indicator of NO2 concentrations at typical ambient levels generally
encountered outside of urban cores. Within the urban core, where many of the regulatory
monitors are sited close to strong NOx sources such as traffic, the positive artifacts are much
smaller on a relative basis, and the measurement is more precise. Importantly, because the
nitrogen species that introduce the positive artifacts in the FRM NO2 measurement are present in
ambient air, these artifacts introduce the same error into epidemiological studies. To alleviate
these problems and provide a better understanding of the relationships between nitrogen oxides
and health outcomes, it may be appropriate either to adopt a different indicator for the mixture of
nitrogen oxides, such as NOy-NO, or to actively aid continued development of the more specific
techniques for measuring N02 with the goal of replacing the current FRM method in the
networks.
5.4 N02 EXPOSURE INDICES
The available NO2 indices used to indicate short-term ambient NO2 exposure are daily
maximum 1-h (1-h max); 24-h average; and 2-week average NO2 concentrations. New data on
short-term exposures have been published since the 1993 AQCD for Oxides of Nitrogen. Some
studies examined only one index, and these studies form an evidence base for that individual
index. A few studies used both 1-h and 24-h data and, thus, allow a comparison of these
averaging periods. These include studies of respiratory symptoms, ED visits for asthma, hospital
admissions for asthma, and mortality.
• Meta-analysis regression results for asthma ED visits comparing effect estimates for the
1-h and 24-h time periods indicate that effect estimates are slightly, but not significantly,
larger with a 24-h average compared with a 1-h max NO2.
• Experimental studies in both animals and humans provided evidence that short-term NO2
exposure (i.e., <1 h to 2-3 h) can result in respiratory effects such as increased airways
responsiveness or inflammation thereby increasing the potential for exacerbation of
August 2007
5-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
asthma. These findings generally support epidemiological evidence on short-term
exposures, but do not provide evidence that distinguishes effects for one short-term
averaging period from another.
• Based on these findings, we have concluded that differences between 1-h and 24-h
exposures are unlikely for several health outcomes.
5.5 HEALTH EFFECTS
5.5.1 The 1993 AQCD Findings
The 1993 AQCD for Oxides of Nitrogen found that there were two key health effects of
greatest concern at ambient or near-ambient concentrations of NO2: (1) increases in airways
responsiveness of asthmatic individuals after short-term exposures and (2) increased occurrence
of respiratory illness among children associated with longer-term exposures to NO2. Evidence
also was found for increased risk of emphysema, but this appeared to be of major concern only
with exposures to levels of NO2 much higher than current ambient levels of NO2 (U.S.
Environmental Protection Agency, 1993). The evidence regarding airways responsiveness was
drawn from controlled human exposure and animal toxicological studies showing both airways
responsiveness and lung function changes, though there was a lack of a concentration-response
relationship. Epidemiological studies reported increased respiratory symptoms with increased
indoor NO2 exposures, and animal toxicological findings of lung host defense system changes
with NO2 exposure provided a biologically plausible basis for these results. Subpopulations
considered potentially more susceptible to the effects of NO2 exposure included persons with
preexisting respiratory disease, children, and the elderly. In the 1993 AQCD, the
epidemiological evidence for respiratory health effects was limited, and no studies had
considered effects such as hospital admissions, ED visits, or mortality.
5.5.2 New Findings
New evidence developed since 1993 has generally confirmed and extended the
conclusions articulated in the 1993 AQCD. Since the 1993 AQCD, the epidemiological
evidence has grown substantially, including new field or panel studies on respiratory health
outcomes, numerous time-series epidemiological studies of effects such as hospital admissions,
August 2007
5-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
and a substantial number of studies evaluating mortality risk with short-term NO2 exposures. As
noted above, no epidemiological studies were available in 1993 that assessed relationships
between oxides of nitrogen and outcomes such as hospital admissions, ED visits, or mortality; in
contrast, there are now dozens of epidemiological studies on such outcomes included in this
evaluation. Several new studies have reported findings from prospective cohort studies on
respiratory health effects with long-term NO2 exposure. Significant new evidence characterizing
the responses of susceptible and vulnerable populations also has developed since 1993,
particularly concerning children, asthmatics, and those living and working near roadways. While
not as marked as the growth in the epidemiological literature, a number of new toxicological and
controlled human exposure studies provide further insights into relationships between NO2 and
health effects.
In the following subsections, we build upon previous chapters to draw conclusions
regarding the overall strength of the evidence and extent to which causal inferences may be
made. Where the associations observed in epidemiological and experimental studies are strong,
consistent, coherent, and plausible, we have concluded that the relationship is "likely causal."
Where the epidemiological or clinical findings are generally strong and consistent, but the
available experimental evidence is too limited to draw conclusions regarding coherence or
plausibility of the results, we have concluded that this relationship is "suggestive." In some
situations, the evidence from epidemiological and experimental studies is not found to be strong
or consistent, and there is limited or no support for coherence and plausibility; these relationships
we judge to be "inconclusive." Where possible, we have also included observations about the
concentrations at which effects have been observed. A series of tables at the end of this chapter
provide specific information supporting these conclusions. Table 5.5-1 summarizes the key
findings of controlled human exposure studies, and the exposure levels at which those effects
have been observed. Table 5.5-2 summarizes the lowest levels at which effects have been seen
in toxicological studies for a series of effect categories. Table 5.5-3 presents results of
epidemiological studies on respiratory health effects, and it includes information about the
distribution of N02 levels used in the study as presented in the study publications (generally
provided as mean and range).
August 2007
5-7
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5.5.2.1 Respiratory Health Effects and Short-Term Exposure to N02
Taken together, recent studies provide strong scientific evidence that N02 is associated
with a range of respiratory effects and describe a likely causal relationship between short-term
NO2 exposure and adverse effects on the respiratory system. This is based on findings from
numerous new epidemiological studies, including multipollutant studies that control for the
effects of other pollutants. This conclusion is supported by evidence from toxicological and
controlled human exposure studies. A number of studies have been conducted in areas where the
full distribution of ambient 24-h average NO2 concentrations was below the current annual-
average NAAQS level of 53 ppb (see data in Tables 5.5-3A and 5.5-3B). Key findings related to
assessing N02 associated health effects are listed below.
• The strongest new epidemiological evidence exists for associations with increased ED
visits and hospital admissions for respiratory causes, especially asthma and COPD, with
ambient concentrations of NO2. In nearly all of these studies, high correlations were
found between ambient measures of NO2 and of CO and PM. The effect estimates for
NO2 were robust after the inclusion of CO and PM in multipollutant models. Significant
associations have been reported in some studies conducted in areas such as Vancouver,
Canada, where daily NO2 concentrations were all below the level of the current annual
NAAQS.
• Results from recent field and panel studies confirm previous studies that short-term NO2
exposure is associated with increased respiratory symptoms (e.g., cough, wheeze),
particularly in children and asthmatics. Few recent epidemiological evaluations of lung
function measures such as FEVi, and PEF exist, providing only limited new evidence for
pulmonary effects of NO2 exposure.
• Recent studies reporting associations between indoor and personal exposure to NO2 and
respiratory symptoms or lung function provide key support for epidemiological findings
of associations with NO2 concentrations (e.g., Pilotto et al., 2004, Chauhan et al., 2004).
In particular, the Pilotto et al. (2004) intervention study provides strong evidence of a
detrimental effect with exposure to N02.
• A recent epidemiological study (Chauhan et al., 2003) provided evidence that increased
personal exposures to NO2 worsen virus-associated symptoms and lung function in
August 2007
5-8
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
children with asthma. The limited evidence from controlled human exposure studies
indicates that NO2 may increase susceptibility to injury by subsequent viral challenge.
• Controlled human exposure studies provide strong evidence in asthmatics for increased
airways responsiveness to bronchoconstricting agents with short-term exposure to 0.2 to
0.3 ppm N02. The clinical significance of increased airways reactivity is the potential for
a flare-up or exacerbation of asthma or other underlying pulmonary disease following
increased bronchial response to nonspecific airborne irritants. These studies do not
provide compelling evidence for other respiratory effects such as changes in lung
function. Toxicological studies have shown that lung host defenses are sensitive to N02
exposure, with numerous measures of such effects observed at concentrations below
1 ppm.
• Biological markers of inflammation are reported in antioxidant-deficient laboratory
animals with exposures to 0.4-ppm NO2. Normal animals do not respond until exposed
to much higher levels, i.e., >5 ppm NO2. Recent epidemiological studies provide
somewhat mixed evidence on short-term exposure to NO2 and inflammatory responses in
the airways. Controlled human exposure studies provide evidence for increased airways
inflammation at NO2 concentrations of <2.0 ppm; the onset of inflammatory responses in
healthy subjects appears to be between 100 and 200 ppm-min, i.e., 1 ppm for 2 to 3 h.
5.5.2.2 Cardiovascular Effects and Short-Term Exposure to N02
Overall, the evidence is inconclusive regarding the effect of N02 on the CV system.
• Numerous epidemiological studies report an association of N02 with hospital admissions
or ED visits for CVD (MI and CHF in particular). However, PM and other ambient air
pollutants were also associated with hospitalizations. Further, results from multipollutant
models were inconsistent, with no clear pattern emerging to suggest that the NO2
associations observed were robust.
• Epidemiological evidence from studies of HRV and cardiac rhythm disorders provide
limited evidence of associations with N02. The parameters measured in these studies
were associated most strongly with PM compared to other ambient pollutants, so the
effects observed for NO2 may have been confounded. Furthermore, a study of
August 2007
5-9
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
repolarization changes found no association between NO2 and the outcomes measured,
while an effect for PM was observed.
• The limited evidence from controlled human exposure studies suggests a reduction in
hemoglobin with NO2 exposure may occur at concentrations between 1.0 and 2.0 ppm
(with 3-h exposures), but the observations require confirmation. The results on the effect
of NO2 on various hematological parameters in animals are inconsistent and, thus,
provide little biological plausibility for effects on the CV system.
5.5.2.3 Mortality and Short-Term Exposure to NO2
• Epidemiological evidence is suggestive of associations between NO2 and nonaccidental
and cardiopulmonary-related mortality, but additional research is needed to establish
underlying mechanisms by which such effects occur.
• Results from several large U.S. and European multicity studies and a meta-analysis study
observed positive associations between ambient N02 concentrations and risk of all-cause
(nonaccidental) mortality, with effect estimates ranging from 0.5 to 3.6% excess risk in
mortality. In general, the effect estimates were robust to adjustment for copollutants.
• Both CV and respiratory mortality have been associated with increased NO2
concentrations in epidemiological studies; however, similar associations were observed
for other pollutants, including PM and SO2.
• Clinical studies showing hematologic effects (noted above) and animal toxicological
studies showing biochemical, lung host defense, permeability, and inflammation changes
with short-term exposures to N02 provide limited evidence of plausible pathways by
which risks of morbidity and, potentially, mortality may be increased, but no coherent
picture is evident at this time.
• While NO2 exposure, alone or in conjunction with other pollutants, may contribute to
increased mortality, evaluation of the specificity of this effect is difficult. Limited
experimental evidence exists to prohibits considering biological plausibility at this time,
and the range of mortality risk estimates is smaller than that for other pollutants such as
PM. It is possible that NO2 is acting as a marker for another pollutants or traffic-related
mixtures.
August 2007
5-10
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
5.5.2.4 Morbidity and Long-Term Exposure to N02
The available epidemiological and toxicological data provide suggestive evidence that
long-term exposure to NO2 affects respiratory health.
• A number of epidemiological studies examined the effects of long-term exposure to NO2
and observed associations with decrements in lung function, and partially irreversible
decrements in lung function growth. In one analysis, results were similar for boys
compared to girls and among children who did not have a history of asthma: clinically
significant differences in lung function remained at age 18. These studies, however, are
confounded by other ambient pollutants. In particular, associations are also found for PM
and proximity to traffic (<500 m). As shown in Table 5.5-3C, the mean NO2
concentrations in these studies range from 21.5 to 34.6 ppb; thus, all have been conducted
in areas where N02 levels are below the level of the NAAQS (53 ppb, annual average).
• A limited number of epidemiological studies examined the effects of long-term exposure
to N02 and observed associations with increases in asthma prevalence. However,
potential confounding by other ambient pollutants introduces uncertainty.
• Animal toxicological studies demonstrate that exposure to NO2 results in morphological
changes in the centriacinar region of the lung and in bronchiolar epithelial proliferation,
which may provide biological plausibility for the observed increased incidence of
respiratory illness.
• Two epidemiological studies conducted in Europe showed an association between long-
term N02 exposure and cancer incidence, although animal studies have provided no clear
evidence that NO2 acts as a carcinogen. There are no in vivo studies suggesting that NO2
causes malignant tumors and no evidence of mutagenicity. Substantial evidence exists
that nitro-PAHs are formed via combination of NOx and other air pollutants, though
many of these are found in the particulate phase. The PAHs are considered to be known
human carcinogens, and nitration of PAHs is thought to increase carcinogenic potential.
• No studies have been conducted on potential CV effects of long-term exposure to oxides
of nitrogen.
• Epidemiological evidence is weak for associations between NO2 exposure and
intrauterine growth retardation and preterm delivery. Limited toxicological evidence
suggests a weak association between NO2 exposure and adverse birth outcomes and
August 2007
5-11
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
provides little mechanistic information or biological plausibility for the epidemiological
findings.
5.5.2.5 Mortality and Long-Term Exposure to N02
Results from the few available epidemiological studies are inconclusive regarding the
association between long-term exposure to NO2 and mortality.
• A limited number of epidemiological studies have investigated the effect of long-term
exposure to NO2 on mortality. In general, inconsistent associations were observed across
study locations and cause-specific mortality outcomes.
• Multipollutant analyses were usually not conducted, but studies indicated high
correlations between NO2 and PM indices (r ~ 0.8).
5.5.2.6 Concentration-Response Relationships and Thresholds
An important consideration in characterizing the public health impacts associated with
N02 exposure is whether the concentration-response relationship is linear across the full
concentration range that is encountered or if nonlinear departures exist along any part of this
range. Of particular interest is the shape of the concentration-response curve at and below the
level of the current annual average standard of 53 ppb (0.053 ppm).
Identifying possible "thresholds" in air pollution epidemiological studies is problematic.
Various factors tend to linearize the concentration-response relationships, obscuring any
thresholds that may exist. Exposure measurement error, response measurement error, and low
data density in the lower concentration range are some factors that complicate determining the
shape of the concentration-response curve. Biological characteristics tending to linearize
concentration-response relationships include interindividual variation in susceptibility to health
effects, additivity of pollutant-induced effects to the naturally occurring background disease
processes, and the extent to which health effects are due to other environmental insults having a
mode of action similar to that of N02. Additionally, if the concentration-response relationship is
shallow, identification of any threshold that may exist will be more difficult.
The slope of the NO2 concentration-response relationship has been explored in several
studies. To examine the shape of the concentration-response relationship between NO2 and daily
physician consultations for asthma and lower respiratory disease in children, Hajat et al. (1999)
used bubble plots to examine residuals of significant models plotted against moving averages of
August 2007
5-12
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
NO2 concentration. They noted a weak trend for asthma and 0-1 day moving average of NO2
and suggested that effects are weaker at low concentrations and stronger at higher concentrations
than predicted by the linear model. These departures are in accord with the sigmoidal dose-
response models. A number of epidemiological studies have reported no evidence for nonlinear
relationships or a threshold response in relationships between NO2 and mortality or morbidity.
One multicity time-series study (Samoli et al., 2006) examined the relationship between
mortality and N02 in 29 European cities. There was no indication of a response threshold, and
the concentration-response curves were consistent with a linear relationship. Kim et al. (2004b)
investigated the presence of a threshold in relationships between air pollutants and mortality in
Seoul, Korea, by analyzing data using a log-linear GAM (linear model), a cubic natural spline
model (nonlinear model), and a B-mode splined model (threshold model). The 24-h average
NO2 level was 32.5 ppb (SD 10.3); there was no evidence thatN02 had a nonlinear association
with mortality. Burnett et al. (1997a) used the LOESS smoothing method to present
nonparametric concentration-response curves for respiratory and cardiac hospitalizations. These
smoothed curves did not have significant departures from the linear model. One problem with
this approach is that the LOESS smoothed curve may lack biological rationale. Burnett et al.
(1997b) tested for nonlinearity by testing the significance of the quadratic term in a study of
hospital admissions for respiratory diseases and reported no evidence for nonlinearity for the
association with NO2.
In studies that have specifically examined concentration-response relationships between
NO2 and health outcomes, there is little evidence of an effect threshold. Factors that make
difficult identification of any threshold that may exist are noted above.
5.5.2.7 Susceptible and Vulnerable Populations
Several susceptible subpopulations can be identified.
• Based on both short- and long-term studies of an array of respiratory and cardiac health
effects data, asthmatics and persons with preexisting cardiopulmonary conditions are at
greater risk from ambient NO2 exposures than the general public, with the most extensive
evidence available for asthmatics as a potentially susceptible group. In addition, studies
suggest that upper respiratory viral infections can trigger susceptibility to the effects of
exposure to NO2.
August 2007
5-13
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
• There is supporting evidence of age-related differences in susceptibility to NO2 health
effects such that the elderly population (>65 years of age) appears to be at increased risk
of mortality and hospitalizations and that children (<18 years of age) experience other
potentially adverse respiratory health outcomes with increased NO2 exposure.
• People with occupations that require them to be in or close to traffic or roadways (i.e.,
bus and taxi drivers, highway patrol officers) may have enhanced exposure to N02
compared to the general population, possibly increasing their vulnerability. Limited
studies, however, provide no evidence that they are more susceptible to the effects of
NO2 than the general population.
• In addition to observed increases in MVexposure-related illnesses, a general shift of the
population response distribution towards greater sensitivity to illness is anticipated. This
shift, in itself is considered adverse.
5.6 CONCLUSIONS
New evidence confirms previous findings in the 1993 AQCD that short-term NO2
exposure is associated with increased airways responsiveness, often accompanied by respiratory
symptoms, particularly in children and asthmatics. Additionally, the new body of
epidemiological data provides strong evidence of associations with increased ED visits and
hospital admissions for respiratory causes, especially asthma and COPD, and short-term ambient
exposure to NO2. These new findings are based on numerous studies, including panel and field
studies, multipollutant studies that control for the effects of other pollutants, and studies
conducted in areas where the full distribution of ambient 24-h average N02 concentrations was
below the current NAAQS of 53 ppb (see data in Table 5.5-3A and 5.5-3B). These conclusions
are supported by evidence from toxicological and controlled human exposure studies.
Individually and together, these data sets form a plausible, consistent, and coherent description of
a relationship between N02 exposures and an array of adverse health effects that range from the
onset of respiratory symptoms to hospital admission.
It is difficult to determine from these new studies if NO2 is the causal agent or if NO2 is a
marker for the effects of another traffic-related pollutant or mix of pollutants (see Chapter 2 and
Section 5.4 for more details on exposure issues). To understand the relationship of N02 and
impacts on public health with more certainty, one must turn to other lines of evidence.
August 2007
5-14
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Other evidence of the effects of NO2 comes from personal exposure studies of indoor
sources and from clinical and animal studies. Recent studies reporting associations between
personal exposure to N02 indoor sources and respiratory symptoms provide key support for
epidemiological findings of associations with ambient NO2 concentrations. In particular, an
intervention study (Pilotto et al., 2004) provides strong evidence of a detrimental effect on
asthmatic children of exposure to NO2 from indoor sources. Additionally, a complex set of
recent controlled human exposure studies provides good evidence for increased airways
responsiveness to allergen-induced inflammation and allergen-induced bronchoconstriction
following short-term exposure to levels of NO2 in the range of 0.26 ppm. The significance of
increased airways responsiveness is the potential for exacerbation of asthma. Increases in
biological markers of inflammation are also reported in antioxidant-deficient laboratory animals
exposed to 0.4-ppm NO2; however, it is not clear how these antioxidant-deficient laboratory
animals differ from humans.
An argument can be made that NO2 exacerbates the response to allergen challenge and
worsens virus-associated symptoms in asthmatic children, although data to support this argument
is more limited. A recent epidemiological study (Chauhan et al., 2003) provided evidence that
an increased personal exposure to NO2 worsens virus-associated symptoms and lung function in
children with asthma. Controlled human exposure studies of healthy adults, conducted at higher
than ambient concentrations, also provide limited evidence thatN02 may increase inflammation
and increase susceptibility to injury associated with subsequent viral challenge.
Lastly, but importantly, large, well-conducted prospective studies provide strong
evidence of partially irreversible decreased lung function growth and lung function capacity
among children with long-term exposure to NO2 and/or traffic. These studies do not suggest that
N02 alone is responsible for these deficits. Chronic animal toxicological studies, at higher than
ambient exposure concentrations, demonstrate that exposure to NO2 results in morphological
changes in the centriacinar region of the lung and bronchiolar epithelial proliferation and provide
biological plausibility for the lung function growth decrements observed in children.
Integrating across the epidemiological, clinical, and animal evidence presented above, we
find that it is plausible, consistent, and coherent that current ambient NO2 exposures directly
result in adverse impacts to public health at concentrations below the current NAAQS for NO2.
In particular, a set of coherent and plausible respiratory health outcomes indicative of
August 2007
5-15
DRAFT-DO NOT QUOTE OR CITE
-------
1 exacerbated asthma are associated with NO2 exposures: increase airways hyperresponsivness,
2 inflammation, impair host defense, a progression of respiratory symptoms, worsened virus
3 infections, emergency room visits, and hospital admission. Additionally, evidence is suggestive
4 of potentially permanent decreased lung function capacity and increased mortality.
5 The evidence presented in Chapters 2, 3, and 4 also leads us to conclude that NO2 can be
6 expected to be an indicator of the effects of traffic-related pollutants. Furthermore, since is it
7 well known that traffic-related pollutants other than N02 produce adverse effects on public
8 health, it is reasonable to conclude that the impact of multiple pollutant mixtures on public health
9 produce greater impacts on public health than would be expected from NO2 alone.
August 2007
5-16
DRAFT-DO NOT QUOTE OR CITE
-------
&
CJQ
c
to
o
o
<1
Ux
TABLE 5.5-1. KEY HUMAN HEALTH EFFECTS OF EXPOSURE TO NITROGEN DIOXIDE—CLINICAL STUDIES"
H
6
o
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
N02 (ppm)
(Exposure Duration)
Observed Effects
References
0.26 (0.5 h)
Asthmatics exposed to N02 during rest experienced enhanced sensitivity to
allergen-induced decrements in lung function and increase the allergen-
induced airways inflammatory response. Inflammatory response to allergen
observed in the absence of allergen-induced lung function response. No
N02-induced change in lung function.
Barck et al. (2002, 2005a)
Strand et al. (1996,1997, 1998)
0.1-0.3
(0.5-2.0 h)
Meta-analysis showed increased airways responsiveness following N02
exposure in asthmatics. Large variability in protocols and responses. Most
studies used nonspecific airways challenges. Airways responsiveness
tended to be greater for resting (mean 45 min) than exercising (mean 102
min) exposures conditions.
Folinsbee (1992)
0.3-0.4 (2-4 h)
Inconsistent effects on FVC and FEVi in COPD patients with mild exercise.
Gong et al. (2005)
Morrow et al. (1992)
Vagaggini et al. (1996)
1.0-2.0(2-6 h)
Increased inflammatory response and airways responsiveness to nonspecific
challenge in healthy adults exposed during intermittent exercise. Effects on
lung function and symptoms in healthy subjects not detected by most
investigators. Small decrements in FEV, reported for asthmatics.
Azadniv et al. (1998)
Blomberg etal. (1997, 1999)
Devlin et al. (1999)
Frampton et al. (2002)
Jorres et al. (1995)
>2.00(1-3 h)
Lung function changes (e.g., increased airways resistance) in healthy
subjects. Effects not found by others at 2-4 ppm.
Beil and Ulmer (1976)
Nieding et al. (1979)
Nieding and Wagner (1977)
Nieding et al. (1980)
a N02 = Nitrogen dioxide
FEV! = Functional expiratory volume in 1 s.
FVC = Forced vital capacity.
COPD = Chronic obstructive pulmonary disease.
-------
&
CJQ
c
to
o
o
<1
Ux
oo
TABLE 5.5-2. SUMMARY OF TOXICOLOGICAL EFFECTS FROM N02 EXPOSURE
(LOEL BASED ON CATEGORY)
H
6
o
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
Concentration
(PPm)
Exposure
Duration
Species
Effect
Category
Reference
0.2
From conception to
12 wks post delivery
Rats
Increase in BALF
lymphocytes
Inflammation
Kume and Arakawa
(2006)
0.5
Weanling period
(from 5 wks old to
12 wks)
Rats
Suppression of ROS
Lung host defense
Kume and Arakawa
(2006)
0.5
0.5-10 days
Rats
Depressed activation
of arachidonic acid
metabolism and
superoxide production
Lung host defense
Robison et al.
(1993)
0.5
with spikes of 1.5
9 wks
Rats
Increase in the
number of fenestrae
in the lungs
Morphological effects
Mercer et al. (1995)
0.8
1 or 3 days
Rats
Increase in
bronchiolar epithelial
proliferation
Morphological effects
Barth et al. (1994a)
-------
&
CJQ
c
to
o
o
<1
Ux
^o
TABLE 5.5-3A. EFFECTS OF SHORT-TERM N02 EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02 Levels
(PPb)
Statistics for N02
Air Quality Data (ppb)
98th % 99th %
Range
Standardized* Percent Excess Risk
(95% CI)
Schwartz et al. (1994),
Six cities,
United States
1984-1988
1,844 elementary school
children in 6 U.S. cities
24-havg: 13.3
NR NR Max: 44.2 Cough incidence:
N02 alone: 61.3% (8.2, 143.4)
NO2 + PM10: 36.9% (-11.6, 113.2)
N02 + 03: 61.3% (8.2, 140.3)
N02 + S02: 18.8% (-11.6, 69.0)
Mortimer et al. (2002)
Eight urban areas,
United States
1993
Asthmatic children
(4-9 yrs) from the National
Cooperative Inner-City
Asthma Study (NCICAS)
cohort
4-h avg: 32
NR
NR
;7, 96
Morning %PEFR
N02 alone: 48% (2, 116)
N02 + 03: 40% (-7, 109)
N02 + 03 + S02: 31% (-13, 109)
N02 + 03 + S02 + PM10: 45% (-37, 234)
o
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
Schildcrout et al.
(2006)
Eight North American
Cities
1993-1995
Ostro etal. (2001)
Los Angeles and
Pasadena, CA,
United States
Aug-Oct, 1993
990 asthmatic children (aged
5-13 yrs) enrolled in
Childhood Asthma
Management Program
(CAMP) cohort
24-havg: 17.8-26.0
NR
NR
NR
138 African-American
asthmatic children
(8-13 yrs)
L.A. 1-h max:
79.5 (43.6)
Pasadena 1-h max:
68.1 (31.3)
NR
NR
L.A.: 20.0,
220.0
Pasadena: 30.0,
170.0
Asthma symptoms:
N02 alone: 4.0% (1.0, 7.0)
N02 + CO: 4.0% (0.0, 8.0)
N02 + PM10: 4.0% (0.0, 7.0)
N02 + S02: 4.0% (-1.0, 8.0)
Rescue inhaler use:
N02 alone: 3.0% (1.0, 5.0)
N02 + CO: 4.0% (0.0, 7.0)
N02 + PM10: 2.0% (0.0, 5.0)
N02 + S02: 3.0% (-2.0, 5.0)
Shortness of breath:
Day w/symptoms: 4.7%) (-0.6, 10.4)
Onset of symptoms: 8.2%) (-0.6, 17.6)
Wheeze:
Day w/symptoms: 4.7% (1.2, 8.7)
Onset of symptoms: 7.6% (2.4,13.8)
Cough:
Day w/symptoms: 1.8% (-1.8, 5.3)
Onset of symptoms: 7.0%) (1.0,13.8)
-------
&
CJQ
c
TABLE 5.5-3A (cont'd). EFFECTS OF SHORT-TERM NOz EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
to
o
o
<1
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02 Levels
(PPb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
to
o
Delfino et al. (2002)
Alpine, CA,
United States
Mar-Apr 1996
22 children with asthma
(9-19 yrs old) living in
nonsmoking households
1-hmax: 24(10)
NR NR 8,53 Asthma symptoms:
N02 alone: 34.6% (-17.9, 122.1)
On medication: -8.9% (-79.1, 297.6)
Not on medication: 80.3%) (-10.7, 263.7)
With (compared to without) respiratory
infection: 299% (-50.6, 1,708)
o
o
2
o
H
o
c
o
H
ffl
o
o
HH
H
W
Delfino et al (2003a)
East Los Angeles
County, CA,
United States
Nov 1999 -Jan 2000
Silkoff et al. (2005)
Denver, CO,
United States
Winters of 1999-2000
and 2000-2001
22 Hispanic school children
(ages 10-15) with asthma
1-hmax: 7.2(2.1)
NR
NR
3, 14
34 subjects with advanced
COPD (>40 yrs), with a
history of more than 10 pack-
yrs of tobacco use, airflow
limitation with FEVi of <70%
of predicted value, and
FEVi/FVC ratio of less than
60%
1999-2000 24-havg:
16(17)
2000-2001 24-havg:
29(11)
NR
NR
Asthma symptoms:
Symptom scores >1, lag 0:
119.7% (-45.8, 2,038.2)
Symptom scores >1, lag 1:
197.4% (-36.7, 5,793.5)
Symptom scores >2, lag 0:
360.6% (-95.8, 3,039,358)
Symptom scores >2, lag 1:
-75.7% (-205.5,138,807.3)
1999-2000:
0, 54
2000-2001:
6, 54
FEV! change:
1999-2000
AM, lag 0
AM, lag 1
AM, lag 2
PM, lag 0
PM, lag 1
PM, lag 2
2000-2001
AM, lag 0
AM, lag 1
AM, lag 2
PM, lag 0:
PM, lag 1:
0.012 (-0.001,0.026)
0.022 (0.013,0.035)
0.015 (0.006, 0.028)
0.014 (0.001,0.030)
0.013 (-0.002, 0.028)
0.011 (-0.005,0.025)
: -0.005 (-0.021, 0.018)
: -0.011 (-0.032,0.008)
: 0.010 (-0.008, 0.024)
0.004 (-0.017, 0.006)
0.004 (-0.017, 0.006)
PM, lag 2 -0.006 (-0.019, 0.003)
PEF change:
-------
&
CJQ
c
to
o
o
<1
to
TABLE 5.5-3A (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02 Levels
(PPb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
o
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
Silkoff (cont'd) et al.
