United States Office of Air Quality EPA-450/5-82-002
Environmental Protection Planning and Standards August 1982
Agency Research Triangle Park NC 27711
__
>EPA Review
of the National
Ambient Air
Quality Standards
for Nitrogen
Oxides: Assessment
of Scientific
and Technical
Information
OAQPS Staff Paper
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REVIEW OF THE NATIONAL AMBIENT AIR QUALITY STANDARDS
FOR NITROGEN OXIDES: ASSESSMENT OF SCIENTIFIC
AND TECHNICAL INFORMATION
OAQPS STAFF PAPER
STRATEGIES AND AIR STANDARDS DIVISION
OFFICE OF AIR QUALITY PLANNING AND STANDARDS
U,S, ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, N,C, 27711
U.S. Environment::! Protection Agency
Region V, !.!?".. "
230 South II- .- .: "> '"h-sst --""
Chicago, !i!ir,0!b h0504 .,.,.
AUGUST 1982
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_, ..,,,.,_.;,;cn Agency
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EXECUTIVE SUMMARY
This paper assesses the scientific evidence concerning the effects of
nitrogen dioxide (NCL) on human health and welfare, discusses the EPA
staff interpretation of this evidence, and presents staff recommendations
on alternative approaches to revising the standards. Review of the
National Ambient Air Quality Standards (NAAQS) is a periodic process
instituted to ensure the scientific adequacy of air quality standards and
is required by section 109 of the 1977 Clean Air Act Amendments. The
staff paper is an important element in this review process and provides an
opportunity for public comment on proposed staff recommendations before
they are submitted to the Administrator.
NCL is an air pollutant which is oxidized from nitric oxide (NO)
emitted from both mobile and stationary sources. At elevated concentrations
N02 can adversely affect human health, vegetation, materials, and visibility.
Nitrogen oxide compounds (NO ) also contribute to increased rates of
/\
acidic deposition. Typical long-term ambient concentrations of N02 range
from 0.001 ppm in isolated rural areas to a maximum annual concentration
of approximately 0.08 ppm in one of the nation's most populated urban
areas. Short-term hourly peak concentrations rarely exceed 0.5 ppm.
While adverse effects have been reported at N02 levels above 1.0 ppm,
little credible evidence exists which links specific human health effects
to N02 concentrations at or near ambient levels. Evidence at these lower
concentrations is not conclusive and in most cases is confounded by
uncertainties regarding the cause of the effect and the effect concentration
level. The existing annual standard (0.053 ppm) was based largely on a
community epidemiology study (Shy et al., 1970) suggesting respiratory
effects in children exposed to long-term low level N02 concentrations.
Reevaluation of this study based on new information (especially regarding
the accuracy of ambient air monitoring for NOp used in the study) appears
to invalidate the reported findings. Therefore, this study no longer is
seen as an adequate basis for retaining the existing standard. Other
outdoor community epidemiology studies attempting to document effects from
long-term low level exposure to N02 are either flawed or report no effects
associated with N02 exposure.
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11
There presently is no reliable scientific evidence reporting adverse
effects in humans due to chronic (long-term) NCL exposure at ambient air
levels. However, there is convincing evidence from animal studies which
reveals serious biological effects from elevated (higher than ambient)
long-term NCL exposures. These findings suggest a definite risk to human
health from chronic exposure to NO,,, but such risks have not been quantified
at ambient air levels.
Effects from both single and repeated short-term peak exposures have
been documented in the scientific literature. Modeling results from
animal infectivity studies suggest that short-term peak exposures probably
are more important in causing adverse effects than long-term low level
exposures of equivalent doses. Effects of definite health concern in
humans resulting from single short-term peak exposures have been observed
only at relatively high NCL concentrations (above 1 ppm). More subtle
effects that are of questionable health significance, such as mild sympto-
matic effects, have been reported for some sensitive human population
groups (e.g. asthmatics) after a single 2-hour exposure to 0.5 ppm.
Animal studies report a variety of responses from single short-term peak
exposures in the range of 0.2 ppm to 5 ppm; but the health significance of
these latter findings for humans is uncertain.
Repeated peak exposures are of special concern because concentrations
at which some effects have been reported are observed in the ambient air.
However, the evidence of adverse health impact at these levels is limited
and inconclusive. The principal evidence from which inferences might be
drawn regarding effects from repeated short-term peak exposures is from a
series of ongoing epidemiological studies. The published results from
these studies report increased rates of acute respiratory illness and
impaired pulmonary function for children living in homes with gas stoves
as compared to children living in homes with electric stoves. The findings
from animal studies demonstrating reduced resistance to infection due to
N02 exposure support the hypothesis that N02 is the primary agent responsible
for the effects observed in the "gas stove" studies. These findings suggest
that multiple exposures to short-term N02 levels below 0.5 ppm should be
avoided. While a precise level cannot be identified, preliminary
epidemiological findings and related indoor air pollution monitoring
studies assessing variations of N02 levels in gas stove homes suggest
that repeated peaks in the range of 0.15 to 0.30 ppm may be of concern
for children.
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Given the uncertainties existing in the available scientific data,
no rigorous rationale can be offered to support a specific NOo standard.
However, not to establish a standard, we believe, would ignore the cumulative
evidence from animal, controlled human exposure, and community indoor air
pollution studies which suggest that NC^ may cause adverse health effects
in sensitive population groups exposed to NC^ at or near existing ambient
levels.
Two approaches to minimizing potential health effects associated with
NC>2 exposure in the ambient air are suggested. The first is to retain an
annual standard at some level between 0.05 ppm and 0.08 ppm to provide a
reasonable level of protection against potential short-term peaks. A
0.08 ppm standard would be expected to limit the number of days with
hourly peak concentrations above 0.30 ppm to about ten per year based on
analysis of existing ambient air quality data. In most areas of the
country attainment of an annual standard of 0.05 ppm should virtually
preclude the occurrence of 0.30 ppm peaks and limit the number of days
with hourly peak concentrations of 0.15 ppm to a range of approximately
10-20 (some southern California sites may exceed 0.15 ppm on as many as
40 days). An annual standard in this range also would provide reasonable
assurance that 1-hour peak concentrations of N02 would not exceed 0.5
ppm. An alternative approach is to establish a new multiple exceedance
1-hour average NOp standard at some level below 0.5 ppm. Such a standard
acknowledges medical evidence suggesting the importance of repeated peak
exposures and would incorporate an allowable rate of exceedance which would
be a function of the standard level.
Either of the above approaches can provide a reasonable degree of
protection against repeated peak exposures in the range of 0.15 to 0.30
ppm. A long-term standard offers the practical advantage of not requiring
formulation and implementation of a new regulatory program. Establishing
a new short-term standard would require more significant changes in
modeling and monitoring procedures than retention of an annual standard.
NO effects on man's environment, personal comfort, and well-being
/\
include impacts on vegetation, materials, visibility, rates of acidic
deposition, and symptomatic effects in humans. Because acidic deposition
is an important and complex problem associated with multi-pollutant
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iv
interactions, it is being addressed as a separate program by EPA and not
as a specific element of the NCU standard review. With respect to the
need for a standard to protect against other possible adverse welfare
effects, there is no evidence to suggest the need for a separate secondary
standard provided a primary standard is established within the ranges
suggested above to protect human health.
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TABLE OF CONTENTS
Page
I. PURPOSE 1
II. BACKGROUND 1
ill. APPROACH 3
IV. AMBIENT N02 CONCENTRATIONS IN URBANIZED AREAS 5
V. CRITICAL ELEMENTS IN THE PRIMARY STANDARDS REVIEW 6
A. Introduction 6
B. Mechanisms of NO^ Toxicity 6
C. Evaluation of Scientific Evidence on Effects Attributed
to NOp Exposures 9
1. Interpretation of Selected Animal Toxicology Studies 9
2. Review and Evaluation of Controlled Human Exposure
with N02 Alone 12
3. Review and Evaluation of Controlled Human Exposure
Studies with N02 and Other Pollutants 20
4. Review and Evaluation of Selected Community Epidemic-
logical Studies 23
5. Review and Evaluation of Epidemiological Studies
Involving Homes With Gas Stoves 26
D. Sensitive Population Groups 41
VI. FACTORS TO BE CONSIDERED IN SELECTING PRIMARY STANDARDS 44
A. Averaging Times 44
B. Form of the Standard 45
C. Level of the Standard 46
D. Staff Conclusions and Recommendations 50
VII. CRITICAL ELEMENTS IN THE REVIEW OF THE SECONDARY STANDARDS 55
A. Personal Comfort and Well-Being 55
B. Vegetation Effects 56
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C. Visibility Impairment 63
D. Acidic Deposition 67
E. Materials Damage 67
F. Staff Conclusions and Recommendations 68
Appendix A - A Review of Selected Animal Toxicology Studies A-l
Appendix B - Ambient NOp Concentrations in Urbanized Areas B-l
Appendix C - CASAC Closure Memorandum C-l
References
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PRELIMINARY ASSESSMENT OF HEALTH AND WELFARE EFFECTS
ASSOCIATED WITH NITROGEN OXIDES FOR STANDARD-SETTING PURPOSES
DRAFT STAFF PAPER
I. PURPOSE
The purpose of this paper is to evaluate the key studies and scientific
information contained in the draft EPA document "Air Quality Criteria for
Oxides of Nitrogen1 and to identify the critical elements that EPA staff
believe should be considered in the review and possible revision of the
current long-term (annual average) primary and secondary National Ambient Air
Quality Standards (NAAQS) for nitrogen dioxide (NO,,). The paper also identifies
the critical factors that must be considered in deciding whether short-term
(1-3 hours) N02 standards are required to protect public health and welfare,
based on the information in the criteria document.
II. BACKGROUND
Since 1970 the Clean Air Act as amended has provided authority and
guidance for the listing of certain ambient air pollutants which may endanger
public health or welfare and the setting and revising of NAAQS for those
pollutants. Primary standards must be based on health effects criteria and
provide an adequate margin of safety to ensure protection of public health.
As several recent judicial decisions have made clear, the economic and
technological feasibility of attaining primary standards are not to be
considered in setting them, although such factors should be considered
2 2a
in the development of state plans to implement the standards.
3
Further guidance provided in the legislative history of the Act indicates
that the standards should be set at "the maximum permissible ambient air
level . . . which will protect the health of any (sensitive) group of the
population." Also, margins of safety are to be provided such that the stan-
dards will afford "a reasonable degree of protection . . . against hazards
3
which research has not yet identified." In the final analysis, the EPA
Administrator must make a policy decision in setting the primary standard
based on her judgment regarding the implications of all the health effects
evidence and the requirement that an adequate margin of safety be
provided.
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2
Secondary ambient air quality standards must be adequate to protect the
public welfare from any known or anticipated adverse effects associated
with the presence of a listed ambient air pollutant. Welfare effects, which
are defined in section 302(h) of the Act, include effects on vegetation,
visibility, water, crops, man-made materials, animals, economic values and
personal comfort and well-being. In specifying a level or levels for secon-
dary standards the Administrator must determine at which point the effects
become "adverse" and base her judgment on the welfare effects criteria.
Both the current primary (to protect public health) and secondary (to
protect public welfare) NAAQS for NOp are 0.053 ppm (100 yg/m ), averaged over
1 year. In 1977, Congress amended section 109(c) of the Clean Air Act to
require the Administrator to promulgate a short-term IMk primary standard for
N02 concentrations over a period of not more than 3 hours unless she finds
no significant evidence that such a standard is required to protect public
health.
A preliminary version of this paper was reviewed by the Clean Air Scientific
Advisory Committee (CASAC) on November 14, 1980,4 February 6, 1981, and
November 18, 1981. a This final product incorporates the suggestions and
recommendations of the CASAC as well as other appropriate comments received
in initial drafts. The CASAC closure memo on the Staff Paper (Friedlander, 1982)
is reprinted in Appendix C.
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III. APPROACH
The approach used in this paper is to identify the critical elements
the staff believes should be considered in the review of the primary and
secondary standards. Particular attention is drawn to those judgments
that must be based on the careful interpretation of incomplete or uncertain
evidence. In such instances, the paper states our evaluation of the
evidence as it relates to a specific judgment, sets forth appropriate
alternatives that should be considered, and recommends a course of action.
To facilitate the review, the paper is organized into sections as outlined
below.
Section IV provides an overview of the ambient levels of NC^ currently
being experienced in various portions of the U.S. This section is intended
to set the stage for the remaining discussion by identifying the present
air quality situation so the reader can relate the available health and
welfare information to what is actually occurring in the real world.
Section V addresses the essential elements examined in reaching
conclusions regarding the primary standards; these include the following:
t the most probable mechanism(s) of toxicity by which health
effects occur,
a description of the scientific evidence on health effects
attributed to nitrogen oxides (NO ) and whether a standard
A
should be considered for N02 alone,
an identification and evaluation of scientific uncertainties
with regard to the health effects evidence and staff judgments
concerning which effects are important for the Administrator to
consider in reviewing and setting primary standards, and
a description of the most sensitive population groups and
estimates of the size of those groups.
Drawing from the discussions in Sections IV and V, Section VI identifies
and assesses the factors that the staff believes should be considered in
selecting averaging times and levels of primary standards. Staff conclusions
and recommendations also are presented in Section VI.
In Section VII the effects of NO on personal comfort, vegetation,
A
visibility, and man-made materials are examined. The elements addressed
in this section include the following:
t the most probable mechanisms of interaction by which such effects
occur,
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a description of the welfare effects attributed to NO ,
/\
an evaluation of which effects are to be considered adverse and
judgments on which adverse effects are critical for standard setting,
and
t the levels of exposure and averaging times associated with critical
adverse effect(s) of concern.
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IV. Ambient NQ2 Concentrations in Urbanized Areas
This section briefly characterizes ambient NCL levels so the reader
may better evaluate the significance of health and welfare effects discussed
later in the paper. A more complete discussion of ambient air quality is
provided in Appendix B.
Based on monitoring data from 186 urbanized areas, annual average N02
concentrations increased by about 10 percent (on the average) between 1974
and 1978 and have held steady from 1979 through 1980. Over 95 percent
of the 186 urbanized areas where monitoring currently is being conducted
are in compliance with the current 0.053 ppm annual average standard,
although annual average concentrations in a number of these areas are
beginning to approach this level. In the remaining 5% of the areas (where
the standard is exceeded), the annual average exceeds 0.060 ppm in
three areas. The highest annual average observed during 1977-1979 was
0.081 ppm.
The mean annual concentration in the above urbanized areas during
1977-1979 was 0.029 ppm as compared to 0.01 ppm in inhabited non-metropolitan
areas and 0.001 ppm in isolated areas essentially unaffected by man-made
NO emissions. Thus, long-term concentrations are considerably higher
A
in the nation's major cities than in rural areas and small cities.
During 1977-1979, peak 1-hour average concentrations of N02 ranged
from 0.06 ppm to about 0.5 ppm in urbanized areas. In most of these
areas, 1-hour average concentrations seldom exceeded 0.30 ppm. Where
the current annual N0« standard is being met, 1-hour average concentrations
exceed 0.15 on 10-20 days per year (exceptions to this latter
observation occur in several California cities where 1-hour levels have
exceeded 0.15 ppm on more than 40 days in a year even though the annual .
standard was met.) One-hour concentrations of N0? exceeded 0.10 ppm on
many days during a given year in essentially all 186 urbanized areas.
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V. CRITICAL ELEMENTS IN THE PRIMARY STANDARD(S) REVIEW
A. Introduction
A variety of nitrogen oxide (NO ) compounds and their transformation
/\
products occur naturally and as a result of human activities. Nitric oxide
(NO), nitrogen dioxide (NOx), gaseous nitric acid (HNO,). in addition to
L. 0
nitrite and nitrate aerosols, have all been found in the ambient air. The
formation of nitrosamines in the atmosphere by reaction of nitrogen oxides
with amines has been suggested, but not yet convincingly demonstrated.
Despite considerable scientific research on the potential health
effects of NO compounds, there exists little evidence linking specific
/\
health effects to near ambient concentrations of most of these substances.
The one significant exception is N02. This section will, therefore, focus
primarily on the health effects that have been reported to be associated
with NOp. Particular emphasis will be placed on the effects of N02 on
the respiratory system, since these effects have been extensively characterized
and appear to be of concern for both short- and long-term exposures.
B. Mechanisms of NO? Toxicity
The mechanisms of toxicity responsible for effects caused by short-term
and long-term exposures to N02 are incompletely understood. The variety of
effects, such as (1) increased airway resistance and alterations in lung
hormone metabolism for short-term exposures and (2) increased susceptibility
to infection and morphological damage for long-term or multiple exposures,
may well be explained by related mechanisms of oxidative damage. However,
the body of data is not yet definitive. Because N02 is relatively insoluble
in water, some fraction normally penetrates to the distal airways during
inhalation. In spite of the insoluble nature of N02, the reactivity of N02
is sufficient to permit chemical interaction and absorption along the entire
tracheobronchial tree.
Although the nasopharyngeal cavity is normally the first region of
removal during N02 inhalation for nasal breathers, few studies provide good
estimates of the rate of uptake in this region. Those which have provided
estimates report nasopharyngeal removal rates of 42% (dogs and rabbits) and
7 8
50% (rabbits). The process of nasopharyngeal removal of NO, involves
both peroxidation reactions with lipids and absorption in the mucous lining
of the nasopharyngeal cavity, where N02 is chemically converted to nitrous
acid (HN07) and nitric acid (HNO-).
c 0
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When N09 enters the lungs, most of the reacting N09 rapidly oxidizes
9
cellular lipids, although some slowly hydrolyzes to form HNCL and HMO.,.
The most destructive reaction involves oxidation of unsaturated lipids
of the cellular membrane and results in the formation of peroxidic
products. The disruption of the cellular membrane, which is essential
for maintaining cellular integrity and function, probably accounts for
many of the biological effects (e.g., hyperplasia, morphological damage,
pulmonary edema) which have been ascribed to NCu.
Understanding the temporal sequence of events following inhalation
of N02 is important to elucidate the mechanisms of toxicity for health effects
caused by both short- and long-term exposures. A temporal sequence of events
is portrayed in Figure 1. This is a composite based on data from different
investigations using experimental rats to illustrate the process of injury
and repair over time following short-term single exposures of 4 hours or less.
It is likely that this sequence of events is similar in all mammals exposed
under the same conditions to low concentrations of NCL, but these experiments
have not been performed for numerous species. The important observation from
Figure 1 is that the effects of NCL exposure may not peak for several hours
after initial exposure, and subjects may require up to several days in an unex-
posed environment to fully recover.
t
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ui
Ul
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u
1C
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O
|mrj-q j
EXPOSURE
j
CHEMICAL REACTION
I I i I I ' ' I
SUSCEPTIBILITY TO
MICROORGANISMS
CELL DEATH (m*x.«t 24 hr.)
BIOCHEMICAL INDICATORS
OF INJURY (max. it 18 hr.) ~H
I.- REPLACEMENT OF DEAD
AND INJURED CELLS
AND BIOCHEMICAL
INDICATORS OF REPAIR
(m*x. »t 48 hr.>
I I I . . I
(logscaU) 4 10 24 48
I hour* I
7 14 30 2 3 6 12
d*ys t month* I
Figure 1. Temporal Sequence of Injury and Repair Hypothesized
From Short-Term Single Exposures of Less than 4 Hours
1
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The initial temporal sequence of events during long-term continuous
exposure to NCL is somewhat similar to the sequence for short-term exposures.
Figure 2 displays the variety of events which take place during N02 exposure.
Cell death and replacement predominate during the first two weeks of exposure.
Cell replication peaks at approximately two days after exposure initiation.
Rate and extent of cell death are dose dependent, just as are other indicators
of NCL-induced damage. A steady state of injury and repair appears to
develop after one or two weeks. Concentrations of several blood enzymes
increase due to cellular injury after the first week. Susceptibility to
infection rises nearly linearly over time due to the increasing destruction
of pulmonary defenses. Morphological alterations and pulmonary function
changes perhaps require the longest exposure for development. Emphysema-
like changes have been demonstrated in experimental animals following extended
29
exposure to relatively low levels of NCL (Port, et al., 1977) .
i
u
ui
a.
u.
ui
O
ui
UI
CHEMICAL REACTION
PULMONARY
FUNCTION
'CHANGES
BIOCHEMICAL
INDICATOR
OF DEATH
AND
INJURY
REPLACEMENT OF DEAD
AND INJURED CELLS
AND BIOCHEMICAL
INDICATORS OF REPAIR
INCREASED.
SUSCEPTIBILITY TO
MICROORGANISMS
LEVATED
.CELL
TURNOVER
INCIDENCE
EMPHYSEMA
-LIKE PATHOLOGY
HYPOTHETICA
TOLERANCE
1 -
10
24 48
14
6 12 (lofltcalt)
hours
days
months
Figure 2. Temporal sequence of injury and repair hypothesized from
continuous exposure to NCL as observed in experimental animals.
(4 on y-axis is equivalent to 100% of Observed Effects)
1
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The influence of exposure mode (concentration x time or C x T) of NCL
has been investigated in animals, and it has been suggested that, for a
constant dose (C x T), brief exposures to high concentrations have a greater
11 12 13
effect than prolonged exposures to lower concentrations of NCL. ' '
C. Evaluation of Scientific Evidence on Effects Attributed to NOp Exposures
A broad spectrum of effects on human and animal respiratory systems has
been associated with N02 exposure. The time-dependent continuum of observed
N0? effects ranges from (1) death or irreversible lung damage associated with
experimental animal exposures and accidental high exposures of humans in the
range of 150-300 ppm or higher; through (2) less severe, but significant
short-term and chronic tissue damage, functional impairment, and aggravation of
other disease processes at levels of 5-100 ppm; to (3) milder irreversible and
reversible effects, such as changes in pulmonary function, which occur at
N02 levels below 5 ppm.
In reviewing the available scientific data, key animal toxicology
studies will be examined to assess what type of effects NCL might be
expected to cause in humans. Human clinical studies will then be reviewed
to identify which effects have been demonstrated to occur in humans. Finally,
available epidemiology studies will be reviewed to identify other effects
which have been reported to occur in humans. Key among these latter studies
are a series of indoor air pollution studies frequently referred to as the
"gas stove studies". Throughout the review of the scientific data, primary
emphasis will be placed on N02 exposures below 5 ppm since concentrations in
the ambient air are generally well below this level.
1. Interpretation of Selected Animal Toxicology Studies
Animal toxicology studies can improve the understanding of
human health effects of acute and chronic exposures to NOp. These studies
provide health effects information based on scientific endpoints and
exposure conditions which would be considered unethical for human chamber
studies. Thus, a fuller array of potential effects from N02 exposure can
be evaluated in animals.
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10
The criteria document contains a review of numerous animal toxicology
studies showing a variety of effects in various animal species from exposure
to NOp. In Appendix A of this paper, many of these studies are reviewed
and summarized in a manner which facilitates an analysis of the observed
health effects. In Table 1 of Appendix A, some of the observed effects
from short-term exposure (several hours) are listed. These effects range
from very serious and irreversible effects to less serious reversible
effects. These effects include: (1) increased mortality from bacterial infection
caused by intermittent exposure to 0.5 ppm NO, and subsequent exposure to
14
Klebsiella pneumoniae; (2) alveolar damage following repeated (6 hr/day)
exposure to 0.5 ppm N00; (3) protein in the urine suggestive of kidney
16
damage following multiple 4 hr exposures of 0.4 ppm NOp, (4) morphological
alterations (swollen collagen fibers) following multiple 4 hr/day exposures
to 0.25 ppm NOp; (5) interference with liver metabolism suggested by an
increase in pentobarbital-induced sleep time following a single exposure to
18
0.25 ppm N09 for 3 hours; (6) interference with hormone metabolism in the
19
lung following a single exposure to 0.20 ppm NOp for 3 hours; and (7) in
vivo nitrosamine biosynthesis following exposure to morpholine and a single
20
exposure to 0.20 ppm NOp for 4 hours.
In critically assessing animal studies involving short-term exposure
to NOp, it is obvious that numerous effects have been observed for a variety
of animal species (dogs, rabbits, guinea pigs, monkeys, rats and mice).