(2005)
Denver, CO, United
States
Winters of 1999-2000
and 2000-2001
Gilliand et al. (2001)
200-mile radius of
Los Angeles, CA,
United States
Jan-June 1996
Cohort of 4th grade school
children (9-10 yrs)
(n = 2,081)
24-h avg 10.9
NR
NR
NR
AM, lag 0
AM, lag 1
AM, lag 2
PM, lag 0:
PM, lag 1
PM, lag 2:
2000-2001
AM, lag 0:
AM, lag 1
AM, lag 2
PM, lag 0
PM, lag 1
PM, lag 2
2.0 (-1.5, 4.0)
5.1 (2.5,7.3)
4.0(1.8, 7.0)
2.4 (-1.0, 5.0)
2.3 (-1.1, 4.9)
2.2 (-1.2, 4.8)
-4.9 (-8.0, -2.0)
-4.7 (-7.8, -0.3)
0.8 (-2.0, 4.5)
-0.5 (-2.7, 2.0)
-0.8 (-3.0, 1.6)
-1.3 (-3.3, 0.2)
School absenteeism:
All absences: 6.9% (-51.8, 137.2)
Non-illness absences: 81.2% (-67.5, 376.1)
All illness absences: -9.0%) (-66.9, 149.0)
Nonrespiratory illness:
-61.1% (-90.7, 71.1)
Respiratory illness: 43.0% (- 59.3,403.6)
URI: -14.3% (-51.4, 51.3)
LRI (wet cough): -60.9% (-93.6, 123.2)
LRI (wet cough/wheeze or asthma):
10.5% (-91.2, 672.8)
Adamkiewicz et al. 29 nonsmoking adults 24-h avg 10.9
(2004) Steubenville, (ages 53+)
OH. United States
Sep-Dec, 2000
NR NR NR Change in fraction of exhaled NO: 24-h
moving average: 0.53 (-0.35,1.41)
-------
&
CJQ
c
to
o
o
<1
TABLE 5.5-3A (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02 Levels
(PPb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
to
to
o
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
Rondeau et al. (2005)
200-mile radius of
Los Angeles, CA,
United States
Jan-June 1996
Linnetal. (1996)
Los Angeles, CA,
United States
1992-1994
Cohort of 4th grade
school children
(9-10 yrs) (n= 1,932)
24-h avg: 5-45
269 school children
(during 4th and 5th
grade school yrs)
24-h avg: 33 (22)
NR NR NR School absenteeism:
All absences, 5 lag days:
-10.6% (-21.0, 1.2)
All absences, 15 lag days:
-25.4% (-37.3, -11.3)
All absences, 30 lag days:
-13.2% (-29.0, 5.9)
All illness absences, 5 lag days:
-9.4% (-15.5, -2.6)
All illness absences, 15 lag days:
-16.3% (-38.3, 13.4)
All illness absences, 30 lag days:
-10.4% (-23.5, 33.6)
Respiratory illness absences, 5 lag days:
2.8% (-12.2, 35.7)
Respiratory illness absences, 15 lag
days: -20.3%(-30.0, 16.9)
Respiratory illness absences, 30 lag
days: -23.8% (-53.9, 25.9)
NR NR 1,96 Total symptom score:
Previous 24-h, am score:
-18.2% (-47.3, 27.1
Current 24-h, pm score:
-42.9% (-65.4, -5.9)
* 24-h avg N02 standardized to 20 ppb increment; 1-h max N02 standardized to 30 ppb increment
NR = Not reported
-------
> TABLE 5.5-3B. EFFECTS OF SHORT-TERM NOz EXPOSURE ON EMERGENCY DEPARTMENT VISITS AND
| HOSPITAL ADMISSIONS FOR RESPIRATORY OUTCOMES IN THE UNITED STATES AND CANADA
" Statistics for N02
to
§ Averaging time, Air Quality Data (ppb)
^ Reference, Study Mean (SD) N02 Standardized Percent
Location and Period Study Population Levels (ppb) 98th % 99th % Range Excess Risk (95% CI)
EMERGENCY DEPARTMENT VISITS—ALL RESPIRATORY
^ Peel et al. (2005) 484,830 ER visits, all 1-h max: 45.9 (17.3) NR NR NR 1.024 (1.009,1.041)
to Atlanta, GA, United States ages from 31 hospitals
Jan 1993-Aug 2000
Stieb* et al. (2000)
Saint John, New
Brunswick, Canada
Jul 1992-Mar 1996
19,821 ER visits
24-h avg: 8.9
NR
NR 0, 82
¦ 14.70%
O
o
2
o
H
o
c
o
H
ffl
o
o
HH
H
ffl
EMERGENCY DEPARTMENT VISITS—ASTHMA
Jaffe et al. (2003) 2 cities,
Ohio, United States,
(Cleveland, Cincinnati)
Jul 91-Jun 96
Norris* et al. (1999)
Seattle, WA, United States,
1995-1996
Lipsett et al (1997)
Santa Clara County, CA,
United States,
1988-1992 (winter only)
4,416 ER visits for
asthma, age 5-34
900 ER visits for
asthma, <18 yrs
24-h avg:
Cincinnati: 50 (15)
Cleveland: 48 (15)
24-h avg: 20.2(7.1)
1-h max: 34.0(11.3)
ER visits for asthma 1-h max: 69 (28)
NR
NR
NR
NR NR
NR
NR
NR
29, 150
6.1% (-2.0, 14.0)
24-h avg: -2.0% (-21, 19)
1-h avg: 5% (-2, 33)
48%
Peel et al. (2005)
Atlanta, GA, United States
Jan 1993-Aug 2000
Asthma ER visits, all 1-hmax: 45.9(17.3) NR NR NR All Ages: 2.1% (-0.4, 4.5)
ages and 2-18 yrs from 2-18: 4.1% (0.8, 7.6)
31 hospitals
-------
&
CJQ
c
to
o
o
<1
to
H
6
O
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
TABLE 5-3B (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON EMERGENCY DEPARTMENT VISITS AND
HOSPITAL ADMISSIONS FOR RESPIRATORY OUTCOMES IN THE UNITED STATES AND CANADA
Reference, Study
Location, and Period
Averaging time,
Mean (SD) N02
Study Population Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
Standardized
98th % 99th %
Range
Risk (95% CI)
EMERGENCY DEPARTMENT VISITS—ASTHMA (cont'd)
Tolbert et al. (2000)
Atlanta, GA,
United States,
1993-1995
5,934 ER visits for asthma, 1-hmax: 81.7(53.8)
age 0-16
NR
NR
5.35, 306
0.7% (-0.8, 2.3)
Cassino* et al. (1999)
New York City, NY,
United States
1989-1993
1,115 ER visits from 24-h avg: 45.0
11 hospitals
NR
NR
NR
lagO: -4%
(-19, 12)
lag 1: 5% (-11, 25)
lag 2: 9% (-8, 28)
Stieb et al. (1996) St. John,
New Brunswick, Canada
1,163 ER visits for asthma,
ages 0-15, 15 + from
1-hmax: 25.2
NR
NR
0, 120
N02 + 0,: -11%
1984-1992 (summers only) 2 hospitals
HOSPITAL ADMISSIONS—ALL RESPIRATORY
Gwynn* et al. (2000)
Buffalo, NY,
United States,
1988-1990, Days: 1,090
Burnett et al. (1997a)
16 Canadian Cities,
Canada,
4/1981-12/1991,
Days: 3,927
Respiratory hospital
admissions
24-h avg: 20.5
NR
NR
4.0,47.5 2.20%
All respiratory admission 1-hmax: 35.5(16.5) NR
from 134 hospitals
87
NR
Only report results
or multipollutant
model adjusted for
CO, 03, S02 and
CoH -0.3%
(-2.4%, 1.8%)
-------
&
CJQ
c
to
o
o
<1
TABLE 5-3B (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON EMERGENCY DEPARTMENT VISITS AND
HOSPITAL ADMISSIONS FOR RESPIRATORY OUTCOMES IN THE UNITED STATES AND CANADA
to
H
6
o
2
o
H
o
c
o
H
W
O
V
o
HH
H
W
Reference, Study
Location, and Period
Averaging time,
Mean (SD) N02
Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
Standardized Percent Excess
Risk (95% CI)
Study Population
98th % 99th %
Range
HOSPITAL ADMISSIONS - ALL RESPIRATORY (cont'd)
Yang et al. (2003)
Vancouver, BC, Canada
1986-1998, Days: 4,748
Respiratory hospital
admissions among
young children
(<3 yrs) and elderly
(>65 yrs)
24-h avg:
18.74 (5.66)
NR NR
NR
<3 yrs: 19.1% (11.2, 36.3)
>65 yrs: 19.1% (7.4, 36.3)
Fung et al. (2006)
Vancouver, BC, Canada
6/1/95-3/31/99
All respiratory
admissions for
elderly (65 + yrs)
24-h avg:
16.83 (4.34)
NR NR
7.22,
33.89
9.1% (1.5, 17.2)
Burnett* etal. (2001)
Toronto, ON, Canada
1980-1994
All respiratory
admissions for young
children (<2 yrs)
1-hmax: 44.1
NR 86
Max =146
18.20%
Luginaah et al. (2005)
Windsor, ON, Canada
4/1/95-12/31/00
All respiratory
admissions ages 0-14,
15-64, and 65 + from
4 hospitals
1-h max:
38.9(12.3)
NR NR
NR
All ages, female:
6.7% (-5.4, 20.4)
All ages, male:
-10.3% (-20.3, 1.1)
0-14, female: 22.4% (-1.2, 51.5)
0-14, male: -8.3% (-13.7, 0.8)
15-64, female: 23.9% (-4.1,
60.0)
15-64, male: 2.3% (-17.7, 44.3)
65+, female: 3.8% (-12.8, 23.5)
65+, male: -14.6 (-29.2, 3.0)
-------
&
CJQ
c
to
o
o
<1
TABLE 5-3B (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON EMERGENCY DEPARTMENT VISITS AND
HOSPITAL ADMISSIONS FOR RESPIRATORY OUTCOMES IN THE UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02
Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
98th % 99th %
Range
Standardized Percent
Excess Risk (95% CI)
HOSPITAL ADMISSIONS - ASTHMA
to
On
Linn et al. (2000)
Los Angeles, CA,
United States 1992-1995
302,600 COPD and
asthma hospital
admissions
24-h avg:
Winter: 3.4(1.3);
Spring: 2.8 (0.9);
Summer 3.4 (1.0);
Autumn: 4.1 (1.4);
all yr: 3.4 (1.3)
NR
NR
NR
2.8% ± 1.0%
O
o
2
o
H
o
c
o
H
ffl
o
o
HH
H
ffl
Lin* et al. (2004)
Vancouver, BC, Canada
1987-1991
Lin et al. (2003)
Toronto, ON, Canada
1981-1993
Burnett et al. (1999)
Toronto, ON, Canada
1980-1994
Asthma hospital
admissions among
6-12 yr olds
Asthma hospital
admissions among 6-12
yr olds
Asthma hospital
admissions
24-h avg:
18.65 (5.59)
NR
NR
4.28, 45.36
24-h avg: 25.24
(9.04)
NR
24-h avg: 25.2(9.1) NR
NR
NR
3.0, 82.0
NR
Boys, low SES:
45.3% (12.7, 88.3)
Boys, high SES:
12.7% (-14.6, 49.3)
Girls, low SES:
23.0% (-11.7, 70.2)
Girls, high SES:
3.1% (-27.6, 45.3)
Boys: 18.9%
(1.8, 39.3)
Girls: 17.0%
(-5.4, 41.4)
2.60%
-------
&
CJQ
c
to
o
o
<1
to
^1
H
6
O
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
TABLE 5.5-3B (cont'd). EFFECTS OF SHORT-TERM N02 EXPOSURE ON EMERGENCY DEPARTMENT VISITS
AND HOSPITAL ADMISSIONS FOR RESPIRATORY OUTCOMES IN THE UNITED STATES AND CANADA
Reference, Study
Location, and Period Study Population
Averaging time,
Mean (SD) N02 Levels
(PPb)
Statistics for N02
Air Quality Data (ppb)
Standardized
Percent Excess Risk
(95% CI)
98th % 99th % Range
HOSPITAL ADMISSIONS - COPD
Moolgavkar (2000)
Chicago, Los Angeles,
Phoenix, United States
1987-1995
Hospital admissions
24-h avg: Chicago: 25;
LA: 38; Phoenix: 19
NR
NR
NR
Chicago: 4.0%
Los Angeles: 4.0%
Phoenix: 9.0%
Linn et al. (2000)
Los Angeles, CA,
United States
1992-1995
302,600 COPD and
asthma hospital
admissions
24-h avg:
Winter: 3.4(1.3);
Spring: 2.8 (0.9);
Summer 3.4 (1.0);
Autumn: 4.1 (1.4);
all yr: 3.4(1.3)
NR
NR
NR
1.6% ± 0.8%
Yang (2005)
Vancouver, BC, Canada,
1994-1998, Days: 1,826
COPD admissions among
elderly (65+)
24-h avg: 17.03 (4.48)
NR
NR
4.28,
33.89
32.3% (7.5, 66.2)
* 24-h avg N02 standardized to 20 ppb increment; 1-h max N02 standardized to 30 ppb increment
NR = Not reported
-------
>
c
OQ
c
to
o
o
^1
TABLE 5.5-3C. EFFECTS OF LONG-TERM N02 EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study
Population
Averaging Time,
Mean (SD) N02
Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
Gauderman et al.
(2004) Southern
California,
United States
1993-2001
1,759 children
followed from
age 10-18
Annual avg: 34.6
NR
NR
NR
Difference in avg growth in lung
function over eight yr study period from
the least to most polluted community:
FVC: -95.0 ml (-189.4,-0.6)
FEVj: -101.4 (-164.5,-38.4)
MMEF: -211.0 (-377.6,-44.4)
to
oo
o
o
o
2
o
H
o
c
o
H
ffl
o
O
HH
H
W
Peters et al. (1999)
Southern California,
United States
1993
3,293 public
school students in
grades 4, 7, and
10
24-havg: 21.5
NR
NR
NR
Regression of pulmonary function tests
on N02 concentrations (1986-1990):
FVC: -42.6(13.5)
Males only: -27.6(25.9)
Females only: -58.5 (15.4)
FEVj: -23.2(12.5)
Males only: -7.6(22.1)
Females only: -39.9(13.9)
PEFR: -19.0(43.2)
Males only: 48.0 (50.6)
Females only: -109.2 (74.8)
MMEF: -27.5(21.7)
Males only: 23.0(27.6)
Females only: -90.1 (36.1)
Regression of pulmonary function tests
onN02 concentrations (1994):
FVC: -46.2(16.0)
Males only: -29.9 (29.5)
Females only: -63.8(18.3)
FEVi: -22.3 (14.8)
Males only: -2.1(25.1)
-------
>
c
OQ
c
to
o
o
^1
TABLE 5.5-3C (cont'd). EFFECTS OF LONG-TERM N02 EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging time,
Mean (SD) N02
Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
Peters et al. (1999)
Southern California,
United States
1993 (cont'd)
Females only: -44.1(16.1)
PEFR: -29.5 (48.5)
Males only: 54.2 (57.3)
Females only: -133.4 (83.1)
MMEF: -32.9 (24.4)
Males only: 30.0 (30.9)
Females only: -109.5 (38.9)
Tager et al. (2005)
Los Angeles and San
Francisco, CA,
United States
2000-2002
255 freshman
undergraduates between
16-19 yrs old at UC-
Berkeley with permanent
residence in LA or SF
24-havg: 28.5
NR
NR
8, 51
Sex-specific effects of estimated
lifetime mean exposure to N02
LnFEF75: Men: -0.029(0.003)
Women: -0.032(0.002)
Millstein et al. (2004)
200 mile radius of
Los Angeles
1995
Cohort of 4th grade
children (age 9) that
entered Children's Health
Study in 1995
Monthly avg: NR
NR
NR
NR
Monthly prevalence of asthma
medication use:
OR: -10.3% (-44.9, 41.4)
High time outdoors:
-27.8% (-65.9, 51.7)
Low time outdoors:
-15.2% (-50.5, 43.4)
Kim et al. (2004)
San Francisco, CA,
United States
2001
1,109 children (grades 3-5)
from neighborhoods that
span a busy traffic corridor
Annual avg: 23.0
NR
NR
NR
Bronchitis: 5.7% (-2.8, 17.6)
Asthma: 5.7% (-8.2, 20.7)
Asthma (no outlier): 17.6% (-2.8,
40.4)
to
vo
O
V
fe
H
6
o
2
o
H
O
c
o
H
W
O
V
o
HH
H
W
-------
TABLE 5.5-3C (cont'd). EFFECTS OF LONG-TERM NOz EXPOSURE ON RESPIRATORY OUTCOMES IN THE
UNITED STATES AND CANADA
Reference, Study
Location, and Period
Study Population
Averaging Time,
Mean (SD) N02
Levels (ppb)
Statistics for N02
Air Quality Data (ppb)
98th %
99th %
Range
Standardized* Percent Excess Risk
(95% CI)
Gauderman et al.
(2005) Southern
California,
United States
2000
208 children originally
enrolled in Children's
Health Study as 4th
graders in 1993 or 1996
Monthly avg:
15.3-51.5
NR
NR
NR Asthma: 188.7% (7.1, 773.8)
Recent wheeze: 158.9% (12.6, 497.4)
Recent wheeze with exercise:
240.3% (14.5, 902.2)
Current asthma medication use:
295.6% (37.7, 1,043.3)
* 24-h avg NO2 standardized to 20 ppb increment; 1-h max NO2 standardized to 30 ppb increment; monthly and yearly NO2 avgs standardized to 10 ppb
NR = Not reported
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
6. REFERENCES
Abbey, D. E.; Nishino, N.; McDonnell, W. F.; Burchette, R. J.; Knutsen, S. F.; Beeson, W. L.;
Yang, J. X. (1999) Long-term inhalable particles and other air pollutants related to
mortality in nonsmokers. Am. J. Respir. Crit. Care Med. 159: 373-382.
Abdul-Kareem, H. S.; Sharma, R. P.; Brown, D. B. (1991) Effects of repeated intermittent
exposures to nitrous oxide on central neurotransmitters and hepatic methionine synthetase
activity in CD-I mice. Toxicol. Ind. Health 7: 97-108.
Abraham, W. M.; Kim, C. S.; King, M. M.; Oliver, W., Jr.; Yerger, L. (1982) Effects of nitric
acid on carbachol reactivity of the airways in normal and allergic sheep. Arch. Environ.
Health 37: 36-40.
Ackermann-Liebrich, U.; Leuenberger, P.; Schwartz, J.; Schindler, C.; Monn, C.; Bolognini, B.;
Bongard, J. P.; Brandli, O.; Domenighetti, G.; Elsasser, S.; Grize, L.; Karrer, W.; Keller,
R.; Keller-Wossidlo, H.; Kiinzli, N.; Martin, B. W.; Medici, T. C.; Perruchoud, A. P.;
Schoni, M. H.; Tschopp, J. M.; Villiger, B.; Wiithrich, B.; Zellweger, J. P.; Zemp, E.
(1997) Lung function and long term exposure to air pollutants in Switzerland. Am. J.
Respir. Crit. Care Med. 155: 122-129.
Acton, J. D.; Myrvik, Q. N. (1972) Nitrogen dioxide effects on alveolar macrophages. Arch.
Environ. Health 24: 48-52.
Adamkiewicz, G.; Ebelt, S.; Syring, M.; Slater, J.; Speizer, F. E.; Schwartz, J.; Suh, H.; Gold, D.
R. (2004) Association between air pollution exposure and exhaled nitric oxide in an
elderly population. Thorax 59: 204-209.
Adams, W. C.; Brookes, K. A.; Schelegle, E. S. (1987) Effects of NO2 alone and in combination
with O3 on young men and women. J. Appl. Physiol. 62: 1698-1704.
Adkins, B., Jr.; Van Stee, E. W.; Simmons, J. E.; Eustis, S. L. (1986) Oncogenic response of
strain A/J mice to inhaled chemicals. J. Toxicol. Environ. Health 17: 311-322.
Aga, E.; Samoli, E.; Touloumi, G.; Anderson, H. R.; Cadum, E.; Forsberg, B.; Goodman, P.;
Goren, A.; Kotesovec, F.; Kriz, B.; Macarol-Hiti, M.; Medina, S.; Paldy, A.; Schindler,
C.; Sunyer, J.; Tittanen, P.; Wojtyniak, B.; Zmirou, D.; Schwartz, J.; Katsouyanni, K.
(2003) Short-term effects of ambient particles on mortality in the elderly: results from 28
cities in the APHEA2 project. Eur. Respir. J. 21(suppl. 40): 28s-33s.
Albritton, D. L.; Greenbaum, D. S., eds. (1998) Atmospheric observations: helping build the
scientific basis for decisions related to airborne particulate matter: report of the PM
Measurements Research Workshop; July; Chapel Hill, NC. Cambridge, MA: Health
Effects Institute.
Aim, S.; Mukala, K.; Pasanen, P.; Tiittanen, P.; Ruuskanen, J.; Tuomisto, J.; Jantunen, M. J.
(1998) Personal NO2 exposures of preschool children in Helsinki. J. Exposure Anal.
Environ. Epidemiol. 8: 79-100.
August 2007
6-1
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Alving, K.; Fornhem, C.; Lundberg, J. M. (1993) Pulmonary effects of endogenous and
exogenous nitric oxide in the pig: relation to cigarette smoke inhalation. Br. J. Pharmacol.
110: 739-746.
American Academy of Pediatrics, Committee on Environmental Health. (2004) Ambient air
pollution: health hazards to children. Pediatrics 114: 1699-1707.
American Thoracic Society. (2000a) Guidelines for methacholine and exercise challenge testing-
1999. Am. J. Respir. Crit. Care Med. 161: 309-329.
American Thoracic Society. (2000b) What constitutes an adverse health effect of air pollution?
Am. J. Respir. Crit. Care Med. 161: 665-673.
Ammann, M.; Kalberer, M.; Jost, D. T.; Tobler, L.; Rossler, E.; Piguet, D.; Gaggeler, H. W.;
Baltensperger, U. (1998) Heterogeneous production of nitrous acid on soot in polluted air
masses. Nature (London) 395: 157-160.
Amoruso, M. A.; Witz, G.; Goldstein, B. D. (1981) Decreased superoxide anion radical
production by rat alveolar macrophages following inhalation of ozone or nitrogen
dioxide. Life Sci. 28: 2215-2221.
Anderson, H. R.; Spix, C.; Medina, S.; Schouten, J. P.; Castellsague, J.; Rossi, G.; Zmirou, D.;
Touloumi, G.; Wojtyniak, B.; Ponka, A.; Bacharova, L.; Schwartz, J.; Katsouyanni, K.
(1997) Air pollution and daily admissions for chronic obstructive pulmonary disease in 6
European cities: results from the APHEA project. Eur. Respir. J. 10: 1064-1071.
Anderson, H. R.; Ponce de Leon, A.; Bland, J. M.; Bower, J. S.; Emberlin, J.; Strachen, D. P.
(1998) Air pollution, pollens, and daily admissions for asthma in London 1987-92.
Thorax 53: 842-848.
Ando, M.; Shima, M.; Adachi, M.; Tsunetoshi, Y. (2001) The role of intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and regulated on
activation, normal T-cell expressed and secreted (RANTES) in the relationship between
air pollution and asthma among children. Arch. Environ. Health 56: 227-233.
Aranyi, C.; Fenters, J.; Erhlich, R.; Gardner, D. (1976) Scanning electron microscopy of alveolar
macrophages after exposure to oxygen, nitrogen dioxide, and ozone. Environ. Health
Perspect. 16: 180.
Arner, E. C.; Rhoades, R. A. (1973) Long-term nitrogen dioxide exposure: effects on lung lipids
and mechanical properties. Arch. Environ. Health 26: 156-160.
Arroyo, P. L.; Hatch-Pigott, V.; Mower, H. F.; Cooney, R. V. (1992) Mutagenicity of nitric
oxide and its inhibition by antioxidants. Mutat. Res. Lett. 281: 193-202.
Atkinson, R. W.; Anderson, H. R.; Strachan, D. P.; Bland, J. M.; Bremner, S. A.; Ponce de Leon,
A. (1999a) Short-term associations between outdoor air pollution and visits to accident
and emergency departments in London for respiratory complaints. Eur. Respir. J. 13:
257-265.
Atkinson, R. W.; Bremner, S. A.; Anderson, H. R.; Strachan, D. P.; Bland, J. M.; Ponce de Leon,
A. (1999b) Short-term associations between emergency hospital admissions for
respiratory and cardiovascular disease and outdoor air pollution in London. Arch.
Environ. Health 54: 398-411.
August 2007
6-2
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Avissar, N. E.; Reed, C. K.; Cox, C.; Frampton, M. W.; Finkelstein, J. N. (2000) Ozone, but not
nitrogen dioxide, exposure decreases glutathione peroxidases in epithelial lining fluid of
human lung. Am. J. Respir. Crit. Care Med. 162: 1342-1347.
Avol, E. L.; Gauderman, W. J.; Tan, S. M.; London, S. J.; Peters, J. M. (2001) Respiratory
effects of relocating to areas of differing air pollution levels. Am. J. Respir. Crit. Care
Med. 164: 2067-2072.
Ayaz, K. L.; Csallany, A. S. (1978) Long-term NO2 exposure of mice in the presence and
absence of vitamin E. II. Effect of glutathione peroxidase. Arch. Environ. Health 33: 292-
296.
Azadniv, M.; Utell, M. J.; Morrow, P. E.; Gibb, F. R.; Nichols, J.; Roberts, N. J., Jr.; Speers, D.
M.; Torres, A.; Tsai, Y.; Abraham, M. K.; Voter, K. Z.; Frampton, M. W. (1998) Effects
of nitrogen dioxide exposure on human host defense. Inhalation Toxicol. 10: 585-602.
Azoulay, E.; Soler, P.; Blayo, M. C.; Basset, F. (1977) Nitric oxide effects on lung structure and
blood oxygen affinity in rats. Bull. Eur. Physiopathol. Respir. 13: 629-644.
Azoulay, E.; Bouley, G.; Blayo, M. C. (1981) Effects of nitric oxide on resistance to bacterial
infection in mice. J. Toxicol. Environ. Health 7: 873-882.
Azoulay-Dupuis, E.; Torres, M.; Soler, P.; Moreau, J. (1983) Pulmonary NO2 toxicity in neonate
and adult guinea pigs and rats. Environ. Res. 30: 322-339.
Balabaeva, L.; Tabakova, S. (1985) Lipidnata peroksidatsiya v dvye pokoleniya zhenski beli
plukhove, inkhalirani s azoten dvuokis [Lipid peroxidation in two progenies of female
albino rats inhaling nitrogen dioxide], Khig. Zdraveopaz. 28: 41-46.
Ballester, F.; Tenias, J. M.; Perez-Hoyos, S. (2001) Air pollution and emergency hospital
admissions for cardiovascular diseases in Valencia, Spain. J. Epidemiol. Community
Health 55: 57-65.
Ballester, F.; Saez, M.; Perez-Hoyos, S.; Iniguez, C.; Gandarillas, A.; Tobias, A.; Bellido, J.;
Taracido, M.; Arribas, F.; Daponte, A.; Alonso, E.; Canada, A.; Guillen-Grima, F.;
Cirera, L.; Perez-Boillos, M. J.; Saurina, C.; Gomez, F.; Tenias, J. M. (2002) The
EMECAM project: a multicentre study on air pollution and mortality in Spain: combined
results for particulates and for sulfur dioxide. Occup. Environ. Med. 59: 300-308.
Ballester, F.; Rodriguez, P.; Iniguez, C.; Saez, M.; Daponte, A.; Galan, I.; Taracido, M.; Arribas,
F.; Bellido, J.; Cirarda, F. B.; Canada, A.; Guillen, J. J.; Guillen-Grima, F.; Lopez, E.;
Perez-Hoyos, S.; Lertxundi, A.; Toro, S. (2006) Air pollution and cardiovascular
admisisons association in Spain: results within the EMECAS project. J. Epidemiol.
Community Health 60: 328-336.
Barck, C.; Sandstrom, T.; Lundahl, J.; Hallden, G.; Svartengren, M.; Strand, V.; Rak, S.; Bylin,
G. (2002) Ambient level of NO2 augments the inflammatory response to inhaled allergen
in asthmatics. Respir. Med. 96: 907-917.
Barck, C.; Lundahl, J.; Hallden, G.; Bylin, G. (2005a) Brief exposures to NO2 augment the
allergic inflammation in asthmatics. Environ. Res. 97: 58-66.
Barck, C.; Lundahl, J.; Holmstrom, M.; Bylin, G. (2005b) Does nitrogen dioxide affect
inflammatory markers after nasal allergen challenge? Am. J. Rhinol. 19: 560-566.
August 2007
6-3
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Barinaga, M. (1991) Is nitric oxide the "retrograde messenger"? Science 254: 1296-1297.
Barnett, A. G.; Williams, G. M.; Schwartz, J.; Neller, A. H.; Best, T. L.; Petroeschevsky, A. L.;
Simpson, R. W. (2005) Air pollution and child respiratory health: a case-crossover study
in Australia and New Zealand. Am. J. Respir. Crit. Care Med. 171: 1272-1278.
Barnett, A. G.; Williams, G. M.; Schwartz, J.; Best, T. L.; Neller, A. H.; Petroeschevsky, A. L.;
Simpson, R. W. (2006) The effects of air pollution on hospitalization for cardiovascular
disease in elderly people in Australian and New Zealand cities. Environ. Health Perspect.
114: 1018-1023.
Barth, P. J.; Miiller, B. (1999) Effects of nitrogen dioxide exposure on Clara cell proliferation
and morphology. Pathol. Res. Pract. 195: 487-493.
Barth, P. J.; Miiller, B.; Wagner, U.; Bittinger, A. (1994a) Assessment of proliferative activity in
type II pneumocytes after inhalation of N02 by agnor-analysis. Exp. Toxicol. Pathol. 46:
335-342.
Barth, P. J.; Uhlarik, S.; Bittinger, A.; Wagner, U.; Riischoff, J. (1994b) Diffuse alveolar damage
in the rat lung after short and long term exposure to nitrogen dioxide. Pathol. Res. Pract.
190: 33-41.
Barth, P. J.; Miiller, B.; Wagner, U.; Bittinger, A. (1995) Quantitative analysis of parenchymal
and vascular alterations in N02-induced lung injury in rats. Eur. Respir. J. 8: 1115-1121.
Bateson, T. F.; Schwartz, J. (2004) Who is sensitive to the effects of particulate air pollution on
mortality? A case-crossover analysis of effect modifiers. Epidemiology 15: 143-149.
Bauer, M. A.; Utell, M. J.; Morrow, P. E.; Speers, D. M.; Gibb, F. R. (1986) Inhalation of 0.30
ppm nitrogen dioxide potentiates exercise-induced bronchospasm in asthmatics. Am.
Rev. Respir. Dis. 134: 1203-1208.
Beckett, W. S.; Russi, M. B.; Haber, A. D.; Rivkin, R. M.; Sullivan, J. R.; Tameroglu, Z.;
Mohsenin, V.; Leaderer, B. P. (1995) Effect of nitrous acid on lung function in
asthmatics: a chamber study. Environ. Health Perspect. 103: 372-375.
Beil, M.; Ulmer, W. T. (1976) Wirkung von NO2 im MAK-Bereich auf Atemmechanik und
bronchiale Acetylcholinempfindlichkeit bei Normalpersonen [Effect of NO2 in workroom
concentrations on respiratory mechanics and bronchial susceptibility to acetylcholine in
normal persons]. Int. Arch. Occup. Environ. Health 38: 31-44.
Belanger, K.; Beckett, W.; Triche, E.; Bracken, M.; Holford, T.; Ren, P.; McSharry, J.-E.; Gold,
D.; Platts-Mills, T.; Leaderer, B. (2003) Symptoms of wheeze and persistent cough in the
first year of life: associations with indoor allergens, air contaminants and maternal history
of asthma. Am. J. Epidemiol. 158: 195-202.
Belanger, K.; Gent, J. F.; Triche, E. W.; Bracken, M. B.; Leaderer, B. P. (2006) Association of
indoor nitrogen dioxide exposure with respiratory symptoms in children with asthma.
Am. J. Respir. Crit. Care Med. 173: 297-303.
Bell, M. L.; Ebisu, K.; Belanger, K. (2007) Ambient air pollution and low birth weight in
Connecticut and Massachusetts. Environ. Health Perspect. 115: 1118-1125.
August 2007
6-4
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Bermiidez, E. (2001) Detection of poly(ADP-ribose) synthetase activity in alveolar macrophages
of rats exposed to nitrogen dioxide and ozone. Inhalation Toxicol. 13: 69-84.
Bernard, N.; Saintot, M.; Astre, C.; Gerber, M. (1998) Personal exposure to nitrogen dioxide
pollution and effect on plasma antioxidants. Arch. Environ. Health 53: 122-128.
Biggeri, A.; Baccini, M.; Bellini, P.; Terracini, B. (2005) Meta-analysis of the Italian studies of
short-term effects of air pollution (MISA), 1990-1999. Int. J. Occup. Environ. Health 11:
107-122.
Bils, R. F. (1976) The connective tissues and alveolar walls in the lungs of normal and oxidant-
exposed squirrel monkeys. J. Cell Biol. 70: 318.
Blaise, G. A.; Gauvin, D.; Gangal, M.; Authier, S. (2005) Nitric oxide, cell signaling and cell
death. Toxicology 208: 177-192.
Blomberg, A.; Krishna, M. T.; Bocchino, V.; Biscione, G. L.; Shute, J. K.; Kelly, F. J.; Frew, A.
J.; Holgate, S. T.; Sandstrom, T. (1997) The inflammatory effects of 2 ppm NO2 on the
airways of healthy subjects. Am. J. Respir. Crit. Care Med. 156: 418-424.
Blomberg, A.; Krishna, M. T.; Helleday, R.; Soderberg, M.; Ledin, M.-C.; Kelly, F. J.; Frew, A.
J.; Holgate, S. T.; Sandstrom, T. (1999) Persistent airway inflammation but accomodated
antioxidant and lung function responses after repeated daily exposure to nitrogen dioxide.
Am. J. Respir. Crit. Care Med. 159: 536-543.
Boezen, M.; Schouten, J.; Rijcken, B.; Vonk, J.; Gerritsen, J.; VanDerZee, S.; Hoek, G.;
Brunekreef, B.; Postma, D. (1998) Peak expiratory flow variability, bronchial
responsiveness, and susceptibility to ambient air pollution in adults. Am. J. Respir. Crit.
Care Med. 158: 1848-1854.
Borja-Aburto, V. H.; Castillejos, M.; Gold, D. R.; Bierzwinski, S.; Loomis, D. (1998) Mortality
and ambient fine particles in southwest Mexico City, 1993-1995. Environ. Health
Perspect. 106: 849-855.
Boutin-Forzano, S.; Adel, N.; Gratecos, L.; Jullian, H.; Gamier, J. M.; Ramadour, M.;
Lanteaume, A.; Hamon, M.; Lafay, V.; Charpin, D. (2004) Visits to the emergency room
for asthma attacks and short-term variations in air pollution. A case-crossover study.
Respiration 71: 134-137.
Brady, T. C.; Crapo, J. D.; Mercer, R. R. (1998) Nitric oxide inhalation transiently elevates
pulmonary levels of DGMP, inos mrna, and tnf-alpha. Am. J. Physiol. 275: L509-L515.
Braga, A. L. F.; Saldiva, P. H. N.; Pereira, L. A. A.; Menezes, J. J. C.; Conceifjao, G. M. C.; Lin,
C. A.; Zanobetti, A.; Schwartz, J.; Dockery, D. W. (2001) Health effects of air pollution
exposure on children and adolescents in Sao Paulo, Brazil. Pediatr. Pulmonol. 31: 106-
113.
Braner, M.; Henderson, S.; Kirkham, T.; Lee, K. S.; Rich, K.; Teschke, K. (2002) Review of the
health risks associated with nitrogen dioxide and sulfur dioxide in indoor air. Vancouver,
BC, Canada: University of British Columbia, School of Occupational and Environmental
Hygiene. Available: http://www.cher.ubc.ca/PDFs/IAQN02S02full.pdffl8 July, 2007],
August 2007
6-5
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Brauer, M.; Ryan, P. B.; Suh, H. H.; Koutrakis, P.; Spengler, J. D.; Leslie, N. P.; Billick, I. H.
(1990) Measurements of nitrous acid inside two research houses. Environ. Sci. Technol.
24: 1521-1527.
Brauer, M.; Rasmussen, T. R.; Kjasrgaard, S. K.; Spengler, J. D. (1993) Nitrous acid formation in
an experimental exposure chamber. Indoor Air 3: 94-105.
Brauer, M.; Hoek, G.; Van Vliet, P.; Meliefste, K.; Fischer, P. H.; Wijga, A.; Koopman, L. P.;
Neijens, H. J.; Gerritsen, J.; Kerkhof, M.; Heinrich, J.; Bellander, T.; Brunekreef, B.
(2002) Air pollution from traffic and the development of respiratory infections and
asthmatic and allergic symptoms in children. Am. J. Respir. Crit. Care Med. 166: 1092-
1098.
Brauer, M.; Hoek, G.; Smit, H. A.; De Jongste, J. C.; Gerritsen, J.; Postma, D. S.; Kerkhof, M.;
Brunekreef, B. (2007) Air pollution and development of asthma, allergy and infections in
a birth cohort. Eur. Respir. J. 29: 879-888.