There is presently no reliable way to relate human and animal dose-
response data. Many of the effects associated with short-term exposures
appear to result not from a single exposure, but from multiple exposures
in the range of 0.2 ppm to 0.5 ppm for several hours. Of particular
interest is that exposure of animals to concentrations slightly above
those currently being experienced in the ambient air appears to cause a
decrease in resistance to bacterial infection. As will be discussed later,
this same type of effect has also been reported to occur in humans.
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11
Table 2 of Appendix A provides a summary of some of the effects which
have been associated with animals exposed to NO,, over relatively long periods
(1 day to several years). These effects include: (1) significantly increased
susceptibility to infection resulting in increased mortality for continuous
11 13 21
and intermittent exposure to >_ 0.5 ppm N02, (2) decreased immunological
response resulting in increased respiratory infection for exposures of
22 23
0.5-1.0 ppm N02, continuous and intermittent; ' (3) increased lung protein
content suggesting edema and cell death for 3-6 week exposures to 0.5 or 1.0 ppm
NO, in Vitamin C deficient animals; (4) hematological disturbances (e.g.
OC_pT
increased cholinesterase and lysozyme levels) suggestive of liver ~ and
heart25'26 damage at 0.5 ppm N02 for 1 week; (5) increased RBC 2,3-diphospho-
glycerate, indicating tissue deoxygenation after 1 week exposure to 0.36 ppm
28
N09; (6) emphysematous alterations resulting from a six month exposure
29
to 0.1 ppm N00 with daily spikes of 1.0 ppm NCL or 68 months exposure to
30
0.64 ppm N02 and 0.25 ppm NO followed by a 2 year period in clean air.
A critical assessment of the available animal toxicological data for
long-term exposure to N02 reveals that many of the above effects occur in
a variety of animal species, and that many of the effects can be considered
serious and irreversible. For example, the emphysematous alterations in
dogs associated with long-term exposure to N02 are of major concern since the
occurrence of this type of effect in humans would clearly be adverse.
While most of the chronic studies were conducted at exposures considerably
higher than those encountered in the ambient air, it should be noted
29
that one study did observe emphysematous alterations in mice when exposed
to N02 levels about twice the current annual standard. However, in this study,
the chronic exposure was supplemented with daily spikes of 1.0 ppm and it is
not possible to determine if the cause of the effect was chronic exposure,
short-term spikes or a combination of these two.
Currently there is no means available to extrapolate the results of the
animal studies (either short-term or chronic) directly to humans. Neverthe-
less, the animal toxicology studies do indicate that N02 exposure causes
serious biological damage to a number of animals. These studies clearly
raise a "warning flag" for potential effects in humans.
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12
2. Review and Evaluation of Controlled Human Exposure with N02 Alone
Attention will now be focused on a series of human clinical studies
in which humans were exposed to NCL in enclosed chambers. We will first
discuss those studies in which NCL was the sole pollutant present. In a
subsequent section similar studies involving simultaneous exposure to NCL
and other air pollutants will be addressed.
Controlled human exposure studies are valuable in the evaluation of
potential health effects related to pollutant exposures because they can
provide accurate measurements of exposure levels and conditions for a single
pollutant or simple combinations of pollutants. However, clinical studies
usually do not provide definitive evidence of effects that might be experienced
in the urban environment where exposure levels are constantly changing and
multiple pollutants are present in the air. Clinical studies have also been
limited to examining the effects of single, short-term exposures and, thus,
do not directly address effects that may be caused by repeated, short-term
exposures over weeks, months, or longer periods of time.
A number of studies have been conducted which examine effects on
healthy adults exposed to single, short-term concentrations of NC^. A
very limited number of clinical studies have tested potentially sensitive
subjects such as individuals with asthma or chronic bronchitis. Other
groups which may be sensitive to NCLS such as children or elderly individuals,
have yet to be tested in clinical studies for effects that may be due to
N02 exposure.
Table 1 summarizes reported effects and exposure levels for a
selected group of human clinical studies conducted with NCL levels at or
below 2.0 ppm. These studies have explored four potential indicators of
adverse health effects associated with NCL exposures: (1) measurable
changes in pulmonary function parameters, (2) symptomatic effects (e.g.,
coughing, chest tightness, etc.), (3) modified response to a pharmacological
bronchoconstrictor, and (4) biochemical changes.
a. Pulmonary Function Changes in Adults Exposed to NCv The
studies summarized in Table 1 and in the Criteria Document (Tables 1-1 and
1-2) indicate that increased airway resistance (R,..) and other physiological
uW
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TABLE 1
COMPILATION OF EFFECTS REPORTED IN SELECTED HUMAN STUDIES EXAMINING NITROGEN DIOXIDE EXPOSURES-
N02
oncentration Exposure
(oom) Durations
0.1 1 hr
O.S 2 hr
O.S to 5.0 15 m1n
O.S to 5.0 approx.
3 min
0.5 2 hr
0.7 to 2.0 10 min
1.0 2 hr
1.0 and 2. S 2 hr
1.0 and 2.0 24 hr
Study
Poou 1 ati on
20 asthmatics
10 healthy
adults
7 chronic
bronchi tics
13 asthmatics
13 healthy
adults
88 chronic
bronchi tics
63 chronic
bronchi tics
15 healthy
exercising
adults
10 healthy
adults
16 healthy
adults
3 healthy
adults
TO healthy
adults
Reoorted Effects References
Specific airway resistance in- Orenek 1976 38
creased and effect of broncho-
constriction enhanced in 13 of 20
subjects after exposure to N02-
Neither effect observed in 7 of
20 subjects. A broncho-
constrictor (carbachol) was used.
1 healthy and 1 bronchitic subject Kerr,et al.,
reported slight nasal discharge. 1979 J
-------
14
changes indicative of impaired pulmonary function have been clearly demon-
strated to occur in healthy adults exposed to single 2-hr NCL concentrations
ranging from 2.5 to 7.0 ppm. Certain studies also indicate statistically
significant pulmonary function changes occur in healthy and sensitive
subjects after shorter duration exposures (3-10 minutes) to N02 concentra-
tions below 2.0 ppm.
31
In regard to the latter point, Suzuki and Ishikawa (1965) reported
increases in inspiratory and expiratory flow resistance of approximately
50 and 10 percent, respectively, over control values for 10 healthy subjects
after a 10-minute exposure to N02 concentrations in the range of 0.7-2.0
ppm. The authors, however, do not indicate at what point, in this concentra-
tion range, effects were first observed, nor do the authors specify whether
subjects were exposed to a constant N09 level.
32-35
Several additional studies of healthy adults reported either no
statistically significant, or relatively small, changes in pulmonary function
33
at or below 1.0 ppm N02. Hackney et al. (1978) reported no statistically
significant changes in 18 different measures of pulmonary function with
the exception of a marginal loss in forced vital capacity (FVC) (1.5%
mean decrease, p < 0.05) for 16 healthy adults exposed to 1.0 ppm N02
for 2 hours on two successive days. The authors questioned the health
significance of this small, but statistically significant, change in FVC
in healthy subjects and suggest that the changes found may be due to
random variation given the large number of measurements analyzed.
32
Kerr et al. (1979) exposed 10 normal healthy adults and 20 individuals
with asthma and chronic bronchitis to 0.5 ppm N02 for 2 hours. A 15-minute
period of exercise (light to moderate) was undertaken during the 2-hour
exposure. The only statistically significant change reported in a number
of pulmonary function measurements examined was in quasistatic compliance
in healthy adults and in the group of 20 individuals with asthma and
chronic bronchitis. The bronchi tics and asthmatics showed no statistically
significant changes for all pulmonary functions tested when analyzed as
separate groups. The differences reported for the combined group of
asthmatics and bronchitics were no larger than the changes reported for
a 2-hour period on the first day, which involved no exposure to NO,,. The
authors, therefore, suggested that the changes reported may be due to normal daily
variation in the subjects rather than to N02 exposure. Due to the slight
-------
15
nature of the changes in quasi static compliance and the absence of
statistically significant changes in other pulmonary function measures
examined, this study did not demonstrate measurable impairment of pulmonary
function in healthy adults or asthmatics and chronic bronchitics exposed for
short periods (2 hours) to NCL concentrations of 0.5 ppm or below.
Folinsbee et al. (1978) concluded that there were no physiologically
significant changes in cardiovascular, metabolic, or pulmonary function
for 3 groups of 5 healthy adults where each group underwent a different
period of exercise (15, 30, or 60 minutes of light to moderate exercise)
and was exposed to 0.6 ppm NO, for 2 hours. Similarly, Beil and Ulmer
35
(1976) reported no increase in airway resistance in 8 healthy adults
after a 2-hour exposure to 1.0 ppm NO^. At f^k concentrations of 2.5 ppm
or above, statistically significant increases in airway resistance were
measured by these investigators. However, no statistically significant
changes in blood gas parameters (e.g., arterial partial pressure of oxygen
and partial pressure of carbon dioxide) were observed.
A limited number of controlled clinical studies have addressed the
issue of whether measurable respiratory effects occur in sensitive human
JC
subjects exposed to N02 levels below 5.0 ppm. Von Nieding et al. (1971)
exposed 63 chronic bronchitics to NO^ concentrations ranging from 0.5 to
5.0 ppm for 30 breaths (approximately 3 minutes). At or below 1.5 ppm no
statistically significant changes in pulmonary function were noted. However,
at exposure levels of 1.6-2.0 ppm N02, statistically significant increases
in airway resistance were reported. At levels greater than 2.0 ppm, the increase
in airway resistance was more pronounced.
Studies by Von Nieding et al. (1971; 1973)36'37 also reported that in
persons with chronic bronchitis, 10-15 minute exposures to concentrations
in the range of 4.0-5.0 ppm produced decreases in arterial partial pressure
of oxygen (Pa02) and increases in the differences between alveolar and
arterial blood partial pressure of oxygen (AaD02). The changes observed in
these parameters are indicative of pulmonary function impairment.
-------
16
b. Symptomatic Effects in Adults Exposed to N00. In the Hackney et al.
33
(1978) study, 5 of 16 healthy adult subjects reported an increase in symptomatic
effects (cough, chest tightness, laryngitis, and nasal discharge) after
exposure to 1.0 ppm NQ2 for 2 hours. However, the difference in symptom
scores was not statistically significant over control-group symptom scores.
The authors noted that only one of the five sensitive subjects reported chest
pain and coughing comparable to typical clinical effects observed in ozone
studies. Two others among the five reported lower-respiratory symptoms
(coughs or chest tightness), and all five reported upper-respiratory symptoms
(nasal discharge or laryngitis). The authors also expressed doubt that the
symptom increases were of health significance. Only 1 of 10 healthy subjects
32
in the Kerr et al. (1979) study reported mild symptomatic effects associated
with exposure to 0.5 ppm N02.
There is evidence that relatively low levels of N02 may cause
symptomatic effects in individuals with chronic lung disease (i.e.,
32
asthmatics and chronic bronchitics). In the Kerr et al. (1979) study ,
1 of 7 chronic bronchitics and 7 of 13 asthmatics reported various
subjective symptoms during or after exposure to 0.5 ppm N02 for 2 hours
with 15 minutes of light or moderate exercise during the exposure. The
authors indicated that the symptoms reported were mild and reversible
and included slight headache, nasal discharge, dizziness, chest tightness,
and labored breathing during exercise.
c. Effect of N00 on Increased Response to a Bronchoconstrictor. The effect
~~ ci
of N00 on increasing bronchial sensitivity of asthmatic individuals to a
38
bronchoconstricting agent has been investigated by Orehek et al. (1976). The
purpose of using a bronchoconstricting agent is to assess possible N02
exacerbation of a response that occurs in some asthmatics when they are
exposed to agents in the natural environment to which they are particularly
sensitive. Orehek obtained dose-response curves for changes in specific
airway resistance (SR ) as a result of subjects inhaling carbachol
(a bronchoconstricting agent) after a 1-hour exposure to either clean air
or 0.1 ppm N02. Only 3 of 20 asthmatics tested showed a marked increase in
SRaw fol"l°win9 N02 exposure; however, when smaller increases in 10 other
subjects were combined with the 3 responders there was a small, but statis-
tically significant, increase in SR for the group of 13. The N09 exposure
aw L-
-------
17
enhanced the effect of the bronchoconstrictor in the same 13 subjects.
Specifically, the mean dose of carbachol producing a twofold increase in
SR in the 13 sensitive individuals was decreased from 0.77 mg to 0.36 mg
dW
as a result of NOo exposure. Seven of the asthmatic subjects showed neither
an increase in SR nor an enhanced effect of carbachol in response to the
exposure to NOp.
The Criteria Document notes that considerable controversy exists over
38
interpretation of the Orehek et al. (1976) study and the health significance of the
increased response to a bronchoconstrictor observed in the study. The use of
a potent laboratory bronchoconstrictor and selection of a responding group for
statistical analysis after the fact make interpretation of this study difficult.
d. Biochemical Changes in Healthy Adults Exposed to N0?. A single study
_ j*
by Posin et al. (1978) reported statistically significant decreases in
hemoglobin, hematocrit, and erythrocyte acetylcholinesterase in 10 healthy
subjects who were exposed to 1.0 ppm N02 for 2.5 hours. Other blood biochemical
changes, such as elevated levels of red blood cell lipids, were reported after
exposure to 2.0 ppm. Some questions have been raised as to the importance
of these findings due to considerable day to day variability in the
physiological parameters that were measured in the absence of NOp exposures.
e. Staff Comments on Controlled Human Exposure Studies (NO,, Alone)
Due to a paucity of controlled human studies involving healthy individuals
and particularly more susceptible members of the population, there is
considerable uncertainty about the lowest exposure levels of N02 that
will cause (1) measurable impairment of pulmonary function, (2) symptomatic
effects, (3) increased responsiveness to bronchoconstricting agents in
the environment, or (4) biochemical changes.
With regard to the lowest level of N09 associated with measurable
32-35
impairment of pulmonary function, most studies involving exposures
in the range of 0.5 to 1.5 have reported little or no change in pulmonary
function. The possible exception is the Suzuki and Ishikawa study, which
reported statistically significant changes in inspiratory and expiratory flow
resistance in 10 healthy adults after a 10-minute exposure to N02 concentra-
tions somewhere in the range 0.7-2.0 ppm. It is not possible, however, to
-------
18
identify the specific concentration(s) within the range that was associated
33
with the observed effects. However, the fact that Hackney et al. (1978) and
oc
Beil and Ulmer (1976) reported no statistically significant changes in
pulmonary function after 2-hour exposures to 1.0 ppm NCL suggests that
the effects observed by Suzuki and Ishikawa were probably associated
with N00 concentrations above 1.0 ppm.
3fi
The Von Nieding et al. (1971) study provides convincing evidence
that chronic bronchitics exposed to N02 concentrations of 1.6 ppm or
greater for approximately 3 minutes experience increases in airway
resistance. Based on a review of the available evidence, the lowest
level of NOp exposure that credible studies have associated with measurable
impairment of pulmonary function appears to be in the range 1.0 - 1.6 ppm.
It should be noted that the exposure periods were considerably less
31 36
than 1 hour in two of the studies ' reporting pulmonary function changes.
The health significance, however, of the small changes in pulmonary function
reported in these two studies is uncertain. Several CASAC members
have expressed concern that a standard designed to prevent relatively
small changes in pulmonary function (such as those observed in the Suzuki
31 36
and Ishikawa and Von Nieding et al. studies) from occurring more
than once per year would be unneccessarily stringent. The CASAC
members indicated that they were more concerned about the health implications
of repeated exposures to the peak concentrations observed in the two
studies than the effects associated with a single exposure.
A judgment that must be made with regard to the above evidence
concerns the degree of change in pulmonary function that should be considered
an adverse health effect. Because the human respiratory system is endowed
with a large reserve capacity, fairly large changes in pulmonary function
(e.g., 50 percent increase in airway resistance) may not ordinarily be perceived
in normal, healthy adults. However, a portion of the population with respira-
tory problems may be operating at or near the limit of their lung function
capacity when engaged in light or moderate exercise. For these individuals,
a relatively small impairment of lung function may affect their ability to
perform certain tasks or may aggravate a pre-existing pulmonary disease.
-------
19
Another area of uncertainty concerns the lowest levels of N02 exposure
that will lead to symptomatic effects in healthy adults and sensitive
individuals. As indicated above, only very limited data are available
from a relatively small number of subjects. The available evidence
suggests that few, if any, healthy adults would experience discomfort
or other subjective symptoms during or after short-term (less than 2-hr)
exposures to N09 concentrations at or below 1.0 ppm. The evidence from the
32
Kerr et al. (1979) study indicates that some sensitive individuals (parti-
cularly asthmatics) may experience mild and reversible symptomatic effects,
such as wheezing and chest tightness, upon exposure to 0.5 ppm NOp for 2 hours.
The symptomatic effects observed in asthmatics are of concern because
they cause discomfort and may restrict normal activity or limit the performance
of tasks. There is also concern, based on reasonable medical judgment or
hypothesis, that the symptomatic effects observed may be indicators of other
deleterious effects occurring in the respiratory system which currently cannot
be measured in human studies due to ethical limits on testing and limitations
of current measurement technique. Therefore, although these symptoms appear
to be reversible and transitory we are concerned that symptomatic effects,
32
such as those observed in the Kerr et al. (1979) study after exposure to
0.5 ppm N02 for 2 hours with intermittent exercise, may constitute adverse
health effects for some individuals. If these symptomatic effects are
not judged by the Administrator to be adverse health effects within the
guidance provided by the Clean Air Act and its legislative history, they still
may be considered as a factor in judging which standard would provide an
adequate margin of safety and/or be considered in setting a short-term
secondary standard for N02.
With regard to possible increased responsiveness of asthmatics to
bronchoconstricting agents in the environment, the results of the Orehek
study are inconclusive. Due to the small magnitude of the responses,
lack of reported symptoms in the subjects, and selection of responders after
the fact in the Orehek study, it remains to be determined which levels of
N02 may produce significant effects in asthmatics under ambient exposure
conditions although it provides suggestive evidence that asthmatics may
respond to N02 at lower levels than healthy persons.
-------
20
3. Review and Evaluation of Controlled Human Exposure Studies
with N02 and Other Pollutants
a. Reported Findings. It has been theorized that concurrent
exposure to multiple pollutants might produce additive or greater than
additive health effects. This has been investigated in several studies
involving N02 and other pollutants such as ozone (03), carbon monoxide
(CO), and sulfur dioxide (S02). Table 2 summarizes the reported findings
and exposure levels for these studies.
Several investigations involving multiple pollutant exposures have
failed to find any additional effects due to the addition of N02 beyond
those found for 03 alone. Hackney et al. (1975) ' reported little or
no change in pulmonary function measurements (FVC, FEV, R , and others)
aw
in healthy volunteers exposed to N02 and other pollutants concurrently.
Four healthy subjects exposed to 0.5 ppm 03; to 03 and 0.3 ppm N02; and to
0-, NO, and 30 ppm CO showed no increase in pulmonary function beyond
40
minimal alterations which were observed for subjects exposed to 03 alone.
Another group of 7 subjects, including some thought to be unusually reactive
to irritants, showed little or no change in pulmonary function following
a 2-hour exposure to 0.25 ppm 03 alone, or with addition of 0.3 ppm N02 or
N02 plus 30 ppm CO.41 Finally, Horvath and Folinsbee (1979)42 found no
additive effects or interaction between 0.5 ppm 03 plus 0.5 ppm NOp under
four different environmental conditions involving changes in temperature and
relative humidity.
Von Nieding et al. (1977) reported no changes in R or difference
aW
between alveolar and arterial blood partial pressure of oxygen (AaD02)
in 11 healthy subjects exposed to 0.05 ppm N02, 0.025 ppm 03, and 0.11
ppm S0? for 2 hours. Nine of these healthy subjects were exposed to the
same mixture of pollutants followed by bronchial challenges involving
inhalation of an aerosol containing 1%, 2%, and 3% acetylcholine. A
statistically significant increase in specific resistance relative to
the control exposure (p < 0.1) was reported for the 2% acetylcholine solution.
The increases in specific resistance with the 1% and 3% acetylcholine solutions
and mixture of pollutants, however, were not statistically significant. The
-------
21
TABLE 2
EFFECTS ON PULMONARY FUNCTION IN SUBJECTS EXPOSED TO NO,
AND OTHER POLLUTANTS i
Concentration Exposure
(ppm) Duration
0.05 NO, * .11 SO, + 2-Hours
0.025 Oj d
0.50 03; 0.50 03 + 4-Hours
0.29 NO-; 0.50 0, +
.29 N02 + 30 CO J
0.25 03; 0.25 03 * 2-Hours
0.29 NOj; 0.25 03 +
0.29 N02 + 30 CO
50 CO + 5 S02;
4.3 N02 + 50 CO + 5 SOj
0.5 03; 0.5 0, *
0.5 N02
UNDER FOLLOWING
CONDITIONS:
1) 25°C, 45% rh Rest-60 min.
2) 30°C, 85* rh Exercise-30 min.
3) 35°C, 40% rh Rest-30 min.
4) 40°C, 50% rh
Study
Population
11 healthy
subjects
4 healthy
male
subjects
7 male
subjects, some
believed to be
unusually
reactive to
respiratory
irritants
3 subjects
8 young
adults
Reported
Effects
Increased sensitivity
to bronchoconstrictor
as shown by increases
in Raw No effect on
A D02 or Raw without
bronchoconstrictor.
Minimal change in
pulmonary function
caused by 0, alone.
Effects not caused
by N02 or CO.
Minimal change in-
pulmonary function
caused by 0, alone.
Effects not increased
by N02 or CO.
Increase in dust
retention from 50%
to 76% after N02
was added to air
containing SO. and CO.
Response found only
for 03; no greater
than additive effect
or interaction between
0, and N02 was observed
References
von Niedininet
al., 1977
Hackney et al.,
197541
Hackney et al.,
1975 4"
Schlipkoter
and Srockhaus,
1963 45
Horvath and <2
Folinsbee, 1979
-------
22
nine healthy subjects were also exposed to a mixture containing 5 ppm
N02, 0.1 ppm Oo, and 5 ppm SCL followed by the same bronchial challenges noted
above. The authors observed a more pronounced response which was statistically
significant for all three acetylcholine concentrations (p < 0.01). Some of
the methods used by Von Nieding and his co-workers differ from those used in
the United States and may not be directly comparable. In spite of the
differences in techniques, it is generally agreed that the methods used by
44
Von Nieding provide valid information on directional changes in R or AaD09.
45
Schlipkdter and Brockhaus (1S63) studied the effects of exposure
to 4.8 ppm NOp, 50 ppm CO, and 5 ppm S02 on lung deposition of inhaled
dusts (0.07 to 1.0 micrometers). Under control conditions and with CO and SOp
exposures, 50 percent of the dust was retained. Dust retention increased
to 76 percent when dust was administered in an atmosphere containing 4.8
ppm NOp along with 50 ppm CO and 5 ppm SCL . This study suggests that elevated
NOo concentrations in inhaled air may result in retention of larger proportions
of inhaled ^articulate matter; but specific dose-effect relationships for
the induction of such effects remain to be determined.
b. Staff Comment on Controlled Human Exposure Studies
wi th Other Pol 1 utants ) . The studies discussed above provide
little support for additive or greater-than-additive effects being associated
with exposure to ambient concentrations of N02 in the presence of other
pollutants such as 03, CO, or S02. The principal exception is the
increase in sensitivity to a bronchoconstrictor (acetylcholine) after
exposure to a mixture containing N09, 0.,, and S09 reported by Von Nieding
4^ to c.
et al . (1977). The Criteria Document explains the difficulty in
interpreting Von Nieding's findings in view of: (1) the uncertain
health significance of altered sensitivity to bronchoconstrictors in
healthy or sensitive subjects; (2) some uncertainties due to methodological
differences between his techniques and other investigators; and (3) lack
46
of confirmation of the findings by other investigators. Due to the
concerns stated above, the results of the Von Nieding study should not
be used in determining the lowest concentration convincingly associated
with adverse health effects. The study should be considered solely as a
factor in judging which standard(s) will provide an adequate margin of
safety.