Braun-Fahrlander, C.; Ackermann-Liebrich, U.; Schwartz, J.; Gnehm, H. P.; Rutishauser, M.;
Wanner, H. U. (1992) Air pollution and respiratory symptoms in preschool children. Am.
Rev. Respir. Dis. 145: 42-47.
Bremner, S. A.; Anderson, H. R.; Atkinson, R. W.; McMichael, A. J.; Strachan, D. P.; Bland, J.
M.; Bower, J. S. (1999) Short term associations between outdoor air pollution and
mortality in London 1992-4. Occup. Environ. Med. 56: 237-244.
Brook, R. D.; Franklin, B.; Cascio, W.; Hong, Y.; Howard, G.; Lipsett, M.; Luepker, R.;
Mittleman, M.; Samet, J.; Smith, S. C., Jr.; Tager, I. (2004) Air pollution and
cardiovascular disease. A statement for healthcare professionals from the Expert Panel on
Population and Prevention Science of the American Heart Association. Circulation 109:
2655-2671.
Brown, S. K.; Mahoney, K. J.; Cheng, M. (2004) Room chamber assessment of the pollutant
emission properties of (nominally) low-emission unflued gas heaters. Indoor Air
14(suppl. 8): 84-91.
Burnett, R. T.; Cakmak, S.; Brook, J. R.; Krewski, D. (1997a) The role of particulate size and
chemistry in the association between summertime ambient air pollution and
hospitalization for cardiorespiratory diseases. Environ. Health Perspect. 105: 614-620.
Burnett, R. T.; Brook, J. R.; Yung, W. T.; Dales, R. E.; Krewski, D. (1997b) Association
between ozone and hospitalization for respiratory diseases in 16 Canadian cities. Environ.
Res. 72: 24-31.
Burnett, R. T.; Cakmak, S.; Brook, J. R. (1998) The effect of the urban ambient air pollution mix
on daily mortality rates in 11 Canadian cities. Can. J. Public Health 89: 152-156.
Burnett, R. T.; Smith-Doiron, M.; Stieb, D.; Cakmak, S.; Brook, J. R. (1999) Effects of
particulate and gaseous air pollution on cardiorespiratory hospitalizations. Arch. Environ.
Health 54: 130-139.
Burnett, R. T.; Brook, J.; Dann, T.; Delocla, C.; Philips, O.; Cakmak, S.; Vincent, R.; Goldberg,
M. S.; Krewski, D. (2000) Association between particulate- and gas-phase components of
August 2007
6-6
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
urban air pollution and daily mortality in eight Canadian cities. In: Grant, L. D., ed.
PM2000: particulate matter and health. Inhalation Toxicol. 12(suppl. 4): 15-39.
Burnett, R. T.; Goldberg, M. S. (2003) Size-fractionated particulate mass and daily mortality in
eight Canadian cities. In: Revised analyses of time-series studies of air pollution and
health. Special report. Boston, MA: Health Effects Institute; pp. 85-89. Available:
http://www.healtheffects.org/news.htm [16 May, 2003],
Burnett, R. T.; Stieb, D.; Brook, J. R.; Cakmak, S.; Dales, R.; Raizenne, M.; Vincent, R.; Dann,
T. (2004) Associations between short-term changes in nitrogen dioxide and mortality in
Canadian cities. Arch. Environ. Health 59: 228-236.
Busch, R. H.; Buschbom, R. L.; Cannon, W. C.; Lauhala, K. E.; Miller, F. J.; Graham, J. A.;
Smith, L. G. (1986) Effects of ammonium nitrate aerosol exposure on lung structure of
normal and elastase-impaired rats and guinea pigs. Environ. Res. 39: 237-252.
Bush, T.; Smith, S.; Stevenson, K.; Moorcroft, S. (2001) Validation of nitrogen dioxide diffusion
tube methodology in the UK. Atmos. Environ. 35: 289-296.
Bylin, G.; Lindvall, T.; Rehn, T.; Sundin, B. (1985) Effects of short-term exposure to ambient
nitrogen dioxide concentrations on human bronchial reactivity and lung function. Eur. J.
Respir. Dis. 66: 205-217.
Cabral-Anderson, L. J.; Evans, M. J.; Freeman, G. (1977) Effects of N02 on the lungs of aging
rats: I. morphology. Exp. Mol. Pathol. 27: 353-365.
California Air Resources Board. (2007a) Review of the California ambient air quality standard
for nitrogen dioxide. Staff report: initial statement of reasons for proposed rulemaking.
Sacramento, CA: California Environmental Protection Agency, Air Resources Board.
Available: http://www.arb.ca.gov/research/aaqs/no2-rs/no2-doc.htm [23 July, 2007],
California Air Resources Board. (2007b) Review of the California ambient air quality standard
for nitrogen dioxide. Technical support document. Sacramento, CA: California
Environmental Protection Agency, Air Resources Board. Available:
http://www.arb.ca.gov/research/aaqs/no2-rs/no2-doc.htm [23 July, 2007],
Campbell, G. W.; Stedman, J. R.; Stevenson, K. (1994) A survey of nitrogen dioxide
concentrations in the United Kingdom using diffusion tubes, July-December 1991.
Atmos. Environ. 28: 477-486.
Carslaw, N. (2007) A new detailed chemical model for indoor air pollution. Atmos. Environ. 41:
1164-1179.
Carson, J. L.; Collier, A. M.; Hu, S. -C.; Delvin, R. B. (1993) Effect of nitrogen dioxide on
human nasal epithelium. Am. J. Respir. Cell. Mol. Biol. 9: 264-270.
Case, G. D.; Dixon, J. S.; Schooley, J. C. (1979) Interactions of blood metalloproteins with
nitrogen oxides and oxidant air pollutants. Environ. Res. 20: 43-65.
Castellsague, J.; Sunyer, J.; Saez, M.; Anto, J. M. (1995) Short-term association between air
pollution and emergency room visits for asthma in Barcelona. Thorax 50: 1051-1056.
Cavanagh, D. G.; Morris, J. B. (1987) Mucus protection and airway peroxidation following
nitrogen dioxide exposure in the rat. J. Toxicol. Environ. Health 22: 313-328.
August 2007
6-7
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Centers for Disease Control and Prevention. (2005) Asthma prevalence, health care use and
mortality: United States, 2003-05. Atlanta, GA: National Center for Health Statistics.
Available: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/ashtma03-05/asthma03-
05.htm [7 August, 2007],
Centers for Disease Control and Prevention. (2007a) Prevalence of heart disease — United
States, 2005. Morb. Mortal. Wkly. Rep. MMWR 56: 113-118.
Centers for Disease Control and Prevention. (2007b) Prevalence of stroke — United States, 2005.
Morb. Mortal. Wkly. Rep. MMWR 56: 469-474.
Chan, C.-C.; Chuang, K.-J.; Su, T.-C.; Lin, L.-Y. (2005) Association between nitrogen dioxide
and heart rate variability in a susceptible population. Eur. J. Cardiovasc. Prev. Rehabil.
12: 580-586.
Chan, C.-C.; Chuang, K.-J.; Chien, L.-C.; Chen, W.-J.; Chang, W.-T. (2006) Urban air pollution
and emergency admissions for cerebrovascular diseases in Taipei, Taiwan. Eur. Heart J.
27: 1238-1244.
Chang, L.-Y.; Graham, J. A.; Miller, F. J.; Ospital, J. J.; Crapo, J. D. (1986) Effects of
subchronic inhalation of low concentrations of nitrogen dioxide. I. The proximal alveolar
region of juvenile and adult rats. Toxicol. Appl. Pharmacol. 83: 46-61.
Chang, L.-Y.; Mercer, R. R.; Stockstill, B. L.; Miller, F. J.; Graham, J. A.; Ospital, J. J.; Crapo, J.
D. (1988) Effects of low levels of NO2 on terminal bronchiolar cells and its relative
toxicity compared to O3. Toxicol. Appl. Pharmacol. 96: 451-464.
Chang, C.-C.; Tsai, S.-S.; Ho, S.-C.; Yang, C.-Y. (2005) Air pollution and hospital admissions
for cardiovascular disease in Taipei, Taiwan. Environ. Res. 98: 114-119.
Chauhan, A. J.; Krishna, M. T.; Frew, A. J.; Holgate, S. T. (1998) Exposure to nitrogen dioxide
(N02) and respiratory disease risk. Rev. Environ. Health 13: 73-90.
Chauhan, A. J.; Inskip, H. M.; Linaker, C. H.; Smith, S.; Schreiber, J. ; Johnston, S. L.; Holgate,
S. T. (2003) Personal exposure to nitrogen dioxide (N02) and the severity of virus-
induced asthma in children. Lancet 361: 1939-1944.
Chiodi, H.; Mohler, J. G. (1985) Effects of exposure of blood hemoglobin to nitric oxide.
Environ. Res. 37: 355-363.
Chow, C. K.; Tappel, A. L. (1972) An enzymatic protective mechanism against lipid
peroxidation damage to lungs of ozone-exposed rats. Lipids 7: 518-524.
Chow, C. K.; Dillard, C. J.; Tappel, A. L. (1974) Glutathione peroxidase system and lysozyme in
rats exposed to ozone or nitrogen dioxide. Environ. Res. 7: 311-319.
Clougherty, J. E.; Levy, J. I.; Kubzansky, L. D.; Ryan, P. B.; Suglia, S. F.; Canner, M. J.;
Wright, R. J. (2007) Synergistic effects of traffic-related air pollution and exposure to
violence on urban asthma etiology. Environ. Health Perspect. 115:1140-1146.
Cocheo, V.; Boaretto, C.; Sacco, P. (1996) High uptake rate radial diffusive sampler suitable for
both solvent and thermal desorption. Am. Ind. Hyg. Assoc. J. 57: 897-904.
Cockcroft, D. W.; Davis, B. E.; Todd, D. C.; Smycniuk, A. J. (2005) Methacholine challenge:
comparison of two methods. Chest 127: 839-844.
August 2007
6-8
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Cockcroft, D. W.; Davis, B. E. (2006) Airway hyperresponsiveness as a determinant of the early
asthmatic response to inhaled allergen. J. Asthma 43: 175-178.
Code of Federal Regulations. (2002) Ambient air quality surveillance; appendix E - probe and
monitoring path citing criteria for ambient air quality monitoring. C. F. R. 40: §58.
Coffin, D. L.; Gardner, D. E. (1972) Interaction of biological agents and chemical air pollutants.
Ann. Occup. Hyg. 15: 219-234.
Coffin, D. L.; Gardner, D. E.; Sidorenko, G. I.; Pinigin, M. A. (1977) Role of time as a factor in
the toxicity of chemical compounds in intermittent and continuous exposures. Part II.
Effects of intermittent exposure. J. Toxicol. Environ. Health 3: 821-828.
Connell, D. P.; Withum, J. A.; Winter, S. E.; Statnick, R. M.; Bilonick,, R. A. (2005) The
Steubenville Comprehensive Air Monitoring Program (SCAMP): associations among
fine particulate matter, co-pollutants, and meteorological conditions. J. Air Waste
Manage. Assoc. 55: 481-496.
Connor, L. M.; Bidani, A.; Goerke, J.; Clements, J. A.; Postlethwait, E. M. (2001) N02
interfacial transfer is reduced by phospholipid monolayers. J. Appl. Physiol. 91: 2024-
2034.
Cotterill, A.; Kingham, S. (1997) Nitrogen dioxide in the home: cooking, double glazing, or
outdoor air? Indoor Built Environ. 6: 344-349.
Cox, R. M. (2003) The use of passive sampling to monitor forest exposure to O3, NO2, and SO2:
a review and some case studies. Environ. Pollut. 126: 301-311.
Crapo, J. D.; Barry, B. E.; Chang, L.-Y.; Mercer, R. R. (1984) Alterations in lung structure
caused by inhalation of oxidants. J. Toxicol. Environ. Health 13: 301-321.
Crosley, D. R. (1996) NOy blue ribbon panel. J. Geophys. Res. [Atmos.] 101: 2049-2052.
Cyrys, J.; Heinrich, J.; Richter, K.; Wolke, G.; Wichmann, H. E. (2000) Sources and
concentrations of indoor nitrogen dioxide in Hamburg (west Germany) and Erfurt (east
Germany). Sci. Total Environ. 250: 51-62.
Cyrys, J.; Stolzel, M.; Heinrich, J.; Kreyling, W. G.; Menzel, N.; Wittmaack, K.; Tuch, T.;
Wichmann, H.-E. (2003) Elemental composition and sources of fine and ultrafine
ambient particles in Erfurt, Germany. Sci. Total Environ. 305: 143-156.
Dab, W.; Medina, S.; Quenel, P.; Le Moullec, Y.; Le Tertre, A.; Thelot, B.; Monteil, C.;
Lameloise, P.; Pirard, P.; Momas, I.; Ferry, R.; Festy, B. (1996) Short term respiratory
health effects of ambient air pollution: results of the APHEA project in Paris. In: St
Leger, S., ed. The APHEA project. Short term effects of air pollution on health: a
European approach using epidemiological time series data. J. Epidemiol. Commun.
Health 50(suppl. 1): S42-S46.
DeMarco, V.; Skimming, J. W.; Ellis, T. M.; Cassin, S. (1996) Nitric oxide inhalation: effects on
the ovine neonatal pulmonary and systemic circulation. Reprod. Fertil. Dev. 8: 431-438.
Delfino, R. J. (2002) Evaluation of health effects of toxic air pollutants in a southern California
community: a pilot study. Sacramento, CA: California State Air Resources Board;
August 2007
6-9
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
contract no. ARB-99-302. Available: ftp://ftp.arb.ca.gov/carbis/research/apr/past/99-
302.pdf [18 December, 2003], Available: NTIS, Springfield, VA; PM2003-107639.
Delfino, R. J.; Gone, H.; Linn, W. S.; Pellizzari, E. D.; Hu, Y. (2003a) Asthma symptoms in
Hispanic children and daily ambient exposures to toxic and criteria air pollutants.
Environ. Health Perspect. Ill: 647-656.
Delfino, R. J.; Gong, H.; Linn, W. S.; Hu, Y.; Pellizzari, E. D. (2003b) Respiratory symptoms
and peak expiratory flow in children with asthma in relation to volatile organic
compounds in exhaled breath and ambient air. J. Exposure Anal. Environ. Epidemiol. 13:
348-363.
Dennekamp, M.; Howarth, S.; Dick, C. A. J.; Cherrie, J. W.; Donaldson, K.; Seaton, A. (2001)
Ultrafine particles and nitrogen oxides generated by gas and electric cooking. Occup.
Environ. Med. 58: 511-516.
Desqueyroux, H.; Pujet, J.-C.; Prosper, M.; Le Moullec, Y.; Momas, I. (2002) Effects of air
pollution on adults with chronic obstructive pulmonary disease. Arch. Environ. Health
57: 554-560.
Devalia, J. L.; Campbell, A. M.; Sapsford, R. J.; Rusznak, C.; Quint, D.; Godard, P.; Bousquet, J.
Davies, R. J. (1993a) Effect of nitrogen dioxide on synthesis of inflammatory cytokines
expressed by human bronchial epithelial cells in vitro. Am. J. Respir. Cell. Mol. Biol. 9:
271-278.
Devalia, J. L.; Sapsford, R. J.; Cundell, D. R.; Rusznak, C.; Campbell, A. M.; Davies, R. J.
(1993b) Human bronchial epithelial cell dysfunction following in vitro exposure to
nitrogen dioxide. Eur. Respir. J. 6: 1308-1316.
Devalia, J. L.; Rusznak, C.; Herdman, M. J.; Trigg, C. J.; Tarraf, H.; Davies, R. J. (1994) Effect
of nitrogen dioxide and sulphur dioxide on airway response of mild asthmatic patients to
allergen inhalation. Lancet 344: 1668-1671.
Devlin, R. B.; Horstman, D. P.; Gerrity, T. R.; Becker, S.; Madden, M. C. (1999) Inflammatory
response in humans exposed to 2.0 PPM nitrogen dioxide. Inhalation Toxicol. 11: 89-
109.
Dewanji, A.; Moolgavkar, S. H. (2000) A Poisson process approach for recurrent event data with
environmental covariates. Environmetrics 11: 665-673.
Dietert, R. R.; Etzel, R. A.; Chen, D.; Halonen, M.; Holladay, S. D.; Jarabek, A. M.; Landreth,
K.; Peden, D. B.; Pinkerton, K.; Smialowicz, R. J.; Zoetis, T. (2000) Workshop to
identify critical window of exposure for children's health: immune and respiratory
systems work group summary. Environ. Health Perspect. Suppl. 108(3): 483-490.
Di Giovanni, V.; Cagiano, R.; Carratu, M. R.; De Salvia, M. A.; Giustino, A.; Cuomo, V. (1994)
Alterations in the ontogeny of rat pup ultrasonic vocalization produced by prenatal
exposure to nitrogen dioxide. Psychopharmacology 116: 423-427.
Dijkstra, L.; Houthuijs, D.; Brunekreef, B.; Akkerman, I.; Boleij, J. S. M. (1990) Respiratory
health effects of the indoor environment in a population of Dutch children. Am. Rev.
Respir. Dis. 142: 1172-1178.
August 2007
6-10
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Dimitroulopoulou, C.; Ashmore, M. R.; Byrne, M. A.; Kinnersley, R. P. (2001) Modelling of
indoor exposure to nitrogen dioxide in the UK. Atmos. Environ. 35: 269-279.
D'Ippoliti, D.; Forastiere, F.; Ancona, C.; Agabiti, N.; Fusco, D.; Michelozzi, P.; Perucci, C. A.
(2003) Air pollution and myocardial infarction in Rome: a case-crossover analysis.
Epidemiology 14: 528-535.
Dockery, D. W.; Speizer, F. E.; Stram, D. O.; Ware, J. H.; Spengler, J. D.; Ferris, B. G., Jr.
(1989) Effects of inhalable particles on respiratory health of children. Am. Rev. Respir.
Dis. 139: 587-594.
Dockery, D. W.; Pope, C. A., Ill; Xu, X.; Spengler, J. D.; Ware, J. H.; Fay, M. E.; Ferris, B. G.,
Jr.; Speizer, F. E. (1993) An association between air pollution and mortality in six U.S.
cities. N. Engl. J. Med. 329: 1753-1759.
Dockery, D. W.; Brunekreef, B. (1996) Longitudinal studies of air pollution effects on lung
function. Am. J. Respir. Crit. Care Med. 154(suppl.): S250-S256.
Dockery, D. W.; Luttmann-Gibson, H.; Rich, D. Q.; Link, M. S.; Schwartz, J. D.; Gold, D. R.;
Koutrakis, P.; Verrier, R. L.; Mittleman, M. A. (2005) Particulate air pollution and
nonfatal cardiac events. Part II. Association of air pollution with confirmed arrhythmias
recorded by implanted defibrillators. Boston, MA: Health Effects Institute; research
report no. 124; pp. 83-126; discussion; pp. 127-148. Available:
http://pubs.healtheffects.org/ [7 June, 2007],
Dominici, F.; McDermott, A.; Zeger, S. L.; Samet, J. M. (2002) On the use of generalized
additive models in time-series studies of air pollution and health. Am. J. Epidemiol. 156:
193-203.
Dominici, F.; McDermott, A.; Daniels, M.; Zeger, S. L.; Samet, J. M. (2003) Mortality among
residents of 90 cities. In: Revised analyses of time-series studies of air pollution and
health. Special report. Boston, MA: Health Effects Institute; pp. 9-24. Available:
http://www.healtheffects.org/Pubs/TimeSeries.pdffl2 May, 2004],
Douglas, G. J.; Price, J. F.; Page, C. P. (1994) A method for the long-term exposure of rabbits to
environmental pollutant gases. Eur. Respir. J. 7: 1516-1526.
Dowell, A. R.; Kilburn, K. H.; Pratt, P. C. (1971) Short-term exposure to nitrogen dioxide:
effects on pulmonary ultrastructure, compliance, and the surfactant system. Arch. Intern.
Med. 128: 74-80.
Drechsler-Parks, D. M. (1995) Cardiac output effects of O3 and NO2 exposure in healthy older
adults. Toxicol. Ind. Health 11: 99-109.
Drozdz, M.; Kucharz, E.; Ludyga, K.; Molska-Drozdz, T. (1976) Studies on the effect of long-
term exposure to nitrogen dioxide on serum and liver proteins level and enzyme activity
in guinea pigs. Eur. J. Toxicol. 9: 287-293.
Dunlea, E. J.; Herndon, S. C.; Nelson, D. D.; Volkamer, R. M.; San Martini, F.; Sheehy, P. M.;
Zahniser, M. S.; Shorter, J. H.; Wormhoudt, J. C.; Lamb, B. K.; Allwine, E. J.; Gaffney,
J. S.; Marley, N. A.; Grutter, M.; Marquez, C.; Blanco, S.; Cardenas, B.; Retama, A.;
Ramon Villegas, C. R.; Kolb, C. E.; Molina, L. T.; Molina, M. J. (2007) Evaluation of
August 2007
6-11
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
nitrogen dioxide chemiluminescence monitors in a polluted urban environment. Atmos.
Chem. Phys. 7: 2691-2704.
Dupuy, P. M.; Shore, S. A.; Drazen, J. M.; Frostell, C.; Hill, W. A.; Zapol, W. M. (1992)
Bronchodilator action of inhaled nitric oxide in guinea pigs. J. Clin. Invest. 90: 421-428.
Dutton, S. J.; Hannigan, M. P.; Miller, S. L. (2001) Indoor pollutant levels from the use of
unvented natural gas fireplaces in Boulder, Colorado. J. Air Waste Manage. Assoc. 51:
1654-1661.
Ehrlich, R. (1966) Effect of nitrogen dioxide on resistance to respiratory infection. Bacteriol.
Rev. 30: 604-614.
Ehrlich, R. (1980) Interaction between environmental pollutants and respiratory infections.
Environ. Health Perspect. 35: 89-100.
Ehrlich, R.; Henry, M. C. (1968) Chronic toxicity of nitrogen dioxide: I. effect on resistance to
bacterial pneumonia. Arch. Environ. Health 17: 860-865.
Ehrlich, R.; Silverstein, E.; Maigetter, R.; Fenters, J. D.; Gardner, D. (1975) Immunologic
response in vaccinated mice during long-term exposure to nitrogen dioxide. Environ. Res.
10:217-223.
Ehrlich, R.; Findlay, J. C.; Fenters, J. D.; Gardner, D. E. (1977) Health effects of short-term
inhalation of nitrogen dioxide and ozone mixtures. Environ. Res. 14: 223-231.
Ehrlich, R.; Findlay, J. C.; Gardner, D. E. (1979) Effects of repeated exposures to peak
concentrations of nitrogen dioxide and ozone on resistance to streptococcal pneumonia. J.
Toxicol. Environ. Health 5: 631-642.
Ekwo, E. E.; Weinberger, M. M.; Lachenbruch, P. A.; Huntley, W. H. (1983) Relationship of
parental smoking and gas cooking to respiratory disease in children. Chest 84: 662-668.
Erbas, B.; Hyndman, R. J. (2005) Sensitivity of the estimated air pollution-respiratory
admissions relationship to statistical model choice. Int. J. Environ. Health Res. 15: 437-
448.
Erbas, B.; Kelly, A.-M.; Physick, B.; Code, C.; Edwards, M. (2005) Air pollution and childhood
asthma emergency hospital admissions: estimating intra-city regional variations. Int. J.
Environ. Health Res. 15: 11-20.
Evans, M. J.; Stephens, R. J.; Cabral, L. J.; Freeman, G. (1972) Cell renewal in the lungs of rats
exposed to low levels of NO2. Arch. Environ. Health 24: 180-188.
Evans, M. J.; Cabral, L. J.; Stephens, R. J.; Freeman, G. (1973a) Cell division of alveolar
macrophages in rat lung following exposure to NO2. Am. J. Pathol. 70: 199-208.
Evans, M. J.; Cabral, L. J.; Stephens, R. J.; Freeman, G. (1973b) Renewal of alveolar epithelium
in the rat following exposure to NO2. Am. J. Pathol. 70: 175-190.
Evans, M. J.; Cabral, L. C.; Stephens, R. J.; Freeman, G. (1974) Acute kinetic response and
renewal of the alveolar epithelium following injury by nitrogen dioxide. Chest 65(suppl.):
62S-65S.
Evans, H. L.; Laties, V. G.; Weiss, B. (1975) Behavioral effects of mercury and methylmercury.
Fed. Proc. 34: 1858-1867.
August 2007
6-12
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Evans, M. J.; Johnson, L. V.; Stephens, R. J.; Freeman, G. (1976) Renewal of the terminal
bronchiolar epithelium in the rat following exposure to N02 or 03. Lab. Invest. 35: 246-
257.
Evans, M. J.; Cabral-Anderson, L. J.; Freeman, G. (1977) Effects of N02 on the lungs of aging
rats: II. cell proliferation. Exp. Mol. Pathol. 27: 366-376.
Evans, J. N.; Hemenway, D. R.; Kelley, J. (1989) Early markers of lung injury. Cambridge, MA:
Health Effects Institute; research report no. 29. Available from: NTIS, Springfield, VA;
PB91-171983.
Ewetz, L. (1993) Absorption and metabolic fate of nitrogen oxides. Scand. J. Work Environ.
Health 19 [suppl. 2]: 21-27.
Fairley, D. (1999) Daily mortality and air pollution in Santa Clara County, California: 1989-
1996. Environ. Health Perspect. 107: 637-641.
Farahani, H.; Hasan, M. (1992) Nitrogen dioxide induced changes in level of free fatty acids,
triglyceride, esterified fatty acid, ganglioside and lipase activity in the guinea pig brain. J.
Environ. Sci. Health B 27: 53-71.
Farhat, S. C. L.; Paulo, R. L. P.; Shimoda, T. M.; Conceicao, G. M. S.; Lin, C. A.; Braga, A. L.
F.; Warth, M. P. N.; Saldiva, P. H. N. (2005) Effect of air pollution on pediatric
respiratory emergency room visits and hospital admissions. Braz. J. Med. Biol. Res. 38:
227-235.
Farrow, A.; Greenwood, R.; Preece, S.; Golding, J. (1997) Nitrogen dioxide, the oxides of
nitrogen, and infants' health symptoms. Arch. Environ. Health 52: 189-194.
Febo, A.; Perrino, C. (1991) Prediction and experimental evidence for high air concentration of
nitrous acid in indoor environments. Atmos. Environ. Part A 25: 1055-1061.
Federal Register. (1971) National primary and secondary ambient air quality standards. F. R.
(April 30)36: 8186-8201.
Federal Register. (1984) Proposed reaffirmation of the National Ambient Air Quality Standards
for Nitrogen Dioxide. F. R. 49 (February 23): 6866-6879.
Federal Register. (1987) Air quality criteria for carbon monoxide; air quality criteria for oxides
of nitrogen. F. R. 52 (July 22): 27580.
Federal Register. (1991) Draft criteria document for oxides of nitrogen. F. R. 56 (November 25):
59285.
Federal Register. (1995) National ambient air quality standards for nitrogen dioxide: proposed
decision. F. R. 60 (October 11): 52874-52889.
Federal Register. (2005) Air quality criteria for oxides of nitrogen. F. R. 70 (December 9):
73236-73237.
Federal Register. (2007) Workshop on assessment of health science for the review of the
NAAQS for nitrogen (NOx) and sulfur oxides (SOx). F. R. 72 (February 9): 6238.
Fehls, A. O. S.; Cohn, Z. A. (1986) The alveolar macrophage. J. Appl. Physiol. 60: 353-369.
August 2007
6-13
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Fehsenfeld, F. C.; Dickerson, R. R.; Hiibler, G.; Luke, W. T.; Nunnermacker, L. J.; Williams, E.
J.; Roberts, J. M.; Calvert, J. G.; Curran, C. M.; Delany, A. C.; Eubank, C. S.; Fahey, D.
W.; Fried, A.; Gandrud, B. W.; Langford, A. O.; Murphy, P. C.; Norton, R. B.; Pickering,
K. E.; Ridley, B. A. (1987) A ground-based intercomparison of NO, NOx, and NOy
measurement techniques. J. Geophys. Res. [Atmos.] 92: 14,710-14,722.
Fels, A. O. S.; Cohn, Z. A. (1986) The alveolar macrophage. J. Appl. Physiol. 60: 353-369.
Fenters, J. D.; Findlay, J. C.; Port, C. D.; Ehrlich, R.; Coffin, D. L. (1973) Chronic exposure to
nitrogen dioxide: immunologic, physiologic, and pathologic effects in virus-challenged
squirrel monkeys. Arch. Environ. Health 27: 85-89.
Filleul, L.; Rondeau, V.; Vandentorren, S.; Le Moual, N.; Cantagrel, A.; Annesi-Maesano, I.;
Charpin, D.; Declercq, C.; Neukirch, F.; Paris, C.; Vervloet, D.; Brochard, P.; Tessier, J.
F.; Kauffmann, F.; Baldi, I. (2005) Twenty five year mortality and air pollution: results
from the French PAARC survey. Occup. Environ. Med. 62: 453-460.
Finlayson-Pitts, B. J.; Pitts, J. N., Jr. (2000) Chemistry of the upper and lower atmosphere:
theory, experiments and applications. San Diego, CA: Academic Press.
Folinsbee, L. J. (1992) Does nitrogen dioxide exposure increase airways responsiveness?
Toxicol. Ind. Health 8: 273-283.
Folinsbee, L. J.; Horvath, S. M.; Bedi, J. F.; Delehunt, J. C. (1978) Effect of 0.62 ppm N02 on
cardiopulmonary function in young male nonsmokers. Environ. Res. 15: 199-205.
Forsberg, B.; Sternberg, N.; Linne, R.; Segerstedt, B.; Wall, S. (1998) Daily air pollution levels
and acute asthma in southern Sweden. Eur. Respir. J. 12: 900-905.
Fortmann, R.; Kariher, P.; Clayton, R. (2001) Indoor air quality: residential cooking exposures.
Final report. Sacramento, CA: State of California Air Resources Board; ARB Contract
No. 97-330. Available: http://arb.ca.gov/research/abstracts/97-330.htm [22 May, 2007],
Frampton, M. W.; Smeglin, A. M.; Roberts, N. J., Jr.; Finkelstein, J. N.; Morrow, P. E.; Utell, M.
J. (1989) Nitrogen dioxide exposure in vivo and human alveolar macrophage inactivation
of influenza virus in vitro. Environ. Res. 48: 179-192.
Frampton, M. W.; Morrow, P. E.; Cox, C.; Gibb, F. R.; Speers, D. M.; Utell, M. J. (1991) Effects
of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal
humans. Am. Rev. Respir. Dis. 143: 522-527.
Frampton, M. W.; Boscia, J.; Roberts, N. J., Jr.; Azadniv, M.; Torres, A.; Cox, C.; Morrow, P.
E.; Nichols, J.; Chalupa, D.; Frasier, L. M.; Gibb, F. R.; Speers, D. M.; Tsai, Y.; Utell, M.
J. (2002) Nitrogen dioxide exposure: effects on airway and blood cells. Am. J. Physiol.
282: L155-L165.
Frampton, M. W.; Pietropaoli, A. P.; Morrow, P. E.; Utell, M. J. (2006) Human clinical studies
of airborne pollutants. In: Gardner, D. E. Toxicology of the lung. Boca Raton, FL: CRC
Press; pp. 29-82. (Target organ toxicology series).
Fratacci, M. D.; Frostell, C. G.; Chen, T. Y.; Wain, J. C.; Robinson, D. R.; Zapol, W. M. (1991)
Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine
vasoconstriction in sheep. Anesthesiology 75: 990-999.
August 2007
6-14
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Freeman, B. A.; Mudd, J. B. (1981) Reaction of ozone with sulfhydryls of human erythrocytes.
Arch. Biochem. Biophys. 208: 212-220.
Freeman, G.; Furiosi, N. J.; Haydon, G. B. (1966) Effects of continuous exposure of 0.8 ppm
NO2 on respiration of rats. Arch. Environ. Health 13: 454-456.
Freeman, G.; Stephens, R. J.; Crane, S. C.; Furiosi, N. J. (1968) Lesion of the lung in rats
continuously exposed to two parts per million of nitrogen dioxide. Arch. Environ. Health
17:181-192.
Freeman, G.; Crane, S. C.; Furiosi, N. J.; Stephens, R. J.; Evans, M. J.; Moore, W. D. (1972)
Covert reduction in ventilatory surface in rats during prolonged exposure to subacute
nitrogen dioxide. Am. Rev. Respir. Dis. 106: 563-579.
Fujimaki, H.; Nohara, O. (1994) Changes in the response of lung mast cells isolated from rats
and guinea pigs exposed to nitrogen dioxide. Inhalation Toxicol. 6: 515-520.
Fujimaki, H.; Shimizu, F.; Kubota, K. (1982) Effect of subacute exposure to NO2 on
lymphocytes required for antibody responses. Environ. Res. 29: 280-286.
Fung, K. Y.; Luginaah, I.; Gorey, K. M.; Webster, G. (2005) Air pollution and daily hospital
admissions for cardiovascular diseases in Windsor, Ontario. Can. J. Public Health 96: 29-
33.
Fung, K. Y.; Khan, S.; Krewski, D.; Chen, Y. (2006) Association between air pollution and
multiple respiratory hospitalizations among the elderly in Vancouver, Canada. Inhalation
Toxicol. 18: 1005-1011.
Furiosi, N. J.; Crane, S. C.; Freeman, G. (1973) Mixed sodium chloride aerosol and nitrogen
dioxide in air: biological effects on monkeys and rats. Arch. Environ. Health 27: 405-
408.
Fusco, D.; Forastiere, F.; Michelozzi, P.; Spadea, T.; Ostro, B.; Area, M.; Perucci, C. A. (2001)
Air pollution and hospital admissions for respiratory conditions in Rome, Italy. Eur.
Respir. J. 17: 1143-1150.
Gair, A. J.; Penkett, S. A. (1995) The effects of wind speed and turbulence on the performance of
diffusion tube samplers. Atmos. Environ. 29: 2529-2533.
Gair, A. J.; Penkett, S. A.; Oyola, P. (1991) Development of a simple passive technique for the
determination of nitrogen-dioxide in remote continental locations. Atmos. Environ. Part
A 25: 1927-1939.
Galan, I.; Tobias, A.; Banegas, J. R.; Aranguez, E. (2003) Short-term effects of air pollution on
daily asthma emergency room admissions. Eur. Respir. J. 22: 802-808.
Garcia-Algar, O.; Zapater, M.; Figueroa, C.; Vail, O.; Basagana, X.; Sunyer, J.; Freixa, A.;
Guardino, X.; Pichini, S. (2003) Sources and concentrations of indoor nitrogen dioxide in
Barcelona, Spain. J. Air Waste Manage. Assoc. 53: 1312-1317.
Garcia Algar, O.; Pichini, S.; Basagana, X.; Puig, C.; Vail, O.; Torrent, M.; Harris, J.; Sunyer, J.;
Cullinan, P. (2004) Concentrations and determinants of NO2 in homes of Ashford, UK
and Barcelona and Menorca, Spain. Indoor Air 14: 298-304.
August 2007
6-15
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Garcia-Aymerich, J.; Tobias, A.; Anto, J. M.; Sunyer, J. (2000) Air pollution and mortality in a
cohort of patients with chronic obstructive pulmonary disease: a time series analysis. J.
Epidemiol. Community Health 54: 73-74.
Gardiner, T. H.; Schanker, L. S. (1976) Effect of oxygen toxicity and nitric acid-induced lung
damage on drug absorption from the rat lung. Res. Commun. Chem. Pathol. Pharmacol.
15: 107-120.
Gardner, D. E. (1980) Influence of exposure patterns of nitrogen dioxide on susceptibility to
infectious respiratory disease. In: Lee, S. D., ed. Nitrogen oxides and their effects on
health. Ann Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 267-288.
Gardner, D. E. (1982) Use of experimental airborne infections for monitoring altered host
defenses. Environ. HealthPerspect. 43: 99-107.
Gardner, D. E.; Coffin, D. L.; Pinigin, M. A.; Sidorenko, G. I. (1977a) Role of time as a factor in
the toxicity of chemical compounds in intermittent and continuous exposures. Part I.
Effects of continuous exposure. J. Toxicol. Environ. Health 3: 811-820.
Gardner, D. E.; Miller, F. J.; Blommer, E. J.; Coffin, D. L. (1977b) Relationships between
nitrogen dioxide concentration, time, and level of effect using an animal infectivity
model. In: Dimitriades, B., ed. International conference on photochemical oxidant
pollution and its control: proceedings, v. I; September 1976; Raleigh, NC. Research
Triangle Park, NC: U.S. Environmental Protection Agency, Environmental Sciences
Research Laboratory; pp. 513-525; EPA report no. EPA-600/3-77-001a. Available from:
NTIS, Springfield, VA; PB-264232. (Ecological research series).
Gardner, D. E.; Miller, F. J.; Blommer, E. J.; Coffin, D. L. (1979) Influence of exposure mode on
the toxicity of NO2. Environ. Health Perspect. 30: 23-29.
Gardner, D. E.; Miller, F. J.; Illing, J. W.; Graham, J. A. (1982) Non-respiratory function of the
lungs: host defenses against infection. In: Schneider, T.; Grant, L., eds. Air pollution by
nitrogen oxides: proceedings of the US-Dutch international symposium; May; Maastricht,
The Netherlands. Amsterdam, The Netherlands: Elsevier Scientific Publishing Company;
pp. 401-415. (Studies in environmental science 21).
Garrett, M. H.; Hooper, M. A.; Hooper, B. M.; Abramson, M. J. (1998) Respiratory symptoms in
children and indoor exposure to nitrogen dioxide and gas stoves. Am. J. Respir. Crit.
Care Med. 158: 891-895.
Garrett, M. H.; Hooper, M. A.; Hooper, B. M. (1999) Nitrogen dioxide in Australian homes:
levels and sources. J. Air Waste Manage. Assoc. 49: 76-81.
Garthwaite, J. (1991) Glutamate, nitric oxide and cell-cell signalling in the nervous system.
Trends Neurosci. 14: 60-67.
Gauderman, W. J.; Avol, E.; Gilliland, F.; Vora, H.; Thomas, D.; Berhane, K.; McConnell, R.;
Kuenzli, N.; Lurmann, F.; Rappaport, E.; Margolis, H.; Bates, D.; Peters, J. (2004) The
effect of air pollution on lung development from 10 to 18 years of age. N. Engl. J. Med.
351: 1057-1067.
August 2007
6-16
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Gauderman, W. J.; Avol, E.; Lurmann, F.; Kuenzli, N.; Gilliland, F.; Peters, J.; McConnell, R.
(2005) Childhood asthma and exposure to traffic and nitrogen dioxide. Epidemiology 16:
737-743.
Gauderman, W. J.; Vora, H.; McConnell, R.; Berhane, K.; Gilliland, F.; Thomas, D.; Lurmann,
F.; Avol, E.; Kunzli, N. (2007) Effect of exposure to traffic on lung development from 10
to 18 years of age: a cohort study. Lancet 369: 571-577.
Gauvin, S.; Le Moullec, Y.; Bremont, F.; Momas, I.; Balducci, F.; Ciognard, F.; Poilve, M.-P.;
Zmirou, D.; VESTA Investigators. (2001) Relationships between nitrogen dioxide
personal exposure and ambient air monitoring measurements among children in three
French metropolitan areas: VESTA study. Arch. Environ. Health 56: 336-341.
Gavras, J. B.; Frampton, M. W.; Ryan, D. H.; Levy, P. C.; Looney, R. J.; Cox, C.; Morrow, P.
E.; Utell, M. J. (1994) Expression of membrane antigens on human alveolar macrophages
after exposure to nitrogen dioxide. Inhalation Toxicol. 6: 633-646.
Gehring, U.; Cyrys, J.; Sedlmeir, G.; Brunekreef, B.; Bellander, T.; Fischer, P.; Bauer, C. P.;
Reinhardt, D.; Wichmann, H. E.; Heinrich, J. (2002) Traffic-related air pollution and
respiratory health during the first 2 yrs. of life. Eur. Respir. J. 19: 690-698.
Gehring, U.; Heinrich, J.; Kramer, U.; Grote, V.; Hochadel, M.; Sugiri, D.; Kraft, M.; Rauchfuss,
K.; Eberwein, H. G.; Wichmann, H.-E. (2006) Long-term exposure to ambient air
pollution and cardiopulmonary mortality in women. Epidemiology 17: 545-551.
Gilbert, N. L.; Gauvin, D.; Guay, M.; Heroux, M.-E.; Dupuis, G.; Legris, M.; Chan, C. C.; Dietz,
R. N.; Levesque, B. (2006) Housing characteristics and indoor concentrations of nitrogen
dioxide and formaldehyde in Quebec City, Canada. Environ. Res. 102: 1-8.
Gilbert, N. L.; Goldberg, M. S.; Beckerman, B.; Brook, J. R.; Jerrett, M. (2005) Assessing spatial
variability of ambient nitrogen dioxide in Montreal, Canada, with a land-use regression
model. J. Air Waste Manage. Assoc. 55: 1059-1063.
Gilliland, F. D.; McConnell, R.; Peters, J.; Gong, H, Jr. (1999) A theoretical basis for
investigation ambient air pollution and children's respiratory health. Environ. Health
Perspect. 107(suppl. 3): 403-407.
Gilliland, F. D.; Berhane, K.; Rappaport, E. B.; Thomas, D. C.; Avol, E.; Gauderman, W. J.;
London, S. J.; Margolis, H. G.; McConnell, R.; Islam, K. T.; Peters, J. M. (2001) The
effects of ambient air pollution on school absenteeism due to respiratory illnesses.
Epidemiology 12: 43-54.
Gilliland, F. D.; Rappaport, E. B.; Berhane, K.; Islam, T.; Dubeau, L.; Gauderman, W. J.;
McConnell, R. (2002) Effects of glutathione ^-Transferasei5/, Ml, and T1 on acute
respiratory illness in school children. Am. J. Respir. Crit. Care Med. 166: 346-351.
Gilmour, M. I.; Park, P.; Selgrade, M. K. (1996) Increased immune and inflammatory responses
to dust mite antigen in rats exposed to 5 ppm NO2. Fundam. Appl. Toxicol. 31: 65-70.
Giordano, A. M.; Morrow, P. E. (1972) Chronic low-level nitrogen dioxide exposure and
mucociliary clearance. Arch. Environ. Health 25: 443-449.
August 2007
6-17
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Girman, J. R.; Apte, M. G.; Traynor, G. W.; Allen, J. R.; Hollowell, C. D. (1982) Pollutant
emission rates from indoor combustion appliances and sidestream cigarette smoke.
Environ. Int. 8: 213-221.
Goings, S. A. J.; Kulle, T. J.; Bascom, R.; Sauder, L. R.; Green, D. J.; Hebel, J. R.; Clements, M.
L. (1989) Effect of nitrogen dioxide exposure on susceptibility to influenza A virus
infection in healthy adults. Am. Rev. Respir. Dis. 139: 1075-1081.
Goldberg, M. S.; Burnett, R. T. (2003) Revised analysis of the Montreal time-series study. In:
Revised analyses of time-series studies of air pollution and health. Special report. Boston,
MA: Health Effects Institute; pp. 113-132. Available:
http://www.healtheffects.org/Pubs/TimeSeries.pdf [18 October, 2004],
Goldstein, E.; Eagle, M. C.; Hoeprich, P. D. (1973) Effect of nitrogen dioxide on pulmonary
bacterial defense mechanisms. Arch. Environ. Health 26: 202-204.
Goldstein, E.; Warshauer, D.; Lippert, W.; Tarkington, B. (1974) Ozone and nitrogen dioxide
exposure: murine pulmonary defense mechanisms. Arch. Environ. Health 28: 85-90.
Goldstein, B. D.; Hamburger, S. J.; Falk, G. W.; Amoruso, M. A. (1977) Effect of ozone and
nitrogen dioxide on the agglutination of rat alveolar macrophages by concanavalin A.
Life Sci. 21: 1637-1644.
Gong, H., Jr., Linn, W. S.; Clark, K. W.; Anderson, K. R.; Geller, M. D.; Sioutas, C. (2005)
Respiratory responses to exposures with fine particulates and nitrogen dioxide in the
elderly with and without COPD. Inhalation Toxicol. 17: 123-132.
Gonzales, M.; Quails, C.; Hudgens, E.; Neas, L. (2005) Characterization of a spatial gradient of
nitrogen dioxide across a United States-Mexico border city during winter. Sci. Total
Environ. 337: 163-173.
Gooch, P. C.; Luippold, H. E.; Creasia, D. A.; Brewen, J. G. (1977) Observations on mouse
chromosomes following nitrogen dioxide inhalation. Mutat. Res. 48: 117-119.
Gorsdorf, S.; Appel, K. E.; Engeholm, C.; Obe, G. (1990) Nitrogen oxide induces DNA single-
strand breaks in cultured Chinese hamster cells. Carcinogenesis 11: 37-41.
Goss, C. H.; Newsom, S. A.; Schildcrout, J. S.; Sheppard, L.; Kaufman, J. D. (2004) Effect of
ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis.
Am. J. Respir. Crit. Care Med. 169: 816-821.
Graham, J. A.; Gardner, D. E.; Blommer, E. J.; House, D. E.; Menache, M. G.; Miller, F. J.
(1987) Influence of exposure patterns of nitrogen dioxide and modifications by ozone on
susceptibility to bacterial infectious disease in mice. J. Toxicol. Environ. Health 21: 113-
125.
Green, N. D.; Schneider, S. L. (1978) Effects of NO2 on the response of baboon alveolar
macrophages to migration inhibitory factor. J. Toxicol. Environ. Health 22: 655-662.
Greenberg, S. D.; Gyorkey, F.; Jenkins, D. E.; Gyorkey, P. (1971) Alveolar epithelial cells
following exposure to nitric acid: electron microscopic study in rats. Arch. Environ.
Health 22: 655-662.
August 2007
6-18
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Gregory, R. E.; Pickrell, J. A.; Hahn, F. F.; Hobbs, C. H. (1983) Pulmonary effects of
intermittent subacute exposure to low-level nitrogen dioxide. J. Toxicol. Environ. Health
11: 405-414.
Hackney, J. D.; Thiede, F. C.; Linn, W. S.; Pedersen, E. E.; Spier, C. E.; Law, D. C.; Fischer, D.
A. (1978) Experimental studies on human health effects of air pollutants. IV. Short-term
physiological and clinical effects of nitrogen dioxide exposure. Arch. Environ. Health 33:
176-181.
Hackney, J. D.; Linn, W. S.; Avol, E. L.; Shamoo, D. A.; Anderson, K. R.; Solomon, J. C.;
Little, D. E.; Peng, R.-C. (1992) Exposures of older adults with chronic respiratory illness
to nitrogen dioxide: a combined laboratory and field study. Am. Rev. Respir. Dis. 146:
1480-1486.
Hajat, S.; Haines, A.; Goubet, S. A.; Atkinson, R. W.; Anderson, H. R. (1999) Association of air
pollution with daily GP consultations for asthma and other lower respiratory conditions in
London. Thorax 54: 597-605.
Harre, E. S. M.; Price, P. D.; Ayrey, R. B.; Toop, L. J.; Martin, I. R.; Town, G. I. (1997)
Respiratory effects of air pollution in chronic obstructive pulmonary disease: a three
month prospective study. Thorax 52: 1040-1044.
Hasselblad, V.; Eddy, D. M.; Kotchmar, D. J. (1992) Synthesis of environmental evidence:
nitrogen dioxide epidemiology studies. J. Air Waste Manage. Assoc. 42: 662-671.
Hatch, G. E.; Slade, R.; Selgrade, M. K.; Stead, A. G. (1986) Nitrogen dioxide exposure and
lung antioxidants in ascorbic acid-deficient guinea pigs. Toxicol. Appl. Pharmacol. 82:
351-359.
Hayden, K. L.; Anlauf, K. G.; Hastie, D. R.; Bottenheim, J. W. (2003) Partitioning of reactive
atmospheric nitrogen oxides at an elevated site in southern Quebec, Canada. J. Geophys.
Res. [Atmos.] 108(D19): 10.1029/2002JD003188.
Hazenkamp-von Arx, M. E.; Gotschi, T.; Ackermann-Liebrich, U.; Bono, R.; Burney, P.; Cyrys,
J.; Jarvis, D.; Lillienberg, L.; Luczynska, C.; Maldonado, J. A.; Jaen, A.; de Marco, R.;
Mi, Y.; Modig, L.; Bayer-Oglesby, L.; Payo, F.; Soon, A.; Sunyer, J.; Villani, S.; Weyler,
J.; Kiinzli, N. (2004) PM2.5 and NO2 assessment in 21 European study centres of ECRHS
II: annual means and seasonal differences. Atmos. Environ. 38: 1943-1953.
Hazucha, M. J.; Ginsberg, J. F.; McDonnell, W. F.; Haak, E. D., Jr.; Pimmel, R. L.; Salaam, S.
A.; House, D. E.; Bromberg, P. A. (1983) Effects of 0.1 ppm nitrogen dioxide on airways
of normal and asthmatic subjects. J. Appl. Physiol.: Respir. Environ. Exercise Physiol.
54: 730-739.
Hazucha, M. J.; Folinsbee, L. J.; Seal, E.; Bromberg, P. A. (1994) Lung function response of
healthy women after sequential exposures to NO2 and O3. Am. J. Respir. Crit. Care Med.
150: 642-647.
Heal, M. R.; O'Donoghue, M. A.; Cape, J. N. (1999) Overestimation of urban nitrogen dioxide
by passive diffusion tubes: a comparative exposure and model study. Atmos. Environ. 33:
513-524.
August 2007
6-19
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Helleday, R.; Sandstrom, T.; Stjernberg, N. (1994) Differences in bronchoalveolar cell response
to nitrogen dioxide exposure between smokers and nonsmokers. Eur. Respir. J. 7: 1213-
1220.
Helleday, R.; Huberman, D.; Blomberg, A.; Stjernberg, N.; Sandstrom, T. (1995) Nitrogen
dioxide exposure impairs the frequency of the mucociliary activity in healthy subjects.
Eur. Respir. J. 8: 1664-1668.
Henneberger, A.; Zareba, W.; Ibald-Mulli, A.; Riickerl, R.; Cyrys, J.; Couderc, J.-P.; Mykins, B.;
Woelke, G.; Wichmann, H.-E.; Peters, A. (2005) Repolarization changes induced by air
pollution in ischemic heart disease patients. Environ. Health Perspect. 113: 440-446.
Henry, M. C.; Findlay, J.; Spangler, J.; Ehrlich, R. (1970) Chronic toxicity of N02 in squirrel
monkeys: III. effect on resistance to bacterial and viral infection. Arch. Environ. Health
20: 566-570.
Hibbs, J. B.; Taintor, R. R.; Vavrin, Z.; Rachlin, E. M. (1988) Nitric oxide: a cytotoxic activated
macrophage effector molecule. Biochem. Biophys. Res. Commun. 157: 87-94.
Higgins, B. G.; Francis, H. C.; Yates, C. J.; Warburton, C. J.; Fletcher, A. M.; Reid, J. A.;
Pickering, C. A. C.; Woodcock, A. A. (1995) Effects of air pollution on symptoms and
peak expiratory flow measurements in subjects with obstructive airways disease. Thorax
50: 149-155.
Higgins, B. G.; Francis, H. C.; Yates, C.; Warburton, C. J.; Fletcher, A. M.; Pickering, C. A. C.;
Woodcock, A. A. (2000) Environmental exposure to air pollution and allergens and peak
flow changes. Eur. Respir. J. 16: 61- 66.
Hiltermann, T. J. N.; Stolk, J.; Van der Zee, S. C.; Brunekreef, B.; De Bruijne, C. R.; Fischer, P.
H.; Ameling, C. B.; Sterk, P. J.; Hiemstra, P. S.; Van Bree, L. (1998) Asthma severity
and susceptibility to air pollution. Eur. Respir. J. 11: 686-693.
Hinwood, A. L.; De Klerk, N.; Rodriguez, C.; Jacoby, P.; Runnion, T.; Rye, P.; Landau, L.;
Murray, F.; Feldwick, M.; Spickett, J. (2006) The relationship between changes in daily
air pollution and hospitalizations in Perth, Australia 1992-1998: a case-crossover study.
Int. J. Environ. Health Res. 16: 27-46.
Hirsch, T.; Weiland, S. K.; Von Mutius, E.; Safeca, A. F.; Grafe, H.; Csaplovics, E.; Duhme, H.;
Keil, U.; Leupold, W. (1999) Inner city air pollution and respiratory health and atopy in
children. Eur. Respir. J. 14: 669-677.
Hochadel, M.; Heinrich, J.; Gehring, U.; Morgenstern, V.; Kuhlbusch, T.; Link, E.; Wichmann,
H.-E.; Kramer, U. (2006) Predicting long-term average concentrations of traffic-related
air pollutants using GIS-based information. Atmos. Environ. 40: 542-553.
Hochscheid, R.; Schuchmann, U.; Kotte, E.; Kranz, S.; Heinrichs, S.; Miiller, B. (2005) NO2-
induced acute and chronic lung injury cause imbalance of glutathione metabolism in type
II pneumocytes. Med. Sci. Monit. 11: BR273-279.
Hoek, G. (2003) Daily mortality and air pollution in The Netherlands. In: Revised analyses of
time-series studies of air pollution and health. Special report. Boston, MA: Health Effects
Institute; pp. 133-141. Available: http://www.healtheffects.org/Pubs/TimeSeries.pdffl2
May, 2004],
August 2007
6-20
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Hoek, G.; Brunekreef, B. (1994) Effects of low-level winter air pollution concentrations on
respiratory health of Dutch children. Environ. Res. 64: 136-150.
Hoek, G.; Brunekreef, B.; Verhoeff, A.; Van Wijnen, J.; Fischer, P. (2000) Daily mortality and
air pollution in the Netherlands. J. Air Waste Manage. Assoc. 50: 1380-1389.
Hoek, G.; Brunekreef, B.; Fischer, P.; Van Wijnen, J. (2001) The association between air
pollution and heart failure, arrhythmia, embolism, thrombosis, and other cardiovascular
causes of death in a time series study. Epidemiology 12: 355-357.
Hoek, G.; Brunekreef, B.; Goldbohm, S.; Fischer, P.; Van den Brandt, P. A. (2002) Association
between mortality and indicators of traffic-related air pollution in the Netherlands: a
cohort study. Lancet 360: 1203-1209.
Hogman, M.; Frostell, C.; Arnberg, H; Hedenstierna, G. (1993) Inhalation of nitric oxide
modulates methacholine-induced bronchoconstriction in the rabbit. Eur. Respir. J. 6: 170-
180.
Holguin, F.; Tellez-Rojo, M. M.; Hernandez, M.; Cortez, M.; Chow, J. C.; Watson, J. G.;
Mannino, D.; Romieu, I. (2003) Air pollution and heart rate variability among the elderly
in Mexico City. Epidemiology 14: 521-527.
Holopainen, R.; Aho, H.; Laine, J.; Halkola, L.; Kaapa, P. (1999) Nitric oxide inhalation inhibits
pulmonary apoptosis but not inflammatory injury in porcine meconium aspiration. Acta
Paediatr. 88: 1147-1155.
Holroyd, K. J.; Eleff, S. M.; Zhang, L.-Y.; Jakab, G. J.; Kleeberger, S. R. (1997) Genetic
modeling of susceptibility to nitrogen dioxide-induced lung injury in mice. Am. J.
Physiol. 273: L595-L602.
Holt, P. G.; Finlay-Jones, L. M.; Keast, D.; Papadimitrou, J. M. (1979) Immunological function
in mice chronically exposed to nitrogen oxides (NOx). Environ. Res. 19: 154-162.
Hooftman, R. N.; Kuper, C. F.; Appelman, L. M. (1988) Comparative sensitivity of histo-
pathology and specific lung parameters in the detection of lung injury. J. Appl. Toxicol.
8: 59-65.
Horowitz, L. W.; Fiore, A. M.; Milly, G. P.; Cohen, R. C.; Perring, A.; Wooldridge, P. J.; Hess,
P. G.; Emmons, L. K.; Lamarque, J. F. (2007) Observational constraints on the chemistry
of isoprene nitrates over the eastern United States. J. Geophys. Res. (Atmos.)
112(D12S08): 10.1029/2006JD007747.
Hurford, W. E. (1997) The biologic basis for inhaled nitric oxide. Respir. Care Clin. N. Am. 3:
357-369.
Ichinose, T.; Sagai, M. (1982) Studies on biochemical effects of nitrogen dioxide: III. changes of
the antioxidative protective systems in rat lungs and of lipid peroxidation by chronic
exposure. Toxicol. Appl. Pharmacol. 66: 1-8.
Ichinose, T.; Sagai, M. (1989) Biochemical effects of combined gases of nitrogen dioxide and
ozone. III. Synergistic effects on lipid peroxidation and antioxidative protective systems
in the lungs of rats and guinea pigs. Toxicology 59: 259-270.
August 2007
6-21
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Ichinose, T.; Sagai, M. (1992) Combined exposure to NO2, O3 and H2S04-aerosol and lung
tumor formation in rats. Toxicology 74: 173-184.
Ichinose, T.; Sagai, M.; Kubota, K. (1983) [Changes of lipid peroxidation and antioxidative
protective systems in lungs of rats exposed acutely, subacutely and chronically to
nitrogen dioxide], Taiki Osen Gakkaishi 18: 132-146.
Ichinose, T.; Fujii, K.; Sagai, M. (1991) Experimental studies on tumor promotion by nitrogen
dioxide. Toxicology 67: 211-225.
Ichinose, F.; Adrie, C.; Hurford, W. E.; Zapol, W. M. (1995) Prolonged pulmonary vasodilator
action of inhaled nitric oxide by Zaprinast in awake lambs. J. Appl. Physiol. 78: 1288-
1295.
Ignarro, L. J. (1989) Biological actions and properties of endothelium-derived nitric oxide
formed and released from artery and vein. Circ. Res. 65: 1-21.
Illing, J. W.; Miller, F. J.; Gardner, D. E. (1980) Decreased resistance to infection in exercised
mice exposed toN02 and O3. J. Toxicol. Environ. Health 6: 843-851.
Inoue, H.; Fukunaga, A.; Okubo, S. (1981) Mutagenic effects of nitrogen dioxide combined with
methylurea and ethylurea in Drosophila melanogaster. Mutat. Res. 88: 281-290.
Iqbal, Z. M. (1984) In-vivo nitrosation of amines in mice by inhaled nitrogen dioxide and
inhibition of biosynthesis of iV-nitrosamines. In: O'Neill, I. K.; VonBorstel, R. C.; Miller,
C. T.; Long, J.; Bartsch, H., eds. N-nitroso compounds: occurrence, biological effects and
relevance to human cancer: proceedings of the VHIth international symposium on N-
nitroso compounds; September 1983; Banff, Canada. Lyon, France: International Agency
for Research on Cancer; pp. 291-300. (IARC scientific publications no. 57).
Iqbal, Z. M.; Dahl, K.; Epstein, S. S. (1980) Role of nitrogen dioxide in the biosynthesis of
nitrosamines in mice. Science (Washington, DC) 207: 1475-1477.
Iqbal, Z. M.; Dahl, K.; Epstein, S. S. (1981) Biosynthesis of dimethylnitrosamine in
dimethylamine-treated mice after exposure to nitrogen dioxide. JNCI J. Natl. Cancer Inst.
67: 137-141.
Islam, T.; Gauderman, W. J.; Berhane, K.; McConnell, R.; Avol, E.; Peters, J. M.; Gilliland, F.
D. (2007) The relationship between air pollution, lung function and asthma in
adolescents. Thorax: 10.1136/thx.2007.078964.
Isomura, K.; Chikahira, M.; Teranishi, K.; Hamada, K. (1984) Induction of mutations and
chromosome aberrations in lung cells following in vivo exposure of rats to nitrogen
oxides. Mutat. Res. 136: 119-125.
Ito, K. (1971) [Effect of nitrogen dioxide inhalation on influenza virus infection in mice],
Nippon Eiseigaku Zasshi 26: 304-314.
Ito, K. (2003) Associations of particulate matter components with daily mortality and morbidity
in Detroit, Michigan. In: Revised analyses of time-series studies of air pollution and
health. Special report. Boston, MA: Health Effects Institute; pp. 143-156. Available:
http://www.healtheffects.org/Pubs/TimeSeries.pdffl2 May, 2004],
August 2007
6-22
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Ito, K. (2004) Revised ozone risk estimates for daily mortality and hospitalizations in Detroit,
Michigan [personal communication with attachments to Jee Young Kim], New York,
NY: New York University School of Medicine, Nelson Institute of Environmental
Medicine; October 31.
Jacob, D. J. (2000) Heterogeneous chemistry and tropospheric ozone. Atmos. Environ. 34: 2131-
2159.
Jacobson, M. Z. (2002) Atmospheric pollution: history, science, and regulation. New York, NY:
Cambridge University Press.
Jaffe, D. H.; Singer, M. E.; Rimm, A. A. (2003) Air pollution and emergency department visits
for asthma among Ohio Medicaid recipients, 1991-1996. Environ. Res. 91: 21-28.
Jakab, G. J. (1987) Modulation of pulmonary defense mechanisms by acute exposures to
nitrogen dioxide. Environ. Res. 42: 215-228.
Jalaludin, B. B.; O'Toole, B. I.; Leeder, S. R. (2004) Acute effects of urban ambient air pollution
on respiratory symptoms, asthma medication use, and doctor visits for asthma in a cohort
of Australian children. Environ Res. 95: 32-42.
Jalaludin, B.; Morgan, G.; Lincoln, D.; Sheppeard, V.; Simpson, R.; Corbett, S. (2006)
Associations between ambient air pollution and daily emergency department attendances
for cardiovascular disease in the elderly (65+ years), Sydney, Australia. J. Exposure Sci.
Environ. Epidemiol. 16: 225-237.
Jarvis, D. L.; Leaderer, B. P.; Chinn, S.; Burney, P. G. (2005) Indoor nitrous acid and respiratory
symptoms and lung function in adults. Thorax 60: 474-479.
Jenkins, H. S.; Devalia, J. L.; Mister, R. L.; Bevan, A. M.; Rusznak, C.; Davies, R. J. (1999) The
effect of exposure to ozone and nitrogen dioxide on the airway response of atopic
asthmatics to inhaled allergen: dose- and time-dependent effects. Am. J. Respir. Crit.
Care Med. 160: 33-39.
Jerrett, M. (2007) Does traffic-related air pollution contribute to respiratory disease formation in
children? Eur. Respir. J. 29: 825-826.
Jet Propulsion Laboratory. (2006) Chemical kinetics and photochemical data for use in
atmospheric studies. Evaluation number 15. Pasadena, CA: California Institute of
Technology. JPL publication 06-2.
Jiang, B. H.; Maruyama, J.; Yokochi, A.; Amano, H.; Mitani, Y.; Maruyama, K. (2002)
Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and
vascular changes. Eur. Respir. J. 20: 52-58.
Jorres, R.; Magnussen, H. (1990) Airways response of asthmatics after a 30 min exposure, at
resting ventilation, to 0.25 ppm NO2 or 0.5 ppm SO2. Eur. Respir. J. 3: 132-137.
Jorres, R.; Magnussen, H. (1991) Effect of 0.25 ppm nitrogen dioxide on the airway response to
methacholine in asymptomatic asthmatic patients. Lung 169: 77-85.
Jorres, R.; Nowak, D.; Grimminger, F.; Seeger, W.; Oldigs, M.; Magnussen, H. (1995) The
effect of 1 ppm nitrogen dioxide on bronchoalveolar lavage cells and inflammatory
mediators in normal and asthmatic subjects. Eur. Respir. J. 8: 416-424.
August 2007
6-23
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Just, J.; Segala, C.; Sahraoui, F.; Priol, G.; Grimfeld, A.; Neukirch, F. (2002) Short-term health
effects of particulate and photochemical air pollution in asthmatic children. Eur. Respir.
J. 20: 899-906.
Karr, C.; Lumley, T.; Shepherd, K.; Davis, R.; Larson, T.; Ritz, B.; Kaufman, J. (2006) A case-
crossover study of wintertime ambient air pollution and infant bronchiolitis. Environ.
Health Perspect. 114: 277-281.
Katsouyanni, K.; Schwartz, J.; Spix, C.; Touloumi, G.; Zmirou, D.; Zanobetti, A.; Wojtyniak, B.;
Vonk, J. M.; Tobias, A.; Ponka, A.; Medina, S.; Bacharova, L.; Andersen, H. R. (1996)
Short term effects of air pollution on health: a European approach using epidemiology
time series data: the APHEA protocol. In: St Leger, S., ed. The APHEA project. Short
term effects of air pollution on health: a European approach using epidemiological time
series data. J. Epidemiol. Community Health 50(suppl. 1): S12-S18.
Katsouyanni, K.; Touloumi, G.; Samoli, E.; Gryparis, A.; Le Tertre, A.; Monopolis, Y.; Rossi,
G.; Zmirou, D.; Ballester, F.; Boumghar, A.; Anderson, H. R.; Wojtyniak, B.; Paldy, A.;
Braunstein, R.; Pekkanen, J.; Schindler, C.; Schwartz, J. (2001) Confounding and effect
modification in the short-term effects of ambient particles on total mortality: results from
29 European cities within the APHEA2 project. Epidemiology 12: 521-531.
Katsouyanni, K.; Touloumi, G.; Samoli, E.; Petasakis, Y.; Analitis, A.; Le Tertre, A.; Rossi, G.;
Zmirou, D.; Ballester, F.; Boumghar, A.; Anderson, H. R.; Wojtyniak, B.; Paldy, A.;
Braunstein, R.; Pekkanen, J.; Schindler, C.; Schwartz, J. (2003) Sensitivity analysis of
various models of short-term effects of ambient particles on total mortality in 29 cities in
APHEA2. In: Revised analyses of time-series studies of air pollution and health. Special
report. Boston, MA: Health Effects Institute; pp. 157-164. Available:
http://www.healtheffects.org/Pubs/TimeSeries.pdf [18 October, 2004],
Katsuki, S.; Arnold, W.; Mittal, C.; Murad, F. (1977) Stimulation of guanylate cyclase by
sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and
comparison to the effects of sodium azide and hydroxylamine. J. Cyclic Nucleotide Res.
3: 23-35.
Kauffmann, F.; Post Genome Respiratory Epidemiology Group. (2004) Post-genome respiratory
epidemiology: a multidisciplinary challenge. Eur. Respir. J. 24: 471-480.
Kawamoto, T.; Matsuno, K.; Arashidani, K.; Yoshikawa, M.; Kayama, F.; Kodama, Y. (1993)
Personal exposure to nitrogen dioxide from indoor heaters and cooking stoves. Arch.
Environ. Contam. Toxicol. 25: 534-538.
Keller, M. D.; Lanese, R. R.; Mitchell, R. I.; Cote, R. W. (1979a) Respiratory illness in
households using gas and electricity for cooking: I. survey of incidence. Environ. Res.
19: 495-503.
Keller, M. D.; Lanese, R. R.; Mitchell, R. I.; Cote, R. W. (1979b) Respiratory illness in
households using gas and electricity for cooking: II. symptoms and objective findings.
Environ. Res. 19: 504-515.
Kelly, F. J.; Tetley, T. D. (1997) Nitrogen dioxide depletes uric acid and ascorbic acid but not
glutathione from lung lining fluid. Biochem. J. 325: 95-99.
August 2007
6-24
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Kelly, F. J.; Blomberg, A.; Frew, A.; Holgate, S. T.; Sandstrom, T. (1996) Antioxidant kinetics
in lung lavage fluid following exposure of humans to nitrogen dioxide. Am. J. Respir.
Crit. Care Med. 154: 1700-1705.
Kelly, F. J.; Dunster, C.; Mudway, I. (2003) Air pollution and the elderly: oxidant/antioxidant
issues worth consideration. Eur. Respir. J. Suppl. 40: 70S-75S.
Kelsall, J. E.; Samet, J. M.; Zeger, S. L.; Xu, J. (1997) Air pollution and mortality in
Philadelphia, 1974-1988. Am. J. Epidemiol. 146: 750-762.