-------
23
4. Review and Evaluation of Selected Community Epidemiclogical
Studies
a. Reported Findings. Interpretation of epidemiological studies on
the effects of individual air pollutants is unavoidably complicated by the
complex mixtures of pollutants in air. The most that can usually be
demonstrated by such studies is an association, and not a cause and effect
relationship between health effects and ambient concentrations of a given
pollutant. Epidemiological studies have often been hampered by methodological
problems and the resultant difficulties in determining actual exposures for
study populations. The major advantage of epidemiological evidence is that
it reflects real world exposures to the pollutant along with exposure to
other pollutants and environmental stresses (e.g., temperature, humidity, etc.).
Community studies on the effects of NCL exposure conducted prior to
1973 are of questionable validity due to the use of the Jacobs-Hocheiser
method of measuring atmospheric concentrations of NCL. This method has
since been withdrawn, and studies which used the Jacobs-Hocheiser method are
of limited value because quantitative NCL exposure levels cannot be reliably
determined.
47 48
Shy et al. ' have reported small, but statistically significant,
decreases in FEV in children (7 to 8 years old) living in areas of relatively
high NCL concentrations compared to children living in areas with lower NCL
47-49 ^
concentrations. Studies by Shy and co-workers also suggested that the
incidence of acute respiratory disease during 1968-69 was 19 percent
higher for families living in apparently high NCL exposure areas of
Chattanooga than for control families in apparently lower NCL exposure areas.
The distances of three study communities from a large point source of NCL .
(a TNT plant which is no longer in operation) resulted in an apparent
gradient of exposure over which illness rates were determined. However,"
47-49
the studies conducted by Shy and co-workers in 1968-69 in Chattanooga,
which in part formed the basis for the existing annual NCL standard, cannot
be used to determine quantitative relationships between NCL levels and specific
health effects due to the problems with the measurement of NQ0 levels. Shy's
50
follow-up study of lung function in school children conducted during the
1971-72 school year failed to report any noticeable pulmonary function deficits.
It should be noted that ambient NO,, levels were lower in 1971-72 due to the
shutdown of the large NOV point source in Chattanooga.
X
-------
24
49
In a retrospective study in Chattanooga, Pearlman et al. (1971)
studied respiratory disease among first- and second-grade school children
and among children born between 1966-68. The Criteria Document states
that from among several respiratory disease indicators assessed, only
some bronchitis rates in children were reported to be higher in the area
of maximum N02 concentration; no significant differences were seen for
bronchitis rates for children living in the study areas for 1 or 2 years.
The bronchitis rates for children who had lived in the same neighborhood
for 3 or more years were reported to be significantly greater (32.2 per
100) than those for children in the low concentration area (23.2 per
100). According to the Criteria Document, however, health survey instrument
validation results indicated somewhat questionable accuracy of parental
recall of whether bronchitis episodes occurred before or after moving into
study areas 3 years earlier. Clear-cut estimates of N02 exposure levels
associated with reported health effects are not available.
Other community epidemiology studies which have often been cited
regarding N02 are summarized in Table 3. While most of these studies
tend to indicate that reported concentrations of NO, had no detectable
51
effects on lung function, an exception is the Kagawa and Toyama (1975) study
which showed some correlation between maximum expiratory flow rate or
specific airway conductance and NQ2 levels at the time of the study.
One-hour N02 concentrations were measured once a day during the study and
ranged from 0.02 to 0.19 ppm, but the data do not allow quantitative
estimation of specific N02 levels that might have been associated with the
occurrence of pulmonary function decrements. Nor do the results allow one
to discern clearly the relative contribution of N02 to induction of observed
respiratory effects versus those due to a complex interaction of pollutants
including N02.
Linn et al. (1976),52 Cohen et al. (1972),53 Burgess et al. (1973),54
and Speizer and Ferris (1973a,b) ' found no differences in pulmonary
function tests in separate epidemiological studies which also involved
complex pollutant mixtures in ambient air. The N02 concentrations were
in the range 0.02-0.51 ppm in these epidemiological studies.
b. Staff Comments on Community Epidemiology Studies. Due to
methodological problems (i.e., use of Jacob-Hocheiser method) with the
Shy et al. ' ' and Pearlman et al. studies performed in Chattanooga,
derivation of a quantitative assessment of the health effects reported to be
-------
25
TABLE 3
EFFECTS OF EXPOSURE TO NO? UN PULMONARY FUNCTION IN
COMMUNITY EPIDEMIOLOGY STUDIES
Exposure Concentrations
(pom)
Study Population
Reported Effects
References
Median hourly 0.07 NO-
"tedian hourly 0.15 Ox
Median hourly 0.35 NO-
tedian hourly 0.02 O/
205 office workers
in L.A.
439 office workers in
San Francisco
No differences in most tests. Linn et al.,
Smokers in both cities showed 1976 2
greater changes in pulmonary
function than non-smokers.
High exposure area
24 hr high 0.055
.035
-hr mean
NO
ligh exposure area 0.14 NO,
to 0.30 NO;
Low exposure area 0.06 N02
to 0.09 NO,
128 traffic policemen
in urban Boston and
140 patrol officers in
nearby suburbs
No dif'erence in various
pulmonary function tests
Speizer and
Ferris,
Burgess et al
19 73"
ligh exposure group:
Estimated 1-flr max 0.2S to
0.51 N02
Annual mean 24-hr 0.051 NO,
.ow Exposure groups:
Estimated 1 hr max 0.12
3.23 N02
Annual mean 24 hr 0.01
to
Nonsmokers in L.A. No differences found in
(adult) several ventilatory
measurements including
spirometry and flow
volume curves
Cohen-,et al.,
1972"
NO,
nr cone, at time
of testing (1:00 p.m.
0.02
)to
0.19
NO,
20 school age children
11 years of age
During warmer part of year,
NOj, S02iand TSP signi-
ficantly correlated with
Vmav at 2SZ 4 SOS FVC
Kagawa and 51
Toyama, 1975
specific airway con-
ductance. Significant
correlation between each
of four pollutants (NO,,
NO, SO, and TSP) and
at 25Jrand SOS FVC;
but no clear delineation
of specific pollutant
concentrations at *hicn
effects occur.
ax
-------
associated with NCL levels from these studies is not possible. There is also
considerable difficulty in trying to sort out any health effects caused by
N02 from effects caused by other pollutants found in the ambient air
(e.g., ozone, particulates, S02) at the time of the study. In our judgment,
these problems severely limit the usefulness of these studies for
standard-setting purposes.
While the Kagawa and Toyama study shows some pulmonary function
effects related to N02 concentration, the results suggest that the
observed respiratory effects are caused by a complex mixture of pollutants.
Also, inadequate characterization of exposure to NCL prevents our drawing
any firm conclusions about the relationship between NCL exposure and
resulting health effects.
At best we can only conclude that the findings of Shy et a!.,47'48'50
Pearlman et al., and Kagawa and Toyama are not inconsistent with
the hypothesis that N02, in a complex mix with other pollutants in the
ambient air, adversely affects respiratory function and illness in
children. That is, although these studies do not provide clear evidence
for positive associations between health effects and ambient exposures to
NCL, neither do they suggest that negative or no associations exist between
such variables. Little or no evidence of health effects at ambient concentration6
of NCL is provided by other community epidemiological studies.
It should be recognized that the community epidemiology studies cited
and discussed above did not take into account exposure to, and effects of,
indoor air pollutants, such as NCL generated by the use of gas stoves. The
next section focuses on evidence of health effects associated with exposure
to NCL concentrations indoors.
5. Review and Evaluation of Epidemiological Studies
Involving Homes with Gas Stoves
A number of epidemiological studies have been conducted in the
United States and Great Britain which investigate the effects of indoor air
pollution on individuals living in homes with gas stoves compared to
those living in homes with electric stoves. Since several investigators
have found significantly higher levels of NCL in gas stove versus electric
stove homes, these studies provide an opportunity to explore the potential
health impacts of repeated short-term peaks and long-term exposures of NCL
on children and adults. The principal studies investigating indoor air
pollution in gas stove homes are summarized in Table 4.
-------
27
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-------
28
a. Increased Incidence of Acute Respiratory Illness and Symptoms
in Children Living in Gas Stove Homes - Reported Findings. Two groups of
investigators, one in Great Britain and one in the United States, have reported
increases in respiratory illness and/or respiratory symptoms in children
living in homes which used gas stoves for cooking compared to children living
in homes which used electric stoves. Results of the British study have been
reported by Melia et al. (1977, 1979)57'58, Goldstein et al. (1979)59, and
Florey et al. (1979).60 The initial study, conducted from 1973 to 1977, invests
gated the effects of indoor and outdoor air pollution on respiratory illness
and symptoms in a large group of young school children from randomly selected
areas in England and Scotland.
Melia et al. (1977) reported that cross-sectional analysis of the 1973
results indicated that crude prevalences of bronchitis, cough, colds going
to the chest, wheeze, and asthma were higher in children ages 6-11 living in
gas stove homes. The increases in prevalence were statistically significant
(p <0.05) for bronchitis, cough, and colds going to the chest in both sexes,
and for wheeze in girls. For bronchitis, the prevalence in gars stove homes
was 5.7 and 4.7 percent for boys and girls, respectively, compared to 3.1 and
2.0 percent for boys and girls living in electric stove homes. The authors
reported that the observed effect appeared to be independent of a number
of possibly confounding factors, including age, social class, latitude,
population density, family size, outdoor levels of smoke and sulfur dioxide,
and home heating fuel. This conclusion was based on the proportion of
children with one or more diseases or symptoms being higher for gas stove
homes when these various factors were taken into account. However, when all
of the factors were considered, the proportion of children with one or more
symptoms or diseases remaining higher only approached significance for girls
(p 21 0.10) but not boys. It should be noted that the data for 1973 did
not include smoking habits of family members which may have contributed
to the effects observed (see Tager et al., 1979).
58
Melia et al. (1979) reported the results of a similar cross-sectional
analysis for a different set of children studied in 1977. The authors found
crude prevalences of cough in boys (p ^ 0.02) and colds going to the chest
-------
29
in girls (p < 0.05) were significantly higher in homes with gas stoves.
When prevalences of the respiratory conditions reported in the 1973 study
were grouped, an association of gas cooking with occurrence of one or more
symptoms was found in both sexes (p ^ 0.01 in boys, p ^0.07 in girls).
When possible confounding factors considered in 1973, plus smoking among
family members, were taken into account, an association between gas cooking
and respiratory conditions was found in urban areas (p < 0.005 in boys,
p ;v0.08 in girls) but not in rural ones.
A major difficulty in interpreting the results from the two Melia
et al. studies described above is the lack of air pollutant measurements in the
specific residences of the subjects studied. In a separate study, Melia
62
et al. (1978) have reported higher NOp concentrations in the kitchens of
two gas stove homes compared to two electric homes. The average hourly
concentration of N02 in gas kitchens was 0.072 ppm, compared to 0.009 ppm in
the electric kitchens.
c-i jro
The Melia et al. studies ' appear to provide some suggestive evidence
for an association between exposure to gas stove combustion products and
increased incidence of acute respiratory symptoms and illness in children.
However, the authors of the Melia et al. studies have expressed concern
that the effects observed in their study may be due to some factors other than
N02, such as increased water vapor in gas stove homes. No information is
available, however, to confirm or refute the possible contribution of other
factors, such as increased humidity, to increases in respiratory illness and
symptoms.
Due to the incomplete analysis of possible confounding or covarying
factors (e.g., temperature and humidity) and the lack of short-term N02
measurements in the homes of the subjects studied, only the above qualitative
conclusions may be drawn regarding the Melia et al. studies.
In related research, a group of British investigators have studied
further the possible impact of N02 exposures in gas stove homes on
increased respiratory infection and decreased lung function. Goldstein
et al. (1979) and Florey et al. (1979) reported higher prevalence of
respiratory symptoms for children in gas stove homes than in electric
stove homes (p % 0.10). The study59 reported that weekly mean N02 concentrations
-------
30
in 428 kitchens with gas stoves ranged from 0.005-0.317 ppm (mean 0.112 ppm)
compared to weekly mean levels from 0.006-0.188 ppm (mean 0.018 ppm) in 87
kitchens where electricity was used for cooking. The weekly mean N02 levels
were 0.02 ppm or greater in all but one gas stove home, while only 11 of the
87 (12.6%) electric stove homes had weekly mean concentrations of 0.02 ppm
or higher. When various confounding factors were considered, the study
found only a weak association between prevalence of respiratory illness in
6- to 7-year old children and gas cooking in their homes. Lung function
tests also were performed on the children, but no statistically significant
associations were found between lung function and N02 concentrations in the
kitchens or bedrooms.
Speizer et al. (I960)64 and Spengler et al. (1979)65 have reported
results from an ongoing prospective epidemiological study of six communities
in the United States. They reported, based on a questionnaire completed
by parents, a statistically significant increase in respiratory illness in their
children before age 2. The study also reported a slight decrease in
pulmonary function, based on actual measurements, for children 6 to 9
years of age who were living in homes where gas was used for cooking.
The rate of acute respiratory illness in children before the age of
2, adjusted for parental smoking, social class, and city-cohort, was
reported as 32.5/1000 higher in gas stove homes than in electric stove
homes. This is an increase of between 16 and 26% compared with the 127 to
204/1000 rates observed in the electric stove homes. The authors have
recently indicated their concern that further analysis of data from
their study be conducted to confirm if differences in socio-economic
status were a major factor associated with the reported increase in rate '
of respiratory illness before age 2.
Speizer et al. (1980) also reported lower pulmonary function levels
in children 6 to 9 years of age who lived in gas stove homes. The
changes in two pulmonary function measures (FEV, and FVC) were small
(average difference 17 ml and 18 ml, respectively) but statistically
significant compared to children living in electric stove homes. The
authors hypothesize that the decrements in pulmonary function measurements
-------
31
observed may be an indicator that the lungs of some of these children may
not reach their full adult lung size. Further, the authors present a
biologically plausible hypothesis that persons with minor impairment
of total lung growth may be more susceptible to developing respiratory
64
problems during their adult life.
64
The Speizer et al. study monitored 24-hour average concentrations
over a 1-year period in the "activity room" (but not the kitchen) of
several (5-11) electric and gas stove homes in each of the six communities
studied. The monitoring results show that 24-hour average concentrations
in electric stove homes approximate levels monitored outside these homes.
An increase in NCL levels was observed in homes with gas stoves in five of
the six communities, which reflects the addition of indoor sources to
outdoor levels of NCL. The 95th percentile of measured indoor 24-hour
average NCL concentrations for homes in 6 cities were reported to be in
the range of 0.02-0.06 ppm for gas stove homes and 0.01-0.05 ppm for
electric stove homes. The measurement method employed to obtain 24-hour
average levels was the Saltzman (sodium arsenite) - bubbler method. The
authors of the study have indicated that the carbon dioxide (COp) levels
expected indoors may have interfered with the NO,, measurements, resulting
fifi
in lower NO, levels being recorded than actually occurred.
cc
As part of the same Six-City Study, Spengler et al. (1979)
monitored NOp levels in one kitchen of a gas stove home for approximately
2 weeks. Short-term peaks in excess of 0.25 ppm, and even 0.5 ppm NOp,
which lasted from minutes to hours, were measured in the kitchen during
cooking. The complete data set from the Spengler et al. (1979) study
are not available and, therefore, EPA is unable to characterize the
frequency distribution of short-term peak NO,, levels based on this
study. Other studies, unrelated to the Six-City Study have monitored NOp
concentrations in gas stove homes under a variety of conditions. The
results of these studies are summarized and discussed in the next
section (Analysis of NOp Levels in Gas and Electric Stove Homes).
-------
32
A series of studies by another group of investigators, Mitchell
CJ CO
et al. (1974) and Keller et al. (1979), found no association between
the use of gas stoves and increased rates of respiratory disease in
either children or adults. However, the number of children used in
these studies was approximately a factor of 10 smaller than in both
the British and U.S. studies, which yielded an association between increased
prevalence of respiratory illness and gas cooking. The relatively small
sample size would tend to lessen the likelihood of these studies finding
statistically significant differences, since the main health effect being
investigated is a relatively small difference in disease and symptom
prevalence rates.
b. Analysis of NO,, Levels in Gas and Electric Stove Homes. Since
the Six-City Study, to date, has not monitored short-term NCL levels
sufficiently, it is necessary to examine other studies which have monitored
NCL levels in other gas stove homes in order to estimate NCL levels that may
have occured in the Six-City Study homes. Table 5 summarizes the available
data on NCL levels in U.S. homes and in experimental buildings.
The study with the greatest amount of data on short-term NCL levels
69
in a variety of gas stove houses is reported in Wade et al. (1975) and
Cote et al. (1974) . They monitored NCL levels in 4 houses in a suburban
community in Connecticut using a chemiluminescent analyzer. Five minute
samples were generally taken 6 times during each 2-hour interval and accumulated
into 2-hour averages. Approximately two weeks of monitoring were performed at
each of four gas stove homes during the spring and summer of 1973 and the
fall and winter of 1973-1974. Values for Home 2 were not summarized in
Table 5, because the home was occupied by a young bachelor who rarely used
the stove; thus, the home tended to show the same levels of NCL that
were found outside.
The mean daily 2-hour peak in the kitchen of 3 of the homes ranged
from 0.10-0.18 ppm NCL. During the study, the occupants of the home kept
a diary of stove use. Comparing these diaries of stove use and occurrence
of peak N0~ concentrations, one can conclude that the peak levels in the
kitchen and living room were directly related to use of the gas stove and
-------
33
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35
oven for cooking. Figure 3 presents the cumulative distribution of 2-hour
daily peak NCL levels in the kitchens (1 meter from the stove) of two gas
stove homes monitored in the Wade et al. study. ' For example, approximately
95 percent of the daily peak 2 hour averages in the kitchens of the two
homes were below 0.21 and 0.35 ppm, respectively.
The Wade et al. study ' also demonstrated the differences that occur
in levels of NOp for kitchens, living rooms, and bedrooms of gas stove homes.
As one moved away from the source of NO,,, the kitchen stove and oven, N02
levels dropped off fairly rapidly. Short-term peaks in the bedrooms of
Homes 1 and 3 were not significantly greater than outdoor peak levels. The
24-hour average concentrations were higher in the kitchens (means 0.04-0.06 ppm)
than levels in other rooms of these homes or outdoors. However, the 24-hour
concentrations were only slightly higher in the living room and bedroom of these
homes (means 0.03-0.04 ppm) than the 24-hour levels observed outdoors (0.02 ppm).
N02 CONCENTRATION, ppm
Figure 3. Cumulative distribution of 2-hr daily peak NO*
concentrations in kitchens of two houses with gas stoves.
-------
36
71-73
A number of studies by the Lawrence Berkeley Laboratory have examined
the contribution of gas stoves and ovens to NO, levels in energy efficient
71
homes and test kitchens. Hollowel et al. (1980) simulated typical gas stove
use patterns, provided by the American Gas Association, in an energy efficient
research house and monitored N02 levels in the kitchen, living room, bedroom,
and outdoors. The peak hourly average observed during a 24-hour period and
the 24-hour average for each of the monitoring locations are presented in
Table 5. The levels were somewhat higher than would be expected in "average"
homes due to the low air exchange rates. Older houses and most new houses
have air exchange (ventilation and infiltration) rates of 0.8 - 1.5 air
72 73
changes per hour (ach) or higher. ' It has been estimated that well-
constructed new single-family houses have air exchange rates in the range of
72
0.5-1.0 ach. In contrast, new houses with energy conservation measures can
72
limit air exchange rates to 0.2-0.5 ach.
72
Hollowel et al. (1978) monitored N02 levels in a test kitchen with
a gas oven on for 1 hour at 350°F. Hourly concentrations of N02 were reported
for a variety of air exchange rates. Increasing the air exchange rate
resulted in lower N02 hourly average levels during use of a gas oven (see
values in Table 5).
73
In another Lawrence Berkeley Laboratory study, the effect of various
ventilation strategies on N02 levels was examined in a test house during
a simulated dinner meal. Figure 4 summarizes the results from this study.
The values in Figure 4 for the range hood indicate the effect of adding
spot ventilation in the kitchen and probably do not reflect the conditions
existing in most homes in the Six-City Study. The difference between
indoor and outdoor temperature is noted by AT in Figure 4. A low AT and
low windspeed contribute to reduced ventilation rate. The peak hourly
average N02 concentrations observed for an air exchange rate of 0.8-0.9
ach (which is approximately the average air exchange rate for existing
residential houses) were approximately 0.18-0.30 ppm in the kitchen,
0.13-0.18 ppm in the living room, and 0.09-0.13 ppm in the bedroom. These
peak hourly averages compare favorably with the range of daily peak 2-hour
averages observed in the 3 gas stove homes monitored by Cote et al.
(1974).70
-------
37
N02 CONCENTRATION VS. VENTILATION
1.0 r- ' ' ' ' '
c .
» " Kitchen
f """"^ ° "*"^
i A AT ^^ ** "^ viviiHi room
LOW ai , "^ OA
Uw w«od | -«,_
" Moderate AT Oa*^8«^rdom
3 Moderate wind *
Heat
«scMnqer
a
t
>^QAQC nQQQ
31 QO c
-------
38
have spent in the various rooms, it is necessary to use a range to
estimate the exposure which may have been associated with the reported
health effects. Using the above data, it would appear that a reasonable
estimate of the 1-hour exposures to which the children may have been
exposed more than a few times would lie in the range 0.15 to 0.30 ppm.
c. Staff Comments on Gas Stove Studies. In evaluating the evidence
from the Melia et al. and Speizer et al. studies, the major uncertainties are
what agent(s) caused the reported health effects and, if N02, then what
exposure levels and patterns (concentration, averaging time, and frequency)
are associated with the reported effects. Possible confounding and covarying
factors which may be related to the increased prevalence rate of respiratory
illness and symptoms observed in children in gas stove homes include humidity,
socio-economic status, and pollutants other than N02, such as carbon monoxide
and hydrogen cyanide, which are emitted when gas combustion occurs. However,
there is no evidence that carbon monoxide or hydrogen cyanide are given off
in dangerous quantities by gas stove combustion, and there is also no evidence
that these pollutants cause effects such as increased respiratory symptoms or
illness. The contribution, if any, to increased respiratory symptoms or illness
due to increased humidity or water vapor in gas stove homes requires further
research.
Other factors, such as outdoor pollution levels and exposure to
parental smoking, may have contributed to the overall effect observed in the
Melia et al. and Speizer et al. studies. There is, however, no evidence in
the studies by Melia et al. and Speizer et al. to suggest that these
factors differ for children living in electric versus gas stove homes.
The cumulative findings from a number of animal and human clinical
studies also suggest that NOp is the principal agent responsible for the
effects reported in the gas stove studies. As discussed in the earlier
section on animal studies (V-C-1), controlled exposure studies of a variety
of animal species have provided sufficient data to demonstrate that N02
impairs respiratory defense mechanisms, providing a plausible basis for
inferring that N02 may have been associated with the reported increased
incidence of acute respiratory illness in children living in homes with gas
stoves. Controlled human exposure studies indicating increased symptomatic
32
effects in asthmatics after exposure to 0.5 ppm N02 for 2 hours and impaired
pulmonary function after brief (3-10 minute) exposures to N0~ concentrations
O "I OC *
in the range 1.0-2.0 ppm ' also support the hypothesis that N02 is the
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39
principal agent causing the increased respiratory system effects observed
in the gas stove homes.
Experimental work in developing an animal infectivity model also provides
some evidence that NCL may be the agent causing the effects observed in the
gas stove studies. The animal infectivity model studies have examined the
influence of exposure mode (concentrations and time of exposure) on the toxicity
of N02 (Gardner et al., 1977;11 Coffin et al., 1977;12 Gardner et al., 197913).
With concentration times time of exposure (CxT) held constant at 7 and vary-
ing concentration (1-14 ppm) and time (0.5-7 hrs.), Gardner et al. (1977)
demonstrated that brief exposures to high concentrations of NCL resulted in
more severe infections and greater mortality than did prolonged exposures
to lower concentrations. The findings of this study suggest that short-term
peak exposures may be a more important factor than long-term, low-level
exposures of equivalent dose in causing or contributing to the effect observed
in gas stove homes.