Kerr, H. D.; Kulle, T. J.; Mcllhany, M. L.; Swidersky, P. (1979) Effects of nitrogen dioxide on
pulmonary function in human subjects: an environmental chamber study. Environ. Res.
19: 392-404.
Khoury, M. J.; Davis, R.; Gwinn, M.; Lindegren, M. L.; Yoon, P. (2005) Do we need genomic
research for the prevention of common diseases with environmental causes? Am. J.
Epidemiol. 161: 799-805.
Kim, S. U.; Koenig, J. Q.; Pierson, W. E.; Hanley, Q. S. (1991) Acute pulmonary effects of
nitrogen dioxide exposure during exercise in competitive athletes. Chest 99: 815-819.
Kim, J. J.; Smorodinsky, S.; Lipsett, M.; Singer, B. C.; Hodgson, A. T.; Ostro, B. (2004a)
Traffic-related air pollution near busy roads: the East Bay children's Respiratory Health
Study. Am. J. Respir. Crit. Care Med. 170: 520-526.
Kim, S.-Y.; Lee, J.-T.; Hong, Y.-C.; Ahn, K.-J.; Kim, H. (2004b) Determining the threshold
effect of ozone on daily mortality: an analysis of ozone and mortality in Seoul, Korea,
1995-1999. Environ. Res. 94: 113-119.
Kim, E.; Hopke, P. K.; Pinto, J. P.; Wilson, W. E. (2005) Spatial variability of fine particle mass,
components, and source contributions during the regional air pollution study in St. Louis.
Environ. Sci. Technol. 39: 4172-4179.
Kim, D.; Sass-Kortsak, A.; Purdham, J. T.; Dales, R. E.; Brook, J. R. (2006) Associations
between personal exposures and fixed-site ambient measurements of fine particulate
matter, nitrogen dioxide, and carbon monoxide in Toronto, Canada. J. Exposure Sci.
Environ. Epidemiol. 16: 172-183.
Kinney, P. L.; Ozkaynak, H. (1991) Associations of daily mortality and air pollution in Los
Angeles County. Environ. Res. 54: 99-120.
Kirby, C.; Fox, M.; Waterhouse, J.; Drye, T. (2001) Influences of environmental parameters on
the accuracy of nitrogen dioxide passive diffusion tubes for ambient measurement. J.
Environ. Monit. 3: 150-158.
Kita, H.; Omichi, S. (1974) [Effects of air pollutants on cilial movement in airway], Nippon
Eiseigaku Zasshi 29: 100.
Kitabatake, M.; Yamamoto, H.; Yuan, P. F.; Manjurul, H.; Murase, S.; Yamauchi, T. (1995)
Effects of exposure to NO2 or SO2 on bronchopulmonary reaction induced by Candida
albicans in guinea pigs. J. Toxicol. Environ. Health 45: 75-82.
August 2007
6-25
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Kleeberger, S. R.; Zhang, L. Y.; Jakab, G. J. (1997) Differential susceptibility to oxidant
exposure in inbred strains of mice: nitrogen dioxide versus ozone. Inhalation Toxicol. 9:
601-621.
Kleinman, M. T.; Mautz, W. J. (1991) The effects of exercise on dose and dose distribution of
inhaled automotive pollutants. Cambridge, MA: Health Effects Institute; research report
no. 45.
Kleinman, M. T.; Bailey, R. M.; Linn, W. S.; Anderson, K. R.; Whynot, J. D.; Shamoo, D. A.;
Hackney, J. D. (1983) Effects of 0.2 ppm nitrogen dioxide on pulmonary function and
response to bronchoprovocation in asthmatics. J. Toxicol. Environ. Health 12: 815-826.
Klepeis, N. E.; Nelson, W. C.; Ott. W. R.; Robinson, J. P. Tsang, A. M.; Switzer, P.; Behar, J.
V.; Hern, S. C.; Engelmann, W. H. (2001) The National Human Activity Pattern Survey
(NHAPS): a resource for assessing exposure to environmental pollutants. J. Exposure
Anal. Environ. Epidemiol. 11: 231-252.
Kobayashi, T.; Miura, T. (1995) Concentration- and time-dependent increase in specific airway
resistance after induction of airway hyperresponsiveness by subchronic exposure of
guinea pigs to nitrogen dioxide. Fundam. Appl. Toxicol. 25: 154-158.
Kodama, Y.; Arashidani, K.; Tokui, N.; Kawamoto, T.; Matsuno, K.; Kunugita, N.; Minakawa,
N. (2002) Environmental N02 concentration and exposure in daily life along main roads
in Tokyo. Environ. Res. A 89: 236-244.
Koenig, J. Q.; Covert, D. S.; Morgan, M. S.; Horike, M.; Horike, N.; Marshall, S. G.; Pierson,
W. E. (1985) Acute effects of 0.12 ppm ozone or 0.12 ppm nitrogen dioxide on
pulmonary function in healthy and asthmatic adolescents. Am. Rev. Respir. Dis. 132:
648-651.
Koenig, J. Q.; Pierson, W. E.; Marshall, S. G.; Covert, D. S.; Morgan, M. S.; Van Belle, G.
(1988) The effects of ozone and nitrogen dioxide on lung function in healthy and
asthmatic adolescents. Cambridge, MA: Health Effects Institute; research report no. 14.
Available from: NTIS, Springfield, VA; PB88-234455.
Koenig, J. Q.; Covert, D. S.; Pierson, W. E.; Hanley, Q. S.; Rebolledo, V.; Dumler, K.;
McKinney, S. E. (1994) Oxidant and acid aerosol exposure in healthy subjects and
subjects with asthma. Part I: effects of oxidants, combined with sulfuric or nitric acid, on
the pulmonary function of adolescents with asthma. Cambridge, MA: Health Effects
Institute; pp. 1-36; research report no. 70.
Kon, K.; Maeda, N.; Shiga, T. (1977) Effect of nitric oxide on the oxygen transport of human
erythrocytes. J. Toxicol. Environ. Health 2: 1109-1113.
Kosaka, H.; Oda, Y.; Uozumi, M. (1985) Induction of umuC gene expression by nitrogen dioxide
in Salmonella typhimurium. Mutat. Res. 142: 99-102.
Kosaka, H.; Yamamoto, K.; Oda, Y.; Uozumi, M. (1986) Induction of SOS functions by nitrogen
dioxide in Escherichia coli with different DNA-repair capacities. Mutat. Res. 162: 1-5.
Kosaka, H.; Uozumi, M.; Nakajima, T. (1987) Induction of SOS functions in Escherichia coli
and biosynthesis of nitrosamine in rabbits by nitrogen dioxide. Environ. Health Perspect.
73:153-156.
August 2007
6-26
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Kosmider, S.; Luciak, M.; Zajusz, K.; Misiewicz, A.; Szygula, J. (1973) Badania nad
rozedmotworczym dzialaniem tlenkow azotu [Studies on emphysogenic action of
nitrogen oxides], Patol. Pol. 24: 107-125.
Kousa, A.; Monn, C.; Rotko, T.; Aim, S.; Oblesby, L.; Jantunen, M. J. (2001) Personal exposures
to NO2 in the EXPOLIS-study: relation to residential indoor, outdoor and workplace
concentrations in Basel, Helsinki and Prague. Atmos. Environ. 35: 3405-3412.
Kramer, U.; Koch, T.; Ranft, U.; Ring, J.; Behrendt, H. (2000) Traffic-related air pollution is
associated with atopy in children living in urban areas. Epidemiology 11: 64-70.
Krewski, D.; Burnett, R. T.; Goldberg, M. S.; Hoover, K.; Siemiatycki, J.; Jerrett, M.;
Abrahamowicz, M.; White, W. H. (2000) Reanalysis of the Harvard Six Cities study and
the American Cancer Society study of particulate air pollution and mortality: a special
report of the Institute's Particle Epidemiology Reanalysis Project. Cambridge, MA:
Health Effects Institute. Available: http://pubs.healtheffects.org/view.php?id=6 [6 March,
2007],
Kripke, B. J.; Sherwin, R. P. (1984) Nitrogen dioxide exposure - influence on rat testes. Anesth.
Analg. (NY) 63: 526-528.
Krishna, M. T.; Chauhan, A. J.; Frew, A. J.; Holgate, S. T. (1998) Toxicological mechanisms
underlying oxidant pollutant-induced airway injury. Rev. Environ. Health 13: 59-71.
Krupa, S. V.; Legge, A. H. (2000) Passive sampling of ambient, gaseous air pollutants: an
assessment from an ecological perspective. Environ. Pollut. 107: 31-45.
Kubota, K.; Murakami, M.; Takenaka, S.; Kawai, K.; Kyono, H. (1987) Effects of long-term
nitrogen dioxide exposure on rat lung: morphological observations. Environ. Health
Perspect. 73: 157-169.
Kulkarni, M. M.; Patil, R. S. (2002) An empirical model to predict indoor N02 concentrations.
Atmos. Environ. 36: 4777-4785.
Kumae, T.; Arakawa, H. (2006) Comparison of effects of in vivo nitrogen dioxide exposure
starting from different periods on alveolar macrophage activity, assessed by a
chemiluminescence technique in Brown-Norway rats. Luminescence 21: 226-232.
Kunimoto, M.; Mochitate, K.; Kaya, K.; Miura, T.; Kubota, K. (1984) Effects of nitrogen
dioxide on red blood cells of rats: alterations of cell membrane components and
populational changes of red blood cells during in vivo exposure to NO2. Environ. Res. 33:
361-369.
Kiinzli, N.; Tager, I. B. (1997) The semi-individual study in air pollution epidemiology: a valid
design as compared to ecologic studies. Environ. Health Perspect. 105: 1078-1083.
Kwon, H.-J.; Cho, S.-H.; Nyberg, F.; Pershagen, G. (2001) Effects of ambient air pollution on
daily mortality in a cohort of patients with congestive heart failure. Epidemiology 12:
413-419.
Kyono, H.; Kawai, K. (1982) Morphometric study on age-dependent pulmonary lesions in rats
exposed to nitrogen dioxide. Ind. Health 20: 73-99.
August 2007
6-27
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Lafuma, C.; Harf, A.; Lange, F.; Bozzi, L.; Poncy, J. L.; Bignon, J. (1987) Effect of low-level
N02 chronic exposure on elastase-induced emphysema. Environ. Res. 43: 75-84.
Lagorio, S.; Forastiere, F.; Pistelli, R.; Iavarone, I.; Michelozzi, P.; Fano, V.; Marconi, A.;
Ziemacki, G.; Ostro, B. D. (2006) Air pollution and lung function among susceptible
adult subjects: a panel study. Environ. Health 5: 11. Available:
http://www.ehjournal.net/content/5/l/ll [16 January, 2006],
Lai, H. K.; Kendall, M.; Ferrier, H.; Lindup, I.; Aim, S.; Hanninen, O.; Jantunen, M.; Mathys, P.;
Colvile, R.; Ashmore, M. R.; Cullinan, P.; Nieuwenhuijsen, M. J. (2004) Personal
exposures and microenvironment concentrations of PM2.5, VOC, NO2 and CO in Oxford,
UK. Atmos. Environ. 38: 6399-6410.
Lai, S.; Patil, R. S. (2001) Monitoring of atmospheric behaviour of NOx from vehicular traffic.
Environ. Monit. Assess. 68: 37-50.
Lanki, T.; Pekkanen, J.; Aalto, P.; Elosua, R.; Berglind, N.; D'Ippoliti, D.; Kulmala, M.; Nyberg,
F.; Peters, A.; Picciotto, S.; Salomaa, V.; Sunyer, J.; Tiittanen, P.; Von Klot, S.;
Forastiere, F.; for the HEAPSS Study Group. (2006) Associations of traffic-related air
pollutants with hospitalisation for first acute myocardial infarction: the HEAPSS study.
Occup. Environ. Med. 63: 844-851.
LaRovere, M. T.; Pinna, G. D.; Maestri, R.; Mortara, A.; Capomolla, S.; Febo, O.; Ferrari, R.;
Franchini, M.; Gnemmi, M.; Opasich, C.; Riccardi, P. G.; Traversi, E.; Cobelli, F. (2003)
Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart
failure patients. Circulation 107: 565-570.
Last, J. A.; Gerriets, J. E.; Hyde, D. M. (1983) Synergistic effects on rat lungs of mixtures of
oxidant air pollutants (ozone or nitrogen dioxide) and respirable aerosols. Am. Rev.
Respir. Dis. 128: 539-544.
Leaderer, B. P.; Zagraniski, R. T.; Berwick, M.; Stolwijk, J. A. J. (1986) Assessment of exposure
to indoor air contaminants from combustion sources: methodology and application. Am.
J. Epidemiol. 124: 275-289.
Lee, K.; Yanagisawa, Y.; Spengler, J. D.; Billick, I. H. (1995) Classification of house
characteristics based on indoor nitrogen dioxide concentrations. Environ. Int. 21: 277-
282.
Lee, K.; Yanagisawa, Y.; Spengler, J. D.; Fukumura, Y.; Billick, I. H. (1996) Classification of
house characteristics in a Boston residential nitrogen dioxide characterization study.
Indoor Air 6: 211-216.
Lee, K.; Levy, J. I.; Yanagisawa, Y.; Spengler, J. D.; Billick, I. H. (1998) The Boston Residential
Nitrogen Dioxide Characterization Study: classification and prediction of indoor NO2
exposure. J. Air Waste Manage. Assoc. 48: 736-742.
Lee, K.; Yang, W.; Bofinger, N. D. (2000) Impact of microenvironmental nitrogen dioxide
concentrations on personal exposures in Australia. J. Air Waste Manage. Assoc. 50:
1739-1744.
August 2007
6-28
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Lee, K.; Xue, J.; Geyh, A. S.; Ozkaynak, H.; Leaderer, B. P.; Weschler, C. J.; Spengler, J. D.
(2002) Nitrous acid, nitrogen dioxide, and ozone concentrations in residential
environments. Environ. Health Perspect. 110: 145-150.
Lee, J.-T.; Kim, H.; Cho, Y.-S.; Hong, Y.-C.; Ha, E.-H.; Park, H. (2003a) Air pollution and
hospital admissions for ischemic heart diseases among individuals 64+ years of age
residing in Seoul, Korea. Arch. Environ. Health 58: 617-623.
Lee, B. E.; Ha, E. H.; Park, H. S.; Kim, Y. J.; Hong, Y. C.; Kim, H.; Lee, J. T. (2003b) Exposure
to air pollution during different gestational phases contributes to risks of low birth
weight. Hum. Reprod. 18: 638-643.
Lee, Y.-L.; Lin, Y.-C.; Lee, Y.-C.; Wang, J.-Y.; Hsiue, T.-R.; Guo, Y. L. (2004) Glutathione S-
transferase PI gene polymorphism and air pollution as interactive risk factors for
childhood asthma. Clin. Exp. Allergy 34: 1707-1713.
Lee, S. L.; Wong, W. H. S.; Lau, Y. L. (2006) Association between air pollution and asthma
admission among children in Hong Kong. Clin. Exp. Allergy 36: 1138-1146.
Lefkowitz, S. S.; McGrath, J. J.; Lefkowitz, D. L. (1986) Effects of NO2 on immune responses.
J. Toxicol. Environ. Health 17: 241-248.
Lehnert, B. E.; Archuleta, D. C.; Ellis, T.; Session, W. S.; Lehnert, N. M.; Gurley, L. R.; Stavert,
D. M. (1994) Lung injury following exposure of rats to relatively high mass
concentrations of nitrogen dioxide. Toxicology 89: 239-277.
Le Tertre, A.; Quenel, P.; Eilstein, D.; Medina, S.; Prouvost, H.; Pascal, L.; Boumghar, A.;
Saviuc, P.; Zeghnoun, A.; Filleul, L.; Declercq, C.; Cassadou, S.; Le Goaster, C. (2002)
Short-term effects of air pollution on mortality in nine French cities: a quantitative
summary. Arch. Environ. Health 57: 311-319.
Levesque, B.; Allaire, S.; Gauvin, D.; Koutrakis, P.; Gingras, S.; Rhainds, M.; Prud'Homme, H.;
Duchesne, J.-F. (2001) Wood-burning appliances and indoor air quality. Sci. Total
Environ. 281: 47-62.
Levy, J. I.; Lee, K.; Yanagisawa, Y.; Hutchinson, P.; Spengler, J. D. (1998a) Determinants of
nitrogen dioxide concentrations in indoor ice skating rinks. Am. J. Public Health 88:
1781-1786.
Levy, J. I.; Lee, K.; Spengler, J. D.; Yanagisawa, Y. (1998b) Impact of residential nitrogen
dioxide exposure on personal exposure: an international study. J. Air Waste Manage.
Assoc. 48: 553-560.
Lewne, M.; Nise, G.; Lind, M. L.; Gustavsson, P. (2006) Exposure to particles and nitrogen
dioxide among taxi, bus and lorry drivers. Int. Arch. Occup. Environ. Health 79: 220-226.
Li, Y.-F.; Gauderman, W. J.; Avol, E.; Dubeau, L.; Gilliland, F. D. (2006) Associations of tumor
necrosis factor G-308A with childhood asthma and wheezing. Am. J. Respir. Crit. Care
Med. 173: 970-976.
Liang, K.-Y.; Zeger, S. L. (1986) Longitudinal data analysis using generalized linear models.
Biometrika 73: 13-22.
August 2007
6-29
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Liao, D.; Duan, Y.; Whitsel, E. A.; Zheng, Z.-J.; Heiss, G.; Chinchilli, V. M.; Lin, H.-M. (2004)
Association of higher levels of ambient criteria pollutants with impaired cardiac
autonomic control: a population-based study. Am. J. Epidemiol. 159: 768-777.
Liard, R.; Zureik, M.; Le Moullec, Y.; Soussan, D.; Glorian, M.; Grimfeld, A.; Neukirch, F.
(1999) Use of personal passive samplers for measurement of NO2, NO, and 03 levels in
panel studies. Environ. Res. 81: 339-348.
Lin, M.; Chen, Y.; Burnett, R. T.; Villeneuve, P. J.; Krewski, D. (2003) Effect of short-term
exposure to gaseous pollution on asthma hospitalisation in children: a bi-directional case-
crossover analysis. J. Epidemiol. Community Health 57: 50-55.
Lin, M.; Chen, Y.; Villeneuve, P. J.; Burnett, R. T.; Lemyre, L.; Hertzman, C.; McGrail, K. M.;
Krewski, D. (2004) Gaseous air pollutants and asthma hospitalization of children with
low household income in Vancouver, British Columbia, Canada. Am. J. Epidemiol. 159:
294-303.
Linaker, C. H.; Chauhan, A. J.; Inskip, H.; Frew, A. J.; Sillence, A.; Coggon, D.; Holgate, S. T.
(1996) Distribution and determinants of personal exposure to nitrogen dioxide in school
children. Occup. Environ. Med. 53: 200-203.
Linaker, C. H.; Chauhan, A. J.; Inskip, H. M.; Holgate, S. T.; Coggon, D. (2000) Personal
exposures of children to nitrogen dioxide relative to concentrations in outdoor air. Occup.
Environ. Med. 57: 472-476.
Linn, W. S.; Solomon, J. C.; Trim, S. C.; Spier, C. E.; Shamoo, D. A.; Venet, T. G.; Avol, E. L.;
Hackney, J. D. (1985a) Effects of exposure to 4 ppm nitrogen dioxide in healthy and
asthmatic volunteers. Arch. Environ. Health 40: 234-239.
Linn, W. S.; Shamoo, D. A.; Spier, C. E.; Valencia, L. M.; Anzar, U. T.; Venet, T. G.; Avol, E.
L.; Hackney, J. D. (1985b) Controlled exposure of volunteers with chronic obstructive
pulmonary disease to nitrogen dioxide. Arch. Environ. Health 40: 313-317.
Linn, W. S.; Shamoo, D. A.; Avol, E. L.; Whynot, J. D.; Anderson, K. R.; Venet, T. G.;
Hackney, J. D. (1986) Dose-response study of asthmatic volunteers exposed to nitrogen
dioxide during intermittent exercise. Arch. Environ. Health 41: 292-296.
Linn, W. S.; Shamoo, D. A.; Anderson, K. R.; Peng, R.-C.; Avol, E. L.; Hackney, J. D.; Gong,
H., Jr. (1996) Short-term air pollution exposures and responses in Los Angeles area
schoolchildren. J. Exposure Anal. Environ. Epidemiol. 6: 449-472.
Linn, W. S.; Szlachcic, Y.; Gong, H., Jr.; Kinney, P. L.; Berhane, K. T. (2000) Air pollution and
daily hospital admissions in metropolitan Los Angeles. Environ. Health Perspect. 108:
427-434.
Lipfert, F. W.; Perry, H. M., Jr.; Miller, J. P.; Baty, J. D.; Wyzga, R. E.; Carmody, S. E. (2000a)
The Washington University-EPRI veterans' cohort mortality study: preliminary results.
In: Grant, L. D., ed. PM2000: particulate matter and health. Inhalation Toxicol. 12(suppl.
4): 41-73.
Lipfert, F. W.; Morris, S. C.; Wyzga, R. E. (2000b) Daily mortality in the Philadelphia
metropolitan area and size-classified particulate matter. J. Air Waste Manage. Assoc. 50:
1501-1513.
August 2007
6-30
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Lipfert, F. W.; Perry, H. M., Jr.; Miller, J. P.; Baty, J. D.; Wyzga, R. E.; Carmody, S. E. (2003)
Air pollution, blood pressure, and their long-term associations with mortality. Inhalation
Toxicol. 15: 493-512.
Lipfert, F. W.; Wyzga, R. E.; Baty, J. D.; Miller, J. P. (2006a) Traffic density as a surrogate
measure of environmental exposures in studies of air pollution health effects: long-term
mortality in a cohort of US veterans. Atmos. Environ. 40: 154-169.
Lipfert, F. W.; Baty, J. D.; Miller, J. P.; Wyzga, R. E. (2006b) PM2.5 constituents and related air
quality variables as predictors of survival in a cohort of U.S. military veterans. Inhalation
Toxicol. 18: 645-657.
Lippmann, M.; Ito, K.; Nadas, A.; Burnett, R. T. (2000) Association of particulate matter
components with daily mortality and morbidity in urban populations. Cambridge, MA:
Health Effects Institute; research report no. 95.
Liu, S.; Krewski, D.; Shi, Y.; Chen, Y.; Burnett, R. T. (2003) Association between gaseous
ambient air pollutants and adverse pregnancy outcomes in Vancouver, Canada. Environ.
HealthPerspect. Ill: 1773-1778.
Llorca, J.; Salas, A.; Prieto-Salceda, D.; Chinchon-Bengoechea, V.; Delgado-Rodriguez, M.
(2005) Nitrogen dioxide increases cardiorespiratory admissions in Torrelavega (Spain). J.
Environ. Health 68: 30-35.
Loomis, D.; Castillejos, M.; Gold, D. R.; McDonnell, W.; Boija-Aburto, V. H. (1999) Air
pollution and infant mortality in Mexico City. Epidemiology 10: 118-123.
Luginaah, I. N.; Fung, K. Y.; Gorey, K. M.; Webster, G.; Wills, C. (2005) Association of
ambient air pollution with respiratory hospitalization in a government designated "area of
concern": the case of Windsor, Ontario. Environ. Health Perspect. 113: 290-296.
Luttmann-Gibson, H.; Suh, H. H.; Coull, B. A.; Dockery, D. W.; Sarnet, S. E.; Schwartz, J.;
Stone, P. H.; Gold, D. R. (2006) Short-term effects of air pollution on heart rate
variability in senior adults in Steubenville, Ohio. J. Occup. Environ. Med. 48: 780-788.
Ma, T.-H.; Anderson, V. A.; Shmed, I. (1982) Environmental clastogens detected by meiotic
pollen mother cells of Tradescantia. Environ. Sci. Res. 25: 141-157.
Mage, D.; Wilson, W.; Hasselblad, V.; Grant, L. (1999) Assessment of human exposure to
ambient particulate matter. J. Air Waste Manage. Assoc. 49: 1280-1291.
Maigetter, R. Z.; Fenters, J. D.; Findlay, J. C.; Ehrlich, R.; Gardner, D. E. (1978) Effect of
exposure to nitrogen dioxide on T and B cells in mouse spleens. Toxicol. Lett. 2: 157-
161.
Mann, J. K.; Tager, I. B.; Lurmann, F.; Segal, M.; Quesenberry, C. P., Jr.; Lugg, M. M.; Shan, J.;
Van den Eeden, S. K. (2002) Air pollution and hospital admissions for ischemic heart
disease in persons with congestive heart failure or arrhythmia. Environ. Health Perspect.
110: 1247-1252.
Mannes, T.; Jalaludin, B.; Morgan, G.; Lincoln, D.; Sheppeard, V.; Corbett, S. (2005) Impact of
ambient air pollution on birth weight in Sydney, Australia. Occup. Environ. Med. 62:
524-530.
August 2007
6-31
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Maples, K. R.; Sandstrom, T.; Su, Y.-F.; Henderson, R. F. (1991) The nitric oxide/heme protein
complex as a biologic marker of exposure to nitrogen dioxide in humans, rats, and in
vitro models. Am. J. Respir. Cell Mol. Biol. 4: 538-543.
Margolis, P. A.; Greenberg, R. A.; Keyes, L. L.; Lavange, L. M.; Chapman, R. S.; Denny, F. W.;
Bauman, K. E.; Boat, B. W. (1992) Lower respiratory illness in infants and low
socioeconomic status. Am. J. Public Health 82: 1119-1126.
Martin, R. V.; Jacob, D. J.; Chance, K. V.; Kurosu, T. P.; Palmer, P. I.; Evans, M. J. (2003)
Global inventory of nitrogen oxide emissions constrained by space-based observations of
N02 columns. J. Geophys. Res. [Atmos.] 108(D17): 10.1029/2003JD003453.
McClenny, W. A.; Williams, E. J.; Cohen, R. C.; Stutz, J. (2002) Preparing to measure the
effects of the NOx SIP Call—methods for ambient air monitoring of NO, NO2, NOy, and
individual NOz species. J. Air Waste Manage. Assoc. 52: 542-562.
McConnell, R.; Berhane, K.; Gilliland, F.; Molitor, J.; Thomas, D.; Lurmann, F.; Avol, E.;
Gauderman, W. J.; Peters, J. M. (2003) Prospective study of air pollution and bronchitic
symptoms in children with asthma. Am. J. Respir. Crit. Care Med. 168: 790-797.
McConnell, R.; Berhane, K.; Yao, L.; Jerrett, M.; Lurmann, F.; Gilliland, F.; Kunzli, N.;
Gauderman, J.; Avol, E.; Thomas, D.; Peters, J. (2006) Traffic, susceptibility, and
childhood asthma. Environ. Health Perspect. 114: 766-772.
Melia, R. J. W.; Du Ve Florey, C.; Altman, D. G.; Swan, A. V. (1977) Association between gas
cooking and respiratory disease in children. Br. Med. J. 2: 149-152.
Melia, R. J. W.; Du Ve Florey, C.; Chinn, S. (1979) The relation between respiratory illness in
primary schoolchildren and the use of gas for cooking: I - results from a national survey.
Int. J. Epidemiol. 8: 333-338.
Melia, R. J. W.; Du Ve Florey, C.; Morris, R. W.; Goldstein, B. D.; Clark, D.; John, H. H.
(1982a) Childhood respiratory illness and the home environment. I. Relations between
nitrogen dioxide, temperature and relative humidity. Int. J. Epidemiol. 11: 155-163.
Melia, R. J. W.; Du Ve Florey, C.; Morris, R. W.; Goldstein, B. D.; John, H. H.; Clark, D.;
Craighead, I. B.; Mackinlay, J. C. (1982b) Childhood respiratory illness and the home
environment: II. association between respiratory illness and nitrogen dioxide, temperature
and relative humidity. Int. J. Epidemiol. 11: 164-169.
Melia, R. J. W.; Chinn, S.; Rona, R. J. (1990) Indoor levels of N02 associated with gas cookers
and kerosene heaters in inner city areas of England. Atmos. Environ. Part B 24: 177-180.
Menzel, D. B. (1976) The role of free radicals in the toxicity of air pollutants (nitrogen oxides
and ozone). In: Pryor, W. A., ed. Free radicals in biology: v. II. New York, NY:
Academic Press, Inc.; pp. 181-202.
Mercer, R. R. (1999) Morphometric analysis of alveolar responses of F344 rats to subchronic
inhalation of nitric oxide. Cambridge, MA: Health Effects Institute; research report no.
88.
Mercer, R. R.; Costa, D. L.; Crapo, J. D. (1995) Effects of prolonged exposure to low doses of
nitric oxide or nitrogen dioxide on the alveolar septa of the adult rat lung. Lab. Invest. 73:
20-28.
August 2007
6-32
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
Mersch, J.; Dyce, B. J.; Haverback, B. J.; Sherwin, R. P. (1973) Diphosphoglycerate content of
red blood cells: measurements in guinea pigs exposed to 0.4 ppm nitrogen dioxide. Arch.
Environ. Health 27: 94-95.
Metzger, K. B.; Tolbert, P. E.; Klein, M.; Peel, J. L.; Flanders, W. D.; Todd, K. H.; Mulholland,
J. A.; Ryan, P. B.; Frumkin , H. (2004) Ambient air pollution and cardiovascular
emergency department visits. Epidemiology 15: 46-56.
Migliaretti, G.; Cavallo, F. (2004) Urban air pollution and asthma in children. Pediatr. Pulmonol.
38: 198-203.
Migliaretti, G.; Cadum, E.; Migliore, E.; Cavallo, F. (2005) Traffic air pollution and hospital
admission for asthma: a case-control approach in a Turin (Italy) population. Int. Arch.
Occup. Environ. Health. 78: 164-169.
Miller, F. J.; Overton, J. H.; Myers, E. T.; Graham, J. A. (1982) Pulmonary dosimetry of nitrogen
dioxide in animals and man. In: Schneider, T.; Grant, L., eds. Air pollution by nitrogen
oxides: proceedings of the US-Dutch international symposium; May; Maastricht, The
Netherlands. Amsterdam, The Netherlands: Elsevier Scientific Publishing Company; pp.
377-386. (Studies in environmental science 21).
Miller, F. J.; Graham, J. A.; Raub, J. A.; Illing, J. W.; Menache, M. G.; House, D. E.; Gardner,
D. E. (1987) Evaluating the toxicity of urban patterns of oxidant gases. II. Effects in mice
from chronic exposure to nitrogen dioxide. J. Toxicol. Environ. Health 21: 99-112.
Miller, K. A.; Siscovick, D. S.; Sheppard, L.; Shepherd, K.; Sullivan J. H.; Anderson, G. L.;
Kaufman, J. D. (2007) Long-term exposure to air pollution and incidence of
cardiovascular events in women. N. Engl. J. Med. 356: 447-458.
Millstein, J.; Gilliland, F.; Berhane, K.; Gauderman, W. J.; McConnell, R.; Avol, E.; Rappaport,
E. B.; Peters, J. M. (2004) Effects of ambient air pollutants on asthma medication use and
wheezing among fourth-grade school children from 12 Southern California communities
enrolled in The Children's Health Study. Arch. Environ. Health 59: 505-514.
Mink, S. N.; Coalson, J. J.; Whitley, L.; Greville, H.; Jadue, C. (1984) Pulmonary function tests
in the detection of small airway obstruction in a canine model of bronchiolitis obliterans.
Am. Rev. Respir. Dis. 130: 1125-1133.
Mirvish, S. S.; Issenberg, P.; Sams, J. P. (1981) iV-nitrosomorpholine synthesis in rodents
exposed to nitrogen dioxide and morpholine. In: Scanlan, R. A.; Tannenbaum, S. R., eds.
iV-nitroso compounds: based on a symposium cosponsored by the Divisions of
Agricultural and Food Chemistry and Pesticide Chemistry at the 181st meeting of the
American Chemical Society; March-April; Atlanta, GA. Washington, DC: American
Chemical Society; pp. 181-191. (ACS symposium series 174).
Mirvish, S. S.; Sams, J. P.; Issenberg, P. (1983) The nitrosating agent in mice exposed to
nitrogen dioxide: improved extraction method and localization in the skin. Cancer Res.
43:2550-2554.
Mirvish, S. S.; Babcook, D. M.; Deshpande, A. D.; Nagel, D. L. (1986) Identification of
cholesterol as a mouse skin lipid that reacts with nitrogen dioxide to yield a nitrosating
agent, and of cholesteryl nitrite as the nitrosating agent produced in a chemical system
from cholesterol. Cancer Lett. (Shannon, Irel.) 31: 97-104.
August 2007
6-33
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Mirvish, S. S.; Ramm, M. D.; Sams, J. P.; Babcook, D. M. (1988) Nitrosamine formation from
amines applied to the skin of mice after and before exposure to nitrogen dioxide. Cancer
Res. 48: 1095-1099.
Miyanishi, K.; Kinouchi, T.; Kataoka, K.; Kanoh, T.; Ohnishi, Y. (1996) In vivo formation of
mutagens by intraperitoneal administration of polycyclic aromatic hydrocarbons in
animals during exposure to nitrogen dioxide. Carcinogenesis 17: 1483-1490.
Mochitate, K.; Miura, T. (1984) In vivo effect of nitrogen dioxide on the activities of glycolytic
enzymes in red blood cells of rats. Toxicol. Lett. 22: 315-321.
Mochitate, K.; Kaya, K.; Miura, T.; Kubota, K. (1984) In vivo effects of nitrogen dioxide on
membrane constituents in lung and liver of rats. Environ. Res. 33: 17-28.
Mochitate, K.; Miura, T.; Kubota, K. (1985) An increase in the activities of glycolytic enzymes
in rat lungs produced by nitrogen dioxide. J. Toxicol. Environ. Health 15: 323-331.
Mochitate, K.; Takahashi, Y.; Ohsumi, T.; Miura, T. (1986) Activation and increment of alveolar
macrophages induced by nitrogen dioxide. J. Toxicol. Environ. Health 17: 229-239.
Modig, L.; Sunesson, A.-L.; Levin, J.-O.; Sundgren, M.; Hagenbjork-Gustafsson, A.; Forsberg,
B. (2004) Can N02 be used to indicate ambient and personal levels of benzene and 1,3-
butadiene in air? J. Environ. Monit. 6: 957-962.
Mohsenin, V. (1987a) Effect of vitamin C on N02-induced airway hyperresponsiveness in
normal subjects: a randomized double-blind experiment. Am. Rev. Respir. Dis. 136:
1408-1411.
Mohsenin, V. (1987b) Airway responses to nitrogen dioxide in asthmatic subjects. J. Toxicol.
Environ. Health 22: 371-380.
Mohsenin, V. (1988) Airway responses to 2.0 ppm nitrogen dioxide in normal subjects. Arch.
Environ. Health 43: 242-246.
Mohsenin, V.; Gee, J. B. L. (1987) Acute effect of nitrogen dioxide exposure on the functional
activity of alpha-1-protease inhibitor in bronchoalveolar lavage fluid of normal subjects.
Am. Rev. Respir. Dis. 136: 646-650.
Molitor, J.; Jerrett, M.; Chang, C.-C.; Molitor, N.-T.; Gauderman, J.; Berhane, K.; McConnell,
R.; Lurmann, F.; Wu, J.; Winer, A.; Thomas, D. (2007) Assessing uncertainty in spatial
exposure models for air pollution health effects assessment. Environ. Health Perspect.
115: 1147-1153.
Moncada, S. (1992) Nitric oxide gas: mediator, modulator, and pathophysiologic entity. J. Lab.
Clin. Med. 120: 187-191.
Moncada, S.; Palmer, R. M. J.; Higgs, E. A. (1991) Nitric oxide: physiology, pathophysiology,
and pharmacology. Pharmacol. Rev. 43: 109-142.
Monn, C.; Fuchs, A.; Hogger, D.; Junker, M.; Kogelschatz, D.; Roth, N.; Wanner, H.-U. (1997)
Particulate matter less than 10 |im (PMio) and fine particles less than 2.5 |im (PM2.s):
relationships between indoor, outdoor and personal concentrations. Sci. Total Environ.
208: 15-21.
August 2007
6-34
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Monn, C.; Brandli, O.; Schindler, C.; Ackermann-Liebrich, U.; Leuenberger, P.; SAPALDIA
team. (1998) Personal exposure to nitrogen dioxide in Switzerland. Sci. Total Environ.
215: 243-251.
Moolgavkar, S. H. (2000) Air pollution and hospital admissions for diseases of the circulatory
system in three U.S. metropolitan areas. J. Air Waste Manage Assoc. 50: 1199-1206.
Moolgavkar, S. H. (2003) Air pollution and daily deaths and hospital admissions in Los Angeles
and Cook counties. In: Revised analyses of time-series studies of air pollution and health.
Special report. Boston, MA: Health Effects Institute; pp. 183-198. Available:
http://www.healtheffects.org/news.htm [16 May, 2003],
Moolgavkar, S. H.; Luebeck, E. G. (1996) A critical review of the evidence on particulate air
pollution and mortality. Epidemiology 7: 420-428.
Morgan, G.; Corbett, S.; Wlodarczyk, J. (1998) Air pollution and hospital admissions in Sydney,
Australia, 1990 to 1994. Am. J. Public Health 88: 1761-1766.
Morgan, G.; Corbett, S.; Wlodarczyk, J.; Lewis, P. (1998) Air pollution and daily mortality in
Sydney, Australia, 1989 through 1993. Am. J. Public Health 88: 759-764.
Morris, R. D.; Naumova, E. N.; Munasinghe, R. L. (1995) Ambient air pollution and
hospitalization for congestive heart failure among elderly people in seven large US cities.
Am. J. Public Health 85: 1361-1365.
Morrow, P. E.; Utell, M. J. (1989) Responses of susceptible subpopulations to nitrogen dioxide.
Cambridge, MA: Health Effects Institute; research report no. 23.
Morrow, P. E.; Utell, M. J.; Bauer, M. A.; Smeglin, A. M.; Frampton, M. W.; Cox, C.; Speers,
D. M.; Gibb, F. R. (1992) Pulmonary performance of elderly normal subjects and
subjects with chronic obstructive pulmonary disease exposed to 0.3 ppm nitrogen
dioxide. Am. Rev. Respir. Dis. 145: 291-300.
Mortimer, K. M.; Neas, L. M.; Dockery, D. W.; Redline, S.; Tager, I. B. (2002) The effect of air
pollution on inner-city children with asthma. Eur. Respir. J. 19: 699-705.
Moseler, M.; Hendel-Kramer, A.; Karmaus, W.; Forster, J.; Weiss, K.; Urbanek, R.; Kuehr, J.
(1994) Effect of moderate NO2 air pollution on the lung function of children with
asthmatic symptoms. Environ. Res. 67: 109-124.
Mosqueron, L.; Momas, I.; Le Moullec, Y. (2002) Personal exposure of Paris office workers to
nitrogen dioxide and fine particles. Occup. Environ. Med. 59: 550-555.
Mukala, K.; Pekkanen, J.; Tiittanen, P.; Aim, S.; Salonen, R. O.; Tuomisto, J. (1999) Personally
measured weekly exposure to NO2 and respiratory health among preschool children. Eur.
Respir. J. 13: 1411-1417.
Mukala, K.; Aim, S.; Tiittanen, P.; Salonen, R. O.; Jantunen, M.; Pekkanen, J. (2000) Nitrogen
dioxide exposure assessment and cough among preschool children. Arch. Environ.
Health. 55: 431-438.
Muller, B.; Schafer, H.; Barth, P.; Von Wichert, P. (1994) Lung surfactant components in
bronchoalveolar lavage after inhalation of NO2 as markers of altered surfactant
metabolism. Lung 172: 61-72.
August 2007
6-35
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Muller, B.; Garn, H.; Hochscheid, R. (2003) Impaired recycling of surfactant-like liposomes in
type II pneumocytes from injured lungs. Thorax 58: 127-134.
Murphy, S. D.; Ulrich, C. E.; Frankowitz, S. H.; Xintaras, C. (1964) Altered function in animals
inhaling low concentrations of ozone and nitrogen dioxide. Am. Ind. Hyg. Assoc. J. 25:
246-253.
Nadziejko, C. E.; Nansen, L.; Mannix, R. C.; Kleinman, M. T.; Phalen, R. F. (1992) Effect of
nitric acid vapor on the response to inhaled ozone. Inhalation Toxicol. 4: 343-358.
Nasss, 0.; Nafstad, P.; Aamodt, G.; Claussen, B.; Rosland, P. (2007) Relation between
concentration of air pollution and cause-specific mortality: four-year exposures to
nitrogen dioxide and particulate matter pollutants in 470 neighborhoods in Oslo, Norway.
Am. J. Epidemiol. 165: 435-443.
Nafstad, P.; Haheim, L. L.; Oftedal, B.; Gram, F.; Holme, I.; Hjermann, I.; Leren, P. (2003)
Lung cancer and air pollution: a 27 year follow up of 16,209 Norwegian men. Thorax 58:
1071-1076.
Nafstad, P.; Haheim, L. L.; Wisloff, T.; Gram, F.; Oftedal, B.; Holme, I.; Hjermann, I.; Leren, P.
(2004) Urban air pollution and mortality in a cohort of Norwegian men. Environ. Health
Perspect. 112: 610-605.
Nakai, S.; Nitta, H.; Maeda, K. (1995) Respiratory health associated with exposure to automobile
exhaust II. Personal NO2 exposure levels according to distance from the roadside. J.
Exposure Anal. Environ. Epidemiol. 5: 125-136.
Nakajima, T.; Kusumoto, S. (1968) [Effect of nitrogen dioxide exposure on the contents of
reduced glutathione in mouse lung], Osaka-Furitsu Koshu Eisei Kenkyusho Kenkyu
Hokoku Rodo Eisei Hen 6: 17-21.
Nakajima, T.; Oda, H.; Kusumoto, S.; Nogami, H. (1980) Biological effects of nitrogen dioxide
and nitric oxide. In: Lee, S. D., ed. Nitrogen oxides and their effects on health. Ann
Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 121-141.
National Research Council. (1986) Environmental tobacco smoke: measuring exposures and
assessing health effects. Washington, DC: National Academy Press.
National Research Council. (2004) Research priorities for airborne particulate matter. IV.
Continuing research progress. Washington, DC: National Academies Press. Available:
http://www.nap.edu/catalog.php?record_id=10957 [1 August, 2007],
Nazaroff, W. W.; Cass, G. R. (1986) Mathematical modeling of chemically reactive pollutants in
indoor air. Environ. Sci. Technol. 20: 924-934.
Nazaroff, W. W.; Weschler, C. J. (2004) Cleaning products and air fresheners: exposure to
primary and secondary air pollutants. Atmos. Environ. 38: 2841-2865.
Neas, L. M.; Dockery, D. W.; Ware, J. H.; Spengler, J. D.; Speizer, F. E.; Ferris, B. G., Jr. (1991)
Association of indoor nitrogen dioxide with respiratory symptoms and pulmonary
function in children. Am. J. Epidemiol. 134: 204-219.
Nerriere, E.; Zmirou-Navier, D.; Blanchard, O.; Momas, I.; Ladner, J.; Le Moullec, Y.;
Personnaz, M.-B.; Lameloise, P.; Delmas, V.; Target, A.; Desqueyroux, H. (2005) Can
August 2007
6-36
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
we use fixed ambient air monitors to estimate population long-term exposure to air
pollutants? The case of spatial variability in the Genotox ER study. Environ. Res. 97: 32-
42.
Ng, T. P.; Seet, C. S. R.; Tan, W. C.; Foo, S. C. (2001) Nitrogen dioxide exposure from domestic
gas cooking and airway response in asthmatic women. Thorax 56: 596-601.
Nguyen, T.; Brunson, D.; Crespi, C. L.; Penman, B. W.; Wishnok, J. S.; Tannenbaum, S. R.
(1992) DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc.
Natl. Acad. Sci. 89: 3030-3034.
Nicolai, T.; Carr, D.; Weiland, S. K.; Duhme, H.; Von Ehrenstein, O.; Wagner, C.; Von Mutius,
E. (2003) Urban traffic and pollutant exposure related to respiratory outcomes and atopy
in a large sample of children. Eur. Respir. J. 21: 956-963.
Nieding, G. von; Wagner, H. M. (1977) Experimental studies on the short-term effect of air
pollutants on pulmonary function in man: two-hour exposure to NO2, O3 and SO2 alone
and in combination. In: Kasuga, S.; Suzuki, N.; Yamada, T.; Kimura, G.; Inagaki, K.;
Onoe, K., eds. Proceedings of the fourth international clean air congress; May; Tokyo,
Japan. Tokyo, Japan: Japanese Union of Air Pollution Prevention Associations; pp. 5-8.
Nieding, G. von; Wagner, H. M.; Krekeler, H.; Loellgen, H.; Fries, W.; Beuthan, A. (1979)
Controlled studies of human exposure to single and combined action of N02, 03, and
SO2. Int. Arch. Occup. Environ. Health 43: 195-210.
Nieding, G. von; Wagner, H. M.; Casper, H.; Beuthan, A.; Smidt, U. (1980) Effect of
experimental and occupational exposure to NO2 in sensitive and normal subjects. In: Lee,
S. D., ed. Nitrogen oxides and their effects on health. Ann Arbor, MI: Ann Arbor Science
Publishers, Inc.; pp. 315-331.
Nitschke, M.; Pilotto, L. S.; Attewell, R. G.; Smith, B. J.; Pisaniello, D.; Martin, J.; Ruffin, R. E.;
Hiller, J. E. (2006) A cohort study of indoor nitrogen dioxide and house dust mite
exposure in asthmatic children. J. Occup. Environ. Med. 48: 462-469.
Nunnermacker, L. J.; Imre, D.; Daum, P. H.; Kleinman, L.; Lee, Y.-N.; Lee, J. H.; Springston,
S. R.; Newman, L.; Weinstein-Lloyd, J.; Luke, W. T.; Banta, R.; Alvarez, R.; Senff, C.;
Sillman, S.; Holdren, M.; Keigley, G. W.; Zhou, X. (1998) Characterization of the
Nashville urban plume on July 3 and July 18, 1995. J. Geophys. Res. [Atmos.] 103:
28,129-28,148.
Nyberg, F.; Gustavsson, P.; Jarup, L.; Bellander, T.; Berglind, N.; Jakobsson, R.; Pershagen, G.
(2000) Urban air pollution and lung cancer in Stockholm. Epidemiology 11: 487-495.
Oda, H.; Kusumoto, S.; Nakajima, T. (1975) Nitrosyl-hemoglobin formation in the blood of
animals exposed to nitric oxide. Arch. Environ. Health 30: 453-456.
Oda, H.; Nogami, H.; Kusumoto, S.; Nakajima, T.; Kurata, A.; Imai, K. (1976) [Long-term
exposure to nitric oxide in mice], Taiki Osen Kenkyu 11: 150-160.
Oda, H.; Nogami, H.; Nakajima, T. (1979) Alteration of hemoglobin reacted with nitrogen
oxides in vitro. J. Toxicol. Sci. 4: 299-300.
Oda, H.; Nogami, H.; Kusumoto, S.; Nakajima, T.; Kurata, A. (1980a) Lifetime exposure to 2.4
ppm nitric oxide in mice. Environ. Res. 22: 254-263.
August 2007
6-37
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Oda, H.; Nogami, H.; Nakajima, T. (1980b) Reaction of hemoglobin with nitric oxide and
nitrogen dioxide in mice. J. Toxicol. Environ. Health 6: 673-678.
Oftedal, B.; Nafstad, P.; Magnus, P.; Bj0rkly, S.; Skrondal, A. (2003) Traffic related air pollution
and acute hospital admission for respiratory diseases in Drammen, Norway 1995-2000.
Eur. J. Epidemiol. 18: 671-675.
Ogawa & Company. (2007) Ambient air passive sampler for NO-NO2, NOx, SO2, O3, NH3.
Pompano Beach, FL. Available: http://www.ogawausa.com/passive.html [18 July, 2007],
Ogston, S. A.; Du Ve Florey, C.; Walker, C. H. M. (1985) The Tayside infant morbidity and
mortality study: effect on health of using gas for cooking. Br. Med. J. 290: 957-960.
Ohashi, Y.; Nakai, Y.; Sugiura, Y.; Ohno, Y.; Okamoto, H.; Tanaka, A.; Kakinoki, Y.; Hayashi,
M. (1994) Nitrogen dioxide-induced eosinophilia and mucosal injury in the nose of the
guinea pig. Acta Oto Laryngol. 114: 547-551.
Ohyama, K.; Ito, T.; Kanisawa, M. (1999) The roles of diesel exhaust particle extracts and the
promotive effects of N02 and/or S02 exposure on rat lung tumorigenesis. Cancer Lett.
139: 189-197.
Ostro, B.; Lipsett, M.; Mann, J.; Braxton-Owens, H.; White, M. (2001) Air pollution and
exacerbation of asthma in African-American children in Los Angeles. Epidemiology 12:
200-208.
Ott, W.; Wallace, L.; Mage, D. (2000) Predicting particulate (PM10) personal exposure
distributions using a random component superposition statistical model. J. Air Waste
Manage. Assoc. 50: 1390-1406.
Overton, J. H., Jr. (1984) Physicochemical processes and the formulation of dosimetry models.
In: Miller, F. J.; Menzel, D. B., eds. Fundamentals of extrapolation modeling of inhaled
toxicants: ozone and nitrogen dioxide. Washington, DC: Hemisphere Publishing
Corporation; pp. 93-114.
Overton, J. H.; Graham, R. C. (1995) Simulation of the uptake of a reactive gas in a rat
respiratory tract model with an asymmetric tracheobronchial region patterned on
complete conducting airway cast data. Comput. Biomed. Res. 28: 171-190.
Overton, J. H.; Graham, R. C.; Menache, M. G.; Mercer, R. R.; Miller, F. J. (1996) Influence of
tracheobronchial region expansion and volume on reactive gas uptake and interspecies
dose extrapolations. Inhalation Toxicol. 8: 723-745.
Pagani, P.; Romano, M.; Erroi, A.; Ferro, M.; Salmona, M. (1994) Biochemical effects of acute
and subacute nitrogen dioxide exposure in rat lung and bronchoalveolar lavage fluid.
Arch. Environ. Contam. Toxicol. 27: 426-430.
Palmes, E. D.; Gunnison, A. F.; DiMattio, J.; Tomczyk, C. (1976) Personal sampler for nitrogen
dioxide. Am. Ind. Hyg. Assoc. J. 37: 570-577.
Pantazopoulou, A.; Katsouyanni, K.; Kourea-Kremastinou, J.; Trichopoulos, D. (1995) Short-
term effects of air pollution on hospital emergency outpatient visits and admissions in the
greater Athens, Greece area. Environ. Res. 69: 31-36.
August 2007
6-38
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Park, J.-H.; Spengler, J. D.; Yoon, D.-W.; Dumyahn, T.; Lee, K.; Ozkaynak, H. (1998)
Measurement of air exchange rate of stationary vehicles and estimation of in-vehicle
exposure. J. Exposure Anal. Environ. Epidemiol. 8: 65-78.
Park, H.; Lee, B.; Ha, E.-H.; Lee, J.-T.; Kim, H.; Hong, Y.-C. (2002) Association of air pollution
with school absenteeism due to illness. Arch. Pediatr. Adolesc. Med. 156: 1235-1239.
Park, J. W.; Lim, Y. H.; Kyung, S. Y.; An, C. H.; Lee, S. P.; Jeong, S. H.; Ju, S.-Y. (2005a)
Effects of ambient particulate matter on peak expiratory flow rates and respiratory
symptoms of asthmatics during Asian dust periods in Korea. Respirology 10: 470-476.
Park, S. K.; O'Neill, M. S.; Vokonas, P. S.; Sparrow, D.; Schwartz, J. (2005b) Effects of air
pollution on heart rate variability: the VA normative aging study. Environ. Health
Perspect. 113: 304-309.
Parrish, D. D.; Fehsenfeld, F. C. (2000) Methods for gas-phase measurements of ozone, ozone
precursors and aerosol precursors. Atmos. Environ. 34: 1921-1957.
Pathmanathan, S.; Krishna, M. T.; Blomberg, A.; Helleday, R.; Kelly, F. J.; Sandstrom, T.;
Holgate, S. T.; Wilson, S. J.; Frew, A. J. (2003) Repeated daily exposure to 2 ppm
nitrogen dioxide upregulates the expression of IL-5, IL-10, IL-13, and ICAM-1 in the
bronchial epithelium of healthy human airways. Occup. Environ. Med. 60: 892-896.
Pattemore, P. K.; Asher, M. I.; Harrison, A. C.; Mitchell, E. A.; Rea, H. H.; Stewart, A. W.
(1990) The interrelationship among bronchial hyperresponsiveness, the diagnosis of
asthma, and asthma symptoms. Am. Rev. Respir. Dis. 142: 549-554.
Peacock, J. L.; Symonds, P.; Jackson, P.; Bremner, S. A.; Scarlett, J. F.; Strachan, D. P.;
Anderson, H. R. (2003) Acute effects of winter air pollution on respiratory function in
schoolchildren in southern England. Occup. Environ. Med. 60: 82-89.
Peel, J. L.; Tolbert, P. E.; Klein, M.; Metzger, K. B.; Flanders, W. D.; Knox, T.; Mulholland, J.
A.; Ryan, P. B.; Frumkin, H. (2005) Ambient air pollution and respiratory emergency
department visits. Epidemiology 16: 164-174.
Peel, J. L.; Metzger, K. B.; Klein, M.; Flanders, W. D.; Mulholland, J. A.; Tolbert, P. E. (2006)
Ambient air pollution and cardiovascular emergency department visits in potentially
sensitive groups. Am. J. Epidemiol. 165: 625-633.
Pekkanen, J.; Brunner, E. J.; Anderson, H. R.; Tiittanen, P.; Atkinson, R. W. (2000) Daily
concentrations of air pollution and plasma fibrinogen in London. Occup. Environ. Med.
57: 818-822.
Pekkanen, J.; Peters, A.; Hoek, G.; Tiittanen, P.; Brunekreef, B.; de Hartog, J.; Heinrich, J.;
Ibald-Mulli, A.; Kreyling, W. G.; Lanki, T.; Timonen, K. L.; Vanninen, E. (2002)
Particulate air pollution and risk of ST-segment depression during repeated submaximal
exercise tests among subjects with coronary heart disease: the exposure and risk
assessment for fine and ultrafine particles in ambient air (ULTRA) study. Circulation
106: 933-938.
Peng. R. D.; Dominici, F.; Louis, T. A. (2006) Model choice in time series studies of air
pollution and mortality. J. R. Stat. Soc. Ser. A 169: 179-203.
August 2007
6-39
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Pereira, L. A. A.; Loomis, D.; Conceifjao, G. M. S.; Braga, A. L. F.; Areas, R. M.; Kishi, H. S.;
Singer, J. M.; Bohm, G. M.; Saldiva, P. H. N. (1998) Association between air pollution
and intrauterine mortality in Sao Paulo, Brazil. Environ. Health Perspect. 106: 325-329.
Peters, J. M.; Avol, E.; Navidi, W.; London, S. J.; Gauderman, W. J.; Lurmann, F.; Linn, W. S.;
Margolis, H.; Rappaport, E.; Gong, H., Jr.; Thomas, D. C. (1999) A study of twelve
southern California communities with differing levels and types of air pollution. I.
Prevalence of respiratory morbidity. Am. J. Respir. Crit. Care Med. 159: 760-767.
Peters, A.; Liu, E.; Verrier, R. L.; Schwartz, J.; Gold, D. R.; Mittleman, M.; Baliff, J.; Oh, J. A.;
Allen, G.; Monahan, K.; Dockery, D. W. (2000) Air pollution and incidence of cardiac
arrhythmia. Epidemiology 11: 11-17.
Peters, A.; Von Klot, S.; Heier, M.; Trentinaglia, I.; Hormann, A.; Wichmann, H. E.; Lowel, H.
(2004) Exposure to traffic and the onset of myocardial infarction. N. Engl. J. Med. 351:
1721-1730.
Pilotto, L. S.; Douglas, R. M.; Attewell, R. G.; Wilson, S. R. (1997a) Respiratory effects
associated with indoor nitrogen dioxide exposure in children. Int. J. Epidemiol. 26: 788-
796.
Pilotto, L. S.; Douglas, R. M.; Samet, J. M. (1997b) Nitrogen dioxide, gas heating and
respiratory illness. Med. J. Aust. 167: 295-296.
Pilotto, L. S.; Nitschke, M.; Smith, B. J.; Pisaniello, D.; Ruffin, R. E.; McElroy, H. J.; Martin, J.;
Hiller, J. E. (2004) Randomized controlled trial of unflued gas heater replacement on
respiratory health of asthmatic schoolchildren. Int. J. Epidemiol. 33: 208-214.
Pino, P.; Walter, T.; Oyarzun, M.; Villegas, R.; Romieu, I. (2004) Fine particulate matter and
wheezing illnesses in the first year of life. Epidemiology 15: 702-708.
Pinto, J. P.; Lefohn, A. S.; Shadwick, D. S. (2004) Spatial variability of PM2.5 in urban areas in
the United States. J. Air Waste Manage. Assoc. 54: 440-449.
Plaisance, H.; Piechocki-Minguy, A.; Garcia-Fouque, S.; Galloo, J. C. (2004) Influences of
meteorological factors on the NO2 measurements by passive diffusion tube. Atmos.
Environ. 38: 573-580.
Plunkett, L. M.; Turnbull, D.; Rodricks, J. V. (1992) Differences between adults and children
affecting exposure assessment. In: Guzelian, P. S.; Henry, D. J.; Olin, S. S., eds.
Similarities and differences between children and adults: implications for risk
assessment. Washington, DC: ILSI Press, pp. 79-96.
Poloniecki, J. D.; Atkinson, R. W.; Ponce de Leon, A.; Anderson, H. R. (1997) Daily time series
for cardiovascular hospital admissions and previous day's air pollution in London, UK.
Occup. Environ. Med. 54: 535-540.
Ponce de Leon, A.; Anderson, H. R.; Bland, J. M.; Strachan, D. P.; Bower, J. (1996) Effects of
air pollution on daily hospital admissions for respiratory disease in London between
1987-88 and 1991-92. In: St Leger, S., ed. The APHEA project. Short term effects of air
pollution on health: a European approach using epidemiological time series data. J.
Epidemiol. Community Health 50(suppl. 1): S63-S70.
August 2007
6-40
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Ponka, A.; Virtanen, M. (1994) Chronic bronchitis, emphysema, and low-level air pollution in
Helsinki, 1987-1989. Environ. Res. 65: 207-217.
Ponka, A.; Virtanen, M. (1996) Asthma and ambient air pollution in Helsinki. In: St Leger, S.,
ed. The APHEA project. Short term effects of air pollution on health: a European
approach using epidemiological time series data. J. Epidemiol. Community Health
50(suppl. 1): S59-S62.
Ponsonby, A.-L.; Glasgow, N.; Gatenby, P.; Mullins, R.; McDonald, T.; Hurwitz, M.; Pradith,
B.; Attewell, R. (2001) The relationship between low level nitrogen dioxide exposure and
child lung function after cold air challenge. Clin. Exp. Allergy 31: 1205-1212.
Pope, C. A., Ill; Thun, M. J.; Namboodiri, M. M.; Dockery, D. W.; Evans, J. S.; Speizer, F. E.;
Heath, C. W., Jr. (1995) Particulate air pollution as a predictor of mortality in a
prospective study of U.S. adults. Am. J. Respir. Crit. Care Med. 151: 669-674.
Pope, C. A., Ill; Burnett, R. T.; Thun, M. J.; Calle, E. E.; Krewski, D.; Ito, K.; Thurston, G. D.
(2002) Lung cancer, cardiopulmonary mortality, and long-term exposure to fine
particulate air pollution. JAMA J. Am. Med. Assoc. 287: 1132-1141.
Port, C. D.; Ketels, K. V.; Coffin, D. L.; Kane, P. (1977) A comparative study of experimental
and spontaneous emphysema. J. Toxicol. Environ. Health 2: 589-604.
Posin, C.; Clark, K.; Jones, M. P.; Patterson, J. V.; Buckley, R. D.; Hackney, J. D. (1978)
Nitrogen dioxide inhalation and human blood biochemistry. Arch. Environ. Health 33:
318-324.
Postlethwait, E. M.; Bidani, A. (1989) Pulmonary disposition of inhaled MVnitrogen in isolated
rat lungs. Toxicol. Appl. Pharmacol. 98: 303-312.
Postlethwait, E. M.; Bidani, A. (1990) Reactive uptake governs the pulmonary air space removal
of inhaled nitrogen dioxide. J. Appl. Physiol. 68: 594-603.
Postlethwait, E. M.; Bidani, A. (1994) Mechanisms of pulmonary NO2 absorption. Toxicology
89: 217-237.
Postlethwait, E. M.; Mustafa, M. G. (1981) Fate of inhaled nitrogen dioxide in isolated perfused
rat lung. J. Toxicol. Environ. Health 7: 861-872.
Postlethwait, E. M.; Mustafa, M. G. (1989) Effect of altered dose rate on NO2 uptake and
transformation in isolated lungs. J. Toxicol. Environ. Health 26: 497-507.
Postlethwait, E. M.; Langford, S. D.; Bidani, A. (1991) Transfer of NO2 through pulmonary
epithelial lining fluid. Toxicol. Appl. Pharmacol. 109: 464-471.
Postlethwait, E. M.; Langford, S. D.; Bidani, A. (1992) Kinetics of NO2 air space absorption in
isolated rat lungs. J. Appl. Physiol. 73: 1939-1945.
Postlethwait, E. M.; Langford, S. D.; Jacobson, L. M.; Bidani, A. (1995) NO2 reactive absorption
substrates in rat pulmonary surface lining fluids. Free Radical Biol. Med. 19: 553-563.
Poynter, M. E.; Persinger, R. L.; Irvin, C. G.; Butnor, K. J.; Van Hirtum, H.; Blay, W.; Heintz,
N. H.; Robbins, J.; Hemenway, D.; Taatjes, D. J.; Janssen-Heininger, Y. (2006) Nitrogen
dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse.
Am. J. Physiol. 290: L144-L152.
August 2007
6-41
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Prescott, G. J.; Cohen, G. R.; Elton, R. A.; Fowkes, F. G. R.; Agius, R. M. (1998) Urban air
pollution and cardiopulmonary ill health: a 14.5 year time series study. Occup. Environ.
Med. 55: 697-704.
Proust, B.; Lacroix, G.; Robidel, F.; Marliere, M.; Lecomte, A.; Vargaftig, B. B. (2002)
Interference of a short-term exposure to nitrogen dioxide with allergic airways responses
to allergenic challenges inBALB/c mice. Mediators Inflammation 11: 251-260.
Raaschou-Nielsen, O.; Skov, H.; Lohse, C.; Thomsen, B. L.; Olsen, J. H. (1997) Front-door
concentrations and personal exposures of Danish children to nitrogen dioxide. Environ.
Health Perspect. 105: 964-970.
Rajini, P.; Gelzleichter, T. R.; Last, J. A.; Witschi, H. (1993) Alveolar and airway cell kinetics in
the lungs of rats exposed to nitrogen dioxide, ozone, and a combination of the two gases.
Toxicol. Appl. Pharmacol. 121: 186-192.
Ramirez-Aguilar, M.; Cicero-Fernandez, P.; Winer, A. M.; Romieu, I.; Meneses-Gonzales, F.;
Hernandez-Avila, M. (2002) Measurements of personal exposure to nitrogen dioxide in
four Mexican cities in 1996. J. Air Waste Manage. Assoc. 52: 50-57.
Ramsay, T. O.; Burnett, R. T.; Krewski, D. (2003) The effect of concurvity in generalized
additive models linking mortality to ambient particulate matter. Epidemiology 14: 18-23.
Ranzi, A.; Gambini, M.; Spattini, A.; Galassi, C.; Sesti, D.; Bedeschi, M.; Messori, A.; Baroni,
A.; Cavagni, G.; Lauriola, P. (2004) Air pollution and respiratory status in asthmatic
children: hints for a locally based preventive strategy. AIRE study. Eur. J. Epidemiol. 19:
567-576.
Rasmussen, T. R.; Kjsergaard, S. K.; Tarp, U.; Pedersen, O. F. (1992) Delayed effects of N02
exposure on alveolar permeability and glutathione peroxidase in healthy humans. Am.
Rev. Respir. Dis. 146: 654-659.
Rasmussen, T. R.; Brauer, M.; Kjsergaard, S. (1995) Effects of nitrous acid exposure on human
mucous membranes. Am. J. Respir. Crit. Care Med. 151: 1504-1511.
Raw, G. J.; Coward, S. K. D.; Brown, V. M.; Crump, D. R. (2004) Exposure to air pollutants in
English homes. J. Exposure Anal. Environ. Epidemiol. 14(suppl. 1): S85-S94.
Rehn, T.; Svartengren, M.; Philipson, K.; Camner, P. (1982) Mukociliaer transport i lunga och
naesa samt luftvaegsmotstand efter exponering foer kvaevedioxid [Mucociliary transport
in the lung and nose after exposure to nitrogen dioxide], Vallingby, Sweden: Swedish
State Power Board; project KHM technical report no. 40.
Restrepo, C.; Zimmerman, R.; Thurston, G.; Clemente, J.; Gorczynski, J.; Zhong, M.; Blaustein,
M.; Chen, L. C. (2004) A comparison of ground-level air quality data with New York
State Department of Environmental Conservation monitoring stations data in South
Bronx, New York. Atmos. Environ. 38: 5295-5304.
Rich, D. Q.; Schwartz, J.; Mittleman, M. A.; Link, M.; Luttmann-Gibson, H.; Catalano, P. J.;
Speizer, F. E.; Dockery, D. W. (2005) Association of short-term ambient air pollution
concentrations and ventricular arrhythmias. Am. J. Epidemiol. 161: 1123-1132.
Rich, D. Q.; Kim, M. H.; Turner, J. R.; Mittleman, M. A.; Schwartz, J.; Catalano, P. J.; Dockery,
D. W. (2006a) Association of ventricular arrhythmias detected by implantable
August 2007
6-42
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
cardioverter defibrillator and ambient air pollutants in the St Louis, Missouri
metropolitan area. Occup. Environ. Med. 63: 591-596.
Rich, D. Q.; Mittleman, M. A.; Link, M. S.; Schwartz, J.; Luttmann-Gibson, H.; Catalano, P. J.;
Speizer, F. E.; Gold, D. R.; Dockery, D. W. (2006b) Increased risk of paroxysmal atrial
fibrillation episodes associated with acute increases in ambient air pollution. Environ.
Health Perspect. 114: 120-123.
Richters, A.; Damji, K. S. (1988) Changes in T-lymphocyte subpopulations and natural killer
cells following exposure to ambient levels of nitrogen dioxide. J. Toxicol. Environ.
Health 25: 247-256.
Richters, A.; Damji, K. S. (1990) The relationship between inhalation of nitrogen dioxide, the
immune system, and progression of a spontaneously occurring lymphoma in AKR mice.
J. Environ. Pathol. Toxicol. Oncol. 10: 225-230.
Richters, A.; Kuraitis, K. (1981) Inhalation of NO2 and blood borne cancer cell spread to the
lungs. Arch. Environ. Health 36: 36-39.
Richters, A.; Kuraitis, K. (1983) Air pollutants and the facilitation of cancer metastasis. Environ.
Health Perspect. 52: 165-168.
Richters, A.; Richters, V. (1983) A new relationship between air pollutant inhalation and cancer.
Arch. Environ. Health 38: 69-75.
Richters, A.; Richters, V.; Alley, W. P. (1985) The mortality rate from lung metastases in
animals inhaling nitrogen dioxide (N02). J. Surg. Oncol. 28: 63-66.
Riediker, M.; Williams, R.; Devlin, R.; Griggs, T.; Bromberg, P. (2003) Exposure to particulate
matter, volatile organic compounds, and other air pollutants inside patrol cars. Environ.