13
In another animal study, Gardner et al. (1979) examined the effect of
background NCL concentrations on mortality in mice given a bacterial challenge
18 hours after a single peak exposure to NCL. The mice were first exposed
either to 1.5 ppm NCL or to no NCL for 64 hours. Then they were exposed to
a single peak of 4.5 ppm NCL (for 1, 3.5, or 7 hours), followed by bacterial
challenge 18 hours after exposure to the 4.5 ppm peak level. There was a
statistically significant increase in mortality for the 3.5-hour and 7-hour
exposure to 4.5 ppm NCL with a 64-hour pre-exposure background (1.5 ppm NCL )
over that observed with no pre-exposure background. The implications of this
finding are that background concentrations (1) may affect the ability of
animals to recover or adapt to the impact of peak exposures and/or (2)
may impair the functioning of the lung's defense mechanisms (e.g.,
alveolar macrophages, leukocytes, and mucociliary system).
13
The same study also examined the impact of multiple spikes (4.5
ppm) with a continuous background (1.5 ppm), compared to a continuous
exposure (1.5 ppm) without spikes, on mortality of mice challenged with
bacteria. The mice exposed to multiple spikes received a 1-hour exposure
to 4.5 ppm NCL twice a day over a two week period. At the end of the two
weeks, there was no statistically significant difference in mortality for
the mice exposed to 1.5 ppm along with multiple spikes (4.5 ppm). The results
of this study indicate the complexity of the relationship between exposure
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40
patterns and health effects and suggest that further research is needed to
clarify the impact on increased susceptibility to infection of repeated peak
N02 exposures with and without background N02 levels.
It also should be noted that, while the animal studies provide some
evidence that NCL impairs respiratory defense mechanisms, this evidence
comes from studies conducted at N02 exposure levels believed to be
considerably higher than those experienced in the gas stove homes.
64
The authors of the Speizer et al. study have hypothesized that
repeated peak values are probably the most important exposures in
causing the effects observed in the gas stove homes. Their judgment is
in part based on the fact that there are no intermittent short-term
(1/2 hour-2 hour) NOp peak concentrations in electric stove homes and
that long-term (24-hour or longer) concentrations in gas stove homes are
not that much higher than in electric stove homes.
The daily peak 2-hour NCL levels observed in 3 homes monitored by
70
Cote et al. (1974) provide the best, although rough, estimate
of the short-term (1-2 hour) levels that may have occurred in the gas stove
homes in the Speizer et al. (1980) study. It is recognized that short-
term levels in particular homes in the Six-City Study may have varied
considerably in magnitude or frequency of peak levels from the homes in the
Cote et al. (1974) study due to variation in gas stove usage,
ventilation conditions, and designs of homes.
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41
D. Sensitive Population Groups
Based upon the health effects information provided in the Criteria
Document and reviewed here, the groups that appear to be most sensitive
to exposures to N02 include children, chronic bronchi tics, asthmatics,
and individuals with emphysema. Other individuals with impaired and/or
sensitive respiratory or nasopharyngeal systems (e.g., individuals with
symptoms of hay fever) may also be more sensitive to NCL. In addition,
there is reason to believe that persons with cirrhosis of the liver or
other liver, hormonal, and blood disorders, or undergoing certain types
of drug therapies may also be more sensitive to NCL because of the implications
from animal studies showing increased systemic, hematological, and hormonal
alterations after exposure to NCL.
Health effects data from epidemiological studies in gas stove homes suggest
that young children are at increased risk of respiratory symptoms and infection
from exposures to elevated ' ' concentrations of NCL. This increased
risk of respiratory symptoms may be due to either the higher activity
level of children (i.e., increased dose) or the inherently greater
biological sensitivity of children or both.
Sensitive groups such as children and asthmatics apparently respond
most readily to acute exposures of NCL. However, these groups and others may
be subject to effects produced by long-term exposures that have not been
adequately addressed in human studies. These include direct or indirect
effects on lung tissue producing or aggravating emphysema, cardiopulmonary
disease, and pneumoconeosis. Available information does not suggest major
risks of such effects at current ambient levels in most U. S. areas.
Other-groups at risk to N09 exposures are asthmatics and
32
bronchi tics. Human clinical study data have provided evidence that
some of these individuals suffer mild symptomatic effects (nasal discharge,
headaches, dizziness, and labored breathing) after light to moderate
exercise during an exposure to 0.5 ppm NOp for two hours. Chronic
bronchi tics showed increased airway resistance following approximately
oc
three-minute exposures at or above 1.6 ppm NO,,. A more controversial
study suggested that asthmatics experience an increased sensitivity to
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42
a bronchoconstricting agent following a one-hour exposure to 0.1 ppm
38
NCL. However, a similar study (not yet published) conducted at the U.S.
EPA facilities in Chapel Hill, North Carolina failed to find any statistically
significant changes. Although there are no human experimental studies
of NCL involving individuals with emphysema, it seems reasonable to
include such persons in the category of high risk individuals since they
suffer from major impairment in breathing capacity even in the absence of NCL.
In 1970, the U.S. Bureau of the Census estimated the total number
of children under five years of age to be 17,163,000 and between five and
13 years of age to be 36,575,000. Data from the U.S. National Health
Survey for 1970 indicate that there were 6,526,000 chronic bronchi tics,
6,031,000 asthmatics, and 1,313,000 emphysematics at the time of the
Survey. Although there is overlap on the order of about one million
persons for these three categories, it could be reasonably estimated that
over twelve million persons experienced these chronic respiratory conditions
in the U.S. in 1970. Table 6 summarizes supporting evidence and population
estimates for the above-mentioned sensitive groups.
On the basis of the available effects data, the staff is focusing
on children and persons with asthma, chronic bronchitis, and emphysema as
the most sensitive population groups. Other persons such as those who
have had hay fever or those with liver, hematological, or hormonal
disorders also may be affected at low levels of NOp. Due to the
lack of human experimental data for these latter groups, however, EPA
staff intends to recommend to the Administrator that the potential effects
on such persons should be considered only in determining the margin of safety
for primary NO standard(s).
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43
TABLE 6
Summary of Potentially Sensitive Groups*
Sensitive
Group
Children
Asthmatics
Chronic
Bronchi tics
Emphysematics
Persons with
Tuberculosis,
Pneumonia,
Pleurisy, Hay
Fever or Other
Allergies
Persons with
Liver, Blood
or Hormonal
Disorders
Supporting
Evidence
Children under age 2 exhibit
increased prevalence of respiratory
infection when living in homes with
gas stoves. Children up to age 11
exhibited increased prevalence of
respiratory infections when living
in gas stove homes.
Asthmatics reacted to lower levels
of NO- than normal subjects in
controlled human exposure studies.
Chronic bronchi tics reacted to
low levels of NO- in controlled
human exposure studies.
Emphysematics have significantly
impaired respiratory systems.
Because studies have shown that
NO- impairs respiration by
increasing airway resistance, it
is reasonable to assume that
emphysematics may be sensitive
to N02.
Studies have shown that NOp increases
airway resistance. Persons who have
or have had these conditions may be
sufficiently impaired to be
sensitive to low levels of NO,-
NO- induces changes in liver drug
metabolism, lung hormone metabolism,
and blood biochemistry.
References for
Supporting Population
Evidence Estimates
Spei?.er et al , age 0-5
198055 17.2 million*
Melia et al, age 5-13
197957 36.6 million*
Kerr et al , 6.0 million*
197932
Orehek et al ,
197638
Kerr et al , 6.5 million*
197932
Von Nieding et
al, 197136
Von Nieding et
al, 197037
Von Nieding et 1.3 million*
al, 1971 36
Beil and Ulmer,
197635
Orehek et al,
197618
Von Nieding et unknown
al, 1971 36
Beil and Ulmer,
197635
Orehek et al,
197638
Menzel , 1980 26 unknown
Miller et al ,
1980 18
Posin et al, ,
197939
*1970 U.S. Bureau of Census and 1970 U.S. National Health Survey
**A11 subgroups listed are not necessarily sensitive to NO- exposure
at low levels. 2
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44
VI. Factors to be Considered in Selecting Primary Standards
This section draws on the previous evaluation of scientific informa-
tion and summarizes the principal factors bearing on selection of primary
N02 standard levels and on designating appropriate averaging times and
forms. Preliminary staff recommendations on alternative approaches for
making those choices are also presented.
A. Averaging Times
31-33 36-38
A number of controlled human exposure studies " ' " have reported
respiratory system effects associated with NCL exposures ranging from 3
minutes to 2 1/2 hours. Evidence from animal studies indicates that a variety
of serious effects on the respiratory and host defense systems are associated
with NCL exposures ranging from hours to years. For example, exposure of
mice to a relatively low N07 concentration (0.1 ppm) for six months with
29
daily 2-hour peaks of 1.0 ppm resulted in emphysematous alterations.
In addition, other morphological changes in the lung and increases in suscep-
tibility to bacterial and viral infection have been demonstrated in several
animal species exposed to long-term N02 concentrations.
Evidence from community indoor ("gas stove") studies ' ' suggests
that the rate of respiratory illness and respiratory symptoms is increased
in homes with elevated N02 levels due to use of gas stoves. As indicated
in Section V-C-5-b, annual average, 24-hour average, and 1-2 hour average N02
concentrations are generally somewhat higher in homes with gas stoves
compared to electric stove homes. The increase in N02 concentrations in
gas stove homes over that observed in electric stove homes becomes more
apparent as the averaging time gets shorter. The authors of the Speizer
64
et al. study have speculated that the observed effects might be largely due
to repeated short-term peaks of an hour or less duration which occur when the
gas stoves are used for cooking. While it is more likely that the repeated
short-term peaks are mainly responsible for the observed effects, the possible
contribution of low-level chronic exposures to N02 cannot be ruled out.
While it is very difficult at this time to derive quantitative exposure-
effect relationships for humans, we believe the health effects evidence
indicates a need to protect against both short- and long-term effects associated
with N02 exposures. This protection could be provided with separate averaing
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45
time standards for each exposure duration of concern or by setting one
standard that effectively protects against several averaging time/
concentration level combinations. For example, EPA could set an annual
average standard to limit the magnitude and frequency of short-term
peaks that occur in the ambient air. Alternatively, EPA could set a 24-
hour standard that required a specific percent of the 24-hour averages in
a year to be below the standard level. Retaining an annual average
standard, as opposed to setting a standard based on a shorter averaging
time such as 24-hours, permits the continued use of current data processing
and reporting requirements.
B. Form of the Standard
The current N02 annual primary NAAQS is based on the arithmetic
mean of all valid daily averages in a calendar year. The arithmetic
mean is more sensitive to repeated short-term peaks than the alter-
native, which is the geometric mean, and its use is consistent with
other standards. Therefore, if a long-term standard is set, we recommend it
be based on the arithmetic mean.
If the Administrator were to establish a short-term (e.g., hourly
average) standard to provide adequate protection against repeated peak
exposures, then the staff recommends that the standard be stated in a
statistical rather than deterministic form. This could be accomplished
by either:
(1) setting a standard where an allowable number of exceedances
of the standard level would be expressed as an average or
expected number per year, or
(2) setting a standard where a given percent of the daily maximum
hourly values would be expected to be less than or equal to
the standard level.
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46
The emissions reductions to be achieved in the required control implementation
program would be based on a statistical analysis of the monitoring data
over a multi-year period (e.g., the preceeding 3-year period).
The statistical form of the standard offers a more stable target for
control programs and is less sensitive to truly unusual meteorological
conditions than a deterministic form. The general limitations of the
deterministic form are discussed in another paper. Recognition of
these limitations has led EPA to promulgate or propose statistical forms
77 78
for the ozone and carbon monoxide standards. '
C. Level of the Standard
Controlled human exposure studies, while providing accurate measurements
of exposure levels and conditions, have been limited to examining effects
on adults of single, short-term exposures to NCL or simple combinations of
pollutants. In addition, these studies are limited to studying "reversible"
effects and only a few studies have involved population groups suspected
of being particularly susceptible to NCL exposures. A variety of animal
studies indicate a range of effects due to chronic and acute exposures,
but whether these effects occur in humans and at what exposure levels
remain uncertain. Finally, community epidemiological studies, while
representing real world conditions, are limited in that they can provide
no more than associations between pollutant exposures and observed health
effects. It follows that, although the scientific literature supports the
conclusion that various levels and exposure patterns of NCL pose risks to
human health, the data only can identify the limits of a range within
which a standard should be set, and specific numeric standard levels,
frequency of exceedance, and averaging times largely are a public health
policy judgment.
Conclusions which can be reached from health effects evidence described
in section V are key to the standards selection process. These conclusions
are summarized below:
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47
(1) While the animal toxicology literature does not provide human
effect levels at this time, it does indicate a variety of effects
from acute, chronic, and combined chronic and acute exposures to
NCL. Findings from animal studies (e.g., emphysematous alterations
in the lung, other morphological changes in the lung, and increased
susceptibility to infection) suggest that chronic exposures or
chronic exposures with repeated peaks may lead to serious adverse
health effects in humans. These effects may include development
or aggravation of chronic respiratory diseases and increased
incidence of acute respiratory infection or disease. Less severe
and generally reversible effects (e.g., biochemical changes,
interference with hormone metabolism, possible interference with
liver metabolism) have been reported in animals exposed to single,
acute levels of NCL less than 0.50 ppm. More severe effects, such
as increased susceptibility to infection and morphological changes
in the lung, appear to be related to multiple exposures to N00.
32
(2) Controlled human exposure evidence (Kerr et al., 1979) indicates
that mild symptomatic effects (e.g., headache, chest tightness,
and nasal discharge) can occur in some asthmatics after a 2-hour
exposure to 0.5 ppm NOp- We conclude that these effects adversely
impact personal comfort and well-being and that they
may constitute adverse health effects for some individuals by
interfering with their normal functioning.
The lowest level at which statistically significant pulmonary
function changes have been shown in controlled human exposure studies
is in the range of 1.0 to 2.0 ppm for short durations (3 to
10 minutes). The effects were observed in healthy adults and
chronic bronchitics at these levels. Other controlled human
exposure studies provide little support for additive or greater-
than-additive effects being associated with exposure to NOp in
the presence of other ambient pollutants.
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48
(3) The Chattanooga and Japanese community epidemiological studies
provide little, if any, quantitative evidence to relate effects to
specific N02 concentrations. The findings of these studies are,
however, not inconsistent with the hypothesis that NCL in a
complex mix with other pollutants in the ambient air adversely
affects lung function and/or respiratory illness in children.
(4) The British and Harvard Six-City "gas stove" studies ' provide
suggestive evidence that young children are at greater risk of
developing acute respiratory disease or respiratory symptoms due
to exposure to gas combustion products of which N02 is a significant
component. The findings from animal studies demonstrating reduced
resistance to infection due to N02 exposure support the hypothesis
that NCL is the primary agent responsible for the effects observed
in the "gas stove" studies. Controlled human exposure studies which
indicate increased symptomatic effects in asthmatics after exposure
32
to 0.5 ppm for 2 hours and impaired pulmonary function after
brief (3-10 minute) exposures to N0~ concentrations in the range
31 OC ^
1.0-2.0 ppm * also support the hypothesis that N02 is the
principal agent causing the increased respiratory symptoms observed
in gas stove homes.
Animal infectivity model studies (e.g., Gardner et al., 1977
12
and Coffin et al., 1977 ) suggest that short-term peak exposures
may be more important than long-term, low-level exposures of
equivalent dose in contributing to the effect observed in gas stove
homes. The authors of the Six-City Study have also indicated that
repeated peak concentrations are probably the most important exposures
in causing the effect observed in the gas stove homes. Their
judgment is in part based on the observation that long-term (24-hour
or longer) N02 concentrations in gas stove homes are not that much
higher than in electric stove homes, while high intermittent short-term
(e.g., 1/2 hour-2 hour) N02 peak concentrations are only observed in
gas stove homes.
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49
(5) Based on the health effects evidence reviewed in the criteria
document and this paper, the groups which appear to be most sensitive
to NCL exposures include asthmatics, chronic bronchitics, children,
and individuals with emphysema and other chronic respiratory diseases.
(6) Selecting an ambient air quality standard with an adequate
margin of safety requires that uncertainties in the health effects
evidence be considered in arriving at the standard. While the lowest
NCL concentration reliably linked to identifiable health effects due to
single or repeated peak exposures appears to be in the range of 0.5 -
32
1.6 ppm NCL (based on symptomatic effects and pulmonary function
4-] -3C
impairment ' ), a clear threshold for adverse health effects has not
been established. Several factors make it difficult, if not impossible,
to identify the minimum NCL level associated with adverse health effects.
For ethical reasons, clinical investigators have generally excluded
from studies individuals who may be very sensitive to NCL exposures,
such as children, elderly individuals, and people with severe pre-
existing cardio-pulmonary diseases. In addition, human susceptibility
to health effects varies considerably among individuals, and it is
not certain that experimental evidence has accounted for the full
range of susceptibility. Finally, there is no assurance that all
adverse health effects related to low level NCL exposures have
been identified.
Factors we believe should be considered in the margin of safety for
NCL include: (a) potentially sensitive populations that have not.
31 36
been adequately tested, (b) concern for repeated peak exposures '
and delayed effects, seen in animal studies but seldom a part of
human clinical study protocols, (c) implications of the Orehek
38
et al. (1976) study in which a bronchoconstrictor was used, (d)
possible synergistic or additive effects with other pollutants or
environmental stresses , and (e) uncertain exposure levels and
averaging times associated with effects reported in the "gas stove"
studies.
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50
D. Staff Conclusions and Recommendations
Mild symptomatic effects in asthmatics have been observed at 0.5 ppm
32
for 2 hours (Kerr et a!., 1979). Potentially more serious pulmonary
function impairment has been demonstrated in chronic bronchitics (Von
Nieding et al., 1971) at or above exposures of 1.6 ppm for 3 minutes.
Another study (Suzuki and Ishikawa, 1965) demonstrated pulmonary function
impairment in healthy adults exposed to 0.7 to 2 ppm for 10 minutes, and a
study by Beil and Ulmer (1976) found pulmonary function impairment for
healthy adults exposed to 2.5 ppm for 2 hours. We conclude from these
studies that single exposures to N02 in excess of about 1.0 ppm for periods
in excess of one hour (equivalent to about 2 ppm for 10 minutes based on the
observed relationship of air quality distributions for different averaging
times) should be avoided. Also, since the mild symptomatic effects observed
in asthmatics may be indicators of more serious effects, it would be
desirable ts prevent frequent exposures to NOp concentration levels above
0.5 ppm. These N02 exposures generally are higher than concentrations of
NOp normally encountered in the ambient air.
At exposure levels less than 0.5 ppm the scientific data for humans
are sparse and the results are inconclusive. The only extensive studies
which report health effects in humans for short-term exposure of N02 at
concentration levels comparable to those observed in the ambient air (less
than 0.5 ppm for 1-hour or more) are the gas stove studies. These studies
are important not only because the exposure levels are low but because
they are the only significant studies involving one of the most sensitive
population groups, namely children. The Criteria Document warns that
considerable caution should be used in drawing firm conclusions from the
gas stove studies. However, the tentative conclusion is that the observed
health effects can be attributed to N02<
Because children living in the gas stove homes were potentially
exposed on many occasions to maximum short-term N02 concentrations below
0.5 ppm, and because biological damage has been reported in animals
exposed repeatedly to short-term peaks of N02, we conclude that it would
be desirable to prevent multiple exposure to short-term N02 levels
below 0.5 ppm. The data do not provide a clear indication of what this
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51
precise level should be, but it would appear that infrequent exposures to
1-hour average N(L concentrations in the range of 0.15 to 0.30 ppm should
present minimal health risks to children and other sensitive population
groups.
No reliable scientific data exist which directly demonstrate effects
in humans as the result of chronic or long-term (days to years) exposure
to NOp at levels comparable to those found in the ambient air but there is
an extensive data base which demonstrates that very serious biological
effects have been caused in a variety of animals as the result of long-
term exposure to NOp at concentration levels above the long-term levels
found in the ambient air. The seriousness of these effects, the similarities
of the biological systems between humans and animals, and the absence of
animal studies showing that these effects do not occur at lower exposure
levels suggest that there is a definite, although unquantifiable, risk to
human health from long-term chronic exposure to NQj-
The data contained in section IV and Appendix B of this report
indicate that in many of the areas where monitoring is currently being
conducted the 1-hour concentrations of N02 seldom exceed the 0.15 to 0.30
ppm range. In fact, a review of the existing monitoring data indicates
that in areas which currently meet the present 0.053 ppm annual standard,
1-hour average levels greater than 0.30 ppm occur only two to three days
per year and these events are rarely on consecutive days. In these same
areas there could be 10 to 20 days with 1-hour levels in excess of 0.15
ppm and such levels have occurred on as many as four consecutive days
(exceptions to this latter observation occur in several California cities
where 1-hour levels have exceeded 0.15 ppm on more than 40 days in a year,
including as many as six consecutive days, even though the annual standard
was met).
There appear to be at least two approaches which would provide
adequate public health protection. First, a 1-hour average N02
standard could be established at some level below 0.5 ppm. Such a
standard would incorporate a frequency of exceedance rate which would be
related to the concentration level selected. Both the concentration
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52
level and exceedance rate would largely be based on judgment since the
data are insufficient to specify either with any degree of precision. For
example, the Administrator might choose a maximum 1-hour standard in the
range of 0.15 ppm to 0.30 ppm which would have to be met for a specified
number of days in the calendar year. Establishing a new short-term standard
would require both EPA and the states to implement a new regulatory program
since there now is no short-term N02 standard.
An alternative to establishing a new short-term NCL standard is to
retain an annual standard at a level which will provide the desired
protection against potential short-term effects. This could be accomplished
without major changes in the existing regulatory program. In using an
annual standard to protect against effects caused by short-term con-
centrations effects, it should be recognized that available human data
on effects from long-term exposures are not sufficient to support a
specific numerical standard.
The existing monitoring data can be used to help determine the
appropriate level of an annual standard which would achieve the desired
health protection objectives. In Figure 5, the expected numbers of days
when 1-hour concentrations exceed 0.15 ppm and 0.30 ppm are plotted as
functions of the annual average concentrations. The curves shown on the
figure are based on data from a number of urban area monitoring sites.
The upper portion of each curve is based primarily on California data
and may overstate the situation in other cities.
From Figure 5, an annual standard of 0.05 ppm would be expected to
prevent 1-hour N0? levels from exceeding 0.15 ppm levels on all but about
20 days per year, and from exceeding 0.30 ppm on all but two days per
year. Thus, an annual standard of 0.05 ppm could be considered as a
conservative surrogate to a short-term standard, and would tend to keep
most 1-hour levels below 0.15 ppm.
The data in Figure 5 indicate that with an annual standard as high as
0.08 ppm, we would expect 1-hour NOg levels not to exceed 0.30 ppm on more
than about 10 days per year, and essentially never to exceed 0.50 ppm.
A possible exception to the above analysis may be in areas in the
immediate vicinity of large low-level point sources. While modeling
results indicate that 1-hour NO^ peaks above 0.5 ppm are theoretically
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53
possible around major NO point sources with low stack heights, the available
J\
monitoring data indicate 1-hour peaks of 0.30 ppm are rarely seen and
hourly peak levels never have been reported at or above 0.50 ppm.
An annual standard in the range of 0.05 to 0.08 ppm would appear to
provide adequate protection against the potential and uncertain health effects
that may be associated with exposure to short-term NO^ levels. Such a standard
could be used as a surrogate for a short-term standard. In addition, an
annual standard would provide some, although unquantifiable, protection
against possible adverse health effects from long-term exposure.
The lack of scientifically demonstrated health effects in humans from
N02 exposure in concentrations below 0.5 ppm could be interpreted to
mean that there is no need for an N02 NAAQS. However, such an interpretation,
we believe, would ignore the cumulative evidence from controlled animal and
human exposure studies and community indoor studies which strongly suggest
that N02 may cause adverse health effects in sensitive population groups
exposed to N02 levels at or near existing ambient levels.
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54
c
1
c/o
o>
At
s-
OJ
-Q
3
100
90
80
70 -
60
50 -
40 -
30
20
10 -
0.15 ppm
0.30 ppm.