Sci. Technol. 37: 2084-2093.
Riesenfeld, E.; Chalupa, D.; Gibb, F. R.; Oberdorster, G.; Gelein, R.; Morrow, P. E.; Utell, M. J.;
Frampton, M. W. (2000) Ultrafine particle concentrations in a hospital. In: Phalen, R. F.,
ed. Inhalation toxicology: proceedings of the third colloquium on particulate air pollution
and human health (second special issue); June, 1999; Durham, NC. Inhalation Toxicol.
12(suppl. 2): 83-94.
Rigas, M. L.; Ben-Jebria, A.; Ultman, J. S. (1997) Longitudinal distribution of ozone absorption
in the lung: effects of nitrogen dioxide, sulfur dioxide, and ozone exposures. Arch.
Environ. Health 52: 173-178.
Ristovski, Z. D.; Tass, I.; Morawska, L.; Saxby, W. (2000) Investigation into the emission of fine
particles, formaldehyde, oxides of nitrogen and carbon monoxide from natural gas
heaters. J. Aerosol. Sci. 31(suppl. 1): S490-S491.
Ritz, B.; Yu, F.; Chapa, G.; Fruin, S. (2000) Effect of air pollution on preterm birth among
children born in Southern California between 1989 and 1993. Epidemiology 11: 502-511.
Roberts, S. (2004) Biologically plausible particulate air pollution mortality concentration-
response functions. Environ. Health Perspect. 112: 309-313.
August 2007
6-43
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Roberts, S. (2006) A new model for investigating the mortality effects of multiple air pollutants
in air pollution mortality time-series studies. J. Toxicol. Environ. Health Part A 69: 417-
435.
Robison, T. W.; Murphy, J. K.; Beyer, L. L.; Richters, A.; Forman, H. J. (1993) Depression of
stimulated arachidonate metabolism and superoxide production in rat alveolar
macrophages following in vivo exposure to 0.5 ppm N02. J. Toxicol. Environ. Health 38:
273-292.
Rodgers, M. O.; Davis, D. D. (1989) A UV-photofragmentation/laser-induced fluorescence
sensor for the atmospheric detection ofHONO. Environ. Sci. Technol. 23: 1106-1112.
Roemer, W.; Hoek, G.; Brunekreef, B.; Haluszka, J.; Kalandidi, A.; Pekkanen, J. (1998) Daily
variations in air pollution and respiratory health in a multicentre study: the PEACE
project. Eur. Respir. J. 12: 1354-1361.
Roemer, W.; Clench-Aas, J.; Englert, N.; Hoek, G.; Katsouyanni, K.; Pekkanen, J.; Brunekreef,
B. (1999) Inhomogeneity in response to air pollution in European children (PEACE
project). Occup. Environ. Med. 56: 86-92.
Roger, L. J.; Horstman, D. H.; McDonnell, W.; Kehrl, H.; Ives, P. J.; Seal, E.; Chapman, R.;
Massaro, E. (1990) Pulmonary function, airway responsiveness, and respiratory
symptoms in asthmatics following exercise in N02. Toxicol. Ind. Health 6: 155-171.
Rogge, W. F.; Hildemann, L. M.; Mazurek, M. A.; Cass, G. R.; Simoneit, B. R. T. (1993)
Sources of fine organic aerosol. 5. Natural gas home appliances. Environ. Sci. Technol.
27: 2736-2744.
Rojas-Bracho, L.; Suh, H. H.; Oyola, P.; Koutrakis, P. (2002) Measurements of children's
exposures to particles and nitrogen dioxide in Santiago, Chile. Sci. Total Environ. 287:
249-264.
Rombout, P. J. A.; Dormans, J. A. M. A.; Marra, M.; Van Esch, G. J. (1986) Influence of
exposure regimen on nitrogen dioxide-induced morphological changes in the rat lung.
Environ. Res. 41: 466-480.
Romieu, I.; Sienra-Monge, J. J.; Ramirez-Aguilar, M.; Moreno-Macias, H.; Reyes-Ruiz, N. I.;
Estela del Rio-Navarro, B.; Hernandez-Avila, M.; London, S. J. (2004) Genetic
polymorphism of GSTM1 and antioxidant supplementation influence lung function in
relation to ozone exposure in asthmatic children in Mexico City. Thorax 59: 8-10.
Romieu, I.; Ramirez-Aguilar, M.; Sienra-Monge, J. J.; Moreno-Macias, H.; Del Rio-Navarro, B.
E.; David, G.; Marzec, J.; Hernandez-Avila, M.; London, S. (2006) GSTM1 and GSTP1
and respiratory health in asthmatic children exposed to ozone. Eur. Respir. J. 28: 953-
959.
Rondeau, V.; Berhane, K.; Thomas, D. C. (2005) A three-level model for binary time-series data:
the effects of air pollution on school absences in the southern California Children's
Health Study. Stat. Med. 24: 1103-1115.
Roorda-Knape, M. C.; Janssen, N. A. H.; De Hartog, J. J.; Van Vliet, P. H. N.; Harssema, H.;
Brunekreef, B. (1998) Air pollution from traffic in city districts near major motorways.
Atmos. Environ. 32: 1921-1930.
August 2007
6-44
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Rose, R. M.; Pinkston, P.; Skornik, W. A. (1989) Altered susceptibility to viral respiratory
infection during short-term exposure to nitrogen dioxide. Cambridge, MA: Health Effects
Institute; research report no. 24. Available from: NTIS, Springfield, VA; PB90-111139.
Rotko, T.; Kousa, A.; Aim, S.; Jantunen, M. (2001) Exposures to nitrogen dioxide in EXPOLIS-
Helsinki: microenvironment, behavioral and sociodemographic factors. J. Exposure Anal.
Environ. Epidemiol. 11: 216-223.
Roy-Burman, P.; Pattengale, P. K.; Sherwin, R. P. (1982) Effect of low levels of nitrogen
dioxide inhalation on endogenous retrovirus gene expression. Exp. Mol. Pathol. 36: 144-
155.
Rubenchik, B. L.; Glavin, A. A.; Galenko, P. M.; Kilkichko, A. A.; Olenick, I. O.; Artemov, K.
V. (1995) Gaseous nitrogen dioxide increases the endogenous synthesis of carcinogenic
iV-nitrosodimethylamine in animals. J. Environ. Pathol. Toxicol. Oncol. 14: 111-115.
Rubenstein, I.; Bigby, B. G.; Reiss, T. F.; Boushey, H. A., Jr. (1990) Short-term exposure to 0.3
ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in
asthmatic subjects. Am. Rev. Respir. Dis. 141: 381-385.
Rubenstein, I.; Reiss, T. F.; Bigby, B. G.; Stites, D. P.; Boushey, H. A., Jr. (1991) Effects of 0.60
PPM nitrogen dioxide on circulating and bronchoalveolar lavage lymphocyte phenotypes
in healthy subjects. Environ. Res. 55: 18-30.
Rudell, B.; Blomberg, A.; Helleday, R.; Ledin, M.-C.; Lundback, B.; Stjernberg, N.; Horstedt,
P.; Sandstrom, T. (1999) Bronchoalveolar inflammation after exposure to diesel exhaust:
comparison between unfiltered and particle trap filtered exhaust. Occup. Environ. Med.
56: 527-534.
Ruidavets, J.-B.; Cassadou, S.; Cournot, M.; Bataille, V.; Meybeck, M.; Ferrieres, J. (2005)
Increased resting heart rate with pollutants in a population based study. J. Epidemiol.
Community Health 59: 685-693.
Rusznak, C.; Devalia, J. L.; Davies, R. J. (1996) Airway response of asthmatic subjects to
inhaled allergen after exposure to pollutants. Thorax 51: 1105-1108.
Sabin, L. D.; Kozawa, K.; Behrentz, E.; Winer, A. M.; Fitz, D. R.; Pankratz, D. V.; Colome, S.
D.; Fruin, S. A. (2005) Analysis of real-time variables affecting children's exposure to
diesel-related pollutants during school bus commutes in Los Angeles. Atmos. Environ.
39: 5243-5254.
Saez, M.; Tobias, A.; Munoz, P.; Campbell, M. J. (1999) A GEE moving average analysis of the
relationship between air pollution and mortality for asthma in Barcelona, Spain. Stat.
Med. 18: 2077-2086.
Saez, M.; Ballester, F.; Barcelo, M. A.; Perez-Hoyos, S.; Bellido, J.; Tenias, J. M.; Ocana, R.;
Figueiras, A.; Arribas, F.; Aragones, N.; Tobias, A.; Cirera, L.; Canada, A.; on behalf of
the EMECAM Group. (2002) A combined analysis of the short-term effects of
photochemical air pollutants on mortality within the EMECAM project. Environ. Health
Perspect. 110: 221-228.
Sagai, M.; Ichinose, T.; Kubota, K. (1984) Studies on the biochemical effects of nitrogen
dioxide. IV. Relation between the change of lipid peroxidation and the antioxidative
August 2007
6-45
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
protective system in rat lungs upon life span exposure to low levels of NO2. Toxicol.
Appl. Pharmacol. 73: 444-456.
Sagai, M.; Arakawa, K.; Ichinose, T.; Shimojo, N. (1987) Biochemical effects on combined
gases of nitrogen dioxide and ozone. I. Species differences of lipid peroxides and
phospholipids in lungs. Toxicology 46: 251-265.
Salam, M. T.; Millstein, J.; Li, Y.-F.; Lurmann, F. W.; Margolis, H. G.; Gilliland, F. D. (2005)
Birth outcomes and prenatal exposure to ozone, carbon monoxide, and particulate matter:
results from the Children's Health Study. Environ. Health Perspect. 113: 1638-1644.
Samet, J. M.; Bell, M. L. (2004) Commentary: nitrogen dioxide and asthma redux. Int. J.
Epidemiol. 33: 215-216.
Samet, J. M.; Utell, M. J. (1990) The risk of nitrogen dioxide: what have we learned from
epidemiological and clinical studies? Toxicol. Ind. Health 6: 247-262.
Samet, J. M.; Lambert, W. E.; Skipper, B. J.; Cushing, A. H.; McLaren, L. C.; Schwab, M.;
Spengler, J. D. (1992) A study of respiratory illnesses in infants and nitrogen dioxide
exposure. Arch. Environ. Health 47: 57-63.
Samet, J. M.; Lambert, W. E.; Skipper, B. J.; Cushing, A. H.; Hunt, W. C.; Young, S. A.;
McLaren, L. C.; Schwab, M.; Spengler, J. D. (1993) Health outcomes. In: Nitrogen
dioxide and respiratory illness in children, part I. Cambridge, MA: Health Effects
Institute; pp. 1-32; Research Report no. 58.
Samet, J. M.; Lambert, W. E.; Skipper, B. J.; Cushing, A. H.; Hunt, W. C.; Young, S. A.;
McLaren, L. C.; Schwab, M.; Spengler, J. D. (1993) Nitrogen dioxide and respiratory
illnesses in infants. Am. Rev. Respir. Dis. 148: 1258-1265.
Samet, J. M.; Zeger, S. L.; Dominici, F.; Curriero, F.; Coursac, I.; Dockery, D. W.; Schwartz, J.;
Zanobetti, A. (2000) The national morbidity, mortality, and air pollution study. Part II:
morbidity, mortality, and air pollution in the United States. Cambridge, MA: Health
Effects Institute; research report no. 94, part II.
Samoli, E.; Analitis, A.; Touloumi, G.; Schwartz, J.; Anderson, H. R.; Sunyer, J.; Bisanti, L.;
Zmirou, D.; Vonk, J. M.; Pekkanen, J.; Goodman, P.; Paldy, A.; Schindler, C.;
Katsouyanni, K. (2005) Estimating the exposure-response relationships between
particulate matter and mortality within the APHEA multicity project. Environ. Health
Perspect. 113: 88-95.
Samoli, E.; Aga, E.; Touloumi, G.; Nisiotis, K.; Forsberg, B.; Lefranc, A.; Pekkanen, J.;
Wojtyniak, B.; Schindler, C.; Niciu, E.; Brunstein, R.; Dodic Fikfak, M.; Schwartz, J.;
Katsouyanni, K. (2006) Short-term effects of nitrogen dioxide on mortality: an analysis
within the APHEA project. Eur. Respir. J. 27: 1129-1137.
Sandstrom, T.; Andersson, M. C.; Kolmodin-Hedman, B.; Sternberg, N.; Angstrom, T. (1990)
Bronchoalveolar mastocytosis and lymphocytosis after nitrogen dioxide exposure in man:
a time-kinetic study. Eur. Respir. J. 3: 138-143.
Sandstrom, T.; Stjernberg, N.; Eklund, A.; Ledin, M.-C.; Bjermer, L.; Kolmodin-Hedman, B.;
Lindstrom, K.; Rosenhall, L.; Angstrom, T. (1991) Inflammatory cell response in
August 2007
6-46
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-
response study. Eur. Respir. J. 4: 332-339.
Sandstrom, T.; Helleday, R.; Bjermer, L.; Sternberg, N. (1992a) Effects of repeated exposure to
4 ppm nitrogen dioxide on bronchoalveolar lymphocyte subsets and macrophages in
healthy men. Eur. Respir. J. 5: 1092-1096.
Sandstrom, T.; Ledin, M.-C.; Thomasson, L.; Helleday, R.; Stjernberg, N. (1992b) Reductions in
lymphocyte subpopulations after repeated exposure to 1.5 ppm nitrogen dioxide. Br. J.
Ind. Med. 49: 850-854.
Santiago, L. Y.; Hann, M. C.; Ben-Jebria, A.; Ultman, J. S. (2001) Ozone adsorption in the
human nose during unidirectional airflow. J. Appl. Physiol. 91: 725-732.
Sarnat, J. A.; Schwartz, J.; Catalano, P. J.; Suh, H. H. (2001) Gaseous pollutants in particulate
matter epidemiology: confounders or surrogates? Environ. Health Perspect. 109: 1053-
1061.
Sarnat, J. A.; Brown, K. W.; Schwartz, J.; Coull, B. A.; Koutrakis, P. (2005) Ambient gas
concentrations and personal particulate matter exposures: implications for studying the
health effects of particles. Epidemiology 16: 385-395.
Sarnat, S. E.; Suh, H. H.; Coull, B. A.; Schwartz, J.; Stone, P. H.; Gold, D. R. (2006) Ambient
particulate air pollution and cardiac arrhythmia in a panel of older adults in Steubenville,
Ohio. Occup. Environ. Med. 63: 700-706.
Sarwar, G.; Corsi, R.; Allen, D.; Weschler, C. (2002a) Production and levels of selected indoor
radicals: a modeling assessment. In: Proceedings of 9th International Conference on
Indoor Air Quality and Climate, Indoor Air 2002; June-July; Monterey, CA.
Sarwar, G.; Corsi, R.; Kumura, Y.; Allen, D.; Weschler, C. J. (2002b) Hydroxyl radicals in
indoor environments. Atmos. Environ. 36: 3973-3988.
Sasaki, Y.; Endo, R.; Koido, Y. (1980) Direct mutagens in the gaseous component of automobile
exhaust detected with Bacillus subtilis spores. Mutat. Res. 79: 181-184.
Scarlett, J. F.; Abbott, K. J.; Peacock, J. L.; Strachan, D. P.; Anderson, H. R. (1996) Acute
effects of summer air pollution on respiratory function in primary school children in
southern England. Thorax 51: 1109-1114.
Schairer, L. A.; Van't Hof, J.; Hayes, C. G.; Burton, R. M.; de Serres, F. J. (1979) Measurement
of biological activity of ambient air mixtures using a mobile laboratory for in situ
exposures: preliminary results from the Tradescantia plant test system. Environ. Sci. Res.
419-440.
Schildcrout, J. S.; Sheppard, L.; Lumley, T.; Slaughter, J. C.; Koenig, J. Q.; Shapiro, G. G.
(2006) Ambient air pollution and asthma exacerbations in children: an eight-city analysis.
Am. J. Epidemiol. 164: 505-517.
Schindler, C.; Ackermann-Liebrich, U.; Leuenberger, P.; Monn, C.; Rapp, R.; Bolognini, G.;
Bongard, J.-P.; Brandli, O.; Domenighetti, G.; Karrer, W.; Keller, R.; Medici, T. G.;
Perruchoud, A. P.; Schoni, M. H.; Tschopp, J.-M.; Villiger, B.; Zellweger, J.-P.;
SAPALDIA Team. (1998) Associations between lung function and estimated average
exposure to NO2 in eight areas of Switzerland. Epidemiology 9: 405-411.
August 2007
6-47
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Schindler, C.; Kiinzli, N.; Bongard, J.-P.; Leuenberger, P.; Karrer, W.; Rapp, R.; Monn, C.;
Ackermann-Liebrich, U.; Swiss Study on Air Pollution and Lung Diseases in Adults
Investigators. (2001) Short-term variation in air pollution and in average lung function
among never-smokers. Am. J. Respir. Crit. Care Med. 163: 356-361.
Schlesinger, R. B. (1987a) Effects of intermittent inhalation exposures to mixed atmospheres of
N02 and H2S04 on rabbit alveolar macrophages. J. Toxicol. Environ. Health 22: 301-312.
Schlesinger, R. B. (1987b) Intermittent inhalation of nitrogen dioxide: effects on rabbit alveolar
macrophages. J. Toxicol. Environ. Health 21: 127-139.
Schlesinger, R. B. (2000) Properties of ambient PM responsible for human health effects:
coherence between epidemiology and toxicology. In: Phalen, R. F., ed. Inhalation
toxicology: proceedings of the third colloquium on particulate air pollution and human
health (first special issue); June, 1999; Durham, NC. Inhalation Toxicol. 12(suppl. 1): 23-
25.
Schlesinger, R. B.; Gearhart, J. M. (1987) Intermittent exposures to mixed atmospheres of
nitrogen dioxide and sulfuric acid: effect on particle clearance from the respiratory region
of rabbit lungs. Toxicology 44: 309-319.
Schlesinger, R. B.; Driscoll, K. E.; Vollmuth, T. A. (1987) Effect of repeated exposures to
nitrogen dioxide and sulfuric acid mist alone or in combination on mucociliary clearance
from the lungs of rabbits. Environ. Res. 44: 294-301.
Schlesinger, R. B.; Driscoll, K. E.; Gunnison, A. F.; Zelikoff, J. T. (1990) Pulmonary
arachidonic acid metabolism following acute exposures to ozone and nitrogen dioxide. J.
Toxicol. Environ. Health 31: 275-290.
Schlesinger, R. B.; El-Fawal, H. A. N.; Zelikoff, J. T.; Gorczynski, J. E.; McGovern, T.;
Nadziejko, C. E.; Chen, L. C. (1994) Pulmonary effects of repeated episodic exposures to
nitric acid vapor alone and in combination with ozone. Inhalation Toxicol. 6: 21-41.
Schouten, J. P.; Vonk, J. M.; de Graaf, A. (1996) Short term effects of air pollution on
emergency hospital admissions for respiratory disease: results of the APHEA project in
two major cities in The Netherlands, 1977-89. In: St Leger, S., ed. The APHEA project.
Short term effects of air pollution on health: a European approach using epidemiological
time series data. J. Epidemiol. Community Health 50(suppl. 1): S22-S29.
Schwartz, J. (1989) Lung function and chronic exposure to air pollution: a cross-sectional
analysis ofNHANES II. Environ. Res. 50: 309-321.
Schwartz, J. (1997) Air pollution and hospital admissions for cardiovascular disease in Tucson.
Epidemiology 8: 371-377.
Schwartz, J. (2006) Comments on the paper by Peng, Dominici and Louis [(2006) Model choice
in time series studies of air pollution and mortality. J. R. Stat. Soc. Ser. A 169: 179-203],
J. R. Stat. Soc. Ser. A 169: 198-200.
Schwartz, J.; Zeger, S. (1990) Passive smoking, air pollution, and acute respiratory symptoms in
a diary study of student nurses. Am. Rev. Respir. Dis. 141: 62-67.
Schwartz, J.; Spix, C.; Wichmann, H. E.; Malin, E. (1991) Air pollution and acute respiratory
illness in five German communities. Environ. Res. 56: 1-14.
August 2007
6-48
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Schwartz, J.; Dockery, D. W.; Neas, L. M.; Wypij, D.; Ware, J. H.; Spengler, J. D.; Koutrakis,
P.; Speizer, F. E.; Ferris, B. G., Jr. (1994) Acute effects of summer air pollution on
respiratory symptom reporting in children. Am. J. Respir. Crit. Care Med. 150: 1234-
1242.
Schwartz, J.; Litonjua, A.; Suh, H.; Verrier, M.; Zanobetti, A.; Syring, M.; Nearing, B.; Verrier,
R.; Stone, P.; MacCallum, G.; Speizer, F. E.; Gold, D. R. (2005) Traffic related pollution
and heart rate variability in a panel of elderly subjects. Thorax 60: 455-461.
Seaton, A.; Dennekamp, M. (2003) Hypothesis: ill health associated with low concentrations of
nitrogen dioxide—an effect of ultrafine particles? Thorax 58: 1012-1015.
Segala, C.; Fauroux, B.; Just, J.; Pascual, L.; Grimfeld, A.; Neukirch, F. (1998) Short-term effect
of winter air pollution on respiratory health of asthmatic children in Paris. Eur. Respir. J.
11: 677-685.
Segala, C.; Poizeau, D.; Neukirch, F.; Aubier, M.; Samson, J.; Gehanno, P. (2004) Air pollution,
passive smoking, and respiratory symptoms in adults. Arch. Environ. Health 59: 669-676.
Seinfeld, J. H.; Pandis, S. N. (1998) Atmospheric chemistry and physics: from air pollution to
climate change. New York, NY: John Wiley & Sons, Inc.
Sekharam, K. M.; Patel, J. M.; Block, E. R. (1991) Plasma membrane-specific phospholipase-Al
activation by nitrogen dioxide in pulmonary artery endothelial cells. Toxicol. Appl.
Pharmacol. 107: 545-554.
Selgrade, M. K.; Mole, M. L.; Miller, F. J.; Hatch, G. E.; Gardner, D. E.; Hu, P. C. (1981) Effect
of NO2 inhalation and vitamin C deficiency on protein and lipid accumulation in the lung.
Environ. Res. 26: 422-437.
Seto, K.; Kon, M.; Kawakami, M.; Yagishita, S.; Sugita, K.; Shishido, M. (1975) [Influence of
nitrogen dioxide inhalation on the formation of protein in the lung], Igaku to
Seibutsugaku 90: 103-106.
Shalamberidze, O. P.; Tsereteli, N. T. (1971) Effect of low concentrations of sulfur and nitrogen
dioxides on the estrual cycle and reproductive functions of experimental animals. Hyg.
Sanit. (USSR) 36: 178-182.
Sheppard, L. (2005) Acute air pollution effects: consequences of exposure distribution and
measurements. J. Toxicol. Environ. Health Part A 68: 1127-1135.
Sheppard, L.; Slaughter, J. C.; Schildcrout, J.; Liu, L.-J. S.; Lumley, T. (2005) Exposure and
measurement contributions to estimates of acute air pollution effects. J. Exposure Anal.
Environ. Epidemiol. 15: 366-376.
Sherwin, R. P.; Carlson, D. A. (1973) Protein content of lung lavage fluid of guinea pigs exposed
to 0.4 ppm nitrogen dioxide: disc-gel electrophoresis for amount and types. Arch.
Environ. Health 27: 90-93.
Sherwin, R. P.; Dibble, J.; Weiner, J. (1972) Alveolar wall cells of the guinea pig: increase in
response to 2 ppm nitrogen dioxide. Arch. Environ. Health 24: 43-47.
Shima, M.; Adachi, M. (2000) Effect of outdoor and indoor nitrogen dioxide on respiratory
symptoms in schoolchildren. Int. J. Epidemiol. 29: 862-870.
August 2007
6-49
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Shiraishi, F.; Bandow, H. (1985) The genetic effects of the photochemical reaction products of
propylene plus N02 on cultured Chinese hamster cells exposed in vitro. J. Toxicol.
Environ. Health 15: 531-538.
Siegel, P. D.; Al-Humadi, N. Ft.; Nelson, E. R.; Lewis, D. M.; Hubbs, A. F. (1997) Adjuvant
effect of respiratory irritation on pulmonary allergic sensitization: time and site
dependency. Toxicol. Appl. Pharmacol. 144: 356-362.
Silkoff, P. E.; Zhang, L.; Dutton, S.; Langmack, E. L.; Vedal, S.; Murphy, J.; Make, B. (2005)
Winter air pollution and disease parameters in advanced chronic obstructive pulmonary
disease panels residing in Denver, Colorado. J. Allergy Clin. Immunol. 115: 337-344.
Simoni, M.; Carrozzi, L.; Baldacci, S.; Scognamiglio, A.; Di Pede, F.; Sapigni, T.; Viegi, G.
(2002) The Po River delta (north Italy) indoor epidemiological study: effects of pollutant
exposure on acute respiratory symptoms and respiratory function in adults. Arch.
Environ. Health 57: 130-136.
Simoni, M.; Scognamiglio, A.; Carrozzi, L.; Baldacci, S.; Angino, A.; Pistelli, F.; Di Pede, F.;
Viegi, G. (2004) Indoor exposures and acute respiratory effects in two general population
samples from a rural and an urban area in Italy. J. Exposure Anal. Environ. Epidemiol.
14(suppl. 1): S144-S152.
Simpson, R.; Williams, G.; Petroeschevsky, A.; Best, T.; Morgan, G.; Denison, L.; Hinwood, A.;
Neville, G. (2005a) The short-term effects of air pollution on hospital admissions in four
Australian cities. Aust. N. Z. J. Public Health 29: 213-221.
Simpson, R.; Williams, G.; Petroeschevsky, A.; Best, T.; Morgan, G.; Denison, L.; Hinwood, A.;
Neville, G.; Neller, A. (2005b) The short-term effects of air pollution on daily mortality
in four Australian cities. Aust. N. Z. J. Public Health 29: 205-212.
Sindhu, R. K.; Mautz, W. J.; Kikkawa, Y. (1998) Chronic exposure to ozone and nitric acid
vapor results in increased levels of rat pulmonary putrescine. Arch. Toxicol. 72: 445-449.
Singer, B. C.; Hodgson, A. T.; Hotchi, T.; Kim, J. J. (2004) Passive measurement of nitrogen
oxides to assess traffic-related pollutant exposure for the East Bay Children's Respiratory
Health Study. Atmos. Environ. 38: 393-403.
Singh, H. B.; Salas, L.; Herlth, D.; Kolyer, R.; Czech, E.; Avery, M.; Crawford, J. H.; Pierce, R.
B.; Sachse, G. W.; Blake, D. R.; Cohen, R. C.; Bertram, T. H.; Perring, A.; Wooldridge,
P. J.; Dibb, J.; Huey, G.; Hudman, R. C.; Turquety, S.; Emmons, L. K.; Flocke, F.; Tang,
Y.; Carmichael, G. R.; Horowitz, L. W. (2007) Reactive nitrogen distribution and
partitioning in the North American troposphere and lowermost stratosphere. J. Geophys.
Res. [Atmos.] 112(D12S04): 10.1029/2006JD007664.
Slack, H. H.; Heumann, M. A. (1997) Use of unvented residential heating appliances—United
States, 1988-1994. Morb. Mortal. Wkly. Rep. 46: 1221-1224.
Slade, R.; Highfill, J. W.; Hatch, G. E. (1989) Effects of depletion of ascorbic acid or nonprotein
sulfhydryls on the acute inhalation toxicity of nitrogen dioxide, ozone, and phosgene.
Inhalation Toxicol. 1: 261-271.
August 2007
6-50
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Smith, B. J.; Nitschke, M.; Pilotto, L. S.; Ruffin, R. E.; Pisaniello, D. L.; Wilson, K. J. (2000)
Health effects of daily indoor nitrogen dioxide exposure in people with asthma. Eur.
Respir. J. 16: 879-885.
Snyder, S. H.; Bredt, D. S. (1992) Biological roles of nitric oxide. Sci. Am. 266(5): 68-71, 74-77.
Solomon, C.; Christian, D. L.; Chen, L. L.; Welch, B. S.; Kleinman, M. T.; Dunham, E.; Erie, D.
J.; Balmes, J. R. (2000) Effect of serial-day exposure to nitrogen dioxide on airway and
blood leukocytes and lymphocyte subsets. Eur. Respir. J. 15: 922-928.
Son, B.; Yang, W.; Breysse, P.; Chung, T.; Lee, Y. (2004) Estimation of occupational and
nonoccupational nitrogen dioxide exposure for Korean taxi drivers using a
microenvironmental model. Environ. Res. 94: 291-296.
S0rensen, M.; Loft, S.; Andersen, H. V.; Raaschou-Nielsen, O.; Skovgaard, L. T.; Knudsen, L.
E.; Nielsen, I. V.; Hertel, O. (2005) Personal exposure to PM2.5, black smoke and N02 in
Copenhagen: relationship to bedroom and outdoor concentrations covering seasonal
variation. J. Exposure Anal. Environ. Epidemiol. 15: 413-422.
Spannhake, E. W.; Reddy, S. P. M.; Jacoby, D. B.; Yu, X.-Y.; Saatian, B.; Tian, J. (2002)
Synergism between rhinovirus infection and oxidant pollutant exposure enhances airway
epithelial cell cytokine production. Environ. Health Perspect. 110: 665-670.
Spengler, J. D.; Brauer, M.; Koutrakis, P. (1990) Acid air and health. Environ. Sci. Technol. 24:
946-956.
Spengler, J.; Schwab, M.; Ryan, P. B.; Colome, S.; Wilson, A. L.; Billick, I.; Becker, E. (1994)
Personal exposure to nitrogen dioxide in the Los Angeles Basin. J. Air Waste Manage.
Assoc. 44: 39-47.
Spengler, J. D.; Lee, K.; Yanagisawa, Y.; Bischof, W.; Braathan, O.; Chung, S.; Coward, K.;
Gutschmidt, V.; Isidorov, V.; Jahng, D.; Jin, K.; Korenaga, T.; Maroni, M.; Ohkoda, Y.;
Pastuszka, J.; Patil, R. S.; Qing, X.; Raizenne, M.; Romieu, I.; Salonen, R.; Sega, K.;
Seifert, B.; Shah, S.; Torres, E.; Yoon, D.; Zhang, X. (1996) Impact of residential
nitrogen exposure on personal exposure: an international study. In: Indoor air '96: the 7th
international conference on indoor air quality, volume I; July; Nagoya, Japan. Tokyo,
Japan: Institute of Public Health; pp. 931-936.
Spicer, C. W.; Coutant, R. W.; Ward, G. F.; Joseph, D. W.; Gaynor, A. J.; Billick, I. H. (1989)
Rates and mechanisms of NO2 removal from indoor air by residential materials. Environ.
Int. 15: 643-654.
Spicer, C. W.; Kenny, D. V.; Ward, G. F.; Billick, I. H. (1993) Transformations, lifetimes, and
sources of NO2, HONO, and HNO3 in indoor environments. Air Waste 43: 1479-1485.
Steerenberg, P. A.; Nierkens, S.; Fischer, P. H.; Van Loveren, H.; Opperhuizen, A.; Vos, J. G.;
Van Amsterdam, J. G. (2001) Traffic-related air pollution affects peak expiratory flow,
exhaled nitric oxide, and inflammatory nasal markers. Arch. Environ. Health 56: 167-
174.
Steerenberg, P. A.; Bischoff, E. W. M. A.; de Klerk, A.; Verlaan, A. P. J.; Jongbloets, L. M. N.;
Van Loveren, H.; Opperhuizen, A.; Zomer, G.; Heisterkamp, S. H.; Hady, M.; Spieksma,
F. T. M.; Fischer, P. H.; Dormans, J. A. M. A.; van Amsterdam, J. G. C. (2003) Acute
August 2007
6-51
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
effect of air pollution on respiratory complaints, exhaled NO and biomarkers in nasal
lavages of allergic children during the pollen season. Int. Arch. Allergy Immunol. 131:
127-137.
Stemmler, K.; Ammann, M.; Donders, C.; Kleffmann, J.; George, C. (2006) Photosensitized
reduction of nitrogen dioxide on humic acid as a source of nitrous acid. Nature (London,
U.K.) 440: 195-198.
Stephens, R. J.; Freeman, G.; Crane, S. C.; Furiosi, N. J. (1971) Ultrastructural changes in the
terminal bronchiole of the rat during continuous, low-level exposure to nitrogen dioxide.
Exp. Mol. Pathol. 14: 1-19.
Stephens, R. J.; Freeman, G.; Evans, M. J. (1972) Early response of lungs to low levels of
nitrogen dioxide: light and electron microscopy. Arch. Environ. Health 24: 160-179.
Stevens, R. K.; Dzubay, T. G.; Russwurm, G.; Rickel, D. (1978) Sampling and analysis of
atmospheric sulfates and related species. Atmos. Environ. 12: 55-68.
Stevens, M. A.; Menache, M. G.; Crapo, J. D.; Miller, F. J.; Graham, J. A. (1988) Pulmonary
function in juvenile and young adult rats exposed to low-level NO2 with diurnal spikes. J.
Toxicol. Environ. Health 23: 229-240.
Stieb, D. M.; Burnett, R. T.; Beveridge, R. C.; Brook, J. R. (1996) Association between ozone
and asthma emergency department visits in Saint John, New Brunswick, Canada.
Environ. Health Perspect. 104: 1354-1360.
Stieb, D. M.; Judek, S.; Burnett, R. T. (2002) Meta-analysis of time-series studies of air pollution
and mortality: effects of gases and particles and the influence of cause of death, age, and
season. J. Air Waste Manage. Assoc. 52: 470-484.
Stieb, D. M.; Judek, S.; Burnett, R. T. (2003) Meta-analysis of time-series studies of air pollution
and mortality: update in relation to the use of generalized additive models. J. Air Waste
Manage. 53: 258-261.
Stolzel, M.; Peters, A.; Wichmann, H.-E. (2003) Daily mortality and fine and ultrafine particles
in Erfurt, Germany. In: Revised analyses of time-series studies of air pollution and health.
Special report. Boston, MA: Health Effects Institute; pp. 231-240. Available:
http://www.healtheffects.org/Pubs/TimeSeries.pdf [18 October, 2004],
Strand, V.; Salomonsson, P.; Lundahl, J.; Bylin, G. (1996) Immediate and delayed effects of
nitrogen dioxide exposure at an ambient level on bronchial responsiveness to histamine in
subjects with asthma. Eur. Respir. J. 9: 733-740.
Strand, V.; Rak, S.; Svartengren, M.; Bylin, G. (1997) Nitrogen dioxide exposure enhances
asthmatic reaction to inhaled allergen in subjects with asthma. Am. J. Respir. Crit. Care
Med. 155: 881-887.
Strand, V.; Svartengren, M.; Rak, S.; Barck, C.; Bylin, G. (1998) Repeated exposure to an
ambient level of NO2 enhances asthmatic response to nonsymptomatic allergen dose. Eur.
Respir. J. 12: 6-12.
Studnicka, M.; Hackl, E.; Pischinger, J.; Fangmeyer, C.; Haschke, N.; Kuhr, J.; Urbanek, R.;
Neumann, M.; Frischer, T. (1997) Traffic-related NO2 and the prevalence of asthma and
respiratory symptoms in seven year olds. Eur. Respir. J. 10: 2275-2278.
August 2007
6-52
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Stutz, J.; Ackermann, R.; Fast, J. D.; Barrie, L. (2002) Atmospheric reactive chlorine and
bromine at the Great Salt Lake, Utah. Geophys. Res. Lett. 29: 10.1029/2002GL014812.
Sunyer, J.; Basagana, X. (2001) Particles, and not gases, are associated with the risk of death in
patients with chronic obstructive pulmonary disease. Int. J. Epidemiol. 30: 1138-1140.
Sunyer, J.; Spix, C.; Quenel, P.; Ponce-de-Leon, A.; Ponka, A.; Barumandzadeh, T.; Touloumi,
G.; Bacharova, L.; Wojtyniak, B.; Vonk, J.; Bisanti, L.; Schwartz, J.; Katsouyanni, K.
(1997) Urban air pollution and emergency admissions for asthma in four European cities:
the APHEA project. Thorax 52: 760-765.
Sunyer, J.; Basagana, X.; Belmonte, J.; Anto, J. M. (2002) Effect of nitrogen dioxide and ozone
on the risk of dying in patients with severe asthma. Thorax 57: 687-693.
Suzuki, A. K.; Tsubone, H.; Ichinose, T.; Oda, H.; Kubota, K. (1981) [Effects of subchronic
nitrogen dioxide exposure on arterial blood pHa, PaCo2 and Pa02 in rats], Nippon
Eiseigaku Zasshi 36: 816-823.
Suzuki, T.; Terada, N.; Ikeda, S.; Ohsawa, M.; Endo, K.; Mizoguchi, I. (1984) [Effect of N02
exposure on the activity of angiotensin converting enzyme in lung], Kenkyu Nenpo
Tokyo-toritsu Eisei Kenkyusho 35: 279-285.
Suzuki, T.; Ikeda, S.; Kanoh, T.; Mizoguchi, I. (1986) Decreased phagocytosis and superoxide
anion production in alveolar macrophages of rats exposed to nitrogen dioxide. Arch.
Environ. Contam. Toxicol. 15: 733-739.
Svartengren, M.; Strand, V.; Bylin, G.; Jarup, L.; Pershagen, G. (2000) Short-term exposure to
air pollution in a road tunnel enhances the asthmatic response to allergen. Eur. Resp. J.
15: 716-724.
Tabacova, S. (1984) Behavioral effects of prenatal exposure to nitrogen dioxide. In: European
Teratology Society 11th conference; August 1983; Paris, France. Teratology 29: 33A-
34A.
Tabacova, S.; Balabaeva, L. (1988) Nitrogen dioxide embryotoxicity and lipid peroxidation.
Teratology 38: 29A.
Tabacova, S.; Balabaeva, L.; Vardev, F. (1984) Nitrogen dioxide: maternal and fetal effects. In:
Abstracts of the 25th congress of the European Society of Toxicology, p. 40; June;
Budapest, Hungary.
Tabacova, S.; Nikiforov, B.; Balabaeva, L. (1985) Postnatal effects of maternal exposure to
nitrogen dioxide. Neurobehav. Toxicol. Teratol. 7: 785-789.
Tager, I. B.; Balmes, J.; Lurmann, F.; Ngo, L.; Alcorn, S.; Kiinzli, N. (2005) Chronic exposure to
ambient ozone and lung function in young adults. Epidemiology 16: 751-759.
Takahashi, Y.; Mochitate, K.; Miura, T. (1986) Subacute effects of nitrogen dioxide on
membrane constituents of lung, liver, and kidney of rats. Environ. Res. 41: 184-194.
Takano, T.; Miyazaki, Y. (1984) Combined effect of nitrogen dioxide and cold stress on the
activity of the hepatic cytochrome iM50 system in rats. Toxicology 33: 239-244.
Takano, H.; Yanagisawa, R.; Inoue, K.-I.; Shimada, A.; Ichinose, T.; Sadakane, K.; Yoshino, S.;
Yamaki, K.; Morita, M.; Yoshikawa, T. (2004) Nitrogen dioxide air pollution near
August 2007
6-53
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
ambient levels is an atherogenic risk primarily in obese subjects: a brief communication.
Exp. Biol. Med. 229: 361-364.
Tenias, J. M.; Ballester, F.; Rivera, M. L. (1998) Association between hospital emergency visits
for asthma and air pollution in Valencia, Spain. Occup. Environ. Med. 55: 541-547.
Tepper, J. S.; Costa, D. L.; Winsett, D. W.; Stevens, M. A.; Doerfler, D. L.; Watkinson, W. P.
(1993) Near-lifetime exposure of the rat to a simulated urban profile of nitrogen dioxide:
pulmonary function evaluation. Fund. Appl. Toxicol. 20: 88-96.
Thompson, A. J.; Shields, M. D.; Patterson, C. C. (2001) Acute asthma exacerbations and air
pollutants in children living in Belfast, Northern Ireland. Arch. Environ. Health 56: 234-
241.
Timonen, K. L.; Pekkanen, J. (1997) Air pollution and respiratory health among children with
asthmatic or cough symptoms. Am. J. Respir. Crit. Care Med. 156: 546-552.
Timonen, K. L.; Pekkanen, J.; Tiittanen, P.; Salonen, R. O. (2002) Effects of air pollution on
changes in lung function induced by exercise in children with chronic respiratory
symptoms. Occup. Environ. Med. 59: 129-134.
Timonen, K. L.; Hoek, G.; Heinrich, J.; Bernard, A.; Brunekreef, B.; De Hartog, J.; Hameri, K.;
Ibald-Mulli, A.; Mirme, A.; Peters, A.; Tiittanen, P.; Kreyling, W. G.; Pekkanen, J.
(2004) Daily variation in fine and ultrafine particulate air pollution and urinary
concentrations of lung Clara cell protein CC16. Occup. Environ. Med. 61: 908-914.
Tolbert, P. E.; Mulholland, J. A.; Macintosh, D. L.; Xu, F.; Daniels, D.; Devine, O. J.; Carlin, B.
P.; Klein, M.; Dorley, J.; Butler, A. J.; Nordenberg, D. F.; Frumkin, H.; Ryan, P. B.;
White, M. C. (2000) Air quality and pediatric emergency room visits for asthma in
Atlanta, Georgia. Am. J. Epidemiol. 151: 798-810.
Totten, R. S.; Moran, T. J. (1961) Cortisone and atypical pulmonary "epithelial" hyperplasia:
effects of pretreatment with cortisone on repair of chemically damaged rabbit lungs. Am.
J. Pathol. 38: 575-586.
Touloumi, G.; Katsouyanni, K.; Zmirou, D.; Schwartz, J.; Spix, C.; Ponce de Leon, A.; Tobias,
A.; Quennel, P.; Rabczenko, D.; Bacharova, L.; Bisanti, L.; Vonk, J. M.; Ponka, A.
(1997) Short-term effects of ambient oxidant exposure on mortality: a combined analysis
within the APHEA project. Am. J. Epidemiol. 146: 177-185.
Touloumi, G.; Samoli, E.; Pipikou, M.; Le Tertre, A.; Atkinson, R.; Katsouyanni, K. (2006)
Seasonal confounding in air pollution and health time-series studies: effect on air
pollution effect estimates. Stat. Med. 25: 4164-4178.
Tozuka, Y.; Watanabe, N.; Ohsawa, M.; Toriba, A.; Kizu, R.; Hayakawa, K. (2004) Transfer of
polycyclic aromatic hydrocarbons to fetuses and breast milk of rats exposed to diesel
exhaust. J. Health Sci. 250: 497-502.
Triche, E. W.; Belanger, K.; Bracken, M. B.; Beckett, W. S.; Holford, T. R.; Gent, J. F.;
McSharry, J.-E.; Leaderer, B. P. (2005) Indoor heating sources and respiratory symptoms
in nonsmoking women. Epidemiology 16: 377-384.
August 2007
6-54
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Tsai, S.-S.; Goggins, W. B.; Chiu, H.-F.; Yang, C.-Y. (2003) Evidence for an association
between air pollution and daily stroke admissions in Kaohsiung, Taiwan. Stroke 34:
2612-2616.
Tsai, S.-S.; Cheng, M.-H.; Chiu, H.-F.; Wu, T.-N.; Yang, C.-Y. (2006) Air pollution and hospital
admissions for asthma in a tropical city: Kaohsiung, Taiwan. Inhalation Toxicol. 18: 549-
554.
Tsubone, H.; Suzuki, A. K. (1984) Reflex cardiopulmonary responses by stimulation to type J
receptors in rats exposed to N02. J. Toxicol. Environ. Health 13: 905-917.
Tsuda, H.; Kushi, A.; Yoshida, D.; Goto, F. (1981) Chromosomal aberrations and sister-
chromatic exchanges induced by gaseous nitrogen dioxide in cultured Chinese hamster
cells. Mutat. Res. 89: 303-309.
Tunnicliffe, W. S.; Burge, P. S.; Ayres, J. G. (1994) Effect of domestic concentrations of
nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet
344:1733-1736.
U.S. Census Bureau. (2001) Statistical abstract of the United States: 2001. The national data
book. 121st ed. Washington, DC: U.S. Census Bureau.
U.S. Code. (2003a) Clean Air Act, §108, air quality criteria and control techniques. U. S. C. 42:
§7408.
U.S. Code. (2003b) Clean Air Act, §109, national ambient air quality standards. U. S. C. 42:
§7409.
U.S. Code. (2005) Clean Air Act, §302, definitions. U. S. C. 42: §7602(h).
U.S. Court of Appeals for the District of Columbia. (1980) Lead Industries v. U.S.
Environmental Protection Agency. 647 F2d 1130, 1154 (DC Cir. 1980).
U.S. Court of Appeals for the District of Columbia. (1981) American Petroleum Institute v.
Costle. 665 F2d 1176, 1186 (DC Cir. 1981).
U.S. Environmental Protection Agency. (1982) Air quality criteria for oxides of nitrogen.
Research Triangle Park, NC: Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office; EPA report no. EPA-600/8-82-026.
Available from: NTIS, Springfield, VA; PB83-131011.
U.S. Environmental Protection Agency. (1993) Air quality criteria for oxides of nitrogen.
Research Triangle Park, NC: Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office; report nos. EPA/600/8-91/049aF-cF. 3v.
Available from: NTIS, Springfield, VA; PB95-124533, PB95-124525, and PB95-124517.
U.S. Environmental Protection Agency. (1994) Methods for derivation of inhalation reference
concentrations and application of inhalation dosimetry. Research Triangle Park, NC:
Office of Health and Environmental Assessment, Environmental Criteria and Assessment
Office; report no. EPA/600/8-88/066F. Available:
http://cfpubl.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993 (11 April, 2005).
U.S. Environmental Protection Agency. (1995) Review of the national ambient air quality
standards for nitrogen dioxide: assessment of scientific and technical information.
August 2007
6-55
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Research Triangle Park, NC: Office of Air Quality Planning and Standards; report no.
EPA/452/R-95-005.
U.S. Environmental Protection Agency. (2004) Air quality criteria for particulate matter.
Research Triangle Park, NC: National Center for Environmental Assessment; report no.
EPA/600/P-99/002aF-bF. 2v. Available: http://cfpub.epa.gov/ncea/ [9 November, 2004],
U.S. Environmental Protection Agency. (2005) Approaches for the application of physiologically
based pharmacokinetic (PBPK) models and supporting data in risk assessment (external
review draft 2005). Washington, DC: U.S. Environmental Protection Agency; report no.
EPA/600/R-05/043A. Available:
http://oaspub.epa.gov/eims/eimsapi.dispdetail?deid=135427 [3 July, 2007],
U.S. Environmental Protection Agency. (2006) Air quality criteria for ozone and related
photochemical oxidants. Research Triangle Park, NC: National Center for Environmental
Assessment; report no. EPA/600/R-05/004aF-cF. 3v. Available:
http://cfpub.epa.gov/ncea/ [24 March, 2006],
U.S. Environmental Protection Agency. (2007) Integrated plan for the primary National Ambient
Air Quality Standard for Nitrogen Dioxide. Research Triangle Park, NC: National Center
for Environmental Assessment.
U.S. Senate. (1970) National Air Quality Standards Act of 1970: report of the Committee on
Public Works, United States Senate together with individual views to accompany S.
4358. Washington, DC: Committee on Public Works; report no. CONG/91-1196.
U.S. Supreme Court. (2001) Whitman v. American Trucking Association. 531 U.S. 457 (nos. 99-
1257 and 99-1426).
Vagaggini, B.; Paggiaro, P. L.; Giannini, D.; Franco, A. D.; Cianchetti, S.; Carnevali, S.;
Taccola, M.; Bacci, E.; Bancalari, L.; Dente, F. L.; Giuntini, C. (1996) Effect of short-
term NO2 exposure on induced sputum in normal, asthmatic and COPD subjects. Eur.
Respir. J. 9: 1852-1857.
Van Der Zee, S. C.; Hoek, G.; Boezen, H. M.; Schouten, J. P.; Van Wijnen, J. H.; Brunekreef, B.
(1999) Acute effects of urban air pollution on respiratory health of children with and
without chronic respiratory symptoms. Occup. Environ. Med. 56: 802-813.
Van Der Zee, S. C.; Hoek, G.; Boezen, M. H.; Schouten, J. P.; Van Wijnen, J. H.; Brunekreef, B.
(2000) Acute effects of air pollution on respiratory health of 50-70 yr old adults. Eur.
Respir. J. 15: 700-709.
Van Stee, E. W.; Sloane, R. A.; Simmons, J. E.; Moorman, M. P.; Brunnemann, K. D. (1995)
Endogenous formation of A-nitrosomorpholine in mice from 15N02 by inhalation and
morpholine by gavage. Carcinogenesis 16: 89-92.
Van Strien, R. T.; Gent, J. F.; Belanger, K.; Triche, E.; Bracken, M. B.; Leaderer, B. P. (2004)
Exposure to NO2 and nitrous acid and respiratory symptoms in the first year of life.
Epidemiology 15: 471-478.
Varshney, C. K.; Singh, A. P. (2003) Passive samplers for NOx monitoring: a critical review.
Environmentalist 23: 127-136.
August 2007
6-56
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Vedal, S.; Schenker, M. B.; Munoz, A.; Samet, J. M.; Batterman, S.; Speizer, F. E. (1987) Daily
air pollution effects on children's respiratory symptoms and peak expiratory flow. Am. J.
Public Health 77: 694-698.
Vedal, S.; Brauer, M.; White, R.; Petkau, J. (2003) Air pollution and daily mortality in a city
with low levels of pollution. Environ. Health Perspect. Ill: 45-51.
Velsor, L. W.; Postlethwait, E. M. (1997) N02-induced generation of extracellular reactive
oxygen is mediated by epithelial lining layer antioxidants. Am. J. Physiol. 17: L1265-
L1275.
Victorin, K. (1994) Review of the genotoxicity of nitrogen oxides. Mutat. Res. 317: 43-55.
Victorin, K.; Stahlberg, M. (1988) A method for studying the mutagenicity of some gaseous
compounds in Salmonella typhimurium. Environ. Mol. Mutagen. 11: 65-77.
Victorin, K.; Busk, L.; Cederberg, H.; Magnusson, J. (1990) Genotoxic activity of 1,3-butadiene
and nitrogen dioxide and their photochemical reaction products in Drosophila and in the
mouse bone marrow micronucleus assay. Mutat. Res. 228: 203-209.
Villeneuve, P. J.; Chen, L.; Stieb, D.; Rowe, B. H. (2006) Associations between outdoor air
pollution and emergency department visits for stroke in Edmonton, Canada. Eur. J.
Epidemiol. 21: 689-700.
Vinzents, P. S.; M0ller, P.; S0rensen, M.; Knudsen, L. E.; Herte, L. Q.; Jensen, F. P.; Schibye,
B.; Loft, S. (2005) Personal exposure to ultrafine particles and oxidative DNA damage.
Environ. Health Perspect. 113: 1485-1490.
Vollmuth, T. A.; Driscoll, K. E.; Schlesinger, R. B. (1986) Changes in early alveolar particle
clearance due to single and repeated nitrogen dioxide exposures in the rabbit. J. Toxicol.
Environ. Health 19: 255-266.
Von Klot, S.; Wolke, G.; Tuch, T.; Heinrich, J.; Dockery, D. W.; Schwartz, J.; Kreyling, W. G.;
Wichmann, H. E.; Peters, A. (2002) Increased asthma medication use in association with
ambient fine and ultrafine particles. Eur. Respir. J. 20: 691-702.
Von Klot, S.; Peters, A.; Aalto, P.; Bellander, T.; Berglind, N.; DTppoliti, D.; Elosua, R.;
Hormann, A.; Kulmala, M.; Lanki, T.; Lowel, H.; Pekkanen, J.; Picciotto, S.; Sunyer, J.;
Forastiere, F.; Health Effects of Particles on Susceptible Subpopulations (HEAPSS)
Study Group. (2005) Ambient air pollution is associated with increased risk of hospital
cardiac readmissions of myocardial infarction survivors in five European cities.
Circulation 112: 3073-3079.
Wade, K. S.; Mulholland, J. A.; Marmur, A.; Russell, A. G.; Hartsell, B.; Edgerton, E.; Klein,
M.; Waller, L.; Peel, J. L.; Tolbert, P. E. (2006) Effects of instrument precision and
spatial variability on the assessment of the temporal variation of ambient air pollution in
Atlanta, Georgia. J. Air Waste Manage. Assoc. 56: 876-888.
Wagner, H.-M. (1970) Absorption von NO und NO2 in MTK- und MAK-Konzentrationen bei der
Inhalation [Absorption of NO and NO2 in mik- and mak-concentrations during
inhalation], Staub Reinhalt. Luft 30: 380-381.
Wagner, W. D.; Duncan, B. R.; Wright, P. G.; Stokinger, H. E. (1965) Experimental study of
threshold limit of NO2. Arch. Environ. Health 10: 455-466.
August 2007
6-57
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Wainman, T.; Weschler, C.; Lioy, P.; Zhang, J. (2001) Effects of surface type and relative
humidity on the production and concentration of nitrous acid in a model indoor
environment. Environ. Sci. Technol. 35: 2200-2206.
Wallace, L. A.; Emmerich, S. J.; Howard-Reed, C. (2004) Source strengths of ultrafine and fine
particles due to cooking with a gas stove. Environ. Sci. Technol. 38: 2304-2311.
Walles, S. A.; Victorin, K.; Lundborg, M. (1995) DNA damage in lung cells in vivo and in vitro
by 1,3-butadiene and nitrogen dioxide and their photochemical reaction products. Mutat.
Res. 328: 11-19.
Wang, J. H.; Devalia, J. L.; Duddle, J. M.; Hamilton, S. A.; Davies, R. J. (1995a) Effect of six-
hour exposure to nitrogen dioxide on early-phase nasal response to allergen challenge in
patients with a history of seasonal allergic rhinitis. J. Allergy Clin. Immunol. 96: 669-
676.
Wang, J. H.; Duddle, J.; Devalia, J. L.; Davies, R. J. (1995b) Nitrogen dioxide increases
eosinophil activation in the early-phase response to nasal allergen provocation. Int. Arch.
Allergy Immunol. 107: 103-105.
Wang, J. H.; Devalia, J. L.; Rusznak, C.; Bagnall, A.; Sapsford, R. J.; Davies, R. J. (1999) Effect
of fluticasone propionate aqueous nasal spray on allergen-induced inflammatory changes
in the nasal airways of allergic rhinitics following exposure to nitrogen dioxide. Clin.
Exp. Allergy 29: 234-240.
Wang, X.-K.; Lu, W.-Z. (2006) Seasonal variation of air pollution index: Hong Kong case study.
Chemosphere 63: 1261-1272.
Ward, D. J.; Miller, M. R.; Walters, S.; Harrison, R. M.; Ayres, J. G. (2000) Impact of correcting
peak flow for nonlinear errors on air pollutant effect estimates from a panel study. Eur.
Respir. J. 15: 137-140.
Ward, D. J.; Roberts, K. T.; Jones, N.; Harrison, R. M.; Ayres, J. G.; Hussain, S.; Walters, S.
(2002) Effects of daily variation in outdoor particulates and ambient acid species in
normal and asthmatic children. Thorax 57: 489-502.
Ware, J. H.; Dockery, D. W.; Spiro, A., Ill; Speizer, F. E.; Ferris, B. G., Jr. (1984) Passive
smoking, gas cooking, and respiratory health of children living in six cities. Am. Rev.
Respir. Dis. 129: 366-374.
Watanabe, N. (2005) Decreased number of sperms and Sertoli cells in mature rats exposed to
diesel exhaust as fetuses. Toxicol. Lett. 155: 51-58.
Watanabe, N.; Kurita, M. (2001) The masculinization of the fetus during pregnancy due to
inhalation of diesel exhaust. Environ. Health Perspect. 109: 111-119.
Watanabe, N.; Nakamura, T. (1996) Inhalation of diesel engine exhaust increases bone mineral
concentrations in growing rats. Arch. Environ. Contam. Toxicol. 30: 407-411.
Watanabe, N.; Oonuki, Y. (1999) Inhalation of diesel engine engine exhaust affects
spermatogenesis in growing male rats. Environ. Health Perspect. 107: 539-544.
August 2007
6-58
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Watanabe, H.; Fukase, O.; Isomura, K. (1980) Combined effects of nitrogen oxides and ozone on
mice. In: Lee, S. D., ed. Nitrogen oxides and their effects on health. Ann Arbor, MI: Ann
Arbor Science Publishers, Inc.; pp. 181-189.
Waxman, M. B.; Cameron, D.; Wald, R. W. (1994) Vagal activity and ventricular
tachyarrhythmias. In: Levy, M.; Schwartz, P. Vagal control of the heart: experimental
basis and clinical implications. Armonk, NY: Futura Publishing Co.; pp. 579-612.
Wayne, R. P.; Barnes, I.; Biggs, P.; Burrows, J. P.; Canosa-Mas, C. E.; Hjorth, J.; Le Bras, G.;
Moortgat, G. K.; Perner, D.; Poulet, G.; Restelli, G.; Sidebottom, H. (1991) The nitrate
radical: physics, chemistry, and the atmosphere. Atmos. Environ. Part A 25: 1-203.
Wegmann, M.; Renz; Herz, U. (2002) Long-term N02 exposure induces pulmonary
inflammation and progressive development of airflow obstruction in C57BL/6 mice: a
mouse model for chronic obstructive pulmonary disease. Pathobiology 70: 284-286.
Weinberg, E. D. (1992) Iron depletion: a defense against intracellular infection and neoplasia.
Life Sci. 50: 1289-1297.
Weinberger, B.; Laskin, D. L.; Heck, D. E.; Laskin, J. D. (2001) The toxicology of inhaled nitric
oxide. Toxicol. Sci. 59: 5-16.
Wellenius, G. A.; Bateson, T. F.; Mittleman, M. A.; Schwartz, J. (2005) Particulate air pollution
and the rate of hospitalization for congestive heart failure among medicare beneficiaries
in Pittsburgh, Pennsylvania. Am. J. Epidemiol. 161: 1030-1036.
Wellenius, G. A.; Schwartz, J.; Mittleman, M. A. (2006) Particulate air pollution and hospital
admissions for congestive heart failure in seven United States cities. Am. J. Cardiol. 97:
404-408.
Wensley, D. C.; Silverman, M. (2001) The quality of home spirometry in school children with
asthma. Thorax 56: 183-185.
Weschler, C. J.; Shields, H. C. (1997) Potential reactions among indoor pollutants. Atmos.
Environ. 31: 3487-3495.
Weschler, C. J.; Hodgson, A. T.; Wooley, J. D. (1992) Indoor chemistry: ozone, volatile organic
compounds, and carpets. Environ. Sci. Technol. 26: 2371-2377.
Weschler, C. J.; Shields, H. C.; Naik, D. V. (1994) Indoor chemistry involving O3, NO, andN02
as evidenced by 14 months of measurements at a site in southern California. Environ. Sci.
Technol. 28: 2120-2132.
Weschler, C. J.; Shields, H. C. (1996) The conversion (reduction) of nitrogen dioxide to nitric
oxide as a consequence of charcoal filtration. In: Yoshizawa, S.; Kimura, K.; Ikeda, K.;
Tanabe, S.; Iwata, T., eds. Indoor Air '96: proceedings of the 7th international conference
on indoor air quality and climate, v. 3, July; Nagoya, Japan. Toykyo, Japan: Indoor Air
'96; pp. 453-458.
Westerdahl, D.; Fruin, S.; Sax, T.; Fine, P. M.; Sioutas, C. (2005) Mobile platform
measurements of ultrafine particles and associated pollutant concentrations on freeways
and residential streets in Los Angeles. Atmos. Environ. 39: 3597-3610.
August 2007
6-59
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Wheeler, A.; Zanobetti, A.; Gold, D. R.; Schwartz, J.; Stone, P.; Suh, H. H. (2006) The
relationship between ambient air pollution and heart rate variability differs for individuals
with heart and pulmonary disease. Environ. Health Perspect. 114: 560-566.
Wichmann, H.-E.; Spix, C.; Tuch, T.; Wolke, G.; Peters, A.; Heinrich, J.; Kreyling, W. G.;
Heyder, J. (2000) Daily mortality and fine and ultrafine particles in Erfurt, Germany. Part
I: role of particle number and particle mass. Cambridge, MA: Health Effects Institute;
research report no. 98.
Wiley, J. A.; Robinson, J. P.; Piazza, T.; Garrett, K.; Cirksena, K.; Cheng, Y.-T.; Martin, G.
(1991a) Activity patterns of California residents. Final report. Sacramento, CA:
California Air Resources Board; report no. ARB/R93/487. Available from: NTIS,
Springfield, VA.; PB94-108719.
Wiley, J. A.; Robinson, J. P.; Cheng, Y.-T.; Piazza, T.; Stork, L.; Pladsen, K. (1991b) Study of
children's activity patterns: final report. Sacramento, CA: California Air Resources
Board; report no. ARB-R-93/489.
Williams, E. J.; Parrish, D. D.; Fehsenfeld, F. C. (1987) Determination of nitrogen oxide
emissions from soils: results from a grassland site in Colorado, United States. J. Geophys.
Res. [Atmos.] 92: 2173-2179.
Winter-Sorkina, R. de; Cassee, F. R. (2002) From concentration to dose: factors influencing
airborne particulate matter deposition in humans and rats. Bilthoven, The Netherlands:
National Institute of Public Health and the Environment (RIVM); report no.
650010031/2002. Available: http://www.rivm.nl/bibliotheek/rapporten/650010031.html
(13 June 2003).
Witschi, H. (1988) Ozone, nitrogen dioxide and lung cancer: a review of some recent issues and
problems. Toxicology 48: 1-20.
Wolff, G. T. (1993) On a NOx-focused control strategy to reduce O3. J. Air Waste Manage.
Assoc. 43: 1593-1596.
Wolff, G. T. (1996) Closure by the Clean Air Scientific Advisory Committee (CASAC) on the
draft Air Quality Criteria for Particulate Matter [letter to Carol M. Browner,
Administrator, U.S. EPA], Washington, DC: U.S. Environmental Protection Agency,
Clean Air Scientific Advisory Committee.; EPA-SAB-CASAC-LTR-96-005; March 15.
Wong, T. W.; Lau, T. S.; Yu, T. S.; Neller, A.; Wong, S. L.; Tam, W.; Pang, S. W. (1999) Air
pollution and hospital admissions for respiratory and cardiovascular diseases in Hong
Kong. Occup. Environ. Med. 56: 679-683.
Wong, G. W.; Ko, F. W.; Lau, T. S.; Li, S. T.; Hui, D.; Pang, S. W.; Leung, R.; Fok, T. F.; Lai,
C. K. (2001) Temporal relationship between air pollution and hospital admissions for
asthmatic children in Hong Kong. Clin. Exp. Allergy 31: 565-569.
World Health Organization. (1997) Nitrogen oxides. 2nd ed. Geneva, Switzerland: World Health
Organization. (Environmental health criteria 188).
Yallop, D.; Duncan, E. R.; Norris, E.; Fuller, G. W.; Thomas, N.; Walters, J.; Dick, M. C.;
Height, S. E.; Thein, S. L.; Rees, D. C. (2007) The associations between air quality and
August 2007
6-60
DRAFT-DO NOT QUOTE OR CITE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
the number of hospital admissions for acute pain and sickle-cell disease in an urban
environment. Br. J. Haematol. 136: 844-848.
Yamanaka, S. (1984) Decay rates of nitrogen oxides in a typical Japanese living room. Environ.
Sci. Technol. 18: 566-570.
Yanagisawa, Y.; Nishimura, H. (1982) A badge-type personal sampler for measurement of
personal exposure to N02 and NO in ambient air. Environ. Int. 8: 235-242.
Yang, W.; Lee, K.; Chung, M. (2004a) Characterization of indoor air quality using multiple
measurements of nitrogen dioxide. Indoor Air 14: 105-111.
Yang, C.-Y.; Chen, Y.-S.; Yang, C.-H.; Ho, S.-C. (2004b) Relationship between ambient air
pollution and hospital admissions for cardiovascular diseases in Kaohsiung, Taiwan. J.
Toxicol. Environ. Health Part A 67: 483-493.
Yang, Q.; Chen, Y.; Krewski, D.; Burnett, R. T.; Shi, Y.; McGrail, K. M. (2005) Effect of short-
term exposure to low levels of gaseous pollutants on chronic obstructive pulmonary
disease hospitalizations. Environ. Res. 99: 99-105.
Yang, C.-Y.; Hsieh, H.-J.; Tsai, S.-S.; Wu, T.-N.; Chiu, H.-F. (2006) Correlation between air
pollution and postneonatal mortality in a subtropical city: Taipei, Taiwan. J. Toxicol.
Environ. Health Part A 69: 2033-2040.
Yokoyama, E. (1968) Uptake of S02 and N02 by the isolated upper airways. Bull. Inst. Public
Health (Tokyo) 17: 302-306.
Yokoyama, E.; Ichikawa, I.; Kawai, K. (1980) Does nitrogen dioxide modify the respiratory
effects of ozone? In: Lee, S. D., ed. Nitrogen oxides and their effects on health. Ann
Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 217-229.
Zanobetti, A.; Schwartz, J. (2006) Air pollution and emergency admissions in Boston, MA. J.
Epidemiol. Community Health 60: 890-895.
Zeger, S. L.; Thomas, D.; Dominici, F.; Samet, J. M.; Schwartz, J.; Dockery, D.; Cohen, A.
(2000) Exposure measurement error in time-series studies of air pollution: concepts and
consequences. Environ. Health Perspect. 108: 419-426.
Zeka, A.; Schwartz, J. (2004) Estimating the independent effects of multiple pollutants in the
presence of measurement error: an application of a measurement-error-resistant
technique. Environ. Health Perspect. 112: 1686-1690.
Zhang, H.; Lindwall, R.; Zhu, L.; Frostell, C.; Sun, B. (2003) Lung physiology and
histopathology during cumulated exposure to nitric oxide in combination with assisted
ventilation in healthy piglets. Pulm. Pharmacol. Ther. 16: 163-169.
Zidek, J. V. (1997) Interpolating air pollution for health impact assessment. In: Barnett, E. V.;
Turkman, K. F., eds. Pollution Assessment and Control. New York, NY: John Wiley &
Sons. (Statistics for the Environment, no. 3).
Zipprich, J. L.; Harris, S. A.; Fox, J. C.; Borzelleca, J. F. (2002) An analysis of factors that
influence personal exposure to nitrogen oxides in residents of Richmond, Virginia. J.
Exposure Anal. Environ. Epidemiol. 12: 273-285.
August 2007
6-61
DRAFT-DO NOT QUOTE OR CITE
-------
1 Zmirou, D.; Schwartz, J.; Saez, M.; Zanobetti, A.; Wojtyniak, B.; Touloumi, G.; Spix, C.; Ponce
2 de Leon, A.; Le Moullec, Y.; Bacharova, L.; Schouten, J.; Ponka, A.; Katsouyanni, K.
3 (1998) Time-series analysis of air pollution and cause-specific mortality. Epidemiology
4 9:495-503.
5 Zota, A.; Adamkiewicz, G.; Levy, J. I.; Spengler, J. D. (2005) Ventilation in public housing:
6 implications for indoor nitrogen dioxide concentrations. Indoor Air 15: 393-401.
7
August 2007
6-62
DRAFT-DO NOT QUOTE OR CITE
-------
&EPA
United States
Environmental Protection
Agency-
Please make all necessary changes in the below label,
detach copy or copy, and return to the address in the upper
left-hand corner.
If you do not wish to receive these reports CHECK HERE ~;
detach copy or copy, and return to the address in the upper
left-hand corner.
PRESORTED STANDARD
POSTAGE & FEES PAID
EPA
PERMIT No. G-35
National Center for
Environmental Assessment
Research Triangle Park, NC 27711
Official Business
Penalty for Private Use
$300
EPA/600/R-07/093
August 2007
------- |