I I
0.02
0.03
1
0.04
I
0.05
1
0.06
1
0.07
I
0.08
Annual Average Concentration (ppm)
Figure 5. Expected Number of Days on Which Maximum 1-Hour N02
Concentrations Exceed 0.15 and 0.30 ppm Associated
with Annual Average Concentrations (based on SAROAD
data for 14 sites during 1979-1980)
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55
VII. CRITICAL ELEMENTS IN THE REVIEW OF THE SECONDARY STANDARDS
This section describes the welfare effects attributed to N02 and,
where possible, sets forth judgments as to which levels of effects may be
defined as adverse for standard setting purposes. The major categories
to be addressed with regard to secondary standards are symptomatic
effects, vegetation effects, visibility impairment and materials damage.
A. Personal Comfort and Well-Being
A secondary ambient air quality standard for a pollutant must specify
a level of air quality that is adequate to protect public welfare from any
known or anticipated adverse effects associated with the presence of the
pollutant. As defined in section 302(h) of the Act, welfare effects
include effects on personal comfort and well-being. Thus, in instances
where observed effects are not clearly adverse to health but do affect
personal comfort and well-being, the Act makes provisions for protecting
against these effects through the secondary standard mechanism.
Effects which may well fall in this category are the mild symptomatic
effects which were observed in 1 of 7 bronchitics and in 7 of 13 asthmatics
during or after exposure to 0.5 ppm N09 for 2 hours in the Kerr et al.
32
(1979) study. The authors indicate that the symptoms were mild and
reversible and included slight headache, nasal discharge, dizziness, chest
tightness, and labored breathing during exercise. Although there is
general agreement that these mild symptomatic effects are identifiable
health effects, there is uncertainty as to whether they are adverse health
effects and as such warrant protection under the primary standard. It does
seem clear, however, that these symptomatic effects could cause personal
discomfort and should be considered in setting either the primary or the
secondary standard.
-------
56
B. Vegetation Effects
I- Nature Of Effects
The most notable feature of the response of vegetation to NCL stress
is the varied degrees of NCL-induced injury. These differing responses can be
explained in part by the physiological processes affecting NCL uptake into
the leaf, pollutant toxicity at target sites, and cellular repair capacity.
This section focuses on three major categories of effects: foliar injury,
growth and yield reduction, and physiological and biochemical changes.
In regard to foliar injury, there is no "typical" leaf symptom or set of
symptoms that reliably indicates plant exposure to N02. Acute and chronic
exposures may produce different types of foliar injury including leaf chlorosis
and necrosis. Data concerning the effects of NCL on plant growth and yield
are limited. However, it is reasonable to assume that NC^-induced reductions in
assimilatory capacity of plants through altered metabolism or leaf injury may
79
also affect the growth of plants. Reductions in growth and yield are not
always accompanied by foliar injury. Finally, pollutant reactions with
cellular constituents can lead to physiological and biochemical changes such
as altered metabolism, reduced photosynthesis, and probably many other effects
which have been suspected but not yet observed or measured. These known and
suspected effects may, in turn, lead to more profound effects at progressively
higher levels of biological organizations (e.g., cellular organization, leaf
injury, growth, yield).
The extent, severity, and type of NCL effects on plants can be altered
by both external and internal factors. Environmental conditions, as well as
the condition or status of the plant itself, influence the response of the
plant to NCL. Susceptibility of plants to NCL varies greatly among plant species
and even among varieties, cultivars or clones of the same species. This varying
susceptibility is due to genetic factors. Another important biological factor
affecting the severity of damage is the stage of development or age of the
plant or plant part. Studies have shown that the stage of development at
79
which plants are exposed to NCL affects the degree of yield reduction. For
example, fumigation of oats during flowering has the greatest effects on
-------
57
the yield of grain. Exposures during the earlier, vegetative stage of develop-
ment, or later when the grain is yellow-ripe, may have no effect on yield.
The age of leaves also can affect their susceptibility to NO,,. Among the
important environmental factors affecting plant sensitivity to N02 are the
presence or absence of other pollutants, soil moisture, temperature, humidity,
light intensity, and time of day at which exposure occurs.
a. Foliar Injury. The diagnosis of injury resulting from N02 is often
difficult. The injury pattern may vary depending on species, cultivar, age of
leaf, season of year, pollutant dose and prevailing environmental conditions.
Acute exposures usually elicit completely different responses than chronic
exposures. In acute exposures leaf injury is usually characterized by leaf
necrosis. This is expressed as light brown irregularly shaped necrotic lesions,
usually at or near the tips of leaves. The area affected varies with the
magnitude of the exposure. Leaf chlorosis is a striking characteristic of the
injury that occurs from long exposures to low N02 concentrations. This type
of injury is expressed as greenish yellow spots or as yellowing of the entire
leaf surface. Chlorosis may be limited to the leaf margin or may spread across
the leaf surface.
b. Growth and Yield. Experimental data documenting the effects of N09 on
^
plant growth and yield are limited. As previously stated, it is reasonable
to assume that NCL-induced disruptions in plant function, such as changes in
photosynthetic rate and leaf injury, affect the growth of plants. Foliar
injury is an imprecise measure of the effect of NCL on growth and yield
parameters. Growth and yield reductions can occur with minimal or no foliar
injury and it is possible to have extensive foliar injury with no significant
effect on crop yield.
c. Physiological and Biochemical Changes. Detection of injury from
pollutants often requires the measurement of subtle responses such as photo-
synthesis, transpiration, and rates of metabolic processes. Effects at the
cellular level have been related to effects on leaves and unusual physiolo-
gical changes in the entire plant. Generally investigations have relied on
visible leaf damage or symptoms of injury such as leaf lesions, color changes,
or reductions in growth and yield as measures of effects. Although leaf injury
is the most obvious effect of N02 on plants, it is only the end result of a
series of events which have occurred at a sub-cellular level of biologic
-------
58
organization. Physiological changes such as reduction in photosynthetic rate
occur in some species after being exposed to low levels of NC^ before there
is any visible injury. The interaction between genetics and environmental
factors determines the sensitivity of plants to NCL. The relative sensitivity
of species or cultivars within a species can change, depending on the environ-
mental conditions that exist. Other variables affecting plant response and
ability to recover from NCL-induced stress include the stage of development of
the plant and the frequency and magnitude with which such stress occurs.
2. Effects From Exposures To NQ? Alone
K_
80
Evidence in the Criteria Document as well as consultations with plant
81 -83
physiologists " have indicated that visible injury to vegetation from N02
alone occurs at levels which are above ambient concentrations generally
occurring within the U.S., except around a few point sources. Several
84-88
studies on the effects of NOp alone on vegetation have failed to show
plant injury at concentrations below 2 ppm for a short-term exposure.
The lowest level of N09 alone that caused foliar injury has been estimated at
80-81
2 ppm for a four hour exposure. The "time concentration model to predict
acute foliar injury" developed by Heck and Tingey (1979) did not predict foliar
89
injury at levels below 2 ppm for any crops tested.
For long term exposures, such as a growing season, the lowest concen-
83
trations reported to depress growth are approximately 0.25 ppm. Very few
long-term studies have been conducted at concentrations below 0.25 ppm
(Table 7). The concentrations reported in these studies are probably higher
than those which would be expected to occur in the atmosphere for extended
90
periods of time. The one exception is Ashenden et a!., 1980 who reported
that 0.11 ppm N02 (continuous exposure for 103.5 hours per week for 20 weeks)
significantly reduced the growth of Kentucky bluegrass and affected some growth
parameters of orchard grass. The exposure of these grasses occurred during
the fall and winter when growth was slow. The author suggested that this
might have made the grasses more susceptible to injury by pollutants and
cites experiments which indicate that nitrogen oxides are more toxic to
plants when growth is slow (Ashenden et al., 1980).
-------
59
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-------
60
More subtle responses such as changes in photosynthesis have been
91
reported by Capron and Mansfield (1976) who found a reduction in photosynthetic
rate of tomato plants exposed to 0.25 ppm N09 or higher concentrations over a
92
20-hour period. Hill and Bennett (1970) reported that N02 inhibited apparent
photosynthesis of oat and alfalfa at concentrations below those that caused
foliar lesions. The threshold dose for this inhibition was 0.6 ppm N02 in
90-minute fumigations. Full recovery from t^-induced inhibition of more
than 25% required more than 4 hours. However, complete recovery of the plants
was noted consistently within 1 day following fumigation.
3. Effects From Combined Exposures
Studies on mixtures of N02 and S02 have shown that the injury threshold
for N02 can be significantly decreased with the addition of S02 (Table 8).
Concentrations at which observable injury has occurred were well within the
range of ambient concentrations of N02 and S02 in some areas of the United
States. Responses to pollutant mixtures appear to vary with concentration,
ratio(s) of pollutant concentrations, sequence of exposure and other variables.
93
Tingey et al. (1971) reported that a 4 hour exposure of several crops
to levels up to 2 ppm N02 and 0.5 ppm S02 caused no injury when administered
singly. Slight foliar injury was observed at 0.05 ppm N02 and 0.05 ppm S0?
for a 4 hour exposure. A mixture of 0.10 ppm N02 and 0.10 ppm S02 for 4 hours
caused significant foliar injury to the upper leaf surface of oats (27%), radish
(27%), soybean (35%), tobacco (11%), and tomato (1%). However, at 0.15
or 0.25 ppm NO^ along with 0.25 ppm S02 foliar injury decreased dramatically.
It is unclear why the pollutants appear to be acting antagonistically at
these higher concentrations. The relative decrease in damage that is associated
with increasing concentrations may result from other biological protective
mechanisms (for example, closing of stomata at higher concentrations) or from
the inability of cells to withstand repeated injury. Other studies on combined
exposures for S02/03 have also shown that the synergistic response was most
pronounced near the threshold doses of the two gases and that, as concentrations
increase beyond the threshold doses, response diminishes (McDowall and Cole,
1971; Tingey et al., 1973). Further research is needed to fully understand
this phenomenon.
-------
61
Exposure Concentration
Duration (ppm) N02/S02 Plant Response
TABLE 8
PLANT RESPONSE TO NITROGEN DIOXIDE AND SULFUR DIOXIDE MIXTURES
Plant Species
Exposure Mixture
Chamber Response References
1 hr
1 hr.
2 hrs.
2 hrs.
4 hrs.
= hrs.
same
same
same
same
same
same
same
same
same
exposed
continu-
ous ly for
5 cays a
iirs/wk
'Or 20
«me
sanie
same
0.5/0.5
0.05/0.05
0.15/0.15
0.25/0.25
0.10/0.10
0.05/0.05
U.lU/O.Ui
0.25/0.05
0.05/0.10
0.10/0.10
0.15/0.10
0.05/0.20
0.20/0.20
0.05/0.25
0.15/0.25
0.11/0.11
0.11/0.11
0.11/0.11
0.11/0.11
0-5X foliar iniury
Significantly decreased net
photosynthesis
7X reducxion in apparent photo-
synthesis. Some tissue oealn
9X reduction in apparent photo-
synthesis
0-lOX foliar injury
0-2X foliar injury in 6 species
n foliar injury in tobacco.
0-1X foliar injury in 5 species.
ir.x foliar Injury In tobacco; 13X
foliar injury in radish. 0-2X
foliar injury 1n 4 species.
OX foliar injury in 6 species
IX foliar injury in tomato. 11-
35% foliar injury in 5 species.
17-24X foliar injury in 6 species.
6X foliar injury in soybean. 0-2X
foliar injury in 4 species.
OX foliar injury in tomato. 4-16X
foliar injury in 5.
7X foliar injury in soybean.
0-3* Foliar injury in 5 speci««.
0-6X injury in J species.
72X reduction in leaf area. 83J
reduction in dry weight
of green leaves
84X reduction in leaf area. 83X
reduction in dry weight of
green leaves
43X reduction in leaf arei. 65X
reduction in dry weight of
green leaves
32X reduction in leaf area. 34X
reduction in dry weight of
green leaves
r!d(sh CE + Bennett et al.,
(Raphenus sativa cv. Scarlet Clove) IQ7<;lin3
oea CE 0 Bull and
(Pisum sativum) tian GH * White et al..
(ffcdiciqo saliva «r. Xirajer) 1974'"'
alfalfa GH * white et al.,
(Hedicaqo sativa var. Ranger) 197411'
tobacco
(Nicotlana tabacum ci. Bel W.| GH * Heck, 1963'""
Pinto GH " Tingey et al.,
(Phaseolus vulgaris cv. Pinto) 19T'1
oats
(Avena sativa cv. Clintland 64)
radish
(Raphanus sativa cv. Cherry Belle)
soybean
(Glycine max. cv. Hark)
tobacco
(HJcotiana tafaacum cv. Bel U,)
tomato
(Lyscopersicon esculentum cv.
Koma Vr )
same GH + >,*me
same GH + same
same GH <
same GH * same
same GH * same
same GH + same
Orchard grass GH * Ashenden, 1979
(Dactylis qlomerata var. Aberystwyth 1930"17'''-1
S37)
Kentucky bluegrass GH * same
(Poa pratensis var. Monopoly)
Italian ryegrass GH * same
(Lolium multif lorum var. 1'ilamo)
Timothy GH + same
(Phleum pratense var. Eskimo)
fE, Controlled environment; GH, greenhouse.
&». Greater than additive; 0, additiv".
-------
62
Ashenden (1978, 1979, I960)90'96"97 also reported growth and yield
suppression from combined exposures of 0.11 ppm NOp and 0.11 ppm SCL
(continuous exposure for 103.5 hours per week for 20 weeks). These exposures
caused significant reductions in the growth parameters (5% significance or
greater) of all four grass species tested. Many of the effects were judged to
be synergistic.
Among the physiological changes reported for combined exposures was
significantly decreased net photosynthesis in peas at 0.05 ppm N0« and
0.05 ppm S02 for 1 hour (Bull and Mansfield, 1974)98. White et al. (1974)99
reported a 7% reduction in apparent photosynthesis and some tissue death
after exposing alfalfa to a combination of 0.15 ppm N02 and 0.15 ppm SQ2
for 2 hours.
4. Staff Comments on Vegetation Effects
Because the Criteria Document cites a variety of effects of varying
severity, a judgment must be made as to which effects are adverse. All
identifiable plant responses, such as reductions in photosynthetic rates,
leaf necrosis, yield reduction, etc., are not necessarily to be considered
adverse.
In regard to N02, visible leaf injury is the most readily detectable and
frequently reported symptom of exposure and for this reason has commonly been
used in attempts to report damage to economic crops. Decreases in growth and
yield can occur without such visible symptoms; however, since leaf injury is
the most readily detectable and frequently reported symptom of N02 damage,
this effect (foliar injury rates) is one possible basis the Administrator could
use in setting a secondary standard. An alternative would be to make a judgment
as to what other effect is to be considered adverse (e.g., slight foliar injury,
growth and yield reduction) and set the standard at the level where this effect
is determined to occur. Also of importance is the averaging time of any
secondary standard established to protect vegetation. In our judgment, an
averaging time of 1-3 hours would be most appropriate for effects on vegetation.
This is because exposure to short-term peaks of N02 causes as much if not more
damage to vegetation than does exposure over a growing season. In addition, by
meeting a 1 to 3 hour standard at appropriate levels, there is a high probability
of protecting against longer term effects based upon the relationship of
short-term peaks to long-term means.
-------
63
A key issue is whether there are enough data to quantify yield reduction at
91
various ambient exposure levels. The Ashenden study suggests that NCL alone
may affect two grass species at relatively low ambient concentrations. The
bulk of the data, however, suggests that the level at which NCL causes plant
injury is well above the existing primary standard level (and presumably
also above those primary standard levels likely to result from the current review
of standards). In our judgment, there is inadequate evidence to demonstrate
that exposure to NCL alone at low levels will lead to significant impacts on
growth and yield for commercially important crops and indigenous vegetation.
Based on our review of the literature and consultations with plant experts, we
have formed a judgment that there are also insufficient data on the combined
effects of NCL and SCL to do a quantitative evaluation of yield reduction for
various ambient exposure levels. Numerous data points would be needed to run
a model of this type effectively and they are not available. In addition,
the limited data on combined exposure indicate that plant responses to NO^
in the presence of other pollutants are extremely variable and are not fully
understood at this point in time.
C. Visibility Impairment
1. Major Categories
Air pollution can degrade the appearance of distant objects and reduce the
range at which they can be distinguished from the background. While visibility
impairment can occur naturally, it is clear that anthropogenic air pollution
in the form of fine suspended particles or NCL always exacerbates the problem.
The effects are manifested both in visible plumes and in large-scale, hazy air
masses over urban areas. For purposes of discussion, we are separating visibility
impairment into two major categories: visible plumes or "plume blight" and urban
scale "regional" haze. "Plume blight" may be defined as a coherent, identifiable
plume, which can be seen as an optical entity against the background sky or a
distant object. This definition assumes that a single source or a small group of
sources produce pollutants that are not widely dispersed. Thus, plume blight is
considered a near source or "local" problem. Absorption of light by NCL could
cause the plume to appear brown in color. The prevalence of the visible brown
plume phenomenon is not known with certainty. Brown plumes have been observed
originating from a limited number of power plants in the Southwest.
-------
64
The second category of impairment, regional haze, is produced from a
multitude of sources and impairs visibility in every direction over a large
area, such as an urban area, or possibly over several states. Objects on
the horizon are masked and the contrast of nearby objects is reduced. In
some cases, the haze may be elevated and appear as layers of discoloration.
Multiple sources may combine over many days to produce haze, which may be
regional in scale. The fate of haze is a function of meteorological processes
that occur concurrently on larger scales of time and distance. For example,
haze can result as a plume travels downwind and diffuses throughout the
mixing layer, becoming less identified as a "plume," but more as a general
haze, which obscures the view of distant objects.
2. Contributors to Visibility Reduction
Visibility impairment is caused by the scattering and absorption of light
by particles and gases in the atmosphere and depends on the concentrations and
properties of the gases present. Under typical ambient conditions, light
scattering by particles dominates total extinction, which is related to reduction
of contrast and visual range. The most significant optical effect of N09, however
I Qg £
involves discoloration. NCL appears as a yellow to reddish-brown gas because
it strongly absorbs blue light, allowing red wavelengths to reach the eye. The
extent to which NCL filters out blue light is determined by the integral of NCL
concentration along the sight path. The Criteria Document reports that less than
0.1 ppm-km N02 is sufficient to produce a color shift which is distinguishable in
carefully controlled, color-matching tests. Reports from one laboratory using
NO,, containing sighting tubes indicate a possible visible color threshold of
107
0.06 ppm-km for the typical observer. These values refer to the effect of
N02 in the absence of atmospheric aerosol.
Although the physical properties of NO^ are well known and its coloration
effect in a controlled environment recognized, there are relatively little data
available for judging the actual importance of N02 to visual air quality. The
data needed to make such a judgment are potentially complex, including wave-
length dependence of scattered light at different angles which can also cause
108
discoloration (Charlson et a!., 1978). In addition to being modified by
particle scattering, discoloration of plumes and haze layers by NOp also is
affected by a number of other factors such as sun angle, surrounding scenery,
viewing angle, human perception parameters, and pollutant concentrations.
-------
65
One unresolved issue concerns the relative contribution of NCL and
particles to atmospheric discoloration. Although the color of urban haze,
often termed "brown," was originally ascribed to NCU, more recently others
have shown that brown color can result from particles alone (Charlson et
al., 1978; Alquist and Charlson, 1969).119>11° The coloration effect of
particles depends on particle size, composition, the scattering angle
between observer and illumination, and the optical characteristics of the
background target. The overall impact of aerosol haze is to reduce visual
range and contrast and possibly, to change color. A definitive assessment
of the contribution made by nitrate aerosols to the degradation of visibility
is not currently possible due to measurement problems, but the contribution
of nitrate to fine particle mass is considered in the draft staff paper on
parti oil ate matter.
3. Staff Comments on Visibility
EPA must assess whether there is any supportable relationship between
N02 concentrations at a given point and visibility impairment due to a
plume or to regional haze. The present NCL standards are intended to protect
against effects at or near ground level, and monitoring for N02 is generally
performed at or near ground level. In the case of visual impairment
due to a plume from a stationary source, there is no reliable relationship
between ground, or near ground, level concentrations at any given point
and discoloration caused by the plume. The plume, trapped in an atmospheric
inversion, would disperse slowly and mix to the ground far downwind of the
source. Concentrations taken at ground level while a coherent plume was
clearly visible would not necessarily exceed an ambient standard. For this
reason it would be difficult to set a NAAQS for NCL, based on ground level
monitoring, that would insure an acceptable level of visibility.
Another approach to establishing a visibility standard would be to
monitor plume level concentrations. Because of the difficulty in making
plume measurements, it may be possible to measure the discoloration itself
using an optical device; e.g., a telephotometer. This instrument could
measure the color contrast between the background and the plume. The
measurements could be used as a possible index of the effect of N0?.
Measuring the actual discoloration would avoid the problems encountered in
the ordinary approach, where a monitor near ground level might not pick up
a violation of the standard, but a plume would be clearly visible, or
-------
66
where high N02 levels detected by remote sensing did not result in a perceptible
plume. One problem in this approach is the uncertainty as to whether the
discoloration that would trigger the telephotometer is caused by NCL or by
particles. Although measurement of discoloration would be a unique way of
expressing the standard, it would be worthy of consideration once these
problems are resolved.
Another regulatory mechanism provided under sections 169A and 165(d) of
the Clean Air Act (CAA) may provide some control over the more noticeable brown
plumes appearing in otherwise pristine areas. On May 22, 1980, EPA proposed a
phased approach to visibility protection (45 FR 34763). Phase I applies to
pristine (class I) areas and requires control of visual impairment that can
be traced to a single source or small group of sources, such as plumes emitted
from tall stacks near class I areas. Mandatory class I Federal areas include
all international parks and certain national parks and wilderness areas as
described in section 162(a) of the CAA. EPA has initiated steps to control
this aspect of visibility impairment because the modeling and monitoring
techniques which address impairment caused by single sources will be available
over the next few years, whereas similar techniques which deal with multiple
source problems (regional haze) need additional research and will not be
available for quite some time.
In regard to urban scale regional haze, because the effect of N02 depends on
the product of the pollution concentration and the viewing path length, the
impression of severity is greater the farther away the viewer can see past (or
around) the haze layer. (The coloration of 0.05 ppm N02 over 10 km is the same
as 0.5 ppm over 1 km.) When NO^ is dispersed over a large area, as in the case
of urban emissions, ground level concentrations at individual points may be
less than a national standard but because an observer views the entire NOp mass,
the urban plume would appear discolored.
In summary, the scientific evidence indicates that light scattering by
particles is generally the primary cause of degraded visual air quality and
that aerosol optical effects alone can impart a reddish brown color to a
haze layer, thus raising the question as to the appropriateness of a NAAQS
for NOp to protect against visibility impairment. While it is clear that
-------
67
particles and N02 contribute to brown haze, in our judgment the improvement
in visual air quality to be gained by reducing NCL concentrations seems
uncertain at best. Therefore, we conclude that an ambient standard for NOp
to protect visibility is not warranted at this time.
D. Acidic Deposition
On August 20-21, 1980, the Clean Air Science Advisory Committee (CASAC)
considered acidic deposition in connection with its review of a draft
revised criteria document for particulate matter and sulfur oxides (PM/SO ).
A
The committee concluded that acidic deposition is a topic of extreme
scientific complexity because of the difficulty in establishing firm quantitative
relationships between emissions of relevant pollutants, formation of acidic wet
and dry deposition products and the effects on terrestrial and aquatic ecosystems.
Secondly, acidic deposition involves, as a minimum, the criteria pollutants of
oxides of sulfur, oxides of nitrogen, and the fine particulate fraction of
suspended particulates. Finally, the committee felt that any document on
this subject should address both wet and dry deposition, since dry deposition
is believed to account for at least one-half of the total acid deposition
problem.
For these reasons, the committee felt that a significantly expanded
and separate document should be prepared prior to any consideration of NAAQS
as a regulatory mechanism for control of acidic deposition. CASAC suggested
that a discussion of acidic precipitation be included in the criteria documents
for both NO and PM/SO , but that plans be made for the development of a
/\ j\
separate, more extensive document on acidic deposition. In response to these
recommendations, EPA is in the process of developing an acidic deposition
document that will provide a more comprehensive treatment of this subject.
Thus, the issue will not be addressed in this staff paper.
E. Materials Damage
Field studies and laboratory research have demonstrated that nitrogen oxides
can have deleterious effects on textile dyes, natural and synthetic fibers,
metals, and various rubber products. Some individual dye fiber combinations
exhibit color fading in response to N02 exposures. Significant fading was
observed after 12 weeks of exposure to 0.05 N02 under high humidity and high
temperature conditions. Studies conducted at levels of 0.2-0.3 ppm N02
for 8 to 16 hours have shown that N02 is the pollutant responsible for yellowing 01
-------
68
various fabrics. Additional data are needed to define the role of nitrogen
oxides in the degradation of textile fibers and rubber compounds and to define
the effects of NCL on the corrosion of metals.
F. Staff Conclusions and Recommendations
The staff concludes that a primary standard within the recommended
range will provide protection for the welfare effects discussed in section
VII. Because acidic deposition is an important and complex problem associated
with multi-pollutant interactions it is being addressed in a separate
document by EPA and not as a specific element of the NCL standard review.
The following conclusions are based on the assumption that a primary standard
within the recommended range will be selected by the Administrator. If
not, the need for a secondary standard must be reevaluated.
1. Symptomatic effects have been reported during or after exposure
of asthmatics to 0.5 ppm NCL for 2 hours. The staff concludes
that the occurrence of such symptoms affects personal comfort
and well-being. Therefore, symptomatic effects may warrant protection
under the secondary standard if they are not protected under the
primary standard.
2. Effects of NCL alone on vegetation generally occur at concentrations
above those which would exist in the atmosphere for any length of
time. Although there is evidence that low levels of NCL and SCL
combined can have a synergistic effect, this type of response
is extremely variable and has not been sufficiently documented.
Therefore the data do not suggest significant effects of NCL
on vegetation below current ambient levels.
3. Although there is evidence that NCL contributes to atmospheric
discoloration, the quantitative relationships between NCL
concentrations and visibility impairment necessary for selecting
the level of the standard have not been sufficiently established.
4. While NCL has been qualitatively associated with materials damage,
the available data do not suggest major effects of NCL on materials
for concentrations at or below the suggested ranges for the primary
standard.
-------
APPENDIX A. Review of Selected Animal Toxicology Studies
At the Clean Air Scientific Advisory Committee (CASAC) meeting held
4
November 13-14, 1980, three alternatives for use of animal data were
considered. Generally, the options were: (1) to use the body of animal
toxicology data qualitatively in developing a margin of safety; (3) to use
the body of animal toxicology data quantitatively in developing a margin
of safety, (3) to assess each type of biological effect (strength of data
base, severity of effect, and relationship to human health effects) and
then, as appropriate, to use the data base for each effect in either
supporting a margin of safety or a lowest effects level in humans, or to
consider the data base for a particular effect to be inadequate for use
in setting NAAQS. The CASAC concluded that the third option was the best
approach for analyzing animal data in the review of NAAQS for NCL. In this
revised version of the staff paper, we have attempted to refocus the dis-
cussion of the animal toxicology data in a manner that is consistent with
the intent of option three.
While most animal studies involving NCL exposures have been conducted
at relatively high concentrations of NCL (2 to 20 ppm), many studies
conducted at lower concentrations (0.2 to 2.0 ppm) have shown that a variety
of pulmonary and non-pulmonary effects do occur at lower levels. This
section focuses primarily on those animal studies which have shown effects
at lower levels (<_ 2.0 ppm) of NO^. When appropriate to show increasing
degrees of toxicity, studies conducted at higher levels of N02 are included.
The relevant toxicology studies are summarized in Tables 1 and 2. For a
more complete review of N00 toxicology studies, the reader is referred to
<- -j
"Air Quality Criteria for Oxides of Nitrogen."
A.I. Pulmonary Effects
Pulmonary effects resulting from exposure of experimental animals
to NOp have been well-documented. These effects range from the relatively
mild and reversible changes in pulmonary function following short-term
single exposures to the more severe and permanent damage of emphysema for
long-term continuous and repeated intermittent exposures to NO^.
At concentrations near those which have been found in urban environ-
ments, the region of the lung bounded by the terminal and respiratory
bronchioles and adjacent alveoli are most affected. This region
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A-6
represents the terminal position of the lung which is primarily involved
in oxygen and carbon dioxide exchange and is, therefore, one of the most
essential regions of the lung for maintenance of life.
a) Respiratory Infection. The pulmonary system normally defends
itself against infection through a combination of mucociliary transport,
phagocytosis, and immunological activities. These defenses, however,
begin to break down during short-term and long-term exposures of animals
to NOp with a resulting increase in susceptibility to respiratory
infection.
Interpretation of studies such as that of Speizer et al (1980),
discussed in Section V-C-5, can be aided by supporting evidence from
animal infectivity studies. Controlled exposure studies of a variety of animal
species have provided sufficient data to demonstrate that NCL impairs
respiratory defense mechanisms. The key animal studies are reviewed and
summarized in this subsection.
One of the more extensive areas of investigation for NOp effects
involves assessing the ability of this gas to enhance susceptibility to
infectious agents. The infectivity model system involves first exposing
randomly selected animals to either a test pollutant or to filtered air.
Following exposure, both experimental (e.g., NOp-exposed) and control
animals are combined in another chamber where they are exposed for about 15
minutes to an aerosol containing one of several different infectious agents.
The animals are then returned to clean air conditions for 15 days, and
mortality rates of the experimental and control groups are compared.
Mortality is normally due to pneumonia or related complications. Typically
N02 increases this mortality.
The influence of exposure mode (concentration x time) on the toxicity
of NOp has been investigated. ll»'^>13 While holding concentration times
time of exposure (C x T) constant at 7 and varying concentration (1 to
14 ppm) and time (0.5 to 7 hr), the authors reported that brief exposures
to high concentrations of N00 resulted in greater mortality to bacterial
11
infection than did prolonged exposures to lower concentrations of l^-
Thus, susceptibility to infection is influenced more by concentration of
I O
NC>2 than by length of exposure. Another study evaluated the effect
-------
A-7
of varying continuous exposure durations on mice exposed to six different
constant concentrations ranging from 0.5 to 28 ppm. The linear dose
response curves observed in this investigation suggested that (1) mortality
increases with increasing time of exposure, (2) mortality increases with
increasing concentrations of N02, and (3) concentration is more important
than time.
The importance of background NCL concentrations in increasing
mortality was demonstrated in a study which reported greater effects for
delayed bacterial challenge when mice received a 64 hour background exposure
of 1.5 ppm NO,,, compared to zero background NOo, with both exposure conditions
21
superimposed on 1-hour peaks of 4.5 ppm N02- This conclusion regarding long-
term background exposures does not detract from the impact of exposure to
short-term higher-level peaks for which several studies ~ have
shown serious effects at or below 3.5 ppm. The above cited studies, in
conjunction with the "gas-stove" studies, ' provide evidence
suggesting impairment of the respiratory defense mechanisms by N02-
The large number of investigators reporting significant effects using
the infectivity model precluded thorough discussion of the individual studies.
An overview of animal infectivity studies indicates that all of the infectivity
studies which show effects below 2.0 ppm N02 are for long-term (continuous
or intermittent) exposures, thus supporting the need for protection against
long-term, low-level exposures to N02. Further discussion of specific
aspects of impairment follows.
b) Respiratory Defense. The mucociliary system is a major line of
defense against respiratory infection. This system extends from the nasal
cavity down to the terminal bronchioles and removes particles of various
types (inhaled particles, cellular debris, etc.) from the tracheobronchial
tree. Concentrations of NO, greater than 5.0 ppm have been shown to cause
114
decreased rates of ciliary beating in vitro and of mucociliary transport
in vivo. These studies suggest that ciliary activity is reduced by
exposure to N09. Other research has shown structural alterations in cilia
"I I Q 1 OC
and cilia-bearing cells. '
Alveolar macrophages are cells that phagocytize (consume) microbes and
residual particles from the deeper portions of the lung. It has been
-------
A-8
demonstrated that 21-to 33-week continuous exposures of mice to concen-
trations as low as 0.5 ppm NOo with 1-hour peaks of 2.0 ppm N02 caused
some morphological changes and complete deterioration of alveolar
macrophage cells, while continuous exposure to 2.0 ppm N09 for 21 weeks
22
caused distinct morphological alterations. Reduced mobility and
activity of alveolar macrophage cells decrease the pulmonary system's
ability to defend itself against infection and may leave defense in non-
ciliated regions of the lung entirely up to the immune system.
The immune system also has an essential role to inactivate bacteria
and viruses. It functions in conjunction with other host defense systems and
in their absence. Even though local immunological responses within
the lung are critical for antimicrobial defense, the effects of pollutants
on these responses are largely unstudied. Continuous exposure of
monkeys to 1 ppm N02 for 493 days, followed by challenge with flu virus
not only increased antibody levels in the blood prior to viral challenge
but also increased the levels sevenfold and elevenfold, after 21 days
and 41 days following viral challenge, respectively. However, mice
exposed for 3 months to a baseline of 0.5 ppm NOo with daily (5 days/week)
1-hour peaks of 2 ppm N0?, exhibited a decrease in serum antibody levels.
23
Immunoglobulin levels were also affected. In a different study involving
guinea pigs, it was claimed that N02 had an adverse effect on the immune
function. This conclusion was drawn after a 6-month exposure to 1.0 ppm
N02> followed by bacterial infection with Diplococcus pneumoniae, resulted in
increased incidence of infection, reductions in all immunoglobulin fractions,
and increased mortality.
The available data suggest serious effects from long-term low-level
N02 exposure for the immune systems of several species. In combination
with the evidence for mucociliary system and alveolar macrophage cell
damage, these data support the contention that pulmonary defense mechanisms
are adversely affected following acute and chronic exposures to NO^- Thus,
it is reasonable to suggest that N02 may be a factor of increased prevalence
of respiratory illness for young children living in homes with gas stoves.
-------
A-9
c) Lung Biochemistry. Lung biochemistry studies generally
involve procedures which would be unethical for human subjects since the
lungs are removed for detailed examination. Therefore, essentially all of
our information on effects of NO^ upon lung biochemistry is from a variety
of animal species. However, human and animal biochemical reactions with
NOp should qualitatively be quite similar due to the similarity of
biochemical mechanisms.
While many lung biochemistry investigations have focused on mechanisms
of toxicity (discussed in Section IV-B), those studies of primary
concern in this discussion deal with detection of biochemical indicators
of early damage from NOp exposure. There is of course a direct relationship
between the mechanism of toxicity, which is primarily oxidative damage,
and the resulting oxidative breakdown products which are involved in
cell injury or death.
The lowest level of NCL for which biochemical effects have been
19
demonstrated for a single exposure of 3 hours is 0.2 ppm. In this study,
40 to 60% inhibition of conversion of prostaglandin E~ (PGEp) to its
metabolite, 15-keto PGE2, was produced in rats exposed to 0.2, 2.0, and
19 ppm N02, but the effect did not occur until 18 hours after exposure.
The results of this particular study suggest the possibility of effects
which may have been missed in human clinical studies due to the long
delay between exposure and effect. In addition, this is the first documented
case of N02 interference with hormone metabolism, and it shows an effect on
a type of cell (endothelial cells of lung capillaries) not previously
studied.
Continuous exposure of guinea pigs, theoretically deficient in Vitamin C,
for one week to 0.4 ppm NO- increased lung protein content, possibly due to
117
plasma leakage. This was indicative of pulmonary edema but no differences
in protein composition were reported. A more recent study by Belgrade
24
et al. 1981 did not report alterations at the 0.4 ppm NOo exposure level;
however, Vitamin C deficient guinea pigs were more susceptible to NO^ as
evidenced by increased protein in lung lavage fluid. The seriousness of
changes in serum enzyme levels found in guinea pig lungs after repeated
8 hr/day for 1 week and long-term continuous exposures to 0.5 ppm N0?
or o/r
is uncertain; ' some changes may be indicative of generalized damage
to the lung.
-------
A-10
These studies report that biochemical alterations are occurring after
exposures to concentrations of N02 in the range of 0.2 to 0.5 ppm and
support other investigations indicating a mechanism of membrane damage
by chemical oxidation of unsaturated fatty acids. The delayed effect of
N0? is important and may occur in humans, thus supporting a need for
extended observation of human subjects following exposure. It is also
possible that existing human studies reporting no biochemical alterations
may have overlooked delayed effects.
d) Lung Morphology. Morphological alterations of lung tissue observed
after long-term exposure to N02 are serious health effects because they
may produce conditions such as emphysema, which are potentially irreversible
and generally disrupt the lungs' ability to exchange oxygen. While those
changes produced by short-term exposures to N02 appear to be generally reversible.
the relationship of the acute effects to chronic effects is unclear at present.
Exposure of mice to 0.1 ppm N02 for six months with daily 2-hour peaks
of 1.0 ppm N09 resulted in structural alterations in bronchioles and
29
alveolar ducts. While the emphysematous alterations were not remarkable
in this study, the fact that the changes were found following extended
exposure to very low concentrations of N02 is a matter of concern.
Several different effects have been reported for extended exposures between
0.5 and 1.0 ppm N02- These effects include: (1) isolated swollen collagen
fibers (morphological damage) in rabbits exposed for 4 hours/day, 5 days/week
for 24 or 36 days to 0.25 ppm N0~; (2) alveolar damage in mice after 6,
-ic
18 or 24 hour/day exposures for 12 months to 0.5 ppm N02 ; (3) damage to
tracheal mucosa and cilia in mice following 1 month of continuous exposure
118
to 0.5-0.8 ppm N02 ; (4) slight emphysema, thickened bronchial and
bronchiolar epithelium in virus challenged monkeys caused by 493 days of
continuous exposure to 1.0 ppm N02 ; and (5) increased presence of
protein in pulmonary air spaces, suggestive of edema, was found in mice
121
following exposures to 0.5 ppm N0? for 5 days/week for 3 or 6 weeks.
The process of emphysema development caused by N0? exposure is
very complex, beginning with essentially mild reversible changes and
leading eventually to irreversible changes and major damage for long-
term exposures. Considering the life span of most experimental animals,
-------
A-11
it is reasonable to compare the time required for morphological damage
in experimental animals with the time required for development of emphysema
in humans. The seriousness of the effect, the large body of scientific
evidence, and the comparability of effects found in humans support the
need for protection of humans from long-term and multiple exposures to NCL.
e) Pulmonary Function. Pulmonary function tests have been
probably the most commonly used measures of pollutant effect for both
epidemiological and controlled experimental human studies. Although pul-
monary function measurements create less discomfort for subjects, are
less invasive, and raise fewer ethical challenges than techniques used
in most morphological or biochemical studies, pulmonary function tests
measure only gross effects and provide less specific information, particularly
for short-term low-level exposures to NCL. There are no studies reporting
serious pulmonary function changes in animals for short-term exposures
below 5.0 ppm NCL and only a few studies reporting significant pulmonary
function effects for long-term exposures below 5.0 ppm. However, it
should be noted that more sophisticated tests for pulmonary function in
small animals have been developed only recently.
Degranulation of mast cells was reported in rats sacrificed immediately
122
after a 4-hour exposure to 0.5 ppm NOo or a 1-hour exposure to 1.0 ppm NO^.
Although the effects reported for the short-term single exposure appeared
to be reversible, the authors contended that release of granular material
from the lung mast cells may suggest a potential onset of acute inflammatory
reaction. Since the granular material (histamine and other chemicals) can cause
bronchoconstriction, this effect may be related to increased airway resistance
caused by N02 in humans.
One of the more common effects of exposure to N02 is tachypnea (increased
respiratory rates). This effect was found for a variety of animal species
exposed for both long-term continuous and short-term durations to N09 in the
123
range of 0.5 to 20 ppm. The large number of studies reporting this effect
precludes discussion; however, it can be surmised that humans exposed to
high N0? doses would also experience increased respiratory rate.
-------
A-12
An overview of pulmonary function effects of short-term and long-term
exposures of animals to 5.0 ppm N02 or less provides little support for
the pulmonary function decrements found in humans. The only consistent
effect found below 5.0 ppm was tachypnea, which was quickly reversible after
removal of N02.
f) Adaptation. Adaptation and tolerance are terms commonly used to
describe the ability of living systems to return to normal physiological
conditions following extended biological stress. Adaptation is suggested
as a possible explanation for results such as those found by Rejthar and
1 24
Rejthar (1974) , which indicated that, after 7 weeks of exposure to 0.5
ppm N02, the lungs of exposed mice were in a state of repair and reversal
of hyperplasia. Since longer-term studies have shown that the lungs
~\ ?R
have become emphysema tous, ~ this reversibility after a shorter
exposure should not cause complacency. For example, dogs exposed to a
combination of 0.64 ppm N09 and 0.25 ppm NO exhibited progressive morphologic
30
alterations after exposure ceased.
A possible explanation for the apparent tolerance which many animal
species exhibit has been offered. At some point after initiating
continuous N02 exposure, the rate of replacement of dead and injured
cells may return to normal (i.e., rates of replacement equivalent to
those in animals breathing clean air). Biochemistry (enzyme levels) of
the adapted cells may have changed to permit degradation of secondary products
formed during N02 inhalation. It has been speculated that levels
of several protective enzymes in the rat may be either increased
as a defense mechanism or may result from increased production of specific
cells which produce more of these enzymes.
It is possible that all pulmonary cells are susceptible to low
levels of N02 and that tolerance in the literal sense never really
develops. Long-term low-level N02 exposure of animals and humans may
create an insensitivity which may minimize pulmonary function response
to N02 inhalation. A major pathophysiological change in pulmonary
tissue may be necessary before pulmonary function is altered sufficiently
to be detected by some pulmonary function test methods. Even though they are
more sensitive, morphological and biochemical techniques cannot be used
on humans due to ethical limitations.
-------
A-13
Short-term peaks of NCL as well as long-term, low-level exposures
to N02, appear to cause adverse health effects in spite of apparent adapta-
tion to NOo- The weight of scientific evidence supports some form of
adaptation in several animal species, but there is also evidence to support
the contention that these "adapted" animals are more likely to develop
n short-
118,30
21
respiratory infections from short-term peak exposures or emphysema from
long-term exposures to N02,
A.2. Extra Pulmonary Effects
Extrapulmonary effects are those biological alterations from
normal physiological conditions which occur outside the pulmonary system.
Extrapulmonary effects of NCL exposure include hematological (blood chemistry)
effects, central nervous system and behavioral effects, and biochemical
alterations in organs. In the following subsections, these effects will
each be described, related studies reviewed, and evidence for the effect
assessed in the context of its seriousness and relationship to human effects.
a) Hematological (Blood Chemistry) Effects. Hematological changes
are continuously occurring in all living mammals, including humans. These
alterations in blood enzyme or electrolyte concentrations are necessary to
maintain homeostasis, the steady-state biological condition of normal,
higher organisms. Hematological perturbations which can be
induced by N02 exposure may be indicative of a biologically significant
interference with normal function.
A continuous exposure of 0.05 ppm NO, for 90 days showed no alterations
128
in the hemoglobin or erythrocyte levels of rats. Depression in the
glutathione (GSH) peroxidase levels of red blood cells was induced by a
7-day exposure of guinea pigs to 0.5 ppm N09 but disappeared after 4
or nr C-
months. ' This suggests a possible compensatory mechanism for dealing
with N02-induced oxidation. Continuous exposures of guinea pigs to 0.40
ppm N02 for one week resulted in significantly increased red blood cell
D-2,3-diphosphoglycerate levels, an alteration which may be an indicator
28
of tissue deoxygenation.
The effects on hematological parameters from exposure to N(L described
above probably occur in humans as well. Decreases in hemoglobin, hematocrit,
and erythrocyte acetylcholinesterase have been found in humans exposed to
-------
A-14
39
1.0-2.0 ppm N02 for as little as 2 1/2 hours. However, it is very
difficult to interpret the biological significance of these hematological
perturbations. Many of the changes may simply be a normal protective
response to an invading toxic agent. Comparable studies of human subjects
will be necessary before the full significance of hematological effects is
understood.
b) Central Nervous System and Behavioral Effects. The central
nervous system controls the senses, behavior and normal functioning of
the organs. A major alteration in central nervous system function could
have serious biological import. However, the data base on central nervous
system effects from NCL exposure of animals is quite limited, and the
extrapolation of these effects to humans is uncertain at best.
The only central nervous system study which reported potentially
serious effects showed that brain enzyme levels of guinea pigs were
129
altered by exposure to 0.53 ppm NO- for 8 hours/day over 180 days.
Although the alterations of brain enzyme levels by NO^ could have biological
importance in human extrapolation, the study has not been replicated.
While other studies have shown central nervous system effects, the
effects reported are not of a sufficiently serious nature to warrant concern.
c) Biochemical Indicators of Extrapulmonary Effects. Biochemical
indicators of extrapulmonary effects can be enzymes, lipids, lipoproteins,
hormones, steroids, immunoglobulins, or electrolytes. These
substances, which are found in the blood and various organs of the body,
may provide an early warning of potentially more serious long-term
effects from N02 inhalation. Numerous studies suggest that NC^ causes
effects including kidney, heart, and liver damage.
Enzyme markers have been identified in several different animal species
including guinea pigs, rats, and hamsters. Levels of some marker enzymes
have been shown to change after exposure to N02 concentrations as low as
0.5 ppm. A seven-day exposure of guinea pigs to 0.5 ppm N02 produced
significantly higher lysozyme and plasma cholinesterase levels, but
-------
A-15
pC pc
long-term exposure caused a decrease in both. ' Release of lysozyme into
the blood can be an indicator of hepatic and myocardial damage. Levels of
cholinesterase tend to be elevated during cardiac surgery or hemachromatosis
(blood disease) but depressed for hepatocellular (liver) disease and
myocardial infarction (heart attack) ' . Alterations in the other
enzymes (SGOT, SGPT, and LDH) measured in the Donovan et al. (1976)25
p/T
and Menzel et al. (1977) studies were suggested as being related to
NCL-induced hepatic (liver) damage or perhaps even hepatic lesions for
the 4 month exposure to 0.5 ppm NOp.
Further support for NOp-induced hepatic damage has come from a study
in which guinea pigs were exposed to 1.1 ppm NOp for 8 hours/day over a
180 day period; decreased plasma cholinesterase, albumin, seromucoid,
07
alanine and aspartate transaminase were found in exposed animals .
Additional evidence was provided by electron micrographs of the liver
which suggested intracellular edema.
A significant increase in pentobarbital-induced sleeping time
18
was caused by 3 hour exposures to NOp concentrations as low as 0.25 ppm
In this study, mice exposed to 0.125 ppm N02 showed no differences from
control, while female mice exposed to 0.25 ppm NOp and higher for 3 hours/day
showed a significant increase in pentobarbital-induced sleep time. The
effect disappeared at all levels after repeated exposure. It was suggested
that NOp may alter metabolism of foreign substances (e.g. drugs, chemicals)
by the liver, thus increasing the time necessary to detoxify pentobarbital
and potentially other related drugs or chemicals. A related study of
the effects of ozone on pentobarbital-induced sleep time revealed that
less exposure time was required for NOp than for ozone to produce a
significant effect (i.e. a single exposure of [^ caused more effect
than a single exposure of ozone)
Consistently higher levels of urinary protein were found in guinea
pigs continuously exposed for 7 to 14 days to 0.5 ppm NOp; proteinuria
was also detected in guinea pigs exposed for only 4 hours/day to 0.4 ppm
NOp . Analysis of the proteins revealed that they were albumin and were
a, 3 , and a globulins, whose presence in the urine suggests nephrotic
syndrome (kidney disease). Histopathological (tissue) investigations of
the kidney were reported to be negative.
-------
A-16
d) Teratogenesis, Mutagenesis and Carcinogenesis. Teratogenic
effects are those biological alterations which have some impact on
development of unborn animals (e.g., fertility, litter size, birth weight,
birth defects). Mutagenic effects are alterations of the chromosomal
structure of normal cells, which may result in mutant cells and can be
inherited.
There is little or no evidence in the literature demonstrating that
exposure to N09 is teratogenic, mutagenic or oncogenic in animals. However,
20
a recent report by Iqbal et al. (1980) suggests concentration related
in vivo biosynthesis of N-nitrosomorpholine in mice exposed to 0.2 ppm
and higher levels of N02 along with morpholine for 4 hours. This is the
first and only report of a direct link between N02 exposure and nitrosamine
formation in vivo. While the nitrosamine quantities formed at the 0.2
ppm N0? exposure were too small for accurate analysis, a maximum of 2230
ng N-nitrosomorpholine/mouse was detected after 4 hours of exposure to
50 ppm N02 along with morpholine. Because the low level exposure to N02
has been related to possible concomitant biosynthesis of nitrosamines
this area of investigation requires further work to assess better the
potential health hazards.
A.3. Extrapolation Modeling
Animal studies permit a complete evaluation of disease in that the
researcher has the choice of a wide range of concentrations, exposure
regimens, chemical agents, biological parameters, and animal species. Many
physiological mechanisms are common to animals and man so it can be
hypothesized that, if a pollutant causes a particular health effect in
several animal species, it will be likely to cause similar effects in exposed
humans. However, this flexibility in animal studies is not gained
without expense. Quantitatively relating effective pollutant concentrations
in animals to concentration responses in man is not currently possible.
The current annual standard for N02 was based primarily on epidemic-
logical data using an N02 chemical-monitoring method which is now known
to be invalid. The only quantitative chronic N02 exposure studies
available used animals. While the animal studies cannot provide direct
evidence of effect levels in man, they do suggest that long-term exposure to
-------
A-17
N02 causes emphysema in animals. If man is to be protected from such a
severe irreversible effect, additional efforts must be undertaken to develop
extrapolation models useful in the setting of NAAQS. Similar examples can be
described for other NAAQS in which the large animal toxicological data base
provides evidence for potentially severe adverse effects in man. But with-
out extrapolation models, this information can only be used qualitatively
in considering which standards provide an adequate margin of safety.
-------
APPENDIX B. Ambient N02 Concentrations in Urbanized Areas
This appendix contains a summary of monitored NCL air quality in 186
urbanized areas of the country. The data discussed is used to develop
section IV and portion of section VI.
Annual Averages
Annual average concentrations of N02 are available for 186 of the
nation's 275 urbanized areas. The mean of the annual averages for these
areas is 0.029 ppm, as compared to a corresponding value of 0.001 for
isolated areas essentially unaffected by man-made NO emissions. The
/\
comparable figure for inhabited non-metropolitan areas is approximately
0.01 ppm. Thus, long-term N02 concentrations are much higher in the
nation's cities than in rural areas and small cities. In addition, data in
the Criteria Document indicate that N02 annual averages in most urbanized
areas are increasing.
Table 1 indicates that 95% of all urbanized areas reporting data in
1977 through 1979 meet the current annual average NAAQS of 0.053 ppm (100
vg/m ). The highest annual average of 0.081 ppm is found in the Los
Angeles area.
Daily Averages
A second method of characterizing ambient concentrations of N02 is
through the statistical distribution of daily or 24-hour average values.
Table 1 also contains this distribution in terms of the 24-hour average
values which would be expected to be exceeded more than once per year. (The
once per year exceedance rate was selected for this distribution because it
has historically been used in setting ambient air quality standards.) For
example, based on 1977-79 ambient monitoring data, no 24-hour average
concentration would be expected to exceed 0.17 ppm more than once per year
in 95% of the 186 areas examined. Moreover, it would not be expected that
a 24-hour value of 0.24 ppm would be exceeded more than once per year in
any of the areas examined.
Short-Term Averages
Similar calculations are also displayed in Table 1 for 3-hour average
values. However, because continuous monitoring is not available in all
186 urbanized areas, 3-hour average data are shown for only 104 areas. As can
be seen, in 95% of the 104 areas, the 3-hour average concentration levels
would not be expected to exceed 0.29 ppm more than once per year. Likewise,
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B-3
the highest 3-hour average which would not be expected to be exceeded more
than once per year in any of the areas examined is 0.40 ppm.
Table 1 also contains several characteristic methods of displaying the
1-hour average N02 concentration levels observed during 1977-79 in the above
104 urbanized areas. The first of these consists of determining the distribution
of maximum 1-hour average concentrations which would not be expected to be
exceeded more than once per year. This distribution corresponds with similar
distributions for 24-hour and 3-hour average values previously discussed.
The second and third approach consist of determining the distribuiton of
maximum 1-hour average concentrations (during any given day) which would not
be exceeded on 95% and 99% of the days in a calendar year. These latter two
approaches afford a means of measuring exposure to short-term repeated
peaks of NOp.
As can be seen from Table 1, in 50% of the areas (52 of 104) the daily
maximum 1-hour concentration of N02 would not be greater than 0.06 ppm on
95% of the days in a calendar year (e.g., on only 18 days would the daily
maximum 1-hour concentration exceed 0.06 ppm in these 52 areas). Similarly,
in these same areas, the daily maximum 1-hour concentration of NOp would not
be greater than 0.09 ppm on 99% of the days in a calendar year. As a further
example, the data in Table 1 illustrate that in 95% of the areas (99 of 104)
the daily maximum 1-hour concentrations would not exceed 0.20 ppm on 95%
of the days or 0.33 ppm on 99% of the days.
The monthly distributon of 1-hour averages greater than 0.10 ppm, 0.15
ppm, and 0.20 ppm in 15 U.S. cities is shown in Figure 1. While in most
areas the highest 1-hour N02 values occur in the summer months, they frequently
occur during the winter in California. This tends to flatten the distribution
somewhat, particularly for the greater than 0.15 ppm and greater than 0.20
ppm cases.
The distribution in Figure 1 indicates that throughout the year there
are many hours when hourly levels of N02 exceed 0.10 ppm in these cities.
However, there are relatively few hours when 1-hour levels exceed 0.20 ppm.
The number of hours at or over 0.10 ppm is highest in February, May and
July. The number of hours at or over 0.15 ppm, while generally represented
by a flat distribution, drops off noticeably in March and September. The
-------
300
B-4
Figure ]
ANALYSIS OF MONTHLY DISTRIBUTION OF
HIGH 1-HOUR N02 VALUES
15 cities * 1977 data
250
200
150
TOO
50
_> .10 ppm
>_ . 15 ppm
> .20 opm
Jan Feb Mar Apr May June July Aug Sep Oct Nov..
-------
B-5
number of hours at or over 0.20 ppm is greatest in October and November;
most of the cities reporting these high values are in California. While
the data on Figure 1 are from 1977, a cursory review of more recent data
indicates that the high 1-hour N02 pattern depicted in Figure 1 still
holds.
High hourly N02 values in urban areas form a bimodal distribution
throughout the day when aggregated, as shown in Figure 2. The highest peak
occurs in late morning, roughly corresponding to the early-morning release
from motor vehicular traffic and subsequent conversion of NO to NO^. The
second peak starts in the late afternoon and declines slowly. This peak is
due to ozone titration, when ozone formed early in the day mixes with fresh
NO emissions to form N02 and oxygen (by the reaction NO + 03 -> N02 + 02).
The bimodal pattern is found in most U.S. urbanized areas although some
report frequent nighttime peaks due to a slow titration reaction with
ozone transported into an area.
While N02 peaks in the general urban scene are closely correlated with
motor vehicular emissions of nitrogen oxides (and carbon monoxide), N02 peaks
in many places do not follow the fairly repetitive pattern associated with
mobile sources. These areas are often affected by nitrogen oxide emissions
from large point sources, such as power plants, steel plants, and gas pipeline
pumping stations. N02 peaks from these sources at any particular location
vary greatly depending upon meteorological conditions. Areas affected by
point sources are characterized by generally low levels of N02 punctuated by
high N02 spikes during a fumigation or inversion situation. When this
occurs, the high N02 concentrations are usually correlated with high levels
of sulfur dioxide and particulate matter, both indicative of a common point-
source origin.
-------
8-6
Figure 2
IDEALIZED CURVE OF HIGH (> .10) HOURLY
N02 VALUES SY TIME-OF-OAY
(8 cities data)
(data from sight selected cities)
12
10 12
-------
APPENDIX C. CASAC CLOSURE MEMORANDUM
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
July 6, 1982
OFFICE OF
THE ADMINISTRATOR
SUBJECT: CASAC Review and Closure of the OAQPS Staff Paper
for Nitrogen Oxides
FROM: Sheldon K. Friedlander, Chairman
Clean Air Scientific Advisory Committee
TO: Anne M. Gorsuch
Administrator
The Clean Air Scientific Advisory Committee has completed
its third and final review of OAQPS1s revised staff paper
entitled Preliminary Assessment of Health and Welfare Effects
Associated with Nitrogen Oxides for Standard-Setting Purposes.
The Committee has prepared this closure memorandum to inform
you of its major conclusions and recommendations concerning
the various scientific and technical issues associated with
the revision of the National Ambient Air Quality Standards
(NAAQS) for nitrogen dioxide, and to advise you of the
scientific quality of the staff paper. This memorandum is
the outcome of three CASAC review meetings of the staff paper
held on November 14, 1980, February 6, 1981, and November 18,
1981. It supplements CASAC1s closure letter on the air
quality criteria document for nitrogen oxides sent to you on
June 19, 1981. In that letter the Committee advised that the
criteria document was scientifically adequate for use in
standard setting.
CASAC is satisfied that its recommendations for improving
the scientific quality of the staff paper have been incorpo-
rated in successive revisions of the document. It is now a
balanced and thorough interpretation of the scientific evidence
pertaining to this pollutant. It is also consistent with the
evidence presented and interpreted in the nitrogen oxides
criteria document. Thus, the Committee believes that the
revised staff paper for nitrogen oxides provides you with the
kind and amount of technical guidance needed to make any
appropriate revisions to the primary and secondary standards.
Attachment
-------
CASAC Conclusions and Recommendations on Major Scientific
Issues and Studies Associated with the Development of Revised
NAAQS for Nitrogen Oxides
A. Critical Elements in the Primary Standard Review
During the review of both the NOX criteria document
and staff paper it became apparent that no single study could
provide the scientific basis for revising the primary standard
for nitrogen dioxide. Rather an accumulation of evidence
from animal toxicology, human clinical, and epidemiological '
studies furnishes both qualitative and quantitative support
for a revised standard* Each class of study is subject to
certain methodological limitations but, taken together, these
studies provide sufficient evidence to guide you in making an
appropriate public "health policy decision. In addition, the
Committee concludes that all of the key studies related to
human health effects were identified and discussed in the
staff paper. Based on a discussion of these issues CASAC
recommends that you retain the annual primary standard and
select the concentration level at the lower end of a range
V
between .05-.08 parts per million"(ppm). Discussed^below
are CASAC's conclusions and recommendations concerning the
critical issues associated with revising the primary N02
standard.
1. Animal Toxicology Studies
Three alternatives regarding the use of animal
toxicology data for standard-setting were reviewed by the
Committee. These included: 1) using animal data as qualitative
support in developing a margin of safety; 2) using data from
animal studies as quantitative support in developing a margin
of safety; 3) identifying each type of biological effect which
-------
has been found to occur in animals from exposure to NC>2 and
assessing the extent to which specific studies reporting a
given effect can be used to estimate the lowest effects level
for humans. CASAC concludes that option 3 is the most
reasonable approach to employ in evaluating a data base whose
quality and relevance of animal response vary widely. Thus,
the Committee recommends that results from animal studies
should be considered on a case-by-case basis in making extra-
polations to human health effects.
2. Human Clinical Studies
The Committee concludes that none of the controlled
human exposure studies offer definitive evidence that adverse
health effects occur at levels below one part per million
(ppm). Studies have reported mild symptomatic effects (e.g.
dizziness, headache, nasal discharge} in some sensitive
population subjects after a two-hour exposure to .5 ppm
(Kerr, et al, 1979). However, the Committee would not go so
*
far as to describe such symptoms as "adverse health effects."
In addition, CASAC recommends that reported results of the
Orehek et al. (1976) and Von Nieding (1977) studies (i.e.
dose-response curves for changes in specific airway resistance
after exposure to 0.1 ppm NC>2 and a bronchoconstrictor)
not be considered in establishing a lowest observed effect
level. This recommendation reflects the Committee's concern
over uncertainties in the statistical analysis and uncertainty
regarding the significance of responses observed in studies
that use a bronchoconstrictor. These studies should instead
-------
be used along .with other qualitative and quantitative evidence
in selecting a margin of safety for a revised standard.
3. Epidemiological Studies
Community epidemiological studies identified and
discussed in the staff paper and criteria document do not
provide quantitative evidence of identifiable public health
effects linked to specific ambient air concentrations of
N02« With respect to specific studies the Committee concludes
that the Chattanooga (Shy et al., 1970, 1973 and 1979) and
the Japanese (Kagawa and Toyama, 1975) studies do not establish
quantitative dose-response information for revising the present
standard. The studies do provide, however, limited qualitative
support for the hypothesis that higher levels of NO2/ in
association with other pollutant., in the ambient air, may affect
lung function and/or the onset of respiratory illness in children.
The Committee devoted considerable discussion to epidemiologies!
*
studies assessing NO? exposures to people residing in
^ ~
homes with gas stoves. These studies have reported a higher
incidence of acute respiratory disease for children living
in homes equipped with such stoves than for those residing
in homes in"which electric stoves were utilized. Although
»
gas stoves tend to emit large amounts of N02, numerous
other factors (e.g. humidity, carbon monoxide, formaldehyde)
may affect and confound the results of the studies. The
-------
Melia et al. (1977, 1979) studies do not provide quantitative
dose-response data for NC>2 exposures due to the absence of
short-term NC>2 measurements in the residences of the subjects
evaluated and due to incomplete analysis of the- aforementioned
possible confounding or covarying factors. In a limited
qualitative sense/ however, the studies do suggest an
association between higher N02 levels and increased respiratory
symptoms and illness in children.
CASAC also evaluated the Harvard "Six Cities Study" during
its (Speizer et. al. 1980) review of the staff paper and
criteria document. This study was designed to gather information
on long-term health effects. The increased incidence of
respiratory disease reported in the "Six Cities Study" may be
caused by repeated short-term peak exposures rather than
long-term KC>2 concentrations of 24 hour or annual averages;
however, this has not yet been conclusively demonstrated due to
the scarcity of short-term indoor NC>2 monitoring data. In
using the Six Cities Study data, both the study authors and
CASAC caution the Agency against data overinterpretation of
thi's study in selecting revised N02 standards.
-------
4. Short-Term vs. Long-Term NC>2 Standard, and Scientifically
Acceptable Ranges for a Revised Standard
The Committee spent considerable time discussing the
extent to which available animal, human clinical, and epidemic-
logical studies cited in the staff paper provide a scientific
basis for retention of an annual primary standard. It also
reviewed whether such evidence would provide scientific
support for the establishment of a short-term (1-3 hour)
primary standard. Evidence reviewed by the Committee clearly
documents the existence of health effects due to short-term
peak exposures that are distinct from the effects associated
with longer-term average exposures. The evidence does not,
however, distinguish whether the latter effects are the
result of a series of short-term peak exposures or the result
of lower level long-term exposures or some combination of both.
The CASAC has concluded that any revised KO2 standard needs
?£
to offer sufficient protection against both the short-term
as well as the long-term reported effects.
For both scientific and practical reasons related to
the implementation of standards, the Committee recommends
that you retain an annual standard and that you do. not need to
establish a separate short-term primary standard at this time.
Qualitative support for an annual standard is based on results
from animal test data. For example, from animal inhalation
studies in which several species were used, investigators have
reported that long-term NC>2 exposures produced structural
-------
alterations' in the distal bronchioles and alveolar regions of
the lung at long-term NC>2 levels in the range of .25 - .50 ppm.
Quantitative evidence of short-term effects at higher NO2
exposure levels (*5 ppm N02) has been reported in human
clinical studies. Community epidemiological and "gas stove"
study data furnish additional support for retaining the
annual primary standard. In particular, the "gas stove"
studies suggest that multiple exposures to short-term NOj
levels below 0.5 ppm are of concern and should be avoided in
the ambient air. For example, the "gas stove" studies and
related studies in which NC>2 was measured in homes utilizing
gas stoves suggest that repeated short-term peaks in the
range of 0.15 - 0.30 ppm may be of concern for children and
thus should be limited in the ambient air. Revision of the
primary annual standard to control long-term N02 concentrations
can hpwever, be set at a level that also provides adequate
£ -
protection against repeated short-term peak exposures.
The staff paper suggests an annual standard set within
the range of .05-.08 ppm. Based on the above discussion, the
need to provide adequate protection against repeated short-term
peak, exposvres, and due to the uncertainties of the data base,
the CASAC recommends that you consider selecting a primary
annual standard level at the lower end of the .05-.08 ppm
range to ensure an adequate margin of safety of protection
against both long-term and short-term health effects. The
-------
7
factors you should consider to determine a margin of safety
and to identify the sensitive population groups are appropriately
discussed in the staff paper.
Factors related to the implementation of the standard
were also discussed by CASAC. Retention of an annual average
standard would be the least burdensome option for the states to
incorporate into revised State Implementation Plans (SIPs)
because individual SIPs already are based on such an approach.
B. Critical Elements in the Secondary Standard Review
The Committee is satisfied with the scientific
quality of the staff paper's presentation of information
concerning welfare effects. The discussion of materials
damage, personal comfort and veil-being, vegetation effects,
and visibility impairment was comprehensive and well written.
Acidic deposition is also a welfare effect associated
wilth the oxides of nitrogen* ..Because of the great complexity
of this issue CASAC had previously recommended that the Agency
prepare a Critical Assessment Document for Acidic Deposition
that would evaluate the contribution of NOX and other precursor
pollutants to the formation, transport, and effects of the total
acidic deposition problem. CASAC thus agrees with the OAQPS
staff decision not to address acidic deposition in the NC>2
staff paper, and it looks forward to the submission of the
critical assessment document for its review.
-------
CASAC concurs with the staff paper recommendation that
an annual primary standard within the range of .05-.08 ppm
will offer sufficient protection for the various welfare
effects of concern.
Summary
CASAC recognizes that your statutory responsibility to
set standards requires both scientific and policy judgments to
protect public health and welfare. While the Committee is
willing to further advise you on the NC>2 standards, we see
no need, in view of the already extensive comments provided,
to.review the proposed NC>2 standards prior to their publication
in the Federal Register. In this instance the public comment
period will provide sufficient opportunity for the Committee
to submit any additional comment or review that may be necessary.
:The Committee made scientific and editorial comments
£.
during the review of the revised staff paper. These remarks,
as well as a more detailed discussion of the conclusions and
recommendations provided above, are included in the transcripts
of the three CASAC meetings (held on November 14, 1980,
February 6, 1981, and November 18, 1981) to review this
document. With the understanding that these minor changes
will be incorporated in the final staff paper, the Committee
is satisfied that this document is scientifically adequate
for use in standard setting.
-------
REFERENCES
1. U.S. EPA. Air Quality Criteria for Oxides of Nitrogen. External Review
Draft. (Hereinafter referred to as Criteria Document). Environmental
Criteria and Assessment Office, Office of Research and Development, U.S.
EPA, Research Triangle Park, N.C.
2. U.S. Court of Appeals for the District of Columbia Circuit, Lead Industries
Association, Inc. vs. EPA. No. 78-2201 and 78-2220. June 27, 1980.
2a. U.S. Court of Appeals for the District of Columbia, American Petroleum
Institute vs EPA. No. 79-1104 and 79-1201, September, 1981.
3. U.S. Senate, 93rd Congress, 2nd Session Committee on Environment and
Public Works (Comm. Print 1974). A Legislative History of the Clean Air
Act Amendments of 1970, Vol. 1, p. 410.
4. CASAC November 14, 1980 transcript.
5. CASAC February 6, 1981 transcript.
5a. CASAC November 18, 1981 transcript.
6. Criteria Document, p. 1-4.
7. Yokoyama, E. Uptake of S09 and N09 by the isolated upper airways. Bull.
Inst. Public Health. 1_7_: 302-306/1968.
8. Dalhamn, T., and J. Sjoholm. Studies on S02» N02 and NH,: effect on
ciliary activity in rabbit trachea of single in vitro exposure and
absorption in rabbit nasal cavity. Acta Physiol. Scand. 58: 287-291,
1963. ~~
9. Roehm, J. N., J. G. Hadley, and D. B. Menzel. Oxidation of unsaturated
fatty acids by 07 and N09: a common mechanism of action. Arch. Environ.
Health 23: 142-T48, 197T.
10. Menzel, D. B. The role of free radicals in the toxicity of air pollutants
(nitrogen oxides and ozone). In; Free Radicals in Biology. W. Pryor (ed.)
Academic Press, Inc., New York, 1976. pp. 181-201.
11. Gardner, D. E., F. J. Miller, E. J. Blommer, and D. L. Coffin. Relationship
between nitrogen dioxide concentration, time and level of effect using an
animal infectivity model. In: Proceedings International Conference on
Photochemical Oxidant Pollution and Its Control, Vol. 1. EPA-600/3-77-001a.
U.S. Environmental Protection Agency, January, 1977. pp. 513-525.
12. Coffin, D. L., D. E. Gardner, and E. J. Blommer. Time-dose response for
nitrogen dioxide exposure in an infectivity model system. Environ. Health
Persp. 1_3: 11-15, 1976.
13. Gardner, D. E., F. J. Miller, E. J. Blommer, and D. L. Coffin. Influence of
exposure mode on the toxicity of NO,. Environ. Health Persp. 30: 23-29,
1979. 2
-------
14. Ehrlich, R., and M. C. Henry. Chronic toxicity of nitrogen dioxide. I.
Effect on resistance to bacterial pneumonia. Arch. Environ. Heal 1th 17:
860-865, 1968.
15. Blair, W. H., M. C. Henry, and R. Ehrlich. Chronic toxicity of nitrogen
dioxide. II. Effect on histopathology of lung tissue. Arch. Environ.
Health !£: 186-192, 1969.
16. Sherwin, R. P., and L. J. Layfield. Proteinuria in guinea pigs exposed
to 0.5 ppm nitrogen dioxide. Arch. Environ. Health 28: 336-341, 1974.
17. Buell, G. C. Biochemical parameters in inhalation carcinogenesis. In:
Inhalation Carcinogenesis. U.S. Atomic Energy Commission Symp. Ser. 18.;
209-228, 1970.
18. Miller, F. J., J. A. Graham, J. W. Illing, and D. E. Gardner. Extrapulmonary
effects of N02 as reflected by pentobarbital-induced sleeping time in
mice. Tox. Lett., 1980. (accepted for publication).
19. Menzel, D. B. Pharmacological Mechanisms in the Toxicity of Nitrogen Dioxide
and its Relation to Obstructive Respiratory Disease. ln_: Nitrogen Oxides
and Their Effect on Health. S. D. Lee, ed., Ann Arbor Science, Ann Arbor,
1980. pp. 199-216.
20. Iqbal, Z. M., K. Dahl, S. S. Epstein. Role of nitrogen dioxide in the
biosynthesis of nitrosamines in mice. Science 207:1475-1477, 1980.
21. Gardner, D. E., J. A. Graham, J. W. Illing, E. J. Blommer, and F. J. Miller.
Impact of Exposure Patterns on the Toxicological Response to N02 and
Modifications by Added Stressors. Env. Health Persp. In Press.
22. Aranyi, C., J. Fenters, R. Ehrlich, and D. Gardner. Scanning electron
microscopy of alveolar macrophages after exposure to 09, N0~ and 0,.
Environ. Health Persp. j_6: 180, 1976. * * J
23. Kosmider, S., A. Misiewicz, E. Felus, M. Drozdz, and K. Ludyga. Exper-
imental and clinical studies on the effects of nitrogen oxides on immunity.
Intern. Arch Arbeitsmed. 31_: 9-23, 1973. (English translation).
24. Selgrade, M. J. K., M. L. Mole, F. J. Miller, G. E. Hatch, D. E. Gardner,
and P. C. Hu. Effect of N02 Inhalation and Vitamin C Deficiency on
Protein and Lipid Accumulation in the Lung. Environ. Res. In Press.
25. Donovan, D. H., M. B. Abou-Donia, D. E. Gardner, D. L. Coffin, C. Roe,
R. Ehrlich, and D. B. Menzel. Effect of long-term low-level exposures of
nitrogen dioxide on enzymatic indicators of damage. The Pharmacol. 18:
244, 1976. (Abstr.)
-------
26. Menzel, D. B., M. D. Abou-donia, C. R. Roe, R. Ehrlich, D. E. Gardner,
and D. L. Coffin. Biochemical indices of nitrogen dioxide intoxication
of guinea pigs following low-levels long-term exposure. In: Proceedings
International Conference on Photochemical Oxidant Pollution and Its
Control. Vol. II, September, 1973, B. Dimitriades (ed.). EPA-600/3-77-
OOlb. U. S. Environmental Protection Agency, Research Triangle Park,
North Carolina, 1977. pp. 577-587.
27. Drozdz, M., E. Kucharz, K. Rudyga, and T. Molska-Droxdz. Studies on the
effect of long-term exposure to nitrogen dioxide on serum and liver
proteins level and enzyme activity in guinea pigs. Europ. J. Toxicol.
1: 287-293, 1976.
28. Mersch, J., B. J. Dyce, B. J. Haverback, and R. P. Sherwin. Diphosphogly-
cerate content of red blood cells. Measurements in guinea pigs exposed to
0.4 ppm nitrogen dioxide. Arch. Environ. Health 27_: 94-95, 1973.
29. Port, C. D., D. L. Coffin, and P. Kane. A comparative study of experi-
mental and spontaneous emphysema. J. Toxicol. Environ. Health 2: 589-604,
1977.
30. Gillespie, J. R., J. D. Berry, and J. C. Stara. Pulmonary function changes
in the period following termination of air pollution exposure in beagles.
Am. Rev. Resp. Dis. 113: 92, 1975.
31. Suzuki, T., and K. Ishikawa. Research of effect of smog on human body.
Research and Report on Air pollution Prevention 2: 199-221, 1965. (In
Japanese)
32. Kerr, H. D., T. J. Kulla, M. L. Mcllhany, and P. Swidersky. Effect of
nitrogen dioxide on pulmonary function in human subjects: An environmental
chamber study. Environ. Res. JJ9:392-404, 1979.
33. Hackney, J. D., F. C. Thiede, W. S. Linn, E. E. Pedersen, C. E. Spier,
D. C. Law, and D. A. Fisher. Experimental studies on human health effects
of air pollutants. IV. Short-term physiological and clinical effects.
Arch. Environ. Health 33(4): 176-181, 1978.
34. Folinsbee, L. J., S. N. Horvath, J. F. Bedi, and J. C. Delehunt. Effect of
0.62 ppm N0? on cardiopulmonary function in young male non-smokers.
Environmental Research ]_5: 199-205, 1978.
35. Beil, M., and W. T. Ulmer. Wirkung von N02 in MAK-Bereich auf Atemmechanik
and Acelytcholinempfindlichkeit bei Normalpersonen. (Effect of N0« in
workroom concentrations on respiratory mechanics and bronchial susceptibility
to acetylcholine in normal persons.) Int. Arch. Occup. Environ. Health. 38:
31-44, 1976.
-------
36. Von Nieding, G., H. M. Wagner, H. Krekeler, U. Smidt, and K. Muysers.
Minimum concentrations of NCL causing acute effects on the respiratory
gas exchange and airway resistance in patients with chronic bronchitis.
Int. Arch. Arbeitsmed. 27.: 338-348, 1971. Translated from German by
Mundus Systems for Air Pollution Technical Information Center, U.S.
Environmental Protection Agency, Research Triangle Park, North Carolina.
37. Von Nieding, G., H. Krekeler, R. Fuchs, H. M. Wagner, and K. Koppenhagen.
Studies of the acute effect of NCL on lung function: influence on
diffusion, perfusion and ventilation in the lungs. Int. Arch. Arbeitsmed.
31_: 61-72, 1973.
38. Orehek, J., J. P. Massari, P. Gayrard, C. Grimaud, and J. Charpin. Effect
of short-term, low-level nitrogen dioxide exposure on bronchial sensitivity
of asthmatic patients. J. Clin. Invest. 57.: 301-307, 1976.
39. Posin, C., K. Clark, M. P. Jones, J. V. Patterson, R. D. Buckley, and J. D.
Hackney. Nitrogen dioxide and human blood biochemistry. Arch. Environ.
Health (Nov/Dec): 318-324, 1978.
40.
with other pollutant gases
41. Hackney, J. D., W. S. Linn, J. G. Mohler, E. E. Pedersen, P. Breisacher, and
A. Russo. Experimental studies on human health effects of air pollutants.
II. Four-hour exposure to ozone alone and in combination with other pollutant
gases. Arch. Environ. Health. 30: 379-384, 1975.
42. Horvath, S. M., and L. J. Folinsbee. Effects of pollutants on cardiopulmonary
function. Report to U.S. Environmental Protection Agency, EPA Contract
68-02-1723, 1979. (Manuscript submitted)
43. Von Neiding, G., H. M. Wagner, H. Lollgen, and K. Krekeler. Acute effects
of ozone on lung function of men. VDI-Ber. 270^:123-129, 1977.
44.. Criteria Document, p. 15-17.
45. Schlipkoter, H. W., and A. Brockhaus. Versuche uber den Einfluss gasformiger
Luftverunreinigungen auf die Deposition and elimination inhalierter Staube.
Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg. Abt. 1. 191: 339-
344, 1963. (In German)
46. Criteria Document, p. 1-10.
47. Shy, C. M., J. P. Creason, M. E. Pearlman, K. E. McClain, F. B. Benson, and
M. M. Young. The Chattanooga school children study: effects of community
exposure of nitrogen dioxide. I. Methods, description of pollutant exposure
and results of ventilatory function testing. J. Air Pollut. Control Assoc.
20(8): 539-545, 1970.
-------
48. Shy, C. M., J. P. Creason, M. E. Pearlman, K. E. McClain, F. B.
Benson, and M. M. Young. The Chattanooga school study: effects
of community exposure to nitrogen dioxide. II. Incidence of acute
respiratory illness. J. Air Pollut. Control Assoc. 20(9): 582-588,
1970.
49. Pearlman, M. E., J. F. Finklea, J. P. Creason, C. M. Shy, M. M.
Young, and R. J. M. Horton. Nitrogen dioxide and lower respiratory
illness. Pediatrics 47(2): 391-398,1971.
50. Shy, C. M., and G. J. Love. Recent evidence on the human health
effects of nitrogen dioxide. Proceedings of the Symposium on Nitrogen
Oxides, Honolulu, Hawaii, April 4-5, 1979.
51. Kagawa, J., and T. Toyama. Photochemical air pollution: Its effects
on respiratory function of elementary school children. Arch. Environ.
Health 30:117-122, 1975.
52. Linn, W. S., J. D. Hackney, E. E. Pedersen, P. Breisacher, J. V.
Patterson, C. A. Mulry, and J. F. Coyle. Respiratory function and
symptoms in urban office workers in relation to oxidant air pollution
exposure. Amer. Rev. Resp. Disease. 114: 477-483, 1976.
53. Cohen, C. A., A. R. Hudson, J. L. Clausen, and J. H. Knelson. Respiratory
symptoms, spirometry, and oxidant air pollution in nonsmoking adults.
Amer. Rev. Resp. Disease lp_5_:251-261, 1972.
54. Burgess, W., L. Di Berardinis, and F. E. Speizer. Exposure to automobile
exhaust. III. An environmental assessment. Arch. Environ. Health. 26:
325-329, 1973.
55. Speizer, F. E. , and B. G. Ferris, Jr. Exposure to automobile exhaust. I.
Prevalence of respiratory symptoms and disease. Arch. Environ. Health.
26: 313-318, 1973a.
56. Speizer, F. E., and B. G. Ferris, Jr. Exposure to automobile exhaust.
II. Pulmonary function measurement. Arch. Environ. Health. 26(6):
319-324, 1973b.
57. Melia, R. J. W., C. du V. Florey, D. S. Altman, and A. V. Swan. As-
sociation between gas cooling and respiratory disease in children. Brit.
Med. J. 2: 149-152, 1977.
58. Melia, R. J. W., C. du V. Florey, and S. Chinn. The relation between
respiratory illness in primary schoolchildren and the use of gas for
cooking. I - Results from a national survey. Int. J. Epid. 8_:333, 1979.
59. Goldstein, B. D., R. J. W. Melia, S. Chinn, C. du V. Florey, D. Clark,
and H. H. John. The relation between respiratory illness in primary
schoolchildren and the use of gas for cooking. II - Factors affecting
nitrogen dioxide levels in the home. Int. J. of Epid. J3:339, 1979.
-------
60. Florey, C. duV., R. J. W. Melia, S. Chinn, B. D. Goldstein, A. G. F.
Brooks, H. H. John, I. B. Craighead, and X. Webster. The relation
between respiratory illness in primary schoolchildren and the use of
gas for cooking. Ill - Nitrogen dioxide, respiratory illness and lung
infection. Int. J. Epid. 8.: 347, 1979.
61. Tager, I. B. et al., "Effect of Parental Cigarette Smoking on the
Pulmonary Function of Children." American Journal of Epidemiology,
110: 15-26, 1979.
62. Melia, R. J. W., C. du V. Florey, S. C. Darby, E. D. Parlmers, and
B. Goldstein. Differences in N09 levels in kitchens with gas cookers.
Atm. Env. 12: 1379-1381, 1978. *
63. Reference deleted.
64. Speizer, F. E., B. G. Ferris, Jr., Y. M. M. Bishop, and J. Spengler.
Respiratory disease rates and pulmonary function in children associated
with N02 exposure. Am. Rev. Resp. Dis. 121_:3-10, 1980.
65. Spengler, J. D., B. G. Ferris, Jr., and D. W. Dockery. Sulfur dioxide
and nitrogen dioxide levels inside and outside homes and the implications
on health effects research. Environ. Sci. Techn. V3:1276-1271, 1979.
66. Correspondence from Dr. Ben Ferris to Dr. Lester Grant, November 19, 1980.
67. Mitchell, R. I., R. Williams, R. W. Cote, R. R. Lanese, and M. D. Keller.
Household survey of the incidence of respiratory disease in relation to
environmental pollutants. WHO International symposium Proceedings:
Recent Advance in the Assessment of the Health Effects of Environmental
Pollutants. Paris, June 24-28, 1974.
68. Keller, M. D., R. R. Lanese, R. I. Mitchell, and R. W. Cote. Respiratory
illness in households using gas and electric cooling. Environ. Res. 19:
495-515, 1979.
69. Wade, W. A., Ill, W. A>. Cote, and J. E. Yocom. A study of indoor air
quality. J. Air Pollut. Control Assoc. 25; 93-939, 1975.
70. Cote, W. A., W. A. Wade, III, and J. E. Yocom. A study of indoor air
quality. Final Report under EPA Contract No. 68-02-0745. EPA-650/4-74-042,
September, 1974.
71. Hollowel, Craig D. et al. Indoor air quality in residential buildings.
Presented at International Congress on Building Energy Management. Poroa
de Varzim, Portugal, May 12-16, 1980. Lawrence Berkeley Lab Report No.
LBL-10391.
-------
72. Hollowel, Craig D. and G. W. Traynor. Combustion-generated indoor air
pollution. Presented at the 13th International Colloquium on Polluted
Atmospheres. Paris, April 25-28, 1978. Lawrence Berkeley Laboratory
Report No. LBL-7832.
73. Lawrence Berkeley Laboratory, Energy and Environment Division. Energy
efficient buildings program. Chapter from the Energy and Environment
Division Annual Report 1979. Lawrence Berkeley Laboratory Report No.
LBL-10704, December, 1979.
74. U.S. Bureau of the Census. U.S. Census of Population: 1960-1970, and
Census Population Reports, Series P-25, No. 614.
75. U.S. Dept. of Health, Education, and Welfare (DHEW). Prevalence of
Selected Chronic Respiratory Conditions, United States, 1970. DHEW
Publication No. (HRA) 74-1511. Series 10, Number 84. Rockville, MD.
September, 1973.
76. Biller, W.F. and T.B. Feagans. Statistical forms of national ambient
air quality standards. Presented at Environmetrics '81 Conference.
Alexandria, Virginia, April 8-10, 1981.
77. 44 Federal Register 8202 (February 8, 1979).
78. 45 Federal Register 55066 (August 18, 1980).
79. Maclean, D.C. Effect of nitrogen oxides on vegetation. In: Nitrogen
Oxides. National Academy of Sciences, Washington, D.C. 1977. p. 197-
214.
80. Criteria Document, p. 12-68.
81. Heck, W. W. NCSU, Raleigh, N.C. Personal Communication with P.M. Johnson,
U.S. EPA, February 1980.
82. Tingey, D.T., U.S. EPA, CERL Corvallis, OR. Personal Communication with
P.M. Johnson, U.S. EPA, February, 1980.
83. Ibid. Written correspondence to P. M. Johnson, U.S. EPA, May 23, 1980.
84. Korth, M. W., A. H. Rose, and R. C. Stahman. Effects of hydrocarbon to
oxides of nitrogen ratios on irradiated auto exhaust. Part 1. J. Air
Pollut. Control Assoc. 11:168-175. 1964.
85. Haagen-Smit, A. J., E. F. Darley, M. Zaithlin, H. Hull, and W. Noble.
Investigation of injury to plants from air pollution in the Los Angeles
area. Plant Physiol. 27:18-34. 1952.
86. Heck, W. W. Plant injury induced by photochemical reaction products of
propylene-nitrogen dioxide mixtures. J. Air Pollut. Control Assoc.
14:255-261. 1964.
-------
87. Taylor, 0. C., C. R. Thompson, D. T. Tingey, and R. A. Reinert. Oxides
of nitrogen. I_n_: Responses of Plants to Air Pollution, J. B. Mudd and
T. T. Kozlowski, eds. Academic Press, Inc., New York, N.Y. 1975, p.
121-139.
88. Thompson, C. R., E. G. Hensel, G. Kats, and 0. C. Taylor. Effects of
continuous exposure of navel oranges to NCL. Atmos. Environ. 4:349-355.
1970.
-------
99. White, K. L., A. C. Hill and J. H. Bennett. Synergistic inhibition
of apparent photosynthesis rate of alfalfa by combinations of sulfur
dioxide and nitrogen dioxide. Environ. Sci. Technol. 8:574-576, 1974.
100. Taylor, 0. C., and F. N. Eaton. Suppression of plant growth by nitrogen
dioxide. Plant Physiol. 41_:132-135, 1966.
101. Thompson, C. R., G. Kats, and E. G. Hensel. Effects of ambient levels
of N02 on navel oranges. Environ. Sci. Technol. 5_:1017-1019, 1971.
102. Spierings, F. H. F. G. Influence of fumigations with NO.-, on growth
and yield of tomato plants. Neth. J. Plant Pathol. 77:t94-200, 1971.
103. Bennett, J. H., A. C. Hill, A. Soleimani, and W. H. Edwards. Acute
effects of combination of sulphur dioxide and nitrogen dioxide on
plants. Environ. Pollut. 2:127-132, 1975.
104. Heck, W. W. Plant injury induced by photochemical reaction products
of propylene-nitrogen dioxide mixtures. JAPCA. 14:255-261, 1968.
105. Bull, J. N. and T. A. Mansfield. Photosynthesis in leaves exposed to
S02 and NOg. Nature 25£:443-444, 1974.
106. Criteria Document, p. 10-2.
*
107. Ibid. p. 10-3.
108. Charlson, R. J., A. P. Waggoner, and J. F. Thielke, Visibility protection
for Class I areas. The technical basis. Report to Council of
Environmental Quality, Washington, D.C, 1978.
109. Ibid.
110. Ahlquist, M. C., and R. J. Charlson. Measurement of the wavelength
dependence of atmospheric extinction due to scatter. Atmos. Environ.
3:551, 1969.
111. Gardner, D. E., and J. A. Graham. Increased pulmonary disease mediated
through altered bacterial defenses, In: Pulmonary Macrophage and
Epithelial Cells. R. P. Schneider, G. E. Doyle, and H. A. Ragan (eds.).
Proceedings Sixteenth Annual Hanford Biology Symposium, Richland,
Washington, 1976. pp. 1-21.
112. Ehrlich, R., 0. C. Findlay, J. D. Fenters, and D. E. Gardner. Health
effects of short-term exposures to inhalation of N0?-0q mixtures.
Environ. Res. V4:223-231, 1977. J
113. Ehrlich, R. Interaction between N0? exposure and respiratory infections.
In: Scientific Seminar on Automotive Pollutants. EPA-600/9-75-003.
U.S. Environmental Protection Agency, Washington, D.C., February, 1975.
-------
114. Kita, H., and S. Omichi. Effects of air pollutants on cilia movement
in airways. Jap. J. Hyg. j!9_:100, 1974. (in Japanese)
115. Giordano, A. M., and P. E. Morrow. Chronic low-level nitrogen dioxide
exposure and mucociliary clearance. Arch. Environ. Health 25:443-449,
1972.
116. Renters, J. D., J. P. Findlay, C. D. Port, R. Ehrlich, and D. L.
Coffin. Chronic exposure to nitrogen dioxide: immunologic, physi-
ologic and pathologic effect in virus-challenged squirrel monkeys.
Arch. Environ. Health 27_:85-89, 1973.
117. Sherwin, R. P., and D. A. Carlson. Protein content of lung lavage
fluid of guinea pigs exposed to 0.4 ppm nitrogen dioxide. Arch.
Environ. Health 27_: 90-93, 1973.
118. Hattori, S., R. Tateishi, T. Horai, and T. Nakajima. Morphological
changes in the bronchial alveolar system of mice following continuous
exposure to N02 and CO. J. Jap. Soc. Chest Disease l_0:16-22, 1972.
(In Japanese)
119. Fenters, J. D., R. Ehrlich, J. Spangler, and V. Tolkacz. Serologic
response in squirrel monkeys exposed to nitrogen dioxide and influenza
virus. Am. Rev. of Resp. Dis. J04_:448-451, 1971.
120. Freeman, G., N. J. Furiosi, and G. B. Haydon. Effects of continuous
exposure of 0.8 ppm N09 on respiration of rats. Arch. Environ. Health
13:454-456, 1966. *
121. Sherwin, R. P., D. Okimoto, and D. Mundy. Sequestration of exogenous
peroxidase in the lungs of animals exposed to continuous 0.5 ppm
nitrogen dioxide. Fed. Proc. 36:1091, 1977.
122. Thomas, H. V., P. K. Mueller, and R. L. Lyman. Lipoperoxidation of
lung lipids in rats exposed to nitrogen dioxide. Science 159:532-534,
1968.
123. Zorn, H. The alveolar-arterial oxygen-tension differential and tissue
oxygen partial pressure during exposure to N0?. VIO Bericht 247:50-51,
1975. (In German)
124. Rejthar, L., and A. Rejthar. Histological changes of terminal bron-
chioles in rats during exposure to nitrogen dioxide. Exp. Path. Bd.
Kh 245-250, 1974.
125. Freeman, G., S. C. Crane, R. J. Stephens, and N. J. Furiosi. Patho-
genesis of the nitrogen dioxide induced lesion in the rat lung. A
review and presentation of new observations. Am. Rev. Resp. Disease
98:429-443, 1968.
-------
126. Stephens, R. J., G. Freeman, and M. J. Evans. Early response of
lungs to low levels of nitrogen dioxidelight and electron microscopy.
Arch. Environ. Health 2^:150-179, 1972.
127. Freeman, G., S. C. Crane, N. J. Furiosi, R. J. Stephens, M. J. Evans,
and VI. D. Moore. Covert reduction in ventilatory surface in rats
during prolonged exposure to subacute nitrogen dioxide. Am. Rev. Resp.
Dis. 1_06_: 563-577, 1972.
128. Shalamberidze, 0. P. The joint action of small concentrations of
sulfurous gas and nitrogen dioxide on the estrual cycle and the
genital function of animals in experiments. Gig. i Sanit. 4_:10-14, 1969.
(In Russian)
129. Drozdz, M., M. Luciak, D. Kosmider, T. Molska-Drozdz, K. Ludyga, and
J. Pasiwicz. Enzymatic and morphological changes in the central nervous
system of guinea pigs after chronic poisoning with nitrogen dioxide.
Bromat. Chem. Toksykol. 8^:241-249, 1975. (In Russian)
130. Graham, J. A., D. B. Menzel, F. J. Miller, J. W. Illing, and D. E. Gardner.
Influence of ozone on pentobarbital-induced sleeping time in mice, rats
and hamsters. Toxicol. Appl. Pharmacol., 1981 (in press).
131. Illing, J.W., F. J. Miller, and D. E. Gardner. Decreased Resistance to
Infection in Exercised Mice Exposed to N0? and Ov J. Toxicol. Envon.
Health. 6.: 843-851, 1980.
132. Sherwin, R. P., J. B. Margolick, and E. A. Aguilar. Acid phophatase in
densite equilibrium fractions of the lungs of guinea pigs exposed inter-
mittently to 0.4 ppm nitrogen dioxide. Fed. Proc. 33_:633, 1974. (Abstr.).
133. Ito, K. Effect of nitrogen dioxide inhalation on influenza virus infection
in mice. Jap. J. Hygiene 26^:304-314, 1971. (in Japanese)
134. Hattori, S., and K. Takemura. Ultrastructural changes in the bronchiolar
alveolar system caused by air pollution and smoking. J. Clin. Electron
Microsc. Soc. Japan 6_:350, 1974. (in Japanese)
135. Hattori, S. Alterations of broncho-alveolar system by polluted air:
Experimental consideration. Clinician 21_9_:4-8, 1973. (in Japanese)
136. Nakajima, T., S. Kusumoto, C. Chen, and K. Okamoto. Effects.of prolonged
continuous exposure to nitrogen dioxide on the quantity of reduced
glutathione in lungs of mice and their histopathological changes. Appendix:
Effects of nitrite and nitrate on the glutathione reductase. Osaka
Pretectural Pub. Health Inst., Res. Reports, Labor Sanitation Series.
7:35-41, 1969. (in Japanese)
137. Furiosi, N. J., S. C. Crane, and G. Freeman. Mixed sodium chloride
aerosol and nitrogen dioxide in air: biological effects on monkeys and
rats. Arch. Environ. Health 27:405-408, 1973.
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-450/5-82-002
2.
3. RECIPIENT'S ACCESSION NO.
4. TITLE AND SUBTITLE
Review of the National Ambient Air Quality Standards for
Nitrogen Oxides: Assessment of Scientific and Technical
Information OAQPS Staff Paper
5. REPORT DATE
August 1982
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Office of Air, Noise and Radiation
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Final
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This paper evaluates and interprets the available scientific and technical infor-
mation that the EPA staff believes is most relevant to the review of primary (health)
and secondary (welfare) National Ambient Air Quality Standards for Nitrogen Oxides
(NOp) and presents staff recommendations on alternative approaches to revising the
standards. The assessment is intended to bridge the gap between the scientific review
in the EPA criteria document for nitrogen oxides and the judgements required of the
Administrator in setting ambient air quality standards for nitrogen oxides.
The major recommendations of the staff paper include the following:
1) that an annual standard be retained at some level between 0.05 ppm and 0.08 ppm
to provide a reasonable level of protection against potential short term peaks in the
range of 0.15 to 0.30 ppm;
2) alternatively, that a new multiple exceedance 1 hour average NOp standard
at some level below 0.5 ppm be established;
3) that there is no evidence to suggest the need for a separate secondary
standard provided a primary standard is established within the ranges suggested above
to protect human health.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COS AT I Field/Group
Nitrogen Oxides
Nitrogen Dioxide
Air Pollution
Air Quality Standards
18. DISTRIBUTION STATEMENT
Release to Public
19. SECURITY CLASS (ThisReport/
Unclassified
21. NO. OF PAGES
112
20 SECURITY CLASS (Thispoge)
22. PRICE
EPA Form 2220-1 (Rev. 4-77)
PREVIOUS EDITION IS OBSOLETE
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n
U.S. Environmental Protection Agency
Region V -' -
230 Sou;.. L- -. -- 'Vast
Chicago, iiiincis t-:;;::04 ._,/
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